Heterocyclic substituted fused γ-carboline derivatives, preparation methods, intermediates and applications thereof

Abstract

The invention relates to a heterocyclic substituted fused γ-carboline derivative, a preparation method thereof, an intermediate and an application thereof. The derivative has a compound structure as shown in formula (I). The compound can be used to prepare a drug for treating neuropsychiatric diseases.

Description

[0001] This application claims the priority of Chinese patent application No. 202011075840.6 filed on October 9, 2020, and claims the priority of Chinese patent application No. 202011074344.9 filed on October 9, 2020. This application cites the full text of the above Chinese patent application. Technical Field

[0002] The present invention belongs to the field of pharmaceutical chemistry, and specifically relates to a heterocyclic substituted fused γ-carboline derivative, synthesis and application thereof. More specifically, the present invention relates to a heterocyclic substituted fused γ-carboline derivative, a preparation method thereof, an intermediate, a pharmaceutical composition comprising the heterocyclic substituted fused γ-carboline derivative, and use of the heterocyclic substituted fused γ-carboline derivative and the pharmaceutical composition thereof in preparing drugs for preventing and / or treating neuropsychiatric diseases. Background Art

[0003] Schizophrenia is a disease characterized by a profound split in cognition and emotion, affecting the most basic human behaviors, such as language, thought, perception, and self-perception. The symptoms of the disease cover a wide range, with the most common being mental disorders such as hallucinations, delusions, and delusions.

[0004] About 1% of the world's population suffers from schizophrenia, but only 5% of all patients who receive treatment will eventually fully recover. In addition, schizophrenia often causes comorbidities such as anxiety disorders, depression or psychotropic drug abuse.

[0005] Traditionally, antipsychotic drugs that exert their pharmacological effects by blocking dopamine D2 receptors are called first-generation antipsychotic drugs, that is, "typical" antipsychotic drugs (such as haloperidol). They have a breakthrough effect on the treatment of positive symptoms of schizophrenia, but fail to treat negative symptoms and cognitive impairment. Typical antipsychotic drugs generally have serious EPS side effects and are ineffective for one-third of schizophrenia patients.

[0006] After the 1960s, a series of new generation antipsychotics were developed, including Ziprasidone, Risperidone, etc., which are called second generation antipsychotics, that is, new antipsychotics. Although their pharmacological effects are not completely consistent, they have common pharmacological characteristics, that is, the affinity for 5-hydroxytryptamine (5-HT) receptors (5-HT1A, 2A, 2c) and norepinephrine (NA) receptors (α1, α2) is much higher than that for D2 receptors, resulting in a higher ratio of D2 / 5-HT2A. Its clinical effect has more advantages than the first generation of antipsychotics. It is not only as effective as traditional antipsychotics for positive symptoms, but also effective for negative symptoms and cognitive deficits, and has a wider spectrum of action. However, these drugs have adverse reactions such as QT interval prolongation, hyperprolactinemia and weight gain. Therefore, finding drugs that are effective for positive and negative symptoms and cognitive impairment of schizophrenia and have fewer side effects is a hot topic of research now.

[0007] The serotonin system plays an important role in regulating the functions of the prefrontal cortex (PFC), including emotional control, cognitive behavior, and working memory. The pyramidal neurons and GABA interneurons of the PFC contain several serotonin receptor subtypes 5-HT1A and 5-HT2A with particularly high densities. Recently, it has been demonstrated that PFC and NMDA receptor channels are targets of 5-HT1AR, which regulate excitatory neurons in the cerebral cortex and thus affect cognitive functions. In fact, various preclinical data suggest that 5-HT1AR may be a new target for the development of antipsychotic drugs. The high affinity of atypical antipsychotic drugs (such as olanzapine, aripiprazole, etc.) for 5-HT1AR and their low EPS side effects indicate that the serotonin system plays an important role in regulating the functions of the prefrontal cortex (PFC), including emotional control, cognitive behavior, and working memory. The pyramidal neurons and GABA interneurons of the PFC contain several serotonin receptor subtypes 5-HT1A and 5-HT2A with particularly high densities. Recent studies have shown that 5-HT1A agonists are associated with atypical antipsychotic treatment and can improve negative symptoms and cognitive impairment. In the treatment of schizophrenia with the atypical antipsychotic clozapine, 5-HT2A has been found to play a very important role in various aspects of perception, emotion regulation, and motor control. Blocking 5-HT2A receptors can normalize the release of dopamine and play an antipsychotic role. In addition, 5-HT2C receptors are closely related to weight gain.

[0008] The distribution of D3 receptors in the brain is mainly selectively distributed in the limbic system. There are two main DA neural pathways in the brain. One is the substantia nigra striatum pathway that regulates motor function, and the other is the ventral tegmental area of ​​the midbrain. The prefrontal cortex DA pathway is closely related to learning, cognition, and emotional activities. Its dysfunction will lead to schizophrenia. This DA pathway is also the main pathway for reward effects in the brain. D3R is distributed in both DA neural pathways and has complex interactions with other DA receptor subtypes. It may be used as a target for antipsychotic drug treatment. The selective D3 receptor antagonism can reduce the negative and cognitive symptoms of schizophrenia. In addition, it can prevent extrapyramidal side effects, including tardive dyskinesia and Parkinson's disease. Therefore, finding an anti-schizophrenia drug with multiple receptor binding and few side effects is of great significance for clinical treatment.

[0009] In 2019, the FDA newly approved the anti-schizophrenia drug Lumateperone (R&D code ITI-007), which acts as an antagonist of the 5-HT2A receptor and antagonizes several dopamine receptor subtypes (D1, D2, and D4). It has a moderate 5-HT transporter reuptake inhibitory effect. It has additional off-target antagonism on α-1 receptors and has no obvious antimuscarinic or antihistamine properties. Its specific structure is shown below:

[0010]

[0011] Patent PCT / US2017 / 015178 discloses Markush compounds, which act on receptors such as 5-HT2A, D2, D1 and SERT (serotonin reuptake transporter), and have potential therapeutic activity for schizophrenia and Parkinson's disease.

[0012]

[0013] Although there are many drugs for treating schizophrenia, the current clinically used schizophrenia drugs still have a variety of adverse reactions. For example, among patients taking aripiprazole, a widely used atypical antipsychotic drug, more than 10% of patients will experience adverse reactions including weight gain, headache, akathisia, insomnia and gastrointestinal discomfort, which will cause patients to stop taking the drug and the disease will recur. In addition, although the current anti-schizophrenia negative symptom drugs (referring to the existence of defects in normal emotional reactions and other thinking processes) have been used in clinical practice, the negative symptoms of some patients have been improved, but the overall effect is limited. There are still many patients who cannot recover and restore normal social functions due to negative symptoms, making it difficult to resume normal social work. In addition, the treatment of cognitive impairment is also a focus of the current treatment of schizophrenia, affecting the verbal memory, semantic processing ability and attention function of most schizophrenia patients, and the anti-schizophrenia drugs currently under development or on the market have very limited improvement in cognitive function.

[0014] In addition to the above problems, the current antipsychotic drugs for schizophrenia are still in a dilemma. Refractory schizophrenia refers to a type of patients who cannot achieve ideal therapeutic effects by following the general treatment method. Such patients have been treated with three different active ingredients of antipsychotic drugs, with sufficient doses and courses, but the treatment response is poor or they cannot tolerate the adverse reactions of antipsychotic drugs, or even with adequate maintenance or preventive treatment, the condition still recurs or worsens. Therefore, the treatment of refractory schizophrenia has always been a difficult problem in current clinical drug research, and it is also a direction that needs to be overcome urgently.

[0015] In summary, antipsychotic drugs that have good and sustained effective negative symptom treatment effects, improve patients' cognitive functions, and can effectively treat refractory schizophrenia should also have lower adverse drug reactions (such as extrapyramidal reactions, weight gain, nausea and vomiting, and other adverse drug reactions). Antipsychotic drugs that act on multiple targets are still a hot research direction in the central nervous system field. Summary of the invention

[0016] The present invention aims to provide a novel anti-schizophrenia drug that acts on 5-hydroxytryptamine receptors and / or dopamine receptors, has good antagonistic activity on 5-HT2A receptors and / or dopamine D2 receptors, and can effectively treat and improve schizophrenia.

[0017] The object of the present invention is to provide a heterocyclic substituted fused γ-carboline derivative having the activity of treating psychoneurological diseases, a pharmaceutical composition thereof and its application in the medical field.

[0018] The present invention provides a compound represented by general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:

[0019]

[0020] in,

[0021] R1 is independently C1-C6 alkyl optionally substituted by halogen, C1-C3 alkoxy, cyano, amino, nitro, hydroxy, C2-C4 alkenyl, C2-C4 alkynyl, C3-C5 cycloalkyl;

[0022] R2 is independently -R7-R8-R9-;

[0023] R3 is independently hydrogen, or any one of C1-C3 alkyl;

[0024] R4 is independently any one of -C(=O)- or -CH2-;

[0025] R5 and R6 are each independently hydrogen, or any one of C1-C3 alkyl optionally substituted by halogen, C1-C3 alkoxy, cyano, amino, nitro, hydroxyl, C2-C4 alkenyl, C2-C4 alkynyl, or R5, R6 and the carbon atom directly connected thereto together form -C(=O)-;

[0026] R7 is independently a C1-C5 alkylene group;

[0027] R8 is independently any one of -C(=O)-, -CH2- or -O-;

[0028] R9 is independently a C1-C3 alkylene group or absent;

[0029] A is phenyl optionally substituted by one or more halogens.

[0030] In one embodiment of the present invention, R1 is independently a C1-C3 alkyl group optionally substituted by halogen, C1-C3 alkoxy, cyano, amino, nitro, hydroxyl, C2-C4 alkenyl, C2-C4 alkynyl, or C3-C5 cycloalkyl.

[0031] In one embodiment of the present invention, R3 is independently hydrogen or any one of C1-C3 alkyl groups.

[0032] In one embodiment of the present invention, in the compound represented by the general formula (I), R4 is -CH2-.

[0033] In one embodiment of the present invention, R4 is -C(=O)-.

[0034] In an embodiment of the present invention, R5 and R6 are each independently hydrogen, or any one of unsubstituted C1-C3 alkyl groups, or R5, R6 and the carbon atom directly connected thereto together form -C(=O)-.

[0035] In one embodiment of the present invention, R5 and R6 are each independently hydrogen.

[0036] In one embodiment of the present invention, in the compound represented by the general formula (I), R4 is -CH2-, and R5 and R6 are each independently hydrogen.

[0037] In one embodiment of the present invention, A is independently phenyl substituted by one or more halogens.

[0038] In one embodiment of the present invention, the R1 is independently an unsubstituted C1-C3 alkyl group.

[0039] In one embodiment of the present invention, R3 is independently hydrogen or any one of unsubstituted C1-C3 alkyl groups.

[0040] In an embodiment of the present invention, the C1-C3 alkyl group in the optionally substituted C1-C3 alkyl group is selected from any one of methyl, ethyl or propyl.

[0041] In an embodiment of the present invention, the unsubstituted C1-C3 alkyl group is selected from any one of methyl, ethyl or propyl.

[0042] In one embodiment of the present invention, the C1-C5 alkylene group is selected from C3-C5 alkylene group.

[0043] In one embodiment of the present invention, the C1-C3 alkylene group is selected from C1-C2 alkylene groups.

[0044] In an embodiment of the present invention, the halogen is any one of fluorine, chlorine, bromine or iodine.

[0045] In one embodiment of the present invention, the compound represented by the general formula (I) is selected from the compounds represented by the general formula (IA) shown below:

[0046]

[0047] in,

[0048] X is a halogen; X is substituted at any substitutable position of the benzene ring; X is monosubstituted or polysubstituted, preferably monosubstituted;

[0049] R1, R3, R4, R5, R6, R7, R8 and R9 are as defined above.

