Aza-ergoline is a compound that exists in crystalline form and in pharmaceutical products containing this compound.

Abstract

The invention relates to an aza-ergoline compound, which is in crystalline form, and a pharmaceutical composition containing the compound. The derivative has the structure shown in formula (I). The aza-ergoline derivative has good affinity, agonist activity, or selectivity for the dopamine D2 receptor.

Description

Azaergoline derivatives and their preparation method and application

[0001] This application claims priority to Chinese Patent Application No. 2021101382499, filed on February 1, 2021, and Chinese Patent Application No. 2021111530798, filed on September 29, 2021. This application incorporates the entirety of the aforementioned Chinese patent applications. Technical Field

[0002] The present invention relates to an azaergoline derivative and a preparation method and application thereof. Background Art

[0003] The dopaminergic signaling pathway is related to many physiological functions of human movement, behavior, emotion, memory, etc., and has been one of the focuses of neurobiological research in recent decades. Dysfunction of the dopaminergic signaling pathway is believed to be the cause of Parkinson's disease, schizophrenia and many other diseases. The dopaminergic signaling pathway is composed of the neurotransmitter dopamine, dopamine receptors, and downstream signaling molecules associated with dopamine receptors. Dopamine receptors belong to the G protein-coupled receptor (GPCR) superfamily and are one of the most important central nervous system (CNS) drug targets. There are five subtypes of dopamine receptors (D1-5), of which D1 and D5 are D1-type receptors, which mainly interact with G s Protein coupling, after activation, increases the intracellular cAMP level; D2, D3, and D4 are D2 receptors, which mainly interact with G i Protein coupling, upon activation, reduces intracellular cAMP levels. Different dopamine receptors have different expression levels and distributions in the central nervous system and play different physiological functions (Martel and McArthur, Front Pharmacol 2020, 11:1003).

[0004] Of the five dopamine receptor subtypes, the D2 receptor has been the most extensively studied. Clinically used drugs such as pramipexole, ropinirole, and rotigotine are primarily used to treat Parkinson's disease and restless legs syndrome. These drugs primarily activate dopamine D2 receptors, but they also have activity at other dopamine receptors such as D3. Antipsychotic drugs such as haloperidol and olanzapine primarily exert their therapeutic effects by antagonizing D2 receptors, while the latest generation of drugs such as aripiprazole and cariprazine are partial agonists of dopamine D2 receptors (Frankel and Schwartz, Ther Adv Psychopharmacol 2017, 7(1):29-41).

[0005] Dopamine D2 receptors share a certain degree of structural homology with other dopamine receptors and other monoamine GPCRs such as 5-hydroxytryptamine (5-HT) receptors. This homology results in the lack of target selectivity for most drugs. Most of the antipsychotic drugs targeting dopamine D2 receptors have no effect on 5-HT receptors such as 5-HT. 2A Receptors have a certain degree of affinity, and some drugs have a certain affinity for 5-HT 2A The affinity of D2 receptors is even stronger than that of 5-HT receptors. 2A The dual role of 5-HT receptors is a common feature of these drugs. In 2018, the US FDA approved the drug Pimavanserin, which is a 5-HT 2A Lumateperone, a selective inverse agonist of 5-HT receptors (Sahli and Tarazi, Expert Opin Drug Discov 2018, 13(1):103-110); Lumateperone, approved by the US FDA in 2019, is a selective inverse agonist of 5-HT receptors. 2A The affinity of the receptor is also about 60 times higher than that of the D2 receptor (Blair, Drugs, 2020, 80(4), 417-423). However, drugs with high selectivity for the D2 receptor are rarely reported in the literature (Fan and Tan et al., Nat Comm, 2020, 11, 1074).

[0006] Krogsgaard-Larsen et al. reported a compound A with an azaergoline skeleton, wherein derivative A1 thereof has binding activity to the 5-HT6 receptor, derivative A2 has agonist activity to the dopamine D2 receptor, and A3 has partial agonist activity to the dopamine D2 receptor (Krogsgaard-Larsen et al., J. Med. Chem. 2014, 57, 5823-5828; WO2011088836; WO2011088838). The target selectivity, in vivo activity in animals, and other drugability of these compounds have not been reported.

[0007]

[0008] Summary of the Invention

[0009] The technical problem to be solved by the present invention is that there are relatively few existing compounds with affinity, agonist activity, or selectivity for dopamine D2 receptors. To address this problem, the present invention provides an azaergoline derivative, a preparation method, and uses thereof. The compounds of the present invention have good affinity, agonist activity, or selectivity for dopamine D2 receptors.

[0010] The present invention provides a compound as shown in Formula I, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof:

[0011]

[0012] Where L is C 1-10 Alkylene, C 2-10 Alkenylene, C 2-10 Alkynylidene or -C 1-6 Alkylene-C 3-6 Cycloalkylene-;

[0013] M is -O-, -NH-, -CH2-, -(CH-OH)- or -C(=O)-;

[0014] Q is C 6-18 Aryl, 1 or more Q 1-1 Substituted C 6-18 Aryl, 5-10 membered heteroaryl, 1 or more Q 1-2 Substituted 5-10 membered heteroaryl, -C(=O)R 1 or -S(=O)2R 2 The heteroatoms in the 5-10 membered heteroaryl group are one or more of N, S or O, and the number of the heteroatoms is 1, 2 or 3; the ... Q 1-2 The heteroatoms in the substituted 5-10 membered heteroaryl group are one or more of N, S or O, and the number of heteroatoms is 1, 2 or 3;

[0015] Q 1-1 are independently halogen or C 1-4 alkyl;

[0016] Q 1-2 Independently C 1-4 Alkyl, oxo or hydroxy;

[0017] R 1 and R 2 are independently -NR 1-1 R 1-2 , 3-6 membered heterocycloalkyl, C 6-18 Aryl, 1 or more R 1-3 Substituted C 6-18 Aryl, 5-10 membered heteroaryl or 1 or more R 1-4 substituted 5-10 membered heteroaryl; the heteroatom in the 3-6 membered heterocycloalkyl is one or more of N, S or O, the number of which is 1, 2 or 3; the heteroatom in the 5-10 membered heteroaryl is one or more of N, S or O, the number of which is 1, 2 or 3; the heteroatom in the 10 membered heteroaryl is one or more of N, S or O, the number of which is 1, 2 or 3; 1-4The heteroatoms in the substituted 5-10 membered heteroaryl group are one or more of N, S or O, and the number of heteroatoms is 1, 2 or 3;

[0018] R 1-1 、R 1-2 、R 1-3 and R 1-4 Independently C 1-4 alkyl;

[0019] R is hydrogen or C 1-4 alkyl.

[0020] In a preferred technical solution, in the compound as shown in Formula I, its pharmaceutically acceptable salt, its solvate or the solvate of its pharmaceutically acceptable salt, the definitions of certain groups may be as described below, and the definitions of the remaining groups are as described in any solution of the present invention, hereinafter referred to as "in a preferred technical solution".

[0021] In a preferred technical solution, the compound shown in Formula I is a compound shown in Formula Ia, Ib or Ic:

[0022]

[0023] In Formula Ic, represents a double bond or a single bond; Y is hydrogen, hydroxyl or oxygen.

[0024] In a preferred technical solution, the compound shown in Formula I is a compound shown in Formula Id and / or Ie, preferably a compound shown in Formula Id;

[0025]

[0026] In a preferred technical solution, when the compound shown in formula I is only When there is a chiral center in

[0027] for and / or Preferred Among them, the carbon atom marked with "*" is a chiral carbon atom; (+) represents a right-handed compound, and (-) represents a left-handed compound.

[0028] In a preferred technical solution,

[0029] L is C 1-10 Alkylene, C 2-10 Alkenylene or -C 1-6 Alkylene-C 3-6 Cycloalkylene-;

[0030] When M is -(CH-OH)- or -C(=O)-, R is hydrogen.

[0031] In a preferred technical solution,

[0032] L is C 1-10 Alkylene or -C 1-6 Alkylene-C 3-6 Cycloalkylene-;

[0033] M is -O-, -NH- or -CH2-;

[0034] Q is C 6-18 Aryl, 5-10 membered heteroaryl, 1 or more Q 1-2 Substituted 5-10 membered heteroaryl, -C(=O)R 1 or -S(=O)2R 2 .

[0035] In a preferred technical solution,

[0036] L is C 1-10 Alkylene or -C 1-6 Alkylene-C 3-6 Cycloalkylene-;

[0037] M is -O-, -NH- or -CH2-;

[0038] Q is C 6-18 Aryl, 5-10 membered heteroaryl, 1 or more Q 1-2 Substituted 5-10 membered heteroaryl, -C(=O)R 1 or -S(=O)2R 2 ;

[0039] When M is -O-, Q 1-2 C 1-4 Alkyl or hydroxyl;

[0040] When the heteroatom in the 5-10 membered heteroaryl group is O, the number of heteroatoms in the 5-10 membered heteroaryl group is 1.

[0041] In a preferred technical solution,

[0042] L is C 1-10 Alkylene or -C 1-6 Alkylene-C 3-6 Cycloalkylene-;

[0043] M is -O-, -NH- or -CH2-;

[0044] Q is C 6-18 Aryl, 5-10 membered heteroaryl, 1 or more Q 1-2Substituted 5-10 membered heteroaryl, -C(=O)R 1 or -S(=O)2R 2 ;

[0045] When L is -C 1-6 Alkylene-C 3-6 When cycloalkylene-, the -C 1-6 Alkylene-C 3-6 C in cycloalkylene- 1-6 Alkylene is ethylene.

[0046] In a preferred technical solution,

[0047] L is C 1-10 Alkylene or -C 1-6 Alkylene-C 3-6 Cycloalkylene-;

[0048] M is -O- or -NH-;

[0049] Q is -C(=O)R 1 or by one or more Q 1-2 substituted 5-10 membered heteroaryl;

[0050] R 1 -NR 1-1 R 1-2 .

[0051] In a preferred technical solution, L is C 1-10 alkylene;

[0052] M is -O-;

[0053] Q is one or more Q 1-2 Substituted 5-10 membered heteroaromatics.

[0054] In a preferred technical solution, L is -C 1-6 Alkylene-C 3-6 Cycloalkylene-;

[0055] M is -NH-;

[0056] Q is -C(=O)R 1 ;

[0057] R 1 -NR 1-1 R 1-2 .

[0058] In a preferred technical solution, the molecular structure shown in Formula I is as shown in Formula Ia:

[0059]

[0060] L is C 1-10 Alkylene or C 2-10 alkenylene;

[0061] Q is a 5-10 membered heteroaryl group, or is replaced by one or more Q 1-2 Substituted 5-10 membered heteroaryl.

[0062] In a preferred technical solution, the molecular structure shown in Formula I is as shown in Formula Ia:

[0063]

[0064] L is C 1-10 Alkylene or C 2-10 alkenylene;

[0065] Q is one or more Q 1-1 Substituted C 6-18 Aryl, 5-10 membered heteroaryl, or, substituted by one or more Q 1-2 substituted 5-10 membered heteroaryl;

[0066] Q 1-1 It is a halogen.

[0067] In a preferred technical solution, the molecular structure shown in Formula I is as shown in Formula Ib:

[0068]

[0069] L is -C 1-6 Alkylene-C 3-6 Cycloalkylene-;

[0070] Q is -C(=O)R 1 or -S(=O)2R 2 ;

[0071] R 1 and R 2 are independently -NR 1-1 R 1-2 , 3-6 membered heterocycloalkyl, C 6-18 aryl or 5-10 membered heteroaryl.

[0072] In a preferred technical solution, the molecular structure shown in Formula I is as shown in Formula Ic:

[0073]

[0074] Indicates a double bond or a single bond;

[0075] Y is hydrogen, hydroxy or oxygen;

[0076] L is C 1-10 alkylene;

[0077] Q is one or more Q 1-1 Substituted C 6-18 Aryl, or, 1 or more Q 1-2 substituted 5-10 membered heteroaryl;

[0078] Q 1-1 is a halogen;

[0079] Q 1-2 Independently C 1-4 Alkyl or oxo.

[0080] In a preferred technical solution, the molecular structure shown in Formula I is as shown in Formula Ic-1:

[0081]

[0082] L is C 1-10 alkylene;

[0083] Q is one or more Q 1-1 Substituted C 6-18 aryl;

[0084] Q 1-1 is a halogen;

[0085] R is hydrogen.

[0086] In a preferred technical solution, the molecular structure shown in Formula I is as shown in Formula Ic-2:

[0087]

[0088] L is C 1-10 alkylene;

[0089] Q is one or more Q 1-1 Substituted C 6-18 aryl;

[0090] Q 1-1 is a halogen;

[0091] R is hydrogen.

[0092] In a preferred technical solution, the molecular structure shown in Formula I is as shown in Formula Ic-3:

[0093]

[0094] L is C 1-10 alkylene;

[0095] Q is one or more Q1-2 substituted 5-10 membered heteroaryl;

[0096] Q 1-1 C 1-4 Alkyl or oxo;

[0097] R is hydrogen.

[0098] In a preferred technical solution, when L is C 1-10 When alkylene, the C 1-10 Alkylene is C 1-4 Alkylene (e.g. methylene, ethylene n-Propylene Isopropylidene n-Butylene Isobutylene or tert-butyl Preferred is n-propylene or n-butylene, and more preferred is n-butylene.

[0099] In a preferred technical solution, when L is C 2-10 Alkenylene, the C 2-10 Alkenylene is C 2-4 In the case of alkenylene, it is preferably

[0100] In a preferred technical solution, when L is -C 1-6 Alkylene-C 3-6 When cycloalkylene-, the C 1-6 Alkylene is connected to N, the C 3-6 The cycloalkylene group is connected to Q.

[0101] In a preferred technical solution, when L is -C 1-6 Alkylene-C 3-6 When cycloalkylene-, the -C 1-6 Alkylene-C 3-6 C in cycloalkylene 1-6 Alkylene is methylene, ethylene n-Propylene Isopropylidene n-Butylene Isobutylene or tert-butyl Methylene or ethylene is preferred, and ethylene is more preferred.

[0102] In a preferred technical solution, when L is -C 1-6 Alkylene-C 3-6 When cycloalkylene-, the -C 1-6 Alkylene-C 3-6 C in cycloalkylene 3-6Cycloalkylene is cyclopropylene, cyclobutylene, cyclopentylene or cyclohexylene (e.g. ), preferably

[0103] In a preferred technical solution, when L is -C 1-6 Alkylene-C 3-6 When cycloalkylene-, the -C 1-6 Alkylene-C 3-6 Cycloalkylene- (For example )or (For example ), wherein the a end is connected to Q, the b end is connected to N, preferably

[0104] In a preferred technical solution, when Q is C 6-18 When the C 6-18 Aryl is C 6-14 The aryl group (such as phenyl, naphthyl, anthracenyl or phenanthrenyl) may further be a phenyl group.

[0105] In a preferred technical solution, when Q is Q 1-1 Substituted C 6-18 When the C 6-18 Aryl is C 6-14 The aryl group (such as phenyl, naphthyl, anthracenyl or phenanthrenyl) may further be a phenyl group.

[0106] In a preferred technical solution, when Q is Q 1-1 Substituted C 6-18 When aryl, the Q 1-1 is 1 or 2. When Q 1-1 When there are multiple 1-1 They may be the same or different, for example different.

[0107] In a preferred technical solution, when Q 1-1 When it is a halogen, the halogen is F, Cl, Br or I, preferably F.

[0108] In a preferred technical solution, when Q is Q 1-1 Substituted C 6-18 When aryl, the Q 1-1 Substituted C 6-18 Aryl

[0109] In a preferred embodiment, when Q is a 5-10 membered heteroaryl group, the 5-10 membered heteroaryl group is a 9- or 10-membered heteroaryl group, and the number of heteroatoms is 1 or 2.

[0110] In a preferred technical solution, when Q is one or more Q 1-2 When the substituted 5-10 membered heteroaryl group is a 9- or 10-membered heteroaryl group, the heteroatoms are N and / or O, the number of which is 1 or 2, preferably tetrahydroquinolinyl Quinolinyl (e.g. ), benzoxazolyl (e.g. ), benzisoxazolyl (e.g. ) or tetrahydropyridopyrimidinyl (e.g., oxo ).

[0111] In a preferred technical solution, when Q is Q 1-2 Substituted C 6-18 When aryl, the Q 1-2 For 1 or 2. When the Q 1-2 When there are multiple, the Q 1-2 Same or different, e.g. different.

[0112] In a preferred technical solution, when Q 1-2 C 1-4 When alkyl, the C 1-4 The alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, preferably methyl.

[0113] In a preferred technical solution, when Q is one or more Q 1-2 When the 5-10 membered heteroaryl is substituted, the 1-2 The substituted 5-10 membered heteroaryl is

[0114] In a preferred technical solution, when R 1 and R 2 When independently 3-6 membered heterocycloalkyl, the 3-6 membered heterocycloalkyl is piperidinyl (e.g. ) or pyrrolidinyl (e.g. ), preferably pyrrolidinyl.

[0115] In a preferred technical solution, when R 1 When it is a 3-6 membered heterocycloalkyl group, the 3-6 membered heterocycloalkyl group is connected to the carbonyl group through a heteroatom.

[0116] In a preferred technical solution, when R 1 and R 2 Independently C 6-18 When the C 6-18 Aryl is C 6-14The aryl group (such as phenyl, naphthyl, anthracenyl or phenanthrenyl) may further be a phenyl group.

[0117] In a preferred technical solution, when R 1 and R 2 Independently by one or more R 1-3 Substituted C 6-18 When the C 6- 18 Aryl is C 6-14 The aryl group (such as phenyl, naphthyl, anthracenyl or phenanthrenyl) may further be a phenyl group.

[0118] In a preferred technical solution, when R 1 and R 2 When they are independently 5-10 membered heteroaryl groups, the 5-10 membered heteroaryl groups are 9- or 10-membered heteroaryl groups, the heteroatom is N, the number of which is 1 or 2, and is preferably indolyl (e.g. ).

[0119] In a preferred technical solution, when R 1-1 、R 1-2 、R 1-3 and R 1-4 Independently C 1-4 When alkyl, the C 1-4 The alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, preferably methyl.

[0120] In a preferred technical solution, when R is C 1-4 When alkyl, the C 1-4 The alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, preferably methyl.

[0121] In a preferred technical solution, L is C 1-10 Alkylene, C 2-10 Alkenylene or -C 1-6 Alkylene-C 3-6 Cycloalkylene.

[0122] In a preferred technical solution, L is C 1-10 Alkylene or -C 1-6 Alkylene-C 3-6 Cycloalkylene.

[0123] In a preferred embodiment, M is -O-, -NH- or -CH2-.

[0124] In a preferred technical solution, Q 1-1 It is a halogen.

[0125] In a preferred technical solution, R1 -NR 1-1 R 1-2 , 3-6 membered heterocycloalkyl, C 6-18 Aryl or 5-10 membered heteroaryl, preferably -NR 1-1 R 1-2 , 3-6 membered heterocycloalkyl or C 6-18 Aryl.

[0126] In a preferred embodiment, R is hydrogen.

[0127] In a preferred technical solution, for

[0128] In a preferred technical solution, the compound as shown in Formula I is any one of the following compounds:

[0129]

[0130]

[0131] In a preferred technical solution, the compound as shown in Formula I is any one of the following compounds:

[0132]

[0133] In a preferred technical solution, the compound as shown in Formula I is any one of the following compounds:

[0134] "An optical rotation value of +50.33° and / or a retention time of 5.805 min under the following chiral preparation conditions" " or "having an optical rotation value of -45.00° and / or a retention time of 7.60 min under the following chiral preparation conditions

[0135] The chiral preparation conditions are as follows: chromatographic column: chiral column CHIRALCEL OD, column volume: 5.0 cm x 25 cm, 10 μm filler; mobile phase: MeOH / diethylamine = 100 / 0.1; flow rate: 30 mL / min; wavelength: UV 214 nm; temperature: 38°C.

