HK40080583B - 1,5-dihydro-2,4-benzodiazepine-3-one derivative and application thereof - Google Patents

Description

1,5-Dihydro-2,4-Benzadiazine-3-one Derivatives and Their Applications

This application claims priority to Chinese Application No. 202010330893.1, filed April 26, 2020, entitled “1,5-dihydro-2,4-benzidine-3-one derivatives and their applications thereof”, and Chinese Application No. 202110288141.8, filed March 17, 2021, entitled “1,5-dihydro-2,4-benzidine-3-one derivatives and their applications thereof”, the entire contents of which are incorporated herein by reference.

Technical Field

This invention relates to the field of chemical pharmaceuticals, and more particularly to 1,5-dihydro-2,4-benzodiazepine-3-one derivatives and their applications.

Technical Background

Schizophrenia has an insidious onset, low treatment rates, and a high lifetime prevalence. Currently, approximately 0.3-0.7% of the world's population will be affected by schizophrenia in their lifetime, and in 2016, it was estimated that there were over 21 million people living with schizophrenia globally. Current antipsychotic drugs include typical and atypical antipsychotics. However, current schizophrenia treatments, due to their strong dopamine receptor blocking, can cause adverse reactions such as extrapyramidal symptoms (EPS), tardive dyskinesia, and increased prolactin levels. In the medical field, although various types of active compounds targeting different sites are available for treating sleep disorders, addiction, drug tolerance, and long-term side effects remain unresolved issues.

Traditionally, antipsychotics that exert their pharmacological effects by blocking dopamine _D2 receptors are referred to as first-generation antipsychotics, or "typical" antipsychotics (such as haloperidol). These drugs have been groundbreaking in treating the positive symptoms of schizophrenia, but have failed to treat the negative symptoms and cognitive impairment. Typical antipsychotics generally have severe EPS (extracorporeal membrane oxygenation) side effects and are ineffective in one-third of schizophrenia patients.

Since the 1960s, a series of new-generation antipsychotics have been developed, including ziprasidone and risperidone, known as second-generation antipsychotics, or novel antipsychotics. Although their individual pharmacological effects are not entirely consistent, they share common pharmacological characteristics: their affinity for serotonin (5-HT) receptors (5-HT1A, 2A, 2c) and norepinephrine (NA) receptors (α1, α2) is much higher than that for D2 receptors, resulting in a lower D2/5-HT2A ratio. Their clinical efficacy is superior to that of first-generation antipsychotics, being effective for both positive and negative symptoms, as well as cognitive impairment, offering a broader spectrum of action. However, these drugs have adverse reactions such as QT interval prolongation, hyperprolactinemia, and weight gain. Therefore, finding drugs that are effective for both positive and negative symptoms and cognitive impairment in schizophrenia, with fewer side effects, is currently a hot research topic.

The serotonin system plays a crucial role in regulating the function of the prefrontal cortex (PFC), including emotion control, cognitive behavior, and working memory. PFC pyramidal neurons and GABA interneurons contain several serotonin receptor subtypes, 5- _HT1A and 5- _HT2A , with particularly high density. Recent studies have demonstrated that the PFC and NMDA receptor channels are targets of 5- _HT1A receptors, which modulate excitatory neurons in the cerebral cortex, thereby influencing cognitive function. Indeed, various preclinical data suggest that 5- _HT1A receptors may be a novel target for antipsychotic drug development. The high affinity of atypical antipsychotics (such as olanzapine, aripiprazole, etc.) for 5- _HT1A receptors and their low EPS side effects underscore the important role of the serotonin system in regulating the function of the prefrontal cortex (PFC), including emotion control, cognitive behavior, and working memory. PFC pyramidal neurons and GABA interneurons contain several serotonin receptor subtypes, 5- _HT1A and 5- _HT2A , with particularly high density. Recent studies have shown that 5-HT _1A agonists are associated with atypical antipsychotic treatment, improving negative symptoms and cognitive impairment. In the use of the atypical antipsychotic clozapine to treat schizophrenia, 5-HT _2A has been found to play a crucial role, involving various aspects of perception, mood regulation, and motor control. Blocking 5-HT _2A receptors normalizes dopamine release, thus exerting an antipsychotic effect. Furthermore, 5-HT _2C receptors are closely related to weight gain.

Pimoserine is an inverse agonist with high affinity for both 5- _HT2A and 5- _HT2C . In vitro studies show that its affinity for the 5- _HT2A receptor [inhibition constant (Ki) 0.4 nm] is higher than that for 5- _HT2C (Ki = 16 nm), while it has no significant affinity for 5- _HT2B receptors, dopamine receptors (including D2 receptors), adrenergic receptors, muscarinic receptors, or calcium channel receptors (Ki > 300 nm). This drug was approved by the U.S. Food and Drug Administration in April 2016 under the brand name Nuplazid™, primarily for the treatment of Parkinson's disease symptoms such as hallucinations and illusions.

Therefore, there is a need to find an antipsychotic drug that is effective for both positive and negative symptoms, improves cognitive impairment, prevents extrapyramidal side effects, including tardive dyskinesia and Parkinson's disease, and reduces weight gain.

Summary of the Invention

This invention aims to at least solve one of the technical problems existing in the prior art. To this end, one object of this invention is to provide a compound of formula I:

The compound shown in Formula I:

In formula I: n1 and n2 are integers from 1 to 3;

R1 is selected from C1-C8 straight-chain or branched alkyl, C2-C8 alkenyl and C2-C8 alkynyl, wherein the alkyl, alkenyl and alkynyl are each independently and optionally substituted by substituents selected from halogens and C1-C8 haloalkyl groups.

R2 is selected from hydrogen, halogens, and C1-C8 haloalkyl groups;

R3, R4, R5, and R6 are each independently selected from hydrogen, halogens, and C1-C8 haloalkyl groups;

R7 is selected from C1-C5 straight-chain or branched alkyl or cycloalkyl groups, and R8 and R9 are each independently selected from C1-C8 straight-chain or branched alkyl groups, wherein the alkyl and cycloalkyl groups are optionally substituted with substituents selected from halogens and C1-C8 haloalkyl groups.

Z is selected from C, O, and N;

Q and W are selected from C and N, respectively;

------ The key indicates that it does not exist or exists as a single key;

------When the bond is absent, Formula I represents the compound shown in Formula II:

In Equation II, n2, R1, R3, R7, W, and Z are defined as described above; or

------ When the bond exists in the form of a single bond, Formula I represents a compound as shown in Formula III.

In Equation III, n1 and n2 are integers from 1 to 3;

R1 is selected from C1-C8 straight-chain or branched alkyl, C2-C8 alkenyl and C2-C8 alkynyl, wherein the alkyl, alkenyl and alkynyl are optionally substituted by substituents selected from halogens and C1-C8 haloalkyl.

R2 is selected from hydrogen or halogen.

R3, R4, R5, and R6 are each independently selected from hydrogen, halogens, and haloalkyl groups;

R7 is selected from C1-8 straight-chain or branched alkyl, cycloalkyl, R8, and R9 are each independently selected from C1-C8 straight-chain or branched alkyl, wherein the alkyl and cycloalkyl are optionally substituted with substituents selected from halogens and C1-C8 haloalkyls;

Z is selected from C, O, and N;

Q and W are selected from C and N, respectively.

In one embodiment, the C1-C8 straight-chain or branched alkyl group is selected from C1-C5 straight-chain or branched alkyl groups and C1-C3 straight-chain or branched alkyl groups; and/or the C2-C8 alkenyl group is a C2-C5 alkenyl group; and/or the C2-C8 ynyl group is a C2-C5 ynyl group; and/or the haloalkyl group is a C1-C5 haloalkyl group; and/or the cycloalkyl group is a C3-C10 cycloalkyl group, preferably a C3-C6 cycloalkyl group.

On the other hand, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of the compound represented by Formula I as described above, optionally further comprising a pharmaceutically acceptable excipient, carrier, adjuvant, solvent, or combination thereof.

On the other hand, the present invention provides the use of the compound of Formula I and its pharmaceutical composition in the preparation of drugs for treating mental illnesses.

In one implementation scheme, the mental illness is schizophrenia or psychosis.

In another implementation, the mental illnesses are Parkinson's disease, dementia-related behavioral disorders, and psychosis.

Detailed Implementation

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 pertains. In case of any conflict, the definitions provided herein shall prevail. When trade names appear herein, they are intended to refer to the corresponding product or its active ingredient. All patents, published patent applications, and publications cited herein are incorporated herein by reference.

General terms and definitions

The term "comprising" is an open-ended expression, meaning it includes the contents specified in this invention but does not exclude other aspects. It should be understood that the term "comprising" can also encompass a closed meaning, meaning "consisting of...".

As described in this invention, the compounds of this invention may optionally be substituted with one or more substituents, such as the general formula compounds above or the specific examples and subclasses described in the embodiments. It should be understood that the terms "optionally substituted" and "substituted or unsubstituted" are used interchangeably. Generally, the term "substituted" means that one or more hydrogen atoms in the given structure are substituted by a specific substituent, provided that the substitution does not exceed the normal valence of the specified atom in the present case and that the substitution forms a stable compound. Combinations of substituents and/or variables are permitted only if such combinations form a stable compound. When a substituent is described as absent, it should be understood that the substituent may be one or more hydrogen atoms, provided that the structure allows the compound to reach a stable state. Unless otherwise indicated, an optionally substituted group may be substituted at each substituted position of the group. When more than one position in the given structural formula can be substituted by one or more substituents selected from a particular group, then the substituents may be substituted at the same or different positions.

Unless otherwise specified, as used herein, the connection point of a substituent may be any suitable location of the substituent. When the bond of a substituent is such that it is a bond that passes through the ring and connects two atoms, such a substituent may be bonded to either cyclic atom in the substituted ring.

Additionally, it should be noted that, unless otherwise explicitly stated, the description used in this invention as “each independently” should be interpreted broadly. It can mean either that the specific options expressed by the same symbols in different groups do not affect each other, or that the specific options expressed by the same symbols in the same group do not affect each other.

When the lower and upper limits of a numerical range are disclosed, any numerical value falling within that range and any included range are specifically disclosed. In particular, each range of values disclosed herein should be understood as representing each numerical value and range encompassed within a wider range. When any variable (e.g., R), and labeled variables (e.g., R1, R2, R3, R4, R5, R6, R7, etc.) appears more than once in the composition or structure of a compound, its definition is independent in each instance. For example, if a group is substituted by 0, 1, 2, 3, or 4 R substituents, the group may optionally be substituted by up to four R substituents, and the option of each R substituent in each instance is independent of each other.

In various parts of this specification, the substituents of the compounds disclosed herein are disclosed according to the type or range of groups. In particular, this invention includes every independent sub-combination of the members of these types and ranges. For example, the expression mn as used herein refers to the range from m to n, as well as the subrange consisting of the individual point values therein, and the individual point values themselves. For example, the term "C1-C5 alkyl" specifically refers to the independently disclosed methyl, ethyl, C3 alkyl, C4 alkyl, and C5 alkyl. Examples of alkyl groups include, but are not limited to, methyl (Me, _-CH3 ), ethyl (Et, _{-CH2CH3 )} , n-propyl (n-Pr, _-CH2CH2CH3 ), isopropyl (i-Pr, _-CH ( _CH3 ) _{2 )} , n-butyl (n-Bu, _{-CH2CH2CH2CH3} ), isobutyl (i-Bu, _-CH2CH ( _{CH3 ) 2} ), sec-butyl (s- _Bu , _-CH ( _CH3 ) _CH2CH3 ), _tert -butyl (t-Bu, -C( _CH3 ) _{3 )} , n-pentyl ( _{-CH2CH2CH2CH2CH3} ), _{2 -} pentyl (-CH(CH3) _CH2CH2CH3 ), ₃ -pentyl (-CH _{( CH2CH3 ) 2} ), and 2-methyl-2-butyl (-C( _CH3 ) _{2CH2CH3 )} . ) ₂ CH ₂ CH ₃ ), 3-methyl-2-butyl(-CH(CH ₃ )CH(CH ₃ ) ₂ ), 3-methyl-1-butyl(-CH ₂ CH ₂ CH(CH ₃ ) ₂ ), 2-methyl-1-butyl(-CH ₂ CH(CH ₃ )CH ₂ CH ₃ ), etc. For example, the expression "C2-C8" or "C2-8" covers a range of 2-8 carbon atoms, and should be understood to also cover any subrange and each point value within it, such as C2-C5, C3-C4, C2-C6, C3-C6, C4-C6, C4-C7, C4-C8, C2-C5, etc., as well as C2, C3, C4, C5, C6, C7, C8, etc. For example, the expression "C3-C10" or "C3-10" should be understood in a similar way. It can encompass any subrange and point value contained within it, such as C3-C9, C6-C9, C6-C8, C6-C7, C7-C10, C7-C9, C7-C8, C8-C9, and C3, C4, C5, C6, C7, C8, C9, C10, etc. Similarly, the expression "C1-C5" or "C1-5" covers a range of 1-5 carbon atoms and should be understood to also encompass any subrange and each point value within it, such as C2-C5, C3-C4, C1-C2, C1-C3, C1-C4, C1-C5, and C1, C2, C3, C4, C5, etc. For example, the expression "C2-C5" or "C2-5" covers a range of 2-5 carbon atoms, and should be understood to also cover any subranges within this range and each point value, such as C2-C5, C3-C4, C2-C3, C2-C4, C3-C5, C4-C5, etc., as well as C2, C3, C4, C5, etc. Similarly, the expression "C3-C6" or "C3-6" covers a range of 3-6 carbon atoms, and should be understood to also cover any subranges within this range and each point value, such as C3-C5, C3-C4, C3-C6, C5-C6, C4-C6, C4-C5, etc., as well as C3, C4, C5, C6, etc. For example, the expression "C1-C8" or "C1-8" covers a range of 1 to 8 carbon atoms, and should be understood to also cover any subrange within it, as well as each point value, such as C2-C5, C3-C4, C2-C6, C3-C6, C4-C6, C4-C7, C4-C8, C2-C5, etc., and C1, C2, C3, C4, C5, C6, C7, C8, etc. For example, the expression "three to ten yuan" should be understood as encompassing any subrange and each point value within it, such as three to five yuan, three to six yuan, three to seven yuan, three to eight yuan, four to five yuan, four to six yuan, four to seven yuan, four to eight yuan, five to seven yuan, five to eight yuan, six to seven yuan, six to eight yuan, nine to ten yuan, etc., as well as three, four, five, six, seven, eight, nine, ten yuan, etc. Other similar expressions in this article should also be understood in a similar manner.

The ranges (such as numerical ranges) listed in this article can encompass every value within that range as well as the subranges formed by those values. Therefore, for example, the statement "n ₂ is any integer between 0 and 3" includes, for example, any integer between 0 and 2, any integer between 2 and 3, such as 1, 2, and 3.

The term "one or more species" or similar expression "at least one species" can mean, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more species.

The term “selected from…” means one or more elements from the groups listed below, selected independently, and may include combinations of two or more elements.

When each carbon atom in the descriptive group can be optionally replaced by a heteroatom, the condition is that the valence of all atoms in the group is not exceeded in the present case, and a stable compound is formed.

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

The term "halogen" or "halogenated" should be understood to mean fluorine (F), chlorine (Cl), bromine (Br) or iodine (I), preferably fluorine, chlorine or bromine atoms, more preferably fluorine atoms.

The term "alkyl" refers to a straight-chain or branched saturated aliphatic hydrocarbon group consisting of carbon and hydrogen atoms, connected to the rest of the molecule by single bonds. An alkyl group can have 1-5 carbon atoms, i.e., "C1-C5 alkyl," such as C1-4 alkyl, C1-3 alkyl, C1-2 alkyl, C3 alkyl, C4 alkyl, C1-5 alkyl, and C3-5 alkyl. It can also have 1-3 carbon atoms, i.e., "C1-C3 alkyl," such as C1-3 alkyl, C1-2 alkyl, and C3 alkyl. For example, the term "C1-C5 alkyl" specifically refers to independently disclosed methyl, ethyl, C3 alkyl, C4 alkyl, and C5 alkyl groups. Examples of alkyl groups include, but are not limited to, methyl (Me, _-CH3 ), ethyl (Et, _{-CH2CH3 )} , n-propyl (n-Pr, _-CH2CH2CH3 ), isopropyl (i-Pr, _-CH ( _CH3 ) _{2 )} , n-butyl (n-Bu, _{-CH2CH2CH2CH3} ), isobutyl (i-Bu, _-CH2CH ( _{CH3 ) 2} ), sec-butyl (s- _Bu , _-CH ( _CH3 ) _CH2CH3 ), _tert -butyl (t-Bu, -C( _CH3 ) _{3 )} , n-pentyl ( _{-CH2CH2CH2CH2CH3} ), _{2 -} pentyl (-CH(CH3) _CH2CH2CH3 ), ₃ -pentyl (-CH _{( CH2CH3 ) 2} ), and 2-methyl-2-butyl (-C( _CH3 ) _{2CH2CH3 )} . ₂ CH ₂ CH ₃ ), 3-methyl-2-butyl (-CH(CH ₃ )CH(CH ₃ ) ₂ ), 3-methyl-1-butyl (-CH ₂ CH ₂ CH(CH ₃ ) ₂ ), 2-methyl-1-butyl (-CH ₂ CH(CH ₃ )CH ₂ CH ₃ ), n-hexyl (-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, etc.

The term "alkenyl" refers to an unsaturated aliphatic hydrocarbon group consisting of a straight or branched chain of carbon and hydrogen atoms, having at least one double bond. Alkenyl groups can have 2-5 carbon atoms, i.e., "C _2-5 alkenyl," such as C _2-4 alkenyl and C _3-4 alkenyl. Non-limiting examples of alkenyl groups include, but are not limited to, vinyl, allyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, (E)-but-2-enyl, (Z)-but-2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl, etc.

