Substituted 1, 2, 4-tetrahydro-3H-benzodiazepine derivative and application thereof

Abstract

The invention relates to a substituted 1, 2, 4-tetrahydro-3H-benzodiazep-3-ketone derivative and an application thereof. The invention belongs to the field of medicine, and particularly relates to a compound shown in a general formula I or pharmaceutically acceptable salt thereof, a pharmaceutical composition containing the compound and application of the compound or the pharmaceutically acceptable salt and the pharmaceutical composition in the field of medicine, and further relates to a method for preparing the compound. # imgabs0 #

Description

[0001] This application claims the priority of Chinese Patent Application No. 2024100656669 with an application date of January 17, 2024, and Chinese Patent Application No. 2024108846163 with an application date of July 3, 2024, the entire contents of which are incorporated herein by reference. Technical Field

[0002] The present invention belongs to the field of medicinal chemistry, and particularly relates to a substituted 1,2,4 - tetrahydro - 3H - benzodiazepine -3 - one derivative, a preparation method thereof, a pharmaceutical composition comprising the substituted 1,2,4 - tetrahydro - 3H - benzodiazepine -3 - one derivative or a pharmaceutical composition thereof, and the use of the substituted 1,2,4 - tetrahydro - 3H - benzodiazepine -3 - one derivative or a pharmaceutical composition thereof in the preparation of a medicament for treating mental diseases. Background Art

[0003] Schizophrenia has a hidden onset and a low admission rate, with a relatively high lifetime prevalence. Currently, the drugs for treating schizophrenia mainly include typical antipsychotic drugs and atypical antipsychotic drugs. However, the current drugs for treating schizophrenia strongly block dopamine receptors, resulting in adverse reactions such as extrapyramidal reactions (EPS), tardive dyskinesia, and increased prolactin. In the medical field, although there are various types of active compounds acting on different targets available for the treatment of sleep disorders, adverse reactions such as addiction, drug resistance, and residual effects are still unsolved problems.

[0004] After the 1960s, a series of new - generation antipsychotics were successively developed, including Ziprasidone, Risperidone, etc., which are called second - generation antipsychotic drugs, namely new antipsychotics. Their affinities for 5 - hydroxytryptamine (5 - HT) receptors (5 - HT 1A , 2A , 2C ) and norepinephrine (NA) receptors (α1, α2) are much higher than those for D2 receptors, resulting in a lower D2 / 5 - HT 2A ratio. Their clinical effects have more advantages. They are not only as effective as traditional antipsychotics for positive symptoms, but also effective for negative symptoms and cognitive deficit symptoms, with a wider spectrum of action. However, these drugs have adverse reactions such as QT - interval prolongation, hyperprolactinemia, and weight gain. Therefore, searching for drugs that are effective for positive, negative symptoms and cognitive impairment of schizophrenia and have fewer side effects is a current research hotspot.

[0005] The serotonin system plays an important role in regulating the functions of the prefrontal cortex (PFC), including emotional control, cognitive behavior, and working memory. Pyramidal neurons and GABA interneurons in the PFC contain several serotonin receptor subtypes 5-HT 1A and 5-HT 2A . Recently, it has been demonstrated that the PFC and NMDA receptor channels are targets of 5-HT 1A R. These two receptors regulate excitatory neurons in the cerebral cortex, thereby affecting cognitive functions. In fact, various preclinical data suggest that 5-HT 1A R may be a new target for the development of antipsychotic drugs. The high affinity of atypical antipsychotics (such as olanzapine, aripiprazole, etc.) for 5-HT 1A R and their low EPS side effects all indicate that the serotonin system plays an important role in regulating the functions of the prefrontal cortex (PFC), including emotional control, cognitive behavior, and working memory. Pyramidal neurons and GABA interneurons in the PFC contain several serotonin receptor subtypes 5-HT 1A and 5-HT 2A .

[0006] Recent studies have shown that 5-HT 1A agonists are related to the treatment of atypical antipsychotics and can improve negative symptoms and cognitive impairment. In the treatment of schizophrenia with the atypical antipsychotic clozapine, it has been found that 5-HT 2A plays a very important role, involving all aspects of perception, emotional regulation, and motor control. Blocking the 5-HT 2A receptor can normalize dopamine release and play an antipsychotic role. In addition, the 5-HT 2C receptor is closely related to weight gain.

