Azaergoline derivatives, methods for producing the same, and their use

Abstract

The present invention discloses an aza-ergoline derivative and its preparation and use, the structure of which is represented by formula (I): The aza-ergoline derivative has good affinity, agonistic activity or selectivity for dopamine D2 receptor. [Formula 1] TIFF2024504499000149.tif37170

Description

Detailed description of the invention

[0001] This application claims priority to Chinese patent application 2021101382499, filed on February 1, 2021, and Chinese patent application 2021111530798, filed on September 29, 2021. This application incorporates the full text of the aforementioned Chinese patent applications.

[0002] [Technical field] This invention relates to aza-ergoline derivatives, methods for producing the same, and uses thereof. [Background technology] The dopaminergic signaling pathway is involved in various physiological functions in humans, including movement, behavior, emotion, and memory, and has been a focus of neurobiological research for the past few decades. Dysfunction of the dopaminergic signaling pathway is thought to be involved in the pathogenesis of many diseases, including Parkinson's disease and schizophrenia. The dopaminergic signaling pathway consists 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-D5), of which D1 and D5 are D1 receptors, mainly G s They are protein-coupled and increase intracellular cAMP levels after activation; D2, D3, and D4 are D2-type receptors, primarily G i It couples with proteins and, upon activation, reduces intracellular cAMP levels. Different dopamine receptors exhibit different expression levels and distributions in the central nervous system, and perform different physiological functions (Martel and McArthur, Front Pharmacol 2020, 11: 1003).

[0003] Of the five subtypes of dopamine receptors, the D2 receptor is the most extensively and deeply studied. Drugs clinically used primarily for the treatment of Parkinson's disease and hypermobile leg syndrome, such as pramipexole, ropinirole, and rotigotine, exert their therapeutic effects mainly by activating dopamine D2 receptors, but they also have activity on other dopamine receptors such as D3. Antischizophrenic drugs such as haloperidol and olanzapine exert their therapeutic effects mainly by antagonizing D2 receptors, but newer generation drugs such as aripiprazole and cariprazine are partial agonists of dopamine D2 receptors (Frankel and Schwartz, Ther Adv Psychopharmacol 2017, 7(1): 29-41).

[0004] The dopamine D2 receptor has some structural homology to other dopamine receptors and other monoamine GPCRs such as the 5-hydroxytryptamine (5-HT) receptor. Due to this homology, most drugs do not exhibit target selectivity. Many antipsychotic drugs that target the dopamine D2 receptor are 5-HT receptors. 2A It has a certain degree of affinity for 5-HT receptors such as receptors, and some drugs have a certain affinity for 5-HT receptors. 2A The affinity for the receptor is even stronger than the affinity for the D2 receptor. D2 receptor and 5-HT 2A Dual receptor action is a common characteristic of these drugs. Pimavanserin, a drug approved for sale by the US FDA in 2018, is a 5-HT receptor. 2A Lumateperone, a selective inverse agonist for receptors (Sahli and Tarazi, Expert Opin Drug Discov 2018, 13(1): 103-110), which was approved for sale by the US FDA in 2019, is also a 5-HT 2AThe affinity for the receptor is approximately 60 times higher than that for the D2 receptor (Blair, Drugs, 2020, 80(4), 417-423). However, drugs with high selectivity for the D2 receptor have rarely been reported in the literature (Fan and Tan et al., Nat Comm, 2020, 11, 1074).

[0005] Krogsgaard-Larsen et al. reported compound A, which has an azagoline skeleton. Its derivative A1 has binding activity to the 5-HT6 receptor, derivative A2 has agonist activity to the dopamine D2 receptor, and derivative 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, and other drug potential of these compounds have not been reported.

[0006] [ka]

[0007] [Overview of the prefecture] The technical problem that the present invention aims to solve is that there are few existing compounds that have affinity, agonist activity, or selectivity for dopamine D2 receptors. Therefore, the present invention provides aza-ergoline derivatives, methods for producing the same, and uses thereof. The compounds of the present invention have good affinity, agonist activity, or selectivity for dopamine D2 receptors.

[0008] The present invention provides a compound represented by formula I, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof.

[0009] [ka]

[0010] However, L is C 1-10 Alkylene, C2-10 Alkenylene, C 2-10 Alkynylene or -C 1-6 Alkylene-C 3-6 Is cycloalkylene-, M is -O-, -NH-, -CH2-, -(CH-OH)- or -C(=O)-, Q is C 6-18 Aryl, one or more Q 1-1 Substituted C 6-18 Aryl, 5- to 10-membered heteroaryl, one or more Q 1-2 Substituted 5- to 10-membered heteroaryl, -C(=O)R 1 Or -S(=O)2R 2 And the heteroatom in the 5- to 10-membered heteroaryl is one or more of N, S or O, and the number is one, two or three, and the one or more Q 1-2 The heteroatom in the 5- to 10-membered heteroaryl substituted by is one or more of N, S or O, and the number is one, two or three, Q 1-1 Is independently halogen or C 1-4 Alkyl, Q 1-2 Is independently C 1-4 Alkyl, oxo or hydroxyl, R 1 And R 2 Are independently -NR 1-1 R 1-2 3- to 6-membered heterocycloalkyl, C 6-18 Aryl, one or more R 1-3 Substituted C 6-18 Aryl, 5- to 10-membered heteroaryl or one or more R 1-4 Substituted 5- to 10-membered heteroaryl, and the heteroatom in the 3- to 6-membered heterocycloalkyl is one or more of N, S or O, and the number is one, two or three, and the heteroatom in the 5- to 10-membered heteroaryl is one or more of N, S or O, and the number is one, two or three, and the one or more R 1-4In the 5-10 membered heteroaryl substituted by, the heteroatoms are one or more N, S, or O atoms, and their number is one, two, or three. R 1-1 , R 1-2 , R 1-3 and R 1-4 C 1-4 It is alkyl, R is either hydrogen or C 1-4 It is alkyl.

[0011] In a preferred embodiment, a compound represented by formula I, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, wherein the definitions of certain groups are as shown below, and the definitions of the remaining groups are as described in any one embodiment of the present invention, and hereafter referred to as "in a preferred embodiment."

[0012] In one preferred embodiment, the compound represented by formula I is a compound represented by formula Ia, Ib, or Ic.

[0013] [ka]

[0014] In formula Ic,

[0015] [ka] The symbol '' represents a double bond or a single bond, and Y is hydrogen, hydroxyl, or oxygen.

[0016] In one preferred embodiment, the compound represented by formula I is a compound represented by formula Id and / or Ie, preferably a compound represented by formula Id.

[0017] [ka]

[0018] In one preferred embodiment, the compound represented by formula I is

[0019] [ka] If it has only one chiral center,

[0020] [ka] Preferably

[0021] [ka] Here, the carbon atom marked with "*" is a chiral carbon atom, (+) indicates a dextrorotatory compound, and (-) indicates a levorotatory compound.

[0022] In one preferred embodiment, L is C 1-10 Alkylene, C 2-10 Alkenylene or -C 1-6 Alkylene-C 3-6 It is a cycloalkylene, If M is -(CH-OH)- or -C(=O)-, then R is hydrogen.

[0023] In one preferred embodiment, L is C 1-10 Alkylene or -C 1-6 Alkylene-C 3-6 It is a cycloalkylene, M is -O-, -NH-, or -CH2-. Q is C 6-18 Aryl, 5-10 member heteroaryl, one or more Q 1-2 5-10 member heteroaryls substituted by -C(=O)R 1 Or -S(=O)2R 2 That is the case.

[0024] In one preferred embodiment, L is C 1-10Alkylene or -C 1-6 Alkylene-C 3-6 It is a cycloalkylene, M is -O-, -NH-, or -CH2-. Q is C 6-18 Aryl, 5-10 member heteroaryl, one or more Q 1-2 5-10 member heteroaryls substituted by -C(=O)R 1 Or -S(=O)2R 2 And, If M is -O-, then Q 1-2 C 1-4 Alkyl or hydroxyl, If the heteroatom in the 5-10 membered heteroaryl is oxygen, then the number of heteroatoms in the 5-10 membered heteroaryl is one.

[0025] In one preferred embodiment, L is C 1-10 Alkylene or -C 1-6 Alkylene-C 3-6 It is a cycloalkylene, M is -O-, -NH-, or -CH2-. Q is C 6-18 Aryl, 5-10 member heteroaryl, one or more Q 1-2 5-10 member heteroaryls substituted by -C(=O)R 1 Or -S(=O)2R 2 And, L is -C 1-6 Alkylene-C 3-6 If it is a cycloalkylene, then -C 1-6 Alkylene-C 3-6 C in cycloalkylene 1-6 Alkylene is ethylene.

[0026] In one preferred embodiment, L is C 1-10 Alkylene or -C 1-6 Alkylene-C 3-6 It is a cycloalkylene, M is -O- or -NH-, Q is -C(=O)R 1 or one or more Qs 1-2 It is a 5-10 member heteroaryl substituted by, R 1 -NR 1-1 R 1-2 That is the case.

[0027] In one preferred embodiment, L is C 1-10 It is alkylene, M is -O-, Q is one or more Qs 1-2 It is a 5-10 member heteroaryl substituted by [the specified compound].

[0028] In one preferred embodiment, L is -C 1-6 Alkylene-C 3-6 It is a cycloalkylene, M is -NH-, Q is -C(=O)R 1 And, R 1 -NR 1-1 R 1-2 That is the case.

[0029] In one preferred embodiment, the molecular structure represented by formula I is as shown by formula Ia.

[0030] [ka]

[0031] L is C 1-10 Alkylene or C 2-10 It is alkenylene. Q is a 5- to 10-membered heteroaryl, or one or more Qs. 1-2 It is a 5-10 member heteroaryl substituted by [the specified compound].

[0032] In one preferred embodiment, the molecular structure represented by formula I is as shown by formula Ia.

[0033] [Chemical]

[0034] L is C 1-10 alkylene or C 2-10 alkenylene. Q is C 1-1 aryl substituted by one or more Q 6-18 heteroaryl having 5 to 10 members, or heteroaryl having 5 to 10 members substituted by one or more Q 1-2 where Q Q 1-1 is halogen.

[0035] In a certain preferred embodiment, the molecular structure represented by the formula I is as represented by the formula Ib.

[0036] [Chemical]

[0037] L is -C 1-6 alkylene-C 3-6 cycloalkylene-. Q is -C(=O)R 1 or -S(=O)2R 2 where R 1 and R 2 are independently -NR 1-1 R 1-2 heterocycloalkyl having 3 to 6 members, C 6-18 aryl or heteroaryl having 5 to 10 members.

[0038] In a certain preferred embodiment, the molecular structure represented by the formula I is as represented by the formula Ic.

[0039] [Chemical]

[0040] "

[0041] [ka] " represents a double bond or a single bond,

[0042] Y is hydrogen, hydroxyl, or oxygen. L is C 1-10 It is alkylene, Q is one or more Qs 1-1 C replaced by 6-18 A aryl, or one or more Qs 1-2 It is a 5-10 member heteroaryl substituted by, Q 1-1 It is a halogen, Q 1-2 C 1-4 It is alkyl or oxo.

[0043] In one preferred embodiment, the molecular structure represented by formula I is as shown by formula Ic-1.

[0044] [ka]

[0045] L is C 1-10 It is alkylene, Q is one or more Qs 1-1 C replaced by 6-18 It is Ariel, Q 1-1 It is a halogen, R is hydrogen.

[0046] In one preferred embodiment, the molecular structure represented by formula I is as shown in formula Ic-2.

[0047] [ka]

[0048] L is C1-10 is an alkylene, Q is one or more Q 1-1 substituted C 6-18 is an aryl, Q 1-1 is a halogen, R is hydrogen.

[0049] In a preferred embodiment, the molecular structure represented by Formula I is as represented by Formula Ic-3.

[0050]

Chemical formula

[0051] L is C 1-10 is an alkylene, Q is one or more Q 1-2 substituted 5- to 10-member heteroaryl, Q 1-1 is C 1-4 alkyl or oxo, R is hydrogen.

[0052] 7]In a preferred embodiment, when L is C 1-10 alkylene, the C 1-10 alkylene is C 1-4 alkylene (e.g., methylene, ethylene (

[0053]

Chemical formula

[0054]

Chemical formula

[0055] [[ID=’74]]

Chemical formula

[0056] [ka] ), isobutylene (

[0057] [ka] ) or tert-butylene (

[0058] [ka] ) is preferably n-propylene or n-butylene, and more preferably n-butylene.

[0059] In one preferred embodiment, L is C 2-10 It is an alkenylene, and the C 2-10 Alkenylene, C 2-4 If it is an alkenylene, preferably

[0060] [ka] That is the case.

[0061] In one preferred embodiment, L is -C 1-6 Alkylene-C 3-6 If it is a cycloalkylene, then C 1-6 Alkylene is linked to N, and the C 3-6 The cycloalkylene is linked to Q.

[0062] In one preferred embodiment, L is -C 1-6 Alkylene-C 3-6 If it is a cycloalkylene, then -C 1-6 Alkylene-C 3-6 C in cycloalkylenes 1-6 Alkylenes include methylene and ethylene.

[0063] [ka] )、n-propylene(

[0064]

Chem.

[0065]

Chem.

[0066]

Chem.

[0067]

Chem.

[0068]

Chem.

[0069] 1-6 , alkylene-C 3-6 cycloalkylene-, when the -C 1-6 alkylene-C 3-6 cycloalkylene in the C 3-6 cycloalkylene is cyclopropylene, cyclobutylene, cyclopentylene or cyclohexylene (e.g.

[0070]

Chem.

[0071]

Chem.

[0072] In one preferred embodiment, L is -C 1-6 Alkylene-C 3-6 If it is a cycloalkylene, then -C 1-6 Alkylene-C 3-6 Cycloalkylene- is,

[0073] [ka] (for example

[0074] [ka] ) or

[0075] [ka] (for example

[0076] [ka] ) where end a is connected to Q and end b is connected to N, preferably

[0077] [ka] That is the case.

[0078] In one preferred embodiment, Q is C 6-18 If it is an aryl, then C 6-18 Ariel is C 6-14 It is an aryl (e.g., phenyl, naphthyl, anthracenyl, or phenantrenyl), and may further be phenyl.

[0079] In one preferred embodiment, Q is Q 1-1 C replaced by 6-18 If it is an aryl, then C 6-18 Ariel is C 6-14It is an aryl (e.g., phenyl, naphthyl, anthracenyl, or phenantrenyl), and may further be phenyl.

[0080] In one preferred embodiment, Q is Q 1-1 C replaced by 6-18 If it is an aryl, then Q 1-1 There is one or two. Q 1-1 If there are multiple, Q 1-1 They may be the same or different; for example, they may be different.

[0081] In one preferred embodiment, Q 1-1 If the halogen is a halogen, the halogen is F, Cl, Br, or I, and is preferably F. In one preferred embodiment, Q is Q 1-1 C replaced by 6-18 If it is an aryl, then Q 1-1 C replaced by 6-18 Ariel,

[0082] [ka] That is the case.

[0083] In one preferred embodiment, if Q is a 5- to 10-membered heteroaryl, then the 5- to 10-membered heteroaryl is a 9 or 10-membered heteroaryl, and the number of heteroatoms is one or two, and more preferably

[0084] [ka] That is the case.