[0050] In one embodiment of the present invention, the halogen is any one of fluorine, chlorine, bromine or iodine, preferably fluorine.

[0051] In one embodiment of the present invention, the compound represented by the general formula (I) is selected from the compounds represented by the general formula (IB) shown below:

[0052]

[0053] R1, R3, R4, R5, R6, R7, R8, R9 and X are as defined above.

[0054] In one embodiment of the present invention, the compound represented by the general formula (I) is selected from the compounds represented by the general formula (IB) shown below:

[0055]

[0056] in,

[0057] R1 is independently any one of methyl, ethyl or propyl;

[0058] R3 is independently any one of hydrogen, methyl, ethyl, or propyl;

[0059] R4 is independently -C(=O)-, or -CH2-;

[0060] R5 and R6 are each independently any one of hydrogen, methyl, or ethyl, or R5, R6 and the carbon atom directly connected thereto together form -C(=O)-;

[0061] R7 is independently any one of -CH2-CH2-, -CH2-CH2-CH2- or -CH2-CH2-CH2-CH2-;

[0062] R8 is independently any one of -C(=O)-, -CH2- or -O-;

[0063] R9 is independently -CH2-CH2-, -CH2- or absent;

[0064] X is independently fluorine or chlorine.

[0065] In one embodiment of the present invention, the C2-C4 alkenyl group includes but is not limited to -CH2=CH2, -CH2-CH=CH2, -CH=CH-CH2, -CH=CH-CH2, -CH=CH-CH2-CH2, -CH2-CH=CH-CH2, -CH2-CH=CH-CH2, -CH2-CH-CH=CH, etc.

[0066] In one embodiment of the present invention, the C2-C4 alkenyl is preferably a C2-C3 alkenyl, selected from any one of -CH2=CH2, -CH2-CH=CH2 or -CH=CH-CH2.

[0067] In one embodiment of the present invention, the C2-C4 alkynyl group includes but is not limited to -C≡C, -CH2-C≡C, -C≡C-CH2, -C≡C-CH2-CH2, -CH2-C≡C-CH2, -CH2-C≡C-CH2, -CH2-CH-C≡C and the like.

[0068] In one embodiment of the present invention, the C2-C4 alkynyl group is preferably a C2-C3 alkynyl group, selected from any one of -C≡C, -CH2-C≡C or -C≡C-CH2.

[0069] In one embodiment of the present invention, the C1-C3 alkoxy group is selected from any one of -O-CH3, -O-CH2-CH3, -O-CH2-CH2-CH3, and -O-CH(CH3)-CH3, preferably any one of -O-CH3 or -O-CH2-CH3.

[0070] In one embodiment of the present invention, the alkylene group is a saturated aliphatic hydrocarbon straight-chain group having 1-20 carbon atoms. The C1-C5 alkylene group of the present invention is any one of -CH2-, -CH2-CH2-, -CH2-CH2-CH2-, -CH2-CH2-CH2-CH2, -CH2-CH2-CH2-CH2-CH2- or -CH2-CH2-CH2-CH2-CH2-CH2-; the C1-C3 alkylene group is any one of -CH2-, -CH2-CH2- or -CH2-CH2-CH2-CH2-; the C1-C2 alkylene group is any one of -CH2- or -CH2-CH2-CH2-.

[0071] In one embodiment of the present invention, the compound represented by the general formula (I) is selected from the compounds represented by the general formula (IC) shown below:

[0072]

[0073] in,

[0074] R1 is independently any one of methyl, ethyl or propyl;

[0075] R3 is independently any one of methyl, ethyl or propyl;

[0076] R4 is independently -C(=O)-, or -CH2-;

[0077] R5 and R6 are each independently any one of hydrogen, methyl, or ethyl, or R5, R6 and the carbon atom directly connected thereto together form -C(=O)-.

[0078] In one embodiment of the present invention, the compound represented by the general formula (I), its stereoisomer or its pharmaceutically acceptable salt is selected from any one of the specific compounds shown below:

[0079]

[0080]

[0081] In one embodiment of the present invention, a pharmaceutically acceptable salt of any compound of formula (I) as described above is selected from fumarate, maleate, phosphate, nitrate, sulfate, benzenesulfonate, or oxalate.

[0082] The present invention also provides a compound represented by the general formula (ID), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:

[0083]

[0084] in:

[0085] R1, R3, R4, R5 and R6 are as defined above.

[0086] In a preferred embodiment of the present invention, in the compound represented by the general formula (ID),

[0087] R1 is independently any one of methyl, ethyl or propyl;

[0088] R3 is independently any one of methyl, ethyl or propyl;

[0089] R4 is independently -C(=O)-, or -CH2-;

[0090] R5 and R6 are each independently any one of hydrogen, methyl, or ethyl, or R5, R6 and the carbon atom directly connected thereto together form -C(=O)-.

[0091] The present invention provides a method for preparing a compound represented by general formula (I), general formula (IA), general formula (IB) or general formula (IC), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, which uses a compound represented by general formula (ID) as a starting material or intermediate; the method may include the following steps:

[0092]

[0093] The compound of formula (ID) and the compound of formula (IE) are reacted by a nucleophilic substitution reaction to obtain a compound of formula (I);

[0094] in:

[0095] X1 is halogen selected from fluorine, chlorine, bromine or iodine, preferably chlorine;

[0096] R1, R2, R3, R4, R5, R6 and A are as defined above.

[0097] In one embodiment of the present invention, a method for preparing a compound represented by general formula (IC), a stereoisomer thereof or a pharmaceutically acceptable salt thereof comprises the following steps:

[0098]

[0099] The compound of formula (IC) is prepared by reacting the compound of formula (ID) with the compound of formula (IE') through a nucleophilic substitution reaction;

[0100] in:

[0101] X1 is halogen selected from fluorine, chlorine, bromine or iodine, preferably chlorine;

[0102] R1, R3, R4, R5 and R6 are as defined above.

[0103] The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of the compound represented by the general formula (I) as described above, its stereoisomers or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier.

[0104] In one embodiment of the present invention, the pharmaceutical composition can be formulated in a conventional manner using one or more pharmaceutically acceptable carriers. Therefore, the active compound of the present invention can be formulated into a dosage form for oral, buccal, intranasal, parenteral (e.g., intravenous, intramuscular or subcutaneous) or rectal administration, or a dosage form suitable for administration by inhalation or insufflation. The compound of the present invention or its pharmaceutically acceptable salt can also be formulated into a sustained release dosage form.

[0105] In one embodiment of the present invention, an effective dose of the compound of the present invention or a pharmaceutically acceptable salt thereof can be taken orally with an inert diluent or a carrier. According to some embodiments of the present invention, the compound of the present invention can be encapsulated in a gelatin capsule or compressed into tablets. For the purpose of oral treatment, the compound of the present invention can be used together with an excipient and in the form of tablets, lozenges, capsules, suspensions, syrups, etc. According to an embodiment of the present invention, the above-mentioned preparation should contain at least 0.5% (w / w) of the active compound of the present invention, but can be changed according to a specific dosage form, wherein 4% to about 70% of the unit weight is convenient. The amount of the active compound in such a pharmaceutical composition should reach an appropriate dose.

[0106] In one embodiment of the present invention, for oral administration, the active compound of the present invention can be formulated into tablets or capsules by conventional means with pharmaceutically acceptable excipients, such as adhesives, fillers, lubricants, disintegrants or wetting agents. Tablets can be coated by methods well known in the art. Liquid preparations for oral administration can be solutions, syrups or suspensions, or evaporated into dry products, and regenerated with water or other suitable carriers before use. Such liquid preparations can be prepared by conventional means using pharmaceutical additives, such as suspending agents, emulsifiers, non-aqueous carriers and preservatives.

[0107] In one embodiment of the present invention, when the active compound of the present invention is used for parenteral administration, the compound provided by the present invention can be combined with sterile water or organic medium to form an injectable solution or suspension.

[0108] In one embodiment of the invention, the active compounds of the invention may be formulated in rectal compositions such as suppositories or retention enemas, eg, containing conventional suppository bases such as cocoa butter or other glycerides.

[0109] The present invention also provides a use of a compound represented by general formula (I), a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the preparation of a drug involving or regulating a 5-hydroxytryptamine receptor, a 5-hydroxytryptamine transporter (SERT), and / or a dopamine receptor, preferably in the preparation of a drug involving or regulating a 5-HT2A receptor, a 5-hydroxytryptamine transporter, a dopamine D1 receptor, and / or a dopamine D2 receptor, more preferably in the preparation of a drug involving or regulating a 5-HT2A receptor and / or a dopamine D2 receptor. The drug optionally contains one or more additional active agents that regulate the mammalian nervous system or alleviate mental illness.

[0110] In one embodiment of the present invention, the regulation (modulation) includes but is not limited to the inhibitory activity or antagonistic activity on the receptor.

[0111] In one embodiment of the present invention, the present invention also provides a use of a compound represented by general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof in the preparation of a drug for treating neuropsychiatric diseases.

[0112] In one embodiment of the present invention, the neuropsychiatric disease is selected from one or more of depression (such as major depressive disorder (MDD)), anxiety, dementia, schizophrenia, sleep disorders, movement disorders, behavioral disorders in patients with dementia, Parkinson's disease, Alzheimer's disease, migraine, hyperactivity disorder (such as attention deficit hyperactivity disorder), obsessive-compulsive disorder, social phobia, neurodegenerative diseases, bipolar disorder, post-traumatic stress syndrome, addictive diseases, withdrawal syndrome or attention deficit.

[0113] In one embodiment of the present invention, the neuropsychiatric disease described in the present invention is preferably any one or more of depression (such as major depressive disorder MDD), anxiety, dementia, schizophrenia, sleep disorders, movement disorders, behavioral disorders in patients with dementia, neurodegenerative diseases or bipolar disorder, more preferably one or more of depression, anxiety, schizophrenia or neurodegenerative diseases.

[0114] In one embodiment of the present invention, the neuropsychiatric disease is preferably schizophrenia.

[0115] The present invention further relates to a method for treating, alleviating and / or preventing diseases involving 5-hydroxytryptamine receptors, 5-hydroxytryptamine transporters (SERT) and / or dopamine receptors, the method comprising administering to a patient in need thereof a therapeutically effective dose of a compound of the aforementioned general formula of the present invention or a pharmaceutically acceptable salt thereof; preferably, it relates to a method for treating, alleviating or preventing diseases involving 5-HT2A receptors, 5-hydroxytryptamine transporters, dopamine D1 receptors and / or dopamine D2 receptors, the method comprising administering to a patient in need thereof a therapeutically effective dose of a compound of the aforementioned general formula of the present invention or a pharmaceutically acceptable salt thereof. In some embodiments of the present invention, the 5-hydroxytryptamine receptor is preferably a 5-HT2A receptor, and the dopamine receptor is preferably a dopamine D2 receptor. The method exhibits outstanding efficacy and fewer side effects.

[0116] In some embodiments of the present invention, the present invention relates to a method for treating, alleviating and / or preventing neuropsychiatric diseases, which comprises administering a therapeutically effective dose of a compound represented by the aforementioned general formula of the present invention or a pharmaceutically acceptable salt thereof to a patient in need thereof.

[0117] In some preferred embodiments of the present invention, the neuropsychiatric disease is selected from one or more of depression (such as major depressive disorder), anxiety, dementia, schizophrenia, sleep disorders, movement disorders, behavioral disorders in patients with dementia, Parkinson's disease, Alzheimer's disease, migraine, ADHD (such as attention deficit hyperactivity disorder), obsessive-compulsive disorder, social phobia, neurodegenerative diseases, bipolar disorder, post-traumatic stress syndrome, addictive diseases, withdrawal syndrome, or attention deficit, preferably any one or more of depression (such as major depressive disorder), anxiety, dementia, schizophrenia, sleep disorders, movement disorders, behavioral disorders in patients with dementia, neurodegenerative diseases or bipolar disorder.

