Tetra-fused ring compound as well as preparation method, pharmaceutical composition and application thereof

Abstract

The invention discloses a tetra-fused ring compound as well as a preparation method, a pharmaceutical composition and application thereof. The invention specifically discloses a tetra-fused ring compound as shown in a formula I or pharmaceutically acceptable salts thereof. The compound disclosed by the invention can be used for effectively treating depression, and has good pharmacokinetic properties and relatively small drug interaction. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to tetracyclic compounds, preparation methods, pharmaceutical compositions and applications thereof. Background Art

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

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

[0004] Stimulation of 5-HT2A receptors can lead to neuronal excitation in multiple brain regions. Among all 14 serotonin receptor subtypes, 5-HT2A receptors are widely present in the central nervous system and have the highest concentration among monoamine receptors in the cerebral cortex. They are distributed in structural areas involved in emotion regulation, such as the median nucleus / dorsal raphe nucleus, locus coeruleus, and ventral tegmental area. A, P, Matosiuk D, et al. Int J Mol Sci. 2021 Dec 21; 23(1): 10). Consistent with their location in the brain, they are not only related to various central physiological functions, including memory, sleep, nociception, eating and reward behavior, but also to many neuropsychiatric diseases, such as schizophrenia, depression and anxiety (Guiard BP, Di Giovanni G. Front Pharmacol. 2015 Mar 17; 6: 46). Many new antipsychotic drugs (such as aripiprazole, brepirazole and pimavanserin) have high affinity for 5-HT2A receptors, which may be the reason for their better efficacy and lower side effects (McCreary AC, Newman-Tancredi A. Curr Pharm Des. 2015; 21(26): 3725-31). Experiments on mice with 5-HT2A receptor knockout have confirmed that cortical 5-HT2AR can play a certain role in anxiety regulation, and serotonin signals in the cortex can have a significant impact on behavior in conflict anxiety tests (Weisstaub NV, Zhou M, Lira A, et al. Science. 2006 Jul 28; 313(5786): 536-40).

[0005] Depression is one of the chronic mental disorders that currently affect humans. Esketamine, approved by the U.S. FDA in 2019, is the first fast-acting antidepressant on the market. It can be combined with oral antidepressants to treat refractory depression. However, as an analog of ketamine, esketamine has a certain risk of addiction and needs to be used under the supervision of medical staff. At the same time, hallucinogens such as ergotamine and psilocybin, which act on the 5-HT2A target, have been widely used by psychotherapists as auxiliary drugs for the treatment of depression, anxiety-related diseases and addiction in the 1960s, with generally encouraging results. Currently, drugs targeting 5-HT2A for the treatment of depression still have problems such as slow onset of action, limited efficacy, large individual differences and large side effects. Summary of the Invention

[0006] The technical problem to be solved by the present invention is to overcome the shortcomings of currently available antidepressant drugs, such as slow onset of action or hallucinogenic side effects. To this end, the present invention provides a tetracyclic compound, a preparation method, a pharmaceutical composition, and uses thereof. While maintaining a good antidepressant effect, the compound of the present invention has the advantages of rapid onset of action, no hallucinogenic side effects, and low drug interactions in the body.

[0007] The present invention overcomes the above technical problems through the following technical solutions.

[0008] The present invention provides a tetracyclic compound represented by Formula I or a pharmaceutically acceptable salt thereof:

[0009]

[0010] The carbon atom with "*" represents a chiral carbon atom, which is in S configuration, R configuration or a mixture thereof;

[0011] The carbon atom with “#” represents a chiral carbon atom, which is in S configuration, R configuration or a mixture thereof;

[0012] X 1 -NR X1 -、-O-、-CR X2 R X3 -, -S-, -S(O)- or -S(O)2-;

[0013] R X1 is H, C1-C6 alkyl, one or more R X1-1 Substituted C1-C6 alkyl, -C(O)-C1-C6 alkyl, or "a 3-12-membered heterocycloalkyl group wherein the heteroatoms are 1, 2 or 3 selected from the group consisting of N, O and S";

[0014] R X1-1 independently OH;

[0015] R X2 and R X3 are independently H or C1-C6 alkyl;

[0016] X 2 N or CR X4 ;

[0017] R X4 is H or C1-C6 alkyl;

[0018] X 3 N or CR 1-1 ;

[0019] X 4 N or CR 1-2 ;

[0020] X 5 N or CR 1-3 ;

[0021] R 1-1 、R 1-2 and R 1-3 are independently H, CN, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C1-C6 haloalkoxy;

[0022] L is -(CRL1 R L2 )n1-、-(CR L1 R L2 )n2-Y 1 -(CR L1 R L2 )n3-or-(CR L1 R L2 )n4-Y 2 -(CR L1 R L2 )n5-;

[0023] R L1 and R L2 are independently H or C1-C6 alkyl;

[0024] n1 is 1, 2, 3, or 4;

[0025] Y 1 -O-, -NR L3 -、-C(O)-、-CR L4 R L5 -、

[0026] n2 is 0, 1, 2, or 3;

[0027] n3 is 0, 1, 2, or 3;

[0028] n2+n3=1, 2 or 3;

[0029] Y 2 -C≡C-, -C(O)-NR L3 -、-CR L6 =CR L7 -、

[0030] n4 is 0, 1, or 2;

[0031] n5 is 0, 1, or 2;

[0032] n4+n5=1 or 2;

[0033] R L3 are independently H or C1-C6 alkyl;

[0034] R L4 is H or halogen;

[0035] R L5 is halogen, OH or C1-C6 alkoxy;

[0036] R L6 and R L7 are independently H or halogen;

[0037] R 2 are independently C1-C6 alkyl, -C(O)-C1-C6 alkyl or oxo (=O);

[0038] m2 is 0, 1, 2, 3, or 4;

[0039] Ring A is "a 9-12 membered bicyclic heterocyclic group having one, two or three heteroatoms selected from N, O and S, with one, two or three heteroatoms", "a 5-6 membered monocyclic heterocyclic group having one, two or three heteroatoms selected from N, O and S", C6-C 10 Aryl or C3-C6 cycloalkyl;

[0040] And when L is -(CR L1 R L2 )n1-、-(CR L1 R L2 )n2-O-or-(CR L1 R L2 )n2-C(O)-, for

[0041]

[0042] R 3 are independently oxo (=O), C1-C6 alkyl, C1-C6 alkoxy, -NR 4 R 5 、-C(O)R 6 、-SR 7 、-S(O)2R 8 , halogen, one or more R 9 Substituted C1-C6 alkoxy, one or more R 10 Substituted C1-C6 alkyl, CN, "a 3-12 membered heterocycloalkyl group having 1, 2 or 3 heteroatoms selected from N, O and S" or -OR 11 ;

[0043] R 4 are independently H or C1-C6 alkyl;

[0044] R 5 are independently H, C1-C6 alkyl or -C(O)R 5-1 ;

[0045] R 6 、R 5-1 、R 7 and R 8 are independently C1-C6 alkyl;

[0046] R9 and R 10 are independently OH, -NR 4 R 5 or halogen;

[0047] R 11 is H or "a 5-10 membered heteroaryl group in which the heteroatoms are 1, 2 or 3 selected from N, O and S";

[0048] m3 is 0, 1, 2, 3 or 4.

[0049] The present invention also provides a tetracyclic compound as shown in Formula I-0 or a pharmaceutically acceptable salt thereof:

[0050]

[0051] The carbon atom with "*" represents a chiral carbon atom, which is in S configuration, R configuration or a mixture thereof;

[0052] The carbon atom with “#” represents a chiral carbon atom, which is in S configuration, R configuration or a mixture thereof;

[0053] X 1 -NR X1 -、-O-、-CR X2 R X3 -, -S-, -S(O)- or -S(O)2-;

[0054] R X1 is H, C1-C6 alkyl, one or more R X1-1 Substituted C1-C6 alkyl, -C(O)-C1-C6 alkyl, C3-C6 cycloalkyl, or "a 3-12 membered heterocycloalkyl group wherein the heteroatoms are one, two or three selected from N, O and S, and the number of heteroatoms is one, two or three";

[0055] R X1-1 are independently deuterium or OH;

[0056] R X2 and R X3 are independently H, deuterium, C1-C6 alkyl or C1-C6 deuterated alkyl;

[0057] X 2 N, N + O - or CR X4 ;

[0058] R X4 is H or C1-C6 alkyl;

[0059] X 3 N or CR 1-1;

[0060] X 4 N or CR 1-2 ;

[0061] X 5 N or CR 1-3 ;

[0062] R 1-1 、R 1-2 and R 1-3 are independently H, CN, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C1-C6 haloalkoxy;

[0063] L is -(CR L1 R L2 )n1-、-(CR L1 R L2 )n2-Y 1 -(CR L1 R L2 )n3-or-(CR L1 R L2 )n4-Y 2 -(CR L1 R L2 )n5-;

[0064] R L1 and R L2 are independently H or C1-C6 alkyl;

[0065] n1 is 3 or 4;

[0066] Y 1 -O-, -NR L3 -、-C(O)-、-CR L4 R L5 -、

[0067] n2 is 0, 1, 2, or 3;

[0068] n3 is 0, 1, 2, or 3;

[0069] n2+n3=1, 2 or 3;

[0070] Y 2 -C≡C-, -C(O)-NR L3 -、-CR L6 =CR L7 -、

[0071] n4 is 0, 1, or 2;

[0072] n5 is 0, 1, or 2;

[0073] n4+n5=1 or 2;

[0074] R L3 are independently H or C1-C6 alkyl;

[0075] R L4 is H or halogen;

[0076] R L5 is halogen, OH or C1-C6 alkoxy;

[0077] R L6 and R L7 are independently H or halogen;

[0078] R 2 are independently deuterium, C1-C6 alkyl, C1-C6 deuterated alkyl, -C(O)-C1-C6 alkyl, oxo (=O), thioxo (=S) or hydroxy;

[0079] m2 is 0, 1, 2, 3, or 4;

[0080] Ring A is "an 8-12-membered bicyclic heterocyclic group having 1, 2 or 3 heteroatoms selected from the group consisting of N, O and S", "a 5-6-membered monocyclic heterocyclic group having 1, 2 or 3 heteroatoms selected from the group consisting of N, O and S", "a 9-16-membered polycyclic heterocyclic group having 1, 2 or 3 heteroatoms selected from the group consisting of N, O and S", or a C3-C6 cycloalkyl group;

[0081] And when L is -(CR L1 R L2 )n1-、-(CR L1 R L2 )n2-O-or-(CR L1 R L2 )n2-C(O)-, for

[0082]

[0083] R 3 are independently oxo (=O), C1-C6 alkyl, C1-C6 alkoxy, -NR 4 R 5 、-C(O)R 6 、-SR 7 、-S(O)2R 8 , halogen, one or more R 9 Substituted C1-C6 alkoxy, one or more R 10Substituted C1-C6 alkyl, CN, "a 3-12 membered heterocycloalkyl group having 1, 2 or 3 heteroatoms selected from N, O and S" or -OR 11 ;

[0084] R 4 are independently H or C1-C6 alkyl;

[0085] R 5 are independently H, C1-C6 alkyl or -C(O)R 5-1 ;

[0086] R 6 、R 5-1 、R 7 and R 8 are independently C1-C6 alkyl;

[0087] R 9 and R 10 are independently OH, -NR 4 R 5 or halogen;

[0088] R 11 is H or "a 5-10 membered heteroaryl group in which the heteroatoms are 1, 2 or 3 selected from N, O and S";

[0089] m3 is 0, 1, 2, 3 or 4;

[0090] m4 is 0, 1, or 2.

[0091] In certain preferred embodiments of the present invention, certain groups in the tetracyclic compound or a pharmaceutically acceptable salt thereof are defined as follows. The groups not mentioned are the same as those described in any embodiment of the present invention (referred to as "in a certain embodiment of the present invention"). 1 -NR X1 -.

[0092] In one embodiment of the present invention, R X2 and R X3 is independently H.

[0093] In one embodiment of the present invention, R X4 For H.

[0094] In one embodiment of the present invention, X 3 CR 1-1 .

[0095] In one embodiment of the present invention, X 4 CR 1-2 .

[0096] In one embodiment of the present invention, X5 CR 1-3 .

[0097] In one embodiment of the present invention, R 1-1 、R 1-2 and R 1-3 are independently H, CN, halogen or C1-C6 alkoxy; for example, R 1-1 and R 1-3 H, R 1-2 is H, F, CN or C1-C6 alkoxy; for example, R 1-1 、R 1-2 and R 1-3 are independently H.

[0098] In one embodiment of the present invention, R 1-1 、R 1-2 and R 1-3 are independently H, CN or C1-C6 alkoxy; for example, R 1-1 and R 1-3 H, R 1-2 is H, CN or C1-C6 alkoxy.

[0099] In one embodiment of the present invention, m4 is 1.

[0100] In one embodiment of the present invention, R L1 and R L2 are independently H.

[0101] In one embodiment of the present invention, n1 is 3.

[0102] In one embodiment of the present invention, Y 1 -O-, -NR L3 -、-C(O)-、-CR L4 R L5 -or For example, Y 1 -C(O)- or -CR L4 R L5 -.

[0103] In one embodiment of the present invention, n2 is 0, 1 or 2, for example, n2 is 1 or 2, and for another example, n2 is 2.

[0104] In one embodiment of the present invention, n3 is 0, 1 or 2, for example, n3 is 0 or 1, and for another example, n3 is 0.

[0105] In one embodiment of the present invention, n2+n3=2.

[0106] In one embodiment of the present invention, Y 2 -C≡C-, -C(O)-NR L3 -、-CRL6 =CR L7 -or For example, Y 2 -CR L6 =CR L7 -.

[0107] In one embodiment of the present invention, n4 is 0 or 1, for example, n4 is 1.

[0108] In one embodiment of the present invention, n5 is 0 or 1, for example, n5 is 0.

[0109] In one embodiment of the present invention, n4+n5=1.

[0110] In one embodiment of the present invention, R L3 For H.

[0111] In one embodiment of the present invention, R L4 For H.

[0112] In one embodiment of the present invention, R L5 It is a halogen.

[0113] In one embodiment of the present invention, R L6 and R L7 are independently H.

[0114] In one embodiment of the present invention, R 2 is independently deuterium, C1-C6 alkyl, oxo (=O), thioxo (=S) or hydroxy; for example, oxo (=O).

[0115] In one embodiment of the present invention, R 2 are independently oxo (=O).

[0116] In one embodiment of the present invention, m2 is 0, 1, 2 or 3, for example, m2 is 1.

[0117] In one embodiment of the present invention, m2 is 0 or 1; for example, m2 is 0.

[0118] In one embodiment of the present invention, when L is -(CR L1 R L2 )n1-、-(CR L1 R L2 )n2-O-or-(CR L1 R L2 )n2-C(O)-,

[0119] for

[0120] In one embodiment of the present invention, when L is -(CRL1 R L2 )n1-、-(CR L1 R L2 )n2-O-or-(CR L1 R L2 )n2-C(O)-,

[0121] for

[0122]

[0123] In one embodiment of the present invention, when L is -(CR L1 R L2 )n1-、-(CR L1 R L2 )n2-O-or-(CR L1 R L2 )n2-C(O)-, for

[0124] In one embodiment of the present invention, R 3 are independently oxo (=O), C1-C6 alkoxy, -NR 4 R 5 、-C(O)R 6 、-SR 7 、-S(O)2R 8 , halogen, one or more R 9 Substituted C1-C6 alkoxy, one or more R 10 Substituted C1-C6 alkyl, CN, "a 3-12 membered heterocycloalkyl group having 1, 2 or 3 heteroatoms selected from N, O and S" or -OR 11 ; For example, R 3 is independently C1-C6 alkoxy, 9 Substituted C1-C6 alkoxy or halogen.

[0125] In one embodiment of the present invention, R 3 Independently -OR 11 , C1-C6 alkyl, C1-C6 alkoxy, one or more R 9 Substituted C1-C6 alkoxy or halogen.

[0126] In one embodiment of the present invention, R 4 are independently H.

[0127] In one embodiment of the present invention, R 5are independently H or -C(O)R 5-1 ; For example, R 5 are independently H.

[0128] In one embodiment of the present invention, R 9 are independently halogen.

[0129] In one embodiment of the present invention, m3 is 0 or 1, for example, m3 is 0.

[0130] In a certain embodiment of the present invention, the "C1-C6 alkyl" in each "C1-C6 alkyl", "substituted C1-C6 alkyl" and "-C(O)-C1-C6 alkyl" is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example, methyl or ethyl.

[0131] In one embodiment of the present invention, the "C1-C6 alkoxy" in each "C1-C6 alkoxy" and "substituted C1-C6 alkoxy" is independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, for example, methoxy or ethoxy.

[0132] In one embodiment of the present invention, each "heteroatoms selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1, 2 or 3 3-membered heterocycloalkyl" is independently "heteroatoms selected from 1 or 2 of N and O, and the number of heteroatoms is 1 or 2 5-6 membered heterocycloalkyl", for example piperidinyl (e.g. ), morpholinyl or oxetane (e.g. ).

[0133] In one embodiment of the present invention, each halogen is independently F, Cl, Br or I, such as F or Cl.

[0134] In one embodiment of the present invention, each C3-C6 cycloalkyl group is independently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, for example cyclobutyl.

[0135] In one embodiment of the present invention, in ring A, the "9-12 membered bicyclic heterocyclic group wherein the heteroatoms are selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1, 2 or 3" is Among them, ring A 1 are independently phenyl or pyridyl, ring A 2 are independently "a 5-6 membered heterocycloalkyl group having one or two heteroatoms selected from N and O, and having one or two heteroatoms" or "a 5-6 membered heteroaryl group having one or two heteroatoms selected from N and O, and having one or two heteroatoms"; for example, Ring A 2are independently "a 5-membered heterocycloalkyl group having 1 or 2 heteroatoms and a heteroatom selected from O" or "a 5-6-membered heteroaryl group having 1 or 2 heteroatoms and a heteroatom selected from N and O"; for example, in ring A, the "a 9-12-membered bicyclic heterocyclic group having 1, 2 or 3 heteroatoms and a heteroatom selected from N, O and S" is

[0136]

[0137] In one embodiment of the present invention, in ring A, the “8-12 membered bicyclic heterocyclic group having 1, 2 or 3 heteroatoms selected from N, O and S” is “an 8-membered bicyclic heterocyclic group having 1, 2 or 3 heteroatoms selected from N, O and S” or “a 9-12 membered bicyclic heterocyclic group having 1, 2 or 3 heteroatoms selected from N, O and S”, wherein the definition of “a 9-12 membered bicyclic heterocyclic group having 1, 2 or 3 heteroatoms selected from N, O and S” is as described in any one of the present invention. For example, in ring A, the “8-12 membered bicyclic heterocyclic group having 1, 2 or 3 heteroatoms selected from N, O and S” is

[0138] In one embodiment of the present invention, in ring A, the "5-6 membered monocyclic heterocyclic group having one, two or three heteroatoms selected from N, O and S, and having one, two or three heteroatoms" is "a 5-6 membered monocyclic heteroaryl group having one or two heteroatoms selected from N and S" or "a 5-6 membered monocyclic heterocycloalkyl group having one or two heteroatoms selected from N", 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 number of heteroatoms is 1, 2 or 3 5-6 membered monocyclic heterocyclic group" is

[0139] In one embodiment of the present invention, in ring A, the "9-16 membered polycyclic heterocyclic group having one, two or three heteroatoms selected from N, O and S, and having one, two or three heteroatoms" is a "10-12 membered tricyclic heterocyclic group having one or two heteroatoms selected from N and O, and having one or two heteroatoms", for example

[0140] In one embodiment of the present invention, in ring A, the C6-C 10 Aryl is phenyl or naphthyl, for example phenyl.

[0141] In one embodiment of the present invention, in ring A, the C3-C6 cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, for example, cyclohexyl.

[0142] In one embodiment of the present invention, each "5-10 membered heteroaryl group having one, two or three heteroatoms selected from N, O and S" is independently "a 5-6 membered heteroaryl group having one or two heteroatoms selected from N", for example, pyridyl (e.g. ).

[0143] In one embodiment of the present invention, for One or more of In one embodiment of the present invention, for For example In one embodiment of the present invention, for In one embodiment of the present invention, for

[0144]

[0145] In one embodiment of the present invention, for

[0146] In a certain embodiment of the present invention, L is For example

[0147] In a certain embodiment of the present invention, L is

[0148] In one embodiment of the present invention, for

[0149] In one embodiment of the present invention, for

[0150] In one embodiment of the present invention, for

[0151] In one embodiment of the present invention, for

[0152]

[0153]

[0154] In one embodiment of the present invention, the tetracyclic compound is a compound as shown in Formula I-1, I-2 or I-3:

[0155]

[0156] Among them, *, #, X 1 , Ring A, R 3 and m3 are defined as described in any one of the present invention.

[0157] In one embodiment of the present invention, the tetracyclic compound is a compound as shown in Formula I-4:

[0158]

[0159] Among them, *, #, X 1 , Ring A, R 3 and m3 are defined as described in any one of the present invention.

[0160] In one embodiment of the present invention, for

[0161] In one embodiment of the present invention, for

[0162]

[0163] In one embodiment of the present invention, the compound of the present invention is not the following compound:

[0164] and their stereoisomers.

[0165] The present invention also provides any of the following tetracyclic compounds or pharmaceutically acceptable salts thereof:

[0166]

[0167]

[0168]

[0169]

[0170]

[0171]

[0172]

[0173] The present invention provides a pharmaceutical composition comprising:

[0174] (1) a tetracyclic compound or a pharmaceutically acceptable salt thereof according to any one of the present invention, and

[0175] (2) Pharmaceutically acceptable excipients.

[0176] The present invention also provides a use of the tetracycline compound, a pharmaceutically acceptable salt thereof, or the pharmaceutical composition as described above according to any one of the present invention, wherein the use is selected from:

[0177] (1) Preparation of 5-HT 2A receptor agonists;

[0178] (2) Preparation for treatment and / or prevention of 5-HT 2A drugs for receptor-related diseases;

[0179] (3) Preparation of drugs for treating and / or preventing depression.

[0180] The present invention also provides a method for treating and / or preventing 5-HT 2A A method for treating a receptor-related disease, comprising: administering to a patient in need thereof a therapeutically effective amount of a tetracyclic compound as represented by Formula I according to any one of the present invention, a pharmaceutically acceptable salt thereof, or the pharmaceutical composition as described above.

[0181] The present invention also provides a method for treating and / or preventing depression, comprising: administering to a patient in need thereof a therapeutically effective amount of a tetracyclic compound as represented by Formula I as described in any one of the present invention, a pharmaceutically acceptable salt thereof, or the pharmaceutical composition as described above.

[0182] In a certain embodiment of the present invention, the 5-HT 2AA receptor-related disease is depression.

[0183] Terminology

[0184] Unless otherwise specified, the terms used in this invention have the following meanings:

[0185] The term "pharmaceutically acceptable" means relatively non-toxic, safe, and suitable for use by patients.

[0186] The term "pharmaceutically acceptable salt" refers to a salt obtained by reacting a compound with a pharmaceutically acceptable acid or base. When the compound contains a relatively acidic functional group, a base addition salt can be obtained by contacting the compound with a sufficient amount of a pharmaceutically acceptable base in a suitable inert solvent. When the compound contains a relatively basic functional group, an acid addition salt can be obtained by contacting the compound with a sufficient amount of a pharmaceutically acceptable acid in a suitable inert solvent. For details, see Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl, Camille G. Wermuth, 2011, 2nd Revised Edition).

[0187] The "-" at the end of a group means that the group is connected to the rest of the molecule through this site; It means that the structural fragment is connected to the rest of the molecule through this site, for example, It refers to cyclohexyl.

[0188] When the linking groups listed in the present invention do not specify their connection direction, their connection direction is the same as the reading order from left to right, as shown below: The connecting group L is -(CR L1 R L2 )n2-Y 1 -(CR L1 R L2 )n3-, at this time-(CR L1 R L2 )n2-Y 1 -(CR L1 R L2 )n3- Connect in the same direction as reading from left to right Rather than constituting

[0189] The term "one or more" means 1, 2 or 3.

[0190] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0191] The term "oxo" refers to =0, an oxygen atom replacing two hydrogens on the same carbon atom, ie, a carbonyl replacing a methylene group.

[0192] The term "alkyl" refers to a linear or branched, saturated, monovalent hydrocarbon group having a specified number of carbon atoms (e.g., C1-C6). Alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, and the like.

[0193] The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein halogen is defined as in the term "halogen" and alkyl is defined as in the term "alkyl." Haloalkyl groups include, but are not limited to, -CF3, -CHF2, -CH2CF3, and the like.

[0194] The term "alkoxy" refers to the group -OR X , R X The same definition as the term "alkyl". Alkoxy includes, but is not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, and the like.

[0195] The term "haloalkoxy" refers to the group -OR X ', R X The same definition as the term "haloalkyl". Halogenated alkoxy includes but is not limited to: -O-CF3, -O-CHF2, -O-CH2CF3, etc.

[0196] The term "cycloalkyl" refers to a saturated cyclic hydrocarbon group having a specified number of carbon atoms (e.g., C3-C6) that is a monocyclic ring. Cycloalkyl groups include, but are not limited to: wait.

[0197] The term "aryl" refers to a group having the specified number of carbon atoms (e.g., C6-C 10 ) unsaturated cyclic hydrocarbon group, which is monocyclic or polycyclic (e.g., 2). In the case of polycyclic, adjacent monocyclic rings share two atoms and one bond, and each ring is aromatic. Aryl groups include, but are not limited to, phenyl, naphthyl, and the like.

[0198] The term "heterocycloalkyl" refers to a cyclic group having a specified number of ring atoms (e.g., 3-12 members), a specified number of heteroatoms (e.g., 1, 2, or 3), a specified type of heteroatom (one, two, or three of N, O, and S), which is monocyclic, bridged, or spirocyclic, and each ring is saturated. Heterocycloalkyl is attached to the rest of the molecule through a carbon atom or a heteroatom. Heterocycloalkyl includes, but is not limited to: wait.

[0199] The term "monocyclic heterocyclyl" refers to a cyclic group having a specified number of ring atoms (e.g., 5-6 members), a specified number of heteroatoms (e.g., 1, 2, or 3), a specified type of heteroatom (one, two, or three of N, O, and S), saturated or unsaturated, aromatic or non-aromatic, which is a single ring. The heterocyclyl is attached to the rest of the molecule through a carbon atom or a heteroatom.

[0200] The term "bicyclic heterocyclyl" refers to a cyclic group having a specified number of ring atoms (e.g., 5-6 members), a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified type of heteroatom (one, two, or three of N, O, and S), which is bicyclic, each ring independently being saturated or unsaturated, aromatic or non-aromatic. The heterocyclyl is attached to the rest of the molecule through a carbon atom or a heteroatom. Bicyclic heterocyclyls include, but are not limited to: wait.

[0201] The term "heteroaryl" refers to an unsaturated cyclic group having a specified number of ring atoms (e.g., 5-10 members, 5-6 members), a specified number of heteroatoms (e.g., 1, 2, or 3), a specified type of heteroatom (one, two, or three of N, O, and S), which is monocyclic or polycyclic. When polycyclic, the monocyclic rings share two atoms and one bond, and each ring is aromatic. A heteroaryl group is attached to the rest of the molecule through a carbon atom or a heteroatom; when polycyclic, the heteroaryl group is attached to the rest of the molecule through a ring with heteroatoms or a ring without heteroatoms. Heteroaryl groups include, but are not limited to: wait.

[0202] 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 by those skilled in the art as appropriate.

[0203] The term "pharmaceutically acceptable excipients" refers to all substances contained in pharmaceutical preparations other than the active pharmaceutical ingredient. These substances are generally classified into two categories: excipients and additives. For details, see the Pharmacopoeia of the People's Republic of China (2020 Edition) and the Handbook of Pharmaceutical Excipients (Paul J Sheskey, Bruno C Hancock, Gary P Moss, David J Goldfarb, 2020, 9th Edition).

[0204] The term "treat" refers to eliminating the cause or alleviating the symptoms of a disease.

[0205] The term "prevent" refers to reducing the risk of developing a disease.

[0206] The term "patient" refers to any animal, typically a mammal, such as a human, that needs to be treated or prevented. Mammals include, but are not limited to, cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, and the like.

[0207] Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention.

[0208] The reagents and raw materials used in the present invention are commercially available.

[0209] The positive and progressive effects of the present invention are that the compounds of the present invention can reduce depression and hallucination while maintaining good antidepressant effects, and have lower drug interactions in the body. DETAILED DESCRIPTION

[0210] The present invention is further illustrated by way of examples below, but the present invention is not limited to the scope of the examples. Experimental methods in the following examples where specific conditions are not specified were performed according to conventional methods and conditions, or selected according to the product specifications.

[0211] Example 1: (6bR,10aS)-8-(3-(2,3-dihydrobenzofuran-7-yl)propyl)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline

[0212]

[0213] Step 1: Dissolve 2,3-dihydrobenzofuran-7-carbaldehyde (1.0 g, 6.7 mmol) and methyl (triphenylphosphino)acetate (3.36 g, 10.05 mmol) in anhydrous tetrahydrofuran (15 mL) at room temperature. Stir the reaction mixture at 80°C for 2 h. Cool the reaction mixture to room temperature and concentrate in vacuo to obtain a crude product. The crude product was purified by column chromatography (EtOAc / PE = 0-10%) to obtain methyl (E)-3-(2,3-dihydrobenzofuran-7-yl) acryloyl ester (1.18 g, yield: 76.1%) as a white solid. MS m / z (ESI): 205.1 [M+H] +

[0214] Step 2: Methyl (E)-3-(2,3-dihydrobenzofuran-7-yl)propanoate (1.18 g, 5.8 mmol) was dissolved in methanol (10 mL) at room temperature, and 10% wet palladium on carbon (310 mg, 0.29 mmol) was added. The reaction mixture was stirred at room temperature for 1 h under a hydrogen atmosphere. The reaction mixture was filtered through celite, washed with methanol, and the filtrates were combined and concentrated under vacuum to afford crude methyl 3-(2,3-dihydrobenzofuran-7-yl)propanoate (1.15 g, yield: 96.6%) as a colorless, viscous oil. The crude product was used directly in the next reaction without purification. MS m / z (ESI): 207.1 [M+H] +

[0215] Step 3: Dissolve methyl 3-(2,3-dihydrobenzofuran-7-yl)propanoate (500 mg, 2.4 mmol) in tetrahydrofuran (8 mL) at room temperature and cool to 0°C under a nitrogen atmosphere. Add 1 M lithium aluminum hydride in tetrahydrofuran (8 mL) and stir at room temperature for 1 hour. The reaction mixture was stirred at 0°C and slowly diluted with ethyl acetate (20 mL). Sodium sulfate decahydrate was added, filtered through celite, washed with methanol, and concentrated in vacuo to obtain the crude product. The crude product was purified by column chromatography (EtOAc / PE = 0-15%) to afford 3-(2,3-dihydrobenzofuran-7-yl)propan-1-ol (340 mg, yield: 78.7%) as a colorless oil. MS m / z (ESI): 179.1 [M+H] +

[0216] Step 4: At room temperature, 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), cooled to 0°C, and methanesulfonyl chloride (145 mg, 1.262 mmol) was added. After returning to room temperature, the reaction solution was stirred for 1 hour and concentrated in vacuo at room temperature. ((6bR,10aS)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline (97 mg, 0.421 mmol) was added. l), potassium iodide (140 mg, 0.842 mmol), dioxane (3 mL), and triethylamine (256 mg, 2.525 mmol). The reaction mixture was stirred at 100°C for 18 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo to obtain a crude product. The crude product was purified by alkaline preparative method to yield (6bR,10aS)-8-(3-(2,3-dihydrobenzofuran-7-yl)propyl)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline (28.61 mg, yield: 17.32%) as a yellow oily liquid. 1 H NMR (400MHz, CDCl3) δ7.03(d,J=7.3Hz,1H),6.92(d,J=7.5Hz,1H),6.76(t,J=7.4 Hz,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] + .

[0217] Example 2: (6bR,10aS)-8-(3-(Benzo[d][1,3]dioxazol-4-yl)propyl)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline

[0218]

[0219] The preparation of E2 was carried out according to the synthesis 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] + .

[0220] Example 3: (6bR,10aS)-8-(3-(2,3-dihydrobenzofuran-4-yl)propyl)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline

[0221]

[0222] Step 1: Add 2,3-dihydrobenzofuran-4-carbaldehyde (200 mg, 1.35 mmol) and ethoxycarbonylmethylenetriphenylphosphine (940 mg, 2.7 mmol) to a 50 mL reaction flask. Then, add THF (10 mL) and heat to 70°C with stirring for 2 h. After completion of the reaction, the reaction mixture was concentrated and purified by column chromatography (petroleum ether:ethyl acetate = 10:1) to afford (E)-ethyl 3-(2,3-dihydrobenzofuran-4-yl)acrylate (colorless liquid, 200 mg, 68% yield). MS m / z (ESI): 219.3 [M+H] +

[0223] Step 2: Add compound (E)-ethyl 3-(2,3-dihydrobenzofuran-4-yl)acrylate (200 mg, 0.92 mmol) to a 50 mL reaction flask, followed by methanol (10 mL) and wet palladium on carbon (10%, 97 mg). Stir under a hydrogen atmosphere at room temperature for 1 hour. After completion of the reaction, the reaction mixture was filtered and concentrated to yield ethyl 3-(2,3-dihydrobenzofuran-4-yl)propanoate (200 mg, 99% yield, colorless liquid). MS m / z (ESI): 221.4 [M+H] +

[0224] Step 3: Add ethyl 3-(2,3-dihydrobenzofuran-4-yl)propanoate (180 mg, 0.82 mmol) to a 50 mL three-necked reaction flask, followed by THF (5 mL). Lithium aluminum tetrahydride (1.5 mL, 1 mol / L) was slowly added dropwise at 0°C. The reaction mixture was stirred at 0°C for 20 min. The reaction solution was quenched with sodium sulfate decahydrate, filtered, concentrated, and purified by normal phase column chromatography (petroleum ether:ethyl acetate = 3:1) to afford 3-(2,3-dihydrobenzofuran-4-yl)propan-1-ol (colorless liquid, 100 mg, yield 68.7%). MS m / z (ESI): 179.3 [M+H] +

[0225] Step 4: Add 3-(2,3-dihydrobenzofuran-4-yl)propan-1-ol (30 mg, 0.17 mmol) to a 25 mL reaction flask, followed by DCM (5 mL), followed by DIEA (65 mg, 0.5 mmol) and Ms2O (44 mg, 0.5 mmol). Stir at room temperature for 1 h. The reaction mixture was extracted with DCM (2 x 20 mL), and the organic phase was washed with saturated brine (2 x 20 mL). After concentration, 3-(2,3-dihydrobenzofuran-4-yl)propyl methanesulfonate (colorless liquid, 35 mg, 81.4% yield) was obtained. MS m / z (ESI): 257.3 [M+H] +

[0226] Step 5: Add the compound 3-(2,3-dihydrobenzofuran-4-yl)propyl methanesulfonate (35 mg, 0.14 mmol) and the raw material (6bR,10aS)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline (31 mg, 0.14 mmol) to a 25 mL reaction bottle, followed by the addition of DMSO (3 mL) and then DIPEA (52 mg, 0.4 mmol). After the addition is complete, stir at 60 ° C for 16 h. The reaction mixture was concentrated and purified by reverse phase column chromatography (acetonitrile / (water + 0.05% NH4HCO3)) to give (6bR,10aS)-8-(3-(2,3-dihydrobenzofuran-4-yl)propyl)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline (gray solid, 20 mg, 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),3.46-3.3 8(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] + .

