Pyrazole derivatives and their applications

Abstract

The present invention relates to pyrazole derivatives and their applications, and relates to the field of chemical medicine. A compound as shown in formula I is provided, which acts on 5-HT 2A , 5‑HT 2C receptors for 5-HT 2A The selectivity is superior to or similar to that of pemasholin. It is used to treat behavioral disorders and psychosis associated with schizophrenia, Parkinson's disease, and dementia. The antipsychotic activity of the compound of the present application is comparable to that of pemasholin, and its cardiotoxicity is less than that of pemasholin. #imgabs0#

Description

Technical Field

[0001] The present invention relates to the field of chemical medicine, in particular to pyrazole derivatives and applications thereof. Background Art

[0002] Schizophrenia has an insidious onset, low treatment rates, and a high lifetime prevalence. Currently, approximately 0.3-0.7% of the world's population is affected by schizophrenia during their lifetime, and in 2016, it was estimated that there were over 21 million schizophrenia patients worldwide. Current antipsychotics primarily include typical and atypical antipsychotics. However, due to their potent dopamine receptor blockade, current schizophrenia treatments can cause adverse reactions such as extrapyramidal syndromes (EPS), tardive dyskinesia, and increased prolactin. In the medical field, although a variety of active compounds acting on different targets are available for the treatment of sleep disorders, adverse reactions such as addiction, drug tolerance, and residual effects remain unresolved.

[0003] Traditionally, antipsychotics that block dopamine D2 receptors are referred to as first-generation antipsychotics, or "typical" antipsychotics (such as haloperidol). These drugs have achieved breakthrough results in treating the positive symptoms of schizophrenia, but have failed to address negative symptoms and cognitive impairment. Typical antipsychotics generally have severe EPS side effects and are ineffective for one-third of schizophrenia patients.

[0004] After the 1960s, a series of new-generation antipsychotic drugs were developed, including ziprasidone, risperidone, etc., which are called second-generation antipsychotic drugs, that is, new antipsychotic drugs. Although their pharmacological effects are not completely consistent, they have common pharmacological characteristics, namely, the effects on 5-hydroxytryptamine (5-HT) receptors (5-HT 1A、2A、2C ) and norepinephrine (NA) receptors (α1 and α2) with a much higher affinity than for D2 receptors. Their clinical efficacy offers advantages over first-generation antipsychotics. They are equally effective against positive symptoms as traditional antipsychotics, and are also effective against negative symptoms and cognitive impairment, thus possessing a broader spectrum of action. However, these drugs are associated with adverse effects such as QT prolongation, hyperprolactinemia, and weight gain. Therefore, the search for drugs that are effective against both positive and negative symptoms and cognitive impairment in schizophrenia, while also exhibiting minimal side effects, is a current research hotspot.

[0005] The serotonin system plays an important role in regulating the functions of the prefrontal cortex (PFC), including emotional control, cognitive behavior, and working memory. Pyramidal neurons and GABA interneurons in the PFC contain several serotonin receptor subtypes with a particularly high density of 5-HT. 1Aand 5-HT 2A Recently, it has been shown that PFC and NMDA receptor channels are 5-HT 1A These two receptors regulate the excitability of neurons in the cerebral cortex, thereby affecting cognitive function. In fact, various preclinical data show that 5-HT 1A R may be a new target for the development of antipsychotic drugs. Atypical antipsychotic drugs (such as olanzapine, aripiprazole, etc.) have an effect on 5-HT 1A The high affinity of R and its low EPS side effects indicate that the serotonin system plays an important role in regulating the functions of the prefrontal cortex (PFC), including emotional control, cognitive behavior and working memory. The pyramidal neurons and GABA interneurons of the PFC contain several serotonin receptor subtypes with a particularly high density of 5-HT 1A and 5-HT 2A Recent studies have shown that 5-HT 1A Agonists are associated with atypical antipsychotics and can improve negative symptoms and cognitive impairment. In the treatment of schizophrenia with the atypical antipsychotic clozapine, it was found that 5-HT 2A It plays an important role in all aspects of perception, emotion regulation and motor control. 2A The receptors can normalize the release of dopamine and play an antipsychotic role. 2C The receptor is closely linked to weight gain.

[0006] Pimasserin is a 5-HT 2A High-affinity inverse agonist, 5-HT 2C Antagonist, in vitro experimental results show that it has an effect on 5-HT 2A The affinity of the receptor [inhibition constant (Ki) is 0.4nm] is higher than that of 5-HT 2C High (Ki=16nm), for 5-HT 2B It has no significant affinity (Ki>300nm) for cytokines, dopamine receptors (including D2 receptors), adrenergic receptors, muscarinic receptors, or calcium channel receptors. The drug was approved for marketing by the U.S. Food and Drug Administration in April 2016 under the trade name Nuplazid TM , mainly used to treat Parkinson's mental symptoms such as hallucinations and delusions.

[0007] Therefore, there is a need to find an antipsychotic drug that is effective for both positive and negative symptoms, can improve cognitive impairment, and can prevent extrapyramidal side effects, including tardive dyskinesia and Parkinson's disease; and can reduce weight gain. Summary of the Invention

[0008] The present invention aims to solve at least one of the technical problems existing in the prior art. To this end, one object of the present invention is to provide pyrazole derivatives and their uses, such as a compound represented by Formula I or a pharmaceutically acceptable salt thereof:

[0009]

[0010] Wherein, R1 is H or a C1-C5 straight or branched chain alkyl group;

[0011] A is a heteroaryl group;

[0012] R2 is a structure of formula II;

[0013]

[0014] R4 is an optionally substituted C1-C5 straight or branched alkyl group, wherein the substituent is selected from halogen; n1 is an integer of 1-3;

[0015] R3 is a structure of formula III,

[0016]

[0017] In formula III, R5 is selected from substituted or unsubstituted C3-C5 cycloalkyl, substituted or unsubstituted aryl, and the substituents of the substituted C3-C5 cycloalkyl and substituted aryl are selected from C1-C5 straight-chain or branched alkyl, and halogen.

[0018] The heteroaryl group is selected from pyrazolyl, imidazolyl, pyridyl and pyrrolyl.

[0019] When A is pyrazolyl, R2 is connected to a nitrogen atom on the pyrazolyl group.

[0020] The compound of formula I is further of formula I-1 or formula I-2,

[0021]

[0022] Wherein, R1 is H or a C1-C5 straight or branched chain alkyl group;

[0023] R2 is a structure of formula II,

[0024]

[0025] R4 is an optionally substituted C1-C5 straight or branched alkyl group, wherein the substituent is selected from halogen; n1 is an integer of 1-3;

[0026] R3 is a structure of formula III,

[0027]

[0028] In formula III, R5 is selected from substituted or unsubstituted C3-C5 cycloalkyl, substituted or unsubstituted aryl, and the substituents of the substituted C3-C5 cycloalkyl and substituted aryl are selected from C1-C5 straight-chain or branched alkyl, and halogen.

