1,5-Dihydro-2,4-benzodiazepin-3-one derivatives and their use

Abstract

The present invention relates to the field of chemical medicine, in particular to 1,5-dihydro-2,4-benzodiazepin-3-one derivatives and their uses. The 1,5-dihydro-2,4-benzodiazepin-3-one derivatives provided by the present invention are compounds represented by formula I, and are 5-HT 2A , 5-HT 2C It acts on the receptor and 5-HT 2A The compounds have selectivity for schizophrenia that is superior to or similar to that of pimavanserin. They are used to treat the behavioral and psychological symptoms of schizophrenia, Parkinson's disease, and dementia. The compounds of the present application have antipsychotic activity equivalent to that of pimavanserin, less sedative and hypokinetic side effects than pimavanserin, and less cardiotoxicity than pimavanserin. TIFF2023522078000122.tif50161

Description

Technical Field

[0001] This application claims the priority of Chinese Patent Application No. 202010330893.1, entitled "1,5-Dihydro-2,4-benzodiazepin-3-one Derivatives and Their Use", filed on April 26, 2020, and Chinese Patent Application No. 202110288141.8, entitled "1,5-Dihydro-2,4-benzodiazepin-3-one Derivatives and Their Use", filed on March 17, 2021, the entire contents of which are incorporated herein by reference.

[0002] [Technical Field] The present invention relates to the field of chemical pharmaceuticals, and particularly to 1,5-dihydro-2,4-benzodiazepin-3-one derivatives and their use.

Background Art

[0003] Schizophrenia is difficult to detect early, has a low hospitalization rate, and a high lifetime prevalence. Currently, about 0.3 - 0.7% of the world's population is affected by schizophrenia throughout their lives, and in 2016, it was estimated that there were over 21 million schizophrenia patients worldwide. Currently, the main therapeutic drugs for schizophrenia are mainly typical antipsychotics and atypical antipsychotics. However, since the therapeutic drugs for schizophrenia strongly block dopamine receptors, side effects such as extrapyramidal symptoms (EPS), tardive dyskinesia, and increased prolactin occur. In the medical field, for the treatment of sleep disorders, various types of active compounds acting on different targets are used, but side effects such as dependence, drug resistance, and sequelae remain unresolved.

[0004] Generally, antipsychotics that exert pharmacological effects by blocking dopamine D2 receptors are called first-generation antipsychotics, that is, "typical" antipsychotics (for example, haloperidol). These therapeutic drugs have shown epoch-making effects in the treatment of positive symptoms of schizophrenia, but cannot treat negative symptoms and cognitive impairment. Typical antipsychotics usually have severe EPS side effects, and are ineffective in one-third of schizophrenia patients.

[0005] After the 1960s, a series of new-generation antipsychotics, namely the second-generation antipsychotics such as Ziprasidone and Risperidone, have been developed one after another. Although the pharmacological actions of these therapeutic agents do not completely coincide, they show the same pharmacological characteristics, that is, the affinity for serotonin (5-HT) receptors (5-HT1A, 2A, 2c) and norepinephrine (NA) receptors (α1, α2) is higher than the affinity for D2 receptors. Therefore, the ratio of D2 / 5-HT 2A is low. As its clinical effect, compared with the first-generation antipsychotics, it has more advantages. It is not only effective for positive symptoms like the conventional antipsychotics, but also effective for negative symptoms and cognitive dysfunction, and its action range is even wider. However, these pharmaceuticals have side effects such as QT interval prolongation, hyperprolactinemia, and weight gain. Therefore, the development of pharmaceuticals that are effective for the positive symptoms, negative symptoms, and cognitive dysfunction of schizophrenia while having few side effects is currently attracting attention.

[0006] The serotonin system plays an important role in regulating the functions of the prefrontal cortex (PFC), such as emotion control, cognitive behavior, and working memory. Some particularly high-density serotonin receptor subtypes 5-HT 1A and 5-HT 2A are included in the pyramidal neurons and GABAergic neurons of the PFC. Recently, the PFC and NMDA receptor channels are targets of 5-HT 1A R, and it has been proven that these two receptors affect cognitive function by regulating the excitatory neurons in the cerebral cortex. In fact, various preclinical data have shown that 5-HT 1A R is a new target for antipsychotic drug development. The 5-HT 1ADue to its high affinity for R and low EPS side effects, the serotonin system has been proven to play an important role in regulating the functions of the prefrontal cortex (PFC), such as emotional control, cognitive behavior, and working memory. The pyramidal neurons and GABAergic neurons in the PFC contain several particularly high-density serotonin receptor subtypes 5-HT 1A and 5-HT 2A . Recent studies have shown that 5-HT 1A agonists are related to the treatment with atypical antipsychotics and can improve negative symptoms and cognitive dysfunction. In the treatment of schizophrenia with the atypical antipsychotic clozapine, 5-HT 2A has been found to play an important role in various aspects including perception, emotional regulation, and motor control. By blocking the 5-HT 2A receptor, the release of dopamine can be normalized, so it functions as an antipsychotic. In addition, the 5-HT 2C receptor is closely related to weight gain.

[0007] Pimavanserin is an inverse agonist that shows high affinity for 5-HT 2A and 5-HT 2C . In in vitro experiments, its affinity for the 5-HT 2A receptor [inhibition constant (Ki): 0.4 nM was higher than that of 5-HT 2C (Ki = 16 nM ), but it showed no significant affinity (Ki > 300 2B ) for the 5-HT nM receptor, dopamine receptors (including D2 receptors), adrenergic receptors, muscarinic receptors, or calcium channel receptors. This drug was approved by the US Food and Drug Administration in April 2016 under the trade name NuplazidTM for the treatment of psychiatric symptoms associated with Parkinson's disease such as hallucinations and delusions.

[0008] Therefore, there is a need to develop a schizophrenia treatment drug that is effective against both positive and negative symptoms, can improve cognitive dysfunction, can suppress extrapyramidal side effects including tardive dyskinesia and Parkinson's disease, and can further reduce weight gain.

Summary of the Invention

[0009] The present invention is intended to solve at least one of the problems existing in the prior art. Therefore, one object of the present invention is to provide a compound represented by formula I.

Chemical Formula

Chemical Formula

Chemical Formula

[0010] In one embodiment, the straight-chain or branched alkyl group of C1-C8 is selected from a straight-chain or branched alkyl group of C1-C5 and a straight-chain or branched alkyl group of C1-C3, and / or the alkenyl group of C2-C8 is a C2-C5 alkenyl group, and / or the alkynyl group of C2-C8 is a C2-C5 alkynyl 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.

[0011] In another aspect, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of the compound represented by formula I described above, and optionally further comprising a pharmaceutically acceptable excipient, carrier, adjuvant, solvent or a combination thereof.

[0012] In another aspect, the present invention provides the use of the compound represented by formula I and its pharmaceutical composition in the manufacture of a medicament for treating psychiatric diseases.

[0013] In one embodiment, the psychiatric disease is schizophrenia or psychosis.

[0014] In another embodiment, the psychiatric disease is Parkinson's disease or behavioral and psychological symptoms of dementia (BPSD).

Mode for Carrying Out the Invention

[0015] Unless otherwise specified, all technical and scientific terms used in this specification shall have the same meaning as commonly understood by those skilled in the art. In case of any conflict, the definitions in this specification shall prevail. The product names described in this specification refer to such products or their active ingredients. All patents, published patent applications and publications cited in this specification are hereby incorporated by reference into this specification.

[0016] General terms and their definitions

[0017] The term "comprising" is an open-ended expression, that is, it includes the content specified in the present invention, but does not exclude other content. The term "comprising" should be understood to also include the meaning of a closed form such as "consisting of".

[0018] As described in this specification, the compounds of the present invention may be substituted with one or more substituents as desired, for example, compounds represented by the general formula described above or specific examples or subclasses in the examples. The term "optionally substituted" should be understood to be interchangeable with the term "substituted or unsubstituted". Generally, without exceeding the normal valence of the specified atom in situ and on the premise of forming a stable compound by the above substitution, the term "substituted" means that one or more hydrogen atoms in the structure are substituted with specific substituents. Combinations of substituents and / or variables are only permitted if such combinations result in the formation of a stable compound. Regarding the description that a certain substituent is absent, on the premise that the compound can be in a stable state due to the above structure, it should be understood that the substituent may be one or more hydrogen atoms. Unless otherwise specified, an optionally substituted group may be substituted at any of its substitutable positions. In its structural formula, when there are one or more positions that may be substituted with one or more substituents selected from specific groups, each position may be substituted with the same or different substituents.

[0019] Unless otherwise specified, in this specification, the bonding point of a substituent may be at any appropriate position of the substituent. When the bonding of a substituent is through a bond connecting two atoms within a ring, such a substituent may be bonded to any ring-forming atom in the ring that can be substituted.

[0020] Also, unless otherwise specified, "each independently" in the present invention should be understood in a broad sense, which can mean that for different groups, the specific options indicated by the same reference numerals do not affect each other, or for the same group, the specific options indicated by the same reference numerals do not affect each other.

[0021] When the lower and upper limits of a numerical range are disclosed, all numerical values falling within the range and any included ranges are specifically disclosed. In particular, each numerical range disclosed in this specification should be understood to include each numerical value and range falling within a broader range. For any variable (e.g., R), and for a variable with a subscript (e.g., R1, R2, R3, R4, R5, R6, R7, etc.) that appears one or more times in the composition or structure of a compound, the definitions in each case are independent. For example, when a group is substituted with 0, 1, 2, 3, or 4 R substituents, the above group may optionally be substituted with up to 4 R substituents, and the options for each R substituent in each case are independent.

[0022] In various parts of this specification, the substituents of the compounds disclosed in the present invention are disclosed by the type or range of the groups. In particular, the present invention includes each independent sub - combination of each member of these types and ranges of groups. For example, the expression m~n in this specification refers to the range from m to n, and the sub - ranges and each numerical value consisting of each numerical value therein. For example, the term "C1 - C5 alkyl group" particularly refers to the respectively disclosed methyl group, ethyl group, C3 alkyl group, C4 alkyl group, C5 alkyl group. Examples of alkyl groups include, but are not limited to, methyl group (Me, -CH3), ethyl group (Et, -CH2CH3), n - propyl group (n - Pr, -CH2CH2CH3), isopropyl group (i - Pr, -CH(CH3)2), n - butyl (n - Bu, -CH2CH2CH2CH3), isobutyl group (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), 2 - methyl - 2 - butyl (-C(CH3)2CH2CH3), 3 - methyl - 2 - butyl (-CH(CH3)CH(CH3)2), 3 - methyl - 1 - butyl (-CH2CH2CH(CH3)2), 2 - methyl - 1 - butyl (-CH2CH(CH3)CH2CH3), etc. For example, the term "C2 - C8" or "C2 - 8" includes the range of 2 to 8 carbon atoms, but also, for example, C2 - C5, C3 - C4, C2 - C6, C3 - C6, C4 - C6, C4 - C7, C4 - C8, C2 - C5, etc., and any sub - ranges and each numerical value among C2, C3, C4, C5, C6, C7, C8, etc. should be understood to be included. For example, the term "C3 - C10" or "C3 - 10" should similarly be understood to include, for example, C3 - C9, C6 - C9, C6 - C8, C6 - C7, C7 - C10, C7 - C9, C7 - C8, C8 - C9, etc. and any sub - ranges and numerical values among C3, C4, C5, C6, C7, C8, C9, C10, etc.Furthermore, for example, the term "C1-C5" or "C1-5" includes a range of 1 to 5 carbon atoms, but also includes, for example, any sub-ranges and each numerical value among C2-C5, C3-C4, C1-C2, C1-C3, C1-C4, C1-C5, etc., and C1, C2, C3, C4, C5, etc. Further, for example, the term "C2-C5" or "C2-5" includes a range of 2 to 5 carbon atoms, but also includes, for example, any sub-ranges and each numerical value among C2-C5, C3-C4, C2-C3, C2-C4, C3-C5, C4-C5, etc., and C2, C3, C4, C5, etc. Further, for example, the term "C3-C6" or "C3-6" includes a range of 3 to 6 carbon atoms, but also includes, for example, any sub-ranges and each numerical value among C3-C5, C3-C4, C3-C6, C5-C6, C4-C6, C4-C5, etc., and C3, C4, C5, C6, etc. Further, for example, the term "C1-C8" or "C1-8" includes a range of 1 to 8 carbon atoms, but also includes, for example, any sub-ranges and each numerical value among 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. Further, for example, the term "3-membered to 10-membered" includes, for example, any sub-ranges and each numerical value among 3-membered to 5-membered, 3-membered to 6-membered, 3-membered to 7-membered, 3-membered to 8-membered, 4-membered to 5-membered, 4-membered to 6-membered, 4-membered to 7-membered, 4-membered to 8-membered, 5-membered to 7-membered, 5-membered to 8-membered, 6-membered to 7-membered, 6-membered to 8-membered, 9-membered to 10-membered, etc., and 3-membered, 4-membered, 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, 10-membered, etc. Other similar expressions in this specification should be understood in the same way.

[0023] The ranges (e.g., numerical ranges) exemplified in this specification can include each individual numerical value and each sub-range formed from the numerical values. Thus, for example, the expression "n2 is any one integer among 0 to 3" includes, for example, any one integer among 0 to 2, any one integer among 2 to 3, etc., and includes, for example, 1, 2, 3.

[0024] The expression "one or more" or a similar expression "at least one" refers to, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more.

[0025] The term "selected from" means that one or more elements can be independently selected from the group exemplified before it, and combinations of two or more elements can be included.

[0026] The description that each carbon atom in a group may optionally be substituted with a heteroatom is based on the premise that all atoms in the group do not exceed their normal valence in situ and form a stable compound.

[0027] The term "hydrogen (H)" refers to one hydrogen atom. Such an atomic group can be bonded to other groups, for example, it can be bonded to an oxygen atom to form a hydroxyl group.

[0028] The term "halogen" or "halogenated" should be understood to represent fluorine (F), chlorine (Cl), bromine (Br) or iodine (I), preferably fluorine, chlorine, bromine atoms, more preferably fluorine atoms.

[0029] The term "alkyl group" refers to a straight-chain or branched saturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms, which is bonded to the rest of the molecule by a single bond. The "alkyl group" may have 1 to 5 carbon atoms, that is, for example, it may be a "C1-C5 alkyl group" such as a C1-4 alkyl group, a C1-3 alkyl group, a C1-2 alkyl group, a C3 alkyl group, a C4 alkyl group, a C1-5 alkyl group, a C3-5 alkyl group, etc., and may also have 1 to 3 carbon atoms, that is, for example, it may be a "C1-C3 alkyl group" such as a C1-3 alkyl group, a C1-2 alkyl group, a C3 alkyl group, etc. Further, for example, the term "C1-C5 alkyl group" specifically represents an independently disclosed methyl group, ethyl group, C3 alkyl group, C4 alkyl group, and C5 alkyl group.Examples of alkyl groups include, but are not limited to, methyl group (Me, -CH3), ethyl group (Et, -CH2CH3), n-propyl group (n-Pr, -CH2CH2CH3), isopropyl group (i-Pr, -CH(CH3)2), n-butyl group (n-Bu, -CH2CH2CH2CH3), isobutyl group (i-Bu, -CH2CH(CH3)2), sec-butyl group (s-Bu, -CH(CH3)CH2CH3), tert-butyl group (t-Bu, -C(CH3)3), n-pentyl group (-CH2CH2CH2CH2CH3), 2-pentyl group (-CH(CH3)CH2CH2CH3), 3-pentyl group (-CH(CH2CH3)2), 2-methyl-2-butyl group (-C(CH3)2CH2CH3), 3-methyl-2-butyl group (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl group (-CH2CH2CH(CH3)2), 2-methyl-1-butyl group (-CH2CH(CH3)CH2CH3), n-hexyl group (-CH2CH2CH2CH2CH2CH3), 2-hexyl group (-CH(CH3)CH2CH2CH2CH3), 3-hexyl group (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl group (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl group (-CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl group (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl group (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl group (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl group (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl group (-CH(CH3)C(CH3)3), n-heptyl group, n-octyl group, etc.