[0227] Example 4: (6bR,10aS)-8-(3-(chroman-8-yl)propyl)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline

[0228]

[0229] Step 1: Add compound 8-bromochroman (500 mg, 2.35 mmol), ethyl acrylate (260 mg, 2.58 mmol), Pd2(dba)3 (43 mg, 0.05 mmol), tri-tert-butylphosphine tetrafluoroborate (14 mg, 0.05 mmol), and N-methyldicyclohexylamine (1370 mg, 7.05 mmol) into a 50 mL single-necked reaction flask, followed by anhydrous dioxane (10 mL). After the addition, replace the mixture with nitrogen three times, slowly heat to 100 ° C and stir to react for 16 h. After the reaction was completed by TLC, water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (3 x 20 mL). The organic phases were combined, washed with saturated brine (1 x 20 mL), dried over anhydrous sodium sulfate, and dried under reduced pressure. The crude product was purified and separated by normal phase column chromatography (Biotage-12 g, eluent gradient: 10% EA / PE) to give ethyl (E)-3-(chroman-8-yl)acrylate (pale yellow oil, 150 mg, yield 28%).

[0230] Step 2: Ethyl (E)-3-(chromen-8-yl) acrylate (150 mg, 0.65 mmol) was added to a 25 mL single-necked reaction flask, followed by ethyl acetate (15 mL) and 10% Pd / C (wet basis, 15 mg). After addition, the atmosphere was replaced with hydrogen three times and the reaction was stirred at room temperature for 16 h. After completion of the reaction as determined by LCMS, the reaction solution was filtered and the filtrate was concentrated under reduced pressure to afford ethyl 3-(chromen-8-yl) propionate (crude product, 150 mg, 99% yield). The crude product was used directly in the next step without further purification. MS m / z (ESI): 235.5 [M+H] + .

[0231] Step 3: Ethyl 3-(chromen-8-yl)propanoate (150 mg, 0.64 mmol) was added to a 25 mL three-necked reaction flask, followed by anhydrous tetrahydrofuran (10 mL). Under nitrogen and an ice-water bath, a 1 M lithium aluminum tetrahydride (THF) solution (48 mg, 1.28 mmol, 1 mol / L) was added portionwise. The reaction was stirred at 0°C for 0.5 h. After completion of the reaction, the mixture was quenched by slowly adding Na₂SO₄.10H₂O, filtered, and the filter cake was washed with 10% MeOH / DCM (30 mL). The filtrate was concentrated under reduced pressure, and the crude product was purified by normal phase column chromatography (eluent gradient: 30% EA / PE) to afford 3-(chromen-8-yl)propan-1-ol (colorless oil, 110 mg, 89% yield).

[0232] Step 4: 3-(Chroman-8-yl)propan-1-ol (15 mg, 0.08 mmol), DMAP (2 mg, 0.01 mmol), DIEA (30 mg, 0.24 mmol), and anhydrous dichloromethane (5 mL) were added to a 25 mL three-necked reaction flask. Methanesulfonic anhydride (27 mg, 0.16 mmol) was slowly added under nitrogen and an ice-water bath. After addition, the mixture was stirred at room temperature for 2 h. After completion of the reaction, water (10 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (2 x 10 mL). The organic phases were combined, washed with saturated brine (1 x 10 mL), dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure to yield 3-(Chroman-8-yl)propyl methanesulfonate (a colorless oil, crude product, 20 mg). The crude product was used directly in the next step without further purification.

[0233] Step 5: Compound 3-(chroman-8-yl)propyl methanesulfonate (20 mg, 0.07 mmol) and (6bR,10aS)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline (20 mg, 0.08 mmol) were added to a 10 mL reaction bottle, followed by anhydrous DMSO (2 mL) and DIPEA (30 mg, 0.21 mmol), respectively. After the addition, the temperature was slowly raised to 60°C and stirred for 16 h. After the reaction, the reaction mixture was filtered, and the filtrate was directly subjected to reverse phase preparative separation (C18 column, eluent gradient: acetonitrile / (water + 0.05% NH4HCO3)) to obtain ((6bR,10aS)-8-(3-(chroman-8-yl)propyl)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline (off-white solid, 4.5 mg, yield 15%). 1 H 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] + .

[0234] Example 5: (6bR,10aS)-8-(3-(Benzofuran-7-yl)propyl)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline

[0235]

[0236] Step 1: Dissolve 7-bromobenzofuran (400 mg, 2.0 mmol) in DMF (5.0 mL). Under nitrogen, 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. Stir at 100°C for 4 h. After completion of the reaction by TLC, water was added for quenching. The mixture was extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and purified by normal phase purification to obtain ethyl (E)-3-(benzofuran-7-yl) acrylate (yellow oil, 220 mg, 50% yield). MS m / z (ESI): 217.3. [M+H] + .

[0237] Step 2: Dissolve ethyl (E)-3-(benzofuran-7-yl) acryloyl ester (45 mg, 0.2 mmol) in THF (2.0 mL), cool to 0°C, add 1M lithium aluminum tetrahydride solution in tetrahydrofuran (0.2 mL, 0.2 mmol), and stir at room temperature for 1 hour. Add sodium sulfate decahydrate and stir for 30 minutes. Filter, concentrate, and purify with normal phase chromatography to obtain compound 3-(benzofuran-7-yl)propan-1-ol (yellow oil, 25 mg, 70% yield). MS m / z (ESI): 177.2. [M+H] + .

[0238] Step 3: Dissolve compound 3-(benzofuran-7-yl)propan-1-ol (25 mg, 0.14 mmol) in DCM (2.0 mL), add DIEA (90 mg, 0.7 mmol), cool to 0°C, add methanesulfonic anhydride (45 mg, 0.26 mmol), and then warm to room temperature and stir for 3 h. Quench with water, extract with DCM, add sodium sulfate, dry, and filter to obtain compound 3-(4-fluoro-2-methoxyphenyl)propyl methanesulfonate (yellow oil, 23 mg), which is used directly in the next reaction.

[0239] Step 4: Dissolve (6bR,10aS)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline (25 mg, 0.10 mmol) in DMSO (2.5 mL) at room temperature, add DIEA (0.5 mL, 3.0 mmol) and 3-(4-fluoro-2-methoxyphenyl)propyl methanesulfonate (23 mg, 0.1 mmol) in turn, and heat to 65°C with stirring. The reaction mixture was stirred for 18 h, cooled to room temperature, filtered, and purified by prep-HPLC (eluent (v / v): acetonitrile / (water + 0.05% NH4HCO3) = 30%–70%) to give compound (6bR,10aS)-8-(3-(benzofuran-7-yl)propyl)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline (colorless oil, 2.0 mg, yield 5%). 1 H 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,2 H),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] + .

[0240] Example 6: (6bR,10aS)-8-(3-(Benzo[b]thiophen-7-yl)propyl)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline

[0241]

[0242] Step 1: 6-7-Bromobenzo[b]thiophene (500 mg, 2.35 mmol), ethyl acrylate (580 mg, 5.79 mmol), Pd2(dab)3 (110 mg, 0.12 mmol), and tri(o-tolyl)phosphine (220 mg, 0.72 mmol) were added to a three-necked flask containing 10 mL of DMF. The atmosphere was replaced with nitrogen three times and the reaction was carried out at 105°C for 16 h. After completion of the reaction by TLC, water and EA were added, the layers were separated, and the aqueous phase was extracted twice with EA. The organic phases were combined, washed three times with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by normal phase column chromatography (PE / EA = 100% to 10 / 1) to give compound (E)-ethyl 3-(benzo[b]thiophen-7-yl)acrylate as a yellow solid, 487 mg, yield: 87%.

[0243] Step 2: Ethyl (E)-3-(benzo[b]thiophen-7-yl)acrylate (470 mg, 2.02 mmol), 50 mg of Pd / C, and 50 mg of Pd(OH)2 / C were added to a three-necked flask containing 30 mL of MeOH. The mixture was replaced with H2 three times and allowed to react at room temperature for 16 h. The reaction was complete as determined by TLC and LMS. The residue was filtered, concentrated, and purified by normal phase column chromatography (PE / EA = 100% to 5 / 1) to afford ethyl 3-(benzo[b]thiophen-7-yl)propanoate (410 mg, colorless oil, yield: 87%).

[0244] Step 3: Add ethyl 3-(benzo[b]thiophen-7-yl)propanoate (110 mg, 0.469 mmol) to a three-necked flask containing 5 mL of THF. The atmosphere was replaced with nitrogen three times, cooled to 0°C, and 0.9 mL of a 1M LAH THF solution was injected. The reaction was continued for 1 hour, and TLC confirmed the reaction was complete. Sodium sulfate decahydrate was added to quench the reaction, followed by EA and Na2SO4. The mixture was stirred at room temperature for half an hour, filtered, concentrated, and purified by normal phase column chromatography (PE / EA = 100% to 10 / 1) to afford 3-(benzo[b]thiophen-7-yl)propan-1-ol (90 mg, colorless oil, yield: 90%).

[0245] Step 4: Preparation of compound 3-(benzo[b]thiophen-7-yl)propyl methanesulfonate Refer to the synthesis method of the fourth step in Example 3.

[0246] Step 5: Preparation of compound (6bR,10aS)-8-(3-(benzo[b]thiophen-7-yl)propyl)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline by the synthetic method of the fifth step of Reference Example 3. 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=7.5Hz1H),6.51(d,J=5.5Hz1H),6.40(d,J=7.5Hz1H),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] + .

[0247] Example 7: 7-(3-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)propyl)benzo[d]oxazole

[0248]

[0249] Step 1: 2-Amino-6-bromophenol (1000 mg, 5.32 mmol), anhydrous p-toluenesulfonic acid (100 mg, 0.53 mmol), and triethyl orthoformate (10 mL) were added to a 25 mL single-necked reaction flask. Under nitrogen, the temperature was slowly raised to 80°C and stirred for 16 h. After completion of the reaction, saturated NaHCO₃ solution was added to the reaction mixture to an alkaline pH. The mixture was then extracted with ethyl acetate (3 x 20 mL). The combined organic phases were washed with saturated brine (1 x 20 mL), dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The crude product was purified by normal phase column chromatography (eluent gradient: 3% EA / PE) to afford 7-bromobenzo[d]oxazole (pale yellow solid, 900 mg, 85% yield).

[0250] Step 2: Add 7-bromobenzo[d]oxazole (250 mg, 1.26 mmol), ethyl (E)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) acrylate (340 mg, 1.51 mmol), Pd(dppf)Cl2.CH2Cl2 complex (20 mg, 0.03 mmol) and sodium carbonate (265 mg, 2.52 mmol) into a 25 mL single-necked reaction bottle, followed by addition of dioxane (5 mL) and water (1 mL). After the addition, replace the atmosphere with nitrogen three times, slowly heat to 80 ° C and stir for 16 h. After the reaction was complete, the reaction mixture was filtered and water (20 mL) was added. The mixture was extracted with ethyl acetate (3 x 10 mL). The organic phases were combined, washed with saturated brine (1 x 20 mL), dried over anhydrous sodium sulfate, and dried under reduced pressure. The crude product was purified by normal phase column chromatography (eluent gradient: 10% EA / PE) to obtain ethyl (E)-3-(benzo[d]oxazol-7-yl)acrylate (pale yellow oil, 150 mg, yield 55%). MS m / z (ESI): 218.5 [M+H] + .

[0251] Step 3: Add ethyl (E)-3-(benzo[d]oxazol-7-yl) acryloyl ester (100 mg, 0.46 mmol) to a 25 mL single-necked reaction vial, followed by ethyl acetate (10 mL) and 10% Pd / C (wet basis, 10 mg). After addition, the atmosphere was replaced with hydrogen three times and the reaction was stirred at room temperature for 16 h. After completion of the reaction as determined by LCMS, the reaction solution was filtered and the filtrate was concentrated under reduced pressure to afford ethyl 3-(benzo[d]oxazol-7-yl) propionate (crude product, 100 mg, 99% yield). The crude product was used directly in the next step without further purification. MS m / z (ESI): 220.4 [M+H] +

[0252] Step 4: Preparation of 3-(Benzo[d]oxazol-7-yl)propan-1-ol: Refer to the synthesis method of Step 3 of Example 3. Ethyl 3-(benzo[d]oxazol-7-yl)propanoate (50 mg, 0.23 mmol) was added to a 25 mL three-necked reaction flask, followed by anhydrous tetrahydrofuran (3 mL). Lithium aluminum tetrahydride (17 mg, 0.46 mmol) was added portionwise under nitrogen and an ice-water bath. The mixture was stirred for 1 h under ice-water bath. After completion of the reaction, LCMS analysis indicated that the reaction mixture was quenched by the slow addition of NaSO / 10HO, filtered, and the filter cake washed with 10% MeOH / DCM (10 mL). The filtrate was concentrated under reduced pressure, and the crude product was purified by normal phase column chromatography (eluent gradient: 40% EA / PE) to afford 3-(Benzo[d]oxazol-7-yl)propan-1-ol as a colorless oil (25 mg, 62% yield). MSm / z(ESI):178.4[M+H] +

[0253] Step 5: 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 to a 10 mL single-necked reaction flask. Methanesulfonic anhydride (12 mg, 0.07 mmol) was added under ice-water bath. After addition, the mixture was allowed to stir at room temperature for 3 h. After completion of the reaction, saturated ammonium chloride solution (5 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (2 x 10 mL). The organic phases were combined, washed with saturated brine (1 x 10 mL), dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The crude product was purified by normal phase chromatography (eluent gradient: 30% EA / PE) to obtain 3-(Benzo[d]oxazol-7-yl)propyl methanesulfonate (pale yellow oil, 8 mg, 60% yield).

[0254] Step 6: Compound 3-(Benzo[d]oxazol-7-yl)propyl methanesulfonate (8 mg, 0.03 mmol, crude) and (6bR,10aS)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline (8 mg, 0.04 mmol) were added to a 10 mL reaction bottle, followed by the addition of DIEA (11 mg, 0.09 mmol) and anhydrous DMSO (1 mL). After the addition, the temperature was raised to 60 °C and stirred for 6 h. After the reaction was completed, the reaction solution was filtered and the filtrate was directly subjected to reverse phase preparative separation (C18 column, eluent gradient: acetonitrile / (water + 0.05% NH4HCO3)) to obtain compound 7-(3-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)propyl)benzo[d]oxazole (pale yellow solid, 2.0 mg, yield 15%). 1 HNMR(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] + .

[0255] Example 8: (6bR,10aS)-3-methyl-8-(3-(quinolin-8-yl)propyl)-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline

[0256]

[0257] Step 1: 8-Bromoquinoline (500 mg, 2.40 mmol), ethyl acrylate (480 mg, 4.80 mmol), Pd(PPh3)2Cl2 (17 mg, 0.02 mmol), and triethylamine (730 mg, 7.20 mmol) were added to a 25 mL single-necked reaction flask. Anhydrous DMF (8 mL) was then added. After the addition, the atmosphere was purged with nitrogen three times, and the temperature was slowly raised to 120°C with stirring for 16 h. After completion of the reaction, water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (3 x 20 mL). The organic phases were combined, washed with saturated brine (1 x 20 mL), dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The crude product was purified by normal phase column chromatography (eluent gradient: 5% EA / PE) to obtain ethyl (E)-3-(quinolin-8-yl)acrylate (a reddish-brown oil, 350 mg, 64% yield). MSm / z(ESI):228.4[M+H] + .

[0258] Step 2: Add ethyl (E)-3-(quinolin-8-yl) acryloyl ester (100 mg, 0.44 mmol) to a 25 mL single-necked reaction flask, followed by ethyl acetate (10 mL) and 10% Pd / C (wet basis, 10 mg). After addition, the atmosphere was purged with hydrogen three times and the reaction was stirred at room temperature for 0.5 h. After completion of the reaction as determined by LCMS, the reaction solution was filtered and the filtrate was concentrated under reduced pressure to afford ethyl 3-(quinolin-8-yl) propionate (crude product, 100 mg, 99% yield). The crude product was used directly in the next step without further purification. MS m / z (ESI): 230.4 [M+H] + .

[0259] Step 3: Ethyl 3-(quinolin-8-yl)propionate (100 mg, 0.44 mmol) was added to a 25 mL three-necked reaction flask, followed by anhydrous tetrahydrofuran (5 mL). Lithium aluminum tetrahydride (33 mg, 0.88 mmol, 1 mol / L) was added portionwise under nitrogen and an ice-water bath. The reaction was stirred for 0.5 h in an ice-water bath. After completion of the reaction, the mixture was quenched by slowly adding NaSO 10H 2 O, filtered, and the filter cake was washed with 10% MeOH / DCM (10 mL). The filtrate was concentrated under reduced pressure, and the crude product was purified by normal phase column chromatography (eluent gradient: 30% EA / PE) to afford 3-(quinolin-8-yl)propan-1-ol as a colorless oil (60 mg, 74% yield). MS m / z (ESI): 188.4 [M+H] + .

[0260] 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 to a 10 mL single-necked reaction flask and stirred at room temperature for 2 h. After the reaction was completed, saturated sodium bicarbonate aqueous solution was added to the reaction solution to adjust the system pH to alkaline. The mixture was extracted with dichloromethane (2 x 10 mL). The organic phases were combined, washed with saturated brine (1 x 10 mL), dried over anhydrous sodium sulfate, and dried under reduced pressure to obtain compound 3-(quinolin-8-yl)propanal (dark brown oil, crude product, 25 mg, 83% yield). The crude product was not further purified and was used directly in the next reaction. MS m / z (ESI): 186.4 [M+H] + .

[0261] Step 5: Add 3-(Quinolin-8-yl)propanal (25 mg, 0.13 mmol) and (6bR,10aS)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline (32 mg, 0.14 mmol) to a 10 mL reaction vial and stir at room temperature for 0.5 h. Then, sodium triacetoxyborohydride (55 mg, 0.26 mmol) was added to the reaction mixture and stirred at room temperature for 16 h. After the reaction, the reaction solvent was removed under reduced pressure, and the crude product was directly subjected to reverse phase preparative separation (C18 column, eluent gradient: acetonitrile / (water + 0.05% NH4HCO3)) to obtain compound (6bR,10aS)-3-methyl-8-(3-(quinolin-8-yl)propyl)-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline (off-white solid, 6.0 mg, 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),2.92-2.8 7(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] + .

[0262] Example 9: (6bR,10aS)-8-(3-isoquinolin-8-propyl)-3-methyl-2,3,6b,7,8,9,10,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline

[0263]

[0264] The preparation of E9 refers to the synthesis method of Example 3. 1 H 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] +.

[0265] Example 10: (6bR,10aS)-3-methyl-8-(3-(1,2,3,4-tetrahydroquinolin-8-yl)propyl)-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline

[0266]

[0267] Step 1: Dissolve 5-bromo-3,4-dihydro-2H-benzo[b][1,4]oxazine (420 mg, 2.0 mmol) in DMF (10.0 mL). Under nitrogen, 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. The mixture was stirred at 100°C for 3 h. After completion of the reaction by TLC, water was added for quenching. The mixture was extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and purified by normal phase purification to obtain ethyl (E)-3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-5-yl)acrylate (yellow oil, 230 mg, 49% yield). MS m / z (ESI): 234.3.[M+H] + .

[0268] Step 2: Dissolve (E)-ethyl 3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-5-yl)acrylate (190 mg, 0.81 mmol) in DCM (20.0 mL). Add TEA (800 mg, 8.0 mmol) and (Boc)2O (700 mg, 3.2 mmol). Stir at 20°C for 16 h. Concentrate under reduced pressure and purify with normal phase to obtain (E)-tert-butyl 5-(3-ethoxy-3-oxoprop-1-en-1-yl)-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylate (yellow oil, 180 mg, 67% yield). MS m / z (ESI): 334.4.[M+H] + .

[0269] Step 3: Dissolve 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 in MeOH (10.0 mL), add 10% palladium on carbon (90 mg), stir at room temperature for 18 h, filter, and concentrate to obtain compound 5-(3-ethoxy-3-oxopropyl)-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylic acid tert-butyl ester (yellow oil, 160 mg, yield 88%). MS m / z (ESI): 336.4.[M+H] + .

[0270] Step 4: Dissolve tert-butyl 5-(3-ethoxy-3-oxopropyl)-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylate (145 mg, 0.43 mmol) in THF (2.0 mL), cool to 0°C, add lithium aluminum tetrahydride solution (0.45 mL, 0.15 mmol), and heat to 20°C with stirring for 1 h. Dry over sodium sulfate decahydrate, filter, and purify with normal phase to obtain tert-butyl 5-(3-hydroxypropyl)-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylate (yellow oil, 85 mg, yield 67%). MS m / z (ESI): 294.3.[M+H] + .

[0271] Step 5: Dissolve tert-butyl 5-(3-hydroxypropyl)-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylate (85 mg, 0.29 mmol) in DCM (5.0 mL), add PCC (128 mg, 0.59 mmol), and stir at 20°C for 3 h. Quench with saturated sodium bicarbonate, extract with DCM, dry over sodium sulfate, and filter and concentrate to afford tert-butyl 5-(3-hydroxypropyl)-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylate (colorless oil, 66 mg, 80% yield), which was used directly in the next reaction. MS m / z (ESI): 292.4.[M+H] + .

[0272] Step 6: (6bR,10aS)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline (62 mg, 0.27 mmol) and tert-butyl 5-(3-oxopropyl)-2,3-dihydro-4H-benzo[b][1,4]oxazine-4-carboxylate (66 mg, 0.23 mmol) were dissolved in DCM (3.0 mL), and triethylamine and acetic acid were added. 5 mg of each was stirred for 10 min, and then sodium triacetoxyborohydride (230 mg, 4.0 mmol) was added. The mixture was stirred at 20 ° C for 18 h, and water was added to quench the mixture. The mixture was extracted with ethyl acetate, and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The intermediate was purified by normal phase purification, dissolved in DCM (3.0 mL), and TFA (0.3 mL, 1.1 mmol) was added. The mixture was stirred at room temperature for 0.5 h, concentrated, and purified by prep-HPLC (eluent (v / v): acetonitrile / (water + 0.05% NH4HCO3)=30%–70%) gave compound (6bR,10aS)-3-methyl-8-(3-(1,2,3,4-tetrahydroquinolin-8-yl)propyl)-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline (off-white solid, 8.0 mg, yield 9%). 1 H 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] + .

[0273] Example 11: (6bR,10aS)-8-(3-(1H-indol-7-yl)propyl)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline

[0274]

[0275] Step 1: 1H-Indole-7-carbaldehyde (500.0 mg, 3.44 mmol) and methyl (triphenylphosphino)acetate (1.4 g, 4.13 mmol) were dissolved in DCM (3 mL) at room temperature. The reaction mixture was stirred at room temperature for 16 hours. 80 mL of water was added to the reaction solution, which was extracted with DCM (70 mL x 3). The combined organic phases were concentrated in vacuo to afford the crude product. The crude product was purified by silica gel column chromatography (PE / EA = 100 / 0 to 90 / 10) to afford methyl (E)-3-(1H-indol-7-yl)acrylate (580 mg, 83.7% yield) as a yellow solid. MS m / z (ESI): 202.1 [M+H] +

[0276] Step 2: Methyl (E)-3-(1H-indol-7-yl) acryloyl ester (480.0 mg, 2.39 mmol) was added to methanol (5 mL), followed by 10% palladium on carbon (101.5 mg). The reaction mixture was stirred at room temperature under a hydrogen atmosphere for 1 hour. After completion of the reaction, the reaction mixture was filtered through celite and washed with methanol to afford methyl 3-(1H-indol-7-yl) propionate (450 mg, 92.8% yield) as a gray solid. MS m / z (ESI): 204.1 [M+H] +

[0277] Step 3: Methyl 3-(1H-indol-7-yl)propanoate (450.0 mg, 2.21 mmol) was added to methanol (5 mL) and tetrahydrofuran (5 mL) at room temperature. Sodium borohydride (418.8 mg, 11.07 mmol) was added, and the reaction mixture was stirred at room temperature under a nitrogen atmosphere for 16 hours. After completion of the reaction, the mixture was quenched with excess methanol and concentrated in vacuo to afford the crude product. The crude product was purified by silica gel column chromatography (PE / EA = 100 / 0 to 60 / 40) to afford 3-(1H-indol-7-yl)propan-1-ol (380 mg, yield: 97.9%) as a light yellow oil. MS m / z (ESI): 176.2 [M+H] +

[0278] Step 4: Dissolve 3-(1H-indol-7-yl)propan-1-ol (50.0 mg, 0.29 mmol) and carbon tetrabromide (141.9 mg, 0.43 mmol) in dichloromethane (10 mL) at room temperature. Add triphenylphosphine (112.2 mg, 0.43 mmol), and stir the reaction mixture at room temperature for 16 hours. After completion of the reaction, concentrate in vacuo to obtain the crude product. The crude product is purified by silica gel column chromatography (PE / EA = 100 / 0 to 90 / 10) to obtain 7-(3-bromopropyl)-1H-indole (40 mg, 58.9% yield) as a clear oil. MS m / z (ESI): 238.1 [M+H] + .

[0279] Step 5: Dissolve 7-(3-bromopropyl)-1H-indole (40.5 mg, 0.17 mmol) in 1,4-dioxane / toluene (1.5 mL / 1.5 mL). Add (6bR,10aS)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline (39.0 mg, 0.17 mmol), potassium iodide (56.4 mg, 0.34 mmol), and triethylamine (51.6 mg, 0.51 mmol). Stir the reaction mixture at 100°C for 18 hours. Cool the reaction mixture to room temperature and concentrate in vacuo to obtain the crude product. The crude product was prepared to give (6bR,10aS)-8-(3-(1H-indol-7-yl)propyl)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline (13.51 mg, 20.16% yield) as a light yellow solid. 1 H 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, 2 H),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),2.9 2-2.86(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] + .

[0280] Example 12: (6bR,10aS)-8-(3-(dihydroindole-7-yl)propyl)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline

[0281]

[0282] At room temperature, (6bR,10aS)-8-(3-(1H-indol-7-yl)propyl)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline (55.0 mg, 0.14 mmol) was dissolved in acetic acid (3 mL). Sodium acetate borohydride (13.4 mg, 0.21 mmol) was added. The reaction mixture was stirred at room temperature for 30 minutes. After the reaction, the mixture was concentrated in vacuo, added into 10 mL of water, and sodium hydroxide solution was added dropwise to adjust the pH to 8. The mixture was diluted with 30 mL of water and extracted with ethyl acetate (30 mL × 3) to obtain a crude product. The crude product was purified by preparative method to obtain (6bR,10aS)-8-(3-(dihydroindole-7-yl)propyl)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline carboxylate (14.04 mg, yield 24.2%) as a brown solid. 1 H 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,2 H),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] + .

[0283] Example 13: (6bR,10aS)-8-(3-(3-methoxypyridin-4-yl)propyl)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline

[0284]

[0285] Step 1: Dissolve 3-fluoro-4-nitropyridine 1-oxide (5 g, 31.6 mmol) in anhydrous methanol (55 mL) at room temperature. Add 5.4 M sodium methoxide in methanol (5.9 mL, 31.6 mmol) at 0°C. Stir the reaction mixture at room temperature for 2 h. Concentrate the mixture under vacuum and dilute with water (80 mL). Extract the aqueous phase with dichloromethane (50 mL x 3). Wash the combined organic phases with brine (50 mL), dry over anhydrous sodium sulfate, filter, and concentrate under vacuum to afford 3-methoxy-4-nitropyridine 1-oxide (5 g, 77.8% yield) as a light yellow solid. The crude product was used directly in the next step without purification. MS m / z (ESI): 171.1 [M+H] + .

[0286] Step 2: 3-Methoxy-4-nitropyridine 1-oxide (5.0 g, 29.4 mmol) was dissolved in ethyl acetate (50 mL) at room temperature. Phosphorus tribromide (22.1 mL, 235.2 mmol) was then added dropwise. The mixture was stirred at room temperature for 10 minutes, then heated to 80°C and stirred at this temperature for 16 hours. The reaction mixture was cooled to room temperature and added dropwise to ice water. Extraction was performed with ethyl acetate. The aqueous phase was adjusted to pH 11 with 10 M aqueous NaOH and extracted three times with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to yield the crude product. The crude product was purified by column chromatography (EtOAc / PE = 0-15%) to afford 4-bromo-3-methoxypyridine (470 mg, 8.5% yield) as a brown solid. MS m / z (ESI): 188.1 [M+H] + .

[0287] Step 3: To a reaction flask containing 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 tri-o-methylphenylphosphine (228.25 mg, 0.75 mmol) was added DMF (5 mL) at room temperature. The reaction flask was purged with nitrogen three times, then heated to 100°C and stirred under nitrogen for 18 h. The reaction mixture was cooled to room temperature and filtered through celite. The filtrate was diluted with water (40 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to yield 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 light yellow solid. MS m / z (ESI): 208.1 [M+H] + .

[0288] Step 4: Dissolve ethyl 3-(3-methoxypyridin-4-yl) acryloyl ester (270 mg, 14.5 mmol) in methanol (5 mL) at room temperature, and add 10% wet palladium on carbon (69 mg, 0.65 mmol). Stir the reaction mixture at room temperature under a hydrogen atmosphere for 16 h. Filter the mixture through celite. Wash with methanol, and the combined filtrates are concentrated under vacuum to afford ethyl 3-(3-methoxypyridin-4-yl) propionate (50 mg, yield: 87.6%) as a yellow oil. The crude product is used directly in the next reaction without purification. MS m / z (ESI): 210.1 [M+H] + .

[0289] Step 5: Dissolve ethyl 3-(3-methoxypyridin-4-yl) propionate (200.0 mg, 0.96 mmol) in anhydrous tetrahydrofuran (5 mL) at room temperature, lower the temperature to 0°C, and add 1 M lithium aluminum hydride solution in tetrahydrofuran (2.4 mL, 2.39 mmol) dropwise. Stir the reaction mixture at room temperature for 1 h under a nitrogen atmosphere. Dilute the reaction mixture with tetrahydrofuran, quench with sodium sulfate decahydrate under an ice bath, and filter through Celite. Sonicate the filter cake with methanol and filter again. The combined filtrate is concentrated in vacuo to yield 3-(3-methoxypyridin-4-yl)propan-1-ol (160 mg, theoretical amount) as a yellow oil. MS m / z (ESI): 168.2 [M+H] + .

[0290] Step 6: Dissolve 3-(3-methoxypyridin-4-yl)propan-1-ol (130.0 mg, 0.78 mmol) and triethylamine (236.0 mg, 2.33 mmol) in anhydrous DCM (1.5 mL) at room temperature, and add a solution of MsCl (133.59 mg, 1.17 mmol) in DCM (0.5 mL) dropwise. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated in vacuo to afford 3-(3-methoxypyridin-4-yl)propyl methanesulfonate (191 mg, theoretical amount) as a white solid. MS m / z (ESI): 246.1 [M+H] + .

[0291] Step 7: (6bR,10aS)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline (90.0 mg, 0.30 mmol), 3-(3-methoxypyridin-4-yl)propyl methanesulfonate (192.6 mg, 0.78 mmol), and potassium iodide (130.2 mg, 0.78 mmol) were dissolved in anhydrous 1,4-dioxane (1.5 mL) and anhydrous toluene (1.5 mL) at room temperature. Triethylamine (238.3 mg, 2.36 mmol) was then added. The reaction mixture was stirred at 100°C for 22 h. The reaction mixture was cooled to room temperature and concentrated in vacuo to obtain the crude product. The crude product was purified by formic acid preparation to give (6bR,10aS)-8-(3-(3-methoxypyridin-4-yl)propyl)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline carboxylate (6.53 mg, yield: 3.8%) as a yellow oil. 1 H 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=9.4H z,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] + .

[0292] Example 14: (6bR,10aS)-8-(3-(2-methoxypyridin-3-yl)propyl)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline

[0293]

[0294] Step 1: To a reaction flask containing 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 tri-o-tolylphosphine (2.43 g, 7.98 mmol) was added DMF (100 mL) at room temperature. The reaction flask was purged with nitrogen three times, then heated to 100°C and stirred under nitrogen for 20 h. The reaction mixture was cooled to room temperature and filtered through celite. The filtrate was diluted with water (80 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to yield the crude product. The crude product was purified by column chromatography (EtOAc / PE = 0-6%) to give ethyl (E)-3-(2-methoxypyridin-3-yl)acrylate (4 g, yield: 71.8%) as a light yellow oil. MS m / z (ESI): 208.1 [M+H] +

[0295] Step 2: Dissolve ethyl (E)-3-(2-methoxypyridin-3-yl) acryloyl ester (3 g, 14.5 mmol) in methanol (30 mL) at room temperature, and add 10% wet palladium on carbon (770 mg, 0.725 mmol). Stir the reaction mixture at room temperature under a hydrogen atmosphere for 7 h. Filter the mixture through celite. Wash with methanol, and the combined filtrates are concentrated under vacuum to afford ethyl 3-(2-methoxypyridin-3-yl) propionate (3 g, 98.6% yield) as a colorless, viscous oil. The crude product is used directly in the next reaction without purification. MS m / z (ESI): 210.1 [M+H] +

[0296] Step 3: Dissolve ethyl 3-(2-methoxypyridin-3-yl)propanoate (1 g, 4.8 mmol) in anhydrous tetrahydrofuran (15 mL) at room temperature. Lower the temperature to 0°C, and add 1 M lithium aluminum hydride in tetrahydrofuran (12 mL, 12 mmol) dropwise. Stir the reaction mixture at room temperature for 1 h under a nitrogen atmosphere. Dilute the mixture with tetrahydrofuran, quench with sodium sulfate decahydrate in an ice bath, and filter through Celite. The filter cake is sonicated with methanol, filtered again, and the combined filtrates are concentrated in vacuo to yield the crude product. The crude product is purified by column chromatography (EtOAc / PE = 0-18%) to afford 3-(2-methoxypyridin-3-yl)propan-1-ol (705 mg, 87.5% yield) as a colorless, viscous oil. MS m / z (ESI): 168.2 [M+H] +

[0297] Step 4: Dissolve 3-(2-methoxypyridin-3-yl)propan-1-ol (200 mg, 1.196 mmol) in anhydrous DCM (2 mL) at room temperature and add thionyl chloride (398.4 mg, 3.35 mmol) dropwise under ice-cooling. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated in vacuo to afford 3-(3-chloropropyl)-2-methoxypyridine (220 mg, theoretical amount) as a white solid. The crude product was used directly in the next reaction without purification. MS m / z (ESI): 186.1 [M+H] +

[0298] Step 5: Dissolve (6bR,10aS)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline (68 mg, 0.296 mmol), 3-(3-chloropropyl)-2-methoxypyridine (110.09 mg, 0.593 mmol), and potassium iodide (98.36 mg, 0.593 mmol) in anhydrous 1,4-dioxane (1.5 mL) and anhydrous toluene (1.5 mL) at room temperature. Add triethylamine (180.02 mg, 1.779 mmol). Stir the reaction mixture at 100°C for 22 h. Cool the reaction mixture to room temperature and concentrate in vacuo to obtain the crude product. The crude product was purified by alkaline preparation to give (6bR,10aS)-8-(3-(2-methoxypyridin-3-yl)propyl)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline (12.10 g, yield: 10.7%) as a yellow oil. 1 H 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,

[0299] 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] + .