[0029] Preferably, the compound of formula I is a compound of formula VI,

[0030]

[0031] R1 is H or a C1-C5 straight or branched chain alkyl group;

[0032] R3 is a structure of formula III;

[0033]

[0034] In formula III, R5 is selected from substituted or unsubstituted C3-C5 cycloalkyl, substituted or unsubstituted aryl, and the substituents of the substituted C3-C5 cycloalkyl and substituted aryl are selected from C1-C5 straight-chain or branched alkyl, and halogen;

[0035] R4 is an optionally substituted C1-C5 straight or branched alkyl group, wherein the substituent is selected from halogen.

[0036] Preferably, the compound of formula I is a compound of formula V,

[0037]

[0038] R1 is H or a C1-C5 straight or branched chain alkyl group;

[0039] R3 is a structure of formula III;

[0040]

[0041] In formula III, R5 is selected from substituted or unsubstituted C3-C5 cycloalkyl, substituted or unsubstituted aryl, and the substituents of the substituted C3-C5 cycloalkyl and substituted aryl are selected from C1-C5 straight-chain or branched alkyl, and halogen;

[0042] R4 is an optionally substituted C1-C5 straight or branched alkyl group, wherein the substituent is selected from halogen.

[0043] In the compounds represented by formula I, I-1, and I-2, the C1-C5 straight-chain or branched-chain alkyl group is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, n-butyl, pentyl, isopentyl, and neopentyl.

[0044] In the compounds represented by formula I, I-1, and I-2, the C3-C5 cycloalkyl group is selected from cyclopropyl, cyclobutyl, and cyclopentyl.

[0045] In the compounds represented by formula I, I-1, and I-2, the aryl group is selected from phenyl and naphthyl.

[0046] The compound represented by formula I-1 or I-2, wherein R1 is selected from one of H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, n-butyl, pentyl, isopentyl, and neopentyl;

[0047] R4 is selected from one of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, n-butyl, pentyl, isopentyl and neopentyl;

[0048] R5 is substituted or unsubstituted cyclopropyl, cyclobutyl or cyclopentyl, substituted or unsubstituted phenyl or naphthyl, and the substituent is selected from methyl, ethyl, propyl, butyl, fluorine, chlorine, bromine and iodine.

[0049] The compound described in this application is selected from any one of the following compounds:

[0050] 4-(5-benzyl-1-(4-isobutoxybenzyl)-1H-pyrazol-3-yl)-1-methylpiperidine;

[0051] 4-(3-Benzyl-1-(4-isobutoxybenzyl)-1H-pyrazol-5-yl)-1-methylpiperidine;

[0052] 4-(4-benzyl-1-(4-isobutoxybenzyl)-1H-pyrazol-3-yl)-1-methylpiperidine;

[0053] 4-(4-benzyl-1-(4-isobutoxybenzyl)-1H-pyrazol-5-yl)-1-methylpiperidine;

[0054] 4-(5-Benzyl-1-(4-isobutoxybenzyl)-1H-pyrazol-3-yl)piperidine

[0055] 4-(3-Benzyl-1-(4-isobutoxybenzyl)-1H-pyrazol-5-yl)piperidine;

[0056] 4-(5-(4-fluorobenzyl)-1-(4-isobutoxybenzyl)-1H-pyrazol-3-yl)-1-methylpiperidine;

[0057] 4-(3-(4-fluorobenzyl)-1-(4-isobutoxybenzyl)-1H-pyrazol-5-yl)-1-methylpiperidine;

[0058] 4-(5-(cyclopropylmethyl)-1-(4-isobutoxybenzyl)-1H-pyrazol-3-yl)-1-methylpiperidine;

[0059] 4-(3-(cyclopropylmethyl)-1-(4-isobutoxybenzyl)-1H-pyrazol-5-yl)-1-methylpiperidine;

[0060] 4-(5-(cyclopropylmethyl)-1-(4-isobutoxybenzyl)-1H-pyrazol-3-yl)piperidine;

[0061] 4-(3-(Cyclopropylmethyl)-1-(4-isobutoxybenzyl)-1H-pyrazol-5-yl)piperidine.

[0062] In another aspect, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of the compound represented by Formula I, I-1, or I-2 or a pharmaceutically acceptable salt thereof and a medically acceptable carrier.

[0063] In another aspect, the present invention provides use of a compound of Formula I, I-1, or I-2, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the preparation of a medicament for treating a psychiatric disorder. The psychiatric disorder is schizophrenia. The psychiatric disorder is Parkinson's disease, dementia-related behavioral disorders, and psychosis.

[0064] Explanation of terms:

[0065] The term "comprising" is an open-ended expression, i.e., including the contents specified in the present invention, but not excluding contents in other aspects. It should be understood that the term "comprising" can also include a closed meaning, i.e., "consisting of..."

[0066] As described herein, the compounds of the present invention may optionally be substituted with one or more substituents, such as those of the general formula above or as specified in the examples and subclasses. It should be understood that the term "optionally substituted" is used interchangeably with the term "substituted or unsubstituted." Generally, the term "substituted" refers to the replacement of one or more hydrogen atoms in a given structure with a specified substituent. Unless otherwise indicated, an optionally substituted group may be substituted at each substitutable position of the group. When more than one position in a given formula is substituted with one or more substituents selected from a specified group, the substituents may be the same or different at each position.

[0067] In addition, it should be noted that, unless otherwise expressly stated, the description method used in the present invention of "respectively and independently" should be understood in a broad sense, which can mean that in different groups, the specific options expressed by the same symbols do not affect each other, or that in the same group, the specific options expressed by the same symbols do not affect each other.

[0068] In various parts of this specification, the substituents of the compounds disclosed in the present invention are disclosed in terms of group types or ranges. It is particularly noted that the present invention includes each independent secondary combination of the various members of these group types and ranges. For example, the term "C1-C5 alkyl" specifically refers to the independently disclosed methyl, ethyl, C3 alkyl, C4 alkyl, and C5 alkyl. Examples of alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), n-propyl (n-Pr, -CH2CH2CH3), isopropyl (i-Pr, -CH(CH3)2), n-butyl (n-Bu, -CH2CH2CH2CH3), isobutyl (i-Bu, -CH2CH(CH3)2), sec-butyl (s-Bu, -CH(CH3)CH2CH3), tert-butyl (t-Bu, -C(CH3)3), n-pentyl (n-C1-C5 alkyl), tert-butyl (t ... 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.

