TW202330528A - Heterocyclic-substituted fused [gamma]-carboline derivative, preparation method thereof, intermediate and application thereof being used for preparing drugs for treating neuropsychiatric diseases - Google Patents

Abstract

This invention belongs to the medical field, in particular relates to a heterocyclic-substituted fused [gamma]-carboline derivative as well as a preparation method, intermediate and application thereof. The heterocyclic-substituted fused [gamma]-carboline derivative has a compound structure shown in formula (I), and such a compound can be used for preparing drugs for treating neuropsychiatric diseases.

Description

Heterocyclic substituted fused γ-carboline derivatives, preparation method, intermediate and application thereof

The invention belongs to the field of medicinal chemistry, and specifically relates to a heterocyclic substituted condensed gamma-carboline derivative, its synthesis and its application. More specifically, the present invention relates to heterocyclic substituted fused γ-carboline derivatives, their preparation methods, intermediates, pharmaceutical compositions comprising the heterocyclic substituted fused γ-carboline derivatives, and Use of the condensed gamma-carboline derivative substituted by the heterocycle and its pharmaceutical composition in the preparation of drugs for preventing and/or treating neuropsychiatric diseases.

Schizophrenia is a disorder characterized by deep cognitive and emotional dissociations that affect the most basic human behaviors, such as language, thought, perception, and self-awareness. The symptoms of the disease include a wide range, the most common being mental disorders, such as hallucinations, paranoia and delusions.

Worldwide, about 1% of people suffer from schizophrenia, and only 5% of all treated patients eventually recover fully. Additionally, schizophrenia often has complications, such as anxiety disorders, depression, or psychotropic substance abuse.

Antipsychotic drugs that exert pharmacological effects by blocking dopamine D2 receptors have traditionally been called first-generation antipsychotic drugs, that is, "classic" antipsychotic drugs (such as haloperidol), which are effective in treating positive symptoms of schizophrenia. Breakthrough, but failed to treat negative symptoms and cognitive impairment. Typical antipsychotic drugs generally have severe EPS side effects and are ineffective for one-third of schizophrenic patients.

After the 1960s, a series of new-generation antipsychotic drugs were successively developed, including Ziprasidone, Risperidone, etc., which were called second-generation antipsychotic drugs, that is, new antipsychotic drugs , although their respective pharmacological effects are not exactly the same, but they have common pharmacological characteristics, that is, to 5-hydroxytryptamine (5-HT) receptors (5-HT1A, 2A, 2c) and norepinephrine (NA) receptors (α1, α2) have a much higher affinity than for the D2 receptor, resulting in a higher ratio of D2/5-HT2A. Compared with the first-generation antipsychotic drugs, its clinical effect has more advantages. It is not only as effective as traditional antipsychotic drugs for positive symptoms, but also effective for negative symptoms and cognitive deficit symptoms, and has a wider spectrum of action. However, these drugs have QT gaps Adverse reactions such as prolongation, hyperprolactinemia and weight gain. Therefore, finding drugs that are effective in treating positive and negative symptoms and cognitive impairment of schizophrenia, and have less side effects is a research hotspot.

The serotonin system plays an important role in regulating the functions of the prefrontal cortex (PFC), including emotional control, cognitive behavior, and working memory. PFC pyramidal neurons and GABA interneurons contain several serotonin receptor subtypes 5-HT1A and 5-HT2A with exceptionally high densities. The PFC and NMDA receptor channels have recently been shown to be targets of 5-HT1AR, and these two receptors modulate excitatory neurons in the cerebral cortex, thereby affecting cognitive function. Indeed, various preclinical data suggest that 5-HT1AR may be a new target for antipsychotic drug development. The high affinity of atypical antipsychotic drugs (such as olanzapine, aripiprazole, etc.) to 5-HT1AR and their low EPS side effects indicate that the 5-HT system plays an important role in regulating the function of the prefrontal cortex (PFC), including Emotional control, cognitive behavior, and working memory. PFC pyramidal neurons and GABA interneurons contain several serotonin receptor subtypes 5-HT1A and 5-HT2A with exceptionally 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 application of the atypical antipsychotic drug clozapine in the treatment of schizophrenia, it was found that 5-HT2A plays an important role in it, involving various aspects of perception, emotion regulation and motor control. Blocking 5-HT2A receptors normalizes the release of dopamine, which acts as an antipsychotic. In addition, 5-HT2C receptors are closely related to weight gain.

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 nigrostriatal pathway to regulate motor function, and the other is the ventral tegmental area of the midbrain. The DA pathway in the prefrontal cortex of the septal nucleus is closely related to learning, cognition and emotional activities, and its dysfunction will lead to schizophrenia. This DA pathway is also the main pathway of reward effects in the brain. D3R is in the two DA neural pathways There are distributions and complex interactions with other DA receptor subtypes, which may serve as a target for antipsychotic drug treatment. Selective D3 receptor antagonism can reduce the negative and cognitive symptoms of schizophrenia. Prevents extrapyramidal side effects, including tardive dyskinesia, Parkinson's disease. Therefore, it is of great significance for clinical treatment to find an anti-schizophrenia drug with few side effects of multi-receptor binding.

In 2019, the FDA newly approved the anti-schizophrenia drug Lumateperone (development code ITI-007), which acts as an antagonist of 5-HT2A receptors and antagonizes several dopamine receptor subtypes (D1, D2 and D4). It has a modest 5-HT transporter reuptake inhibitory effect. It has additional off-target antagonism of alpha-1 receptors, no obvious antimuscarinic or antihistaminergic properties, and its specific structure is shown below: .

Patent PCT/US2017/015178 discloses the general formula compound of Marcus, which acts on receptors such as 5-HT2A, D2, D1 and SERT (serotonin reuptake transporter), and has potential schizophrenia and Parkinson's disease therapeutic activity, .

Although there are many anti-schizophrenia drugs, there are still a variety of adverse reactions in the clinically used schizophrenia drugs, such as aripiprazole, an atypical anti-schizophrenia drug widely used Among the patients taking the drug, more than 10% of the patients will experience adverse reactions including weight gain, headache, akathisia, insomnia and gastrointestinal discomfort, which lead to the withdrawal of the drug and relapse of the disease. In addition, although the current anti-negative symptoms of schizophrenia (referring to the existence of defects in normal emotional responses and other thinking processes) drugs have been used in clinical practice, which can improve the negative symptoms of some patients, but the overall effect is limited, and there are still many patients Due to negative symptoms, it is impossible to recover and restore normal social functions, making it difficult to resume normal social work. In addition, the treatment of cognitive impairment is also a key point in the treatment of schizophrenia, which affects the verbal memory, semantic processing ability and attention function of most patients with schizophrenia. Improvements are also very limited.

In addition to the above-mentioned problems with current antipsychotic drugs, the treatment of refractory schizophrenia is still in a dilemma. Refractory schizophrenia refers to a group of patients who cannot obtain ideal curative effect after being treated according to general methods. These patients have been treated with three antipsychotic drugs with different active ingredients. Adverse reactions of psychiatric drugs, or relapse or deterioration even with adequate maintenance or preventive treatment, anti-refractory schizophrenia drugs have always been a difficult problem in current clinical drug research, and it is also a direction that needs to be overcome urgently.

In summary, it has good and continuous effective treatment of negative symptoms, improves the cognitive function of patients, and can effectively treat refractory schizophrenia. In addition, it needs to have low adverse drug reactions (such as extrapyramidal system reactions, weight gain, etc.) , adverse drug reactions such as nausea and vomiting), and anti-schizophrenia drugs that act on multiple targets are still hot research directions in the field of central nervous system.

Therefore the present invention aims at providing a kind of brand-new antischizophrenia drug acting on 5-hydroxytryptamine receptor and/or dopamine receptor, has good antagonistic activity to 5-HT2A receptor and/or dopamine D2 receptor, can effectively Treatment and improvement of schizophrenia.

The object of the present invention is to provide a heterocyclic substituted fused γ-carboline derivative with the activity of treating mental and nervous diseases, its pharmaceutical composition and its application in the medical field.

The present invention provides a kind of compound as shown in general formula (I), its stereoisomer or its pharmaceutically acceptable salt: , wherein, R _{is independently} halogen, C1-C3 alkoxy, cyano, amino, nitro, hydroxyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C5 cycloalkane C1-C6 alkyl optionally substituted by radical; R ₂ is independently -R ₇ -R ₈ -R ₉ -; R ₃ is independently hydrogen, or any one of C1-C3 alkyl; R ₄ is independently Ground is any one of -C(=O)- or -CH ₂ -; R ₅ and R ₆ are each independently hydrogen, or halogen, C1-C3 alkoxy, cyano, amino, nitro , hydroxyl, C2-C4 alkenyl, C2-C4 alkynyl optionally substituted C1-C3 alkyl, or R ₅ , R ₆ and the carbon atom directly connected to it jointly form -C(= O)-; R ₇ is independently a C1-C5 alkylene group; R ₈ is independently any one of -C(=O)-, -CH ₂ - or -O-; R ₉ is independently C1-C3 Any of the alkylene or absence; A is phenyl optionally substituted with one or more halogen.

In one embodiment of the present invention, said _R is independently halogen, C1-C3 alkoxy, cyano, amino, nitro, hydroxyl, C2-C4 alkenyl, C2-C4 alkyne A group, C3-C5 cycloalkyl optionally substituted C1-C3 alkyl.

In one embodiment of the present invention, the R ₃ is independently hydrogen, or any one of C1-C3 alkyl groups.

In one embodiment of the present invention, in the compound represented by the general formula (I), R ₄ is -CH ₂ -.

In one embodiment of the present invention, the R ₄ is -C(=O)-.

In one embodiment of the present invention, the R ₅ and R ₆ are each independently hydrogen, or any one of unsubstituted C1-C3 alkyl groups, or R ₅ , R ₆ and the carbon atom directly connected to them Together form -C(=O)-.

In one embodiment of the present invention, the R ₅ and R ₆ are each independently hydrogen.

In one embodiment of the present invention, in the compound represented by general formula (I), R ₄ is -CH ₂ -, and R ₅ and R ₆ are each independently hydrogen.

In one embodiment of the present invention, A is independently phenyl substituted with one or more halogens.

In one embodiment of the present invention, the R ₁ is independently an unsubstituted C1-C3 alkyl group.

In one embodiment of the present invention, the R ₃ is independently hydrogen, or any one of unsubstituted C1-C3 alkyl groups.

In one 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.

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

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

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

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

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) as shown below: , wherein, X is a halogen; said X is substituted at any substitutable position of the benzene ring; X is any one of mono-substitution or multi-substitution, preferably mono-substitution; R ₁ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ and R ₉ are as defined above.

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

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) as shown below: , wherein, R ₁ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ and X are all as defined above.

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) as shown below: , wherein, R ₁ is independently any one of methyl, ethyl or propyl; R ₃ is independently any one of hydrogen, methyl, ethyl, or propyl; R ₄ is independently -C( =O)-, or any one of -CH ₂ -; R ₅ and R ₆ are each independently hydrogen, methyl, or any one of ethyl, or R ₅ , R ₆ and the carbon atom directly connected to it Together form -C(=O)-; R ₇ is independently any of -CH ₂ -CH ₂ -, -CH ₂ -CH ₂ -CH ₂ - or -CH ₂ -CH ₂ -CH ₂ -CH ₂ - One; R ₈ is independently any one of -C(=O)-, -CH ₂ - or -O-; R ₉ is independently -CH ₂ -CH ₂ -, -CH ₂ - or nonexistent Any one; X is independently any one of fluorine or chlorine.