[0300] Example 15: (6bR,10aS)-8-(3-(4-methoxypyridin-3-yl)propyl)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline

[0301]

[0302] Step 1: Add 3-(4-methoxypyridin-3-yl)prop-2-yn-1-ol (150 mg, 0.92 mmol) to a 50 mL three-necked reaction flask, followed by methanol (10 mL) and wet palladium on carbon (10%, 50 mg). The mixture was then heated to 60°C and stirred for 4 h under a hydrogen atmosphere. After completion of the reaction, the reaction mixture was filtered, concentrated, and purified by column chromatography (DCM:MeOH = 3:1) to afford the title compound, 3-(4-methoxypyridin-3-yl)propan-1-ol (colorless liquid, 80 mg, 80% yield). MS m / z (ESI): 168.4 [M+H] + .

[0303] Step 2: Preparation of 3-(4-methoxypyridin-3-yl)propyl methanesulfonate: Refer to the synthesis method of the third step in Example 3.

[0304] Step 3: Preparation of (6bR,10aS)-8-(3-(4-methoxypyridin-3-yl)propyl)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline was carried out by referring to the synthesis method of the fourth step of Example 3. 1 H 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] + .

[0305] Example 16: (6bR,10aS)-8-(3-(3-methoxypyridin-2-yl)propyl)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline

[0306]

[0307] The preparation was carried out according to the synthesis method of Example 8. 1H NMR (500 MHz, DMSO) δ 8.03 (dd, J = 4.7, 1.3 Hz, 1H), 7.31 (dd, J = 8.3, 1.3 Hz, 1H), 7.18 (dd, J = 8.2, 4.7 Hz, 1H), 6.54-6.46 (m, 1H), 6.41 (dd, J = 7.3, 0.9 Hz, 1H), 6.32 (dd, J = 8.0, 1.0 Hz, 1H), 3.8 0(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] +

[0308] Example 17: Preparation of (6bR,10aS)-8-((E)-3-(2-methoxypyridin-3-yl)allyl)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline

[0309]

[0310] Step 1: Dissolve ethyl (E)-3-(2-methoxypyridin-3-yl) acryloyl ester (800.0 mg, 3.82 mmol) in dichloromethane (10 mL) at room temperature. Lower the temperature to 0°C, and add dropwise a 1 M solution of diisobutylaluminum hydride (7.6 mL, 7.65 mmol) in THF. Stir the reaction mixture at room temperature for 1 h under a nitrogen atmosphere. Dilute the reaction mixture with dichloromethane and quench with saturated ammonium chloride solution dropwise under an ice bath. Dilute the mixture with 40 mL of water, extract the mixture with dichloromethane (40 mL x 3), combine the organic phases, and concentrate in vacuo to obtain the crude product. The crude product was purified by column chromatography (EtOAc / PE = 0-18%) to afford (E)-3-(2-methoxypyridin-3-yl)prop-2-en-1-ol (437 mg, 69.3% yield) as a light yellow oil. MS m / z(ESI):166.2[M+H] +

[0311] Step 2: Dissolve (E)-3-(2-methoxypyridin-3-yl)prop-2-en-1-ol (100 mg, 0.60 mmol) in anhydrous DCM (3 mL) at room temperature and add SOCl2 (144 mg, 1.21 mmol) dropwise under ice-cooling. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated in vacuo to afford (E)-3-(3-chloroprop-1-en-1-yl)-2-methoxypyridine (110 mg, theoretical amount) as a white solid. The crude product was used directly in the next reaction without purification. MS m / z (ESI): 184.1 [M+H] +

[0312] Step 3: (E)-3-(3-chloroprop-1-en-1-yl)-2-methoxypyridine (112.1 mg, 0.61 mmol) was dissolved in 1,4-dioxane / toluene (1.5 mL / 1.5 mL) at room temperature. (6bR,10aS)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline (70.0 mg, 0.30 mmol), potassium iodide (101 mg, 0.61 mmol), and triethylamine (185.3 mg, 1.83 mmol) were added. The reaction mixture was stirred at 100°C for 18 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo to obtain the crude product. The crude product was purified by alkaline preparation to give (6bR,10aS)-8-((E)-3-(2-methoxypyridin-3-yl)allyl)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]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] + .

[0313] Example 18: Preparation of (6bR,10aS)-8-(2-(2-methoxyphenoxy)ethyl)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline

[0314]

[0315] At room temperature, (6bR,10aS)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline (23 mg, 0.1 mmol) was dissolved in DMSO (2.5 mL), and DIEA (0.5 mL, 3.0 mmol) and 1-(2-bromoethoxy)-2-methoxybenzene (23 mg, 0.1 mmol) were added in sequence. The mixture was heated to 65°C and stirred for 18 h. The mixture was cooled to room temperature and filtered, and then purified and separated by prep-HPLC (eluent (v / v): acetonitrile / (water + 0.05% NH4HCO3)=30%–70%) gave compound (6bR,10aS)-8-(2-(2-methoxyphenoxy)ethyl)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline (yellow solid, 10.2 mg, yield 27%). 1HNMR(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] + .

[0316] Example 19: 2-Methoxy-N-(2-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)ethyl)aniline

[0317]

[0318] Step 1: Dissolve 2-methoxyaniline (505 mg, 2.0 mmol) and dibromoethane (1.104 g, 6.0 mmol) in DMF (5.0 mL) and stir at 60°C for 3 h. After TLC, the reaction is quenched with water and extracted with ethyl acetate. The organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. Purify with normal phase to obtain 1-(2-bromoethoxy)-2-methoxybenzene (yellow solid, 115 mg, 25% yield). MS m / z (ESI): 232.3.[M+H] + .

[0319] Step 2: The synthesis of 2-methoxy-N-(2-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-yl)ethyl)aniline was carried out by referring to the synthesis method of the fourth step of Example 3. 1 H 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),3.4 7-3.42(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). MSm / z(ESI):379.9[M+H]+ .

[0320] Example 20: N-(2-methoxyphenyl)-2-(6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-acetamide

[0321]

[0322] Compound (6bR,10aS)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]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 at 60 ° C for 12 h. The reaction solution was filtered and then subjected to reverse phase preparation (eluent (v / v): acetonitrile / (water + 0.05% NH4HCO3)). The acetonitrile was removed under reduced pressure and the mixture was lyophilized to obtain the compound N-(2-methoxyphenyl)-2-(6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-acetamide (pale yellow solid, 20 mg, yield 46%). 1 H 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=7.6H z,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] + .

[0323] Example 21: 3-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)-1-(pyridin-4-yl)propan-1-one

[0324]

[0325] Step 1: Ethyl 3-carbonyl-3-(pyridin-4-yl)propanoate (300 mg, 1.55 mmol) was added to a 50 mL three-necked reaction flask. THF (5 mL) was then added. LiHMDS (1.7 mL, 1 mol / L) was slowly added dropwise at -78°C. The reaction was stirred at 0°C for 0.5 h. Lithium aluminum tetrahydride (3.1 mL, 1 mol / L) was then slowly added dropwise at 0°C. The temperature was slowly raised to 0°C and the reaction was continued with stirring for 1 h. The reaction solution was quenched with saturated aqueous ammonium chloride, extracted with dichloromethane (2 x 50 mL), concentrated, and filtered to afford 1-(pyridin-4-yl)propane-1,3-diol (yellow liquid, 200 mg, 84.0% yield). MS m / z (ESI): 154.0 [M+H] + .

[0326] Step 2: Add 1-(pyridin-4-yl)propane-1,3-diol (200 mg, 1.3 mmol) to a 100 mL reaction flask, followed by dichloromethane (20 mL) and MnO2 (568 mg, 6.5 mmol) and stir at 40°C for 4 h. The reaction mixture was filtered, concentrated, and then purified by reverse-phase column chromatography to afford 3-hydroxy-1-(pyridin-4-yl)propan-1-one (colorless solid, 100 mg, 50.1% yield). MS m / z (ESI): 152.1 [M+H] + .

[0327] Step 3: Preparation of 3-carbonyl-3-(pyridin-4-yl)propyl methanesulfonate: Refer to the synthesis method of the third step in Example 3.

[0328] Step 4: The preparation of 3-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-yl)-1-(pyridin-4-yl)propan-1-one was carried out according to the synthesis method of the fourth step of Example 3. 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] + .

[0329] Example 22: 1-(2-methoxyphenyl)-3-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)yl)propan-1-one

[0330]

[0331] Step 1: Dissolve 1-(2-methoxyphenyl)ethane-1-one (500 mg, 3.33 mmol) and paraformaldehyde (200 mg, 6.66 mmol) in tetrahydrofuran (10 mL). Add N,N-diisopropylethylamine trihydrofluoride (716 mg, 3.33 mmol) and TFA (40 mg, 0.33 mmol) and stir at 70°C for 12 h. Add water (80 mL) to the reaction solution, extract with ethyl acetate (80 mL x 2). Dry the organic phase over anhydrous sodium sulfate, filter, and concentrate the filtrate. Purify and isolate the compound using normal phase column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain 1-(2-methoxyphenyl)prop-2-en-1-one (yellow solid, 430 mg crude product, 80% yield). MS m / z (ESI): 163.2 [M+H] +

[0332] Step 2: Dissolve 1-(2-methoxyphenyl)prop-2-en-1-one (100 mg, 0.62 mmol) in acetonitrile (5 mL), then add water (67 mg, 3.70 mmol) and chromium trichloride (20 mg, 0.12 mmol) and stir at room temperature for 24 h. Add water (30 mL) to the reaction solution, and extract with ethyl acetate (30 mL x 2). Dry the organic phase over anhydrous sodium sulfate, filter, and concentrate the filtrate. Reverse phase preparation (eluent (v / v): acetonitrile / (water + 0.05% NH4HCO3)) is performed. The acetonitrile is removed under reduced pressure, and the product is lyophilized to afford 3-hydroxy-1-(2-methoxyphenyl)propan-1-one (white solid, 10 mg, 9% yield).

[0333] Step 3: Preparation of 3-(2-methoxyphenyl)-3-oxopropyl methanesulfonate: Refer to the synthesis method of the third step in Example 3.

[0334] Step 4: The preparation of 1-(2-methoxyphenyl)-3-((6bR,10aS)3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)yl)propan-1-one was carried out by referring to the synthesis method of the fourth step of Example 3. 1 H 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] + .

[0335] Example 23: 1-(2,3-dihydrobenzofuran-7-yl)-3-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)propan-1-one

[0336]

[0337] Compound 23-1 (115 mg, 0.5 mmol) was dissolved in EtOH (5 mL), and paraformaldehyde (120 mg, 4.0 mmol) and concentrated hydrochloric acid (0.125 mL, 1.5 mmol) were added. The mixture was heated with stirring and refluxed for 16 h. After concentration, it was purified by normal phase column chromatography to obtain compound 1-(2,3-dihydrobenzofuran-7-yl)-3-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-yl)propan-1-one (gray solid, 45 mg, yield 22%). 1 H 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,3 H),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] + .

[0338] Example 24: (6bR, 10aS)-8-(3-(2,3-dihydrobenzofuran-7-yl)-3-fluoropropyl)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline

[0339]

[0340] Step 1: Compound 1-(2,3-dihydrobenzofuran-7-yl)-3-((6bR,10aS)-3-methyl-2,3,6b,9,10,10aS hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]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, and the mixture was stirred at 20° C. for 1 h and then filtered. The mixture was purified and separated by prep-HPLC (eluent (v / v): acetonitrile / (water + 0.05% NH4HCO3)=30%–70%) gave compound 1-(2,3-dihydrobenzofuran-7-yl)-3-((6bR,10aS)-3-methyl-2,3,6b,9,10,10aShexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-yl)propan-1-ol (off-white solid, 12.5 mg, yield 50%).

[0341] Step 2: Dissolve the compound 1-(2,3-dihydrobenzofuran-7-yl)-3-((6bR,10aS)-3-methyl-2,3,6b,9,10,10aS hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-yl)propan-1-ol in DCM (2 mL), cool to 0°C, add DAST (10 mg, 0.06 mmol), stir at 0°C for 0.5 h, add saturated sodium bicarbonate to quench, extract with DCM, and concentrate. After prep-HPLC purification and separation (eluent (v / v): acetonitrile / (water + 0.05% NH4HCO3) = 30%–70%), the compound (6bR,10aS)-8-(3-(2,3-dihydrobenzofuran-7-yl)-3-fluoropropyl)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline was obtained as an off-white solid, 2.23 mg, yield 18%). 1H NMR (500 MHz, CD3OD) δ7.17 (d, J = 5.0 Hz, 1H), 7.12 (d, J = 5.0 Hz, 1H), 6.85 (t, J = 7.5 Hz, 1H), 6.60 (t, J = 7.5 Hz, 1H), 6.48 (d, J = 5.0 Hz,1H),6.42(d,J=10.0 Hz,1H),5.68-5.59(m,2H),5.25-5.15(m,2H),4.66-4.55(m,1H),3.52-3.48(m,1H),3.34-3.31(m,4 H),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] + .

[0342] Example 25: (6bR,10aS)-8-(2-(2,3-dihydrobenzofuran-3-yl)ethyl)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline

[0343]

[0344] Step 1: Add 2-(benzofuran-3-yl)ethan-1-ol (150 mg, 1.3 mmol) to a 50 mL three-necked reaction flask, followed by methanol (10 mL), wet palladium on carbon (10%, 0.1 g), and palladium hydroxide on carbon (20%, 0.1 g). The mixture was then heated to 40°C and stirred under a hydrogen atmosphere for 16 h. After completion of the reaction, the reaction mixture was filtered, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 3:1) to afford the title compound, 2-(2,3-dihydrobenzofuran-3-yl)ethan-1-ol (colorless liquid, 0.1 g, 66% yield).

[0345] Step 2: Preparation of 2-(2,3-dihydrobenzofuran-3-yl)ethyl methanesulfonate Refer to the synthesis method of the third step of Example 3

[0346] Step 3: Preparation of (6bR,10aS)-8-(2-(2,3-dihydrobenzofuran-3-yl)ethyl)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline was performed by referring to the synthesis method of the fourth step 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=3.2,1.6Hz,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] + .

[0347] Example 26: (6bR,10aS)-8-(2-(Benzofuran-3-yl)ethyl)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline

[0348]

[0349] Step 1: Add ethyl 2-(benzofuran-3-yl)acetate (1000 mg, 4.87 mmol) to a 50 mL three-necked reaction flask, followed by THF (20 mL). Lithium aluminum tetrahydride (2 mL, 1 mol / L) was slowly added dropwise at 0°C. The mixture was stirred at 0°C for 0.2 h. The reaction solution was quenched with sodium sulfate decahydrate, filtered, concentrated, and purified by normal phase column chromatography (petroleum ether:ethyl acetate = 3:1) to afford 2-(benzofuran-3-yl)ethan-1-ol (colorless liquid, 700 mg, 88.7% yield).

[0350] Procedure: Add 2-(Benzofuran-3-yl)ethan-1-ol (200 mg, 1.23 mmol) to a 25 mL reaction flask, followed by DCM (50 mL), followed by DIEA (635 mg, 4.9 mmol) and Ms2O (430 mg, 2.47 mmol). Stir at room temperature for 1 h. The reaction mixture is extracted with DCM (2 x 20 mL), and the organic phase is washed with saturated brine (2 x 20 mL). After concentration, 2-(Benzofuran-3-yl)ethyl methanesulfonate (colorless liquid, 0.25 g, 84.7% yield) is obtained.

[0351] Step 3: Compound 2-(Benzofuran-3-yl)ethyl methanesulfonate (60 mg, 0.25 mmol) and raw material (6bR,10aS)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline (68 mg, 0.3 mmol) were added to a 25 mL reaction bottle, followed by DMSO (5 mL) and then DIPEA (0.2 g, 1.58 mmol). After the addition, stir at 60 ° C for 16 h. The reaction mixture was added with ethyl acetate (30 mL), washed with water (30 mL), and then with brine (50 mL). The organic phase was concentrated and initially purified by normal phase column chromatography (dichloromethane:methanol = 10:1), followed by reverse phase column chromatography (acetonitrile / (water + 0.05% HCl)) to give the compound (6bR,10aS-8-(2-(benzofuran-3-yl)ethyl)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline) (gray solid, 20 mg, yield 21.5%). 1 H 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] + .

[0352] Example 27: 2-(3-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)propyl)aniline

[0353]

[0354] Step 1: tert-Butyl (2-bromophenyl)carbamate (1 g, 3.68 mmol), ethyl acrylate (400 mg, 4.00 mmol), tri(o-tolyl)phosphine (110 mg, 0.36 mmol), palladium acetate (80 mg, 0.36 mmol), and triethylamine (728 mg, 7.19 mmol) were added to a 100 mL reaction flask. DMF (15 mL) was then added and stirred at 100°C for 12 h. Water (80 mL) was added to the reaction solution, which was then extracted with ethyl acetate (2 x 80 mL). The organic phase was washed with brine (3 x 80 mL), concentrated, and purified by normal phase column chromatography (petroleum ether:ethyl acetate = 10:1) to afford (Z)-ethyl 3-(2-((tert-butoxycarbonyl)amino)phenylacrylate as a yellow oil, 290 mg, 27% yield. 1 H 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).

[0355] Step 2: Add compound (Z)-3-(2-((tert-Butoxycarbonyl)amino)phenyl)acrylate (290 mg, 0.995 mmol) to a 100 mL 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). After complete addition, stir at 60°C under hydrogen for 3 h. The reaction mixture was filtered, concentrated, and purified by normal phase column chromatography (petroleum ether:ethyl acetate = 3:1) to afford ethyl 3-(2-((tert-Butoxycarbonyl)amino)phenyl)propanoate (white solid, 240 mg, 82% yield). MS m / z (ESI): 294.4 [M+H] + .

[0356] Step 3: Add ethyl 3-(2-((tert-butoxycarbonyl)amino)phenyl)propanoate (140 mg, 0.48 mmol) to a 50 mL three-necked flask, followed by anhydrous tetrahydrofuran (5 mL). Then, under nitrogen at 0°C, add a 1M solution of LiAlH4 in tetrahydrofuran (0.95 mL, 0.95 mmol, 1 M). Stir at room temperature for 2 h. Sodium sulfate decahydrate (50 mg) was added to the reaction solution, which was stirred at room temperature for 10 min. The reaction solution was filtered, concentrated, and purified by normal phase column chromatography (petroleum ether:ethyl acetate = 3:1) to afford tert-butyl (2-(3-hydroxypropyl)phenyl)carbamate as a colorless oil (100 mg, 83% yield).

[0357] Step 4: tert-Butyl (2-(3-hydroxypropyl)phenyl)carbamate (100 mg, 0.40 mmol) was added to a 50 mL reaction flask, followed by dichloromethane (4 mL), followed by DIEA (155 mg, 1.20 mmol), DMAP (25 mg, 0.20 mmol), and MsO (174 mg, 1.00 mmol). After stirring at room temperature for 1 h, water (10 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (10 mL x 2). The organic phase was washed twice with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated to yield 3-(2-(((tert-butoxycarbonyl)amino)phenyl)propyl methanesulfonate (yellow oil, 100 mg, 77% yield). MS m / z (ESI): 230.5 [M+H-Boc] +

[0358] Step 5: Compound 3-(2-(((tert-Butoxycarbonyl)amino)phenyl)propyl methanesulfonate (100 mg, 0.30 mmol) was added to a 50 mL reaction bottle, followed by DMSO (4 mL), and then DIEA (118 mg, 0.91 mmol) and (6bR,10aS)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline (83 mg, 0.36 mmol). After stirring at 60 ° C for 12 h, water (10 mL) was added to the reaction solution and extracted with ethyl acetate (10 mL*2). The organic phase was washed twice with saturated brine (10 mL). Then, the organic phase was dried over anhydrous sodium sulfate and concentrated, and purified and separated by normal phase column chromatography (dichloromethane:methanol=10:1) to give compound 2-(3-((6bR,10aS)-3-methyl-2,3,6b,9,10,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-propyl)propyl)phenyl)carbamate (2-(3-(6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-propyl)phenyl)carbamate (white solid, 80 mg, yield 57%). MS m / z(ESI):463.8[M+H] + .

[0359] Step 6: Butyl 2-(3-((6bR,10aS)-3-methyl-2,3,6b,9,10,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-propyl)propyl)phenyl)carbamate (20 mg, 0.043 mmol) was dissolved in HCl / Dioxane (2 mL) and stirred at 25 °C for 1 h. The reaction solution was spin-dried, dissolved in MeOH (2 mL) and then subjected to reverse phase preparation (eluent (v / v): acetonitrile / (water + 0.05% NH4HCO3)). The acetonitrile was removed under reduced pressure and lyophilized to obtain compound 2-(3-(6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydropyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-propyl)aniline (yellow solid, 7 mg, yield 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=7.3H z,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] + .

[0360] Example 28: N-(2-(3-(6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-propyl)propyl)phenyl)acetamide

[0361]

[0362] Compound 2-(3-(6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydropyrido[3',4':4,5]pyrrolo[1,2,3-de]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 at 25 °C for 2 h. Water (10 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (2*10 mL). The organic phase was concentrated, dissolved with MeOH (2 mL), and then subjected to reverse phase preparation (eluent (v / v): acetonitrile / (water + 0.05% NH4HCO3)). The acetonitrile was removed under reduced pressure and lyophilized to give the compound N-(2-(3-(6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-propyl)propyl)phenyl)acetamide (yellow oil, 5 mg, 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),2.5 7(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] + .

[0363] Example 29: 1-(2-(3-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)propyl)phenyl)ethan-1-one

[0364]

[0365] Step 1: 1-(2-iodophenyl)ethane-1-one (500 mg, 2.03 mmol), trimethyl orthoformate (1 mL), and anhydrous ethylene glycol (2 mL) were added to a 25 mL three-necked flask. Anhydrous dichloromethane (10 mL) was then added and stirred under nitrogen in an ice-water bath for 0.5 h. Finally, concentrated sulfuric acid (0.5 mL) was slowly added dropwise. After completion, the mixture was allowed to stir at room temperature for 24 h. After TLC, saturated NaHCO₃ solution was slowly added dropwise to alkaline the reaction mixture. The mixture was then extracted with DCM (3 x 20 mL). The organic phases were combined, washed with saturated brine (1 x 20 mL), dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The crude product was purified by normal phase column chromatography (eluent gradient: 5% EA / PE) to afford 2-(2-iodophenyl)-2-methyl-1,3-dioxolane as a pale yellow oil, 350 mg, 59% yield.

[0366] Step 2: Add the compound 2-(2-iodophenyl)-2-methyl-1,3-dioxolane (350 mg, 1.20 mmol), ethyl acrylate (360 mg, 3.60 mmol), Pd(OAc)2 (13 mg, 0.06 mmol), tri(o-methylphenyl)phosphine (18 mg, 0.06 mmol), and triethylamine (360 mg, 3.60 mmol) into a 25 mL single-necked reaction bottle, followed by anhydrous DMF (5 mL). After the addition, replace the atmosphere with nitrogen three times, slowly heat to 100 ° C and stir to react for 16 h. After the reaction was completed as determined by TLC, the reaction solution was filtered, and water (20 mL) was added to the reaction solution. The mixture was extracted with ethyl acetate (3 x 20 mL). The organic phases were combined, washed with saturated brine (1 x 20 mL), dried over anhydrous sodium sulfate, and dried under reduced pressure. The crude product was purified and separated by normal phase column chromatography (eluent gradient: 3% EA / PE) to obtain compound (E)-ethyl 3-(2-(2-methyl-1,3-dioxolan-2-yl)phenyl)acrylate (pale yellow oil, 200 mg, yield 63%).

[0367] Step 3: Add ethyl (E)-3-(2-(2-methyl-1,3-dioxolan-2-yl)phenyl)acrylate (200 mg, 0.76 mmol) to a 25 mL single-necked reaction flask. Ethyl acetate (15 mL) and 10% Pd / C (wet basis, 20 mg) were then added. After addition, the atmosphere was replaced with hydrogen three times and the reaction was stirred at room temperature for 0.5 h. After TLC analysis, the reaction solution was filtered and the filtrate was concentrated under reduced pressure to afford ethyl 3-(2-(2-methyl-1,3-dioxolan-2-yl)phenyl)propanoate (crude product, 200 mg, 99% yield). The crude product was used directly in the next step without further purification.

[0368] Step 4: Preparation of 3-(2-(2-methyl-1,3-dioxolane-2-yl)phenyl)propan-1-ol: Refer to the synthesis method of the first step in Example 26.

[0369] Step 5: Compound 3-(2-(2-methyl-1,3-dioxolane-2-yl)phenyl)propan-1-ol (35 mg, 0.16 mmol), DMAP (2 mg, 0.02 mmol), DIEA (62 mg, 0.48 mmol), and anhydrous dichloromethane (5 mL) were added to a 25 mL three-necked reaction flask. Methanesulfonic anhydride (55 mg, 0.32 mmol) was slowly added under nitrogen and an ice-water bath. After the addition, the mixture was stirred at room temperature for 2 h. After completion of the reaction, water (10 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (2 x 10 mL). The organic phases were combined, washed with saturated brine (1 x 10 mL), dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure to obtain compound 3-(2-(2-methyl-1,3-dioxolane-2-yl)phenyl)propyl methanesulfonate (a colorless oil, crude product, 50 mg). The crude product was not further purified and was used directly in the next reaction.

[0370] Step 6: The preparation of (6bR,10aS)-3-methyl-8-(3-(2-(2-methyl-1,3-dioxolane-2-yl)phenyl)propyl)-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline was carried out by referring to the synthesis method of the third step of Example 26.

[0371] Step 7: Compound (6bR,10aS)-3-methyl-8-(3-(2-(2-methyl-1,3-dioxolane-2-yl)phenyl)propyl)-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline (5 mg, 0.75 mmol) was added to a 10 mL single-necked reaction bottle, followed by the addition of 4 M HCl / Dioxane (1 mL). The reaction was stirred at room temperature for 1.0 h. After the reaction was completed, LCMS detection was performed and the solvent was removed under reduced pressure. The crude product was dissolved in MeOH (1 mL), and the solution was directly subjected to reverse phase preparative separation (C18 column, eluent gradient: acetonitrile / (water + 0.05% NH4HCO3)) to give compound 1-(2-(3-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)propyl)phenyl)ethan-1-one (white solid, 3.0 mg, 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] + .

[0372] Example 30: 3-(2-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)ethyl)benzo[d]isothiazole

[0373]

[0374] Compound 3-(2-bromoethyl)benzo[d]isothiazole (15 mg, 0.07 mmol) and (6bR,10aS)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline (15 mg, 0.07 mmol) were added to a 10 mL reaction bottle, followed by anhydrous DMF (2 mL), K2CO3 (19 mg, 0.14 mmol) and NaI (10 mg, 0.07 mmol), respectively. After the addition, the temperature was slowly raised to 45 ° C and stirred for 16 h. After the reaction, the reaction mixture was filtered, and the filtrate was directly subjected to reverse phase preparative separation (C18 column, eluent gradient: acetonitrile / (water + 0.05% NH4HCO3)) to obtain compound 3-(2-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-yl)ethyl)benzo[d]isothiazole (pale yellow oil, 8 mg, yield 33%). 1HNMR (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),2.93-2.8 1(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] + .

[0375] Example 31: 3-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)-1-phenylpropan-1-ol

[0376]

[0377] At room temperature, (6bR,10aS)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline (18 mg, 0.078 mmol) was dissolved in DMSO (2.0 mL), and DIEA (0.5 mL, 3.0 mmol) and 3-chloro-1-phenylpropan-1-ol (14 mg, 0.08 mmol) were added in sequence. The mixture was heated to 65°C and stirred for 18 h. The mixture was cooled to room temperature and filtered, and then purified by prep-HPLC (eluent (v / v): acetonitrile / (water + 0.05% NH4HCO3)=30%–70%) gave compound 3-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)-1-phenylpropan-1-ol (pale yellow oil, 9.8 mg, yield 33%). 1HNMR(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] + .

[0378] Example 32: (6bR,10aS)-3-methyl-8-(3-(2-(methylthio)phenyl)propyl)-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline)

[0379]

[0380] The preparation of E32 refers to the synthetic method of Example 26. 1 H 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] + .

[0381] Example 33: (6bR,10aS)-3-methyl-8-(3-(2-(methylsulfonyl)phenyl)propyl)-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline

[0382]

[0383] Step 1: Compound (2-iodophenyl)(methyl)sulfane 33-1 (1 g, 4 mmol), ethyl acrylate (1 g, 10 mmol), Pd(OAc)2 (50 mg, 0.22 mmol), K2CO3 (1.36 g, 9.86 mmol), and TBAB (1.32 g, 4.09 mmol) were added to a three-necked flask containing 10 mL of DMF. The atmosphere was replaced with nitrogen three times and the reaction was carried out at 50°C for 16 h. After the reaction was completed by TLC, water and EA were added, the layers were separated, and the aqueous phase was extracted twice with EA. The organic phases were combined, washed three times with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by normal phase column chromatography (PE / EA = 100% to 5 / 1) to give compound (E)-ethyl 3-(2-(methylthio)phenyl)acrylate (920 mg, yield 90%).

[0384] Step 2: Ethyl (E)-3-(2-(methylthio)phenyl)acrylate (800 mg, 3.6 mmol), 50 mg of 10% Pd / C, and 50 mg of Pd(OH)2 / C were added to a three-necked flask containing 30 mL of THF and 30 mL of EtOH. The atmosphere was replaced with hydrogen three times and allowed to react at room temperature for 16 h. After completion of the reaction as determined by TLC and LCMS, the mixture was filtered and concentrated to afford the crude product (860 mg) of ethyl 3-(2-(methylthio)phenyl)propanoate. MS m / z (ESI): 225.17 [M+H] + .

[0385] Step 3: Add 3-(2-(methylthio)phenyl)propionic acid ethyl ester (300 mg, 1.34 mmol) to a single-necked vial containing 5 mL of DCM, followed by the addition of m-CPBA (231 mg, 1.14 mmol). The mixture was allowed to react at room temperature for 16 h. TLC confirmed the reaction was complete. The mixture was washed three times with saturated NaHCO₃, separated, dried, filtered, concentrated, and then purified by normal phase column chromatography (PE / EA = 100% to 5 / 1) to afford 3-(2-(methylsulfonyl)phenyl)propionic acid ethyl ester (150 mg, yield: 49%).

[0386] Step 4: Add ethyl 3-(2-(methylsulfonyl)phenyl)propanoate (116 mg, 0.45 mmol) to a three-necked flask containing 4 mL of THF. The atmosphere was replaced with nitrogen three times, cooled to 0°C, and 0.9 mL of a 1M LAH THF solution was injected. The reaction was continued for 1 hour, and TLC confirmed the reaction was complete. Sodium sulfate decahydrate was added to quench the reaction, followed by EA and Na2SO4. The mixture was stirred at room temperature for half an hour, filtered, and concentrated to afford 3-(2-(methylsulfonyl)phenyl)propan-1-ol (70 mg, yield: 72%).

[0387] Step 5: Preparation of 3-(2-(methylsulfonyl)phenyl)propyl methanesulfonate: Refer to the synthesis method of the third step in Example 3.

[0388] Step 6: Preparation of (6bR,10aS)-3-methyl-8-(3-(2-(methylsulfonyl)phenyl)propyl)-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline was performed by referring to the synthesis method of the fourth step of Example 3. 1 H 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] + .

[0389] Example 34: (6bR, 10aS)-8-(3-cyclohexylpropyl)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline

[0390]

[0391] The preparation of E34 was carried out according to the synthesis method of Example 20. 1 H 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-

[0392] 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] + .

[0393] Example 35: (6bR, 10aS)-3-methyl-8-(3-(piperidin-1-yl)propyl)-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline

[0394]

[0395] The preparation of E35 refers to the synthesis method of Example 20. 1 H 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),1.9 0(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] + .

[0396] Example 36: 3-(6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydropyrido[3,4′:4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)yl)-1-(piperidin-1-yl)propan-1-one

[0397]

[0398] The preparation of compound E36 was carried out according to the synthesis method of Example 20. 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] + .

[0399] Example 37: 2-(((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)methyl)benzo[d]oxazole

[0400]

[0401] The preparation of E37 refers to the synthetic method of Example 30. 1 H 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] + .

[0402] Example 38: 2-(2-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)ethyl)benzo[d]oxazole

[0403]

[0404] Step 1: Dissolve ethyl 2-(benzoxazol-2-yl)acetate (60 mg, 0.29 mmol) in methanol (3 mL). Add sodium borohydride (55 mg, 1.45 mmol) at 0°C and stir at room temperature for 2 h. Add water (10 mL) to the reaction mixture at 0°C and extract with ethyl acetate (10 mL x 2). Dry the organic phase over anhydrous sodium sulfate, filter, and concentrate. Purify and isolate the organic phase using normal phase column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain the title compound, 2-(benzo[d]oxazol-2-yl)ethan-1-ol (yellow oil, 30 mg, 64% yield). MS m / z (ESI): 164.4 [M+H] +

[0405] Step 2: Preparation of 2-(benzo[d]oxazol-2-yl)ethyl methanesulfonate: Refer to the synthesis method of the third step in Example 3.

[0406] Step 3: Preparation of 2-(2-(6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydropyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-ethyl)benzoxazole was carried out by referring to the synthesis method of the fourth step of Example 3. 1 HNMR (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] + .

[0407] Example 39: (6bR, 10aS)-3-methyl-8-(3-(thien-2-yl)propyl)-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline

[0408]

[0409] Step 1: Preparation of 3-(thiophen-2-yl)propyl methanesulfonate: Refer to the synthesis method of the third step in Example 3.

[0410] Step 2: Preparation of (6bR,10aS)-3-methyl-8-(3-(thien-2-yl)propyl)-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline was carried out by referring to the synthesis method of the fourth step of Example 3. 1 H 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] + .