[0069] Ranges recited herein (e.g., numerical ranges) may encompass each value within the range and each subrange formed by each value. Thus, for example, the expression "n1 is any integer between 1 and 3" includes, for example, any integer between 1 and 2, any integer between 2 and 3, and the like, for example, 1, 2, and 3.

[0070] The expression "one or more" may mean 1, 2, 3, 4, 5, 6 or more.

[0071] The term "hydrogen (H)" refers to a single hydrogen atom. Such a hydrogen atom may be linked to other groups, such as an oxygen atom, to form a hydroxyl group.

[0072] The term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

[0073] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., rings that share adjacent pairs of carbon atoms) group having a conjugated electron system. The term "aryl" can be used interchangeably with the terms "aromatic ring" or "aromatic ring." Examples of aryl groups include 6- to 14-membered aryl groups and 6- to 10-membered aryl groups, specifically phenyl and naphthyl.

[0074] The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from one or more of oxygen, sulfur and nitrogen. The term "heteroaryl" can be used interchangeably with the term "heteroaromatic ring" or "heteroaromatic compound". Examples of heteroaryl groups include 5-14 membered heteroaryl, 5-10 membered heteroaryl, 5-10 membered monocyclic or polycyclic heteroaryl, 5-6 membered monocyclic heteroaryl, specifically including pyrimidinyl, pyridinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl, pyrazolyl, pyrrolyl, triazolyl, thiadiazolyl, thienyl, furanyl, pyridazinyl, triazinyl, oxadiazolyl, isoxazolyl, pyranyl, triazolyl, furopyrimidinyl, thienopyrimidinyl, pyrrolopyridinyl, pyranopyrimidinyl, benzothiazolyl, benzoxazolyl, thienopyrimidinyl, indolyl, and the like.

[0075] The term "pharmaceutically acceptable salt" refers to an inorganic or organic salt of a compound of the present invention.

[0076] Compounds of formula I

[0077]

[0078] Wherein, R1 is H or a C1-C5 straight or branched chain alkyl group;

[0079] A is a heteroaryl group;

[0080] R2 is a structure of formula II;

[0081]

[0082] R4 is an optionally substituted C1-C5 straight or branched alkyl group, wherein the substituent is selected from halogen; n1 is an integer of 1-3;

[0083] R3 is a structure of formula III,

[0084]

[0085] In formula III, R5 is selected from substituted or unsubstituted C3-C5 cycloalkyl, substituted or unsubstituted aryl, and the substituents of the substituted C3-C5 cycloalkyl and substituted aryl are selected from C1-C5 straight-chain or branched alkyl, and halogen.

[0086] In one embodiment, the heteroaryl group is selected from pyrazolyl, imidazolyl, pyridinyl, and pyrrolyl. In a preferred embodiment, the heteroaryl group is selected from pyrazolyl, imidazolyl, and pyridinyl. In a more preferred embodiment, the heteroaryl group is selected from pyrazolyl and imidazolyl. In a particularly preferred embodiment, the heteroaryl group is selected from pyrazolyl.

[0087] In a specific embodiment, the compound represented by formula I is formula I-1

[0088]

[0089] Wherein, R1 is H or a C1-C5 straight or branched chain alkyl group;

[0090] R2 is a structure of formula II,

[0091]

[0092] R4 is an optionally substituted C1-C5 straight or branched alkyl group, wherein the substituent is selected from halogen; n1 is an integer of 1-3;

[0093] R3 is a structure of formula III,

[0094]

[0095] In formula III, R5 is selected from substituted or unsubstituted C3-C5 cycloalkyl, substituted or unsubstituted aryl, and the substituents of the substituted C3-C5 cycloalkyl and substituted aryl are selected from C1-C5 straight-chain or branched alkyl, and halogen.

[0096] In another specific embodiment, the compound represented by formula I is formula I-2

[0097]

[0098] Wherein, R1 is H or a C1-C5 straight or branched chain alkyl group;

[0099] R2 is a structure of formula II,

[0100]

[0101] R4 is an optionally substituted C1-C5 straight or branched alkyl group, wherein the substituent is selected from halogen; n1 is an integer of 1-3;

[0102] R3 is a structure of formula III,

[0103]

[0104] In formula III, R5 is selected from substituted or unsubstituted C3-C5 cycloalkyl, substituted or unsubstituted aryl, and the substituents of the substituted C3-C5 cycloalkyl and substituted aryl are selected from C1-C5 straight-chain or branched alkyl, and halogen.

[0105] In one embodiment, R1 is H or a C1-C5 straight or branched alkyl group. In a preferred embodiment, R1 is H or a C1-C3 straight or branched alkyl group. In a more preferred embodiment, R1 is selected from H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, and isopentyl. In a specific embodiment, R1 is selected from H, methyl, ethyl, propyl, and isopropyl. In a particularly specific embodiment, R1 is H. In another particularly specific embodiment, R1 is methyl.

[0106] In one embodiment, R2 is a structure of Formula II:

[0107] Wherein, R4 is an optionally substituted C1-C5 straight or branched alkyl group; n1 is an integer of 1-3.

[0108] In a preferred embodiment, n1 is selected from 1, 2, and 3. In a more preferred embodiment, n1 is selected from 1 and 2. In a particularly preferred embodiment, n1 is 1.

[0109] In a specific embodiment, the structure of Formula II is wherein R4 is an optionally substituted C1-C5 straight or branched alkyl group, wherein the substituent is selected from halogen. In a more specific embodiment, R4 is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, and isopentyl. In a particularly specific embodiment, R4 is isobutyl.

[0110] In one embodiment, R3 is a structure of formula III, Wherein, R5 is selected from substituted or unsubstituted C3-C5 cycloalkyl, substituted or unsubstituted aryl, and the substituents of the substituted C3-C5 cycloalkyl and substituted aryl are selected from C1-C5 straight chain or branched alkyl, and halogen.

[0111] In a preferred embodiment, R5 is selected from substituted or unsubstituted C3-C5 cycloalkyl, substituted or unsubstituted aryl, and the substituents of the substituted C3-C5 cycloalkyl and substituted aryl are selected from C1-C5 straight-chain or branched alkyl, and halogen. In a more preferred embodiment, R5 is selected from substituted or unsubstituted C3-C5 cycloalkyl, substituted or unsubstituted aryl, and the substituents are selected from methyl, ethyl, propyl, isopropyl, fluorine, chlorine, bromine, and iodine. In a particularly preferred embodiment, R5 is selected from substituted or unsubstituted C3-C5 cycloalkyl, substituted or unsubstituted phenyl, and the substituents are selected from methyl, ethyl, propyl, isopropyl, fluorine, and chlorine. In a specific embodiment, R5 is selected from substituted or unsubstituted cyclopropyl, substituted or unsubstituted phenyl, and the substituents are selected from fluorine and chlorine. In a more specific embodiment, R5 is selected from substituted or unsubstituted cyclopropyl, substituted or unsubstituted phenyl, and the substituents are fluorine. In a particularly specific embodiment, R5 is cyclopropyl. In another particularly specific embodiment, R5 is phenyl.In yet another particularly specific embodiment, R5 is fluorophenyl.