[0118] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood by those of ordinary skill in the art to which the invention belongs. In the event of a conflict, the definitions provided herein shall prevail. When a trade name appears in this article, it is intended to refer to the corresponding commodity or its active ingredient. All patents, published patent applications and publications cited herein are incorporated herein by reference.

[0119] The terms "optional", "optionally" or "optionally present" mean that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not occur. For example, "optionally present bond" means that the bond may or may not exist, and that the description includes single, double or triple bonds, etc.

[0120] The terms "include", "comprising", "having", "containing" or "involving" are open expressions, i.e., including the contents specified in the present invention, but not excluding other aspects. It should be understood that the above terms such as "comprising" can include closed meanings, i.e., "consisting of...".

[0121] As described herein, the compounds of the present invention may be optionally substituted with one or more substituents, such as the general formula compounds above or as specific examples, subclasses in the examples. It should be understood that the term "optionally substituted" and the term "substituted or unsubstituted" can be used interchangeably. In general, the term "substituted" means that one or more hydrogen atoms in a given structure are replaced by a specific substituent. Unless otherwise indicated, an optionally substituted group can be substituted at each substitutable position of the group. When more than one position in the given structural formula can be substituted by one or more substituents selected from a specific group, then the substituents can be substituted at each position in the same or different manner.

[0122] In addition, it should be noted that, unless explicitly stated otherwise, the description method of "respectively and independently" used in the present invention should be understood in a broad sense, which can mean that in different groups, the specific options expressed by the same symbols do not affect each other, or that in the same group, the specific options expressed by the same symbols do not affect each other.

[0123] Herein, "Z" and "-Z-" both represent the same specific group and can be used interchangeably.

[0124] Different expressions used herein such as “X is selected from A, B or C”, “X is selected from A, B and C”, “X is A, B or C”, “X is A, B and C” all express the same meaning, that is, X can be any one or more of A, B, C.

[0125] When any variable (e.g., R), as well as variables with labels (e.g., R1, R2, R3, R4, R5, R6, R7, etc.) occurs more than once in the composition or structure of a compound, its definition at each occurrence is independent. For example, if a group is substituted with 0, 1, 2, 3, or 4 R substituents, the group may be optionally substituted with up to four R substituents, and the options for each R substituent in each case are independent of each other.

[0126] The term "pharmaceutically acceptable" refers to a substance that is, within the scope of normal medical judgment, suitable for contact with the tissues of patients without undue toxicity, irritation, allergic response, etc., commensurate with a reasonable benefit-risk ratio, and effective for its intended use.

[0127] The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention which are safe and effective when used in mammals and have the desired biological activity.

[0128] The term "pharmaceutically acceptable carrier" refers to those substances that have no significant irritation to organisms and do not impair the biological activity and performance of the active compound. "Pharmaceutically acceptable carrier" includes, but is not limited to, glidants, sweeteners, diluents, preservatives, dyes / colorants, flavoring agents, surfactants, wetting agents, dispersants, disintegrants, stabilizers, solvents or emulsifiers.

[0129] The term "administration" or "administering" refers to a method that enables a compound or composition to be delivered to a desired biological site of action. These methods include, but are not limited to, oral or parenteral (including intraventricular, intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular injection or infusion), topical, rectal administration, etc. In particular, injection or oral administration.

[0130] As used herein, the term "treat" includes alleviating, reducing or ameliorating a disease or symptom, preventing other symptoms, ameliorating or preventing the underlying metabolic factors of a symptom, inhibiting a disease or symptom, for example, preventing the disease or symptom from developing, alleviating a disease or symptom, promoting remission of a disease or symptom, or stopping the symptoms of a disease or symptom, and extends to include prevention. "Treatment" also includes achieving a therapeutic benefit and / or a prophylactic benefit. A therapeutic benefit refers to the eradication or improvement of the condition being treated. In addition, a therapeutic benefit is achieved by eradicating or improving one or more physiological signs associated with the underlying disease, and although the patient may still suffer from the underlying disease, an improvement in the patient's disease can be observed. A prophylactic benefit refers to the use of the composition by a patient to prevent the risk of a certain disease, or when a patient takes it when one or more physiological symptoms of a disease occur, although the disease has not yet been diagnosed.

[0131] The terms "active ingredient," "therapeutic agent," "active substance," or "active agent" refer to a chemical entity that is effective in treating or preventing a target disorder, disease, or condition.

[0132] The term "neuropsychiatric disease" refers to the general term for neurological diseases and mental diseases, including neurological diseases and / or mental diseases.

[0133] With respect to a drug, drug unit or active ingredient, the term "effective amount", "therapeutically effective amount" or "prophylactically effective amount" refers to a sufficient amount of the drug or pharmaceutical agent that can achieve the desired effect with acceptable side effects. The determination of the effective amount varies from person to person, depending on the age and general condition of the individual and on the specific active substance. The appropriate effective amount in each case can be determined by a person skilled in the art based on routine experiments.

[0134] As used herein, "individual" includes humans or non-human animals. Exemplary human individuals include human individuals (referred to as patients) suffering from diseases (e.g., diseases described herein) or normal individuals. "Non-human animals" in the present invention include all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, livestock and / or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).

[0135] In various parts of this specification, the substituents of the compounds disclosed in the present invention are disclosed according to the group type or range. It is particularly pointed out that the present invention includes each independent secondary combination of the individual members of these group types and ranges. For example, the term "C1-C6 alkyl" specifically refers to the independently disclosed methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl and C6 alkyl. Examples of alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), n-propyl (n-Pr, -CH2CH2CH3), isopropyl (i-Pr, -CH(CH3)2), n-butyl (n-Bu, -CH2CH2CH2CH3), isobutyl (i-Bu, -CH2CH2CH2CH3), -CH2CH(CH3)2), sec-butyl (s-Bu, -CH(CH3)CH2CH3), tert-butyl (t-Bu, -C(CH3)3), n-pentyl (-CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl (-CH2CH2CH(CH3)2), 2-methyl-1-butyl (-CH2CH(CH3)CH2CH3), n-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH 3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3), n-heptyl, n-octyl, and the like.

[0136] The term "hydrogen (H)" refers to a single hydrogen atom. Such an atom group may be linked to other groups, such as an oxygen atom, to form a hydroxyl group.

[0137] The term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

[0138] The term "aryl" refers to a monocyclic, bicyclic and tricyclic carbocyclic ring system containing 6-14 ring atoms, or 6-12 ring atoms, or 6-10 ring atoms, wherein at least one ring is aromatic. The aryl group is usually, but not necessarily connected to the parent molecule through the aromatic ring of the aryl group. The example of the aryl group can include phenyl, naphthyl and anthracene. The aryl group is optionally substituted by one or more substituents described in the present invention.

[0139] Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH3), ethoxy (EtO, -OCH2CH3), 1-propoxy (n-PrO, n-propoxy, -OCH2CH2CH3), 2-propoxy (i-PrO, i-propoxy, -OCH(CH3)2), 1-butoxy (n-BuO, n-butoxy, -OCH2CH2CH2CH3), 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH(CH3)2), alkyl, -OCH2CH(CH3)2), 2-butoxy (s-BuO, s-butoxy, -OCH(CH3)CH2CH3), 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC(CH3)3), 1-pentyloxy (n-pentyloxy, -OCH2CH2CH2CH2CH3), 2-pentyloxy (-OCH(CH3)CH2CH2CH3), 3-pentyloxy (-OCH(CH2CH3)2).

[0140] The term "-C(=O)-" refers to a carbonyl group.

[0141] The following detailed description of the invention is intended to illustrate non-limiting embodiments so that other technical personnel in the art can more fully understand the technical solutions, principles and practical applications of the present invention, so that other technical personnel in the art can modify and implement the present invention in many forms to best adapt it to the requirements of specific uses.

[0142] Beneficial technical effects of the present invention

[0143] The compound provided by the present invention is a kind of compound acting on 5-HT 2A receptors and / or D2 receptor antagonists, 5-HT 2A receptors and / or D2(D 2L , D 2s ) receptors; and / or have a high D2 / 5-HT2A ratio and good selectivity; and / or have good pharmacokinetic properties; and / or have good in vivo pharmacodynamic effects; and / or are not only as effective as traditional antipsychotics for positive symptoms, but also have a stronger improvement effect on negative symptoms and cognitive deficits, and have lower side effects (such as reducing the possibility of inducing EPS reactions, etc.). DETAILED DESCRIPTION

[0144] The embodiments of the present invention are described in detail below. The embodiments described below are exemplary and are only used to explain the present invention, and cannot be understood as limiting the present invention. Unless otherwise specified, the ratios, percentages, etc. referred to herein are all by weight.

[0145] Synthesis Example

[0146] Example 1, 8-(4-(4-fluorophenyl)-4-oxobutyl)-3,6b-dimethyl-6b,7,8,9,10,10a-hexahydro-1H-pyridin[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-2(3H)-one (Compound 1)

[0147] Step 1: Preparation of 4-nitroso-3,4-dihydroquinoxaline-2(1H)-one (Intermediate 1-2)

[0148]

[0149] The raw material 3,4-dihydroquinoxaline-2(1H)-one (2.3 g, 16 mmol) was dissolved in a mixed solvent of acetic acid and water (25 / 12 mL), and an aqueous solution (12 mL) of sodium nitrite (1.1 g, 16 mmol) was slowly added dropwise under ice bath conditions. After the reaction was kept warm for 2 h, the reaction solution was filtered, the filter cake was washed with water (12 mL), and dried to obtain intermediate 1-2, a yellow solid of 2.2 g, with a yield of 81%. LCMS m / z (M+H) + :178.1.

[0150] Step 2: Preparation of 4-amino-3,4-dihydroquinoxaline-2(1H)-one hydrochloride (Intermediate 1-3)

[0151]

[0152] The intermediate 1-2 (1.5 g, 8.47 mmol) was dissolved in a mixed solvent of glacial acetic acid and water (25 / 25 mL), and zinc powder (3.0 g, 46.1 mmol) was slowly added under ice bath conditions. After the reaction was kept warm for 30 min, the mixture was moved to room temperature and stirred for 2 h. After the reaction solution was filtered and concentrated, the concentrate was redissolved in ethyl acetate (100 mL) and stirred for 30 min. The reaction solution was filtered again, and the filtrate was dried and a 4N hydrogen chloride dioxane solution (3 mL) was added. After stirring for 30 min, the reaction solution was concentrated to obtain the intermediate 1-3, 1.5 g of a crude yellow solid, which was directly used as a raw material in the next step without further purification.

[0153] Step 3: Preparation of 6b-methyl-8-(2,2,2-trifluoroacetyl)-6b,7,8,9,10,10a-hexahydro-1H-pyridin[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-2(3H)-one (Intermediate 1-5)

[0154]

[0155] Intermediate 1-3 (1.5 g, 7.54 mmol) and intermediate 1-4 (1.4 g, 6.78 mmol) were added to isopropanol (50 mL) and reacted at 110°C for 15 h. The reaction solution was cooled to room temperature and concentrated. The product was separated and purified by column chromatography (DCM / MeOH=1 / 20) to obtain intermediate 1-5, a yellow solid of 620 mg, with a yield of 27%. LCMS m / z (M+H) + :340.1.

