N-substituted quinolinone compounds, methods for producing the same, and uses thereof

Abstract

The present invention belongs to the field of medicinal chemistry, specifically relates to N-substituted quinolinone compounds, their preparation methods and their medical uses. The structure of the compound of the present invention is shown in formula (I), which has excellent oil solubility and is capable of 5-HT 2A Receptor, dopamine D 2 / 3 Receptor, 5-HT 1A It has a multi-targeting effect on the receptor and 5-HT transporter, which is useful for regulating the balance of neurotransmitters in the brain. It has relatively good therapeutic effects on various central nervous system diseases, and has low toxicity and side effects, high safety and tolerance, good comprehensive drug discovery potential, and good prospects for clinical application. JPEG2025511343000219.jpg42110

Description

Technical Field

[0001] This application claims the priority of a Chinese patent application with the application number 202210333341.5 and the invention title "N-Substituted Quinolinone Compound, Its Production Method and Use", filed on March 30, 2022, and all of its contents are incorporated herein by reference.

[0002] The present invention belongs to the field of medicinal chemistry, and specifically relates to N-substituted quinolinone compounds, their production methods, and their pharmaceutical uses.

Background Art

[0003] With the rapid development of society, people's living rhythms and stresses are increasing day by day. Mental disorders have become diseases that seriously affect people's health, bringing serious consequences to patients and their families. Due to factors such as being prone to suicide, lacking medical care, and having a relatively high risk of complications, the average lifespan of patients with mental disorders is significantly shortened. Many studies have shown that mental disorders are related to the abnormal functions of various neurotransmitters and receptors in the central nervous system. For example, it has been shown that monoamine neurotransmitters in the brain, especially the dopamine (DA) system and the 5-hydroxytryptamine (5-HT) system, are closely related to the normal mental activities of the human body. When the DA and 5-HT systems are dysfunctional, various neuropsychiatric diseases such as schizophrenia, depression, neuropathic pain, mania, anxiety disorders, and Parkinson's disease are likely to occur.

[0004] Neuropsychiatric disorders often coexist with each other; for example, schizophrenia patients frequently have comorbid depression and anxiety, and schizophrenia patients with depression or anxiety symptoms have a worse prognosis. The 5-HT transporter is an important target of antidepressants and anxiolytics, and conventional SSRIs (selective 5-HT reuptake inhibitors) all selectively inhibit the 5-HT transporter, increasing the concentration of 5-HT in the synaptic cleft and thereby exerting their therapeutic effects. Clinically, antipsychotics are often used in combination with SSRIs to treat depression and anxiety symptoms in schizophrenia. Therefore, antipsychotics with 5-HT transporter inhibitory activity can theoretically better improve depression and anxiety comorbidity in schizophrenia.

[0005] Therefore, drugs with multi-targeting activity, including those involving 5-HT transporters, are advantageous for better treating diseases in the central nervous system by better regulating the balance of various receptors in the brain and modulating the DA / 5-HT system.

[0006] Patent WO2015131856 reports a heterocyclic compound with broad therapeutic effects against central nervous system disorders (e.g., schizophrenia), the general formula of which is as follows: [ka]

[0007] The above compounds, particularly the compound of Example 85 (7-(2-(4-(6-fluorobenzothiophen-4-yl)piperazine-1-yl)ethyl)-3,4-dihydroquinoline-2(1H)-one, named "compound 1-a" in this invention), have a broader therapeutic range, fewer side effects, and superior safety and tolerance compared to conventional typical and atypical antipsychotics.

[0008] However, these compounds are poorly soluble in oily media (e.g., sesame oil and benzyl benzoate), which limits their application to oily injectable preparations.

[0009] This invention was made in view of these considerations. [Overview of the project] [Problems that the invention aims to solve]

[0010] The present invention aims to provide a novel N-substituted quinolinone compound that has improved and even better solubility in oily media (e.g., sesame oil and benzyl benzoate), as well as a method for producing the same and its pharmaceutical use. At the same time, the prototype or in vivo metabolite of the compound is 5-HT 2A It has antagonistic effects on dopamine D2 receptors and 5-HT transporters, and on dopamine D3 receptors and 5-HT 1A It has agonist activity against receptors and exhibits relatively high safety and tolerance. [Means for solving the problem]

[0011] In a first embodiment, the present invention provides N-substituted quinolinone compounds represented by general formula (I), or pharmaceutically acceptable salts, solvates, stereoisomers, geometric isomers, isotopically labeled compounds, or prodrugs thereof: [ka] Eventually, R6, R7, R8, and R9 are each independently selected from hydrogen, deuterium, halogen, methyl group, ethyl group, hydroxyl group, amino group, or acetamide group. [ka] represents a single bond or a double bond, and if it is a double bond, one of R6 and R7 is absent, and one of R8 and R9 is absent, preferably, [ka] This represents a single bond, R1 is -Y1-OC(=O)-R2, -Y1-OC(=O)-O-R3, -Y1-O-R4, or -C(=O)-R5. Each Y1 is independently a C1-C6 alkylene group, preferably a C1-C4 alkylene group, and more preferably a methylene group, an ethylene group, or a propylene group. R2 is a C1-C30 alkyl group, a halogenated C1-C30 alkyl group, a C2-C30 alkenyl group, an amino C1-C30 alkyl group, an amino group substituted with a C1-C30 alkyl group, an amino group substituted with a C2-C30 alkenyl group, an amino group substituted with a halogenated C1-C30 alkyl group, an amino group substituted with a phenyl C1-C30 alkyl group, an amino group substituted with a hydroxy C1-C30 alkyl group, an amino group substituted with a C3-C10 cycloalkyl group, or an amino group substituted with a C3-C10 cycloalkyl C1-C6 alkyl group. C3-C10 cycloalkyl groups, 5-10 membered heterocyclyl groups, C6-C12 aryl groups, C6-C12 aryl C1-C30 alkyl groups, C1-C30 alkylcarbonyl C1-C30 alkyl groups, C1-C30 alkylC1-C30 alkyl groups, C1-C30 alkylC1-C30 alkylC1-C30 alkyl groups, or C1-C30 alkylC1-C30 alkylC1-C30 alkylC1-C30 alkyl groups, preferably R2 is a C1-C30 alkyl group, a halogenated C1-C30 alkyl group, or a C2-C30 alke Nyl group, amino C1-C16 alkyl group, C1-C16 alkyl-substituted amino group, C2-C16 alkenyl group-substituted amino group, halogenated C1-C16 alkyl-substituted amino group, phenyl C1-C16 alkyl-substituted amino group, hydroxy C1-C16 alkyl-substituted amino group, C3-C10 cycloalkyl-substituted amino group, C3-C10 cycloalkyl-C1-C6 alkyl-substituted amino group, C3-C10 cycloalkyl group, 5-10 membered heterocyclyl group, C6-C12 aryl group, C R2 is a 6-C12 aryl C1-C16 alkyl group, a C1-C16 alkylcarbonyl C1-C16 alkyl group, a C1-C16 alkyl C1-C16 alkyl group, a C1-C16 alkyl C1-C16 alkyl C1-C16 alkyl group, or a C1-C16 alkyl C1-C16 alkyl C1-C16 alkyl group, and moreover, R2 is a C1-C30 alkyl group, a halogenated C1-C30 alkyl group, a C2-C30 alkenyl group, an amino C1-C12 alkyl group, or an amino group substituted with a C1-C12 alkyl group.amino groups substituted with C2-C12 alkenyl groups, amino groups substituted with halogenated C2-C12 alkyl groups, amino groups substituted with phenyl C1-C12 alkyl groups, amino groups substituted with hydroxy C1-C12 alkyl groups, amino groups substituted with C3-C7 cycloalkyl groups, amino groups substituted with C3-C7 cycloalkyl or C1-C4 alkyl groups, C3-C7 cycloalkyl groups, 5-10 membered heterocyclyl groups, C6-C12 aryl groups, C6-C12 aryl or C1-C12 alkyl groups, C1-C12 alkoxycarbonyl or C1-C12 alkyl groups, C1-C12 alkoxy C1-C12 alkyl group, C1-C12 alkoxy C1-C12 alkoxy C1-C12 alkyl group, or C1-C12 alkoxy C1-C12 alkoxy C1-C12 alkyl group, and more preferably R2 is a C1-C30 alkyl group (e.g., C1-C30 linear alkyl group, isopropyl group, tert-butyl group, 1-methylpropyl group, 3-methylbutyl group, 1-methylbutyl group, 1,1-dimethylpentyl group, 1-methylpentyl group, 1-methylhexyl group, 1-pentylhexyl group, etc.), halo Genoforming C1-C30 alkyl groups (e.g., halogenated C1-C16 alkyl groups, halogenated C1-C12 alkyl groups, or halogenated C1-C6 alkyl groups, and also, for example, 3,3,3-trifluoropropyl group), C2-C30 alkenyl groups (e.g., C2-C20 alkenyl group), amino C1-C6 alkyl groups (e.g., NH2-methyl group), amino groups substituted with C1-C12 alkyl groups (e.g., decyl-NH-, heptyl-NH-), amino groups substituted with C2-C6 alkenyl groups (e.g., allyl-NH-), halogenated C1-C6 alkyl groups amino groups substituted with (e.g., 3,3,3-trifluoropropyl-NH-), amino groups substituted with phenyl C1-C6 alkyl groups (e.g., benzyl-NH-), amino groups substituted with hydroxy C1-C6 alkyl groups (e.g., hydroxyethyl-NH-), amino groups substituted with C3-C7 cycloalkyl groups (e.g., cycloalkyl-NH-), amino groups substituted with C3-C7 cycloalkyl C1-C6 alkyl groups (e.g., C3-C7 cycloalkylmethyl-NH-), C3-C7 cycloalkyl groups, 5-10 membered heterocyclyl groups (e.g.,These are pyridyl groups, piperidinyl groups, 4-tetrahydropyranyl groups, morpholinyl groups, furyl groups, thienyl groups, pyrimidine groups, quinolyl groups, etc.), phenyl groups, naphthyl groups, phenyl C1-C6 alkyl groups (e.g., benzyl groups), C1-C6 alkoxycarbonyl C1-C6 alkyl groups (e.g., tert-butoxycarbonylmethyl groups), C1-C6 alkoxy C1-C6 alkyl groups (e.g., methoxymethyl groups), C1-C6 alkoxy C1-C6 alkoxy C1-C6 alkyl groups (e.g., methoxyethoxymethyl groups, butoxyethoxymethyl groups), or C1-C6 alkoxy C1-C6 alkoxy C1-C6 alkyl groups (e.g., methoxyethoxyethoxymethyl groups). For example, R2 is a C1-C16 alkyl group, a halogenated C1-C16 alkyl group, a C2-C16 alkenyl group, an amino C1-C16 alkyl group, an amino group substituted with a C1-C16 alkyl group, an amino group substituted with a C2-C16 alkenyl group, an amino group substituted with a halogenated C1-C16 alkyl group, an amino group substituted with a phenyl C1-C16 alkyl group, an amino group substituted with a hydroxy C1-C16 alkyl group, an amino group substituted with a C3-C10 cycloalkyl group, an amino group substituted with a C3-C10 cycloalkyl group or a C1-C6 alkyl group, a C3-C10 cycloalkyl group, a 5-10 membered heterocyclyl group, a C6-C12 aryl group, a C6-C12 aryl C1-C16 alkyl group, a C1-C16 alkoxycarbonyl C1-C16 alkyl group, a C1-C16 alkoxy C1-C16 alkyl group, a C1-C16 aryl R2 is a lucoxy C1-C16 alkoxy C1-C16 alkyl group or a C1-C16 alkoxy C1-C16 alkoxy C1-C16 alkyl group, for example, R2 is a C1-C16 alkyl group, a halogenated C1-C16 alkyl group, a 5-10 membered heterocyclyl group, a C6-C12 aryl group, a C6-C12 aryl C1-C16 alkyl group, or a C1-C16 alkoxy C1-C16 alkyl group, or for example, R2 is a C1-C16 alkyl group (e.g., methyl group, ethyl group, isopropyl group, tert-butyl group, etc.), a halogenated C1-C16 alkyl group, a phenyl group, a naphthyl group, a phenyl C1-C16 alkyl group, a pyridyl group, a piperidinyl group, a morpholinyl group, a furyl group, a thienyl group, a pyrimidine group, a quinolyl group, and most particularly, R2 is a C1-C16 alkyl group or a phenyl group. R3 is a C1-C30 alkyl group, a halogenated C1-C30 alkyl group, a phenyl group, a phenyl C1-C30 alkyl group, or a C3-C10 cycloalkyl group, preferably a C1-C16 alkyl group, a halogenated C1-C16 alkyl group, a phenyl group, a phenyl C1-C16 alkyl group, or a C3-C10 cycloalkyl group, preferably a C1-C16 alkyl group, a halogenated C1-C12 alkyl group, a phenyl group, a phenyl C1-C12 alkyl group, or a C3-C7 cycloalkyl group (e.g., a cyclohexyl group), and more preferably a C1-C16 alkyl group, a halogenated C1-C6 alkyl group (e.g., 2,2,2-trifluoroethyl), a phenyl group, a phenyl C1-C6 alkyl group (e.g., a benzyl group), or a C3-C7 cycloalkyl group (e.g., a cyclohexyl group). For example, R3 is a C1-C16 alkyl group, a halogenated C1-C16 alkyl group, a phenyl group, a phenyl C1-C16 alkyl group, or a C3-C10 cycloalkyl group. For example, R3 is a C1-C16 alkyl group or a halogenated C1-C16 alkyl group. Also, for example, R3 is a C1-C12 alkyl group. R4 is hydrogen, a C1-C30 alkyl group, a halogenated C1-C30 alkyl group, a phenyl C1-C30 alkyl group, or a phenyl C1-C30 alkoxy C1-C30 alkyl group, preferably R4 is hydrogen, a C1-C16 alkyl group, a halogenated C1-C16 alkyl group, a phenyl C1-C16 alkyl group, or a phenyl C1-C16 alkoxy C1-C16 alkyl group, preferably R4 is hydrogen, a C1-C12 alkyl group, a halogenated C1-C12 alkyl group, a phenyl C1-C12 alkyl group, or a phenyl C1-C12 alkoxy C1-C12 alkyl group, and more preferably R4 is hydrogen, a C1-C6 alkyl group (e.g., an isopropyl group), a halogenated C1-C6 alkyl group (e.g., a 2,2,2-trifluoroethyl group), a phenyl C1-C6 alkyl group (e.g., a benzyl group), or a phenyl C1-C6 alkoxy C1-C6 alkyl group (e.g., a benzyloxymethyl group). Preferably, R4 is hydrogen, a C1-C16 alkyl group, a halogenated C1-C16 alkyl group, a phenyl C1-C16 alkyl group, or a phenyl C1-C16 alkoxy C1-C16 alkyl group. R5 is a C1-C30 alkyl group, a C2-C30 alkenyl group, a morpholinyl group, a phenyl group, a phenyl C1-C30 alkyl group, a hydroxy C1-C30 alkyl group, a C3-C10 cycloalkyl group, a C1-C30 alkoxy group, a phenyl oxy group, a phenyl C1-C30 alkoxy group, a C1-C30 alkoxy group, an amino C1-C30 alkyl group, an amino group substituted with a C1-C30 alkyl group, an amino group substituted with a hydroxy C1-C30 alkyl group, an amino group substituted with a phenyl C1-C30 alkyl group, a C3- C10 cycloalkyl group, C1-C30 alkanoyloxy C1-C6 alkalkyl group, C1-C30 alkalkyl C1-C30 alkyl, C1-C30 alkalkyl C1-C30 alkalkyl C1-C30 alkyl or C1-C30 alkalkyl C1-C30 alkalkyl C1-C30 alkyl, preferably R5 is C1-C16 alkyl, C2-C16 alkenyl group, morpholinyl group, phenyl group, phenyl C1-C16 alkyl, hydroxy C1-C16 alkyl, C3-C10 cycloalkyl, C1-C1 6-alkoxy group, phenyloxy group, phenyl C1-C16 alkoxy group, C1-C16 alkoxy C1-C16 alkoxy group, amino C1-C16 alkyl group, amino group substituted with C1-C16 alkyl group, amino group substituted with hydroxy C1-C16 alkyl group, amino group substituted with phenyl C1-C16 alkyl group, C3-C10 cycloalkoxy group, C1-C16 alkanoyloxy C1-C6 alkoxy group, C1-C16 alkoxy C1-C16 alkyl group, C1-C16 alkoxy C1-C16 alkoxy C1-C16 alkyl group or R5 is a C1-C16 alkoxy, C1-C16 alkoxy, C1-C16 alkoxy, C1-C16 alkyl group, preferably R5 is a C1-C12 alkyl group, a C2-C12 alkenyl group, a morpholinyl group, a phenyl group, a phenyl C1-C12 alkyl group, a hydroxy C1-C12 alkyl group, a C3-C10 cycloalkyl group, a C1-C12 alkoxy group, a phenyl oxy group, a phenyl C1-C12 alkoxy group, a C1-C12 alkyl group, or an amino group substituted with a C1-C12 alkyl group.It is an amino group substituted with a hydroxy C1-C12 alkyl group, an amino group substituted with a phenyl C1-C12 alkyl group, a C3-C10 cycloalkoxy group, a C1-C12 alkanoyloxy C1-C6 alkoxy group, a C1-C12 alkoxy C1-C12 alkyl group, a C1-C12 alkoxy C1-C12 alkoxy C1-C12 alkyl group, or a C1-C12 alkoxy C1-C12 alkoxy C1-C12 alkyl group. Preferably, R5 is a C1-C6 alkyl group (e.g., methyl group, ethyl group, propyl group, etc.), a C2-C16 alkenyl group (e.g., decenyl group), a morpholinyl group, a phenyl group, a phenyl C1-C6 alkyl group, a hydroxy C1-C6 alkyl group, a C3-C10 cycloalkyl group (e.g., cyclopentyl group, cyclohexyl group), a C1-C6 alkoxy group (e.g., methoxy group, ethoxy group, propoxy group, isopropoxy group, etc.), or a phenoxy group. These are C1-C6 alkoxy groups, C1-C6 alkoxy groups (e.g., methoxyethoxy group), amino C1-C6 alkyl groups (NH2-methyl group), amino groups substituted with C1-C6 alkyl groups (e.g., propylamino group), amino groups substituted with hydroxy C1-C6 alkyl groups (e.g., hydroxyethyl-NH-), amino groups substituted with phenyl C1-C6 alkyl groups (e.g., benzyl-NH-), C1-C16 alkanoyloxy C1-C6 alkoxy groups (decanoyloxymethyloxy group), C1-C6 alkoxy C1-C6 alkyl groups (e.g., methoxymethyl group), C1-C6 alkoxy C1-C6 alkoxy C1-C6 alkyl groups (e.g., methoxyethoxymethyl group), or C1-C6 alkoxy C1-C6 alkoxy C1-C6 alkyl groups (e.g., methoxyethoxyethoxymethyl group). For example, R5 is a C1-C16 alkyl group, a C2-C16 alkenyl group, a morpholinyl group, a phenyl group, a phenyl C1-C16 alkyl group, a hydroxy C1-C16 alkyl group, a C3-C10 cycloalkyl group, a C1-C16 alkoxy group, a phenyl C1-C16 alkoxy group, a C1-C16 alkoxy group, an amino C1-C16 alkyl group, a C1-C16 R5 is an amino group substituted with a 16 alkyl group, an amino group substituted with a hydroxy C1-C16 alkyl group, an amino group substituted with a phenyl C1-C16 alkyl group, a C3-C10 cycloalkoxy group, a C1-C16 alkoxy C1-C16 alkyl group, a C1-C16 alkoxy C1-C16 alkoxy C1-C16 alkyl group, or a C1-C16 alkoxy C1-C16 alkoxy C1-C16 alkyl group. For example, R5 is a C1-C12 alkyl group, a phenyl C1-C12 alkyl group, or a C1-C12 alkyl group. R5 is a lucoxy group, a phenyl C1-C12 alkoxy group, a C1-C12 alkyloxy C1-C12 alkoxy group, or a C1-C12 alkoxy C1-C12 alkyl group. For example, R5 is a C1-C6 alkyl group (e.g., methyl group, ethyl group, propyl group, etc.), a phenyl C1-C6 alkyl group, a C1-C6 alkoxy group (e.g., methoxy group, ethoxy group, propoxy group, etc.), a phenyl C1-C6 alkoxy group, a C1-C6 alkoxy C1-C6 alkoxy group, or a C1-C6 alkoxy C1-C6 alkyl group.