[0112] In a specific embodiment, C1-C5 straight chain or branched alkyl and C1-C3 straight chain or branched alkyl are independently selected from methyl, ethyl, propyl, butyl, isobutyl, pentyl and isopentyl. In a more specific embodiment, C1-C5 straight chain or branched alkyl and C1-C3 straight chain or branched alkyl are independently selected from methyl, ethyl, propyl and isobutyl.

[0113] In one embodiment, the propyl group includes but is not limited to n-propyl (n-Pr, -CH2CH2CH3) or isopropyl (i-Pr, -CH(CH3)2). The butyl group includes but is not limited to n-butyl (n-Bu, -CH2CH2CH2CH3), isobutyl (i-Bu, -CH2CH(CH3)2), sec-butyl (s-Bu, -CH(CH3)CH2CH3) or tert-butyl (t-Bu, -C(CH3)3). The pentyl group includes, but is not limited to, n-pentyl (-CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl (-CH2CH2CH(CH3)2) or 2-methyl-1-butyl (-CH2CH(CH3)CH2CH3).

[0114] In a specific embodiment, the halogen is selected from fluorine, chlorine, bromine, and iodine.

[0115] In a specific embodiment, the compound of formula I is represented by formula VI:

[0116]

[0117] Wherein, R1 is H or a C1-C5 straight or branched chain alkyl group;

[0118] R3 is a structure of formula III,

[0119]

[0120] In formula III, R5 is selected from substituted or unsubstituted C3-C5 cycloalkyl, substituted or unsubstituted aryl, and the substituents of the substituted C3-C5 cycloalkyl and substituted aryl are selected from C1-C5 straight-chain or branched alkyl, and halogen.

[0121] R4 is an optionally substituted C1-C5 straight or branched alkyl group, wherein the substituent is selected from halogen. In another specific embodiment, the compound of formula I is as shown in formula V:

[0122]

[0123] Wherein, R1 is H or a C1-C5 straight or branched chain alkyl group;

[0124] R3 is a structure of formula III,

[0125]

[0126] In formula III, R5 is selected from substituted or unsubstituted C3-C5 cycloalkyl, substituted or unsubstituted aryl, and the substituents of the substituted C3-C5 cycloalkyl and substituted aryl are selected from C1-C5 straight-chain or branched alkyl, and halogen;

[0127] R4 is an optionally substituted C1-C5 straight or branched alkyl group, wherein the substituent is selected from halogen.

[0128] Beneficial technical effects of the present invention:

[0129] The compounds provided herein act on 5-HT2A and 5-HT2C receptors, with selectivity for 5-HT2A superior to or similar to that of pemosarin. They are used to treat behavioral disturbances and psychoses associated with schizophrenia, Parkinson's disease, and dementia. The compounds have comparable antipsychotic activity to pemosarin and exhibit less cardiotoxicity than pemosarin.

[0130] The present invention will be further described by the following examples, however, the scope of the present invention is not limited to the following examples. Those skilled in the art will appreciate that various changes and modifications can be made to the present invention without departing from the spirit and scope of the present invention.

[0131] Table 1 Compound structures and compound names

[0132]

[0133]

[0134]

[0135] Specific implementation methods

[0136] The following examples are for illustrative purposes only and are not intended to limit the present invention.

[0137] General synthesis method 1:

[0138]

[0139] N-substituted acetylpiperidine undergoes condensation reaction with substituted formic acid ester, then undergoes cyclization reaction with hydrazine hydrate, and finally undergoes condensation reaction with halogenated hydrocarbon to obtain a compound of the general formula.

[0140] General synthesis method 2:

[0141]

[0142] The N-substituted methyl piperidine carboxylate is condensed with substituted magnesium chloride, then condensed with DMF, then cyclized with hydrazine hydrate, and finally condensed with halogenated hydrocarbon to obtain a general compound structure.

[0143] The general synthetic method is only used to briefly summarize the synthetic method of some compounds of the present invention. The specific synthetic routes and synthetic steps are subject to the examples.

[0144] The synthetic examples are for illustrative purposes only and are not to be construed as limiting the present invention.

[0145] Synthetic Examples

[0146] Example 1. 4-(5-Benzyl-1-(4-isobutoxybenzyl)-1H-pyrazol-3-yl)-1-methylpiperidine (1)

[0147] Reaction 1

[0148]

[0149] 1.1 Preparation of tert-butyl 4-(3-oxo-4-phenylbutyryl)piperidine-1-carboxylate

[0150] 60% sodium hydride (1.07 g) was added to 15 mL of tetrahydrofuran and cooled to 0°C. Tert-butyl 4-acetylpiperidine-1-carboxylate (3.00 g, 13.198 mmol) and methyl phenylacetate (6.01 g, 39.9 mmol) were slowly added dropwise. After the addition was complete, the mixture was allowed to react at room temperature for 4 hours. After the reaction was complete, 30 mL of ethyl acetate was added to dilute the reaction solution, and the mixed solution was poured into 1N HCl solution. The organic phase was separated and the aqueous phase was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the solution was evaporated to dryness under reduced pressure. Purification by column chromatography (PE:EA = 5:1) was performed to obtain 3 g of tert-butyl 4-(3-oxo-4-phenylbutyryl)piperidine-1-carboxylate in a yield of 65.80%.

[0151] 1.2 Preparation of tert-butyl 4-(5-benzyl-1H-pyrazol-3-yl)piperidine-1-carboxylate

[0152] Dissolve tert-butyl 4-(3-oxo-4-phenylbutyryl)piperidine-1-carboxylate (3.00 g, 8.685 mmol) in 30 mL of methanol, add hydrazine hydrate (1.00 g, 19.976 mmol), and heat and reflux for 3 hours. The solvent was concentrated under reduced pressure to give 2.5 g of crude tert-butyl 4-(5-benzyl-1H-pyrazol-3-yl)piperidine-1-carboxylate (yield 84.31%) as a colorless oil.