[0136] In a preferred technical solution, the compound shown in Formula I is the following compound:

[0137]

[0138] The present invention also provides a method for preparing the compound of Formula I, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, comprising the following steps:

[0139] In the presence of an alkaline agent, the compound represented by Formula II and the compound represented by Formula III are subjected to an alkylation reaction as shown below in a solvent to obtain a compound represented by Formula I;

[0140]

[0141] wherein X is a halogen; and L, M, Q and R are as defined above.

[0142] The conditions and operations of the alkylation reaction may be conventional conditions and operations for such reactions in the art. The present invention particularly prefers the following conditions:

[0143] The alkaline agent is, for example, K2CO3 (for example, the molar ratio of the alkaline agent to the compound of formula II is 6:1).

[0144] The solvent is, for example, tetrahydrofuran and dimethyl sulfoxide (for example, the volume ratio of the two is 3:1).

[0145] The temperature of the alkylation reaction is, for example, 60°C.

[0146] The present invention also provides a method for preparing the compound of Formula I, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, comprising the following steps:

[0147] In the presence of an alkaline agent, the compound shown in formula II and the compound shown in formula III are

[0148] The present invention also provides a pharmaceutical composition comprising the compound of formula I, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, and pharmaceutical excipients.

[0149] The present invention also provides a use of a substance A in the preparation of a dopamine D2 receptor agonist, wherein the substance A is the compound represented by Formula I, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, or the pharmaceutical composition described above.

[0150] The present invention also provides a use of a substance A in the preparation of a medicament for treating and / or preventing diseases associated with dopamine D2 receptors; the substance A is the compound represented by Formula I, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, or the pharmaceutical composition described above.

[0151] The dopamine D2 receptor-related diseases refer to one or more neurodegenerative diseases, mental disorders and metabolic diseases related to mental disorders, such as Parkinson's disease, Alzheimer's disease, dementia, schizophrenia, bipolar disorder, depression, attention deficit hyperactivity disorder, restless legs syndrome, Huntington's disease, male erectile dysfunction, prolactinoma or drug addiction.

[0152] The present invention also provides a use of a substance A in the preparation of a drug for treating and / or preventing a disease M; the substance A is the compound shown in Formula I, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, or the pharmaceutical composition described above; the disease M is one or more of a neurodegenerative disease, a mental disorder, and a metabolic disease related to a mental disorder.

[0153] In the application, the disease M is preferably Parkinson's disease, Alzheimer's disease or dementia, schizophrenia, bipolar disorder, depression, attention deficit hyperactivity disorder, restless legs syndrome, Huntington's disease, male erectile dysfunction, prolactinoma or drug addiction.

[0154] The present invention also provides a method for preventing or treating diseases related to dopamine D2 receptors, comprising administering to a subject a therapeutically effective amount of substance A, wherein substance A is the compound represented by formula I, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, or the pharmaceutical composition described above.

[0155] The dopamine D2 receptor-related diseases refer to one or more neurodegenerative diseases, mental disorders and metabolic diseases related to mental disorders, such as Parkinson's disease, Alzheimer's disease, dementia, schizophrenia, bipolar disorder, depression, attention deficit hyperactivity disorder, restless legs syndrome, Huntington's disease, male erectile dysfunction, prolactinoma or drug addiction.

[0156] The present invention also provides a method for preventing or treating disease M, which comprises administering to a subject a therapeutically effective amount of substance A, wherein substance A is the above-mentioned compound as shown in Formula I, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, or the above-mentioned pharmaceutical composition; and the disease M is one or more of a neurodegenerative disease, a mental disorder, and a metabolic disease related to a mental disorder.

[0157] In the method, the disease M is preferably Parkinson's disease, Alzheimer's disease or dementia, schizophrenia, bipolar disorder, depression, attention deficit hyperactivity disorder, restless legs syndrome, Huntington's disease, male erectile dysfunction, prolactinoma or drug addiction.

[0158] The present invention also provides a crystal as shown in the formula pNs-(+)-I-10, which belongs to the triclinic system, the P1 space group, and the unit cell parameters are α=90.15°, β=99.368°, γ=90.25°;

[0159]

[0160] Unless otherwise specified, the terms used in this invention have the following meanings:

[0161] As used herein, a substituent may be preceded by a single dash "-" to indicate that the named substituent is attached to the parent moiety by a single bond. In addition, substituents are described by writing the conventional chemical formula "from left to right" or "from top to bottom" as is customary, for example, "-C 1- 6-alkylene-C 3-6 "Cycloalkylene" means C 1-6 The alkylene group is connected to the nitrogen in the parent group through a single bond.

[0162] The terms "compound" and "pharmaceutically acceptable salt" may exist as a single tautomer or a mixture thereof, if tautomers exist, preferably in a form in which the more stable tautomer predominates.

[0163] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0164] The term "alkyl" refers to a group having a specified number of carbon atoms (e.g., C1 to C 10 ) is a straight or branched chain alkyl group. The alkyl group includes, but is not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, etc.

[0165] The term "alkylene" refers to a divalent group of a straight or branched saturated aliphatic hydrocarbon radical having the specified number of carbon atoms. The two valencies can be concentrated on the same atom, such as methylene (-CH2-), ethylene The two valences can also be attached to two atoms respectively, such as 1,2-ethylene (-CH2CH2-).

[0166] The term "alkenylene" refers to a group having the specified number of carbon atoms (e.g., C2-C 10 ) containing one or more double bonds, straight or branched chain aliphatic hydrocarbon divalent group. The two valences can be concentrated on the same atom, for example The two valences can also be attached to two atoms respectively, for example -CH2CH=CHCH2-.

[0167] The term "alkynylene" refers to a group having a specified number of carbon atoms (e.g., C2 to C 10) containing one or more triple bonds, straight or branched chain aliphatic hydrocarbon divalent group. The two valences can be concentrated on the same atom, for example The two valences can also be attached to two atoms separately, for example

[0168] The term "cycloalkyl" refers to a saturated monocyclic ring group consisting only of carbon atoms with a specified number of carbon atoms (e.g., C3 to C6). Cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0169] The term "cycloalkylene" refers to a divalent radical of a saturated cyclic alkylene group, for example: cyclopentylene (e.g. or cyclohexylene, etc.).

[0170] The term "heterocycloalkyl" refers to a cyclic group having a specified number of ring atoms (e.g., 5-10 members), a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified type of heteroatom (one or more of N, O, and S). It is monocyclic, bridged, or spirocyclic, and each ring is saturated. Heterocycloalkyl includes, but is not limited to, azetidinyl, tetrahydropyrrolyl, tetrahydrofuranyl, morpholinyl, piperidinyl, and the like.

[0171] The term "aryl" refers to a group having a specified number of carbon atoms (e.g., C6 to C 10 ) cyclic groups consisting only of carbon atoms, which are monocyclic or polycyclic, and at least one ring is aromatic (in accordance with Huckel's rule). Aryl groups are connected to other fragments in the molecule through aromatic or non-aromatic rings. Aryl groups include but are not limited to phenyl, naphthyl, etc.

[0172] The term "heteroaryl" refers to a cyclic group with a specified number of ring atoms (e.g., 5 to 10 members), a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified type of heteroatom (one or more of N, O, and S). It is monocyclic or polycyclic, and at least one ring is aromatic (in accordance with Huckel's rule). The heteroaryl group is connected to other fragments in the molecule through an aromatic ring or a non-aromatic ring. Heteroaryl includes, but is not limited to, furyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, pyridyl, pyrimidinyl, indolyl, and the like. Heteroaryl is also, for example,

[0173] The "-" at the end of a group means that the group is connected to other fragments in the molecule through this site. For example, CH3-C(=O)- refers to acetyl.

[0174] In the structure fragment It means that the structural fragment is connected to other fragments in the molecule through this site. For example, It refers to cyclohexyl.

[0175] The term "plurality" refers to 2, 3, 4 or 5.

[0176] When any variable (such as the group R 1-1 ) appears multiple times in the definition of a compound, their definitions are independent of each other and do not affect each other. For example, 1-1 Substituted C6~C 10 Aryl refers to C6~C 10 The aromatic group will be 3 R 1-1 Replacement, 3 R 1-1 The definitions are independent of each other and do not affect each other.

[0177] The term "pharmaceutically acceptable salt" refers to a salt obtained by reacting a compound with a pharmaceutically acceptable (relatively non-toxic, safe, and suitable for patient use) acid or base. When the compound contains a relatively acidic functional group, a base addition salt can be obtained by contacting the free form of the compound with a sufficient amount of a pharmaceutically acceptable base in a suitable inert solvent. Pharmaceutically acceptable base addition salts include, but are not limited to, sodium salts, potassium salts, calcium salts, aluminum salts, magnesium salts, bismuth salts, ammonium salts, and the like. When the compound contains a relatively basic functional group, an acid addition salt can be obtained by contacting the free form of the compound with a sufficient amount of a pharmaceutically acceptable acid in a suitable inert solvent. Pharmaceutically acceptable acid addition salts include, but are not limited to, hydrochlorides, sulfates, methanesulfonates, and the like. For details, see Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl, 2002).

[0178] The term "solvate" refers to a substance formed by crystallization of a compound with a solvent (including but not limited to water, methanol, ethanol, etc.). Solvates are divided into stoichiometric solvates and non-stoichiometric solvates.

[0179] The term "pharmaceutically acceptable salt solvate" refers to a compound formed by combining with a pharmaceutically acceptable (relatively non-toxic, safe, and suitable for patient use) acid or base and a solvent (including but not limited to water, methanol, ethanol, etc.), wherein the pharmaceutically acceptable salt has the same meaning as the term "pharmaceutically acceptable salt" above, and the solvent may be stoichiometric or non-stoichiometric. Pharmaceutically acceptable salt solvates include but are not limited to hydrochloride monohydrate.

[0180] The term "pharmaceutical excipients" refers to excipients and additives used in the production of pharmaceuticals and the preparation of prescriptions. These excipients are all substances contained in pharmaceutical preparations, other than the active ingredient. For details, see the Pharmacopoeia of the People's Republic of China (2020 edition) or the Handbook of Pharmaceutical EMcipients (Raymond C Rowe, 2009).

[0181] The term "treat" refers to any of the following: (1) alleviating one or more biological manifestations of a disease; (2) interfering with one or more points in the biological cascade that leads to a disease; or (3) slowing the progression of one or more biological manifestations of a disease.

[0182] The term "prevent" refers to reducing the risk of developing a disease.

[0183] The term "patient" refers to any animal that has been or is about to be treated, preferably a mammal, most preferably a human. Mammals include but are not limited to cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, etc.

[0184] 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.

[0185] The reagents and raw materials used in the present invention are commercially available.

[0186] The positive and progressive effects of the present invention are that the compounds of the present invention have good affinity, agonist activity or selectivity for dopamine D2 receptors. BRIEF DESCRIPTION OF THE DRAWINGS

[0187] FIG1 is an X-ray single crystal diffraction pattern of a crystal of the compound represented by pNs-(+)-I-10. DETAILED DESCRIPTION

[0188] 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.

[0189] Materials and methods

[0190] 1. Cell culture

[0191] Human renal epithelial 293T cells were cultured in DMEM supplemented with 10% fetal bovine serum (FBS) in a 37°C, 5% CO2 culture dish. Once the cells adhered to the dish, the culture medium was removed with a pipette, and 1 mL of phosphate buffer (pH 7.4) was added for gentle washing to remove excess serum. 800 μL of 0.25% trypsin was then added, and the cells were digested in an incubator for 2 minutes. Cells were removed and observed under a microscope. If the cells appeared rounded and freely swimming at the bottom of the dish, 2 mL of culture medium supplemented with 10% serum was added to terminate digestion. The cells were gently pipetted with a 1 mL pipette to disperse into single cells. Subculture or further experiments were performed as needed.

[0192] 2. Cell transfection

[0193] The day before transfection, subculture 293T cells from a confluent 10-cm dish into a 6-cm dish at a 1:4 split ratio. After 20 hours, when the cell density reaches 50%-70%, prepare for transfection. Place 500 μL of 150 mM sodium chloride in a clean EP tube and add the appropriate amount of plasmid. Simultaneously, add PEI (transfection reagent) at a volume four times the amount of plasmid and mix thoroughly. Incubate at room temperature for 20 minutes. Add 500 μL of transfection solution dropwise to the dish and gently shake to mix.

[0194] 3. Preparation of cell membrane fractions containing specific dopamine D2 receptors

[0195] A 10-cm diameter culture dish was transfected with 10 ng of dopamine D2 receptor and 40 μL of PEI. After 48 hours, the 10-cm culture dish containing cells expressing dopamine D2 receptors was removed from the cell chamber. The culture medium was removed using a vacuum pump, and 3 mL of lysis buffer (50 mM Tris-HCl buffer, pH 7.4) was added to each well. The cells were placed in a 4°C refrigerator and allowed to stand for 10 minutes. After the cells detached, they were transferred to a 15 mL centrifuge tube and centrifuged at 1500 rpm for 5 minutes at 4°C. The supernatant was discarded. The cell pellet was transferred to a tissue homogenizer, and 3 mL of lysis buffer was added. The cells were thoroughly ground until the cells were broken. The cell suspension was then aliquoted into multiple EP tubes and centrifuged at 12000 rpm for 5 minutes at 4°C. The supernatant was discarded. The pellet, representing the cell membrane fraction containing dopamine D2 receptors, was stored at -80°C.

[0196] 4. Radioligand receptor binding assay

[0197] Ligand-receptor binding experiments were performed on 293T membrane fractions transiently expressing dopamine D2 receptors. First, standard binding buffer (50mM HEPES, 50mM NaCl, 5mM MgCl2, 0.5mM EDTA, pH 7.4) was added to the cell membrane fraction containing dopamine D2 receptors, and the cell membrane was broken and resuspended using an electric tissue homogenizer. 30μL of membrane protein suspension was added to each well of a 96-well plate. Then, 30μL of different drugs were added from left to right of the 96-well plate to ensure that the final drug concentration was 10 from bottom to top. -5 M, 10 -6 M, 10 -7 M, 10 -8 M, 10 -9 M, 0M, two replicates for each treatment. Then, 30 μL [ 3 H]-N-Methylspiperone was incubated at room temperature in the dark for 2 hours. Unbound isotope was removed using a Whatman GF / C filter and a vacuum pump, and receptor-bound isotope was detected using a MicroBeta isotope liquid scintillation spectrometer.

[0198] 5. G protein Gαi1-γ9 dissociation assay based on bioluminescence resonance energy transfer (BRET)

[0199] In order to detect the downstream G protein signaling pathway mediated by dopamine D2 receptor, 1 μg dopamine D2 receptor, 1 μg Gα fused to algae luciferase were added to 6 cm culture dishes. i1 (Gα i1 -Rluc), 1μg Gβ3, 1μg Gγ9 fused to green fluorescent protein (Gγ9-GFP), and 16μL of transfection reagent PEI were transfected. The next day, confluent cells were digested with 0.25% trypsin, and a 96-well plate was plated with the amount of cells from a confluent 6-cm culture dish, with 100μL of culture medium per well. On the third day, drug addition was performed. The 96-well plate was removed from the cell chamber and the culture medium was removed. 40μL of buffer (1X HBSS, 20mM HEPES, pH 7.4) containing the substrate coelenterazine 400a (7.5μM) was added to each well. Subsequently, 20μL of different drugs were added from left to right, ensuring that the final drug concentration decreased gradually from bottom to top. Each treatment was repeated in two replicates. The 395nm and 510nm readings were measured using an LB940 Mithras plate reader (Berthold Technologies), and the ratio of the 510nm value to the 395nm value was used as the final value.

[0200] 6. β-arrestin2 recruitment assay based on bioluminescence resonance energy transfer (BRET)

[0201] To examine the downstream β-arrestin2 signaling pathway mediated by the dopamine D2 receptor, 6-cm culture dishes were transfected with 500 μg of dopamine D2 receptor fused to algal luciferase (D2-Rluc), 500 μg of G protein-coupled receptor kinase 2 (GRK2), 2500 μg of β-arrestin2 fused to green fluorescent protein (GFP2-ARRB2), and 14 μL of PEI transfection reagent. The next day, confluent cells were digested and plated onto a 96-well plate using the same amount of cells from one confluent 6-cm culture dish, with 100 μL of culture medium per well. On the third day, drug addition was performed. The 96-well plate was removed from the cell chamber, the culture medium removed, and 40 μL of buffer (1X HBSS, 20 mM HEPES, pH 7.4) containing the substrate coelenterazine 400a (7.5 μM) was added to each well. Subsequently, 20 μL of each drug was added sequentially from left to right, ensuring a decreasing final drug concentration from bottom to top. Each treatment was replicated in duplicate. The readings at 395 nm and 510 nm were detected using an LB940 Mithras plate reader (Berthold Technologies), and the ratio of the 510 nm value to the 395 nm value was used as the final value.

[0202] Preparation of raw material (A) (6,6a,7,8,9,10-hexahydro-4H-pyrazino[1,2-a]pyrrolo[4,3,2-de]quinoline)

[0203]

[0204] Prepared according to the method of the literature (Krogsgaard-Larsen et al., J. Med. Chem. 2014, 57, 5823-5828). Brown solid. 1 H NMR (800 MHz, deuterated chloroform) δ 7.82 (s, 1H), 7.08 (t, J = 7.8 Hz, 1H), 6.81 (d, J = 8.1 Hz, 1H), 6.73 (t, J = 1.9 Hz, 1H), 6.34 (d, J = 7.6 Hz, 1H), 3.81 (d, J = 11.5 Hz, 1H), 3.21 (dd, J = 12.4, 3.2 Hz, 2H), 3.10–3.03 (m, 2H), 2.97 (dd, J = 15.2, 3.7 Hz, 1H), 2.83–2.79 (m, 3H).

[0205] Example 1: 7-(4-(4,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyrrolo[4,3,2-de]quinolin-8-yl)butoxy)-3,4-dihydroquinolin-2(1H)-one (Compound I-1)

[0206]

[0207] Step 1: To a round-bottom flask were added 7-hydroxy-3,4-dihydroquinolin-2(1H)-one (1.5 g, 9.19 mmol), 1,4-dibromobutane (5.92 g, 27.6 mmol), KCO (1.9 g, 13.7 mmol), and DMF (20 mL). The reaction was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and the residue was purified by flash column chromatography (eluent: ethyl acetate / petroleum ether containing 20-50% ethyl acetate) to afford intermediate wha71 (1.75 g, 64%) as a white solid. 1 H NMR (800 MHz, deuterated chloroform) δ7.74 (s, 1H), 7.05 (d, J = 8.3 Hz, 1H), 6.52 (dd, J = 8.3, 1.9 Hz, 1H), 6.30 (d, J = 2.3 Hz, 1H), 3.97 (t, J = 6.1 Hz, 2H), 3.48 (t, J = 6.6 Hz, 2H), 2.90 (t, J = 7.5 Hz, 2H), 2.65–2.60 (m, 2H), 2.09–2.03 (m, 2H), 1.95–1.93 (m, 2H). HR-MS (ESI, m / z): C 13 H 17 BrNO2 + [M+H] + , calculated value: 298.0437; measured values: 298.0432 and 300.0412.