[0012] In some embodiments, the above N-substituted quinolinone compound, or a pharmaceutically acceptable salt, solvate, stereoisomer, geometric isomer, isotope-labeled compound, or prodrug thereof, is represented by the following general formula (I-1) or (I-2): [ka] Of these, R1, R6, R7, R8, and R9 have the definitions described in the general formula (I) above.

[0013] In some preferred embodiments, R1 is -Y1-OC(=O)-R2, -Y1-OC(=O)-O-R3, -Y1-O-R4, or -C(=O)-R5, preferably -Y1-OC(=O)-R2. Y1 is independently a C1-C4 alkylene group, preferably -CH2- or -CH(CH3)-. R2 is a C1-C30 alkyl group, a halogenated C1-C30 alkyl group, a C2-C30 alkenyl group, an amino C1-C16 alkyl group, an amino group substituted with a C1-C16 alkyl group, an amino group substituted with a C2-C16 alkenyl group, an amino group substituted with a halogenated C1-C16 alkyl group, an amino group substituted with a phenyl C1-C16 alkyl group, an amino group substituted with a hydroxy C1-C16 alkyl group, an amino group substituted with a C3-C10 cycloalkyl group, or an amino group substituted with a C3-C10 cycloalkyl C1-C6 alkyl group. C3-C10 cycloalkyl groups, 5-10 membered heterocyclyl groups, C6-C12 aryl groups, C6-C12 aryl C1-C16 alkyl groups, C1-C16 alkoxycarbonyl C1-C16 alkyl groups, C1-C16 alkoxyC1-C16 alkyl groups, C1-C16 alkoxyC1-C16 alkoxyC1-C16 alkyl groups, or C1-C16 alkoxyC1-C16 alkoxyC1-C16 alkyl groups, preferably R2 is a C1-C30 alkyl group, a halogenated C1-C30 alkyl group, or a C2-C30 alke Nyl group, amino C1-C12 alkyl group, amino group substituted with C1-C12 alkyl group, amino group substituted with C2-C12 alkenyl group, amino group substituted with halogenated C1-C12 alkyl group, amino group substituted with phenyl C1-C12 alkyl group, amino group substituted with hydroxy C1-C12 alkyl group, amino group substituted with C3-C7 cycloalkyl group, amino group substituted with C3-C7 cycloalkyl group or C1-C4 alkyl group, C3-C7 cycloalkyl group, 5-10 membered heterocyclyl group, C6-C12 aryl group, C6-C 12-aryl C1-C12 alkyl group, C1-C12 alkoxycarbonyl C1-C12 alkyl group, C1-C12 alkoxy C1-C12 alkyl group, C1-C12 alkoxy C1-C12 alkoxy C1-C12 alkyl group, or C1-C12 alkoxy C1-C12 alkoxy C1-C12 alkyl group, or more preferably R2 is a C1-C30 alkyl group (e.g., C1-C30 linear alkyl group, isopropyl group, tert-butyl group, 1-methylpropyl group, 3-methylbutyl group, 1-methylbutyl group, 1,1-dimethylpentyl group, 1-methylpentyl group, 1-methylhexyl group, 1-pentylhexyl group, etc.), halogenated C1-C30 alkyl groups (e.g., halogenated C1-C16 alkyl groups, halogenated C1-C12 alkyl groups, halogenated C1-C6 alkyl groups, and also, for example, 3,3,3-trifluoropropyl group), C2-C30 alkenyl groups (e.g., C2-C20 alkenyl groups), amino C1-C6 alkyl groups (e.g., NH2-methyl group), C1-C12 alkyl groups amino groups substituted with (e.g., decyl-NH-, heptyl-NH-), amino groups substituted with C2-C6 alkenyl groups (e.g., 2-allyl-NH-), amino groups substituted with halogenated C1-C6 alkyl groups (e.g., 3,3,3-trifluoropropyl-NH-), amino groups substituted with phenyl C1-C6 alkyl groups (e.g., benzyl-NH-), amino groups substituted with hydroxy C1-C6 alkyl groups (e.g., hydroxyethyl-NH-), C3-C77 cyclopropyl groups amino groups substituted with a cyclic group (e.g., C3-C7 cycloalkyl-NH-), amino groups substituted with C3-C7 cycloalkyl or C1-C6 alkyl groups (e.g., C3-C7 cycloalkylmethyl-NH-), C3-C7 cycloalkyl groups, 5-10 membered heterocyclyl groups (e.g., pyridyl group, piperidinyl group, morpholinyl group, furyl group, thienyl group, pyrimidine group, quinolyl group, etc.), phenyl groups, naphthyl groups, phenyl C1-C6 alkyl groups (e.g., benzyl group), C1-C6 alkoxycarbonyl C1-C6 alkyl group (e.g., tert-butoxycarbonylmethyl group), C1-C6 alkoxy C1-C6 alkyl group (e.g., methoxymethyl group), C1-C6 alkoxy C1-C6 alkoxy C1-C6 alkyl group (e.g., methoxyethoxymethyl group, butoxyethoxymethyl group), or C1-C6 alkoxy C1-C6 alkoxy C1-C6 alkyl group (e.g., methoxyethoxyethoxymethyl group), R3 is a C1-C16 alkyl group, a halogenated C1-C16 alkyl group, a phenyl group, a phenyl C1-C16 alkyl group, or a C3-C10 cycloalkyl group, preferably R3 is a C1-C12 alkyl group, a halogenated C1-C12 alkyl group, a phenyl group, a phenyl C1-C12 alkyl group, or a C3-C7 cycloalkyl group (e.g., a cyclohexyl group), and more preferably R3 is a C1-C6 alkyl group, a halogenated C1-C6 alkyl group (e.g., a 2,2,2-trifluoroethyl group), a phenyl group, a phenyl C1-C6 alkyl group (e.g., a benzyl group), or a C3-C7 cycloalkyl group (e.g., a cyclohexyl group). R4 is hydrogen, a C1-C16 alkyl group, a halogenated C1-C16 alkyl group, a phenyl C1-C16 alkyl group, or a phenyl C1-C16 alkoxy C16-C16 alkyl group, preferably R4 is hydrogen, a C1-C12 alkyl group, a halogenated C1-C12 alkyl group, a phenyl C1-C12 alkyl group, or a phenyl C1-C12 alkoxy C1-C12 alkyl group, more preferably R4 is hydrogen, a C1-C6 alkyl group (e.g., an isopropyl group), a halogenated C1-C6 alkyl group (e.g., a 2,2,2-trifluoroethyl group), a phenyl C1-C6 alkyl group (e.g., a benzyl group), or a phenyl C1-C6 alkoxy C1-C6 alkyl group (e.g., a benzyloxymethyl group). R5 is a C1-C16 alkyl group, a C2-C16 alkenyl group, a morpholinyl group, a phenyl group, a phenyl C1-C16 alkyl group, a hydroxy C1-C16 alkyl group, a C3-C10 cycloalkyl group, a C1-C16 alkoxy group, a phenyl oxy group, a phenyl C1-C16 alkoxy group, a C1-C16 alkoxy group, an amino C1-C16 alkyl group, an amino group substituted with a C1-C16 alkyl group, an amino group substituted with a hydroxy C1-C16 alkyl group, an amino group substituted with a phenyl C1-C16 alkyl group, and a C3-C10 The group is a cycloalkoxy group, a C1-C16 alkanoyloxy C1-C6 alkoxy group, a C1-C16 alkoxy C1-C16 alkyl group, a C1-C16 alkoxy C1-C16 alkoxy C1-C16 alkyl group, or a C1-C16 alkoxy C1-C16 alkoxy C1-C16 alkyl group, preferably R5 is a C1-C12 alkyl group, a C2-C12 alkenyl group, a morpholinyl group, a phenyl group, a phenyl C1-C12 alkyl group, a hydroxy C1-C12 alkyl group, a C3-C10 cycloalkyl group, or a C1-C12 alkoxy group. C1-C12 alkyl group, phenyloxy group, phenyl C1-C12 alkoxy group, C1-C12 alkyloxy C1-C12 alkoxy group, amino C1-C12 alkyl group, amino group substituted with C1-C12 alkyl group, amino group substituted with hydroxy C1-C12 alkyl group, amino group substituted with phenyl C1-C12 alkyl group, C3-C10 cycloalkoxy group, C1-C12 alkanoyloxy C1-C6 alkoxy group, C1-C12 alkoxy C1-C12 alkyl group, C1-C12 alkoxy C1-C12 alkoxy C1-C12 alkyl group or C1-C 12-alkoxy C1-C12-alkoxy C1-C12-alkoxy C1-C12-alkyl group, more preferably R5 is a C1-C6 alkyl group (e.g., methyl group, ethyl group, propyl group, etc.), a C2-C16 alkenyl group (e.g., decenyl group), a morpholinyl group, a phenyl group, a phenyl C1-C6 alkyl group, a hydroxy C1-C6 alkyl group, a C3-C10 cycloalkyl group (e.g., cyclopentyl group, cyclohexyl group), a C1-C6 alkoxy group (e.g., methoxy group, ethoxy group, propoxy group, isopropoxy group, etc.), a phenoxy group,These are phenyl C1-C6 alkoxy groups, C1-C6 alkoxy C1-C6 alkoxy groups (e.g., methoxyethoxy group), amino C1-C6 alkyl groups (NH2-methyl group), amino groups substituted with C1-C6 alkyl groups (e.g., propylamino group), amino groups substituted with hydroxy C1-C6 alkyl groups (e.g., hydroxyethyl-NH-), amino groups substituted with phenyl C1-C6 alkyl groups (e.g., benzyl-NH-), C1-C16 alkanoyloxy C1-C6 alkoxy groups (decanoyloxymethoxy group), C1-C6 alkoxy C1-C6 alkyl groups (e.g., methoxymethyl group), C1-C6 alkoxy C1-C6 alkoxy C1-C6 alkyl groups (e.g., methoxyethoxymethyl group), or C1-C6 alkoxy C1-C6 alkoxy C1-C6 alkyl groups (e.g., methoxyethoxyethoxymethyl group). The remaining elements are as defined above.

[0014] In some preferred embodiments, R1 is -Y1-OC(=O)-R2 or -Y1-OC(=O)-O-R3, preferably -Y1-OC(=O)-R2. Y1 is independently a C1-C4 alkylene group, preferably -CH2- or -CH(CH3)-. R2 is a C1-C12 alkyl group, a halogenated C1-C12 alkyl group, a C2-C12 alkenyl group, an amino C1-C12 alkyl group, an amino group substituted with a C1-C12 alkyl group, an amino group substituted with a C2-C12 alkenyl group, an amino group substituted with a halogenated C1-C12 alkyl group, an amino group substituted with a phenyl C1-C12 alkyl group, an amino group substituted with a hydroxy C1-C12 alkyl group, an amino group substituted with a C3-C6 cycloalkyl group, an amino group substituted with a C3-C6 cycloalkyl group or a C1-C4 alkyl group, a C3-C6 cycloalkyl group, a pyridyl group, a piperidinyl group, a morpholinyl group, a furyl group, a thienyl group, a pyrimidine group, a quinolyl group, a phenyl group, The C1-C12 alkyl group is a phenyl C1-C12 alkyl carbonyl C1-C12 alkyl group, a C1-C12 alkyl C1-C12 alkyl C1-C12 alkyl C1-C12 alkyl group, or a C1-C12 alkyl C1-C12 alkyl C1-C12 alkyl C1-C12 alkyl group, preferably a C1-C12 alkyl group, a halogenated C1-C12 alkyl group, a C3-C6 cycloalkyl group, a phenyl group, a phenyl C1-C12 alkyl group, a C1-C12 alkyl carbonyl C1-C12 alkyl group, a C1-C12 alkyl C1-C12 alkyl C1-C12 alkyl group, or a C1-C12 alkyl C1-C12 alkyl C1-C12 alkyl C1-C12 alkyl group. R3 is a C1-C12 alkyl group, a halogenated C1-C12 alkyl group, a phenyl group, a phenyl C1-C12 alkyl group, or a C3-C6 cycloalkyl group, preferably a C1-C12 alkyl group, a halogenated C1-C12 alkyl group, a phenyl group, or a C3-C6 cycloalkyl group.

[0015] In some preferred embodiments, R1 is -Y1-OC(=O)-R2, Y1 is a C1-C4 alkylene group, preferably -CH2- or -CH(CH3)-. R2 is a C3-C16 alkyl group, halogenated C3-C16 alkyl group, C3-C16 alkenyl group, amino C3-C16 alkyl group, amino group substituted with a C3-C16 alkyl group, amino group substituted with a C3-C16 alkenyl group, halogenated C3-C16 alkyl group substituted with an amino group, phenyl C3-C16 alkyl group substituted with an amino group, hydroxy C3-C16 alkyl group substituted with an amino group, C3-C6 cycloalkyl group substituted with an amino group, C3-C6 cycloalkyl group substituted with a C3-C16 alkyl group, pyridyl group, piperidinyl group, morpholinyl group, furyl group, thienyl group, pyrimidine group, quinolyl group, phenyl group The group is a phenyl C3-C16 alkyl group, a C1-C12 alkoxycarbonyl C3-C16 alkyl group, a C1-C12 alkoxyC1-C12 alkoxyC3-C16 alkyl group, or a C1-C12 alkoxyC1-C12 alkoxyC1-C12 alkoxyC3-C16 alkyl group, preferably a C3-C16 alkyl group, a halogenated C3-C16 alkyl group, a C3-C6 cycloalkyl group, a phenyl group, a phenyl C3-C16 alkyl group, a C1-C12 alkoxycarbonyl C3-C16 alkyl group, a C1-C12 alkoxyC1-C12 alkoxyC3-C16 alkyl group, or a C1-C12 alkoxyC1-C12 alkoxyC1-C12 alkoxyC3-C16 alkyl group.

[0016] In some preferred embodiments, R1 is -Y1-O-R4, R4 is hydrogen, a C1-C12 alkyl group, a halogenated C1-C12 alkyl group, a phenyl C1-C12 alkyl group, or a phenyl C1-C12 alkyl C1-C12 alkyl group, preferably hydrogen, a C1-C12 alkyl group, a halogenated C1-C12 alkyl group, or a phenyl C1-C12 alkyl group.

[0017] In some preferred embodiments, R1 is -C(=O)-R5, R5 is a C1-C12 alkyl group, a C2-C12 alkenyl group, a morpholinyl group, a phenyl group, a phenyl C1-C12 alkyl group, a hydroxy C1-C12 alkyl group, a C3-C6 cycloalkyl group, a C1-C12 alkoxy group, a phenyl C1-C12 alkoxy group, an amino C1-C12 alkyl group, an amino group substituted with a C1-C12 alkyl group, an amino group substituted with a hydroxy C1-C12 alkyl group, an amino group substituted with a phenyl C1-C12 alkyl group, a C3-C6 cycloalkoxy group, a C1-C12 alkoxy group, a C1-C12 alkoxy group. The C1-C12 alkyl group or C1-C12 alkoxy C1-C12 alkoxy C1-C12 alkoxy C1-C12 alkyl group, preferably a C1-C12 alkyl group, a phenyl group, a phenyl C1-C12 alkyl group, a C3-C6 cycloalkyl group, a C1-C12 alkoxy group, a phenyl C1-C12 alkoxy group, a C3-C6 cycloalkyl group, a C1-C12 alkoxy C1-C12 alkoxy C1-C12 alkyl group, or a C1-C12 alkoxy C1-C12 alkoxy C1-C12 alkyl group.