[0153] 1.3 Preparation of tert-butyl 4-(5-benzyl-1-[[4-(2-methylpropyloxy)phenyl]methyl]pyrazol-3-yl)piperidine-1-carboxylate

[0154] tert-Butyl 4-(5-benzyl-1H-pyrazol-3-yl)piperidine-1-carboxylate (1.00 g, 2.929 mmol), 1-(chloromethyl)-4-(2-methylpropoxy)benzene (0.70 g, 3.514 mmol), and Cs2CO3 (1.91 g, 5.857 mmol) were added to 10 mL of DMF and the mixture was heated to 60°C and reacted overnight. After completion of the reaction, the reaction mixture was poured into water and extracted with ethyl acetate. The solvent was evaporated under reduced pressure, and the product was purified by column chromatography (PE:EA=3:1) to obtain tert-butyl 4-(5-benzyl-1-[[4-(2-methylpropoxy)phenyl]methyl]pyrazol-3-yl)piperidine-1-carboxylate (160 mg, yield 10.85%).

[0155] 1.4 Preparation of 4-(5-benzyl-1-[[4-(2-methylpropyloxy)phenyl]methyl]pyrazol-3-yl)piperidine

[0156] Tert-butyl 4-(5-benzyl-1-[[4-(2-methylpropoxy)phenyl]methyl]pyrazol-3-yl)piperidine-1-carboxylate (140 mg) was added to a 4M HCl solution in dioxane (10 mL) and reacted at room temperature for 2 hours. The solvent was removed under reduced pressure to afford 120 mg of 4-(5-benzyl-1-[[4-(2-methylpropoxy)phenyl]methyl]pyrazol-3-yl)piperidine in a 100% yield.

[0157] 1.5 Preparation of 4-(5-benzyl-1-[[4-(2-methylpropyloxy)phenyl]methyl]pyrazol-3-yl)-1-methylpiperidine

[0158] 4-(5-Benzyl-1-[[4-(2-methylpropoxy)phenyl]methyl]pyrazol-3-yl)piperidine (120.00 mg, 0.297 mmol), formaldehyde (17.86 mg, 0.595 mmol), NaBH3CN (37.37 mg, 0.595 mmol), and HOAc (1 mL) were added to 10 mL of methanol and reacted at room temperature overnight. After completion of the reaction, the reaction solution was poured into saturated NaHCO3 solution and extracted with ethyl acetate. The solvent was evaporated under reduced pressure and purified by column chromatography (DCM:MeOH = 40:1) to obtain 67.2 mg of the compound 4-(5-benzyl-1-[[4-(2-methylpropoxy)phenyl]methyl]pyrazol-3-yl)-1-methylpiperidine, in a yield of 54.12%. 1 H-NMR (400MHz, DMSO-d6, ppm): δ10.08 (s, 1H), 7.32–7.26 (m, 2H), 7.25–7.19 (m, 1H), 7.16 (dd, J = 6.8 ,1.8Hz,2H),7.04–6.95(m,2H),6.89–6.81(m,2H),5.87(d,J=54.3Hz,1H),5.15(d,J=10.2Hz,2H),3. 93(d,J=4.0Hz,2H),3.71(d,J=6.5Hz,2H),3.42(d,J=11.7Hz,2H),3.00(dt,J=13.6,10.7Hz,2H),2.8 0–2.68(m,4H),2.10–1.92(m,3H),1.88–1.73(m,1H),0.97(d,J=6.7Hz,6H).LCMS(ES,m / z):418[M+H] + .

[0159] Example 2. 4-(3-Benzyl-1-(4-isobutoxybenzyl)-1H-pyrazol-5-yl)-1-methylpiperidine (2)

[0160] The target compound was prepared according to the method of Example 1, and the structural formula is shown in No. (2) in Table 1. 1 H-NMR (400MHz, DMSO-d6): δ7.38–7.13(m,5H),7.04(d,J=8.3Hz,2H),6.88(d,J=8.2 Hz,2H),5.86(s,1H),5.19(s,2H),3.83(s,2H),3.71(d,J=6.5Hz,2H),2.72(d,J=11 .3Hz,2H),2.13(s,3H),1.99(dt,J=13.2,6.6Hz,1H),1.85(t,J=11.4Hz,2H),1.54( d,J=12.4Hz,2H),1.51–1.37(m,2H),0.96(d,J=6.6Hz,6H).LCMS(ES,m / z):452[M+H] + .

[0161] Example 3. 4-(4-benzyl-1-(4-isobutoxybenzyl)-1H-pyrazol-3-yl)-1-methylpiperidine Reaction Formula 2

[0162]

[0163] 3.1 Preparation of 1-(1-benzylpiperidin-4-yl)-3-phenylpropan-1-one

[0164] 1-Benzylpiperidine-4-carboxylic acid methyl ester (2.00 g, 8.572 mmol) was added to 10 mL of tetrahydrofuran, followed by the addition of N,O-dimethylhydroxylamine (0.79 g, 12.858 mmol). The mixture was cooled to -5°C, and (2-phenylethyl) magnesium chloride (40 mL, 1 M in THF) was slowly added dropwise. After completion of the addition, the mixture was allowed to react at room temperature for 2 hours. After completion of the reaction, NH4Cl solution was added to quench the reaction mixture, followed by extraction with ethyl acetate, removal of the solvent, and purification by column chromatography (PE:EA = 10:1) to afford 2.5 g of 1-(1-benzylpiperidin-4-yl)-3-phenylpropan-1-one in a yield of 94.86%.

[0165] 3. Preparation of 2-(2Z)-2-benzyl-1-(1-benzylpiperidin-4-yl)-3-(dimethylamino)propyl-2-en-1-one

[0166] 1-(1-Benzylpiperidin-4-yl)-3-phenylpropan-1-one (2.50 g) and DMF-DMA (10.00 g) were added to toluene and the mixture was heated to reflux for 2 hours. The solvent was removed under pressure to obtain 2.2 g of a crude product of compound (2Z)-2-benzyl-1-(1-benzylpiperidin-4-yl)-3-(dimethylamino)propyl-2-en-1-one.

[0167] 3.3 Preparation of 1-benzyl-4-(4-benzyl-1H-pyrazol-3-yl)piperidine

[0168] (2Z)-2-Benzyl-1-(1-benzylpiperidin-4-yl)-3-(dimethylamino)propyl-2-en-1-one (2.20 g, 6.069 mmol) and hydrazine hydrate (10.00 g, 199.759 mmol) were added to 20 mL of ethanol, and the mixture was heated and refluxed for 2 hours. The solvent was removed under reduced pressure, and the mixture was purified by column chromatography (PE:EA=5:1) to obtain 1.8 g of the compound 1-benzyl-4-(4-benzyl-1H-pyrazol-3-yl)piperidine in a yield of 90.91%.