[0208] Step 2: To a round-bottom flask were added Intermediate A (50 mg, 0.23 mmol), Intermediate wha71 (82 mg, 0.28 mmol), and K2CO3 (0.2 g, 1.38 mmol), followed by THF (3 mL) and DMSO (1 mL). The reaction system was heated and stirred at 60°C for 16 hours. After completion of the reaction, the solvent was removed and the product was purified by flash silica gel column chromatography (eluent: 0-10% methanol / dichloromethane) to afford compound I-1 (90 mg, 91%) as an off-white solid. 1H NMR (800 MHz, deuterated dimethyl sulfoxide) δ 10.51 (s, 1H), 9.97 (d, J = 7.1 Hz, 1H), 7.03 (d, J = 8.2 Hz, 1H), 6.88 (t, J = 7.7 Hz, 1H), 6.78 (s, 1H), 6.70 (d, J = 8.1 Hz, 1H), 6.48 (dd, J = 8.2, 2.5 Hz, 1H), 6.43 (d, J = 2.5 Hz, 1H), 6.20 (d, J = 7.5 Hz, 1H), 3 .96–3.86(m,2H),3.74-3.69(m,1H),3.09–3.00(m,2H),2.96–2.87(m,2H),2.76(t,J=6.8Hz,2H),2.71–2.6 1(m,2H),2.40(t,J=7.7Hz,4H),2.20–2.14(m,1H),2.03–1.88(m,1H),1.76–1.68(m,2H),1.65–1.60(m,2H); 13 C NMR (201 MHz, deuterated dimethyl sulfoxide) δ 170.40, 157.75, 140.00, 139.26, 134.17, 128.46, 123.05, 117.70, 116.56, 115.74, 107.57, 106.08, 103.24, 101.80, 98.96, 66.72, 55.71, 55.00, 53.69, 50.62, 43.43, 30.79, 26.26, 25.87, 24.03, 20.32. HR-MS (ES, m / z): C 26 H 31 N4O2 + [M+H] + , calculated value: 431.2442; measured value: 431.2440.

[0209] Example 2: 7-(4-(4,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyrrolo[4,3,2-de]quinolin-8-yl)butoxy)quinolin-2(1H)-one (Compound I-2)

[0210]

[0211] Step 1: Following the method of Step 1 of Example 1, alkylation reaction was carried out using "7-hydroxy-quinolin-2(1H)-one" and 1,4-dibromobutane as raw materials to prepare intermediate wha70 (1.06 g, 38%) as a white solid. 1H NMR (800 MHz, deuterated chloroform) δ7.79 (d, J = 9.4 Hz, 1H), 7.48 (d, J = 8.4 Hz, 1H), 6.87–6.83 (m, 2H), 6.60 (d, J = 9.3 Hz, 1H), 4.11 (t, J = 6.0 Hz, 2H), 3.51 (t, J = 6.6 Hz, 2H), 2.12–2.07 (m, 2H), 2.04–1.97 (m, 2H). HR-MS (ESI, m / z): C 13 H 15 BrNO2 + [M+H] + , calculated value: 296.0281; measured value: 296.0220.

[0212] Step 2: Following the method of step 2 of Example 1, the intermediate wha70 was alkylated with the raw material (A) to obtain compound I-2 (60 mg, 61%), which was purified by preparative HPLC: R = 18.5 min (20-80% MeOH / H2O), white solid. 1 H NMR (800 MHz, deuterated methanol) δ7.91 (d, J = 9.4 Hz, 1H), 7.61 (d, J = 8.7 Hz, 1H), 7.03 (t, J = 7.8 Hz, 1H), 6.92 (dd, J = 8.7, 2.4 Hz, 1H), 6.89–6.84 (m, 3H), 6.47 (d, J = 9.4 Hz, 1H), 6.40 (d, J = 7.5 Hz, 1H), 4.19(t,J=5.8Hz,3H),3.79(t,J=10.0Hz,2H),3.41–3.33(m,4H),3.19(dd,J=15.2,3.9Hz, 1H),3.14–3.06(m,2H),2.90(dd,J=15.0,9.5Hz,1H),2.09–2.05(m,2H),2.00–1.96(m,2H); 13 C NMR (201 MHz, deuterated dimethyl sulfoxide) δ 162.35, 160.31, 140.68, 140.08, 139.97, 134.18, 129.32, 123.06, 118.61, 117.70, 116.57, 113.46, 110.81, 106.06, 103.25, 98.97, 98.73, 67.01, 55.65, 54.95, 53.67, 50.59, 43.41, 26.25, 25.76, 20.25; HR-MS (ESI, m / z): C 26 H 29 N4O2 + [M+H]+ , calculated value: 429.2285; measured value: 429.2281.

[0213] Chiral separation of compound I-2.

[0214] Chiral analysis conditions: Chiral column: Chiralcel OD-H (ODHOCD-TC013) (Daicicel), column volume: 0.46 cm (diameter) x 15 cm (column length) (5 μm packing); mobile phase: MeOH / diethylamine = 100 / 0.1 (v / v / ); flow rate: 1.0 mL / min; wavelength: UV 214 nm; temperature: 35°C; HPLC instrument: Shimadzu LC-20AD. Peak 1 (front peak) t R =5.805min; peak2 (latter peak): t R =7.548min.

[0215] Chiral preparation conditions: Chiral column CHIRALCEL OD (Dacelide), column volume: 5.0 cm (diameter) x 25 cm (column length) (10 μm filler); mobile phase: MeOH / diethylamine = 100 / 0.1 (v / v / ); flow rate: 30 mL / min; wavelength: UV 214 nm; temperature: 38°C.

[0216] Separation preparation: racemic compound I-2 (0.103 g). peak 1 (front peak) t R =5.830min, yield 0.048g, >98%ee; optical rotation value [α] D 25 =+50.33°(c=0.1,MeOH),>98%ee(the compound is trifluoroacetate). peak2(latter peak)t R =7.60min, yield 0.042g, >98%ee; optical rotation value [a] D 25 =-45.00° (c=0.1, MeOH), >98% ee (the compound is trifluoroacetate).

[0217] Example 3: 5-(4-(4,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyrazolo[4,3,2-de]quinolin-8-yl)butoxy)benzo[d]thiazole (Compound I-3)

[0218]

[0219] Step 1: Following the method of Step 1 of Example 1, intermediate wha72 (1.23 g, 65%) was prepared using "5-hydroxy-benzo[d]thiazole" and 1,4-dibromobutane as raw materials as white solid. 1 H NMR (800 MHz, deuterated chloroform) δ 8.98 (s, 1H), 7.80 (d, J = 8.7 Hz, 1H), 7.60 (d, J = 2.4 Hz, 1H), 7.09 (dd, J = 8.7, 2.4 Hz, 1H), 4.10 (t, J = 6.1 Hz, 2H), 3.51 (t, J = 6.6 Hz, 2H), 2.13–2.09 (m, 2H), 2.04–1.97 (m, 2H). HR-MS (ESI, m / z): C 11 H 13 BrNOS + [M+H] + , calculated value: 285.9896; measured values: 285.9894 and 287.9875.

[0220] Step 2: Following the method of Step 2 of Example 1, the intermediate wha72 was alkylated with the raw material (A) to obtain compound I-3 (30 mg, 51%) as a yellow solid. 1 H NMR (800 MHz, deuterated methanol) δ9.18 (s, 1H), 7.90 (d, J = 8.8 Hz, 1H), 7.59 (d, J = 2.4 Hz, 1H), 7.16 (dd, J = 8.8, 2.4 Hz, 1H), 6.96 (t, J = 7.8 Hz, 1H), 6.78 (d, J = 8.1 Hz, 1H), 6.73 (d, J = 1.6 Hz, 1H), 6.29 (d, J = 7.5 Hz, 1H), 4.15–4.08 (m, 2H), 3.80 (d, J=12.0Hz,1H),3.15–3.10(m,2H),3.09–3.05(m,1H),2.95(dd,J=15.2,3.6Hz,1H),2.86–2.83(m,1H),2.79–2.7 6(m,1H),2.53(t,J=4.8Hz,2H),2.37–2.34(m,1H),2.12(t,J=10.9Hz,1H),1.92–1.85(m,2H),1.83–1.77(m,2H). 13C NMR (201 MHz, deuterated chloroform) δ 158.55, 155.05, 154.79, 142.34, 134.44, 125.59, 124.18, 122.15, 118.18, 116.59, 115.04, 109.55, 106.60, 102.06, 99.12, 68.28, 60.25, 58.35, 56.28, 53.13, 46.38, 27.63, 27.36, 23.60. HR-MS (ESI, m / z): C 24 H 27 N4OS + [M+H] + , calculated value: 419.1900; measured value: 419.1901.

[0221] Example 4: 5-(4-(4,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyrrolo[4,3,2-de]quinolin-8-yl)butoxy)-2-methylbenzo[d]oxazole (Compound I-4)

[0222]

[0223] Step 1: Following the procedure of Step 1 of Example 1, intermediate whb35 (0.15 g, 31%) was prepared using 2-methyl-5-hydroxybenzo[d]thiazole and 1,4-dibromobutane as raw materials as a light yellow solid. 1 H NMR (800 MHz, deuterated chloroform) δ 7.35 (d, J = 8.8 Hz, 1H), 7.14 (d, J = 2.5 Hz, 1H), 6.89 (dd, J = 8.8, 2.5 Hz, 1H), 4.03 (t, J = 6.1 Hz, 2H), 3.50 (t, J = 6.7 Hz, 2H), 2.64 (s, 3H), 2.12–2.06 (m, 2H), 2.00–1.94 (m, 2H). 13 C NMR (201 MHz, deuterated chloroform) δ 164.83, 156.41, 145.75, 142.33, 113.34, 110.45, 103.63, 68.18, 67.83, 33.58, 29.64, 28.06, 14.75. HR-MS (ESI, m / z): C 12 H 15 BrNO2 + [M+H] + , calculated value: 284.0281; measured values: 284.0280 and 286.0281.

[0224] Step 2: Following the method of Step 2 of Example 1, the intermediate whb35 was alkylated with the raw material (A) to obtain compound I-4 (41 mg, 43%) as an off-white solid. 1 H NMR (600 MHz, deuterated chloroform) δ 7.90 (s, 1H), 7.33 (d, J = 8.8 Hz, 1H), 7.13 (d, J = 1.3 Hz, 1H), 7.07 (t, J = 7.7 Hz, 1H), 6.88 (dd, J = 8.8, 1.8 Hz, 1H), 6.79 (d, J = 8.1, 1.2 Hz, 1H), 6.71 (t, J = 1.8 Hz, 1H), 6.33 (d, J = 7.6 Hz, 1H), 4.03 (t, J = 6.2 Hz, 2H), 3.80 (d, J = 12.1Hz,1H),3.23(t,J=11.0Hz,1H),3.11(d,J=3.8Hz,2H),3.01–2.93(m,2H),2.81(dd,J=13.8,11.0Hz,1H),2.60(d, J=1.2Hz,3H),2.52(t,J=7.6Hz,2H),2.41–2.34(m,1H),2.14(t,J=10.9Hz,1H),1.88–1.85(m,2H),1.82–1.74(m,2H). 13 C NMR (201 MHz, deuterated chloroform) δ 164.76, 156.53, 145.69, 142.42, 134.44, 124.15, 118.17, 115.10, 113.33, 110.39, 109.40, 103.68, 102.12, 99.14, 68.64, 60.00, 58.31, 56.13, 52.96, 46.24, 29.82, 27.69, 27.43, 23.45, 14.73. HR-MS (ESI, m / z): C 25 H 29 N4O2 + [M+H] + , calculated value: 417.2285; measured value: 417.2289.

[0225] Example 5: 6-(4-(4,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyrrolo[4,3,2-de]quinolin-8-yl)butoxy)-3-methylbenzo[d]isoxazole (Compound I-5)

[0226]

[0227] Step 1: Following the procedure of Step 1 of Example 1, intermediate whb37 (0.16 g, 42%) was prepared from 3-methyl-6-hydroxybenzo[d]isoxazole and 1,4-dibromobutane as raw materials as a light yellow solid. 1 H NMR (800 MHz, deuterated chloroform) δ 7.52 (d, J = 8.6 Hz, 1H), 7.00 (d, J = 2.3 Hz, 1H), 6.89 (dd, J = 8.7, 2.4 Hz, 1H), 4.03 (t, J = 6.1 Hz, 2H), 3.50 (t, J = 6.6 Hz, 2H), 2.62 (s, 3H), 2.11–2.07 (m, 2H), 2.01–1.95 (m, 2H). 13 C NMR (201 MHz, deuterated chloroform) δ 162.98, 157.05, 151.85, 135.32, 119.44, 112.62, 96.17, 67.79, 33.52, 29.57, 28.00, 14.58. HR-MS (ESI, m / z): C 12 H 15 BrNO2 + [M+H] + , calculated value: 284.0281; measured values: 284.0261 and 286.0241.

[0228] Step 2: Following the method of Step 2 of Example 1, the intermediate whb37 was alkylated with the raw material (A) to obtain compound I-5 (58 mg, 60%) as an off-white solid. 1 H NMR (600 MHz, deuterated chloroform) δ8.03 (s, 1H), 7.49 (d, J = 8.7 Hz, 1H), 7.06 (t, J = 7.8 Hz, 1H), 7.00 (d, J = 2.5 Hz, 1H), 6.89 (dd, J = 8.7, 2.4 Hz, 1H), 6.77 (d, J = 8.1 Hz, 1H), 6.69 (s, 1H), 6.32 (d, J = 7.6 Hz, 1H), 4.02 (t, J = 6.3 Hz, 2H), 3.79 (d, J = 1 2.0Hz,1H),3.21(t,J=10.8Hz,1H),3.09–3.06(m,2H),2.98–2.90(m,2H),2.81(dd,J=15.4,10.9Hz,1H),2.58( s,3H),2.52–2.46(m,2H),2.34(t,J=11.7Hz,1H),2.11(t,J=10.9Hz,1H),1.91–1.82(m,2H),1.79–1.73(m,2H). 13C NMR (201 MHz, deuterated chloroform) δ 162.87, 157.17, 151.85, 142.22, 135.21, 134.41, 124.09, 119.37, 118.15, 115.09, 112.65, 109.35, 102.12, 99.07, 96.13, 68.58, 60.10, 58.25, 56.19, 53.01, 46.28, 27.69, 27.34, 23.43, 14.53. HR-MS (ESI, m / z): C 25 H 29 N4O2 + [M+H] + , calculated value: 417.2285; measured value: 417.2290.

[0229] Example 6: 8-(4-((2,3-dihydrobenzofuran-6-yl)oxy)butyl)-6,6a,7,8,9,10-hexahydro-4H-pyrazino[1,2-a]pyrrolo[4,3,2-de]quinoline (Compound I-6)

[0230]

[0231] Step 1: Following the procedure of Step 1 of Example 1, intermediate whb53 (0.29 g, 81%) was prepared using 6-hydroxy-2,3-dihydrobenzofuran and 1,4-dibromobutane as raw materials as a white solid. 1 H NMR (800 MHz, deuterated chloroform) δ 7.05 (d, J = 7.9 Hz, 1H), 6.39–6.35 (m, 2H), 4.57 (t, J = 8.6 Hz, 2H), 3.95 (t, J = 6.1 Hz, 2H), 3.48 (t, J = 6.7 Hz, 2H), 3.13 (t, J = 8.6 Hz, 2H), 2.08–2.02 (m, 2H), 1.95–1.89 (m, 2H). 13 C NMR (201 MHz, deuterated chloroform) δ 161.44, 159.64, 124.93, 119.03, 106.53, 96.87, 72.16, 67.24, 33.65, 29.64, 29.22, 28.14.

[0232] Step 2: Following the method of Step 2 of Example 1, the intermediate wha53 was alkylated with the raw material (A) to obtain compound I-6 (30 mg, 32%) as a white solid. 1H NMR (800 MHz, deuterated chloroform) δ7.82 (s, 1H), 7.08 (t, J = 7.8 Hz, 1H), 7.06–7.01 (m, 1H), 6.80 (d, J = 8.1 Hz, 1H), 6.73 (s, 1H), 6.40–6.37 (m, 2H), 6.33 (d, J = 7.6 Hz, 1H), 4.56 (t, J = 8.6 Hz, 2H), 3.96 (t, J = 6.2 Hz, 2H), 3.82–3.78 ( m,1H),3.23–3.16(m,1H),3.15–3.10(m,2H),3.11–3.06(m,2H),3.00–2.95(m,2H),2.82(dd,J=15.3,10. 8Hz,1H),2.51–2.46(m,2H),2.39–2.31(m,1H),2.14–2.07(m,1H),1.85–1.80(m,2H),1.79–1.71(m,2H). 13 C NMR (201 MHz, deuterated chloroform) δ 161.41, 159.77, 134.44, 124.90, 124.18, 118.85, 118.17, 115.09, 109.46, 106.60, 102.11, 99.16, 96.90, 72.13, 68.06, 59.98, 58.30, 56.12, 52.95, 46.23, 29.21, 27.69, 27.40, 23.40. HR-MS (ESI, m / z): C 25 H 30 N3O2 + [M+H] + , calculated value: 404.2333; measured value: 404.2330.

[0233] Example 7: 7-(3-(4,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyrrolo[4,3,2-de]quinolin-8-yl)propoxy)-3,4-dihydroquinolin-2(1H)-one (Compound I-7)

[0234]

[0235] Step 1: Following the procedure of Step 1 of Example 1, intermediate whb71 (2.85 g, 81%) was prepared using 7-hydroxy-3,4-dihydroquinolin-2(1H)-one and 1,3-dibromopropane as raw materials as a white solid. 1H NMR (800 MHz, deuterated chloroform) δ 8.94 (s, 1H), 7.05 (d, J = 8.1 Hz, 1H), 6.54 (dd, J = 7.9, 2.4 Hz, 1H), 6.41 (d, J = 2.4 Hz, 1H), 4.07 (t, J = 5.8 Hz, 2H), 3.59 (t, J = 6.4 Hz, 2H), 2.90 (t, J = 8.7 Hz, 2H), 2.63 (t, J = 8.7 Hz, 2H), 2.31–2.28 (m, 2H). HR-MS (ESI, m / z): C 12 H 15 BrNO2 + [M+H] + , measured value: 284.0281, calculated value: 284.0273 and 286.0255.

[0236] Step 2: Following the method of Step 2 of Example 1, the intermediate whb71 was alkylated with the raw material (A) to obtain compound I-7 (60 mg, 63%) as an off-white solid. 1 H NMR (800 MHz, deuterated chloroform) δ 7.95 (s, 1H), 7.89 (s, 1H), 7.08 (t, J = 7.8 Hz, 1H), 7.04 (d, J = 8.3 Hz, 1H), 6.80 (d, J = 8.1 Hz, 1H), 6.72 (s, 1H), 6.54 (dd, J = 8.3, 2.4 Hz, 1H), 6.34 (d, J = 7.6 Hz, 1H), 6.32 (d, J = 2.4 Hz, 1H), 4.02 (t, J = 6.3 Hz, 2H), 3.81(d,J=11.8Hz,1H),3.22(t,J=9.7Hz,1H),3.12–3.07(m,2H),3.02–2.93(m,2H),2.89(t,J=7.5Hz,2H),2.83 (dd,J=15.2,11.0Hz,1H),2.39(t,J=11.6Hz,1H),2.16(t,J=10.56Hz,1H),2.05–2.01(m,2H),1.81-1.67(m,4H). 13 C NMR (201 MHz, deuterated dimethyl sulfoxide) δ 170.31, 157.88, 141.95, 139.21, 134.02, 128.42, 122.97, 117.86, 115.56, 107.66, 102.07, 101.69, 98.01, 65.86, 59.55, 56.06, 54.40, 52.51, 45.91, 30.76, 27.09, 26.17, 24.00. HR-MS (ESI, m / z): C 25 H29 N4O2 + [M+H] + , calculated value: 417.2285; measured value: 417.2284.

[0237] Example 8: 7-(3-(4,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyrrolo[4,3,2-de]quinolin-8-yl)propoxy)quinolin-2(1H)-one (Compound I-8)

[0238]

[0239] Step 1: Following the method of Step 1 of Example 1, intermediate whb73 (1.36 g, 39%) was prepared from 7-hydroxyquinoline-2(1H)-one and 1,3-dibromopropane as raw materials as a white solid. 1 H NMR (800 MHz, deuterated chloroform) δ 12.45 (s, 1H), 7.74 (d, J = 9.3 Hz, 1H), 7.46 (d, J = 8.6 Hz, 1H), 6.88 (d, J = 2.3 Hz, 1H), 6.82 (dd, J = 8.0 and 2.4 Hz, 1H), 6.57 (d, J = 9.4 Hz, 1H), 4.21 (t, J = 5.7 Hz, 2H), 3.62 (t, J = 6.5 Hz, 2H), 2.37–2.34 (m, 2H). HR-MS (ESI, m / z): C 12 H 13 BrNO2 + [M+H] + , calculated value: 282.0124; measured values: 282.0128 and 284.0109.