[0085] In one preferred embodiment, Q is one or more Q 1-2 In the case of a 5-10 membered heteroaryl substituted by, the 5-10 membered heteroaryl is a 9 or 10 membered heteroaryl, and the heteroatoms are N and / or O, and there are one or two of them, preferably tetrahydroquinolyl(

[0086] [ka] ), quinolyl (for example)

[0087] [ka] ), benzoxazolyl (for example)

[0088] [ka] ), benzisoxazolyl (for example)

[0089] [ka] ) or tetrahydropyridopyrimidinyl (e.g., oxo

[0090] [ka] )

[0091] In one preferred embodiment, Q is Q 1-2 C replaced by 6-18 If it is an aryl, then Q 1-2 There is one or two of the above Q. 1-2 If there are multiple instances of Q, 1-2 They may be the same or different; for example, they may be different.

[0092] In one preferred embodiment, Q 1-2 C 1-4 If it is alkyl, then C 1-4 The alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl, and is preferably methyl.

[0093] In one preferred embodiment, Q is one or more Q 1-2In the case of a 5-10 member heteroaryl substituted by, one or more Q 1-2 The 5-10 member heteroaryls substituted by are

[0094] [ka] That is the case.

[0095] In one preferred embodiment, R 1 and R 2 However, if they are independently 3-6 member heterocycloalkyls, then the 3-6 member heterocycloalkyls are piperidinyl (for example)

[0096] [ka] ) or pyrrolidinil (for example)

[0097] [ka] ) and preferably pyrrolidinyl.

[0098] In one preferred embodiment, R 1 If the group is a 3- to 6-membered heterocycloalkyl group, the 3- to 6-membered heterocycloalkyl group is linked to the carbonyl group via a heteroatom. In one preferred embodiment, R 1 and R 2 However, independently C 6-18 If it is an aryl, then C 6-18 Ariel is C 6-14 It is an aryl (e.g., phenyl, naphthyl, anthracenyl, or phenantrenyl), and may further be phenyl.

[0099] In one preferred embodiment, R 1 and R 2 However, one or more R independently 1-3 C replaced by 6-18 If it is an aryl, then C 6-18 Ariel is C6-14 It is an aryl (e.g., phenyl, naphthyl, anthracenyl, or phenantrenyl), and may further be phenyl.

[0100] In one preferred embodiment, R 1 and R 2 However, if the 5-10 membered heteroaryl is independent, then the 5-10 membered heteroaryl is a 9 or 10 membered heteroaryl, the heteroatom is N, there is one or two of them, preferably indolyl (for example)

[0101] [ka] )

[0102] In one preferred embodiment, R 1-1 , R 1-2 , R 1-3 and R 1-4 However, independently C 1-4 If it is alkyl, then C 1-4 The alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, and is preferably methyl.

[0103] In one preferred embodiment, R is C 1-4 If it is alkyl, then C 1-4 The alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, and is preferably methyl.

[0104] In one preferred embodiment, L is C 1-10 Alkilen, C 2-10 Alkenylene or -C 1-6 Alkylene-C 3-6 It is a cycloalkylene. In one preferred embodiment, L is C 1-10 Alkylene or -C 1-6 Alkylene-C 3-6 It is a cycloalkylene.

[0105] In one preferred embodiment, M is -O-, -NH-, or -CH2-. In one preferred embodiment, Q 1-1 It is a halogen. In one preferred embodiment, R 1 -NR 1-1 R 1-2 , 3-6 member heterocycloalkyl, C 6-18 It is an aryl or 5-10 member heteroaryl, preferably -NR 1-1 R 1-2 , 3-6 member heterocycloalkyl or C 6-18 It is Ariel.

[0106] In one preferred embodiment, R is hydrogen. In one preferred embodiment,

[0107] [ka] teeth,

[0108] [ka] That is the case.

[0109] In one preferred embodiment, the compound represented by formula I is optionally one of the following compounds.

[0110] [ka] TIFF0007842414000051.tif69170

[0111] In one preferred embodiment, the compound represented by formula I is optionally one of the following compounds.

[0112] [ka] That is the case.

[0113] In one preferred embodiment, the compound represented by formula I is optionally one of the following compounds. "Optical rotation is +50.33" o and / or under the following chiral manufacturing conditions, the retention time is 5.805 min.

[0114] [ka] " or "Optical rotation is -45.00 o and / or under the following chiral manufacturing conditions, the retention time is 7.60 min.

[0115] [ka] The chiral manufacturing conditions were as follows: Column: Chiral column CHIRALCEL OD, Column volume: 5.0 cm × 25 cm, 10 μm filler; Mobile phase: MeOH / diethylamine = 100 / 0.1; Flow rate: 30 mL / min; Wavelength: UV 214 nm; Temperature: 38 °C.

[0116] In one preferred embodiment, the compound represented by formula I is the following compound.

[0117] [ka]

[0118] The present invention further provides a method for producing a compound represented by formula I, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, comprising the following steps.

[0119] In the presence of a basic reagent, the compound represented by formula II is subjected to the alkylation reaction shown below with the compound represented by formula III in a solvent to obtain the compound represented by formula I.

[0120] [ka]

[0121] However, X is a halogen, and the definitions of L, M, Q, and R are the same as above. The conditions and procedures for the alkylation reaction may be those that are common for such reactions in the art, and the present invention particularly prefers the following conditions: The basic reagent is, for example, K2CO3 (for example, the molar ratio of the basic reagent to the compound of formula II is 6:1).

[0122] The solvent is, for example, tetrahydrofuran and dimethyl sulfoxide (for example, in a volume ratio of 3:1). The temperature of the alkylation reaction is, for example, 60°C.

[0123] The present invention further provides a method for producing a compound represented by formula I, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, comprising the following steps.

[0124] In the presence of a basic reagent, the compound represented by formula II is converted to the compound represented by formula III. The present invention further provides a pharmaceutical composition comprising a compound represented by formula I, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, and a pharmaceutical adjuvant.

[0125] The present invention further provides the use of substance A in the production of a dopamine D2 receptor agonist, wherein substance A is a compound represented by formula I above, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, or the above pharmaceutical composition.

[0126] The present invention further provides the use of substance A in the manufacture of a pharmacopoeia for the treatment and / or prevention of diseases relating to the dopamine D2 receptor, wherein substance A is a compound represented by the above formula I, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, or the above pharmacopoeia.

[0127] The aforementioned diseases relating to dopamine D2 receptors refer to one or more neurodegenerative diseases, mental disorders, and metabolic diseases associated with mental disorders, such as Parkinson's disease, Alzheimer's disease, dementia, schizophrenia, bipolar disorder, depression, ADHD, restless legs syndrome, Huntington's disease, male erectile dysfunction, prolactinoma, or drug addiction.

[0128] The present invention further provides the use of substance A in the manufacture of a medicament for the treatment and / or prevention of disease M, wherein substance A is a compound represented by formula I above, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, or the above medicament composition, and disease M is one or more of neurodegenerative diseases, mental disorders, and metabolic diseases associated with mental disorders.

[0129] In the above use, the disease M is preferably Parkinson's disease, Alzheimer's disease or dementia, schizophrenia, bipolar disorder, depression, ADHD, restless legs syndrome, Huntington's disease, male erectile dysfunction, prolactinoma, or drug addiction.

[0130] The present invention provides a method for preventing or treating a disease relating to the dopamine D2 receptor, further comprising administering a therapeutically effective amount of substance A to a subject, wherein substance A is a compound represented by the above formula I, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, or the above pharmaceutical composition.

[0131] The aforementioned diseases relating to dopamine D2 receptors refer to one or more neurodegenerative diseases, mental disorders, and metabolic diseases associated with mental disorders, such as Parkinson's disease, Alzheimer's disease, dementia, schizophrenia, bipolar disorder, depression, ADHD, restless legs syndrome, Huntington's disease, male erectile dysfunction, prolactinoma, or drug addiction.

[0132] The present invention provides a method for preventing or treating disease M, further comprising administering a therapeutically effective amount of substance A to a subject, wherein substance A is a compound represented by formula I above, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, or the above-mentioned pharmaceutical composition, and disease M is one or more of neurodegenerative diseases, mental disorders, and metabolic diseases associated with mental disorders.

[0133] In the above method, the disease M is preferably Parkinson's disease, Alzheimer's disease or dementia, schizophrenia, bipolar disorder, depression, ADHD, restless legs syndrome, Huntington's disease, male erectile dysfunction, prolactinoma, or drug addiction.

[0134] The present invention further provides a crystal represented by the formula pNs-(+)-I-10, which is a triclinic crystal system belonging to the P1 space group, with cell parameters a=9.315Å, b=6.564Å, c=23.792Å, α=90.15°, β=99.368°, and γ=90.25°.

[0135] [ka]

[0136] Unless otherwise specified, the terms used in this invention have the following meanings: In this specification, a single dash "-" precedes any substituent used to indicate that the specified substituent is attached to the parent molecule by a single bond. Furthermore, substituents are described by conventional chemical formulas written from left to right or from top to bottom, for example, "-C 1-6 Alkylene-C 3-6 "Cycloalkylene" is C 1-6 This means that the alkylene is connected to the parent nitrogen atom via a single bond.

[0137] The terms "compound" and "pharmaceutically acceptable salt" exist, if tautomers are present, as a single tautomer or a mixture thereof, preferably in a more stable tautomer-based form.

[0138] The term "halogen" refers to fluorine, chlorine, bromine, or iodine. The term "alkyl" refers to a specific number of carbon atoms (for example, C1-C1). 10 This refers to linear or branched alkyl groups having ) ). Alkyls include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-amyl, n-hexyl, n-heptyl, and n-octyl.

[0139] The term "alkylene" refers to a divalent group of a linear or branched saturated aliphatic hydrocarbon group having a specific number of carbon atoms. Examples include methylene (-CH2-) and ethylene (

[0140] [ka] The two valencies may be concentrated on the same atom, as in ) and the two valencies may each be bonded to two atoms, as in 1,2-ethylene (-CH2CH2-).

[0141] The term "alkenylene" refers to a specific number of carbon atoms (for example, C2-C2). 10 This refers to a divalent group of a straight-chain or branched-chain aliphatic hydrocarbon group having one or more double bonds. For example,

[0142] [ka] As shown above, the two valencies may be concentrated on the same atom, for example, the two valencies may each be bonded to two atoms, as in -CH2CH=CHCH2-.

[0143] The term "alkynylene" refers to a specific number of carbon atoms (for example, C2-C2). 10 This refers to a divalent group of a straight-chain or branched-chain aliphatic hydrocarbon group having one or more triple bonds. For example,

[0144] [ka] As shown above, two valencies may be concentrated on the same atom, for example,

[0145] [ka] The two valencies may each bond to two atoms, as shown above.

[0146] The term "cycloalkyl" refers to a saturated monocyclic cyclic group consisting only of carbon atoms, having a specific number of carbon atoms (e.g., C3-C6). Cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0147] The term "cycloalkylene" refers to the divalent group of a saturated cyclic alkylene, for example, cyclopentylene (for example,

[0148] [ka] This refers to (or cyclohexylene, etc.).

[0149] The term "heterocycloalkyl" refers to a cyclic group having a specific number of ring atoms (e.g., 5-10 members), a specific number of heteroatoms (e.g., 1, 2, or 3), and a specific type of heteroatom (one or more of N, O, and S), which can be monocyclic, bridging, or spirocyclic, and all rings are saturated. Heterocycloalkyls include, but are not limited to, azetidinyl, tetrahydropyrrolyl, tetrahydrofuranyl, morpholinyl, and piperidinyl.

[0150] The term "aryl" refers to a specific number of carbon atoms (for example, C6-C6). 10 Aryls are cyclic groups consisting only of carbon atoms, which can be monocyclic or polycyclic, with at least one ring being aromatic (according to the Shock-Soul rule). Aryls are attached to other fragments within the molecule via aromatic or non-aromatic rings. Aryls include, but are not limited to, phenyl and naphthyl.

[0151] The term "heteroaryl" refers to a cyclic group having a specific number of ring atoms (e.g., 5-10 members), a specific number of heteroatoms (e.g., 1, 2, or 3), or a specific type of heteroatom (one or more of N, O, and S), which may be monocyclic or polycyclic, and at least one ring is aromatic (according to the shock-soul rule). Heteroaryls are bonded to other fragments within the molecule via aromatic or non-aromatic rings. Heteroaryls include, but are not limited to, furyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, pyridyl, pyrimidinyl, and indolyl. Heteroaryls are also, for example,

[0152] [ka] That is the case.

[0153] The hyphen "-" at the end of a group indicates that the group is bonded to another fragment within the molecule via that site. For example, CH3-C(=O)- refers to acetyl. In structural fragments

[0154] [ka] " " refers to the fact that the structural fragment is bound to other fragments within the molecule via that site. For example,

[0155] [ka] This refers to cyclohexyl.

[0156] The term "plural" refers to two, three, four, or five items. In the definition of a compound, any variable (for example) R1-1 If the R(R) appears multiple times, their definitions are independent of each other and do not affect each other. For example, three R(R) 1-1 C6~C substituted by 10 Aryl is C6~C10 The aryl has three R's 1-1 This refers to being replaced by three R's. 1-1 The definitions are mutually independent and do not influence each other.

[0157] 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 a compound contains relatively acidic functional groups, 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, potassium, calcium, aluminum, magnesium, bismuth, and ammonium. When a compound contains relatively basic functional groups, 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, hydrochloride, sulfate, and methanesulfonate salts. For specifics, refer to Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl, 2002).

[0158] The term "solvate" refers to a substance formed after a compound is crystallized in a solvent (including, but not limited to, water, methanol, and ethanol). Solvates are classified into stoichiometric solvates and non-stoichiometric solvates.

[0159] The term "pharmaceutically acceptable salt solvate" refers to a substance formed by the combination of 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, and ethanol). Here, "pharmaceutically acceptable salt" has the same meaning as the term "pharmaceutically acceptable salt" above, and the solvent can be stoichiometric or non-stoichiometric. Pharmaceutically acceptable salt solvates include, but are not limited to, hydrochloric acid monohydrate.

[0160] The term "pharmaceutical adjuvants" refers to excipients and additives used in the manufacture and preparation of pharmaceutical formulations, encompassing all substances contained in drug preparations excluding the active ingredient. For further details, refer to the People's Republic of China Pharmacopoeia 2020 I-IV or the Handbook of Pharmaceutical EMcipients (Raymond C Rowe, 2009).

[0161] The term "treatment" refers to any of the following situations: (1) alleviating one or more biological manifestations of a disease; (2) disrupting one or more points in the biological cascade leading to the disease; or (3) delaying the progression of one or more biological manifestations of the disease.

[0162] The term "prevention" refers to reducing the risk of developing a disease. The term "patient" refers to any animal that has received or is seeking treatment, preferably a mammal, and most preferably a human. Mammals include, but are not limited to, cattle, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, and humans.

[0163] The aforementioned preferred conditions can be combined in any way, without violating the ordinary knowledge of the art, to obtain each preferred embodiment of the present invention. The reagents and raw materials used in this invention are commercially available.

[0164] The positive progressive effect of the present invention is that the compounds of the present invention have good affinity, agonist activity, or selectivity for dopamine D2 receptors. [Brief explanation of the drawing]

[0165] [Figure 1] This is the X-axis single-crystal diffraction pattern of a crystalline compound represented as pNs-(+)-I-10. [Modes for carrying out the invention]

[0166] The present invention will be further described below with reference to embodiments, but this does not limit the present invention to the scope of the above embodiments. In the following embodiments, experimental methods for which specific conditions are not described are selected according to conventional methods and conditions or according to the product description.