In one embodiment of the present invention, the C2-C4 alkenyl group includes but not limited to -CH ₂ =CH ₂ , -CH ₂ -CH=CH ₂ , -CH=CH-CH ₂ , -CH=CH- CH ₂ -CH ₂ , -CH ₂ -CH=CH-CH ₂ , -CH ₂ -CH-CH=CH, etc.

In one embodiment of the present invention, the C2-C4 alkenyl group is preferably a C2-C3 alkenyl group selected from -CH ₂ =CH ₂ , -CH ₂ -CH=CH ₂ or -CH=CH-CH ₂ any of the.

In one embodiment of the present invention, the C2-C4 alkynyl group includes but not limited to -C≡C, -CH ₂ -C≡C, -C≡C-CH ₂ , -C≡C-CH ₂ - CH ₂ , -CH ₂ -C≡C-CH ₂ , -CH ₂ -CH-C≡C, etc.

In one embodiment of the present invention, the C2-C4 alkynyl group is preferably a C2-C3 alkynyl group, selected from any of -C≡C, -CH ₂ -C≡C or -C≡C-CH ₂ A sort of.

In one embodiment of the present invention, the C1-C3 alkoxy group is selected from -O-CH ₃ , -O-CH ₂ -CH ₃ , -O-CH ₂ -CH ₂ -CH ₃ , -O- Any one of CH(CH ₃ )-CH ₃ , preferably any one of -O-CH ₃ or -O-CH ₂ -CH ₃ .

In one embodiment of the present invention, the alkylene group is a straight-chain saturated aliphatic hydrocarbon group with 1-20 carbon atoms, and the C1-C5 alkylene group in the present invention is -CH ₂ -, -CH ₂ -CH ₂ -, -CH ₂ -CH ₂ -CH ₂ -, -CH ₂ -CH ₂ -CH ₂ -CH ₂ , -CH ₂ -CH ₂ -CH ₂ -CH ₂ -CH ₂ - or -CH ₂ - Any one of CH ₂ -CH ₂ -CH ₂ -CH ₂ -; the C1-C3 alkylene group is -CH ₂ -, -CH ₂ -CH ₂ - or -CH ₂ -CH ₂ -CH ₂ - Any one of them; the C1-C2 alkylene group is any one of -CH ₂ - or -CH ₂ -CH ₂ -.

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: , wherein, R ₁ is independently any one of methyl, ethyl or propyl; R ₃ is independently any one of methyl, ethyl or propyl; R ₄ is independently -C(=O) -, or any one of -CH ₂ -; R ₅ and R ₆ are each independently hydrogen, methyl, or any one of ethyl, or R ₅ , R ₆ and the carbon atom directly connected to them jointly form- C(=O)-.

In one embodiment of the present invention, the compound represented by the general formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof is selected from any one of the following specific compounds: , , , , , , , , , , , , , , , , , , , , .

In one embodiment of the present invention, the pharmaceutically acceptable salt of any of the above-mentioned compounds represented by general formula (I), the salt is selected from fumarate, maleate, phosphate, Nitrates, sulfates, benzenesulfonates, or oxalates.

The present invention also provides a compound represented by the general formula (ID), its stereoisomer or a pharmaceutically acceptable salt thereof: , wherein: R ₁ , R ₃ , R ₄ , R ₅ and R ₆ are as defined above.

In a preferred embodiment of the present invention, in the compound represented by general formula (ID), R ₁ is independently any one of methyl, ethyl or propyl; R ₃ is independently methyl, ethyl Any one of radical or propyl; R ₄ is independently any one of -C(=O)-, or -CH ₂ -; R ₅ and R ₆ are each independently hydrogen, methyl, or ethyl Any one of , or R ₅ , R ₆ and the carbon atom directly connected to them jointly form -C(=O)-.

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), its stereoisomer or a pharmaceutically acceptable salt thereof, which Use the compound shown in general formula (ID) as starting material or intermediate; It may comprise the following steps: General formula compound (ID) and general formula compound (IE) prepare the compound shown in formula (I) by nucleophilic substitution reaction; Wherein: X ₁ is a halogen, is selected from fluorine, chlorine, bromine or iodine, preferably chlorine; R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ and A are as defined above.

In one embodiment of the present invention, the method for preparing a compound represented by general formula (IC), its stereoisomer or a pharmaceutically acceptable salt thereof, comprises the following steps: Compound of general formula (ID) and compound of general formula (I-E') prepare the compound shown in formula (IC) by nucleophilic substitution reaction; Wherein: X ₁ is halogen, is selected from fluorine, chlorine, bromine or iodine, preferably chlorine; R ₁ , R ₃ , R ₄ , R ₅ and R ₆ are as defined above.

The present invention also provides a pharmaceutical composition, which comprises a therapeutically effective amount of the compound represented by general formula (I) above, its stereoisomer or its pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier.

In one embodiment of the present invention, the pharmaceutical composition can be formulated in a conventional manner using one or more pharmaceutically acceptable carriers. Accordingly, the active compounds of the present invention may be formulated for oral, buccal, intranasal, parenteral (e.g. intravenous, intramuscular or subcutaneous) or rectal administration, or for administration by inhalation or insufflation. dosage form. A compound of the invention, or a pharmaceutically acceptable salt thereof, may also be formulated as a sustained release dosage form.

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 together with an inert diluent or some kind of carrier. According to some embodiments of the invention, compounds of the invention may be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapy, the compounds of the present invention may be administered with excipients and in the form of tablets, lozenges, capsules, suspensions, syrups and the like. According to an embodiment of the invention, the above formulations should contain at least 0.5% (w/w) of the active compound of the invention, but this may vary according to the particular dosage form, with 4% to about 70% by weight of the unit being convenient. The amount of active compound in such pharmaceutical compositions should be such as to achieve a suitable dosage.

In one embodiment of the present invention, regarding oral administration, the active compound of the present invention, for example, can be formulated into tablets or capsules by conventional means with pharmaceutically acceptable excipients, such as binders, fillers, etc. , lubricant, disintegrant or wetting agent. Tablets may be coated by methods well known in the art. Liquid preparations for oral administration may be, for example, solutions, syrups or suspensions, or evaporated to dry products to be reconstituted with water or other suitable carriers before use. Such liquid preparations can be prepared by conventional means using pharmaceutically acceptable additives such as suspending agents, emulsifying agents, non-aqueous vehicles and preservatives.

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.

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.

The present invention also provides a compound represented by general formula (I), its stereoisomer or its pharmaceutically acceptable salt or its pharmaceutical composition in the preparation of 5-hydroxytryptamine receptor, 5-hydroxytryptamine transporter (SERT) ) and/or dopamine receptors, preferably in the preparation of medicaments involving or regulating 5-HT2A receptors, serotonin transporters, dopamine D1 receptors and/or dopamine D2 receptors, more preferably Use in the preparation of medicaments involving or modulating 5-HT2A receptors and/or dopamine D2 receptors. Wherein the medicament optionally contains another one or more active agents for regulating the nervous system of mammals or alleviating mental diseases.

In one embodiment of the present invention, the regulation (modulation) includes but not limited to inhibitory activity or antagonistic activity on receptors.

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

In one embodiment of the present invention, the neuropsychiatric disease is selected from depression (such as major depressive disorder (MDD)), anxiety, dementia, schizophrenia, sleep disorders, movement disorders, dementia Behavior disorders in people with schizophrenia, Parkinson's disease, Alzheimer's disease, migraines, ADHD (e.g. ADHD), obsessive-compulsive disorder, social phobia, neurodegenerative disorders, bipolar disorder, post-traumatic stress disorder, One or more of an addictive disorder, withdrawal syndrome, or attention deficit.

In one embodiment of the present invention, the neuropsychiatric diseases described in the present invention are preferably depression (such as major depressive disorder MDD), anxiety, dementia, schizophrenia, sleep disorders, movement disorders, behaviors of dementia patients disorder, neurodegenerative disease or bipolar disorder, more preferably one or more of depression, anxiety, schizophrenia or neurodegenerative disease.

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

The present invention further relates to a method of treating, alleviating and/or preventing diseases involving serotonin receptors, serotonin transporter (SERT) and/or dopamine receptors, the method comprising administering to a patient in need thereof a therapeutically effective dose of A compound represented by the aforementioned general formula of the present invention or a pharmaceutically acceptable salt thereof; preferably relates to a treatment, alleviation or prevention of 5-HT2A receptors, serotonin transporter, dopamine D1 receptors and/or dopamine D2 receptors A method for a disease in the body, the method comprising administering a therapeutically effective dose of the compound represented by the aforementioned general formula of the present invention or a pharmaceutically acceptable salt thereof to a patient in need 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. This method exhibits outstanding curative effect and less side effects.

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

In some preferred embodiments of the present invention, the neuropsychiatric diseases are selected from depression (such as major depressive disorder), anxiety, dementia, schizophrenia, sleep disorders, movement disorders, behavior disorders of dementia patients , Parkinson's disease, Alzheimer's disease, migraine, ADHD (e.g. ADHD), obsessive-compulsive disorder, social phobia, neurodegenerative disease, bipolar disorder, post-traumatic stress disorder, addictive disorder, One or more of withdrawal syndrome, or attention deficit, preferably depression (e.g. major depressive disorder), anxiety, dementia, schizophrenia, sleep disturbance, movement disturbance, behavioral disturbance in dementia, neurodegenerative Any one or more of the illnesses or bipolar disorder.

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

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

The terms "comprising", "comprising", "having", "comprising" or "involving" are open expressions, that is, including the content specified in the present invention, but not excluding other aspects. It should be understood that the above terms such as "comprising" may cover a closed meaning, ie "consisting of".

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

In addition, it should be noted that, unless otherwise clearly stated, the description method "respectively and independently" used in the present invention should be interpreted in a broad sense, which can refer to different groups, between the same symbol The specific options expressed do not affect each other, and it can also mean that in the same group, the specific options expressed by the same symbols do not affect each other.

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

As used herein, the expression "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" etc. expresses The same meaning means that X can be any one or several of A, B, and C.

When any variable (such as R), as well as marked variables (such as R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R _{7 ,} etc.) occur more than once in the composition or structure of the compound, Its definition is independent in each case at each occurrence. For example, if a group is substituted with 0, 1, 2, 3 or 4 R substituents, said group may optionally be substituted with up to four R substituents, and each instance of The options for R substituents are all independent of each other.

The term "pharmaceutically acceptable" means a substance which, within the scope of normal medical judgment, is suitable for use in contact with the tissues of a patient without undue toxicity, irritation, allergic reaction, etc., with a reasonable ratio of benefit to harm, and can be effectively used for its intended purpose.

The term "pharmaceutically acceptable salt" refers to the salt of the compound of the present invention, which is safe and effective when used in mammals, and has proper biological activity.

The term "pharmaceutically acceptable carrier" refers to those substances that have no obvious stimulating effect on the organism and will 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, agents, solvents or emulsifiers.

The terms "administering" or "administering" and the like refer to methods that enable the delivery of a compound or composition to the desired site of biological action. These methods include, but are not limited to, oral or parenteral (including intracerebroventricular, intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular injection or infusion), topical, rectal administration, and the like. Especially by injection or by mouth.