[0030] The term "alkenyl group" refers to a straight-chain or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms and having at least one double bond. The alkenyl group may have 2 to 5 carbon atoms, that is, for example, C 2-4 alkenyl group, C 3-4 alkenyl group, etc., such as "C 2-5It may be an "alkenyl group." 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, and the like.

[0031] The term "cycloalkyl group" refers to a saturated cyclic hydrocarbon group consisting of carbon and hydrogen atoms, preferably containing one or two rings. The cycloalkyl group may be a monocyclic, fused polycyclic, bridged or spirocyclic structure. The cycloalkyl group may have 3 to 6 carbon atoms, i.e., a "C3-C6 cycloalkyl group", such as a C6 cycloalkyl group, a C5 cycloalkyl group, a C4 cycloalkyl group, a C3 cycloalkyl group, etc. Non-limiting examples of cycloalkyl groups include, but are not limited to, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, etc. The term also includes the case where the C atom is replaced by oxo (=O).

[0032] The term "alkynyl group" refers to a linear or branched unsaturated aliphatic hydrocarbon group consisting of carbon and hydrogen atoms and having at least one triple bond. The alkynyl group may have 2 to 5 carbon atoms, i.e., for example, C 2~3 Alkynyl group, C 2~4 Alkynyl groups, etc. 2~5 Non-limiting examples of alkynyl groups include, but are not limited to, ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, but-3-ynyl, and the like.

[0033] The bond "---" means either a single bond "-" or nothing.

[0034] The absence of a chemical bond means that only one of the two atoms bonded by the chemical bond exists, and on the premise that the compound structure is stable, the above atom is bonded to the atoms of other parts, and the atoms of the other parts are bonded to the two atoms originally bonded by the chemical bond.

[0035] In this specification, the absence of the "---" bond in Formula I means that only one of the carbon atoms among the carbon atom and the Q atom at both ends of the "---" bond exists, and on the premise that the compound structure is stable, the existing one carbon atom is bonded to the atoms of other parts, meaning to form a compound represented by Formula II.

Chemical formula

[0036] The term "pharmaceutically acceptable" means that such a substance is within the scope of reliable medical judgment, without excessive toxicity, irritation, allergic reaction, etc., suitable for use in contact with the tissues of patients, commensurate with a reasonable benefit / risk ratio, and can be effectively used for its intended purpose.

[0037] The term "pharmaceutically acceptable carrier" refers to a substance that does not significantly stimulate the living body and does not impair the biological activity and properties of the active compound. "Pharmaceutically acceptable carriers" include, but are not limited to, flow promoters, sweeteners, diluents, anticorrosives, dyes / colorants, flavoring agents, surfactants, wetting agents, dispersants, disintegrants, stabilizers, solvents or emulsifiers.

[0038] The terms "administer" or "administering", etc. refer to methods by which a compound or composition can be delivered to a desired biological action site. These methods include, but are not limited to, oral administration or parenteral administration (including intracerebroventricular, intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular injection or infusion), topical administration, rectal administration, etc., especially injection or oral administration.

[0039] As used herein, the term "treatment" includes alleviation, reduction, or improvement of a disease or symptom, prevention of other symptoms, improvement or prevention of potential metabolic factors of a symptom, and includes, for example, inhibition of the progression of a disease or symptom, reduction of a disease or symptom, promotion of alleviation of a disease or symptom, or disappearance, and thus prevention, of a disease or symptom. "Treatment" also includes achieving a benefit by treatment and / or a benefit by prevention. A benefit by treatment refers to eradicating or improving the medical condition to be treated. Further, a benefit by treatment is achieved by eradicating or improving physiological signs associated with one or more potential diseases, where the patient may be at risk of having a potential disease, but improvement of this disease is seen. A benefit by prevention refers to using this composition to prevent a patient from suffering from a certain disease, or taking this composition because one or more physiological signs of a disease have occurred although the patient has not been diagnosed as having suffered from this disease.

[0040] The terms "active ingredient", "therapeutic agent", "active substance", or "active agent" refer to a chemical substance that can effectively treat or prevent a targeted disorder, disease, or medical condition.

[0041] The term "mental disorder" refers to a disorder of the nervous system.

[0042] With respect to a pharmaceutical, pharmaceutical unit, or active ingredient, the terms "effective amount", "therapeutically effective amount", or "preventively effective amount" refer to an amount of the pharmaceutical or agent that is within an acceptable range of side effects and sufficient to achieve the desired effect. The determination of the effective amount varies from person to person and depends on the age and general condition of the patient, and also depends on the specific active substance. In each case, the appropriate effective amount can be determined by ordinary experimentation by a person skilled in the art.

[0043] As used herein, "subject" includes a human or a non-human animal. Exemplary human subjects include human subjects (referred to as patients) suffering from a disease (including, for example, the diseases described herein) or normal subjects. As used herein, "non-human animals" include all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles), and mammals such as non-human primates, domestic animals and / or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).

[0044] The following detailed description is intended to illustrate non-limiting embodiments by way of example so that other technicians in the art can better understand the invention, its principles and practical applications according to the present invention, and can freely modify and implement the present invention to meet specific application requirements.

[0045] Compound represented by formula I

[0046] In one aspect, the present invention provides a compound represented by Formula I.

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0047] In one embodiment, n1 and n2 are integers selected from 1 to 3. For example, n1 and n2 are each independently selected from 1, 2, and 3, for example, 1, 2, or 3. In one preferred embodiment, n1 is selected from 2 and 3. In one more preferred embodiment, n1 is 1. In another preferred embodiment, n2 is 1. In one more preferred embodiment, n1 is 2. In another more preferred embodiment, n2 is 2. In one more preferred embodiment, n1 is 3. In another more preferred embodiment, n2 is 3. In one particularly preferred embodiment, n1 is 2 and n2 is 1.

[0048] In one embodiment, R1 is selected from a straight-chain or branched alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, and an alkynyl group having 2 to 8 carbon atoms. Each of the alkyl group, alkenyl group, and alkynyl group may be independently substituted, if desired, with a substituent selected from halogen and a haloalkyl group having 1 to 8 carbon atoms. In one preferred embodiment, R1 is a straight-chain or branched alkyl group having 1 to 8 carbon atoms, and the alkyl group may be substituted, if desired, with a substituent selected from halogen and a haloalkyl group having 1 to 8 carbon atoms. In one more preferred embodiment, R1 is a straight-chain alkyl group having 1 to 8 carbon atoms. In one particularly preferred embodiment, R1 is a straight-chain or branched alkyl group having 1 to 5 carbon atoms. In another particularly preferred embodiment, R1 is a straight-chain or branched alkyl group having 1 to 3 carbon atoms. In one specific embodiment, R1 is selected from a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a pentyl group, and an isopentyl group. In one more specific embodiment, R1 is selected from a methyl group, an ethyl group, and a propyl group, and is, for example, a methyl group, an ethyl group, or a propyl group. In one particularly specific embodiment, R1 is a methyl group. In another particularly specific embodiment, R1 is an ethyl group. In yet another particularly specific embodiment, R1 is a propyl group.

[0049] In one embodiment, R2 is selected from hydrogen, halogen, and a haloalkyl group having 1 to 8 carbon atoms. In one preferred embodiment, R2 is selected from hydrogen and halogen. In one more preferred embodiment, R2 is hydrogen. In another more preferred embodiment, R2 is halogen. In one specific embodiment, R2 is selected from hydrogen, fluorine, chlorine, bromine, and iodine. In one more specific embodiment, R2 is selected from hydrogen, fluorine, chlorine, and bromine. In one more specific embodiment, R2 is fluorine. In another more specific embodiment, R2 is chlorine. In yet another more specific embodiment, R2 is bromine.

[0050] In one embodiment, R3, R4, R5, and R6 are each independently selected from hydrogen, halogen, and C1-C8 haloalkyl groups.

[0051] In one preferred embodiment, R3 is selected from hydrogen and halogen. In one more preferred embodiment, R3 is hydrogen. In another more preferred embodiment, R3 is halogen. In one particularly preferred embodiment, R3 is selected from fluorine, chlorine, bromine, and iodine. In one more preferred embodiment, R3 is selected from fluorine, chlorine, and bromine. In one specific embodiment, R3 is selected from hydrogen, fluorine, chlorine, and bromine. In one more specific embodiment, R3 is selected from hydrogen, fluorine, and chlorine. In one particularly specific embodiment, R3 is fluorine. In another particularly specific embodiment, R3 is chlorine.

[0052] In one preferred embodiment, R4 is selected from hydrogen and halogen. In one more preferred embodiment, R4 is hydrogen. In another more preferred embodiment, R4 is halogen. In one particularly preferred embodiment, R4 is selected from fluorine, chlorine, bromine, and iodine. In one more preferred embodiment, R4 is selected from fluorine, chlorine, and bromine. In one specific embodiment, R4 is selected from hydrogen, fluorine, chlorine, and bromine. In one more specific embodiment, R4 is selected from hydrogen, fluorine, and chlorine. In one particularly specific embodiment, R4 is fluorine. In another particularly specific embodiment, R4 is chlorine.

[0053] In one preferred embodiment, R5 is selected from hydrogen and halogen. In one more preferred embodiment, R5 is hydrogen. In another more preferred embodiment, R5 is halogen. In one particularly preferred embodiment, R5 is selected from fluorine, chlorine, bromine and iodine. In one more preferred embodiment, R5 is selected from fluorine, chlorine and bromine. In one specific embodiment, R5 is selected from hydrogen, fluorine, chlorine and bromine. In one more specific embodiment, R5 is selected from hydrogen, fluorine and chlorine. In one particularly specific embodiment, R5 is fluorine. In another particularly specific embodiment, R5 is chlorine.

[0054] In one preferred embodiment, R6 is selected from hydrogen and halogen. In one more preferred embodiment, R6 is hydrogen. In another more preferred embodiment, R6 is halogen. In one particularly preferred embodiment, R6 is selected from fluorine, chlorine, bromine and iodine. In one more preferred embodiment, R6 is selected from fluorine, chlorine and bromine. In one specific embodiment, R6 is selected from hydrogen, fluorine, chlorine and bromine. In one more specific embodiment, R6 is selected from hydrogen, fluorine and chlorine. In one particularly specific embodiment, R6 is fluorine. In another particularly specific embodiment, R6 is chlorine.

[0055] In one embodiment, R7 is a linear or branched C1-C8 alkyl group, a cycloalkyl group, and [Chemical formula] (wherein R8 and R9 are each independently selected from linear or branched C1-C8 alkyl groups). The above alkyl group and cycloalkyl group may optionally be substituted with substituents selected from halogen and C1-C8 haloalkyl groups.

[0056] In one preferred embodiment, R7 is a linear or branched alkyl group having 1 to 8 carbon atoms. In a more preferred embodiment, R7 is a linear or branched alkyl group having 1 to 5 carbon atoms. In a particularly preferred embodiment, R7 is a linear or branched alkyl group having 1 to 3 carbon atoms. In a specific embodiment, R7 is selected from a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a pentyl group, and an isopentyl group. In a more specific embodiment, R7 is selected from a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, and an isobutyl group, and is, for example, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, or an isobutyl group. In a particularly specific embodiment, R7 is an isopropyl group.

[0057] In one preferred embodiment, R7 is a cycloalkyl group. In a more preferred embodiment, R7 is a cycloalkyl group having 3 to 10 carbon atoms. In a particularly preferred embodiment, R7 is a cycloalkyl group having 3 to 6 carbon atoms. In a specific embodiment, R7 is selected from a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group. In a more specific embodiment, R7 is selected from a cyclopropyl group, a cyclobutyl group, and a cyclopentyl group, and is, for example, a cyclopropyl group, a cyclobutyl group, or a cyclopentyl group.

[0058] In one preferred embodiment, R7 is

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0059] In one embodiment, Z is selected from C, O, and N. In one preferred embodiment, Z is C. In another preferred embodiment, Z is O. In yet another preferred embodiment, Z is N.

[0060] In one embodiment, Q and W are each independently selected from C and N. In one preferred embodiment, Q is N. In one preferred embodiment, Q is C. In one preferred embodiment, W is C. In one preferred embodiment, W is N.

[0061] In one embodiment, the straight-chain or branched alkyl group of C1-C8 is selected from a straight-chain or branched alkyl group of C1-C5 and a straight-chain or branched alkyl group of C1-C3. In one specific embodiment, the straight-chain or branched alkyl group of C1-C8, the straight-chain or branched alkyl group of C1-C5, and the straight-chain or branched alkyl group of C1-C3 are each independently selected from a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, and an isopentyl group. In one more specific embodiment, the straight-chain or branched alkyl group of C1-C8, the straight-chain or branched alkyl group of C1-C5, and the straight-chain or branched alkyl group of C1-C3 are each independently selected from a methyl group, an ethyl group, a propyl group, and a butyl group.

[0062] In one embodiment, the propyl group includes, but is not limited to, an n-propyl group (n-Pr, -CH2CH2CH3) or an isopropyl group (i-Pr, -CH(CH3)2). The butyl group includes, but is not limited to, an n-butyl (n-Bu, -CH2CH2CH2CH3), an isobutyl group (i-Bu, -CH2CH(CH3)2), a sec-butyl group (s-Bu, -CH(CH3)CH2CH3), or a tert-butyl group (t-Bu, -C(CH3)3). The pentyl group includes, but is not limited to, an n-pentyl group (-CH2CH2CH2CH2CH3), a 2-pentyl group (-CH(CH3)CH2CH2CH3), a 3-pentyl group (-CH(CH2CH3)2), a 2-methyl-2-butyl group (-C(CH3)2CH2CH3), a 3-methyl-2-butyl group (-CH(CH3)CH(CH3)2), a 3-methyl-1-butyl group (-CH2CH2CH(CH3)2), or a 2-methyl-1-butyl group (-CH2CH(CH3)CH2CH3).

[0063] In one embodiment, the C2-C8 alkenyl group is a C2-C5 alkenyl group. In one specific embodiment, the C2-C8 alkenyl group and the C2-C5 alkenyl group are each independently selected from a vinyl group, a propenyl group, a butenyl group, and a pentenyl group. In one more preferred embodiment, the C2-C8 alkenyl group and the C2-C5 alkenyl group are each independently selected from a vinyl group, a propenyl group, and a butenyl group.

[0064] In one embodiment, the propenyl group is -CH2-CH2=CH 2. -CH2=CH2-CH3, including but not limited to these. The butenyl group is -CH2-CH2-CH2=CH 2. -CH2-CH2=CH2-CH 3. -CH2=CH2-CH2-CH 3. -CH=C(CH3) 2. -C(CH3)=CH2CH 3. -CH(CH3)CH=CH2, including but not limited to these. The pentenyl group is -CH=CHCH2CH2CH 3. -CH2CH=CHCH2CH 3. -CH2CH2CH=CHCH 3. -CH2CH2CH2CH=CH 2. -C(CH3)=CHCH2CH 3. -CH(CH3)CH=CHCH 3. -CH(CH3)CH2CH=CH2, including but not limited to these.