The term "cycloalkyl" refers to a saturated cyclic hydrocarbon group consisting of carbon and hydrogen atoms, preferably containing one or two rings. The cycloalkyl group can be monocyclic, fused polycyclic, bridged, or spirocyclic. Cycloalkyl groups can have 3-6 carbon atoms, i.e., " _C3 - _C6 cycloalkyl," such as _C6 cycloalkyl, _C5 cycloalkyl, _C4 cycloalkyl, and _C3 cycloalkyl. Non-limiting examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. The term also covers cases where the carbon atom can be substituted with an oxygen (=O).

The term "alkynyl" refers to an unsaturated aliphatic hydrocarbon group consisting of a straight or branched chain of carbon and hydrogen atoms, having at least one triple bond. Alynyl groups can have 2-5 carbon atoms, i.e., "C _2-5 alkynyl," such as C _2-3 alkynyl and C _2-4 alkynyl. Non-limiting examples of alkynyl groups include, but are not limited to, ethynyl, propynyl-1-alkynyl, propynyl-2-alkynyl, butynyl-1-alkynyl, butynyl-2-alkynyl, butynyl-3-alkynyl, etc.

The key can be either a single key "—" or none at all.

When describing the absence of a chemical bond, it should be understood that only one of the two atoms connected by the chemical bond exists, and that the atom is connected to the atoms in the other parts of the compound, provided that the compound structure has reached a stable state. The atoms in the other parts are connected to the two atoms originally connected by the chemical bond.

In this paper, when the bond in Formula I is absent, only one carbon atom is present at each end of the bond, and provided that the compound structure reaches a stable state, this one carbon atom is bonded to the atoms in the other parts to form the compound shown in Formula II.

The term "pharmaceutically acceptable" refers to a substance that, within the bounds of normal medical judgment, is suitable for contact with a patient's tissues without causing undue toxicity, irritation, allergic reactions, etc., has a reasonable benefit-risk ratio, and is effective for its intended use.

The term "pharmaceutically acceptable carrier" refers to substances that do not cause significant irritation to the organism and do not impair the biological activity and properties of the active compound. "Pharmaceutically acceptable carriers" include, but are not limited to, glidants, sweeteners, diluents, preservatives, dyes/colorants, flavoring agents, surfactants, wetting agents, dispersants, disintegrants, stabilizers, solvents, or emulsifiers.

The terms "administration" or "giving" refer to methods that enable the delivery of a compound or composition to a desired biological site of action. These methods include, but are not limited to, oral or parenteral administration (including intraventricular, intravenous, subcutaneous, intraperitoneal, intramuscular, and intravascular injection or infusion), local administration, and rectal administration. In particular, injection or oral administration.

As used herein, the term "treatment" includes relieving, reducing, or improving a disease or symptom; preventing other symptoms; improving or preventing underlying metabolic factors of symptoms; inhibiting a disease or symptom, for example, preventing the development of a disease or symptom; reducing a disease or symptom; promoting the remission of a disease or symptom; or causing the symptom of a disease or symptom to cease; and extends to include prevention. "Treatment" also includes achieving therapeutic and/or preventive benefits. A therapeutic benefit refers to the eradication or improvement of the condition being treated. Furthermore, a therapeutic benefit is achieved by eradicating or improving one or more physical symptoms associated with an underlying disease, and an improvement in the patient's condition can be observed even though the patient may still have the underlying disease. A preventive benefit refers to the use of a composition by a patient to prevent the risk of a certain disease, or the use by a patient when experiencing one or more physical symptoms of a disease, even though the disease has not yet been diagnosed.

The terms “active ingredient,” “therapeutic agent,” “active substance,” or “active agent” refer to a chemical entity that can effectively treat or prevent a target disorder, disease, or symptom.

The term "mental illness" refers to a disorder of the nervous system.

For the purposes of pharmaceuticals, pharmaceutical units, or active ingredients, the terms "effective amount," "therapeutic effective amount," or "preventive effective amount" refer to a sufficient quantity of a drug or agent that provides acceptable side effects while achieving the desired therapeutic effect. The determination of the effective amount varies from person to person, depending on the individual's age and general condition, as well as the specific active substance. The appropriate effective amount in a given case can be determined by a person skilled in the art based on routine testing.

As used herein, “individual” includes both human and non-human animals. Exemplary human individuals include human individuals suffering from a disease (such as the disease described herein) (referred to as patients) or normal individuals. In this invention, “non-human animals” includes all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, livestock, and/or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).

The following detailed description of the invention is intended to illustrate non-limiting embodiments, enabling other skilled in the art to more fully understand the technical solutions, principles, and practical applications of the invention, so that other skilled in the art can modify and implement the invention in many forms to best suit the requirements of a particular application.

Formula I compound

In one aspect, the present invention provides compounds represented by Formula I:

In formula I: n1 and n2 are integers from 1 to 3;

R1 is selected from C1-C8 straight-chain or branched alkyl, C2-C8 alkenyl and C2-C8 alkynyl, wherein the alkyl, alkenyl and alkynyl are each independently and optionally substituted by substituents selected from halogens and C1-C8 haloalkyl groups.

R2 is selected from hydrogen, halogens, and C1-C8 haloalkyl groups;

R3, R4, R5, and R6 are each independently selected from hydrogen, halogens, and C1-C8 haloalkyl groups;

R7 is selected from C1-C8 straight-chain or branched alkyl or cycloalkyl groups, and R8 and R9 are each independently selected from C1-C8 straight-chain or branched alkyl groups, wherein the alkyl and cycloalkyl groups are optionally substituted with substituents selected from halogens and C1-C8 haloalkyl groups.

Z is selected from C, O, and N;

Q and W are selected from C and N, respectively;

------ The key indicates that it does not exist or exists as a single key;

------When the bond is absent, Formula I represents the compound shown in Formula II:

In Equation II, n2, R1, R3, R7, W, and Z are defined as described above; or

------ When the bond exists in the form of a single bond, Formula I represents a compound as shown in Formula III.

In Equation III, n1 and n2 are integers from 1 to 3;

R1 is selected from C1-C8 straight-chain or branched alkyl, C2-C8 alkenyl and C2-C8 alkynyl, wherein the alkyl, alkenyl and alkynyl are optionally substituted by substituents selected from halogens and C1-C8 haloalkyl.

R2 is selected from hydrogen, halogens, and C1-C8 haloalkyl groups;

R3, R4, R5, and R6 are each independently selected from hydrogen, halogens, and haloalkyl groups;

R7 is selected from C1-8 straight-chain or branched alkyl or cycloalkyl groups, and R8 and R9 are each independently selected from C1-C8 straight-chain or branched alkyl groups, wherein the alkyl and cycloalkyl groups are optionally substituted with substituents selected from halogens and C1-C8 haloalkyl groups.

Z is selected from C, O, and N;

Q and W are selected from C and N, respectively.

In one embodiment, n1 and n2 are integers selected from 1 to 3. For example, n1 and n2 are independently selected from 1, 2, and 3, respectively, such as 1, 2, or 3. In a preferred embodiment, n1 is selected from 2 and 3. In a more preferred embodiment, n1 is 1. In another preferred embodiment, n2 is 1. In a more preferred embodiment, n1 is 2. In another more preferred embodiment, n2 is 2. In a more preferred embodiment, n1 is 3. In another more preferred embodiment, n2 is 3. In a particularly preferred embodiment, n1 is 2 and n2 is 1.

In one embodiment, R1 is selected from C1-C8 straight-chain or branched alkyl, C2-C8 alkenyl, and C2-C8 alkynyl groups, wherein the alkyl, alkenyl, and alkynyl groups are independently and optionally substituted with substituents selected from halogens and C1-C8 haloalkyl groups. In a preferred embodiment, R1 is a C1-C8 straight-chain or branched alkyl group, wherein the alkyl group is optionally substituted with substituents selected from halogens and C1-C8 haloalkyl groups. In a more preferred embodiment, R1 is a C1-C8 straight-chain or branched alkyl group. In a particularly preferred embodiment, R1 is a C1-C5 straight-chain or branched alkyl group. In another particularly preferred embodiment, R1 is a C1-C3 straight-chain or branched alkyl group. In a specific embodiment, R1 is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, and isopentyl. In a more specific embodiment, R1 is selected from methyl, ethyl, and propyl. For example, methyl, ethyl, or propyl. In a particularly specific embodiment, R1 is methyl. In another particularly specific embodiment, R1 is ethyl. In yet another particularly specific implementation, R1 is propyl.

In one embodiment, R2 is selected from hydrogen, halogens, and C1-C8 haloalkyl groups. In a preferred embodiment, R2 is selected from hydrogen and halogens. In a more preferred embodiment, R2 is hydrogen. In another more preferred embodiment, R2 is a halogen. In a specific embodiment, R2 is selected from hydrogen, fluorine, chlorine, bromine, and iodine. In a more specific embodiment, R2 is selected from hydrogen, fluorine, chlorine, and bromine. In a more specific embodiment, R2 is fluorine. In another more specific embodiment, R2 is chlorine. In yet another more specific embodiment, R2 is bromine.

In one embodiment, R3, R4, R5, and R6 are each independently selected from hydrogen, halogens, and C1-C8 haloalkyl groups.

In a preferred embodiment, R3 is selected from hydrogen and halogens. In a more preferred embodiment, R3 is hydrogen. In another more preferred embodiment, R3 is a halogen. In a particularly preferred embodiment, R3 is selected from fluorine, chlorine, bromine, and iodine. In a more preferred embodiment, R3 is selected from fluorine, chlorine, and bromine. In a specific embodiment, R3 is selected from hydrogen, fluorine, chlorine, and bromine. In a more specific embodiment, R3 is selected from hydrogen, fluorine, and chlorine. In a particularly specific embodiment, R3 is fluorine. In another particularly specific embodiment, R3 is chlorine.

In a preferred embodiment, R4 is selected from hydrogen and halogens. In a more preferred embodiment, R4 is hydrogen. In another more preferred embodiment, R4 is a halogen. In a particularly preferred embodiment, R4 is selected from fluorine, chlorine, bromine, and iodine. In a more preferred embodiment, R4 is selected from fluorine, chlorine, and bromine. In a specific embodiment, R4 is selected from hydrogen, fluorine, chlorine, and bromine. In a more specific embodiment, R4 is selected from hydrogen, fluorine, and chlorine. In a particularly specific embodiment, R4 is fluorine. In another particularly specific embodiment, R4 is chlorine.

In a preferred embodiment, R5 is selected from hydrogen and halogens. In a more preferred embodiment, R5 is hydrogen. In another more preferred embodiment, R5 is a halogen. In a particularly preferred embodiment, R5 is selected from fluorine, chlorine, bromine, and iodine. In a more preferred embodiment, R5 is selected from fluorine, chlorine, and bromine. In a specific embodiment, R5 is selected from hydrogen, fluorine, chlorine, and bromine. In a more specific embodiment, R5 is selected from hydrogen, fluorine, and chlorine. In a particularly specific embodiment, R5 is fluorine. In another particularly specific embodiment, R5 is chlorine.

In a preferred embodiment, R6 is selected from hydrogen and halogens. In a more preferred embodiment, R6 is hydrogen. In another more preferred embodiment, R6 is a halogen. In a particularly preferred embodiment, R6 is selected from fluorine, chlorine, bromine, and iodine. In a more preferred embodiment, R6 is selected from fluorine, chlorine, and bromine. In a specific embodiment, R6 is selected from hydrogen, fluorine, chlorine, and bromine. In a more specific embodiment, R6 is selected from hydrogen, fluorine, and chlorine. In a particularly specific embodiment, R6 is fluorine. In another particularly specific embodiment, R6 is chlorine.

In one embodiment, R7 is selected from C1-C8 straight-chain or branched alkyl, cycloalkyl, and R8 and R9 are each independently selected from C1-C8 straight-chain or branched alkyl, wherein the alkyl and cycloalkyl are optionally substituted with substituents selected from halogens and C1-C8 haloalkyls.

In a preferred embodiment, R7 is a C1-C8 straight-chain or branched alkyl group. In a more preferred embodiment, R7 is a C1-C5 straight-chain or branched alkyl group. In a particularly preferred embodiment, R7 is a C1-C3 straight-chain or branched alkyl group. In a specific embodiment, R7 is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, and isopentyl. In a more specific embodiment, R7 is selected from methyl, ethyl, propyl, isopropyl, butyl, and isobutyl. For example, methyl, ethyl, propyl, isopropyl, butyl, or isobutyl. In a particularly specific embodiment, R7 is isopropyl.

In a preferred embodiment, R7 is a cycloalkyl group. In a more preferred embodiment, R7 is a C3-C10 cycloalkyl group. In a particularly preferred embodiment, R7 is a C3-C6 cycloalkyl group. In a specific embodiment, R7 is selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In a more specific embodiment, R7 is selected from cyclopropyl, cyclobutyl, and cyclopentyl. For example, cyclopropyl, cyclobutyl, or cyclopentyl.

In a preferred embodiment, R7 is wherein R8 and R9 are each independently selected from C1-C8 straight-chain or branched alkyl groups. In a preferred embodiment, R7 is wherein R8 and R9 are each independently selected from C1-C3 straight-chain or branched alkyl groups. In a specific embodiment, R7 is wherein R8 and R9 are each independently selected from methyl, ethyl, propyl, butyl, and pentyl. In a more specific embodiment, R7 is wherein R8 and R9 are each independently selected from methyl, ethyl, and propyl. For example, methyl, ethyl, n-propyl, and isopropyl. In a particularly specific embodiment, R8 and R9 are methyl.

In one embodiment, Z is selected from C, O, and N. In a preferred embodiment, Z is C. In another preferred embodiment, Z is O. In yet another preferred embodiment, Z is N.

In one embodiment, Q and W are selected from C and N, respectively. In a preferred embodiment, Q is N. In a preferred embodiment, Q is C. In a preferred embodiment, W is C. In a preferred embodiment, W is N.

In one embodiment, the C1-C8 straight-chain or branched alkyl groups are selected from C1-C5 straight-chain or branched alkyl groups and C1-C3 straight-chain or branched alkyl groups. In a specific embodiment, the C1-C8 straight-chain or branched alkyl groups, C1-C5 straight-chain or branched alkyl groups, and C1-C3 straight-chain or branched alkyl groups are each independently selected from methyl, ethyl, propyl, butyl, pentyl, and isopentyl. In a more specific embodiment, the C1-C8 straight-chain or branched alkyl groups, C1-C5 straight-chain or branched alkyl groups, and C1-C3 straight-chain or branched alkyl groups are each independently selected from methyl, ethyl, propyl, and butyl.

In one embodiment, the propyl group includes, but is not limited to _, n-propyl (n-Pr, _{-CH₂CH₂CH₃} ) or isopropyl (i-Pr, -CH( _CH₃ ) _{₂ )} . The butyl group includes, but is not limited to _{, n-butyl (n-Bu, -CH₂CH₂CH₂CH₃), isobutyl (i-Bu, -CH₂CH(CH₃)₂ ) , sec -} butyl (s-Bu, -CH( _CH₃ ) _CH₂CH₃ ), or tert-butyl _{( t -} Bu, -C( _CH₃ ) _₃ ). The pentyl group includes _, but is not limited to _{, n-pentyl (-CH2CH2CH2CH2CH3 )} , 2-pentyl (-CH( _{CH3 ) CH2CH2CH3} ), _3- pentyl (-CH( _CH2CH3 ) ₂ ), ₂ -methyl-2 _- butyl (-C _{( CH3} )2CH2CH3), ₃ -methyl-2-butyl (-CH( _CH3 )CH _{( CH3} ) _{2 )} , 3-methyl-1 _- butyl (-CH2CH2CH( _CH3 ) _{2 )} or 2-methyl- ₁ -butyl (-CH2CH( _CH3 ) _{CH2CH3 )} .

In one embodiment, the C2-C8 alkenyl group is a C2-C5 alkenyl group. In a specific embodiment, the C2-C8 alkenyl group and the C2-C5 alkenyl group are each independently selected from vinyl, propenyl, butenyl, and pentenyl groups. In a more preferred embodiment, the C2-C8 alkenyl group and the C2-C5 alkenyl group are each independently selected from vinyl, propenyl, and butenyl groups.

In one embodiment, the propylene group includes, but is not limited to, _-CH₂ - _CH₂ = _CH₂ and _-CH₂ = _CH₂ - _CH₃ . The butenyl group includes, but is not limited to, _-CH₂ - _CH₂ - _CH₂ = _CH₂ , _-CH₂ - _CH₂ = _CH₂ - _CH₃ , _-CH₂ = _CH₂ - _CH₂ - _CH₃ , -CH=C( _CH₃ ) _₂ , -C( _CH₃ )= _CH₂CH₃ , _and -CH( _CH₃ )CH= _CH₂ . The pentenyl group includes but is not limited to -CH= _CHCH2CH2CH3 , _-CH2CH = _CHCH2CH3 , _-CH2CH2CH = _CHCH3 , -CH2CH2CH2CH _{= CH2 , -C ( CH3} )= _CHCH2CH3 , -CH _{( CH3 )} CH= _CHCH3 , _-CH ( _CH3 ) _{CH2CH =} CH ₂ .

In one embodiment, the C2-C8 ynyl group is a C2-C5 ynyl group. In a specific embodiment, the C2-C8 and C2-C5 ynyl groups are independently selected from ethynyl, propynyl, butynyl, and pentylyl, respectively. In a more specific embodiment, the C2-C8 and C2-C5 ynyl groups are independently selected from ethynyl, propynyl, and butynyl, respectively.