As used herein, the term "treating" includes alleviating, alleviating or ameliorating a disease or symptom, preventing other symptoms, ameliorating or preventing underlying metabolic factors of a symptom, inhibiting a disease or symptom, e.g. Amelioration of a disease or condition, or cessation of symptoms of a disease or condition, and extends to include prophylaxis. "Treatment" also includes achieving therapeutic benefit and/or prophylactic benefit. Therapeutic benefit refers to eradication or amelioration of the condition being treated. In addition, therapeutic benefit is achieved by eradicating or ameliorating one or more physiological symptoms associated with the underlying disease, whereby improvement in the patient's disease is observed although the patient may still suffer from the underlying disease. Prophylactic benefit means that the patient uses the composition to prevent the risk of a certain disease, or takes it when the patient has one or more physiological symptoms of the disease, although the disease has not yet been diagnosed.

The terms "active ingredient", "therapeutic agent", "active substance" or "active agent" refer to a chemical entity that is effective in the treatment or prevention of the disorder, disease or condition of interest.

The term "neuropsychiatric disease" refers to a general term for neurological diseases and mental diseases, including neurological diseases and/or mental diseases.

For a drug, a drug unit or an active ingredient, the term "effective amount", "therapeutically effective amount" or "prophylactically effective amount" refers to a sufficient amount of the drug or agent that has acceptable side effects but can achieve the desired effect. The determination of the effective amount varies from person to person, depending on the individual's age and general condition, and also depends on the specific active substance. The appropriate effective amount in each case can be determined by those skilled in the art according to routine experiments.

"Individual" as used herein includes a human or non-human animal. Exemplary human subjects include human subjects suffering from a disease (eg, a disease described herein) (referred to as a patient) or normal subjects. "Non-human animals" in the present invention include all vertebrates, such as non-mammals (such as birds, amphibians, reptiles) and mammals, such as non-human primates, livestock and/or domesticated animals (such as sheep, dogs, cats, cows, pigs, etc.).

In each part of this specification, the substituents of the compounds disclosed in the present invention are disclosed according to the type or range of the group. It is specifically intended that the invention includes each individual subcombination of individual members of these radical classes and ranges. For example, the term "C ₁ -C ₆ alkyl" specifically refers to independently disclosed methyl, ethyl, C ₃ alkyl, C ₄ alkyl, C ₅ alkyl and C ₆ alkyl. Examples of alkyl groups include, but are not limited to, methyl (Me, -CH ₃ ), ethyl (Et, -CH ₂ CH ₃ ), n-propyl (n-Pr, -CH ₂ CH ₂ CH ₃ ), iso Propyl (i-Pr, -CH(CH ₃ ) ₂ ), n-Butyl (n-Bu, -CH ₂ CH ₂ CH ₂ CH ₃ ), isobutyl (i-Bu, -CH ₂ CH(CH ₃ ) ₂ ), second butyl (s-Bu, -CH(CH ₃ )CH ₂ CH ₃ ), tertiary butyl (t-Bu, -C(CH ₃ ) ₃ ), n-pentyl (-CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ ), 2-pentyl (-CH(CH ₃ )CH ₂ CH ₂ CH ₃ ), 3-pentyl (-CH(CH ₂ CH ₃ ) ₂ ), 2-methyl- 2-butyl (-C(CH ₃ ) ₂ CH ₂ CH ₃ ), 3-methyl-2-butyl (-CH(CH ₃ )CH(CH ₃ ) ₂ ), 3-methyl-1-butyl group (-CH ₂ CH ₂ CH(CH ₃ ) ₂ ), 2-methyl-1-butyl group (-CH ₂ CH(CH ₃ )CH ₂ CH ₃ ), n-hexyl group (-CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ ), 2-hexyl (-CH(CH ₃ )CH ₂ CH ₂ CH ₂ CH ₃ ), 3-hexyl (-CH(CH ₂ CH ₃ )(CH ₂ CH ₂ CH ₃ )), 2 -Methyl-2-pentyl (-C(CH ₃ ) ₂ CH ₂ CH ₂ CH ₃ ), 3-methyl-2-pentyl (-CH(CH ₃ )CH(CH ₃ )CH ₂ CH ₃ ) , 4-methyl-2-pentyl (-CH(CH ₃ )CH ₂ CH(CH ₃ ) ₂ ), 3-methyl-3-pentyl (-C(CH ₃ )(CH ₂ CH ₃ ) ₂ ), 2-methyl-3-pentyl (-CH(CH ₂ CH ₃ )CH(CH ₃ ) ₂ ), 2,3-dimethyl-2-butyl (-C(CH ₃ ) ₂ CH( CH ₃ ) ₂ ), 3,3-dimethyl-2-butyl (-CH(CH ₃ )C(CH ₃ ) ₃ ), n-heptyl, n-octyl, and the like.

The term "hydrogen (H)" means a single hydrogen atom. Such atomic groups can be linked to other groups, such as oxygen atoms, to form hydroxyl groups.

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

The term "aryl" denotes monocyclic, bicyclic and tricyclic carbocyclic ring systems 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, attached to the parent molecule through the aromatic ring of the aryl group. Examples of aryl groups may include phenyl, naphthyl and anthracene. The aryl group is optionally substituted with one or more substituents described herein.

Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH ₃ ), ethoxy (EtO, -OCH ₂ CH ₃ ), 1-propoxy (n-PrO, n-propoxy group, -OCH ₂ CH ₂ CH ₃ ), 2-propoxy (i-PrO, i-propoxy, -OCH(CH ₃ ) ₂ ), 1-butoxy (n-BuO, n-butoxy radical, -OCH ₂ CH ₂ CH ₂ CH ₃ ), 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH ₂ CH(CH ₃ ) ₂ ), 2-butoxy (s-BuO, s-butoxy, -OCH(CH ₃ )CH ₂ CH ₃ ), 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC(CH ₃ ) ₃ ), 1-pentyloxy (n-pentyloxy, -OCH ₂ CH ₂ CH ₂ CH ₂ CH ₃ ), 2-pentyloxy (-OCH(CH ₃ )CH ₂ CH ₂ CH ₃ ), 3- Pentyloxy (—OCH(CH ₂ CH ₃ ) ₂ ).

The term "-C(=O)-" denotes a carbonyl group.

The following detailed description of the invention is intended to illustrate non-limiting embodiments, so that other skilled in the art can more fully understand the technical solution of the present invention, its principle and its practical application, so that other skilled in the art can modify and modify in many forms The invention is implemented such that it can be optimally adapted to the requirements of a particular application.

Beneficial technical effect of the present invention

The compound provided by the present invention is an antagonist acting on 5-HT _2A receptors and/or D ₂ receptors, and has good antagonistic effect on 5-HT _2A receptors and/or D2 (D _2L , D _2s ) receptors and/or have a higher D2/5-HT2A ratio, with good selectivity; and/or have good pharmacokinetic properties; and/or have good pharmacodynamic effects in vivo; and/or not only for Positive symptoms are as effective as traditional antipsychotics, and have a stronger improvement effect on negative symptoms and cognitive deficit symptoms, with lower side effects (such as reducing the possibility of inducing EPS reactions, etc.).

Embodiments of the present invention are described in detail below. The embodiments described below are exemplary only for explaining the present invention and should not be construed as limiting the present invention. Unless otherwise specified, ratios, percentages, etc. referred to herein are by weight.

Synthetic example

Example 1 , 8-(4-(4- Fluorophenyl )-4- Oxobutyl )-3,6b- Dimethyl -6b,7,8,9,10,10a- Hexahydro -1H- pyridine [3',4':4,5] pyrrole [1,2,3- take off ] quinoxaline -2(3H)- Ketones (compounds 1 )

The first step: Preparation of 4-nitroso-3,4-dihydroquinoxalin-2(1 H )-one (intermediate 1-2)

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

The second step: Preparation of 4-amino-3,4-dihydroquinoxalin-2(1 H )-one hydrochloride (intermediate 1-3)

Intermediate 1-2 (1.5g, 8.47mmol) was dissolved in a mixed solvent of glacial acetic acid and water (25/25 mL), and zinc powder (3.0g, 46.1 mmol) was slowly added under ice-cooling conditions, and the reaction was carried out at constant temperature for 30 min Afterwards, move to room temperature and continue to stir 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. After the filtrate was dried, 4N hydrogen chloride dioxygen Hexacyclic solution (3 mL), after stirring for 30 min, the reaction solution was concentrated to obtain intermediate 1-3 , 1.5 g of crude yellow solid, which was directly used as the raw material in the next step without further purification.

The third step: 6b-methyl-8-(2,2,2-trifluoroacetyl)-6b,7,8,9,10,10a-hexahydro-1 H -pyridine[3',4' : Preparation of 4,5]pyrrole[1,2,3-des]quinoxaline-2(3 H )-one (intermediate 1-5)

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), reacted at 110 ° C for 15 h, and the reaction solution was cooled to room temperature After warming and concentrating, the product was separated and purified by column chromatography (DCM (dichloromethane)/MeOH (methanol) = 1/20) to obtain intermediate 1-5 , 620 mg of yellow solid, yield: 27%. LCMS m/z (M+H) ⁺ : 340.1.

The fourth step: 3,6b-dimethyl-8-(2,2,2-trifluoroacetyl)-6b,7,8,9,10,10a-hexahydro-1 H -pyridine[3' Preparation of ,4':4,5]pyrrole[1,2,3-de]quinoxaline-2(3 H )-one (intermediate 1-6)

Intermediate 1-5 (0.62 g, 1.83 mmol) was dissolved in DMF (dimethylformamide) (10 mL), sodium hydride (110 mg, 2.75 mmol) was added under ice-cooling conditions, and after constant temperature reaction for 30 min, Add methyl iodide (390 mg, 2.75 mmol), then move the reaction solution to room temperature and stir for 2 h. After the reaction is complete, put the reaction solution back into the ice bath, add water (5 mL) to the reaction solution, and then rinse the reaction solution with acetic acid After extraction with ethyl ester (20 mL x 3), the organic phase was dried with sodium sulfate, and the product was separated and purified by column chromatography to obtain the target intermediate 1-6 , 500 mg of yellow solid, yield: 77%. LCMS m/z (M+H) ⁺ : 354.1.

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

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 heated at 40°C After reacting for 15 h under the same conditions, it was concentrated to remove THF. The residue was extracted with a mixed solvent of dichloromethane and methanol (10/1, 20 mL x 3), the organic phase was dried over sodium sulfate, and column chromatography (DCM (dichloromethane)/MeOH (methanol)=10/1- 5/1) After purification, the target intermediate 1-7 was obtained, 200 mg of yellow solid, yield: 55%. LCMS m/z (M+H) ⁺ : 258.2.

The sixth step: 8-(4-(4-fluorophenyl)-4-oxobutyl)-3,6b-dimethyl-6b,7,8,9,10,10a-hexahydro-1H- Preparation of pyridin[3',4':4,5]pyrrole[1,2,3-de]quinoxalin-2(3H)-one (Compound 1)

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 ( N,N -diisopropylethylamine) ( 1.1 g, 8.56 mmol) was added to DMF (dimethylformamide) (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 (CH ₃ CN (acetonitrile): H ₂ O (water) (0.1% NH ₄ HCO ₃ (ammonium bicarbonate)) = 10-70%, ultraviolet light (UV): 214nm, flow rate (flow rate) 15mL/min) to prepare the compound 1 , off-white solid 245 mg, yield: 13%. LRMS m/z (M+H) ⁺ : 422.2. ¹ H NMR (CDCl ₃ , 400 MHz): δ 8.06-8.03 (m, 2H), 7.19-7.15 (m, 2H), 6.88-6.76 (m, 3H), 4.45 (d, J = 14.4 Hz, 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).