[0240] Step 2: Following the method of Step 2 of Example 1, the intermediate whb73 was alkylated with the raw material (A) to obtain compound I-8 (0.10 g, 51%) as a white solid. 1H NMR (600 MHz, deuterated methanol) δ7.91 (d, J = 9.4 Hz, 1H), 7.62 (d, J = 8.7 Hz, 1H), 7.07–7.01 (m, 1H), 6.94 (dd, J = 8.7, 2.4 Hz, 1H), 6.91–6.85 (m, 3H), 6.48 (d, J = 9.4 Hz, 1H), 6.42 (d, J = 7.6 Hz, 1H), 4.26 (t, J = 5.7 Hz,2H),3.88–3.82(m,2H),3.52–3.46(m,2H),3.42–3.38(dd,J=12.6,3.5Hz,1H),3.24–3.08(m ,3H),2.92(dd,J=15.3,9.6Hz,1H),2.41–2.36(m,2H),2.07–2.03(m,1H),1.62(t,J=7.4Hz,1H). 13 C NMR (201 MHz, deuterated dimethyl sulfoxide) δ 162.32, 160.03, 140.63, 140.05, 134.16, 129.37, 123.05, 118.78, 117.70, 116.56, 113.60, 110.58, 106.08, 103.23, 98.90, 65.09, 53.78, 53.50, 50.77, 48.62, 43.51, 26.29, 23.44. HR-MS (ESI, m / z): C 25 H 27 N4O2 + [M+H] + , calculated value: 415.2129; measured value: 415.2129.

[0241] Example 9: 8-(3-(Benzo[d][1,3]dioxol-5-yloxy)propyl)-6,6a,7,8,9,10-hexahydro-4H-pyrazino[1,2-a]pyrrolo[4,3,2-de]quinoline (Compound I-9)

[0242]

[0243] Step 1: Following the procedure of Step 1 of Example 1, using sesamol (CAS#533-31-3) and 1,3-dibromopropane as starting materials, intermediate whb74 (1.67 g, 45%) was prepared as a white solid. 1H NMR (800 MHz, deuterated chloroform) δ 6.70 (d, J = 8.5 Hz, 1H), 6.49 (d, J = 2.5 Hz, 1H), 6.33 (dd, J = 8.5, 2.5 Hz, 1H), 5.91 (s, 2H), 4.02 (t, J = 5.8 Hz, 2H), 3.59 (t, J = 6.4 Hz, 2H), 2.29–2.26 (m, 2H).

[0244] Step 2: Following the method of Step 2 of Example 1, the intermediate whb74 and the raw material (A) were subjected to alkylation reaction to prepare compound I-9 (20 mg, 22%) as an off-white solid. 1 H NMR (600 MHz, deuterated chloroform) δ7.87 (s, 1H), 7.07 (t, J = 7.8 Hz, 1H), 6.79 (d, J = 8.1 Hz, 1H), 6.72–6.67 (m, 2H), 6.50 (d, J = 2.4 Hz, 1H), 6.37–6.30 (m, 2H), 5.90 (s, 2H), 3.97 (t, J = 6.3 Hz, 2H), 3 .80(d,J=11.9Hz,1H),3.21(t,J=10.7Hz,1H),3.08–3.07(m,2H),3.02–2.89(m,2H),2.8 2(dd,J=15.3,11.0Hz,1H),2.59(t,J=7.4Hz,2H),2.37(t,J=11.7Hz,1H),2.14(t,J=10.8 Hz,1H),2.05–1.96(m,2H). 13 C NMR (201 MHz, deuterated dimethyl sulfoxide) δ 154.09, 147.91, 141.95, 141.01, 134.01, 122.96, 117.85, 115.54, 108.02, 107.65, 105.72, 102.05, 100.92, 97.99, 97.82, 66.64, 59.54, 56.05, 54.40, 52.50, 45.91, 27.09, 26.22. HR-MS (ESI, m / z): C 23 H 26 N3O3 + [M+H] + , calculated value: 392.1969; measured value: 392.1970.

[0245] Example 10: 3-(4-(2-(4,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyrrolo[4,3,2-de]quinolin-8-yl)ethyl)trans-cyclohexyl)-1,1-dimethylurea (Compound I-10)

[0246]

[0247] Step 1: A round-bottom flask was charged with 2-(4-((tert-butoxycarbonyl)amino)trans-cyclohexyl)acetic acid (2.0 g, 7.77 mmol) and DMF (15 mL). CsCO (7.6 g, 23.3 mmol) and benzyl bromide (5.32 g, 11.7 mmol) were then added sequentially. The mixture was stirred at room temperature overnight. After completion of the reaction, the mixture was filtered, the filtrate was concentrated, and the residue was purified by column chromatography (eluent: 0-20% methanol in dichloromethane) to afford the target compound whb52 (2.36 g, 87% yield) as a white solid. 1 H NMR (800 MHz, deuterated chloroform) δ 7.39–7.30 (m, 5H), 5.11 (s, 2H), 4.36 (s, 1H), 3.36 (s, 1H), 2.24 (d, J = 6.7 Hz, 2H), 2.00–1.96 (m, 2H), 1.79–1.72 (m, 3H), 1.43 (s, 9H), 1.14–1.04 (m, 4H). HR-MS (ESI, m / z): C 20 H 29 NO4Na + [M+Na] + , calculated value: 370.1989; found value: 370.1989 (M+Na).

[0248] Step 2: Dissolve whb52 (0.16 g, 0.46 mmol) from the previous step in dichloromethane (3 mL), add trifluoroacetic acid (1.5 mL), and stir at room temperature for 3 hours. The mixture was concentrated under reduced pressure, and the residue was dissolved in THF (5 mL). Et3N (1 mL) and dimethylcarbamoyl chloride (54 mg, 0.5 mmol) were then added sequentially. The reaction was stirred at room temperature overnight. After completion of the reaction, the solvent was removed and the product was purified by silica gel column chromatography (eluent: 0-20% methanol in dichloromethane) to afford the target compound whb54 (0.78 g, 83%) as a white solid. 1 H NMR (800 MHz, deuterated chloroform) δ 7.38–7.30 (m, 5H), 5.11 (s, 2H), 3.60–3.55 (m, 1H), 2.88 (s, 6H), 2.26 (d, J = 6.7 Hz, 2H), 2.04–1.99 (m, 2H), 1.80–1.76 (m, 3H), 1.17–1.09 (m, 4H). 13C NMR (151 MHz, deuterated chloroform) δ 172.80, 157.86, 136.07, 128.59, 128.23, 128.19, 66.12, 49.49, 41.47, 36.19, 34.23, 33.69, 31.76. HR-MS (ESI, m / z): C 18 H 27 N2O3 + [M+H] + , calculated value: 319.2016; measured value: 319.2201.

[0249] Step 3: whb54 (0.78 g, 2.45 mmol) was dissolved in THF (20 mL) and cooled to -10°C under argon (Ar). DABAL-H (14.7 mL, 1 M) was then added. The reaction system was stirred at 0°C for 5 hours. After completion of the reaction, the reaction was quenched with saturated potassium sodium tartrate solution (5 mL). After removal of the solvent, the product was purified by silica gel column chromatography (eluent: 0-20% methanol in dichloromethane) to afford whb59 (0.50 g, 95% yield) as a white solid. 1 H NMR (600 MHz, deuterated chloroform) δ 4.27 (d, J = 7.7 Hz, 1H), 3.65 (t, J = 6.7 Hz, 2H), 3.59-3.52 (m, 1H), 2.88 (s, 6H), 2.00 (d, J = 10.6 Hz, 2H), 1.81-1.75 (m, 2H), 1.49-1.46 (m, 2H), 1.40-1.34 (m, 1H), 1.15-1.01 (m, 4H). HR-MS (ESI, m / z): C 11 H 23 N2O2 + [M+H] + , calculated value: 215.1754; measured value: 215.1983.

[0250] Step 4: Dissolve whb59 (0.65 g, 3.04 mmol) and CBr4 (1.5 g, 4.56 mmol) in dichloromethane (15 mL). Cool in an ice-water bath and stir. Add PPh3 (1.2 g, 4.56 mmol), then stir at room temperature for 4 hours. Evaporate the solvent under reduced pressure, and purify the residue by silica gel column chromatography (mobile phase: dichloromethane containing 0-3% methanol) to yield whb60 (0.25 g, 38%) as a white solid. 1H NMR (800 MHz, deuterated chloroform) δ 4.16–4.00 (m, 1H), 3.61–3.57 (m, 1H), 3.43 (t, J = 7.0 Hz, 1H), 2.88 (s, 6H), 2.03 (d, J = 10.0, Hz, 2H), 1.80–1.74 (m, 4H), 1.47–1.43 (m, 1H), 1.14–1.03 (m, 4H). HR-MS (ESI, m / z): C 11 H 22 BrN2O + [M+H] + , calculated value: 277.0910; measured values: 277.0924 and 279.0925.

[0251] Step 5: The experimental method was the same as that of Step 2 in Example 1, and whb60 and the raw material (A) were subjected to an alkylation reaction to prepare compound I-10 (0.18 g, 95%) as an off-white solid. 1 H NMR (800 MHz, deuterated chloroform) δ7.93 (s, 1H), 7.07 (t, J = 7.8 Hz, 1H), 6.79 (d, J = 8.1 Hz, 1H), 6.72 (t, J = 1.7 Hz, 1H), 6.33 (d, J = 7.6 Hz, 1H), 4.12 (d, J = 7.6 Hz, 1H), 3.79 (d, J = 11.7, 2.7 Hz, 1H), 3.61–3.56 (m, 1H), 3.21 (s, 1H), 3.07 (d, J = 10.2 Hz, 2H), 2.97 (dd, J=15.2,3.7Hz,1H),2.93(t,J=11.8Hz,1H),2.88(s,6H),2.84–2.78(m,1H),2.43(t,J=7.9Hz,2H),2.32(t,J=10.9Hz,1H ),2.09(t,J=10.8Hz,1H),2.04–1.99(m,2H),1.81–1.75(m,2H),1.49–1.46(m,2H),1.29–1.24(m,1H),1.14–1.04(m,3H). 13 C NMR (201 MHz, deuterated chloroform) δ 157.97, 142.19, 134.40, 123.92, 118.14, 115.13, 109.19, 102.14, 98.90, 65.92, 60.19, 56.70, 56.18, 53.11, 49.93, 46.26, 40.99, 36.22, 35.70, 34.05, 33.80, 32.14, 27.70, 15.34. HR-MS (ESI, m / z): C 24 H36 N5O + [M+H] + , calculated value: 410.2914, measured value: 410.2914.

[0252] Chiral resolution of compound I-10

[0253] Chiral analysis conditions: Chiral column CHIRALPAK IG (Dacel), column volume: 0.46 cm (diameter) x 15 cm (length) (5 μm particle size packing); mobile phase: methanol / acetonitrile / diethylamine = 80 / 20 / 0.1 (v / v / v); flow rate: 1.0 mL / min; wavelength: UV 210 nm; temperature: 25°C; HPLC instrument: Shimadzu LC-2010BJ. Peak 1 (front peak) t R =3.113min; peak2 (latter peak): t R =4.622min.

[0254] Chiral preparation conditions: Chiral column CHIRALPAK IG (Dacel), column volume: 2.5 cm (diameter) x 25 cm (length) (10 μm particle size packing); mobile phase: methanol / acetonitrile / diethylamine = 80 / 20 / 0.1 (v / v / v); flow rate: 1.0 mL / min; wavelength: UV 210 nm; temperature: 25°C; HPLC instrument: Shimadzu LC-2010BJ. Peak 1 (front peak) t R =3.113min; peak2 (latter peak): t R =4.622min.

[0255] Chiral separation: racemic compound I-10 (1.20 g), (-)-I-10 is the front peak (peak 1), t R =3.057min, yield 0.566g, >99%ee, optical rotation [α] D 25 =-56.67°(c=0.1,CHCl3);(+)-I-10 is the latter peak (peak 2), t R =4.512min, yield 0.599g, >99%ee, optical rotation [α] D 25 =+50.33°(c=0.1,CHCl3).

[0256] Synthesis of pNs-(+)-I-10 and determination of its chiral configuration:

[0257]

[0258] Procedure: (+)-I-10 (23 mg, 0.056 mmol) was dissolved in DMF (3 mL), followed by the addition of potassium tert-butoxide (13 mg, 0.116 mmol) and p-nitrobenzenesulfonyl chloride (14 mg, 0.063 mmol). The reaction mixture was stirred at room temperature for one hour. After completion of the reaction, water was added, followed by extraction three times with dichloromethane. The organic phases were combined and concentrated. The resulting crude product was purified by flash silica gel column chromatography (eluent: 0-10% methanol / dichloromethane) to afford pNs-(+)-I-10 as an orange-yellow solid (20 mg, 60% yield). 1 H NMR (800MHz, CDCl3) δ8.27–8.23(m,2H),8.05–8.01(m,2H),7.32(d,J=8.2Hz,1H),7.22(t,J=8.0Hz,1H),7.01 (d,J=1.9Hz,1H),6.50(d,J=7.9Hz,1H),4.10(d,J=7.6Hz,1H),3.71-3.68(m,1H),3.60-3.55(m,1H),3.16-3. 12(m,1H),3.07-3.04(m,2H),2.90-2.88(m,7H),2.69-2.65(m,1H),2.44-2.40(m,2H),2.28-2.25(m,1H),2.1 1–1.96(m,3H),1.78-1.75(m,2H),1.47-1.42(m,2H),1.33–1.27(m,1H),1.13–1.03(m,4H).HR-MS(ESI,m / z):C 30 H 39 N6O5S + [M+H] + Calculated value: 595.2697; Measured value: 595.2663. Optical rotation value [α] D 25 =+47.67°(c=0.1,CDCl3).

[0259] Preparation of single crystal of compound represented by formula pNs-(+)-I-10

[0260] Cultivate single crystals by evaporation: Weigh 10 mg of compound pNs-(+)-I-10 into 1 mL of chloroform and add 10 mL of petroleum ether. Place the test tube at room temperature to slowly evaporate and crystallize.

[0261] Detection method: X-ray single crystal diffraction

[0262] After testing, the crystal system of the compound represented by formula pNs-(+)-I-10 belongs to the triclinic system, P1 space group, and the unit cell parameters are α=90.15°,β=99.368°,γ=90.25°,the number of asymmetric units Z in the unit cell is 2; its X-ray single crystal diffraction is shown in FIG1 .

[0263] The characterization results of X-ray single crystal diffraction can determine the configuration of compound pNs-(+)-I-10 as follows: Thus, the configuration of (+)-I-10 compound can be deduced as Accordingly, the configuration of (-)-I-10 compound is

[0264] Example 11: N-(4-(2-(4,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyrrolo[4,3,2-de]quinolin-8-yl)ethyl)trans-cyclohexyl)tetrahydropyrrole-1-carboxamide (Compound I-11)

[0265]

[0266] Step 1: Using whb52 as starting material, following the method of Step 2 of Example 10, substituting tetrahydropyrrole-1-carbonyl chloride for dimethylcarbamoyl chloride, the intermediate whb77 (0.54 g, 87%) was prepared as a white solid. 1 H NMR (800 MHz, deuterated chloroform) δ 7.39–7.30 (m, 5H), 5.11 (s, 2H), 3.95 (br, 1H), 3.61-3.56 (m, 1H), 3.31–3.29 (m, 4H), 2.25 (d, J = 6.8 Hz, 2H), 2.06–2.00 (m, 2H), 1.91–1.87 (m, 4H), 1.65-1.59 (m, 2H), 1.17–1.07 (m, 4H).

[0267] Step 2: Following the procedure of Step 3 of Example 10, whb77 was converted to whb81 (0.36 g, 96%), a white solid. 1 H NMR (800 MHz, deuterated chloroform) δ 3.69 (t, J = 6.7 Hz, 2H), 3.63-3.59 (m, 1H), 3.34-3.32 (d, J = 6.4 Hz, 4H), 2.06-2.01 (m, 2H), 1.93-1.88 (m, 4H), 1.82-1.77 (m, 2H), 1.50-1.47 (m, 2H), 1.40-1.36 (m, 1H), 1.15-1.05 (m, 4H). HR-MS (ESI, m / z): C 13 H 25 N2O2 + [M+H]+ , calculated value: 241.1911; measured value: 241.1945.

[0268] Step 3: Following the procedure of Step 4 of Example 10, the intermediate whb81 was converted into whb87 (0.34 g, yield 76%), a white solid. 1 H NMR (600 MHz, deuterated chloroform) δ 3.99–3.93 (m, 1H), 3.63–3.58 (m, 1H), 3.44 (t, J = 7.0 Hz, 2H), 3.32–3.29 (m, 4H), 2.08–2.01 (m, 2H), 1.93–1.85 (m, 3H), 1.83–1.73 (m, 4H), 1.50–1.40 (m, 1H), 1.17–1.02 (m, 4H). HR-MS (ESI, m / z): C 13 H 24 BrN2O + [M+H] + , calculated value: 303.1067; measured values: 303.1073and305.1080.

[0269] Step 4: Following the method of Step 5 of Example 10, whb87 was alkylated with the raw material (A) to obtain the target compound I-11 (50 mg, 50%) as an off-white solid. 1 H NMR (800 MHz, deuterated chloroform) δ7.97 (d, J = 4.7 Hz, 1H), 7.07 (t, J = 7.8 Hz, 1H), 6.79 (d, J = 8.1 Hz, 1H), 6.72 (d, J = 1.8 Hz, 1H), 6.33 (d, J = 7.6 Hz, 1H), 3.95 (d, J = 7.8 Hz, 1H), 3.79 (d, J = 11.9 Hz, 1H), 3.63–3.58 (m, 1H), 3.32–3.29 (m, 4H), 3.22 (t, J = 10.24 Hz, 1H), 3.10–3.06 (m, 2H), 2 .98(dd,J=15.3,3.8Hz,1H),2.94(d,J=11.9Hz,1H),2.82(dd,J=15.3,10.9Hz,1H),2.44(t,J=7.9Hz,2H),2.36–2.30(m,1H),2.10( t,J=10.8Hz,1H),2.05–2.01(m,2H),1.92–1.85(m,3H),1.80–1.75(m,2H),1.51–1.44(m,2H),1.29–1.24(m,1H),1.13–1.05(m,4H). 13C NMR (201 MHz, deuterated chloroform) δ 156.13, 141.91, 134.14, 123.77, 117.87, 114.85, 114.83, 109.04, 101.83, 98.74, 98.72, 59.86, 56.45, 55.87, 52.82, 49.30, 45.97, 45.29, 35.45, 33.93, 33.52, 31.91, 27.42, 25.37. HR-MS (ESI, m / z): C 26 H 38 N5O + [M+H] + , calculated value: 436.3071; measured value: 436.3072.

[0270] Example 12: N-(4-(2-(4,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyrrolo[4,3,2-de]quinolin-8-yl)ethyl)trans-cyclohexyl)piperidine-1-carboxamide (Compound I-12)

[0271]

[0272] Step 1: Following the procedure of Step 2 of Example 10, replacing dimethylcarbamoyl chloride with piperidine-1-carbonyl chloride, the intermediate whb80 was prepared as a white solid. 1 H NMR (800 MHz, deuterated chloroform) δ 4.28–4.17 (m, 1H), 4.12 (q, J = 7.1 Hz, 2H), 3.62–3.56 (m, 1H), 3.31–3.27 (m, 4H), 2.19 (d, J = 7.0 Hz, 2H), 2.02 (m, 2H), 1.80–1.77 (m, 2H), 1.59–1.57 (m, 2H), 1.56–1.53 (m, 4H), 1.25 (t, J = 7.1 Hz, 3H), 1.15–1.08 (m, 4H). HR-MS (ESI, m / z): C 16 H 29 N2O3 + [M+H] + , calculated value: 297.2173; measured value: 297.2373.