[0156] Step 4: Preparation of 3,6b-dimethyl-8-(2,2,2-trifluoroacetyl)-6b,7,8,9,10,10a-hexahydro-1H-pyridin[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-2(3H)-one (Intermediate 1-6)

[0157]

[0158] The intermediate 1-5 (0.62 g, 1.83 mmol) was dissolved in DMF (10 mL), sodium hydrogen (110 mg, 2.75 mmol) was added under ice bath conditions, and the reaction was kept warm for 30 min, and iodomethane (390 mg, 2.75 mmol) was added, and then the reaction solution was moved to room temperature and stirred for 2 h. After the reaction was completed, the reaction solution was placed in an ice bath again, and the reaction solution was quenched by adding water (5 mL). The reaction solution was extracted with ethyl acetate (20 mL x 3), and the organic phase was dried over sodium sulfate. The product was separated and purified by column chromatography to obtain the target intermediate 1-6, a yellow solid of 500 mg, with a yield of 77%. LCMS m / z (M+H) + :354.1.

[0159] Step 5: Preparation of 3,6b-dimethyl-6b,7,8,9,10,10a-hexahydro-1H-pyridin[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-2(3H)-one (Intermediate 1-7)

[0160]

[0161] The intermediate 1-6 (0.5 g, 1.41 mmol) was dissolved in a mixed solvent of tetrahydrofuran and water (50 / 5 mL), sodium hydroxide (113 mg, 2.82 mmol) was added to the above solution, and the reaction solution was reacted at 40°C for 15 h, and then concentrated to remove tetrahydrofuran. The residue was extracted with a mixed solvent of dichloromethane and methanol (10 / 1, 20 mL x 3), and the organic phase was dried over sodium sulfate and purified by column chromatography (DCM / MeOH=10 / 1-5 / 1) to obtain the target intermediate 1-7, a yellow solid 200 mg, yield: 55%. LCMSm / z(M+H) + :258.2.

[0162] Step 6: Preparation of 8-(4-(4-fluorophenyl)-4-oxobutyl)-3,6b-dimethyl-6b,7,8,9,10,10a-hexahydro-1H-pyridin[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-2(3H)-one (Compound 1)

[0163]

[0164] Intermediate 1-7 (1.1 g, 4.28 mmol), intermediate 1-8 (1.7 g, 8.56 mmol), potassium iodide (1.4 g, 8.56 mmol) and DIEA (1.1 g, 8.56 mmol) were added to DMF (20 mL), the reaction solution was reacted at 78 ° C for 3 h and then cooled to room temperature. The reaction solution was directly concentrated, and the product was prepared by liquid phase (CH3CN:H2O (0.1% NH4HCO3) = 10-70%, UV: 214nm, flow rate 15mL / min) to obtain compound 1, 245 mg of off-white solid, yield: 13%. LRMS m / z (M+H) + :422.2.

[0165] 1 H NMR (CDCl3, 400MHz): δ8.06-8.03(m,2H),7.19-7.15(m,2H),6.88-6.76(m,3H),4.45(d,J=14.4Hz,1H),3. 41-3.37(m,4H),3.05-3.02(m,2H),2.95(s,1H),2.71-2.28(m,5H),1.99-1.87(m,4H),1.67-1.50(m,4H).

[0166] Example 1-A, Preparation of (6bR, 10aS)-8-(4-(4-fluorophenyl)-4-oxobutyl)-3,6b-dimethyl-6b,7,8,9,10,10a-hexahydro-1H-pyridin[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-2(3H)-one (Compound 1-A)

[0167]

[0168] Compound 1 (1.6 g) was subjected to chiral separation to obtain compound 1-A (427.7 mg). The chiral separation conditions are as follows:

[0169] instrument Gilson GX-281 Column Type Chiralpak IE 250mm*30mm 5μm Injection volume 1500μL Mobile phase Hex:EtOH=40:60 Flow rate 25mL / min Detection wavelength 254nm Column temperature 30℃

[0170] t R =6.968min

[0171] LCMS m / z(M+H) + :422.2.

[0172] 1 H NMR (400MHz, CDCl3): δ8.02-7.99(m,2H),7.16-7.10(m,2H),6.83-6.73(m,3H),4.01(d,J=14.0Hz,1H),3.35(d,J=14. 0Hz,1H),3.33(s,3H),3.00-2.91(m,3H),2.67-2.55(m,2H),2.40-2.19(m,3H),1.98-1.81(m,4H),1.55-1.46(m,4H).

[0173] Example 1-B, Preparation of (6bS, 10aR)-8-(4-(4-fluorophenyl)-4-oxobutyl)-3,6b-dimethyl-6b,7,8,9,10,10a-hexahydro-1H-pyridin[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-2(3H)-one (Compound 1-B)

[0174]

[0175] Compound 1 (1.6 g) was subjected to chiral separation to obtain compound 1-B (467.8 mg). The chiral separation conditions are as follows:

[0176] instrument Gilson GX-281 Column Type Chiralpak IE 250mm*30mm 5μm Injection volume 1500μL Mobile phase Hex:EtOH=40:60 Flow rate 25mL / min Detection wavelength 254nm Column temperature 30℃

[0177] t R =8.030min

[0178] LCMS m / z(M+H) +:422.2.

[0179] 1 H NMR (400MHz, CDCl3): δ8.02-7.99(m,2H),7.16-7.10(m,2H),6.84-6.73(m,3H),4.01(d,J=14.0Hz,1H),3.36(d,J=14. 0Hz,1H),3.33(s,3H),3.00-2.91(m,3H),2.67-2.55(m,2H),2.40-2.19(m,3H),1.98-1.81(m,4H),1.55-1.46(m,4H).

[0180] Example 2, Preparation of 6b-ethyl-8-(4-(4-fluorophenyl)-4-oxobutyl)-3-methyl-6b,7,8,9,10,10a-hexahydro-1H-pyridin[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-2(3H)-one (Compound 2)

[0181] Step 1: Preparation of 6b-ethyl-8-(2,2,2-trifluoroacetyl)-6b,7,8,9,10,10a-hexahydro-1H-pyridin[3',4':4,5]pyrrolo[1,2,3-di]quinoxaline-2(3H)-one (Intermediate 2-2)

[0182]

[0183] Intermediate 2-1 (800 mg, 3.58 mmol) and intermediate 1-3 (1.5 g, 9.2 mmol) were dissolved in isopropanol (50 mL), and the reaction solution was reacted at 110 ° C for 15 h. After the reaction solution was cooled to room temperature, it was evaporated under reduced pressure to obtain a crude product. The product was separated and purified by column chromatography (EA / PE=1 / 2) to obtain intermediate 2-2, a yellow solid of 360 mg, with a yield of 28.4%. LRMS m / z (M+H) + :354.2.

[0184] Step 2: Preparation of 6b-ethyl-3-methyl-8-(2,2,2-trifluoroacetyl)-6b,7,8,9,10,10a-hexahydro-1H-pyridin[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-2(3H)-one (Intermediate 2-3)

[0185]

[0186] Under ice bath conditions, NaH (68 mg, 1.70 mmol) was added to a DMF (15 mL) solution of intermediate 2-2 (400 mg, 1.13 mmol), and the mixture was kept warm for 30 min. Then, CH3I (241 mg, 1.70 mmol) was added to the reaction system. After the addition, the reaction solution was moved to room temperature for 16 h, quenched with water (15 mL) under ice bath conditions, and extracted with ethyl acetate (20 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (PE / EA=5:1, v / v) to obtain intermediate 2-3, 200 mg of a yellow solid, with a yield of 48%. LCMS m / z (M+H) + :368.3.

[0187] Step 3: 6b-ethyl-3-methyl-6b,7,8,9,10,10a-hexahydro-1H-pyridin[3',4':4,5]pyrrolo[1,2,3-di]quinoxaline-2(3H)-one (Intermediate 2-4)

[0188]

[0189] K2CO3 (150 mg, 1.09 mmol) was added to a solution of intermediate 2-3 (200 mg, 0.54 mmol) in MeOH / H2O (10 mL / 1 mL) at room temperature. After the addition, the reaction solution was reacted at 70°C for 4 h. After the reaction solution was cooled to room temperature, water (10 mL) was added, and then extracted with dichloromethane (20 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to obtain a crude product. Intermediate 2-4 was obtained by column chromatography (DCM / MeOH=20:1, v / v) as a yellow oil 120 mg, yield: 65%. LCMSm / z(M+H) + :272.2.

[0190] Step 4: Preparation of 6b-ethyl-8-(4-(4-fluorophenyl)-4-oxobutyl)-3-methyl-6b,7,8,9,10,10a-hexahydro-1H-pyridin[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-2(3H)-one (Compound 2)

[0191]

[0192] Intermediate 2-4 (100 mg, 0.37 mmol), intermediate 1-8 (590 mg, 2.95 mmol), KI (245 mg, 1.48 mmol) and DIEA (190 mg, 1.48 mmol) in DMF (10 mL) were stirred at 78 ° C for 16 h. After the reaction solution was cooled to room temperature, 10 mL of water was added and extracted with ethyl acetate (20 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to obtain a crude product, which was separated and purified by preparative liquid phase separation (CH3CN:H2O (0.1% NH4HCO3) = 40-80%, UV: 214nm, flow rate 15mL / min) to obtain compound 2, 45.0 mg, yield 23%. LCMS m / z (M+H) + :436.2.

[0193] 1 H NMR (CDCl3, 400MHz): δ8.03-7.95(m,2H),7.13(t,J=8.4Hz,2H),6.83-6.74(m,2 H),6.74-6.68(m,1H),4.01(d,J=14.0Hz,1H),3.37(d,J=14.4Hz,1H),3.32(s,3H ),3.10-3.04(m,1H),2.98(t,J=7.2Hz,2H),2.69-2.51(m,2H),2.43-2.31(m,1H) ,2.30-2.15(m,2H),2.11-1.99(m,1H),1.97-1.76(m,6H),0.88(t,J=7.6Hz,3H).

[0194] Example 3. Preparation of 3-ethyl-8-(4-(4-fluorophenyl)-4-oxobutyl)-6b-methyl-6b,7,8,9,10,10a-hexahydro-1H-pyridin[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-2(3H)-one (Compound 3)

[0195] Step 1: Preparation of 3-ethyl-6b-methyl-8-(2,2,2-trifluoroacetyl)-6b,7,8,9,10,10a-hexahydro-1H-pyridin[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-2(3H)-one (Intermediate 3-1)

[0196]

[0197] Under ice bath conditions, sodium hydride (28 mg, 0.71 mmol) was added to a DMF (10 mL) solution of intermediate 1-5 (0.2 g, 0.59 mmol, prepared according to the method described in the third step of Example 1). After keeping the temperature for 30 minutes, iodoethane (148 mg, 0.89 mmol) was added. After the addition was completed, the mixture was moved to room temperature and stirred for 1 hour. The reaction solution was moved to an ice bath again and quenched with water (5 mL). The reaction solution was extracted with ethyl acetate (10 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was subjected to column chromatography (DCM / MeOH=20 / 1) to obtain intermediate 3-1 as a yellow solid (150 mg). Yield: 69%. LCMS m / z (M+H) + :368.2.

[0198] Step 2: Preparation of 3-ethyl-6b-methyl-6b,7,8,9,10,10a-hexahydro-1H-pyridin[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-2(3H)-one (Intermediate 3-2)

[0199]

[0200] Sodium hydroxide (32 mg, 0.82 mmol) was added to a solution of intermediate 3-1 (150 mg, 0.41 mmol) in tetrahydrofuran / water (10 mL / 2 mL). After the addition, the reaction solution was reacted at 40 ° C for 2 h. After the solvent was dried under reduced pressure, the crude product was separated and purified by column chromatography (DCM / MeOH / NH3H2O=100 / 10 / 1) to obtain intermediate 3-2, yellow oil 91 mg, yield 82%. LCMSm / z(M+H) + :272.2.