[0167] Materials and methods 1.Cell culture Human kidney epithelial cells 293T were cultured in DMEM medium containing 10% fetal bovine serum (FBS), and cultured in a culture dish at 37°C under 5% CO2 conditions. After the cells covered the culture dish, the medium was aspirated using a pipette, and excess serum was removed by slowly washing with 1 mL of phosphate buffer (pH 7.4). Next, 800 μL of 0.25% trypsin was added, and the cells were digested in a constant temperature bath for 2 minutes. After removing the cells and observing them under a microscope, the cells were rounded and swimming freely at the bottom of the petri dish. Digestion was then completed by adding 2 mL of medium containing 10% serum, and the cells were gently blown out with a 1 mL canister to disperse into single cells. Finally, subculturing or further experiments were performed as needed.

[0168] 2. Cell transfection The day before transfection, 293T cells grown in a 10cm diameter culture dish were subcultured in a 6cm culture dish at a 1:4 ratio. After 20 hours, when the cell density reached 50%-70%, preparation for transfection was made. 500 μL of 150 mM sodium chloride was placed in a clean EP tube, an appropriate amount of plasmid was added, and simultaneously, four times the amount of transfection reagent PEI was added and mixed uniformly. The mixture was incubated at room temperature for 20 minutes. 500 μL of the transfection solution was added dropwise to the culture dish in suspension and gently shaken to mix uniformly.

[0169] 3. Production of cell membrane components containing specific dopamine D2 receptors Cells were transfected with 10 ng of dopamine D2 receptor and 40 μL of PEI in a 10 cm diameter culture dish. After 48 hours, the 10 cm culture dish was removed from the cell chamber, and the cultured cells expressed dopamine D2 receptor. The culture medium was removed by aspirating with a vacuum pump, and 3 mL of lysate (50 mM Tris hydrochloride buffer, pH 7.4) was added to each well. The cells were then allowed to stand in a refrigerated room at 4°C for 10 minutes. After the cells had detached, they were transferred to a 15 mL centrifuge tube and centrifuged at 1500 rpm at 4°C for 5 minutes, discarding the supernatant. The cell precipitate was transferred to a tissue homogenizer, 3 mL of lysate was added, and the cells were thoroughly pulverized until they were destroyed. Next, the cell suspension was dispensed into several EP tubes and centrifuged at 12000 rpm at 4°C for 5 minutes, discarding the supernatant. The precipitate consists of cell membrane components containing dopamine D2 receptors and was stored at -80°C.

[0170] 4. Radioactive ligand receptor binding experiment Ligand receptor binding experiments were performed on the 293T membrane fraction, which transiently expresses dopamine D2 receptors. First, standard binding buffer (50 mM HEPES, 50 mM NaCl, 5 mM MgCl2, 0.5 mM EDTA, pH 7.4) was added to the cell membrane fraction containing dopamine D2 receptors, and the cell membrane was disrupted and resuspended using an electrotissue homogenizer. 30 L of membrane protein suspension was added to each well of a 96-well plate. Next, 30 μL of different drugs were added to the 96-well plate from left to right, and the final drug concentrations were measured from bottom to top. -5 M, 10 -6 M, 10 -7 M, 10 -8 M, 10 -9 The levels were adjusted to M and 0M, and each treatment was repeated twice. Immediately afterward, 30 μL of [ 3 [H]-N-Methylspiperone was added, and the mixture was incubated at room temperature for 2 hours, avoiding light exposure. Unbound isotopes were removed using a WhatmanGF / C filter membrane and a vacuum pump, and receptor-bound isotopes were detected using a MicroBeta isotope liquid scintillation system.

[0171] 5. G protein Gαi1-γ9 dissociation experiment based on bioluminescence resonance energy transfer (BRET) To detect the downstream G protein signaling pathway mediated by the dopamine D2 receptor, a 6 cm culture dish was prepared containing 1 μg of dopamine D2 receptor and 1 μg of seaweed luciferase fused with Gα i1 (Gα i1 Transfection was performed with -Rluc), 1 μg of Gβ3, 1 μg of fusion green fluorescent protein Gγ9 (Gγ9-GFP), and 16 μL of transfection reagent PEI. On day 2, overgrown cells were digested using 0.25% trypsin, and the cell volume from a 6 cm culture dish filled with cells was spread into one 96-well plate, with 100 μL of medium in each well. On day 3, drugs were administered and detected. The 96-well plate was removed from the cell chamber, the medium was removed, and 40 μL of buffer (1X HBSS, 20 mM HEPES, pH 7.4) containing the substrate coelenterazine 400a (7.5 M) was added to each well. 20 μL of different drugs were added sequentially from left to right, so that the final drug concentration decreased in a gradient from bottom to top, and each treatment was repeated twice. The readings at 395nm and 510nm were detected 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.

[0172] 6. β-arrestin2 recruitment experiment based on bioluminescence resonance energy transfer (BRET) To detect the downstream β-arrestin2 signaling pathway mediated by the dopamine D2 receptor, 6 cm culture dishes were transfected with 500 μg of seaweed luciferase-fused dopamine D2 receptor (D2-Rluc), 500 μg of G protein-coupled receptor kinase 2 (GRK2), 2500 μg of fused green fluorescent protein β-arrestin2 (GFP2-ARRB2), and 14 μL of transfection reagent PEI. On day 2, overgrowthed cells were digested, and the cell volume from the 6 cm culture dish filled with cells was spread into a single 96-well plate, with 100 μL of medium in each well. On day 3, the drug was administered for detection. The 96-well plate was removed from the cell chamber, the culture medium was 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. 20 μL of different drugs were added sequentially from left to right, so that the final drug concentration decreased in a gradient from bottom to top, and each treatment was repeated twice. 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.

[0173] Manufacturing of raw material (A) (6,6a,7,8,9,10-hexahydro-4H-pyrazine[1,2-a]pyrrole[4,3,2-de]quinoline)

[0174] [ka]

[0175] It was prepared according to the method described in the literature (Krogsgaard-Larsen et al., J. Med. Chem. 2014, 57, 5823-5828). It was a brown solid. 1H 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). Example 1: 7-(4-(4,6,6a,7,9,10-hexahydro-8H-pyrazine[1,2-a]pyrrole[4,3,2-de]quinoline-8-yl)butoxy)-3,4-dihydroquinoline-2(1H)-one (Compound I-1)

[0176] [ka]

[0177] Step 1: 7-hydroxyl-3,4-dihydroquinoline-2(1H)-one (1.5 g, 9.19 mmol), 1,4-dibromobutane (5.92 g, 27.6 mmol), K2CO3 (1.9 g, 13.7 mmol), and solvent DMF (20 mL) were sequentially added to a round-bottom flask, and the reaction system was stirred overnight at room temperature. The solvent was removed by evaporation under reduced pressure, and the residue was purified by flash column chromatography (eluent: ethyl acetate / petroleum ether mixture containing 20-50% ethyl acetate) to obtain intermediate wha71 (1.75 g, 64%), a white solid. 1H NMR (800 MHz, deuterated chloroform) δ 7.74 (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 HR-MS (ESI, m / z): C 13 H 17 BrNO2 + [M+H] + Calculated value: 298.0437; Measured values: 298.0432 and 300.0412.

[0178] Step 2: Intermediate A (50 mg, 0.23 mmol), intermediate wha71 (82 mg, 0.28 mmol), and K2CO3 (0.2 g, 1.38 mmol) were sequentially added to a round-bottom flask, followed by the addition of solvents THF (3 mL) and DMSO (1 mL). The reaction system was heated at 60°C and stirred for 16 hours. After the reaction was complete, the solvent was removed and the compound was purified by flash silica gel column chromatography (eluent: 0-10% methanol / dichloromethane) to obtain compound I-1 (90 mg, 91%), 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 = 6.8 Hz, 2H), 2.71 - 2.61 (m, 2H), 2.40 (t, J = 7.7 Hz, 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 ¹C 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.

[0179] Example 2: 7-(4-(4,6,6a,7,9,10-hexahydro-8H-pyrazine[1,2-a]pyrrole[4,3,2-de]quinoline-8-yl)butoxy)quinoline-2(1H)-one (compound I-2)

[0180] [ka]

[0181] Step 1: Referring to the method of Step 1 of Example 1, an alkylation reaction was carried out using "7-hydroxyl-quinoline-2(1H)-one" and 1,4-dibromobutane as starting materials to produce the intermediate wha70 (1.06 g, 38%), a white solid. 1 H NMR (800 MHz, deuterated chloroform) δ 7.79 (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 = HR-MS (ESI, m / z): C 13 H 15 BrNO2 + [M+H] + Calculated value: 296.0281; Measured value: 296.0220.

[0182] Step 2: Referring to the method of Step 2 of Example 1, the intermediate wha70 and starting material (A) are subjected to an alkylation reaction to obtain compound I-2 (60 mg, 61%), and preparative HPLC (t R A white solid was obtained by purifying the solution with 20-80% MeOH / H2O for 18.5 minutes. 1¹H NMR (800 MHz, heavy water metallization) δ 7.91 (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 = 5.8 Hz, 3H), 3.79 (t, J = 10.0 Hz, 2H), 3.41 - 3.33 (m, 4H), 3.19 (dd, J = 15.2, 3.9 Hz, 1H), 3.14 - 3.06 (m, 2H), 2.90 (dd, J = 15.0, 9.5 Hz, 1H), 2.09 - 2.05 (m, 2H), 2.00 - 1.96 (m, 2H); 13 C NMR (201 MHz, heavy hydrolyzate) 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.

[0183] Compound I-2をキラル was divided into two parts. Chiral separation conditions: Chiral column Daicel CHIRALCEL OD-H (ODH0CD-TC013) (Daicel), column volume: 0.46 cm (diameter) × 15 cm (column length) (5 μm filler); 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. peak1 (previous peak) t R =5.805min;peak2(later peak):t R = 7.548 min.

[0184] Chiral manufacturing conditions: Chiral column CHIRALCEL OD (Daicel), column volume: 5.0 cm (diameter) × 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.

[0185] Split manufacturing: Racemic compound I-2 (0.103g). Peak 1 (previous peak) t R =5.830min, 0.048g obtained, >98%ee; optical rotation [α] D 25 = +50.33 o (c=0.1, MeOH), >98%ee (compound is trifluoroacetate). peak2 (post-peak) t R =7.60 min, 0.042 g obtained, >98%ee; optical rotation [a] D 25 =-45.00 o (c=0.1, MeOH), >98%ee (the compound is a trifluoroacetate).

[0186] Example 3: 5-(4-(4,6,6a,7,9,10-hexahydro-8H-pyrazine[1,2-a]pyrazole[4,3,2-de]quinoline-8-yl)butoxy)benzo[d]thiazole (Compound I-3)

[0187] [ka]

[0188] Step 1: Referring to the method of Step 1 of Example 1, intermediate wha72 (1.23 g, 65%), a white solid, was prepared using "5-hydroxyl-benzo[d]thiazole" and 1,4-dibromobutan as raw materials. 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 HR-MS (ESI, m / z): C 11 H 13 BrNOS + [M+H] + Calculated value: 285.9896; Measured values: 285.9894 and 287.9875.

[0189] Step 2: Referring to the method of Step 2 of Example 1, the intermediate wha72 and starting material (A) were subjected to an alkylation reaction to obtain compound I-3 (30 mg, 51%), a yellow solid. 1H NMR (800 MHz, deuterated methanol) δ 9.18 (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 = 12.0 Hz, 1H), 3.15 - 3.10 (m, 2H), 3.09 - 3.05 (m, 1H), 2.95 (dd, J = 15.2, 3.6 Hz, 1H), 2.86 - 2.83 (m, 1H), 2.79 - 2.76 (m, 1H), 2.53 (t, J = 4.8 Hz, 2H), 2.37 - 2.34 (m, 1H), 2.12 (t, J = 10.9 Hz, 1H), 1.92 - 1.85 (m, 2H), 1.83 - 1.77 (m, 2H). 13 C 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, HR-MS (ESI, m / z): C 24 H 27 N4OS + [M+H] + Calculated value: 419.1900; Measured value: 419.1901.

[0190] Example 4: 5-(4-(4,6,6a,7,9,10-hexahydro-8H-pyrazine[1,2-a]pyrrole[4,3,2-de]quinoline-8-yl)butoxy)-2-methylbenzo[d]oxazole (Compound I-4)

[0191] [ka]

[0192] Step 1: Referring to the method of Step 1 of Example 1, an intermediate whb35 (0.15 g, 31%), a pale yellow solid, was prepared using "2-methyl-5-hydroxyl-benzo[d]thiazole" and 1,4-dibromobutan as raw materials. 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.

[0193] Step 2: Referring to the method of Step 2 of Example 1, the intermediate whb35 and starting material (A) were subjected to an alkylation reaction to obtain compound I-4 (41 mg, 43%), an off-white solid. 1¹H NMR (600 MHz, dehydrated chlorohydrin) 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 = 12.1 Hz, 1H), 3.23 (t, J = 11.0 Hz, 1H), 3.11 (d, J = 3.8 Hz, 2H), 3.01 - 2.93 (m, 2H), 2.81 (dd, J = 13.8, 11.0 Hz, 1H), 2.60 (d, J = 1.2 Hz, 3H), 2.52 (t, J = 7.6 Hz, 2H), 2.41 - 2.34 (m, 1H), 2.14 (t, J = 10.9 Hz, 1H), 1.88 - 1.85 (m, 2H), 1.82 - 1.74 (m, 2H). 13 C NMR (201 MHz, dehydrated chlorohydrin) 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.

[0194] Example 5: 6-(4-(4,6,6a,7,9,10-hexahydro-8H-pyrazine[1,2-a]pyrrole[4,3,2-de]quinoline-8-yl)butoxy)-3-methylbenzo[d]isoxazole (Compound I-5)

[0195] [ka]

[0196] Step 1: Referring to the method of Step 1 of Example 1, an intermediate whb37 (0.16 g, 42%), a pale yellow solid, was prepared using "3-methyl-6-hydroxyl-benzo[d]isoxazole" and 1,4-dibromobutane as raw materials. 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 HR-MS (ESI, m / z): C 12 H 15 BrNO2 + [M+H] + Calculated value: 284.0281; Measured value: 284.0261 sum 286.0241.

[0197] Step 2: Referring to the method of Step 2 of Example 1, the intermediate whb37 and starting material (A) were subjected to an alkylation reaction to obtain compound I-5 (58 mg, 60%), an off-white solid. 1H NMR (600 MHz, deuterated chloroform) δ 8.03 (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 = 12.0 Hz, 1H), 3.21 (t, J = 10.8 Hz, 1H), 3.09 - 3.06 (m, 2H), 2.98 - 2.90 (m, 2H), 2.81 (dd, J = 15.4, 10.9 Hz, 1H), 2.58 (s, 3H), 2.52 - 2.46 (m, 2H), 2.34 (t, J = 11.7 Hz, 1H), 2.11 (t, J = 10.9 Hz, 1H), 1.91 - 1.82 (m, 2H), 1.79 - 1.73 (m, 2H). 13 C 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; 25 H 29 N4O2 + [M+H] + Calculated value: 417.2285; Measured value: 417.2290.