[0273] Step 2: Following the procedure of Step 3 of Example 11, whb80 was converted to whb86, a white solid. 1H NMR (800 MHz, deuterated chloroform) δ 4.27 (s, 1H), 3.69 (t, J = 6.6 Hz, 2H), 3.59 (s, 1H), 3.31–3.27 (m, 4H), 2.02 (dd, J = 7.0, 3.7 Hz, 2H), 1.81–1.75 (m, 2H), 1.59–1.53 (m, 6H), 1.48 (q, J = 6.7 Hz, 2H), 1.40–1.36 (m, 1H), 1.12–1.04 (m, 4H). HR-MS (ESI, m / z): C 14 H 27 N2O2 + [M+H] + , calculated value: 255.2067; measured value: 255.2057.

[0274] Step 3: Following the procedure of Step 4 in Example 10, the intermediate whb86 was converted to whb89 (yield 80%), a white solid. 1 H NMR (600 MHz, deuterated chloroform) δ 4.25 (s, 1H), 3.59 (s, 1H), 3.44 (t, J = 7.0 Hz, 2H), 3.32–3.27 (m, 4H), 2.04–2.02 (m, 2H), 1.78–1.75 (m, 4H), 1.62–1.50 (m, 5H), 1.48–1.43 (m, 1H), 1.17–1.00 (m, 4H). HR-MS (ESI, m / z): C 14 H 26 BrN2O + [M+H] + , calculated value: 317.1223; measured values: 317.1260 and 319.1141.

[0275] Step 4: Following the method of Step 5 of Example 10, whb89 was subjected to alkylation reaction with raw material (A) to obtain the target compound I-12 (62 mg, 98%) as a white solid. 1H NMR (800MHz, deuterated chloroform) δ7.91(s,1H),7.07(t,J=7.8Hz,1H),6.80(d,J=8.1Hz,1H),6.72(t,J=1.8Hz,1H),6.33(d,J=7.6Hz,1H),4.20( d,J=7.5Hz,1H),3.79(d,J=11.9Hz,1H),3.61–3.57(m,1H),3.29(t,J=5.5Hz,4H),3.22(s,1H),3.07(d,J=10.9Hz,2H),2.98(dd,J= 15.2,3.8Hz,1H),2.94(d,J=12.0Hz,1H),2.82(dd,J=15.3,11.0Hz,1H),2.44(t,J=8.0Hz,2H),2.33(t,J=11.6Hz,1H),2.09(t,J=1 0.8Hz,1H),2.04–1.99(m,2H),1.79(d,J=12.3Hz,2H),1.61–1.54(m,5H),1.49–1.46(m,2H),1.29–1.23(m,1H),1.14–1.03(m,4H). 13 C NMR (201 MHz, deuterated chloroform) δ 156.97, 141.98, 134.13, 123.79, 117.86, 114.77, 109.13, 101.78, 98.74, 65.67, 59.95, 56.46, 55.91, 52.87, 49.61, 49.50, 46.01, 44.66, 40.82, 35.49, 33.77, 33.60, 31.90, 27.43, 25.39, 24.25. HR-MS (ESI, m / z): C 27 H 40 N5O + [M+H] + , calculated value: 450.3227; measured value: 450.3227.

[0276] Example 13: N-(4-(2-(4,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyrrolo[4,3,2-de]quinolin-8-yl)ethyl)trans-cyclohexyl)-1H-indole-2-carboxamide (Compound I-13)

[0277]

[0278] Step 1: To a round-bottom flask, methyl 2-(4-amino-trans-cyclohexyl)acetate (0.19 g, 1.02 mmol) was dissolved in tetrahydrofuran (5 mL). HATU (0.505 g, 1.33 mmol), DIPEA (1 mL), and 1H-indole-2-carboxylic acid (0.214 g, 1.33 mmol) were then added. The reaction was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: 40-50% ethyl acetate in petroleum ether) to afford intermediate WHB108 (0.30 g, 90%) as a white solid. 1 H NMR (800 MHz, deuterated chloroform) δ9.41 (d, J = 62.1 Hz, 1H), 7.64 (d, J = 8.0 Hz, 1H), 7.43 (d, J = 8.2 Hz, 1H), 7.28 (d, J = 8.3 Hz, 1H), 7.13 (t, J = 7.4 Hz, 1H), 6.85 (d, J = 4.9 Hz, 1H), 6.16 (d, J = 33.4 Hz, 1H), 4.14 (q, J = 7.1 Hz, 2H), 3.9 8–3.93(m,1H),2.24(dd,J=13.8,7.0Hz,2H),2.12(d,J=13.4Hz,2H),1.86(d,J=13.4Hz,2H),1.83–1.79 (m,1H),1.31(q,J=12.8Hz,2H),1.26(t,J=7.2Hz,3H),1.21–1.17(q,J=12.8Hz,2H).HR-MS(ESI,m / z):C 19 H 25 N2O3 + [M+H] + , calculated value: 329.1860; measured value: 329.1795.

[0279] Step 2: Following the procedure described in Step 3 of Example 10, intermediate whb108 was reduced to give intermediate whb149 (80 mg, 47%) as a white solid. 1H NMR (800 MHz, deuterated chloroform) δ9.23 (s, 1H), 7.64 (d, J = 8.0 Hz, 1H), 7.43 (d, J = 8.3 Hz, 1H), 7.28 (t, J = 8.2 Hz, 1H), 7.14 (t, J = 7.8 Hz, 1H), 6.82–6.79 (m, 1H), 3.97–3.93 (m, 1H), 3.72 (t, J = 6.6 Hz, 2H), 2.15–2.10 (m, 2H), 1.89–1.83 (m, 2H), 1.54–1.51 (m, 2H), 1.49–1.43 (m, 1H), 1.31–1.23 (m, 2H), 1.18–1.13 (m, 2H). HR-MS (ESI, m / z): C 17 H 23 N2O2 + [M+H] + , calculated value: 287.1754; measured value: 287.1752.

[0280] Step 3: Following the procedure of Step 4 of Example 10, the alcohol intermediate whb149 was converted into the bromide whb150 (0.11 g, 45%), a white solid. 1 H NMR (800 MHz, deuterated chloroform) δ9.31 (s, 1H), 7.64 (d, J = 8.0 Hz, 1H), 7.43 (d, J = 8.4 Hz, 1H), 7.31–7.27 (m, 1H), 7.13 (t, J = 7.12 Hz, 1H), 6.84 (d, J = 2.2 Hz, 1H), 6.10 (d, J = 8.2 Hz, 1H), 3.97–3. 91(m,1H),3.46(t,J=7.0Hz,2H),2.13(d,J=13.4Hz,2H),1.88–1.83(m,2H),1.81(q,J= 6.9Hz,2H),1.55–1.51(m,1H),1.33–1.29(m,2H),1.16–1.11(m,2H).HR-MS(ESI,m / z):C 17 H 22 BrN2O + [M+H] + , calculated value: 349.0910; measured values: 349.0901 and 351.0884.

[0281] Step 4: Following the method of Step 5 of Example 10, whb150 was alkylated with the raw material (A) to obtain compound I-13 (33 mg, yield 30%) as a white solid. 1H NMR (800 MHz, deuterated chloroform) δ9.16 (s, 1H), 7.83 (s, 1H), 7.64 (dd, J = 8.0, 1.1 Hz, 1H), 7.43 (dd, J = 8.3, 1.1 Hz, 1H), 7.28 (dd, J = 8.2, 7.0 Hz, 1H), 7.14 (dd, J = 8.0, 7.0 Hz, 1H), 7.08 (t, J = 7.8 Hz, 1H), 6.82–6.79 (m, 2H), 6.73 (d, J = 1.9 Hz, 1H), 6.34 (d, J = 7.6 Hz, 1H), 5.95 (d, J = 8.2Hz,1H),3.97–3.93(m,1H),3.82–3.78(m,1H),3.21(s,1H),3.08(d,J=10.8Hz,2 H),2.98(dd,J=15.2,3.8Hz,1H),2.94(t,J=11.8Hz,1H),2.83(dd,J=15.2,11.1Hz, 1H),2.46(t,J=7.9Hz,2H),2.35–2.30(m,1H),2.16–2.06(m,3H),1.87(d,J=11.96H z,2H),1.52–1.50(m,2H),1.36–1.32(m,1H),1.29–1.24(m,2H),1.20–1.14(m,2H). 13 C NMR (201 MHz, deuterated dimethyl sulfoxide) δ 160.22, 141.98, 136.35, 134.02, 132.02, 127.10, 123.11, 122.97, 121.39, 119.61, 117.86, 115.54, 112.26, 107.69, 102.46, 102.05, 98.00, 59.62, 56.07, 55.75, 52.55, 48.21, 45.92, 34.90, 33.46, 32.35, 31.74, 27.12. HR-MS (ESI, m / z): C 30 H 36 N5O + [M+H] + , calculated value: 482.2914; measured value: 482.2918.

[0282] Example 14: N-(4-(2-(4,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyrrolo[4,3,2-de]quinolin-8-yl)ethyl)trans-cyclohexyl)benzamide (Compound I-14)

[0283]

[0284] Step 1: Using ethyl 2-(4-(tert-butoxycarbonylamino-trans-cyclohexyl)acetate as starting material, the reaction mixture was pursuant to the procedure of Step 2 of Example 10, substituting benzoyl chloride for dimethylcarbamoyl chloride, to afford intermediate whb104 (0.20 g, 69% yield) as a white solid. 1 H NMR (800 MHz, deuterated chloroform) δ 7.74 (d, J = 7.6 Hz, 2H), 7.49 (t, J = 7.4 Hz, 1H), 7.42 (t, J = 7.5 Hz, 2H), 5.95–5.91 (br, 1H), 4.14 (q, J = 7.1 Hz, 2H), 3.96–3.91 (m, 1H), 2.23 (dd, J = 13.9, 7.0 Hz, 2H), 2.11 (d, J = 12.2 Hz, 2H), 1.85 (d, J = 13.3 Hz, 2H), 1.82–1.77 (m, 1H), 1.30–1.23 (m, 5H), 1.21–1.16 (m, 2H). HR-MS (ESI, m / z): C 17 H 24 NO3 + [M+H] + , calculated value: 290.1751; found value: 290.1748 and 312.1526 (M+23Na).

[0285] Step 2: Following the method described in Step 3 of Example 10, intermediate whb104 was reduced to obtain intermediate whb156 (0.11 g, yield 65%) as a white solid. 1 H NMR (800 MHz, deuterated chloroform) δ 7.77–7.73 (m, 2H), 7.51–7.46 (m, 1H), 7.45–7.40 (m, 2H), 5.89 (d, J = 8.1 Hz, 1H), 3.96–3.91 (m, 1H), 3.71 (t, J = 6.8 Hz, 2H), 2.14–2.09 (m, 2H), 1.87–1.83 (m, 2H), 1.53–1.50 (m, 2H), 1.47–1.42 (m, 1H), 1.28–1.20 (m, 2H), 1.18–1.11 (m, 2H). HR-MS (ESI, m / z): C 15 H 22 NO2 + [M+H] + , calculated value: 248.1645; measured value: 248.1772.

[0286] Step 3: Following the procedure of Step 4 of Example 10, the alcohol intermediate whb156 was converted into the bromide whb158 (78 mg, 57%), a white solid. 1H NMR (800 MHz, deuterated chloroform) δ 7.76–7.73 (m, 2H), 7.51–7.47 (m, 1H), 7.43 (dd, J = 8.3, 7.1 Hz, 2H), 5.89 (d, J = 8.1 Hz, 1H), 3.97–3.90 (m, 1H), 3.46 (t, J = 7.0 Hz, 2H), 2.13 (d, J = 13.2 Hz, 2H), 1.87–1.82 (m, 2H), 1.81–1.79 (m, 2H), 1.54–1.48 (m, 1H), 1.27–1.22 (m, 2H), 1.16–1.11 (m, 2H). HR-MS (ESI, m / z): C 15 H 21 BrNO + [M+H] + , calculated value: 310.0801; measured values: 310.0792 and 312.0772.

[0287] Step 4: Following the method of Step 5 of Example 10, whb158 was alkylated with the raw material (A) to obtain the target compound I-14 (30 mg, yield 32%) as a yellow solid. 1 H NMR (800 MHz, deuterated chloroform) δ7.84 (s, 1H), 7.76–7.73 (m, 2H), 7.52–7.46 (m, 1H), 7.43 (dd, J = 8.3, 7.1 Hz, 2H), 7.08 (t, J = 7.8 Hz, 1H), 6.80 (d, J = 8.1 Hz, 1H), 6.73 (d, J = 1.9 Hz, 1H), 6.34 (d, J = 7.5 Hz, 1H), 5.89 (d, J = 8.1 Hz, 1H), 3.97–3.92 (m, 1H), 3.81 (d, J = 11.7 Hz, 2H). z,1H),3.25–3.21(m,1H),3.08(d,J=10.9Hz,2H),2.99–2.93(m,2H),2.83(dd,J=15.3,11.0Hz,1H),2.48–2.44(s,2H),2.36 –2.32(m,1H),2.12(dd,J=12.1,3.8Hz,3H),1.85(d,J=12.8Hz,2H),1.53–1.50(m,2H),1.37–1.30(m,1H),1.26–1.13(m,4H). 13C NMR (201 MHz, deuterated dimethyl sulfoxide) δ 165.87, 142.44, 135.36, 134.48, 131.38, 128.59, 127.71, 123.43, 118.32, 116.02, 108.13, 102.53, 98.47, 56.51, 56.20, 53.01, 49.04, 46.36, 40.91, 35.37, 33.88, 32.65, 32.23, 27.58. HR-MS (ESI, m / z): C 28 H 35 N4O + [M+H] + , calculated value: 443.2805; measured value: 443.2807.

[0288] Example 15: N-(4-(2-(4,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyrrolo[4,3,2-de]quinolin-8-yl)ethyl)cyclohexyl)phenylsulfonamide (Compound I-15)

[0289]

[0290] Step 1: Using ethyl 2-(4-(tert-butoxycarbonylamino-trans-cyclohexyl)acetate as starting material, the reaction mixture was purged following the procedure of Step 2 of Example 10, substituting benzenesulfonyl chloride for dimethylcarbamoyl chloride, to afford intermediate whb105 (0.30 g, 89% yield) as a white solid. 1 H NMR (800 MHz, deuterated chloroform) δ 7.88 (d, J = 7.7 Hz, 2H), 7.57 (t, J = 7.4 Hz, 1H), 7.51 (t, J = 7.6 Hz, 2H), 4.51 (br, 1H), 4.09 (q, J = 7.1 Hz, 2H), 3.1–3.07 (m, 1H), 2.14 (dd, J = 14.4, 6.9 Hz, 2H), 1.83 (d, J = 13.3 Hz, 2H), 1.72 (d, J = 13.6 Hz, 2H), 1.69–1.65 (m, 1H), 1.23 (t, J = 7.1 Hz, 3H), 1.20–1.15 (m, 2H), 1.00–0.96 (m, 2H). HR-MS (ESI, m / z): [C 16 H 23 NO4S+Na] + [M+Na] + , calculated value: 348.1240; measured value: 348.1245.

[0291] Step 2: Following the procedure described in Step 3 of Example 10, intermediate whb105 was reduced to give intermediate whb155 (0.22 g, 87%) as a white solid. 1 H NMR (800 MHz, deuterated chloroform) δ 7.90–7.86 (m, 2H), 7.59–7.55 (m, 1H), 7.51 (dd, J = 8.4, 7.1 Hz, 2H), 4.34 (s, NH, 1H), 3.64 (t, J = 6.6 Hz, 2H), 3.11–3.06 (m, 1H), 1.86–1.82 (m, 2H), 1.72 (d, J = 13.2 Hz, 2H), 1.42 (q, J = 6.7 Hz, 2H), 1.36–1.28 (m, 1H), 1.16–1.11 (m, 2H), 0.96–0.90 (m, 2H). HR-MS (ESI, m / z): C 14 H 22 NO3S + [M+H] + , calculated value: 284.1315; measured value: 284.1332.

[0292] Step 3: Following the procedure of Step 4 of Example 10, the alcohol intermediate whb155 was converted into the bromide whb159 (0.10 g, 37%), a white solid. 1 H NMR (800 MHz, deuterated chloroform) δ 7.90–7.86 (m, 2H), 7.59–7.55 (m, 1H), 7.53–7.49 (m, 2H), 4.38 (br, 1H), 3.38 (t, J = 7.0 Hz, 2H), 3.12–3.07 (m, 1H), 1.88–1.82 (m, 2H), 1.74–1.68 (m, 4H), 1.43–1.35 (m, 1H), 1.19–1.12 (m, 2H), 0.96–0.86 (m, 2H). HR-MS (ESI, m / z): C 14 H 21 BrNO2S + [M+H] + , calculated value: 346.0471; measured values: 346.0457 and 348.0435.

[0293] Step 4: Following the method of Step 5 of Example 10, whb159 was alkylated with the raw material (A) to obtain the target compound I-15 (40 mg, 98%) as a light yellow solid. 1H NMR (800 MHz, deuterated chloroform) δ7.90–7.86 (m, 2H), 7.83 (s, 1H), 7.59–7.55 (m, 1H), 7.51 (dd, J = 8.3, 7.1 Hz, 2H), 7.07 (t, J = 7.8 Hz, 1H), 6.80 (d, J = 8.1 Hz, 1H), 6.72 (s, 1H), 6.32 (d, J = 7.6 Hz, 1H), 4.28 (d, J = 7.6 Hz, 1H), 3.80–3.77 (s, 1H), 3.23–3.16 (m, 1H), 3.12–3.08 (m ,1H),3.06–3.01(m,2H),2.97(d,J=15.0Hz,1H),2.80(dd,J=15.3,10.6Hz,1H),2.43-2.36(s,2H),2.31(s,1H),2.08-2.04(s,1 H),1.84(d,J=12.8Hz,3H),1.73(d,J=13.4Hz,2H),1.45-1.39(m,2H),1.23-1.19(m,1H),1.17–1.09(m,2H),0.99–0.92(m,2H). 13 C NMR (201 MHz, deuterated chloroform) δ 142.12, 141.61, 141.59, 134.37, 132.46, 129.10, 126.89, 123.98, 118.12, 115.15, 109.17, 102.19, 99.00, 60.04, 56.50, 56.09, 53.20, 52.98, 46.17, 40.89, 35.08, 33.88, 33.48, 31.90, 27.65. HR-MS (ESI, m / z): C 27 H 35 N4O2S + [M+H] + , calculated value: 479.2475; measured value: 479.2487.

[0294] Example 16: 3-(4-((4,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyrrolo[4,3,2-de]quinolin-8-yl)methyl)trans-cyclohexyl)-1,1-dimethylurea (Compound I-16)

[0295]

[0296] Step 1: Dissolve tert-butyl (4-(hydroxymethyl)trans-cyclohexyl)carbamate (0.23 g, 1 mmol) in DMF (5 mL), followed by the addition of triethylamine (1 mL) and 4-nitrobenzenesulfonyl chloride (0.27 g, 1.2 mmol). The reaction was stirred overnight at room temperature. After completion of the reaction, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: 0-10% methanol in dichloromethane) to afford intermediate whb132 (0.12 g, 29%) as a white solid. 1 H NMR (800 MHz, deuterated chloroform) δ8.43–8.38 (m, 2H), 8.12–8.08 (m, 2H), 3.93 (d, J=6.5 Hz, 2H), 3.42–3.29 (m, 1H), 2.06–2.00 (m, 2H), 1.78–1.76 (m, 2H), 1.70–1.65 (m, 1H), 1.43 (s, 9H), 1.17–1.07 (m, 4H). HR-MS (ESI, m / z): C 18 H 26 N2O7SNa + [M+Na] + , calculated value: 437.1358; measured value: 437.1323.