[0018] In some preferred embodiments, in the above general formula (I-1) or (I-2), R6, R7, R8, and R9 are each independently hydrogen. R1 is -Y1-OC(=O)-R2, -Y1-OC(=O)-O-R3, -Y1-O-R4, or -C(=O)-R5. Y1 is independently a C1-C4 alkylene group, preferably -CH2- or -CH(CH3)-. R2 is a C1-C16 alkyl group or a phenyl group. R3 is a C1-C12 alkyl group. R4 is hydrogen, R5 is a C1-C6 alkyl group or a C1-C6 alkoxy group.

[0019] In some preferred embodiments, R6, R7, R8, and R9 are each independently hydrogen. R1 is -Y1-OC(=O)-R2, Y1 is a C1-C4 alkylene group, preferably -CH2- or -CH(CH3)-. R2 is a C1-C30 alkyl group.

[0020] In a second aspect, the present invention provides the following N-substituted quinolinone compounds, or pharmaceutically acceptable salts, solvates, stereoisomers, geometric isomers, isotopically labeled compounds or prodrugs thereof: (1) 7-(2-(4-(6-fluorobenzo[b]thiophen-4-yl)piperazine-1-yl)ethyl)-1-(hydroxymethyl)-3,4-dihydroquinoline-2(1H)-one, [ka] (2)(7-(2-(4-(6-fluorobenzothiophen-4-yl)piperazine-1-yl)ethyl)-2-oxo-3,4-dihydroquinoline-1(2H)-yl)methylisopropyl carbonate, [ka] (3)(7-(2-(4-(6-fluorobenzothiophen-4-yl)piperazine-1-yl)ethyl)-2-oxo-3,4-dihydroquinoline-1(2H)-yl)dodecanoate methyl, [ka] (4)7-(2-(4-(6-fluorobenzothiophen-4-yl)piperazine-1-yl)ethyl)-2-oxo-3,4-dihydroquinoline-1(2H)-isopropyl carboxylate, [ka] (5)(7-(2-(4-(6-fluorobenzothiophen-4-yl)piperazine-1-yl)ethyl)-2-oxo-3,4-dihydroquinoline-1(2H)-yl)methyl acetate, [ka] (6)(7-(2-(4-(6-fluorobenzothiophen-4-yl)piperazine-1-yl)ethyl)-2-oxo-3,4-dihydroquinoline-1(2H)-yl)methyl pentanoate, [ka] (7)(7-(2-(4-(6-fluorobenzothiophen-4-yl)piperazine-1-yl)ethyl)-2-oxo-3,4-dihydroquinoline-1(2H)-yl)decanoate methyl, [ka] (8)(7-(2-(4-(6-fluorobenzothiophen-4-yl)piperazine-1-yl)ethyl)-2-oxo-3,4-dihydroquinoline-1(2H)-yl)methyl palmitate, [ka] (9)(7-(2-(4-(6-fluorobenzothiophen-4-yl)piperazine-1-yl)ethyl)-2-oxo-quinoline-1(2H)-yl)methyl palmitate, [ka] (10)(7-(2-(4-(6-fluorophenylthiophen-4-yl)piperazine-1-yl)ethyl)-2-oxo-quinoline-1(2H)-yl)decanoate methyl, [ka] (11) 1-Acetyl-7-(2-(4-(6-fluorobenzothiophen-4-yl)piperazine-1-yl)ethyl)-3,4-dihydroquinoline-2(1H)-one, [ka] (12)(7-(2-(4-(6-fluorobenzothiophen-4-yl)piperazine-1-yl)ethyl)-2-oxo-3,4-dihydroquinoline-1(2H)-yl)methyl benzoate, [ka] (13) 1-(7-(2-(4-(6-fluorobenzothiophen-4-yl)piperazine-1-yl)ethyl)-2-oxo-3,4-dihydroquinoline-1(2H)-yl)dodecanoate ethyl, [ka] (14)(7-(2-(4-(6-fluorobenzothiophen-4-yl)piperazine-1-yl)ethyl)-2-oxo-3,4-dihydroquinoline-1(2H)-yl)methylundecylcarbonate, [ka] (15) 1-(7-(2-(4-(6-fluorobenzothiophen-4-yl)piperazine-1-yl)ethyl)-2-oxo-3,4-dihydroquinoline-1(2H)-yl)methyl palmitate, [ka] (16) 1-(7-(2-(4-(6-fluorobenzothiophen-4-yl)piperazine-1-yl)ethyl)-2-oxo-3,4-dihydroquinoline-1(2H)-yl)isobutyrate ethyl, [ka] (17)(7-(2-(4-(6-fluorobenzothiophen-4-yl)piperazine-1-yl)ethyl)-2-oxo-3,4-dihydroquinoline-1(2H)-yl) pivalate methyl, [ka] (18)(7-(2-(4-(6-fluorobenzothiophen-4-yl)piperazine-1-yl)ethyl)-2-oxo-3,4-dihydroquinoline-1(2H)-yl)methyl hexanoate, [ka] (19)(7-(2-(4-(6-fluorobenzothiophen-4-yl)piperazine-1-yl)ethyl)-2-oxo-3,4-dihydroquinoline-1(2H)-yl)methyl carbonate, [ka] (20)(7-(2-(4-(6-fluorobenzothiophen-4-yl)piperazine-1-yl)ethyl)-2-oxoquinoline-1(2H)-yl)methyl carbonate, [ka] (21)(7-(2-(4-(6-fluorobenzothiophen-4-yl)piperazine-1-yl)ethyl)-2-oxo-3,4-dihydroquinoline-1(2H)-yl)methylethyl carbonate, [ka] (22)(7-(2-(4-(6-fluorobenzothiophen-4-yl)piperazine-1-yl)ethyl)-2-oxo-3,4-dihydroquinoline-1(2H)-yl)methylpropyl carbonate, [ka] (23)(7-(2-(4-(6-fluorobenzothiophen-4-yl)piperazine-1-yl)ethyl)-2-oxo-3,4-dihydroquinoline-1(2H)-yl)methylbutyl carbonate, [ka] (24)(7-(2-(4-(6-fluorobenzothiophen-4-yl)piperazine-1-yl)ethyl)-2-oxo-3,4-dihydroquinoline-1(2H)-yl)methylhexyl carbonate, [ka] (25)(7-(2-(4-(6-fluorobenzothiophen-4-yl)piperazine-1-yl)ethyl)-2-oxo-3,4-dihydroquinoline-1(2H)-yl)methylheptyl carbonate, [ka] (26)(7-(2-(4-(6-fluorobenzothiophen-4-yl)piperazine-1-yl)ethyl)-2-oxo-3,4-dihydroquinoline-1(2H)-yl)methyloctyl carbonate, [ka] (27)(7-(2-(4-(6-fluorobenzothiophen-4-yl)piperazine-1-yl)ethyl)-2-oxo-3,4-dihydroquinoline-1(2H)-yl)methylnonyl carbonate, [ka] (28)(7-(2-(4-(6-fluorobenzothiophen-4-yl)piperazine-1-yl)ethyl)-2-oxo-3,4-dihydroquinoline-1(2H)-yl)methyldecyl carbonate, [ka] (29)(7-(2-(4-(6-fluorobenzothiophen-4-yl)piperazine-1-yl)ethyl)-2-oxo-3,4-dihydroquinoline-1(2H)-yl)methyldodecyl carbonate, [ka] (30)(7-(2-(4-(6-fluorobenzothiophen-4-yl)piperazine-1-yl)ethyl)-2-oxo-3,4-dihydroquinoline-1(2H)-yl)methyltetradecyl carbonate, [ka] (31)(7-(2-(4-(6-fluorobenzothiophen-4-yl)piperazine-1-yl)ethyl)-2-oxo-3,4-dihydroquinoline-1(2H)-yl)methylhexadecyl carbonate, [ka] (32)(7-(2-(4-(6-fluorobenzothiophen-4-yl)piperazine-1-yl)ethyl)-2-oxo-3,4-dihydroquinoline-1(2H)-yl)methylphenyl carbonate, [ka] (33)(7-(2-(4-(6-fluorobenzothiophen-4-yl)piperazine-1-yl)ethyl)-2-oxoquinoline-1(2H)-yl)methylphenyl carbonate, [ka] (34)(7-(2-(4-(6-fluorobenzothiophen-4-yl)piperazine-1-yl)ethyl)-2-oxo-3,4-dihydroquinoline-1(2H)-yl)methylbenzyl carbonate, [ka] (35)(7-(2-(4-(6-fluorobenzothiophen-4-yl)piperazine-1-yl)ethyl)-2-oxo-3,4-dihydroquinoline-1(2H)-yl)methyl(2,2,2-trifluoroethyl)carbonate, [ka] (36)(7-(2-(4-(6-fluorobenzothiophen-4-yl)piperazine-1-yl)ethyl)-2-oxo-3,4-dihydroquinoline-1(2H)-yl)methylcyclohexyl carbonate, [ka] (37)(4-fluoro-7-(2-(4-(6-fluorobenzothiophen-4-yl)piperazine-1-yl)ethyl)-2-oxoquinoline-1(2H)-yl)methyl hexanoate, [ka] (38)(4-fluoro-7-(2-(4-(6-fluorobenzothiophen-4-yl)piperazine-1-yl)ethyl)-2-oxoquinoline-1(2H)-yl)dodecanoate methyl, [ka] (39)(4-chloro-7-(2-(4-(6-fluorobenzothiophen-4-yl)piperazine-1-yl)ethyl)-2-oxoquinoline-1(2H)-yl)methyl hexanoate, [ka] (40)(4-amino-7-(2-(4-(6-fluorobenzothiophen-4-yl)piperazine-1-yl)ethyl)-2-oxoquinoline-1(2H)-yl)methyl hexanoate, [ka] (41)(4-acetamido-7-(2-(4-(6-fluorobenzothiophen-4-yl)piperazine-1-yl)ethyl)-2-oxoquinoline-1(2H)-yl)methyl hexanoate, [ka] (42)(7-(2-(4-(6-fluorobenzothiophen-4-yl)piperazine-1-yl)ethyl)-4,4-dimethyl-2-oxo-3,4-dihydroquinoline-1(2H)-yl)methyl hexanoate, [ka] (43)(7-(2-(4-(6-fluorobenzothiophen-4-yl)piperazine-1-yl)ethyl)-4,4-dimethyl-2-oxo-3,4-dihydroquinoline-1(2H)-yl)dodecanoate methyl, [ka] (44)(7-(2-(4-(6-fluorobenzothiophen-4-yl)piperazine-1-yl)ethyl)-4-methyl-2-oxoquinoline-1(2H)-yl)methyl hexanoate, [ka] (45)(7-(2-(4-(6-fluorobenzothiophen-4-yl)piperazine-1-yl)ethyl)-3-methyl-2-oxoquinoline-1(2H)-yl)methyl hexanoate, [ka] (46)(3-ethyl-7-(2-(4-(6-fluorobenzothiophen-4-yl)piperazine-1-yl)ethyl)-2-oxoquinoline-1(2H)-yl)methyl hexanoate, [ka] (47)(7-(2-(4-(6-fluorobenzothiophen-4-yl)piperazine-1-yl)ethyl)-3-hydroxy-2-oxoquinoline-1(2H)-yl)methyl hexanoate, [ka] (48)(7-(2-(4-(6-fluorobenzothiophen-4-yl)piperazine-1-yl)ethyl)-4-hydroxy-2-oxoquinoline-1(2H)-yl)methyl hexanoate, [ka] (49)(7-(2-(4-(6-fluorobenzothiophen-4-yl)piperazine-1-yl)ethyl)-4-hydroxy-2-oxoquinoline-1(2H)-yl)dodecanoate methyl, [ka] (50)7-(2-(4-(6-fluorobenzothiophen-4-yl)piperazine-1-yl)ethyl)-2-oxoquinoline-1(2H)-yl-4-deuterium)methyl hexanoate, [ka] (51)(7-(2-(4-(6-fluorobenzothiophen-4-yl)piperazine-1-yl)ethyl)-2-oxoquinoline-1(2H)-yl-4-deuterium)dodecanoate methyl, [ka] (52)7-(2-(4-(6-fluorobenzothiophen-4-yl)piperazine-1-yl)ethyl)-1-(isopropoxymethyl)-3,4-dihydroquinoline-2(1H)-one, [ka] (53)7-(2-(4-(6-fluorobenzothiophen-4-yl)piperazine-1-yl)ethyl)-1-(isopropoxymethyl)quinoline-2(1H)-one, [ka] (54)7-(2-(4-(6-fluorobenzothiophen-4-yl)piperazine-1-yl)ethyl)-1-((2,2,2-trifluoroethoxy)methyl)-3,4-dihydroquinoline-2(1H)-one, [ka] (55)1-((benzyloxy)methyl)-7-(2-(4-(6-fluorobenzothiophen-4-yl)piperazine-1-yl)ethyl)-3,4-dihydroquinoline-2(1H)-one, [ka] (56)1-((benzyloxy)methoxy)methyl)-7-(2-(4-(6-fluorobenzothiophen-4-yl)piperazine-1-yl)ethyl)-3,4-dihydroquinoline-2(1H)-one, [ka] (57)(7-(2-(4-(6-fluorobenzothiophen-4-yl)piperazine-1-yl)ethyl)-2-oxo-3,4-dihydroquinoline-1(2H)-yl)methyl propionate, [ka] (58)(7-(2-(4-(6-fluorobenzothiophen-4-yl)piperazine-1-yl)ethyl)-2-oxo-3,4-dihydroquinoline-1(2H)-yl)methyl butyrate, [ka] (59)(7-(2-(4-(6-fluorobenzothiophen-4-yl)piperazine-1-yl)ethyl)-2-oxo-3,4-dihydroquinoline-1(2H)-yl)-2-methyl methoxyacetate, [ka] (60)(7-(2-(4-(6-fluorobenzothiophen-4-yl)piperazine-1-yl)ethyl)-2-oxo-3,4-dihydroquinoline-1(2H)-yl)heptanoate methyl, [ka] (61)(7-(2-(4-(6-fluorobenzothiophen-4-yl)piperazine-1-yl)ethyl)-2-oxo-3,4-dihydroquinoline-1(2H)-yl)methyl octyl, [ka] (62)(7-(2-(4-(6-fluorobenzothiophen-4-yl)piperazine-1-yl)ethyl)-2-oxo-3,4-dihydroquinoline-1(2H)-yl)nonanoate methyl, [ka] (63)(7-(2-(4-(6-fluorobenzothiophen-4-yl)piperazine-1-yl)ethyl)-2-oxo-3,4-dihydroquinoline-1(2H)-yl)undecanoate methyl, [ka] (64)(7-(2-(4-(6-fluorobenzothiophen-4-yl)piperazine-1-yl)ethyl)-2-oxo-3,4-dihydroquinoline-1(2H)-yl)tridecanoate methyl, [ka] (65)(7-(2-(4-(6-fluorobenzothiophen-4-yl)piperazine-1-yl)ethyl)-2-oxo-3,4-dihydroquinoline-1(2H)-yl)tetradecanoate methyl, [ka] (66)(7-(2-(4-(6-fluorobenzothiophen-4-yl)piperazine-1-yl)ethyl)-2-oxo-3,4-dihydroquinoline-1(2H)-yl)methyl pentadecanoate, [ka] (67)(7-(2-(4-(6-fluorobenzothiophen-4-yl)piperazine-1-yl)ethyl)-2-oxo-3,4-dihydroquinoline-1(2H)-yl)heptadecanate methyl, [ka] (68)(7-(2-(4-(6-fluorobenzothiophen-4-yl)piperazine-1-yl)ethyl)-2-oxo-3,4-dihydroquinoline-1(2H)-yl)methyl stearate, [ka] (69)(7-(2-(4-(6-fluorobenzothiophen-4-yl)piperazine-1-yl)ethyl)-2-oxo-3,4-dihydroquinoline-1(2H)-yl)eicosanoate methyl, [ka] (70)(7-(2-(4-(6-fluorobenzothiophen-4-yl)piperazine-1-yl)ethyl)-2-oxo-3,4-dihydroquinoline-1(2H)-yl)methylallylcarbamate, [ka] (71)(7-(2-(4-(6-fluorobenzothiophen-4-yl)piperazine-1-yl)ethyl)-2-oxo-3,4-dihydroquinoline-1(2H)-yl)methyldecylcarbamate, [ka] (72)(7-(2-(4-(6-fluorobenzothiophen-4-yl)piperazine-1-yl)ethyl)-2-oxo-3,4-dihydroquinoline-1(2H)-yl)undecenoic acid methyl, [ka] (73)(7-(2-(4-(6-fluorobenzothiophen-4-yl)piperazine-1-yl)ethyl)-2-oxo-3,4-dihydroquinoline-1(2H)-yl)methyl oleate, [ka] (74)(7-(2-(4-(6-fluorobenzothiophen-4-yl)piperazine-1-yl)ethyl)-2-oxo-3,4-dihydroquinoline-1(2H)-yl)docosanoate methyl, [ka] (75)(7-(2-(4-(6-fluorobenzothiophen-4-yl)piperazine-1-yl)ethyl)-2-oxo-3,4-dihydroquinoline-1(2H)-yl)tetracosanoate methyl, [ka] (76)(7-(2-(4-(6-fluorobenzothiophen-4-yl)piperazine-1-yl)ethyl)-2-oxo-3,4-dihydroquinoline-1(2H)-yl)heptadecanate methyl, [ka] (77)(7-(2-(4-(6-fluorobenzothiophen-4-yl)piperazine-1-yl)ethyl)-2-oxoquinoline-1(2H)-yl)methyl oleate, [ka] (78)(7-(2-(4-(6-fluorobenzothiophen-4-yl)piperazine-1-yl)ethyl)-2-oxo-3,4-dihydroquinoline-1(2H)-yl)methylcyclobutanecarboxylate, [ka] (79)(7-(2-(4-(6-fluorobenzothiophen-4-yl)piperazine-1-yl)ethyl)-2-oxo-3,4-dihydroquinoline-1(2H)-yl)methylcyclopentanecarboxylate, [ka] (80)(7-(2-(4-(6-fluorobenzothiophen-4-yl)piperazine-1-yl)ethyl)-2-oxo-3,4-dihydroquinoline-1(2H)-yl)cyclohexanecarboxylate, [ka] (81)(7-(2-(4-(6-fluorobenzothiophen-4-yl)piperazine-1-yl)ethyl)-2-oxo-3,4-dihydroquinoline-1(2H)-yl)methylpiperidine-1-carboxylate, [ka] (82)(7-(2-(4-(6-fluorobenzothiophen-4-yl)piperazine-1-yl)ethyl)-2-oxo-3,4-dihydroquinoline-1(2H)-yl)cycloheptanecarboxylate, [ka] (83)(7-(2-(4-(6-fluorobenzothiophen-4-yl)piperazine-1-yl)ethyl)-2-oxo-3,4-dihydroquinoline-1(2H)-yl)methylcyclohexylcarbamate, [ka] (84)(7-(2-(4-(6-fluorobenzothiophen-4-yl)piperazine-1-yl)ethyl)-2-oxo-3,4-dihydroquinoline-1(2H)-yl)methyl(3,3,3-trifluoropropyl)carbamate, [ka] (85)(7-(2-(4-(6-fluorobenzothiophen-4-yl)piperazine-1-yl)ethyl)-2-oxo-3,4-dihydroquinoline-1(2H)-yl)methyl(cyclohexylmethyl)carbamate, [ka] (86)7-(2-(4-(6-fluorobenzothiophen-4-yl)piperazine-1-yl)ethyl)-2-oxo-3,4-dihydroquinoline-1(2H)-yl)furan-2-formate methyl, [ka] (87)(7-(2-(4-(6-fluorobenzothiophen-4-yl)piperazine-1-yl)ethyl)-2-oxo-3,4-dihydroquinoline-1(2H)-yl)furan-3-formate methyl, [ka] (88)(7-(2-(4-(6-fluorobenzothiophen-4-yl)piperazine-1-yl)ethyl)-2-oxoquinoline-1(2H)-yl)furan-2-formate methyl, [ka] (89)(7-(2-(4-(6-fluorobenzothiophen-4-yl)piperazine-1-yl)ethyl)-2-oxo-3,4-dihydroquinoline-1(2H)-yl)thiophen-2-formate methyl, [ka] (90)(7-(2-(4-(6-fluorobenzothiophen-4-yl)piperazine-1-yl)ethyl)-2-oxo-3,4-dihydroquinoline-1(2H)-yl)methyltetrahydro-2H-pyran-4-carboxylic acid ester, [ka] (91)(7-(2-(4-(6-fluorobenzothiophen-4-yl)piperazine-1-yl)ethyl)-2-oxo-3,4-dihydroquinoline-1(2H)-yl)methyl picolinate, [ka] (92)(7-(2-(4-(6-fluorobenzothiophen-4-yl)piperazine-1-yl)ethyl)-2-oxo-3,4-dihydroquinoline-1(2H)-yl)methyl nicotinate, [ka] (93)(7-(2-(4-(6-fluorobenzothiophen-4-yl)piperazine-1-yl)ethyl)-2-oxo-3,4-dihydroquinoline-1(2H)-yl)methylpyrimidine-5-carboxylic acid ester, [ka] (94)(7-(2-(4-(6-fluorobenzothiophen-4-yl)piperazine-1-yl)ethyl)-2-oxo-3,4-dihydroquinoline-1(2H)-yl)methylquinoline-6-carboxylate, [ka] (95)(7-(2-(4-(6-fluorobenzothiophen-4-yl)piperazine-1-yl)ethyl)-2-oxo-3,4-dihydroquinoline-1(2H)-yl)methyl benzoate, [ka] (96)(7-(2-(4-(6-fluorobenzothiophen-4-yl)piperazine-1-yl)ethyl)-2-oxo-3,4-dihydroquinoline-1(2H)-yl)-2-phenylmethyl acetate, [ka] (97)(7-(2-(4-(6-fluorobenzothiophen-4-yl)piperazine-1-yl)ethyl)-2-oxo-3,4-dihydroquinoline-1(2H)-yl)4,4,4-trifluorobutyrate ethyl, [ka] (98)(7-(2-(4-(6-fluorobenzothiophen-4-yl)piperazine-1-yl)ethyl)-2-oxo-3,4-dihydroquinoline-1(2H)-yl)methylbenzylcarbamate, [ka] (99)(7-(2-(4-(6-fluorobenzothiophen-4-yl)piperazine-1-yl)ethyl)-2-oxo-3,4-dihydroquinoline-1(2H)-yl)methyl(2-hydroxyethyl)carbamate, [ka] (100)(7-(2-(4-(6-fluorobenzothiophen-4-yl)piperazine-1-yl)ethyl)-2-oxo-3,4-dihydroquinoline-1(2H)-yl)methylheptylcarbamate, [ka] (101)(7-(2-(4-(6-fluorobenzothiophen-4-yl)piperazine-1-yl)ethyl)-2-oxo-3,4-dihydroquinoline-1(2H)-yl)-2-(2-methoxyethoxy)methyl acetate, [ka] (102)(7-(2-(4-(6-fluorobenzothiophen-4-yl)piperazine-1-yl)ethyl)-2-oxo-3,4-dihydroquinoline-1(2H)-yl)-2-(2-(2-methoxyethoxy)ethoxyacetate methyl, [ka] (103)(7-(2-(4-(6-fluorobenzothiophen-4-yl)piperazine-1-yl)ethyl)-2-oxo-3,4-dihydroquinoline-1(2H)-yl)-2-(2-butoxyethoxy)methyl acetate, [ka] (104)((7-(2-(4-(6-fluorobenzothiophen-4-yl)piperazine-1-yl)ethyl)-2-oxo-3,4-dihydroquinoline-1(2H)-yl)methyl) tert-butyl malonate, [ka] (105)(7-(2-(4-(6-fluorobenzothiophen-4-yl)piperazine-1-yl)ethyl)-2-oxo-3,4-dihydroquinoline-1(2H)-yl)-2-methylbutyrate methyl, [ka] (106)(7-(2-(4-(6-fluorobenzothiophen-4-yl)piperazine-1-yl)ethyl)-2-oxo-3,4-dihydroquinoline-1(2H)-yl)-4-methylpentanoate methyl, [ka] (107)(7-(2-(4-(6-fluorobenzothiophen-4-yl)piperazine-1-yl)ethyl)-2-oxo-3,4-dihydroquinoline-1(2H)-yl)-2-methylpentanoate, [ka] (108)(7-(2-(4-(6-fluorobenzothiophen-4-yl)piperazine-1-yl)ethyl)-2-oxo-3,4-dihydroquinoline-1(2H)-yl)2,2-methyl dimethylhexanoate, [ka] (109)(7-(2-(4-(6-fluorobenzothiophen-4-yl)piperazine-1-yl)ethyl)-2-oxo-3,4-dihydroquinoline-1(2H)-yl)-2-methylhexanoate, [ka] (110)(7-(2-(4-(6-fluorobenzothiophen-4-yl)piperazine-1-yl)ethyl)-2-oxo-3,4-dihydroquinoline-1(2H)-yl)-2-methylheptanoate, [ka] (111)(7-(2-(4-(6-fluorobenzothiophen-4-yl)piperazine-1-yl)ethyl)-2-oxoquinoline-1(2H)-yl) pivalate methyl, [ka] (112)(7-(2-(4-(6-fluorobenzothiophen-4-yl)piperazine-1-yl)ethyl)-2-oxo-3,4-dihydroquinoline-1(2H)-yl)-2-methyl pentylheptanoate, [ka] (113)(7-(2-(4-(6-fluorophenylthiophen-4-yl)piperazine-1-yl)ethyl)-2-oxoquinoline-1(2H)-yl)-2-pentylheptanoate methyl, [ka] (114)(7-(2-(4-(6-fluorobenzothiophen-4-yl)piperazine-1-yl)ethyl)-2-oxo-3,4-dihydroquinoline-1(2H)-yl)methyl glycinate, [ka] (115) 1-Benzoyl-7-(2-(4-(6-fluorobenzothiophen-4-yl)piperazine-1-yl)ethyl)-3,4-dihydroquinoline-2(1H)-one, [ka] (116)7-(2-(4-(6-fluorobenzothiophen-4-yl)piperazine-1-yl)ethyl)-1-(2-phenylacetyl)-3,4-dihydroquinoline-2(1H)-one, [ka] (117)7-(2-(4-(6-fluorobenzothiophen-4-yl)piperazine-1-yl)ethyl)-2-oxo-3,4-dihydroquinoline-1(2H)-phenylcarboxylic acid ester, [ka] (118)7-(2-(4-(6-fluorobenzothiophen-4-yl)piperazine-1-yl)ethyl)-2-oxo-3,4-dihydroquinoline-1(2H)-carboxylate benzyl, [ka] (119)1-(cyclopentanecarbonyl)-7-(2-(4-(6-fluorobenzothiophen-4-yl)piperazine-1-yl)ethyl)-3,4-dihydroquinoline-2(1H)-one, [ka] (120)7-(2-(4-(6-fluorobenzothiophen-4-yl)piperazine-1-yl)ethyl)-1-(2-hydroxyacetyl)-3,4-dihydroquinoline-2(1H)-one, [ka] (121)7-(2-(4-(6-fluorobenzothiophen-4-yl)piperazine-1-yl)ethyl)-1-glycine-3,4-dihydroquinoline-2(1H)-one, [ka] (122)7-(2-(4-(6-fluorobenzothiophen-4-yl)piperazine-1-yl)ethyl)-N-(2-hydroxyethyl)-2-oxo-3,4-dihydroquinoline-1(2H)-carboxamide, [ka] (123)7-(2-(4-(6-fluorobenzothiophen-4-yl)piperazine-1-yl)ethyl)-2-oxo-N-propyl-3,4-dihydroquinoline-1(2H)-carboxamide, [ka] (124)7-(2-(4-(6-fluorobenzothiophen-4-yl)piperazine-1-yl)ethyl)-1-(2-(2-methoxyethoxy)acetyl)-3,4-dihydroquinoline-2(1H)-one, [ka] (125)7-(2-(4-(6-fluorobenzothiophen-4-yl)piperazine-1-yl)ethyl)-1-(2-(2-methoxyethoxy)acetyl)quinoline-2(1H)-one, [ka] (126)7-(2-(4-(6-fluorobenzo[b]thiophen-4-yl)piperazine-1-yl)ethyl)-1-(2-(2-(2-methoxyethoxy)ethoxyethyl)acetyl)-3,4-dihydroquinoline-2(1H)-one, [ka] (127) N-benzyl-7-(2-(4-(6-fluorobenzothiophen-4-yl)piperazine-1-yl)ethyl)-2-oxo-3,4-dihydroquinoline-1(2H)-carboxamide, [ka] (128)7-(2-(4-(6-fluorobenzothiophen-4-yl)piperazine-1-yl)ethyl)-1-(morpholine-4-carbonyl)-3,4-dihydroquinoline-2(1H)-one, [ka] (129)1-(cyclohexanecarbonyl)-7-(2-(4-(6-fluorobenzothiophen-4-yl)piperazine-1-yl)ethyl)-3,4-dihydroquinoline-2(1H)-one, [ka] (130)7-(2-(4-(6-fluorobenzothiophen-4-yl)piperazine-1-yl)ethyl)-1-(2-methoxyacetyl)-3,4-dihydroquinoline-2(1H)-one, [ka] (131)7-(2-(4-(6-fluorobenzothiophen-4-yl)piperazine-1-yl)ethyl)-2-oxo-3,4-dihydroquinoline-1(2H)-carboxylic acid-2-methoxyethyl ester, [ka] (132) 7-(2-(4-(6-Fluorobenzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)-1-(undec-10-enoyl)-3,4-dihydroquinolin-2(1H)-one, [Chemical formula] (133) Methyl (decanoyloxy)7-(2-(4-(6-fluorobenzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)-2-oxo-3,4-dihydroquinoline-1(2H)-carboxylate, [Chemical formula] (134) Methyl (7-(2-(4-(6-fluorobenzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)-2-oxoquinolin-1(2H)-yl)dodecanoate, [Chemical formula]