[0411] Example 40: (6bR,10aS)-8-(3-(3-methoxythiophen-2-yl)propyl)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline

[0412]

[0413] Step 1: Dissolve 3-methoxythiophene-2-carboxaldehyde (350 mg, 2.46 mmol) in THF (25.0 mL). Add ethoxycarbonylmethylenetriphenylphosphine (1.20 g, 3.45 mmol) under nitrogen. Stir at 75°C for 18 h. After completion of the reaction, confirm with TLC. Concentrate under reduced pressure and purify with normal phase chromatography to obtain ethyl (E)-3-(3-methoxythiophen-2-yl) acryloyl ester (yellow oil, 420 mg, 74% yield). MS m / z (ESI): 213.3.[M+H] + .

[0414] Step 2: Dissolve ethyl (E)-3-(3-methoxythiophen-2-yl) acryloyl ester (270 mg, 1.27 mmol) in MeOH (15.0 mL), add 10% Pd / C (135 mg), and hydrogenate at room temperature for 18 h. Filter and concentrate to obtain ethyl 3-(3-methoxythiophen-2-yl) propionate (colorless oil, 230 mg, 85% yield). MS m / z (ESI): 215.3. [M+H] + .

[0415] Step 3: Dissolve ethyl 3-(3-methoxythiophen-2-yl)propanoate (112 mg, 0.52 mmol) in THF (1.0 mL), cool to 0°C, add 1M lithium aluminum tetrahydride solution in tetrahydrofuran (0.5 mL, 0.5 mmol), and stir at room temperature for 1 hour. Add sodium sulfate decahydrate and stir for 30 minutes. Filter, concentrate, and purify with normal phase chromatography to obtain 3-(3-methoxythiophen-2-yl)propan-1-ol (colorless oil, 68 mg, 76% yield). MS m / z (ESI): 173.3.[M+H] + .

[0416] Step 4: Dissolve the compound 3-(3-methoxythiophen-2-yl)propan-1-ol (68 mg, 0.40 mmol) in DCM (3.0 mL), add DIEA (260 mg, 2.0 mmol), cool to 0°C, add methanesulfonic anhydride (140 mg, 0.8 mmol), then warm to 20°C and stir for 3 h. Quench with water, extract with DCM, add sodium sulfate, dry, and filter to obtain the compound 3-(3-methoxythiophen-2-yl)propyl methanesulfonate (yellow oil, 100 mg), which is used directly in the next reaction.

[0417] Step 5: (6bR,10aS)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline (55 mg, 0.24 mmol) was dissolved in DMSO (3.0 mL) at room temperature, and DIEA (0.5 mL, 3.0 mmol) and 3-(3-methoxythiophen-2-yl)propyl methanesulfonate (100 mg, 0.4 mmol) were added in sequence. The mixture was heated to 65°C and stirred for 18 min. h, cooled to room temperature, filtered and purified by prep-HPLC (eluent (v / v): acetonitrile / (water + 0.05% NH4HCO3) = 30%–70%) to obtain compound (6bR,10aS)-8-(3-(3-methoxythiophen-2-yl)propyl)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline (pale yellow oil, 16.0 mg, yield 17%). 1 H 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] + .

[0418] Example 41: (6bR, 10aS)-8-(3-(2-methoxythiophen-3-yl)propyl)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline

[0419]

[0420] Step 1: Dissolve 2-methoxythiophene (575 mg, 5.05 mmol) in DCM (20.0 mL), cool to 0°C, add NBS (1.78 g, 10.0 mmol), warm to 20°C, and stir for 3 h. Concentrate under reduced pressure and purify with normal phase chromatography to obtain 3,5-dibromo-2-methoxythiophene (yellow oil, 380 mg, 27% yield). MS m / z (ESI): 272.4. [M+H] + .

[0421] Step 2: Dissolve 3,5-dibromo-2-methoxythiophene (380 mg, 1.40 mmol) in THF (5.0 mL), cool to -78°C, add n-butyllithium solution (0.56 mL, 1.4 mmol), and stir at -78°C for 30 min. Quench the reaction by adding methanol, extract with dichloromethane, wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, and purify with normal phase to obtain 3-bromo-2-methoxythiophene (yellow oil, 195 mg, 71% yield). MS m / z (ESI): 194.4.[M+H] + .

[0422] Step 3: Dissolve 3-bromo-2-methoxythiophene (190 mg, 1.0 mmol) in DMF (5.0 mL). Under nitrogen, triethylamine (800 mg, 8.0 mmol), ethyl acrylate (120 mg, 1.2 mmol), o-trimethylphenylphosphine (60 mg, 0.2 mmol), and palladium acetate (22 mg, 0.1 mmol) were added sequentially. Stir at 100°C for 3 h. After completion of the reaction by TLC, water was added for quenching. The product was extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and purified by normal phase purification to obtain ethyl (E)-3-(2-methoxythiophen-3-yl)acrylate (yellow oil, 48 mg, 23% yield). MS m / z (ESI): 213.3.[M+H] + .

[0423] Step 4: Dissolve (E)-ethyl 3-(2-methoxythiophen-3-yl)acrylate (48 mg, 0.23 mmol) in MeOH (5.0 mL), add 10% palladium on carbon (30 mg), and stir at room temperature for 18 h. Filter and concentrate to obtain ethyl 3-(2-methoxythiophen-3-yl)propanoate (yellow oil, 32 mg, yield 66%). MS m / z (ESI): 215.3. [M+H] + .

[0424] Step 5: Dissolve ethyl 3-(2-methoxythiophen-3-yl)propanoate (32 mg, 0.15 mmol) in THF (1.5 mL), cool to 0°C, add lithium aluminum tetrahydride solution (0.15 mL, 0.15 mmol), and heat to 20°C with stirring for 1 h. Quench with water, dry over sodium sulfate, filter, and purify with normal phase chromatography to obtain 3-(2-methoxythiophen-3-yl)propan-1-ol (yellow oil, 18 mg, 69% yield). MS m / z (ESI): 173.3.[M+H] + .

[0425] Step 6: Dissolve the compound 3-(2-methoxythiophen-3-yl)propan-1-ol (18 mg, 0.53 mmol) in DCM (3.0 mL), add TEA (50 mg, 0.5 mmol), cool to 0°C, add methanesulfonic anhydride (36 mg, 0.2 mmol), and then warm to 20°C and stir for 3 h. Quench with water, extract with DCM, add sodium sulfate, and dry. Filter to obtain the compound 3-(2-methoxythiophen-3-yl)propyl methanesulfonate (colorless oil, 37 mg, yield 99%), which is directly used in the next reaction.

[0426] Step 7: At room temperature, (6bR,10aS)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline (26 mg, 0.11 mmol) was dissolved in DMSO (3.0 mL), and DIEA (195 mg, 1.5 mmol) and compound 3-(2-methoxythiophen-3-yl)propyl methanesulfonate (37 mg, 0.15 mmol) were added in sequence. The mixture was heated to 65 ° C and stirred for 18 h. After cooling to room temperature, it was filtered and purified by prep-HPLC (eluent (v / v): acetonitrile / (water + 0.05% NH4HCO3)=30%–70%) gave compound (6bR,10aS)-8-(3-(2-methoxythiophen-3-yl)propyl)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline (yellow solid, 2.0 mg, yield 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] + .

[0427] Example 42: 8-(3-(2,3-dihydrobenzofuran-7-yl)propyl)-1,2,6b,7,8,9,10,10a-octahydro-[1,4]oxazino[2,3,4-hi]pyrido[4,3-b]indole

[0428]

[0429] Step 1: Dissolve benzomorpholine (815 mg, 6.0 mmol) in acetic acid (12 mL) and cool to 0°C. Add aqueous NaNO2 (414 mg, 6.0 mmol, 4 mL of water) with stirring. Stir at 20°C for 3 h. After completion of the reaction, quench with water and extract with DCM. The organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to yield 4-nitroso-3,4-dihydro-2H-benzo[b][1,4]oxazine (yellow oil, 680 mg, 69% yield). MS m / z (ESI): 163.3.[M+H] + .

[0430] Step 2: Lithium aluminum tetrahydride (158 mg, 4.15 mmol) was suspended in THF (10 mL) and cooled to 0°C. A solution of 4-nitroso-3,4-dihydro-2H-benzo[b][1,4]oxazine (680 mg, 4.15 mmol) in tetrahydrofuran (5 mL) was added with stirring. The mixture was heated to 20°C and stirred for 18 h. The mixture was quenched with 2M aqueous sodium hydroxide solution, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by normal phase purification to obtain 4-amino-3,4-dihydro-2H-benzo[b][1,4]oxazine (yellow oil, 413 mg, 67% yield). MS m / z (ESI): 164.3.[M+H] + .

[0431] 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 to a 25 mL reaction flask and heated to 88°C with stirring for 2 h. Concentrated HCl (0.23 mL, 2.8 mmol) was added and heated to 88°C with stirring for 3 h. The mixture was cooled to room temperature and filtered to obtain 1,2,7,8,9,10-hexahydro-[1,4]oxazino[2,3,4-hi]pyrido[4,3-b]indole (yellow solid, 335 mg, 55% yield). MS m / z (ESI): 213.4.[M+H] + .

[0432] Step 4: Dissolve 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) and cool to 0°C. Add NaBH3CN (296 mg, 4.65 mmol) with stirring, and stir at 20°C for 3 h. After completion of the reaction, saturated sodium bicarbonate solution was added, and the mixture was extracted with DCM. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. Purification with normal phase gave compound 1,2,6b,7,8,9,10,10a-octahydro-[1,4]oxazino[2,3,4-hi]pyrido[4,3-b]indole (pale yellow solid, 115 mg, 66% yield). MS m / z (ESI): 215.3.[M+H] + .

[0433] Step 5: At room temperature, 1,2,6b,7,8,9,10,10a-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), and DIEA (0.5 mL, 3.0 mmol) and 3-(2,3-dihydrobenzofuran-7-yl)propyl methanesulfonate (52 mg, 0.20 mmol) were added in sequence. The mixture was heated to 65 ° C and stirred for 18 h. After filtration, the mixture was purified by prep-HPLC (eluent (v / v): acetonitrile / (water + 0.05%) The reaction mixture was stirred for 2 h at 4 ℃ for 1 hr. The mixture was stirred for 2 h at 4 ℃ for 30 hr. The mixture was stirred for 2 h at 4 ℃ for 30 hr. The mixture was stirred for 2 h at 4 ℃ for 30 hr. The mixture was stirred for 2 h at 4 ℃ for 30 hr. The mixture was stirred for 2 h at 4 ℃ for 30 hr. The mixture was stirred for 2 h at 4 ℃ for 30 hr. The mixture was stirred for 2 h at 4 ℃ for 30 hr. The mixture was stirred for 2 h at 4 ℃ for 30 hr. The mixture was stirred for 2 h at 4 ℃ for 30 hr. The mixture was stirred for 2 h at 4 ℃ for 30 hr. .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] + .

[0434] Example 43: 10-(3-(2,3-dihydrobenzofuran-7-yl)propyl)-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3',4':4,5]pyrrolo[3,2,1-iJ]quinoline

[0435]

[0436] The preparation of E43 followed the synthetic method of 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,1 H),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] + .

[0437] Example 44: (6bR,10aS)-8-(3-(2,3-dihydrobenzo[b][1,4]dioxin-5-yl)propyl)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline

[0438]

[0439] The preparation of E44 was carried out according to the synthesis method of Example 3. 1 H 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] + .

[0440] Example 45-1: 1-((6bR,10aS)-8-(3-(2,3-dihydrobenzofuran-7-yl)propyl)-1,2,6b,7,8,9,10,10a-octahydro-3H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-3-yl)ethan-1-one

[0441]

[0442] Step 1: Ethyl (4aS,9bR)-6-bromo-1,3,4,4a,5,9b-hexahydro-2H-pyrido[4,3-b]indole-2-carboxylate (2.08 g, 6.4 mmol), benzophenone imine (1.5 g, 7.7 mmol), NaOt-Bu (1.23 g, 12.8 mmol), BINAP (120 mg, 0.19 mmol), 40 mL Toluene was added to a 250 mL three-necked flask, and the mixture was replaced with nitrogen three times. The temperature was raised to 60°C and the reaction was continued for 16 hours. The reaction was then cooled to room temperature, and Pd2(dba)3 (59 mg, 0.064 mmol) was added. The mixture was replaced with nitrogen three times, and the temperature was raised to 105°C and the reaction was continued for 16 hours. LCMS analysis indicated a small amount of starting material remaining. The reaction solution was cooled to room temperature, MTBE was added, filtered, and concentrated to afford ethyl (4aS,9bR)-6-((diphenylmethylene)amino)-1,3,4,4a,5,9b-hexahydro-2H-pyrido[4,3-b]indole-2-carboxylate (3.4 g, crude), which was directly used in the next step. MS m / z (ESI): 426.5 [M+H] + .

[0443] Step 2: Ethyl (4aS,9bR)-6-((diphenylmethylene)amino)-1,3,4,4a,5,9b-hexahydro-2H-pyrido[4,3-b]indole-2-carboxylate (3.4 g, 8.0 mmol), ethyl bromoacetate (2.67 g, 7.7 mmol), Na2CO3 (1.7 g, 16.04 mmol), KI (1.99 g, 12.76 mmol), 40 mL Acetone was added to a 250 mL three-necked flask, and the mixture was replaced with nitrogen three times. The temperature was raised to 60°C and the reaction was continued for 16 h. A small amount of starting material remained, as monitored by Lcms. The reaction solution was concentrated to dryness, and DCM and water were added. The organic phase was separated, washed with saturated sodium chloride, dried, filtered, and concentrated to obtain the compound (4aS,9bR)-6-((diphenylmethylene)amino)-1,3,4,4a,5,9b-hexahydro-2H-pyrido[4,3-b]indole-2-carboxylic acid ethyl ester (4 g, crude product), which was directly used in the next step. MS m / z (ESI): 513.6 [M+H] + .

[0444] Step 3: Ethyl (4aS,9bR)-6-((diphenylmethylene)amino)-1,3,4,4a,5,9b-hexahydro-2H-pyrido[4,3-b]indole-2-carboxylate (4 g, crude) was added to a one-necked bottle containing 40 mL of THF, 8 mL of 2N HCl was added at room temperature and stirred at room temperature for another half an hour. The reaction was complete as monitored by LCMS. The THF was concentrated and added to DCM. The layers were separated and the organic phase was washed three times with saturated sodium chloride, dried, concentrated, mixed with neutral alumina, and passed through a column. The mixture was first purified with PE / EA = 100% to 1 / 10 and then with MeOH / DCM = 0 to 3% to obtain 800 mg of the compound ethyl (6bR,10aS)-2-oxo-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate. MS m / z (ESI): 302.2 [M+H]. + .

[0445] Step 4: Ethyl (6bR,10aS)-2-oxo-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate (170 mg, 0.56 mmol) was added to a three-necked flask containing 10 mL of THF. The atmosphere was replaced with N2 three times, and 1.7 mL of 1M BH3Me2S was added at 0°C. After the addition was complete, the temperature was raised to 70°C and the reaction was allowed to react for 3 h. LCMS monitoring indicated that the reaction was complete. The reaction solution was cooled to 0°C, and 6N HCl was added dropwise until no bubbles were generated. The THF was concentrated, and NaOH (aq) was added to adjust the pH to 9. The solution was extracted twice with DCM, dried, and concentrated to obtain the compound ethyl (6bR,10aS)-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate (100 mg, yellow oil, yield: 62.5%).

[0446] Step 5: Ethyl (6bR,10aS)-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate (100 mg, 0.348 mmol) and 3 mL of HBr in HBr were reacted at 100°C for 16 h. The reaction was completed as monitored by LCMS. The product was concentrated to give 70 mg of (6bR,10aS)-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline, which was used directly in the next step.

[0447] Step 6: (6bR,10aS)-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline (70 mg, 0.33 mmol), 7 (110 mg, 0.4 mmol), and 0.1 mL of DIEA were added to a single-necked bottle containing 1 mL of DMSO. The atmosphere was replaced with nitrogen three times, and the temperature was raised to 60°C. The reaction was reacted for 2 h and the reaction was monitored by LCMS to completion. Water and EA were added, the layers were separated, the aqueous phase was extracted with EA, the organic phases were combined, washed three times with saturated sodium chloride solution, dried, concentrated, and column purified (MeOH / DCM = 0-5%) to afford (6bR,10aS)-8-(3-(2,3-dihydrobenzofuran-7-yl)propyl)-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline (40 mg, beige solid, yield: 32%). MS m / z (ESI): 376.6.[M+H] + .

[0448] Step 7: (6bR,10aS)-8-(3-(2,3-dihydrobenzofuran-7-yl)propyl)-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline (40 mg, 0.10 mmol) and TEA (20 mg, 0.20 mmol) were added to a single-necked bottle containing 1 mL of DCM. The atmosphere was replaced with nitrogen three times, and the temperature was lowered to 0°C. Acetylchloride (13 mg, 0.15 mmol) was added, and the mixture was reacted at this temperature for 0.5 h. The reaction was monitored by LCMS to be complete. Water and DCM were added, the layers were separated, the aqueous phase was extracted with DCM, the organic phases were combined, washed three times with saturated sodium chloride solution, dried, concentrated, and purified by Prep-HPLC (30-70% CJJ 30 min, 0.05% NH4HCO3 in H2O) to give compound 1-((6bR,10aS)-8-(3-(2,3-dihydrobenzofuran-7-yl)propyl)-1,2,6b,7,8,9,10,10a-octahydro-3H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-3-yl)ethan-1-one (15 mg, yellow solid, yield: 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] + .

[0449] Example 45-2: 1-((6bR,10aS)-8-(3-(2,3-dihydrobenzofuran-7-yl)propyl)-1,2,6b,7,8,9,10,10a-octahydro-3H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-3-yl)ethan-1-one

[0450]

[0451] Step 1: The preparation of 45-2-1 follows the synthetic method of step 2 of E73-1.

[0452] Step 2: Add 45-2-1 (860 mg, 4 mmol), TEA (808 mg, 8 mmol), and 10 mL of MeOH to a 100 mL single-necked flask, then add Boc2O (872 mg, 4 mmol) and react at room temperature for 2 h. The reaction was complete by TLC. The product was concentrated and filtered through a column (PE / EA = 2 / 1) to afford 45-2-2 (yellow oil, 1.2 g). MS m / z (ESI): 316.5 [M+H] + .

[0453] Step 3: 45-2-2 (300 mg, 0.95 mmol), TEA (192 mg, 1.9 mmol), and 5 mL of DCM were added to a 50 mL single-necked flask. Acetyl chloride (90 mg, 1.14 mmol) was then added and the mixture was allowed to react at room temperature for 10 min. LCMS confirmed the reaction was complete. Saturated sodium chloride was added, the layers were separated, and the product was dried and concentrated by column chromatography (PE / EA = 1 / 1) to afford 45-2-3 (330 mg, yellow oil). MS m / z (ESI): 358.2 [M+H] + .

[0454] Step 4: Add 45-2-3 (330 mg, 0.924 mmol), 1 mL of TFA, and 3 mL of DCM to a 50 mL single-necked vial and react at room temperature for 2 h. LCMS confirmed the reaction was complete, concentrated, and saturated sodium bicarbonate was added to adjust the pH to 7-8. The layers were separated, and the aqueous phase was extracted five times with DCM / MeOH = 10 / 1 (v / v). The mixture was dried and concentrated to yield 45-2-4 (210 mg of a yellow solid). MS m / z (ESI): 258.2 [M+H] + .

[0455] Step 5: Under nitrogen, 45-2-4 (100 mg, 0.389 mmol) was dissolved in MeOH (50 mL) and DCM (30 mL). 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 mixture was reacted at 25°C for 1 h. LCMS confirmed the reaction was complete. Water was added, the mixture was extracted with EA, dried over sodium sulfate, filtered, concentrated, and purified on a silica gel column (DCM:MeOH = 10:1) to afford compound 45-2-5 (yellow solid, 100 mg, 61% yield). MS m / z (ESI): 418.2 [M+H] + .

[0456] Step 6: 45-2-5 (100 mg, 0.239 mmol) was purified by SFC (Daicel ChiralPak IH, 40 mm ID×250 mm, 10 μm; Mobile phase: Supercritical CO2 / Methanol [0.1% NH 3. H2O (V / V)] = 65 / 35; Flow rate: 140 mL / min) to give white solid E45-2 (PK1: 26.0 mg, purity 99%, yield 26%, ee 100%, RT = 1.687, OROT = -97.9 and white solid E45-1 (PK2: 29.1 mg, purity 99%, yield 29%, ee 98%, RT = 2.267, OROT = +89.1). E45-2: 1HNMR(400MHz,DMSO-d6)δ8.10(s,1H),7.04(d,J=7.2Hz,1H),6.91(d,J=7.2Hz,1 H),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: 1 H 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).

[0457] Example 46: (6bR, 10aS)-8-(3-(3-chloropyridin-2-yl)propyl)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline

[0458]

[0459] Step 1: Dissolve tert-butyl (2-formylpyridin-3-yl)carbamate (750 mg, 3.37 mmol) in tetrahydrofuran (20 mL), add ethoxycarbonylmethylenetriphenylphosphine (1.4 g, 4.04 mmol), and stir at 70°C for 2 h. The reaction mixture was condensed and purified by normal phase column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain (E)-ethyl 3-(tert-butoxycarbonyl)amino)pyridin-2-ylacrylate (pale yellow oil, 940 mg, yield 96%). MS m / z (ESI): 293.6 [M+H] + .

[0460] Step 2: Dissolve (E)-ethyl 3-(tert-butoxycarbonyl)amino)pyridin-2-ylacrylate (940 mg, 3.22 mmol) in ethyl acetate (15 mL). Add 10% wet palladium on carbon (35 mg, 0.32 mmol) and stir under hydrogen at 28°C for 15 min. The reaction mixture was filtered and concentrated to afford ethyl 3-(3-(((tert-butoxycarbonyl)amino)pyridin-2-yl)propanoate as a pale yellow oil, 830 mg, 88% yield. MS m / z (ESI): 295.7 [M+H] + .

[0461] Step 3: Ethyl 3-(3-(((tert-Butoxycarbonyl)amino)pyridin-2-yl)propanoate (830 mg, 2.82 mmol) was dissolved in tetrahydrofuran (15 mL). LiAlH₄ (4.23 mL, 1 M in THF, 4.23 mmol) was added under nitrogen at 0°C. The reaction mixture was allowed to react at room temperature for 30 min. Sodium sulfate decahydrate was then added until no bubbles were generated during stirring. The reaction mixture was filtered, concentrated, and purified by normal phase column chromatography (dichloromethane:methanol = 10:1) to obtain tert-butyl (2-(3-hydroxypropyl)pyridin-3-yl)carbamate (colorless oil, 460 mg, 65% yield). MS m / z (ESI): 253.6 [M+H] + .

[0462] Step 4: Dissolve tert-butyl (2-(3-hydroxypropyl)pyridin-3-yl)carbamate (460 mg, 1.82 mmol) in hydrochloric acid / dioxane (10 mL). After reacting at room temperature for 30 min, the reaction solution was reverse-phase treated (eluent (v / v): acetonitrile / (water + 0.05% NH4HCO3)). Remove the acetonitrile under reduced pressure and lyophilize to obtain 3-(3-aminopyridin-2-yl)propanol (white solid, 240 mg, 88% yield). MS m / z (ESI): 153.2 [M+H] + .

[0463] Step 5: Dissolve 3-(3-aminopyridin-2-yl)propanol (240 mg, 1.58 mmol), cupric chloride (45 mg, 0.32 mmol), cuprous chloride (311 mg, 3.15 mmol), and tert-butyl nitrite (325 mg, 3.15 mmol) in acetonitrile (15 mL). Under nitrogen, react at 25°C for 0.5 h and then at 50°C for 2 h. The reaction solution was filtered and purified by normal phase column chromatography (dichloromethane:methanol = 10:1) to obtain 3-(3-chloropyridin-2-yl)propanol (yellow oil, 50 mg, yield 19%). MS m / z (ESI): 172.1 [M+H]+ .

[0464] Step 6: Dissolve 3-(3-chloropyridin-2-yl)propanol (50 mg, 0.29 mmol) in dichloromethane (5 mL) and add PCC (440 mg, 2.04 mmol). After reacting at room temperature for 0.5 h, filter the reaction solution and wash the filtrate with saturated sodium bicarbonate solution (10 mL x 2). Concentrate the organic phase to obtain the title compound 3-(3-chloropyridin-2-yl)propanal (brown solid, 45 mg crude product, 92% yield). MS m / z (ESI): 170.1 [M+H] + .

[0465] Step 7: Compound 3-(3-chloropyridin-2-yl)propanal (35 mg, 0.31 mmol) was dissolved in dichloromethane (2 mL), and (6bR, 10aS)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline (49 mg, 0.21 mmol) was added thereto. After reacting at room temperature for 0.5 h, sodium acetate borohydride (135 mg, 0.63 mmol) was added thereto. After reacting at room temperature for 0.5 h, the reaction solution was filtered and then subjected to reverse phase preparation (eluent (v / v): acetonitrile / (water + 0.05% The mixture was stirred for 2 hours at room temperature for 1 h. After 4 hours, the acetonitrile was removed under reduced pressure and the mixture was lyophilized to give the compound (6bR, 10aS)-8-(3-chloropyridin-2-propyl)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline (yellow solid, 23 mg, yield 19%). 1 H 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] + .

[0466] Example 47: 2-(3-(6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydropyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-propyl)pyridin-3-amine

[0467]

[0468] Step 1: Dissolve tert-butyl (2-(3-hydroxypropyl)pyridin-3-yl)carbamate (20 mg, 0.079 mmol) in dichloromethane (2 mL). Add PCC (85 mg, 0.40 mmol). React at room temperature for 12 h. Filter the reaction solution and wash the filtrate with saturated sodium bicarbonate solution (10 mL x 2). Concentrate the organic phase to obtain tert-butyl (2-(3-oxopropyl)pyridin-3-yl)carbamate (brown solid, 20 mg crude product, 100% yield). MS m / z (ESI): 251.5 [M+H] + .

[0469] Step 2: Dissolve the compound (2-(3-oxopropyl)pyridin-3-yl)carbamic acid tert-butyl ester (20 mg, 0.079 mmol) in dichloromethane (2 mL), add (6bR, 10aS)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline (19 mg, 0.079 mmol), react at room temperature for 0.5 h, then add sodium acetate borohydride (51 mg, 0.24 mmol), react at room temperature for 0.5 h, filter the reaction solution, and perform reverse phase chromatography (eluent (v / v): acetonitrile / (water + 0.05%). The mixture was stirred for 2 h at 4 ℃ for 1 h. After 4 h, acetonitrile was removed under reduced pressure and the mixture was lyophilized to give tert-butyl 2-(3-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(H)-propyl)pyridine-3-carbamate (yellow solid, 8 mg, yield 22%). MS m / z (ESI): 464.9 [M+H] + .

[0470] Step 3: Compound 2-(3-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(H)-propyl)pyridine-3-carbamic acid tert-butyl ester (8 mg, 0.017 mmol) was dissolved in dichloromethane (3 mL), and hydrochloric acid / dioxane (3 mL) was added thereto at 0°C. After reacting at 0°C for 10 minutes, the reaction solution was filtered and then subjected to reverse phase preparation (eluent (v / v): acetonitrile / (water + 0.05% NH4HCO3)), the acetonitrile was removed under reduced pressure, and the mixture was lyophilized to give compound 2-(3-(6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydropyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-propyl)pyridin-3-amine (yellow solid, 2 mg, yield 33%). 1 H 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] + .

[0471] Example 48: (6bR, 10aS)-8-(3-(5-fluoro-2,3-dihydrobenzofuran-4-yl)propyl)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline

[0472]

[0473] The preparation of E48 was carried out according to the synthesis 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,2 H),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] + .

[0474] Example 49: (6bR, 10aS)-8-(3-(5-fluorobenzofuran-4-yl)propyl)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline

[0475]

[0476] The preparation of E49 was carried out according to the synthesis method of Example 3. 1 H NMR (500MHz, CDCl3) δ7.63 (d, J = 2.0Hz, 1H), 7.28-7.26 (m, 1H), 7.02-6.92 (m, 1H), 6.79 (d d,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),3.5 8(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] + .

[0477] Example 50: (6bR, 10aS)-8-(2-(1H-indol-3-yl)ethyl)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline

[0478]

[0479] 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°C, and methanesulfonyl chloride (74.9 mg, 0.65 mmol) was added. The mixture was allowed to return to room temperature and stirred for 1 hour before being concentrated in vacuo at room temperature. The crude product was dissolved in anhydrous dimethyl sulfoxide (3 mL), and (6bR,10aS)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline (50.0 mg, 0.22 mmol), potassium iodide (72.3 mg, 0.44 mmol), and DIPEA (0.5 mL) were added. The reaction mixture was stirred at 100°C for 16 hours. LCMS (ENBW230404-026-6-R1, 2023.8.8) indicated the formation of the product. The reaction mixture was cooled to room temperature, added to 50 mL of water, and extracted with ethyl acetate (40 mL x 3). The mixture was washed with saturated brine and dried over anhydrous sodium sulfate. The organic phases were combined and concentrated to yield the crude product. The crude product was purified to yield (6bR,10aS)-8-(2-(1H-indol-3-yl)ethyl)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline (7.80 mg, 9.5% yield) as a white solid. 1 H 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] + .

[0480] Example 52: 2-Methyl-1-(2-(3-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)propyl)phenoxy)propan-2-ol

[0481]

[0482] Step 1: Dissolve chroman-2-one (5.0 g, 33.7 mmol) in tetrahydrofuran (50 mL) at room temperature and add sodium borohydride (1.9 g, 50.5 mmol). Stir the reaction mixture at 60°C for 2 hours. After completion of the reaction, cool to room temperature and quench with saturated ammonium chloride solution. Concentrate in vacuo and slurry with 50 mL of dichloromethane. Filter and concentrate the filtrate in vacuo to yield 2-(3-hydroxypropyl)phenol (5.5 g, 99.1% yield) as a colorless oil. MS m / z (ESI): 153.2 [M+H] +

[0483] Step 2: Dissolve 2-(3-hydroxypropyl)phenol (5.5 g, 36.1 mmol) in acetone (50 mL), add benzyl bromide (7.4 g, 43.3 mmol) and potassium carbonate (7.5 g, 54.2 mmol). The reaction mixture is stirred at 50°C for 48 hours. The reaction mixture is cooled to room temperature, 120 mL of water is added, and extraction with ethyl acetate (100 mL x 3) yields 3-(2-(benzyloxy)phenyl)propan-1-ol (3 g, 34.4% yield) as a clear oil. MS m / z (ESI): 243.2 [M+H] +

[0484] Step 3: 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°C, and methanesulfonyl chloride (899.1 mg, 7.8 mmol) was added. The mixture was allowed to return to room temperature and stirred for 1 hour. The reaction mixture was concentrated in vacuo at room temperature, added to water, and extracted with dichloromethane. The organic phase was then dried to dryness to obtain a white solid. (6bR,10aS)-3-Methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline (600.0 mg, 2.6 mmol) was dissolved in DMSO (9 mL), and the white solid and DIPEA (1.5 mL) were added. The reaction mixture was stirred at 60°C for 18 hours. The reaction mixture was cooled to room temperature, added to 50 mL of water, and extracted with ethyl acetate (40 mL x 3). The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, and the organic phases were combined and concentrated to give the crude product. The crude product was purified by silica gel column chromatography (DCM / MeOH = 0 / 100-8 / 92) to give (6bR,10aS)-8-(3-(2-(benzyloxy)phenyl)propyl)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline (1.0 g, 84.3% yield) as a yellow oil. MS m / z (ESI): 454.2 [M+H] +

[0485] Step 4: Boron tribromide in dichloromethane (22 mL, 22 mmol) was added dropwise to (6bR,10aS)-8-(3-(2-(benzyloxy)phenyl)propyl)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline (1 g, 2.2 mmol) in DCM (30 mL) at room temperature under nitrogen atmosphere at 0°C. The reaction was stirred at room temperature for 2 h. After completion of the reaction, methanol was added to quench the reaction in an ice bath. The reaction mixture was concentrated in vacuo and water (30 mL) was added. 1 M sodium hydroxide solution was added to adjust the pH to 10, and ethyl acetate (40 mL x 3) was added for extraction. The combined organic phases were concentrated in vacuo to give the crude product, which was then purified by silica gel column chromatography (DCM / MeOH = 100 / 0 to 90 / 10) to afford 2-(3-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)propyl)phenol (600 mg, yield: 77.3%) as a yellow solid. MS m / z (ESI): 364.2 [M+H]. +

[0486] Step 5: 2-(3-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)propyl)phenol (100.0 mg, 0.28 mmol) and 1-chloropropane-2-one (50.9 mg, 0.55 mmol) were dissolved in DMF (1.5 mL) at room temperature, and cesium carbonate (268.9 g, 0.83 mmol) was added. The reaction mixture was stirred at 60°C for 16 hours. The reaction mixture was cooled to room temperature, 40 mL of water was added, and the mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phases were concentrated in vacuo to give a crude product, which was then purified by silica gel column chromatography (PE / EA = 100 / 0 to 0 / 100) to give 1-(2-(3-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]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] +

[0487] Step 6: Dissolve 1-(2-(3-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)propyl)phenoxy)propan-2-one (50.0 mg, 0.12 mmol) in tetrahydrofuran (2 mL) at room temperature. Purge the system with nitrogen. Cool the reaction mixture to 0°C, and add methylmagnesium bromide (3 M, 0.1 mL, 0.36 mmol) dropwise. Stir the reaction mixture at room temperature for 1 hour. After the reaction was completed, saturated ammonium chloride solution was added to quench the reaction, 40 mL of water was added to dilute the reaction, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined and concentrated in vacuo to give a crude product. The crude product was prepared to give 2-methyl-1-(2-(3-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-yl)propyl)phenoxy)propan-2-ol (5.77 mg, yield: 10.2%) as a brown solid. 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] + .

[0488] Example 53: 2-(2-(3-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)propyl)phenoxy)ethan-1-ol

[0489]

[0490] 2-(3-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)propyl)phenol (50.0 mg, 0.14 mmol) and 1,3-dioxolane-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°C for 16 hours. The reaction solution was cooled to room temperature, 40 mL of water was added, and the crude product was extracted with ethyl acetate (30 mL × 3). The crude product was prepared to give 2-(2-(3-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]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] + .

[0491] Example 54: (6bR,10aS)-8-(3-(2,2-difluorobenzo[d][1,3]dioxazol-4-yl)propyl)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline

[0492]

[0493] Step 1: Dissolve 2,2-difluorobenzo[d][1,3]dioxazole (500.0 mg, 3.16 mmol) in tetrahydrofuran (8 mL) at room temperature. Add sec-butyllithium (202.6 mg, 3.16 mmol). Purge the system with nitrogen. Cool the reaction mixture to -65°C. Add oxetane (183.7 mg, 3.16 mmol) and boron trifluoride etherate (189.6 mg, 1.3 mmol) dropwise. Stir the reaction mixture at -65°C for 1 hour. After the reaction, saturated aqueous ammonium chloride solution was added to quench the reaction, 60 mL of water was added, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phase was concentrated in vacuo to give a crude product, which was purified by silica gel column chromatography (DCM / MeOH = 100 / 0-90 / 10) to give 3-(2,2-difluorobenzo[d][1,3]dioxazol-4-yl)propan-1-ol (470 mg, yield 68.8%) as a transparent oil. 1 HNMR (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).