[0198] Example 6: 8-(4-((2,3-dihydrobenzofuran-6-yl)oxy)butyl)-6,6a,7,8,9,10-hexahydro-4H-pyrazine[1,2-a]pyrrole[4,3,2-de]quinoline (compound I-6)

[0199] [ka]

[0200] Step 1: Referring to the method of Step 1 of Example 1, intermediate whb53 (0.29 g, 81%), a white solid, was prepared using "6-hydroxyl-2,3-dihydrobenzofuran" and 1,4-dibromobutan as raw materials. 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 ¹³C 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.

[0201] Step 2: Referring to the method of Step 2 of Example 1, the intermediate wha53 and starting material (A) were subjected to an alkylation reaction to obtain compound I-6 (30 mg, 32%), a white solid. 1H NMR (800 MHz, deuterated chloroform) δ 7.82 (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, 10.8 Hz, 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) δ161.41, 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.

[0202] Example 7: 7-(3-(4,6,6a,7,9,10-hexahydro-8H-pyrazine[1,2-a]pyrrole[4,3,2-de]quinoline-8-yl)propoxy)-3,4-dihydroquinoline-2(1H)-one (compound I-7)

[0203] [ka]

[0204] Step 1: Referring to the method of Step 1 of Example 1, the intermediate whb71 (2.85 g, 81%), a white solid, was prepared using "7-hydroxyl-3,4-dihydroquinoline-2(1H)-one" and 1,3-dibromopropane as raw materials. 1 H 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 HR-MS (ESI,m / z): C 12 H 15 BrNO2 + [M+H] + Actual value: 284.0281, calculated values: 284.0273 and 286.0255.

[0205] Step 2: Referring to the method of Step 2 of Example 1, the intermediate whb71 and starting material (A) were subjected to an alkylation reaction to obtain compound I-7 (60 mg, 63%), an off-white solid. 1H 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 = 11.8 Hz, 1H), 3.22 (t, J = 9.7 Hz, 1H), 3.12 - 3.07 (m, 2H), 3.02 - 2.93 (m, 2H), 2.89 (t, J = 7.5 Hz, 2H), 2.83 (dd, J = 15.2, 11.0 Hz, 1H), 2.39 (t, J = 11.6 Hz, 1H), 2.16 (t, J = 10.56 Hz, 1H), 2.05 - 2.01 (m, 2H), 1.81-1.67 (m, 4H). 13 ¹¹C 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): ¹¹C 25 H 29 N4O2 + [M+H] + Calculated value: 417.2285; Measured value: 417.2284.

[0206] Example 8: 7-(3-(4,6,6a,7,9,10-hexahydro-8H-pyrazine[1,2-a]pyrrole[4,3,2-de]quinoline-8-yl)propoxy)quinoline-2(1H)-one (compound I-8)

[0207] [ka]

[0208] Step 1: Referring to the method of Step 1 of Example 1, the intermediate whb73 (1.36 g, 39%), a white solid, was prepared using "7-hydroxyl-quinoline-2(1H)-one" and 1,3-dibromopropane as raw materials. 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 HR-MS (ESI,m / z): C 12 H 13 BrNO2 + [M+H] + Calculated value: 282.0124; Measured value: 282.0128, sum: 284.0109.

[0209] Step 2: Referring to the method of Step 2 of Example 1, the intermediate whb73 and starting material (A) were subjected to an alkylation reaction to obtain compound I-8 (0.10 g, 51%), a white solid. 1H NMR (600 MHz, deuterated methanol) δ 7.91 (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, 3.5 Hz, 1H), 3.24 - 3.08 (m, 3H), 2.92 (dd, J = 15.3, 9.6 Hz, 1H), 2.41 - 2.36 (m, 2H), 2.07 - 2.03 (m, 1H), 1.62 (t, J = 7.4 Hz, 1H). 13 ¹¹C 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): ¹¹C 25 H 27 N4O2 + [M+H] + Calculated value: 415.2129; Measured value: 415.2129.

[0210] Example 9: 8-(3-(benzo[d][1,3]dioxol-5-yloxy)propyl)-6,6a,7,8,9,10-hexahydro-4H-pyrazine[1,2-a]pyrrolo[4,3,2-de]quinoline (compound I-9)

[0211] [ka]

[0212] Step 1: Referring to the method of Step 1 of Example 1, sesamol (CAS #533-31-3) and 1,3-dibromopropane were used as raw materials to produce the intermediate whb74 (1.67 g, 45%), a white solid. 1 H 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).

[0213] Step 2: Referring to the method of Step 2 of Example 1, the intermediate whb74 and starting material (A) were subjected to an alkylation reaction to produce compound I-9 (20 mg, 22%), an off-white solid. 1 H NMR (600 MHz, deuterated chloroform) δ 7.87 (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 = 11.9 Hz, 1H), 3.21 (t, J = 10.7 Hz, 1H), 3.08 - 3.07 (m, 2H), 3.02 - 2.89 (m, 2H), 2.82 (dd, J = 15.3, 11.0 Hz, 1H), 2.59 (t, J = 7.4 Hz, 2H), 2.37 (t, J = 11.7 Hz, 1H), 2.14 (t, J = 10.8 Hz, 1H), 2.05 - 1.96 (m, 2H). 13¹¹C 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): ¹¹C 23 H 26 N3O3 + [M+H] + Calculated value: 392.1969; Measured value: 392.1970.

[0214] Example 10: 3-(4-(2-(4,6,6a,7,9,10-hexahydro-8H-pyrazine[1,2-a]pyrrole[4,3,2-de]quinoline-8-yl)ethyl)trans-cyclohexyl)-1,1-dimethylurea (compound I-10)

[0215] [ka]

[0216] Step 1: Add 2-(4-((tert-butoxycarbonyl)amino)trans-cyclohexyl)acetic acid (2.0 g, 7.77 mmol) and solvent DMF (15 mL) to a round-bottom flask. Then, sequentially add Cs2CO3 (7.6 g, 23.3 mmol) and benzyl bromide (BnBr) (5.32 g, 11.7 mmol), and stir overnight at room temperature. After the reaction was complete, filter the mixture, concentrate the filtrate, and purify the residue by column chromatography (eluent: dichloromethane containing 0-20% methanol) to obtain the target compound whb52 (2.36 g, yield 87%), a white solid. 1H 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, HR-MS (ESI,m / z): C 20 H 29 NO4Na + [M+Na] + Calculated value: 370.1989; Measured value: 370.1989 (M+Na).

[0217] Step 2: The whb52 (0.16 g, 0.46 mmol) from the previous step was dissolved in dichloromethane (3 mL), trifluoroacetic acid (1.5 mL) was added, and the mixture was stirred at room temperature for 3 hours. The mixture was concentrated under reduced pressure, and the residue was dissolved in THF (5 mL). Then, Et3N (1 mL) and dimethylcarbamoyl chloride (54 mg, 0.5 mmol) were added sequentially. The reaction system was stirred at room temperature overnight. After the reaction was complete, the solvent was removed, and the mixture was purified by silica gel column chromatography (eluent: dichloromethane containing 0-20% methanol) to obtain the target compound whb54 (0.78 g, 83%), 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). 13 C NMR (151 MHz, deuterated chloroform) δ172.80, 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 27N2O3 + [M+H] + Calculated value: 319.2016; Measured value: 319.2201.

[0218] Step 3: Whb54 (0.78 g, 2.45 mmol) was dissolved in THF (20 mL) and cooled to -10°C under the protection of argon gas (Ar). Next, DABAL-H (14.7 mL, 1 M) was added. The reaction system was stirred at 0°C for 5 hours. After the reaction was complete, the mixture was quenched with saturated sodium potassium tartrate solution (5 mL). After removing the solvent, the mixture was purified by silica gel column chromatography (eluent: dichloromethane containing 0-20% methanol) to obtain whb59 (0.50 g, yield 95%), 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.

[0219] Step 4: Whb59 (0.65 g, 3.04 mmol) and CBr4 (1.5 g, 4.56 mmol) were dissolved in dichloromethane (15 mL), cooled in an ice bath, and stirred. PPh3 (1.2 g, 4.56 mmol) was added, and the mixture was then transferred to room temperature and stirred for 4 hours. The solvent was removed by evaporation under reduced pressure, and the residue was purified by silica gel column chromatography (mobile phase: dichloromethane containing 0-3% methanol) to obtain whb60 (0.25 g, 38%), 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.

[0220] Step 5: The experimental procedure was the same as in Step 2 of Example 1, and the alkylation reaction was carried out with whb60 and starting material (A) to produce compound I-10 (0.18 g, 95%), an off-white solid. 1¹H NMR (800 MHz, dehydrated chlorohydrin) δ 7.93 (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, 3.7 Hz, 2H). 1H), 2.93 (t, J = 11.8 Hz, 1H), 2.88 (s, 6H), 2.84 - 2.78 (m, 1H), 2.43 (t, J = 7.9 Hz, 2H), 2.32 (t, J = 10.9 Hz, 1H), 2.09 (t, J = 10.8 Hz, 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 C10 NMR (201 MHz, dehydrated chlorohydrin) 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): C10 24 H 36 N5O + [M+H] + , calculated value: 410.2914, measured value: 410.2914.

[0221] Fractionation of compound I-10のキラル Chiral analysis conditions: Chiral column CHIRALPAK IG (Daicel), column volume: 0.46 cm (diameter) × 15 cm (column length) (5 μm particle size filler); 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-2010 BJ. peak1 (previous peak) t R =3.113min;peak2(later peak):t R = 4.622 min.

[0222] Chiral manufacturing conditions: Chiral column CHIRALPAK IG (Daicel), column volume: 2.5 cm (diameter) × 25 cm (column length) (10 μm particle size filler); 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-2010 BJ. peak1 (previous peak) t R =3.113min;peak2(later peak):t R = 4.622 min.

[0223] Chiral resolution: Racemic compound I-10 (1.20g), (-)-I-10 is the pre-peak (peak1), t R =3.057min, 0.566g obtained, >99%ee, optical rotation [α] D 25 =-56.67 o (c=0.1, CHCl3); (+)-I-10 is a later peak (peak2), t R =4.512min, 0.599g obtained, >99%ee, optical rotation [α] D 25 = +50.33 o (c=0.1, CHCl3).

[0224] pNs-(+)-I-10 was synthesized and its chiral configuration was determined:

[0225] [ka]

[0226] Step: (+)-I-10 (23 mg, 0.056 mmol) was dissolved in DMF (3 mL), and then potassium tert-butoxide (13 mg, 0.116 mmol) and p-nitrobenzenesulfonyl chloride (14 mg, 0.063 mmol) were added sequentially. The reaction solution was stirred at room temperature for 1 hour. After the reaction was complete, water was added, and the mixture was extracted three times with dichloromethane solvent. The organic phases were combined and concentrated. The crude product obtained by concentration was purified by flash silica gel column chromatography (eluent: 0-10% methanol / dichloromethane) to obtain an orange-yellow solid pNs-(+)-I-10 (20 mg, yield: 60%). 1 H NMR (800 MHz, CDCl3) δ 8.27 - 8.23 ​​(m, 2H), 8.05 - 8.01 (m, 2H), 7.32 (d, J = 8.2 Hz, 1H), 7.22 (t, J = 8.0 Hz, 1H), 7.01 (d, J = 1.9 Hz, 1H), 6.50 (d, J = 7.9 Hz, 1H), 4.10 (d, J = 7.6 Hz, 1H), 3.71-3.68 (m, 1H), 3.60-3.55 (m, 1H), 3.16-3.12 (m, 1H), 3.07-3.04 (m, 2) H), 2.90-2.88 (m, 7H), 2.69-2.65 (m, 1H), 2.44-2.40 (m, 2H), 2.28-2.25 (m, 1H), 2.11 - 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 [α] D 25 = +47.67 o (c = 0.1, CDCl3).

[0227] Preparation of single crystals of the compound represented by the formula pNs-(+)-I-10 Single crystal culture by volatilization: 10 mg of the compound pNs-(+)-I-10 product was weighed and added to 1 mL of chloroform, followed by 10 mL of petroleum ether. The test tube was left at room temperature to slowly volatilize the crystals.

[0228] Detection method: X-ray single crystal diffraction Detection revealed that the crystalline system of the compound represented by the formula pNs-(+)-I-10 is triclinic, belonging to the P1 space group. The cell parameters are a=9.315 Å, b=6.564 Å, c=23.792 Å, α=90.15°, β=99.368°, and γ=90.25°. The number of intracrystalline asymmetric units Z is 2, and its X-ray single-crystal diffraction is shown in Figure 1.

[0229] From the characterization results of X-ray single crystal diffraction, the configuration of compound pNs-(+)-I-10 is

[0230] [ka] Since it can be determined that this is the case, the configuration of the (+)-I-10 compound is

[0231] [ka] It can be inferred that this is the case. Correspondingly, the configuration of the (-)-I-10 compound is

[0232] [ka] That is the case.

[0233] Example 11: N-(4-(2-(4,6,6a,7,9,10-hexahydro-8H-pyrazine[1,2-a]pyrrole[4,3,2-de]quinoline-8-yl)ethyl)trans-cyclohexyl)tetrahydropyrrole-1-carboxamide (Compound I-11)

[0234] [ka]

[0235] Step 1: Using whb52 as a raw material, and referring to the method of Step 2 of Example 10, "dimethylcarbamoyl chloride" was replaced with "tetrahydropyrrole-1-formyl chloride" and intermediate whb77 (0.54 g, 87%), a white solid, was obtained by manufacturing. 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).

[0236] Step 2: Referring to the method of Step 3 of Example 10, whb77 was converted to whb81 (0.36 g, 96%), which was 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. Step 3: Referring to the method of Step 4 of Example 10, the intermediate whb81 was converted to whb87 (0.34 g, 76% yield), which was a white solid. 1H 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: 303.1073 and 305.1080.

[0237] Step 4: Following the method of Step 5 of Example 10, the alkylation reaction was carried out with whb87 and starting material (A) to obtain target compound I-11 (50 mg, 50%), an off-white solid. 1¹H NMR (800 MHz, dehydrated chlorohydrin) δ 7.97 (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, 3.8 Hz, 1H), 2.94 (d, J = 11.9 Hz, 1H), 2.82 (dd, J = 15.3, 10.9 Hz, 1H), 2.44 (t, J = 7.9 Hz, 2H), 2.36 - 2.30 (m, 1H), 2.10 (t, J = 10.8 Hz, 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). 13 C NMR (201 MHz, dehydrated chlorohydrin) 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. Example 12: N-(4-(2-(4,6,6a,7,9,10-hexahydro-8H-pyrazine[1,2-a]pyrrole[4,3,2-de]quinoline-8-yl)ethyl)trans-cyclohexyl)piperidine-1-carboxamide (Compound I-12)

[0238] [ka]

[0239] Step 1: Referring to the method in Step 2 of Example 10, "dimethylcarbamoyl chloride" was replaced with "piperidine-1-carboxyl chloride," and intermediate whb80, a white solid, was obtained by preparation. 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.

[0240] Step 2: Referring to the method in Step 3 of Example 11, whb80 was converted to whb86, which was 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.

[0241] Step 3: Referring to the method of Step 4 of Example 10, the intermediate whb86 was converted to whb89 (yield: 80%), which was 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.