[0021] In a third aspect, the present invention provides a method for producing the above N-substituted quinolinone compound, or a pharmaceutically acceptable salt, solvate, stereoisomer, geometric isomer, isotope-labeled substance or prodrug thereof, and the above production method is any one of Methods 1 to 4.

[0022] Method 1: The compound represented by formula (II) or a salt thereof and the compound represented by formula (III) or a salt thereof are subjected to an N-alkylation reaction, [Chemical formula] Among them, [Chemical formula] , R1, R6, R7, R8 and R9 are the same as defined above, X represents a leaving group and is a halogen, a C1-C6 alkylsulfonyloxy group, a benzenesulfonyloxy group, or a naphthalenesulfonyloxy group, and the above C1-C6 alkylsulfonyloxy group, benzenesulfonyloxy group, or naphthalenesulfonyloxy group is optionally substituted with one or more groups selected from halogen, C1-C6 alkyl, C1-C6 alkoxy group, nitro group, hydroxy group, amino group, and C1-C6 alkanoyl group, preferably X is a halogen, a C1-C4 alkylsulfonyloxy group, a benzenesulfonyloxy group, or a naphthalenesulfonyloxy group, and the above C1-C4 alkylsulfonyloxy group, benzenes The sulfonyloxy group or naphthalenesulfonyloxy group is optionally substituted with one or more groups selected from halogens, C1-C4 alkyl groups, C1-C4 alkoxy groups, nitro groups, hydroxyl groups, amino groups, and C1-C4 alkanoyl groups, more preferably X is chlorine, bromine, methanesulfonyloxy group, trifluoromethanesulfonyloxy group, benzenesulfonyloxy group, naphthalenesulfonyloxy group, methylbenzenesulfonyloxy group, nitrobenzenesulfonyloxy group, aminobenzenesulfonyloxy group, chlorobenzenesulfonyloxy group, bromobenzenesulfonyloxy group, or methoxybenzenesulfonyloxy group.

[0023] The above reaction is carried out in the presence or absence of a solvent, preferably in a solvent in the presence or absence of a base.

[0024] The above solvents include water, dioxane, tetrahydrofuran, diethyl ether, methyl tert-butyl ether, diisopropyl ether, diethylene glycol dimethyl ether, ethylene glycol dimethyl ether, and other ethers; aromatic hydrocarbons such as benzene, toluene, xylene, nitrobenzene, and chlorobenzene; alcohols such as methanol, ethanol, isopropanol, butanol, tert-butanol, and ethylene glycol; ketones such as acetone, methyl ethyl ketone, and 4-methyl-2-pentanone; amides such as N,N-dimethylformamide, N,N-dimethylacetamide, and 1-methyl-2-pyrrolidone; halogenated hydrocarbons such as chloroform, dichloromethane, dichloroethane, and carbon tetrachloride; esters such as ethyl acetate, ethyl formate, methyl acetate, and isopropyl acetate; and other solvents such as dimethyl sulfoxide and acetonitrile, or mixtures of the above solvents.

[0025] The above bases are selected from inorganic or organic bases. Inorganic bases include alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, cesium hydroxide, and lithium hydroxide; alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate, and lithium carbonate; alkali metal bicarbonates such as sodium bicarbonate, potassium bicarbonate, and lithium bicarbonate; alkali metals such as potassium and sodium; sodium amides, potassium amides, sodium hydride, potassium hydride, and others. Organic bases include sodium methoxide, sodium ethoxide, and potassium methoxide. This includes potassium ethoxide, sodium acetate, triethylamine, pyridine, diisopropylamine, diisopropylethylamine, tripropylamine, diethylamine, pyrimidine, quinoline, piperidine, piperazine, imidazole, dimethylaminopyridine, trimethylamine, N-ethyldiisopropylamine, N-methylmorpholine, dimethylaniline, 1,8-diazabicyclo[5.4.0]undeca-7-ene (DBU), 1,5-diazabicyclo[4.3.0]nona-5-ene (DBN), and 1,4-diazabicyclo[2.2.2]octane (DABCO). These bases may be used individually, or in combination of two or more types.

[0026] Preferably, the above reaction is carried out in the presence of an alkali metal iodide containing potassium iodide and sodium iodide as a reaction accelerator.

[0027] Preferably, the reaction temperature is from room temperature to 200°C, preferably from room temperature to 150°C, and the reaction time is 1 to 120 hours, preferably 5 to 80 hours.

[0028] Method 2: A compound represented by formula (IV) or a salt thereof is subjected to a coupling reaction with a compound represented by formula (V) or a salt thereof. [ka] Eventually, [ka] R1, R6, R7, R8 and R9 are the same as defined above. X1 is a halogen or a trifluoromethanesulfonyloxy group, preferably bromine, iodine, chlorine, or a trifluoromethanesulfonyloxy group. Preferably, the coupling reaction is carried out in the presence of a palladium catalyst and a base.

[0029] The above palladium catalysts include palladium acetate (Pd(OAc)2), bis(triphenylphosphine)palladium(II) dichloride ((Ph3P)2PdCl2), bis(benzonitrile)palladium(II) chloride ((PhCN)2PdCl2), tetrakis(triphenylphosphine)palladium (Pd(PPh3)4), bis(triphenylphosphinepalladium) acetate ((Ph3P)2Pd(OAc)2), and [1,2-bis(diphenylphosphine)ethane]dichloropalladium(II) (PdCl2(dppe)2). ), bis[1,2-bis(diphenylphosphino)ethane]palladium(0)(Pd(dppe)2), bis(dibenzylideneacetone)palladium(0)(Pd(dba)2), tris(dibenzylideneacetone)dipalladium(0)(Pd2(dba)3), dichloro[1,3-bis(diphenylphosphino)propane]palladium(II)(PdCl2(dippp)), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)(Pd(dppf)Cl2) are one or more of the above.