[0169] 3.4 Preparation of tert-butyl 4-(4-benzyl-1H-pyrazol-3-yl)piperidine-1-carboxylate

[0170] 1-Benzyl-4-(4-benzyl-1H-pyrazol-3-yl)piperidine (1.00 g, 3.017 mmol), Pd / C (100.00 mg, 0.940 mmol), and Boc2O (1.32 g, 6.034 mmol) were added to THF (20 mL), and hydrogen was introduced into the system. The reaction was allowed to proceed overnight at room temperature. After completion of the reaction, the solution was filtered and the solvent was removed to obtain 400 mg of tert-butyl 4-(4-benzyl-1H-pyrazol-3-yl)piperidine-1-carboxylate in a yield of 38.83%.

[0171] 3.5 Preparation of tert-butyl 4-(4-benzyl-1-(4-isobutoxybenzyl)-1H-pyrazol-5-yl)piperidine-1-carboxylate

[0172] 4-(4-benzyl-1H-pyrazol-3-yl)piperidine-1-carboxylic acid tert-butyl ester (400.00 mg, 1.171 mmol), [4-(2-methylpropyloxy)phenyl]methanesulfonic acid methyl ester (363.15 mg, 1.406 mmol), and Cs2CO3 (763.37 mg, 2.343 mmol) were added to DMF (10 mL) and heated to 80°C for overnight reaction. After completion of the reaction, the reaction solution was poured into water and extracted with ethyl acetate. The solvent was removed and the mixture was separated by column chromatography (PE:EA=5:1) to obtain 120 mg of tert-butyl 4-(4-benzyl-1-(4-isobutoxybenzyl)-1H-pyrazol-5-yl)piperidine-1-carboxylate, in a yield of 20.34%.

[0173] 3.6 Preparation of 4-(4-benzyl-1-[[4-(2-methylpropyloxy)phenyl]methyl]pyrazol-3-yl)piperidine

[0174] tert-Butyl 4-(4-benzyl-1-(4-isobutoxybenzyl)-1H-pyrazol-5-yl)piperidine-1-carboxylate (120.00 mg) was added to 4M HCl / dioxane (5 mL) and reacted at room temperature for 2 hours. The solvent was removed to obtain 100 mg of crude 4-(4-benzyl-1-[[4-(2-methylpropyloxy)phenyl]methyl]pyrazol-3-yl)piperidine. 3.7 Preparation of 4-(4-benzyl-1-[[4-(2-methylpropyloxy)phenyl]methyl]pyrazol-3-yl)-1-methylpiperidine

[0175] 4-(4-Benzyl-1-[[4-(2-methylpropoxy)phenyl]methyl]pyrazol-3-yl)piperidine (100.00 mg, 0.248 mmol), formaldehyde (14.88 mg, 0.496 mmol), NaBH3CN (31.14 mg, 0.496 mmol), and HOAc (1 mL) were added to methanol (10 mL) and allowed to react overnight at room temperature. After completion of the reaction, the reaction solution was poured into saturated NaHCO3 and extracted with ethyl acetate. The solvent was removed and the product was separated by column chromatography (DCM:MeOH = 40:1) to obtain 62 mg of the compound 4-(4-benzyl-1-[[4-(2-methylpropoxy)phenyl]methyl]pyrazol-3-yl)-1-methylpiperidine in a yield of 59.62%. 1 H-NMR(400MHz,Methanol-d4)δ7.76(s,1H),7.35–7.29(m,2H),7.28–7.19(m, 6H),6.98–6.89(m,2H),5.38(s,2H),3.92(s,2H),3.75(d,J=6.5Hz,2H),3.60 –3.51(m,2H),3.11(dtd,J=21.5,12.5,3.4Hz,3H),2.89(s,3H),2.15–1.98(m ,2H),1.95(d,J=14.1Hz,2H),1.04(d,J=6.7Hz,6H).LCMS(ES,m / z):418[M+H] + .

[0176] Example 4. 4-(4-Benzyl-1-(4-isobutoxybenzyl)-1H-pyrazol-5-yl)-1-methylpiperidine

[0177] The target compound was prepared according to the method of Example 3, and the structural formula is shown in No. (4) in Table 1. 1H-NMR (400MHz, Methanol-d4): δ7.51 (d, J=66.8Hz, 1H), 7.33 (ddd, J=9.2, 7.2, 2.4Hz, 2H), 7.28–7. 18(m,3H),7.14(s,2H),6.94(td,J=6.6,2.0Hz,2H),5.55(d,J=4.9Hz,1H),4.06–3.97(m,2H),3.74 (dd,J=6.5,1.7Hz,2H),3.50(d,J=12.2Hz,2H),3.06(s,2H),2.86(d,J=1.4Hz,3H),2.22(s,2H),2. 05(dt,J=13.2,6.7Hz,1H),1.69(d,J=14.3Hz,2H),1.04(d,J=6.7Hz,6H).LCMS(ES,m / z):418[M+H] + .

[0178] Example 5. 4-(5-Benzyl-1-(4-isobutoxybenzyl)-1H-pyrazol-3-yl)piperidine

[0179] The target compound was prepared according to the method of Example 1, and the structural formula is shown in No. (5) in Table 1. 1 H NMR (400MHz, DMSO-d6): δ8.79(s,1H),8.52(s,1H),7.34–7.26(m,2H),7.26–7.18(m,1H),7.16(dd,J=6.9, 1.8Hz,2H),7.04–6.95(m,2H),6.89–6.80(m,2H),5.80(s,1H),5.14(s,2H),3.93(s,2H),3.70(d,J=6.5Hz ,2H),3.40(s,1H),3.26(d,J=12.6Hz,2H),2.95(q,J=11.6Hz,2H),2.83(ddd,J=11.2,7.4,3.8Hz,1H),1.9 9(ddd,J=13.2,7.9,5.0Hz,3H),1.75(s,1H),1.72(s,1H),0.97(d,J=6.7Hz,6H).LCMS(ES,m / z):404[M+H] + .

[0180] Example 6. 4-(3-Benzyl-1-(4-isobutoxybenzyl)-1H-pyrazol-5-yl)piperidine

[0181] The target compound was prepared according to the method of Example 1, and the structural formula is shown in No. (6) in Table 1. 1H NMR(400MHz,DMSO-d6)δ8.68(d,J=10.5Hz,1H),7.33–7.14(m,5H),7.12–7.04(m,2H) ,6.92–6.84(m,2H),5.84(s,1H),5.21(s,2H),3.84(s,2H),3.71(d,J=6.5Hz,2H),3. 40(s,1H),3.24(d,J=12.5Hz,2H),3.08–2.84(m,3H),1.99(hept,J=6.7Hz,1H),1.75 (d,J=13.6Hz,2H),1.72–1.58(m,2H),0.97(d,J=6.7Hz,6H).LCMS(ES,m / z):404[M+H] + .