[0242] Step 4: Following the method of Step 5 of Example 10, the alkylation reaction was carried out with whb89 and starting material (A) to obtain target compound I-12 (62 mg, 98%), a white solid. 1¹H NMR (800 MHz, dehydrated chlorohydrin) δ 7.91 (s, 1H), 7.07 (t, J = 7.8 Hz, 1H), 6.80 (d, J = 8.1 Hz, 1H), 6.72 (t, J = 1.8 Hz, 1H), 6.33 (d, J = 7.6 Hz, 1H), 4.20 (d, J = 7.5 Hz, 1H), 3.79 (d, J = 11.9 Hz, 1H), 3.61 - 3.57 (m, 1H), 3.29 (t, J = 5.5 Hz, 4H), 3.22 (s, 1H), 3.07 (d, J = 10.9 Hz, 2H), 2.98 (dd, J = 15.2, 3.8 Hz, 1H), 2.94 (d, J = 12.0 Hz, 1H), 2.82 (dd, J = 15.3, 11.0 Hz, 1H), 2.44 (t, J = 8.0 Hz, 2H), 2.33 (t, J = 11.6 Hz, 1H), 2.09 (t, J = 10.8 Hz, 1H), 2.04 - 1.99 (m, 2H), 1.79 (d, J = 12.3 Hz, 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, dehydrated chlorohydrin) 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.

[0243] Example 13: N-(4-(2-(4,6,6a,7,9,10-hexahydro-8H-pyrazine[1,2-a]pyrrole[4,3,2-de]quinoline-8-yl)ethyl)trans-cyclohexyl)-1H-indole-2-carboxamide (Compound I-13)

[0244] [ka]

[0245] Step 1: Methyl 2-(4-aminotrans-cyclohexyl)acetate (0.19 g, 1.02 mmol) was dissolved in tetrahydrofuran (5 mL) and added to a round-bottom flask. Then, HATU (0.505 g, 1.33 mmol), DIPEA (1 mL), and 1H-indole-2-carboxylic acid (0.214 g, 1.33 mmol) were added, and the reaction system was stirred overnight at room temperature. The solvent was removed by evaporation under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether containing 40-50% ethyl acetate) to obtain the intermediate whb108 (0.30 g, 90%), a white solid. 1H NMR (800 MHz, deuterated chloroform) δ 9.41 (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), 3.98 - 3.93 (m, 1H), 2.24 (dd, J = 13.8, 7.0 Hz, 2H), 2.12 (d, J = 13.4 Hz, 2H), 1.86 (d, J = 13.4 Hz, 2H), 1.83 - 1.79 (m, 1H), 1.31 (q, J = 12.8 Hz, 2H), 1.26 (t, J = 7.2 Hz, 3H), 1.21 - 1.17 (q, J = 12.8 Hz, 2H). HR-MS (ESI, m / z): C 19 H 25 N2O3 + [M+H] + Calculated value: 329.1860; Measured value: 329.1795.

[0246] Step 2: Refer to the method described in Step 3 of Example 10 to reduce intermediate whb108 to obtain intermediate whb149 (80 mg, 47%), a white solid. 1H NMR (800 MHz, deuterated chloroform) δ 9.23 (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.

[0247] Step 3: Referring to the method of Step 4 of Example 10, the alcohol intermediate whb149 was converted to bromide whb150 (0.11 g, 45%), which was a white solid. 1 H NMR (800 MHz, deuterated chloroform) δ 9.31 (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 = 7.0 Hz, 2H), 2.13 (d, J = 13.4 Hz, 2H), 1.88 - 1.83 (m, 2H), 1.81 (q, J = 1.55 - 1.51 (m, 1H), 1.33 - 1.29 (m, 2H), 1.16 - 1.11 (m, 2H). HR-MS (ESI,m / z): 17 H22 BrN2O + [M+H] + Calculated value: 349.0910; Measured values: 349.0901 and 351.0884.

[0248] Step 4: Following the method of Step 5 of Example 10, the alkylation reaction was carried out with whb150 and starting material (A) to obtain compound I-13 (33 mg, yield 30%), a white solid. 1 H NMR (800 MHz, deuterated chloroform) δ 9.16 (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 = 8.2 Hz, 1H), 3.97 - 3.93 (m, 1H), 3.82 - 3.78 (m, 1H), 3.21 (s, 1H), 3.08 (d, J = 10.8 Hz, 2H), 2.98 (dd, J = 15.2, 3.8 Hz, 1H), 2.94 (t, J = 11.8 Hz, 1H), 2.83 (dd, J = 15.2, 11.1 Hz, 1H), 2.46 (t, J = 7.9 Hz, 2H), 2.35 - 2.30 (m, 1H), 2.16 - 2.06 (m, 3H), 1.87 (d, J = 11.96 Hz, 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). 13¹¹C 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): ¹¹C 30 H 36 N5O + [M+H] + Calculated value: 482.2914; Measured value: 482.2918.

[0249] Example 14: N-(4-(2-(4,6,6a,7,9,10-hexahydro-8H-pyrazine[1,2-a]pyrrole[4,3,2-de]quinoline-8-yl)ethyl)trans-cyclohexyl)benzamide (compound I-14)

[0250] [ka]

[0251] Step 1: Using "2-(4-((tert-butoxycarbonylamino-trans-cyclohexyl)ethyl acetate" as a starting material, and referring to the method of Step 2 of Example 10, "dimethylcarbamoyl chloride" was replaced with "benzoyl chloride" to obtain intermediate whb104 (0.20 g, yield 69%), a white solid. 1H 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; Measured values: 290.1748 and 312.1526 (M+23Na).

[0252] Step 2: Refer to the method described in Step 3 of Example 10, intermediate whb104 was reduced to intermediate whb156 (0.11 g, yield 65%), 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.

[0253] Step 3: Referring to the method of Step 4 of Example 10, the alcohol intermediate whb156 was converted to bromide whb158 (78 mg, 57%), which was a white solid. 1 H 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.

[0254] Step 4: Following the method of Step 5 of Example 10, the alkylation reaction was carried out with whb158 and starting material (A) to obtain target compound I-14 (30 mg, yield 32%), a yellow solid. 1¹H NMR (800 MHz, dehydrated chlorohydrin) δ 7.84 (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, 1H), 3.25 - 3.21 (m, 1H), 3.08 (d, J = 10.9 Hz, 2H), 2.99 - 2.93 (m, 2H), 2.83 (dd, J = 15.3, 11.0 Hz, 1H), 2.48 - 2.44 (s, 2H), 2.36 - 2.32 (m, 1H), 2.12 (dd, J = 12.1, 3.8 Hz, 3H), 1.85 (d, J = 12.8 Hz, 2H), 1.53 - 1.50 (m, 2H), 1.37 - 1.30 (m, 1H), 1.26 - 1.13 (m, 4H). 13 C NMR (201 MHz, heavy hydrolyzate) 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.

[0255] Example 15: N-(4-(2-(4,6,6a,7,9,10-hexahydro-8H-pyrazine[1,2-a]pyrrole[4,3,2-de]quinoline-8-yl)ethyl)cyclohexyl)phenylsulfonamide (Compound I-15)

[0256] [ka]

[0257] Step 1: Using "2-(4-((tert-butoxycarbonylamino-trans-cyclohexyl)ethyl acetate" as a starting material, and referring to the method of Step 2 of Example 10, "dimethylcarbamoyl chloride" was replaced with "benzoyl chloride" to obtain intermediate whb105 (0.30 g, yield: 89%), 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.

[0258] Step 2: Referring to the method described in Step 3 of Example 10, intermediate whb105 was reduced to obtain intermediate whb155 (0.22 g, 87%), a white solid. 1H 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.

[0259] Step 3: Referring to the method of Step 4 of Example 10, the alcohol intermediate whb155 was converted to bromide whb159 (0.10 g, 37%), which was 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.

[0260] Step 4: Following the method of Step 5 of Example 10, the alkylation reaction was carried out with whb159 and starting material (A) to obtain target compound I-15 (40 mg, 98%), a pale yellow solid. 1 H NMR (800 MHz, deuterated chloroform) δ 7.90 - 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 = 15.0 Hz, 1H), 2.80 (dd, J = 15.3, 10.6 Hz, 1H), 2.43-2.36 (s, 2H), 2.31 (s, 1H), 2.08-2.04 (s, 1H), 1.84 (d, J = 12.8 Hz, 3H), 1.73 (d, J = 13.4 Hz, 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) δ142.12, 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; 27 H 35 N4O2S + [M+H] + Calculated value: 479.2475; Measured value: 479.2487.

[0261] Example 16: 3-(4-((4,6,6a,7,9,10-Hexahydro-8H-pyrazine[1,2-a]pyrrole[4,3,2-de]quinoline-8-yl)methyl)trans-cyclohexyl)-1,1-dimethylurea (Compound I-16)

[0262] [ka]

[0263] Step 1: Tert-butyl (4-(hydroxymethyl)trans-cyclohexyl)carbamate (0.23 g, 1 mmol) was dissolved in DMF (5 mL), and then triethylamine (1 mL) and 4-nitrobenzenesulfonyl chloride (0.27 g, 1.2 mmol) were added sequentially. The reaction system was stirred overnight at room temperature. After the reaction was complete, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane containing 0-10% methanol) to obtain the intermediate whb132 (0.12 g, 29%), a white solid. 1 H NMR (800 MHz, deuterated chloroform) δ 8.43 - 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.

[0264] Step 2: Intermediate whb132 (0.12 g, 0.29 mmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (1.5 mL) was added, and the mixture was stirred at room temperature for 3 hours. After the reaction was complete, the mixture was concentrated under reduced pressure, and the residue was dissolved in tetrahydrofuran (5 mL). Then, triethylamine (2 mL) and dimethylcarbamoyl chloride (37 mg, 0.35 mmol) were added, and the reaction system was stirred at room temperature overnight. After the reaction was complete, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane containing 10-20% methanol) to obtain intermediate whb133 (30 mg, 27%), 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.

[0265] Step 3: Starting material (A) (50 mg, 0.23 mmol), intermediate whb133 (30 mg, 0.078 mmol), and K2CO3 (127 mg, 0.92 mmol) were added to a round-bottom flask, followed by the addition of solvents tetrahydrofuran (3 mL) and dimethyl sulfoxide (1 mL). The reaction system was heated to 60°C and stirred for 16 hours. After the reaction was complete, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane containing 0-10% methanol) to obtain compound I-16 (12 mg, 13%), an off-white solid. 1H NMR (800 MHz, deuterated chloroform) δ 7.92 (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, 10.9 Hz, 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.

[0266] Example 17: 3-(2-(4,6,6a,7,9,10-hexahydro-8H-pyrazine[1,2-a]pyrrole[4,3,2-de]quinoline-8-yl)ethyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-4-one (Compound I-17)

[0267] [ka]

[0268] Referring to the method in Step 2 of Example 1, the starting material (A) and "3-(2-chloroethyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-4-one" (cas#63234-80-0, commercially available) were subjected to an alkylation reaction to obtain compound I-17, a dark green solid. Further purification was performed by preparative HPLC (mobile phase: 20-80% MeOH / H2O) to obtain t R =16 min, 10 mg (yield: 10%) was obtained. 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 = 15.4 Hz, 2H), 3.00 - 2.95 (m, 1H), 2.93 - 2.84 (m, 2H), 2.79 (t, J = 6.7 Hz, 2H), 2.75 (dd, J = 15.4, 9.2 Hz, 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 ¹³C 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):C24 H 30 N5O + [M+H] + Calculated value: 404.2445; Measured value: 404.2444.

[0269] Example 18: 7-(4-(4-methyl-4,6,6a,7,9,10-hexahydro-8H-pyrazine[1,2-a]pyrrole[4,3,2-de]quinoline-8-yl)butoxy)quinoline-2(1H)-one (Compound I-18)

[0270] [ka]

[0271] Step 1: In a round-bottom flask, add starting material (A) (0.20 g, 0.94 mmol), triethylamine (0.4 g, 3.76 mmol), DMAP (12 mg, 0.094 mmol), and solvent DMF (5 mL). Then, add Boc2O (0.23 g, 1.03 mmol) and stir at room temperature for 12 hours. After the reaction was complete, concentrate under reduced pressure to remove the solvent, and purify the residue by silica gel column chromatography (eluent: dichloromethane containing 0-10% methanol) to obtain the intermediate whb163 (0.22 g, 75%), 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.

[0272] Step 2: Add intermediate whb163 (0.21 g, 0.67 mmol), potassium tert-butoxide (0.091 g, 0.81 mmol), and DMF (8 mL) to a round-bottom flask and stir for 30 minutes. Add methyl iodide (0.19 g, 1.34 mmol) and continue stirring at room temperature for 3 hours. After the reaction is complete, add water (3 mL) to the reaction system to quench the reaction, precipitate the solid, filter to obtain crude intermediate whb165 product (0.18 g, 82%), a yellow solid, which was used directly in the next step. 1 H 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.

[0273] Step 3: The intermediate whb165 (50 mg) was dissolved in dichloromethane (3 mL), TFA (1 mL) was added, and the mixture was stirred at room temperature for 1 hour. The solvent was removed by evaporation under reduced pressure to obtain the crude product, which was used directly in the next step.

[0274] Step 4: The crude product obtained in Step 3 was dissolved in tetrahydrofuran THF (3 mL), then DMSO (1.5 mL), K2CO3 (0.12 g, 0.87 mmol), and the intermediate wha70 (49 mg, 0.17 mmol) described in Example 2 were added, and the mixture was heated at 60°C and stirred for 16 hours. The solvent was removed by evaporation under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane containing 0-10% methanol) to obtain target compound I-18 (30 mg, 45%), a pale yellow solid. 1 H 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 = 12.0 Hz, 1H), 3.74 (s, 3H), 3.21 - 3.16 (s, 2H), 3.11 - 3.05 (m, 1H), 2.96 (d, J = 15.3 Hz, 1H), 2.87 (t, J = 12.0 Hz, 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). 13C 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. (ESI,m / z): C 27 H 31 N4O2 + [M+H] + Calculated value: 443.2442; Measured value: 443.2445.

[0275] Example 19: 1,1-dimethyl-3-(4-(2-(4-methyl-4,6,6a,7,9,10-hexahydro-8H-pyrazine[1,2-a]pyrrole[4,3,2-de]quinoline-8-yl)ethyl)trans-cyclohexyl)urea (compound I-19)

[0276] [ka]

[0277] Using the same method as in Example 17, the Boc protecting group was removed with whb165, followed by alkylation with the intermediate whb60 to obtain target compound I-19 (50 mg, 79%), a pale yellow solid. Further purification was performed by HPLC (mobile phase: 20-80% MeOH / H2O) to obtain t R = 19.5 min, 40 mg obtained. 1H NMR (800 MHz, deuterated methanol) δ 7.08 - 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 = 13.32 Hz, 1H), 3.00 (t, J = 11.9 Hz, 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.