[0007] WO2021218863A1 discloses a class of 1,5-dihydro-2,4-benzodiazepine -3-one derivatives effective against positive and negative symptoms of schizophrenia, and its general formula structure is shown as follows: wherein R1 is a straight-chain or branched-chain alkyl, alkenyl, alkynyl, etc. There is still a need in the art for new compounds that can further improve drug half-life, bioavailability, and other drug-forming properties. Summary of the Invention

[0008] The present invention aims to provide a substituted 1,2,4-tetrahydro-3H-benzodiazepine having 5-HT 2A , 5-HT 2C receptor activity -3-ketone derivatives, their stereoisomers or pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof. The compounds and pharmaceutical compositions are effective against both positive and negative symptoms of schizophrenia, can improve cognitive impairment, and can be used to treat schizophrenia or behavioral disorders and psychosis related to Parkinson's disease and dementia. The compounds of the present invention have a suitable half-life, have the advantages of potentially reducing the frequency of drug administration and increasing patient compliance; have a high bioavailability, can reduce the exposure of the drug in the periphery at the effective dose, and reduce the occurrence of peripheral adverse reactions; have less cardiotoxicity and higher safety.

[0009] On the one hand, the present invention provides a compound represented by the general formula I, its stereoisomer or pharmaceutically acceptable salt thereof:

[0010]

[0011] Wherein: each R1 is independently selected from hydrogen, halogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C2-C8 alkenyl and optionally substituted C2-C8 alkynyl; the optional substituent is halogen;

[0012] Each R2 is independently selected from hydrogen, halogen and optionally substituted C1-C8 alkyl; the optional substituent is halogen;

[0013] Each R3 is independently selected from hydrogen, halogen, optionally substituted C1-C8 alkyl and optionally substituted C1-C8 alkoxy; the optional substituent is halogen;

[0014] n is an integer selected from 0-4;

[0015] m is an integer selected from 0-4, preferably 0;

[0016] p is an integer selected from 0-8, preferably 0;

[0017] q is an integer selected from 1-3.

[0018] In a further preferred embodiment of the present invention, the halogen is selected from fluorine, chlorine and bromine, preferably fluorine.

[0019] In one embodiment, each R1 is independently selected from hydrogen, halogen, optionally substituted C1-C5 alkyl and optionally substituted C1-C5 alkoxy; the optional substituent is halogen.

[0020] In one embodiment, each R2 is independently selected from hydrogen, halogen and optionally substituted C1-C5 alkyl; the optional substituent is halogen.

[0021] In one embodiment, each R3 is independently selected from hydrogen, halogen, optionally substituted C1-C5 alkyl, and optionally substituted C1-C5 alkoxy; the optional substituent is halogen.

[0022] In one embodiment, n is selected from integers from 0 to 2, preferably 1.

[0023] In one embodiment, q is selected from integers from 1 to 3, preferably integers from 1 to 2, and more preferably 2.

[0024] In a preferred embodiment, each R1 is independently selected from hydrogen, fluorine, chlorine, bromine, optionally substituted C1-C5 alkyl, and optionally substituted C1-C5 alkoxy; the optional substituent is selected from fluorine and chlorine.

[0025] In a preferred embodiment, each R2 is independently selected from hydrogen, fluorine, chlorine, bromine, and optionally substituted C1-C5 alkyl; the optional substituent is selected from fluorine and chlorine.

[0026] In a preferred embodiment, each R3 is independently selected from hydrogen, fluorine, chlorine, bromine, and optionally substituted C1-C5 alkyl; the optional substituent is selected from fluorine and chlorine.

[0027] In a preferred embodiment, each R1 is independently selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, methoxy, and ethoxy; each R2 is independently selected from hydrogen, fluorine, chlorine, methyl, and ethyl; each R3 is independently selected from hydrogen, fluorine, chlorine, methyl, and ethyl.

[0028] In a particularly preferred embodiment, the compound of formula I, its stereoisomers, or its pharmaceutically acceptable salts are selected from the following compounds:

[0029]

[0030] In a particularly preferred embodiment, the compound of formula I, its stereoisomers, or its pharmaceutically acceptable salts are characterized in that they are selected from the following compounds:

[0031] On the other hand, the present invention provides a pharmaceutical composition comprising a therapeutically effective dose of the compound of formula I, its stereoisomers, or its pharmaceutically acceptable salts, and one or more pharmaceutically acceptable carriers or excipients.

[0032] On the other hand, the present invention provides the use of the compound of formula I, its stereoisomers, or its pharmaceutically acceptable salts, or its pharmaceutical composition in the preparation of a drug for treating mental diseases.

[0033] On the other hand, the present invention provides a method for preventing and / or treating mental diseases, which comprises administering to the mammal a therapeutically effective dose of any of the shown compounds, their stereoisomers or their pharmaceutically acceptable salts, esters, prodrugs, solvates, hydrates or derivatives, or their pharmaceutical compositions.

[0034] In a further preferred embodiment of the present invention, the disease is psychosis.

[0035] In a further preferred embodiment of the present invention, the disease is schizophrenia.