[0182] Example 7. 4-(5-(4-fluorobenzyl)-1-(4-isobutoxybenzyl)-1H-pyrazol-3-yl)-1-methylpiperidine

[0183] The reaction raw material methyl phenylacetate was replaced by methyl 4-fluorophenylacetate, and the target compound was prepared according to the method of Example 1. The structural formula is shown in No. (7) in Table 1. 1 H-NMR (400MHz, DMSO-d6): δ7.32–7.26(m,2H),7.25–7.19(m,1H),7.16(dd,J=6.8,1.8Hz,2H),7 .04–6.95(m,2H),6.89–6.81(m,2H),5.87(d,J=54.3Hz,1H),5.15(d,J=10.2Hz,2H),3.93(d,J=4 .0Hz,2H),3.71(d,J=6.5Hz,2H),3.42(d,J=11.7Hz,2H),3.00(dt,J=13.6,10.7Hz,2H),2.80–2. 68(m,4H),2.10–1.92(m,3H),1.88–1.73(m,1H),0.97(d,J=6.7Hz,6H).LCMS(ES,m / z):436[M+H] + .

[0184] Example 8. 4-(3-(4-fluorobenzyl)-1-(4-isobutoxybenzyl)-1H-pyrazol-5-yl)-1-methylpiperidine

[0185] The target compound was prepared according to the method of Example 7, and the structural formula is shown in No. (8) in Table 1. 1H NMR(400MHz,DMSO-d6)δ7.22–7.13(m,2H),7.17–7.04(m,2H),7.03–6.94(m,2H), 6.88–6.79(m,2H),5.16(d,J=10.2Hz,2H),3.93(d,J=3.9Hz,2H),3.70(d,J=6.5Hz ,2H),3.41(d,J=12.2Hz,2H),3.07–2.93(m,2H),2.81–2.68(m,4H),2.10–1.91(m, 3H),1.82(qd,J=13.5,3.8Hz,2H),0.96(d,J=6.7Hz,6H).LCMS(ES,m / z):436[M+H] + .

[0186] Example 9. 4-(5-(Cyclopropylmethyl)-1-(4-isobutoxybenzyl)-1H-pyrazol-3-yl)-1-methylpiperidine

[0187] The reaction raw material methyl phenylacetate was replaced with methyl 2-cyclopropylacetate, and the target compound was prepared according to the method of Example 1. The structural formula is shown in No. (9) in Table 1. 1 H NMR(400MHz, Methanol-d4)δ7.01–6.93(m,2H),6.89–6.81(m,2H),6.14(s,1H),4.87(s,2H),3.72(d, J=6.5Hz,2H),2.98(d,J=11.3Hz,2H),2.63(tt,J=11.8,3.9Hz,1H),2.45(d,J=6.9Hz,2H),2.33(s,3H ),2.18(td,J=12.0,2.6Hz,2H),2.11–1.99(m,1H),2.01–1.92(m,2H),1.86–1.71(m,2H),1.03(d,J=6 .7Hz,6H),1.00–0.88(m,1H),0.57–0.46(m,2H),0.13(dt,J=6.0,4.5Hz,2H).LCMS(ES,m / z):382[M+H] + .

[0188] Example 10. 4-(3-(Cyclopropylmethyl)-1-(4-isobutoxybenzyl)-1H-pyrazol-5-yl)-1-methylpiperidine

[0189] The target compound was prepared according to the method of Example 9, and the structural formula is shown in Table 1 as No. (10). 1H NMR (400MHz, Methanol-d4): δ7.06–6.96(m,2H),6.92–6.82(m,2H),6.10(s,1H),5.25(s, 2H),3.72(d,J=6.4Hz,2H),3.33(p,J=1.7Hz,1H),2.89(dt,J=12.3,3.2Hz,2H),2.62(tt, J=10.1,4.9Hz,1H),2.51(d,J=6.8Hz,2H),2.29(s,3H),2.13–1.94(m,3H),1.70–1.61(m, 4H),1.03(d,J=6.6Hz,7H),0.60–0.46(m,2H),0.26–0.15(m,2H).LCMS(ES,m / z):382[M+H] + .

[0190] Example 11. 4-(5-(cyclopropylmethyl)-1-(4-isobutoxybenzyl)-1H-pyrazol-3-yl)piperidine

[0191] The target compound was prepared according to the method of Example 9, and the structural formula is shown in Table 1 as No. (11). 1 H NMR (400MHz, Methanol-d4) δ7.15–6.93(m,2H),6.96–6.81(m,2H),6.47(d,J=2.0Hz, 1H),5.37(s,2H),3.74(d,J=6.5Hz,2H),3.51(dt,J=13.0,3.5Hz,2H),3.24–3.05(m,3 H),2.59(d,J=7.0Hz,2H),2.24(dd,J=14.6,3.5Hz,2H),2.12–1.91(m,3H),1.03(d,J =6.7Hz,7H),0.67–0.53(m,2H),0.21(dt,J=5.9,4.5Hz,2H).LCMS(ES,m / z):368[M+H] + .

[0192] Example 12. 4-(3-(Cyclopropylmethyl)-1-(4-isobutoxybenzyl)-1H-pyrazol-5-yl)piperidine

[0193] The target compound was prepared according to the method of Example 10, and the structural formula is shown in No. (12) in Table 1. 1H NMR(400MHz,Methanol-d4)δ7.21–7.13(m,2H),6.99–6.91(m,2H),6.56(s,1H),5.53(s,2H) ,3.75(d,J=6.4Hz,2H),3.47(dt,J=12.8,3.3Hz,2H),3.29(dt,J=10.3,5.3Hz,1H),3.15(td ,J=12.4,5.0Hz,2H),2.65(d,J=7.1Hz,2H),2.06(dt,J=13.3,6.6Hz,1H),2.01–1.85(m,4H) ,1.14–1.00(m,6H),0.65–0.54(m,2H),0.29(dt,J=6.0,4.6Hz,2H).LCMS(ES,m / z):368[M+H] + .

[0194] Pharmacological Examples:

[0195] Example 13 In vitro receptor binding assay

[0196] 1 Experimental Methods

[0197] 1.1 Preparation of solutions required for the experiment

[0198] A: (for the preparation of 5-HT 2C Receptor membrane): 50 mM Tris-HCl buffer: Dissolve 96.8 g of Tris in double-distilled water to a total volume of 4000 ml, adjust the pH to 7.5 with HCl, and dilute to 16000 ml, pH = 7.4.