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

Compound 1 (1.6 g) was resolved by chiral resolution to obtain compound 1-A (427.7 mg). Chiral resolution conditions are as follows: instrument Gilson GX-281 Column type Chiralpak IE 250 mm*30 mm 5 μm Injection volume 1500 μL mobile phase Hex (hexane) : EtOH (ethanol) = 40 : 60 flow rate 25 mL/min Detection wavelength 254 nm Column temperature 30℃ t _R = 6.968 min; LCMS m/z (M+H) ⁺ : 422.2; ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.02-7.99 (m, 2H), 7.16-7.10 (m, 2H), 6.83 -6.73 (m, 3H), 4.01 (d, J = 14.0 Hz, 1H), 3.35 (d, J = 14.0 Hz, 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).

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

Compound 1 (1.6 g) was resolved by chiral resolution to obtain compound 1-B (467.8 mg). Chiral resolution conditions are as follows: instrument Gilson GX-281 Column type Chiralpak IE 250 mm*30 mm 5 μm Injection volume 1500 μL mobile phase Hex (hexane) : EtOH (ethanol) = 40 : 60 flow rate 25 mL/min Detection wavelength 254 nm Column temperature 30℃ t _R = 8.030 min; LCMS m/z (M+H) ⁺ : 422.2; ¹ H NMR (400 MHz, CDCl ₃ ): δ 8.02-7.99 (m, 2H), 7.16-7.10 (m, 2H), 6.84 -6.73 (m, 3H), 4.01 (d, J = 14.0 Hz, 1H), 3.36 (d, J = 14.0 Hz, 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).

Example 2 , 6b- Ethyl -8-(4-(4- Fluorophenyl )-4- Oxobutyl )-3- methyl -6b,7,8,9,10,10a- Hexahydro -1H- pyridine [3',4':4,5] pyrrole [1,2,3- take off ] quinoxaline -2(3H ) - Preparation of ketones (compounds 2 )

The first step: 6b-ethyl-8-(2,2,2-trifluoroacetyl)-6b,7,8,9,10,10a-hexahydro-1 H -pyridine[3',4' : Preparation of 4,5]pyrrole[1,2,3-di]quinoxaline-2(3 H )-one (intermediate 2-2)

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, and the reaction solution was cooled to room temperature Afterwards, the crude product was obtained by rotary evaporation under reduced pressure, and the product was separated and purified by column chromatography (EA (ethyl acetate)/PE (petroleum ether) = 1/2) to obtain intermediate 2-2 , 360 mg of yellow solid, with a yield of 28.4%. LRMS m/z (M+H) ⁺ : 354.2.

The second step: 6b-ethyl-3-methyl-8-(2,2,2-trifluoroacetyl)-6b,7,8,9,10,10a-hexahydro-1 H -pyridine[ Preparation of 3',4':4,5]pyrrole[1,2,3-de]quinoxalin-2( 3H )-one (Intermediate 2-3)

Add NaH (sodium hydride) (68 mg, 1.70 mmol) to a solution of intermediate 2-2 (400 mg, 1.13 mmol) in DMF (dimethylformamide) (15 mL) under ice-cooling conditions, and react at constant temperature for 30 min , then add CH ₃ I (methyl iodide) (241 mg, 1.70 mmol) to the reaction system, after the addition is complete, the reaction solution is moved to room temperature for 16 h, quenched with water (15 mL) in an ice bath, and the reaction solution is washed with ethyl acetate Esters (20 mL x 3) were extracted. The combined organic phases were dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was subjected to column chromatography (PE (petroleum ether)/EA (ethyl acetate) =5:1, v/v) to obtain intermediate 2-3 , yellow solid 200 mg, yield 48%. LCMS m/z (M+H) ⁺ : 368.3.

The third step: 6b-ethyl-3-methyl-6b,7,8,9,10,10a-hexahydro-1 H -pyridine[3',4':4,5]pyrrole[1,2, 3-di]quinoxaline-2(3 H )-one (intermediate 2-4)

Add K _{2 CO 3} ( potassium carbonate) (150 mg, _1.09mmol ), after the addition, the reaction solution was reacted at 70°C for 4 h, the reaction solution was cooled to room temperature and water (10 mL) was added, then extracted with dichloromethane (20 mL x 3), the combined organic phase was dried over anhydrous sodium sulfate, filtered , the filtrate was rotary evaporated under reduced pressure to obtain the crude product, and the intermediate 2-4 was obtained by column chromatography (DCM (dichloromethane)/MeOH (methanol) =20:1, v/v), yellow oil 120 mg, and Rate: 65%. LCMS m/z (M+H) ⁺ : 272.2.

The fourth step: 6b-ethyl-8-(4-(4-fluorophenyl)-4-oxobutyl)-3-methyl-6b,7,8,9,10,10a-hexahydro- Preparation of 1 H -pyridin[3',4':4,5]pyrrole[1,2,3-de]quinoxalin-2(3 H )-one (Compound 2)

Intermediate 2-4 (100 mg, 0.37 mmol), Intermediate 1-8 (590 mg, 2.95 mmol), KI (potassium iodide) (245 mg, 1.48 mmol) and DIEA ( N,N -diisopropylethylamine ) (190 mg, 1.48 mmol) in DMF (dimethylformamide) (10 mL), stirred at 78°C for 16 h, cooled the reaction solution to room temperature, added 10 mL of water, extracted with ethyl acetate (20 mL x 3), the combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was rotary evaporated under reduced pressure to obtain the crude product, which was separated and purified by preparative liquid phase (CH ₃ CN(acetonitrile):H ₂ O(water) (0.1% NH ₄ HCO ₃ (ammonium bicarbonate))=40-80%, UV:214nm, flow rate 15 mL/min) to obtain compound 2 , 45.0 mg, yield 23%. LCMS m/z (M+H) ⁺ : 436.2. ¹ H NMR (CDCl ₃ , 400 MHz): δ 8.03-7.95 (m, 2H), 7.13 (t, J = 8.4 Hz, 2H), 6.83-6.74 (m, 2H), 6.74-6.68 (m, 1H) , 4.01 (d, J = 14.0 Hz, 1H), 3.37 (d, J = 14.4 Hz, 1H), 3.32 (s, 3H), 3.10-3.04 (m, 1H), 2.98 (t, J = 7.2 Hz, 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 = 7.6 Hz, 3H).

Example 3 , 3- Ethyl -8-(4-(4- Fluorophenyl )-4- Oxobutyl )-6b- methyl -6b,7,8,9,10,10a- Hexahydro -1 H - pyridine [3',4':4,5] pyrrole [1,2,3- take off ] quinoxaline -2(3 H )- Preparation of ketones (compounds 3 )

The first step: 3-ethyl-6b-methyl-8-(2,2,2-trifluoroacetyl)-6b,7,8,9,10,10a-hexahydro-1 H -pyridine[ Preparation of 3',4':4,5]pyrrole[1,2,3-de]quinoxaline-2( 3H )-one (Intermediate 3-1)

Under ice-bath conditions, to intermediate 1-5 (0.2g, 0.59mmol, prepared with reference to the method described in the third step of Example 1) in DMF (dimethylformamide) (10 mL) solution, add sodium hydride (28 mg, 0.71 mmol), after constant temperature reaction for 30 minutes, add iodoethane (148 mg, 0.89 mmol), after addition, move to room temperature and stir for 1 hour, then move the reaction solution to ice bath again and add water (5 mL) to quench, The reaction solution was extracted with ethyl acetate (10mL x 3), the combined organic phase was dried over anhydrous sodium sulfate and concentrated, and the crude product was chromatographed (DCM (dichloromethane)/MeOH (methanol) = 20/1) to obtain intermediate 3 -1 , yellow solid 150 mg, yield: 69%. LCMS m/z (M+H) ⁺ : 368.2.

The second step: 3-ethyl-6b-methyl-6b,7,8,9,10,10a-hexahydro-1 H -pyridine[3',4':4,5]pyrrole[1,2, Preparation of 3-de]quinoxalin-2(3 H )-one (intermediate 3-2)

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 was complete, the reaction solution was reacted at 40°C for 2 h, after the solvent was spin-dried under reduced pressure, the crude product was separated and purified by column chromatography (DCM (dichloromethane)/MeOH (methanol)/NH ₃ H ₂ O (ammonia water)=100/10/1) to obtain intermediate 3-2 , yellow oil 91 mg, yield 82%. LCMS m/z (M+H) ⁺ : 272.2.

The third step: 3-ethyl-8-(4-(4-fluorophenyl)-4-oxobutyl)-6b-methyl-6b,7,8,9,10,10a-hexahydro- Preparation of 1 H -pyridin[3',4':4,5]pyrrole[1,2,3-de]quinoxalin-2(3 H )-one (compound 3)

Intermediate 1-8 ( 136 mg, 0.68 mmol), potassium iodide (10 mg) and N , N -diisopropylethylamine (88 mg, 0.68 mmol), after the addition, the reaction solution was reacted at 78°C for 3 h, the reaction solution was cooled to room temperature and then concentrated to obtain the crude product, which was prepared by using the preparative liquid phase (CH ₃ CN (acetonitrile ): H ₂ O (water) (0.1% NH ₄ HCO ₃ (ammonium bicarbonate))=10-60%, ultraviolet light (UV): 214nm, flow rate (flow rate) 15mL/min) separation and purification to obtain compound 3 , 42.3 mg, yield: 28%. LCMS m/z (M+H) ⁺ : 436.2. ¹ H NMR (CDCl ₃ , 400 MHz): δ 8.04-8.01 (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 = 14.4 Hz, 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).

Example 4 , 8-(4-(4- Fluorophenyl )-4- Oxobutyl )-1,1,3,6b- Tetramethyl -6b,7,8,9,10,10a- Hexahydro -1 H - pyridine [3',4':4,5] pyrrole [1,2,3- take off ] quinoxaline -2(3 H )- Preparation of ketones (compounds 4 )

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

To intermediate 1-7 (1.2 g, 4.6 mmol, prepared with reference to the fifth step of the preparation method of Example 1) in DCM (dichloromethane) (20 mL) solution, triethylamine (1.3 g, 13.2 mmol) was sequentially added, Di-tert-butyl dicarbonate (4.3 g, 19.8 mmol) was reacted at room temperature for 2 h and then quenched by adding water (15 mL). The organic phase was obtained by separation, and the crude product obtained by drying and concentrating was subjected to column chromatography (EA (ethyl acetate ester)/PE (petroleum ether)=1/3) separation and purification to obtain intermediate 4-1 , white solid 1.6 g, yield: 68%. LCMS m/z (M-56+H) ⁺ : 302.2.

Second step: 1,1,3,6b-tetramethyl-2-oxo-2,3,6b,9,10,10a-hexahydro-1 H -pyridine[3',4':4,5 Preparation of ]pyrrole[1,2,3-de]quinoxaline-8(7 H )-carboxylate (intermediate 4-2)

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) was slowly added dropwise under the protection of argon , 2.0 M, 3.7 mL, 7.4 mmol), and reacted at constant temperature for 1 h after dropping. Then methyl iodide (2.1 g, 14.8 mmol) was slowly added dropwise, and the reaction was carried out at constant temperature for 2 h. After the reaction solution was moved to room temperature, water (20 mL) was added to quench the reaction solution. The reaction solution was extracted with ethyl acetate (15 mL x 3) , the organic phase was dried and concentrated, and the crude product obtained was separated and purified by column chromatography (EA (ethyl acetate)/PE (petroleum ether) = 1/2), intermediate 4-2 , yellow oil 410 mg, yield: 58% . LCMS m/z (M+H) ⁺ : 386.2.