[0297] Step 2: Dissolve intermediate whb132 (0.12 g, 0.29 mmol) in dichloromethane (3 mL), add trifluoroacetic acid (1.5 mL), and stir at room temperature for 3 hours. After the reaction is complete, concentrate under reduced pressure, and the residue is dissolved in tetrahydrofuran (5 mL). Triethylamine (2 mL) and dimethylcarbamoyl chloride (37 mg, 0.35 mmol) are then added, and the reaction system is stirred at room temperature overnight. After the reaction is complete, concentrate under reduced pressure, and the residue is purified by silica gel column chromatography (eluent: 10-20% methanol in dichloromethane) to afford intermediate whb133 (30 mg, 27%) as a white solid. 1 H NMR (800 MHz, deuterated dimethyl sulfoxide) δ 8.48–8.43 (m, 2H), 8.21–8.17 (m, 2H), 5.86 (d, J = 7.8 Hz, 1H), 3.98 (d, J = 6.4 Hz, 2H), 3.29–3.25 (m, 1H), 2.73 (s, 6H), 1.76–1.71 (m, 2H), 1.66–1.60 (m, 2H), 1.57–1.51 (m, 1H), 1.17–1.12 (m, 2H), 0.97–0.92 (m, 2H). HR-MS (ESI, m / z): C 16 H 24 N3O6S + [M+H] +, calculated value: 386.1380; measured value: 386.1391.

[0298] Step 3: A round-bottom flask was charged with starting material (A) (50 mg, 0.23 mmol), intermediate whb133 (30 mg, 0.078 mmol), and KCO (127 mg, 0.92 mmol), followed by tetrahydrofuran (3 mL) and dimethyl sulfoxide (1 mL). The reaction system was heated and stirred at 60°C for 16 hours. After completion of the reaction, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane containing 0-10% methanol) to afford compound I-16 (12 mg, 13%) as an off-white solid. 1 H NMR (800 MHz, deuterated chloroform) δ7.92 (s, 1H), 7.06 (t, J = 7.8 Hz, 1H), 6.79 (d, J = 8.1 Hz, 1H), 6.71 (d, J = 1.8 Hz, 1H), 6.32 (d, J = 7.6 Hz, 1H), 4.14 (d, J = 7.6 Hz, 1H), 3.76 (d, J = 11.8 Hz, 1H), 3.63–3.58 (m, 1H), 3.26–3.21 (m ,1H),3.03–2.94(m,3H),2.88(s,6H),2.80(dd,J=15.3,10.9Hz,1H),2.34–2.30(m,1H),2.24–2.21(m ,2H),2.11–2.07(m,1H),2.07–2.03(m,2H),1.91–1.85(m,2H),1.55–1.50(m,1H),1.14–1.02(m,4H). 13 C NMR (201 MHz, deuterated chloroform) δ 157.94, 142.25, 134.37, 123.81, 118.13, 115.09, 109.13, 102.07, 98.78, 65.01, 60.65, 56.13, 53.38, 50.10, 46.23, 40.93, 36.19, 34.49, 33.83, 30.61, 27.62. HR-MS (ESI, m / z): C 23 H 34 N5O + [M+H] + , calculated value: 396.2758; measured value: 396.2755.

[0299] Example 17: 3-(2-(4,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyrrolo[4,3,2-de]quinolin-8-yl)ethyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one (Compound I-17)

[0300]

[0301] Following the procedure of step 2 of Example 1, the raw material (A) was alkylated with 3-(2-chloroethyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one (cas#63234-80-0, commercially available) to obtain compound I-17 as a dark green solid. The product was further purified by preparative HPLC (mobile phase: 20-80% MeOH / H2O). R =16 min, 10 mg (yield 10%). 1 H NMR (800 MHz, deuterated dimethyl sulfoxide) δ 10.68 (s, 1H), 10.03 (s, 1H), 6.97–6.92 (m, 1H), 6.90 (s, 1H), 6.80 (d, J = 8.1 Hz, 1H), 6.33 (d, J = 7.5 Hz, 1H), 4.11–4.05 (m, 1H), 3.90–3.82 (m, 2H), 3.80 (t, J = 6.2 Hz, 2H), 3.23–3.15 (m, 2H ),3.08(d,J=15.4Hz,2H),3.00–2.95(m,1H),2.93–2.84(m,2H),2.79(t,J=6.7Hz,2H),2.75(dd,J=15. 4,9.2Hz,1H),2.26(s,3H),2.03–1.96(m,1H),1.88–1.85(m,2H),1.79–1.75(m,2H),1.48–1.43(m,1H). 13 C NMR (201 MHz, deuterated dimethyl sulfoxide) δ 161.57, 158.89, 157.56, 139.89, 134.14, 123.03, 117.65, 116.57, 114.91, 105.99, 103.20, 98.97, 54.84, 53.65, 50.49, 43.45, 42.42, 30.65, 26.26, 21.14, 21.12, 20.79, 20.76, 18.35. HR-MS (ESI, m / z): C 24 H 30 N5O + [M+H] +, calculated value: 404.2445; measured value: 404.2444.

[0302] Example 18: 7-(4-(4-methyl-4,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyrrolo[4,3,2-de]quinolin-8-yl)butoxy)quinolin-2(1H)-one (Compound I-18)

[0303]

[0304] Step 1: To a round-bottom flask were added starting material (A) (0.20 g, 0.94 mmol), triethylamine (0.4 g, 3.76 mmol), DMAP (12 mg, 0.094 mmol), and DMF (5 mL). Then, Boc2O (0.23 g, 1.03 mmol) was added and stirred at room temperature for 12 hours. After completion of the reaction, the solvent was removed by concentration under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: 0-10% methanol in dichloromethane) to afford intermediate whb163 (0.22 g, 75%) as an off-white solid. 1 H NMR (800 MHz, deuterated chloroform) δ 7.85 (s, 1H), 7.09 (t, J = 7.8 Hz, 1H), 6.82 (d, J = 8.0 Hz, 1H), 6.75 (d, J = 1.9 Hz, 1H), 6.35 (d, J = 7.6 Hz, 1H), 4.31–4.21 (m, 1H), 4.20–4.08 (m, 1H), 3.81 (d, J = 11.9 Hz, 1H), 3.19–3.11 (m, 1H), 3.11–3.01 (m, 2H), 2.94–2.72 (m, 3H), 1.49 (s, 9H). HR-MS (ESI, m / z): C 18 H 24 N3O2 + [M+H] + , calculated value: 314.1863; measured value: 314.1862.

[0305] Step 2: To a round-bottom flask, intermediate whb163 (0.21 g, 0.67 mmol), potassium tert-butoxide (0.091 g, 0.81 mmol), and DMF (8 mL) were added and stirred for 30 minutes. Methyl iodide (0.19 g, 1.34 mmol) was added and stirring continued at room temperature for 3 hours. After the reaction was completed, water (3 mL) was added to quench the reaction system. A solid precipitated and was filtered to obtain the crude intermediate whb165 (0.18 g, 82%) as a yellow solid, which was used directly in the next step. 1H NMR (800 MHz, deuterated chloroform) δ 7.13–7.08 (m, 1H), 6.75 (d, J = 8.1 Hz, 1H), 6.59 (s, 1H), 6.33 (d, J = 7.6 Hz, 1H), 4.29–4.24 (m, 1H), 4.21–4.08 (m, 2H), 3.82–3.80 (m, 1H), 3.73 (s, 3H), 3.17–3.10 (m, 1H), 3.09–3.04 (m, 1H), 3.01 (d, J = 15.2 Hz, 1H), 2.80 (t, J = 13.0 Hz, 2H), 1.48 (s, 9H). HR-MS (ESI, m / z): C 19 H 26 N3O2 + [M+H] + , calculated value: 328.2020; measured value: 328.1990.

[0306] Step 3: Dissolve intermediate whb165 (50 mg) in dichloromethane (3 mL), add TFA (1 mL), and stir at room temperature for 1 hour. Evaporate the solvent under reduced pressure to obtain the crude product, which is used directly in the next step.

[0307] Step 4: The crude product obtained in Step 3 was dissolved in tetrahydrofuran (THF) (3 mL), followed by the addition of DMSO (1.5 mL), KCO (0.12 g, 0.87 mmol), and intermediate wha70 described in Example 2 (49 mg, 0.17 mmol). The mixture was stirred and heated at 60°C for 16 hours. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane containing 0-10% methanol) to afford the title compound I-18 (30 mg, 45%) as a pale yellow solid. 1H NMR (800 MHz, deuterated methanol) δ 7.89 (d, J = 9.4 Hz, 1H), 7.59 (d, J = 8.7 Hz, 1H), 7.03 (t, J = 7.8 Hz, 1H), 6.91 (dd, J = 8.7, 2.4 Hz, 1H), 6.87 (d, J = 2.4 Hz, 1H), 6.78 (d, J = 8.2 Hz, 1H), 6.67 (s, 1H), 6.45 (d, J = 9.4 Hz, 1H), 6.34 (d, J = 7.5 Hz, 1H), 4.18–4.14 (m, 2H) ,3.85(d,J=12.0Hz,1H),3.74(s,3H),3.21–3.16(s,2H),3.11–3.05(m,1H),2.96(d,J=15.3Hz,1H),2.87(t,J=12.0Hz, 1H),2.80–2.76(m,1H),2.63–2.57(m,2H),2.46–2.40(m,1H),2.23–2.16(m,1H),1.94–1.90(m,2H),1.86–1.81(m,2H). 13 C NMR (201 MHz, deuterated chloroform) δ 165.14, 161.51, 142.23, 141.00, 140.50, 135.48, 129.14, 123.76, 119.86, 118.39, 117.98, 114.32, 112.78, 108.19, 100.42, 99.15, 98.64, 68.23, 60.01, 58.27, 56.31, 53.00, 46.31, 32.96, 27.67, 27.28, 23.39. HR-MS (ESI, m / z): C 27 H 31 N4O2 + [M+H] + , calculated value: 443.2442; measured value: 443.2445.

[0308] Example 19: 1,1-dimethyl-3-(4-(2-(4-methyl-4,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyrrolo[4,3,2-de]quinolin-8-yl)ethyl)trans-cyclohexyl)urea (Compound I-19)

[0309]

[0310] Using a method similar to Example 17, whb165 was first deprotected with the Boc protecting group, and then alkylated with the intermediate whb60 to obtain the target compound I-19 (50 mg, 79%) as a light yellow solid. It was further purified by HPLC (mobile phase: 20-80% MeOH / H2O). R =19.5min, yield 40mg. 1 H NMR (800 MHz, deuterated methanol) δ7.08–7.04 (m, 1H), 6.83 (d, J = 8.2 Hz, 1H), 6.75 (s, 1H), 6.39 (d, J = 7.6 Hz, 1H), 4.15 (d, J = 14.1 Hz, 1H), 3.73 (s, 3H), 3.73–3.68 (m, 2H), 3.51–3.47 (m, 1H), 3.37–3.32 (m, 1H), 3.26–3.20 (m, 3H), 3 .15–3.12(m,1H),3.05(t,J=13.32Hz,1H),3.00(t,J=11.9Hz,1H),2.87(s,6H),2.87–2.81(m,1H),1.95–1 .89(m,2H),1.85–1.84(m,2H),1.74–1.65(m,2H),1.39–1.32(m,1H),1.32–1.26(m,2H),1.16–1.10(m,2H). 13 C NMR (201 MHz, deuterated methanol) δ 159.12, 139.54, 135.63, 123.24, 120.54, 118.09, 105.75, 101.38, 99.12, 55.68, 55.45, 54.33, 50.96, 49.78, 43.76, 35.04, 34.70, 32.64, 31.54, 31.52, 30.33, 26.24. HR-MS (ESI, m / z): C 25 H 38 N5O + [M+H] + , calculated value: 424.3071; measured value: 424.3089.

[0311] Example 20: (E)-7-((4-(4,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyrrolo[4,3,2-de]quinolin-8-yl)-2-buten-1-yl)oxy)-3,4-dihydroquinolin-2(1H)-one (Compound I-20)

[0312]

[0313] Step 1: Following the procedure of Step 1 of Example 1, alkylation reaction was carried out using 7-hydroxy-3,4-dihydroquinolin-2(1H)-one and (E)-1,4-dibromo-2-butene as raw materials to prepare intermediate whc102 (0.82 g, 45%) as a yellow solid. 1 H NMR (800MHz, CDCl3) δ8.45(s,1H),7.05(d,J=8.2Hz,1H),6.57–6.49(m,1H),6.37(d,J=2.5Hz,1H),6.07(dt,J=15.2 ,7.4Hz,1H),5.97(dt,J=15.2,5.3Hz,1H),4.52(d,J=5.4Hz,2H),3.99(d,J=7.5Hz,2H),2.90(t,J=7.5Hz,2H),2.62 (t,J=7.5Hz,2H).HR-MS(ESI,m / z):C 13 H 15 BrNO2 + [M+H] + , calculated value: 296.0281; measured values: 296.0294 and 298.0277.

[0314] Step 2: Following the method of step 2 in Example 1, intermediate A was alkylated with whc102 to obtain compound I-20 (40 mg, 33%) as a light yellow solid. HR-MS (ESI, m / z): C 26 H 29 N4O2 + [M+H] + , calculated value: 429.2285; measured value: 429.2288.

[0315] Example 21: (E)-7-((4-(4,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyrrolo[4,3,2-de]quinolin-8-yl)-2-buten-1-yl)oxy)quinolin-2(1H)-one (Compound I-21)

[0316]

[0317] Step 1: Following the method of Step 1 of Example 1, alkylation reaction was carried out using 7-hydroxy-quinolin-2(1H)-one and (E)-1,4-dibromo-2-butene as raw materials to prepare intermediate whc72 (0.25 g, 14%) as a yellow solid. 1H NMR (600MHz, CDCl3) δ7.74(d,J=9.4Hz,1H),7.46(d,J=8.7Hz,1H),6.88(d,J=2.4Hz,1H),6.86–6.80(m,1H),6.59–6.47(m,1H ),6.14(dt,J=15.0,7.4Hz,1H),6.01(dt,J=15.4,5.5Hz,1H),4.66(d,J=5.3Hz,2H),4.01(d,J=7.5Hz,2H).HR-MS(ESI,m / z):C 13 H 13 BrNO2 + [M+H] + , calculated value: 294.0124; measured values: 294.0124 and 296.0106.

[0318] Step 2: Following the method of Step 2 of Example 1, intermediate A was alkylated with whc72 to obtain compound I-21 (50 mg, 51%) as an off-white solid. 1 H NMR (800MHz, CDCl3) δ10.12(s,1H),7.83(s,1H),7.69(d,J=9.4Hz,1H),7.45(d,J=8.7Hz,1H),7.07(t,J=7.8Hz,1H),6.85–6.82(m ,1H),6.80(d,J=8.1Hz,1H),6.72(d,J=2.0Hz,1H),6.69(s,1H),6.51(d,J=9.4Hz,1H),6.32(d,J=7.6Hz,1H),6.03–5.98(m,1H),5 .95–5.91(m,1H),4.65(d,J=5.6Hz,2H),4.14–4.10(m,1H),3.80(d,J=11.7Hz,1H),3.22–3.20(m,1H),3.14(t,J=8.7Hz,1H),3.07 (t,J=14.4Hz,2H),2.94(dd,J=15.1,3.7Hz,2H),2.83–2.77(m,1H),2.40–2.36(m,1H),2.12(t,J=10.8Hz,1H).HR-MS(ESI,m / z):C 26 H 27 N4O2 + [M+H] + , calculated value: 427.2129; measured value: 427.2129.

[0319] Example 22: (E)-7-((4-(4-methyl-4,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyrrolo[4,3,2-de]quinolin-8-yl)-2-buten-1-yl)oxy)-3,4-dihydroquinolin-2(1H)-one (Compound I-22)

[0320]

[0321] Following the method of step 3 of Example 18, the Boc protecting group of intermediate whb165 was removed, and then alkylated with intermediate whc102 to obtain the target compound I-22 (90 mg, 30%) as a brown foamy solid. 1 H NMR(800MHz,MeOD)δ7.09–7.04 (m,2H),6.82(d,J=8.2Hz,1H),6.72(s,1H),6.58(dd,J=8.3,2.5Hz,1H),6.49(d,J=2.5Hz,1H),6.3 6(d,J=7.5Hz,1H),6.26–6.22(m,1H),5.97–5.93(m,1H),4.66–4.62(m,2H),4.11–4.05(m,1H),3.8 4–3.75(m,2H),3.71(s,3H),3.64–3.59(m,1H),3.56–3.52(m,1H),3.13–3.09(m,1H),3.08–3.00(m ,2H),2.82(t,J=8.0Hz,3H),2.77(dd,J=15.6,8.0Hz,1H),2.48(t,J=8.0Hz,2H).HR-MS(ESI,m / z):C 27 H 31 N4O2 + [M+H] + , calculated value: 443.2442; measured value: 443.2442.

[0322] Example 23: (E)-7-((4-(4-methyl-4,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyrrolo[4,3,2-de]quinolin-8-yl)-2-buten-1-yl)oxy)quinolin-2(1H)-one (Compound I-23)

[0323]

[0324] Following the method of step 3 of Example 18, the Boc protecting group of intermediate whb165 was removed, and then alkylated with intermediate whc72 to obtain the target compound I-23 (23 mg, 20%) as a brown solid.1 H NMR (800MHz, DMSO) δ11.60(s,1H),7.80(d,J=9.5Hz,1H),7.56(d,J=8.3Hz,1H),6.94(t,J=7.8Hz,1H),6 .84–6.80(m,2H),6.76–6.71(m,2H),6.31(d,J=9.4Hz,1H),6.22(d,J=7.5Hz,1H),5.94–5.90(m,2H),4.6 3(d,J=5.1Hz,2H),3.72–3.69(m,1H),3.68(s,3H),3.06–3.02(m,2H),2.98–2.94(m,3H),2.82(d,J=15. 2Hz,1H),2.69–2.65(m,1H),2.63–2.57(m,1H),2.21–2.17(m,1H),1.97–1.93(m,1H).HR-MS(ESI,m / z):C 27 H 29 N4O2 + [M+H] + , calculated value: 441.2285; measured value: 441.2286.

[0325] Example 24: 1-(4-Fluorophenyl)-4-(4,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyrrolo[4,3,2-de]quinolin-8-yl)-1-butanone (Compound I-24)

[0326]

[0327] Step 1: Cyclopropane(4-fluorophenyl)methanone (0.5 g, 3 mmol) and aqueous hydrobromic acid (3 mL) were added to a round-bottom flask and stirred at 80°C for 2 hours. After completion of the reaction, the mixture was cooled, water was added, and extraction was performed three times with DCM. The organic phases were combined and concentrated under reduced pressure to afford crude product whc48 (0.73 g, 98%) as a yellow liquid. 1 H NMR (800MHz, CDCl3) δ8.04–7.99(m,2H),7.17–7.12(m,2H),3.55(t,J=6.3Hz,2H),3.16(t,J=6.9Hz,2H),2.31(p,J=6.6Hz,2H).