In one embodiment, the propynyl group includes, but is not limited to, _-H₂CC≡CH and -C≡C- _CH₃ . The butynyl group includes, but is not limited to, _-H₂C - _CH₂ -C≡CH, _-H₂CC≡C - _CH₃ , and _H₃C - _CH₂- C≡C-. The pentyynyl group includes, but is not limited to _{, H₃CH₂C} - _{CH₂ -} C≡C-, _{-H₂CH₂CC≡C} - _{CH₃ , H₃CH₂CC≡C - CH₂-} , and ( _H₃C ) _₂CC≡C- .

In one embodiment, the C1-C8 haloalkyl group is a C1-C5 haloalkyl group. In a specific embodiment, in the C1-C8 and C1-C5 haloalkyl groups, the C1-C8 or C1-C5 alkyl group is substituted with 1, 2, 3, or 4 halogens. In a preferred embodiment, the C1-C8 or C1-C5 alkyl group is -( _CH2 ) _{aCX3 ,} where a is selected from 1, 2, 3, 4, 5, 6, and 7, and X represents a halogen. In a specific embodiment, the halogen is selected from fluorine, chlorine, bromine, and iodine. In a preferred embodiment, a is selected from 1, 2, 3, and 4. In a preferred embodiment, the halogen is fluorine.

In one embodiment, the C1-C8 haloalkyl or C1-C5 haloalkyl includes, but is _not limited to _{, -CF3} , _-CCl3 , _-CBr3 , _-CI3 , -CH2CF3, -CH2CCl3, _-CH2CBr3 , _{-CH2CI3 , -} ( _CH2 ) _2CF3 , -( _{CH2 ) 2CCl3} , - _{( CH2} ) _2CBr3 , - _{( CH2 ) 2CI3 , etc.}

In one embodiment, the halogen is selected from fluorine, chlorine, bromine, and iodine. In a preferred embodiment, the halogen is selected from fluorine, chlorine, and bromine. For example, fluorine, chlorine, bromine, or iodine. In a specific embodiment, the halogen is fluorine.

In one specific embodiment, Z is O, and R1, R2, R3, R4, R5, R6, R7, n1, n2, Q, and ------ bonds are as defined above. In a more specific embodiment, Z is O; R1 is a C1-C5 straight-chain or branched alkyl group; R2 is selected from hydrogen and halogens; R3, R4, R5, and R6 are each independently selected from hydrogen and halogens; R7 is selected from C1-C5 straight-chain or branched alkyl groups and C3-C6 cycloalkyl groups. In a preferred embodiment, Z is O; R1 is selected from methyl, ethyl, propyl, isopropyl, butyl, and isobutyl; R2 is selected from hydrogen, fluorine, chlorine, bromine, and iodine; R3, R4, R5, and R6 are each independently selected from hydrogen, fluorine, chlorine, bromine, and iodine; R7 is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, cyclopropyl, cyclobutyl, and cyclopentyl.

In one specific implementation, Z is O, the ------ bond is a single bond, and the compound of formula I is the compound shown in formula I-1:

Wherein R1, R2, R3, R4, R5, R6, R7, n1, n2, and Q are as defined above. In a preferred embodiment, Z is O, the ------ bond is a single bond, the compound of formula I is the compound shown in formula I-1, R1 is a C1-C5 straight-chain or branched alkyl group; R2 is selected from hydrogen and halogen; R3, R4, R5, and R6 are each independently selected from hydrogen and halogen; R7 is selected from C1-C5 straight-chain or branched alkyl groups and C3-C6 cycloalkyl groups; and Q is N. In a preferred embodiment, Z is O, the ------ bond is a single bond, the compound of formula I is the compound shown in formula I-1, R1 is selected from methyl, ethyl, propyl, isopropyl, butyl and isobutyl; R2 is selected from hydrogen, fluorine, chlorine, bromine and iodine; R3, R4, R5 and R6 are independently selected from hydrogen, fluorine, chlorine, bromine and iodine respectively; R7 is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, cyclopropyl, cyclobutyl and cyclopentyl.

In one embodiment, the compound of formula I is the compound of formula IV:

Where: n1 and n2 are integers from 1 to 3; R1 is selected from methyl, ethyl, propyl, and butyl; R2 is selected from hydrogen, fluorine, chlorine, bromine, and iodine; R3, R4, R5, and R6 are selected from hydrogen, fluorine, and chlorine, respectively; R7 is selected from isopropyl, isobutyl, ethyl, propyl, methyl, cyclopropyl, and cyclobutyl; Z is selected from C, O, and N; Q and W are selected from C and N, respectively; ------ bond indicates that it does not exist or exists in the form of a single bond.

In one specific implementation, the ------ bond in Formula I is absent, and Formula I is the compound shown in Formula V:

Where n2 is an integer from 1 to 2; R1 is selected from methyl, ethyl, propyl, and butyl; R3 is selected from hydrogen, fluorine, and chlorine; R7 is selected from isopropyl, isobutyl, ethyl, propyl, methyl, cyclopropyl, and cyclobutyl.

In one embodiment, the ------ bond in the compound of formula I is a single bond, and the compound of formula I is the compound shown in formula VI:

Wherein, n1 and n2 are integers from 1 to 3; R1 is methyl; R2 is selected from fluorine and hydrogen; R3, R4, R5, and R6 are selected from hydrogen, fluorine, and chlorine, respectively; R7 is selected from isopropyl, cyclopropyl, isobutyl, and methyl; Z is selected from C, O, and N; and Q and W are selected from C and N, respectively.

In one embodiment, the compound represented by Formula I is selected from any one of the following compounds:

Method for preparing compound I

This invention provides a method for preparing a compound of formula I, comprising:

The substituted o-carboxybenzylamine undergoes a condensation reaction with a primary amine to obtain intermediate I-a, wherein the amino group of the o-carboxybenzylamine is protected by Boc. Subsequently, hydrochloric acid is added to intermediate I-a to remove the Boc protection, thereby obtaining intermediate I-b. I-b then undergoes a reductive amination reaction with a substituted aryl aldehyde to obtain intermediate I-c. I-c then reacts with borane to reduce the amide moiety, thereby obtaining intermediate I-d. I-d undergoes a cyclization reaction with triphosgene to obtain intermediate I-e. Finally, I-e undergoes an alkylation reaction to obtain the compound shown in Formula I.

Pharmaceutical compositions and pharmaceutical preparations

Another object of the present invention is to provide a pharmaceutical composition comprising a therapeutically effective amount of the compound of the present invention, and optionally comprising a pharmaceutically acceptable excipient, carrier, adjuvant, solvent, or combination thereof.

Pharmaceutically acceptable carriers that can be used in the pharmaceutical compositions of the present invention include, but are not limited to, sterile liquids such as water and oil. The compositions may also, as needed, contain small amounts of wetting agents, emulsifiers, lubricants, stabilizers, or pH buffers. Oral formulations may contain standard carriers.

In one embodiment of the present invention, the pharmaceutical composition can be formulated using one or more pharmaceutically acceptable carriers in a conventional manner. Therefore, the active compounds of the present invention can be formulated into dosage forms for oral, sublingual, intranasal, parenteral (e.g., intravenous, intramuscular, or subcutaneous) or rectal administration, or dosage forms suitable for inhalation or insufflation.

The pharmaceutical compositions of the present invention can be administered in any manner, provided that they achieve the effect of preventing, alleviating, preventing, or curing symptoms in human or animal patients. For example, they can be formulated into various suitable dosage forms, especially injections, depending on the route of administration, such as lyophilized powder for injection, injection solution, or sterile powder for injection.

In one embodiment of the invention, an effective dose of the compound of the invention may be taken orally with an inert diluent or a carrier. According to some embodiments of the invention, the compound of the invention may be encapsulated in gelatin capsules or compressed into tablets. For oral therapeutic purposes, the compound of the invention may be used with excipients and in the form of tablets, lozenges, capsules, suspensions, syrups, etc. According to embodiments of the invention, the above-described formulations should contain at least 0.5% (w/w) of the active compound of the invention, but this may vary depending on the specific dosage form, wherein 4% to about 70% by weight is convenient. In such pharmaceutical compositions, the amount of the active compound should reach an appropriate dosage.

In one embodiment of the invention, regarding oral administration, the active compound of the invention can be formulated into tablets or capsules, for example, by conventional means with pharmaceutically acceptable excipients, such as binders, fillers, lubricants, disintegrants, or wetting agents. Tablets can be coated using methods well known in the art. Liquid formulations for oral administration can be solutions, syrups, or suspensions, or evaporated into a dried product, regenerated with water or other suitable carriers before use. Such liquid formulations can be prepared using pharmaceutically acceptable additives by conventional means, such as suspending agents, emulsifiers, non-aqueous carriers, 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 an organic medium to form an injectable solution or suspension.

In one embodiment of the present invention, the active compound of the present invention can be formulated into a rectal composition, such as a suppository or retention enema, for example containing a conventional suppository base, such as cocoa butter or other glycerides.

Therapeutic uses and methods

The present invention also provides the use of the compound of Formula I in the preparation of a medicament for treating mental illnesses.

The present invention also provides a method for treating mental illnesses, comprising administering to an individual in need a compound of Formula I or a pharmaceutical composition thereof. The method may also optionally include administering another active agent for treating mental illnesses.

The present invention also provides compounds of Formula I or pharmaceutical compositions thereof for the treatment of mental illnesses.

In one implementation, the mental illness is selected from schizophrenia and psychosis.

In another implementation, the mental illness is selected from Parkinson's disease, dementia-related behavioral disorders, and psychosis.

Exemplary Implementation

1. The compound shown in Formula I:

In formula I: n1 and n2 are integers from 1 to 3;

R1 is a C1-C5 straight-chain or branched alkyl group;

R2 is selected from hydrogen or halogen.

R3, R4, R5, and R6 are each independently selected from hydrogen and halogens;

R7 is selected from C1-C5 straight-chain or branched alkyl or cycloalkyl groups, and R8 and R9 are each independently selected from C1-C3 straight-chain or branched alkyl groups.

Z is selected from C, O, and N;

Q and W are selected from C and N, respectively;

------ indicates that the key does not exist or exists as a single key;

------When the bond is absent, Formula I represents the compound shown in Formula II:

In Equation II, n2, R1, R3, R7, W, and Z are defined as described above;

------ When the bond exists in the form of a single bond, Formula I represents a compound as shown in Formula III.

In Equation III, n1 and n2 are integers from 1 to 3;

R1 is a C1-C5 straight-chain or branched alkyl group;

R2 is selected from hydrogen or halogen.

R3, R4, R5, and R6 are each independently selected from hydrogen and halogens;

R7 is selected from C1-5 straight-chain or branched alkyl or cycloalkyl groups; R8 and R9 are each independently selected from C1-C3 straight-chain or branched alkyl groups.

Z is selected from C, O, and N;

Q and W are selected from C and N, respectively.

2. The compound of formula I described in item 1, characterized in that the halogen is fluorine, chlorine, bromine, or iodine.

3. The compound of Formula I according to claim 1, characterized in that the straight-chain or branched alkyl group of C1-C5 is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, and isopentyl; the cycloalkyl group is selected from cyclopropyl, cyclobutyl, and cyclopentyl; and the straight-chain or branched alkyl group of C1-C3 is methyl, ethyl, propyl, or isopropyl.

4. The compound of formula I according to claim 1, characterized in that the compound of formula I is a compound of formula IV:

Where: n1 and n2 are integers from 1 to 3;

R1 is selected from methyl, ethyl, propyl, and butyl;

R2 is selected from hydrogen, fluorine, chlorine, bromine, and iodine;

R3, R4, R5, and R6 are selected from hydrogen, fluorine, and chlorine, respectively;

R7 is selected from isopropyl, isobutyl, ethyl, propyl, methyl, cyclopropyl, cyclobutyl,

Z is selected from C, O, and N;

Q and W are selected from C and N, respectively;

------ indicates that the key does not exist or exists as a single key.

5. The compound of formula I according to item 1, characterized in that, when the ------ bond is absent, the compound of formula I is the compound of formula V:

Where n2 is an integer from 1 to 2;

R1 is selected from methyl, ethyl, propyl, and butyl;

R3 is selected from hydrogen, fluorine, and chlorine;

R7 is selected from isopropyl, isobutyl, ethyl, propyl, methyl, cyclopropyl, cyclobutyl,

6. The compound of Formula I according to claim 1, characterized in that, when the --- bond is in the form of a single bond, Formula I represents the compound as shown in Formula VI.

Where n1 and n2 are integers from 1 to 3;

R1 is a methyl group;

R2 is selected from fluorine and hydrogen;

R3, R4, R5, and R6 are selected from hydrogen, fluorine, and chlorine, respectively;

R7 is selected from isopropyl, cyclopropyl, isobutyl, methyl,

Z is selected from C, O, and N;

Q and W are selected from C and N, respectively.

7. The compound represented by Formula I as described in any one of items 1-4, characterized in that the compound is selected from any one of the following compounds:

8. A pharmaceutical composition characterized by comprising the compound of any one of claims 1 to 7, optionally further comprising a pharmaceutically acceptable excipient, carrier, adjuvant, solvent, or combination thereof.

9. The use of any one of the compounds described in items 1 to 7 or the pharmaceutical composition described in item 8 in the preparation of a drug for treating mental illnesses.

10. The application according to item 9, wherein the mental illness is schizophrenia or psychosis.

11. The application according to item 9, characterized in that the mental illness is Parkinson's disease, dementia-related behavioral disorders, and psychosis.

Beneficial effects

The compounds provided by this invention act on 5-HT _2A and 5-HT _2C receptors, exhibiting selectivity for 5-HT _2A superior to or similar to that of piperoxetine. These compounds are intended for the treatment of schizophrenia, Parkinson's disease, dementia-related behavioral disorders, and psychosis. The antipsychotic activity of these compounds is comparable to that of piperoxetine, with fewer sedative and motor deterioration side effects, and less cardiotoxicity.

Example

The present invention can be further described through the following embodiments; however, the scope of the present invention is not limited to the following embodiments. Those skilled in the art will understand that various changes and modifications can be made to the present invention without departing from its spirit and scope.

Synthesis Examples

Example 1: Preparation of 2-(1-methylpiperidin-4-yl)-4-{[4-(2-methylpropoxy)phenyl]methyl}-1,5-dihydro-2,4-benzidine-3-one (A19020):

Synthesis route:

1.1 Preparation of 2-[(tert-butyldimethylsilyl)oxy]methyl]benzyl alcohol:

1,2-Benzenedimethanol (22.0 g, 159.2 mmol), tert-butyldimethylchlorosilane (24.0 g, 159.2 mmol), triethylamine (16.1 g, 159.2 mmol), and DCM (200.00 mL) were added to a 500 mL three-necked round-bottom flask, and stirred overnight at room temperature under nitrogen protection. The mixture was then quenched with water, extracted with 3 × 100 mL of DCM, washed with 200 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give 30 g (74.64% yield) of a colorless oil.

1.2 Preparation of 2-[(tert-butyldimethylsilyl)oxymethyl]benzaldehyde:

2-[(tert-butyldimethylsilyl)oxymethyl]benzyl alcohol (30.00 g, 118.8 mmol), Dess Martin (50.4 g, 118.8 mmol), and DCM (300 mL) were added to a 1 L three-necked round-bottom flask. The mixture was reacted under nitrogen protection at room temperature for 4 h, then quenched with water, extracted with 3 × 100 mL DCM, washed with 200 mL saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by ethyl acetate/petroleum ether (1/35) column chromatography to give 17 g (yield 58.62%) of colorless oil.

1.3 Preparation of 2-[(tert-butyldimethylsilyl)oxymethyl]phenyl-[4-(2-methylpropoxy)phenyl]methylamine:

2-[(tert-butyldimethylsilyl)oxymethyl]benzaldehyde (1.00 g, 3.9 mmol), 1-(4-isopropoxyphenyl)methylamine (0.66 g, 3.9 mmol), MgSO4 (0.1 g, 0.83 mmol), and EtOH (10 mL) were added to a 50 mL three-necked round-bottom flask, purged with nitrogen and maintained at room temperature for 3 h. Then, _NaBH4 (0.76 g, 19.9 mmol) was added, and the mixture was stirred at room temperature for 1 h. 30 mL of water was added, and the mixture was extracted with 3 × 20 mL of ethyl acetate, followed by washing with 30 mL of saturated brine. The ethyl acetate phase was dried over anhydrous sodium sulfate and concentrated by filtration to give 1.6 g (yield 96.85%) of a colorless oil.

1.4 Preparation of benzyl-[N-2-[((tert-butyldimethylsilyl)oxy)methyl]phenyl]-N-[4-(2-methylpropoxy)phenyl]carbamate:

2-[(tert-butyldimethylsilyl)oxymethyl]phenyl-[4-(2-methylpropoxy)phenyl]methylamine (1.6 g, 0.004 mmol), tetrahydrofuran (5 mL), water (5 mL), benzyl chloroformate (0.79 g, 0.005 mmol), and potassium methylbenzoate (1.08 g, 0.008 mmol) were added to a 50 mL round-bottom flask and stirred at 50 °C for 2 h. Then, 30 mL of water was added, and the mixture was extracted with 3 × 20 mL of ethyl acetate. The extract was then washed with 50 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 2.27 g of oil.

Preparation of 1,5-benzyl-[N-2-(hydroxymethyl)phenyl]-N-[4-(2-methylpropoxy)phenyl]carbamate:

Benzyl-[N-2-[((tert-butyldimethylsilyl)oxy)methyl]phenyl]-N-[4-(2-methylpropoxy)phenyl]carbamate (2.27 g, 4.14 mmol), dioxane (20.00 mL), and HCl (5.2 mL) were placed in a 50 mL three-necked round-bottom flask and purged with inert nitrogen. The mixture was stirred at room temperature for 1 h. The reaction mixture was then concentrated and purified by silica gel column chromatography with ethyl acetate/petroleum ether (1/5) to give 0.87 g (yield 48.6%) of a colorless oil.