[0201] Step 3: Preparation of 3-ethyl-8-(4-(4-fluorophenyl)-4-oxobutyl)-6b-methyl-6b,7,8,9,10,10a-hexahydro-1H-pyridin[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-2(3H)-one (Compound 3)

[0202]

[0203] To a DMF (10 mL) solution of intermediate 3-2 (91 mg, 0.34 mmol), intermediate 1-8 (136 mg, 0.68 mmol), potassium iodide (10 mg) and N,N-diisopropylethylamine (88 mg, 0.68 mmol) were added. After the addition, the reaction solution was reacted at 78°C for 3 h. The reaction solution was cooled to room temperature and concentrated to obtain a crude product. The crude product was separated and purified by preparative liquid phase (CH3CN:H2O (0.1% NH4HCO3) = 10-60%, UV: 214 nm, flow rate 15 mL / min) to obtain compound 3, 42.3 mg, yield: 28%. LCMS m / z (M+H) + :436.2.

[0204] 1 H NMR (CDCl3, 400MHz): δ8.04-8.01(m,2H),7.17-7.13(m,2H),6.86-6.76(m,3H),4.06-3.98(m,2H),3.90-3.84(m,1H),3.37(d,J=14 .4Hz,1H),3.03-2.99(m,2H),2.91(s,1H),2.68-2.56(m,2H),2.43-2.21(m,3H),1.97-1.84(m,5H),1.47(s,3H),1.30-1.27(m,3H).

[0205] Example 4. Preparation of 8-(4-(4-fluorophenyl)-4-oxobutyl)-1,1,3,6b-tetramethyl-6b,7,8,9,10,10a-hexahydro-1H-pyridin[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-2(3H)-one (Compound 4)

[0206] Step 1: Preparation of 3,6b-dimethyl-2-oxo-2,3,6b,9,10,10a-hexahydro-1H-pyridinium[3',4':4,5]pyrrole[1,2,3-de]quinoxaline-8(7H)-carboxylate (Intermediate 4-1)

[0207]

[0208] To a DCM (20 mL) solution of intermediate 1-7 (1.2 g, 4.6 mmol, prepared according to the preparation method in step 5 of Example 1) triethylamine (1.3 g, 13.2 mmol) and di-tert-butyl dicarbonate (4.3 g, 19.8 mmol) were added in sequence, reacted at room temperature for 2 h, and then water (15 mL) was added to quench the reaction. The organic phase was separated and dried and concentrated to obtain a crude product, which was separated and purified by column chromatography (EA / PE=1 / 3) to obtain intermediate 4-1, a white solid of 1.6 g, with a yield of 68%. LCMS m / z (M-56+H) + :302.2.

[0209] Step 2: Preparation of 1,1,3,6b-tetramethyl-2-oxo-2,3,6b,9,10,10a-hexahydro-1H-pyridinium[3',4':4,5]pyrrole[1,2,3-de]quinoxaline-8(7H)-carboxylate (Intermediate 4-2)

[0210]

[0211] The intermediate 4-1 (0.66 g, 1.85 mmol) was dissolved in tetrahydrofuran (20 mL), placed in a low-temperature reactor at -78 ° C, and LDA (lithium diisopropylamide, 2.0 M, 3.7 mL, 7.4 mmol) was slowly added dropwise under argon protection, and the reaction was kept warm for 1 h. Then iodomethane (2.1 g, 14.8 mmol) was slowly added dropwise, and the reaction was kept warm for 2 h. After the reaction solution was moved to room temperature, water (20 mL) was added to quench, and the reaction solution was extracted with ethyl acetate (15 mL x 3). The organic phase was dried and concentrated to obtain a crude product, which was separated and purified by column chromatography (EA / PE=1 / 2) to obtain intermediate 4-2, which was a yellow oil of 410 mg, with a yield of 58%. LCMS m / z (M+H) + :386.2.

[0212] Step 3: Preparation of 1,1,3,6b-tetramethyl-6b,7,8,9,10,10a-hexahydro-1H-pyridin[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-2(3H)-one (Intermediate 4-3)

[0213]

[0214] Under ice bath conditions, TMSOTf (trimethylsilyl trifluoromethanesulfonate, 380 mg, 1.71 mmol) was added to a DCM (50 mL) solution of intermediate 4-2 (0.44 g, 1.14 mmol) and 1,6-Lutidine (0.24 g, 2.28 mmol). After keeping warm for 30 min, the reaction solution was quenched with aqueous ammonium chloride solution (15 mL). After separation, the organic phase was dried and concentrated to obtain a crude product. The product was separated and purified by column chromatography (DCM / MeOH=10 / 1) to obtain intermediate 4-3, yellow oil 200 mg, yield: 61%. LCMS m / z (M+H) + :286.2.

[0215] Step 4: 8-(4-(4-fluorophenyl)-4-oxobutyl)-1,1,3,6b-tetramethyl-6b,7,8,9,10,10a-hexahydro-1H-pyridin[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-2(3H)-one (Compound 4)

[0216]

[0217] Intermediate 4-3 (180 mg, 0.63 mmol), intermediate 1-8 (252 mg, 1.26 mmol), potassium iodide (20 mg, 0.12 mmol) and DIEA (244 mg, 1.89 mmol) were added to DMF (10 mL) in sequence and reacted at 78 ° C for 5 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure and directly separated and purified by preparative liquid phase (CH3CN:H2O (0.1% NH4HCO3) = 10-70%, UV: 214nm, flow rate 15mL / min) to obtain compound 4, 100 mg, yield: 38%. LCMS m / z (M+H) + :450.2.

[0218] 1 H NMR (CDCl3, 400MHz): δ8.02-7.95(m,2H),7.16-7.12(m,2H),6.79-6.70(m,3H),3.52(s,1H) ,3.31(s,3H),2.95-2.94(m,2H),2.78-1.92(m,10H),1.72(s,3H),1.45(s,3H),1.15(s,3H).

[0219] Example 5, 8-(4-(4-fluorophenyl)-4-oxobutyl)-3,6b-dimethyl-6b,7,8,9,10,10a-hexahydro-1H-pyridinium[3',4':4,5]pyrrole[1,2,3-de]quinoxaline-1,2(3H)-dione (Compound 5)

[0220] Step 1: Preparation of 3,6b-dimethyl-8-(2,2,2-trifluoroacetyl)-6b,7,8,9,10,10a-hexahydro-1H-pyridinium[3',4':4,5]pyrrole[1,2,3-de]quinoxaline-1,2(3H)-dione (Intermediate 5-1)

[0221]

[0222] RuO2 (37 mg, 0.28 mmol) and NaIO4 (300 mg, 1.4 mmol) were added to a solution of intermediate 1-6 (200 mg, 0.50 mmol) in carbon tetrachloride (20 mL). After reacting at room temperature for 48 h, the reaction solution was directly concentrated to obtain a crude product. The product was purified by column chromatography (EA / PE=1 / 1) to obtain intermediate 5-1, a yellow solid of 114 mg, with a yield of 54%. LCMS m / z (M+H) + :368.2.

[0223] Step 2: 3,6b-dimethyl-6b,7,8,9,10,10a-hexahydro-1H-pyridinium[3',4':4,5]pyrrole[1,2,3-de]quinoxaline-1,2(3H)-dione (Intermediate 5-2)

[0224]

[0225] Potassium carbonate (136 mg, 0.98 mmol) was added to a solution of intermediate 5-1 (180 mg, 0.49 mmol) in methanol / water (2 mL, v / v = 10 / 1), and the reaction solution was reacted at 70 ° C for 3 h. After the reaction was completed, the intermediate 5-2 was concentrated to obtain 150 mg of yellow oil. The product was directly used as a raw material for the next step without further purification. LCMS m / z (M+H) + :272.2.

[0226] Step 3: Preparation of 8-(4-(4-fluorophenyl)-4-oxobutyl)-3,6b-dimethyl-6b,7,8,9,10,10a-hexahydro-1H-pyridinium[3',4':4,5]pyrrole[1,2,3-de]quinoxaline-1,2(3H)-dione (Compound 5)

[0227]

[0228] To a DMF (3 mL) solution of intermediate 5-2 (150 mg, 0.55 mmol), intermediate 1-8 (150 mg, 0.75 mmol) and potassium carbonate (37 mg, 0.27 mmol) were added in sequence. After the addition, the reaction solution was reacted at 78°C for 3 hours. After the reaction was completed, the reaction solution was directly concentrated under reduced pressure to obtain a residue, which was separated and purified by preparative liquid phase (CH3CN:H2O (0.1% NH4HCO3) = 10-70%, UV: 214 nm, flow rate 15 mL / min) to obtain compound 5, 35 mg, yield: 15%. LCMS m / z (M+H) + :436.2.

[0229] 1 H NMR (CDCl3, 400MHz): δ8.02-7.98 (m, 2H), 7.15-7.10 (t, J = 8.4Hz, 1H), 6.59-6.56 (m, 3H), 4.32-4.29 (m, 2H), 4.32-4.29(d,J=11.2Hz,2H),3.07-2.99(m,5H),2.66-2.45(m,5H),2.12(t,J=7.6Hz,2H),2.03-1.97(m,4H).

[0230] Example 6. Preparation of 8-(3-(4-fluorophenoxy)propyl)-3,6b-dimethyl-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-2(3H)-one (Compound 6)

[0231]

[0232] Intermediate 1-7 (2.0 g, 7.78 mmol, prepared by the method described in step 5 of Example 1), intermediate 6-1 (2.9 g, 15.56 mmol), potassium iodide (2.0 g, 15.56 mmol) and DIEA (2.0 g, 15.56 mmol) were added to DMF (40 mL) in sequence and reacted at 78°C for 3 h. After the reaction was completed, the reaction solution was directly concentrated to obtain a crude product, which was separated and purified by preparative liquid phase to obtain compound 6, 1.5 g, yield: 47%. LCMS m / z (M+H) + :410.2.

[0233] 1H NMR (CDCl3, 400MHz): δ6.98-6.93(m,2H),6.84-6.28(m,5H),4.03-3.96(m,3H),3.38 (s,1H),3.33(s,3H),2.92(s,1H),2.68-2.22(m,5H),1.96-1.89(m,5H),1.49(s,3H).

[0234] Example 7, Preparation of 4-(3,6b-dimethyl-2,3,6b,9,10,10a-hexahydro-1H-pyridin[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-yl)-1-(4-fluorophenyl)butane-1-one (Compound 7)

[0235] Step 1: Preparation of 3,6b-dimethyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline (Intermediate 7-1)

[0236]

[0237] Dissolve the intermediate 1-7 (0.2 g, 0.78 mmol) in THF (10 mL), slowly add a 1 M borane tetrahydrofuran solution (1.56 mL, 1.56 mmol), stir the reaction solution at room temperature for 15 h, then add 1 N hydrochloric acid solution (2 mL) dropwise under ice bath conditions to quench, and the quenched reaction solution is directly concentrated and column chromatographed to obtain the intermediate 7-1, 80 mg, yield: 42%. LCMS m / z (M+H) + :244.2.

[0238] Step 2: Preparation of 4-(3,6b-dimethyl-2,3,6b,9,10,10a-hexahydro-1H-pyridin[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-yl)-1-(4-fluorophenyl)butane-1-one (Compound 7)

[0239]

[0240] Intermediate 7-1 (75 mg, 0.308 mmol), intermediate 1-8 (184 mg, 0.924 mmol), potassium iodide (101 mg, 0.616 mmol), DIEA (119 mg, 0.924 mmol) were added to DMF (3 mL), and the reaction solution was reacted at 78 ° C for 3 h. After the reaction solution was cooled to room temperature, it was directly concentrated to remove DMF. The product was separated and purified by preparative liquid phase (CH3CN:H2O (0.1% NH4HCO3) = 10-70%, UV: 214nm, flow rate 15mL / min) to obtain the target compound 7, 32 mg, yield: 25%. LCMS m / z (M+H) + :407.9.