[0065] In one embodiment, the C2-C8 alkynyl group is a C2-C5 alkynyl group. In one specific embodiment, the C2-C8 alkynyl group and the C2-C5 alkynyl group are each independently selected from an ethynyl group, a propynyl group, a butynyl group, and a pentynyl group. In one more specific embodiment, the C2-C8 alkynyl group and the C2-C5 alkynyl group are each independently selected from an ethynyl group, a propynyl group, and a butynyl group.

[0066] In one embodiment, the propynyl group includes, but is not limited to, -H2C-C≡CH, -C≡C-CH3. The butynyl group includes, but is not limited to, -H2C-CH2-C≡CH, -H2C-C≡C-CH 3. H3C-CH2-C≡C-. The pentynyl group includes, but is not limited to, H3C-H2C-CH2-C≡C-, -H2C-H2C-C≡C-CH 3. H3C-H2C-C≡C-CH2-, (H3C)2C-C≡C-, but is not limited thereto.

[0067] In one embodiment, the C1-C8 haloalkyl group is a C1-C5 haloalkyl group. In one specific embodiment, in the C1-C8 haloalkyl group and the C1-C5 haloalkyl group, the C1-C8 alkyl group or the C1-C5 alkyl group is substituted with 1, 2, 3, or 4 halogens. In one preferred embodiment, the C1-C8 alkyl group or the C1-C5 alkyl group is -(CH2) a CX3 (wherein a is selected from 1, 2, 3, 4, 5, 6, and 7, and X represents a halogen). In one specific embodiment, the halogen is selected from fluorine, chlorine, bromine, and iodine. In one preferred embodiment, a is selected from 1, 2, 3, and 4. In one preferred embodiment, the halogen is fluorine.

[0068] In one embodiment, the C1-C8 haloalkyl group or the C1-C5 haloalkyl group includes, but is not limited to, -CF3, -CCl3, -CBr3, -CI3, -CH2CF3, -CH2CCl3, -CH2CBr3, -CH2CI3, -(CH2)2CF3, -(CH2)2CCl3, -(CH2)2CBr3, -(CH2)2CI3, etc.

[0069] In one embodiment, the halogen is selected from fluorine, chlorine, bromine, and iodine. In one preferred embodiment, the halogen is selected from fluorine, chlorine, and bromine, for example, fluorine, chlorine, bromine, or iodine. In one specific embodiment, the halogen is fluorine.

[0070] In one specific embodiment, Z is O, and R1, R2, R3, R4, R5, R6, R7, n1, n2, Q and

Chemical formula

[0071] In one specific embodiment, Z is O,

Chemical formula

Chemical formula

[0072] wherein R1, R2, R3, R4, R5, R6, R7, n1, n2 and Q are as defined above. In one preferred embodiment, Z is O,

Chemical formula

[0073] In one embodiment, the compound represented by Formula I is the compound represented by Formula IV. [Chemical formula] (In the formula, n1 and n2 are integers from 1 to 3, R1 is selected from a methyl group, an ethyl group, a propyl group, and a butyl group, R2 is selected from hydrogen, fluorine, chlorine, bromine, and iodine, R3, R4, R5, and R6 are each selected from hydrogen, fluorine, and chlorine, R7 is selected from an isopropyl group, an isobutyl group, an ethyl group, a propyl group, a methyl group, a cyclopropyl group, a cyclobutyl group, [Chemical formula] selected from, Z is selected from C, O, and N, and Q and W are each selected from C and N, [Chemical formula] It means that there is no bond or there is a single bond.

[0074] In one specific embodiment, in the compound represented by formula I

Chemical formula

Chemical formula

Chemical formula

[0075] In one embodiment, in the compound represented by formula I

Chemical formula

Chemical formula

Chemical formula

[0076] In one embodiment, the compound represented by formula I is selected from any one of the compounds represented by the following formulae.

Chemical formula

Chemical formula

[0077] Method for producing a compound represented by formula I

[0078] The present invention provides a method for producing a compound represented by formula I, which includes subjecting a substituted o-carboxybenzylamine with an amino group protected by Boc to a condensation reaction with a primary amine to obtain intermediate I-a, then adding hydrochloric acid to intermediate I-a to perform Boc deprotection to obtain intermediate I-b, further subjecting I-b to a reductive amination reaction with a substituted aryl aldehyde to obtain intermediate I-c, then reacting I-c with borane to reduce the amide moiety to obtain intermediate I-d, subjecting I-d to a cyclization reaction with triphosgene to obtain intermediate I-e, and finally subjecting I-e to an alkylation reaction to obtain the compound represented by formula I.

Chemical formula

[0079] Pharmaceutical composition and pharmaceutical preparation

[0080] Another object of the present invention is to provide a pharmaceutical composition containing a therapeutically effective amount of the compound of the present invention and optionally containing a pharmaceutically acceptable excipient, carrier, adjuvant, solvent or a combination thereof.

[0081] The pharmaceutically acceptable carriers used in the pharmaceutical composition of the present invention include, but are not limited to, sterile liquids such as water and oily substances. The above composition can also contain a small amount of wetting agent, emulsifier, lubricant, stabilizer or pH buffer, etc. as required. Oral dosage forms can contain standard carriers.

[0082] In one embodiment of the present invention, the pharmaceutical composition can be prepared by conventional methods using one or more pharmaceutically acceptable carriers. Therefore, the active compound of the present invention can be prepared into dosage forms suitable for oral administration, buccal administration, intranasal administration, parenteral (e.g., intravenous, intramuscular or subcutaneous) administration or rectal administration, or dosage forms suitable for administration by inhalation or insufflation.

[0083] The pharmaceutical composition of the present invention can be administered by any method as long as it can achieve the effect of preventing, alleviating, preventing or curing the symptoms of human or animal patients. For example, according to the administration route, it can be prepared into various appropriate dosage forms, especially injection dosage forms such as freeze-dried powder injections, injection solutions or sterile powders for injection.

[0084] In one embodiment of the present invention, an effective amount of the compound of the present invention can be orally administered, for example, together with an inert diluent or a certain carrier. According to some examples of the present invention, the compound of the present invention can be encapsulated in gelatin capsules or pressed into tablets. For the purpose of oral therapeutic administration, the compound of the present invention can be used in the form of tablets, lozenges, capsules, suspensions, syrups, etc. together with excipients. According to the examples of the present invention, the above preparations should contain at least 0.5% (w / w) of the active compound of the present invention, but can vary according to the specific dosage form, and 4% to about 70% by weight is convenient. The amount of the active compound in such a pharmaceutical composition should reach an appropriate dosage.

[0085] In one embodiment of the present invention, for oral administration, the active compound of the present invention can be prepared, for example, by general means, in tablets or capsules together with pharmaceutically acceptable excipients such as binders, fillers, lubricants, disintegrants or wetting agents. The tablets can also be coated by methods well known in the art. As liquid formulations for oral administration, for example, solutions, syrups or suspensions, or those which are volatilized to dry products and reconstituted with water or other suitable carriers before use can be used. Such liquid formulations can be prepared by general means using pharmaceutically acceptable additives such as suspending agents, emulsifying agents, non-aqueous carriers and preservatives.

[0086] In one embodiment of the present invention, when the active compound of the present invention is for parenteral administration, the compound provided by the present invention can be prepared in an injectable solution or suspension in combination with sterile water or an organic vehicle.

[0087] In one embodiment of the present invention, the active compound of the present invention can be prepared in rectal compositions such as suppositories or enemas containing conventional suppository bases such as cocoa butter or other glycerides.

[0088] Therapeutic uses and methods

[0089] The present invention also provides the use of the compound according to formula I in the manufacture of a medicament for treating mental disorders.

[0090] The present invention also provides a method for treating mental disorders, which includes administering to a patient in need thereof a compound represented by formula I or a pharmaceutical composition thereof. The above method may optionally include administering another active agent for treating mental disorders.

[0091] The present invention also provides a compound according to formula I or a pharmaceutical composition thereof for treating mental disorders.

[0092] In one embodiment, the above mental disorders are selected from schizophrenia and mental disorders.

[0093] In another embodiment, the mental disorder is selected from Parkinson's disease and behavioral and psychological symptoms of dementia.

[0094] Exemplary embodiments

[0095] 1. A compound represented by formula I. [Chemical formula] (In formula I, n1 and n2 are integers from 1 to 3, R1 is a straight-chain or branched alkyl group having 1 to 5 carbon atoms, R2 is selected from hydrogen and halogen, R3, R4, R5, and R6 are each independently selected from hydrogen and halogen, R7 is a straight-chain or branched alkyl group having 1 to 5 carbon atoms, a cycloalkyl group, [Chemical formula] (wherein R8 and R9 are each independently selected from straight-chain or branched alkyl groups having 1 to 3 carbon atoms).) is selected from Z is selected from C, O, and N, Q and W are each selected from C and N, [Chemical formula] The bond means that it does not exist or exists as a single bond, [Chemical formula] When it means that the bond does not exist, the compound represented by formula I is a compound represented by formula II, [Chemical formula] (In formula II, n2, R1, R3, R7, W, and Z have the same definitions as above.) [Chemical formula] When the bond exists as a single bond, the compound represented by formula I is the compound represented by formula III.

Chemical formula

Chemical formula

[0096] 2. The compound represented by formula I according to claim 1, wherein the halogen is fluorine, chlorine, bromine, and iodine.

[0097] 3. The compound represented by formula I according to claim 1, wherein the straight-chain or branched alkyl group having 1 to 5 carbon atoms is selected from a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a pentyl group, and an isopentyl group, the cycloalkyl group is selected from a cyclopropyl group, a cyclobutyl group, and a cyclopentyl group, and the straight-chain or branched alkyl group having 1 to 3 carbon atoms is a methyl group, an ethyl group, a propyl group, and an isopropyl group.

[0098] 4. The compound represented by formula I according to claim 1, wherein the compound represented by formula I is the compound represented by formula IV.

Chemical formula

[0099] 5. The compound represented by the formula I is [Chemical formula] When it means that the bond does not exist, the compound represented by the formula I according to claim 1, which is a compound represented by the formula V. [Chemical formula] (wherein, n2 is an integer from 1 to 2, R1 is selected from a methyl group, an ethyl group, a propyl group, and a butyl group, R3 is selected from hydrogen, fluorine, and chlorine, R7 is selected from an isopropyl group, an isobutyl group, an ethyl group, a propyl group, a methyl group, a cyclopropyl group, and a cyclobutyl group, [Chemical formula] selected from.)

[0100] 6. The compound represented by the formula I is

Chemical formula

Chemical formula

Chemical formula

[0101] 7. The compound represented by the formula I according to any one of claims 1 to 4, characterized in that the compound is any one of the following compounds.

Chemical formula

Chemical formula

[0102] 8. A pharmaceutical composition comprising the compound according to any one of claims 1 to 7, and further comprising, optionally, a pharmaceutically acceptable excipient, carrier, adjuvant, solvent, or a combination thereof.

[0103] 9. Use of the compound according to any one of Items 1 to 7 or the pharmaceutical composition according to Item 8 in the manufacture of a medicament for treating mental disorders.

[0104] 10. The use according to Item 9, wherein the mental disorder is schizophrenia or a mental disorder.

[0105] 11. The use according to Item 9, wherein the mental disorder is Parkinson's disease or behavioral and psychological symptoms of dementia. Advantageous effects

[0106] The compound provided by the present invention acts on 5-HT 2A , 5-HT 2C receptors and has better selectivity for 5-HT 2A than or similar to pimavanserin. The compound provided by the present invention is used for the treatment of schizophrenia or Parkinson's disease, behavioral and psychological symptoms of dementia. The compound of the present invention has antipsychotic activity equivalent to that of pimavanserin, fewer side effects of sedation and bradykinesia than pimavanserin, and less cardiotoxicity than pimavanserin. Examples

[0107] The present invention will be further described by the following examples, but the scope of the present invention is not limited to the following examples. Those skilled in the art can make various changes and modifications without departing from the spirit and gist of the present invention.

[0108] Synthesis Example

[0109] Example 1: Preparation of 2-(1-methylpiperidin-4-yl)-4-{[4-(2-methylpropoxy)phenyl]methyl}-1,5-dihydro-2,4-benzodiazepin-3-one (A19020)

Chemical formula

[0110] Synthesis route [Chem.]

[0111] 1.1 Preparation of 2- [ [(tert-butyldimethylsilyl)oxy]methyl]benzyl alcohol 1,2-Benzenedimethanol (22.0 g, 159.2 mmol), tert-butyldimethylsilyl chloride (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 gas protection. Next, water was added to quench the reaction, and the mixture was extracted with DCM (3 × 100 mL), then washed with 200 mL of saturated brine. The DCM phase was dried over anhydrous sodium sulfate, filtered by suction, concentrated, and a colorless oil (30 g, yield 74.64%) was obtained.

[0112] 1.2 Preparation of 2- [ [(tert-butyldimethylsilyl)oxy ] methyl]benzaldehyde 2- [ [(tert-butyldimethylsilyl)oxy ] methyl]benzyl alcohol (30.00 g, 118.8 mmol), DessMartin (50.4 g, 118.8 mmol), and DCM (300 mL) were added to a 1 L three-necked round-bottom flask and reacted at room temperature for 4 h under nitrogen gas protection. Next, water was added to quench the reaction, and the mixture was extracted with DCM (3 × 100 mL), then washed with 200 mL of saturated brine. The DCM phase was dried over anhydrous sodium sulfate, filtered by suction, concentrated, and separated by column chromatography (ethyl acetate / petroleum ether (1 / 35)), and a colorless oil (17 g, yield 58.62%) was obtained.

[0113] 1.3 Preparation of 2-[(tert-butyldimethylsilyl)oxymethyl] Benzyl -[4-(2-methylpropoxy)phenyl]methanamine 2-[(tert-butyldimethylsilyl)oxymethyl]benzaldehyde (1.00 g, 3.9 mmol), 1-(4-isopropyl Butoxy phenyl)methanamine (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 and maintained with nitrogen gas, reacted at room temperature for 3 h, then NaBH4 (0.76 g, 19.9 mmol) was added, and stirred at room temperature for 1 h. 30 ml of water was added, extracted with ethyl acetate (3 × 20 mL), then washed with 30 mL of saturated brine, the ethyl acetate phase was dried over anhydrous sodium sulfate, suction filtered and concentrated to obtain 1.6 g (yield 96.85%) of a colorless oil.

[0114] 1.4 Preparation of Benzyl-[N-2- [ (tert-butyldimethylsilyl)oxy ] methyl] Benzyl -N-[4-(2-methylpropoxy) Benzyl carbamate 2-[(tert-butyldimethylsilyl)oxymethyl] Benzyl -[4-(2-methylpropoxy)phenyl]methanamine (1.6 g, 0.004 mol ), tetrahydrofuran (5 mL) and water (5 mL), benzyl chloroformate (0.79 g, 0.005 mol ), potassium toluate (1.08 g, 0.008 mmol) were added to a 50 mL round-bottom flask, stirred at 50 °C for 2 h, then 30 ml of water was added, extracted with ethyl acetate (3 × 20 mL), then washed with 50 mL of saturated brine, the ethyl acetate phase was dried over anhydrous sodium sulfate, suction filtered and concentrated to obtain 2.27 g of an oil.