[0036] In a further preferred embodiment of the present invention, the disease is Parkinson's disease, dementia-related behavioral disorders or psychosis.

[0037] Detailed Description of the Invention

[0038] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In case of contradiction, the definitions provided in this application shall prevail. When trade names appear in this text, they are intended to refer to the corresponding products or their active ingredients. All patents, published patent applications and publications cited herein are incorporated herein by reference.

[0039] The term "alkyl" refers to a saturated straight-chain or branched aliphatic hydrocarbon group having 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) carbon atoms, i.e., "C 1-20 alkyl". The alkyl preferably has an alkyl group having 1 to 12 carbon atoms (i.e., C 1-12 alkyl), more preferably an alkyl group having 1 to 8 carbon atoms (i.e., C 1-8 alkyl), still more preferably an alkyl group having 1 to 5 carbon atoms (i.e., C 1-5 alkyl), and most preferably an alkyl group having 1 to 3 carbon atoms (i.e., C 1-3(alkyl). Non-limiting examples include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and their various branched isomers, etc. The alkyl group can be substituted or unsubstituted. When substituted, the substituent can be substituted at any available linking point. The substituent is preferably one or more of the following groups, which are independently selected from deuterium, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, halogen, mercapto, hydroxy, nitro, amino, cyano, carboxyl, oxo, cycloalkyl, heterocyclic group, aryl or heteroaryl. When the alkyl group is substituted by a substituent, the substituent is not further substituted.

[0040] The term "halo" or "halogen" or "halo-substituted" should be understood to mean a fluorine (F), chlorine (Cl), bromine (Br) or iodine (I) atom, preferably selected from fluorine, chlorine and bromine atoms, more preferably a fluorine or chlorine atom.

[0041] The terms "comprising", "including", "having", "containing" or "involving" and their other variant forms herein are inclusive or open-ended and do not exclude other unenumerated elements or method steps. Those skilled in the art should understand that the above terms such as "comprising" cover the meaning of "consisting of".

[0042] The term "one or more" or a similar expression "at least one" can mean, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more.

[0043] When the lower and upper limits of a numerical range are disclosed, any value and any included range falling within the range is specifically disclosed. In particular, each range of values disclosed herein should be understood to mean each value and range encompassed within the broader range.

[0044] The expression mn used herein refers to a range from m to n and a subrange consisting of individual point values therein and individual point values. For example, the expression "C2-C8" or "C 2-8 " covers the range of 2-8 carbon atoms and should be understood to also cover any subranges and each point value therein, such as C2-C5, C3-C4, C2-C6, C3-C6, C4-C6, C4-C7, C4-C8, etc., as well as C2, C3, C4, C5, C6, C7, C8, etc. For example, the expression "C3-C 10 " or "C 3-10 " should also be understood in a similar manner, for example, any sub-ranges and point values contained therein may be included, such as C3-C9, C6-C9, C6-C8, C6-C7, C7-C 10 , C7-C9, C7-C8, C8-C9, etc. and C3, C4, C5, C6, C7, C8, C9, C 10 For example, the expression "C1-C6" or "C 1-6 " covers a range of 1-6 carbon atoms, and should be understood to also cover any sub-ranges and each point value therein, such as C2-C5, C3-C4, C1-C2, C1-C3, C1-C4, C1-C5, C1-C6, etc., as well as C1, C2, C3, C4, C5, C6, etc. For another example, the expression "three-membered to ten-membered" should be understood to cover any sub-ranges and each point value therein, such as three-membered to five-membered, three-membered to six-membered, three-membered to seven-membered, three-membered to eight-membered, four-membered to five-membered, four-membered to six-membered, four-membered to seven-membered, four-membered to eight-membered, five-membered to seven-membered, five-membered to eight-membered, six-membered to seven-membered, six-membered to eight-membered, nine-membered to ten-membered, etc., as well as three, four, five, six, seven, eight, nine, ten-membered, etc. Other similar expressions in this article should also be understood in a similar manner.

[0045] Different expressions such as "X is selected from A, B and C" and "X is A, B or C" used herein all express the same meaning, that is, X can be any one or more of A, B and C.

[0046] The term "optional" or "optionally" means that the event or situation described subsequently may or may not occur, and the description includes the occurrence of the event or situation and the non-occurrence of the event or situation. For example, "cycloalkyl optionally substituted with alkyl" means that alkyl can but does not have to be present, and the description includes the situation that cycloalkyl is substituted with alkyl and the situation that cycloalkyl is not substituted with alkyl.