The third step: 1,1,3,6b-tetramethyl-6b,7,8,9,10,10a-hexahydro-1H-pyridine[3',4':4,5]pyrrole[1,2 , Preparation of 3-de]quinoxalin-2(3H)-one (intermediate 4-3)

Intermediate 4-2 (0.44 g, 1.14 mmol) and 1,6-Lutidine (1,6-lutidine) (0.24 g, 2.28 mmol) in DCM (dichloromethane) (50 mL ) solution was added TMSOTf (trimethylsilyl trifluoromethanesulfonate, 380 mg, 1.71 mmol), after constant temperature reaction for 30 min, the reaction solution was quenched with ammonium chloride aqueous solution (15 mL), and the organic phase was separated by The crude product was obtained by drying and concentrating, and the product was separated and purified by column chromatography (DCM (dichloromethane)/MeOH (methanol) = 10/1) to obtain intermediate 4-3 , yellow oil 200 mg, yield: 61%. LCMS m/z (M+H) ⁺ : 286.2.

The fourth step: 8-(4-(4-fluorophenyl)-4-oxobutyl)-1,1,3,6b-tetramethyl-6b,7,8,9,10,10a-hexa Hydrogen-1H-pyridin[3',4':4,5]pyrrole[1,2,3-de]quinoxalin-2(3H)-one (Compound 4)

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 ( N,N -diisopropylethylamine) ( 244 mg, 1.89 mmol) were sequentially added to DMF (dimethylformamide) (10 mL), and reacted at 78°C for ₅ h. ₂ O (water) (0.1% NH ₄ HCO ₃ (ammonium bicarbonate))=10-70%, ultraviolet light (UV): 214nm, flow rate (flow rate) 15mL/min) separation and purification to obtain compound 4 , 100 mg, Yield: 38%. LCMS m/z (M+H) ⁺ : 450.2. ¹ H NMR (CDCl ₃ , 400 MHz): δ 8.02-7.95 (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).

Example 5 , 8-(4-(4- Fluorophenyl )-4- Oxobutyl )-3,6b- Dimethyl -6b,7,8,9,10,10a- Hexahydro -1H- pyridine [3',4':4,5] pyrrole [1,2,3- take off ] quinoxaline -1,2(3H)- Diketones (compounds 5 )

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

To Intermediate 1-6 (200 mg, 0.50 mmol) in carbon tetrachloride (20 mL) was added RuO ₂ (ruthenium dioxide) (37 mg, 0.28 mmol), NaIO ₄ (sodium periodate) (300 mg, 1.4 mmol), after reacting at room temperature for 48h, the reaction solution was directly concentrated to obtain the crude product. The product was subjected to column chromatography (EA (ethyl acetate)/PE (petroleum ether) = 1/1) to obtain intermediate 5-1 , yellow solid 114 mg, yield: 54%. LCMS m/z (M+H) ⁺ : 368.2.

The second step: 3,6b-dimethyl-6b,7,8,9,10,10a-hexahydro-1H-pyridin[3',4':4,5]pyrrole[1,2,3-de ]quinoxaline-1,2(3H)-dione (intermediate 5-2)

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, it was concentrated to obtain Intermediate 5-2 , 150 mg of yellow oil, which was directly used as a raw material in the next step without further purification. LCMS m/z (M+H) ⁺ : 272.2.

The third step: 8-(4-(4-fluorophenyl)-4-oxobutyl)-3,6b-dimethyl-6b,7,8,9,10,10a-hexahydro-1 H - Preparation of pyridin[3',4':4,5]pyrrole[1,2,3-de]quinoxaline-1,2(3 H )-dione (compound 5)

Intermediate 1-8 ( 150 mg, 0.75 mmol), potassium carbonate (37 mg , 0.27 mmol), 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, and the residue was prepared by preparing the liquid phase (CH ₃ CN (acetonitrile):H ₂ O (water) (0.1 % NH ₄ HCO ₃ (ammonium bicarbonate) = 10-70%, ultraviolet light (UV): 214nm, flow rate (flow rate) 15mL/min) separation and purification to obtain compound 5 , 35 mg, yield: 15%. LCMS m/z (M+H) ⁺ : 436.2. ¹ H NMR (CDCl ₃ , 400 MHz): δ 8.02-7.98 (m, 2H), 7.15-7.10 (t, J = 8.4 Hz, 1H), 6.59-6.56 (m, 3H), 4.32-4.29 (m, 2H), 4.32-4.29 (d, J = 11.2 Hz, 2H), 3.07-2.99 (m, 5H), 2.66-2.45 (m, 5H), 2.12 (t, J = 7.6 Hz, 2H), 2.03-1.97 (m, 4H).

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

Intermediate 1-7 (2.0 g, 7.78 mmol, prepared according to the method described in the fifth step of Example 1), intermediate 6-1 (2.9 g, 15.56 mmol), potassium iodide (2.0 g, 15.56 mmol) and DIEA ( N,N -diisopropylethylamine) (2.0 g, 15.56 mmol) was sequentially added to DMF (dimethylformamide) (40 mL), and reacted at 78°C for 3h. After the reaction was completed, the reaction solution was directly concentrated, and the crude product obtained was separated and purified by preparative liquid phase to obtain compound 6 , 1.5 g, yield: 47%. LCMS m/z (M+H) ⁺ : 410.2. ¹ H NMR (CDCl ₃ , 400 MHz): δ 6.98-6.93 (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).

Example 7 , 4-(3,6b- Dimethyl -2,3,6b,9,10,10a- Hexahydro -1 H - pyridine [3',4':4,5] pyrrole [1,2,3- take off ] quinoxaline -8(7 H )- base )-1-(4- Fluorophenyl ) butane -1- Preparation of ketones (compound 7 )

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

Intermediate 1-7 (0.2 g, 0.78 mmol) was dissolved in THF (tetrahydrofuran) (10 mL), and a 1M solution of borane in tetrahydrofuran (1.56 mL, 1.56 mmol) was slowly added, and the reaction solution was stirred at room temperature for 15 h Finally, it was quenched by adding 1N hydrochloric acid aqueous solution (2 mL) dropwise under ice bath conditions, and the quenched reaction solution was directly concentrated and column chromatographed to obtain intermediate 7-1 , 80 mg, yield: 42%. LCMS m/z (M+H) ⁺ : 244.2.

The second step: 4-(3,6b-dimethyl-2,3,6b,9,10,10a-hexahydro-1 H -pyridine[3',4':4,5]pyrrole[1,2 , Preparation of 3-de]quinoxalin-8(7 H )-yl)-1-(4-fluorophenyl)butan-1-one (compound 7)

Intermediate 7-1 (75 mg, 0.308 mmol), Intermediate 1-8 (184 mg, 0.924 mmol), potassium iodide (101 mg, 0.616 mmol), DIEA ( N,N -diisopropylethylamine) ( 119 mg, 0.924 mmol) was added to DMF (dimethylformamide) (3 mL), and the reaction solution was reacted at 78°C for 3h. After the reaction solution was cooled to room temperature, it was directly concentrated to remove DMF (dimethylformamide), and the product was prepared by liquid phase (CH ₃ CN (acetonitrile):H ₂ O (water) (0.1% NH ₄ HCO ₃ (ammonium bicarbonate ))=10-70%, ultraviolet light (UV): 214nm, flow rate (flow rate) 15mL/min) separation and purification to obtain the target compound 7 , 32 mg, yield: 25%. LCMS m/z (M+H) ⁺ : 407.9. ¹ H NMR (CDCl ₃ , 400 MHz): δ 8.06-8.03 (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).

comparative example 1 , 8-(4-(4- Fluorophenyl )-4- Carbonyl Butyl )-3- methyl -6b,7,8,9,10,10a- Hexahydro -1H- pyridine and [3',4':4,5] pyrrole and [1,2,3- take off ] quinoxaline -2(3H)- ketone

The first step: 8-(2,2,2-trifluoroacetyl)-7,8,9,10-tetrahydro-1H-pyrido[3',4':4,5]pyrrole[1, Synthesis of 2,3-de]quinoxalin-2(3H)one (Intermediate D1-2)

Add Intermediate 1-3 (3 g, 15 mmol), Intermediate D1-1 (2.9 g, 15 mmol), and isopropanol (30 mL) into a 100 mL single-necked bottle in sequence, and heat up to reflux for overnight reaction, and the reaction is complete Finally, pour the reaction solution into ice water (5 mL), extract with ethyl acetate (15 mL), dry over anhydrous sodium sulfate, concentrate under reduced pressure and use silica gel column chromatography (petroleum ether: ethyl acetate = 2:1) to obtain Intermediate D1-2 , 1.8 g, yield: 30%. LCMS m/z (M+H) ⁺ : 324.2.

The second step: 8-(2,2,2-trifluoroacetyl)-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5] Synthesis of pyrrolo[1,2,3-de]quinoxalin-2(3H)-one (intermediate D1-3)

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

The third step: 3-methyl-8-(2,2,2-trifluoroacetyl)-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4' Synthesis of :4,5]pyrrolo[1,2,3-de]quinoxalin-2(3H)-one (intermediate D1-4)

Intermediate D1-3 (700 mg, 2.15 mmol) was dissolved in DMF (dimethylformamide) (10 mL), and sodium hydride (100 mg, 2.58 mmol) and deuteroiodomethane (340 mg, 2.37 mmol), and reacted in 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 intermediate Body D1-4 , 500 mg, yield: 69%. LCMS m/z (M+H) ⁺ : 340.1.

The fourth step: 3-methyl-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de] Synthesis of quinoxalin-2(3H)-one (intermediate D1-5)

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

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

Dissolve intermediate D1-5 (200 mg, 0.82 mmol) and intermediate D1-6 (324 mg, 1.23 mmol) in acetonitrile (5 mL), add cesium carbonate (400 mg, 1.23 mmol), and react overnight at room temperature , after the reaction was completed, suction filtered, concentrated to dryness under reduced pressure, and prepared by preparative high performance liquid chromatography (Pre HPLC) (MeCN (acetonitrile): H ₂ O (water) = 40:60) to obtain the final product Comparative Example 1 , 56 mg, yield: 18%. LCMS m/z (M+H) ⁺ : 408.2. ¹ H NMR (600 MHz, CD ₃ OD): δ 8.08 – 8.06 (m, 2H), 7.24 – 7.21 (m, 2H), 6.97 – 6.85 (m, 3H), 4.03 (d, J = 13.8 Hz, 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).

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 ] quinoxalin -8(7H) -yl ) butane - 1- one

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, then cesium carbonate (1.42 g, 4.36 mmol) and 1-(4-fluorophenyl)-4-iodobutan-1-one were added (955.27 mg, 3.27 mmol), the reaction solution was stirred at room temperature for 4 hours, and the product formation was monitored by liquid chromatography mass spectrometry (LCMS). The reaction solution was dissolved in water (50 mL), extracted twice with ethyl acetate (50 mL×2), the collected organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by a flash preparation column machine (petroleum Ether: ethyl acetate=10:1~1:4) to obtain comparative example 2 , 600 mg, 2.18 mmol, yield: 69.93%. ¹ H NMR (600MHz ,DMSO- d ₆ ) δ: 8.06-8.01 (m, 2 H), 7.33 (t, J = 9.0 Hz, 2 H), 6.49 (t, J = 7.2 Hz, 1 H), 6.39 (d, J = 7.2 Hz, 1 H), 6.31 (d, J = 7.8 Hz, 1 H), 3.45 - 3.22 (m, 3 H), 3.03 (br. s., 1 H), 2.98 (t, J = 6.6 Hz, 2 H), 2.90 - 2.84 (m, 1 H), 2.77 (s, 3 H), 2.73-2.68 (m, 1 H), 2.65 (dt, J = 9.6, 3.0 Hz, 1 H ), 2.55-2.50 (m, 1H), 2.32 - 2.20 (m, 2H), 2.06 (dt, J = 11.4, 2.4 Hz, 1H), 1.85 - 1.76 (m, 3H), 1.73 (t , J = 10.8 Hz, 1 H), 1.67 - 1.59 (m, 1 H).

biological test case

The following ITI-007 of the present invention is as follows, and is prepared with reference to the method of Example 261 of the patent PCT/US2000/016498, .