[0328] Step 2: Following the method of Step 2 of Example 1, intermediate A was alkylated with whc48 to obtain compound I-24 (0.3 g, 57%) as a light yellow solid. 1H NMR(800MHz, CDCl3)δ8.03–7.98(m,2H),7.81(s,1H),6.80(d,J=8.1Hz,1H),6.72(d, J=1.9Hz,1H),6.32(d,J=7.6Hz,1H),3.77(d,J=11.7Hz,1H),3.16–3.12(m,1H),3.05 –3.01(m,4H),2.96(dd,J=15.2,3.7Hz,1H),2.88–2.78(m,2H),2.49(t,J=7.1Hz,2H) ,2.35(t,J=8.0Hz,1H),2.11(t,J=8.0Hz,1H),2.03–2.00(m,2H).HR-MS(ESI,m / z):C 23 H 25 FN3O + [M+H] + , calculated value: 378.1976; measured value: 378.1976.

[0329] Example 25: 1-(4-Fluorophenyl)-4-(4,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyrrolo[4,3,2-de]quinolin-8-yl)-1-butanol (Compound I-25)

[0330]

[0331] I-24 (50 mg, 0.13 mmol) was dissolved in methanol (5 mL), followed by the addition of NaBH4 (7.6 mg, 0.19 mmol), and the reaction system was stirred at room temperature for 2 hours. After completion of the reaction, the reaction was quenched with water and concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography (eluent: 20-30% methanol in dichloromethane) to afford I-25 (30 mg, 61%) as an off-white solid. 1H NMR (600MHz, CDCl3) δ7.82(s,1H),7.36–7.30(m,2H),7.10–7.04(m,1H),7.01–6.97(m,2H),6.81(d,J=8.1 ,1.3Hz,1H),6.73(d,J=7.7Hz,1H),6.34(dd,J=7.6,2.4Hz,1H),4.69(td,J=8.2,2.8Hz,1H),3.87–3.80(m, 1H),3.34–3.30(m,1H),3.23–3.19(m,1H),3.08–2.91(m,3H),2.83–2.79(m,1H),2.54–2.50(m,2H),2.48–2 .37(m,1H),2.25–2.14(m,1H),2.00–1.96(m,1H),1.88–1.84(m,1H),1.76–1.72(m,2H).HR-MS(ESI,m / z):C 23 H 27 FN3O + [M+H] + , calculated value: 380.2133; measured value: 380.2133.

[0332] Example 26: 1-(4-fluorophenyl)-4-(4-methyl-4,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyrrolo[4,3,2-de]quinolin-8-yl)-1-butanone (Compound I-26)

[0333]

[0334] Following the method of step 3 of Example 18, the Boc protecting group of intermediate whb165 was removed, and then alkylated with intermediate whc48 to obtain the target compound I-26 (20 mg, 15%) as a light yellow solid. 1H NMR (800MHz, DMSO) δ8.04(dd,J=8.6,5.5Hz,2H),7.32(t,J=8.7Hz,2H),6.93(t,J=7.8Hz,1H) ,6.75(s,1H),6.71(d,J=8.1Hz,1H),6.20(d,J=7.5Hz,1H),3.69–3.68(m,1H),3.67(s,3H),3. 04–3.00(m,3H),2.99–2.95(m,1H),2.91–2.84(m,2H),2.63–2.60(m,1H),2.59–2.55(m,1H),2 .42–2.38(m,2H),2.20–2.16(m,1H),2.00–1.95(m,1H),1.88–1.84(m,2H).HR-MS(ESI,m / z):C 24 H 27 FN3O + [M+H] + , calculated value: 392.2133; measured value: 393.2133.

[0335] Example 27: 1-(4-Fluorophenyl)-4-(4-methyl-4,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyrrolo[4,3,2-de]quinolin-8-yl)-1-butanol (Compound I-27)

[0336]

[0337] I-26 (63 mg, 0.16 mmol) was dissolved in methanol (8 mL), followed by the addition of NaBH4 (9 mg, 0.24 mmol), and the reaction system was stirred at room temperature for 2 hours. After completion of the reaction, the reaction was quenched with water and concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography (eluent: 20-30% methanol in dichloromethane) to afford I-27 (10 mg, 16%) as a light yellow solid. 1H NMR (800MHz, CDCl3) δ7.36–7.31(m,2H),7.09(t,J=7.7Hz,1H),7.00–6.97(m,2H),6.73(d,J=7.8Hz,1H),6 .59–6.55(m,1H),6.31(d,J=7.7Hz,1H),4.70–4.67(m,1H),3.86–3.79(m,1H),3.72(s,3H),3.33–3.29(m,1 H),3.19–3.15(m,1H),3.05–2.92(m,3H),2.85–2.76(m,1H),2.52–2.48(m,2H),2.43–2.39(m,1H),2.19–2 .15(m,1H),2.00–1.96(m,1H),1.87–1.83(m,1H),1.77–1.73(m,1H),1.72–1.68(m,1H).HR-MS(ESI,m / z):C 24 H 29 FN3O + [M+H] + , calculated value: 394.2289; measured value: 394.2297.

[0338] Test Example 1: Affinity test of the compound of the present invention for dopamine D2 receptor

[0339] The affinity of the compounds of the present invention for dopamine D2 receptors was determined using a radioligand competition assay. The first step was to prepare a cell membrane fraction containing specific dopamine D2 receptors. A 10 cm culture dish was transfected with 10 ng of dopamine D2 receptor and 40 μL of PEI. After 48 hours, the 10 cm culture dish containing cells expressing dopamine D2 receptors was removed from the cell chamber. The culture medium was removed using a vacuum pump, and 3 mL of lysis buffer was added to each well. The cells were placed in a 4°C refrigerator and allowed to stand for 10 minutes. After the cells detached, they were transferred to a 15 mL centrifuge tube and centrifuged at 1500 rpm for 5 minutes at 4°C. The supernatant was discarded. The cell pellet was transferred to a tissue homogenizer, and 3 mL of lysis buffer was added. The cell suspension was thoroughly ground until the cells were broken. The cell suspension was then aliquoted into multiple EP tubes and centrifuged at 12000 rpm for 5 minutes at 4°C. The supernatant was discarded. The pellet was the cell membrane fraction containing dopamine D2 receptors. The second step is to perform a ligand-receptor binding experiment on the 293T membrane fraction transiently expressing dopamine D2 receptors. First, add standard binding buffer to the cell membrane fraction containing dopamine D2 receptors, and use an electric tissue homogenizer to break the cell membrane and resuspend it. Add 30μL of membrane protein suspension to each well of the 96-well plate. Then, add 30μL of different drugs from left to right in the 96-well plate to ensure that the final drug concentration is 10 -5 M, 10-6 M, 10 -7 M, 10 -8 M, 10 -9 M, 0M, two replicates for each treatment. Then, 30 μL [ 3 H]-Methylspiperone. Incubate at room temperature in the dark for 2 hours. Detection. Machine reading of the reaction membrane binding [ 3 H]-Methylspiperone, and further data processing yielded the affinity K of different compounds for dopamine D2 receptors. i value.

[0340] The results are shown in Table 1. The results show that compounds I-1 to I-27 all have a certain affinity activity for dopamine D2 receptors, indicating that the compounds of the present invention all have a certain affinity activity for dopamine D2 receptors.

[0341] Table 1

[0342] Compound affinity Ki (pKi ± SEM) I-133.65nM (7.47 ± 0.16) I-29.03nM (8.04 ± 0.12) (+)-I-28.87nM (8.05 ± 0.05)

[0343] (-)-I-21.75nM(8.76±0.13)I-349.58nM(7.30±0.20)I-430.34nM(7.52±0.08)I- 537.07nM(7.43±0.09)I-651.56nM(7.29±0.10)I-7402.71nM(6.40±0.12)I-80.49 nM(9.31±0.15)I-9751.97nM(6.12±0.10)I-1050.64nM(7.30±0.08)(-)-I-1022.4 4nM(7.65±0.08)(+)-I-101135.01nM(5.95±0.17)I-1122.23nM(7.65±0.06)I-122 7.14nM (7.57±0.03)I-1316.31nM (7.79±0.07)I-1440.71nM (7.39±0.05)I-1577. 45nM(7.11±0.12)I-161992.20nM(5.70±0.14)I-1755.75nM(7.25±0.12)I-1860.9 5nM(7.22±0.02)I-1952.68nM(7.28±0.15)I-2070.9nMI-2133.2nMI-22176nMI-23100.5nMI-2432.4nMI-2510.8nMI-261352nMI-27383.1nMAripiprazole5.95nM(8.23±0.08)

[0344] Note: Data usage[ 3 The average K values ​​of the competition binding experiments with [H]-Methylspiperone (0.3-0.5 nM) as a radioligand were i (pK i ± SEM). Among them, all data of compounds I-1 to 19 are mean ± SEM of three independent determinations (n ​​= 3 independent experiments); compounds I-20 to 27 were determined by single determination.

[0345] Test Example 2: Functional activity test of compounds on dopamine D2 receptors

[0346] In order to detect the downstream G protein signaling pathway mediated by dopamine D2 receptor, on the first day, 1 μg dopamine D2 receptor, 1 μg Gα containing C-terminal algae luciferase were added to 6 cm culture dishes. i1 (Gα i1 -Rluc), 1 μg G β3, 1 μg of Gγ9 containing C-terminal green fluorescent protein (Gγ9-GFP), and 16 μL of PEI were transfected. Simultaneously, to detect the downstream β-arrestin2 signaling pathway mediated by the dopamine D2 receptor, on the first day, 6 cm culture dishes were transfected with 500 μg of dopamine D2 receptor containing C-terminal algal luciferase (D2-Rluc), 500 μg of G protein-coupled receptor kinase 2 (GRK2), 2500 μg of β-arrestin2 containing N-terminal green fluorescent protein (GFP2-ARRB2), and 14 μL of PEI. On the second day, confluent cells were digested and a 96-well plate was plated with the same amount of cells as one confluent 6 cm culture dish, with 100 μL of culture medium per well. On the third day, drug addition was performed. The 96-well plate was removed from the cell chamber, the culture medium removed, and 40 μL of the substrate coelenterazine 400a (final concentration 5 μM) was added to each well. Subsequently, 20 μL of each drug was added sequentially from left to right, ensuring a gradient decrease in final drug concentration from bottom to top. Each treatment was repeated in duplicate. Finally, the plate was analyzed by a flow cytometer. The flow cytometer readouts reflect the intracellular β-arrestin2 surface membrane and G protein trimer dissociation. The former indicates the degree of activation of the β-arrestin2 signaling pathway downstream of the dopamine D2 receptor, while the latter indicates the degree of activation of the G protein signaling pathway downstream of the dopamine D2 receptor. Thus, the agonist effects of various compounds on the dopamine D2 receptor can be revealed. The results are shown in Table 2.

[0347] The results showed that compounds I-1 to I-25 all had certain agonist activity on dopamine D2 receptors.

[0348] Table 2

[0349]

[0350]

[0351] Note: All data for compounds I-1 to 19 are mean ± SEM of three independent determinations (n ​​= 3 independent experiments); compounds I-20 to 27 were determined individually. 1 EC 50 It is the concentration of compound that gives a half-maximal response in the experiment. 2 Bracket E max % represents the maximum reaction intensity (E max ) relative to the percentage of the endogenous ligand dopamine.

[0352] Example 3: Affinity test of the compounds of the present invention for 5-HT2A receptor

[0353] The compounds of the present invention have an effect on 5-HT 2AThe affinity of the receptor was determined by radioligand competition assay. 2A 10 ng 5-HT 2A The receptor was transfected with 40 μL PEI. After 48 hours, a 10 cm culture dish was taken out from the cell room. The cultured cells had expressed 5-HT. 2A Receptor. Use a vacuum pump to suck away the culture medium, add 3mL of lysis solution to each well, place the cells in a 4℃ cold storage, and let them stand for 10 minutes. After the cells fall off, transfer them to a 15mL centrifuge tube, centrifuge at 1500rpm at 4℃ for 5 minutes, and discard the supernatant. Transfer the cell pellet to a tissue homogenizer, add 3mL of lysis solution to it, and grind it thoroughly until the cells are broken. Then, divide the cell suspension equally into multiple EP tubes, centrifuge at 12000rpm at 4℃ for 5 minutes, and discard the supernatant. The precipitate contains 5-HT 2A The second step is to transiently express 5-HT 2A The ligand-receptor binding experiment was performed on the 293T membrane fraction containing 5-HT. 2A The cell membrane fraction of the receptor was added to the standard binding buffer and the cell membrane was broken and resuspended using an electric tissue homogenizer. 30 μL of membrane protein suspension was added to each well of the 96-well plate. Then, 30 μL of different drugs were added from left to right in the 96-well plate to ensure that the final drug concentration was 10 from bottom to top. -5 M, 10 -6 M, 10 -7 M, 10 -8 M, 10 - 9 M, 0M, two replicates for each treatment. Then, 30 μL [ 3 H]-ketanserin. Incubate at room temperature in the dark for 2 hours. Detection. Machine reading of the reaction membrane binding [ 3 H]-ketanserin, and further data processing revealed the effects of different compounds on 5-HT 2A Receptor affinity K i The results are shown in Table 3.

[0354] Table 3

[0355] Compound K i ,nM(pK i ±SEM)I-13639.15(5.44±0.02)

[0356] I-2906.78(6.04±0.01)I-102371.37(5.63±0.04)(-)-I-102627.24(5.58±0.09)(+)-I-102480.28(5.61±0.09) Aripiprazole 42.17(7.38±0.03)

[0357] The results in Table 3 show that compounds I-1, I-2, I-10, (-)-I-10 and (+)-I-10 have an effect on 5-HT 2A Comparing the data in Table 1, the affinity of compounds I-1, I-2, and (-)-I-10 for 5-HT receptor is very weak. 2A The receptor binding selectivity is greater than 100 times, indicating that the compound of the present invention has good selectivity for dopamine D2 receptors.

[0358] Test Example 3: Pharmacokinetic properties of the compounds of the present invention in mice

[0359] 1. Pharmacokinetic properties of compound (-)-I-10 were tested by single oral, intraperitoneal, and intravenous administration to C57 male mice

[0360] (1) Experimental purpose

[0361] After a single dose of compound (-)-I-10 was administered to C57 male mice, blood samples were collected at different time points. The concentration of the compound in mouse plasma was determined by LC-MS / MS, and relevant pharmacokinetic parameters were calculated to investigate the pharmacokinetics of the compound in mice.

[0362] (2) Experimental design

[0363] Twenty-seven male C57 mice were provided by Suzhou Zhaoyan Laboratory Animal Co., Ltd. The experiments were performed according to Table 4 below.

[0364] Table 4

[0365]

[0366] (3) Sample collection

[0367] From each animal, 0.030 mL of blood was collected intraorbitally and anticoagulated with EDTA-K2 at 0, 5, 15, 30 minutes, and 1, 2, 4, 6, 8, and 24 hours after administration of the test substance. Blood samples were placed on ice and centrifuged within 30 minutes to separate plasma (5000 rpm, 10 minutes, 4°C). The samples were stored at –80°C until analysis.

[0368] (4) Data processing

[0369] The data acquisition and control system software was Analyst 1.5.1 (Applied Biosystems). Chromatographic sample peak integration was performed automatically; the ratio of the sample peak area to the internal standard peak area was used as an indicator for regression with the sample concentration. Regression method: linear regression with a weighting factor of 1 / χ². Pharmacokinetic parameters were analyzed using WinNonlin Professional v6.3 (Pharsight, USA) using a non-compartmental model. Cmax is the maximum measured plasma drug concentration, and the area under the plasma concentration-time curve (AUC(0→t)) was calculated by the trapezoidal method. Tmax is the time to peak plasma drug concentration after administration. Experimental data are expressed as "mean ± standard deviation" (ICR, n ≥ 3) or "mean" (n = 2).

[0370] (5) Experimental results

[0371] The pharmacokinetic results of compound (-)-I-10 are shown in the following table. It can be seen that the compound has good pharmacokinetic properties in C57 male mice. See Table 5 for details.

[0372] Table 5

[0373]

[0374] Note: “--” means not applicable.

[0375] 2. Brain penetrance test of compound (-)-I-10 in C57 male mice by single oral administration, intraperitoneal injection and intravenous injection

[0376] Using methods consistent with pharmacokinetic studies, 0.030 mL of blood was collected from each animal via the orbital cavity at 0.5 and 2.0 hours. Blood samples were anticoagulated with EDTA-K2 and placed on ice. Plasma was separated by centrifugation within 30 minutes (5000 rpm, 10 minutes, 4°C) and stored at –80°C until analysis. Brain tissue samples were obtained after exsanguination and euthanasia, and homogenized with 50% methanol at a 1:3 body weight ratio (m / v = 1:3). The homogenate was stored at –80°C until analysis. Drug concentrations in plasma and brain tissue were analyzed and compared by LC / MS / MS. The plasma and brain tissue drug concentrations and ratios of compound (-)-I-10 at 0.5 and 2.0 hours are shown in Table 6.

[0377] Table 6

[0378]

[0379] Test Example 4: Efficacy test of the compound on a schizophrenia-like animal behavioral model

[0380] 1. Empty-field athletic ability test

[0381] Experimental Methods: C57B6 male mice were used as experimental animals, with n = 8 per group. This model was established using C57B6 mice. Acute injection of the NMDA antagonist MK801 induced hyperlocomotor behavior in an open field environment, allowing for the evaluation of the inhibitory effects of various compounds on the MK801-induced hyperlocomotor phenotype. All behavioral experiments were conducted during the light phase of the experiment. The experiments were recorded using a video camera and automated behavioral tracking software for statistical analysis. Compounds were administered via intraperitoneal injection. Following injection, mice immediately entered an open field, and movement patterns were recorded. Thirty minutes later, mice received 0.2 mg / kg of MK801 via intraperitoneal injection and immediately returned to the open field, where movement patterns were recorded for an additional 120 minutes. Cumulative distance traveled was calculated using a five-minute sampling interval. Data were analyzed using Student's t-tests. P < 0.05 is indicated as *, P < 0.01 is indicated as **, P < 0.001 is indicated as ***, and P < 0.0001 is indicated as ****. The total movement distance of mice within 0-45 minutes under the combined action of different doses of (-)-I-10 and MK801 (0.2 mg / kg) is shown in Table 7.

[0382] The results of the open field exercise ability test showed that compound (-)-I-10 at 0.4 / 0.1 / 0.025 mg / kg could significantly inhibit the improvement of mouse exercise ability induced by MK801.

[0383] Table 7

[0384]

[0385] 2. Animal "depression-like" behavior test

[0386] The experimental animals were C57B6 male mice, with n=8 per group. First, the C57B6 mice were restrained for 5 hours to induce depression-related behavioral manifestations in the mice, and then the effects of the compounds on their "depression-like" behavior were detected by tail suspension and forced swimming tests. The specific experimental process is as follows: first, the mice were restrained using a mouse fixator for tail vein injection. During the restraint process, all behavioral abilities of the mice were restricted while ensuring that minimal pain was caused to the mice. The mice were administered the drug once by intraperitoneal injection before and after the restraint. After the restraint, the mice were returned to the cage to recover for 30 minutes. After 30 minutes, the mice in different groups were subjected to tail suspension or forced swimming to detect their "depression-like" behavior.

[0387] Tail Suspension Test: The tip of the mouse's tail was fixed to a suspension rod on a metal stand with adhesive tape. The mouse remained suspended for 6 minutes. The first 2 minutes served as an acclimatization period, during which no data were collected. During the next 4 minutes, the duration of intermittent periods of immobility was recorded. The duration of these periods of immobility was used to measure the degree of behavioral despair. Data were analyzed using the Student's t-test. P < 0.05 is indicated as *, P < 0.01 is indicated as **, P < 0.001 is indicated as ***, and P < 0.0001 is indicated as ****.

[0388] Forced swim test: Mice were placed in a 5L glass beaker filled with water at a height of 15cm and were required to swim continuously for 6 minutes. The first two minutes were an acclimation period, during which no data was collected. During the next four minutes, intermittent periods of immobility were recorded. Immobility was defined as passive floating on the water surface without movement, with only minor local movements required to maintain afloat. The duration of this immobility was used to measure the degree of behavioral despair. Data were analyzed using the Student's t-test. P < 0.05 is indicated as *, P < 0.01 is indicated as **, P < 0.001 is indicated as ***, and P < 0.0001 is indicated as ****. The statistical results of the tail-hanging test and forced swim test for restrained and unrestrained mice are shown in Table 8.