[0494] Step 2: 3-(2,2-Difluorobenzo[d][1,3]dioxazol-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). The mixture was cooled to 0°C and methanesulfonyl chloride (74.9 mg, 0.65 mmol) was added. The mixture was allowed to warm to room temperature and stirred for 1 hour. The reaction mixture was concentrated in vacuo at room temperature. The crude product was dissolved in DMSO (3 mL) and (6bR,10aS)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline (50 mg, 0.22 mmol) and DIPEA (0.5 mL) were added. The reaction mixture was stirred at 60°C for 18 hours. The reaction mixture was cooled to room temperature, added to 50 mL of water, and extracted with ethyl acetate (40 mL x 3). The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, and the organic phases were combined and concentrated to obtain a crude product. The crude product was subjected to preparative purification to afford (6bR,10aS)-8-(3-(2,2-difluorobenzo[d][1,3]dioxazol-4-yl)propyl)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline (41.33 mg, 43.72% yield) as a brown oil. 1 H 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). 19 F NMR(377MHz, CDCl3)δ-49.80(s,2F).MS m / z(ESI):428.2[M+H] + .

[0495] Example 55: (6bR,10aS)-3-methyl-8-(3-(2-(2,2,2-trifluoroethoxy)phenyl)propyl)-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline

[0496]

[0497] 2-(3-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)propyl)phenol (50.0 mg, 0.14 mmol) and 2,2,2-trifluoroethyl 4-methylbenzenesulfonate (52.7 mg, 0.21 mmol) were dissolved in DMF (1 mL) at room temperature, and potassium carbonate (57.1 mg, 0.41 mmol) was added. The reaction mixture was stirred at 110°C for 16 hours. The reaction mixture was cooled to room temperature, 40 mL of water was added, and the mixture was extracted with ethyl acetate (30 mL x 3). The mixture was concentrated to obtain the crude product. The crude product was prepared to give (6bR,10aS)-3-methyl-8-(3-(2-(2,2,2-trifluoroethoxy)phenyl)propyl)-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline (5.32 mg, 8.2% yield) as a brown solid. 1 H NMR (400MHz, CDCl3) δ7.20-7.15(m,2H),6.99-6.95(m,1H),6.77(d,J=8.3H z,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). 19 F NMR(377MHz, CDCl3)δ-73.98(s,3F).MS m / z(ESI):446.2[M+H] + .

[0498] Example 56: (6bR,10aS)-3-methyl-8-(3-(2-(pyridin-4-oxy)phenyl)propyl)-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline

[0499]

[0500] 2-(3-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)propyl)phenol (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°C for 16 hours. The reaction solution was cooled to room temperature, 40 mL of water was added, and the crude product was extracted with ethyl acetate (30 mL × 3). The crude product was prepared to give (6bR, 10aS)-3-methyl-8-(3-(2-(pyridin-4-oxy)phenyl)propyl)-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline 2,2,2-trifluoroacetate (18.42 mg, yield 25.02%) as a black oil. 1 H 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] + .

[0501] Example 57: Preparation of (6bR,10aS)-8-(3-(2-(difluoromethoxy)phenyl)propyl)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline

[0502]

[0503] 2-(3-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)propyl)phenol (50.0 mg, 0.14 mmol) and ((difluoromethyl)sulfonyl)benzene (60.8 mg, 0.32 mmol) were dissolved in acetonitrile (1 mL) at room temperature. A 25% solution of potassium hydroxide (84.9 mg, 1.5 mmol) in water (0.255 mL) was added, and the reaction system was flushed with nitrogen. The reaction mixture was stirred at 60°C for 16 hours. After the reaction was completed, 40 mL of water was added to dilute the mixture, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined and concentrated in vacuo to obtain a crude product. The crude product was prepared to give (6bR,10aS)-8-(3-(2-(difluoromethoxy)phenyl)propyl)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline (6.39 mg, yield: 11.0%) as a brown solid. 1 HNMR (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). 19 F NMR(377MHz, CDCl3)δ-75.78(s,6F),-79.97(d,J=2.7Hz,2F).MS m / z(ESI):414.2[M+H] + .

[0504] Example 58: (6bR,10aS)-3-methyl-8-(3-(pyridin-2-yl)propyl)-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline

[0505]

[0506] Step 1: Dissolve 3-(pyridin-2-yl)propan-1-ol (30.0 mg, 0.22 mmol) in dichloromethane (3 mL) at room temperature, cool to 0°C, add PCC (94.3 mg, 0.44 mmol), return to room temperature, and stir for 16 hours. The reaction mixture was filtered through celite, added to 10 mL of water, and the pH was adjusted to 8 with saturated aqueous sodium bicarbonate. The mixture was diluted with 40 mL of water and extracted with dichloromethane (30 mL x 3). The organic phases were dried over anhydrous sodium sulfate, and the combined organic phases were concentrated to yield 3-(pyridin-2-yl)propanal (29 mg, 78.5% yield) as a clear oil. The crude product was used directly in the next reaction. MS m / z (ESI): 136.2 [M+H] +

[0507] Step 2: Dissolve (6bR,10aS)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline (45.0 mg, 0.20 mmol) and 3-(pyridin-2-yl)propanal (29.2 mg, 0.22 mmol) in dichloromethane (2 mL) at room temperature. The mixture was stirred at room temperature for 30 minutes. Sodium acetate borohydride (83.2 mg, 0.39 mmol) was added, and the reaction mixture was stirred at room temperature for 3.5 hours. After completion of the reaction, the mixture was added to 40 mL of water and extracted with ethyl acetate (30 mL x 3). The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, and the organic phases were combined and concentrated to obtain the crude product. The crude product was purified by preparative method to give (6bR,10aS)-3-methyl-8-(3-(pyridin-2-yl)propyl)-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline 2,2,2-trifluoroacetate (7.24 mg, 10.1% yield) as a brown oil. 1 H 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),3.52-3.3 5(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). 19 F NMR(376MHz, CDCl3)δ-75.72(s,3F).MS m / z(ESI):349.2[M+H]+ .

[0508] Example 59: 2-(3-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)propyl)benzonitrile

[0509]

[0510] Step 1: Dissolve 3-(2-cyanophenyl)propionic acid (500.0 mg, 2.85 mmol) in dichloromethane (5 mL) at room temperature, add oxalyl chloride (543.4 mg, 4.28 mmol), and stir at room temperature for 1 hour. The reaction mixture is concentrated in vacuo to obtain a crude product. The crude product is dissolved in THF / MeOH (4 mL / 4 mL), and sodium borohydride (539.9 mg, 14.27 mmol) is added. The reaction mixture is stirred at room temperature for 16 hours. After completion of the reaction, the mixture is diluted with methanol, concentrated in vacuo, added to 50 mL of water, and extracted with ethyl acetate (40 mL x 3). The mixture is washed with saturated brine and dried over anhydrous sodium sulfate. The organic phases are combined and concentrated to obtain a crude product. The crude product is purified by silica gel column chromatography (PE / EA = 100 / 0 to 60 / 40) to obtain 2-(3-hydroxypropyl)benzonitrile (300 mg, 59.2% yield) as a clear oil. MS m / z(ESI):162.1[M+H] +

[0511] Step 2: Dissolve 2-(3-hydroxypropyl)benzonitrile (300.0 mg, 1.86 mmol) and carbon tetrabromide (925.8 mg, 2.79 mmol) in dichloromethane (35 mL) at room temperature. Add triphenylphosphine (732.2 mg, 2.79 mmol), and stir the reaction mixture at room temperature for 16 hours. After completion of the reaction, concentrate in vacuo to obtain the crude product. The crude product is purified by silica gel column chromatography (PE / EA = 100 / 0 to 90 / 10) to obtain 2-(3-bromopropyl)benzonitrile (250 mg, 59.9% yield) as a clear oil. MS m / z (ESI): 226.1 [M+H] +

[0512] Step 3: Dissolve 2-(3-bromopropyl)benzonitrile (48.8 mg, 0.22 mmol) in 1,4-dioxane / toluene (1.5 mL / 1.5 mL) at room temperature. Add (6bR,10aS)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline (50.0 mg, 0.22 mmol), potassium iodide (72.4 mg, 0.44 mmol), and triethylamine (66.2 mg, 0.65 mmol). Stir the reaction mixture at 100°C for 18 hours. Cool the reaction mixture to room temperature and concentrate in vacuo to obtain the crude product. The crude product was prepared to give 2-(3-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)propyl)benzonitrile (14.34 mg, 16.8% yield) as a yellow solid. 1 H 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] + .

[0513] Example 60: 7-(3-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)propyl)-2,3-dihydrofuro[2,3-c]pyridine

[0514]

[0515] Step 1: Add 7-chlorofuro[2,3-c]pyridine (300 mg, 1.96 mmol), ethyl (E)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) acrylate (660 mg, 2.92 mmol), Pd(dppf)Cl2.CH2Cl2 complex (30 mg, 0.04 mmol) and potassium carbonate (540 mg, 3.92 mmol) into a 25 mL single-necked reaction bottle, followed by the addition of dioxane (4 mL) and water (1 mL). After the addition, the atmosphere was replaced with nitrogen three times, and the temperature was slowly raised to 100°C and stirred for 16 h. After the reaction was complete, the reaction mixture was filtered and water (30 mL) was added. The mixture was extracted with ethyl acetate (3 x 20 mL). The organic phases were combined, washed with saturated brine (1 x 50 mL), dried over anhydrous sodium sulfate, and dried under reduced pressure. The crude product was purified by normal phase column chromatography (eluent gradient: 10% EA / PE) to obtain ethyl (E)-3-(furo[2,3-c]pyridin-7-yl)acrylate (white solid, 180 mg, yield 42%). MS m / z (ESI): 218.4 [M+H] +

[0516] Step 2: Ethyl (E)-3-(furo[2,3-c]pyridin-7-yl) acryloyl ester (50 mg, 0.23 mmol) was added to a 25 mL single-necked reaction vial. Methanol (10 mL) and 10% Pd / C (wet basis, 10 mg) were then added. After addition, the atmosphere was replaced with hydrogen three times and the reaction was stirred at room temperature for 16 h. After completion of the reaction as determined by LCMS, the reaction solution was filtered and the filtrate was concentrated under reduced pressure to obtain the target compound, ethyl 3-(2,3-dihydrofuro[2,3-c]pyridin-7-yl) propionate (crude product, 50 mg, 99% yield). The crude product was used directly in the next step without further purification. MS m / z (ESI): 222.5 [M+H] +

[0517] Step 3: Ethyl 3-(2,3-dihydrofuro[2,3-c]pyridin-7-yl)propanoate (50 mg, 0.23 mmol) was added to a 25 mL three-necked reaction flask. Anhydrous tetrahydrofuran (3 mL) was then added. Lithium aluminum tetrahydride (25 mg, 0.69 mmol) was added portionwise under nitrogen and an ice-water bath. The reaction was stirred for 0.5 h under ice-water bath. After completion of the reaction, the mixture was quenched by slowly adding NaSO.10H2O, filtered, and the filter cake was washed with 10% MeOH / DCM (10 mL). The filtrate was concentrated under reduced pressure. The crude product was purified by normal phase column chromatography (eluent gradient: 30% EA / PE) to afford 3-(2,3-dihydrofuro[2,3-c]pyridin-7-yl)propan-1-ol as a pale yellow oil, 25 mg, 62% yield. MS m / z(ESI):180.5[M+H] +

[0518] Step 4: Compound 3-(2,3-dihydrofuro[2,3-c]pyridin-7-yl)propan-1-ol (25 mg, 0.14 mmol) and anhydrous dichloromethane (3 mL) were added to a 10 mL single-necked reaction bottle, followed by addition of PCC (60 mg, 0.28 mmol). After addition, the mixture was stirred at room temperature for 16 h. After completion of the reaction, dichloromethane (10 mL) was added to the reaction solution, followed by adjustment to alkaline pH with saturated sodium bicarbonate solution, extraction with dichloromethane (2 x 10 mL), and the organic phases were combined, washed with saturated brine (1 x 10 mL), dried over anhydrous sodium sulfate, and dried under reduced pressure to give a crude compound 3-(2,3-dihydrofuro[2,3-c]pyridin-7-yl)propanal (reddish-brown oil, 30 mg). The crude product was not further purified and was used directly in the next reaction. MS m / z(ESI):258.5[M+H] +

[0519] Step 5: Preparation of 7-(3-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)propyl)-2,3-dihydrofuro[2,3-c]pyridine

[0520] Compound 3-(2,3-dihydrofuro[2,3-c]pyridin-7-yl)propanal (10 mg, 0.06 mmol, crude) and (6bR,10aS)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline (13 mg, 0.06 mmol) were added to a 10 mL reaction bottle, followed by DIEA (35 mg, 0.30 mmol) and anhydrous DCM (2 mL). After the addition was complete, the mixture was stirred at room temperature for 16 h. After the reaction was completed, the reaction solution was evaporated to dryness under reduced pressure, and the filtrate was directly subjected to reverse phase preparative separation (C18 column, eluent gradient: acetonitrile / (water + 0.05% NH4HCO3)) to give the title compound 7-(3-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)propyl)-2,3-dihydrofuro[2,3-c]pyridine (pale yellow solid, 8.0 mg, yield 36%). 1 HNMR(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,1 H),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] + .

[0521] Example 61: 4-(2-(3-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)propyl)phenyl)morpholine

[0522]

[0523] The preparation of E61 was carried out according to the 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] + .

[0524] Example 62: (6bR,10aS)-8-(3-(4-methoxypyridin-3-yl)prop-2-yn-1-yl)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline

[0525]

[0526] Step 1: Add 3-iodo-4-methoxypyridine (1.5 g, 6.38 mmol) to a 100 mL reaction bottle, followed by bistriphenylphosphine palladium dichloride (0.13 g, 0.19 mmol), cuprous iodide (0.12 g, 0.64 mmol), and then add DMF (20 mL), TEA (30 mL), and 2-(prop-2-yn-1-oxy)tetrahydro-2H-pyran (1.3 g, 9.6 mmol) under nitrogen protection, and then stir at room temperature for 2 hours. The reaction mixture was concentrated, and then water (50 mL) was added to the reaction mixture. The mixture was extracted with ethyl acetate (50 mL x 3) and washed with brine (50 mL x 3). The organic phase was concentrated and purified by normal phase column chromatography (dichloromethane:methanol = 20:1) to obtain the compound 4-methoxy-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)prop-1-yn-1-yl)pyridine (white solid, 1.2 g, yield 76%). MS m / z (ESI): 248.5 [M+H] + .

[0527] Step 2: 4-methoxy-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)prop-1-yn-1-yl)pyridine (400 mg, 1.62 mmol) was added to a 100 mL reaction flask, followed by dichloromethane (10 mL) and TFA (5 mL) and stirred at room temperature for 1 h. The reaction solution was concentrated and then added with saturated sodium bicarbonate (50 mL). Extraction was performed with dichloromethane (2 x 50 mL). The concentrated solution was purified by normal phase column chromatography (dichloromethane:methanol = 10:1) to obtain 3-(4-methoxypyridin-3-yl)prop-2-yn-1-ol (colorless liquid, 200 mg, yield 75.2%). MS m / z (ESI): 164.4.[M+H] + .

[0528] Step 3: 4-methoxy-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)prop-1-yn-1-yl)pyridine (100 mg, 0.61 mmol) was added to a 25 mL reaction flask, followed by DCM (50 mL), followed by DIEA (390 mg, 3 mmol) and Ms2O (320 mg, 1.84 mmol). The mixture was stirred at room temperature for 1 h. The reaction mixture was extracted with DCM (2 x 20 mL), and the organic phase was washed with saturated brine (2 x 20 mL). After concentration, 3-(4-methoxypyridin-3-yl)prop-2-yn-1-yl methanesulfonate was obtained (a colorless liquid, 120 mg, 81.3% yield). MS m / z (ESI): 242.5 [M+H] + .

[0529] Step 4: Compound 3-(4-methoxypyridin-3-yl)prop-2-yn-1-yl methanesulfonate (50 mg, 0.21 mmol) and starting material (6bR,10aS)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline (57 mg, 0.25 mmol) were added to a 25 mL reaction bottle, followed by addition of DMSO (5 mL) and then DIPEA (81 mg, 0.63 mmol). After complete addition, the mixture was stirred at 60 °C for 16 h. The reaction mixture was added with ethyl acetate (30 mL), washed with water (30 mL), and then with brine (50 mL). The organic phase was concentrated and initially purified by normal phase column chromatography (dichloromethane:methanol=10:1) to give 50 mg of a crude product. 20 mg was removed and purified by reverse phase column chromatography (acetonitrile / (water + 0.05% NH4HCO3)) to give the compound (6bR,10aS)-8-(3-(4-methoxypyridin-3-yl)prop-2-yn-1-yl)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline (gray solid, 10 mg, yield 31.5%). 1 H 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] + .

[0530] Example 63: (6bR,10aS)-8-((E)-3-(Benzofuran-7-yl)allyl)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline

[0531]

[0532] Step 1: Dissolve ethyl (E)-3-(benzofuran-7-yl) acryloyl ester (65 mg, 0.3 mmol) in THF (2.0 mL), cool to -78°C, add 1 M DABL-H solution in tetrahydrofuran (0.45 mL, 0.45 mmol), and stir at -78°C for 1 h. Add sodium sulfate decahydrate and stir for 15 minutes. Filter, concentrate, and purify with normal phase chromatography to obtain (E)-3-(benzofuran-7-yl)prop-2-en-1-ol (yellow oil, 21 mg, 40% yield). MS m / z (ESI): 175.3. [M+H] + .

[0533] Step 2: Dissolve (E)-3-(Benzofuran-7-yl)prop-2-en-1-ol (21 mg, 0.12 mmol) in DCM (2.0 mL). Add activated MnO2 (104 mg, 1.2 mmol). Stir at 20°C for 3 h. Filter to obtain (E)-3-(Benzofuran-7-yl)acryloylaldehyde (yellow oil, 20 mg), which is used directly in the next reaction. MS m / z (ESI): 173.3 [M+H]. + .

[0534] Step 3: (6bR,10aS)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline (25 mg, 0.10 mmol) and (E)-3-(benzofuran-7-yl)acryloylaldehyde (20 mg, 0.12 mmol) were dissolved in DCM (2.5 mL) at room temperature. Triethylamine (5.0 mg, 0.05 mmol) and acetic acid (6.0 mg, 0.1 mmol) were added. After stirring for 10 minutes, NaBH(OAc)3 (120 mg, 0.6 mmol) was added. The mixture was stirred at 20°C for 16 hours, concentrated and filtered, and then purified by prep-HPLC (eluent (v / v): acetonitrile / (water + 0.05% NH4HCO3)=30%–70%) gave compound (6bR,10aS)-8-((E)-3-(benzofuran-7-yl)allyl)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline (pale yellow oil, 10.1 mg, yield 26%). 1HNMR(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] + .

[0535] Example 64: 4-(3-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)propyl)-2,3-dihydrofuro[3,2-c]pyridine

[0536]

[0537] The preparation of E64 refers to the synthetic method of Example 60. 1 H 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,1 H),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] +

[0538] Example 65-1: (6bR,10aS)-8-(3-(2,3-dihydrobenzofuran-7-yl)propyl)-3-ethyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline

[0539]

[0540] Step 1: Compound 3-(2,3-dihydrobenzofuran-7-yl)propan-1-ol (3 g, 16.8 mmol) and dichloromethane (50 mL) were added to a 100 mL single-necked flask at room temperature. Dess-Martin reagent (21.4 g, 50.5 mmol) was then added. The mixture was stirred at room temperature for 5 h. After TLC, the reaction mixture was filtered through celite. The filtrate was adjusted to an alkaline pH with saturated sodium bicarbonate solution and extracted with DCM (50 mL x 2). The organic phases were combined, washed with saturated brine (50 mL x 1), dried over anhydrous Na2SO4, and evaporated to dryness under reduced pressure. The crude product was purified by column chromatography (EtOAc / PE = 0-20%) to obtain compound 65-1-1 (colorless oil, 2.5 g, yield: 84%).

[0541] Step 2: Compound 45-1-5 (2.0 g, 7.0 mmol), acetaldehyde aqueous solution (40% wt, 10 mL), and methanol (40 mL) were added to a 100 mL single-necked flask. Na(OAc)3BH (8.8 g, 42 mmol) was then added portionwise. The mixture was stirred at room temperature for 3 h. After completion of the reaction, the reaction solution was concentrated under reduced pressure to remove most of the solvent. The crude product was then dissolved in EA, washed with water (50 mL x 1), saturated NaHCO3 solution (50 mL x 1), and extracted with EA (30 mL x 2). The organic phases were combined, washed with saturated brine (50 mL x 1), dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The crude product was purified by column chromatography (EtOAc / PE = 0-25%) to obtain compound 65-1-2 (pale yellow oil, 1.8 g, 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] + .

[0542] Step 3: Preparation of 65-1-3 was carried out according to the synthesis method of the second step in Example 73-1. MS m / z (ESI): 244.5 [M+H] + .

[0543] Step 4: Preparation of E65-1 refers to the synthesis method of the third step of Example 73-1. 1 H 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=1 4.5,7.6Hz,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] + .

[0544] Example 65-2: (6bS, 10aR)-8-(3-(2,3-dihydrobenzofuran-7-yl)propyl)-3-ethyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline

[0545]

[0546] Step 1: Dissolve 67-2-6 (2.10 g, 7.31 mmol) in THF (20.0 mL) and add BH3 / THF (21.9 mL, 1 M). React at 70°C for 3 h. LCMS indicates the reaction is complete. Add water, extract with EA, dry over sodium sulfate, filter, concentrate, and purify on a silica gel column (PE:EA = 5:1) to obtain compound 65-2-1 (yellow solid, 1.80 g, 90% yield). MS m / z (ESI): 274.4 [M+H] + .

[0547] Step 2: Methyl-2,3,6b,7,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]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 mixture was reacted at 25°C for 3 h. LCMS confirmed the reaction was complete. Water was added, the mixture was extracted with EA, dried over sodium sulfate, filtered, concentrated, and purified on a silica gel column (PE:EA = 3:1) to afford compound 65-2-2 (yellow solid, 1.04 g, 55% yield). MS m / z (ESI): 302.2 [M+H] + .

[0548] Step 3: Dissolve 65-2-2 (1.00 g, 3.31 mmol) in a solution of hydrobromic acid in acetic acid (20 mL) and allow to react at 25°C for 20 h. LCMS confirmed the reaction was complete, and the reaction solution was concentrated to afford compound 65-2-3 (gray solid, 1.04 g, yield 96%). MS m / z (ESI): 244.2 [M+H] + .

[0549] Step 4: Under nitrogen, 65-2-3 (400 mg, 1.64 mmol) was dissolved in MeOH (200 mL) and DCM (120 mL). 3-(2,3-dihydrobenzofuran-7-yl)propanal (347 mg, 1.97 mmol) and NaBH(AcO)3 (1.73 mg, 8.21 mmol) were added. The mixture was allowed to react at 25°C for 1 h. LCMS confirmed the reaction was complete. Water was added, the mixture was extracted with EA, dried over sodium sulfate, filtered, concentrated, and purified on a silica gel column (DCM:MeOH = 10:1) to afford compound 65-2-4 (yellow solid, 1.04 g, 55% yield). MS m / z (ESI): 404.3 [M+H] + .

[0550] Step 5: 65-2-4 (100 mg, 0.248 mmol) was purified by SFC (Daicel ChiralPak IJ, 40 mm ID×250 mm, 10 μm; Mobile phase: n-Hexane / Ethanol [0.1% NH 3. HO (V / V)] = 95 / 5; Flow rate: 80 mL / min) to give white solid E65-1 (PK1: 42.8 mg, purity 98%, yield 42%, ee 98%, RT = 4.512, OROT = +0.13.8 and white solid E65-2 (PK2: 37.4 mg, purity 97%, yield 37%, ee 100%, RT = 5.303, OROT = -10.2)). E65-1: 1 H NMR (400 MHz, DMSO-d6) 1 H 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: 1 H NMR (400 MHz, DMSO-d6) δ 1H 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] + .

[0551] Example 66: (6bR,10aS)-8-(3-(2,3-dihydrobenzofuran-7-yl)propyl)-3-(oxetan-3-yl)-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline

[0552]

[0553] Step 1: Dissolve 45-1-6 (1 g, 2.67 mmol) and TEA (13.5 g, 13.3 mmol) in DCM / MeOH = 10:1 (150 ml), then add (Boc)2O (540 mg, 2.67 mmol). The reaction was allowed to proceed at room temperature for 6 h. LCMS indicated completion of the reaction. The product was extracted with DCM and filtered through a silica gel column (PE / EA = 100 / 0 to 70 / 30) to afford product 66-1 (600 mg, white solid, yield: 71.3%). MS m / z (ESI): 316.3 [M+H] + .

[0554] Step 2: Dissolve 66-1 (70 mg, 0.22 mmol) in MeOH (50 ml), then add oxetan-3-one (80 mg, 1.11 mmol). Quickly add Na(OAc)3BH (71 mg, 1.11 mmol) and react for 1 h. LCMS showed complete reaction. Extract with DCM and filter through a silica gel column (PE / EA = 100 / 0 to 60 / 40) to obtain product 66-2 (70 mg, colorless liquid, yield: 84.9%). MS m / z (ESI): 372.1 [M+H] +

[0555] Step 3: Compound 66-2 (60 mg, 0.16 mmol) was added to a 25 mL reaction flask, followed by dichloromethane (5 mL) and TFA (2 mL) and stirred at room temperature for 1 h. The reaction solution was concentrated to afford compound 66-3 (colorless liquid, 60 mg, TFA salt, yield 96.3%). MS m / z (ESI): 272.2 [M+H] + .

[0556] Step 4: 66-3 (30 mg, 0.11 mmol) was dissolved in MeOH (5 ml) and DCM (5 ml), and then 65-1-1 (21 mg, 0.12 mmol) was added. Na(OAc)3BH (116 mg, 0.55 mmol) was quickly added and the reaction was allowed to proceed for 1 h. LCMS showed that the reaction was complete. The product was extracted with DCM, concentrated and filtered, and then purified and separated by prep-HPLC (eluent (v / v): acetonitrile / (water + 0.05% NH4HCO3) = 30%–70%) to 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,1 H),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] + .

[0557] Example 67-1: (6bR,10aS)-8-(3-(2,3-dihydrobenzofuran-7-yl)propyl)-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-2(3H)-one

[0558]

[0559] Step 1: 45-1-4 (5 g, 16.6 mmol) and 50 mL of HBr in HOAc were reacted at 50°C for 16 h. LCMS showed the reaction was complete. The reaction solution 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] + .

[0560] Step 5: Dissolve 67-1-1 (2 g, 6.47 mmol) in 100 mL of DCM and 100 mL of MeOH, then add NaBH(OAc)3 (6.8 g, 32.2 mmol) and finally add 65-1-1 (910 mg, 5.18 mmol). The mixture was allowed to react at room temperature for 0.5 h. LCMS showed a small amount of 67-1-1 remaining. Saturated sodium bicarbonate solution was added to the reaction mixture to adjust the pH to 7-8. The DCM and MeOH were concentrated, and EA and water were added. The mixture was filtered, and the aqueous phase was extracted twice with EA. The combined organic phases were dried, concentrated, and purified by column chromatography (100% DCM to 2% MeOH / DCM) to afford compound E67-1 (990 mg). The product was then purified by HPLC (0-95% over 30 min, 0.05% NH4HCO3 in H2O, basic C18 column) to afford 790 mg of compound E67-1 (36% yield). 1 H 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] + .

[0561] Example 67-2: (6bS, 10aR)-8-(3-(2,3-dihydrobenzofuran-7-yl)propyl)-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-2(3H)-one

[0562]

[0563] Step 1: Dissolve (2-bromophenyl)hydrazine hydrochloride (16.0 g, 71.4 mmol) and piperidin-4-one hydrochloride (12.1 g, 89.8 mmol) in isopropanol (200.0 mL) and add concentrated hydrochloric acid (16.0 mL). React at 100°C for 12 h. LCMS analysis confirmed the reaction was complete. Filter and concentrate to obtain compound 67-2-1 (yellow solid, 20.0 g, 98% yield). MS m / z (ESI): 251.0, 253.0 [M+H] + .

[0564] Step 2: Dissolve 67-2-1 (19.0 g, 60.5 mmol) in TFA (20 mL) and add triethylsilyl hydride (70.3 g, 605 mmol). React at 40°C for 48 h. LCMS indicates the reaction is complete. The reaction solution is concentrated, added with saturated sodium bicarbonate solution, extracted with EA, dried over sodium sulfate, and filtered to obtain compound 67-2-2 (gray solid, 15.0 g, yield 89%). MS m / z (ESI): 253.0, 255.0 [M+H] + .

[0565] Step 3: Under nitrogen, 67-2-2 (15.0 g, 59.5 mmol) was dissolved in DCM (200 mL), and TEA (13.1 mL, 94.8 mmol) and dimethyl dicarbonate (6.99 g, 52.1 mmol) were added. The mixture was reacted at 25°C for 3 h. LCMS confirmed the reaction was complete. Water was added, and the mixture was extracted with EA. The mixture was dried over sodium sulfate, filtered, concentrated, and purified on a silica gel column (PE:EA = 5:1) to afford compound 67-2-3 (white solid, 15.0 g, 81% yield). MS m / z (ESI): 311.0 [M+H] + .

[0566] Step 4: Under nitrogen, 67-2-3 (14.0 g, 26.9 mmol) was dissolved in toluene (200 mL). Benzophenone imine (5.87 g, 32.3 mmol), NaOt-Bu (5.19 g, 53.9 mmol), and BINAP (0.50 g, 0.810 mmol) were added. The reaction was carried out at 60°C for 3 h. Pd2(dba)3 (0.25 g, 0.270 mmol) was added to the reaction solution. The reaction was continued at 105°C for 16 h. LCMS confirmed the reaction was complete. Water was added, and the mixture was extracted with EA. The mixture was dried over sodium sulfate, filtered, concentrated, and purified on a silica gel column (PE:EA = 5:1) to afford compound 67-2-4 (yellow solid, 8.10 g, 73% yield). MS m / z (ESI): 412.2 [M+H] + .

[0567] Step 5: Under nitrogen, 67-2-4 (8.10 g, 19.0 mmol) was dissolved in acetone (100 mL). Ethyl 2-bromoacetate (4.27 g, 25.5 mmol), Na2CO3 (3.13 g, 29.5 mmol), and KI (4.08 g, 24.6 mmol) were added. The mixture was reacted at 65°C for 12 h. LCMS confirmed the reaction was complete. Water was added, and the mixture was extracted with EA. The mixture was dried over sodium sulfate, filtered, concentrated, and purified on a silica gel column (PE:EA = 5:1) to afford compound 67-2-5 (yellow solid, 8.50 g, 86% yield).

[0568] Step 6: Under nitrogen, dissolve 67-2-5 (3.00 g, 5.86 mmol) in THF (10 mL) and add hydrochloric acid (3.4 mL, 2N). React at 25°C for 1.5 h. LCMS analysis confirmed the completion of the reaction. Concentrate to afford compound 67-2-6 (yellow solid, 1.40 g, 80% yield). MS m / z (ESI): 288.2 [M+H] + .

[0569] Step 7: Under nitrogen, 67-2-6 (660 mg, 2.29 mmol) was dissolved in a solution of hydrobromic acid in acetic acid (5 mL). The reaction was allowed to proceed at 50°C for 18 h. LCMS confirmed the completion of the reaction, and the product was concentrated to afford compound 67-2-7 (yellow solid, 450 mg, 85% yield). MS m / z (ESI): 230.2 [M+H] + .

[0570] Step 8: Under nitrogen, 67-2-7 (200 mg, 0.872 mmol) was dissolved in THF (5 mL), and 3-(2,3-dihydrobenzofuran-7-yl)propanal (184 mg, 1.05 mmol) and NaBH3CN (274 mg, 4.36 mmol) were added. The mixture was allowed to react at 25°C for 3 h. LCMS confirmed the reaction was complete. Water was added, the mixture was extracted with EA, dried over sodium sulfate, filtered, concentrated, and purified on a silica gel column (DCM:MeOH = 10:1) to afford compound 67-2-8 (yellow solid, 100 mg, 29% yield). MS m / z (ESI): 390.2 [M+H] + .

[0571] Step 9: 67-2-8 (100 mg, 0.257 mmol) was separated by SFC (Daicel ChiralPak IH, 40 mm ID×250 mm, 10 μm; Mobile phase: n-Hexane+TFA0.1 / Ethanol=60 / 40; Flow rate: 70 mL / min) to give compound E67-2 (PK1: 27.4 mg, purity 91%, yield 27%, ee 100%, RT=3.441, OROT=-219.5) and compound E67-1 (PK2: 30.3 mg, purity 83%, yield 30%, ee 99%, RT=4.936, OROT=+52.6). E67-2: 1 H 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: 1 H 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] + .

[0572] Example 67-3: trans-8-(3-(2,3-dihydrobenzofuran-7-yl)propyl)-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-2(3H)-one

[0573]

[0574] Step 1: Dissolve 67-2-1 (20.00 g, 79.6 mmol) in DMF (250.0 mL) and add K2CO3 (44.0 g, 318 mmol). The reaction was allowed to proceed at 25°C for 0.5 h. Then, benzyl bromide (0.75 g, 4.380 mmol) was added and the reaction continued at room temperature for 2 h. LCMS confirmed the reaction was complete. Water was added, extracted with EA, dried over sodium sulfate, filtered, concentrated, and purified on a silica gel column (PE = 100%) to afford compound 67-3-1 (white solid, 11.0 g, yield 40.7%). MS m / z (ESI): 341.2, 343.2 [M+H] + .

[0575] Step 2: 67-3-1 (3.0 g, 8.79 mmol) was dissolved in THF (20.0 mL). Borane dimethyl sulfide (90.0 mL, 176 mmol, 2 M) was added under nitrogen. The reaction was continued at 80°C for 48 h. LCMS analysis indicated that a quarter of the starting material remained in the reaction and two peaks of the desired molecular weight were present. 6N HCl was added and the reaction was continued at 100°C for half an hour. The mixture was then pumped dry and purified by reverse phase purification (ACN:H2O = 25%) to afford compound 67-3-2 (yellow solid, 1.9 g, yield 63%). MS m / z (ESI): 343.2, 345.0 [M+H] + .