The following comparative example 1-A of the present invention is as follows, and is prepared with reference to the method of scheme 1 in paragraph [0339] of the patent PCT/US2017/015178 description, .

test case 1 , Functional activity test of each compound on the receptor (frozen cells)

1. Materials and equipment cells cell name supplier CHO-K1/D2L/Gα15 GenScript Biotechnology Co., Ltd. CHO-K1/5HT2A perkin elmer ltd. Experimental Reagent Consumables Reagent supplier model Hank's Balanced Salt Solution (HBSS) Gibco 14175095 HEPES Gibco 15630080 Fluo4 Direct Calcium Assay kit Invitrogen F10471 Advanced DMEM/F-12 Gibco 12634010 Fetal bovine serum (FBS) Gibco 10099141 L-Glutamine - 200mM (100X) Invitrogen 25030081 Ham's F-12 Gibco C11765500BT Dialyzed Fetal Bovine Serum (Dialyzed FBS) Biological Industries 04-011-1A Dimethylsulfone (DMSO) Sigma D8418 384-well Poly-D-Lysine plate Greiner 781946 384-well PP microplate, V-Form Greiner 781280 FLIPR Pipette Tips Molecular Device 9000-0764 equipment name supplier cell counter Countstar FLIPR Molecular Device centrifuge Cence Skin upgrade microdoser Tecan test drug name supplier model Dopamine Sigma H8502 Serotonin Sigma H9523 Spiperone Targetmol T0280 Ketanserin Targetmol T1066

2. Experimental method

Day 1: Cell Plating (1) Remove the cells from the liquid nitrogen tank, unscrew the cap and invert the tube to let the liquid nitrogen flow out of the tube, then screw the cryovial back on. (2) Shake the cryopreservation tube quickly at 37°C. After the ice has completely melted, wipe the surface of the cryopreservation tube with 75% alcohol and place it in a biological safety cabinet. (3) Transfer the cell suspension to a 50mL centrifuge tube that has been added with 10 mL of pre-warmed growth medium (without screening antibiotics). (4) Centrifuge at 1000 rpm for 5 minutes. (5) Discard the supernatant, add 8 mL of growth medium (without screening antibiotics), and blow off gently. Take out 20 μL and use a cell counter for counting. (6) Dilute according to the specified conditions: 1×10 ⁶ cells/mL, add 20 μL of cell suspension to each well of the cell plate, and the final concentration in each well is 20,000 cells/well (7) Place the cell plate in 5% CO ₂ , Incubate in a 37°C incubator for 16-24 hours.

Day 2: Experimental Testing

Detection reagent preparation: (1) Preparation of 250 mM probenecid solution: Take 1 mL of experimental buffer solution and add it to a tube containing 77 mg powder, vortex to dissolve. (2) Preparation of 2× fluorescent probe solution: take 1 bottle of fluorescent probe dry powder and equilibrate 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 Dissolve completely, then vortex again.

Experimental operation steps:

(1) Compound preparation. a) Agonist compound plate preparation (test EC ₈₀ ): Dopamine and Serotonin were diluted 3-fold at 10 concentration points in the compound plate (Greiner-781280) using experimental buffer, the initial concentration was 1.2 μM, 30 μL per well, The DMSO concentration is not higher than 3%. b) Antagonist-positive compound and test compound disk preparation: the compound to be tested is diluted 3-fold at 10 concentration points in the compound disk (Greiner-781280) with assay buffer, the initial concentration is 3 μM, 30 μL per well; antagonist positive Compounds Spiperone and Ketanserin were diluted 3-fold at 10 concentration points using the assay buffer, with a starting concentration of 1 μM and 30 μL per well. The DMSO concentration is not higher than 3%.

(2) Cell preparation: Take out the 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.

(3) Agonist EC ₈₀ test a) Place the cell plate and agonist compound plate into the instrument, and run the plate reading program. b) Transfer 10 μL from the agonist compound plate to the cell plate and read the fluorescent signal. c) Use Screenworks software to calculate the EC ₈₀ of the agonist, and prepare a concentration of 6×EC ₈₀ for use.

(4) Compound EC ₅₀ and IC ₅₀ test a) Put the cell plate and the compound plate to be tested into the instrument, and run the plate reading program. b) Transfer 10 μL from the test compound plate to the cell plate, and read the fluorescent signal. c) Then put in 6×EC ₈₀ agonist plate, transfer 10μL to the cell plate, and read the fluorescent signal. d) Export the "Max-Min" value from 1-maximum times as raw data for analysis, and calculate the EC ₅₀ and IC ₅₀ values of the compound.

3. Experimental results: See Table 1 for specific results.

Table 1 In vitro functional activity test results of each compound Example number D ₂ IC ₅₀ (nM) 5-HT _2A IC ₅₀ (nM) D ₂ /5-HT _2A ratio Example 1 661.58 50.54 13.09 ITI-007 568.91 119.7 4.75

4. Experimental conclusion:

Current studies have found that high activity on 5-HT2A receptors can improve the clinical efficacy of atypical and typical antipsychotics; in addition, it has high selectivity for D2/5-HT2A (the greater the ratio of D2/5-HT2A, the higher the selectivity Sex) can reduce the possibility of inducing an EPS response and is an important design goal for antischizophrenia drugs.

According to the results in Table 1 above, the compound of the present invention has good functional activity on 5-HT2A and/or D2, and the ratio of D2/5-HT2A is relatively high, suggesting that the compound of the present invention has a good therapeutic effect on schizophrenia. Reduces the possibility of inducing EPS.

test case 2 ,right 5-HT _2A Functional assay of receptors (cultured cells)

1. Experimental purpose: To detect the antagonistic effect of the compounds of the present invention on 5-HT _2A receptors by means of a cell-level calcium ion influx detection method.

2. Experimental plan:

2.1 Experimental materials: (1) Test compound: the compound of the embodiment of the present invention, self-made. (2) Control compounds: Serotonin hydrochloride 5-hydroxytryptamine (Sigma, H9523), Ketanserin (Targetmol, T1066). (3) Stably transformed cell lines: cell name growth medium Freezing Medium Plating medium CHO-K1/5-HT2A (PerkinElmer) Advanced DMEM/F12, 1% Dialyzed FBS, 4 mM L-Glutamine, 0.4 mg/ml Geneticin Advanced DMEM/F12, 1% Dialyzed FBS, 4 mM L-Glutamine, 10% DMSO Advanced DMEM/F12, 1% Dialyzed FBS, 4 mM L-Glutamine (4) Experimental reagents: Reagent name brand Item No. DMSO Sigma D8418 Fluo-4 Direct Calcium Assay Kit Invitrogen F10471 HBSS Gibco 14175103 HEPES Gibco 15630080 DMEM Gibco C11965500CP Advanced DMEM/F12, Gibco 12634010 Ham's F12 Gibco C11965500CP FBS Invitrogen 10099141 Dialyzed FBS Biological Industries 04-011-1A Zeocin Invitrogen R25001 Puromycin Gibco A11138-03 Geneticin Gibco 10131-027 L-Glutamine Invitrogen 25030081 Penicillin-Streptomycin (PS-100X) Gibco 15140122 PBS Gibco C10010500BT 0.05% Trypsin-EDTA Gibco 25300062 (5) Experimental consumables: consumable name brand Item No. cell counting tray 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 (6) Experimental equipment: equipment name brand model Electronic balance Sartorius SQP FLIPR Molecular Device TETRA Bravo Agilent Bravo cell counter Countstar BioTech Ultrapure water meter Millipore IQ 7000 centrifuge Cence TDZ5-WS Multifuge X4R Pro Centrifuge Thermo Fisher 75009915

2.2 Solution preparation: (1) Preparation of test compounds: Dissolve the compounds of the examples of the present invention in DMSO to prepare 10 mM mother solutions, and store them in a nitrogen cabinet for later use. (2) Preparation of the reference compound: Dissolve the reference compound in DMSO to prepare a 10 mM stock solution, store it in a -80°C refrigerator for later use. (3) Preparation of 250 mM Probenecid solution: Take 1 mL of experimental buffer solution and add it to a tube containing 77 mg powder, vortex to dissolve. (4) Preparation of 2× fluorescent probe solution: Take 1 bottle of fluorescent probe dry powder and equilibrate 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 dissolve. (5) Experimental buffer HBSS: Mix HBSS and HEPES at a ratio of 50:1, store in a refrigerator at 4°C, and heat at 37°C when used.

2.3 Experimental method:

Cell recovery: (1) Take out the cells from the liquid nitrogen tank, melt them in a 37°C water bath, wipe the surface of the cryotube with 75% alcohol, and place them in a biological safety cabinet. (2) Transfer the cell suspension to a 15 mL centrifuge tube with 4 mL of preheated plating medium, and centrifuge at 1000 rpm for 5 minutes. (3) Discard the supernatant, add 10 mL of spreading medium, gently blow off, and transfer to a petri dish for growth. After 24 hours, the cells were replaced with growth medium to continue culturing.

Cell plating: (1) Take the cells grown in the logarithmic phase, grow to about 85%-90%, and perform the following operations: cell washing, digestion, termination, and then transfer to a 15 mL centrifuge tube, at room temperature, 1000 rpm Centrifuge for 5 min. (2) Discard the supernatant, add a certain amount of spreading medium, and blow off gently. Remove 20 μL of cell suspension for counting. (3) Dilute the cells to 1×10 ⁶ cells/mL, add 20 μL of cell suspension to each well of the cell plate (Greiner-781946), so that the density of each well is 2×10 ⁴ cells/well. (4) Place the cell plate in an incubator with 5% CO ₂ and 37°C for 16-24 hours.

Experimental detection steps:

(1) Compound preparation a) Agonist compound disk preparation (test EC ₈₀ ): agonists were diluted 4-fold at 10 concentration points with experimental buffer in the compound disk (Greiner-781280), 30 μL per well. b) Preparation of the test compound and positive compound plate: Both the test compound and the positive compound were diluted 4-fold at 10 concentration points with experimental buffer in the compound plate (Greiner-781280), 30 μL per well.

(2) Cell preparation: Take the cells out of the incubator, add 20 μL/well of 2× fluorescent probe solution, incubate at 37°C for 50 minutes, and equilibrate at room temperature for 10 minutes.

(3) EC ₈₀ test of agonist a) Place the cell disk and agonist compound disk into the instrument and run the program. b) Transfer 10 μL from the agonist compound plate to the cell plate and read the fluorescent signal. c) Use Screenworks software to calculate the EC ₈₀ of the agonist, and prepare a concentration of 6×EC ₈₀ for use.

(4) IC ₅₀ test of compound a) Put the cell disk and the compound disk to be tested into the instrument, and run the corresponding program. b) Transfer 10 μL from the test compound plate to the cell plate, and read the fluorescent signal. c) Take out the compound plate, put it into a 6×EC ₈₀ agonist plate, transfer 10 μL from the 6×EC ₈₀ agonist plate to the cell plate, and read the fluorescent signal. d) Export the "Max-Min" value from 1 to the maximum number of readings as raw data for analysis, and calculate the IC ₅₀ value of the compound.