Preparation of 1,6-benzyl-[N-2-(formylphenyl)]-N-[4-(2-methylpropoxy)phenyl]carbamate:

Benzyl-[N-2-(hydroxymethyl)phenyl]-N-[4-(2-methylpropoxy)phenyl]carbamate (0.87 g, 2.0 mmol), manganese dioxide (2.62 g, 30.1 mmol), and DCM (20 mL) were placed in a 50 mL round-bottom flask, heated to 80 °C, and stirred overnight. The solid was then filtered off, and the filtrate was directly concentrated to give 0.75 g (yield 86.61%) of an oily substance.

1.7 Preparation of benzyl-[N-2-(tert-butoxycarbonylpiperidine)phenyl]amino-N-[4-(2-methylpropoxy)carbamate:

Benzyl-[N-2-(formylphenyl)]-N-[4-(2-methylpropoxy)phenyl]carbamate (0.75 g, 1.74 mmol), 4-amino-tert-butoxycarbonylpiperidine (0.42 g, 2.08 mmol), magnesium sulfate (0.10 g, 0.001 mmol), and ethanol (10 mL) were added to a 50 mL three-necked round-bottom flask. The mixture was purged with nitrogen and stirred at room temperature for 3 h. Then, _NaBH4 (0.33 g, 8.69 mmol) was added, and the mixture was stirred at room temperature for 1 h. Then, 30 mL of water was added, and the mixture was extracted with 3 × 20 mL of ethyl acetate. The extract was washed with 50 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 1.1 g of oil.

1.8 Preparation of N-[2-(tert-butoxycarbonylpiperidine)phenyl]amino-N-[4-(2-methylpropoxy)amino]

Benzyl-[N-2-(tert-butoxycarbonylpiperidine)phenyl]amino-N-[4-(2-methylpropoxy)carbamate (1.1 g), palladium/carbon (0.1 g), methanol (5 mL), and tetrahydrofuran (5 mL) were placed in a 50 mL three-necked round-bottom flask, hydrogen gas was introduced, and the mixture was stirred at room temperature for 3 h. The solid was then filtered off, and the filtrate was directly concentrated to obtain 0.65 g of oil.

1.9 Preparation of 2-(tert-butoxycarbonylpiperidine)-4-{[4-(2-methylpropoxy)phenyl]methyl}-1,5-dihydro-2,4-benzodiazepine-3-one:

N-[2-(tert-Butoxycarbonylpiperidine)phenyl]amino-N-[4-(2-methylpropoxy)amino (0.65 g, 1.34 mmol) and tetrahydrofuran (10 mL) were added to a 50 mL round-bottom flask, purged with inert nitrogen and kept at -40 °C, and BTC (0.16 g, 0.54 mmol) was added. The reaction was maintained at this temperature for 1 h, and then 30 mL of water was added. The mixture was extracted with 3 × 20 mL of ethyl acetate, washed with 50 mL of saturated brine, dried over anhydrous sodium sulfate in ethyl acetate, filtered and concentrated to obtain 0.78 g of oil.

1.10 Preparation of 2-(piperidin-4-yl)-4-{[4-(2-methylpropoxy)phenyl]methyl}-1,5-dihydro-2,4-benzidine-3-one:

2-(tert-Butoxycarbonylpiperidine)-4-{[4-(2-methylpropoxy)phenyl]methyl}-1,5-dihydro-2,4-benzidine-3-one (0.78 g, 1.53 mmol), DCM (10 mL), and HCl/dioxane 4M (0.22 g, 1.6 mmol) were added to a 50 mL round-bottom flask and stirred at room temperature for 1 h. The reaction solution was then directly concentrated to obtain 0.66 g of oil.

1.11 Preparation of 2-(1-methylpiperidin-4-yl)-4-{[4-(2-methylpropoxy)phenyl]methyl)-1,5-dihydro-2,4-benzidine-3-one:

2-(piperidin-4-yl)-4-{[4-(2-methylpropoxy)phenyl]methyl}-1,5-dihydro-2,4-benzidine-3-one (0.66 g, 1.6 mmol), formaldehyde (0.1 g, 3.2 mmol), triethylamine (0.66 g, 6.4 mmol), magnesium sulfate (0.02 g, 0.16 mmol), and methanol (10 mL) were added to a 50 mL round-bottom flask and stirred at room temperature for 3 h. Then, _NaBH₄ (0.31 g, 8.1 mmol) was added, and the mixture was stirred at room temperature for 1 h. Next, 30 mL of water was added, and the mixture was extracted with 3 × 20 mL of ethyl acetate, washed with 30 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Finally, the mixture was purified using an Intel Flash-1 column to give 11.6 mg (yield 1.7%) of a pale yellow oil. ^¹H NMR (400 MHz, Methanol- _d4) was performed. )δ7.40-7.19 (m, 5H), 7.03 (d, J=7.3Hz, 1H), 6.91-6.82 (m, 2H), 4.51 (s, 2H), 4.46 (s, 2H), 4.41 (s, 2H), 4.34 (tt, J=12.2, 3.9Hz, 1H), 3.74 (d, J=6.5Hz, 2H), 3.64-3. 56 (m, 2H), 3.21-3.04 (m, 2H), 2.91 (s, 3H), 2.32-2.17 (m, 2H), 2.07 (dq, J=13.3, 6 .6Hz, 1H), 1.97 (t, J=15.8Hz, 2H), 1.04 (d, J=6.7Hz, 6H), LCMS (ES, m/z): 422[M+H] ⁺ .

Example 2: Preparation of 7-fluoro-2-(1-methylpiperidin-4-yl)-4-{[4-(2-methylpropoxy)phenyl]methyl}-1,5-dihydro-2,4-benzidine-3-one (A19001):

Synthesis route:

2.1 Preparation of methyl 2-[(tert-Butoxycarbonyl)aminomethyl]-5-fluorobenzoate:

Methyl 2-cyano-5-fluorobenzoate (1.8 g, 10.05 mmol), Raney-Ni (0.5 mg), _Boc₂O (2.63 g, 12.06 mmol), _NaHCO₃ (1.69 g, 20.1 mmol), and THF (20 mL) were added to a 50 mL three-necked round-bottom flask, hydrogen gas was introduced, and the mixture was stirred at 50 °C for 48 h. The reaction solution was then filtered, and the filtrate was directly concentrated to obtain 2 g (70.26%) of solid.

2.2 Preparation of 2-[(tert-Butoxycarbonyl)aminomethyl]-5-fluorobenzoic acid:

2-[(tert-Butoxycarbonyl)aminomethyl]-5-fluorobenzoate (2.0 g, 7.06 mmol), sodium hydroxide (1.41 g, 35.3 mmol), and THF/ _H₂O (10/10 mL) were placed in a 50 mL three-necked round-bottom flask and stirred overnight at room temperature. The pH was then adjusted to 5 with 3N HCl, extracted with 3 × 20 mL EA, washed with 30 mL saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give 1.2 g (63.13%) of solid.

2.3 Preparation of 2-[(tert-Butoxycarbonyl)aminomethyl]-5-fluoro-4-(2-methylpropoxy)benzamide:

2-[(tert-Butoxycarbonyl)aminomethyl]-5-fluorobenzoic acid (1.2 g, 4.4 mmol), 4-isobutoxybenzylamine (0.88 g, 4.9 mmol), HATU (2.2 g, 5.8 mmol), DIEA (1.15 g, 8.9 mmol), and DMF (20 mL) were placed in a 50 mL three-necked round-bottom flask and stirred overnight at room temperature. Then, 30 mL of water was added, and the mixture was extracted with 3 × 20 mL EA solution. The extract was washed with 30 mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated by filtration. The solution was then subjected to silica gel column chromatography in ethyl acetate/petroleum ether (1/3) to give 1 g (yield 52.12%) of solid.

2.4 Preparation of 2-(aminomethyl)-5-fluoro-4-(2-methylpropoxy)phenylformamide:

Prepared according to the method in 1.10 of Example 1, 1g of oily substance was obtained.

2.5 Preparation of 2-[(1-methylpiperidin-4-yl)amino]-5-fluoro-4-(2-methylpropoxy)phenylformamide:

1 g (3.02 mmol) of 2-(aminomethyl)-5-fluoro-4-(2-methylpropoxy)phenylformamide, 0.41 g (3.6 mmol) of 1-methylpiperidin-4-one, 0.38 g (6.05 mmol) of _NaBH3CN , 10 mL of EtOH and 1 mL of HOAc were placed in a 50 mL round-bottom flask and stirred overnight at room temperature. Then, 30 mL of saturated _NaHCO3 solution was added, and the mixture was extracted with 3 × 20 mL of EA. The extract was washed with 30 mL of saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The solution was then purified by dichloromethane/methanol (10/1) silica gel column chromatography to give 0.75 g (57.96%) of solid.

2.6 Preparation of 2-[(1-methylpiperidin-4-yl)amino]-5-fluoro-4-(2-methylpropoxy)benzylamine:

0.3 g (0.702 mmol) of 2-[(1-methylpiperidin-4-yl)amino]-5-fluoro-4-(2-methylpropoxy)phenylformamide and 10.00 mL of BH3 _- THF were placed in a 50 mL round-bottom flask and stirred overnight at room temperature. The mixture was then quenched with 2N HCl, and 30 mL of EA was added. The aqueous phase was extracted with EA (2 × 20 mL). The pH of the aqueous phase was then adjusted to 10 with 15% NaOH solution, and the solvent was removed by DCM extraction. The mixture was then purified by reverse chromatography to obtain 0.1 g (yield 34.46%) of a white solid.

2.6 Preparation of 7-fluoro-2-(1-methylpiperidin-4-yl)-4-{[4-(2-methylpropoxy)phenyl]methyl}-1,5-dihydro-2,4-benzodiazepine-3-one:

Prepared according to the method in 1.9 of Example 1, yielding 2.8 mg (yield 2.63%) of white solid. ¹H-NMR (400 MHz, Methanol- _d⁴ ): δ 7.34 (dd, J = 8.4, 5.4 Hz, 1H), 7.25–7.17 (m, 2H), 7.00 (td, J = 8.6, 2.7 Hz, 1H), 6.91–6.82 (m, 2H), 6.77 (dd, J = 9.1, 2.7 Hz, 1H), 4.47 (d, J = 15.2 Hz, 4H), 4.39 (s, 2H), 4.43–4.27 (m, 1H), 3.74 (d, J = 6.4 Hz, 2H), 3. 64-3.56 (m, 2H), 3.21-3.10 (m, 2H), 2.90 (s, 3H), 2.32 (dd, J=13.4, 4.0Hz, 1H), 2.25 (dd, J=13.1, 4.1Hz, 1 H), 2.06 (dp, J=13.3, 6.7Hz, 1H), 1.95 (d, J=13.9Hz, 2H), 1.04 (d, J=6.7Hz, 6H); LCMS (ES, m/z): 440[M+H] ⁺ .

Example 3: Preparation of 7-chloro-2-(1-methylpiperidin-4-yl)-4-{[4-(2-methylpropoxy)phenyl]methyl}-1,5-dihydro-2,4-benzidine-3-one (A190017):

Synthesis route:

3.1 Preparation of methyl 2-[(tert-Butoxycarbonyl)aminomethyl]-4-chlorobenzoate:

Prepared according to the method in 2.1 of Example 2, 1.58 g (103.10%) of white solid was obtained.

3.2 Preparation of 2-[(tert-Butoxycarbonyl)aminomethyl]-4-chlorobenzoic acid:

Prepared according to the method in 2.2 of Example 2, 1.12 g (74.37%) of white solid was obtained.

3.3 Preparation of 2-[(tert-Butoxycarbonyl)aminomethyl]-4-chloro-4-(piperidine-1-carboxylic acid benzyl ester)benzamide:

Prepared according to the method in 2.3 of Example 2, 2g (101.63%) of yellow oily substance was obtained.

3.4 Preparation of 2-(aminomethyl)-4-chloro-4-(piperidine-1-carboxylic acid benzyl ester) benzamide:

Prepared according to the method in 1.10 of Example 1, 2g (124.91%) of white solid was obtained.

3.5 Preparation of 2-(2-methylpropoxy)-benzylamine-4-chloro-4-(piperidine-1-carboxylic acid benzyl ester) benzamide:

Prepared according to the method in 2.5 of Example 2, 1g (35.62%) of yellow oily substance was obtained.

3.6 Preparation of 2-(2-methylpropoxy)-benzylamine-4-chloro-4-(piperidine-1-carboxylic acid benzyl ester) benzylamine:

Prepared according to the method in 2.6 of Example 2, 0.22 g (22.56%) of yellow oily substance was obtained.

3.7 Preparation of 7-chloro-2-(piperidin-1-carboxylic acid benzyl ester)-4-{[4-(2-methylpropoxy)phenyl]methyl}-1,5-dihydro-2,4-benzodiazepine-3-one:

Prepared according to the method in 1.9 of Example 1, 0.21 g (yield 91.15%) of yellow oily substance was obtained.

3.8 Preparation of 7-chloro-2-(1-methylpiperidin-4-yl)-4-{[4-(2-methylpropoxy)phenyl]methyl}-1,5-dihydro-2,4-benzodiazepine-3-one:

7-Chloro-2-(piperidin-1-carboxylic acid benzyl ester)-4-{[4-(2-methylpropoxy)phenyl]methyl}-1,5-dihydro-2,4-benzidine-3-one (0.21 g, 0.365 mmol), Pd(OH) _₂ /C (0.1 g, 0.729 mmol), Pd/C (77.58 mg, 0.729 mmol), HCHO (43.78 mg, 1.46 mmol), and MeOH (3 mL) were placed in a 50 mL round-bottom flask and stirred at room temperature for 10 h. The mixture was filtered, the filtrate was concentrated, and purified by preparative liquid chromatography to give 2.4 mg (yield 1.44%) of a white solid. ^¹H NMR (400 MHz, DMSO- _d₄) was performed. )δ9.62 (s, 1H), 7.33 (dd, J=8.0, 2.2Hz, 1H), 7.28-7.18 (m, 6H), 6.90-6.83 (m, 3H), 4. 37-4.30 (m, 8H), 4.17 (d, J = 12.6Hz, 2H), 3.72 (d, J = 6.5Hz, 3H), 3.05 (d, J = 10.8Hz, 2H) , 2.76 (d, J=4.7Hz, 4H), 2.38 (s, 4H), 2.18-2.08 (m, 3H), 2.00 (dt, J=13.4, 6.7Hz, 1H) , 1.75 (d, J=13.3Hz, 3H), 1.24 (s, 1H), 0.98 (d, J=6.7Hz, 9H); LCMS (ES, m/z): 456[M+H] ⁺ .

Example 4: Preparation of 8-fluoro-2-(1-methylpiperidin-4-yl)-4-{[4-(2-methylpropoxy)phenyl]methyl}-1,5-dihydro-2,4-benzadiazon-3-one (A19005):

Synthesis route:

4.1 Preparation of 2-[(tert-Butoxycarbonyl)aminomethyl]-5-fluoro-4-(1-piperidine)benzamide:

Prepared according to the method in 2.3 of Example 2, 8g (84.21%) of oil was obtained.

4.2 Preparation of 2-(2-methylpropoxy)-benzylamine-5-fluoro-4-(1-piperidine)benzamide:

Prepared according to the method in 1.10 of Example 1, 2g of oily substance was obtained.

4.3 Preparation of 2-(2-methylpropoxy)-benzylamine-5-fluoro-4-(piperidine-1-carboxylic acid benzyl ester) benzamide:

Prepared according to the method in 2.5 of Example 2, 0.65 g (20.17%) of yellow oily substance was obtained.

4.4 Preparation of 2-(2-methylpropoxy)-benzylamine-5-fluoro-4-(piperidine-1-carboxylic acid benzyl ester) benzylamine:

Prepared according to the method in 2.6 of Example 2, 0.25 g (12.31%) of yellow oily substance was obtained.

Preparation of 8-fluoro-2-(1-methylpiperidin-4-yl)-4-{[4-(2-methylpropoxy)phenyl]methyl}-1,5-dihydro-2,4-benzodiazepine-3-one:

Prepared according to the method in 1.9 of Example 1, yielding 35 mg (yield 13.17%) of white solid. ¹H-NMR (400 MHz, Methanol- _d⁴ ) δ 7.24–7.17 (m, 2H), 7.11 (dd, J = 9.0, 2.6 Hz, 1H), 7.03 (dd, J = 8.4, 5.5 Hz, 1H), 6.95 (td, J = 8.6, 2.6 Hz, 1H), 6.90–6.83 (m, 2H), 4.52–4.36 (m, 7H), 4.31 (tt, J = 12.3, 3.9 Hz, 1H), 3.73 (d, J = 6.5 Hz, 2H), 3.6 0 (d, J=12.4Hz, 2H), 3.40 (s, 0H), 3.15 (t, J=12.7Hz, 2H), 2.91 (s, 3H), 2.25 (qd, J=13.3, 4.0Hz, 2H), 2.06 (dt, J=13.3, 6.6Hz, 1H), 1.96 (d, J=13.8Hz, 2H), 1.04 (d, J=6.7Hz, 6H); LCMS (ES, m/z): 440[M+H] ⁺ .

Example 5: Preparation of 8-fluoro-2-(1-methylpiperidin-4-yl)-4-{[4-(2-methylpropylamino)phenyl]methyl}-1,5-dihydro-2,4-benzodiazepine-3-one (A19007):

Synthesis route:

5.1 Preparation of methyl 2-[(tert-Butoxycarbonyl)aminomethyl]-5-fluorobenzoate:

The oil was prepared according to the method in 2.1 of Example 2, yielding 4.7g of oil.

5.2 Preparation of 2-[(tert-Butoxycarbonyl)aminomethyl]-5-fluorobenzoic acid:

Prepared according to the method in 2.2 of Example 2, 4.0 g (89.54%) of oil was obtained.