[0115] 1.5 Preparation of Benzyl-[N-2-(hydroxymethyl) Benzyl -N-[4-(2-methylpropoxy) Benzyl carbamate Benzyl-[N-2-[((tert-butyldimethylsilyl)oxy)methyl] Benzyl -N-[4-(2-methylpropoxy) BenzylCarbamate (2.27 g, 4.14 mmol), dioxane (20.00 mL), and HCl (5.2 mL) were added to a 50 mL three-necked round-bottom flask, which was purged and maintained with inert nitrogen gas. The mixture was stirred at room temperature for 1 h. Next, the reaction solution was concentrated and separated by silica gel column chromatography (ethyl acetate / petroleum ether (1 / 5)) to obtain 0.87 g (yield 48.6%) of a colorless oil.

[0116] 1.6 Benzyl - [N-2-(formyl Benzyl )]-N-[4-(2-methylpropoxy) Benzyl Production of carbamate Benzyl - [N-2-(hydroxymethyl) Benzyl -N-[4-(2-methylpropoxy) Benzyl Carbamate (0.87 g, 2.0 mmol), manganese dioxide (2.62 g, 30.1 mmol), and DCM (20 mL) were added to a 50 mL round-bottom flask. The temperature was raised to 80 °C and stirred overnight. Next, the solid was filtered, and the filtrate was concentrated as it was to obtain 0.75 g (yield 86.61%) of an oil.

[0117] 1.7 tert-Butyl 4-[[2-[[[(benzyloxy)carbonyl](4-isobutoxybenzyl)amino]methyl]benzyl]amino]piperidine-1-carboxylate Production of Benzyl - [N-2-(formyl Benzyl )]-N-[4-(2-methylpropoxy) Benzyl 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, which was purged and maintained with nitrogen gas. The mixture was stirred at room temperature for 3 h. Further, NaBH4 (0.33 g, 8.69 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 ethyl acetate (3 × 20 mL). Further, it was washed with 50 mL of saturated brine. The ethyl acetate phase was dried over anhydrous sodium sulfate, suction filtered, and concentrated to obtain 1.1 g of an oil.

[0118] 1.8 tert-Butyl 4-[[2-[[(4-isobutoxybenzyl)amino]methyl]benzyl]amino]piperidine-1-carboxylate Production of tert-Butyl 4-[[2-[[[(benzyloxy)carbonyl](4-isobutoxybenzyl)amino]methyl]benzyl]amino]piperidine-1-carboxylate(1.1 g), palladium carbon (0.1 g), methanol (5 mL), and tetrahydrofuran (5 mL) were added to a 50 mL three-necked round-bottom flask. Hydrogen gas was introduced, and the mixture was stirred at room temperature for 3 h. Next, the solid was filtered, and the filtrate was concentrated as it was to obtain 0.65 g of an oily substance.

[0119] 1.9 2-(tert-Butoxycarbonylpiperidine)-4- [ [4-(2-Methylpropoxy)phenyl]methyl ] Production of -1,5-dihydro-2,4-benzodiazepin-3-one tert-Butyl 4-[[2-[[(4-isobutoxybenzyl)amino]methyl]benzyl]amino]piperidine-1-carboxylate (0.65 g, 1.34 mmol) and tetrahydrofuran (10 mL) were added to a 50 mL round-bottom flask, purged and maintained with inert nitrogen gas, BTC (0.16 g, 0.54 mmol) was added at -40 °C, and the reaction was carried out for 1 h while keeping warm. Next, 30 ml of water was added, and the mixture was extracted with ethyl acetate (3 × 20 mL). Further, it was washed with 50 mL of saturated brine, the ethyl acetate phase was dried over anhydrous sodium sulfate, filtered by suction, and concentrated to obtain 0.78 g of an oily substance.

[0120] 1.10 2-(Piperidin-4-yl)-4- [ [4-(2-Methylpropoxy)phenyl]methyl ] Production of -1,5-dihydro-2,4-benzodiazepin-3-one 2-(tert-Butoxycarbonylpiperidine)-4- [ [4-(2-Methylpropoxy)phenyl]methyl ] 2-(tert-Butoxycarbonylpiperidine)-4-

[0121] 1.11 2-(1-Methylpiperidin-4-yl)-4- [ [4-(2-Methylpropoxy)phenyl]methyl ] Production of -1,5-dihydro-2,4-benzodiazepin-3-one 2-(Piperidin-4-yl)-4- [ [4-(2-Methylpropoxy)phenyl]methyl ] -1,5-dihydro-2,4-benzodiazepin-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. Next, NaBH4 (0.31 g, 8.1 mmol) was added and stirred at room temperature for 1 h. Then, 30 mL of water was added, and the mixture was extracted with ethyl acetate (3 × 20 mL), washed with 30 mL of saturated brine, dried over anhydrous sodium sulfate, filtered by suction, and concentrated. Finally, it was purified by an Intel Flash-1 column to obtain 11.6 mg (yield 1.7%) of a pale yellow oily substance. 1 1H NMR (400 MHz, Methanol-d4) δ 7.40 - 7.19 (m, 5H), 7.03 (d, J = 7.3 Hz, 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, 3.9 Hz, 1H), 3.74 (d, J = 6.5 Hz, 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, 6.6 Hz, 1H), 1.97 (t, J = 15.8 Hz, 2H), 1.04 (d, J = 6.7 Hz, 6H), LCMS (ES, m / z): 422 [M + H] +

[0122] Example 2: Preparation of 7-Fluoro-2-(1-methylpiperidin-4-yl)-4- [ [4-(2-Methylpropoxy)phenyl]methyl ] -1,5-dihydro-2,4-benzodiazepin-3-one (A19001)

Chemical Structure

[0123] Synthetic Route [Chemistry]

[0124] 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. Then, the reaction solution was filtered, and the filtrate was concentrated directly to obtain 2 g (70.26%) of a solid.

[0125] 2.2 Preparation of 2-[(tert-Butoxycarbonyl)aminomethyl]-5-fluorobenzoic Acid Methyl 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 added to a 50 mL three-necked round-bottom flask. The mixture was stirred overnight at room temperature. Then, the pH was adjusted to 5 with 3N HCl, and the mixture was extracted with EA (3 × 20 mL), washed further with 30 mL of saturated brine, dried over anhydrous sodium sulfate, suction filtered, and concentrated to obtain 1.2 g (yield 63.13%) of a solid.

[0126] 2.3 tert-Butyl [[4-fluoro-2-[(4-isobutoxybenzyl)carbamoyl]benzyl]carbamate Preparation 2-[(tert-Butoxycarbonyl)aminomethyl]-5-fluoro-benzoic 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 added to a 50 mL three-necked round-bottom flask, stirred overnight at room temperature, then 30 mL of water was added, extracted with EA (3 × 20 mL), washed with 30 mL of saturated brine, dried over anhydrous sodium sulfate, suction filtered, concentrated, and separated by silica gel column chromatography (ethyl acetate / petroleum ether (1 / 3)) to obtain 1 g of solid (yield 52.12%).

[0127] 2.4 Preparation of 2-(aminomethyl)-5-fluoro- N -( 4-Isobutoxybenzyl ) Benzamide The preparation of Prepared according to the method of 1.10 in Example 1 to obtain 1 g of an oily substance.

[0128] 2.5 5-Fluoro-N-(4-isobutoxybenzyl)-2-[[(1-methylpiperidin-4-yl)amino]methyl]benzamide The preparation of 2-(aminomethyl)-5-fluoro- N -( 4-Isobutoxybenzyl ) Benzamide 1 g, 3.02 mmol), 1-methylpiperidin-4-one (0.41 g, 3.6 mmol), NaBH3CN (0.38 g, 6.05 mmol), EtOH (10 mL), and HOAc (1 mL) were added to a 50 mL round-bottom flask, stirred overnight at room temperature, then 30 mL of saturated NaHCO3 solution was added, extracted with EA (3 × 20 mL), washed with 30 mL of saturated brine, dried over anhydrous sodium sulfate, suction filtered, concentrated, and separated by silica gel column chromatography (dichloromethane / methanol (10 / 1)) to obtain 0.75 g of solid (yield 57.96%).

[0129] 2.6 N-[4-Fluoro-2-[(4-isobutoxybenzyl)amino]methyl]benzyl-1-methylpiperidin-4-amine The preparation of 5-Fluoro-N-(4-isobutoxybenzyl)-2-[[(1-methylpiperidin-4-yl)amino]methyl]benzamide(0.3 g, 0.702 mmol), BH3-THF (10.00 mL) were added to a 50 mL round-bottom flask, stirred overnight at room temperature, then the reaction was quenched with 2N HCl, EA (30 mL) was added, the aqueous phase was extracted with EA (2×20 mL), then the pH of the aqueous phase was adjusted to 10 with 15% NaOH solution, extracted with DCM, the solvent was removed, and further purified by reverse-phase chromatography to obtain 0.1 g of a white solid (yield 34.46%).

[0130] 2.7 7-Fluoro-2-(1-methylpiperidin-4-yl)-4- [ [4-(2-methylpropoxy)phenyl]methyl ] -1,5-dihydro-2,4-benzodiazepin-3-one production

[0131] Prepared according to the method of 1.9 in Example 1, and 2.8 mg of a white solid was obtained (yield 2.63%). H-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, 4.0 Hz, 1H), 2.25 (dd, J = 13.1, 4.1 Hz, 1H), 2.06 (dp, J = 13.3, 6.7 Hz, 1H), 1.95 (d, J = 13.9 Hz, 2H), 1.04 (d, J = 6.7 Hz, 6H); LCMS (ES, m / z): 440 [M+H] +

[0132] Example 3: 7-Chloro-2-(1-methylpiperidin-4-yl)-4- [ [4-(2-methylpropoxy)phenyl]methyl ] -1,5-dihydro-2,4-benzodiazepin-3-one production (A190017) [Chemistry]

[0133] Synthesis route [Chemistry]

[0134] 3.1 Production of methyl 2-[(tert-butoxycarbonyl)aminomethyl]-4-chloro-benzoate Prepared according to the method of 2.1 in Example 2, and 1.58 g (103.10%) of a white solid was obtained.

[0135] 3.2 Production of 2-[(tert-butoxycarbonyl)aminomethyl]-4-chloro-benzoic acid Prepared according to the method of 2.2 in Example 2, and 1.12 g (74.37%) of a white solid was obtained.

[0136] 3.3 Production of 2-[(tert-butoxycarbonyl)aminomethyl]-4-chloro-4-(benzyl piperidine-1-carboxylate)benzamide Prepared according to the method of 2.3 in Example 2, and 2 g (101.63%) of a yellow oil was obtained.

[0137] 3.4 Production of 2-(aminomethyl)-4-chloro-4-(benzyl piperidine-1-carboxylate)benzamide Prepared according to the method of 1.10 in Example 1, and 2 g (124.91%) of a white solid was obtained.

[0138] 3.5 Production of 2-(2-methylpropoxy)-benzylamine-4-chloro-4-(benzyl piperidine-1-carboxylate)benzamide Prepared according to the method of 2.5 in Example 2, and 1 g (35.62%) of a yellow oil was obtained.

[0139] 3.6 Production of 2-(2-methylpropoxy)-benzylamine-4-chloro-4-(benzyl piperidine-1-carboxylate)benzylamine It was produced according to the method of 2.6 in Example 2, and 0.22 g (22.56%) of a yellow oily substance was obtained.

[0140] 3.7 7-Chloro-2-(benzyl piperidine-1-carboxylate)-4- [ [4-(2-Methylpropoxy)phenyl]methyl ] Production of -1,5-dihydro-2,4-benzodiazepin-3-one It was produced according to the method of 1.9 in Example 1, and 0.21 g (yield 91.15%) of a yellow oily substance was obtained.

[0141] 3.8 7-Chloro-2-(1-methylpiperidin-4-yl)-4- [ [4-(2-Methylpropoxy)phenyl]methyl ] Production of -1,5-dihydro-2,4-benzodiazepin-3-one 7-Chloro-2-(benzyl piperidine-1-carboxylate)-4- [ [4-(2-Methylpropoxy)phenyl]methyl ] -1,5-Dihydro-2,4-benzodiazepin-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 added to a 50 mL round-bottom flask, stirred at room temperature for 10 h, suction filtered, the filtrate was concentrated, and purified by preparative liquid chromatography to obtain 2.4 mg (yield 1.44%) of a white solid. 1HNMR(400MHz, DMSO-d4) δ 9.62 (s, 1H), 7.33 (dd, J = 8.0, 2.2 Hz, 1H), 7.28 - 7.18 (m, 6H), 6.90 - 6.83 (m, 3H), 4.37 - 4.30 (m, 8H), 4.17 (d, J = 12.6 Hz, 2H), 3.72 (d, J = 6.5 Hz, 3H), 3.05 (d, J = 10.8 Hz, 2H), 2.76 (d, J = 4.7 Hz, 4H), 2.38 (s, 4H), 2.18 - 2.08 (m, 3H), 2.00 (dt, J = 13.4, 6.7 Hz, 1H), 1.75 (d, J = 13.3 Hz, 3H), 1.24 (s, 1H), 0.98 (d, J = 6.7 Hz, 9H); LCMS (ES, m / z): 456 [M + H] +

[0142] Example 4: 8-Fluoro-2-(1-methylpiperidin-4-yl)-4- [ [4-(2-methylpropoxy)phenyl]methyl ] -1,5-dihydro-2,4-benzodiazepin-3-one production (A19005)

Chemical Structure

[0143] Synthesis route

Chemical Structure

[0144] 4.1 tert-Butyl 4-fluoro-2-[[(1-methylpiperidin-4-yl)carbamoyl]benzyl]carbamate Production Prepared according to the method of 2.3 in Example 2, and 8 g (84.21%) of an oily substance was obtained.

[0145] 4.2 2-(Aminomethyl)-5-fluoro-N-(1-methylpiperidin-4-yl)benzamide Production Prepared according to the method of 1.10 in Example 1, and 2 g of an oily substance was obtained.

[0146] 4.3 5-Fluoro-2-[[(4-isobutoxybenzyl)amino]methyl]-N-(1-methylpiperidin-4-yl)benzamide Production Prepared according to the method of 2.5 in Example 2, and 0.65 g (20.17%) of a yellow oily substance was obtained.

[0147] 4.4 N-[5-Fluoro-2-[[(4-isobutoxybenzyl)amino]methyl]benzyl]-1-methylpiperidin-4-amine Production Prepared according to the method of 2.6 in Example 2, and 0.25 g (12.31%) of a yellow oily substance was obtained.

[0148] 4.5 8-Fluoro-2-(1-methylpiperidin-4-yl)-4- [ [4-(2-methylpropoxy)phenyl]methyl ] -1,5-Dihydro-2,4-benzodiazepin-3-one production Prepared according to the method of 1.9 in Example 1, and 35 mg (yield 13.17%) of a white solid was obtained. H-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), 3.60 (d, J = 12.4 Hz, 2H), 3.40 (s, 0H), 3.15 (t, J = 12.7 Hz, 2H), 2.91 (s, 3H), 2.25 (qd, J = 13.3, 4.0 Hz, 2H), 2.06 (dt, J = 13.3, 6.6 Hz, 1H), 1.96 (d, J = 13.8 Hz, 2H), 1.04 (d, J = 6.7 Hz, 6H); LCMS (ES, m / z): 440 [M+H] +

[0149] Example 5: 8-Fluoro-2-(1-methylpiperidin-4-yl)-4- [ [4-(2-methylpropylamino)phenyl]methyl ] -1,5-Dihydro-2,4-benzodiazepin-3-one production (A19007)

Chemical Structure

[0150] Synthesis route

Chemical Structure

[0151] 5.1 Production of Methyl 2-[(tert-Butoxycarbonyl)aminomethyl]-5-fluorobenzoate Produced according to the method of 2.1 in Example 2, and 4.7 g of an oily substance was obtained.