[0047] The terms "substituted" and "substituent" refer to the replacement of one or more (e.g., one, two, three, or four) hydrogens on the designated atom with a selection from the indicated groups, provided that the normal valence of the designated atom in the current context is not exceeded and the substitution results in a stable compound. Combinations of substituents and / or variables are permitted only if such combinations result in a stable compound. When a particular 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 achieve a stable state. When each carbon atom in a group may optionally be replaced by a heteroatom, the condition is that the normal valence of all atoms in the group in the current context is not exceeded and a stable compound is formed.

[0048] If a substituent is described as "optionally... substituted", the substituent may be unsubstituted or may be substituted. If an atom or group is described as optionally substituted by one or more of a list of substituents, one or more hydrogens on that atom or group may be replaced by independently selected optional substituents. When the substituent is oxo (i.e., =O), it means that two hydrogen atoms are replaced. When the substituent is hydrogen, this may also indicate that the corresponding group is "unsubstituted" or "not substituted". Unless otherwise specified, as used herein, the point of attachment of a substituent may be from any suitable position of the substituent.

[0049] When the bond of a substituent is shown passing through a bond connecting two atoms in a ring, such a substituent may be bonded to any ring-forming atom in the ring that can be substituted.

[0050] When any variable (e.g., R), and variables with subscripts (e.g., R1, R2, R3, etc.) appear more than once in the composition or structure of a compound, their definitions are independent of each other in each occurrence. 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 options for each R substituent in each case are independent of each other.

[0051] The compounds of the present invention may exist in specific geometric or stereoisomeric forms. All such compounds of the present invention, including cis- and trans-isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereoisomers, (D)-isomers, (L)-isomers, and their racemic mixtures and other mixtures, such as enantiomer- or diastereomer-enriched mixtures, all of these mixtures are within the scope of the present invention. Additional asymmetric carbon atoms may be present in the substituents of the compounds of the present invention. All such isomers and their mixtures are included within the scope of the present invention. In certain embodiments, preferred compounds are those isomeric compounds that exhibit superior biological activity. The purified or partially purified isomers and stereoisomers of the compounds of the present invention, or racemic mixtures or diastereomeric mixtures, are also included within the scope of the present invention. The purification and separation of such substances can be achieved by standard techniques known in the art.

[0052] The term "pharmaceutically acceptable" substance refers to a substance that, within the scope of normal medical judgment, is suitable for contact with the tissues of a patient without undue toxicity, irritation, allergic response, etc., has a reasonable benefit / risk ratio, and is effective for its intended use.

[0053] The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention that are safe and effective when used in mammals and have the desired biological activity.

[0054] The term "pharmaceutical composition" refers to a composition containing one or more of the compounds described herein or their physiologically / pharmaceutically acceptable salts or prodrugs, and other components such as physiologically / pharmaceutically acceptable carriers or excipients. The purpose of the pharmaceutical composition is to facilitate the administration to an organism, promote the absorption of the active ingredient, and thereby exert its biological activity.

[0055] The term "pharmaceutically acceptable carrier" refers to those substances that do not cause significant irritation to an 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.

[0056] The term "administer" or "administration" etc. refers to methods that enable a compound or composition to be delivered to a desired biological site of action. These methods include, but are not limited to, oral or parenteral (including intracerebroventricular, intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular injection or infusion), topical, rectal administration, etc. In particular, injection or oral administration.

[0057] As used herein, the term "treatment" includes alleviating, reducing, or ameliorating a disease or symptom, preventing other symptoms, ameliorating or preventing the underlying metabolic causes of a symptom, inhibiting a disease or symptom, e.g., arresting the development of a disease or symptom, reducing a disease or symptom, promoting remission of a disease or symptom, or causing the manifestations of a disease or symptom to cease, and extends to include prevention. "Treatment" also includes achieving a therapeutic benefit and / or a prophylactic benefit. A therapeutic benefit is defined as eradicating or ameliorating the treated condition. Additionally, a therapeutic benefit is achieved by eradicating or ameliorating one or more of the physiological manifestations associated with the underlying disease, and although the patient may still suffer from the underlying disease, an improvement in the patient's disease is observable. A prophylactic benefit is defined as the use of a composition by a patient to prevent the risk of a disease, or the administration of a composition to a patient when the patient exhibits one or more physiological manifestations of a disease, even though the disease has not yet been diagnosed.

[0058] 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 condition. The term "neuropsychiatric disease" refers to the general term for neurological diseases and psychiatric diseases, including neurological diseases and / or psychiatric diseases.

[0059] For a drug, drug unit, or active ingredient, the terms "effective amount", "therapeutically effective amount", or "prophylactically effective amount" refer to a sufficient amount of the drug or agent that has acceptable side effects but can achieve the desired effect. The determination of the effective amount varies from person to person, depending on the individual's age and general condition, and also depends on the specific active substance. The appropriate effective amount in a particular case can be determined by those skilled in the art based on routine tests.