[0241] 1 H NMR (CDCl3, 400MHz): δ8.06-8.03(m,2H),7.19-7.15(m,2H),6.73-6.71(m,1H),6.49-6.44(m,2H),3.67 -3.61(m,1H),3.36-3.27(m,2H),3.07-3.04(m,2H),2.90-2.83(m,5H),2.71-2.07(m,10H),1.30(s,3H).

[0242] Comparative Example 1, 8-(4-(4-fluorophenyl)-4-carbonylbutyl)-3-methyl-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-2(3H)-one

[0243] Step 1: Synthesis of 8-(2,2,2-trifluoroacetyl)-7,8,9,10-tetrahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-2(3H)one (Intermediate D1-2)

[0244]

[0245] Intermediate 1-3 (3 g, 15 mmol), intermediate D1-1 (2.9 g, 15 mmol), and isopropanol (30 mL) were added to a 100 mL single-mouth bottle in sequence, and the temperature was raised to reflux for overnight reaction. After the reaction was complete, the reaction solution was poured into ice water (5 mL), extracted with ethyl acetate (15 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and chromatographed on a silica gel column (petroleum ether: ethyl acetate = 2:1) to obtain intermediate D1-2, 1.8 g, yield: 30%. LCMS m / z (M+H) + :324.2.

[0246] Step 2: Synthesis of 8-(2,2,2-trifluoroacetyl)-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-2(3H)-one (Intermediate D1-3)

[0247]

[0248] The intermediate D1-2 (1 g, 31 mmol) was dissolved in trifluoroacetic acid (10 mL), sodium cyanoborohydride (388 mg, 6.2 mmol) was added under ice bath, and the reaction was carried out under ice bath for 2 hours. After the reaction was complete, the reaction solution was poured into ice water (50 mL), the pH was adjusted to 7, and the solution was extracted with ethyl acetate (15 mL), dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure to obtain the intermediate D1-3, 700 mg, yield: 70%.

[0249] Step 3: Synthesis of 3-methyl-8-(2,2,2-trifluoroacetyl)-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-2(3H)-one (Intermediate D1-4)

[0250]

[0251] The intermediate D1-3 (700 mg, 2.15 mmol) was dissolved in DMF (10 mL), sodium hydride (100 mg, 2.58 mmol) and deuterated iodomethane (340 mg, 2.37 mmol) were added under ice bath, and the reaction was carried out under ice bath for 1 hour. After the reaction was complete, the reaction solution was poured into ice water (5 mL), extracted with ethyl acetate (15 mL), dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure to obtain the intermediate D1-4, 500 mg, yield: 69%. LCMS m / z (M+H) + :340.1.

[0252] Step 4: Synthesis of 3-methyl-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-2(3H)-one (Intermediate D1-5)

[0253]

[0254] Dissolve the intermediate D1-4 (300 mg, 0.88 mmol) in methanol (5 mL), add potassium carbonate (235 mg, 1.7 mmol), react at 80°C for 2 hours, and concentrate under reduced pressure after the reaction is complete. Add water (15 mL), extract with dichloromethane (10 mL×3), dry with anhydrous sodium sulfate, and concentrate under reduced pressure to obtain the intermediate D1-5, 200 mg, yield: 93%. LCMS m / z (M+H) + :244.0.

[0255] Step 5: Synthesis of 8-(4-(4-fluorophenyl)-4-carbonylbutyl)-3-methyl-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-2(3H)-one

[0256]

[0257] Intermediate D1-5 (200 mg, 0.82 mmol) and intermediate D1-6 (324 mg, 1.23 mmol) were dissolved in acetonitrile (5 mL), cesium carbonate (400 mg, 1.23 mmol) was added, and the mixture was reacted at room temperature overnight. After the reaction was completed, the mixture was filtered and concentrated to dryness under reduced pressure. The final product comparative example 1 was prepared by Pre HPLC (MeCN: H2O = 40: 60), 56 mg, yield: 18%. LCMS m / z (M+H) + :408.2.

[0258] 1 H NMR (600MHz, CD3OD): δ8.08–8.06(m,2H),7.24–7.21(m,2H),6.97–6.85(m,3H),4.03(d,J=13.8Hz,1H),3.47–3.38( m,4H),3.32(s,3H),3.22–3.20(m,1H),3.13–3.08(m,2H),2.87–2.80(m,3H),2.30–2.20(m,2H),2.11–2.05(m,3H).

[0259] Comparative Example 2, 1-(4-fluorophenyl)-4-(3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-yl)butan-1-one

[0260]

[0261] 3-Methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline (500 mg, 2.18 mmol) was dissolved in 15 mL of anhydrous acetonitrile, and then cesium carbonate (1.42 g, 4.36 mmol) and 1-(4-fluorophenyl)-4-iodobutane-1-one (955.27 mg, 3.27 mmol) were added. The reaction solution was stirred at room temperature for 4 hours, and the product was monitored by LCMS. The reaction solution was dissolved in water (50 mL), extracted twice with ethyl acetate (50 mL×2), and the collected organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by rapid preparative column machine (petroleum ether: ethyl acetate = 10:1 to 1:4) to obtain comparative example 2, 600 mg, 2.18 mmol, yield: 69.93%.

[0262] 1 H NMR(600MHz, DMSO-d6)δ:8.06-8.01(m,2H),7.33(t,J=9.0Hz,2H),6.49(t,J=7.2Hz,1H),6.39(d,J= 7.2Hz,1H),6.31(d,J=7.8Hz,1H),3.45-3.22(m,3H),3.03(br.s.,1H),2.98(t,J=6.6Hz,2H),2.90-2 .84(m,1H),2.77(s,3H),2.73-2.68(m,1H),2.65(dt,J=9.6,3.0Hz,1H),2.55-2.50(m,1H),2.32-2.2 0(m,2H),2.06(dt,J=11.4,2.4Hz,1H),1.85-1.76(m,3H),1.73(t,J=10.8Hz,1H),1.67-1.59(m,1H).

[0263] Biological test cases

[0264] The following ITI-007 of the present invention is as follows, and is prepared by referring to the method of Example 261 of patent PCT / US2000 / 016498,

[0265]

[0266] The following comparative example 1-A of the present invention is as follows, and is prepared by referring to the method of scheme 1 in paragraph

[0339] of the specification of patent PCT / US2017 / 015178,

[0267]

[0268] Test Example 1: Functional activity test of each compound on receptors (frozen cells)

[0269] 1. Materials and Equipment

[0270] cell

[0271] Cell Name supplier CHO-K1 / D2L / Gα15 GenScript Biotech Corporation CHO-K1 / 5HT2A PerkinElmer Inc.

[0272] Experimental reagents and consumables

[0273]

[0274] Instruments and Equipment

[0275]

[0276]

[0277] Testing drugs

[0278] name supplier model Dopamine Sigma H8502 Serotonin Sigma H9523 Spiperone Targetmol T0280 Ketanserin Targetmol T1066

[0279] 2. Experimental methods

[0280] Day 1: Cell plating

[0281] (1) Take the cells out of the liquid nitrogen tank, loosen the cap of the tube and invert it to allow the liquid nitrogen to flow out of the tube, then tighten the cap of the cryotube.

[0282] (2) Shake the cryotube rapidly at 37°C until all the ice has melted. Wipe the surface of the cryotube with 75% alcohol and place it in a biosafety cabinet.

[0283] (3) Transfer the cell suspension into a 50 mL centrifuge tube pre-filled with 10 mL of pre-warmed growth medium (without selection antibiotics).

[0284] (4) Centrifuge at 1000 rpm for 5 minutes.

[0285] (5) Discard the supernatant, add 8 mL of growth medium (without selection antibiotics), and gently blow it away. Take out 20 μL and count using a cell counter.

[0286] (6) Dilution according to specified conditions: 1×10 6 20 μL of cell suspension was added to each well of the cell plate, and the final concentration of each well was 20,000 cells / well.

[0287] (7) Place the cell plate in a 5% CO2, 37°C incubator for 16-24 hours.

[0288] Day 2: Experimental testing

[0289] Preparation of test reagents:

[0290] (1) Preparation of 250 mM probenecid solution: Add 1 mL of experimental buffer to a tube containing 77 mg of powder and vortex to dissolve.

[0291] (2) Preparation of 2× fluorescent probe solution: Take 1 bottle of fluorescent probe dry powder and equilibrate it to room temperature, add 10 mL of experimental buffer and 200 μL of 250 mM probenecid solution, vortex and let stand for 5 minutes to ensure complete dissolution, and then vortex again.

[0292] Experimental steps:

[0293] (1) Compound preparation.

[0294] a) Agonist compound plate preparation (test EC 80 ): Dopamine and Serotonin were diluted 3-fold in a compound plate (Greiner-781280) using assay buffer at 10 concentration points, with a starting concentration of 1.2 μM, 30 μL per well, and a DMSO concentration not higher than 3%.

[0295] b) Preparation of antagonist positive compounds and test compound plates: Test compounds were diluted 3-fold at 10 concentration points using assay buffer in a compound plate (Greiner-781280), with a starting concentration of 3 μM and 30 μL per well; antagonist positive compounds Spiperone and Ketanserin were diluted 3-fold at 10 concentration points using assay buffer, with a starting concentration of 1 μM and 30 μL per well. DMSO concentration was not higher than 3%.

[0296] (2) Cell preparation: Remove cells from the incubator, add 20 μL of the prepared 2× fluorescent probe solution, incubate at 37°C for 50 minutes, and then equilibrate at room temperature for 10 minutes.

[0297] (3) Agonist EC 80 test

[0298] a) Place the cell plate and agonist compound plate into the instrument and run the plate reading program.

[0299] b) Transfer 10 μL from the agonist compound plate to the cell plate and read the fluorescence signal.

[0300] c) Calculate the EC of the agonist using Screenworks software 80 , prepare 6×EC 80 Concentration for later use.

[0301] (4) Compound EC 50 and IC 50 test

[0302] a) Place the cell plate and the test compound plate into the instrument and run the plate reading program.

[0303] b) Transfer 10 μL from the test compound plate to the cell plate and read the fluorescence signal.

[0304] c) Then add 6×EC 80 For agonist plate, transfer 10 μL to the cell plate and read the fluorescence signal.

[0305] d) Export the “Max-Min” value from 1 to the maximum number as raw data for analysis and calculate the EC of the compound 50 and IC 50 value.

[0306] 3. Experimental results: See Table 1 for specific results.

[0307] Table 1 In vitro functional activity test results of each compound

[0308]

[0309] 4. Experimental conclusion:

[0310] Current studies have found that high activity at the 5-HT2A receptor can improve the clinical efficacy of atypical and typical antipsychotics; in addition, high selectivity for D2 / 5-HT2A (the larger the D2 / 5-HT2A ratio, the higher the selectivity) can reduce the possibility of inducing EPS reactions, which is also an important design goal of antipsychotic drugs.

[0311] According to the results in Table 1 above, the compounds of the present invention have good functional activity on 5-HT2A and / or D2, and the D2 / 5-HT2A ratio is high, indicating that the compounds of the present invention have good therapeutic effects on schizophrenia and reduce the possibility of inducing EPS.

[0312] Test Example 2: 5-HT 2A Functional detection experiment of receptor (cultured cells)

[0313] 1. Experimental purpose:

[0314] The effect of the compounds of the present invention on 5-HT was detected by the calcium ion influx detection method at the cellular level. 2A Receptor antagonism.

[0315] 2. Experimental plan:

[0316] 2.1 Experimental Materials:

[0317] (1) Test compound: Compound of the present invention, prepared in-house.

[0318] (2) Control compounds: Serotonin hydrochloride 5-hydroxytryptamine (Sigma, H9523), Ketanserin (Targetmol, T1066).