[0152] 5.2 Production of 2-[(tert-Butoxycarbonyl)aminomethyl]-5-fluorobenzoic acid Produced according to the method of 2.2 in Example 2, and 4.0 g (89.54%) of an oily substance was obtained.

[0153] 5.3 2-[(tert-Butoxycarbonyl)aminomethyl]-5-fluoro- N-( 4-(Benzyl piperidine-1-carboxylate) ) Benzamide Produced according to the method of 2.3 in Example 2, and 4.6 g of an oily substance was obtained.

[0154] 5.4 Production of 2-(Aminomethyl)-5-fluoro-4-(benzyl piperidine-1-carboxylate)benzamide Produced according to the method of 1.10 in Example 1, and 5.6 g of an oily substance was obtained.

[0155] 5.5 Benzyl 4-[2-[(4-bromobenzamide)methyl]-5-fluorobenzamide]piperidine-1-carboxylate Production of Produced according to the method of 2.3 in Example 2, and 3.2 g (38.75%) of a white solid was obtained.

[0156] 5.6 Benzyl 4-[5-fluoro-2-[[4-(isobutylamino)benzamide]methyl]benzamide]piperidine-1-carboxylate Production of Benzyl 4-[2-[(4-bromobenzamide)methyl]-5-fluorobenzamide]piperidine-1-carboxylate(1g, 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 added to a 50 mL round-bottom flask, heated to 80 °C, stirred for 1 h, suction filtered, the filtrate was concentrated, and separated by silica gel column chromatography (PE / EA = 3:1) to obtain 0.797 g of a yellow solid (yield 80.8%).

[0157] 5.7 8-Fluoro-2-(benzyl piperidine-1-carboxylate)-4- [ [4-(2-Methylpropylamino)phenyl]methyl ] -1,5-Dihydro-2,4-benzodiazepin-3-one production Prepared according to the method of 1.9 in Example 1 to obtain 0.26 g of an oily substance.

[0158] 5.8 8-Fluoro-2-(1-methylpiperidin-4-yl)-4- [ [4-(2-Methylpropylamino)phenyl]methyl ] -1,5-Dihydro-2,4-benzodiazepin-3-one production Prepared according to the method of 3.7 in Example 3 to obtain 4.1 mg of a white solid (yield 2.61%). 1 HNMR(400MHz,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,2H), 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] +

[0159] The general synthesis methods of compounds A19006, A19008, A19009, A19011, A19012, A19013, and A19015 are as follows.

Chemical formula

[0160] Example 6: 7-Fluoro-2-[(4-cyclopropoxyphenyl)methyl]-4- (1-Methylpiperidine- -yl)-1,5- Production of dihydro-2,4-benzodiazepin-3-one (A19006)

Chemical formula

[0161] 6.1 Production of 2-[(tert-butoxycarbonyl)aminomethyl]-5-fluoro- N-( 4-(benzyl piperidine-1-carboxylate) ) benzamide Prepared according to the method of 2.3 in Example 2, and 23 g (63.77%) of a yellow solid was obtained.

[0162] 6.2 Benzyl 4-[2-(aminomethyl)-5-fluorobenzamide]piperidine-1-carboxylate hydrochloride Production of Prepared according to the method of 1.10 in Example 1, and 1.9 g of an oily substance was obtained.

[0163] 6.3 Benzyl 4-[2-[[(4-cyclopropoxybenzyl)amino]methyl]-5-fluorobenzamide]piperidine-1-carboxylate Production of Prepared according to the method of 1.7 in Example 1, and 1.3 g of an oily substance was obtained.

[0164] 6.4 Benzyl 4-[2-[[(4-cyclopropoxybenzyl)amino]methyl]-5-fluorobenzylamino]piperidine-1-carboxylate Production of Prepared according to the method of 2.6 in Example 2, and 0.23 g (18.17%) of a yellow oily substance was obtained.

[0165] 6.5 Benzyl 4-[4-(4-cyclopropoxybenzyl)-8-fluoro-3-oxo-1,3,4,5-tetrahydro-2H-benzo[e][1,3]diazepin-2-yl]piperidine-1-carboxylate Production of Prepared according to the method of 1.9 in Example 1, and 0.2 g of an oily substance was obtained.

[0166] 6.6 7-Fluoro-2-[(4-cyclopropoxyphenyl)methyl]-4- (1-Methylpiperidine- -yl)-1,5-Production of Dihydro-2,4-benzodiazepin-3-one Prepared according to the method of 3.7 in Example 3, and 37.9 mg (yield 24.32%) of a brown solid was obtained. 1 HNMR(400MHz,DMSO-d6)δ7.30-7.19(m,3H), 7.11(dd,J=8.4,5.7Hz,1H), 7.05-6.94(m,3H), 4.36(d,J=7.1Hz,4H), 4.29(s,2H), 3.96(tt,J=11.4,4.0Hz,1H), 3.80(tt,J=6.0,3.0Hz,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] +

[0167] Example 7: 8-Fluoro-2-(1-methylpiperidin-4-yl)-4- [ [4-(2-methylpropyl)phenyl]methyl ] -1,5-Dihydro-2,4-benzodiazepin-3-one production (A19008)

Chemical formula

[0168] 7.1 Production of 2-(2-methylpropyl)-benzylamine-5-fluoro-4-(benzyl piperidine-1-carboxylate)benzamide Prepared according to the method of 1.7 in Example 1, and 2.3 g (yield 61.76%) of a yellow oil was obtained.

[0169] 7.2 Production of 2-(2-methylpropyl)-benzylamine-5-fluoro-4-(benzyl piperidine-1-carboxylate)benzylamine Prepared according to the method of 2.6 in Example 2, and 0.69 g of a yellow oil was obtained.

[0170] 7.3 Preparation of 8-fluoro-2-(benzyl piperidine-1-carboxylate)-4- [ [4-(2-methylpropyl)phenyl]methyl ] -1,5-dihydro-2,4-benzodiazepin-3-one Prepared according to the method of 1.9 in Example 1 to obtain 0.7 g of a yellow oil.

[0171] 7.4 Preparation of 8-fluoro-2-(1-methylpiperidin-4-yl)-4- [ [4-(2-methylpropyl)phenyl]methyl ] -1,5-dihydro-2,4-benzodiazepin-3-one Prepared according to the method of 3.7 in Example 3 to obtain 21 mg (yield 3.85%) of a yellow solid. 1 HNMR(400MHz,DMSO-d6)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] +

[0172] Example 8: Preparation of 8-fluoro-2-(1-methylpiperidin-4-yl)-4-[(4-methoxyphenyl)methyl]-1,5-dihydro-2,4-benzodiazepin-3-one (A19009)

Chemical Structure

[0173] 8.1 Preparation of 2-(4-methoxy)-benzylamine-5-fluoro-4-(benzyl piperidine-1-carboxylate)benzamide Prepared according to the method of 1.7 in Example 1 to obtain 0.48 g of a yellow oil.

[0174] 8.2 Production of 2-(4-methoxy)-benzylamine-5-fluoro-4-(benzyl piperidine-1-carboxylate) benzylamine Prepared according to the method of 2.6 in Example 2, and 0.13 g of a yellow oil was obtained.

[0175] 8.3 Production of 8-fluoro-2-(benzyl piperidine-1-carboxylate)-4-[(4-methoxyphenyl)methyl]-1,5-dihydro-2,4-benzodiazepin-3-one Prepared according to the method of 1.9 in Example 1, and 0.09 g of a yellow oil was obtained.

[0176] 8.4 Production of 8-fluoro-2-(1-methylpiperidin-4-yl)-4-[(4-methoxyphenyl)methyl]-1,5-dihydro-2,4-benzodiazepin-3-one Prepared according to the method of 3.7 in Example 3, and 9 mg (yield 13.2%) of a white solid was obtained. 1 HNMR(400MHz,DMSO-d6)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] +

[0177] Example 9: 8-Fluoro-2-(1-methylpiperidin-4-yl)-4- [ [(2-fluoro-4-isopropoxyphenyl)methyl] ] -1,5-dihydro-2,4-benzodiazepin-3-one Production (A19011)

Chemical Structure

[0178] 9.1 Preparation of 2-(2-Fluoro-4-isopropoxy)-benzylamine-5-fluoro-4-(benzyl piperidine-1-carboxylate) benzamide Prepared according to the method of 1.7 in Example 1, and 0.88 g of a yellow oil was obtained.

[0179] 9.2 Preparation of 2-(2-Fluoro-4-isopropoxy)-benzylamine-5-fluoro-4-(benzyl piperidine-1-carboxylate) benzylamine Prepared according to the method of 2.6 in Example 2, and 0.117 g of a yellow oil was obtained.

[0180] 9.3 8-Fluoro-2-(benzyl piperidine-1-carboxylate)-4- [ [(2-Fluoro-4-isopropoxy)phenyl]methyl ] -1,5-Dihydro-2,4-benzodiazepin-3-one Preparation Prepared according to the method of 1.9 in Example 1, and 0.09 g of a yellow oil was obtained.

[0181] 9.4 8-Fluoro-2-(1-methylpiperidin-4-yl)-4- [ [(2-Fluoro-4-isopropoxy)phenyl]methyl ] -1,5-Dihydro-2,4-benzodiazepin-3-one Preparation Prepared according to the method of 3.7 in Example 3, and 5.3 mg (yield 7.5%) of an orange solid was obtained. 1 HNMR(400MHz,DMSO-d6)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), 4.36(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] +

[0182] Example 10: 8-Fluoro-2-(1-methylpiperidin-4-yl)-4- [ [(3-Fluoro-4-isopropoxyphenyl)methyl] ] -1,5-dihydro-2,4-benzodiazepin-3-one production (A19012)

Chemical Structure

[0183] 10.1 Production of 2-(3-Fluoro-4-isopropoxy)-benzylamine-5-fluoro-4-(benzyl piperidine-1-carboxylate)benzamide Produced according to the method of 1.7 in Example 1, and 1.0 g of a yellow oily substance was obtained.

[0184] 10.2 Production of 2-(3-Fluoro-4-isopropoxy)-benzylamine-5-fluoro-4-(benzyl piperidine-1-carboxylate)benzylamine Produced according to the method of 2.6 in Example 2, and 0.118 g of a yellow oily substance was obtained.

[0185] 10.3 Production of 8-Fluoro-2-(benzyl piperidine-1-carboxylate)-4- [ [(3-Fluoro-4-isopropoxyphenyl)methyl] ] -1,5-dihydro-2,4-benzodiazepin-3-one Produced according to the method of 1.9 in Example 1, and 0.11 g of a yellow oily substance was obtained.

[0186] 10.4 Production of 8-Fluoro-2-(1-methylpiperidin-4-yl)-4- [ [(3-Fluoro-4-isopropoxyphenyl)methyl] ] -1,5-dihydro-2,4-benzodiazepin-3-one Produced according to the method of 3.7 in Example 3, and 4.3 mg (yield 4.9%) of a yellow oily substance was obtained. 1HNMR(400MHz, DMSO-d6) δ 9.16 (s, 1H), 7.18 (dd, J = 8.3, 5.6 Hz, 1H), 7.15 - 7.01 (m, 5H), 4.58 (p, J = 6.0 Hz, 1H), 4.40 - 4.32 (m, 6H), 4.16 (s, 1H), 2.78 (d, J = 4.4 Hz, 3H), 2.44 (s, 12H), 2.05 (q, J = 12.9, 12.3 Hz, 2H), 1.78 (d, J = 13.5 Hz, 2H), 1.27 (d, J = 6.0 Hz, 6H), 1.24 (s, 1H); LCMS (ES, m / z): 444 [M + H] +

[0187] Example 11: 8-Fluoro-2-(1-methylpiperidin-4-yl)-4- [ [( 6 -isopropoxy)pyridin-3-yl]methyl ] -1,5-dihydro-2,4-benzodiazepin-3-one production (A19013)

Chemical Structure

[0188] 11.1 Production of 2-[(4-isopropoxypyridin-3-yl)]-aminomethyl-5-fluoro-4-(benzyl piperidine-1-carboxylate)benzamide Produced according to the method of 1.7 in Example 1 to obtain 2.4 g of a yellow oil.

[0189] 11.2 Production of 2-[4-(4-isopropoxypyridin-3-yl)]-aminomethyl-5-fluoro-4-(benzyl piperidine-1-carboxylate)benzylamine Produced according to the method of 2.6 in Example 2 to obtain 0.38 g of a yellow oil.

[0190] 11.3 Production of 8-fluoro-2-(benzyl piperidine-1-carboxylate)-4- [ [(4-isopropoxy)pyridin-3-yl]methyl ] -1,5-dihydro-2,4-benzodiazepin-3-one Prepared according to the method of 1.9 in Example 1 to obtain 0.37 g of a yellow oily substance.

[0191] 11.4 8-Fluoro-2-(1-methylpiperidin-4-yl)-4- [ [( 6 -isopropoxy)pyridin-3-yl]methyl ] -1,5-Dihydro-2,4-benzodiazepin-3-one production Prepared according to the method of 3.7 in Example 3 to obtain 50.6 mg (yield 17.3%) of a white solid. 1 HNMR(400MHz,DMSO-d6)δ 1 HNMR(400MHz,DMSO-d6)δ 8.09(s,1H), 7.62(d,J = 8.6Hz,1H), 7.27(d,J = 9.3Hz,1H), 7.15(t,J = 7.1Hz,1H), 7.02(t,J = 8.3Hz,1H), 6.67(d,J = 8.6Hz,1H), 5.21(dt,J = 13.0,6.6Hz,1H), 4.39 - 4.31(m,6H), 3.98(d,J = 12.3Hz,1H), 2.82(d,J = 10.3Hz,2H), 2.17(s,3H), 1.88(dt,J = 28.7,12.2Hz,4H), 1.48 - 1.40(m,2H), 1.27(d,J = 6.1Hz,6H); LCMS(ES,m / z): 427[M + H] +

[0192] Example 12: 8-Fluoro-2-(1-methylpyrrol-3-yl)-4- [ [(4-iso Butoxy )phenyl]methyl ] -1,5-Dihydro-2,4-benzodiazepin-3-one production (A19015)

Chemical formula

[0193] 12.1 Production of 2-[(4-isopropoxypyrrol-3-yl)]-aminomethyl-5-fluoro-4-(benzyl piperidine-1-carboxylate)benzamide Produced according to the method of 1.7 of Example 1, 3.3 g of a yellow oily substance was obtained.

[0194] 12.2 Production of 2-[4-(4-isopropoxypyrrol-3-yl)]-aminomethyl-5-fluoro-4-(benzyl piperidine-1-carboxylate) benzylamine Produced according to the method of 2.6 of Example 2, 0.32 g of a colorless oily substance was obtained.

[0195] 12.3 8-Fluoro-2-(benzyl pyrrole-1-carboxylate)-4- [ [(4-isopropoxy)phenyl]methyl ] -1,5-dihydro-2,4-benzodiazepin-3-one production Produced according to the method of 1.9 of Example 1, 0.31 g of a yellow oily substance was obtained.