[0060] The following detailed description of the invention is intended to illustrate non-limiting embodiments, enabling other technicians in the art to more fully understand the technical solutions of the invention, its principles, and its practical applications, so that other technicians in the art can modify and implement the invention in many forms to best meet the requirements of a specific use.

[0061] Advantageous Effects

[0062] The present invention provides a novel structural compound, and such compounds exhibit good 5-HT 2A 、5-HT 2C receptor activity and can be used to prepare drugs for treating schizophrenia, Parkinson's disease, behavioral disorders associated with dementia, and psychosis. At the same time, such compounds also exhibit good pharmacokinetic properties. Specifically, the compounds have a suitable half-life, which has the potential to reduce the frequency of drug administration and increase patient compliance; have a high bioavailability, which can reduce the exposure of the drug in the periphery at the effective dose and reduce the occurrence of peripheral adverse reactions; have less cardiotoxicity and higher safety. Detailed Description of the Invention

[0063] The present invention will be further described below in conjunction with specific embodiments. It should be understood that these embodiments are only used to illustrate the present invention and not to limit the scope of the present invention. In addition, it should be understood that after reading the content taught by the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims of this application.

[0064] Examples

[0065] The embodiments of the present invention will be described in detail below in conjunction with the embodiments, but those skilled in the art will understand that the following embodiments are only used to illustrate the present invention and should not be regarded as limiting the scope of the present invention. For those conditions not specified in the embodiments, they are carried out according to the conventional conditions or the conditions recommended by the manufacturer. For those reagents or instruments whose manufacturers are not specified, they are all conventional products that can be obtained through commercial purchase. Unless otherwise specified, the ratios or percentages used herein are by weight.

[0066] The compound structure of the present invention is determined by nuclear magnetic resonance (NMR) or / and liquid chromatography-mass spectrometry (LC-MS).

[0067] The NMR chemical shift (δ) is given in parts per million (ppm). The NMR measurement is carried out using a Bruker Advanced 400 nuclear magnetic resonance instrument, the measurement solvent is deuterated dimethyl sulfoxide (DMSO-d6), and the internal standard is tetramethylsilane (TMS).

[0068] The measurement of liquid chromatography-mass spectrometry (LC-MS) is carried out using a Shimadzu LCMS2020 liquid chromatography-mass spectrometer from Japan.

[0069] The HPLC measurement is carried out using an Agilent 1260 liquid chromatography instrument.

[0070] The thin-layer chromatography silica gel plate uses a Qingdao Marine silica gel plate. The TLC specification is 0.2 mm - 0.25 mm, and the specification for thin-layer chromatography separation and purification of products is 0.2 mm - 0.25 mm.

[0071] General synthetic route of the compounds in the embodiments of the present invention:

[0072]

[0073] Using I-a as the starting material, reacting with to carry out reductive amination reaction to obtain intermediate I-b. Intermediate I-b then undergoes intramolecular cyclization reaction with bis(p-nitrophenyl) carbonate to obtain intermediate I-c. Intermediate I-c is deprotected by trifluoroacetic acid to remove the Boc (tert-butoxycarbonyl) group to obtain the compound shown in Formula I.

[0074] Example:

[0075] Example 1 Synthesis of 2-(4-cyclopropoxybenzyl)-7-fluoro-4-(piperidin-4-yl)-1,2,4-trihydro-3H-benzo[e][1,3]diazepin-3-one -3-one

[0076]

[0077] 1a (5.00 g, 12.07 mmol) was added to dichloromethane (50 mL) and sodium carbonate solution (50 mL) for liberation, followed by extraction and separation of the liquid phases. The aqueous phase was extracted with dichloromethane (2 × 50 mL). The combined organic phases were washed with saturated sodium chloride solution (1 × 50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was added to dichloromethane (50 mL), cooled in an ice bath, and sodium triacetoxyborohydride (5.11 g, 24.13 mmol) was added portionwise to the above mixture at 0 °C. 1-Boc-4-piperidone (2.64 g, 13.27 mmol) was added, and the reaction was carried out at room temperature for 3 hours. After the reaction was completed, the reaction was quenched by adding sodium carbonate solution (50 mL) at room temperature. The mixture was extracted with dichloromethane (2 × 50 mL), the combined organic phases were washed with saturated sodium chloride solution (1 × 50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 4-[2-[[(4-cyclopropoxybenzyl)amino]methyl]-5-fluorobenzyl]amino-piperidine-1-carboxylic acid tert-butyl ester (1b) 4.30 g.