[0030] The above bases are one or more of the following: sodium bis(trimethylsilyl)amide, potassium tert-butoxide, sodium tert-butoxide, cesium carbonate, potassium phosphate, sodium phosphate, sodium methoxide, sodium ethoxide, potassium hydroxide, sodium hydroxide, potassium fluoride, sodium fluoride, tetrabutylammonium fluoride (TBAF), sodium acetate, potassium acetate, cesium carbonate, potassium carbonate, and sodium carbonate.

[0031] The reaction solvent for the above reaction is not particularly limited as long as it does not inhibit the reaction, and includes water, ethers such as dioxane and tetrahydrofuran, aromatic hydrocarbons such as toluene and xylene, alcohols such as tert-butanol, ketones such as acetone, amides such as N,N-dimethylformamide, dimethyl sulfoxide, acetonitrile, etc., or mixtures of the above solvents.

[0032] Preferably, the above reaction is carried out in the presence of a ligand, and the above ligand is, as a reaction accelerator, one or more of 2,2'-diphenylphosphino-1,1'-binaphthyl (BINAP), tri-tert-butylphosphine (P(t-Bu)3), 1,1'-di-(diphenylphosphino)ferrocene (dppf), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (x-phos), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos), tri-tert-butylphosphine tetrafluoroborate, and tris(2-methylphenyl)phosphine (P(o-tolyl)3).

[0033] Preferably, the above reaction temperature is from room temperature to 200 °C, preferably from room temperature to 150 °C, the reaction time is 1 to 30 hours, preferably 5 to 20 hours.

[0034] Method 3: A substitution reaction is carried out between the compound represented by formula (I-a) or a salt thereof and the compound represented by R1X,

Chemical formula

Chemical formula

[0035] Method 4: A compound represented by formula (Ib) or a salt thereof is subjected to a substitution reaction with a compound represented by XC(=O)-R2, XOC(=O)-O-R3, or X-R4. [ka] Of these, R1 is -Y1-OC(=O)-R2, -Y1-OC(=O)-O-R3, or -Y1-O-R4. [ka] R6, R7, R8, R9, Y1, R2, R3 and R4 are the same as defined above. X is a halogen, preferably bromine, iodine, or chlorine. The reaction conditions in Method 4 are the same as those in Method 1.

[0036] Each target compound obtained in each reaction is separated and purified from the reaction mixture by cooling the reaction mixture, separating the crude product by methods such as filtration, extraction, or concentration, and then purifying it by conventional methods such as column chromatography, slurrying, or recrystallization.

[0037] In a fourth aspect, the present invention provides a drug composition comprising the above-mentioned N-substituted quinolinone compound, or a pharmaceutically acceptable salt, solvate, stereoisomer, geometric isomer, isotope-labeled product, or prodrug thereof, and at least one pharmaceutically acceptable vector.

[0038] In a fifth aspect, the present invention provides a method for producing a drug composition comprising the step of mixing the above-mentioned N-substituted quinolinone compound, or a pharmaceutically acceptable salt, solvate, stereoisomer, geometric isomer, isotope-labeled product, or prodrug thereof, with a pharmaceutically acceptable vector.

[0039] The drug composition of the present invention can be selected in multiple pharmaceutical formulation forms depending on the therapeutic purpose, and includes, but is not limited to, tablets, pills, capsules, granules, suspensions, solutions, creams, ointments, powders, suppositories, aerosols, and injections (e.g., lipid-soluble or oil-soluble injections).

[0040] In a sixth aspect, the present invention provides the use of the above-mentioned N-substituted quinolinone compounds, or pharmaceutically acceptable salts, solvates, stereoisomers, geometric isomers, isotope-labeled compounds or prodrugs thereof, or drug compositions, in the manufacture of drugs for preventing and / or treating central nervous system diseases, conditions or disorders.

[0041] In a seventh aspect, the present invention provides a method for treating and / or preventing a disease, condition, or disorder of the central nervous system, comprising administering to a human or animal an effective amount of the above-mentioned N-substituted quinolinone compound, or a pharmaceutically acceptable salt, solvate, stereoisomer, geometric isomer, isotope-labeled product, or prodrug thereof, or the above-mentioned drug composition.

[0042] In the eighth aspect, the N-substituted quinolinone compound provided by the present invention, or a pharmaceutically acceptable salt, solvate, stereoisomer, geometric isomer, isotope-labeled product or prodrug thereof, or the drug composition thereof, is 5-HT 1A Receptor agonist / 5-HT 2A It can be used as a receptor antagonist / D2 receptor antagonist / D3 receptor agonist / 5-HT transporter inhibitor.

[0043] The above-mentioned central nervous system disorders, conditions, or disabilities are selected from schizophrenia (preferably, uncontrollable, difficult to manage, or chronic schizophrenia), affective disorders, psychiatric disorders, mood disorders, bipolar I disorder, bipolar II disorder, depression (preferably endogenous, severe, or uncontrollable depression), dysthymic disorder, cyclothymic disorder, panic attacks, panic disorder, social anxiety disorder, obsessive-compulsive disorder, impulsivity disorder, post-traumatic stress disorder, anxiety disorders, acute stress disorder, hysteria, anorexia nervosa, sleep disorders, adjustment disorders, cognitive impairment, autism, neurotic headache, mania, Parkinson's disease, Huntington's disease, Alzheimer's disease, dementia, memory impairment, hyperactivity disorder, attention deficit / hyperactivity disorder, and tic disorders. [Effects of the Invention]

[0044] To address the problem of low solubility of compounds in oily media in the prior art, the inventors conducted various studies and discovered that the lipophilicity of quinolinone can be significantly improved by introducing substituents at specific positions on the compound. Based on this finding, the present invention was completed. The beneficial effects of the present invention are as follows:

[0045] 1) Excellent oil solubility The compounds of the present invention exhibit remarkably excellent solubility in oils (such as sesame oil and benzyl benzoate) and can be applied to oily injectable preparations. Oily injectable solutions offer advantages over aqueous suspensions in terms of sustained blood concentration (diffusion control at the administration site by oily groups), reduced preparation time for the drug solution (no mixing or agitation required), ensured sterilization by filtration (oily groups are filterable), avoidance of physical irritation at the administration site (stability of oily groups), and improved accuracy of syringe filling (containers filled with oily groups).

[0046] 2) Multitarget action: High therapeutic effect with few side effects. The compound of the present invention or its in vivo metabolite is 5-HT 2A Receptors, dopamine D 2 / 3 Receptor, 5-HT 1A It has multi-target activity against receptors and 5-HT transporters, specifically, 5-HT2A It has antagonistic effects on the receptor, D2 receptor and 5-HT transporter, and has a partial agonist effect on the D3 receptor and 5-HT 1A receptor, and the IC 50 or EC 50 reaches the level of 0.1 - 10 nM, and the antagonistic / agonist effect is remarkable.

[0047] The characteristics of this multi-target effect can regulate the DA / 5-HT system, help regulate the balance of neurotransmitters in the brain, and have a good therapeutic effect on various central nervous system diseases. At the same time, the characteristics of this multi-target effect can reduce or avoid side effects caused by single D2 receptor antagonists or D2 / 5-HT 2A receptor antagonists, such as side effects like extrapyramidal symptoms (EPS), hyperprolactinemia, etc.

[0048] The compounds of the present invention have multi-target effects and are superior in drug discovery potential to the compounds in Patent WO2015131856, and can be used for the treatment of various central nervous system diseases, especially diseases such as depression, major depressive disorder (MDD), bipolar disorder, schizophrenia, negative symptoms of schizophrenia, anxiety disorder, phobia, autism, Alzheimer's disease, bipolar disorder, cognitive impairment, Parkinson's disease, hysteria, obsessive-compulsive disorder, attention deficit hyperactivity disorder, etc.

[0049] The compounds of the present invention or their in vivo metabolites have a good inhibitory effect on the 5-HT transporter and can improve co-morbidities such as anxiety and depression in schizophrenia and other central nervous system diseases.

[0050] The compounds of the present invention or their in vivo metabolites have a good regulatory effect on the 5-HT 1A receptor, can improve the negative symptoms and cognitive deficits of schizophrenia, and do not cause central or peripheral side effects by completely agonizing the 5-HT 1A receptor.

[0051] 3) Better safety and tolerance The compound of the present invention has a lower hERG inhibitory effect than the compound in patent WO2015131856, and is expected to have a higher clinical safety.

[0052] The compounds of the present invention can gradually release active metabolites in vivo, resulting in minimal fluctuations in blood concentration and improving drug safety and tolerance. The compounds of the present invention can be converted into multi-target active metabolites in the bloodstream and are excellent in maintaining blood concentrations of the active metabolites with desired therapeutic effects over a long period. Therefore, the compounds of the present invention exhibit excellent metabolic stability and sustained blood concentration, making them more suitable for the manufacture of long-acting formulations.

[0053] The compound of the present invention is effective orally and may be manufactured as an oral formulation or as an oily injection formulation. It exhibits a long-lasting effect, has a low effective dose, and has low toxicity and side effects, thereby improving patient medication compliance.

[0054] 4) Easily crystallizes and has excellent stability. The compounds of the present invention are easily crystallized, easy to handle, and have excellent chemical stability.

[0055] 5) High efficacy when administered in combination The compounds of the present invention, when administered in combination with at least one clinically used drug selected from (1) mood stabilizers, (2) serotonin reuptake inhibitors, (3) norepinephrine reuptake inhibitors, (4) serotonin and norepinephrine reuptake inhibitors, and (5) antidepressants, can exert effects that cannot be achieved with conventional treatment, such as reduced dosage, improved side effects, and enhanced therapeutic effects.

[0056] In short, the compounds of the present invention have advantages over conventional antipsychotics, including superior oil solubility, multi-target activity, lower effective dose, less toxicity and side effects, higher safety and tolerance, and thus have high overall drug potential and a good prospect for clinical application. [Brief explanation of the drawing]

[0057] [Figure 1] This graph shows the time-active metabolite concentration after intramuscular injection of compounds 3, 5, and 7 into SD rats. [Figure 2] This graph shows the time-active metabolite concentration after intramuscular injection of compounds 2, 6, and 8 into SD rats. [Modes for carrying out the invention]

[0058] The definitions of each group in this invention are as follows: Halogen means fluorine, chlorine, bromine, and iodine, preferably fluorine, chlorine, or bromine, more preferably fluorine or chlorine. In this invention, Cn~Cm indicates that it contains n~m carbon atoms, and the following carbon number examples are given.

[0059] Alkyl groups refer to linear or branched saturated hydrocarbon groups, and C1-C30 alkyl groups refer to linear or branched saturated hydrocarbon groups containing 1 to 30 carbon atoms, such as C1-C16 alkyl groups, C1-C12 alkyl groups, C1-C6 alkyl groups, and for example, C1-C30 linear alkyl groups, C1-C26 linear alkyl groups, and examples include methyl group, ethyl group, n-propyl group, n-butyl group, n-pentyl group, n-hexyl group, undecyl group, pentadecyl group, nonadecyl group, tricosyl group, etc., for example, C1-C30 branched alkyl groups, C1-C The group is a 12-branched alkyl group, and examples include isopropyl group, isobutyl group, tert-butyl group, sec-butyl group, 1-methylpropyl group, 1-ethylpropyl group, isopentyl group, neopentyl group, 1-methylbutyl group, 3-methylbutyl group, isohexyl group, 1-methylpentyl group, 3-methylpentyl group, 1,1-dimethylpentyl group, n-hexyl group, 1-methylhexyl group, 1-pentylhexyl group, and the like, preferably a methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, or n-hexadecyl group. C1-C6 alkylene groups refer to divalent alkyl groups containing 1 to 6 carbon atoms, such as -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH2CH(CH3)-, -CH2C(CH3)2-, -CH2CH2CH2-, or -(CH2)6-. Halogenated C1-C30 alkyl groups refer to linear or branched saturated hydrocarbon groups containing 1 to 30 carbon atoms, such as halogenated C1-C16 alkyl groups, halogenated C1-C12 alkyl groups, and halogenated C1-C6 alkyl groups, in which one or more hydrogen atoms are substituted with homologous or heterologous halogen atoms. Examples include trifluoromethyl, fluoromethyl, difluoromethyl, chloromethyl, bromomethyl, dichlorofluoromethyl, chloroethyl, bromopropyl, 2-chlorobutyl, pentafluoroethyl, or -(CH2) 15 CF3, etc. C1-C30 alkoxy groups refer to linear or branched alkoxy groups containing 1 to 30 carbon atoms, such as C1-C16 alkoxy groups, C1-C12 alkoxy groups, and C1-C6 alkoxy groups. Examples include methoxy groups, ethoxy groups, n-propoxy groups, isopropoxy groups, n-butoxy groups, isobutoxy groups, tert-butoxy groups, sec-butoxy groups, n-pentyloxy groups, isopentyloxy groups, neopentyloxy groups, isohexyloxy groups, 3-methylpentyloxy groups, or n-hexyloxy groups. Preferably, these are methoxy groups, ethoxy groups, n-propoxy groups, isopropoxy groups, n-butoxy groups, isobutoxy groups, or n-hexadecyloxy groups. Halide-treated C1-C30 alkoxy groups refer to linear or branched alkoxy groups containing 1 to 30 carbon atoms, such as halide-treated C1-C16 alkoxy groups, halide-treated C1-C12 alkoxy groups, and halide-treated C1-C6 alkoxy groups, in which one or more hydrogen atoms are substituted with homologous or heterologous halogen atoms. Examples include -OCF3, -OCH2CH2Cl, -OCHBrCH2Cl, -OCF2CF3, or -O(CH2). 15 CF3, etc. C2-C30 alkenyl groups refer to straight-chain or branched unsaturated hydrocarbon groups containing 1, 2, or 3 double bonds and 2-16 carbon atoms, including both cis and trans configurations. Examples include C2-C16 alkenyl groups, C2-C12 alkenyl groups, and C2-C6 alkenyl groups. Examples include vinyl groups, 1-propenyl groups, 2-propenyl groups, 1-methyl-1-propenyl groups, 2-methyl-1-propenyl groups, and 2- These include methyl-2-propenyl group, 1-butenyl group, 2-butenyl group, 3-butenyl group, 1-pentenyl group, 2-pentenyl group, 3-pentenyl group, 4-pentenyl group, 1,3-butadienyl group, 1,3-pentadienyl group, 1-hexenyl group, 2-hexenyl group, 3-hexenyl group, 4-hexenyl group, 5-hexenyl group, 3,3-dimethyl-1-propenyl group, or 2-ethyl-1-propenyl group, etc. Phenyl C1-C30 alkyl groups refer to groups in which one carbon atom of a linear or branched saturated hydrocarbon group containing 1 to 30 carbon atoms is linked to a carbon atom of a phenyl group, such as phenyl C1-C16 alkyl groups, phenyl C1-C12 alkyl groups, and phenyl C1-C6 alkyl groups. Examples include benzyl groups, phenethyl groups, and phenylpropyl groups. Phenyl C1-C30 alkoxy groups refer to groups in which one carbon atom of a linear or branched alkoxy group containing 1 to 30 carbon atoms is linked to a carbon atom of a phenyl group. Examples include benzyloxy groups, -OCH(CH3)Ph, phenylethoxy groups, and phenylpropoxy groups. Amino groups substituted with C1-C30 alkyl groups are -NHMe, -NHEt, -N(Me)Et, -NEt2, or -NH(CH2) 15 This refers to groups such as CH3, in which one or two hydrogen atoms on the amino group are substituted with homologous or homologous C1-C30 alkyl groups.