[0196] 12.4 8-Fluoro-2-(1-methylpyrrol-3-yl)-4- [ [(4-iso Butoxy )phenyl]methyl ] -1,5-dihydro-2,4-benzodiazepin-3-one production Produced according to the method of 3.7 of Example 3, 47.3 mg (yield 18.6%) of a white solid was obtained. 1 HNMR(400MHz,DMSO-d6)δ 1HNMR(400MHz, 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, 8.8 Hz, 1H), 3.04 (td, J = 10.5, 8.2 Hz, 1H), 2.87 (s, 3H), 2.55 - 2.43 (m, 1H), 2.15 (ddt, J = 13.6, 8.8, 4.6 Hz, 1H), 2.05 (dq, J = 13.3, 6.7 Hz, 1H), 1.04 (d, J = 6.7 Hz, 6H); LCMS (ES, m / z): 426 [M + H] +

[0197] Example 13: 7-Fluoro-1-methyl-2- [ [4-(2-methylpropoxy)phenyl]methyl ] -1,5-dihydrospiro[2-benzodiazepine-4,4'-piperidine]-3-one production (A19019)

Chemical formula

[0198] Synthesis route

Chemical formula

[0199] 13.1 Production of 1-tert-butyl-4-ethyl 4-[(2-cyano-5-fluorophenyl)methyl]piperidine-1,4- Dicarboxylate of 2-(Bromomethyl)-4-fluorobenzonitrile (2.5 g, 11.680 mmol), LDA (1.38 g, 12.88 mmol), and THF (25 mL) were added to a 100 mL three-necked round-bottom flask, stirred overnight at room temperature, purged with nitrogen gas for 30 min, and then, at -78 °C, 1-tert-butyl 4-ethyl piperidine-1,4- Dicarboxylate(3.01 g, 0.012 mmol) was added dropwise. After the addition was complete, the mixture was stirred overnight at room temperature under a nitrogen atmosphere. Next, the reaction was quenched with saturated NH4Cl (200 mL) solution, and the mixture was further 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. Elution by silica gel column chromatography (PE / EtOAc (3:1)) gave 3.5 g (76.74%) of a yellow solid.

[0200] 13.2 1-tert-butyl-4-ethyl 4-[(2-aminomethyl-5-fluorophenyl)methyl]piperidine-1,4- Dicarboxylate Production Prepared according to the method of 2.1 of Example 2, and 1.5 g (55.4%) of a white solid was obtained.

[0201] 13.3 tert-Butyl 7-fluoro-3-oxo-1,2,3,5-tetrahydrospiro[benzo[c]azepine-4,4'-piperidine]-1'-carboxylate Production 1-tert-butyl-4-ethyl 4-[(2-aminomethyl-5-fluorophenyl)methyl]piperidine-1,4- Dicarboxylate (1 g, 2.54 mmol), Cs2CO3 (2.48 g, 0.008 mmol), and DMF (10 mL) were added to a 50 mL three-necked round-bottom flask, purged with nitrogen gas, and stirred at 80 °C for 2 h. Next, it was filtered, 20 mL of water was added to the filtrate, and the mixture was extracted with EtOAc (3 × 20 mL). The resulting mixture was washed with brine (3 × 20 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give 0.83 g (93.9%) of a yellow solid.

[0202] 13.4 1-tert-butyl 7-fluoro-2- [ [4-(2-methylpropoxy)phenyl]methyl ] -3-oxo-1,5-dihydrospiro[2-benzodiazepine-4,4'-piperidine]-1- Carboxylate Production tert-Butyl 7-fluoro-3-oxo-1,2,3,5-tetrahydrospiro[benzo[c]azepine-4,4'-piperidine]-1'-carboxylate(0.83 g, 1.14 mmol), tetrahydrofuran (4 mL) were added to a 50 mL three-necked round-bottom flask. Under a nitrogen gas atmosphere, NaH (91 mg, 2.29 mmol) was added at 0 °C. Next, 1-(chloromethyl)-4-(2-methylpropoxy)benzene ( 0.27 g, 1.37 mmol) was added dropwise. After completion of the reaction, water was added to quench the reaction, 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 to obtain 0.5 g (85.2%) of a yellow solid.

[0203] 13.5 7-Fluoro-2- [ [4-(2-methylpropoxy)phenyl]methyl ] -1,5-dihydrospiro[2-benzodiazepine-4,4'-piperidine]-3-one production Prepared according to the method of 1.10 in Example 1 to obtain 0.4 g of an oily substance.

[0204] 13.6 7-Fluoro-1-methyl-2- [ [4-(2-methylpropoxy)phenyl]methyl ] -1,5-dihydrospiro[2-benzodiazepine-4,4'-piperidine]-3-one production 7-Fluoro-2- [ [4-(2-methylpropoxy)phenyl]methyl ] -1,5-dihydrospiro[2-benzalazine-4,4'-piperidine]-3-one (0.4 g, 0.97 mmol), HCHO (58 mg, 1.9 mmol), HOAc (292 mg, 4.8 mmol), MeOH (4 mL) were added to a 50 mL three-necked round-bottom flask. Under a nitrogen gas atmosphere, the mixture was stirred for 30 min, then STAB (309 mg, 1.461 mmol) was added at room temperature. After completion of the reaction, 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 to obtain 7.6 mg (yield 1.84%) of a white solid. 1HNMR(400MHz, DMSO-d6) δ 7.20 - 7.06 (m, 4H), 6.96 (td, J = 8.7, 2.7 Hz, 1H), 6.91 - 6.83 (m, 2H), 4.56 (s, 2H), 4.42 (s, 2H), 3.72 (d, J = 6.5 Hz, 2H), 3.09 (s, 2H), 2.58 (dt, J = 11.4, 3.6 Hz, 2H), 2.32 - 2.21 (m, 2H), 2.21 (s, 3H), 2.15 (td, J = 12.7, 4.2 Hz, 2H), 2.01 (dq, J = 13.3, 6.6 Hz, 1H), 1.34 (d, J = 12.9 Hz, 2H), 0.98 (d, J = 6.7 Hz, 6H); LCMS (ES, m / z): 424 [M + H] +

[0205] The general synthetic methods of compound A19014 - 0 and A19014 - 0A are as follows.

Chemical Structure

[0206] Example 14: (3R,4 S ) - 8 - fluoro - 2 - (1 - methyl - 3 - fluoropiperidin - 4 - yl) - 4 - [ [4 - (2 - methylpropoxy)phenyl]methyl ] -1,5 - dihydro - 2,4 - benzodiazepin - 3 - one production (A19014 - 0)

Chemical Structure

[0207] 14.1 Production of benzyl 4 - amino - 3 - fluoropiperidine - 1 - carboxylate 3-Benzyl fluoro-4-oxopiperidine-1-carboxylate (2 g, 7.9 mmol), acetamide (2.35 g, 39.8 mmol), NaBH3CN (1 g, 62.8 mmol), and methanol (10 mL) were added to a 25 mL three-necked round-bottom flask, purged with nitrogen gas, and reacted overnight at room temperature. After the reaction was completed, the mixture was extracted with EtOAc (3 × 30 mL), and the resulting mixture was washed with brine (2 × 20 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. It was separated by silica gel column chromatography using an ethyl acetate / petroleum ether (1:1) system to obtain 0.7 g of a colorless oil (yield 34.86%).

[0208] 14.2 4- [ 2-[(tert-Butoxycarbonyl)amino]methyl ] Preparation of benzyl 2-[(tert-butoxycarbonyl)amino]methyl-5-fluorobenzamide-3-fluoropiperidine-1-carboxylate Prepared according to the method of 2.3 in Example 2 to obtain 1.3 g of an oil.

[0209] 14.3 4-[2-(Aminomethyl)-5-fluoro Benzamide -benzyl 3-fluoropiperidine-1-carboxylate preparation Prepared according to the method of 1.10 in Example 1 to obtain 1 g of a pale yellow oil.

[0210] 14.4 3-Fluoro-4-[5-fluoro- 2-[ 4-(2-methylpropoxy) Benzyl methylamino ] Preparation of benzyl 3-fluoro-4-[5-fluoro-4-(2-methylpropoxy)methylamino]benzamide-piperidine-1-carboxylate Prepared according to the method of 2.5 in Example 2 to obtain 0.6 g (42.8%) of a yellow oil.

[0211] 14.5 3-Fluoro-4-[5-fluoro-2- [ [4-(2-methylpropoxy) Benzyl methyl ] amino ] Preparation of benzyl 3-fluoro-4-[5-fluoro-2-[4-(2-methylpropoxy)methylamino]benzylamino]piperidine-1-carboxylate Prepared according to the method of 2.6 of Example 2 to obtain 0.23 g (18.32%) of a yellow oily substance.

[0212] 14.6 8-Fluoro-2-(benzyl 3-fluoropiperidine-1-carboxylate)-4- [ [4-(2-methylpropoxy)phenyl]methyl ] -1,5-Dihydro-2,4-benzodiazepin-3-one production Prepared according to the method of 1.9 of Example 1 to obtain 0.13 g (yield 88.7%) of a colorless oily substance.

[0213] 14.7 (3R,4 S )-8-Fluoro-2-(1-methyl-3-fluoropiperidin-4-yl)-4- [ [4-(2-methylpropoxy)phenyl]methyl ] -1,5-Dihydro-2,4-benzodiazepin-3-one production Prepared the racemate according to the experimental method of 3.7 of Example 3, and then obtained 18.1 mg (yield 17.03%) of a yellow solid by Flash-Prep-HPLC. 1 HNMR(400MHz,Methanol-d4)δ7.23-7.18(m,2H), 7.13(dd,J=9.0,2.6Hz,1H), 7.00(dd,J=8.4,5.5Hz,1H), 6.93(td,J=8.6,2.6Hz,1H), 6.88-6.84(m,2H), 4.85-4.77(m,1H), 4.71(d,J=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), 2.98 2.84(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] +

[0214] Example 15: (3S,4 S )-8-Fluoro-2-(1-methyl-3-fluoropiperidin-4-yl)-4- [[4-(2-Methylpropoxy)phenyl]methyl ] -Production of 1,5-dihydro-2,4-benzodiazepin-3-one (A19014-0A)

Chemical formula

[0215] Example 16: Production of 7,8-difluoro-2-(4-isobutoxybenzyl)-4-(1-methylpiperidin-4-yl)-1,2,4,5-tetrahydro-3H-benzo[e][1.3]diazepin-3-one (A20001)

Chemical formula

[0216] Example 17: Preparation of 6-Fluoro-N-(1-methylpiperidin-4-yl)-2-[[4-(2-methylpropoxy)phenyl]methyl]-3-oxoimidazo[1,5-a]pyridine-8-carboxamide (A19016)

Chemical Structure

[0217] Example 18: Preparation of 7-Fluoro-2-[[4-(2-Hydroxyl-2-Methylpropyl)phenyl]methyl]-4-(1-Methylpiperidin-4-yl)-1,5-Dihydro-2,4-Benzodiazepin-3-One (A19010) [Chemical formula]

[0218] Synthesis Route [Chemical formula]

[0219] 18.1 Preparation of Benzyl 4-[4-[(4-Bromophenyl)methyl]-8-Fluoro-3-Oxo-1,5-Dihydro-2,4-Benzodiazepin-2-Yl]Piperidine-1-Carboxylate Prepared according to the method of Example 4 to obtain 1 g of a pale yellow oily substance.

[0220] 18.2 Benzyl- Preparation of [4-([4-[(E)-2-Ethoxyvinyl]phenyl]methyl)-8-Fluoro-3-Oxo-1,5-Dihydro-2,4-Benzodiazepin-2-Yl]Piperidine-1-Carboxylate Into a 100 ml three-necked flask Benzyl -[4-[(4-Bromophenyl)methyl]-8-Fluoro-3-Oxo-1,5-Dihydro-2,4-Benzodiazepin-2-Yl]Piperidine-1-Carboxylate (1.00 g, 1.765 mmol), (E)-1-Ethoxyvinyl-2-boronic acid pinacol ester (0.70 g, 3.531 mmol), dioxane (10.00 mL), water (2.00 mg) and K3PO4 (1.12 g, 5.296 mmol) were added respectively, and the resulting solution was stirred at 25 °C for 10 minutes, and Pd(dppf) Cl 2 (0.14 g (0.177 mmol) was added, and the temperature was raised to 100 °C and reacted for 2 hours. After completion of the reaction, water was added to the system 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), further washed with saturated brine (2 x 20 mL), dried over anhydrous sodium sulfate, and the solvent was evaporated under pressure. It was separated and purified by column chromatography (EA:PE = 1:30) to obtain the compound Benzyl- [4-([4-[(E)-2-Ethoxyvinyl]phenyl]methyl)-8-fluoro-3-oxo-1,5-dihydro-2,4-benzodiazepin-2-yl]piperidine-1-carboxylate (400 mg, yield 40.63%, brown oil) was obtained.

[0221] 18.3 Preparation of Benzyl 4-(8-Fluoro-3-oxo-4-[[4-(2-oxoethyl)phenyl]methyl]-1,5-dihydro-2,4-benzodiazepin-2-yl)piperidine-1-carboxylate Into a 50 mL three-necked flask Benzyl- [4-([4-[(E)-2-Ethoxyvinyl]phenyl]methyl)-8-fluoro-3-oxo-1,5-dihydro-2,4-benzodiazepin-2-yl]piperidine-1-carboxylate (200.00 mg, 0.359 mmol), tetrahydrofuran (2.00 mL) and HCl (6 M) (2.00 mL) were added respectively, and the mixture was stirred at 25 °C for 2 hours. After completion of the reaction, water was added to quench the reaction, and the mixture was extracted with methyl tert-butyl ether (3 x 10 mL). The organic phase was washed with 30 mL of saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain benzyl 4-(8-fluoro-3-oxo-4-[[4-(2-oxoethyl)phenyl]methyl]-1,5-dihydro-2,4-benzodiazepin-2-yl)piperidine-1-carboxylate (200 mg, yield 105.30%, yellow oil).

[0222] Preparation of Benzyl 4-(8-Fluoro-4-[[4-(2-hydroxypropyl)phenyl]methyl]-3-oxo-1,5-dihydro-2,4-benzodiazepin-2-yl)piperidine-1-carboxylate To a 50 mL three-necked flask were added benzyl 4-(8-fluoro-3-oxo-4-[[4-(2-oxoethyl)phenyl]methyl]-1,5-dihydro-2,4-benzodiazepin-2-yl)piperidine-1-carboxylate (200.00 mg, 0.378 mmol) and tetrahydrofuran (3.00 mL) respectively. The temperature was lowered to 0 °C and stirred for 5 minutes. Then bromo(methyl)magnesium (180.12 mg, 1.511 mmol) was added, and the temperature was raised to 60 °C and reacted for 2 hours. After the reaction was completed, 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 over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain benzyl 4-(8-fluoro-4-[[4-(2-hydroxypropyl)phenyl]methyl]-3-oxo-1,5-dihydro-2,4-benzodiazepin-2-yl)piperidine-1-carboxylate (200 mg, yield 97.06%, yellow oil).