[0078] 1b (4.30 g, 8.89 mmol) was added to DMF (20 mL) under nitrogen protection, and a DMF solution (20 mL) of bis(p-nitrophenyl) carbonate (2.70 g, 8.89 mmol) was added dropwise. Anhydrous potassium carbonate (2.46 g, 17.78 mmol) was added, and the reaction was carried out at 130 °C for 2 hours. After the reaction was completed, water (200 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (3 × 50 mL). The combined organic phases were washed with sodium hydroxide solution (2 × 100 mL) and saturated sodium chloride solution (1 × 100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Purification by column chromatography (dichloromethane / methanol = 20:1) gave 4-[4-(4-cyclopropoxybenzyl)-8-fluoro-3-oxo-1,3,4,5-tetrahydro-2H-benzo[e][1,3]diazepin -2-yl]piperidine-1-carboxylic acid tert-butyl ester (1c) 2.45 g.

[0079] 1c (2.45 g, 4.81 mmol) was added to dichloromethane (30 mL). Trifluoroacetic acid (5 mL) was added dropwise at 0 °C, and the reaction was carried out at room temperature for 4 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure. Sodium carbonate solution (50 mL) was added to the residue, and the mixture was extracted with dichloromethane (2 × 50 mL). The organic phases were combined, washed with saturated sodium chloride solution (1 × 100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Purification by column chromatography (dichloromethane / methanol = 10:1) gave 2-(4-cyclopropoxybenzyl)-7-fluoro-4-(piperidin-4-yl)-1,2,4,5-tetrahydro-3H-benzo[e][1,3]diazepin -3-one (Compound I-1) 1.35 g. 1 H NMR (400 MHz, DMSO-d6) δ 7.27–7.20 (m, 3H), 7.15–7.07 (m, 1H), 7.05–6.92 (m, 3H), 4.37 (d, J = 9.3 Hz, 4H), 4.28 (s, 2H), 4.12–4.01 (m, 1H), 3.85–3.75 (m, 1H), 3.18 (d, J = 1.7 Hz, 2H), 3.00 (d, J = 11.9 Hz, 2H), 2.50–2.44 (m, 1H), 1.75–1.60 (m, 2H), 1.45 (d, J = 11.8 Hz, 2H), 0.82–0.71 (m, 2H), 0.67–0.51 (m, 2H). LCMS (ES, m / z): 410 [M+H] + .

[0080] Compounds I-2, I-3, I-4, I-5, I-6 and I-7 can be prepared by referring to the steps similar to those in Example 1.

[0081] The reference compound 8-fluoro-2-(1-methylpiperidin-4-yl)-4-[[4-(cyclopropoxy)phenyl]methyl]-1,5-dihydro-2,4-benzodiazepin -3-one can be prepared by referring to Example 6 of WO2021218863A1.

[0082] Biological Test Evaluation

[0083] The present invention will be further described and explained with reference to the test examples below, but these examples are not intended to limit the scope of the present invention.

[0084] Test Example 1 In vitro receptor binding assay

[0085] 1.1 Preparation of receptor membrane

[0086] After the cells were taken out of the -80 °C refrigerator and thawed naturally, they were centrifuged at 1000 g and 4 °C for 10 minutes. The precipitate was taken and the supernatant was discarded. Buffer was added to the precipitate. The cells were mixed for 20 - 30 seconds, and then centrifuged at 48000 g and 4 °C for 25 min. The upper layer of liquid was carefully discarded, buffer was added again, mixed, centrifuged at 48000 g and 4 °C for 25 min, the supernatant was discarded, and the precipitate was stored at -80 °C.

[0087] 1.2 Conditions for radioligand binding assay

[0088] Table 1 Conditions for radioligand binding assay

[0089]

[0090] 1.3 Procedures for receptor binding assay

[0091] First step: 50 μL of solvent (1% DMSO) was added to the total binding tube (TB), 50 μL of non-specific ligand (final concentration 1.0×10 -5 M) was added to the non-specific binding tube (NB), and 50 μL of the test compound was added to each test compound tube (CB).

[0092] Second step: 100 μL of buffer was added to each reaction tube.

[0093] Third step: 50 μL of the corresponding radioligand was added to each reaction tube.

[0094] Fourth step: 50 μL of the prepared membrane solution was added to each reaction tube.

[0095] Fifth step: Each reaction tube was incubated according to the incubation conditions. After the reaction was completed, the bound ligand was filtered quickly under reduced pressure. The UniFilter GF / C plate was saturated with 0.5% PEI solution 1 h in advance, washed thoroughly with ice-cold Tris-HCl buffer, dried in a constant temperature drying oven for 30 min after suction filtration. The filter plate was taken out and 40 μL of scintillation fluid was added per well.

[0096] Sixth step: The scintillation vial was placed in a liquid scintillation counter for counting.