5.3 2-[(tert-Butoxycarbonyl)aminomethyl]-5-fluoro-4-(piperidine-1-carboxylic acid benzyl ester)benzamide

The oil was prepared according to the method in 2.3 of Example 2, yielding 4.6g of oil.

5.4 Preparation of 2-(aminomethyl)-5-fluoro-4-(piperidine-1-carboxylic acid benzyl ester) benzamide:

Prepared according to the method in 1.10 of Example 1, 5.6g of oily substance was obtained.

5.5 Preparation of 2-(4-bromobenzamide)-5-fluoro-4-(piperidine-1-carboxylic acid benzyl ester)benzamide:

Prepared according to the method in 2.3 of Example 2, 3.2 g (38.75%) of white solid was obtained.

5.6 Preparation of 2-[(2-methylpropyl)aminobenzamide]-5-fluoro-4-(piperidine-1-carboxylic acid benzyl ester)benzamide:

2-(4-bromobenzamide)-5-fluoro-4-(piperidin-1-carboxylic acid benzyl ester)benzamide (1 g, 1.76 mmol), isobutylamine (0.193 g, 2.64 mmol), sodium tert-butoxide (0.34 g, 3.52 mmol), Ruphos (82.1 mg, 0.176 mmol), _Pd₂ (dba) _₃ (0.161 mg, 0.176 mmol), and toluene (13 mL) were placed in a 50 mL round-bottom flask, heated to 80 °C, stirred for 1 h, filtered, concentrated the filtrate, and subjected to silica gel column chromatography (PE/EA = 3:1) to give 0.797 g (yield 80.8%) of a yellow solid.

5.7 Preparation of 8-fluoro-2-(piperidin-1-carboxylic acid benzyl ester)-4-{[4-(2-methylpropylamino)phenyl]methyl}-1,5-dihydro-2,4-benzodiazepine-3-one:

The oily substance was prepared according to the method in 1.9 of Example 1, yielding 0.26 g of oil.

5.8 Preparation of 8-fluoro-2-(1-methylpiperidin-4-yl)-4-{[4-(2-methylpropylamino)phenyl]methyl}-1,5-dihydro-2,4-benzodiazepine-3-one:

Prepared according to the method in 3.7 of Example 3, yielding 4.1 mg (yield 2.61%) of white solid. ^¹H NMR (400 MHz, Methanol- _d4) was used. )δ8.48 (s, 1H, FA), 7.10-6.98 (m, 4H), 6.93 (td, J=8.6, 2.7Hz, 1H), 6.58 (d, 2H), 4.42 (s, 4H), 4.36 (s, 2H), 4.30-4.18 (m, 1H), 3.46-3.39 (m, 2 H), 2.96-2.83(m, 4H), 2.77(s, 3H), 2.25-2.05(m, 2H), 1.96-1.84(m, 3H), 1.36-1.30(m, 1H), 0.99(d, J=6.6Hz, 6H); LCMS (ES, m/z): 439[M+H] ⁺ .

The general formulas for the synthesis of compounds A19006, A19008, A19009, A19011, A19012, A19013, and A19015 are as follows:

Example 6: Preparation of 8-fluoro-2-(1-methylpiperidin-4-yl)-4-{[4-(cyclopropoxy)phenyl]methyl}-1,5-dihydro-2,4-benzidine-3-one (A19006):

6.1 Preparation of 2-[(tert-Butoxycarbonyl)aminomethyl]-5-fluoro-4-(piperidine-1-carboxylic acid benzyl ester)benzamide:

Prepared according to the method in 2.3 of Example 2, 23g (63.77%) of yellow solid was obtained.

6.2 Preparation of 2-(2-methylpropoxy)-benzylamine-5-fluoro-5-(1-piperidine-1-carboxylic acid benzyl ester) benzamide:

Prepared according to the method in 1.10 of Example 1, 1.9g of oily substance was obtained.

6.3 Preparation of 2-(cyclopropoxy)-benzylamine-5-fluoro-5-(piperidine-1-carboxylic acid benzyl ester) benzamide:

Prepared according to the method in 1.7 of Example 1, 1.3g of oily substance was obtained.

6.4 Preparation of 2-(cyclopropoxy)-benzylamine-5-fluoro-4-(piperidine-1-carboxylic acid benzyl ester) benzylamine:

Prepared according to the method in 2.6 of Example 2, 0.23 g (18.17%) of yellow oily substance was obtained.

6.5 Preparation of 8-fluoro-2-(piperidin-1-carboxylic acid benzyl ester)-4-{[4-(cyclopropoxy)phenyl]methyl}-1,5-dihydro-2,4-benzodiazepine-3-one:

Prepared according to the method in 1.9 of Example 1, 0.2 g of oily substance was obtained.

6.6 Preparation of 8-fluoro-2-(1-methylpiperidin-4-yl)-4-{[4-(cyclopropoxy)phenyl]methyl}-1,5-dihydro-2,4-benzodiazepine-3-one:

Prepared according to the method in 3.7 of Example 3, 37.9 mg (yield 24.32%) of brown solid was obtained. ^¹H NMR (400 MHz, DMSO- _d₆ ) δ 7.30–7.19 (m, 3H), 7.11 (dd, J = 8.4, 5.7 Hz, 1H), 7.05–6.94 (m, 3H), 4.36 (d, J = 7.1 Hz, 4H), 4.29 (s, 2H), 3.96 (tt, J = 11.4, 4.0 Hz, 1H), 3.80 (tt, J = 6.0, 3.0 Hz, 1H), 2.86–2.78 (m, 2H), 2.16 (s, 3H), 1.95–1.85 (m, 2H), 1.89–

1.75 (m, 2H), 1.45 (dd, J=11.0, 3.9Hz, 2H), 0.81-0.67 (m, 2H), 0.67-0.59 (m, 2H); LCMS (ES, m/z): 424[M+H] ⁺ .

Example 7: Preparation of 8-fluoro-2-(1-methylpiperidin-4-yl)-4-{[4-(2-methylpropyl)phenyl]methyl}-1,5-dihydro-2,4-benzadiazon-3-one (A19008):

7.1 Preparation of 2-(2-methylpropyl)-benzylamine-5-fluoro-4-(piperidine-1-carboxylic acid benzyl ester)benzamide:

Prepared according to the method in 1.7 of Example 1, 2.3 g (yield 61.76%) of yellow oily substance was obtained.

7.2 Preparation of 2-(2-methylpropyl)-benzylamine-5-fluoro-4-(piperidine-1-carboxylic acid benzyl ester) benzylamine:

Prepared according to the method in 2.6 of Example 2, 0.69g of yellow oily substance was obtained.

7.3 Preparation of 8-fluoro-2-(piperidin-1-carboxylic acid benzyl ester)-4-{[4-(2-methylpropyl)phenyl]methyl}-1,5-dihydro-2,4-benzodiazepine-3-one:

Prepared according to the method in 1.9 of Example 1, 0.7 g of yellow oily substance was obtained.

7.4 Preparation of 8-fluoro-2-(1-methylpiperidin-4-yl)-4-{[4-(2-methylpropyl)phenyl]methyl}-1,5-dihydro-2,4-benzodiazepine-3-one:

Prepared according to the method in 3.7 of Example 3, 21 mg (yield 3.85%) of yellow solid was obtained. ¹ H NMR (400MHz, DMSO-d ₆ )δ10.87 (s, 1H), 7.23-6.96 (m, 7H), 4.43 (d, J=7.8Hz, 4H), 4.34 (s, 3H), 3.86 (s, 1H), 3.45-3.37 (m, 2H), 3.17 (s, 1H), 3.11-2.95 (m, 2H), 2 .71 (d, J=4.8Hz, 3H), 2.44-2.27 (m, 4H), 1.80 (dp, J=13.5, 6.8Hz, 1H), 1.72-1.59 (m, 2H), 0.85 (d, J=6.6Hz, 6H); LCMS (ES, m/z): 424[M+H] ⁺ .

Example 8: Preparation of 8-fluoro-2-(1-methylpiperidin-4-yl)-4-[(4-methoxyphenyl)methyl]-1,5-dihydro-2,4-benzidine-3-one (A19009):

8.1 Preparation of 2-(4-methoxy)-benzylamine-5-fluoro-4-(piperidine-1-carboxylic acid benzyl ester) benzamide:

Prepared according to the method in 1.7 of Example 1, 0.48g of yellow oily substance was obtained.

8.2 Preparation of 2-(4-methoxy)benzylamine-5-fluoro-4-(piperidine-1-carboxylic acid benzyl ester) benzylamine:

Prepared according to the method in 2.6 of Example 2, 0.13g of yellow oily substance was obtained.

8.3 Preparation of 8-fluoro-2-(piperidin-1-carboxylic acid benzyl ester)-4-[(4-methoxyphenyl)methyl]-1,5-dihydro-2,4-benzodiazepine-3-one:

Prepared according to the method in 1.9 of Example 1, 0.09 g of yellow oily substance was obtained.

8.4 Preparation of 8-fluoro-2-(1-methylpiperidin-4-yl)-4-[(4-methoxyphenyl)methyl]-1,5-dihydro-2,4-benzidine-3-one:

Prepared according to the method in 3.7 of Example 3, yielding 9 mg (yield 13.2%) of white solid. ^¹H NMR (400 MHz, DMSO- _d6) was used. )δ7.25 (dd, J=11.0, 7.5Hz, 3H), 7.10 (dd, J=8.5, 5.7Hz, 1H), 7.01 (td, J=8 .7, 2.7Hz, 1H), 6.87 (d, J=8.4Hz, 2H), 4.36 (d, J=7.2Hz, 4H), 4.28 (s, 2H), 4.03-3.92(m, 1H), 3.73(s, 3H), 2.85(d, J=9.8Hz, 2H), 2.20(s, 3H), 1.96( s, 2H), 1.91-1.77 (m, 2H), 1.46 (d, J=11.2Hz, 2H); LCMS (ES, m/z): 398[M+H] ⁺ .

Example 9: Preparation of 8-fluoro-2-(1-methylpiperidin-4-yl)-4-{[(2-fluoro-4-isopropoxy)phenyl]methyl}-1,5-dihydro-2,4-benzodiazepine-3-one (A19011):

9.1 Preparation of 2-(2-fluoro-4-isopropoxy)-benzylamine-5-fluoro-4-(piperidine-1-carboxylic acid benzyl ester) benzamide:

Prepared according to the method in 1.7 of Example 1, 0.88g of yellow oily substance was obtained.

9.2 Preparation of 2-(2-fluoro-4-isopropoxy)-benzylamine-5-fluoro-4-(piperidine-1-carboxylic acid benzyl ester) benzylamine:

Prepared according to the method in 2.6 of Example 2, 0.117g of yellow oily substance was obtained.

9.3 Preparation of 8-fluoro-2-(piperidin-1-carboxylic acid benzyl ester)-4-{[(2-fluoro-4-isopropoxy)phenyl]methyl}-1,5-dihydro-2,4-benzodiazepine-3-one:

Prepared according to the method in 1.9 of Example 1, 0.09 g of yellow oily substance was obtained.

9.4 Preparation of 8-fluoro-2-(1-methylpiperidin-4-yl)-4-{[(2-fluoro-4-isopropoxy)phenyl]methyl}-1,5-dihydro-2,4-benzodiazepine-3-one:

Prepared according to the method in 3.7 of Example 3, 5.3 mg (yield 7.5%) of orange-yellow solid was obtained. ¹ H NMR (400MHz, DMSO-d ₆ )δ9.54 (s, 1H), 7.22-7.00 (m, 4H), 6.76 (dd, J=12.4, 2.5Hz, 1H), 6.69 (dd, J=8.5, 2.5Hz, 1H), 4.60 (p, J=6.0Hz, 1H), 4.42 (s, 2H), 4.3 6 (d, J=16.6Hz, 4H), 2.76 (d, J=4.7Hz, 3H), 2.14-2.04 (m, 1H), 1.74 (d, J=14.9Hz, 2H), 1.25 (d, J=5.9Hz, 7H); LCMS (ES, m/z): 444[M+H] ⁺ .

Example 10: Preparation of 8-fluoro-2-(1-methylpiperidin-4-yl)-4-{[(3-fluoro-4-isopropoxy)phenyl]methyl}-1,5-dihydro-2,4-benzadiazine-3-one (A19012):

10.1 Preparation of 2-(3-fluoro-4-isopropoxy)-benzylamine-5-fluoro-4-(piperidine-1-carboxylic acid benzyl ester)benzamide:

Prepared according to the method in 1.7 of Example 1, 1.0 g of yellow oily substance was obtained.

10.2 Preparation of 2-(3-fluoro-4-isopropoxy)-benzylamine-5-fluoro-4-(piperidine-1-carboxylic acid benzyl ester) benzylamine:

Prepared according to the method in 2.6 of Example 2, 0.118g of yellow oily substance was obtained.

10.3 Preparation of 8-fluoro-2-(piperidin-1-carboxylic acid benzyl ester)-4-{[(3-fluoro-4-isopropoxy)phenyl]methyl}-1,5-dihydro-2,4-benzodiazepine-3-one:

Prepared according to the method in 1.9 of Example 1, 0.11 g of yellow oily substance was obtained.

10.4 Preparation of 8-fluoro-2-(1-methylpiperidin-4-yl)-4-{[(3-fluoro-4-isopropoxy)phenyl]methyl}-1,5-dihydro-2,4-benzodiazepine-3-one:

The yellow oil was prepared according to the method in 3.7 of Example 3, yielding 4.3 mg (yield 4.9%). ¹ H NMR (400MHz, DMSO-d ₆ )δ9.16 (s, 1H), 7.18 (dd, J=8.3, 5.6Hz, 1H), 7.15-7.01 (m, 5H), 4.58 (p, J=6.0Hz, 1H), 4.40-4.32 (m, 6H), 4.16 (s, 1H), 2.78 (d, J=4.4Hz , 3H), 2.44 (s, 12H), 2.05 (q, J=12.9, 12.3Hz, 2H), 1.78 (d, J=13.5Hz, 2H), 1.27 (d, J=6.0Hz, 6H), 1.24 (s, 1H); LCMS (ES, m/z): 444[M+H] ⁺ .

Example 11: Preparation of 8-fluoro-2-(1-methylpiperidin-4-yl)-4-{[(4-isopropoxy)pyridin-3-yl]methyl}-1,5-dihydro-2,4-benzodiazepine-3-one (A19013):

11.1 Preparation of 2-[(4-isopropoxypyridin-3-yl)]-aminomethyl-5-fluoro-4-(piperidine-1-carboxylic acid benzyl ester)benzamide:

Prepared according to the method in 1.7 of Example 1, 2.4 g of yellow oily substance was obtained.

11.2 Preparation of 2-[4-(4-isopropoxypyridin-3-yl)]-aminomethyl-5-fluoro-4-(piperidine-1-carboxylic acid benzyl ester)benzylamine:

Prepared according to the method in 2.6 of Example 2, 0.38g of yellow oily substance was obtained.

11.3 Preparation of 8-fluoro-2-(piperidin-1-carboxylic acid benzyl ester)-4-{[(4-isopropoxy)pyridin-3-yl]methyl}-1,5-dihydro-2,4-benzodiazepine-3-one:

Prepared according to the method in 1.9 of Example 1, 0.37g of yellow oily substance was obtained.

11.4 Preparation of 8-fluoro-2-(1-methylpiperidin-4-yl)-4-{[(4-isopropoxy)pyridin-3-yl]methyl}-1,5-dihydro-2,4-benzodiazepine-3-one:

Prepared according to the method in 3.7 of Example 3, 50.6 mg (yield 17.3%) of white solid was obtained. ^¹H NMR (400 MHz, DMSO- _d₆ ) ^δ : 8.09 (s, _1H ), 7.62 (d, J = 8.6 Hz, 1H), 7.27 (d, J = 9.3 Hz, 1H), 7.15 (t, J = 7.1 Hz, 1H), 7.02 (t, J = 8.3 Hz, 1H), 6.67 (d, J = 8.6 Hz, 1H), 5.21 (dt, J = 13.0, 6.6 Hz, 1H), 4.39–4.3 1 (m, 6H), 3.98 (d, J = 12.3Hz, 1H), 2.82 (d, J = 10.3Hz, 2H), 2.17 (s, 3H), 1.88 (dt, J = 2 8.7, 12.2Hz, 4H), 1.48-1.40 (m, 2H), 1.27 (d, J=6.1Hz, 6H); LCMS (ES, m/z): 427[M+H] ⁺ .

Example 12: Preparation of 8-fluoro-2-(1-methylpyrrolo-3-yl)-4-{[(4-isopropoxy)phenyl]methyl}-1,5-dihydro-2,4-benzadiazon-3-one (A19015):

12.1 Preparation of 2-[(4-isopropoxypyrrole-3-yl)]-aminomethyl-5-fluoro-4-(piperidine-1-carboxylic acid benzyl ester)benzamide:

Prepared according to the method in 1.7 of Example 1, 3.3g of yellow oily substance was obtained.

12.2 Preparation of 2-[4-(4-isopropoxypyrrole-3-yl)]-aminomethyl-5-fluoro-4-(piperidine-1-carboxylic acid benzyl ester)benzylamine:

Prepared according to the method in 2.6 of Example 2, 0.32g of colorless oily substance was obtained.

12.3 Preparation of 8-fluoro-2-(pyrrole-1-carboxylic acid benzyl ester)-4-{[(4-isopropoxy)phenyl]methyl}-1,5-dihydro-2,4-benzodiazepine-3-one:

Prepared according to the method in 1.9 of Example 1, 0.31g of yellow oily substance was obtained.