[0223] 18.5 Benzyl- 4- [ 8-Fluoro-3-oxo-4-[[4-(2-oxopropyl)phenyl]methyl]-1,5-dihydro-2,4-benzodiazepin-2-yl ] piperidine-1- Carboxylate Preparation To a 50 mL three-necked flask was added benzyl 4-(8-fluoro-4-[[4-(2-hydroxypropyl)phenyl]methyl]-3-oxo-1,5-dihydro-2,4-benzodiazepin-2-yl)piperidine-1- Carboxylate(200.00 mg, 0.367 mmol) and dichloromethane (20.00 mL) were each added, cooled to 0 °C under nitrogen gas protection and stirred for 5 minutes. Further, DMP (310.92 mg, 0.733 mmol) was added and stirred at 25 °C for 3 hours to react. After completion of the reaction, an NaHCO3 solution was added to quench the reaction, extracted with dichloromethane (3 x 20 mL), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain the compound Benzyl- 4- [ 8-fluoro-3-oxo-4-[[4-(2-oxopropyl)phenyl]methyl]-1,5-dihydro-2,4-benzodiazepin-2-yl ] piperidine-1- Carboxylate (180 mg, yield 90.33%, yellow oil) was obtained.

[0224] 18.6 Benzyl-4-(8-fluoro-4-[[4-(2-hydroxy-2-methylpropyl)phenyl]methyl]-3-oxo-1,5-dihydro-2,4-benzodiazepin-2-yl)piperidine-1- Carboxylate Production of Into a 50 mL three-necked flask Benzyl- 4- [ 8-fluoro-3-oxo-4-[[4-(2-oxopropyl)phenyl]methyl]-1,5-dihydro-2,4-benzodiazepin-2-yl ] piperidine-1- Carboxylate (150.00 mg, 0.276 mmol), tetrahydrofuran (5.00 mL, 0.069 mmol) and MeMgBr (2.00 mL, 0.017 mmol) were each added, heated to 60 °C under nitrogen gas protection and reacted for 3 hours. After completion of the reaction, the reaction was quenched with an NH4Cl solution, extracted with ethyl acetate (3 x 10 mL), the organic phase was washed with 10 mL of saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain the compound benzyl-4-(8-fluoro-4-[[4-(2-hydroxy-2-methylpropyl)phenyl]methyl]-3-oxo-1,5-dihydro-2,4-benzodiazepin-2-yl)piperidine-1- Carboxylate (140 mg, yield 90.66%, yellow oil) was obtained.

[0225] Preparation of 18.7 7-Fluoro-2-[[4-(2-Hydroxyl-2-Methylpropyl)phenyl]methyl]-4-(1-Methylpiperidin-4-yl)-1,5-Dihydro-2,4-Benzodiazepin-3-One To a 100 ml three-necked flask, add benzyl-4-(8-fluoro-4-[[4-(2-hydroxyl-2-methylpropyl)phenyl]methyl]-3-oxo-1,5-dihydro-2,4-benzodiazepin-2-yl)piperidine-1- Carboxylate (150.00 mg, 0.268 mmol), methanol (10.00 mL, 246.989 mmol), formaldehyde (2.00 mL, 0.067 mmol) and Pd(OH)2 / C (20.00 mg, 0.142 mmol) respectively. Introduce hydrogen gas into the reaction system, stir at 25 °C for 5 hours, add water to quench the reaction, extract with ethyl acetate (3 x 10 mL), wash the organic phase with 10 ml of saturated brine, dry over anhydrous sodium sulfate, evaporate the solvent under reduced pressure, and separate and purify by column chromatography (DCM:MeOH = 30:1) to obtain the compound 7-fluoro-2-[[4-(2-hydroxyl-2-methylpropyl)phenyl]methyl]-4-(1-methylpiperidin-4-yl)-1,5-dihydro-2,4-benzodiazepin-3-one (45 mg, yield 38.19%, yellow oil). 1 HNMR(400MHz,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,2H), 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] +

[0226] Example 19: Preparation of 4-[(4-cyclopropoxyphenyl)methyl]-7-fluoro-2-(1-methylpiperidin-4-yl)-1,5-dihydro-2,4-benzodiazepin-3-one (A19022)

Chemical formula

[0227] Pharmacological experiment example Example 20: In vitro receptor binding experiment

[0228] Experimental method

[0229] 1. Preparation of solutions required for the experiment A: (For 5-HT 2C For receptor membrane preparation): 50 mM Tris-HCl buffer: Dissolve 96.8 g of Tris in redistilled water, adjust the total volume to 4000 ml, adjust the pH to 7.5 with HCl, and dilute to 16000 mL, with pH = 7.4. B: (For 5-HT 2A For receptor membrane preparation): Weigh 11.7 mg of EDTA and 380.84 mg of MgCl2, add 50 mM Tris-HCl buffer, adjust the total volume to 400 mL, and adjust the pH to 7.4. The final concentrations are 0.1 mM for EDTA and 10 mM for MgCl2 respectively. C: (for manufacturing dopamine receptor membrane): 2.978 g of HEPES, 1.17 g of NaCl, 0.119 g of MgCl 2. Weighed 36.5 mg of EDTA, added pure water to make the total volume 250 ml, and adjusted the pH to 7.4. The final concentrations were 50 mM HEPES, 50 mM NaCl, 5 mM MgCl 2. 0.5 mM EDTA, pH 7.4.

[0230] 2. Manufacturing of receptor membrane 1) CHO-5-HT 2A Manufacturing of receptor membrane CHO-5-HT 2A The cells were taken out from a -80 °C refrigerator, thawed naturally, centrifuged at 2000 g for 15 minutes at 4 °C. The precipitate was taken out and the supernatant was discarded. Solution B was added to the precipitate. The cells were mixed uniformly for 20 - 30 seconds, and then centrifuged at 50000 g for 25 minutes at 4 °C. The supernatant was carefully discarded, solution B was added again and mixed uniformly, and then centrifuged at 50000 g for 25 minutes at 4 °C. The precipitate was stored at -80 °C.

[0231] 2) 5-HT 2C Manufacturing of membrane Rat cortex was taken out from a -80 °C refrigerator, thawed naturally, solution A was added and homogenized at four-stage speed for 3 - 4 s, and this was done 4 times. Then it was centrifuged at 50000 g for 25 minutes at 4 °C, the supernatant was discarded, solution A was added, and it was mixed uniformly with a vortex mixer, then centrifuged at 50000 g for 25 minutes at 4 °C, and this was repeated 2 times. After centrifugation, the supernatant was discarded, and the precipitate was stored at -80 °C.

[0232] 3) Manufacturing of CHO-D2 receptor membrane Cells CHO-D2 were taken out from a -80 °C refrigerator, thawed naturally, centrifuged at 2000 g for 15 minutes, homogenate C was added to the precipitate, and it was mixed uniformly with a vortex mixer, then centrifuged at 50000 g for 25 minutes at 4 °C, and the supernatant was discarded. The precipitate was taken out, buffer C was added again for washing, resuspended and centrifuged. After centrifugation, the supernatant was discarded, and the precipitate was stored at -80 °C.

[0233] 3. Receptor Competition Binding Experiment 1) 5-HT 2A Receptor Competition Binding Experiment Step 1: First, prepare the manufactured membrane into a membrane suspension of 10 mg / mL with Homogenate 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 non-specific 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 3 3H-Ketanserin to each reaction tube to make the final concentration 2.98 nM. Step 5: Incubate each reaction tube at 37 °C for 25 min. After the reaction is completed, quickly filter the bound ligand under reduced pressure (Whatman test paper GF / C plate has been pre-impregnated with 0.5% PEI for more than 1 h). After filtration, dry the filter membrane at 60 °C. After attaching the base membrane, add 40 μL of scintillation liquid, seal the upper membrane, and let it stand. Step 6: Put the scintillation cup into a liquid scintillation counter and count.

[0234] 2) 5-HT 2C Receptor Competition Binding Experiment Step 1: First, prepare the manufactured membrane into a membrane suspension of 210 mg / mL with Homogenate 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 Ketanserin (final concentration 1.0×10 -5 M) to the non-specific 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 3Add H-Mesulergine to make the final concentration 3 nM. Step 5: Incubate each reaction tube at 37 °C for 25 min. After the reaction is complete, quickly filter the bound ligand under reduced pressure (Whatman test paper GF / C was saturated with 0.5% PEI solution 1 h ago), wash thoroughly with ice-cold Tris buffer, remove the filter sheet and place it in a 4 mL scintillation vial, add 1 mL of toluene scintillation fluid and mix uniformly. Step 6: Place the scintillation vial in a liquid scintillation counter and count.

[0235] 3) CHO-D2 receptor competition binding experiment Step 1: First, prepare the prepared membrane with homogenate C into a membrane suspension of 8 mg / mL. Step 2: Add 100 μL of the membrane preparation to each reaction tube. Step 3: Add 100 μL of Solution C to the total binding tube (TB), add 100 μL of Haloperidol (final concentration 1.0×10 -5 M) to the non-specific 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 3 H-Spiperone to each reaction tube to make the final concentration 1.176 nM. Step 5: Incubate each reaction tube at 37 °C for 25 min. After the reaction is complete, quickly filter the bound ligand under reduced pressure (Whatman test paper GF / B plate was impregnated with 0.5% PEI for more than 1 h in advance). After filtration, dry the filter membrane at 60 °C. After attaching the base membrane, add 40 μL of scintillation fluid, seal the upper membrane, and let it stand. Step 6: Place the suction-filtered plate in a liquid scintillation counter and count.

[0236] 4. Experimental results The Ki values of pimavanserin for 5-HT2A and 5-HT2C receptors are 0.036 and 2.94 nM respectively, and the Ki values of compound NH-K-A19016-OA for 5-HT2A and 5-HT2C receptors are 0.002 and 26.1 nM respectively, which are superior to those of pimavanserin. The Ki values of compound NH-K-A19001 for 5-HT2A and 5-HT2C receptors are 0.028 and 2.4 nM respectively, which are superior to those of pimavanserin. The Ki values of compound NH-K-A19005 for 5-HT2A and 5-HT2C receptors are 0.429 and 3.39 nM respectively, which are at the same level as pimavanserin. The details are shown in the following table.

[0237]

Table 1

[0238] Example 21: hERG experiment in vitro

[0239] 1. Preparation of compounds a. The experimental compound stock solution was successively diluted with DMSO into diluted solutions of 0.3 mM, 1 mM and 3 mM. b. The experimental compound stock solution was diluted with extracellular fluid to obtain test compound working solutions with concentrations of 0.3 μΜ, 1 μΜ, 3 μM, 10 μΜ and 30 μΜ, and all the test compound working solutions were ultrasonicated for more than 20 min. c. 10 mg of cisapride (positive control compound) was prepared into a stock solution of 10.113 mM with 2002.42 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. 10 μL of each concentration was added to 10 mL of extracellular fluid so that the DMSO concentration was 0.1%. f. The final concentrations of the cisapride working solutions were 1 nM, 10 nM, 100 nM and 1000 nM. g. As a result of visually observing the concentrations of all the test working solutions, there was no visible precipitate.

[0240] 2. Cell line information In this experiment, experiments were conducted using a HEK-293 cell line that stably expresses the hERG potassium channel.

[0241] The HEK-293 cell line that stably expresses the hERG potassium channel was cultured in DMEM medium containing 10% fetal bovine serum and 0.8 mg / mL G418, with the culture temperature set at 37 °C and the carbon dioxide concentration at 5%.

[0242] Cell passage: Remove the old medium, wash once with PBS, then add 0.5 mL of TrypLE TM Express solution, and incubate at 37 °C for 1 minute. Once the cells detached from the bottom of the dish, add 3 mL of pre-warmed complete medium at 37 °C. Pipette the cell suspension to dissociate the aggregated cells. Transfer the cell suspension to a sterile centrifuge tube and centrifuge at 300 G for 5 minutes to collect the cells. For proliferation or maintenance culture, seed the cells in a 6-cm cell culture dish, with the seeding amount in each cell culture dish being 1×10 5 cells (final volume: 5 mL).

[0243] For patch-clamp experiments, 5×10 3 cells were plated on a cover glass and cultured in a 24-well plate (final volume: 500 μL), and detected after 18 hours.

[0244] To maintain the electrophysiological activity of the cells, the cell density should not exceed 80%.

[0245] 3. Patch-clamp experiment Under an inverted microscope, operate a glass electrode micromanipulator (micromanipulator) to bring the recording electrode into contact with the cell, and then apply negative pressure to promote the formation of a GΩ seal on the cell. After the formation of the GΩ seal, perform high-speed capacitance compensation, and then continuously apply negative pressure to break the cell membrane to form the whole-cell recording mode. In the whole-cell recording mode, perform low-speed capacitance compensation and record the values of the membrane capacitance and series resistance.

[0246] Voltage stimulation protocol for cellular hERG potassium current: The clamp voltage of the cell membrane was set at -80 mV, then depolarized from -80 mV to +30 mV in 2.5 seconds, and then immediately maintained at -50 mV for 4 seconds to excite the tail current of the hERG channel. Data collection was repeated every 10 seconds. Leakage current detection was performed at -50 mV.

Number

[0247] The cover glass seeded with cells was placed in the recording chamber of an inverted microscope, and the negative control and the test compound were sequentially flowed into the recording chamber from low concentration to high concentration by gravity perfusion method to act quickly on the cells. During recording, the external solution was continuously circulated using a vacuum pump. The current detected in the negative control of each cell was used as the control group of the cell itself. Each drug concentration was allowed to act for 5 minutes or until the current stabilized. All experiments were performed at room temperature.

[0248] 4. Data analysis First, the current after the action of each drug concentration

Number

Number

Number

[0249] 5. Experimental results The IC50 of pimavanserin in the hERG experiment was 208 nM, and the IC50s of NH-K-A19001, NH-K-A19005, and NH-K-A19006 in the hERG experiment were 206, 3173, and 1194 nM, respectively. Since the cardiotoxicity of these three compounds is lower than that of pimavanserin, it was shown that the compounds of the present invention have lower cardiotoxicity compared to pimavanserin. The results are shown in the following table.

[0250]

Table 2

[0251] Example 22: Animal experiment

[0252] 1. Experimental method

[0253] 1.1 Experiment on the effect on MPTP+MK-801 Parkinson's mental disorder mouse model (anti-PDP drug efficacy model) In the morning, animals were intraperitoneally injected with different doses of MPTP continuously for 5 days. On the 5th day, MPTP was injected in the morning, and 1.5 h later, pimavanserin or NS was intraperitoneally injected. Furthermore, 0.5 h later, MK-801 at 0.3 mg / kg (or NS) was intraperitoneally injected. Also, 0.25 h later, the mice were placed in an open-field activity box (a black polyethylene box with a specification of 29 cm×29 cm×30 cm), and video recording was performed. The recording time was set to 20 min. After the recording was completed, video analysis was performed to evaluate the activity of the mice.

[0254] 1.2 Effect on the climbing behavior of male mice by MPTP+APO (DA motor decline model) In the morning, different doses of MPTP were intraperitoneally administered to animals continuously for 5 days. On the 5th day, MPTP was injected in the morning, and 1.5 h later, pimavanserin, clozapine, quetiapine or NS was intraperitoneally injected. Furthermore, 0.5 h later, 1 mg / kg of APO (dose: 0.1 ml / 10 g body weight) was subcutaneously injected. Immediately after subcutaneous injection, the animals were placed in a climbing cage (a self-made 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 bottom made of a translucent polyethylene plate, and a lid made of a stainless steel lid). The behaviors at 10 - 11 minutes, 20 - 21 minutes, and 30 - 31 minutes after APO injection were observed and scored.

[0255] Scoring criteria: Mice with all four feet on the floor received 0 points; mice with both front feet on the cage received 1 point; mice with all four feet on the cage received 2 points.