3. Experimental results: as shown in Table 2.

Table 2 The functional activity test results of the compounds of the present invention to 5-HT _2A receptors Example number 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

4. Experimental conclusion: It can be concluded from the above scheme that the compound of the present invention has a good antagonistic effect on the 5-HT _2A receptor.

test case 3 , the compound of the present invention D _2L , D _2s Functional Activity Testing of Receptors

1. Experimental purpose: The antagonistic effect of the compound of the present invention on D _2L and D _2s receptors was detected by the cell-level cyclic adenosine monophosphate (cAMP) detection method.

2. Experimental plan

2.1 Experimental materials: (1) Test compound: the compound of the embodiment of the present invention, self-made. (2) Control compounds: Dopamine hydrochloride (Sigma, H8502), (+)-Butaclamol hydrochloride (+)-Butaclamol hydrochloride (Sigma, D033). (3) Stably transformed cell lines: cell name growth medium Freezing medium CHO-K1/D2L/Gα15 (GenScript) Ham's F12, 10% FBS, 200 μg/ml Zeocin, 100 μg/ml Hygromycin B 45% culture medium, 45% FBS, 10% DMSO HEK293/D _2S DMEM, 10%FBS, 0.6 μg/mL puromycin 70% DMEM, 20% FBS, 10% DMSO (4) Experimental reagents: Reagent name brand Item No. 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 (5) Experimental consumables: consumable name brand Item No. cell counting tray Countstar IC1000 T8+ Dispensehead Cassettes HP F0L59A ProxiPlate-384 Plus, White 384-shallow well Microplate PerkinElmer 6008280 384-well-PP microplate, V-Form Greiner 781280 384 Tips/RACK Agilent 19133-102 96-well V bottom Storage Plate costar 3357 (6) Experimental equipment: equipment name brand model Electronic balance Sartorius SQP EnVision PerkinElmer 2104 Pico-upgraded micro-sampling system Tecan D300e Bravo Agilent Bravo cell counter Countstar BioTech Ultrapure water meter Millipore IQ 7000 centrifuge Cence TDZ5-WS

2.2 Preparation of solutions: (1) Preparation of test compounds: Dissolve the compounds of the examples of the present invention in DMSO to prepare 10 mM mother solutions, and store them in a nitrogen cabinet for later use. (2) Preparation of reference compound: Dissolve reference compound in DMSO to make 10 mM stock solution, store in -80°C refrigerator for later use. (3) IBMX was dissolved in DMSO to prepare a 0.5 M stock solution and stored at -80°C. (4) Forskolin was dissolved in DMSO to prepare a 1 mM stock solution, which was frozen at -80°C for later use. (5) Experimental buffer: Dilute 5×stimulation buffer to 1× with ddH ₂ O, add IBMX with a final concentration of 0.5 mM, mix well and set aside.

2.3 Experimental method (Gi antagonist test): (1) Compound preparation: the test compound and the positive control compound (+)-Butaclamol hydrochloride were serially diluted in the compound plate (Greiner-781280) using Bravo, and the initial concentration of the working solution was To 20 μM, use the experimental buffer to dilute 10 concentrations by 4 times, and centrifuge at 1000 rpm for 1 minute for later use. (2) Frozen D _2L cells: take it out of the liquid nitrogen tank and thaw it 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. Cultured D _2S cells: Aspirate the medium, wash the cells with 3mL of PBS, aspirate, digest with 0.05% Trypsin for 3 minutes, stop with an equal volume of medium, transfer to a centrifuge tube, and centrifuge at 750 rpm for 5 minutes. After aspirating the liquid, add HBSS buffer to resuspend, and centrifuge at 750 rpm for 5 minutes. (3) Discard the supernatant, resuspend the pellet with an appropriate amount of experimental buffer, and take 20 μL for cell counting. (4) Pipette an appropriate amount of cell suspension, dilute to 2×10 ⁵ cells/mL with experimental buffer, add 5 μL/well of cell suspension to the cell plate (PerkinElmer-6008280), and centrifuge at 1000 rpm for 1 minute. (5) Transfer 5 μL/well to the cell plate with Bravo, centrifuge at 1000 rpm for 1 minute, and incubate at room temperature for 15 minutes after the cell plate is closed. (6) Use Tecan-D300e to transfer Forskolin to the cell dish, and transfer Dopamine hydrochloride with a final concentration of EC ₉₀ to the cell dish. (7) Centrifuge the cell plate at 1000 rpm for 1 minute, seal the plate, and incubate at room temperature for 45 minutes. (8) Standard curve: cAMP with a stock solution concentration of 2848 nM was serially diluted 4 times at 8 points according to the initial maximum concentration of 712 nM, and 10 μL/well was added to the cell plate. (9) Add 10 μL/well detection solution containing cAMP-d2 and Anti-cAMP-Cryptate (1:20 diluted with lysis buffer) to the cell plate, centrifuge at 1000rpm for 1 minute, and incubate at room temperature for 1 hour in the dark. (10) Detection: Centrifuge the cell disc at 1000rpm for 1 minute, and read the disc using Envision (excitation light 340 nm, emission light 620 nm and 665 nm). The ratio of the two channel signals (665nm/620nm) multiplied by 10000 was used as the final raw data for analysis, and the IC ₅₀ value of the compound was calculated.

3. Experimental results: as shown in Table 3.

Table 3 The test results of the functional activity of the compounds of the present invention on D _2L and D _2s receptors Example number D _2L IC ₅₀ ( nM ) 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

4. Experimental conclusions: It can be concluded from the above scheme that the compounds of the present invention have good antagonistic effects on both D _2L and D _2s receptors.

test case 4 , the compound of the present invention in ICR on the mouse PK test

1. Purpose of the test: Male ICR mice were administered orally, the blood concentration of the compound of the present invention in the mice was measured, PK parameters were calculated, and the pharmacokinetics of the compound of the present invention was evaluated.

2. Test materials: (1) Test drug: the compound of the embodiment of the present invention, self-made. (2) Experimental animals: ICR mice, SPF grade, male, Shanghai Slack Experimental Animal Co., Ltd. (3) Main test instruments: name model Manufacturer AB company triple quadrupole liquid mass spectrometer Triple Quad 5500+ QTRAP SCIEX Sartorius dual range balance SECURA225D-ICN Sartorius Scientific Instruments Ltd. Desktop High Speed Refrigerated Centrifuge Thermo 75009915 Thermo Scientific RAININ micropipette 20/200/1000 μL American RAININ® (Raining) Company Microplate shaker 88882006 Thermo Scientific Desktop Ultrasonic Cleaner KQ5200DE Kunshan Ultrasonic Instrument Co., Ltd. Vortex shaker Vortex genie 2 American Scientific Industries Pure water meter Milli-Q IQ7000 Merck AG (4) Main test reagents: name batch number Manufacturer Acetonitrile Chromatographically pure/204198 Fisher chemical Methanol Chromatographically pure/203509 Fisher chemical formic acid A118P-500/192549 Fisher chemical

3. Test plan: (1) Dosing information: Drug preparation: take the test compound, add normal saline and perform ultrasound. Administration route and dose: Oral gavage administration, dosage: 5 mg/kg, administration volume: 10mL/kg. Dosing frequency and duration: single administration. (2) Test method: ICR mice were randomly divided into groups according to body weight, 3 mice in each group, fasted overnight before the test. Oral gavage administration respectively, at 0, 0.033, 0.083, 0.5, 1, 2, 4, 6 and 8 hours, take 250 μL of blood from the mouse mandibular vein or saphenous vein, put it in a sample tube containing the anticoagulant heparin sodium Plasma was separated by centrifugation at 4000 r·min ^-1 for 10 min in wet ice, and stored in a freezer at -80°C until testing.

4. Test results and analysis:

The plasma concentration-time data of the compounds of the present invention measured by intragastric administration were substituted into the Winnonlin 8.2 program to calculate the main pharmacokinetic parameters. T _max and C _max were measured values, AUC _0-t value and AUC _{0- ∞} value were calculated by trapezoidal method, and t _1/2 was calculated from the concentration point at the end of elimination phase by semi-logarithmic plotting method. The specific results are shown in Table 4.

Table 4 Results of pharmacokinetic experiments in mice group t _1/2 (h) C _max (ng/mL) T _max (h) AUC _(inf) (ng h/mL) AUC _(0-t) (ng h/mL) Example 1-A 3.14 109.33 0.17 189.85 155.11 ITI-007 5.00 13.48 0.28 59.09 39.33

5. Experimental conclusion: From the results of pharmacokinetic experiments on mice in the table, it can be seen that the compound of the present invention can be rapidly absorbed after administration, showing good metabolic properties, and both the exposure AUC and the maximum blood concentration C _max are good.

test case 5 , The compounds of the present invention are MK-801 Experiments on the Effects of Inducing High Activity Behavior in Mice

1. The purpose of the experiment: By intraperitoneal injection of MK-801 to induce a mouse model of high activity, the drug efficacy of the compound of the present invention is evaluated.

2. Experimental plan

(1) Experimental materials: Test compound: the compound of the embodiment of the present invention, self-made. MK-801 (didazepine maleate, (+)-MK-801 hydrogen maleate), SIGMA, M107-250MG. Solvent: pure water, Guangzhou Watsons Food & Beverage Co., Ltd., 20200928 C; Normal saline, Shandong Hualu Pharmaceutical Co., Ltd., SD20080806.

(2) The main instruments of the experiment: name model Manufacturer Precision electronic balance XSE105DU METTLER TOLEDO Electronic balance TD50001 Tianjin Tianma Hengji Instrument Co., Ltd. Hikvision video system H.265 series NVR Hangzhou Hikvision Digital Technology Co., Ltd. TopScan Version 3.00 (animal video analysis system) Version 3.00 Clever Sys, Inc.

(3) Experimental animals: Experimental animals: ICR mice, male, 8 mice/group, SPEF (Beijing) Biotechnology Co., Ltd.

(4) Dosing information: Drug preparation: Take the test compound, add pure water and perform ultrasound. Administration route and method: intragastric administration, 10mL/kg body weight. Dosing frequency and duration: single administration. The animals were stratified by body weight and randomly divided into blank group, model group, and drug administration group. The detailed drug administration information is shown in the table below: group Dosage (mg/kg, ig) MK-801 modeling dose (mg/kg, ip) Number of groups Number of animals (8/group, ♂) blank group 0 0 1 8 model group 0 0.3 1 8 Example 1 0.1, 0.3, 0.1, 0.3, 1, 0.3 3 twenty four Implementation 1-A 0.03, 0.1, 0.3, 1, 3 0.3 5 40 Example 7 0.03, 0.1, 0.3, 1, 3 0.3 5 40 Comparative example 1 0.3, 1, 3 0.3 3 twenty four ITI-007 0.3, 1, 3 0.3 3 twenty four

(5) Experimental method: The mice were stratified according to body weight and randomly divided into model group, blank group and each administration group. One hour after intragastric administration of vehicle or drug, 0.3 mg/kg of MK-801 was injected intraperitoneally (the blank group was injected with an equal volume of normal saline), and then the mice were put into an autonomous activity box (a black box with a size of 29cm×29cm×30cm). Polyethylene box) for video recording, the video recording time is 60 min, and the video analysis is performed after the video recording to evaluate the activity of the mice.

(6) Data processing and statistics: for experimental data ±SD means that SPSS statistical software was used, and the homogeneity of variance test was performed first, and if the variance was homogeneous, one-way analysis of variance was performed, and Dunnett's t test was used for pairwise comparison. ED ₅₀ was calculated by nonlinear fitting method with GraphPad Primis5 software.