12.4 Preparation of 8-fluoro-2-(1-methylpyrrolo-3-yl)-4-{[(4-isopropoxy)phenyl]methyl}-1,5-dihydro-2,4-benzodiazepine-3-one:

Prepared according to the method in 3.7 of Example 3, 47.3 mg (yield 18.6%) ^of white solid was obtained. ^¹H NMR (400 MHz, DMSO- _d₆ ) δ 8.53 (s, _1H ), 7.23–7.17 (m, 2H), 7.09 (dd, J = 9.0, 2.6 Hz, 1H), 7.02 (dd, J = 8.3, 5.5 Hz, 1H), 6.94 (td, J = 8.6, 2.6 Hz, 1H), 6.89–6.82 (m, 2H), 4.67–4.28 (m, 7H), 3.73 (d, J = 6.4 Hz, 2H), 3.70–3.55 (m, 2H), 3. 28 (dd, J=11.9, 8.8Hz, 1H), 3.04 (td, J=10.5, 8.2Hz, 1H), 2.87 (s, 3H), 2.55-2.43 (m, 1H), 2.15 (ddt, J =13.6, 8.8, 4.6Hz, 1H), 2.05 (dq, J = 13.3, 6.7Hz, 1H), 1.04 (d, J = 6.7Hz, 6H); LCMS (ES, m/z): 426 [M+H] ⁺ .

Example 13: Preparation of 7-fluoro-1-methyl-2-{[4-(2-methylpropoxy)phenyl]methyl}-1,5-dihydrospirocyclic [2-benzazine-4,4-piperidin]-3-one (A19019):

Synthesis route:

13.1 Preparation of 1-tert-butyl-4-ethyl-4-[(2-cyano-5-fluorophenyl)methyl]piperidine-1,4-dicarboxylic acid:

2-(bromomethyl)-4-fluorobenzonitrile (2.5 g, 11.680 mmol), LDA (1.38 g, 12.88 mmol), and THF (25 mL) were placed in a 100 mL three-necked round-bottom flask and stirred overnight at room temperature. The mixture was then purged with nitrogen for 30 min. Next, 1-tert-butyl-4-ethylpiperidine-1,4-dicarboxylic acid (3.01 g, 0.012 mmol) was added dropwise at -78 °C. After the addition was complete, the mixture was stirred overnight at room temperature under nitrogen. The solution was then quenched with saturated _NH₄Cl (200 mL) solution and extracted with EtOAc (3 × 25 mL). The resulting mixture was washed with brine (2 × 25 mL), dried over anhydrous _Na₂SO₄ , filtered, and the filtrate was concentrated under reduced pressure. The filtrate was then eluted by silica gel column chromatography with PE/EtOAc (3:1).

3.5 g (76.74%) of yellow solid was obtained.

13.2 Preparation of 1-tert-butyl-4-ethyl-4-[(2-aminomethyl-5-fluorophenyl)methyl]piperidine-1,4-dicarboxylic acid:

Prepared according to the method in 2.1 of Example 2, 1.5 g (55.4%) of white solid was obtained.

13.3 Preparation of 1-tert-butyl-7-fluoro-3-oxo-2,5-dihydro-1H-spirocyclic [2-benzazine-4,4-piperidine]-1-carboxylic acid:

1-tert-butyl-4-ethyl-4-[(2-aminomethyl-5-fluorophenyl)methyl]piperidine-1,4-dicarboxylic acid (1 g, 2.54 mmol), _Cs₂CO₃ (2.48 g, 0.008 mmol), _and DMF (10 mL) were placed in a 50 mL three-necked round-bottom flask, purged with nitrogen, and stirred at 80 °C for 2 h. The mixture was then filtered, and 20 mL of water was added to the filtrate. The filtrate was extracted with EtOAc (3 × 20 mL), and the resulting mixture was washed with brine (3 × 20 mL), dried over anhydrous _Na₂SO₄ , filtered, and concentrated under reduced pressure to give 0.83 g (93.9%) of a yellow solid.

13.4 Preparation of 1-tert-butyl-7-fluoro-2-{[4-(2-methylpropoxy)phenyl]methyl}-3-oxo-1,5-dihydrospirocyclic [2-benzazine-4,4-piperidine]-1-carboxylic acid:

1-tert-butyl-7-fluoro-3-oxo-2,5-dihydro-1H-spirocyclic [2-benzazine-4,4-piperidine]-1-carboxylic acid (0.83 g, 1.14 mmol) and tetrahydrofuran (4 mL) were placed in a 50 mL three-necked round-bottom flask. NaH (91 mg, 2.29 mmol) was added at 0 °C under a nitrogen atmosphere. Then, 1-(chloromethyl)-4-(2-methylpropoxy)benzene (0.83 g, 1.37 mmol) was added dropwise at room temperature. After the reaction was complete, the mixture was quenched with water and extracted with EtOAc (3 × 10 mL). The resulting mixture was washed with brine (2 × 20 mL), dried over anhydrous _Na₂SO₄ , filtered, and the filtrate was concentrated under reduced pressure to give 0.5 g (85.2%) of a yellow solid.

13.4 Preparation of 7-fluoro-2-{[4-(2-methylpropoxy)phenyl]methyl}-1,5-dihydrospirocyclic [2-benzazine-4,4-piperidine]-3-one:

Prepared according to the method in 1.10 of Example 1, 0.4 g of oily substance was obtained.

13.5 Preparation of 7-fluoro-1-methyl-2-{[4-(2-methylpropoxy)phenyl]methyl}-1,5-dihydrospirocyclic [2-benzazine-4,4-piperidine]-3-one:

The following substances were added: 7-fluoro-2-{[4-(2-methylpropoxy)phenyl]methyl}-1,5-dihydrospirocyclic [2-benzazine-4,4-piperidin]-3-one (0.4 g, 0.97 mmol), HCHO (58 mg, 1.9 mmol), and HOAc (292 mg, 4.8 mmol).

MeOH (4 mL) was placed in a 50 mL three-necked round-bottom flask and stirred for 30 min under a nitrogen atmosphere. Then, STAB (309 mg, 1.461 mmol) was added at room temperature. After the reaction was complete, water was added, and the mixture was extracted with EtOAc (3 × 10 mL). The resulting mixture was washed with brine (2 × 20 mL), dried over anhydrous _Na₂SO₄ , filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative high-performance liquid chromatography (HPLC) to give 7.6 mg (yield 1.84%) of a white solid. ^¹H NMR (400 MHz, DMSO- _d₆) was performed. )δ7.20-7.06 (m, 4H), 6.96 (td, J=8.7, 2.7Hz, 1H), 6.91-6.83 (m, 2H), 4.56 (s, 2H) , 4.42 (s, 2H), 3.72 (d, J = 6.5Hz, 2H), 3.09 (s, 2H), 2.58 (dt, J = 11.4, 3.6Hz, 2H), 2 .32-2.21 (m, 2H), 2.21 (s, 3H), 2.15 (td, J=12.7, 4.2Hz, 2H), 2.01 (dq, J=13.3, 6. 6Hz, 1H), 1.34 (d, J＝12.9Hz, 2H), 0.98 (d, J＝6.7Hz, 6H); LCMS (ES, m/z): 424[M+H] ⁺ .

General synthetic method for compounds A19014-0 and A19014-0A:

Example 14: Preparation of (3R,4R)-8-fluoro-2-(1-methyl-3-fluoropiperidin-4-yl)-4-{[4-(2-methylpropoxy)phenyl]methyl}-1,5-dihydro-2,4-benzadiazine-3-one (A19014-0):

14.1 Preparation of 4-amino-3-fluoropiperidine-1-carboxylic acid benzyl ester:

Benzyl 3-fluoro-4-oxopiperidin-1-carboxylic acid benzyl ester (2 g, 7.9 mmol), acetamide (2.35 g, 39.8 mmol), _NaBH3CN (1 g, 62.8 mmol), and methanol (10 mL) were placed in a 25 mL three-necked round-bottom flask, purged with nitrogen, and reacted at room temperature overnight. After the reaction was complete, the mixture was extracted with EtOAc (3 × 30 mL), washed with brine (2 × 20 mL), dried over anhydrous _Na2SO4 , filtered, concentrated under reduced pressure, and precipitated by silica gel column chromatography in an ethyl acetate/petroleum ether (1:1) system to give 0.7 g (yield 34.86%) of colorless oil.

14.2 Preparation of 4-{2-[(tert-Butoxycarbonyl)amino]methyl}-5-fluorobenzamido}-3-fluoropiperidine-1-carboxylic acid benzyl ester:

1.3g of oil was prepared according to the method in 2.3 of Example 2.

14.3 Preparation of 4-[2-(aminomethyl)-5-fluorobenzoyl]-3-fluoropiperidine-1-carboxylic acid benzyl ester:

1g of light yellow oil was prepared according to the method in 1.10 of Example 1.

14.4 Preparation of 3-fluoro-4-[5-fluoro-2-{[4-(2-methylpropoxy)phenyl]methylamino}benzamide-piperidine-1-carboxylic acid benzyl ester:

The yellow oil was prepared according to the method in 2.5 of Example 2, yielding 0.6 g (42.8%).

14.5 Preparation of 3-fluoro-4-[5-fluoro-2-{[4-(2-methylpropoxy)phenyl]methylamino}benzylamino-piperidine-1-carboxylic acid benzyl ester:

The yellow oil was prepared according to the method in 2.6 of Example 2, yielding 0.23 g (18.32%).

14.6 Preparation of 8-fluoro-2-(3-fluoropiperidine-1-carboxylic acid benzyl ester)-4-{[4-(2-methylpropoxy)phenyl]methyl}-1,5-dihydro-2,4-benzodiazepine-3-one:

Prepared according to the method in 1.9 of Example 1, 0.13 g (yield 88.7%) of colorless oil was obtained.

Preparation of 14.7(3R,4R)-8-fluoro-2-(1-methyl-3-fluoropiperidin-4-yl)-4-{[4-(2-methylpropoxy)phenyl]methyl}-1,5-dihydro-2,4-benzodiazepine-3-one:

The racemic mixture was prepared according to the experimental method in 3.7 of Example 3, and then 18.1 mg (yield 17.03%) of yellow solid was obtained by Flash-Prep-HPLC. ^¹H NMR (400 MHz, Methanol- _d4 ) δ 7.23–7.18 (m, 2H), 7.13 (dd, J = 9.0, 2.6 Hz, 1H), 7.00 (dd, J = 8.4, 5.5 Hz, 1H), 6.93 (td, J = 8.6, 2.6 Hz, 1H), 6.88–6.84 (m, 2H), 4.85–4.77 (m, 1H), 4.71 (d, J = 9.0, 2.6 Hz, 1H), δ ... 5.1Hz, 1H), 4.59-4.40 (m, 5H), 4.35-4.21 (m, 2H), 3.74 (d, J=6.5Hz, 2H), 3.26 (dt, J=10.5, 5.3Hz, 0H), 2.982.84 (m, 1H), 2.38 (s, 3H), 2.221.90 (m, 4H), 1.87 1.71 (m, 1H), 1.04 (d, J=6.7Hz, 6H); LCMS (ES, m/z): 458[M+H] ⁺ .

Example 15: Preparation of (3S,4R)-8-fluoro-2-(1-methyl-3-fluoropiperidin-4-yl)-4-{[4-(2-methylpropoxy)phenyl]methyl}-1,5-dihydro-2,4-benzadiazine-3-one (A19014-0A):

84 mg (yield 74.25%) of colorless oil was prepared according to the experimental method in Example 14. ^¹H NMR (400 MHz, Methanol- _d⁴ ) δ 7.22 (d, J = 8.5 Hz, 2H), 7.07 (dd, J = 9.1, 2.7 Hz, 1H), 7.01 (dd, J = 8.4, 5.5 Hz, 1H), 6.93 (td, J = 8.6, 2.7 Hz, 1H), 6.89–6.84 (m, 2H), 4.80–4.19 (m, 8H), 3.74 (d, J = 6.5 Hz) , 2H), 3.24-3.11 (m, 1H), 3.03 (d, J=11.5Hz, 1H), 2.49-2.17 (m, 6H), 2.06 (dt, J=13 .3, 6.6Hz, 1H), 1.60 (d, J=12.4Hz, 1H), 1.09-0.99 (m, 6H); LCMS (ES, m/z): 458[M+H] ⁺ .

Example 16: Preparation of 7,8-difluoro-2-(4-isobutoxybenzyl)-4-(1-methylpiperidin-4-yl)-1,2,4,5-tetrahydro-3H-benzo[e][1,3]diaza-3-one (A20001):

51.9 mg of a white solid was prepared according to the experimental method in Example 1. ^¹H NMR (400 MHz, Methanol- _d⁴ ) δ 7.34 (dd, J = 10.0, 8.4 Hz, 1H), 7.20 (d, J = 8.4 Hz, 2H), 6.92 (dd, J = 10.0, 8.4 Hz, 1H), 6.90–6.82 (m, 2H), 4.47 (d, J = 14.0 Hz, 4H), 4.36 (s, 2H), 4.40–4.28 (m, 1H), 3.73 (d, J = 6.5 Hz, 2H), 3.60 (d, J = 12.2 Hz, 2H). Hz, 2H), 3.21-3.11 (m, 2H), 2.90 (s, 3H), 2.35 (dd, J=13.5, 3.8Hz, 1H), 2.29 (dd, J=13.1, 3.8Hz, 1H) , 2.05 (hept, J=6.7Hz, 1H), 1.94 (d, J=13.6Hz, 2H), 1.04 (d, J=6.7Hz, 6H). LCMS (ES, m/z): 458[M+H] ⁺ .

Example 17: Preparation of 6-fluoro-N-(1-methylpiperidin-4-yl)-2-[[4-(2-methylpropoxy)phenyl]methyl]-3-oxoimidazol[1,5-a]pyridine-8-carboxamide (A19016):

308 mg of a red solid was prepared according to the experimental method in Example 14. ^¹H NMR (400 MHz, DMSO- _d₆ ) δ 8.33 (d, J = 7.7 Hz, 1H), 7.76 (ddd, J = 4.1, 1.9, 0.9 Hz, 1H), 7.29–7.17 (m, 2H), 7.10 (dd, J = 8.6, 1.9 Hz, 1H), 7.06 (d, J = 0.9 Hz, 1H), 6.94–6.83 (m, 2H), 4.91 (s, 2H), 3.72 (d, J = 6.5 Hz). z, 2H), 3.69-3.56 (m, 1H), 2.78-2.71 (m, 2H), 2.15 (s, 3H), 2.06-1.86 (m, 3H), 1.73 (d, J=1 2.5Hz, 2H), 1.51 (qt, J=12.0, 6.0Hz, 2H), 0.96 (d, J=6.7Hz, 6H). LCMS (ES, m/z): 455[M+H] ⁺ .

Example 18: Preparation of 7-fluoro-2-[[4-(2-hydroxy-2-methylpropyl)phenyl]methyl]-4-(1-methylpiperidin-4-yl)-1,5-dihydro-2,4-benzodiazepine-3-one (A19010):

Synthesis route:

18.1 Preparation of benzyl 4-[4-[(4-bromophenyl)methyl]-8-fluoro-3-oxo-1,5-dihydro-2,4-benzodiazepine-2-yl]piperidine-1-carboxylic acid ester

Prepared according to the method in Example 4, 1g of light yellow oil was obtained.

18.2 Preparation of 4-[4-([4-[(E)-2-ethoxyvinyl]phenyl]methyl)-8-fluoro-3-oxo-1,5-dihydro-2,4-benzodiazepine-2-yl]piperidine-1-carboxylic acid ester

Add 4-[4-[(4-bromophenyl)methyl]-8-fluoro-3-oxo-1,5-dihydro-2,4-benzodiazepine-2-yl]piperidine-1-carboxylate (1.00 g, 1.765 mmol), 2-[(E)-2-ethoxyvinyl]-4,4,5,5-tetramethyl-1,3,2-dioxacyclopentane (0.70 _g , 3.531 mmol), dioxane (10.00 mL), water (2.00 mg), and _K₃PO₄ (1.12 g, 5.296 mmol) to a 100 mL three-necked flask. Stir the resulting solution at 25 °C for 10 minutes. Add Pd(dppf) _{Cl₂CH₂Cl₂} (0.14 g, 0.177 mmol ₎ to the solution and heat to 100 °C for ₂ hours. After the reaction was complete, water was added to quench the reaction, and the mixture was extracted with ethyl acetate (3 x 20 mL). The organic phase was washed with 1 N hydrochloric acid solution (2 x 20 mL), then with saturated brine (2 x 20 mL). The organic phase was dried with anhydrous sodium sulfate, the solvent was removed by pressure evaporation, and the mixture was purified by column chromatography (EA:PE = 1:30) to give 400 mg of compound 4-[4-([4-[(E)-2-ethoxyvinyl]phenyl]methyl)-8-fluoro-3-oxo-1,5-dihydro-2,4-benzodiazepine-2-yl]piperidine-1-carboxylic acid ester, with a yield of 40.63%, as a brown oil.

18.3 Preparation of 4-(8-fluoro-3-oxo-4-[[4-(2-oxoethyl)phenyl]methyl]-1,5-dihydro-2,4-benzodiazepine-2-yl)piperidine-1-carboxylic acid benzyl ester

Add 4-[4-([4-[(E)-2-ethoxyvinyl]phenyl]methyl)-8-fluoro-3-oxo-1,5-dihydro-2,4-benzodiazepine-2-yl]piperidine-1-carboxylic acid ester (200.00 mg, 0.359 mmol), tetrahydrofuran (2.00 mL), and HCl (6 M) (2.00 mL) to a 50 mL three-necked flask, and stir at 25 °C for 2 hours. After the reaction was complete, the reaction was quenched with water, extracted with methyl tert-butyl ether (3 x 10 mL), the organic phase was washed with 30 mL of saturated brine, dried with anhydrous sodium sulfate, and the solvent was removed by vacuum distillation to give 200 mg of benzyl 4-(8-fluoro-3-oxo-4-[[4-(2-oxoethyl)phenyl]methyl]-1,5-dihydro-2,4-benzodiazepine-2-yl)piperidine-1-carboxylic acid ester, yield 105.30%, as a yellow oil.