[0319] (3) Stable cell lines:

[0320]

[0321] (4) Experimental reagents:

[0322]

[0323]

[0324] (5) Experimental consumables:

[0325] Consumables Name brand Part Number Cell counting chamber Countstar IC1000 Poly-D-Lysine coated 384 well plate Greiner 781946 384-well-PP microplate, V-Form Greiner 781280 Tera Pipette Tip Black,384 Molecular Device 9000-0764

[0326] (6) Experimental instruments:

[0327] Instrument Name brand model Electronic balance Sartorius SQP FLIPR Molecular Device TETRA Bravo Agilent Bravo Cell Counter Countstar BioTech Ultrapure water instrument Millipore IQ 7000 Centrifuge Cence TDZ5-WS Multifuge X4R Pro Centrifuge Thermo Fisher 75009915

[0328] 2.2 Solution preparation:

[0329] (1) Preparation of test compounds: The compounds of the examples of the present invention were dissolved in DMSO to prepare 10 mM stock solutions, which were stored in a nitrogen cabinet for later use.

[0330] (2) Preparation of control compound: The control compound was dissolved in DMSO to prepare a 10 mM stock solution, which was then divided and stored in a -80°C refrigerator for later use.

[0331] (3) Preparation of 250 mM Probenecid solution: Add 1 mL of assay buffer to a tube containing 77 mg of powder and vortex to dissolve.

[0332] (4) Preparation of 2× fluorescent probe solution: Take 1 bottle of fluorescent probe dry powder and equilibrate it to room temperature, add 10 mL of experimental buffer and 200 μL of 250 mM probenecid solution, vortex and let it stand for 5 minutes to ensure complete dissolution.

[0333] (5) Experimental buffer HBSS: Mix HBSS and HEPES at a ratio of 50:1 and store in a 4°C refrigerator. Heat to 37°C when needed.

[0334] 2.3 Experimental methods:

[0335] Cell Recovery:

[0336] (1) Take out the cells from the liquid nitrogen tank, thaw them in a 37°C water bath, wipe the surface of the cryotube with 75% alcohol, and place it in a biosafety cabinet.

[0337] (2) Transfer the cell suspension into a 15 mL centrifuge tube containing 4 mL of pre-warmed plating medium and centrifuge at 1000 rpm for 5 minutes.

[0338] (3) Discard the supernatant, add 10 mL of plating medium, gently blow off, and transfer to a culture dish for growth. After the cells have attached for 24 hours, replace with growth medium and continue culturing.

[0339] Cell plating:

[0340] (1) Take cells in logarithmic phase and grow them to about 85%-90%, and perform the following operations: wash, digest, and terminate the cells, then transfer them to a 15 mL centrifuge tube and centrifuge them at 1000 rpm for 5 min at room temperature.

[0341] (2) Discard the supernatant, add a certain amount of plating medium, and gently blow it away. Take out 20 μL of cell suspension for counting.

[0342] (3) Dilute the cells to 1×10 6 20 μL of cell suspension was added to each well of the cell plate (Greiner-781946) to make the density of each well 2×10 4 Pieces / hole.

[0343] (4) The cell plate was placed in an incubator at 5% CO2 and 37°C for 16-24 hours.

[0344] Experimental testing steps:

[0345] (1) Compound preparation

[0346] a) Agonist compound plate preparation (test EC 80 ): The agonist was diluted 4-fold in the assay buffer at 10 concentration points in a compound plate (Greiner-781280), 30 μL per well.

[0347] b) Preparation of test compound and positive compound plates: The test compound and positive compound were diluted 4-fold in a compound plate (Greiner-781280) using an assay buffer at 10 concentration points, 30 μL per well.

[0348] (2) Cell preparation: Remove cells from the incubator, add 20 μL / well of 2× fluorescent probe solution, incubate at 37°C for 50 min, and equilibrate at room temperature for 10 min.

[0349] (3) EC of agonist 80 test

[0350] a) Place the cell plate and agonist compound plate into the instrument and run the program.

[0351] b) Transfer 10 μL from the agonist compound plate to the cell plate and read the fluorescence signal.

[0352] c) Calculate the EC of the agonist using Screenworks software 80 , prepare 6×EC 80 Concentration for later use.

[0353] (4) IC of the compound 50 test

[0354] a) Place the cell plate and the test compound plate into the instrument and run the corresponding program.

[0355] b) Transfer 10 μL from the test compound plate to the cell plate and read the fluorescence signal.

[0356] c) Take out the compound plate and put it into 6×EC 80 Agonist plate, from 6×EC 80 Transfer 10 μL from the agonist plate to the cell plate and read the fluorescence signal.

[0357] d) Export the "Max-Min" value from 1 to the maximum number of readings as raw data for analysis and calculation of the IC of the compound 50 value.

[0358] 3. Experimental results: as shown in Table 2.

[0359] Table 2 Effect of the compounds of the present invention on 5-HT 2A Results of receptor functional activity test

[0360] Example No. <![CDATA[5-HT 2A IC 50 (nM)]]> Example 1 3.72 Example 1-A 0.78 Example 1-B 107.60 Example 4 19.69 Example 7 3.50 Comparative Example 1 44.36 Comparative Example 1-A 9.11 ITI-007 3.35

[0361] 4. Experimental conclusion:

[0362] The above scheme shows that the compounds of the present invention have an effect on 5-HT 2A The receptor has a good antagonistic effect.

[0363] Test Example 3: Effect of the compounds of the present invention on D 2L , D 2s Functional activity test of receptors

[0364] 1. Experimental purpose:

[0365] The effect of the compounds of the present invention on D was detected by the cyclic adenosine monophosphate (cAMP) detection method at the cell level. 2L , D 2s Receptor antagonism.

[0366] 2. Experimental plan

[0367] 2.1 Experimental Materials:

[0368] (1) Test compound: Compound of the present invention, prepared in-house.

[0369] (2) Reference compounds: Dopamine hydrochloride (Sigma, H8502), (+)-Butaclamol hydrochloride (Sigma, D033).

[0370] (3) Stable cell lines:

[0371]

[0372]

[0373] (4) Experimental reagents:

[0374] Reagent name brand Part Number DMEM Gibco C11965500CP PBS Gibco C10010500CP 0.05%Trypsin Invitrogen 25300062 DMSO Sigma D8418 cAMP Gi Assay Kit Cisbio 62AM9PEJ IBMX Sigma I5879 HBSS Gibco 14175103 Forskolin Sigma F6886

[0375] (5) Experimental consumables:

[0376]

[0377] (6) Experimental instruments:

[0378] Instrument Name brand model Electronic balance Sartorius SQP EnVision PerkinElmer 2104 Picoliter Micro-Volume Dosing System Tecan D300e Bravo Agilent Bravo Cell Counter Countstar BioTech Ultrapure water instrument Millipore IQ 7000 Centrifuge Cence TDZ5-WS

[0379] 2.2 Solution preparation:

[0380] (1) Preparation of test compounds: The compounds of the examples of the present invention were dissolved in DMSO to prepare 10 mM stock solutions, which were stored in a nitrogen cabinet for later use.

[0381] (2) Preparation of control compound: The control compound was dissolved in DMSO to prepare a 10 mM stock solution, which was then divided and stored in a -80°C refrigerator for later use.

[0382] (3) IBMX was dissolved in DMSO to prepare a 0.5 M stock solution and stored at -80°C.

[0383] (4) Forskolin was dissolved in DMSO to prepare a 1 mM stock solution and stored at -80°C until use.

[0384] (5) Experimental buffer: Dilute 5× stimulation buffer to 1× with ddH2O, add IBMX to a final concentration of 0.5 mM, mix well and set aside.

[0385] 2.3 Experimental method (Gi antagonist test):

[0386] (1) Compound preparation: The test compound and the positive control compound (+)-Butaclamol hydrochloride were gradiently diluted in a compound plate (Greiner-781280) using Bravo. The starting concentration of the working solution was 20 μM. The experimental buffer was used to dilute the solution 4-fold to 10 concentrations and centrifuged at 1000 rpm for 1 minute for later use.

[0387] (2) Cryopreserved D 2L Cells: Take out from the liquid nitrogen tank and thaw in a 37°C water bath. Transfer the cell suspension to a centrifuge tube containing HBSS buffer and centrifuge at 750 rpm for 5 minutes.

[0388] Cultivated D 2S Cells: After absorbing the culture medium, wash the cells with 3 mL of PBS, aspirate until all the cells are digested, and digest with 0.05% Trypsin for 3 min. Add an equal volume of culture medium to terminate the digestion, transfer to a centrifuge tube, and centrifuge at 750 rpm for 5 minutes. After aspirating all the liquid, add HBSS buffer to resuspend the cells, and centrifuge at 750 rpm for 5 minutes.

[0389] (3) Discard the supernatant, resuspend the pellet with an appropriate amount of experimental buffer, and take 20 μL for cell counting.

[0390] (4) Take an appropriate amount of cell suspension and dilute it to 2×10 5 5 μL / well of the cell suspension was added to a cell plate (PerkinElmer-6008280) and centrifuged at 1000 rpm for 1 minute.

[0391] (5) Use Bravo to transfer 5 μL / well to the cell plate, centrifuge at 1000 rpm for 1 minute, block the cell plate and incubate at room temperature for 15 minutes.

[0392] (6) Use Tecan-D300e to transfer Forskolin to the cell plate, and the final concentration is EC 90 Dopaminehydrochloride was added to the cell plate.

[0393] (7) The cell plate was centrifuged at 1000 rpm for 1 minute, sealed, and incubated at room temperature for 45 minutes.

[0394] (8) Standard curve: The cAMP stock solution with a concentration of 2848 nM was diluted 4-fold at 8 points with a starting maximum concentration of 712 nM. 10 μL / well was added to the cell plate.

[0395] (9) Add 10 μL / well of detection solution containing cAMP-d2 and Anti-cAMP-Cryptate (diluted with lysis buffer at 1:20) to the cell plate, centrifuge at 1000 rpm for 1 minute, and incubate at room temperature in the dark for 1 hour.

[0396] (10) Detection: The cell plate was centrifuged at 1000 rpm for 1 minute and the plate was read using Envision (excitation light 340 nm, emission light 620 nm and 665 nm). The ratio of the two channel signals (665 nm / 620 nm) multiplied by 10,000 was used as the final raw data for analysis to calculate the IC of the compound. 50 value.

[0397] 3. Experimental results: as shown in Table 3.

[0398] Table 3 Compounds of the present invention for D 2L , D 2s Results of receptor functional activity test

[0399] Example No. <![CDATA[D 2L IC 50 (nM)]]> <![CDATA[D 2s IC 50 (nM)]]> Example 1 20.28 95.44 Example 1-A 30.86 261.00 Example 1-B 15.53 63.07 Example 3 51.42 207.10 Example 4 13.40 82.83 Example 5 13.11 93.37 Example 7 40.84 294.60 Comparative Example 1 199.70 363.60 Comparative Example 1-A 88.77 264.30 Comparative Example 2 35.77 622.40 ITI-007 131.30 343.70

[0400] 4. Experimental conclusion:

[0401] Through the above scheme, it can be concluded that the compounds of the present invention have an effect on D 2L , D 2s Receptors have good antagonistic effects.

[0402] Test Example 4: PK test of the compound of the present invention on ICR mice

[0403] 1. Test purpose:

[0404] The compound of the present invention was administered orally to male ICR mice, the blood concentration of the compound of the present invention in the mice was determined, the PK parameters were calculated, and the pharmacokinetic evaluation of the compound of the present invention was performed.

[0405] 2. Test materials:

[0406] (1) Test drugs: Compounds of the present invention, prepared in-house.

[0407] (2) Experimental animals: ICR mice, SPF grade, male, obtained from Shanghai Slake Laboratory Animal Co., Ltd.

[0408] (3) Main test instruments:

[0409]

[0410]

[0411] (4) Main test reagents:

[0412]

[0413] 3. Test plan:

[0414] (1) Dosage information:

[0415] Drug preparation: Take the test compound, add physiological saline and perform ultrasound.