3. Experimental results: as shown in Table 5.

Table 5 The test results of the compound of the present invention on the influence of MK-801-induced high activity behavior in mice group _ED50 ( mg/kg ) MED ( mg/kg ) Example 1 0.11 0.1 Example 1-A 0.08 0.03 Example 7 0.09 0.1 Comparative example 1 1.28 1 ITI-007 1.03 1 Note: ED ₅₀ is the half effective dose, and MED is the minimum effective dose.

4. Experimental conclusion: It can be concluded from the above scheme that the compound of the present invention can significantly inhibit the high activity induced by MK-801, and compared with the comparative example, the minimum onset dose of the compound of the present invention is lower, and the inhibitory effect is stronger.

test case 6 , The compounds of the present invention are DOI Experiment on Inducing the Effects of Head Shaking Behavior in Mice

1. The purpose of the experiment: The drug efficacy of the compound of the present invention was evaluated by inducing the head shaking behavior of mice by intraperitoneal injection of (±) DOI (a hallucinogenic agent, commonly used to replicate anti-schizophrenia animal models).

2. Experimental plan:

(1) Experimental materials: Test compound: the compound of the embodiment of the present invention, self-made. (±)-DOI hydrochloride, SIGMA, D101-100MG. Solvent: pure water, Guangzhou Watsons Food & Beverage Co., Ltd., 20200928 C; Normal saline, Shandong Hualu Pharmaceutical Co., Ltd., SD20080806.

(2) The main instruments of the experiment: name model Manufacturer Precision electronic balance XSE105DU METTLER TOLEDO Electronic balance TD50001 Tianjin Tianma Hengji Instrument Co., Ltd.

(3) Experimental animals: Experimental animals: ICR mice, male, 8 mice/group, SPEF (Beijing) Biotechnology Co., Ltd.

(4) Dosing information: Drug preparation: Take the test compound, add the solvent and perform ultrasound. Administration route and method: Oral gavage administration, 10mL/kg body weight. Dosing frequency and duration: single administration. The animals were stratified by body weight and randomly divided into blank group, model group, and drug administration group. The detailed drug administration information is shown in the table below: group Dosage (mg/kg, ig) DOI modeling dose (mg/kg, ip) Number of groups Number of animals (8/group, ♂) blank group 0 0 1 8 model group 0 1 1 8 Example 1-A 0.01, 0.03, 0.1 1 3 twenty four Example 3 0.1, 0.3, 1 1 3 twenty four Example 4 0.1, 0.3, 1, 3 1 4 32

(5) Experimental method: The mice were stratified according to body weight and randomly divided into model group, blank group and each administration group. One hour after the vehicle or drug was given to the animal by gavage, the animal was placed in a beaker (13 cm in diameter and 19 cm in height) covered with fresh bedding, and the DOI of the modeling drug was injected intraperitoneally at a dose of 1 mg/kg, and the mice were recorded. Number of head shakes within 0-20 minutes after intraperitoneal injection of DOI. Head flick behavior was defined as a rapid rotational twitch or wet dog shake of the mouse's head, which was to be distinguished from normal grooming or probing behaviors.

(6) Data processing and statistics: for experimental data ±SD means that SPSS statistical software was used, and the homogeneity of variance test was performed first, and if the variance was homogeneous, one-way analysis of variance was performed, and Dunnett's t test was used for pairwise comparison. ED ₅₀ was calculated by nonlinear fitting method with GraphPad Primis5 software.

3. Experimental results: as shown in Table 6.

Table 6 The test results of the compounds of the present invention on the impact of DOI-induced head shaking behavior in mice group _ED50 ( mg/kg ) Example 1-A 0.024 Example 3 0.21 Example 4 0.42 Note: ED ₅₀ is the half effective dose.

4. Experimental conclusion: It can be concluded from the above scheme that the compound of the present invention can obviously inhibit DOI-induced head shaking behavior.

Although the embodiments of the present invention have been shown and described above, it can be understood that the above embodiments are exemplary and should not be construed as limiting the present invention, those skilled in the art can make the above-mentioned The embodiments are subject to changes, modifications, substitutions and variations.

none.

Claims (15)

A compound as shown in general formula (I), its stereoisomer or its pharmaceutically acceptable salt: , wherein, R is _{independently} halogen, C1-C3 alkoxy, cyano, amino, nitro, hydroxyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C5 cycloalkane C1-C6 alkyl optionally substituted by radical; R ₂ is independently -R ₇ -R ₈ -R ₉ -; R ₃ is independently hydrogen, or any one of C1-C3 alkyl; R ₄ is independently Ground is any one of -C(=O)- or -CH ₂ -; R ₅ and R ₆ are each independently hydrogen, or halogen, C1-C3 alkoxy, cyano, amino, nitro , hydroxyl, C2-C4 alkenyl, C2-C4 alkynyl optionally substituted C1-C3 alkyl, or R ₅ , R ₆ and the carbon atom directly connected to it jointly form -C(= O)-; R ₇ is independently a C1-C5 alkylene group; R ₈ is independently any one of -C(=O)-, -CH ₂ - or -O-; R ₉ is independently C1-C3 Any of the alkylene or absence; A is phenyl optionally substituted with one or more halogen. The compound represented by general formula (I), its stereoisomer or its pharmaceutically acceptable salt as described in Claim 1, wherein, it satisfies one or more of the following conditions: (1) said R ₁ is independently C1 optionally substituted by halogen, C1-C3 alkoxy, cyano, amine, nitro, hydroxyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C5 cycloalkyl -C3 alkyl; (2) said R ₃ is independently hydrogen, or any one of C1-C3 alkyl; (3) said R ₅ and R ₆ are each independently hydrogen, or unsubstituted Any one of the C1-C3 alkyl groups, or R ₅ , R ₆ and the carbon atom directly connected to it together form -C(=O)-; (4) A is independently benzene substituted by one or more halogens base; (5) R ₄ is -C(=O)-. The compound represented by general formula (I), its stereoisomer or its pharmaceutically acceptable salt as described in Claim 2, wherein, it satisfies one or more of the following conditions: (1) said R ₁ is independently is unsubstituted C1-C3 alkyl; (2) said R ₃ is independently hydrogen, or any one of unsubstituted C1-C3 alkyl. The compound represented by the general formula (I), its stereoisomer or its pharmaceutically acceptable salt as described in Claim 3, wherein, it satisfies one or more of the following conditions: (1) The unsubstituted C1-C3 alkyl group is selected from any one of methyl, ethyl or propyl; (2) The C1-C5 alkylene group is selected from the C3-C5 alkylene group; (3) The C1-C3 alkylene group is selected from the C1-C2 alkylene group; (4) The C1-C3 alkyl group in the optionally substituted C1-C3 alkyl group is selected from any one of methyl, ethyl or propyl; (5) The halogen is any one of fluorine, chlorine, bromine or iodine. The compound represented by general formula (I) as described in any one of claims 1-4, its stereoisomer or pharmaceutically acceptable salt thereof, wherein the compound represented by general formula (I) is selected from Compounds represented by general formula (IA) as shown below: , wherein, X is a halogen; the X is substituted at any substitutable position of the benzene ring; X is any one of mono-substitution or multi-substitution, preferably mono-substitution; the halogen is fluorine, chlorine, bromine or iodine Any one; R ₁ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ and R ₉ are as defined in any one of claims 1-4. The compound represented by the general formula (I) as described in Claim 5, its stereoisomer or its pharmaceutically acceptable salt, wherein, the compound represented by the general formula (I) is selected from the following general formula Compounds shown in (IB): . The compound represented by the general formula (I) as described in Claim 6, its stereoisomer or its pharmaceutically acceptable salt, wherein, the compound represented by the general formula (I) is selected from the following general formula Compounds shown in (IB): , wherein, R ₁ is independently any one of methyl, ethyl or propyl; R ₃ is independently any one of hydrogen, methyl, ethyl, or propyl; R ₄ is independently -C( =O)-, or any one of -CH ₂ -; R ₅ and R ₆ are each independently hydrogen, methyl, or any one of ethyl, or R ₅ , R ₆ and the carbon atom directly connected to it Together form -C(=O)-; R ₇ is independently any of -CH ₂ -CH ₂ -, -CH ₂ -CH ₂ -CH ₂ - or -CH ₂ -CH ₂ -CH ₂ -CH ₂ - One; R ₈ is independently any one of -C(=O)-, -CH ₂ - or -O-; R ₉ is independently -CH ₂ -CH ₂ -, -CH ₂ - or nonexistent Any one; X is independently any one of fluorine or chlorine. The compound represented by the general formula (I) as described in any one of claims 1-7, its stereoisomer or pharmaceutically acceptable salt thereof, wherein the compound represented by the general formula (I) is selected from Compounds represented by general formula (IC) as shown below: , wherein, R ₁ is independently any one of methyl, ethyl or propyl; R ₃ is independently any one of methyl, ethyl or propyl; R ₄ is independently -C(=O) -, or any one of -CH ₂ -; R ₅ and R ₆ are each independently hydrogen, methyl, or any one of ethyl, or R ₅ , R ₆ and the carbon atom directly connected to them jointly form- C(=O)-. The compound represented by general formula (I), its stereoisomer or its pharmaceutically acceptable salt as described in claims 1-8, wherein, it satisfies one or more of the following conditions: (1) The compound shown in general formula (I) is selected from any one of the specific compounds shown below: , , , , , , , , , , , , , , , , , , , , , (2) The salt is selected from fumarate, maleate, phosphate, nitrate, sulfate, benzenesulfonate, or oxalate. A compound represented by the general formula (ID), its stereoisomer or a pharmaceutically acceptable salt thereof: Wherein: R ₁ , R ₃ , R ₄ , R ₅ and R ₆ are as defined in any one of claims 1-9. A method for preparing a compound represented by general formula (I) as described in claims 1-9, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, comprising the steps of: General formula compound (ID) and general formula compound (IE) prepare the compound shown in formula (I) by nucleophilic substitution reaction; Wherein: X ₁ is a halogen, is selected from fluorine, chlorine, bromine or iodine, preferably chlorine; R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ and A are as defined in any one of claims 1-9. A pharmaceutical composition comprising a therapeutically effective amount of the compound represented by general formula (I) as described in any one of claim items 1-9, its stereoisomer or its pharmaceutically acceptable salt, and pharmaceutically acceptable Accepted carrier. A compound represented by general formula (I) as described in any one of claim items 1-9, its stereoisomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in claim item 12 in the preparation Involving or regulating serotonin receptors, serotonin transporters and/or dopamine receptors in the use of drugs; preferably in the preparation of 5-HT2A receptors, serotonin transporters, dopamine D1 receptors and/or regulation or dopamine D2 receptors in medicines, more preferably in the preparation of medicines involving or regulating 5-HT2A receptors and/or dopamine D2 receptors. A compound represented by general formula (I) as described in any one of claim items 1-9, its stereoisomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in claim item 12 in the preparation Use in drugs for the treatment of neuropsychiatric diseases. The use as described in claim 14, wherein the neuropsychiatric diseases are selected from depression, anxiety, dementia, schizophrenia, sleep disorders, movement disorders, behavior disorders in dementia patients, Parkinson's disease, A One or more of Alzheimer's disease, migraines, ADHD, OCD, social phobia, neurodegenerative disease, bipolar disorder, post-traumatic stress disorder, addictive disorder, withdrawal syndrome, or attention deficit disorder , preferably any one or more of depression, anxiety, dementia, schizophrenia, sleep disorders, movement disorders, behavior disorders in dementia patients, neurodegenerative diseases or bipolar disorder; the depression such as Major depressive disorder, said hyperactivity disorder such as attention deficit hyperactivity disorder.