[0576] Step 3: 67-3-2 (1.9 g, 5.12 mmol) was dissolved in toluene (20.0 mL). LiHMDS (17 ml, 5.12 mmol) was added under nitrogen at 0°C and allowed to react for 0.5 h. 2-Chloroacetamide (510 mg, 5.448 mmol) was then added and allowed to react overnight at 25°C. LCMS confirmed the reaction was complete. The product was quenched with sodium sulfite and washed with DCM and water. The product was filtered, concentrated, and purified on a silica gel column (DCM:MeOH = 10:1) to afford compound 67-3-3 (brown solid, 500 mg, 25% yield). MS m / z (ESI): 400.3, 402.4 [M+H] + .

[0577] Step 4: Dissolve 67-3-3 (500 mg, 1.25 mmol) in dioxane (5.0 mL), add CuI (70 mg, 0.375 mmol), cesium carbonate (1.9 g, 3.74 mmol), and 2,5-diazahexane (135 mg, 1.5 mmol), and react at 110°C for 2 h. LCMS confirmed the reaction was complete, and the mixture was extracted with EA and water. The mixture was filtered, concentrated, and purified on a silica gel column (EA:PE = 42%) to afford compound 67-3-4 (brown solid, 260 mg, 65% yield). MS m / z (ESI): 320.2 [M+H] + .

[0578] Step 5: Under nitrogen, 67-3-4 (260 mg, 0.814 mmol) was dissolved in MeOH (3.0 mL), and Pd / C (50 mg) and (Boc)2O (355 mg, 1.63 mmol) were added. The mixture was allowed to react at 25°C for 18 h. LCMS confirmed the reaction was complete. The palladium on carbon was filtered out, the sample was washed with silica gel, concentrated, and purified on a silica gel column (EA:PE = 56%) to afford compound 67-3-5 (yellow solid, 130 mg, 48% yield). MS m / z (ESI): 275.2 [M-56+H] + .

[0579] Step 6: Dissolve 67-3-5 (50 mg, 0.152 mmol) in DCM (1.0 mL) and add HCl-dioxane (0.5 mL). Allow to react at 25°C for 3 h. LCMS analysis confirmed the reaction was complete. The reaction solution was drained and used directly in the next step to yield compound 67-3-6 (yellow solid, 35 mg, 100% yield). MS m / z (ESI): 230.4 [M+H] + .

[0580] Step 8: Under nitrogen, 67-3-6 (35 mg, 0.153 mmol) was dissolved in MeOH (20 mL) and DCM (12 mL). 3-(2,3-dihydro-1-benzofuran-7-yl)propanal (60 mg, 0.305 mmol) and sodium acetate borohydride (97 mg, 0.458 mmol) were added, and the mixture was allowed to react at 25°C overnight. LCMS confirmed the completion of the reaction. The reaction solution was drained, filtered, concentrated, and then purified using preparative purification (eluent (v / v): acetonitrile / (water + 0.05% NH4HCO3) = 25%-78%) to afford compound E67-3 as a white solid, 15.35 mg, 25.8% yield. 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).MSm / z(ESI):390.2[M+H]+.

[0581] Example 68: 8-(3-(2,3-dihydrobenzofuran-7-yl)propyl)-1,2,6b,7,8,9,10,10a-octahydropyrido[4,3-b][1,4]thiazido[2,3,4-hi]indole

[0582]

[0583] The preparation of E68 was carried out according to the synthesis method of Example 42. 1 H 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] + .

[0584] Example 69: (6bR, 10aS)-8-(3-(2,3-dihydrobenzofuran-7-yl)-2-fluoropropyl)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline

[0585]

[0586] Step 1: 7-Bromo-2,3-dihydrobenzofuran (2 g, 10 mmol), allyltributyltin (3.5 g, 11 mmol), Pd(PPh3)4, and CsF (3.04 g, 20 mmol) in 10 mL of 1,4-dioxane were purged with N2 three times, heated to 110°C, and reacted for 16 h. The reaction was complete by TLC, filtered, concentrated, and water and EA were added. The layers were separated, and the aqueous phase was extracted once with EA. The combined organic phases were dried, concentrated, and purified by column chromatography (PE / EA = 50 / 1) to afford 69-1 (1.3 g, colorless liquid).

[0587] Step 2: 69-1 (1.1 g, 6.88 mmol) was added to a single-necked vial containing 20 mL of DCM, followed by the addition of m-CPBA (2.79 g, 13.75 mmol) in portions. The reaction was allowed to react at room temperature for 16 h. TLC indicated the reaction was complete. The reaction was filtered, and the solid was washed with DCM. Saturated sodium bicarbonate was added to the filtrate, the layers were separated, and the mixture was dried and concentrated by column chromatography (PE / EA = 50 / 1) to afford 69-2 (600 mg, colorless liquid).

[0588] Step 3: (6bR,10aS)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline (300 mg, 1.3 mmol), 69-2 (276 mg, 1.57 mmol), K2CO3 (360 mg, 2.6 mmol) and 5 mL DMF were microwaved at 150°C for 1.5 h. LCMS showed a small amount of starting material remaining. Water and EA were added, the layers were separated, the aqueous phase was extracted once with EA, the organic phases were combined, dried and concentrated, and the mixture was purified by column chromatography (DCM / MeOH = 50 / 1) to afford 69-3 (430 mg yellow liquid). MS m / z (ESI): 406.5 [M+H] + .

[0589] Step 4: BAST (55 mg, 0.24 mmol) was added to a three-necked flask containing 2 mL of DCM. The mixture was purged with nitrogen three times, cooled to -78°C, and a solution of 69-3 (50 mg, 0.12 mmol) in DCM was added. The mixture was slowly warmed to room temperature and allowed to react for 16 h. LCMS indicated the main peak was the desired product. The reaction was quenched with saturated sodium bicarbonate. The layers were separated, and the aqueous phase was extracted once with DCM. The combined organic phases were dried, concentrated, and purified by prep-HPLC (eluent (v / v): acetonitrile / (water + 0.05% NH4HCO3) = 30%–70%) to afford compound E69 (7.5 mg, white solid, yield: 15.4%).

[0590] 1 H 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] + .

[0591] Example 70: (6bR,10aS)-8-(3-(3-chloro-6-methylpyridin-2-yl)propyl)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxaline

[0592]

[0593] Step 1: CuBr (832 mg, 5.8 mmol) was added to a three-necked flask containing 30 mL of THF. The atmosphere was purged with nitrogen three times, the temperature was lowered to -78°C, and 0.5 M (2-(1,3-dioxan-2-yl)ethyl)magnesium bromide (23 mL, 11.6 mmol) was added dropwise. The reaction was allowed to proceed at this temperature for 20 min. 2-Bromo-3-chloro-6-methylpyridine (300 mg, 1.45 mmol) was added and the reaction was continued at -78°C for 3 h. The reaction was then warmed to room temperature and allowed to proceed for 16 h. LCMS confirmed the reaction was complete. Ammonia was added to adjust the pH to 9-10. EA and water were then added. The mixture was filtered and separated. The aqueous phase was extracted twice with EA. The combined organic phases were washed once with saturated sodium chloride solution, dried, concentrated, and column purified (PE / EA = 3 / 1) to afford 70-1 (300 mg, colorless liquid). MS m / z (ESI): 242.1, 243.9 [M+H] + .

[0594] Step 2: 70-1 (300 mg, 1.24 mmol) was added to a single-necked vial containing 3 mL of THF, followed by 4 M HCl (1 mL, 4 mmol). The reaction was allowed to proceed at 50°C for 3 h. LCMS indicated the reaction was complete. The THF was concentrated, and the pH was adjusted to 8-9 with saturated sodium bicarbonate. EA and water were then added, and the layers were separated. The aqueous phase was extracted twice with EA. The combined organic phases were washed once with saturated sodium chloride solution, dried, concentrated, and purified by column chromatography (PE / EA = 3 / 1) to afford 70-2 (90 mg, brown oil). MS m / z (ESI): 184.0, 185.9 [M+H] + .

[0595] Step 3: The preparation of E70 refers to the synthesis method of Step 7 of E46. 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] + .

[0596] Example 71: (6bR,10aS)-8-(3-(2,3-dihydrobenzofuran-7-yl)-3-fluoropropyl)-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-2(3H)-one

[0597]

[0598] Step 1: Dissolve 2,3-dihydrobenzofuran-7-carbaldehyde (1.0 g, 6.76 mmol) in THF (50 mL), cool to -78°C, add vinylmagnesium chloride (6.6 mL, 10 mmol), and warm to room temperature with stirring for 2 hours. Quench the reaction by adding aqueous ammonium chloride (50 mL), extract with ethyl acetate (50 mL x 2), wash with saturated brine, and dry over anhydrous sodium sulfate. The organic phase is concentrated to obtain the crude product, which is then purified by normal phase column chromatography to afford compound 71-1 (colorless oil, 1.1 g, yield: 92%). MS m / z (ESI): 177.4 [M+H] + .

[0599] Step 2: The preparation of 71-2 was carried out according to the synthesis method of the first step in Example E65.

[0600] Step 3: 67-1-1 (150 mg, 0.66 mmol), 71-2 (135 mg, 0.79 mmol), and anhydrous DCM (15 mL) were added to a 50 mL single-necked flask, followed by the addition of TEA (200 mg, 1.98 mmol). After the addition was complete, the mixture was stirred at room temperature for 16 h. After completion of the reaction by LCMS, the reaction mixture was washed with saturated NH4Cl solution (50 mL x 1) and extracted with DCM (30 mL x 2). The organic phases were combined, washed with saturated brine (50 mL x 1), dried over anhydrous Na2SO4, and dried under reduced pressure. The crude product was purified by column chromatography (MeOH / DCM = 0-5%) to afford 71-3 (pale yellow oil, 150 mg, yield: 57%). 1 H NMR (500MHz, CDCl3) δ7.78 (s, 1H), 7.67 (d, J = 7.6Hz, 1H), 7.36 (dd, J = 7.2, 1.1Hz, 1H), 6.9 2-6.87(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] + .

[0601] Step 4: Compound 71-3 (150 mg, 0.37 mmol) and anhydrous MeOH (10 mL) were added to a 50 mL single-necked flask. NaBH4 (45 mg, 1.11 mmol) was then added portionwise at room temperature. The mixture was stirred at room temperature for 1 h. After completion of the reaction, LCMS confirmed that the reaction was complete. The reaction mixture was washed with saturated NH4Cl solution (20 mL x 1) and extracted with DCM (20 mL x 2). The organic phases were combined, washed with saturated brine (30 mL x 1), dried over anhydrous Na2SO4, and dried under reduced pressure. The crude product was purified by column chromatography (MeOH / DCM = 0-10%) to afford 71-4 (white solid, 120 mg, 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] + .

[0602] Step 5: Compound 71-4 (20 mg, 0.05 mmol) and anhydrous DCM (3 mL) were added to a 25 mL three-necked flask. A solution of DAST (55 mg, 0.25 mmol) in dichloromethane was slowly added dropwise under nitrogen and a dry ice-ethanol bath. The mixture was allowed to stir at room temperature for 3 h. After completion of the reaction as determined by LCMS, the reaction mixture was quenched by washing with saturated NH4Cl solution (10 mL x 1). The mixture was then extracted with DCM (10 mL x 2). The organic phases were combined, washed with saturated brine (30 mL x 1), dried over anhydrous Na2SO4, and dried under reduced pressure. The crude product was purified by prep-HPLC (eluent (v / v): acetonitrile / (water + 0.05% NH4HCO3) = 30%–70%) to afford the title compound E71 (white solid, 6 mg, yield: 30%). 1 H 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] + .

[0603] Example 72: (6bR,10aS)-8-(3-(2,3-dihydrobenzofuran-7-yl)-2-fluoropropyl)-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-2(3H)-one

[0604]

[0605] E72 was prepared by referring to the synthesis method of Example 69. 1 H 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).MSm / z(ESI):408.6[M+H] + .

[0606] Example 73-1: (6bR, 10aS)-8-(3-(2,3-dihydrobenzofuran-7-yl)propyl)-3-methyl-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-2(3H)-one

[0607]

[0608] Step 1: Under nitrogen, compound 45-1-4 (210 mg, 0.69 mmol) was dissolved in dry tetrahydrofuran (5.0 mL) and sodium hydroxide (55.7 mg, 1.39 mmol, 60% dispersion in mineral oil) was added. After reacting at 0°C for 0.5 h, iodomethane (55.7 mg, 1.39 mmol) was added and the reaction continued at room temperature for 2 h. After completion of the reaction, LCMS analysis indicated that the reaction was quenched with 10.0 mL of ice water and extracted with dichloromethane (10.0 mL x 2). The organic phase was then dried and the crude product was purified on a normal silica gel column to afford 73-1-1 (brown solid, 190 mg, 96% yield). MS m / z (ESI): 316.2 [M+H] + .

[0609] Step 2: Dissolve compound 73-1-1 (190 mg, 0.60 mmol) in 30% hydrobromic acid / acetic acid solution (3.0 mL) and stir at 50°C for 16 h. LCMS analysis indicated the disappearance of the starting material. After cooling to room temperature, the product was filtered to obtain compound 73-1-2 (brown solid, 45 mg, 20% yield). MS m / z (ESI): 244.2 [M+H] + .

[0610] Step 3: Under nitrogen, compound 73-1-2 (45.0 mg, 0.19 mmol), 3-(2,3-dihydrobenzofuran-7-yl)propanal (31.0 mg, 0.19 mmol), and acetic acid (0.05 mL, 0.93 mmol) were dissolved in THF (3.0 mL). Sodium cyanoborohydride (24.7 mg, 0.39 mmol) was added and reacted at 0°C for 2 h. The reaction was complete after LCMS analysis. The mixture was filtered, dried, and purified by reverse phase purification (eluent (v / v): acetonitrile / (water + 0.05% NH4HCO3) = 30%–70%) to afford compound E73-1 (white solid, 10.1 mg, 14% yield). 1H NMR(400MHz, CDCl3)δ7.01(d,J=7.2Hz,1H),6.91(d,J=7.6Hz,1H),6.86-6.8 4(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]+.

[0611] Example 73-2: (6bS, 10aR)-8-(3-(2,3-dihydrobenzofuran-7-yl)propyl)-3-methyl-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-2(3H)-one

[0612]

[0613] Step 1: Dissolve 67-2-6 (840 mg, 2.92 mmol) in THF (5.0 mL). Add NaH (9.12 g, 62.1 mmol) and iodomethane (77.3 mg, 0.636 mmol) under ice-cooling. React at 0°C for 2 h. LCMS analysis indicates the reaction is complete. Add water, extract with EA, dry over sodium sulfate, filter, concentrate, and purify on a silica gel column (DCM:MeOH = 20:1) to afford compound 73-2-1 (yellow solid, 770 mg, 87% yield). MS m / z (ESI): 302.1 [M+H] + .

[0614] Step 2: Dissolve 73-2-1 (770 mg, 2.55 mmol) in a solution of hydrobromic acid in acetic acid (5 mL) and react at 50°C for 18 h. LCMS confirmed the reaction was complete, and the reaction solution was concentrated to give compound 73-2-2 (gray solid, 526 mg, 84% yield). MS m / z (ESI): 244.2 [M+H] + .

[0615] Step 3: Under nitrogen, 73-2-2 (300 mg, 1.23 mmol) was dissolved in THF (5.0 mL), and 3-(2,3-dihydrobenzofuran-7-yl)propanal (260 mg, 1.48 mmol) and NaBH3CN (387 mg, 6.16 mmol) were added. The mixture was reacted at 25°C for 3 h. LCMS confirmed the reaction was complete. Water was added, the mixture was extracted with EA, dried over sodium sulfate, filtered, concentrated, and purified on a silica gel column (DCM:MeOH = 10:1) to afford compound 73-2-3 (yellow solid, 30.0 mg, 6% yield). MS m / z (ESI): 404.2 [M+H] + .

[0616] Step 4: 73-2-3 (30.0 mg, 0.0744 mmol) was purified by SFC (Daicel ChiralCel OD, 40 mm ID×250 mm, 10 μm; Mobile phase: n-Hexane / Ethanol [0.1% NH 3. H2O (V / V)] = 70 / 30; Flowrate: 80 mL / min) to give white solid E73-2 (PK1: 2.20 mg, purity 96%, yield 7%, ee 100%, RT = 3.543, OROT = -205.3 and white solid E73-1 (PK2: 6.00 mg, purity 72%, yield 20%, ee 99%, RT = 4.604, OROT = +163.3). 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: 1 H NMR(400MHz, CDCl3)δ7.01(d,J=7.2Hz,1H),6.91(d,J=7.6Hz,1H),6.86-6.8 4(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),2.9 4-2.72(m,2H),2.57(t,J=7.6Hz,2H),2.39-2.16(m,3H),2.02-1.77(m,5H).

[0617] Example 74: (6bR,10aS)-8-(3-(2,3-dihydrobenzofuran-7-yl)propyl)-3-ethyl-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-2(3H)-one

[0618]

[0619] Step 1: 45-1-4 (70 mg, 0.23 mmol) was added to a 50 mL three-necked reaction flask, followed by DMF (5 mL). The mixture was stirred at 0°C for 5 min under a nitrogen atmosphere, followed by the addition of sodium hydride (9 mg, 0.35 mmol). Ethyl iodide (43 mg, 0.28 mmol) was then added dropwise, and the mixture was allowed to react at room temperature for 5 h. After completion of the reaction, the reaction mixture was quenched with saturated aqueous NH4Cl solution, water (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL x 2). The organic phase was washed twice with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated to afford compound 74-1 (a dark brown oil, 50 mg, 66% yield). MS m / z (ESI): 330.5 [M+H]. + .

[0620] Step 2: Preparation of 74-2 refers to the synthesis method of the first step of Example 72

[0621] Step 3: The preparation of E74 was carried out according to the synthesis method of the fifth step of Example 8. 1 H 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] + .

[0622] Example 75: (6bR, 10aS)-8-(2-((2,3-dihydrobenzofuran-7-yl)oxy)ethyl)-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-2(3H)-one

[0623]

[0624] Step 1: 7-Methoxybenzofuran (500 mg, 3.37 mmol) and 10 mL of DCM were purged with N₂ three times, cooled to -78°C, and 2M BBr₃ (2.5 mL, 5 mmol) was added dropwise. The mixture was allowed to warm to room temperature and allowed to react for 3 h. TLC indicated complete reaction. Sat. NH₄Cl was added to the reaction mixture, and the layers were separated. The aqueous phase was extracted once more with DCM. The combined organic phases were dried, concentrated, and purified by column chromatography (PE / EA = 10 / 1) to afford 75-1 (280 mg, colorless liquid). MS m / z (ESI): 133.2 [MH] - .

[0625] Step 2: Compound 75-1 (280 mg, 2.09 mmol) was added to a 100 mL single-necked reaction flask. Methanol (10 mL) and 10% Pd / C (wet basis, 50 mg) and 20% Pd(OH)2 / C (wet basis, 50 mg) were then added. The atmosphere was replaced with hydrogen three times and the reaction was stirred at 60°C for 16 h. After the reaction was complete as determined by LCMS, the reaction solution was filtered and the filtrate was concentrated under reduced pressure to obtain the target compound 75-2 (crude product, 260 mg, 92% yield). The crude product was used directly in the next step without further purification. MS m / z (ESI): 135.2

[0626] [MH] - .

[0627] Step 3: 75-2 (200 mg, 1.47 mmol), 1,2-dibromoethane (1.37 g, 7.35 mmol), NaOH (176 mg, 4.41 mmol), TBAB (142 mg, 0.44 mmol), and 10 mL of water were replaced with nitrogen three times, heated to 90°C, and reacted for 16 h. TLC showed a small amount of starting material remaining. EA was added to the reaction solution, the layers were separated, and the aqueous phase was extracted twice more with EA. The combined organic phases were dried, concentrated, and purified by column chromatography (PE / EA = 10 / 1) to afford 75-3 (130 mg, yellow oil).

[0628] Step 4: 67-1-1 (20 mg, 0.087 mmol), 75-3 (32 mg, 0.131 mmol), DIEA (23 mg, 0.174 mmol), KI (29 mg, 0.174 mmol), and 2 mL of DMF were purged with N₂ three times, heated to 80°C, and reacted for 16 h. LCMS showed the reaction was complete. The reaction solution was cooled to room temperature, filtered, and purified by prep-HPLC (eluent (v / v): acetonitrile / (water + 0.05% NH₄HCO₃) = 30%–70%) to afford compound E75 (8 mg, pink solid, yield: 23.5%). 1 H 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] + .

[0629] Example 76: (6bR,10aS)-8-(3-(2,3-dihydrobenzofuran-7-yl)-3-hydroxypropyl)-3-methyl-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-2(3H)-one (HJM-2119, CJJ120-093)

[0630]

[0631] The preparation of E76 refers to the synthetic method of Example 71. 1 H 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] + .

[0632] Example 77: (6bR,10aS)-8-(3-(2,3-dihydrofuro[2,3-c]pyridin-7-yl)propyl)-3-methyl-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-2(3H)-one

[0633]

[0634] The preparation of E77 refers to the synthetic method of Example 60. 1 H 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] + .

[0635] Example 78: (6bR, 10aS)-8-(3-(3-chloropyridin-2-yl)propyl)-3-methyl-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-2(3H)-one

[0636]

[0637] The preparation of E78 was based on the synthetic method of step 5 of E67-1. 1H NMR (500 MHz, CD3OD) δ8.54 (d, J = 4.5 Hz, 1H), 8.06 (d, J = 8.1 Hz, 1H), 7.50-7.41 (m, 1H), 7.04-6.99 (m, 1H), 6.96 (d, J = 7.4 Hz, 1H), 6.90 (t, J = 7.7 Hz, 1H), 4.07 (d, J = 14.5 Hz, 1H), 3.78-3.63 (m, 2H), 3.58-3.53 (m, 1H), 3.49-3.43 (m, 2H), 3.32 (s, 3H), 3.28-3.19 (m, 3H), 3.12 (t, J = 7.5 Hz, 2H), 2.70 -2.56(m,1H),2.40(d,J=16.0Hz,1H),2.30-2.22(m,3H).MS m / z(ESI):397.9,399.9[M+H] + .

[0638] Example 79: (6bR, 10aS)-3-cyclobutyl-8-(3-(2,3-dihydrobenzofuran-7-yl)propyl)-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-2(3H)-one

[0639]

[0640] Step 1: 2-Bromoacetyl chloride (1 g, 6.36 mmol) and NaHCO3 (1.07 g, 12.72 mmol) were added to a three-necked flask containing 10 mL of THF. The atmosphere was replaced with N2 three times, cooled to 0°C, cyclobutylamine (544 mg, 7.63 mmol) was added, and the temperature was slowly raised to room temperature. The reaction was allowed to proceed for 2 h. EA and saturated sodium chloride solution were added, the layers were separated, and the aqueous phase was extracted once with EA. The organic phases were combined, dried, and concentrated to give 79-1 (800 mg, white solid), which was used directly in the next step.

[0641] Step 2: Ethyl (4aS,9bR)-6-bromo-1,3,4,4a,5,9b-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), and TBAB (200 mg, 0.6 mmol) were added to a single-necked vial containing 5 mL of DMAc. The atmosphere was replaced with nitrogen three times, and the temperature was raised to 110°C. The reaction was allowed to proceed for 48 h. EA and water were added, and the layers were separated. The aqueous phase was extracted three times with EA. The combined organic phases were washed three times with saturated sodium chloride, dried, concentrated, and purified by column chromatography (PE / EA = 3 / 1) to afford 79-2 (180 mg, brown oil). MS m / z (ESI): 436.6, 438.6 [M+H] + .

[0642] Step 3: 79-2 (180 mg, 0.414 mmol), Pd2(dba)3 (38 mg, 0.0414 mmol), NaOt-Bu (80 mg, 0.828 mmol), BINAP (77 mg, 0.124 mmol), and 10 mL of dioxane were added to a 100 mL single-necked flask. The atmosphere was replaced with nitrogen three times, the temperature was raised to 110°C, and the reaction was allowed to proceed for 16 h. LCMS confirmed the complete reaction of the starting materials. The reaction solution was cooled to room temperature, and water and EA were added. The layers were separated, and the aqueous phase was extracted twice with EA. The organic phases were combined, dried, and concentrated to afford compound 79-3 (150 mg, crude), which was used directly in the next step. MS m / z (ESI): 356.2 [M+H] + .

[0643] Step 4: 79-3 (150 mg, 0.422 mmol) and 2 mL of HBr in HOAc were reacted at 50°C for 16 h. LCMS indicated the reaction was complete. The reaction solution was cooled to room temperature, most of the HOAc was concentrated, and the product was purified by HPLC (0.05% HCl in H2O, 0-95% ACN over 30 min) to afford 79-4 (45 mg, brown solid). MS m / z (ESI): 230.2 [M+H] + .

[0644] Step 5: The preparation of E79 was carried out according to the synthetic method of Step 5 of E67-1.

[0645] 1H NMR (500MHz, CDCl3) δ7.03(d,J=8.5Hz,1H),6.92(d,J=7.5Hz,1H),6.84(dd,J=6.5,1.0 Hz,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] + .

[0646] Example 80: (6bR,10aS)-8-(2-((2,3-dihydrobenzofuran-7-yl)amino)ethyl)-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-2(3H)-one

[0647]

[0648] Step 1: Dissolve 2,3-dihydrobenzofuran-7-amine (900 mg, 6.66 mmol) in DMF (10.0 mL) and add 1,2-dibromoethane (3.75 g, 19.9 mmol). The mixture was reacted at 60°C for 2 h. TLC confirmed the reaction was complete, and the product was quenched with water, extracted with EA, dried over sodium sulfate, filtered, concentrated, and purified (PE:EA = 10:1) to afford compound 80-1 (white solid, 300 mg, 18% yield). MS m / z (ESI): 242.0, 244.0 [M+H] + .

[0649] Step 2: Compound 80-1 (135 mg, 0.591 mmol) was dissolved in DMSO (10.0 mL), and DIEA (208 mg, 1.61 mmol) and (6bR,10aS)-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-2(3H)-one (130 mg, 0.537 mmol) were added. The mixture was stirred at 65°C for 16 h. The reaction was determined to be complete by TLC. The mixture was quenched with water, extracted with EA, dried over sodium sulfate, filtered, and concentrated for purification (eluent (v / v): acetonitrile / (water + 0.05% NH4HCO3) = 30%-70%) to afford compound E80 as a white solid, 29.0 mg, 13% yield. 1 H 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),3.35-3.1 7(m,4H),3.18-3.04(m,4H),2.96-2.83(m,1H),2.71-2.59(m,1H),2.49-

[0650] 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] + .

[0651] Example 81: (8aS,12aR)-11-(3-(2,3-dihydrobenzofuran-7-yl)propyl)-6,7,8a,9,10,11,12,12a-octahydro-[1,4]diazoheptaquino[3,2,1-hi]pyrido[4,3-b]indol-5(4H)-one

[0652]

[0653] Step 1: The preparation of 81-1 refers to the synthetic method of step 5 of E83.

[0654] Step 2: The preparation of 81-2 refers to the synthetic method of step 3 of E45-1.

[0655] Step 3: 81-3 was prepared according to the synthetic method of step 4 of E67-1.

[0656] Step 4: The preparation of E81 refers to the synthetic method of Step 5 of E67-1. δ1H NMR (500 MHz, CDCl3) δ7.48 (s, 1H), 7.04 (d, J = 7.5 Hz, 1H), 6.91 (d, J = 8.0 Hz, 1H), 6.85 (d, J = 7.0 Hz, 1H), 6.77-6.71 (m, 2H), 6.60 (d, J = 8.0 Hz, 1H), 4.53 (t, J = 9.0 Hz, 2H), 3.62-3.31 (m, 3H), 3.24-3.09 (m, 3H), 3.05-2.75 (m, 4H), 2.61-2.44 (m, 5H), 2.30-1.88 (m, 5H). MS m / z (ESI): 404.5 [M+H] + .

[0657] Example 82: (8aS,12aR)-11-(3-(2,3-dihydrobenzofuran-7-yl)propyl)-4-methyl-6,7,8a,9,10,11,12,12a-octahydro-[1,4]diazoheptaquino[3,2,1-hi]pyrido[4,3-b]indol-5(4H)-one

[0658]

[0659] Step 1: The preparation of 82-1 refers to the synthetic method of step 1 of E73-1.

[0660] Step 2: The preparation of 82-2 refers to the synthetic method of step 2 of E73-1.

[0661] Step 3: Preparation of E82 Refer to the synthesis method of step 3 of E73-1 1 H 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] + .

[0662] Example 83: 8-(3-(2,3-dihydrobenzofuran-7-yl)propyl)-5-fluoro-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-2(3H)-one

[0663]

[0664] Step 1: 4-Fluoro-2-bromoaniline (5.0 g, 26.3 mmol) and 5M HCl solution (50 mL) were added to a 250 mL three-necked flask. The mixture was cooled to 0°C in an ice-water bath. Then, 20 mL of NaNO₂ (2.8 g, 39.4 mmol) was slowly added dropwise. The mixture was stirred at 0°C for 2 h. Subsequently, a solution of SnCl₂ (10 g, 52.6 mmol) in hydrochloric acid (5.5 mL) was slowly added dropwise in an ice-water bath. The mixture was stirred at room temperature overnight. After TLC analysis, the reaction mixture was filtered, the filter cake was washed with a small amount of concentrated HCl, and lyophilized to obtain crude compound 83-1 (off-white solid, 4.4 g, 82% yield). The crude product was used directly in the next step without further purification.

[0665] Step 2: Dissolve compound 83-1 (2.0 g, 9.8 mmol) in isopropanol (30 mL), then add 4-oxopiperidone hydrochloride (1.5 g, 10.7 mmol) and concentrated HCl (2 mL). After addition, heat to 90°C under nitrogen and stir overnight. After completion of the reaction, LCMS analysis confirmed that a large amount of solid precipitated. Filter the filter cake, wash with isopropanol, and dry under reduced pressure to obtain crude compound 83-2 (off-white solid, 2.0 g, yield: 76%). The crude product was used directly in the next step without further purification. MS m / z (ESI): 269.2, 271.2 [M+H] + .

[0666] Step 3: Crude compound 83-2 (200 mg, 0.74 mmol), TEA (225 mg, 2.22 mmol), and anhydrous DCM (10 mL) were added to a 25 mL three-necked flask. (Boc)2O (200 mg, 0.90 mmol) was then slowly added dropwise under N2 protection. The mixture was stirred at room temperature for 2 h. After completion of the reaction as determined by LCMS, water (20 mL) was added to the reaction solution, and the mixture was extracted with DCM (2 x 20 mL). The organic phases were combined, washed with saturated brine (1 x 30 mL), dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The crude product was purified by normal phase column chromatography (eluent gradient: 2% MeOH / DCM) to obtain compound 83-3 (white solid, 190 mg, yield 69%).

[0667] Step 4: Compound 83-3 (100 mg, 0.27 mmol), benzophenone imine (60 mg, 0.32 mmol), t-BuONa (1.23 g, 12.8 mmol), t-BuXPhos-Pd-G3 (11 mg, 0.01 mmol), and toluene (5 mL) were added to a 35 mL microwave tube. Argon was bubbled through the tube for 2 minutes, and the mixture was then heated to 120°C and stirred for 1 hour. After completion of the reaction as determined by LCMS, water (30 mL) was added to the reaction solution, and the mixture was extracted with EA (20 mL x 2). The organic phases were combined, washed with saturated brine (30 mL x 1), dried over anhydrous Na2SO4, and evaporated to dryness under reduced pressure. The crude product was purified by column chromatography (EA / PE = 0-20%) to obtain compound 83-4 (pale yellow solid, 110 mg, yield: 70%). MS m / z (ESI): 470.9 [M+H] + .

[0668] Step 5: Compound 83-4 (100 mg, 0.21 mmol), ethyl bromoacetate (70 mg, 0.42 mmol), Cs2CO3 (240 mg, 0.63 mmol), KI (1.99 g, 12.76 mmol), and anhydrous CH3CN (10 mL) were added to a 25 mL single-necked flask and refluxed overnight under a nitrogen atmosphere. After completion of the reaction as determined by LCMS, the reaction solution was filtered, water (20 mL) was added to the filtrate, and the mixture was extracted with EA (30 mL x 2). The organic phases were combined, washed with saturated brine (30 mL x 1), dried over anhydrous Na2SO4, and evaporated to dryness under reduced pressure. The crude product was purified by column chromatography (EA / PE = 0-15%) to obtain compound 83-5 (yellow oil, 100 mg, yield: 85%). MS m / z (ESI): 556.6 [M+H] + .

[0669] Step 6: Compound 83-5 (100 mg, 0.18 mmol) and THF (10 mL) were added to a 25 mL single-necked flask, followed by the addition of 2N HCl solution (3 mL). The mixture was stirred at room temperature for 2 h. After completion of the reaction as monitored by LCMS, saturated NaHCO₃ solution was added to the reaction mixture to adjust the pH to alkaline. The mixture was extracted with EA (20 mL x 3). The organic phases were combined, washed with saturated brine (30 mL x 1), dried over anhydrous Na₂SO₄, and dried under reduced pressure. The crude product was purified by column chromatography (MeOH / DCM = 0-2%) to afford compound 83-6 (yellow oil, 40 mg, 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] + .

[0670] Step 7: Compound 83-6 (40 mg, 0.12 mmol) and anhydrous DCM (5 mL) were added to a 25 mL single-necked flask, followed by the addition of TFA (1 mL). The reaction was stirred at room temperature for 1 h. After completion of the reaction as determined by LCMS, the solvent was removed under reduced pressure. The crude product was then dissolved in 10% MeOH / DCM (20 mL), and the pH was adjusted to alkaline by the addition of saturated NaHCO₃ solution. The product was extracted with 10% MeOH / DCM (10 mL x 3). The organic phases were combined, washed with saturated brine (10 mL x 1), dried over anhydrous Na₂SO₄, and dried under reduced pressure to afford crude compound 83-7 (brown oil, 30 mg). The crude product was used directly in the next step without further purification. MS m / z (ESI): 246.7 [M+H] + .

[0671] Step 8: Compound 83-8 was prepared by referring to the synthesis method of Step 3 of Example E73-1. MS m / z (ESI): 406.7 [M+H] + .

[0672] Step 9: Crude compound 83-8 (20 mg, 0.05 mmol) and TFA (5 mL) were added to a 25 mL single-necked vial, followed by the addition of NaCN)BH3 (30 mg, 0.50 mmol). The mixture was stirred at room temperature overnight. After completion of the reaction as determined by LCMS, the solvent was removed under reduced pressure. EA and water were then added to the crude product, and the mixture was extracted with EA (10 mL x 3). The combined organic phases were washed with saturated brine (10 mL x 1), dried over anhydrous Na2SO4, and evaporated to dryness under reduced pressure. The crude product was purified by prep-HPLC (eluent (v / v): acetonitrile / (water + 0.05% NH4HCO3) = 30%–70%) to afford compound E83 as a white solid, 4 mg, yield: 20%. 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] + .