[0097] 1.4 Experimental results

[0098] The results of the in vitro receptor assay showed that the Ki values of compound I-1 binding to 5-HT 2A and 5-HT 2C receptors were 2.92 and 1.57 nM respectively, and its activity was similar to that of the control compound 8-fluoro-2-(1-methylpiperidin-4-yl)-4-[[4-(cyclopropoxy)phenyl]methyl]-1,5-dihydro-2,4-benzodiazepin -3-one, indicating its potential for the treatment of Parkinson's disease. See Table 2 for details.

[0099] Table 2 Ki value of in vitro binding assay

[0100]

[0101] Test Example 2 In vitro hERG experiment

[0102] 2.1 Test method

[0103] The stably transfected cells were seeded on glass slides at a cell density of less than 50% and cultured overnight. The experimental cells were transferred to a bath of about 1 mL embedded in the inverted microscope stage, and the extracellular fluid was perfused at a perfusion rate of 2.7 mL / min. After stabilization for 5 minutes, the experiment could be started. The membrane current was recorded using a HEKA EPC-10 patch clamp amplifier and a PATCHMASTER acquisition system (HEKA Instruments Inc., D-67466 Lambrecht, Pfalz, Germany). All experiments were completed at room temperature (22 - 24 °C).

[0104] In the experiment, a P-97 microelectrode puller (Sutter Instrument Company, One Digital Drive, Novato, CA 94949) was used to pull the electrodes (BF150-110-10). The inner diameter of the electrode was 1 - 1.5 mm, and the access resistance after being filled with the internal solution was 2 - 4 MΩ.

[0105] The electrophysiological stimulation protocol for the hERG potassium channel was to first clamp the membrane voltage at -80 mV, apply a +20 mV voltage stimulation to the cell for 2 s to activate the hERG potassium channel, and then repolarize to -50 mV for 5 s to generate an outward tail current, with a stimulation frequency of once every 15 s. The current value was the peak value of the tail current.

[0106] In the experiment, the whole-cell recording mode was used to record the channel current. First, the extracellular fluid was perfused (about 2 mL per minute) and continuously recorded, and waited for the current to stabilize (the current decay (Run-Down) within 5 minutes was less than 5%). At this time, the peak value of the tail current was the control current value. Then, the extracellular fluid containing the test drug was perfused and continuously recorded until the inhibitory effect of the drug on the hERG current reached a steady state. At this time, the peak value of the tail current was the current value after adding the drug. The standard of the steady state was judged by whether the last three consecutive current recording lines coincided. After reaching the steady state, if the hERG current recovered or approached the size before adding the drug after perfusion and rinsing with the extracellular fluid, other concentrations or drugs could be continuously perfused for testing.

[0107] 2.2 Experimental results:

[0108] The results are shown in Table 3 below, indicating that the possibility of the compound I-1 of the present application causing cardiotoxicity is less than that of the control compound 8-fluoro-2-(1-methylpiperidin-4-yl)-4-[[4-(cyclopropoxy)phenyl]methyl]-1,5-dihydro-2,4-benzodiazepin -3-one, and it has higher safety. The results are shown in Table 3 below.

[0109] Table 3 Results of in vitro hERG assay

[0110]

[0111]

[0112] Test Example 3 Pharmacokinetics Test of Rats

[0113] Using 8-fluoro-2-(1-methylpiperidin-4-yl)-4-[[4-(cyclopropoxy)phenyl]methyl]-1,5-dihydro-2,4-benzodiazepin -3-one as a control example, through the rat oral gavage administration test, the pharmacokinetic parameters such as the half-life and exposure of the compound of the present application and the control example were compared to evaluate the in vivo pharmacokinetic characteristics.

[0114] 3.1 Test Method

[0115] Preparation of intravenous administration solution: The compound was formulated into a 0.2 mg / mL solution using a 20% hydroxypropyl-β-cyclodextrin solution. The administration volume was 0.5 mL / 100 g body weight, and the dose was 1 mg / kg body weight according to the concentration conversion.

[0116] Preparation of gavage administration solution: It was suspended and dispersed using a 0.5% aqueous methylcellulose solution to form a 1 mg / mL suspension. The administration volume was 1 mL / 100 g body weight, and the dose was 10 mg / kg body weight according to the concentration conversion.

[0117] Three rats were in each group, and oral gavage and tail vein administration were carried out respectively according to the above doses. Orbital blood collection was performed at 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 7 h, and 10 h after administration to prepare plasma samples, and the drug concentration in the plasma samples was measured by LC / MS / MS.