[0060] Amino groups substituted with C2-C30 alkenyl groups are -NHCH=CH2, -NHCH=CHCH3, -NHCH=CHCH2CH3, or -NHCH=CH(CH2). 13This refers to groups such as CH3, in which one or two hydrogen atoms on the amino group are substituted with homologous or homologous C2-C30 alkenyl groups. The amino group substituted with a halogenated C1-C30 alkyl group is -NHCH2CF3, -NHCF2CF3, -N(CH2CF3)2, or -NH(CH2) 15 This refers to groups such as CF3, in which one or two hydrogen atoms on the amino group are substituted with homologous or homologous C1-C30 alkyl groups. Amino groups substituted with phenyl C1-C30 alkyl groups are -NHCH2Ph, -N(CH2Ph)2, or -NH(CH2) 15 This refers to groups such as Ph, in which one or two hydrogen atoms on the amino group are substituted with homologous or homologous phenyl C1-C30 alkyl groups. Amino groups substituted with hydroxy C1-C30 alkyl groups are -NHCH2CH2OH, -N(CH2CH2OH)2, or -NH(CH2) 16 This refers to groups such as OH, in which one or two hydrogen atoms on the amino group are substituted with homologous or homologous hydroxy C1-C30 alkyl groups. An amino group substituted with a C3-C10 cycloalkyl group refers to a group such as -NHCH(CH2)2 or -NHCH(CH2)4, in which one or two hydrogen atoms on the amino group are substituted with homologous or heterologous C3-C10 cycloalkyl groups. An amino group substituted with a C3-C10 cycloalkyl C1-C6 alkyl group means a group in which one or two hydrogen atoms on the amino group are substituted with homologous or homologous C3-C10 cycloalkyl C1-C6 alkyl groups, such as -NHCH2CH(CH2)2, -NHCH2CH2CH(CH2)2, or -NHCH2CH(CH2)4. C1-C30 alkoxycarbonyl alkyl groups are -CH2(CO)OCH2CH3, -CH2CH2(CO)OCH2CH3, or -CH2(CO)O(CH2) 15 This refers to a group such as CH3, where the carbonyl carbon atom of a C1-C30 alkoxycarbonyl group is linked to a C1-C30 alkyl group. C3-C10 cycloalkyl groups refer to saturated cyclic hydrocarbon groups containing 3 to 10 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl groups. C3-C10 cycloalkoxy groups refer to groups such as -OCH(CH2)2, -OCH(CH2)3, or -OCH(CH2)4, in which a hydrogen atom on the hydroxyl group is substituted with a C3-C10 cycloalkyl group. C1-C30 alkalkyl groups are -CH2OCH2CH3, -CH2CH2OCH2CH3, or -CH2O(CH2) 15 This refers to groups such as CH3, where C1-C30 alkoxy groups and C1-C30 alkyl groups are linked by single bonds. C1-C30 alkoxy groups are -OCH2OCH2CH3, -OCH2CH2OCH2CH3, or -OCH2O(CH2) 15 This refers to groups such as CH3, which are C1-C30 alkoxy groups, or groups in which C1-C30 alkoxy groups are linked by single bonds. Phenyl C1-C30 alkoxy C1-C30 alkyl groups are -CH2OCH2CH2Ph, -CH2CH2OCH2CH2Ph, or -CH2O(CH2) 16 Ph refers to a group in which a phenyl group, a C1-C30 alkoxy group, and a C1-C30 alkyl group are linked in order by single bonds. C1-C30alkyl groups are -CH2OCH2CH2OCH2CH3, -CH2CH2OCH2CH2OCH2CH3, or -CH2OCH2CH2O(CH2) 15 This refers to a group such as CH3, where C1-C30 alkoxy groups, C1-C30 alkoxy groups, and C1-C30 alkyl groups are linked sequentially by single bonds. C1~C30alkaldehyde C1~C30alkaldehyde C1~C30alkaldehyde C1~C30 alkyl groups are -CH2OCH2CH2OCH2CH2OCH2CH3, -CH2CH2OCH2CH2OCH2CH2OCH2CH3, or -CH2OCH2CH2OCH2CH2O(CH2) 15This refers to a group such as CH3, where C1-C30 alkoxy groups, C1-C30 alkoxy groups, C1-C30 alkoxy groups, and C1-C30 alkyl groups are linked in sequence by single bonds. Hydroxy C1-C30 alkyl groups are -CH2OH, -CH2CH2OH, -CH(OH)CH3, -CH2CH2CH2OH, -CH2CH2CH2CH2OH, or -CH2CH(CH3)CH2OH, or -(CH2) 15 This refers to a group in which one carbon atom of a linear or branched alkyl group containing 1 to 30 carbon atoms, such as CH2OH, is linked to a hydroxyl group. Amino C1-C30 alkyl groups are -CH2NH2, -CH2CH2NH2, -CH(NH2)CH3, -CH2CH2CH2NH2, or -(CH2) 15 This refers to a group in which one carbon atom of a linear or branched alkyl group containing 1 to 30 carbon atoms, such as CH2NH2, is linked to an amino group. C6-C12 aryl groups refer to monocyclic or polycyclic aromatic ring groups, such as phenyl groups and naphthyl groups, that contain 6 to 12 ring atoms but do not contain heteroatoms among the ring atoms. C6-C12 aryl C1-C30 alkyl groups refer to groups in which one carbon atom of a linear or branched saturated hydrocarbon group containing 1 to 30 carbon atoms, such as a benzyl group, naphthylmethyl group, or naphthylethyl group, is linked to a carbon atom of a C6-C12 aryl group. A heterocyclyl group includes a "heterocycloalkyl group" and a "heteroaryl group," and refers to a monocyclic or polycyclic group containing at least one heteroatom selected from nitrogen, oxygen, and sulfur as a ring member, which may be an aromatic or non-aromatic group. A 5-10 membered heterocyclyl group refers to a heterocyclyl group containing 5-10 ring atoms, such as a pyridyl group, piperidinyl group, morpholinyl group, furyl group, thienyl group, thiazolyl group, imidazolyl group, pyrrolyl group, pyrazinyl group, pyridadinyl group, or pyrimidine group.

[0061] The term "pharmaceutically acceptable salt" refers to a salt of the compound of the present invention, such as a pharmaceutically acceptable acid addition salt and a pharmaceutically acceptable base addition salt, that is suitable for use in contact with human and lower animal tissues without excessive toxicity, irritation, allergic reactions, etc., within the bounds of reasonable medical judgment, and is commensurate with a reasonable benefit / risk ratio and, where possible, effective for the intended use.

[0062] The term "solvate" refers to a variable stoichiometric complex formed by a solute (e.g., a compound of the present invention) and a solvent (e.g., water, ethanol, or acetic acid). This physical association may involve varying degrees of ionic and covalent bonding, including hydrogen bonding. In some cases, solvates can be isolated (e.g., if one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid). Generally, such solvents selected by the present invention do not impede the biological activity of the solute. Typical solvates include hydrates, ethanol hydrates, methanol hydrates, and the like. The term "hydrate" refers to a solvate in which the solvent is water.

[0063] The terms “stereoisomer” or “optical isomer” refer to stable isomers that have at least one chiral element, for example, a chiral atom, or have a perpendicular asymmetric plane as a result of restricted rotation (e.g., some biphenyl, propadiene, and spiro compounds), and that can rotate plane-polarized light. Because the compounds of the present invention (and their salts, solvates, or derivatized forms such as prodrugs) contain an asymmetric carbon atom, they can exist as a single stereoisomer, a racemate, and a mixture of enantiomers and diastereomers.

[0064] The terms "geometric isomers" or "cis-trans isomers" refer to stable isomers resulting from the restriction of rotational degrees of freedom in double bonds (e.g., cis-2-butene and trans-2-butene) or ring structures (e.g., cis-1,3-dichlorocyclobutane and trans-1,3-dichlorocyclobutane). The specific configuration of the isomers is expressed using the cis / trans convention or the E or Z system, where "E" or "E-type" refers to a higher-order substituent on the opposite side of the double bond, and "Z" or "Z-type" refers to a higher-order substituent on the same side of the double bond. The determination of E-type and Z-type isomers is done using X-ray crystallography. 1 H-NMR and 13 This can be done using analytical methods such as 1C-NMR.

[0065] The term "isotope-labeled compound" refers to a derivative compound formed by replacing a specific atom in the compound of the present invention with its isotopic atom. Unless otherwise indicated, the compounds of the present invention can be labeled with various isotopes of H, C, N, O, F, P, S, and Cl, for example, 2 H(D), 3 H(T), 13 C, 14 C, 15 N, 17 O, 18 O, 18 F, 31 P, 32 P, 35 S, 36 S and 37 Includes Cl.

[0066] The terms “prodrug” or “prodrug derivative” refer to covalent derivatives or vectors of a parent compound or active drug substance that undergo at least several biotransformations before exhibiting one or more pharmacological effects. Generally, such prodrugs have metabolically cleavable groups and are rapidly converted in vivo to produce the parent compound. Prodrugs are typically formulated to improve chemical stability, improve individual acceptability and compliance, improve bioavailability, extend duration of action, improve organ selectivity, improve formulation (e.g., increase water solubility), and / or reduce side effects (e.g., toxicity). Generally, prodrugs have weak biological activity or no biological activity of their own, are stable under normal conditions, and can be readily produced from the parent compound using methods known in the art.

[0067] The compounds of formulas (II), (III), (IV), (V), and (Ia) in the present invention are commercially available compounds, or compounds produced by technically known methods or by synthetic methods of similar compounds.

[0068] The starting compounds used in each reaction formula of the present invention may be pharmaceutically acceptable salts thereof, and these pharmaceutically acceptable salts include alkali metal salts and alkaline earth metal salts such as sodium salts, potassium salts, calcium salts, and magnesium salts, organic base salts such as pyridine salts and triethylamine salts, inorganic salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, and phosphate, and organic salts such as formate, acetate, propionate, glycolate, oxalate, malonate, succinate, fumarate, maleate, lactate, malate, citrate, tartrate, picrate, glutamate, methanesulfonate, and benzenesulfonate.

[0069] Furthermore, the starting compounds used in each reaction equation of the present invention may be in the form of solvates such as hydrates and alkoxides.

[0070] The N-substituted quinolinone compound represented by general formula (I) of the present invention and its stereoisomers may be in the form of solvates such as hydrates and alkoxides, and the above solvates are included within the scope of the present invention.

[0071] The pharmaceutically acceptable salts of the N-substituted quinolinone compounds represented by general formula (I) of the present invention and their stereoisomers refer to those obtained by treating the N-substituted quinolinone compounds represented by general formula (I) or their stereoisomers with an appropriate acid to convert them into therapeutically active, non-toxic addition salt forms. The salts include hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, nitrate, phosphate, acidic phosphate, perchlorate, formate, acetate, trifluoroacetate, propionate, pyruvate, glycolate, oxalate, malonate, succinate, glutarate, maleate, fumarate, lactate, malate, citrate, tartrate, picrate, glutamate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, salicylate, ascorbate, camphorate, or camphorsulfonate. Conversely, the salt form can also be converted back into the free base form by treating it with a base.

[0072] The term "pharmaceutically acceptable salt" as used above may also refer to its solvate, which is included within the scope of the present invention. Examples of solvates include hydrates and alkoxides.

[0073] In this invention, "room temperature" means 10 to 30°C.

[0074] The abbreviations and definitions used in this invention are as shown in the table below: [Table 1] [Examples]

[0075] The following examples and experimental cases further illustrate the present invention, but do not limit its scope. Unless otherwise specified, the raw materials, reagents, and methods used in the examples and experimental cases are all commonly used in the field, and all raw materials and reagents used are commercially available.

[0076] <Manufacturing Examples> Example 1: Preparation of 7-(2-(4-(6-fluorobenzo[b]thiophen-4-yl)piperazine-1-yl)ethyl)-1-(hydroxymethyl)-3,4-dihydroquinoline-2(1H)-one [ka] In a 100 mL neck flask, compound 1-a (4.8 g, 1 eq), 37% formaldehyde aqueous solution (15 mL), triethylamine (593 mg, 0.5 eq), and DMF (15 mL) were added and the mixture was reacted at 85 °C for 3 hours, and the reaction was monitored by TLC. Workup: The reaction solution was diluted with 100 mL of DCM, washed with water (100 mL x 4), and concentrated under reduced pressure to obtain the crude product. Acetonitrile (10 mL) was added to the crude product, and it was slurryed at room temperature. The mixture was filtered to obtain 3.6 g of wet product. DCM (6 mL) was added to the wet product, and it was slurryed at 0-10 °C. The mixture was filtered to obtain 2.3 g of wet product. DCM (4.6 mL) was then used to slurry at 0-10 °C, filtered, and dried to obtain 2 g of the target compound (white solid, HPLC purity 98%). 1HNMR (400MHz, DMSO-d6): δ ppm 7.66(d, J=5.5 Hz, 1H), 7.49(dd, J=8.6, 1.7 Hz, 1H), 7.37(d, J=5.5 Hz, 1H), 7.19(s, 1H), 7.11(d, J=7.6 Hz, 1H), 6.90(d, J=7.4 Hz, 1H), 6.75(dd, J=11.5, 2.0 Hz, 1H), 6.15(t, J=6.8 Hz, 1H), 5.23(d, J=6.8 Hz, 2H), 3.10(br, 4H), 2.78(m, 4H), 2.69(br, 4H), 2.62(m, 2H), 2.51(m, 2H). ESI-MS (m / z): 440.28 [M+H] + .

[0077] Example 2: Preparation of (7-(2-(4-(6-fluorobenzothiophen-4-yl)piperazine-1-yl)ethyl)-2-oxo-3,4-dihydroquinoline-1(2H)-yl)methylisopropyl carbonate [ka] Compound 1-a (400 mg, 1 eq) was taken, dissolved in DMF (10 mL), protected with nitrogen gas, and the temperature was controlled to approximately 20°C. Sodium hydrogen (4 eq) was added, and the reaction was allowed to proceed at room temperature for 30 minutes. Isopropyl chloromethyl carbonate (4 eq) was added dropwise, and the reaction was continued for 2 hours at a temperature of 60-65°C. The reaction was stopped by monitoring for a small amount of remaining starting material by TLC, and the reaction solution was poured into ethyl acetate and ice water (30 mL each), stirred, allowed to stand, and separated into layers. The organic phases were washed with water and saturated brine (30 mL each), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 440 mg of oily substance. 1HNMR (400MHz, CDCl3): δ ppm 7.33(m, 2H), 7.21(dd, J=8.2, 1.9 Hz, 1H), 7.11(d, J=7.6 Hz, 1H), 6.98(s, 1H), 6.94(d, J=7.6 Hz, 1H), 6.66(dd, J=11.1, 2.1 Hz, 1H), 5.96(s, 2H), 4.94(m, 1H), 3.20(br, 4H), 2.89(m, 2H), 2.85(m, 2H), 2.77(br, 4H), 2.70(m, 4H), 1.31(d, J=6.3 Hz, 6H). ESI-MS (m / z): 526.50 [M+H] + .

[0078] Example 3: Preparation of methyl (7-(2-(4-(6-fluorobenzothiophen-4-yl)piperazine-1-yl)ethyl)-2-oxo-3,4-dihydroquinoline-1(2H)-yl)dodecanoate [ka] Compound 1-a (500 mg, 1 eq) was taken, dissolved in DMF (10 mL), protected with nitrogen gas, and the temperature was controlled to approximately 20°C. Sodium hydrogen (4 eq) was added, and the reaction was allowed to proceed at room temperature for 30 minutes. Chloromethyldodecanoic acid (4 eq) was added dropwise, and the reaction was continued for 2 hours at a temperature of 60-65°C. The reaction was stopped by monitoring for a small amount of remaining starting material by TLC, and the reaction solution was poured into ethyl acetate and ice water (30 mL each), stirred, allowed to stand, and separated into layers. The organic phases were washed with water and saturated brine (30 mL each), dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to obtain 670 mg of oil. Isopropyl ether (6.7 mL) was added to clarify the solution, freeze crystallization was performed (-40°C), filtered, and dried to obtain 500 mg of white solid. 1HNMR (400MHz, CDCl3): δ ppm 7.33(m, 2H), 7.21(dd, J=8.2, 1.9 Hz, 1H), 7.11(d, J=7.6 Hz, 1H), 6.94(d, J=7.6 Hz, 1H), 6.90(s, 1H), 6.66(dd, J=11.1, 2.1 Hz, 1H), 5.94(s, 2H), 3.20(br, 4H), 2.90(m, 2H), 2.85(m, 2H), 2.77(br, 4H), 2.70(m, 4H), 2.36(t, J=7.6 Hz, 2H), 1.64(m, 2H), 1.35-1.17(m, 16H), 0.86(t, J=6.9Hz, 3H). ESI-MS (m / z): 622.52 [M+H] + .

[0079] Example 4: Preparation of 7-(2-(4-(6-fluorobenzothiophen-4-yl)piperazine-1-yl)ethyl)-2-oxo-3,4-dihydroquinoline-1(2H)-isopropyl carboxylate [ka] Compound 1-a (400 mg, 1 eq) was taken, dissolved in DMF (10 mL), protected with nitrogen gas, and the temperature was controlled to approximately 20°C. Sodium hydrogen (4 eq) was added, and the reaction was allowed to proceed at room temperature for 30 minutes. Isopropyl chloroformate (4 eq) was added dropwise, and the reaction was continued at a temperature of 60-65°C for 2 hours. The reaction was stopped by monitoring for a small amount of starting material remaining by TLC, and the reaction solution was poured into ethyl acetate and ice water (30 mL each), stirred, allowed to stand, and separated into layers. The organic phases were washed with water and saturated brine (30 mL each), dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to obtain 440 mg of oily substance. 1HNMR (400MHz, CDCl3): δ ppm 7.33(m, 2H), 7.21(dd, J=8.2, 2.0 Hz, 1H), 7.11(d, J=7.6 Hz, 1H), 6.95(dd, J=7.6, 1.1 Hz, 1H), 6.84(s, 1H), 6.66(dd, J=11.1, 2.1 Hz, 1H), 5.24(m, 1H), 3.20(br, 4H), 2.93(m, 2H), 2.82(m, 2H), 2.77(br, 4H), 2.67(m, 4H), 1.41(d, J=6.3 Hz, 6H). ESI-MS (m / z): 496.25 [M+H] + .

[0080] Example 5: Preparation of (7-(2-(4-(6-fluorobenzothiophen-4-yl)piperazine-1-yl)ethyl)-2-oxo-3,4-dihydroquinoline-1(2H)-yl)methyl acetate [ka] Compound 1-a (200 mg, 1 eq) and DMF (4 mL) were added to a 25 mL reaction flask, protected with nitrogen gas, and the temperature was controlled to <30°C. 60% sodium hydrogen (78 mg, 4 eq) was added, and the mixture was stirred at room temperature for 30 min. Chloromethyl acetate (212 mg, 4 eq) and sodium iodide (73 mg, 1 eq) were added in sequence, and the mixture was reacted at room temperature for 2-3 hours. Water (1 mL) was added to quench the reaction and stop it. Ethyl acetate was added to dilute the mixture (8 mL), and the mixture was washed three times (8 mL x 3) with water to concentrate the organic phase. The mixture was purified by column chromatography to obtain an oily substance. Isopropyl ether was added, and the mixture was stirred at room temperature to crystallize, yielding a white solid of 115 mg in yield with 49%. 1HNMR (400MHz, CDCl3): δ ppm 7.33(m, 2H), 7.21(dd, J=8.2, 1.8 Hz, 1H), 7.12(m, 1H), 6.95(d, J=7.6 Hz, 1H), 6.91(s, 1H), 6.66(dd, J=11.1, 2.1 Hz, 1H), 5.93(s, 2H), 3.21(br, 4H), 2.93-2.82(m, 4H), 2.78(br, 4H), 2.70(m, 4H), 2.12(s, 3H). ESI-MS (m / z): 482.29 [M+H] + .