[0278] Example 20: (E)-7-((4-(4,6,6a,7,9,10-Hexahydro-8H-pyrazine[1,2-a]pyrrole[4,3,2-de]quinoline-8-yl)-2-buten-1-yl)oxy)-3,4-dihydroquinoline-2(1H)-one (Compound I-20)

[0279] [ka]

[0280] Step 1: Referring to the method of Step 1 of Example 1, an alkylation reaction was carried out using 7-hydroxyl-3,4-dihydroquinoline-2(1H)-one and (E)-1,4-dibromo-2-butene as starting materials to produce the intermediate whc102 (0.82 g, 45%), a yellow solid. 1 H NMR (800 MHz, CDCl3) δ 8.45 (s, 1H), 7.05 (d, J = 8.2 Hz, 1H), 6.57 - 6.49 (m, 1H), 6.37 (d, J = 2.5 Hz, 1H), 6.07 (dt, J = 15.2, 7.4 Hz, 1H), 5.97 (dt, J = 15.2, 5.3 Hz, 1H), 4.52 (d, J = 5.4 Hz, 2H), 3.99 (d, J = 7.5 Hz, 2H), 2.90 (t, J = 7.5 Hz, 2H), 2.62 (t, J = 7.5 Hz, 2H).HR-MS (ESI,m / z): C 13 H 15 BrNO2 + [M+H] + Calculated value: 296.0281; Measured values: 296.0294 and 298.0277. Step 2: Following the method of Step 2 in Example 1, intermediate A and whc102 were alkylated to obtain compound I-20 (40 mg, 33%), a pale yellow solid. HR-MS (ESI, m / z): C 26 H 29 N4O2 + [M+H] + Calculated value: 429.2285; Measured value: 429.2288. Example 21: (E)-7-((4-(4,6,6a,7,9,10-Hexahydro-8H-pyrazine[1,2-a]pyrrole[4,3,2-de]quinoline-8-yl)-2-buten-1-yl)oxy)quinoline-2(1H)-one (Compound I-21)

[0281] [ka]

[0282] Step 1: Referring to the method of Step 1 of Example 1, an alkylation reaction was carried out using 7-hydroxyl-quinoline-2(1H)-one and (E)-1,4-dibromo-2-butene as starting materials to produce the intermediate whc72 (0.25 g, 14%), a yellow solid. 1 H NMR (600 MHz, CDCl3) δ 7.74 (d, J = 9.4 Hz, 1H), 7.46 (d, J = 8.7 Hz, 1H), 6.88 (d, J = 2.4 Hz, 1H), 6.86 - 6.80 (m, 1H), 6.59 - 6.47 (m, HR-MS (ESI,m / z): C 13 H 13 BrNO2 + [M+H] + Calculated value: 294.0124; Measured values: 294.0124 and 296.0106. Step 2: Following the method of Step 2 of Example 1, intermediate A and whc72 were alkylated to obtain compound I-21 (50 mg, 51%), an off-white solid. 1H NMR (800 MHz, CDCl3) δ 10.12 (s, 1H), 7.83 (s, 1H), 7.69 (d, J = 9.4 Hz, 1H), 7.45 (d, J = 8.7 Hz, 1H), 7.07 (t, J = 7.8 Hz, 1H), 6.85 - 6.82 (m, 1H), 6.80 (d, J = 8.1 Hz, 1H), 6.72 (d, J = 2.0 Hz, 1H), 6.69 (s, 1H), 6.51 (d, J = 9.4 Hz, 1H), 6.32 (d, J = 7.6 Hz, 1H), 6.03 - 5.98 (m, 1H), 5.95 - 5.91 (m, 1H), 4.65 (d, J = 5.6 Hz, 2H), 4.14 - 4.10 (m, 1H), 3.80 (d, J = 11.7 Hz, 1H), 3.22 - 3.20 (m, 1H), 3.14 (t, J = 8.7 Hz, 1H), 3.07 (t, J = 14.4 Hz, 2H), 2.94 (dd, J = 15.1, 3.7 Hz, 2H), 2.83 - 2.77 (m, 1H), 2.40 - 2.36 (m, 1H), 2.12 (t, J = 10.8 Hz, 1H). HR-MS (ESI,m / z): C 26 H 27 N4O2 + [M+H] + Calculated value: 427.2129; Measured value: 427.2129. Example 22: (E)-7-((4-(4-methyl-4,6,6a,7,9,10-hexahydro-8H-pyrazine[1,2-a]pyrrole[4,3,2-de]quinoline-8-yl)-2-buten-1-yl)oxy)-3,4-dihydroquinoline-2(1H)-one (Compound I-22)

[0283] [ka]

[0284] Referring to the method in Step 3 of Example 18, the Boc protecting group was removed with intermediate whb165, and then an alkylation reaction was carried out with intermediate whc102 to obtain target compound I-22 (90 mg, 30%), a brown foamy solid. 1 H NMR (800 MHz, MeOD) δ 7.09 - 7.04 (m, 2H), 6.82 (d, J = 8.2 Hz, 1H), 6.72 (s, 1H), 6.58 (dd, J = 8.3, 2.5 Hz, 1H), 6.49 (d, J = 2.5 Hz, 1H), 6.36 (d, J = 7.5 Hz, 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), 3.84 - 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 = 8.0 Hz, 3H), 2.77 (dd, J = 15.6, 8.0 Hz, 1H), 2.48 (t, J = 8.0 Hz, 2H). HR-MS (ESI,m / z): C 27 H 31 N4O2 + [M+H] + Calculated value: 443.2442; Measured value: 443.2442. Example 23: (E)-7-((4-(4-methyl-4,6,6a,7,9,10-hexahydro-8H-pyrazine[1,2-a]pyrrole[4,3,2-de]quinoline-8-yl)-2-buten-1-yl)oxy)quinoline-2(1H)-one (Compound I-23)

[0285] [ka]

[0286] Referring to the method in Step 3 of Example 18, the Boc protecting group was removed with intermediate whb165, and then an alkylation reaction was carried out with intermediate whc72 to obtain target compound I-23 (23 mg, 20%), a brownish-yellow solid. 1 H NMR (800 MHz, DMSO) δ 11.60 (s, 1H), 7.80 (d, J = 9.5 Hz, 1H), 7.56 (d, J = 8.3 Hz, 1H), 6.94 (t, J = 7.8 Hz, 1H), 6.84 - 6.80 (m, 2H), 6.76 - 6.71 (m, 2H), 6.31 (d, J = 9.4 Hz, 1H), 6.22 (d, J = 7.5 Hz, 1H), 5.94 - 5.90 (m, 2H), 4.63 (d, J = 5.1 Hz, 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 = 15.2 Hz, 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. Example 24: 1-(4-fluorobenzene)-4-(4,6,6a,7,9,10-hexahydro-8H-pyrazine[1,2-a]pyrrole[4,3,2-de]quinoline-8-yl)-1-butanone (compound I-24)

[0287] [ka]

[0288] Step 1: Add cyclopropyl(4-fluorobenzene)methanone (0.5 g, 3 mmol) and hydrobromic acid aqueous solution (3 mL) to a round-bottom flask and stir the reaction system at 80°C for 2 hours. After the reaction was complete, the mixture was cooled, water was added, and DCM was added and extracted three times. The organic phases were combined and concentrated under reduced pressure to obtain the crude product whc48 (0.73 g, 98%), a yellow liquid. 1 H NMR (800 MHz, CDCl3) δ 8.04 - 7.99 (m, 2H), 7.17 - 7.12 (m, 2H), 3.55 (t, J = 6.3 Hz, 2H), 3.16 (t, J = 6.9 Hz, 2H), 2.31 (p, J = 6.6 Hz, 2H). Step 2: Following the method of Step 2 of Example 1, the alkylation reaction was carried out with intermediate A and whc48 to obtain compound I-24 (0.3 g, 57%), a pale yellow solid. 1 H NMR (800 MHz, CDCl3) δ 8.03 - 7.98 (m, 2H), 7.81 (s, 1H), 6.80 (d, J = 8.1 Hz, 1H), 6.72 (d, J = 1.9 Hz, 1H), 6.32 (d, J = 7.6 Hz, 1H), 3.77 (d, J = 11.7 Hz, 1H), 3.16 - 3.12 (m, 1H), 3.05 - 3.01 (m, 4H), 2.96 (dd, J = 15.2, 3.7 Hz, 1H), 2.88 - 2.78 (m, 2H), 2.49 (t, J = 7.1 Hz, 2H), 2.35 (t, J = 8.0 Hz,1H), 2.11 (t, J = 8.0 Hz, 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.

[0289] Example 25: 1-(4-fluorobenzene)-4-(4,6,6a,7,9,10-hexahydro-8H-pyrazine[1,2-a]pyrrole[4,3,2-de]quinoline-8-yl)-1-butanol (compound I-25)

[0290] [ka]

[0291] I-24 (50 mg, 0.13 mmol) was dissolved in methanol (5 mL), then NaBH4 (7.6 mg, 0.19 mmol) was added, and the reaction system was stirred at room temperature for 2 hours. After the reaction was complete, water was added to quench the reaction system, and the mixture was concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography (eluent: dichloromethane containing 20-30% methanol) to obtain I-25 (30 mg, 61%), an off-white solid. 1 H NMR (600 MHz, CDCl3) δ 7.82 (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, 1.3 Hz, 1H), 6.73 (d, J = 7.7 Hz, 1H), 6.34 (dd, J = 7.6, 2.4 Hz, 1H), 4.69 (td, J = 8.2, 2.8 Hz, 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.

[0292] Example 26: 1-(4-fluorobenzene)-4-(4-methyl-4,6,6a,7,9,10-hexahydro-8H-pyrazine[1,2-a]pyrrole[4,3,2-de]quinoline-8-yl)-1-butanone (Compound I-26)

[0293] [ka]

[0294] Referring to the method in Step 3 of Example 18, the Boc protecting group was removed with intermediate whb165, and then an alkylation reaction was carried out with intermediate whc48 to obtain target compound I-26 (20 mg, 15%), a pale yellow solid. 1 H NMR (800 MHz, DMSO) δ 8.04 (dd, J = 8.6, 5.5 Hz, 2H), 7.32 (t, J = 8.7 Hz, 2H), 6.93 (t, J = 7.8 Hz, 1H), 6.75 (s, 1H), 6.71 (d, J = 8.1 Hz, 1H), 6.20 (d, J = 7.5 Hz, 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.

[0295] Example 27: 1-(4-fluorobenzene)-4-(4-methyl-4,6,6a,7,9,10-hexahydro-8H-pyrazine[1,2-a]pyrrole[4,3,2-de]quinoline-8-yl)-1-butanol (Compound I-27)

[0296] [ka]

[0297] I-26 (63 mg, 0.16 mmol) was dissolved in methanol (8 mL), then NaBH4 (9 mg, 0.24 mmol) was added, and the reaction system was stirred at room temperature for 2 hours. After the reaction was complete, water was added to quench the reaction system, and the mixture was concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography (eluent: dichloromethane containing 20-30% methanol) to obtain I-27 (10 mg, 16%), a pale yellow solid. 1 H NMR (800 MHz, CDCl3) δ 7.36 - 7.31 (m, 2H), 7.09 (t, J = 7.7 Hz, 1H), 7.00 - 6.97 (m, 2H), 6.73 (d, J = 7.8 Hz, 1H), 6.59 - 6.55 (m, 1H), 6.31 (d, J = 7.7 Hz, 1H), 4.70 - 4.67 (m, 1H), 3.86 - 3.79 (m, 1H), 3.72 (s, 3H), 3.33 - 3.29 (m, 1H), 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.

[0298] Test Example 1: Affinity test of the compound of the present invention against dopamine D2 receptors The affinity of the compounds of the present invention for dopamine D2 receptors was measured using radioligand competition experiments. Step 1: Cell membrane components containing specific dopamine D2 receptors were prepared. 10 ng of dopamine D2 receptors and 40 μL of PEI were transfected into a 10 cm culture dish. After 48 hours, the 10 cm culture dish was removed from the cell chamber, and the cultured cells expressed dopamine D2 receptors. The culture medium was removed by aspirating with a vacuum pump, 3 mL of lysate was added to each well, and the cells were left to stand in a refrigerated room at 4°C for 10 minutes. After the cells had detached, they were transferred to a 15 mL centrifuge tube and centrifuged at 1500 rpm at 4°C for 5 minutes, and the supernatant was discarded. The cell precipitate was transferred to a tissue homogenizer, 3 mL of lysate was added, and the cells were thoroughly pulverized until they were destroyed. Next, the cell suspension was dispensed into several EP tubes and centrifuged at 12,000 rpm for 5 minutes at 4°C, and the supernatant was discarded. The precipitate was cell membrane components containing dopamine D2 receptors. Step 2, ligand receptor binding experiments were performed on the 293T membrane fraction that transiently expresses dopamine D2 receptors. First, standard binding buffer was added to the cell membrane fraction containing dopamine D2 receptors, and the cell membrane was disrupted and resuspended using an electrotissue homogenizer. 30 μL of membrane protein suspension was added to each well of a 96-well plate. Next, 30 μL of different drugs were added to the 96-well plate sequentially from left to right, until the final drug concentration was 10 degrees from bottom to top. -5 M, 10 -6 M, 10 -7 M, 10 -8 M, 10 -9 The mixture was adjusted to M and 0M, and each treatment was repeated twice. Immediately afterward, 30 μL was added to each well of a 96-well plate. 3 [H]-Methylspiperone was added. The culture was incubated at room temperature for 2 hours, avoiding light irradiation, and then detected. The instrument reading was for the membrane-bound [ 3Reflecting the amount of [H]-Methylspiperone, after further data processing, the affinity K of different compounds to the dopamine D2 receptor was determined. i The value was obtained.

[0299] The results are shown in Table 1. The results indicate that compounds I-1 to I-27 all possess the predetermined affinity activity for dopamine D2 receptors, and that all compounds of the present invention possess the predetermined affinity activity for dopamine D2 receptors.

[0300] [Table 1] TIFF0007842414000099.tif91169

[0301] Test Example 2: Functional Activity Test of Compounds on Dopamine D2 Receptors To detect the downstream G protein signaling pathway mediated by the dopamine D2 receptor, on day 1, a 6 cm culture dish was prepared containing 1 μg of dopamine D2 receptor and 1 μg of C-terminal seaweed luciferase in a Gα i1 (Gα i1 -Rluc), 1 μg G β3On day 1, cells were transfected with 1 μg of C-terminal green fluorescent protein Gγ9 (Gγ9-GFP) and 16 μL of PEI. Simultaneously, to detect the downstream β-arrestin 2 signaling pathway mediated by the dopamine D2 receptor, on day 1, 6 cm culture dishes were transfected with 500 μg of dopamine D2 receptor containing C-terminal seaweed luciferase (D2-Rluc), 500 μg of G protein-coupled receptor kinase 2 (GRK2), 2500 μg of β-arrestin 2 containing N-terminal green fluorescent protein (GFP2-ARRB2), and 14 μL of PEI. On day 2, overgrown cells were digested, and the cell volume from the 6 cm culture dish filled with cells was spread into one 96-well plate, with 100 μL of medium added to each well. On day 3, the drugs were administered for detection. The 96-well plate was removed from the cell chamber, the culture medium was removed, and 40 μL of the substrate coelenterazine 400a (final concentration: 5 μM) was added to each well. Subsequently, 20 μL of different drugs were added from left to right, so that the final drug concentration decreased in a gradient from bottom to top. Each treatment was repeated twice, and finally, the results were detected using an instrument. The instrument readings reflected the dissociation of β-arrestin2 and G protein trimers in the cells on the membrane. The former indicated the degree of activation of the β-arrestin2 signaling pathway downstream of the dopamine D2 receptor, and the latter indicated the degree of activation of the G protein signaling pathway downstream of the dopamine D2 receptor. From this, we were able to clarify the agonist effects of various compounds on the dopamine D2 receptor. The results are shown in Table 2.

[0302] The results showed that compounds I-1 through I-25 all possessed the specified agonist activity against the dopamine D2 receptor.