[0673] Example 84: (6bR, 10aS)-8-(3-(2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)propyl)-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-2(3H)one

[0674]

[0675] Step 1: Dissolve 2,2-dimethyl-2,3-dihydrobenzofuran-7-ol (1.8 g, 11 mmol) in dichloromethane (50 mL) at room temperature. Add pyridine (1.8 mL, 22.8 mmol), cool to 0°C, and then add Tf2O (2.3 mL, 13.5 mmol). Return to room temperature and stir for 1 hour. The reaction mixture is washed with 1M HCl (50 mL), water (50 mL), and saturated sodium bicarbonate solution (50 mL). Dry over anhydrous sodium sulfate, and the organic phase is concentrated to obtain compound 84-1 (yellow oil, 3.1 g). The crude product is used directly in the next step. MS m / z (ESI): 296.6 [M+H] +

[0676] Step 2: Compound 84-1 (3.1 g, 10.5 mmol) was dissolved in DMF (24 mL) at room temperature. Et3N (6 mL) and ethyl acrylate (2.0 g, 20 mmol) were added, followed by Pd(dppf)2Cl2 (770 mg, 1.05 mmol). The mixture was heated to 98°C under N2 protection for 18 hours. The mixture was concentrated to remove triethylamine and DMF, added to 50 mL of water, and extracted with ethyl acetate (50 mL). The mixture was washed with saturated brine and dried over anhydrous sodium sulfate. The organic phase was concentrated to obtain the crude product, which was purified by normal phase column chromatography to afford compound 84-2 (yellow oil, 760 mg, yield: 31%). MS m / z (ESI): 247.3 [M+H] +

[0677] Step 3: Prepare according to the synthetic method of step 2 in Example 1. MS m / z (ESI): 249.1 [M+H] +

[0678] Step 4: Prepare according to the synthetic method of step 3 of Example 1. MS m / z (ESI): 207.1 [M+H] +

[0679] Step 5: At room temperature, compound 84-4 (40 mg, 0.194 mmol) and triethylamine (78 mg, 0.78 mmol) were dissolved in dichloromethane (4 mL), cooled to 0°C, methanesulfonic anhydride (67 mg, 0.39 mmol) was added, and the mixture was returned to room temperature and stirred for 1.5 hours. DCM (15 mL) and water (15 mL) were added to separate the layers. The organic phase was washed with water (15 mL) and dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product, which was dissolved in acetonitrile (5 mL). Compound 67-1-1 (30 mg, 0.194 mmol) and potassium carbonate (32 mg, 0.23 mmol) were added, and the mixture was heated to 80°C for 16 hours. After the reaction, the mixture was cooled to room temperature, filtered, concentrated, and purified by prep-HPLC (eluent (v / v): acetonitrile / (water + 0.05% NH4HCO3) = 30%-70%) to give compound E84 (white solid, 9.0 mg, 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,1 H),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] + .

[0680] Example 85: (6bR, 10aS)-8-(3-(2H-spiro[benzofuran-3,1'-cyclopropane]-7-yl)propyl)-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-2(3H)-one

[0681]

[0682] Step 1: Dissolve methyltriphenylphosphonium bromide (5.06 g, 14.2 mmol) in THF (150 mL), cool to 0°C, add potassium tert-butoxide (1.67 g, 14.9 mmol), heat to 25°C and stir for 1 hour, add 7-bromo-3-benzofuranone (2.0 g, 9.39 mmol, dissolved in 150 mL THF), stir at 25°C for 16 hours. Add 100 mL of water to quench, and use ethyl acetate (150 mL) to obtain a 100 mL solution of methyltriphenylphosphonium bromide. X 2) Extraction, washing with saturated brine, drying over anhydrous sodium sulfate, and concentration of the organic phase to obtain a crude product, which was purified by normal phase column chromatography to obtain compound 85-1 (colorless oil, 1.58 g, yield: 79%). MS m / z (ESI): 212.4 [M+H] +

[0683] Step 2: Dissolve diethylzinc (27 mL, 27 mmol) in DCM (150 mL), cool to 0°C, add TFA (2.32 mL, 31.4 mmol), and stir at 0°C for 15 min. Add diiodomethane (8.0 g, 30 mmol) and stir at 0°C for 15 min. Then add compound 85-1 (1.58 g, 7.49 mmol, dissolved in DCM (150 mL)) and stir at 0°C for 15 min. Then warm to 25°C and stir for 16 hr. Quench the reaction with 2M HCl (150 mL), separate the layers, and wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, and concentrate to obtain the crude product, which was purified by normal phase column chromatography to afford compound 85-2 (colorless oil, 390 mg, yield: 23%). MS m / z (ESI): 226.4 [M+H] +

[0684] 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)Cl2 (224 mg, 0.308 mmol). Under nitrogen, the reaction mixture was heated to 95°C and stirred for 18 hours. The solvent was dried by rotary evaporation, ethyl acetate (50 mL) was added, and the mixture was filtered. The filtrate was washed with water (50 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. Compound 85-3 was isolated and purified by normal phase column chromatography (300 mg, yield: 79%). MS m / z (ESI): 245.3 [M+H] +

[0685] Step 4: Dissolve compound 85-3 (290 mg, 1.18 mmol) in ethyl acetate (30 mL), add platinum dioxide (80 mg), and hydrogenate at 25°C for 16 hours. Filter and concentrate the filtrate to obtain the product (colorless oil, 220 mg, yield 76%). MS m / z (ESI): 247.1 [M+H] +

[0686] Step 5: Prepare according to the synthetic method of step 3 in Example 1. MS m / z (ESI): 205.3 [M+H] +

[0687] Step 6: Prepare by referring to the synthetic method of Step 5 of Example 84 to obtain 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] + .

[0688] Example 86: (6bR,10aS)-8-(3-(6-fluoro-2,3-dihydrobenzofuran-7-yl)propyl)-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-2(3H)-one

[0689]

[0690] Step 1: Under nitrogen, 2-bromo-3-fluorophenol (2 g, 10.5 mmol) and 2-bromo-1,1-diethoxyethane (2.47 g, 12.6 mmol) were dissolved in dry DMF (50 mL), followed by the addition of KCO (4.3 g, 31.4 mmol). The reaction was incubated at 145°C for 3 h. After completion of the reaction as determined by LCMS, the product was quenched with 100.0 mL of ice water, extracted with ethyl acetate (100 mL x 3), and washed with saturated brine (100 mL x 3). The organic phase was then dried and the crude product was purified on a normal silica gel column to afford 86-1 (colorless liquid, 3 g, 93% yield).

[0691] Step 2: Dissolve compound 86-1 (2 g, 9.77 mmol) in toluene (30 mL), then add PPA (3 mL) and stir at 90°C for 3 h. After cooling to room temperature, the solvent was evaporated, and the mixture was quenched with 100.0 mL of ice water. Extraction was performed with ethyl acetate (100 mL x 3), and the mixture was washed with saturated brine (100 mL x 3). The organic phase was evaporated, and the crude product was purified on a normal silica gel column to obtain 86-2 (colorless liquid, 1 g, yield 47.6%).

[0692] Step 3: Compound E86 was prepared by referring to the synthetic method of Steps 1-5 of 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] + .

[0693] Example 87: (6bR,10aS)-8-(3-(4-fluoro-2,3-dihydrobenzofuran-7-yl)propyl)-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-2(3H)-one

[0694]

[0695] Step 1: The preparation of 87-1 refers to the synthesis method of the first step in Example 3.

[0696] Step 2: The preparation of 87-2 was carried out according to the synthesis method of the second step of Example 3.

[0697] Step 3: The preparation of 87-3 refers to the synthesis method of the third step of Example 3.

[0698] Step 4: The preparation of 87-4 was carried out according to the synthesis method of the fourth step in Example 8.

[0699] Step 5: The preparation of E87 was carried out according to the synthesis method of the fifth step 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] + .

[0700] Example 88: (6bR,10aS)-8-(3-(5-fluoro-2,3-dihydrobenzofuran-7-yl)propyl)-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-2(3H)-one

[0701]

[0702] The preparation of E88 refers to the synthetic method of Example 60. 1 H 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,1 H),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] + .

[0703] Example 89: (6bR,10aS)-8-(3-(6-chloro-2,3-dihydrobenzofuran-7-yl)propyl)-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-2(3H)-one

[0704]

[0705] The preparation of E89 was carried out according to the synthesis method of Example 60. 1 H 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=15.0,8.5 Hz,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] + .

[0706] Example 90: (6bR,10aS)-8-(3-(2,3-dihydrobenzofuran-7-yl)propyl)-2-carbonyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline 8-oxidation

[0707]

[0708] Step 1: E67-1 (10 mg, 2.67 mmol) was dissolved in DCM (5 ml), and then m-CPBA (540 mg, 2.67 mmol) was added. The reaction was allowed to proceed at room temperature for 2 h. LCMS showed complete reaction. The product was extracted with DCM, concentrated and filtered, and then purified and separated by prep-HPLC (eluent (v / v): acetonitrile / (water + 0.05% NH4HCO3) = 30%–70%) to give 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),3.9 1(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] + .

[0709] Example 91: 8-(3-(2,3-dihydrobenzofuran-7-yl)propyl)-6-fluoro-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-2(3H)-one

[0710]

[0711] The preparation of E91 refers to the synthetic method of Example 83. 1 H 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=7.5H z,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] + .

[0712] Example 92: (6bR,10aS)-8-(3-(2,3-dihydrofuro[3,2-c]pyridin-7-yl)propyl)-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-2(3H)-one

[0713]

[0714] The preparation of E92 refers to the synthetic method of Example 60. 1 H 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] + .

[0715] Example 93: (6bR, 10aS)-8-(3-(3-methoxythiophen-2-yl)propyl)-6b, 7, 8, 9, 10, 10a-hexahydro-1H-pyrido [3', 4': 4, 5] pyrrolo [1, 2, 3-de] quinoxalin-2 (3H) -one

[0716]

[0717] The preparation of E93 refers to the preparation method of Example 40. 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] + .

[0718] Example 94: (6bR,10aS)-8-(4-(2,3-dihydrobenzofuran-7-yl)butan-2-yl)-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-2(3H)-one

[0719]

[0720] Step 1: Dissolve 1-3 (320 mg, 1.47 mmol) in methanol (5 mL) and saturated aqueous sodium hydroxide solution (2 mL) at room temperature. The reaction mixture was stirred at room temperature for 12 h. The reaction mixture was extracted with water and ethyl acetate. The aqueous phase was adjusted to pH 3-4 with dilute hydrochloric acid and then extracted with water and ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and dried to afford 94-1 (260 mg, 94% yield) as a white solid.

[0721] Step 2: Dissolve 94-1 (260 mg, 1.35 mmol), N,O-dimethylhydroxylamine hydrochloride (158 mg, 1.62 mmol), HATU (772 mg, 2.03 mmol), and DIEA (525 mg, 4.06 mmol) in DMF (5 mL) at room temperature. Stir the reaction mixture at room temperature for 2 h. Extract the mixture with water and ethyl acetate, and dry the organic phase over anhydrous sodium sulfate. Concentrate and purify by column chromatography (PE:EA = 3:1) to obtain the title compound 94-2 as a white solid, 300 mg, 94% yield. MS m / z (ESI): 236.4 [M+H] +

[0722] Step 3: At -78°C under nitrogen, 94-2 (250 mg, 1.06 mmol) was dissolved in THF (5 mL). A 3M solution of methylmagnesium bromide in tetrahydrofuran (0.7 mL, 2.13 mmol) was added dropwise. The reaction mixture was then gradually warmed and stirred at room temperature for 2 h. A saturated aqueous solution of ammonium chloride (5 mL) was added to the reaction mixture, which was then extracted with water and ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (PE:EA = 3:1) to afford the title compound 94-3 as a white solid, 180 mg, 90% yield.

[0723] Step 4: Dissolve 94-3 (50 mg, 0.26 mmol) and sodium borohydride (30 mg, 0.79 mmol) in methanol (3 mL) at room temperature. Stir the reaction mixture at room temperature for 20 min. Extract the mixture with water and ethyl acetate, and dry the organic phase over anhydrous sodium sulfate and spin-dry to obtain the title compound 94-4 as a colorless oil (40 mg, 82% yield).

[0724] Step 5: Preparation of 94-5 ester was carried out by referring to the synthesis method of the fourth step in Example 3.

[0725] Step 6: Dissolve 94-5 (15 mg, 0.055 mmol), 67-1-1 (13 mg, 0.055 mmol), and sodium iodide (3 mg, 0.11 mmol) in DMF (2 mL) at room temperature, and add potassium carbonate (23 mg, 0.17 mmol). The reaction mixture is stirred at 80°C for 12 h. The reaction mixture is filtered, and the filtrate is directly subjected to reverse-phase preparative separation (C18 column, eluent gradient: acetonitrile / (water + 0.05% NH4HCO3)) to afford compound E94 (2 mg, 9% yield) as a white solid. 1 H NMR (500MHz, CDCl3) δ7.53 (s, 1H), 7.07-7.01 (m, 1H), 6.94 (d, J = 7.5Hz, 1H), 6.8 7-6.81(m,1H),6.80-6.69(m,2H),6.58(d,J=7.8Hz,1H),4.58-4.47(m,2H),3.9 5(dd,J=14.5,1.7Hz,1H),3.40-3.33(m,2H),3.23-3.17(m,2H),2.87-2.57(m,5 H),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] + .

[0726] Example 95: (6bR, 10aS)-8-(3-(6-fluoro-2,3-dihydrobenzofuran-7-yl)propyl)-3-methyl-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-2(3H)-one

[0727]

[0728] The preparation of E95 refers to the preparation method of Example 86. 1 H 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] + .

[0729] Example 96: (6bR,10aS)-8-(2-((2,3-dihydrobenzofuran-7-yl)oxy)ethyl)-3-methyl-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-2(3H)-one

[0730]

[0731] Step 1: At room temperature, 73-1-2 (10 mg, 0.041 mmol) was dissolved in DMF (2 mL). 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. The reaction mixture was stirred at 80°C for 2 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo to obtain the crude product. The crude product was concentrated, filtered, and purified by prep-HPLC (eluent (v / v): acetonitrile / (water + 0.05% NH4HCO3) = 30%–70%) to afford compound E96 (4.7 mg, 28% yield) as a white solid. 1 H 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] + .

[0732] Example 97: (6bR,10aS)-8-(3-(2,3-dihydrofuro[2,3-c]pyridin-7-yl)propyl)-3-(methyl-d3)-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-2(3H)-one

[0733]

[0734] Step 1: Compound 45-1-4 (120 mg, 0.40 mmol) and anhydrous THF (5 mL) were added to a 25 mL three-necked reaction flask. NaH (30 mg, 0.80 mmol, 60% in oil) was then added. After addition, the mixture was stirred at room temperature under nitrogen for 0.5 h. CD3I (170 mg, 1.20 mmol) was then added. After addition, the mixture was stirred at room temperature for 3 h. After completion of the reaction as determined by LCMS, water (30 mL) was added to the reaction solution, and the mixture was extracted with EtOAc (20 mL x 2). The organic phases were combined, washed with saturated brine (1 x 20 mL), dried over anhydrous sodium sulfate, and dried under reduced pressure to afford crude compound 97-2 (pale yellow oil, 120 mg, yield: 95%). The crude product was used directly in the next step without further purification. MS m / z (ESI): 319.5 [M+H]+ .

[0735] Step 2: The preparation of 97-3 refers to the synthesis method of step 5 in Example 45-1. MS m / z (ESI): 247.6 [M+H] + .

[0736] Step 3: The preparation of E97 was carried out according to the synthetic method of Step 5 of Example E60. 1 H 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(d d,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),2.6 5(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] + .

[0737] Example 98: (6bR,10aS)-8-(3-(3-methoxypyridin-2-yl)propyl)-3-methyl-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-2(3H)-one

[0738]

[0739] E98 was prepared according to the synthesis method of 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=15.0,8.5 Hz,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] + .

[0740] Example 99: (6bR,10aS)-8-(3-(2-methoxyphenyl)propyl)-3-methyl-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-2(3H)-one

[0741]

[0742] The preparation was carried out according to the synthesis method of Example 3. 1 H 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] + .

[0743] Example 100: (6bR,10aS)-8-(3-(3-methoxypyridin-2-yl)propyl)-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-2(3H)-one

[0744]

[0745] E100 was prepared according to the synthesis method of 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] + .

[0746] Example 101: (6bR, 10aS)-8-(3-(3-methoxythiophen-2-yl)propyl)-3-methyl-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-2(3H)-one

[0747]

[0748] The preparation was carried out according to the synthesis method of Example 3. 1 H 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,3 H), 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] + .

[0749] Example 102: (6bR,10aS)-8-(3-(2,3-dihydrofuro[3,2-c]pyridin-7-yl)propyl)-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-2(3H)-one

[0750]

[0751] The preparation of E102 was carried out according to the synthesis method of Example E60. 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] + .

[0752] Example 103: 8-(3-(2,3-dihydrobenzofuran-7-yl)propyl)-4-fluoro-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-2(3H)-one

[0753]

[0754] The preparation was carried out according to the synthesis method of Example 83. 1 H NMR(500MHz,CD3OD)δ6.83-6.80(m,1H),6.73(d,J=10.0Hz,1H),6.61(t,J=10.0 Hz,1H),6.54(d,J=5.0Hz,1H),6.38(t,J=7.5Hz,1H),4.49(t,J=7.5Hz,2H),3.7 7(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] + .

[0755] Example 104: (5bR,9aS)-7-(3-(2,3-dihydrobenzofuran-7-yl)propyl)-5b,6,7,8,9,9a-hexahydroimidazo[4,5,1-hi]pyrido[4,3-b]indol-1(2H)-one

[0756]

[0757] Step 1: Preparation of 104-1: Refer to the synthesis method of step 3 of E45-1. MS m / z (ESI): 262.2 [M+H] + .

[0758] Step 2: The preparation of 104-2 was carried out according to the synthetic method of step 5 of E45-1. MS m / z (ESI): 190.3 [M+H] + .

[0759] Step 3: The preparation of 104-3 was carried out according to the synthetic method of E67-1 step 2. MS m / z (ESI): 350.2 [M+H] +

[0760] Step 4: 104-3 (140 mg, 0.4 mmol), DMAP (38 mg, 0.4 mmol), and pyridine (2 mL) were added to a 25 mL three-necked flask. The atmosphere was replaced with nitrogen three times, cooled to 0°C, and methyl chloroformate (38 mg, 0.4 mmol) was added. The mixture was reacted at 0°C for 1 h. Water and DCM were added, and the layers were separated. The aqueous phase was extracted once with DCM. The combined organic phases were washed three times with saturated sodium chloride, dried, and concentrated to obtain 104-4 (90 mg, white solid, yield: 55%). MS m / z (ESI): 408.6 [M+H] + .

[0761] Step 5: 104-4 (90 mg, 0.22 mmol) and toluene (2 mL) were added to a 25 mL three-necked flask, replaced with N2 three times, and 1M LiHMDS (0.9 mL, 0.9 mmol) was added and reacted at 75°C for 1 h. Water and EA were added, the layers were separated, the aqueous phase was extracted once with EA, the organic phases were combined, washed three times with saturated sodium chloride, dried, concentrated, and purified by prep-HPLC (eluent (v / v): acetonitrile / (water + 0.05% NH4HCO3) = 30%–70%) to give E104 (13 mg, yellow solid, yield: 15.7%).

[0762] 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),3.9 2(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] + .

[0763] Example 105: (6bR,10aS)-8-(2-((2,3-dihydrofuro[2,3-c]pyridin-7-yl)oxy)ethyl)-3-methyl-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-2(3H)-one

[0764]

[0765] Step 1: Furo[2,3-c]pyridin-7(6H)-one (120 mg, 0.89 mmol), bromoethanol (330 mg, 2.64 mmol), and anhydrous toluene (10 mL) were added to a 25 mL single-necked reaction flask. AgCO (730 mg, 2.6 mmol) and NaI (330 mg, 2.6 mmol) were then added, respectively. After addition, the atmosphere was purged with nitrogen three times, and the temperature was slowly raised to 115°C and stirred for 48 h. After completion of the reaction, the reaction mixture was filtered, the filtrate was evaporated to dryness under reduced pressure, and the crude product was purified by normal phase column chromatography (eluent gradient: 5% MeOH / DCM) to afford compound 105-2 (pale yellow oil, 60 mg, 42% yield). 1 H NMR (500MHz, CD3OD) δ7.93(d,J=2.1Hz,1H),7.86(d,J=5.5Hz,1H),7.26(d,J=5.5 Hz,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] +

[0766] Step 2: Preparation of 105-3: Refer to the synthetic method of Example E60, Step 2. MS m / z (ESI): 182.4 [M+H]+ .

[0767] Step 3: Preparation of 105-4: Refer to the synthetic method of Example E60, Step 3. MS m / z (ESI): 180.6 [M+H] + .

[0768] Step 4: Preparation of E105 Refer to the synthetic method of Step 4 of Example E60. 1 H 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),2.96-2.9 0(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] + .

[0769] Example 106: (6bR,10aS)-8-(3-(2,3-dihydrobenzofuran-4-yl)propyl)-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-2(3H)-one

[0770]

[0771] Step 1: Preparation of 106-1 follows the synthetic method of the fourth step of Reference Example E8.

[0772] Step 2: Preparation of E106: Refer to the synthesis method of the fifth step of Example E8. 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] + .

[0773] Example 107: (6bR,10aS)-8-(3-(5-hydroxy-2,3-dihydrobenzofuran-7-yl)propyl)-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-2(3H)-one

[0774]

[0775] The preparation of steps 1-5 was carried out according to the synthetic method of steps 1-5 of Example 86.

[0776] Step 6: Preparation of 107-6 refers to the synthesis method of the sixth step of Example 13

[0777] Step 7: Preparation of 107-7 refers to the synthesis method of step 6 of Example 7

[0778] Step 8: Compound 107-7 (30 mg, 0.07 mmol) and anhydrous dichloromethane (3 mL) were added to a 25 mL three-necked reaction flask. BBr (2.1 mL, 2.1 mmol) was added at -78°C. After addition, the temperature was slowly raised to -10°C and the reaction was stirred for 3 h. After completion of the reaction, LCMS analysis confirmed the reaction was complete. Ammonia (1 mL) was added to the reaction solution, which was concentrated and filtered, and then purified by prep-HPLC (eluent (v / v): acetonitrile / (water + 0.05% NH4HCO3) = 30%–70%) to afford compound E107 (5 mg, white solid, yield: 16.9%).

[0779] 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] + .

[0780] Example 108: (6bR, 10aS)-8-(3-(6-hydroxy-2,3-dihydrobenzofuran-7-yl)propyl)-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-2(3H)-one hydrochloride

[0781]

[0782] The preparation was carried out according to the synthetic method of Example 107. 1 H 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] + .

[0783] Example 109: (6bR, 10aS)-8-(3-(2,3-dihydrobenzofuran-7-yl)propyl)-1,1-dimethyl-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-2(3H)-one

[0784]

[0785] Step 1: Dissolve compound 45-1-4 (300 mg, 1.0 mmol) in DMF (10 mL), cool to 0°C in an ice-water bath, add sodium hydroxide (120 mg, 3.0 mmol), and stir at 0°C for 30 minutes. Then, add p-methoxybenzyl chloride (310 mg, 2.0 mmol), and stir at room temperature for 16 hours. After the reaction is complete as determined by LCMS, add water (20 mL) to the reaction solution, extract with EtOAc (2 x 25 mL), combine the organic phases, wash with saturated brine (1 x 25 mL), dry over anhydrous sodium sulfate, and evaporate to dryness under reduced pressure. The crude product is slurried with methyl tert-butyl ether to obtain compound 109-1 (white solid, 185 mg, 44% yield). MS m / z (ESI): 422.5 [M+H] +

[0786] Step 2: Compound 109-1 (150 mg, 0.36 mmol) was dissolved in THF (5 mL), cooled to -78°C, and LiHMDS (1.45 mL, 1.45 mmol) was added. After stirring at -78°C for 1 hour, iodomethane (200 mg, 1.42 mmol) was added and the mixture was warmed to room temperature and stirred for 18 hours. After completion of the reaction as determined by LCMS, water (15 mL) was added to the reaction solution, and the mixture was extracted with EtOAc (2 x 25 mL). The organic phases were combined, washed with saturated brine (1 x 25 mL), dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The crude product was purified by normal phase column chromatography (eluent gradient: 0-50% EtOAc / petroleum ether) to obtain compound 109-2 (yellow oil, 130 mg, yield 83%). MS m / z (ESI): 437.0 [M+H] +

[0787] Step 3: Compound 109-2 (240 mg, 0.55 mmol) was dissolved in THF (5 mL), cooled to -78°C, and n-BuLi (1 mL, 1.6 mmol) was added. The mixture was stirred at -78°C for 1 h, followed by the addition of iodomethane (235 mg, 1.6 mmol). The mixture was warmed to room temperature and stirred for 16 h. After completion of the reaction by LCMS, water (15 mL) was added to the reaction solution, and the mixture was extracted with EtOAc (2 x 25 mL). The organic phases were combined, washed with saturated brine (1 x 25 mL), dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The crude product was purified by normal phase column chromatography (eluent gradient: 0-50% EtOAc / petroleum ether) to obtain compound 109-3 (yellow oil, 66 mg, yield 26%). MS m / z (ESI): 450.5 [M+H] +

[0788] Step 4: Compound 109-3 (66 mg, 0.15 mmol) was dissolved in TFA (205 uL), and TfOH (90 mg, 0.6 mmol) was added. The mixture was stirred at room temperature for 3 h. After completion of the reaction by LCMS, the reaction mixture was diluted with DCM (20 mL), washed with saturated sodium bicarbonate (20 mL), then with saturated brine (20 mL), dried over anhydrous sodium sulfate, and dried under reduced pressure. HBr acetic acid solution (1.5 mL) was added, heated to 50°C, stirred for 3 h, and concentrated. The crude product was purified by prep-HPLC (eluent (v / v): acetonitrile / (water + 0.05% NH4HCO3) = 30%–70%) to afford compound 109-4 (a colorless oil, 18 mg, 46% yield). MS m / z (ESI): 258.4 [M+H] +

[0789] Step 5: Prepare according to the synthetic method of step 5 in 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),2.47-2.3 5(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] + .

[0790] Example 110: (6bR, 10aS)-8-(3-(2,3-dihydrofuro[3,2-b]pyridin-7-yl)propyl)-3-methyl-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-2(3H)-one

[0791]

[0792] Step 1: Compound 7-chlorofuro[3,2-B]pyridine (500 mg, 3.3 mmol), (E)-ethyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)acrylate (1.47 g, 6.5 mmol), Pd(dtbpf)Cl2 (425 mg, 0.65 mmol), and K2CO3 (1.4 g, 9.8 mmol) were added to a three-necked flask containing dioxane (6 mL) and water (1 mL). The atmosphere was replaced with nitrogen three times and the reaction was carried out at 110°C for 16 h. After the reaction was completed by LCMS, water and EA were added, the layers were separated, and the aqueous phase was extracted twice with EA. The organic phases were combined, washed twice with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by normal phase column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain 110-1 (colorless oil, 600 mg, yield 84%).

[0793] Step 2: Preparation of 110-2 follows the synthetic method of the second step in Reference Example 1.

[0794] Step 3: Preparation of 110-3 follows the synthesis method of the third step in Reference Example 1.

[0795] Step 4: Preparation of 110-4 follows the synthesis method of the fourth step in reference example 3.

[0796] Step 5: Preparation of E110 follows the synthesis method of the fifth step in Reference Example 3. 1 H 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] + .

[0797] Example 111: (6bR, 10aS)-8-(3-(2,3-dihydrofuro[3,2-b]pyridin-7-yl)propyl)-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-2(3H)-one

[0798]

[0799] The preparation was carried out according to the synthetic method of Example 110. 1 H 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] + .

[0800] Example 112: (6bR, 10aS)-8-(3-(4-hydroxy-2,3-dihydrobenzofuran-7-yl)propyl)-6b, 7, 8, 9, 10, 10a-hexahydro-1H-pyrido [3', 4': 4, 5] pyrrolo [1, 2, 3-de] quinoxalin-2 (3H) -one

[0801]

[0802] The preparation was carried out according to the synthetic method of Example 107. 1 H 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] +

[0803] Example 114: (6bR,10aS)-8-(3-(2,3-dihydrobenzofuran-7-yl)propyl)-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-2(3H)-one-1,1-d2

[0804]

[0805] Step 1: Deuterated acetyl chloride (1.4 g, 17.2 mmol), thionyl chloride (5 mL), and NCS (3.5 g, 25.7 mmol) were added to a 25 mL single-necked flask. Two drops of deuterated hydrochloric acid (35% wt in D2O) were then added. The mixture was slowly heated to 85°C and stirred for 4 h under a nitrogen atmosphere. The reaction mixture was then cooled to 0°C and anhydrous ethanol (4 mL) was slowly added dropwise. Stirring was continued at 0°C for 0.5 h. After the reaction was complete, water (20 mL) was added to the mixture, and the mixture was extracted with n-heptane (20 mL x 3). The organic phases were combined and washed with saturated NaHCO3 (20 mL x 1) and saturated brine (50 mL x 1), dried over anhydrous sodium sulfate, and the n-heptane removed under reduced pressure to yield compound 114-1 (yellow oil, 600 mg, 28% yield). The crude product was used directly in the next step without further purification.

[0806] Step 2: Preparation of compound 114-2: Refer to the synthesis method of step 2 in Example 45-1. MS m / z (ESI): 514.8 [M+H] + .

[0807] Step 3: Preparation of compound 114-3: Refer to the synthesis method of step 3 in Example 45-1. MS m / z (ESI): 304.4 [M+H]+ .

[0808] Step 4: Preparation of compound 114-4: Refer to the synthesis method of step 5 in Example 45-1. MS m / z (ESI): 232.5 [M+H] + .

[0809] Step 5: Preparation of Compound E114: Refer to the synthetic method of Step 5 in Example E60. 1 H 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] + .

[0810] Example 116: 6bR, 10aS)-8-(3-(2,3-dihydrothieno[3,4-b]furan-6-yl)propyl)-3-methyl-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-2(3H)-one

[0811]

[0812] 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 to a 250 mL three-necked flask and stirred at 80°C for 16 h. After completion of the reaction by TLC, water (80 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (80 mL x 3). The solution was then washed with brine (50 mL x 3). The organic phase was concentrated and purified by normal phase column chromatography (petroleum ether:ethyl acetate = 5:1) to afford 116-1 as a white solid, 6.2 g, 85% yield.

[0813] Step 2: 116-1 (3.5 g, 10.17 mmol) and anhydrous THF (35 mL) were added to a 250 mL three-necked flask and cooled to -78°C. Then, n-BuLi (2.5 M in hexanes, 4.5 mL, 11.19 mmol) was slowly added dropwise. After completion of the dropwise addition, the mixture was stirred at -78°C for 2 h. After completion of the reaction, saturated aqueous ammonium chloride (40 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (60 mL x 3) and washing with brine (50 mL x 3). The organic phase was concentrated and purified by normal phase column chromatography (petroleum ether:ethyl acetate = 5:1) to afford 116-2 (white solid, 400 mg, yield 21%). MS m / z (ESI): 185.2 [M+H] + .

[0814] Step 3: Preparation of 116-3 follows the synthesis method of the third step in Reference Example 1.

[0815] Step 4: Preparation of 116-4 follows the synthesis method of the fourth step in reference Example 8.

[0816] Step 5: Preparation of 116-5 follows the synthetic method of the first step in Reference Example 1.

[0817] Step 6: Preparation of 116-6 follows the synthetic method of the second step in Reference Example 1.

[0818] Step 7: Preparation of 116-7 follows the synthesis method of the third step in Reference Example 1.

[0819] Step 8: The preparation of 116-8 follows the synthetic method of the fourth step in reference Example 8.

[0820] Step 9: Preparation of E116 follows the synthesis method of step 5 of Example 8. 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] + .

[0821] Example 117: (6bR, 10aS)-8-(3-(2,3-dihydrobenzofuran-7-yl)propyl)-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-1,2(3H)-dione

[0822]

[0823] Step 1: 45-1-4 (60 mg, 0.2 mmol), NaIO4 (120 mg, 0.56 mmol), RuO2 (15 mg, 0.11 mmol), and CCl4 (5 mL) were added to a 50 mL single-necked flask and stirred at room temperature for 80 h. After completion of the reaction, water and EA were added, the layers were separated, and the aqueous phase was extracted twice with EA. The combined organic phases were washed three times with saturated sodium chloride and dried over anhydrous sodium sulfate to obtain 117-1 (gray solid, 40 mg, 63% yield). The crude product was used directly in the next reaction without further purification. MS m / z (ESI): 316.5 [M+H] + .

[0824] Step 2: Preparation of E117-2 Refer to the synthesis method of the fifth step of Example 45-1.

[0825] Step 3: Preparation of E117 follows the synthesis method of the fifth step in reference Example 8. 1H NMR (500MHz, CDCl3) δ10.05 (s, 1H), 7.16 (t, J = 7.7Hz, 1H), 7.10 (dt, J = 7.5, 1.1Hz, 1H), 7.0 6-7.01(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] + .

[0826] Example 118: (6bR,10aS)-8-(3-(2,3-dihydrobenzofuran-7-yl)propyl)-1-methyl-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-2(3H)-one

[0827]

[0828] Step 1: Dissolve ethyl (4aS,9bR)-6-bromo-1,3,4,4a,5,9b-hexahydro-2H-pyrido[4,3-b]indole-2-carboxylate (320 mg, 1.0 mmol) in dioxane (5 mL). Add 2-bromopropionamide (228 mg, 1.5 mmol), KI (165 mg, 1.0 mmol), and DIEA (260 mg, 2.0 mmol) sequentially. Heat to 105°C and stir for 16 h. Cool the reaction mixture to room temperature, add EtOAc (50 mL), filter, and evaporate to dryness. The crude product is purified by normal phase column chromatography (eluent gradient: 20-100% EtOAc / petroleum ether) to obtain compound 118-1 (colorless oil, 180 mg, 45% yield). MS m / z (ESI): 398.5 [M+H] +

[0829] Step 2: Dissolve compound 118-1 (145 mg, 0.37 mmol) in dioxane (3 mL). Add CuI (18 mg, 0.092 mmol), KCO (112 mg, 0.82 mmol), and N,N-dimethylethylenediamine (24 μL, 0.22 mmol) sequentially. Nitrogen was then applied to the mixture, heated to 110°C, and stirred for 18 h. The reaction mixture was cooled to room temperature, filtered, and dried under reduced pressure. The crude product was purified by normal phase column chromatography (eluent gradient: 20-100% EtOAc / Petroleum ether) to afford compound 118-2 (yellow oil, 86 mg, 73% yield). MS m / z (ESI): 317.8 [M+H] + .

[0830] Step 3: Compound 118-2 (86 mg, 0.273 mmol) was added to HBr acetic acid solution (2.0 mL), heated to 50°C, stirred for 3 h, and concentrated to obtain compound 118-3 (yellow oil, 80 mg, crude product). MS m / z (ESI): 244.4 [M+H] +

[0831] Step 4: Prepare according to the synthetic method of step 5 in reference example 8. 1 H 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] + .