[0256] 1.3 Consideration experiment on the side effect of sedation (anti-sedation model) Qualified SPF-grade C57BL / 6j mice were adopted and randomly divided into 13 groups of 8 mice each, including a blank group, a pimavanserin administration group, an NH-K-A1900 administration group, an NH-K-A19005 administration group, and an NH-K-A19006 administration group. According to the dosage of each group, solutions with different concentrations were respectively formulated and intraperitoneally injected. The final dosage was 10 ml / kg.

[0257] 45 min after the administration of compounds such as pimavanserin, the spontaneous activities of all groups were monitored, the movement status at 0 - 20 min was video-recorded, and the movement distance at 20 min was analyzed by TopScan 3.00 software. The inhibition rate of each group after administration relative to the blank group was calculated, and with reference to the statistical conclusion, the sedative effect of the compound was comprehensively evaluated.

[0258] 1.4 Experimental results As is apparent from the experiments, the PDP efficacy, sedation, and hypokinesia ED50 of pimavanserin were 0.37 mg / kg, 6.79 mg / kg, and >30 mg / kg, respectively, the ratio of sedation / PDP efficacy was 18.35, and the ratio of hypokinesia / PDP efficacy was >81.08. The PDP efficacy and sedation ED50 of NH-K-A19001 were 0.33 mg / kg and 3.74 mg / kg, respectively, and the ratio of sedation / PDP efficacy was 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. Thus, the drug effects of NH-K-A19001 and NH-K-A19006 were equivalent to those of pimavanserin. The PDP effective amount of NH-K-A19005 was slightly higher than that of pimavanserin. In addition, the compounds of the present invention (e.g., NH-K-A19001, NH-K-A19005, and NH-K-A190016) did not have a DA action mechanism, and no hypokinesia was observed.

[0259]

Table 3

[0260] Example 23: In Vivo and In Vitro Experimental Methods and Data of Pimavanserin Project A01 Series Compounds

[0261] 1. Head-Shaking Experiment on Mice

[0262] 1.1 Experimental Method After separating the mice by body weight, they were randomly divided into a model control group, a blank group, and each administration group. One hour after intragastric administration of the solvent or drug to the animals, the animals were placed in a beaker (13 cm in diameter and 19 cm in height) lined with fresh dressing, and the modeling drug DOI ((±)-1-(2,5-dimethoxyphenyl)-2-aminopropane hydrochloride, (±)-2,5-dimethoxy-4-iodoamphetamine hydrochloride) was intraperitoneally injected at a dose of 1 mg / kg. The number of head shakes of the mice within 0 - 20 minutes after intraperitoneal injection of DOI was recorded. The head shake behavior refers to the rapid rotational convulsions of the mouse's head and the swaying behavior like a wet dog, which is different from normal grooming and exploratory behaviors.

[0263] 1.2 Experimental data According to the results of this experiment, the ED50 of pimavanserin in inhibiting the DOI-induced head shake behavior of mice is 0.39 mg / kg, and the DOI-induced head-twitch behavior ED50s of NH-K-A19001, NH-K-A19005, NH-K-A19006, and NH-K-A19012 in inhibiting are 0.06, 0.15, 0.012, and 0.30 mg / kg respectively. It is shown that the compounds of the present invention have a more excellent antipsychotic effect and more excellent drug efficacy. The detailed results are shown in the following table.

[0264]

Table 4

[0265] 2. MK-801-induced hyperactivity experiment in mice

[0266] 2.1 Experimental method After separating the mice by body weight, they were randomly divided into a model control group, a blank group, and each administration group. After administering the test substance (or control substance), the mice were placed in an open field activity box (a black polyethylene box with specifications of 29 cm × 29 cm × 30 cm) to get used to it. One hour after intragastric administration, 0.3 mg / kg of MK-801 was intraperitoneally injected. Then, the mice were placed back in the open field activity box for video recording. The recording time was set to 60 minutes. After the recording was completed, video analysis was performed to evaluate the activity of the mice.

[0267] 2.2 Experimental Results According to the results of this experiment, the ED50 of pimavanserin in inhibiting MK-801-induced hyperactivity behavior in mice was 3.288 mg / kg, and the ED50 of NH-K-A19005, NH-K-A19006, and NH-K-A19012 in inhibiting MK-801-induced hyperactivity behavior in mice were 1.01, 0.2648, and 3.728 mg / kg, respectively. It was shown that the compounds of the present invention have a more excellent antipsychotic effect and more excellent medicinal efficacy. The detailed results are shown in the following table.

[0268]

Table 5

[0269] 3. Experiment on the Effect of DOI ((±)-1-(2,5-Dimethoxy-4-iodophenyl)-2-aminopropane Hydrochloride, (±)-2,5-Dimethoxy-4-iodoamphetamine Hydrochloride) on PPI Impairment in Rats

[0270] 3.1 Experimental Method

[0271] Intervention Test Thirty minutes after intragastric administration (or solvent administration) of the animals, 0.5 mg / kg of DOI was subcutaneously injected into the neck. Thirty minutes later, that is, 60 minutes after intragastric administration, the rats were placed in a startle reflex test box for the test.

[0272] As an experimental method, it was carried out with reference to the literature and preliminary experiments, specifically as follows. First, a 5-minute adaptation period (background sound of 62 dB) was given. After the end of the adaptation period, the startle reflex stimulus was presented alone 5 times (block1, this is to lower the initial response of the animal to a basic level and the results are not used for analysis). Next, 1) a single startle reflex stimulus (pulse-alone, 120 dB, 20 ms duration), 2) a single prepulse stimulus that is 13 dB higher than the background sound (prepulse-alone, 75 dB, 20 ms duration), 3) prepulse stimulus + startle reflex stimulus (prepulse + pulse, each 20 ms duration, stimulus interval: 100 ms), and 4) a non-stimulus experiment (no stimulus) that only presents the background sound. Four different experiments (trials) (block2) were each carried out 5 times in a pseudo-random manner, and the average interval between each experiment was 20 s (10 - 30 s).

[0273] The magnitude of the response to the single startle reflex stimulus or prepulse stimulus + startle reflex stimulus was expressed as the AVG (device-specific unit) value, and the magnitude of the rat's body flinch response was indirectly indicated by the AVG value.

[0274] Evaluation index: PPI% = (1 - magnitude of the response to prepulse stimulus + startle reflex stimulus / magnitude of the response to the single startle reflex stimulus) × 100. The higher the numerical value, the higher the inhibition rate.

[0275] Administration test Except that the 0.5 mg / kg DOI administered to the animals in each of the above groups was changed to physiological saline (NS), the administration, measurement, etc. were carried out in the same manner as the intervention test.

[0276] 3.2 Experimental results PPI refers to the inhibitory effect on the startle reflex by a weak stimulus (30 - 500 ms) before a strong startle reflex stimulus. According to research, since the neural nuclei that regulate PPI and their pharmacological mechanisms are very similar in humans and rodents, it can be seen that it is a cross-species behavioral indicator. Clinical research has also found that patients with schizophrenia have PPI impairment, and some antipsychotics show an improvement effect. Due to the above characteristics, this model is widely used in research on the etiology of schizophrenia and the pharmacological effects of antipsychotics, and is also used as a tool for selecting antipsychotics, especially for predicting the therapeutic effects on the negative symptoms and cognitive dysfunction of schizophrenia.

[0277] In this experiment, when 0.5 mg / kg of DOI was administered to rats, significant impairment of PPI (P < 0.05) was observed. With 0.3 mg / kg of NH-K-A19006, 3 mg / kg of NH-K-A19005, and 3 mg / kg of pimavanserin, the DOI-induced PPI impairment in rats (P < 0.05) was significantly reversed. The details are shown in the following table. In the table, "MEAN" indicates the mean value, "SD" indicates the standard deviation, and "P" indicates the P value. The numerical values in the table indicate the reversal of impairment, and the higher the numerical value, the more the symptoms are alleviated compared to the model group.

[0278] According to this study, 0.3 mg / kg of NH-K-A19006 and 3 mg / kg of NH-K-A19005 can significantly reverse the DOI-induced PPI in rats, and at this dosage, there is no significant effect on normal rats. Therefore, it was found that NH-K-A19005 and NH-K-A19006 are effective for mental disorders and are effective for the negative symptoms and cognitive dysfunction of schizophrenia.

[0279]

Table 6

[0280]

Table 7

[0281]

Table 8

[0282]

Table 9

Claims

1. A compound represented by Formula I. 【Chemical Formula 1】 (In Formula I, n1 and n2 are integers from 1 to 3, R1 is selected from a linear or branched alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, and an alkynyl group having 2 to 8 carbon atoms, and the alkyl group, alkenyl group, and alkynyl group are each independently and optionally substituted with a substituent selected from halogen and a haloalkyl group having 1 to 8 carbon atoms, R2 is selected from hydrogen, halogen, and a haloalkyl group having 1 to 8 carbon atoms, R3, R4, R5, and R6 are each independently selected from hydrogen, halogen, and a haloalkyl group having 1 to 8 carbon atoms, R7 is a linear or branched alkyl group having 1 to 8 carbon atoms, a cycloalkyl group, and 【Chemical Formula 2】 (In the formula, R8 and R9 are each independently selected from a linear or branched alkyl group having 1 to 8 carbon atoms.) and is selected from, and the alkyl group and cycloalkyl group may optionally be substituted with a substituent selected from halogen and a haloalkyl group having 1 to 8 carbon atoms, Z is selected from CH2, O, and NH, W is selected from CH and N, 【Chemical Formula 3】 The bond means that it does not exist or exists as a single bond, Q is, 【Chemical Formula 4】 When the bond means that it does not exist, it is C, 【Chemical Formula 5】 When the bond means that it exists as a single bond, it is selected from CH and N, 【Chemical Formula 6】 When the bond means that it does not exist, the compound represented by Formula I is a compound represented by Formula II, 【Chemical Formula 7】 (In formula II, n2, R1, R3, R7, W, and Z have the same definitions as above.) Or, 【Chemical Formula 8】 When the bond exists as a single bond, the compound represented by formula I is the compound represented by formula III. 【Chemical Formula 9】 (In formula III, n1 and n2 are integers from 1 to 3, R1 is selected from a linear or branched alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, and an alkynyl group having 2 to 8 carbon atoms, and the alkyl group, alkenyl group, and alkynyl group may optionally be substituted with substituents selected from halogen and a haloalkyl group having 1 to 8 carbon atoms, R2 is selected from hydrogen, halogen, and a haloalkyl group having 1 to 8 carbon atoms, R3, R4, R5, and R6 are each independently selected from hydrogen, halogen, and a haloalkyl group, R7 is a linear or branched alkyl group having 1 to 8 carbon atoms, a cycloalkyl group, and 【Chemical Formula 10】 (In the formula, R8 and R9 are each independently selected from a linear or branched alkyl group having 1 to 8 carbon atoms.) and are selected from, and the alkyl group and cycloalkyl group may optionally be substituted with substituents selected from halogen and a haloalkyl group having 1 to 8 carbon atoms, Z is selected from CH2, O, and NH, Q is selected from CH and N, and W is selected from CH and N.))

2. The linear or branched alkyl group having 1 to 8 carbon atoms is selected from a linear or branched alkyl group having 1 to 5 carbon atoms and a linear or branched alkyl group having 1 to 3 carbon atoms, and / or, The alkenyl group having 2 to 8 carbon atoms is an alkenyl group having 2 to 5 carbon atoms, and / or, The alkynyl group having 2 to 8 carbon atoms is an alkynyl group having 2 to 5 carbon atoms, and / or, The haloalkyl group having 1 to 8 carbon atoms is a haloalkyl group having 1 to 5 carbon atoms, and / or, The compound represented by formula I according to claim 1, wherein the cycloalkyl group is a C3-C10 cycloalkyl group.

3. The compound represented by formula I according to claim 1, wherein the halogen is fluorine, chlorine, bromine or iodine.

4. The linear or branched C1-C5 alkyl group is selected from a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a pentyl group, an isopentyl group, The cycloalkyl group is selected from a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, The compound represented by formula I according to claim 2, wherein the linear or branched C1-C3 alkyl group is a methyl group, an ethyl group, a propyl group or an isopropyl group.

5. Z is O, R1, R2, R3, R4, R5, R6, R7, n1, n2, Q and 【Chemical Formula 11】 The bond is as defined in any one of claims 1 to 4, and the compound represented by formula I according to claim 1.

6. The compound represented by formula I according to claim 1, wherein the compound represented by formula I is a compound represented by formula I-1. 【Chemical Formula 12】 (In the formula, R1, R2, R3, R4, R5, R6, R7, n1, n2 and Q are as defined in any one of claims 1 to 4.)

7. The compound represented by formula I according to claim 1 or 2, wherein the compound represented by formula I is a compound represented by formula IV. 【Chemical Formula 13】 (In the formula, n1 and n2 are integers from 1 to 3, R1 is selected from a methyl group, an ethyl group, a propyl group, a butyl group, R2 is selected from hydrogen, fluorine, chlorine, bromine, and iodine, R3, R4, R5, and R6 are each independently selected from hydrogen, fluorine, and chlorine, R7 is selected from an isopropyl group, an isobutyl group, an ethyl group, a propyl group, a methyl group, a cyclopropyl group, a cyclobutyl group, [Chemical Formula 14] and is selected from the group consisting of: Z is selected from CH2, O, and NH, W is selected from CH and N, [Chemical Formula 15] A bond means either it does not exist or it exists as a single bond, Q is, [Chemical Formula 16] When a bond means it does not exist, Q is C, [Chemical Formula 17] When a bond means it exists as a single bond, Q is selected from CH and N.

8. The compound represented by Formula I is, [Chemical Formula 18] When a bond means it does not exist, the compound represented by Formula I according to Claim 1 or 2, characterized in that it is a compound represented by Formula V. [Chemical Formula 19] (In the formula, n2 is an integer from 1 to 2, R1 is selected from a methyl group, an ethyl group, a propyl group, and a butyl group, R3 is selected from hydrogen, fluorine, and chlorine, R7 is selected from an isopropyl group, an isobutyl group, an ethyl group, a propyl group, a methyl group, a cyclopropyl group, a cyclobutyl group, [Chemical Formula 20] and is selected from the group consisting of:

9. The compound represented by Formula I is, [Chemical Formula 21] The compound represented by formula I according to claim 1 or 2, wherein the bond is a single bond. 【Chemical formula 22】 (wherein 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 each selected from hydrogen, fluorine, and chlorine, R7 is selected from an isopropyl group, a cyclopropyl group, an isobutyl group, a methyl group, 【Chemical formula 23】 and is selected from, Z is selected from CH2, O, and NH, Q is selected from CH and N, and W is selected from CH and N. )

10. The compound represented by formula I according to any one of claims 1 to 9, wherein the compound is any one of the following compounds. 【Chemical formula 24】 【Chemical formula 25】

11. A pharmaceutical composition comprising the compound according to any one of claims 1 to 10, and optionally further comprising a pharmaceutically acceptable excipient, carrier, adjuvant, solvent, or a combination thereof.

12. Use of the compound according to any one of claims 1 to 10 or the pharmaceutical composition according to claim 11 in the manufacture of a medicament for treating mental disorders.

13. The use according to claim 12, wherein the mental disorder is schizophrenia or a mental disorder.

14. The use according to claim 12, wherein the mental disorder is Parkinson's disease or behavioral and psychological symptoms of dementia.

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