[0081] Example 6: Preparation of methyl (7-(2-(4-(6-fluorobenzothiophen-4-yl)piperazine-1-yl)ethyl)-2-oxo-3,4-dihydroquinoline-1(2H)-yl)pentanoate [ka] Compound 1-a (200 mg, 1 eq) and DMF (4 mL) were added to a 25 mL reaction flask, protected with nitrogen gas, and the temperature was controlled to <30°C. 60% sodium hydrogen (78 mg, 4 eq) was added, and the mixture was stirred at room temperature for 30 min. Chloromethyl n-valerate (294 mg, 4 eq) and sodium iodide (73 mg, 1 eq) were added in sequence, and the mixture was reacted at room temperature for 2-3 hours. Water (1 mL) was added to quench the reaction and stop it. Ethyl acetate was added to dilute the mixture (8 mL), and the mixture was washed three times with water (8 mL x 3). The organic phase was concentrated and purified by column chromatography to obtain an oily substance. Isopropyl ether was added, and the mixture was stirred at low temperature to crystallize, yielding a white solid of 100 mg in yield of 39%. 1HNMR (400MHz, CDCl3): δ ppm 7.33(m, 2H), 7.21(dd, J=8.2, 1.9 Hz, 1H), 7.12(m, 1H), 6.95(d, J=7.6 Hz, 1H), 6.89(s, 1H), 6.66(dd, J=11.1, 2.1 Hz, 1H), 5.94(s, 2H), 3.21(br, 4H), 2.94-2.81(m, 4H), 2.77(br, 4H), 2.69(m, 4H), 2.37(t, J=7.5 Hz, 2H), 1.63(m, 2H), 1.35(m, 2H), 0.90(t, J=7.3 Hz (3H). ESI-MS (m / z): 524.31 [M+H] + .

[0082] Example 7: Preparation of methyl (7-(2-(4-(6-fluorobenzothiophen-4-yl)piperazine-1-yl)ethyl)-2-oxo-3,4-dihydroquinoline-1(2H)-yl)dodecanoate [ka] Step 1: The preparation of compound 3-a can be found in patent WO2015131856. Starting material 3-a (250 mg, 1 eq) and DMF (5 mL, 20V) were added to a 25 mL reaction flask, protected with nitrogen gas, and the temperature was controlled to <30°C. 60% sodium hydrogen (56 mg, 1.5 eq) was added, and the mixture was stirred at room temperature for 30 min. Chloromethyl dodecanoate (347 mg, 1.5 eq) and sodium iodide (140 mg, 1 eq) were added in sequence, and the mixture was reacted at room temperature for 2-3 hours. Water (1 mL) was added to quench the reaction and stop it. The reaction mixture was diluted with ethyl acetate (10 mL), washed three times with water (10 mL x 3), the organic phase was concentrated, and purified by column chromatography (PE / EA = 30 / 1 to 20 / 1) to obtain 300 mg of an oily substance (intermediate 3-b) in 67% yield. Step 2: In a 25 mL reaction flask, 3-c (161 mg, 1 eq), 3-b (300 mg, 1.2 eq), sodium bicarbonate (218 mg, 5 eq), sodium iodide (78 mg, 1 eq), and DMF (3.2 mL, 20V) were added, the flask was protected with nitrogen gas, and the reaction was carried out at 85°C for 2 hours. The reaction mixture was diluted with dichloromethane (6.4 mL), washed with water (6.4 mL x 4), concentrated, and purified by column chromatography (PE / EA = 5 / 1 to 2 / 1) to obtain the title compound (200 mg white solid, 62% yield).

[0083] Example 8: Preparation of methyl (7-(2-(4-(6-fluorobenzothiophen-4-yl)piperazine-1-yl)ethyl)-2-oxo-3,4-dihydroquinoline-1(2H)-yl)decanoate [ka] Referring to the above examples, the title compound (yield 52%, white solid) was prepared using compound 1-a and chloromethyl decacarboxylate as raw materials. 1 HNMR (400MHz, CDCl3): δ ppm 7.33(m, 2H), 7.21(dd, J=8.2, 1.8 Hz, 1H), 7.11(d, J=7.6 Hz,1H), 6.94(d, J=7.6 Hz, 1H), 6.90(s, 1H), 6.66(dd, J=11.1, 2.0 Hz, 1H), 5.94(s, 2H), 3.21(br, 4H), 2.91(m, 2H), 2.85(m, 2H), 2.77(br, 4H), 2.69(m, 4H), 2.35(t, J=7.6 Hz, 2H), 1.64(m, 2H), 1.25(br, 12H), 0.85 (t, J=6.8 Hz, 3H). ESI-MS (m / z): 594.43 [M+H] + .

[0084] Example 9: Preparation of methyl (7-(2-(4-(6-fluorobenzothiophen-4-yl)piperazine-1-yl)ethyl)-2-oxo-3,4-dihydroquinoline-1(2H)-yl)palmitate [ka] Referring to the above examples, the title compound (yield 38%, white solid) was prepared using compound 1-a and chloromethyl hexadecanate as raw materials. 1 HNMR (400MHz, CDCl3): δ ppm 7.33(m, 2H), 7.21(dd, J=8.2, 1.9 Hz, 1H), 7.12(m, 1H), 6.95(d, J=7.6 Hz, 1H), 6.89(s, 1H), 6.66(dd, J=11.1, 2.1 Hz, 1H), 5.94(s, 2H), 3.21(br, 4H), 2.90(m, 2H), 2.85(m, 2H), 2.77(br, 4H), 2.69(m, 4H), 2.36(t, J=7.5 Hz, 2H), 1.63(m, 2H), 1.25(br, 24H), 0.87 (t, J=7.3 Hz, 3H). ESI-MS (m / z): 678.51 [M+H] + .

[0085] Example 10: Preparation of methyl (7-(2-(4-(6-fluorobenzothiophen-4-yl)piperazine-1-yl)ethyl)-2-oxo-3,4-dihydroquinoline-1(2H)-yl)docosanoate [ka] Docosanoic acid (1.0 g, 1.5 eq) was taken, thionyl chloride (10 mL) was added, a small amount of DMF was added to catalyze the reaction, refluxed for 3 hours, and the completion of the reaction was detected by TLC. The mixture was then concentrated under reduced pressure to obtain docosanoic acid chloride. A separate reaction flask was taken, compound 1 (220 mg, 1.0 eq) was added, dichloromethane (5 mL) and triethylamine (150 mg, 3 eq) were added, and then the newly prepared docosanate chloride was added to the reaction system and stirred for 15 minutes to allow the reaction to proceed. Water was added to quench the reaction, liquid-liquid was separated, the organic phase was retained, and the mixture was concentrated under reduced pressure and purified by chromatography to obtain 127 mg of compound 74, which was a white solid. 1 HNMR (400MHz, CDCl3): δ ppm 7.67(m, 1H), 7.50(m,1H), 7.36(m, 1H), 7.16(d, J=8.0 Hz, 1H), 7.10-6.97(m, 2H), 6.75(m, 1H), 5.86(s, 2H), 3.10(m, 4H), 2.86-2.60(m, 12H), 2.32(t, J=8.0 Hz, 2H), 1.51(m, 2H), 1.22-1.17(m, 36H), 0.84(t, t, J=8.0 Hz, 3H). ESI-MS (m / z): 763.41 [M+H] + .

[0086] Example 11: Preparation of methyl (7-(2-(4-(6-fluorobenzothiophen-4-yl)piperazine-1-yl)ethyl)-2-oxo-3,4-dihydroquinoline-1(2H)-yl)heptadecanate [ka] Heptacosanoic acid (0.3 g, 1.5 eq) was taken, thionyl chloride (3 mL) was added, and a small amount of DMF was added to catalyze the reaction. The mixture was refluxed for 2 hours, and the completion of the reaction was detected by TLC. The mixture was then concentrated under reduced pressure to obtain heptacosanoyl chloride. A separate reaction flask was taken, compound 1 (150 mg, 1.0 eq) was added, dichloromethane (3 mL) and triethylamine (100 mg, 3 eq) were added, and then the freshly prepared heptacosanoyl chloride was added to the reaction system and stirred for 15 minutes to allow the reaction to proceed. Water was added to quench the reaction, liquid-liquid was separated, the organic phase was retained, and the mixture was concentrated under reduced pressure and purified by chromatography to obtain 167 mg of compound 76, which was a white solid. 1 HNMR (400MHz, CDCl3): δ ppm 7.35-7.32(m, 2H), 7.24-7.21(m,1H), 7.12(d, J=8.0 Hz, 1H), 6.95(d, J=8.0 Hz, 1H), 6.90(s,1H), 6.69-6.65(m, 1H), 5.95(s, 2H), 3.20(m, 4H), 2.92-2.70(m, 12H), 2.36(t, J=16 Hz, 2H), 1.66-1.61(m, 2H), 1.28-1.22(m, 48H), 0.88(t, t, J=12.0 Hz, 3H). ESI-MS (m / z): 833.21 [M+H] + .

[0087] The compounds shown in the table below were prepared using the same method as in the above examples, except that the starting materials and intermediates corresponding to the final product were used. [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 2-6] Table 2-7 Table 2-8 Table 2-9 Table 2-10 Table 2-11 Table 2-12 Table 2-13 Table 2-14 Table 2-15 Table 2-16 Table 2-17 Table 2-18 Table 2-19 Table 2-20 Table 2-21 Table 2-22 Table 2-23 [Table 2-24] [Table 2-25] [Table 2-26]

[0088] 1) 5-HT 1A Measurement of receptor agonist activity Human recombinant 5-HT 1A 5-HT cells expressing the receptor HEK293 1A The agonist effect of compounds on receptors, LANCE TM The measurement was performed using the cAMP 384 Kit (a product of PerkinElmer, USA). By measuring the inhibitory effect of the compound on cAMP production in HEK293 cells, the 5-HT of the compound was determined. 1A The receptor agonist activity was evaluated. cAMP concentration was measured according to the method described in the kit instructions, with compound concentrations ranging from 0.0128 nM to 1000 nM. 8-OH-DPAT was used as a positive control. The specific procedure was as follows: a) The compound was added to an assay plate (384-well plate) using Echo 550, the final concentration of DMSO was <1%, and cells were collected using Stimulation Buffer (HBSS + 5 mM HEPES + 0.5 mM IBMX + 0.1% BSA). b) Transfer 10 μL of the prepared cell solution to an assay plate containing the compound. c) Centrifuge at 600 rpm for 3 minutes, then incubate at room temperature for 1 hour. d) 5 μL of 4X Eu-cAMP tracer solution and 5 μL of 4X ULight TM - Add anti-cAMP solution, centrifuge at 600 rpm for 3 minutes, and incubate at room temperature for 1 hour. e) Read the data with EnVision and use Graphpad Prism software for EC 50 The calculation is performed, and the results are shown in Table 1.

[0089] 2) D 2L Measurement of receptor antagonistic activity Human recombinant D 2L D expresses receptor CHO cells 2L The antagonistic effects of compounds on receptors were measured using the LANCE® Ultra cAMP Kit (a product of PerkinElmer, Inc., USA). The antagonistic effects of compounds on the D2 receptor were evaluated by measuring the inhibitory effect of dopamine-antagonizing compounds on cAMP production in CHO cells. cAMP concentration was measured according to the method described in the kit instructions. The starting concentration of the compound was 1000 nM, diluted 5-fold, and amisulpride was used as a positive control. The specific procedure was as follows: a) Prepare the 1×Stimulation Buffer according to the kit instructions and prepare it for use. b) After gradient diluting the positive compound and the compound awaiting measurement with DMSO to 10 different concentrations, dilute the positive compound & DMSO with 1× Stimulation Buffer to 10×. c)D 2L -CHO cells were trypsin-treated, centrifuged, the culture medium was removed, the cells were resuspended in 1× Stimulation Buffer, and after cell counting, inoculated into a 384-well plate at an inoculation density of 3000 cells / well / 5μL. d) Take 1 μL of the compound diluted in step b) and add it to the corresponding experimental wells (compound is 10×, 10 concentrations, 2 replicates). Add 1 μL of the positive compound at the initial concentration of 10× to the PC well, and 1 μL of 10× DMSO buffer (2%) to the VC well. Centrifuge and incubate at 37°C for 20 minutes. e) Take 4 μL of a 10 μM Forskolin & 25 nM Dopamine solution and D 2L In addition to the receptor inhibitor experimental wells, the mixture was incubated at 37°C for 30 minutes after centrifugation to induce cAMP production. f) Dilute Eu-cAMP to the working concentration with detection buffer, take 5 μL / well and add it to the corresponding experimental well. g)ULight TM - Dilute anti-cAMP to working concentration with detection buffer, take 5 μL / well and add it to the corresponding experimental well, then centrifuge and incubate at room temperature for 1 hour. h) After incubation was complete, readings at 665 nm and 620 nm were detected. The inhibition rates of the compound at different concentrations were calculated, and IC 50 This was calculated using Graphpad Prism software, and the results are shown in Table 1.

[0090] 3) 5-HT 2A Measurement of receptor antagonistic activity Human recombinant 5-HT 2A 5-HT cells expressing receptor CHO cells 2A The antagonistic effects of compounds on receptors were measured using the IP-One-Gq kit (a product of Cisbio). Measurements were performed according to the kit instructions, with a starting concentration of 5000 nM of compound, diluted 5-fold, and risperidone used as a positive control. The measurement procedure was as follows: a) 5-HT 2A -CHO cells were trypsin-treated, centrifuged, the medium was removed, the cells were resuspended in F12 + 10% Dialyzed FBS medium, and after cell counting, inoculated into a 384-well plate at an inoculation density of 7000 cells / well / 25μL. After centrifugation, the plate was placed in an incubator and incubated for approximately 18-20 hours. b) Prepare the 1×Stimulation Buffer according to the kit instructions and prepare it for use. c) After gradient diluting the positive compound and the compound awaiting measurement with DMSO to a concentration of 10, dilute the compound with 1× Stimulation Buffer to 10×, shake to mix uniformly, and prepare for use. d) Remove the cell plate, invert it and centrifuge to discard the culture medium, then add 9.1 μL of 1× Stimulation Buffer to each well. e) Take 1.4 μL of the 10× compound diluted in step c) and add it to the corresponding experimental wells (10× compound, 10 concentrations, 2 replicates). Add 1.4 μL of the 10× initial concentration of the positive compound to the PC well, and add 1.4 μL of 10× DMSO buffer (1%) to the VC well. Centrifuge and incubate at 37°C for 10 min. f) Prepare a 160 nM serotonin solution using 1 × Stimulation Buffer, take 3.5 μL and add it to each experimental well, then centrifuge and incubate at 37°C for 60 min. g) Dilute d2-IP1 and Anti-IP1-Cryptate to working concentrations using Lysis & Detection Buffer. h) After incubation is complete, add 3 μL of d2-IP1 to all experimental wells. i) Next, add 3 μL of Anti-IP1-Cryptate to all experimental wells, centrifuge, and let stand at room temperature for 1 hour. j) After incubation was complete, readings at 665nm and 620nm were detected.

[0091] The inhibition rate of the compound at different concentrations is calculated, and IC 50 This was calculated using Graphpad Prism software, and the results are shown in Table 1. [Table 3]

[0092] 4) Measurement of 5-HT transporter (SERT) inhibitory activity The transporter inhibitory effects of compounds on HEK-293 cells expressing human SERT were evaluated using the Neurotransmitter transporter uptake assay kit (Molecular Devices product). Measurements were performed according to the instructions in the kit, with citalopram used as a positive control. The specific procedure was as follows: a) HEK-hSERT cells were inoculated into a 384-well plate at a rate of 20,000 cells / well, then transferred to an incubator and incubated overnight at 37°C. b) The following day, citalopram was transferred to a 384-well plate using a 0.1% BSA solution. The final concentrations of citalopram measured were 2 μM, 0.5 μM, 0.125 μM, 30 nM, 10 nM, 3 nM, 1 nM, 0.3 nM, 0.1 nM, and 0.03 nM. The starting concentration for the compounds awaiting measurement was 10 μM, and the measurements were repeated twice at each concentration after 3 × dilution. c) Remove the 384-well plate from the incubator, aspirate the culture medium from the wells, add the compound solution to be measured at a rate of 25 μL / well, incubate at 37°C for 30 min, add 25 μL of fluorescent dye detection solution per well, incubate at 37°C for 30 min, d) Fluorescence values ​​were read from Flexstation3, and the data was analyzed using Graphpad Prism software. The results are shown in Table 2. [Table 4]

[0093] 5) Dopamine D3 receptor agonist action The D3 receptor agonist activity of compounds against human D3 receptor-expressing CHO cells was evaluated by measuring the effect of compounds on cAMP regulation using HTRF detection.

[0094] Experimental protocol: Cells were suspended in HBSS buffer containing 20 mM Hepes / NaOH (pH 7.4), 70 mM NaCl, 5.33 mM KCl, 1.25 mM CaCl2, 0.5 mM MgCl2, 0.41 mM MgSO4, 0.441 mM KH2PO4, 0.3 mM Na2HPO4, 0.1% glucose, 0.1% BSA, and 500 μM IBMX. Then, HBSS (basic control), 300 nM dopamine (stimulation control), or different concentrations of dopamine (EC2) were administered. 50 In the presence of either the compound for measurement or the compound awaiting measurement, 10 4Cells were distributed in microplates at a specific cell / well density. Then, the adenylyl cyclase activator NKH477 was added at a final concentration of 1.5 μM. After culturing at 37°C for 30 minutes, the cells were lysed, and a fluorescent receptor (D2-labeled cAMP) and a fluorescent donor (europium-labeled anti-cAMP antibody) were added. After incubation at room temperature for 60 minutes, fluorescence transfer was measured at em=337 nm, em=620, and em=665 nm using a microplate reader (Envision, Perkin Elmer). The cAMP concentration was determined by dividing the signal measured at em=665 nm by the signal measured at em=620 nm (ratio). The data was analyzed using Graphpad Prism software, and the results are shown in Table 3. [Table 5]

[0095] 6) Measurement of hERG potassium channel activity hERG potassium channel blockade experiments use fully automated patch clamp technology (QPatch). HTX The preparation was completed using Sophion, Stockholm, and Sweden. The cell line used was CHO cells that stably express hERG potassium channels. The highest measured concentration of the compound was 20 μM, which was diluted 3-fold (n=3). The DMSO content at the final measured concentration did not exceed 0.2%. The data was analyzed using Graphpad Prism software, and the results are shown in Table 4. [Table 6]

[0096] As can be seen from the results in Tables 1 to 4 above, Compound 1-a and Compound 1 are D2 receptor antagonists / 5-HT receptor antagonists. 1A Receptor agonist / 5-HT 2ACompound 1 exhibits similar receptor antagonistic activity and inhibitory effects on the 5-HT transporter, and is expected to relatively effectively improve comorbidities such as anxiety and depression associated with schizophrenia. Compared to compound 1-a, compound 1 has dopamine D3 receptor agonist activity and is expected to have better therapeutic effects on neuropsychiatric disorders and fewer extrapyramidal side effects. Compared to compound 1-a, compound 1 has lower hERG inhibitory activity, which is expected to reduce the risk of hERG-related cardiotoxicity and improve clinical safety.