[0832] Example 119: (6bR,10aS)-8-(2-((2,3-dihydrofuro[2,3-c]pyridin-7-yl)oxy)ethyl)-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-2(3H)-one

[0833]

[0834] The preparation of E119 was carried out according to the synthetic method of Example E105. 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] +

[0835] Example 120: (6bR, 10aS)-8-(3-(2,3-dihydrobenzofuran-4-yl)propyl)-3-methyl-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-2(3H)-one

[0836]

[0837] The preparation was carried out according to the synthetic method of Example 106. 1 H 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,2 H),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] + .

[0838] 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

[0839]

[0840] The preparation of E121 followed the synthetic method of step 2 of reference example E67-1. 1 H 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] + .

[0841] Example 122: (6bR, 10aS)-8-(2-(Benzofuran-7-yl)ethyl)-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-2(3H)-one

[0842]

[0843] Step 1: Benzofuran-7-carbaldehyde (1.0 g, 6.85 mmol), methyltriphenylphosphonium bromide (3.0 g, 8.22 mmol), and anhydrous THF (20 mL) were added to a 100 mL three-necked flask. Anhydrous t-BuOK (1.15 g, 10.28 mmol) was added portionwise under a nitrogen atmosphere (i.e., an ice-water bath). After addition, the mixture was allowed to stir overnight at room temperature. After TLC, the reaction mixture was added with saturated aqueous NH4Cl (50 mL). The mixture was extracted with ethyl acetate (50 mL x 2). The organic phases were combined, washed with saturated brine (50 mL x 1), dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The crude product was purified by column chromatography (EtOAc / PE = 0-5%) to afford 122-1 as a pale yellow oil (0.70 g, 71% yield).

[0844] Step 2: Compound 122-1 (700 mg, 4.86 mmol) and anhydrous THF (15 mL) were added to a 100 mL three-necked flask. A 2M B2H6 / dimethyl sulfide solution (4 mL) was slowly added dropwise under N2 and an ice-water bath. After completion, the mixture was stirred at room temperature for 5 h. Subsequently, a 10% aqueous NaOH solution (5 mL) and a 30% H2O2 solution (0.5 mL) were slowly added dropwise under an ice-water bath. After completion, the mixture was stirred at room temperature overnight. After TLC, water (30 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL x 2). The organic phases were combined, washed with saturated brine (30 mL x 1), dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The crude product was purified by column chromatography (EtOAc / PE = 0-10%) to obtain compound 122-2 (pale yellow oil, 400 mg, yield: 50%). 1 H 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).

[0845] Step 3: At room temperature, 122-2 (100 mg, 0.62 mmol) and anhydrous DCM (10 mL) were added to a 50 mL single-necked flask. Dess-Martin reagent (0.32 g, 0.74 mmol) was then added and stirred at room temperature for 1 hour. After completion of the reaction by TLC, the reaction solution was filtered and the filtrate was slowly added dropwise with saturated NaHCO₃ solution to adjust the pH to alkaline. The filtrate was extracted with DCM (20 mL x 2). The organic phases were combined, washed with saturated brine (20 mL x 1), dried over anhydrous sodium sulfate, and dried under reduced pressure to afford crude compound 112-3 (90 mg, 90% yield). The crude product was used in the next step without further purification.

[0846] Step 4: Preparation of Compound E122: Refer to the synthetic method of Step 5 in Example E60. 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),2.9 1-2.76(m,2H),2.58-2.42(m,1H),2.20-2.06(m,2H),2.04-2.00(m,1H).MSm / z(ESI):374.6[M+H] + .

[0847] Example 123: (6bR,10aS)-8-(2-(Benzofuran-7-yl)ethyl)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline

[0848]

[0849] The preparation of E123 was carried out according to the synthetic method of Example E122. 1 H 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] + .

[0850] Example 124: (6bR,10aS)-8-(3-(Benzofuran-7-yl)propyl)-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-2(3H)-one

[0851]

[0852] Step 1: Preparation of 124-1 follows the synthetic method of the fourth step of Reference Example E8.

[0853] Step 2: Preparation of E124: Refer to the synthesis method of the fifth step of Example E8. 1 H 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] + .

[0854] Example 125: (6bR,10aS)-8-(3-(2,3-dihydrobenzofuran-7-yl)propyl)-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-2(3H)-thione

[0855]

[0856] Compound E67-1 (40 mg, 0.103 mmol) was dissolved in THF (3 mL), and Lawesson's reagent (62 mg, 0.15 mmol) was added. The reaction mixture was stirred at 70°C for 1 hour, concentrated in vacuo, and separated by adding ethyl acetate (25 mL) and water (25 mL). The organic phase was washed with water and concentrated to obtain the crude product. The crude product was concentrated, filtered, and purified by prep-HPLC (eluent (v / v): acetonitrile / (water + 0.05% NH4HCO3) = 30%–70%) to afford compound E125 (7.8 mg, white solid, 18% yield). 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=15.0 Hz,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]+.

[0857] Example 126: (6bR,10aS)-8-(3-(2,3-dihydrobenzofuran-7-yl)propyl)-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline

[0858]

[0859] The preparation of E126 was carried out according to the synthetic method of Example E45-1. 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] + .

[0860] Example 127: 2-((6bR,10aS)-8-(3-(2,3-dihydrobenzofuran-7-yl)propyl)-1,2,6b,7,8,9,10,10a-octahydro-3H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-3-yl)ethan-1-ol

[0861]

[0862] Step 1: Dissolve compound 66-1 (50 mg, 0.16 mmol) in CH3CN (5 mL), add bromoethanol (98 mg, 0.8 mmol) and cesium carbonate (204 mg, 0.63 mmol) sequentially, and heat to 80°C with stirring for 16 h. The reaction solution was cooled to room temperature, filtered, and the crude product was purified on a reverse-phase C18 column to obtain compound 127-1 (colorless oil, 18 mg, yield 31.6%). MS m / z (ESI): 360.1 [M+H] +

[0863] Step 2: Dissolve compound 127-1 (25 mg, 0.07 mmol) in methanol (3 mL), then add HCl / dioxane (3 mL, 12 mmol) and stir at room temperature for 2 h. Drain the reaction mixture to obtain compound 127-2 (brown solid, 20 mg, hydrochloride salt). MS m / z (ESI): 259.8 [M+H] +

[0864] Step 3: Preparation of E127: Refer to the synthetic method of Step 2 in Example E67-1. 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,1 H),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),2.6 6-2.57(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] + .

[0865] Example 128: (6bR,10aS)-8-(3-(2,3-dihydrobenzofuran-7-yl)propyl)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-5-carbonitrile

[0866]

[0867] Step 1: 45-1-4 (600 mg, 2.0 mmol) and 6 mL of DMF were added to a 25 mL single-necked flask. The atmosphere was replaced with nitrogen three times, cooled to 0°C, and NBS (356 mL, 2.0 mmol) was added. The reaction was allowed to proceed at 0°C for 0.5 h. LC-MS indicated the reaction was complete. Saturated NaHCO3 solution and EA were added, and the layers were separated. The aqueous phase was extracted three times with EA. The organic phases were combined, washed three times with saturated sodium chloride, dried, and concentrated to afford 128-1 (750 mg, crude product). MS m / z (ESI): 380.2, 382.2 [M+H] + .

[0868] Step 2: 128-1 (750 mg, 2.0 mmol), CH3I (5.1 g, 36.0 mmol), K2CO3 (552 mg, 4.0 mmol), and acetonitrile (20 mL) were added to a 100 mL single-necked flask. The atmosphere was replaced with N2 three times, the temperature was raised to 80°C, and the reaction was allowed to proceed for 16 h. LC-MS showed the reaction was complete. The solvent was concentrated to dryness, and water and EA were added. The layers were separated, and the aqueous phase was extracted once with EA. The organic phases were combined, washed three times with saturated sodium chloride, dried, and concentrated to afford 128-2 (750 mg, crude product). MS m / z (ESI): 394.3, 396.4 [M+H] + .

[0869] Step 3: Preparation of 128-3 refers to the synthetic method of E45-1 Step 4. MS m / z (ESI): 380.2, 382.2 [M+H] + .

[0870] Step 4: Add 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) to a 25 mL microwave tube, heat to 150°C, and react for 1.5 h. Add water and EA, separate the layers, extract the aqueous phase three times with EA, combine the organic phases, wash three times with saturated sodium chloride, dry, and concentrate to give 128-4 (140 mg, crude). MS m / z (ESI): 308.2, 310.2 [M+H] + .

[0871] Step 5: Preparation of 128-5 refers to the synthetic method of E45-2 Step 2. MS m / z (ESI): 408.2, 410.2 [M+H] + .

[0872] Step 6: Dissolve compound 128-5 (18.0 mg, 0.04 mmol) in DMF (2.0 mL). Add tetrakis(triphenylphosphine)palladium (1.20 g, 3.45 mmol), zinc cyanide (5.18 mg, 0.044 mmol), and zinc powder (0.860 mg, 0.013 mmol) under nitrogen. Microwave and stir at 150°C for 3 h. After completion of the reaction, as determined by TLC, concentrate under reduced pressure and purify with normal phase chromatography to obtain compound 128-6 (yellow solid, 150 mg, 74% yield). MS m / z (ESI): 355.2. [M+H] + .

[0873] Step 7: Dissolve 128-6 (15.0 mg, 0.04 mmol) in dichloromethane (3.0 mL) and add trifluoroacetic acid (1.0 mL). React at room temperature for 1 h. Filter and concentrate to obtain compound 128-7 (brown oil, 12.0 mg, 85% yield). MS m / z (ESI): 255.2. [M+H] + .

[0874] Step 8: Under nitrogen, compound 128-7 (15.0 mg, 0.05 mmol), 2-(2,3-dihydro-1-benzofuran-6-yl)acetaldehyde (9.57 mg, 0.05 mmol), and acetic acid (0.052 mL, 0.93 mmol) were dissolved in THF (2 mL), and sodium cyanoborohydride (12.3 mg, 0.15 mmol) was added. The reaction was incubated at 0°C for 2 h. After TLC, the reaction was completed, filtered, and purified by reverse phase preparative chromatography (eluent (v / v): acetonitrile / (water + 0.05% NH4HCO3) = 30%–70%) to afford E128 (white solid, 1.0 mg, 4% yield). 1 HNMR (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] + .

[0875] Example 129: 8-(3-(2,3-dihydrobenzofuran-7-yl)propyl)-5-methoxy-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline

[0876]

[0877] Step 1: Dissolve glycine methyl ester hydrochloride (7.2 g, 57.9 mmol) and K2CO3 (4.72 mg, 34.2 mmol) in 90 mL of NMP, add 1-fluoro-4-methoxy-2-nitrobenzene (9.0 g, 52.6 mmol), and heat to 80°C for 16 h. TLC confirmed the reaction was complete. Water and EtOAc were added, and the layers were separated. The aqueous phase was extracted with EtOAc. The combined organic phases were washed three times with saturated sodium chloride solution, dried, concentrated, and purified by normal phase silica gel chromatography (PE / EtOAc = 5 / 1) to afford compound 129-1 (2.2 g, yellow solid, 17% yield). MS m / z (ESI): 240.4 [M+H] + .

[0878] Step 2: Dissolve 129-1 (2.2 g, 9.17 mmol) in 30 mL of methanol, add 1 g of 10% Pd / C, stir at room temperature for 16 h, filter and concentrate to obtain 129-2 (1.6 g, off-white solid, yield 98%), which was used directly in the next step. MS m / z (ESI): 179.2 [M+H] + .

[0879] Step 3: The preparation of 129-3 was carried out according to the synthetic method of step 1 of E42. MS m / z (ESI): 208.3 [M+H] + .

[0880] Step 4: Dissolve compound 129-3 (320 mg, 1.54 mmol) in 10 mL of methanol. Add ammonium chloride (447 mg, 7.7 mmol) at room temperature, followed by zinc powder (492 mg, 7.7 mmol). Stir at room temperature for 3 h. Filter and concentrate to obtain compound 129-4 (220 mg, off-white solid, 74% yield), which was used directly in the next step. MS m / z (ESI): 194.4 [M+H] + .

[0881] Step 5: The preparation of 129-5 was carried out according to the synthetic method of step 3 of E42. MS m / z (ESI): 357.4 [M+H] + .

[0882] Step 6: The preparation of 129-6 was carried out according to the synthetic method of step 1 of E73-1. MS m / z (ESI): 371.5 [M+H] + .

[0883] Step 7: The preparation of 129-7 was carried out according to the synthetic method of step 4 of E42. MS m / z (ESI): 273.3 [M+H] + .

[0884] Step 8: The preparation of 129-8 was carried out according to the synthetic method of step 4 of E45. MS m / z (ESI): 259.4 [M+H] + .

[0885] Step 9: The preparation of E129 was carried out according to the synthetic method of Step 5 of E42. 1 H 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=1 0.0Hz,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] + .

[0886] Example 130: 8-(3-(2,3-dihydrobenzofuran-7-yl)propyl)-1,2,6b,7,8,9,10,10a-octahydropyrido[4,3-b][1,4]thiazin[2,3,4-hi]indole 3,3-dioxide

[0887]

[0888] Step 1: Compound E68 (12 mg, 0.031 mmol) was dissolved in DCM (3 mL), cooled to ℃, and m-CPBA (12 mg, 0.067 mmol) was added. The reaction was stirred at room temperature for 2 hours and concentrated in vacuo to yield the crude product. The crude product was concentrated, filtered, and purified by prep-HPLC (eluent (v / v): acetonitrile / (water + 0.05% NH4HCO3) = 30%–70%) to afford compound E130 (5.0 mg, white solid, 38% yield). 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] + .

[0889] Example 131: 1-((6bR,10aS)-8-((2-(2,3-dihydrobenzofuran-7-yl)cyclopropyl)methyl)-1,2,6b,7,8,9,10,10a-octahydro-3H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-3-yl)ethan-1-one

[0890]

[0891] Step 1: Compound 122-2 (1.6 g, 12.5 mmol) was dissolved in toluene (20 mL). Ethyl diazoacetate (2.2 g, 18.75 mmol), NMI (3.08 g, 37.5 mmol), and Co(II)(Co(TPP) (84 mg, 0.125 mmol) were added under nitrogen. The reaction was stirred at 80°C for 48 h. After completion of the reaction, the mixture was concentrated under reduced pressure and purified by normal phase purification to obtain compound 131-1 (purple solid, 1 g, yield 34.5%). MS m / z (ESI): 233.1. [M+H] + .

[0892] Step 2: The preparation of 131-2 was carried out according to the synthetic method of Step 3 of E60.

[0893] Step 3: Preparation of 131-3 refers to the synthesis method of step 4 of E60

[0894] Step 4: Preparation of E131 Refer to the synthesis method of step 45 of E60 1H NMR (500MHz, CDCl3) δ7.01(d,J=7.2Hz,1H),6.88(d,J=7.3Hz,2H),6.76(t,J=7.5H z,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=50.9H z, 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] + .

[0895] Example 132: 1-((6bR,10aS)-8-(3-(2,3-dihydrobenzofuran-7-yl)-2-hydroxypropyl)-1,2,6b,7,8,9,10,10a-octahydro-3H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-3-yl)ethan-1-one

[0896]

[0897] Step 1: Preparation of 132-1 refers to the synthetic method of E45-2 Step 3. MS m / z (ESI): 358.2 [M+H] + .

[0898] Step 2: Preparation of 132-2 refers to the synthetic method of E45-2 step 4. MS m / z (ESI): 258.2 [M+H] + .

[0899] Step 3: 132-2 (50 mg, 0.19 mmol), 69-2 (69 mg, 0.4 mmol), K2CO3 (52 mg, 0.4 mmol), and 2 mL of DMF were added to a 25 mL single-necked flask. The atmosphere was purged with N2 three times, and the temperature was raised to 120°C for 16 h. Water and EA were added, and the layers were separated. The aqueous phase was extracted three times with EA. The combined organic phases were washed three times with saturated sodium chloride, dried, and concentrated to afford E132 (30 mg, crude product). 15 mg of the crude product was purified by prep-HPLC (eluent (v / v): acetonitrile / (water + 0.05% NH4HCO3) = 30%–70%) to afford 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] + .

[0900] Example 133: (6bR, 10aS)-8-((2,3-dihydrobenzofuran-7-yl)methyl)-6b, 7, 8, 9, 10, 10a-hexahydro-1H-pyrido [3', 4': 4, 5] pyrrolo [1, 2, 3-de] quinoxalin-2 (3H) -one

[0901]

[0902] E67-1-1 (50 mg, 0.16 mmol) was dissolved in MeOH (2.00 mL), and sodium cyanoborohydride (30 mg, 0.484 mmol) was added. The mixture was stirred at room temperature for 20 minutes, followed by the addition of 2,3-dihydrobenzofuran-7-carbaldehyde (47 mg g, 0.322 mmol). The reaction was continued at room temperature for 2 hours. LCMS confirmed the reaction was complete, and HPLC purification (NH3.H2O system) afforded compound E133 (white solid, 22 mg, 37.7% yield). 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).MSm / z(ESI):362.4[M+H]+

[0903] Example 134: (6bR, 10aS)-8-(2-(2,3-dihydrobenzofuran-7-yl)ethyl)-6b, 7, 8, 9, 10, 10a-hexahydro-1H-pyrido [3', 4': 4, 5] pyrrolo [1, 2, 3-de] quinoxalin-2 (3H) -one

[0904]

[0905] Preparation of E134: Reference Example E67-1, Step 2. 1H NMR (400 MHz, CDCl3) δ 7.39 (s, 1H), 7.04 (d, J = 7.2 Hz, 1H), 6.94 (d, J = 7.3 Hz, 1H), 6.85 (d, J = 7.3 Hz, 1H), 6.79-6.70 (m, 2H), 6.57 (d, J = 7.8 Hz, 1H), 4.52 (t, J = 8.7 Hz, 2H), 3.97 (d, J = 14.6 Hz, 1H). H),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]+.

[0906] Example 135: (6bR, 10aS)-8-(4-(2,3-dihydrobenzofuran-7-yl)butyl)-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-2(3H)-one

[0907]

[0908] Step 1: Dissolve 7-bromobenzofuran (600 mg, 3 mmol) and 3-butyn-1-ol (420 mg, 6 mmol) in DMF (5 mL). Add Et3N (5 mL), CuI (114 mg, 0.6 mmol), and Pd(PPh3)2Cl2 (210 mg, 0.3 mmol) sequentially with stirring. Stir the mixture at 90°C under nitrogen for 16 hours, and the reaction is complete. Pour the reaction mixture into ice water (30 mL), and the aqueous phase is extracted with ethyl acetate (30 mL x 2). The organic layer is washed with brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated. Column chromatography (ethyl acetate / petroleum ether: 0% to 50%) afforded compound 135-1 (white solid, 520 mg, 92% yield). MS m / z (ESI): 189.2 [M+H]+.

[0909] Step 2: Compound 135-1 (360 mg, 2 mmol) was dissolved in MeOH (10 mL). Wet 20% Pd(OH)2 / C (50 mg) was added under nitrogen and stirred. The atmosphere was replaced with hydrogen three times. The reaction was stirred at 25°C under hydrogen for 16 hours. The reaction was completed. The reaction mixture was filtered and concentrated to obtain product 135-2 (colorless oil, 190 mg, yield: 50%). MS m / z (ESI): 193.3 [M+H].

[0910] Step 3: 135-2 was dissolved in DCM (5.0 mL) and Dess-Martin periodinane (390 mg, 0.91 mmol) was added. The reaction was allowed to proceed at 25°C for 1 h. LCMS confirmed the reaction was complete. Water was added, and the mixture was extracted with EA. The mixture was dried over sodium sulfate, filtered, concentrated, and purified on a silica gel column (EA / PE = 5%) to afford compound 135-3 (white solid, 35 mg, yield 35.4%). MS m / z (ESI): 162.2, [M+H].

[0911] Step 4: Preparation of E135: Refer to the synthetic method of Step 2 in Example E67-1. 1H NMR (400MHz, CDCl3) δ7.40 (s, 1H), 7.03 (d, J = 7.2Hz, 1H), 6.92 (d, J = 7.6Hz, 1H), 6.8 3(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...

Claims

1. A tetracyclic compound as shown in Formula I or a pharmaceutically acceptable salt thereof: The carbon atom with "*" represents a chiral carbon atom, which is in S configuration, R configuration or a mixture thereof; The carbon atom with "#" indicates a chiral carbon atom, which is in S configuration, R configuration or a mixture thereof; X 1 For-NR X1 -、-O-、-CR X2 R X3 -, -S-, -S(O)- or -S(O)2-; R X1 is H, C1-C6 alkyl, or one or more R X1-1 Substituted C1-C6 alkyl, -C(O)-C1-C6 alkyl, or "a 3-12-membered heterocycloalkyl group having 1, 2 or 3 heteroatoms selected from N, O and S"; R X1-1 independently OH; R X2 and R X3 are independently H or C1-C6 alkyl; X 2 N or CR X4 ; R X4 is H or C1-C6 alkyl; X 3 N or CR 1-1 ; X 4 N or CR 1-2 ; X 5 N or CR 1-3 ; R 1-1 , R 1-2 and R 1-3 are independently H, CN, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C1-C6 haloalkoxy; L is -(CR L1 R L2 )n1-, -(CR L1 R L2 )n2-Y 1 -(CR L1 R L2 )n3- or -(CR L1 R L2 )n4-Y 2 -(CR L1 R L2 )n5-; R L1 and R L2 are independently H or C1-C6 alkyl; n1 is 1, 2, 3 or 4; Y 1 is -O-, -NR L3 -, -C(O)-, -CR L4 R 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≡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 are independently H or C1-C6 alkyl; R L4 is H or halogen; R L5 is halogen, OH or C1-C6 alkoxy; R L6 and R L7 are independently H or halogen; R 2 are independently C1-C6 alkyl, -C(O)-C1-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", C6-C 10 Aryl or C3-C6 cycloalkyl; And when L is -(CR L1 R L2 )n1-、-(CR L1 R L2 )n2-O-or-(CR L1 R L2 )n2-C(O)-, for R 3 are independently oxo (=O), C1-C6 alkyl, C1-C6 alkoxy, -NR 4 R 5 、-C(O)R 6 、-SR 7 、-S(O)2R 8 , halogen, one or more R 9 Substituted C1-C6 alkoxy, one or more R 10 Substituted C1-C6 alkyl, CN, "a 3-12 membered heterocycloalkyl group having 1, 2 or 3 heteroatoms selected from N, O and S" or -OR 11 ; R 4 are independently H or C1-C6 alkyl; R 5 are independently H, C1-C6 alkyl or -C(O)R 5-1 ; R 6 , R 5-1 , R 7 and R 8 are independently C1-C6 alkyl; R 9 and R 10 are independently OH, -NR 4 R 5 or halogen; R 11 H or "a 5-10 membered heteroaryl group having 1, 2 or 3 heteroatoms selected from N, O and S"; m3 is 0, 1, 2, 3 or 4.

2. The tetracyclic compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: It meets one or more of the following conditions: (1)R X2 and R X3 independently H; (2)R X4 is H; (3)X 5 CR 1-3 ; (4)R 1-1 , R 1-2 and R 1-3 are independently H, CN or C1-C6 alkoxy; (5)R L1 and R L2 independently H; (6) n1 is 1, 2 or 3; (7)Y 1 -O-, -NR L3 -、-C(O)-、-CR L4 R L5 -or (8) n2 is 0, 1 or 2; (9) n3 is 0, 1 or 2; (10) n2+n3=2; (11)Y 2 -C≡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 a halogen; (17)R L6 and R L7 independently H; (18)R 2 are independently oxo; (19) m2 is 0 or 1; (20) When L is -(CR L1 R L2 )n1-、-(CR L1 R L2 )n2-O-or-(CR L1 R L2 )n2-C(O)-, for (21)R 3 are independently oxo (=O), C1-C6 alkoxy, -NR 4 R 5 、-C(O)R 6 、-SR 7 、-S(O)2R 8 , halogen, one or more R 9 Substituted C1-C6 alkoxy, one or more R 10 Substituted C1-C6 alkyl, CN, "a 3-12 membered heterocycloalkyl group having 1, 2 or 3 heteroatoms selected from N, O and S" or -OR 11 ; (22)R 4 independently H; (23)R 5 are independently H or -C(O)R 5-1 ; (24)R 9 are independently halogen; and (25)m3 is 0 or 1.

3. The tetracyclic compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: It meets one or more of the following conditions: (1)R 1-1 and R 1-3 For H, R 1-2 is H, CN or C1-C6 alkoxy; (2) n1 is 3; (3)Y 1 -C(O)- or -CR L4 R 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 are independently C1-C6 alkoxy, 9 Substituted C1-C6 alkoxy or halogen; (11)R 5 are independently H; and (12)m3 is 0.

4. The tetracyclic compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: It meets one or more of the following conditions: (1) The "C1-C6 alkyl" in each of "C1-C6 alkyl", "substituted C1-C6 alkyl" and "-C(O)-C1-C6 alkyl" is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; (2) The "C1-C6 alkoxy" in each "C1-C6 alkoxy" and "substituted C1-C6 alkoxy" is independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy; (3) each "3-12-membered heterocycloalkyl group having one, two or three heteroatoms selected from the group consisting of N, O and S" is independently "5-6-membered heterocycloalkyl group having one or two heteroatoms selected from the group consisting of N and O"; (4) each halogen is independently F, Cl, Br or I; (5) In ring A, the "9-12 membered bicyclic heterocyclic group having 1, 2 or 3 heteroatoms selected from N, O and S" is Among them, ring A 1 are independently phenyl or pyridyl, ring A 2 are independently "a 5-6 membered heterocycloalkyl group having one or two heteroatoms selected from N and O, and having one or two heteroatoms" or "a 5-6 membered heteroaryl group having one or two heteroatoms selected from N and O, and having one or two heteroatoms"; for example, ring A 2 are independently "a 5-membered heterocycloalkyl group having 1 or 2 heteroatoms and a heteroatom selected from O" or "a 5-6-membered heteroaryl group having 1 or 2 heteroatoms and a heteroatom selected from N and O"; (6) In ring A, the "5-6 membered monocyclic heterocyclic group having 1, 2 or 3 heteroatoms selected from N, O and S" is "5-6 membered monocyclic heteroaryl having 1 or 2 heteroatoms selected from N and S" or "5-6 membered monocyclic heterocycloalkyl having 1 or 2 heteroatoms selected from N", for example, pyridyl (e.g. ), thienyl (e.g. ) or piperidinyl (e.g. ); (7) In ring A, the C6-C 10 Aryl is phenyl or naphthyl; (8) In ring A, the C3-C6 cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; (9) each "5-10 membered heteroaryl group having 1, 2 or 3 heteroatoms selected from the group consisting of N, O and S" is independently "5-6 membered heteroaryl group having 1 or 2 heteroatoms selected from the group consisting of N"; and (10) for and / or 5. The tetracyclic compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: It meets one or more of the following conditions: (1) "C1-C6 alkyl" in each of "C1-C6 alkyl", "substituted C1-C6 alkyl" and "-C(O)-C1-C6 alkyl" is independently methyl or ethyl; (2) The "C1-C6 alkoxy" in each "C1-C6 alkoxy" and "substituted C1-C6 alkoxy" is independently methoxy or ethoxy; (3) Each "3-12 membered heterocycloalkyl group having one, two or three heteroatoms selected from N, O and S" is independently a piperidinyl group (e.g. ), morpholinyl or oxetane (e.g. ); (4) each halogen is independently F or Cl; (5) In ring A, the "9-12 membered bicyclic heterocyclic group having 1, 2 or 3 heteroatoms selected from N, O and S" is (6) In ring A, the "5-6 membered monocyclic heterocyclic group having 1, 2 or 3 heteroatoms selected from N, O and S" is (7) In ring A, the C6-C 10 Aryl is phenyl; (8) In ring A, the C3-C6 cycloalkyl group is a cyclohexyl group; (9) Each "5-10 membered heteroaryl group having 1, 2 or 3 heteroatoms selected from N, O and S" is independently pyridyl (e.g. );and (10) for 6. The tetracyclic compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: It meets one or more of the following conditions: (1) L is and (2) for 7. The tetracyclic compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: It meets one or more of the following conditions: (1) for and (2) for 8. The tetracyclic compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The tetracyclic compound as shown in formula I is a compound as shown in formula I-1, I-2 or I-3: Among them, *, #, X 1 , Ring A, R 3 and m3 are defined as in any one of claims 1-7.

9. The tetracyclic compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: for 10. The tetracyclic compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The tetracyclic compound represented by formula I is not the following compound: and their stereoisomers.

11. The tetracyclic compound of formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, characterized in that: The tetracyclic compound shown in Formula I is replaced with a tetracyclic compound shown in Formula I-0: The carbon atom with "*" represents a chiral carbon atom, which is in S configuration, R configuration or a mixture thereof; The carbon atom with "#" indicates a chiral carbon atom, which is in S configuration, R configuration or a mixture thereof; X 1 For-NR X1 -、-O-、-CR X2 R X3 -, -S-, -S(O)- or -S(O)2-; R X1 is H, C1-C6 alkyl, or one or more R X1-1 Substituted C1-C6 alkyl, -C(O)-C1-C6 alkyl, C3-C6 cycloalkyl, or "3-12 membered heterocycloalkyl having 1, 2 or 3 heteroatoms selected from N, O and S"; R X1-1 independently deuterium or OH; R X2 and R X3 are independently H, deuterium, C1-C6 alkyl or C1-C6 deuterated alkyl; X 2 N, N + O - or CR X4 ; R X4 is H or C1-C6 alkyl; X 3 N or CR 1-1 ; X 4 N or CR 1-2 ; X 5 N or CR 1-3 ; R 1-1 , R 1-2 and R 1-3 are independently H, CN, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C1-C6 haloalkoxy; L is -(CR L1 R L2 )n1-, -(CR L1 R L2 )n2-Y 1 -(CR L1 R L2 )n3- or -(CR L1 R L2 )n4-Y 2 -(CR L1 R L2 )n5-; R L1 and R L2 are independently H or C1-C6 alkyl; n1 is 3 or 4; Y 1 is -O-, -NR L3 -, -C(O)-, -CR L4 R 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≡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 are independently H or C1-C6 alkyl; R L4 is H or halogen; R L5 is halogen, OH or C1-C6 alkoxy; R L6 and R L7 are independently H or halogen; R 2 are independently deuterium, C1-C6 alkyl, C1-C6 deuterated alkyl, -C(O)-C1-C6 alkyl, oxo (=O), thio (=S) or hydroxy; m2 is 0, 1, 2, 3 or 4; Ring A is "an 8-12-membered bicyclic heterocyclic group having 1, 2 or 3 heteroatoms selected from the group consisting of N, O and S", "a 5-6-membered monocyclic heterocyclic group having 1, 2 or 3 heteroatoms selected from the group consisting of N, O and S", "a 9-16-membered polycyclic heterocyclic group having 1, 2 or 3 heteroatoms selected from the group consisting of N, O and S", or a C3-C6 cycloalkyl group; And when L is -(CR L1 R L2 )n1-、-(CR L1 R L2 )n2-O-or-(CR L1 R L2 )n2-C(O)-, for R 3 are independently oxo (=O), C1-C6 alkyl, C1-C6 alkoxy, -NR 4 R 5 、-C(O)R 6 、-SR 7 、-S(O)2R 8 , halogen, one or more R 9 Substituted C1-C6 alkoxy, one or more R 10 Substituted C1-C6 alkyl, CN, "a 3-12 membered heterocycloalkyl group having 1, 2 or 3 heteroatoms selected from N, O and S" or -OR 11 ; R 4 are independently H or C1-C6 alkyl; R 5 are independently H, C1-C6 alkyl or -C(O)R 5-1 ; R 6 , R 5-1 , R 7 and R 8 are independently C1-C6 alkyl; R 9 and R 10 are independently OH, -NR 4 R 5 or halogen; R 11 H or "a 5-10 membered heteroaryl group having 1, 2 or 3 heteroatoms selected from N, O and S"; m3 is 0, 1, 2, 3 or 4; m4 is 0, 1, or 2.

12. The tetracyclic compound of formula I or a pharmaceutically acceptable salt thereof according to claim 11, characterized in that: It meets one or more of the following conditions: (1)X 1 For-NR X1 -; (2)X 3 CR 1-1 ; (3)X 4 CR 1-2 ; (4)R 1-1 , R 1-2 and R 1-3 are independently H, CN, halogen or C1-C6 alkoxy; for example, R 1-1 and R 1-3 For H, R 1-2 is H, F, CN or C1-C6 alkoxy; for example, R 1-1 , R 1-2 and R 1-3 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 are independently deuterium, C1-C6 alkyl, oxo, thio or hydroxy; for example oxo; (10) m2 is 0, 1, 2 or 3; for example, m2 is 1; (11) When L is -(CR L1 R L2 )n1-、-(CR L1 R L2 )n2-O-or-(CR L1 R L2 )n2-C(O)-, for and (12)R 3 Independently -OR 11 , C1-C6 alkyl, C1-C6 alkoxy, one or more R 9 Substituted C1-C6 alkoxy or halogen.

13. The tetracyclic compound of formula I or a pharmaceutically acceptable salt thereof according to claim 11, characterized in that: It meets one or more of the following conditions: (1) Each C3-C6 cycloalkyl group is independently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, for example cyclobutyl; (2) In ring A, the "heteroatoms selected from 1, 2 or 3 of N, O and S, and the number of heteroatoms is 1, 2 or 3, 8-12 membered bicyclic heterocyclic group" is (3) In ring A, the "9-16 membered polycyclic heterocyclic group having 1, 2 or 3 heteroatoms selected from N, O and S" is "a 10-12 membered tricyclic heterocyclic group having 1 or 2 heteroatoms selected from N and O", for example and (4) for One or more of Another example 14. The tetracyclic compound of formula I or a pharmaceutically acceptable salt thereof according to claim 11, characterized in that: It meets one or more of the following conditions: (1) for (2) L is For example and (3) for 15. The tetracyclic compound of formula I or a pharmaceutically acceptable salt thereof according to claim 11, characterized in that: for 16. The tetracyclic compound of formula I or a pharmaceutically acceptable salt thereof according to claim 11, characterized in that: for 17. The tetracyclic compound of formula I or a pharmaceutically acceptable salt thereof according to claim 11, characterized in that: The tetracyclic compound is a compound as shown in formula I-4: Among them, *, #, X 1 , Ring A, R 3 and m3 are defined as in any one of claims 11-16.

18. A tetracyclic compound or a pharmaceutically acceptable salt thereof as shown below:

19. A pharmaceutical composition, comprising: (1) a tetracyclic compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 18, and (2) Pharmaceutically acceptable excipients.

20. Use of the tetracyclic compound according to any one of claims 1 to 18, a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 19, wherein the use is selected from: (1) Preparation of 5-HT 2A Receptor agonists; (2) Preparation of therapeutic and / or preventive agents with 5-HT 2A Drugs for diseases related to 5-HT receptors; for example, 2A Receptor-related diseases are depression; (3) Preparation of drugs for treating and / or preventing depression.

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