[0416] Administration route and dosage: oral administration, dosage: 5 mg / kg, administration volume: 10 mL / kg.

[0417] Frequency and duration of administration: Single administration.

[0418] (2) Test method:

[0419] ICR mice were stratified by body weight and randomly divided into groups, with 3 mice in each group. They were fasted overnight before the experiment. The mice were given drugs by oral gavage, and 250 μL of blood was collected from the mandibular vein or saphenous vein of the mice at 0, 0.033, 0.083, 0.5, 1, 2, 4, 6 and 8 hours into a sample tube containing sodium heparin, an anticoagulant, and placed on wet ice at 4000 r·min. -1 The samples were centrifuged for 10 min to separate the plasma, which was then frozen and stored in a -80°C refrigerator until testing.

[0420] 4. Test results and analysis:

[0421] The blood drug concentration-time data of the compound of the present invention measured by intragastric administration were substituted into Winnonlin 8.2 program to calculate the main pharmacokinetic parameters. max and C max Using the measured values, the AUC was calculated using the trapezoidal method 0-t Value and AUC 0-∞ The semi-logarithmic plot method was used to calculate the t value from the concentration point at the end of the elimination phase. 1 / 2 The specific results are shown in Table 4.

[0422] Table 4 Results of mouse pharmacokinetic experiments

[0423]

[0424]

[0425] 5. Test conclusion:

[0426] It can be seen from the results of the mouse pharmacokinetic experiment in the table that the compound of the present invention can be rapidly absorbed after administration, showing good metabolic properties, exposure AUC and maximum blood drug concentration C max All performed well.

[0427] Test Example 5: Effect of the compounds of the present invention on MK-801-induced hyperactivity behavior in mice

[0428] 1. Experimental purpose:

[0429] The efficacy of the compounds of the present invention was evaluated by intraperitoneal injection of MK-801 to induce a mouse hyperactivity model.

[0430] 2. Experimental plan

[0431] (1) Experimental materials:

[0432] Test compound: Compound of the present invention, homemade.

[0433] MK-801 (dizocilpine maleate, (+)-MK-801 hydrogen maleate), SIGMA, M107-250MG.

[0434] Solvent: pure water, Guangzhou Watsons Food and Beverage Co., Ltd., 20200928C;

[0435] Physiological saline, Shandong Hualu Pharmaceutical Co., Ltd., SD20080806.

[0436] (2) Main experimental instruments:

[0437]

[0438] (3) Experimental animals:

[0439] Experimental animals: ICR mice, male, 8 mice / group, provided by Sibeifu (Beijing) Biotechnology Co., Ltd.

[0440] (4) Medication information:

[0441] Drug preparation: Take the test compound, add pure water and perform sonication.

[0442] Administration route and method: Oral administration, 10mL / kg body weight.

[0443] Frequency and duration of administration: Single administration.

[0444] The animals were randomly divided into a blank group, a model group, and a drug-treated group after being stratified by body weight. Detailed drug administration information is shown in the table below:

[0445]

[0446]

[0447] (5) Experimental methods:

[0448] Mice were randomly divided into model group, blank group and each drug group according to body weight. One hour after oral administration of solvent or drug, 0.3 mg / kg of MK-801 was injected intraperitoneally (the blank group was injected with an equal volume of saline), and then the mice were placed in a self-activity box (a black polyethylene box with a size of 29 cm × 29 cm × 30 cm) for video recording for 60 minutes. After the recording, video analysis was performed to evaluate the activity of the mice.

[0449] (6) Data processing and statistics:

[0450] Experimental data SPSS statistical software was used to perform a variance homogeneity test. If the variance was homogeneous, a one-way ANOVA was performed, and the Dunnett t test was used for pairwise comparison. GraphPad Primis5 software was used to calculate ED using the nonlinear fitting method. 50 .

[0451] 3. Experimental results: as shown in Table 5.

[0452] Table 5 Test results of the effects of the compounds of the present invention on the hyperactive behavior of mice induced by MK-801

[0453]

[0454] Note: ED 50 MED is the minimum effective dose.

[0455] 4. Experimental conclusion:

[0456] The above scheme shows that the compounds of the present invention can significantly inhibit the high activity induced by MK-801, and compared with the comparative example, the compounds of the present invention have a lower minimum effective dose and a stronger inhibitory effect.

[0457] Test Example 6: Effect of the compounds of the present invention on DOI-induced head shaking behavior in mice

[0458] 1. Experimental purpose:

[0459] The efficacy of the compounds of the present invention was evaluated by intraperitoneal injection of (±) DOI (a hallucinogen, commonly used to replicate an anti-schizophrenia animal model) to induce head shaking behavior in mice.

[0460] 2. Experimental plan:

[0461] (1) Experimental materials:

[0462] Test compound: Compound of the present invention, homemade.

[0463] (±)-DOI hydrochloride, SIGMA, D101-100MG.

[0464] Solvent: pure water, Guangzhou Watsons Food and Beverage Co., Ltd., 20200928C;

[0465] Physiological saline, Shandong Hualu Pharmaceutical Co., Ltd., SD20080806.

[0466] (2) Main experimental instruments:

[0467]

[0468] (3) Experimental animals:

[0469] Experimental animals: ICR mice, male, 8 mice / group, provided by Sibeifu (Beijing) Biotechnology Co., Ltd.

[0470] (4) Medication information:

[0471] Drug preparation: Take the test compound, add the solvent and perform sonication.

[0472] Administration route and method: Oral gavage, 10mL / kg body weight.

[0473] Frequency and duration of administration: Single administration.

[0474] The animals were randomly divided into a blank group, a model group, and a drug-treated group after being stratified by body weight. Detailed drug administration information is shown in the table below:

[0475]

[0476] (5) Experimental methods:

[0477] Mice were randomly divided into model group, blank group and each drug group according to body weight. One hour after the animals were given the vehicle or drug by gavage, they were placed in a beaker (13 cm in diameter, 19 cm in height) covered with fresh bedding, and the modeling drug DOI was intraperitoneally injected at a dose of 1 mg / kg. The number of head shaking of the mice within 0-20 minutes after intraperitoneal injection of DOI was recorded.

[0478] Head-flick behavior is defined as rapid rotational twitches or wet-dog shakes of the mouse's head that are distinguished from normal grooming or exploratory behavior.

[0479] (6) Data processing and statistics:

[0480] Experimental data SPSS statistical software was used to perform a variance homogeneity test. If the variance was homogeneous, a one-way ANOVA was performed, and the Dunnett t test was used for pairwise comparison. GraphPad Primis5 software was used to calculate ED using the nonlinear fitting method. 50 .

[0481] 3. Experimental results: as shown in Table 6.

[0482] Table 6 Test results of the effects of the compounds of the present invention on DOI-induced head shaking behavior in mice

[0483]

[0484] Note: ED 50 It is half effective dose.

[0485] 4. Experimental conclusion:

[0486] The above scheme shows that the compounds of the present invention can significantly inhibit the head shaking behavior induced by DOI.

[0487] Although the embodiments of the present invention have been shown and described above, it is to be understood that the above embodiments are exemplary and are not to be construed as limitations of the present invention. A person skilled in the art may change, modify, replace and vary the above embodiments within the scope of the present invention.

Claims

1. A compound represented by general formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof: in, R1 is a C1-C6 alkyl group; R2 is independently -R7-R8-R9-; R3 is independently any one of hydrogen or C1-C3 alkyl; R4 is independently any one of -C(=O)- or -CH2-; R5 and R6 are each independently hydrogen or a C1-C3 alkyl group, or R5, R6 and the carbon atom directly connected thereto together form -C(=O)-; R7 is independently a C1-C5 alkylene group; R8 is independently any one of -C(=O)-, -CH2- or -O-; R9 does not exist; A is phenyl substituted by one or more halogens.

2. The compound represented by the general formula (I) according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: R4 is -C(=O)-.

3. The compound represented by the general formula (I) according to claim 2, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: The R1 is independently a C1-C3 alkyl group.

4. The compound represented by the general formula (I) according to claim 3, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: It meets one or more of the following conditions: (1) The C1-C3 alkyl group is selected from any one of methyl, ethyl or propyl; (2) the C1-C5 alkylene group is selected from C3-C5 alkylene groups; (3) The halogen is any one of fluorine, chlorine, bromine or iodine.

5. The compound represented by the general formula (I) according to any one of claims 1 to 4, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: The compound represented by the general formula (I) is selected from the compounds represented by the general formula (IA) shown below: in, X is a halogen; X is substituted at any substitutable position of the benzene ring; X is either monosubstituted or polysubstituted; The halogen is any one of fluorine, chlorine, bromine or iodine; R1, R3, R4, R5, R6, R7, R8 and R9 are as defined in any one of claims 1-4.

6. The compound represented by the general formula (I) according to claim 5, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: The X is monosubstituted at any substitutable position of the benzene ring.

7. The compound represented by the general formula (I) according to claim 5, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: The compound represented by the general formula (I) is selected from the compounds represented by the general formula (IB) shown below:

8. The compound represented by the general formula (I) according to claim 7, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: The compound represented by the general formula (I) is selected from the compounds represented by the general formula (IB) shown below: in, R1 is independently any one of methyl, ethyl or propyl; R3 is independently any one of hydrogen, methyl, ethyl or propyl; R4 is independently any one of -C(=O)- or -CH2-; R5 and R6 are each independently any one of hydrogen, methyl or ethyl, or R5, R6 and the carbon atom directly connected thereto together form -C(=O)-; R7 is independently any one of -CH2-CH2-, -CH2-CH2-CH2- or -CH2-CH2-CH2-CH2-; R8 is independently any one of -C(=O)-, -CH2- or -O-; R9 does not exist; X is independently fluorine or chlorine.

9. The compound represented by the general formula (I) according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: The compound represented by the general formula (I) is selected from the compounds represented by the general formula (IC) shown below: in, R1 is independently any one of methyl, ethyl or propyl; R3 is independently any one of methyl, ethyl or propyl; R4 is independently any one of -C(=O)- or -CH2-; R5 and R6 are each independently any one of hydrogen, methyl or ethyl, or R5, R6 and the carbon atom directly connected thereto together form -C(=O)-.

10. The compound represented by the general formula (I) according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: It meets one or more of the following conditions: (1) The compound represented by the general formula (I) is selected from any one of the following specific compounds: (2) The salt is selected from fumarate, maleate, phosphate, nitrate, sulfate, benzenesulfonate or oxalate.

11. A compound represented by the general formula (ID), a stereoisomer thereof or a pharmaceutically acceptable salt thereof: in: R1, R3, R4, R5 and R6 are as defined in any one of claims 1 to 10.

12. A method for preparing a compound represented by general formula (I) as claimed in any one of claims 1 to 10, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, characterized in that: The steps include: The compound of formula (ID) and the compound of formula (IE) are reacted by a nucleophilic substitution reaction to obtain a compound of formula (I); in: X1 is halogen selected from fluorine, chlorine, bromine or iodine; R1, R2, R3, R4, R5, R6 and A are as defined in any one of claims 1-10.

13. The method according to claim 12, characterized in that X1 is chlorine.

14. A pharmaceutical composition, characterized in that It comprises a therapeutically effective amount of a compound represented by the general formula (I) as described in any one of claims 1 to 10, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

15. Use of the compound represented by the general formula (I) according to any one of claims 1 to 10, its stereoisomer or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 14 in the preparation of a drug for treating neuropsychiatric diseases, characterized in that: The neuropsychiatric disease is selected from one or more of depression, schizophrenia, sleep disorders, Parkinson's disease, Alzheimer's disease and bipolar disorder.

16. The use according to claim 15, characterized in that The mental illness is selected from any one or more of depression, schizophrenia, sleep disorder and bipolar disorder.

17. The use according to claim 15, characterized in that The depression is major depressive disorder.

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