[0303] [Table 2] TIFF0007842414000101.tif220170

[0304] Example 3: Affinity test of the compound of the present invention against the 5-HT2A receptor 5-HT2A The affinity of the compound of the present invention for the receptor was measured using radioligand competition experiments. Step 1, specific 5-HT 2A Cell membrane components containing receptors were prepared. 10 ng of 5-HT was added to a 10 cm culture dish. 2A When the receptor and 40 μL of PEI were transfected and the 10 cm culture dish was removed from the cell chamber after 48 hours, the cultured cells were 5-HT. 2A The receptor was expressed. The culture medium was removed by aspirating with a vacuum pump, 3 mL of lysate was added to each well, and the cells were allowed to stand in a refrigerated room at 4°C for 10 minutes. After the cells had detached, they were transferred to a 15 mL centrifuge tube and centrifuged at 1500 rpm at 4°C for 5 minutes, discarding the supernatant. The cell precipitate was transferred to a tissue homogenizer, 3 mL of lysate was added, and the cells were thoroughly pulverized until they were destroyed. Next, the cell suspension was dispensed into several EP tubes and centrifuged at 12000 rpm at 4°C for 5 minutes, discarding the supernatant. The precipitate was 5-HT 2A It was a cell membrane component containing a receptor. Step 2, 5-HT 2A Ligand-receptor binding experiments were performed on the 293T membrane fraction, which transiently expresses the receptor. First, 5-HT 2A Standard binding buffer was added to the cell membrane fraction containing the receptor, and the cell membrane was disrupted and resuspended using an electrotissue homogenizer. 30 μL of membrane protein suspension was added to each well of a 96-well plate. Next, 30 μL of different drugs were added to the 96-well plate sequentially from left to right, until the final drug concentration was 10 degrees from bottom to top. -5 M, 10 -6 M, 10 -7 M, 10 -8 M, 10 -9 The levels were adjusted to M and 0M, and each treatment was repeated twice. Immediately afterward, 30 μL of [ 3 [3H]-ketanserin was added. The cultures were incubated at room temperature for 2 hours, avoiding light exposure, and then detected. The instrument readings reflected the amount of [3H]-ketanserin bound to the membrane, and after further data processing, 5-HT 2A Affinity Ki values ​​for different compounds against the receptor were obtained. The results are shown in Table 3.

[0305] [Table 3]

[0306] The results in Table 3 show that compounds I-1, I-2, I-10, (-)-I-10, and (+)-I-10 are 5-HT 2A This demonstrated weak affinity for the receptor. Comparing the data in Table 1, compounds I-1, I-2, and (-)-I-10 exhibited weak affinity for the receptor. 2A The binding selectivity to the receptor exceeds 100 times, indicating that the compound of the present invention has good selectivity for the dopamine D2 receptor.

[0307] Test Example 3: Pharmacokinetic Properties Test of the Compound of the Present Invention in Mouse 1. Pharmacokinetic studies of compound (-)-I-10 after single-dose administration to C57 male mice via intragastric, intraperitoneal, and intravenous injection. (1) Experimental Objectives After administering compound (-)-I-10 as a single dose to C57 male mice, blood samples were collected at different times. The concentration of the compound in mouse plasma was measured by LC-MS / MS, and relevant pharmacokinetic parameters were calculated to investigate the pharmacokinetics of the compound in mice.

[0308] (2) Experimental plan Twenty-seven male C57 mice were provided by Suzhou Zhaoyan Experimental Animal Co., Ltd., and experiments were conducted according to Table 4 below.

[0309] [Table 4]

[0310] (3) Sample collection Each time, 0.030 mL of blood was collected from each animal through the orbit and treated with EDTA-K2 anticoagulation. Collection times were: 0, 5, 15, 30 min, 1, 2, 4, 6, 8, and 24 h after administration. After blood sample collection, the samples were placed on ice and the plasma was centrifuged within 30 minutes (centrifugation conditions: 5000 rpm / min, 10 min, 4°C). Before analysis, the samples were stored at -80°C.

[0311] (4) Data processing Data acquisition and control system software used was Analyst 1.5.1 software (Applied Biosystem). Spectral sample peak integration was performed automatically, and regression was performed using the ratio of sample peak area to internal standard peak area as an indicator, based on sample concentration. Regression method: Linear regression, weight coefficient 1 / X². Pharmacokinetic parameters were analyzed using a non-compartment model in WinNonlin Professional v6.3 (Pharsight, USA). Cmax is the measured maximum blood drug concentration, AUC (area under the blood drug concentration-time curve, 0→t) was calculated using the trapezoidal rule, and Tmax is the peak time of blood drug concentration after administration. Experimental data are expressed as "mean ± standard deviation" (Mean ± ICR, n≧3) or "mean" (Mean, n=2).

[0312] (5) Experimental results The pharmacokinetic results for compound (-)-I-10 are shown in the table below. Therefore, it can be seen that this compound has good pharmacokinetic properties in C57 male mice. See Table 5 for details.

[0313] [Table 5]

[0314] 2. Brain permeability test after single-dose administration of compound (-)-I-10 to C57 male mice via intragastric, intraperitoneal, and intravenous injection. Using the same method as in the pharmacokinetic experiments, 0.030 mL of blood was collected from each animal through the orbit at 0.5 and 2.0 hours, respectively. The blood samples were treated with EDTA-K2 for anticoagulation, and after collection, the samples were placed on ice. Plasma was centrifuged within 30 minutes (centrifugation conditions: 5000 rpm / min, 10 min, 4°C). The samples were stored at -80°C before analysis. After euthanasia by bloodletting, brain tissue samples were collected, homogenized with 50% methanol at a ratio of 1:3 (m / v=1:3) according to body weight, and stored at -80°C before analysis. Drug concentrations in plasma and brain tissue were analyzed and compared using LC / MS / MS. The drug concentrations and ratios of compound (-)-I-10 in plasma and tissue at 0.5 and 2.0 hours are shown in Table 6.

[0315] [Table 6]

[0316] Test Example 4: Efficacy study of a compound on an animal behavior model resembling schizophrenia. 1. Open field test Experimental Methods: C57B6 male mice were used as experimental animals, with n=8 in each group. This model was constructed to induce hyperkinesia behavioral expression in mice in an open field environment by acute injection of the NMDA antagonist MK801, using C57B6 mice as experimental animals, and to detect the inhibitory effects of different compounds on the hyperkinesia phenotype induced by MK801. All mouse behavioral experiments were performed during the mice's light period, the entire experiment was recorded by camera, and automated tracking and data statistics were performed by behavioral tracking software. The compound was administered by intraperitoneal injection, and immediately after the completion of the injection, the mouse entered the open field and recording of its movement trajectory began. After 30 minutes, the mouse was intraperitoneally injected with 0.2 mg / kg of MK801, returned to the open field immediately after administration, and its movement trajectory was recorded for a further 120 minutes. The cumulative distance traveled by the mouse was calculated based on data sampling points every 5 minutes. Data statistics were performed using the Student's t-test, with p<0.05 being *, p<0.01 being **, p<0.001 being ***, and p<0.0001 being ****. The total distance traveled by mice from 0 to 45 minutes under the combined effects of different doses of (-)-I-10 and MK801 (0.2 mg / kg) are shown in Table 7.

[0317] Results from open field tests showed that compound (-)-I-10 significantly inhibited the MK801-induced increase in mouse motor skills at doses of 0.4 / 0.1 / 0.025 mg / kg.

[0318] [Table 7]

[0319] 2. Animal "depression-like" behavior tests The experimental animals used were C57B6 male mice, with n=8 in each group. First, the C57B6 mice were restrained for 5 hours to induce depression-related behavioral expressions. Then, the effects of the compound on the mice's "depression-like" behavior were tested through tail suspension experiments and forced swimming experiments. Specifically, the mice were first restrained using a mouse holder for tail vein injection, limiting all of their behavioral abilities while minimizing discomfort to the mice. The mice were given one intraperitoneal injection before and after restraint. After restraint was complete, the mice were returned to their cages and allowed to recover for 30 minutes. After 30 minutes, the mice in the different groups were subjected to either tail suspension or forced swimming to detect "depression-like" behavior.

[0320] Tail suspension experiment: The tip of the mouse's tail was secured to a suspension bar on an iron stand with adhesive tape, and the mouse was held in the suspended position for 6 minutes. The first 2 minutes were an adaptation period during which no data collection was performed, and during the following 4 minutes, the mouse performed intermittent immobility behavior and the time was recorded. The duration of this immobility was used to measure the degree of behavioral desperation in the mouse. Data statistics were performed by Student's t-test, with p<0.05 being *, p<0.01 being **, p<0.001 being ***, and p<0.0001 being ****.

[0321] Forced Swimming Experiment: Mice were placed in a 5L glass beaker filled with water, with a water level of 15cm. The mice were made to swim continuously in the beaker for 6 minutes. The first 2 minutes were an adaptation period during which no data was collected. For the following 4 minutes, the mice were made to perform intermittent immobility, and the time was recorded. Immobility in mice was defined as: the mouse passively floating on the water surface without moving, with only small, localized movements necessary to maintain buoyancy. The duration of this immobility was used to measure the degree of behavioral desperation in the mice. Data statistics were performed using the Student's t-test, with p<0.05 being *, p<0.01 being **, p<0.001 being ***, and p<0.0001 being ****. The results of the statistical data for the tail-hanging and forced swimming experiments of restrained and unrestrained mice are shown in Table 8.

[0322] Results from the detection of "depression-like" behaviors showed that compound (-)-I-10 can significantly inhibit the generation of restraint-induced "depression-like" behaviors at doses of 0.4 mg / kg and 0.1 mg / kg.

[0323] [Table 8]

[0324] 3. Old and new object recognition The experimental animals used were C57B6 male mice, with n=8 in each group. First, to construct a model of cognitive impairment, the mice were intraperitoneally injected with 0.3 mg / kg of MK801 twice daily for 7 consecutive days, while the control mice were intraperitoneally injected with the same amount of saline containing DMSO. The mice were then allowed to recover in cages for 7 days. After the recovery period, the mice were subjected to a new and old object recognition experiment to detect the effect of the compound on their cognitive abilities.

[0325] New and Old Object Recognition Experiment: The experiment was conducted in a low-light environment. Before the start of the experiment, mice were placed in the experimental area and allowed to acclimate to the environment under low light for 1 hour. After acclimatization, the mice were administered a drug by intraperitoneal injection. Thirty minutes after administration, the mice were placed in an open field (with a diameter of 40 cm) where two identical objects had been placed beforehand. The mice were allowed to freely explore the open field for 10 minutes, after which they were removed and returned to their cages. After a 1-hour interval, the mice returned to the open field, where the old and new objects were placed in the same positions beforehand. The mice were allowed to freely explore the open field for another 10 minutes. The recognition time of the mice for the new and old objects was recorded, and the recognition index was calculated. The recognition index was calculated as (time spent exploring the new object - time spent exploring the old object) / (time spent exploring the new object + time spent exploring the old object). Object exploration by the mice was defined as sniffing, climbing, and directly touching the object. Data statistics were performed using Student-t-test, with p<0.05 being *, p<0.01 being **, p<0.001 being ***, and p<0.0001 being ****. The statistical data results for the new / old object recognition index are shown in Table 9.

[0326] Based on the results of recognizing old and new objects, compound (-)-I-10 was shown to significantly improve cognitive impairment induced by MK801 in mice at doses of 0.1 mg / kg and 0.025 mg / kg.

[0327] [Table 9]

[0328] 4.Morris water maze The experimental animals used were C57B6 male mice, with n=8 in each group. First, to construct a model of cognitive impairment, the mice were intraperitoneally injected with 0.2 mg / kg of MK801 twice daily for 10 consecutive days, while the control mice were intraperitoneally injected with the same amount of saline containing DMSO. Subsequently, the mice underwent the Morris water maze experiment.

[0329] Experimental Preparation: The experiment was conducted in a blue circular reservoir with a diameter of 130 cm. The reservoir was filled with approximately 30 cm of pure water. The pool was divided into four intersecting fan-shaped areas, with a refuge platform (6 cm in diameter) in the center of one of these fan-shaped areas, hidden 0.5 cm below the water surface. The mice's entry points into the water were fixed at the edges of the other three fan-shaped areas. The straight-line distance between the water entry point and the platform was essentially the same.

[0330] Acquisition Training: Thirty minutes before the start of the experiment, mice were given an intraperitoneal injection. After the start of the experiment, the mice were placed in the water with their heads facing the pool wall. One of three starting positions (east, west, or south) was randomly selected, and a hidden underwater platform was placed in the north quadrant. The time it took the mice to find the underwater platform was recorded. If the mouse could not find the platform within one minute, it was guided to the platform and made to remain on it for 30 seconds. The above steps were then repeated twice at a different starting position. Each animal was trained three times a day for five consecutive days.

[0331] Exploration Training: The day after the final acquisition training, the platform was removed and 60-second exploration training was initiated. The animals were placed in the water from the opposite quadrant of the original platform. As an indicator of spatial memory detection, the number of times the animals crossed the original platform location was recorded. Data statistics were performed using the Student's t-test, with p<0.05 being *, p<0.01 being **, p<0.001 being ***, and p<0.0001 being ****. The results for water maze acquisition training and daily platform exploration time are shown in Table 10.

[0332] Results from the Morris water maze showed that compound (-)-I-10 significantly improved MK801-induced spatial cognitive impairment in mice at a dose of 0.1 mg / kg; and compound (-)-I-10 significantly improved MK801-induced memory impairment in mice at doses of 0.1 mg / kg and 0.025 mg / kg.

[0333] [Table 10] TIFF0007842414000110.tif55170

[0334] 5. Freezing behavior test Experimental Method: C57B6 male mice were used as experimental animals, with n=8 in each group. First, different compounds were injected into the mice, and after a predetermined time (30 or 60 minutes), the mice's forelimbs were placed on a tall glass suspension rod (approximately 5 cm above the ground) to create an unnatural upright position. Next, the time the mice maintained this position without moving was measured, and the freezing effect of the drugs produced in the mice was detected based on the length of this time. The results of detecting the freezing behavior of mice 30 and 60 minutes after injection of different drugs are shown in Table 11.

[0335] Freezing behavior tests showed that compound (-)-I-10 did not have a freezing-inducing effect on mice at a dose of 10 mg / kg. [Table 11]

Claims

1. A compound represented by formula I, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof. 【Chemistry 1】 (However, L is C １－１０ Alkylene, C ２－１０ Alkenylene, C ２－１０ Alkynylene or -C １－６ Alkylene-C ３－６ It is a cycloalkylene, M is -O-, -NH-, -CH ２ -, -(CH-OH)- or -C(=O)-, Q is C ６－１８ aryl, one or more Q １－１ substituted C ６－１８ aryl, 5- to 10-membered heteroaryl, one or more Q １－２ substituted 5- to 10-membered heteroaryl, -C(=O)R １ or -S(=O) ２ R ２ wherein the heteroatom in the 5- to 10-membered heteroaryl is one or more of N, S or O, the number is one, two or three, and the heteroatom in the 5- to 10-membered heteroaryl substituted by the one or more Q １－２ is one or more of N, S or O, and the number is one, two or three, Q １－１ These are, independently, halogen or C １－４ It is alkyl, Q １－２ C is independent １－４ Alkyl, oxo, or hydroxyl, R １ and R ２ It is independently -NR １－１ R １－２ , 3-6 member heterocycloalkyl, C ６－１８ aryl, one or more R １－３ C replaced by ６－１８ Aryl, 5-10 membered heteroaryl, or one or more R １－４ A 5-10 member heteroaryl substituted by, wherein the heteroatoms in the 3-6 member heterocycloalkyl are one or more N, S, or O, and the number is one, two, or three, and the heteroatoms in the 5-10 member heteroaryl are one or more N, S, or O, and the number is one, two, or three, and the one or more R １－４ In the 5- to 10-membered heteroaryl substituted by, the heteroatoms are one or more N, S, or O atoms, and their number is one, two, or three. R １－１ , R １－２ , R １－３ and R １－４ C is independent １－４ It is alkyl, R is hydrogen or C １－４ It is alkyl.