Preparation of 18.4 benzyl-4-(8-fluoro-4-[[4-(2-hydroxypropyl)phenyl]methyl]-3-oxo-1,5-dihydro-2,4-benzodiazepine-2-yl)piperidine-1-carboxylic acid ester

Add 200.00 mg (0.378 mmol) of 4-(8-fluoro-3-oxo-4-[[4-(2-oxoethyl)phenyl]methyl]-1,5-dihydro-2,4-benzodiazepine-2-yl)piperidin-1-carboxylic acid benzyl ester and 3.00 mL of tetrahydrofuran to a 50 mL three-necked flask, cool to 0 °C and stir for 5 minutes. Then add 180.12 mg (1.511 mmol) of bromo(methyl)magnesium and heat to 60 °C and react for 2 hours. After the reaction was complete, the reaction was quenched with _NH4Cl solution, extracted with ethyl acetate (3 x 20 mL), the organic phase was washed with 20 mL of saturated brine, dried with anhydrous sodium sulfate, and the solvent was removed by vacuum distillation to give 200 mg of benzyl-4-(8-fluoro-4-[[4-(2-hydroxypropyl)phenyl]methyl]-3-oxo-1,5-dihydro-2,4-benzodiazepine-2-yl)piperidine-1-carboxylic acid ester, yield 97.06%, as a yellow oil.

18.5 Preparation of 4-(8-fluoro-3-oxo-4-[[4-(2-oxopropyl)phenyl]methyl]-1,5-dihydro-2,4-benzodiazepine-2-yl)piperidine-1-carboxylic acid ester

Add benzyl-4-(8-fluoro-4-[[4-(2-hydroxypropyl)phenyl]methyl]-3-oxo-1,5-dihydro-2,4-benzodiazepine-2-yl)piperidine-1-carboxylic acid ester (200.00 mg, 0.367 mmol) and dichloromethane (20.00 mL) to a 50 mL three-necked flask, respectively. Under nitrogen protection, cool to 0 °C and stir for 5 minutes. Then add DMP (310.92 mg, 0.733 mmol) and stir the mixture at 25 °C for 3 hours. After the reaction was complete, _NaHCO3 solution was added to quench the reaction, and the mixture was extracted with dichloromethane (3 x 20 mL). The organic phase was washed with saturated brine, dried with anhydrous sodium sulfate, and the solvent was removed by vacuum evaporation to give 180 mg of compound 4-(8-fluoro-3-oxo-4-[[4-(2-oxopropyl)phenyl]methyl]-1,5-dihydro-2,4-benzodiazepine-2-yl)piperidine-1-carboxylic acid ester, with a yield of 90.33%, as a yellow oil.

Preparation of 18,6-benzyl-4-(8-fluoro-4-[[4-(2-hydroxy-2-methylpropyl)phenyl]methyl]-3-oxo-1,5-dihydro-2,4-benzodiazepine-2-yl)piperidine-1-carboxylic acid ester

Add 4-(8-fluoro-3-oxo-4-[[4-(2-oxopropyl)phenyl]methyl]-1,5-dihydro-2,4-benzodiazepine-2-yl)piperidine-1-carboxylic acid ester (150.00 mg, 0.276 mmol), tetrahydrofuran (5.00 mL, 0.069 mmol), and MeMgBr (2.00 mL, 0.017 mmol) to a 50 mL three-necked flask, respectively, under nitrogen protection, and heat to 60 °C for 3 hours. After the reaction was complete, the reaction was quenched with _NH4Cl solution, extracted with ethyl acetate (3 x 10 mL), the organic phase was washed with 10 mL of saturated brine, dried with anhydrous sodium sulfate, and the solvent was removed under reduced pressure to give 140 mg of benzyl-4-(8-fluoro-4-[[4-(2-hydroxy-2-methylpropyl)phenyl]methyl]-3-oxo-1,5-dihydro-2,4-benzodiazepine-2-yl)piperidine-1-carboxylic acid ester, yield 90.66%, as a yellow oil.

18.7 Preparation of 7-fluoro-2-[[4-(2-hydroxy-2-methylpropyl)phenyl]methyl]-4-(1-methylpiperidin-4-yl)-1,5-dihydro-2,4-benzodiazepine-3-one

Add benzyl-4-(8-fluoro-4-[[4-(2-hydroxy-2-methylpropyl)phenyl]methyl]-3-oxo-1,5-dihydro-2,4-benzodiazepine-2-yl)piperidine-1-carboxylic acid ester (150.00 mg, 0.268 mmol), methanol (10.00 mL, 246.989 mmol), formaldehyde (2.00 mL, 0.067 mmol), and Pd(OH) _₂ to a 100 mL three-necked flask, respectively. /C (20.00 mg, 0.142 mmol), hydrogen gas was introduced into the reaction system, and the mixture was stirred at 25 °C for 5 hours. The reaction was quenched with water, extracted with ethyl acetate (3 x 10 mL), washed with 10 mL of saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The mixture was purified by column chromatography (DCM:MeOH = 30:1) to give 45 mg of compound 7-fluoro-2-[[4-(2-hydroxy-2-methylpropyl)phenyl]methyl]-4-(1-methylpiperidin-4-yl)-1,5-dihydro-2,4-benzodiazepine-3-one, yield 38.19%, as a yellow oil. ^¹H NMR (400 MHz, methanol-d4 ₎ )δ8.48 (s, 1H, FA), 7.10-6.98 (m, 4H), 6.93 (td, J=8.6, 2.7Hz, 1H), 6.58 (d, 2H), 4.42 (s, 4H), 4.36 (s, 2H), 4.30-4.18 (m, 1H), 3.46-3.39 (m, 2 H), 2.96-2.83 (m, 4H), 2.77 (s, 3H), 2.25-2.05 (m, 2H), 1.96-1.84 (m, 3H), 1.36-1.30 (m, 1H), 0.99 (d, J=6.6Hz, 6H). LCMS (ES, m/z): 400[M+H] ⁺ .

Example 19: Preparation of 4-[(4-cyclopropoxyphenyl)methyl]-7-fluoro-2-(1-methylpiperidin-4-yl)-1,5-dihydro-2,4-benzodiazepine-3-one (A19022):

9.5 mg of a white solid was prepared according to the experimental method described in Example 2. ^¹H -NMR (400 MHz, Chloroform-d): δ 7.25 (d, J = 8.5 Hz, 2H), 7.15 (t, J = 7.0 Hz, 1H), 7.04–6.97 (m, 2H), 6.90 (td, J = 8.4, 2.6 Hz, 1H), 6.65 (dd, J = 9.1, 2.6 Hz, 1H), 4.45 (s, 2H), 4.40 (s, 2H), 4.25 (s, 3H), 3.74 (p, J=4.5Hz, 1H), 3.03 (s, 2H), 2.42-2.38 (m, 3H), 2.22 (s, 2H ), 1.99 (s, 2H), 1.73 (d, J = 12.5Hz, 2H), 0.78 (d, J = 4.5Hz, 4H). LCMS (ES, m/z): 424 [M+1] ⁺ .

Pharmacological Examples:

Example 20: In vitro receptor binding experiment

Experimental methods

1. Preparation of solutions required for the experiment

A: (For the preparation of 5-HT _2C receptor membrane): 50mM Tris-HCl buffer: Dissolve 96.8g of Tris in double-distilled water to a total volume of 4000ml, adjust the pH to 7.5 with HCl, and dilute to 16000mL, pH=7.4.

B: (For the preparation of 5-HT _2A receptor membrane): Weigh 11.7 mg EDTA and 380.84 mg _MgCl₂ , add 50 mM Tris-HCl buffer to a total volume of 400 mL, and adjust the pH to 7.4. The final concentrations are 0.1 mM EDTA and ₁₀ mM MgCl₂.

C: (For preparing the Dopamine receptor membrane): Weigh 2.978g HEPES, 1.17g NaCl, 0.119g MgCl₂, _and 36.5mg EDTA and add them to 250ml of pure water. Adjust the pH to 7.4. The final concentrations are 50mM HEPES, 50mM NaCl, 5mM _MgCl₂ , and 0.5mM EDTA, with a pH of 7.4.

2. Preparation of receptor membrane

1) Preparation of CHO-5-HT _2A receptor membrane

CHO-5-HT _2A cells were removed from the -80°C freezer and thawed naturally. They were then centrifuged at 2000g at 4°C for 15 minutes. The pellet was collected, and the supernatant was discarded. Solution B was added to the pellet. The cells were mixed for 20-30 seconds, then centrifuged at 50000g at 4°C for 25 minutes. The supernatant was carefully discarded, and solution B was added again and mixed. The pellet was then centrifuged at 50000g at 4°C for 25 minutes. The pellet was stored at -80°C.

2) Preparation of 5-HT _2C membrane

Remove the rat skin from the -80℃ freezer and thaw naturally. Add solution A and homogenize at speed 4 for 3-4 seconds. Repeat the homogenization process 4 times. Centrifuge at 50000g and 4℃ for 25 minutes. Discard the supernatant. Add solution A again and mix with a vortex mixer. Centrifuge at 50000g and 4℃ for 25 minutes. Repeat the centrifugation process twice. After centrifugation, discard the supernatant and store the precipitate at -80℃ for later use.

3) Preparation of CHO- _D2 receptor membrane

After the CHO- _D2 cells were taken out of the -80℃ freezer and thawed naturally, they were centrifuged at 2000g for 15min. The precipitate was added to homogenate buffer C and mixed with a vortex mixer. The precipitate was centrifuged at 50000g at 4℃ for 25min. The supernatant was discarded, the precipitate was collected, and it was washed and resuspended with buffer C and centrifuged again. After centrifugation, the supernatant was discarded, and the precipitate was stored at -80℃ for later use.

3. Receptor competition binding experiment

1) 5-HT _2A receptor competitive binding assay

Step 1: First, prepare a 10 mg/mL membrane suspension using homogenizing solution B.

Step 2: Add 100 μL of the membrane preparation to each reaction tube.

Step 3: Add 100 μL of solution B to the total binding tube (TB), add 100 μL of Methysergide (final concentration 1.0 × ^10⁻⁵ M) to the nonspecific binding tube (NB), and add 100 μL of the test compound to each test compound tube (CB).

Step 4: Add 10 μL of radioactive ligand ^3H -Ketanserin to each reaction tube to a final concentration of 2.98 nM.

Step 5: Incubate each reaction tube at 37°C for 25 minutes. After the reaction is complete, the bound ligands are rapidly filtered under reduced pressure. Whatman test paper GF/C plate was soaked in 0.5% PEI for more than 1 hour before filtration. After filtration, the filter membrane is dried at 60°C. After attaching the bottom membrane, add 40 μL of scintillation solution, seal the top membrane, and let it stand.

Step 6: Place the scintillation cup into the liquid scintillation counter for counting.

2) 5-HT _2C receptor competitive binding assay

Step 1: First, prepare the membrane into a 210 mg/mL membrane suspension using homogenizing solution B for later use.

Step 2: Add 100 μL of the membrane preparation to each reaction tube.

Step 3: Add 100 μL of solution B to the total binding tube (TB), add 100 μL of Ketanserin (final concentration 1.0 × ^10⁻⁵ M) to the nonspecific binding tube (NB), and add 100 μL of the test compound to each test compound tube (CB).

Step 4: Add 10 μL of radioactive ligand ^3H -Mesulergine to each reaction tube, to a final concentration of 3 nM.

Step 5: Incubate each reaction tube at 37°C for 25 minutes. After the reaction is complete, the bound ligands are rapidly filtered under reduced pressure. The Whatman test strip GF/C is saturated with 0.5% PEI solution 1 hour in advance, and thoroughly washed with ice-cold Tris buffer. The filter is then placed in a 4 mL scintillation cup, 1 mL of toluene scintillation solution is added and mixed well.

Step 6: Place the scintillation cup into the liquid scintillation counter for counting.

3) CHO- _D2 receptor competitive binding assay

Step 1: First, prepare the membrane into a suspension of 8 mg/mL membrane using homogenizing solution C for later use.

Step 2: Add 100 μL of the membrane preparation to each reaction tube.

Step 3: Add 100 μL of C solution to the total binding tube (TB), add 100 μL of Haloperidol (final concentration 1.0 × ^10⁻⁵ M) to the nonspecific binding tube (NB), and add 100 μL of the test compound to each test compound binding tube (CB).

Step 4: Add 10 μL of radioactive ligand ^3H -Spiperone to each reaction tube, to a final concentration of 1.176 nM.

Step 5: Incubate each reaction tube at 37°C for 25 minutes. After the reaction is complete, the bound ligands are rapidly filtered under reduced pressure. Whatman test paper GF/B plate was soaked in 0.5% PEI for more than 1 hour before filtration. After filtration, the filter membrane is dried at 60°C. After attaching the bottom membrane, add 40 μL of scintillation solution, seal the top membrane, and let it stand.

Step 6: Place the filter plate into the liquid scintillation counter for counting.

4. Experimental Results

Pimosserin has Ki values of 0.036 and 2.94 nM for 5-HT _2A and 5-HT _2C receptors, respectively. Compound NH-K-A19016-OA has Ki values of 0.002 and 26.1 nM for 5-HT _2A and 5-HT _2C receptors, respectively, which are superior to piperasserin. Compound NH-K-A19001 has Ki values of 0.028 and 2.4 nM for 5-HT _2A and 5-HT _2C receptors, respectively, which are also superior to piperasserin. Compound NH-K-A19005 has Ki values of 0.429 and 3.39 nM for 5-HT _2A and 5-HT _2C receptors, respectively, which are at the same level as piperasserin. See the table below for details.

Table 1

compound <![CDATA[5-HT_2A(Ki value, nM)]]> <![CDATA[5-HT_2C(Ki value, nM)]]> 2C/2A NH-K-A19001 0.028 2.4 86.327 NH-K-A19005 0.429 3.39 7.907 NH-K-A19006 0.277 1.621 5.856 NH-K-A19007 2.721 27.32 10.040 NH-K-A19008 5.294 42.35 7.999 NH-K-A19009 2.994 2.03 0.679 NH-K-A19011 12.699 - - NH-K-A19012 0.947 9.363 9.882 NH-K-A19013 9.775 - - NH-K-A19014 4.187 0.20 0.049 NH-K-A19015 1.690 0.41 0.241 NH-K-A19017 1.626 4858 298.694 NH-K-A19019 53.312 - - NH-K-A19020 1.740 - - NH-K-A19016-0A 0.002 26.10 16029.47 NH-K-A20001 5.98 - - NH-K-A19010 20.05 18.23 0.91 NH-K-A19022 0.15 1.33 8.76 Piperazine 0.036 2.94 81.667

Example 21: In vitro hERG experiment

1. Compound preparation

a. Dilute the test compound stock solution sequentially to 0.3 mM, 1 mM and 3 mM diluents using DMSO.

b. Dilute the stock solution of the test compound with extracellular fluid to obtain working solutions of the test compound with concentrations of 0.3 μM, 1 μM, 3 μM, 10 μM and 30 μM. Sonicate all working solutions of the test compound for 20 min.

c. Prepare a 10.113 mM stock solution by dissolving 10 mg of cisapride (a positive compound in the system) in 200 2.42 μL of dimethyl sulfoxide (DMSO).

d. The cisapride stock solution was successively diluted with dimethyl sulfoxide (DMSO) to 1 μM, 10 μM, 100 μM and 1 mM.

e. Take 10 μL of each concentration and add it to 10 mL of extracellular fluid, ensuring that the DMSO concentration is 0.1%.

f. The final working solution concentrations of cisapride are 1 nM, 10 nM, 100 nM, and 1000 nM.

g. No visible precipitate was observed when all working solution concentrations were tested with the naked eye.

2. Cell line information

In this experiment, we used the HEK-293 cell line, which stably expresses the hERG potassium channel, for experimental detection.

HEK-293 cell lines stably expressing hERG potassium channels were cultured in DMEM medium containing 10% fetal bovine serum and 0.8 mg/mL G418 at 37 °C and 5% carbon dioxide.

Cell passage: Remove the old culture medium and wash once with PBS, then add 0.5 mL of TrypLE ^™ Express solution and incubate at 37°C for 1 minute. When the cells detach from the bottom of the dish, add 3 mL of preheated (37°C) complete culture medium. Gently pipette the cell suspension to separate aggregated cells. Transfer the cell suspension to a sterile centrifuge tube and centrifuge at 300G for 5 minutes to collect the cells. Seed the cells in 6 cm cell culture dishes at a seeding density of 1* ^10⁵ cells per dish (final volume: 5 mL) for expansion or maintenance culture.

For patch-clamp assays, seed 5 x 10^ ³ cells onto a coverslip and incubate in a 24-well plate (final volume: 500 μL). Perform assays after 18 hours.

To maintain the electrophysiological activity of cells, the cell density must not exceed 80%.

3. Patch clamp testing

Under an inverted microscope, a glass electrode micromanipulator (micromanipulation) is used to bring the recording electrode into contact with the cell, and then negative pressure is applied to promote the formation of GΩ seals. After GΩ seals are formed, rapid capacitance compensation is performed, and then negative pressure is continuously applied to rupture the cell membrane, thus establishing whole-cell recording mode. In whole-cell recording mode, slow capacitance compensation is performed, and the values of membrane capacitance and series resistance are recorded.

The voltage stimulation protocol for cellular hERG potassium current is as follows: the cell membrane clamp voltage is -80mV, then depolarized from -80mV to +30mV and maintained for 2.5 seconds, then rapidly maintained at -50mV for 4 seconds to excite the tail current of the hERG channel. Data is collected repeatedly every 10 seconds. Leakage current is detected using -50mV.