[0118] 3.2 Test Results

[0119] The results of the rat pharmacokinetic test are shown in Table 4 in detail. The results show that the t of the compound I-1 of the present application 1 / 2 Compared with the control example 8-fluoro-2-(1-methylpiperidin-4-yl)-4-[[4-(cyclopropoxy)phenyl]methyl]-1,5-dihydro-2,4-benzodiazepin -3-one was significantly increased, and the exposure at the same dose was higher than that of 8-fluoro-2-(1-methylpiperidin-4-yl)-4-[[4-(cyclopropoxy)phenyl]methyl]-1,5-dihydro-2,4-benzodiazepine -3-one was increased, indicating its potential advantages such as reducing the number of drug administrations and increasing patient compliance. Moreover, compared with the control example 8-fluoro-2-(1-methylpiperidin-4-yl)-4-[[4-(cyclopropoxy)phenyl]methyl]-1,5-dihydro-2,4-benzodiazepine -3-one improved the bioavailability, could reduce the peripheral exposure of the drug at the effective dose, and could reduce the occurrence of peripheral adverse reactions.

[0120] In summary, the present application represented by Compound I-1 has an appropriate half-life, with potential advantages such as reducing the number of drug administrations and increasing patient compliance; and has a high bioavailability, can reduce the peripheral exposure of the drug at the effective dose, and reduce the occurrence of peripheral adverse reactions.

[0121] Table 4 Pharmacokinetic Parameters of Rats

[0122]

[0123] #imgpt28#

Claims

1. A compound of formula I, its stereoisomers or its pharmaceutically acceptable salts: Wherein: Each R1 is independently selected from hydrogen, halogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C2-C8 alkenyl and optionally substituted C2-C8 alkynyl; the optional substituent is halogen; Each R2 is independently selected from hydrogen, halogen and optionally substituted C1-C8 alkyl; the optional substituent is halogen; Each R3 is independently selected from hydrogen, halogen, optionally substituted C1-C8 alkyl and optionally substituted C1-C8 alkoxy; the optional substituent is halogen; n is an integer selected from 0-4; m is an integer selected from 0-4, preferably 0; p is an integer selected from 0-8, preferably 0; q is an integer selected from 1-3.

2. The compound, stereoisomer or pharmaceutically acceptable salt thereof represented by general formula I according to claim 1, characterized in that, It satisfies one or more of the following conditions: (1) Each R1 is independently selected from hydrogen, halogen, optionally substituted C1-C5 alkyl and optionally substituted C1-C5 alkoxy; the optional substituent is halogen; (2) Each R2 is independently selected from hydrogen, halogen and optionally substituted C1-C5 alkyl; the optional substituent is halogen; (3) Each R3 is independently selected from hydrogen, halogen, optionally substituted C1-C5 alkyl and optionally substituted C1-C5 alkoxy; the optional substituent is halogen; (4) n is an integer selected from 0-2, preferably 1; (5) q is an integer selected from 1-3, preferably an integer from 1-2, more preferably 2.

3. The compound of formula I, its stereoisomers or its pharmaceutically acceptable salts according to any one of claims 1-2, characterized in that Each R1 is independently selected from hydrogen, fluorine, chlorine, bromine, optionally substituted C1-C5 alkyl and optionally substituted C1-C5 alkoxy; the optional substituents are selected from fluorine and chlorine; Each R2 is independently selected from hydrogen, fluorine, chlorine, bromine and optionally substituted C1-C5 alkyl; the optional substituents are selected from fluorine and chlorine; Each R3 is independently selected from hydrogen, fluorine, chlorine, bromine and optionally substituted C1-C5 alkyl; the optional substituents are selected from fluorine and chlorine.

4. The compound represented by the general formula I according to any one of claims 1-3, its stereoisomer or its pharmaceutically acceptable salt, characterized in that, Each R1 is independently selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, methoxy and ethoxy; Each R2 is independently selected from hydrogen, fluorine, chlorine, methyl and ethyl; Each R3 is independently selected from hydrogen, fluorine, chlorine, methyl and ethyl.

5. The compound, stereoisomer or pharmaceutically acceptable salt thereof represented by General Formula I according to any one of claims 1-4, characterized in that, Selected from the following compounds:

6. A pharmaceutical composition comprising a therapeutically effective dose of the compound of formula I, its stereoisomers or its pharmaceutically acceptable salts according to any one of claims 1-5 and one or more pharmaceutically acceptable carriers or excipients.

7. Use of the compound of formula I, its stereoisomers or its pharmaceutically acceptable salts according to any one of claims 1-5, or the pharmaceutical composition according to claim 6 in the preparation of a medicament for treating mental diseases.

8. The use according to claim 7, characterized in that, The disease is psychosis.

9. The use according to claim 7, characterized in that, The disease is schizophrenia.

10. The use according to claim 7, characterized in that, The disease is Parkinson's disease, dementia-related behavioral disorders and psychosis.

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