[0389] The results of the "depression-like" behavior test showed that compound (-)-I-10 at 0.4 mg / kg and 0.1 mg / kg could significantly inhibit the occurrence of restraint-induced "depression-like" behavior.

[0390] Table 8

[0391]

[0392] 3. Recognition of new and old objects

[0393] The experimental animals were C57B6 male mice, with n=8 per group. Mice were first injected intraperitoneally with 0.3 mg / kg of MK801 twice daily for seven consecutive days to establish a cognitive impairment model. Control mice were injected intraperitoneally with saline containing an equal volume of DMSO. The mice were then allowed to recover in their home cages for seven days. After the recovery period, the mice were subjected to a new and old object recognition test to examine the compound's effects on cognitive abilities.

[0394] New and old object recognition experiment: The experiment was conducted in a dim light environment. Mice were placed in the experimental arena before the experiment and acclimated to the dim light environment for one hour. After acclimation, the mice were administered the drug via intraperitoneal injection. 30 minutes after drug administration, the mice were placed in an empty arena (40 cm diameter) with two identical objects pre-placed. The mice explored the empty arena freely for 10 minutes and were then removed from the arena and returned to their home cages. After a one-hour interval, the mice were returned to the empty arena, where an old object and a new object were placed in the same locations. The mice explored the empty arena freely for another 10 minutes. The time it took the mice to recognize the new and old objects was recorded, and the recognition index was calculated. The recognition index was calculated as (new object exploration time - old object exploration time) / (new object exploration time + old object exploration time). Object exploration was defined as sniffing, climbing, and direct contact with the object. Data were analyzed using the Student t-test. P < 0.05 is indicated as *, p < 0.01 is indicated as **, p < 0.001 is indicated as ***, and p < 0.0001 is indicated as ****. The statistical results for the new and old object recognition metrics are shown in Table 9.

[0395] The results of new and old object recognition showed that compound (-)-I-10 at 0.1 mg / kg and 0.025 mg / kg could significantly improve the cognitive impairment of mice induced by MK801.

[0396] Table 9

[0397]

[0398]

[0399] 4. Morris Water Maze

[0400] C57B6 male mice were used for the experiment, with n = 8 per group. Mice were first injected intraperitoneally with 0.2 mg / kg of MK801 twice daily for ten consecutive days to establish a cognitive impairment model. Control mice were injected intraperitoneally with saline containing an equal amount of DMSO. The mice were then subjected to the Morris water maze test.

[0401] Experimental Setup: The experiment was conducted in a blue, circular reservoir with a diameter of 130 cm. The reservoir was filled with purified water to a depth of approximately 30 cm. The reservoir was divided into four sectors, each with a cross. The escape platform (6 cm in diameter) was located in the center of one sector, hidden 0.5 cm below the water surface. The mice entered the water at fixed points at the edges of the other three sectors. The distance between the entry point and the platform was kept roughly constant.

[0402] Acquisition training: 30 minutes before the start of the experiment, mice were administered the drug via intraperitoneal injection. At the start of the experiment, mice were placed headfirst into the pool wall in one of three random starting positions: east, west, and south. The submerged platform was located in the north quadrant. The time it took for the mouse to find the submerged platform was recorded. If the platform was not found within 1 minute, the mouse was guided to the platform and allowed to remain there for 30 seconds. This procedure was then repeated two times, starting from the other starting point. Each animal was trained three times daily for five consecutive days.

[0403] Exploration Training: The day after the last acquisition training session, the platform was removed and a 60-second exploration session was initiated. The animal was placed in the water from the quadrant opposite the original platform. The number of times the animal crossed the original platform position was recorded as a measure of spatial memory. Data were analyzed using the Student's t-test. p < 0.05 is indicated as *, p < 0.01 is indicated as **, p < 0.001 is indicated as ***, and p < 0.0001 is indicated as ****. The results of daily platform exploration time during water maze acquisition training are shown in Table 10.

[0404] The results of Morris water maze showed that compound (-)-I-10 at 0.1 mg / kg could significantly improve the spatial cognitive ability impairment of mice induced by MK801; compound (-)-I-10 at 0.1 mg / kg and 0.025 mg / kg could significantly improve the memory ability impairment of mice induced by MK801.

[0405] Table 10

[0406]

[0407]

[0408] 5. Freeze Behavior Test

[0409] Experimental Methods: C57B6 male mice were used as experimental animals, with n = 8 per group. Mice were first injected with different compounds. After a specific time (30 or 60 minutes), the mice were placed in an unnatural upright position by placing their forelimbs on a high glass suspension rod (approximately 5 cm above the ground). The duration of the mice's immobility in this position was then measured, which served as a measure of the drug's effect on the immobility. The results of the immobility test 30 and 60 minutes after the different drug injections are shown in Table 11.

[0410] The freezing behavior test showed that compound (-)-I-10 had no freezing-inducing effect on mice at 10 mg / kg.

[0411] Table 11

[0412]

Claims

1. A compound of formula I, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof: Wherein, L is C 1-10 alkylene, C 2-10 alkenylene, C 2-10 alkynylene or -C 1-6 alkylene-C 3-6 cycloalkylene-; M is -O-, -NH-, -CH 2 -, -(CH-OH)- or -C(=O)-; Q is C 6-18 aryl, C substituted with one or more Q 1-1 aryl, 5-10 membered heteroaryl, C substituted with one or more Q 6-18 aryl, 5-10 membered heteroaryl, -C(=O)R 1-2 substituted 5-10 membered heteroaryl, -C(=O)R 1 or -S(=O) 2 R 2 ; the heteroatoms in the 5-10 membered heteroaryl are one or more of N, S or O, and the number is 1, 2 or 3; the heteroatoms in the 5-10 membered heteroaryl substituted with one or more Q 1-2 are one or more of N, S or O, and the number is 1, 2 or 3; Q 1-1 independently is halogen or C 1-4 alkyl; Q 1-2 independently C 1-4 alkyl, oxo or hydroxy; R 1 and R 2 independently is -NR 1-1 R 1-2 , a 3- to 6-membered heterocycloalkyl group, C 6-18 aryl, C 1-3 aryl substituted with one or more R 6-18 aryl, a 5- to 10-membered heteroaryl group or a 5- to 10-membered heteroaryl group substituted with one or more R 1-4 ; the heteroatom in the 3- to 6-membered heterocycloalkyl group is one or more of N, S or O, and the number is 1, 2 or 3; the heteroatom in the 5- to 10-membered heteroaryl group is one or more of N, S or O, and the number is 1, 2 or 3; the heteroatom in the 5- to 10-membered heteroaryl group substituted with one or more R 1-4 is one or more of N, S or O, and the number is 1, 2 or 3; R 1-1 、R 1-2 、R 1-3 and R 1-4 are independently C 1-4 alkyl; R is hydrogen or C 1-4 alkyl group.

2. The compound of formula I, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof according to claim 1, Characterized in that, The compound of formula I is any of the following: Case 1: The compound of formula I is a compound of formula Ia, Ib or Ic: In formula Ic, represents a double bond or a single bond; Y is hydrogen, hydroxyl or oxygen; Case 2: The compound of formula I is a compound of formula Id and / or Ie, preferably a compound of formula Id; Case 3: When the compound shown by Formula I is only at When there is a chiral center in, For and / or Preferably 3. The compound of formula I, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof according to claim 1, Characterized in that, The compound of formula I is any of the following schemes: Scheme 1: L is C 1-10 alkylene or -C 1-6 alkylene-C 3-6 cycloalkylene-; M is -O-, -NH- or -CH 2 -; Q is C 6-18 aryl, 5- to 10-membered heteroaryl, 5- to 10-membered heteroaryl substituted with one or more Q 1-2 -C(=O)R 1 or -S(=O) 2 R 2 ; Scheme 2: L is C 1-10 an alkylene or -C 1-6 an alkylene-C 3-6 a cycloalkylene-; M is -O-, -NH- or -CH 2 -; Q is C 6-18 aryl, 5- to 10-membered heteroaryl, 5- to 10-membered heteroaryl substituted with one or more Q 1-2 -C(=O)R 1 or -S(=O) 2 R 2 ; When M is -O-, Q 1-2 is C 1-4 alkyl or hydroxy; When the heteroatom in the 5- to 10-membered heteroaryl is O, the number of heteroatoms in the 5- to 10-membered heteroaryl is 1; Scheme 3: L is C 1-10 alkylene or -C 1-6 alkylene-C 3-6 cycloalkylene-; M is -O-, -NH- or -CH 2 -; Q is C 6-18 aryl, 5- to 10-membered heteroaryl, 5- to 10-membered heteroaryl substituted with one or more Q 1-2 -C(=O)R 1 or -S(=O) 2 R 2 ; When L is -C 1-6 alkylene-C 3-6 cycloalkylene- when the -C 1-6 alkylene-C 3-6 cycloalkylene- the C in 1-6 the alkylene is ethylene; Scheme 4: L is C 1-10 alkylene or -C 1-6 alkylene-C 3-6 cycloalkylene-; M is -O- or -NH-; Q is -C(=O)R 1 or a 5- to 10-membered heteroaryl group substituted by one or more Q 1-2 groups; R 1 is - NR 1-1 R 1-2 ; Scheme 5: The molecular structure of the compound of formula I is as shown in formula Ia: L is C 1-10 alkylene or C 2-10 alkenylene; Q is C substituted by one or more Q 1-1 aryl, 5- to 10-membered heteroaryl, 5- to 10-membered heteroaryl substituted by one or more Q 6-18 aryl, 5-10 membered heteroaryl, 5-10 membered heteroaryl substituted by one or more Q 1-2 substituted 5-10 membered heteroaryl; Q 1-1 is a halogen; Scheme 6: The molecular structure of the compound of formula I is as shown in formula Ib: L is -C 1-6 alkylene-C 3-6 cycloalkylene-; Q is -C(=O)R 1 or -S(=O) 2 R 2 ; R 1 and R 2 are independently -NR 1-1 R 1-2 , a 3 - 6 membered heteroalkyl, C 6-18 aryl or a 5 - 10 membered heteroaryl; Scheme 7: The molecular structure of the compound of formula I is as shown in formula Ic: represents a double bond or a single bond; Y is hydrogen, hydroxyl or oxygen; L is C 1-10 an alkylene group; Q is C aryl substituted by one or more Q 1-1 aryl, or 5- to 10-membered heteroaryl substituted by one or more Q 6-18 aryl, or, 5-10 membered heteroaryl substituted by one or more Q 1-2 ; Q 1-1 is a halogen; Q 1-2 independently C 1-4 alkyl or oxo; Scheme 8: L is C 1-10 alkylene, C 2-10 alkenylene or -C 1-6 alkylene-C 3-6 cycloalkylene-; When M is -(CH-OH)- or -C(=O)-, R is hydrogen; Scheme 9: L is C 1-10 an alkylene group; M is -O-; Q is a 5- to 10-membered heteroaryl substituted by one or more Q 1-2 ; Scheme 10: L is -C 1-6 alkylene-C 3-6 cycloalkylene-; M is -NH-; Q is -C(=O)R 1 ; R 1 is -NR 1-1 R 1-2 ; Scheme 11: The molecular structure of the compound of formula I is as shown in formula Ia: L is C 1-10 an alkylene or C 2-10 an alkenylene; Q is a 5- to 10-membered heteroaryl, or a 5- to 10-membered heteroaryl substituted by one or more Q 1-2 substituents; Scheme 12: The molecular structure of the compound of formula I is as shown in formula Ic-1: L is C 1-10 an alkylene group; Q is C substituted by one or more Q 1-1 aryl; 6-18 aryl; Q 1-1 is a halogen; R is hydrogen; Scheme 13: The molecular structure of the compound of formula I is as shown in formula Ic-2: L is C 1-10 an alkylene group; Q is C aryl substituted by one or more Q 1-1 aryl; 6-18 substituted by one or more Q Q 1-1 is a halogen; R is hydrogen; Scheme 14: The molecular structure of the compound of formula I is as shown in formula Ic-3: L is C 1-10 an alkylene group; Q is a 5- to 10-membered heteroaryl group substituted by one or more Q 1-2 groups; Q 1-1 is C 1-4 alkyl or oxo; R is hydrogen.

4. The compound of formula I, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof according to claim 1, Characterized in that, When L is C 1-10 an alkylene group, the C 1-10 alkylene group is methylene, ethylene, n-propylene, isopropylidene, n-butylene, isobutylene or tert-butylene, preferably and / or, when L is C 2-10 alkenylene, the C 2-10 alkenylene is C 2-4 alkenylene, preferably and / or, when L is -C 1-6 alkylene-C 3-6 cycloalkylene- , the C 1-6 alkylene is connected to N, and the C 3-6 cycloalkylene is connected to Q; and / or, when L is -C 1-6 alkylene-C 3-6 cycloalkylene-, the -C 1-6 alkylene-C 3-6 in cycloalkylene, C 1-6 the alkylene is methylene, ethylene, n-propylene, isopropyl, n-butyl, isobutyl or tert-butyl, preferably methylene or More preferably and / or, when L is -C 1-6 alkylene-C 3-6 cycloalkylene-, the -C 1-6 alkylene-C 3-6 in cycloalkylene, C 3-6 the cycloalkylene is cyclopropylene, cyclobutylene, cyclopentylene or cyclohexylene, preferably and / or, when Q is C 6-18 aryl, the C 6-18 aryl is phenyl, naphthyl, anthryl or phenanthryl, preferably phenyl; and / or, when Q is Q 1-1 substituted C 6-18 aryl, said C 6-18 aryl is phenyl, naphthyl, anthryl or phenanthryl, preferably phenyl; and / or, when Q is Q 1-1 substituted C 6-18 aryl, the said Q 1-1 is one or two; and / or, when Q 1-1 is a halogen, the halogen is F, Cl, Br or I, preferably F; and / or, when Q is a 5- to 10-membered heteroaryl group, the 5- to 10-membered heteroaryl group is a 9- or 10-membered heteroaryl group, and the number of heteroatoms is 1 or 2, and more preferably and / or, when Q is a 5- to 10-membered heteroaryl substituted by one or more Q 1-2 the 5- to 10-membered heteroaryl is a 9- or 10-membered heteroaryl, the heteroatoms are N and / or O, the number is one or two, preferably tetrahydroquinolinyl, quinolinyl, benzoxazolyl, benzisoxazolyl or tetrahydropyridopyrimidinyl; and / or, when Q is Q 1-2 substituted C 6-18 aryl, the said Q 1-2 is one or two; and / or, when Q 1-2 is C 1-4 alkyl, the C 1-4 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, preferably methyl; and / or, when R 1 and R 2 are each independently a 3- to 6-membered heterocycloalkyl group, the 3- to 6-membered heterocycloalkyl group is a piperidinyl group or a pyrrolidinyl group, preferably a pyrrolidinyl group; and / or, when R 1 is a 3- to 6-membered heterocycloalkyl group, the 3- to 6-membered heterocycloalkyl group is connected to the carbonyl group through a heteroatom; and / or, when R 1 and R 2 are independently C 6-18 aryl, the C 6-18 aryl is phenyl, naphthyl, anthryl or phenanthryl, preferably phenyl; and / or, when R 1 and R 2 are independently C 1-3 aryl substituted by one or more R 6-18 groups, the C 6-18 aryl is phenyl, naphthyl, anthracenyl or phenanthryl, preferably phenyl; and / or, when R 1 and R 2 are independently 5- to 10-membered heteroaryl, the 5- to 10-membered heteroaryl is 9- or 10-membered heteroaryl, the heteroatom is N, and the number is 1 or 2, preferably indolyl; and / or, when R 1-1 、R 1-2 、R 1-3 and R 1-4 are independently C 1-4 alkyl, the C 1-4 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, preferably methyl; and / or, when R is C 1-4 alkyl, the C 1-4 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, preferably methyl.

5. The compound of formula I, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof according to claim 4, Characterized in that, When L is -C 1-6 alkylene-C 3-6 cycloalkylene- when the -C 1-6 alkylene-C 3-6 cycloalkylene- is where the a end is connected to Q and the b end is connected to N; and / or, when Q is Q 1-1 substituted C 6-18 aryl, the said Q 1-1 substituted C 6-18 aryl is and / or, when Q is a 5- to 10-membered heteroaryl group substituted by one or more Q 1-2 substituted 5- to 10-membered heteroaryl group, the one or more Q 1-2 substituted 5- to 10-membered heteroaryl group is and / or, when R 1 is 3- to 6-membered heterocycloalkyl, the 3- to 6-membered heterocycloalkyl is and / or, For 6. The compound of formula I, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof according to claim 1, Characterized in that, L is C 1-10 alkylene, C 2-10 alkenylene or -C 1-6 alkylene-C 3-6 cycloalkylene, preferably C 1-10 alkylene or -C 1-6 alkylene-C 3-6 cycloalkylene; and / or, M is -O-, -NH- or -CH 2 -; and / or, Q 1-1 is a halogen; and / or, R 1 is -NR 1-1 R 1-2 a 3- to 6-membered heteroalkyl, C 6-18 aryl or a 5- to 10-membered heteroaryl, preferably -NR 1-1 R 1-2 a 3- to 6-membered heteroalkyl or C 6-18 aryl; and / or, R is hydrogen.

7. The compound of formula I, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof according to claim 1, Characterized in that, The compound of formula I is any of the following compounds: Preferably "The specific rotation value is +50.33° and / or the retention time is 5.805 min under the following chiral preparation conditions of ” or "the optical rotation value is -45.00° and / or the retention time is 7.60 min under the following chiral preparation conditions ”； The chiral preparation conditions are as follows: chromatographic column: chiral column CHIRALCEL OD, column volume: 5.0 cm x 25 cm, 10 μm packing material; mobile phase: MeOH / diethylamine = 100 / 0.1; flow rate: 30 mL / min; Wavelength: UV 214 nm; temperature: 38 °C.

8. A crystal represented by formula pNs-(+)-I-10, characterized in that, Its crystal system belongs to the triclinic system, space group P1, and the unit cell parameters are α = 90.15°, β = 99.368°, γ = 90.25°; 9. A pharmaceutical composition comprising a compound represented by formula I as described in any one of claims 1-7, its pharmaceutically acceptable salt, its solvate, its solvate of the pharmaceutically acceptable salt, or a crystal represented by formula pNs-(+)-I-10 as described in claim 8, and pharmaceutical excipients.

10. An application of substance A; the application is for preparing a dopamine D2 receptor agonist, for treating and / or preventing a drug for a disease related to the dopamine D2 receptor or for treating and / or preventing a drug for disease M; The disease M is one or more of neurodegenerative diseases, mental disorders, and metabolic diseases related to mental disorders; The substance A is a compound represented by formula I as described in any one of claims 1-7, its pharmaceutically acceptable salt, its solvate, or its solvate of the pharmaceutically acceptable salt, a crystal represented by formula pNs-(+)-I-10 as described in claim 8, or a pharmaceutical composition as described in claim 9.

11. A method for preventing or treating a disease related to the dopamine D2 receptor or disease M, which comprises administering a therapeutically effective amount of substance A to a subject; The disease M is one or more of neurodegenerative diseases, mental disorders, and metabolic diseases related to mental disorders; The substance A is a compound represented by formula I as described in any one of claims 1-7, its pharmaceutically acceptable salt, its solvate, or its solvate of the pharmaceutically acceptable salt, a crystal represented by formula pNs-(+)-I-10 as described in claim 8, or a pharmaceutical composition as described in claim 9; In the method, the disease M is preferably Parkinson's disease, Alzheimer's disease or dementia, schizophrenia, bipolar disorder, depression, attention deficit hyperactivity disorder, restless legs syndrome, Huntington's disease, male erectile disorder, prolactinoma or drug addiction.

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