2. The compound represented by formula I is characterized in that it is as described in any one of the following situations, the compound represented by formula I according to claim 1, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof. (Situation 1: The compound represented by formula I is a compound represented by formula Ia, Ib, or Ic: 【Chemistry 2】 In formula Ic, 【Transformation 3】 " represents a double bond or a single bond, and Y is hydrogen, hydroxyl, or oxygen. Situation 2: The compound represented by formula I is a compound represented by formula Id and / or Ie, 【Chemistry 4】 Situation 3: The compound represented by the above formula I is 【Transformation 5】 In the case where there is only one chiral center, 【Transformation 6】 teeth, 【Transformation 7】 (That is the case.)

3. The compound represented by formula I is characterized in that it is as described in any one of the following schemes, the compound represented by formula I according to claim 1, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof. (Scheme 1: L is C １－１０ Alkylene or -C １－６ Alkylene-C ３－６ It is a cycloalkylene, M is -O-, -NH-, or -CH ２ - and Q is C ６－１８ Aryl, 5-10 member heteroaryl, one or more Q １－２ 5- to 10-membered heteroaryls substituted with -C(=O)R １ or -S (=O) ２ R ２ And, Scheme 2: L is C １－１０ Alkylene or -C １－６ Alkylene-C ３－６ It is a cycloalkylene, M is -O-, -NH-, or -CH ２ - and Q is C ６－１８ Aryl, 5-10 member heteroaryl, one or more Q １－２ 5- to 10-membered heteroaryls substituted with -C(=O)R １ or -S (=O) ２ R ２ And, If M is -O-, then Q １－２ C １－４ Alkyl or hydroxyl, When the heteroatom in the 5-10 membered heteroaryl is O, the number of heteroatoms in the 5-10 membered heteroaryl is 1. Scheme 3: L is C １－１０ Alkylene or -C １－６ Alkylene-C ３－６ It is a cycloalkylene, M is -O-, -NH-, or -CH ２ - and Q is C ６－１８ Aryl, 5-10 member heteroaryl, one or more Q １－２ 5- to 10-membered heteroaryls substituted with -C(=O)R １ or -S (=O) ２ R ２ And, L is -C １－６ Alkylene-C ３－６ If it is a cycloalkylene, then -C １－６ Alkylene-C ３－６ C in cycloalkylene １－６ Alkylene is ethylene, Scheme 4: L is C １－１０ Alkylene or -C １－６ Alkylene-C ３－６ It is a cycloalkylene, M is -O- or -NH-, Q is -C(=O)R １ or one or more Qs １－２ A 5-10 member heteroaryl substituted by, R １ -NR １－１ R １－２ And, Scheme 5: The molecular structure represented by formula I is as shown by formula Ia: 【Transformation 8】 L is C １－１０ Alkylene or C ２－１０ It is alkenylene, Q is one or more Qs １－１ C replaced by ６－１８ Aryl, 5-10 membered heteroaryl, or one or more Q １－２ A 5-10 member heteroaryl substituted by, Q １－１ It is a halogen, Scheme 6: The molecular structure represented by formula I is as shown by formula Ib: 【Chemistry 9】 L is -C １－６ Alkylene-C ３－６ It is a cycloalkylene, Q is -C(=O)R １ or -S (=O) ２ R ２ And, R １ and R ２ are independently -NR １－１ R １－２ a 3- to 6-membered heterocycloalkyl, C ６－１８ aryl or a 5- to 10-membered heteroaryl,; Scheme 7: The molecular structure represented by formula I is as shown by formula Ic: 【Chemistry 10】 「 【Chemistry 11】 " represents a double bond or a single bond, Y is hydrogen, hydroxyl, or oxygen. L is C １－１０ It is alkylene, Q is one or more Qs １－１ C replaced by ６－１８ A letter, or one or more Qs １－２ A 5-10 member heteroaryl substituted by, Q １－１ It is a halogen, Q １－２ is independently C １－４ alkyl or oxo, and Scheme 8: L is C １－１０ Alkylene, C ２－１０ Alkenylene or -C １－６ Alkylene-C ３－６ It is a cycloalkylene, When M is -(CH-OH)- or -C(=O)-, R is hydrogen. Scheme 9: L is C １－１０ It is alkylene, M is -O-, Q is one or more Qs １－２ A 5-10 member heteroaryl substituted by, Scheme 10: L is -C １－６ Alkylene-C ３－６ It is a cycloalkylene, M is -NH-, Q is -C(=O)R １ And, R １ -NR １－１ R １－２ And, Scheme 11: The molecular structure represented by formula I is as shown by formula Ia: 【Chemistry 12】 L is C １－１０ Alkylene or C ２－１０ It is alkenylene, Q is a 5- to 10-membered heteroaryl, or one or more Qs. １－２ A 5-10 member heteroaryl substituted by, Scheme 12: The molecular structure represented by formula I is as shown in formula Ic-1: 【Chemistry 13】 L is C １－１０ It is alkylene, Q is one or more Qs １－１ C replaced by ６－１８ It is Ariel, Q １－１ It is a halogen, R is hydrogen, Scheme 13: The molecular structure represented by formula I is as shown in formula Ic-2: 【Chemistry 14】 L is C １－１０ It is alkylene, Q is one or more Qs １－１ C replaced by ６－１８ It is Ariel, Q １－１ It is a halogen, R is hydrogen, Scheme 14: The molecular structure represented by formula I is as shown in formula Ic-3: 【Chemistry 15】 L is C １－１０ It is alkylene, Q is one or more Qs １－２ A 5-10 member heteroaryl substituted by, Q １－１ C １－４ Alkyl or oxo, R is hydrogen.

4. L is C １－１０ In the case of alkylene, the above C １－１０ Alkylenes include methylene, ethylene, n-propylene, isopropylene, n-butylene, isobutylene, or tert-butylene. and / or L is C ２－１０ In the case of alkenylene, the above C ２－１０ Alkenylene is C ２－４ It is alkenylene, and / or, L is -C １－６ Alkylene-C ３－６ If it is a cycloalkylene, Said C １－６ Alkylene is linked to N, and the C ３－６ The cycloalkylene is linked to Q, and / or, L is -C １－６ Alkylene-C ３－６ If it is a cycloalkylene, then -C １－６ Alkylene-C ３－６ In cycloalkylenes, C １－６ Alkylenes include methylene, ethylene, n-propylene, isopropylene, n-butylene, isobutylene, or tert-butylene. and / or, L is -C １－６ Alkylene-C ３－６ If it is a cycloalkylene, then -C １－６ Alkylene-C ３－６ In cycloalkylenes, C ３－６ Cycloalkylenes are cyclopropylene, cyclobutylene, cyclopentylene, or cyclohexylene. And / or Q is C ６－１８ If it is an aryl, then C ６－１８ The aryl is phenyl, naphthyl, anthracenyl, or phenantrenyl. And / or Q is Q １－１ C replaced by ６－１８ If it is an aryl, then C ６－１８ The aryl is phenyl, naphthyl, anthracenyl, or phenantrenyl. And / or Q is Q １－１ C replaced by ６－１８ If it is an aryl, then Q １－１ There is one or two of them. and / or, Q １－１ However, if it is a halogen, the halogen is F, Cl, Br, or I. And / or, if Q is a 5- to 10-membered heteroaryl, then the 5- to 10-membered heteroaryl is a 9 or 10-membered heteroaryl, and the number of heteroatoms is one or two. and / or Q is one or more Qs １－２ In the case of a 5- to 10-membered heteroaryl substituted by, the 5- to 10-membered heteroaryl is a 9 or 10-membered heteroaryl, and the heteroatoms are N and / or O, and there is one or two of them. And / or Q is Q １－２ C replaced by ６－１８ If it is an aryl, then Q １－２ There is one or two of them. and / or, Q １－２ However, C １－４ If it is alkyl, then C １－４ Alkyl compounds are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl. and / or, R １ and R ２ However, if they are independently 3-6 member heterocycloalkyl groups, then the 3-6 member heterocycloalkyl group is piperidinyl or pyrrolidinyl. and / or, R １ However, in the case of a 3- to 6-membered heterocycloalkyl, the 3- to 6-membered heterocycloalkyl is linked to the carbonyl via a heteroatom. and / or, R １ and R ２ However, C ６－１８ If it is an aryl, then C ６－１８ The aryl is phenyl, naphthyl, anthracenyl, or phenantrenyl. and / or, R １ and R ２ However, one or more R independently １－３ C replaced by ６－１８ If it is an aryl, then C ６－１８ The aryl is phenyl, naphthyl, anthracenyl, or phenantrenyl. and / or, R １ and R ２ However, if the 5-10 membered heteroaryl is independent, then the 5-10 membered heteroaryl is a 9- or 10 membered heteroaryl, and the heteroatom is N, and there is one or two of them. and / or, R １－１ , R １－２ , R １－３ and R １－４ However, C １－４ If it is alkyl, then C １－４ Alkyl compounds include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl. and / or R is C １－４ If it is alkyl, then C １－４ A compound represented by formula I according to claim 1, characterized in that the alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl; a pharmaceutically acceptable salt thereof; a solvate thereof; or a solvate of a pharmaceutically acceptable salt thereof.

5. When L is C1-10 alkylene, the C1-10 alkylene is 【Chemistry 16】 And, And / or, if L is C2-10 alkenylene, then the C2-10 alkenylene is 【Chemistry 17】 And, And / or, if L is -C1-6 alkylene-C3-6 cycloalkylene-, then in the -C1-6 alkylene-C3-6 cycloalkylene-, the C1-6 alkylene is [Chemistry 18] And, And / or, if L is -C1-6 alkylene-C3-6 cycloalkylene-, then in the -C1-6 alkylene-C3-6 cycloalkylene, the C3-6 cycloalkylene is 【Chemistry 19】 And, and / or, if Q is a C6-18 aryl, then the C6-18 aryl is phenyl, and / or, if Q is a C6-18 aryl substituted with Q1-1, then the C6-18 aryl is phenyl, And / or, if Q1-1 is a halogen, then the halogen is F, And / or, if Q is a 5- to 10-membered heteroaryl, the 5- to 10-membered heteroaryl is 【Chemistry 20】 And, and / or, if Q is a 5- to 10-membered heteroaryl substituted with one or more Q1-2, the 5- to 10-membered heteroaryl is a 9 or 10-membered heteroaryl, and the heteroatom is tetrahydroquinolyl, quinolyl, benzoxazolyl, benzisoxazolyl, or tetrahydropyridopyrimidinyl. And / or, if Q1-2 is a C1-4 alkyl group, then the C1-4 alkyl group is methyl. And / or, if R1 and R2 are independently 3-6 member heterocycloalkyls, the 3-6 member heterocycloalkyl is pyrrolidinyl. And / or, if R1 and R2 are independently C6-18 aryl, then the C6-18 aryl is phenyl. And / or, if R1 and R2 are independently C6-18 aryls substituted with R1-3, then the C6-18 aryl is phenyl. And / or, if R1 and R2 are independently 5- to 10-membered heteroaryls, the 5- to 10-membered heteroaryl is an indolyl, And / or, if R1-1, R1-2, R1-3 and R1-4 are independently C1-4 alkyl groups, then the C1-4 alkyl group is methyl. and / or, if R is a C1-4 alkyl group, the C1-4 alkyl group is methyl, characterized in that a compound represented by formula I according to claim 4, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof.

6. L is -C １－６ Alkylene-C ３－６ If it is a cycloalkylene, then -C １－６ Alkylene-C ３－６ Cycloalkylene is, 【Chemistry 21】 Here, end a is connected to Q, and end b is connected to N. And / or Q is Q １－１ C replaced by ６－１８ If it is an aryl, then Q １－１ C replaced by ６－１８ Ariel, 【Chemistry 22】 And, and / or Q is one or more Qs １－２ In the case of a 5- to 10-membered heteroaryl substituted by, one or more Q １－２ The 5-10 member heteroaryls substituted by are 【Chemistry 23】 And, and / or, R １ However, if it is a 3- to 6-membered heterocycloalkyl, the 3- to 6-membered heterocycloalkyl is 【Chemistry 24】 And, and / or, 【Chemistry 25】 teeth, 【Chemistry 26】 A compound represented by formula I according to claim 4 or claim 5, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, characterized in that it is such.

7. L is C １－１０ Alkylene, C ２－１０ Alkenylene or -C １－６ Alkylene-C ３－６ It is a cycloalkylene, And / or, M is -O-, -NH-, or -CH ２ - and and / or, Q １－１ It is a halogen, and / or, R １ -NR １－１ R １－２ , 3-6 member heterocycloalkyl, C ６－１８ It is an aryl or a 5-10 membered heteroaryl. and / or, a compound represented by formula I according to claim 1, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, characterized in that R is hydrogen.

8. L is C1-10 alkylene or C1-6 alkylene-C3-6 cycloalkylene, and / or, a compound represented by formula I according to claim 7, characterized in that R 1 is -NR 1-1 R 1-2, a 3-6 member heterocycloalkyl or C 6-18 aryl, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof.

9. The compound represented by formula I is one of the following compounds, as described in claim 1: the compound represented by formula I, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof. 【Chemistry 27】 【change】

10. The compound represented by formula I is 【Chemistry 28】 "Optical rotation of +50.33° and / or holding time of 5.805 mins under the following chiral manufacturing conditions" 【Chemistry 29】 " or "Optical rotation of -45.00 and / or holding time of 7.60 min under the following chiral manufacturing conditions 【Transformation 30】 " and The chiral manufacturing conditions are as follows: column: chiral column CHIRALCEL OD, column volume: 5.0 cm × 25 cm, 10 μm filler; mobile phase: MeOH / diethylamine = 100 / 0.1; flow rate: 30 mL / min; wavelength: UV 214 nm; temperature: 38 °C, characterized in that the compound represented by formula I according to claim 9, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof.

11. A crystal represented by the formula pNs-(+)-I-10, characterized by being a triclinic crystal system belonging to the P1 space group, with cell parameters a = 9.315 Å, b = 6.564 Å, c = 23.792 Å, α = 90.15°, β = 99.368°, and γ = 90.25°. 【Chemistry 31】

12. A pharmaceutical composition comprising a compound represented by formula I according to any one of claims 1 to 10, a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, or a crystal represented by formula pNs-(+)-I-10 according to claim 11, and a pharmaceutical adjuvant.

13. Use of a compound represented by formula I according to any one of claims 1 to 10, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, wherein the use is in the manufacture of a dopamine D2 receptor agonist, a pharmacopoeia for the treatment and / or prevention of a disease relating to the dopamine D2 receptor, or a pharmacopoeia for the treatment and / or prevention of disease M. The aforementioned disease M is one or more of the following: neurodegenerative diseases, mental disorders, and metabolic diseases associated with mental disorders.

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