[0097] 7) Human liver microsome experiment Preparation of magnesium potassium buffer: 100 mM potassium buffer was preheated with 5 mM MgCl2 to form a magnesium potassium buffer with a pH of 7.41. Preparation of 0.5 mM working solution: 10 mM compound preservation solution was added to 95 μL of acetonitrile. Preparation of working solution containing 1.5 μM microsomes (0.75 mg / mL): 1.5 μL of the above 0.5 mM working solution was taken and added to 479.75 μL of magnesium potassium buffer along with 18.75 μL of 20 mg / mL human liver microsome solution. Preparation of NADPH preservation solution (6 mM, 5 mg / mL): NADPH was dissolved in potassium magnesium buffer. 30 μL of 1.5 μM working solution containing 0.75 mg / mL human liver microsomes was sequentially added to a 96-well plate and pre-incubated at 37°C for 5 minutes. For the 0 min sample, the reaction was started by adding 150 μL of acetonitrile solution containing an internal standard, followed by 15 μL of NADPH preservative (6 mM). For the other time point samples, the reaction was started by directly adding 15 μL of NADPH preservative (6 mM). Final content of each component: compound (1 μM), human liver microsomes (0.5 mg / mL), NADPH (2 mM). At 5 min, 15 min, 30 min, and 45 min, 150 μL of stop solution containing an internal standard was added to stop the sample reaction. The samples were then centrifuged at 600 rpm for 10 min and at 6000 rpm for 15 min, and the supernatant was collected for LC-MS / MS analysis.

[0098] Using Excel software, plot the incubation time against the ln residual rate of the drug in the incubation system, perform linear regression to obtain the slope k, and calculate the half-life T 1 / 2 (min) and the intrinsic clearance CL int (mL / min / kg) values were determined according to the following formula:

Equation

Equation

[0099] The experimental results are shown in Table 5 below:

Table 7

[0100] The above data indicate that Compound 3, Compound 7, and Compound 8 have good metabolic stability in human liver microsomes.

[0101] 8) Oil Solubility Experiment Solubility was measured by quantitative analysis using the external standard method of high performance liquid chromatography.

[0102] Instrument Information:

Table 8

[0103] Chromatography Conditions:

Table 9

[0104] Solution Preparation: Reference Solution: Weighed 10 mg of the reference substance, placed it in a 20 mL volumetric flask, diluted to the mark with 80% acetonitrile, and shaken evenly to obtain.

[0105] Test solution: An appropriate amount of sample was taken and dissolved in benzyl benzoate to form a saturated solution. The solution was placed in a shaker and shaken at 25°C and 800 rpm for 2 hours. The sample was filtered, 100 μL of filtrate was taken and placed in a 10 mL volumetric flask, diluted to the marked level with 80% acetonitrile, and shaken uniformly to obtain the final solution.

[0106] The solubility measurement results are shown in Table 6: [Table 10]

[0107] As can be seen from the table above, the compounds of the examples of the present invention have better solubility in benzyl benzoate, an oily medium, compared to compound 1-a, and their good lipophilicity makes them more suitable for the production of long-acting formulations.

[0108] 9) Pharmacokinetic experiments in rats Pharmacokinetic experiments were conducted in rats (non-fasted SD male rats, intramuscular administration, dose 43.3 mmol / kg, n=3) for compounds 2, 3, 5, 6, 7, and 8. The solvent was benzyl benzoate, and the injection site was the hind limb thigh muscle. Approximately 0.3 mL of blood samples were collected from the rat jugular vein at the blood collection point on days 0.25, 2, 4, 6, 8, 15, 22, 29, and 36. The collected blood was stored under ice-cold conditions, and the plasma was rapidly separated by centrifugation. A precipitating agent was added, and the concentration of compound 1 (active metabolite) was quantitatively detected by LCMS. The time-active metabolite concentration graphs after administration of each compound are shown in Figures 1 and 2.

[0109] As can be seen from the experimental results, the compounds of the examples of the present invention (excluding compound 1) were able to gradually release the active metabolite (compound 1) in rats after intramuscular administration, reducing fluctuations in blood concentration and improving drug safety and tolerance. In particular, the fluctuations in blood concentration of the active metabolite after administration of compounds 3 and 8 were minimal. Examples of embodiments of the present invention are listed in the following sections [Aspect 1] to [Aspect 14]. [Aspect 1] N-substituted quinolinone compounds represented by general formula (I), or pharmaceutically acceptable salts, solvates, stereoisomers, geometric isomers, isotope-labeled compounds, or prodrugs thereof,

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Claims

1. N-substituted quinolinone compounds represented by general formula (I), or pharmaceutically acceptable salts, solvates, stereoisomers, geometric isomers, or isotope-labeled compounds thereof, 【Chemistry 1】 Eventually, R ６ , R ７ , R ８ and R ９ These are, independently, hydrogen, deuterium, halogen, methyl group, ethyl group, hydroxyl group, amino group, or acetamide group. 【Chemistry 2】 This represents a single bond or a double bond. 【Transformation 3】 If R is a double bond, ６ and R ７ One of them does not exist, and R ８ and R ９ One of them does not exist. R １ is -Y １ -O-C(=O)-R ２ -Y １ -O-C(=O)-O-R ３ -Y １ -O-R ４ or -C(=O)-R ５ and Y １ These are each independently C1-C6 alkylene groups, R ２ This is a C1-C30 alkyl group, a halogenated C1-C30 alkyl group, a C2-C30 alkenyl group, an amino C1-C30 alkyl group, an amino group substituted with a C1-C30 alkyl group, an amino group substituted with a C2-C30 alkenyl group, or an amino group substituted with a halogenated C1-C30 alkyl group. R ３ These are C1-C30 alkyl groups or halogenated C1-C30 alkyl groups. R ４ is hydrogen or a C1-C30 alkyl group, R ５ These are C1-C30 alkyl groups, C2-C30 alkenyl groups, C1-C30 alkoxy groups, or C1-C30 alkanoyloxy C1-C6 alkoxy groups. N-substituted quinolinone compounds, or pharmaceutically acceptable salts, solvates, stereoisomers, geometric isomers, or isotopically labeled compounds thereof.

2. In general formula (I), R １ is, -Y １ -OC(=O)-R ２ , -Y １ -OC(=O)-OR ３ , -Y １ -O-R ４ or -C(=O)-R ５ And, Y １ These are each independently C1-C4 alkylene groups, R ２ This is an amino group substituted with a C1-C30 alkyl group, a C2-C30 alkenyl group, or a C1-C16 alkyl group. R ３ These are C1-C16 alkyl groups or halogenated C1-C16 alkyl groups. R ４ is hydrogen or a C1-C16 alkyl group, R ５ These are C1-C16 alkyl groups, C2-C16 alkenyl groups, C1-C16 alkoxy groups, or C1-C16 alkanoyloxy C1-C6 alkoxy groups. An N-substituted quinolinone compound as described in feature 1, or a pharmaceutically acceptable salt, solvate, stereoisomer, geometric isomer, or isotope-labeled product thereof.

3. In general formula (I), Y １ These are independently -CH2- or -CH(CH3)-, R ２ This is an amino group substituted with a C1-C30 alkyl group, a C2-C30 alkenyl group, or a C1-C12 alkyl group. R ３ These are C1-C16 alkyl groups or halogenated C1-C16 alkyl groups. R ４ is hydrogen or a C1-C16 alkyl group, R ５ These are C1-C12 alkyl groups, C2-C12 alkenyl groups, C1-C12 alkoxy groups, or C1-C12 alkanoyloxy C1-C6 alkoxy groups. An N-substituted quinolinone compound as described in feature 1, or a pharmaceutically acceptable salt, solvate, stereoisomer, geometric isomer, or isotope-labeled product thereof.

4. In general formula (I), Y1 is independently -CH2- or -CH(CH3)-, R2 is a C1-C30 linear alkyl group, tert-butyl group, 1-methylpropyl group, 3-methylbutyl group, 1-methylbutyl group, 1,1-dimethylpentyl group, 1-methylpentyl group, 1-methylhexyl group, 1-pentylhexyl group, C2-C20 alkenyl group, decyl-NH-, or heptanyl-NH-. R3 is a C1-C16 alkyl group, R4 is hydrogen or a C1-C16 alkyl group. R5 is a decenyl group, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, or a decanoyloxymethoxy group. An N-substituted quinolinone compound as described in feature 1, or a pharmaceutically acceptable salt, solvate, stereoisomer, geometric isomer, or isotope-labeled product thereof.

5. It is represented by the following general formula (I-1) or (I-2), 【Chemistry 4】 Eventually, R １ , R ６ , R ７ , R ８ and R ９ Each of the claims has the definitions set forth in that claim. An N-substituted quinolinone compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt, solvate, stereoisomer, geometric isomer, or isotope-labeled product thereof.

6. R １ is, -Y １ -OC(=O)-R ２ And, Y １ is, -CH ２ - or -CH(CH ３ ) - and R ２ This is a C3-C16 alkyl group, a C3-C16 alkenyl group, or an amino group substituted with a C3-C16 alkyl group. An N-substituted quinolinone compound as described in feature 1, or a pharmaceutically acceptable salt, solvate, stereoisomer, geometric isomer, or isotope-labeled product thereof.

7. R １ is, -Y １ -O-R ４ or -C(=O)-R ５ And, R ４ is hydrogen or a C1-C12 alkyl group, R ５ This is a C2-C12 alkenyl group or a C1-C12 alkoxy group. An N-substituted quinolinone compound according to feature 3, or a pharmaceutically acceptable salt, solvate, stereoisomer, geometric isomer, or isotope-labeled product thereof.

8. R ６ , R ７ , R ８ and R ９ These are each hydrogen atoms, independently of each other. R １ is, -Y １ -OC(=O)-R ２ , -Y １ -OC(=O)-OR ３ , -Y １ -O-R ４ or -C(=O)-R ５ And, Y １ is, -CH ２ - or -CH(CH ３ ) - and R ２ These are C1-C16 alkyl groups, R ３ These are C1-C12 alkyl groups, R ４ It is hydrogen, R ５ is a C1-C6 alkyl group or a C1-C6 alkoxy group. An N-substituted quinolinone compound as described in feature 1, or a pharmaceutically acceptable salt, solvate, stereoisomer, geometric isomer, or isotope-labeled product thereof.

9. R ６ , R ７ , R ８ and R ９ These are each hydrogen atoms, independently of each other. R １ is, -Y １ -OC(=O)-R ２ And, Y １ is, -CH ２ - or -CH(CH ３ ) - and R ２ These are C1-C30 alkyl groups. An N-substituted quinolinone compound as described in feature 1, or a pharmaceutically acceptable salt, solvate, stereoisomer, geometric isomer, or isotope-labeled product thereof.

10. The following N-substituted quinolinone compounds, or their pharmaceutically acceptable salts, solvates, stereoisomers, geometric isomers, or isotope-labeled compounds, 【Chemistry 5-1】 【Chemistry 5-2】 【Chemistry 5-3】 【Chemistry 5-4】 【Transformation 5-5】 [Transformation 5-6] [Transformation 5-7] [Transformation 5-8] That is, N-substituted quinolinone compounds, or pharmaceutically acceptable salts, solvates, stereoisomers, geometric isomers, or isotopically labeled compounds thereof.

11. A method for producing an N-substituted quinolinone compound according to any one of claims 1 to 4 and 10, or a pharmaceutically acceptable salt, solvate, stereoisomer, geometric isomer or isotope-labeled product thereof, which is one of methods 1 to 4. Method 1: React the compound represented by formula (II) or a salt thereof with the compound represented by formula (III) or a salt thereof. 【Transformation 6】 Eventually, 【Transformation 7】 , R １ , R ６ , R ７ , R ８ and R ９ is as defined in any one of claims 1 to 4 and 10, X is a halogen, a C1-C6 alkylsulfonyloxy group, a benzenesulfonyloxy group, or a naphthalenesulfonyloxy group, and the C1-C6 alkylsulfonyloxy group, benzenesulfonyloxy group, or naphthalenesulfonyloxy group is optionally substituted with one or more groups selected from halogens, C1-C6 alkyl groups, C1-C6 alkoxy groups, nitro groups, hydroxyl groups, amino groups, and C1-C6 alkanoyl groups. The above reaction is carried out in the presence or absence of a solvent, and in the presence or absence of a base. The reaction temperature ranges from room temperature to 200°C, and the reaction time is 1 to 120 hours. Method 2: React the compound represented by formula (IV) or a salt thereof with the compound represented by formula (V) or a salt thereof. 【Transformation 8】 Eventually, 【Chemistry 9】 , R １ , R ６ , R ７ , R ８ and R ９ is as defined in any one of claims 1 to 4 and 10, X １ This is a halogen or a trifluoromethanesulfonyloxy group. The above reaction is carried out in the presence of a palladium catalyst and a base. The reaction temperature ranges from room temperature to 200°C, and the reaction time is 1 to 30 hours. Method 3: A compound represented by formula (I-a) or a salt thereof and R １ Reacting with X, 【Chemistry 10】 Eventually, 【Chemistry 11】 , R １ , R ６ , R ７ , R ８ and R ９ This is as defined in any one of claims 1 to 4 and 10, X is a halogen, a C1-C6 alkylsulfonyloxy group, a benzenesulfonyloxy group, or a naphthalenesulfonyloxy group, and the C1-C6 alkylsulfonyloxy group, benzenesulfonyloxy group, or naphthalenesulfonyloxy group is optionally substituted with one or more groups selected from halogens, C1-C6 alkyl groups, C1-C6 alkoxy groups, nitro groups, hydroxyl groups, amino groups, and C1-C6 alkanoyl groups. The above reaction is carried out in the presence or absence of a solvent, and in the presence or absence of a base. The reaction temperature ranges from room temperature to 200°C, and the reaction time is 1 to 120 hours. Method 4: Compound represented by formula (I-b) or a salt thereof and X-C(=O)-R ２ Or X-O-C(=O)-O-R ３ or X-R ４ The compound shown is subjected to a substitution reaction, 【Chemistry 12】 Eventually, R １ is, -Y １ -OC(=O)-R ２ , -Y １ -OC(=O)-OR ３ or -Y １ -O-R ４ And, 【Chemistry 13】 , R ６ , R ７ , R ８ , R ９ , Y １ , R ２ , R ３ and R ４ This is as defined in any one of claims 1 to 4 and 10, X is a halogen, The above reaction is carried out in the presence or absence of a solvent, and in the presence or absence of a base. The reaction temperature ranges from room temperature to 200°C, and the reaction time is 1 to 120 hours. method.

12. A drug composition comprising an N-substituted quinolinone compound according to any one of claims 1 to 4 and 10, or a pharmaceutically acceptable salt, solvate, stereoisomer, geometric isomer or isotope-labeled product thereof, and at least one pharmaceutically acceptable vector. Drug composition.

13. A method for producing the drug composition described in claim 12, comprising the step of mixing an N-substituted quinolinone compound described in any one of claims 1 to 4 and 10, or a pharmaceutically acceptable salt, solvate, stereoisomer, geometric isomer or isotope-labeled product thereof, with a pharmaceutically acceptable vector. method.

14. The use of an N-substituted quinolinone compound according to any one of claims 1 to 4 and 10, or a pharmaceutically acceptable salt, solvate, stereoisomer, geometric isomer or isotope-labeled product thereof, in the manufacture of a drug for preventing and / or treating a central nervous system disease, condition or disorder, The aforementioned central nervous system disorders, conditions, or disorders are selected from schizophrenia, affective disorders, mental disorders, mood disorders, bipolar I disorder, bipolar II disorder, depression, dysthymic disorder, cyclothymic disorder, panic attacks, panic disorder, social anxiety disorder, obsessive-compulsive disorder, impulsivity disorder, post-traumatic stress disorder, anxiety disorders, acute stress disorder, hysteria, anorexia nervosa, sleep disorders, adjustment disorders, cognitive impairment, autism, neurotic headache, mania, Parkinson's disease, Huntington's disease, Alzheimer's disease, dementia, memory impairment, hyperactivity disorder, attention deficit / hyperactivity disorder, and tic disorders. use.

15. The use of the drug composition according to claim 12 in the manufacture of a drug for preventing and / or treating a central nervous system disease, condition or disorder, The aforementioned central nervous system disorders, conditions, or disorders are selected from schizophrenia, affective disorders, mental disorders, mood disorders, bipolar I disorder, bipolar II disorder, depression, dysthymic disorder, cyclothymic disorder, panic attacks, panic disorder, social anxiety disorder, obsessive-compulsive disorder, impulsivity disorder, post-traumatic stress disorder, anxiety disorders, acute stress disorder, hysteria, anorexia nervosa, sleep disorders, adjustment disorders, cognitive impairment, autism, neurotic headache, mania, Parkinson's disease, Huntington's disease, Alzheimer's disease, dementia, memory impairment, hyperactivity disorder, attention deficit / hyperactivity disorder, and tic disorders. use.

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