Coverslips containing seeded cells were placed in the recording chamber of an inverted microscope. Negative controls and test compounds were applied to the cells via gravity perfusion, increasing in concentration sequentially. A vacuum pump continuously circulated the external solution during recording. The current detected in each negative control cell served as the cell's control group. Each drug concentration was applied for 5 minutes or until the current stabilized. All experiments were performed at room temperature. 4. Data Analysis

First, standardize the current after each drug concentration, then calculate the corresponding inhibition rate. For each concentration, calculate the basic statistics, including the mean, standard deviation (SD), standard error (SE), and number of replicates (n). Fit the dose-dependent curve using the following equation and calculate the half-maximal inhibitory concentration ( _IC50 ) of the test compound:

Where C represents the concentration of the test compound, _IC50 represents the half-inhibitory concentration, and h represents the Hill coefficient. Curve fitting and _IC50 calculation were performed using GraphPad Prism 5.0 software.

5. Experimental Results

The hERG IC50 of piperoxide was 208 nM, while the hERG IC50s of NH-K-A19001, NH-K-A19005, and NH-K-A19006 were 206, 3173, and 1194 nM, respectively. These three compounds showed lower cardiotoxicity than piperoxide, suggesting that the compounds of this invention have lower cardiotoxicity compared to piperoxide. The results are shown in the table below.

Table 2

compound hERG(nM) NH-K-A19001 260 NH-K-A19005 3173 NH-K-A19006 1194 Piperazine 208

Example 22: Animal Experiment

1. Test Methods

1.1 Effects of MPTP+MK-801 on a mouse model of Parkinson's disease (anti-PDP efficacy model)

Animals received intraperitoneal injections of different doses of MPTP every morning for 5 consecutive days. On the morning of the 5th day, 1.5 hours after the MPTP injection, they were given an intraperitoneal injection of piperazine or normal saline (NS). 0.5 hours later, they were given an intraperitoneal injection of MK-801 0.3 mg/kg (or NS). 0.25 hours later, the mice were placed in a self-activation box (a black polyethylene box measuring 29cm×29cm×30cm) for 20 minutes of video recording. After the recording, the video was analyzed to evaluate the mice's activity.

1.2 Effects on MPTP+APO-induced climbing behavior in male mice (DA motor deterioration model)

Animals received intraperitoneal injections of different doses of MPTP every morning for 5 consecutive days. On the morning of the 5th day, 1.5 hours after the MPTP injection, they were given intraperitoneal injections of piperazine, clozapine, quetiapine, or normal saline. 0.5 hours later, they were given subcutaneous injections of 1 mg/kg APO (administration volume 0.1 ml/10 g body weight). Immediately after the subcutaneous injection, the animals were placed in a climbing cage (the climbing cage was self-made by our company, a cylindrical cage with a diameter of 13 cm and a height of 15 cm, made of stainless steel wire mesh with a diameter of about 0.1 cm, a semi-transparent polyethylene plate bottom, and a stainless steel lid). Their behavior was observed and scored at 10-11, 20-21, and 30-31 minutes after the APO injection.

The scoring criteria are as follows: 0 points for all four legs on the floor; 1 point for both front legs on the net cage; and 2 points for all four legs on the net cage.

1.3 Experiment on the effects of sedation (anti-sedation model)

Qualified SPF-grade C57BL/6j mice were randomly divided into 13 groups of 8 mice each: blank control group, piperciserine, NH-K-A1900, NH-K-A19005, and NH-K-A19006. Different concentration solutions were prepared for intraperitoneal injection according to different dosages for each group, with a final administration volume of 10 ml/kg.

Forty-five minutes after administration of compounds such as piperazine, spontaneous activity was monitored in all groups. Movement was recorded via video from 0 to 20 minutes, and the distance traveled in the 20-minute period was analyzed using Top Scan 3.00 software. The inhibition rate of each group relative to the control group was calculated, and the sedative effect of the compounds was comprehensively evaluated based on statistical findings.

1.4 Test Results

Experiments showed that the PDP efficacy, sedation, and exercise-induced exacerbation ED50 of piperaserin were 0.37 mg/kg, 6.79 mg/kg, and >30 mg/kg, respectively, with a sedation/PDP efficacy ratio of 18.35 and an exercise-induced exacerbation/PDP efficacy ratio of >81.08. The PDP efficacy and sedation ED50 of NH-K-A19001 were 0.33 mg/kg and 3.74 mg/kg, respectively, with a sedation/PDP efficacy ratio of 11.33. The PDP efficacy of NH-K-A19005 was 1.85 mg/kg. The PDP efficacy and sedation ED50 of NH-K-A19006 were 0.31 mg/kg and 11.9 mg/kg, respectively. Therefore, the efficacy of NH-K-A19001 and NH-K-A19006 is comparable to that of piperaserin. The effective dose of NH-K-A19005PDP is slightly higher than that of piperaserin. Furthermore, the compounds of this invention (e.g., NH-K-A19001, NH-K-A19005, and NH-K-A190016) do not possess a dopamine (DA) mechanism of action, and no motor deterioration was observed.

Table 3

Example 23: In vitro and in vivo experimental methods and data for the A01 series compounds of the Pyrmethrin project

1. Mouse head-shaking test

1.1 Test Methods

Mice were stratified by body weight and randomly divided into a model control group, a blank control group, and each drug-treated group. One hour after gavage administration of the solvent or drug, the animals were placed in beakers (13 cm in diameter and 19 cm in height) lined with fresh bedding and intraperitoneally injected with the modeling drug DOI ((±)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride, (±)-2,5-dimethoxy-4-iodophenylpropanamine hydrochloride). The number of head-shaking behaviors was recorded within 0-20 minutes after intraperitoneal injection of DOI. Head-shaking behavior was defined as rapid, rotating twitching or wet-dog-like shaking of the mouse's head, which was to be distinguished from normal grooming or exploratory behavior.

1.2 Experimental Data

The results of this experiment show that the ED50 of piperaserin in inhibiting DOI-induced head-shaking behavior in mice was 0.39 mg/kg, and the ED50s of NH-K-A19001, NH-K-A19005, NH-K-A19006, and NH-K-A19012 in inhibiting MK-801-induced hyperactivity behavior in mice were 0.06, 0.15, 0.012, and 0.30 mg/kg, respectively. This suggests that the compounds of this invention have better antipsychotic effects and superior efficacy. Detailed results are shown in the table below.

Table 4. ED50 values of compounds such as piperoserine for inhibiting DOI-induced head-shaking behavior in mice.

compound ED50 (mg/kg) Piperazine 0.39 NH-K-A19001 0.06 NH-K-A19005 0.15 NH-K-A19006 0.012 NH-K-A19012 0.30

Note: ED50 is the half effective dose.

2. MK-801-induced hyperactivity test in mice

2.1 Test Methods

Mice were stratified by body weight and randomly divided into a model control group, a blank control group, and each drug-treated group. After administration of the test substance (or control substance), the mice were placed in a self-adaptation box (a black polyethylene box with dimensions of 29cm×29cm×30cm) for acclimatization. One hour after gavage administration, 0.3mg/kg of MK-801 was injected intraperitoneally. The mice were then placed in the self-adaptation box for video recording for 60 minutes. After the recording, the video was analyzed to evaluate the mice's activity.

2.2 Test Results

The results of this experiment show that the ED50 of piperaserin in inhibiting MK-801-induced hyperactivity in mice was 3.288 mg/kg, while the ED50s of NH-K-A19005, NH-K-A19006, and NH-K-A19012 in inhibiting MK-801-induced hyperactivity in mice were 1.01, 0.2648, and 3.728 mg/kg, respectively. This suggests that the compounds of this invention have better antipsychotic effects and superior efficacy. Detailed results are shown in the table below.

Table 5. ED50 values of compounds such as piperoserine that inhibit MK-801-induced hyperactivity in mice.

compound ED50 (mg/kg) Piperazine 3.288 NH-K-A19005 1.01 NH-K-A19006 0.2648 NH-K-A19012 3.728

Note: ED50 is the half effective dose.

3. Effects of DOI ((±)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride, (±)-2,5-dimethoxy-4-iodophenylpropanamine hydrochloride) on PPI-induced damage in rats

3.1 Test Methods

Intervention test:

Animals were administered the drug via gavage (or solvent) 30 minutes later, and then 30 minutes later, 0.5 mg/kg of DOI was injected subcutaneously into the neck, which is 60 minutes after gavage administration. The rats were then placed in a shock reflex test chamber for testing.

The experimental method was based on the literature and preliminary experiments. The specific process was as follows: First, there was a 5-minute adaptation period (62 dB background sound). After the adaptation period, five separate shock reflex stimuli were given (block 1, the results of which were not included in the analysis, used to reduce the animals' initial response to a plateau level). Then, four different types of trials were presented (block 2) in a sham-random manner: 1) a separate shock reflex stimulus (pulse-alone, 120 dB, lasting 20 ms); 2) a separate prepulse stimulus 13 dB higher than the background sound (prepulse-alone, 75 dB, lasting 20 ms); 3) a combined prepulse and shock reflex stimulus (prepulse + pulse, each lasting 20 ms, with a 100 ms interval between them); 4) a no-stimulus trial with only background sound. Each trial was presented five times, with an average interval of 20 s (10-30 s) between each trial.

The amplitude of the response to a single shock reflex stimulus or a pre-pulse combined with a shock reflex stimulus is expressed as the AVG (instrument-specific unit) value, which indirectly reflects the magnitude of the rat's withdrawal response.

Evaluation index: PPI% = (1 - response amplitude of pre-pulse combined shock reflex stimulus / response amplitude of shock reflex stimulus alone) × 100. The higher the value, the deeper the inhibition.

Drug administration test:

For all the animals in the above groups, the 0.5 mg/kg DOI was replaced with normal saline (NS), and all other procedures, including drug administration and testing, were the same as those in the intervention test.

3.2 Experimental Results

PPI (Prognostic Inhibition Point) refers to the inhibitory effect of a weak stimulus occurring 30–500 ms prior to a strong shock reflex stimulus on the shock reflex. Studies have shown that the neural nuclei and pharmacological mechanisms regulating PPI in humans and rodents are very similar, making it a cross-species behavioral indicator. Clinical studies have also found impaired PPI in patients with schizophrenia, and some antipsychotic drugs have a mitigating effect. Based on these characteristics, this model is widely used to study the pathogenesis of schizophrenia and the pharmacological effects of antipsychotic drugs, and also serves as a tool for screening antipsychotics, especially for predicting the efficacy of treatments for negative symptoms and cognitive deficits in schizophrenia.

In this experiment, administration of DOI 0.5 mg/kg to rats significantly disrupted PPI (P < 0.05), while NH-K-A19006 0.3 mg/kg, NH-K-A19005 3 mg/kg, and pimecrolimus 3 mg/kg significantly reversed DOI-induced PPI damage in rats (P < 0.05), as detailed in the table below. In the table, "MEAN" represents the mean, "SD" represents the standard deviation, and "P" represents the p-value. The values in the table indicate the reversal of damage, with larger values indicating greater symptom relief compared to the model group.

This study shows that NH-K-A19006 0.3 mg/kg and NH-K-A19005 3 mg/kg can significantly reverse DOI-induced PPI damage in rats, and no significant effect was observed on normal rats at this dose. This suggests that NH-K-A19005 and NH-K-A19006 are effective for mental illnesses, and are also effective for negative symptoms and cognitive deficits in schizophrenia.

Table 6 Effects of NH-K-A19006 on PPI-induced damage in rats at 0.5 mg/kg DOI

Note: Model group vs. blank group; each drug administration group vs. model group.

Table 7 Effects of piperoxide and NH-K-A19005 on PPI-induced damage in rats at 0.5 mg/kg DOI

Note: Model group vs. blank group; each drug administration group vs. model group.

Table 8 Effects of NH-K-A19006 on PPI in normal rats

Note: Each treatment group vs. the blank group.

Table 9. Effects of piperoserine and NH-K-A19005 on PPI in normal rats.

#imgpt124#

Note: Each treatment group vs. the blank group.

Claims (19)

1. The compound shown in Formula II: Where n2 is an integer from 1 to 3; R1 is selected from C1-C8 straight-chain or branched alkyl, C2-C8 alkenyl and C2-C8 alkynyl, wherein the alkyl, alkenyl and alkynyl are each independently and optionally substituted by substituents selected from halogens and C1-C8 haloalkyl groups. R3 is selected from hydrogen, halogens, and C1-C8 haloalkyl groups; R7 is selected from C1-C8 straight-chain or branched alkyl groups, C3-C10 cycloalkyl groups, and R8 and R9 are each independently selected from C1-C8 straight-chain or branched alkyl groups, wherein the alkyl and cycloalkyl groups are optionally substituted with substituents selected from halogens and C1-C8 haloalkyl groups. Z is selected from C, O, and N; W is selected from C and N. 2. The compound shown in Formula III Where n1 and n2 are integers from 1 to 3; R1 is selected from C1-C8 straight-chain or branched alkyl, C2-C8 alkenyl and C2-C8 alkynyl, wherein the alkyl, alkenyl and alkynyl are optionally substituted by substituents selected from halogens and C1-C8 haloalkyl. R2 is selected from hydrogen, halogens, and C1-C8 haloalkyl groups; R3, R4, R5, and R6 are each independently selected from hydrogen, halogens, and haloalkyl groups; R7 is selected from C1-8 straight-chain or branched alkyl groups, C3-C10 cycloalkyl groups, and R8 and R9 are each independently selected from C1-C8 straight-chain or branched alkyl groups, wherein the alkyl and cycloalkyl groups are optionally substituted with substituents selected from halogens and C1-C8 haloalkyl groups. Z is selected from C, O, and N; Q is N; W can be C or N. 3. The compound of formula II or III according to claim 1 or 2, characterized in that, The C1-C8 straight-chain or branched alkyl group is a C1-C5 straight-chain or branched alkyl group; and/or The C2-C8 alkenyl group is a C2-C5 alkenyl group; and/or The C2-C8 ynyl group is a C2-C5 ynyl group; and/or The C1-C8 haloalkyl group is a C1-C5 haloalkyl group; and/or The C3-C10 cycloalkyl group is a C3-C6 cycloalkyl group. 4. The compound of formula II or III according to claim 1 or 2, characterized in that, The C1-C8 straight-chain or branched alkyl group is a C1-C3 straight-chain or branched alkyl group; and/or The C2-C8 alkenyl group is a C2-C5 alkenyl group; and/or The C2-C8 ynyl group is a C2-C5 ynyl group; and/or The C1-C8 haloalkyl group is a C1-C5 haloalkyl group; and/or The C3-C10 cycloalkyl group is a C3-C6 cycloalkyl group. 5. The compound of formula II or III according to claim 1 or 2, characterized in that, The halogens mentioned are fluorine, chlorine, bromine, and iodine. 6. The compound of formula II or formula III according to claim 3, characterized in that, The C1-C5 straight-chain or branched alkyl groups are selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, and isopentyl. The C3-C6 cycloalkyl group is selected from cyclopropyl, cyclobutyl, and cyclopentyl. 7. The compound of formula II or formula III according to claim 4, wherein the straight-chain or branched alkyl group of C1-C3 is methyl, ethyl, propyl, or isopropyl. 8. The compound of formula II or III according to claim 1 or 2, characterized in that, Z is O. 9. The compound of formula II or formula III according to claim 8, wherein R1 is a C1-C5 straight-chain or branched alkyl group; R2 is selected from hydrogen and halogens; R3, R4, R5, and R6 are each independently selected from hydrogen and halogens; R7 is selected from C1-C5 straight-chain or branched alkyl groups and C3-C6 cycloalkyl groups. 10. The compound represented by Formula III according to claim 2, characterized in that, The compound of formula III is the same as the compound shown in formula I-1: Q is N. 11. The compound of formula I-1 according to claim 10, characterized in that, R1 is a C1-C5 straight-chain or branched alkyl group; R2 is selected from hydrogen and halogens; R3, R4, R5, and R6 are each independently selected from hydrogen and halogens; R7 is selected from C1-C5 straight-chain or branched alkyl groups and C3-C6 cycloalkyl groups. 12. The compound of formula II or formula III according to claim 1 or 2, characterized in that n1 and n2 are integers from 1 to 3; R1 is selected from methyl, ethyl, propyl, and butyl; R2 is selected from hydrogen, fluorine, chlorine, bromine, and iodine; R3, R4, R5, and R6 are selected from hydrogen, fluorine, and chlorine, respectively; R7 is selected from isopropyl, isobutyl, ethyl, propyl, methyl, cyclopropyl, cyclobutyl, Z is selected from C, O, and N; W is selected from C and N; Q is N. 13. The compound of formula II according to claim 1, characterized in that the compound of formula II is as shown in formula V: Where n2 is an integer from 1 to 2; R1 is selected from methyl, ethyl, propyl, and butyl; R3 is selected from hydrogen, fluorine, and chlorine; R7 is selected from isopropyl, isobutyl, ethyl, propyl, methyl, cyclopropyl, cyclobutyl, 14. The compound of formula III according to claim 2, characterized in that, Where n1 and n2 are integers from 1 to 3; R1 is a methyl group; R2 is selected from fluorine and hydrogen; R3, R4, R5, and R6 are selected from hydrogen, fluorine, and chlorine, respectively; R7 is selected from isopropyl, cyclopropyl, isobutyl, methyl, Z is selected from C, O, and N; Q is N; W is selected from C and N. 15. The compound of formula II or formula III as claimed in claim 1 or 2, characterized in that the compound is selected from any one of the following compounds: 16. A pharmaceutical composition characterized by comprising the compound according to any one of claims 1-15, optionally further comprising a pharmaceutically acceptable excipient, carrier, adjuvant, solvent, or combination thereof. 17. The use of the compound according to any one of claims 1-15 or the pharmaceutical composition according to claim 16 in the preparation of a medicament for treating mental disorders. 18. The application according to claim 17, wherein the mental illness is schizophrenia. 19. The application according to claim 17, wherein the mental illness is Parkinson's disease, dementia-related behavioral disorders, and psychosis.