[0199] B: (for the preparation of 5-HT 2A Receptor membrane: Weigh 11.7 mg EDTA and 380.84 mg MgCl2, add 50 mM Tris-HCl buffer to a total volume of 400 mL, and adjust the pH to 7.4. The final concentrations are 0.1 mM EDTA and 10 mM MgCl2.

[0200] C: (For preparation of dopamine receptor membrane): Weigh 2.978g HEPES, 1.17g NaCl, 0.119g MgCl2, and 36.5mg EDTA and add to a total volume of 250ml of pure water. Adjust the pH to 7.4, resulting in final concentrations of 50mM HEPES, 50mM NaCl, 5mM MgCl2, and 0.5mM EDTA, pH 7.4.

[0201] 1.2 Preparation of receptor membrane

[0202] 1) CHO-5-HT2A Preparation of receptor membranes

[0203] CHO-5-HT 2A Thaw cells naturally after removal from a -80°C freezer. Centrifuge at 2000g at 4°C for 15 minutes. Collect the pellet and discard the supernatant. Add Solution B to the pellet. Mix well for 20-30 seconds, then centrifuge at 50,000g at 4°C for 25 minutes. Carefully discard the supernatant, add Solution B again, mix well, and centrifuge at 50,000g at 4°C for 25 minutes. Store the pellet at -80°C.

[0204] 2) 5-HT 2C Membrane preparation

[0205] The rat cortex was taken out of the -80°C refrigerator and thawed naturally. Solution A was added and homogenized at gear 4 for 3-4 seconds, and the mixture was homogenized four times. The mixture was centrifuged at 50,000 g and 4°C for 25 min, and the supernatant was discarded. Solution A was added and mixed using a vortex mixer. The mixture was centrifuged at 50,000 g and 4°C for 25 min. The centrifugation was repeated twice. After the centrifugation was completed, the supernatant was discarded and the precipitate was stored at -80°C for later use.

[0206] 3) Preparation of CHO-D2 receptor membrane

[0207] CHO-D2 cells were taken out of a -80°C freezer and thawed naturally. They were centrifuged at 2000 g for 15 min, and the pellet was added to homogenate C. The pellet was mixed using a vortex mixer and centrifuged at 50,000 g at 4°C for 25 min. The supernatant was discarded, and the pellet was washed again with buffer C, resuspended, and centrifuged. After centrifugation, the supernatant was discarded and the pellet was stored at -80°C for later use.

[0208] 1.3 Receptor competition binding assay

[0209] 1) 5-HT 2A Receptor competition binding assay

[0210] Step 1: First, use the prepared membrane to prepare a 10 mg / mL membrane suspension using homogenate B.

[0211] Step 2: Add 100 μL of membrane preparation to each reaction tube.

[0212] Step 3: Add 100 μL of Solution B to the total binding tube (TB) and 100 μL of Methysergide (final concentration 1.0×10 -5 M), and 100 μL of test compound was added to each test compound tube (CB).

[0213] Step 4: Add radioligand to each reaction tube 3 H-Ketanserin 10 μL, final concentration 2.98 nM.

[0214] Step 5: Incubate each reaction tube at 37°C for 25 minutes. After the reaction is complete, the bound ligand is quickly filtered under reduced pressure. The Whatman test paper GF / C plate should be soaked in 0.5% PEI for more than 1 hour in advance. After filtration, the filter membrane is dried at 60°C, and 40μL scintillation fluid is added after the base film is attached. The upper film is sealed and allowed to stand.

[0215] Step 6: Place the scintillation cup into the liquid scintillation counter for counting.

[0216] 2) 5-HT 2C Receptor competition binding assay

[0217] Step 1: First, use the prepared membrane to prepare a 210 mg / mL membrane suspension using homogenate B.

[0218] Step 2: Add 100 μL of membrane preparation to each reaction tube.

[0219] Step 3: Add 100 μL of Solution B to the total binding tube (TB) and Ketanserin (final concentration 1.0×10 -5 M) 100 μL, and 100 μL of test compound was added to each test compound tube (CB).

[0220] Step 4: Add radioligand to each reaction tube 3 H-Mesulergine 10 μL, final concentration 3 nM.

[0221] Step 5: Incubate each reaction tube at 37°C for 25 minutes. After the reaction is complete, the bound ligand is rapidly filtered under reduced pressure. Saturate the Whatman GF / C test paper with 0.5% PEI solution 1 hour in advance and wash thoroughly with ice-cold Tris buffer. Remove the filter and place it in a 4mL scintillation cup. Add 1mL of toluene scintillation fluid and mix well.

[0222] Step 6: Place the scintillation cup into the liquid scintillation counter for counting.

[0223] 3) CHO-D2 receptor competition binding assay

[0224] Step 1: First, use the prepared membrane to prepare a suspension of 8 mg / mL using homogenate C.

[0225] Step 2: Add 100 μL of membrane preparation to each reaction tube.

[0226] Step 3: Add 10 μL of Solution C to the total binding tube (TB) and 100 μL of Haloperidol (final concentration 1.0×10 -5 M), and 100 μL of the test compound was added to each test compound binding tube (CB).

[0227] Step 4: Add radioligand to each reaction tube 3 H-Spiperone 10 μL, final concentration 1.176 nM.

[0228] Step 5: Incubate each reaction tube at 37°C for 25 minutes. After the reaction is complete, the bound ligand is quickly filtered under reduced pressure. The Whatman test paper GF / B plate should be soaked in 0.5% PEI for more than 1 hour in advance. After filtration, the filter membrane is dried at 60°C, and 40μL scintillation fluid is added after the base film is attached. The upper film is sealed and allowed to stand.

[0229] Step 6: Place the filter plate into the liquid scintillation counter for counting.

[0230] 2 Experimental results

[0231] Pamoserin and 5-HT 2A , 5-HT 2C The receptor Ki values ​​were 0.036 and 2.94 nM, respectively. Compound 1, Compound 2, Compound 3 and 5-HT 2A , 5-HT 2C It has higher selectivity than pemoserine. See the table below for details.

[0232] Table 2 In vitro receptor binding activity of each compound (Ki value, nM)

[0233] Compound number <![CDATA[5-HT 2A (Ki value, nM) <![CDATA[5-HT 2C (Ki value, nM) 2C / 2A Pemoserin 0.036 2.94 81.667 1 0.18 20.50 113.44 2 2.71 340.00 125.43 3 0.19 553.00 2846.56

[0234] Example 14 In vitro hERG experiment

[0235] Stably transfected cells were plated on glass slides at a cell density of less than 50% and cultured overnight. The experimental cells were transferred to a 1 ml bath embedded in an inverted microscope stage and perfused with extracellular fluid at a rate of 2.7 ml / min. After stabilization for 5 minutes, the experiment was started. Membrane currents were recorded using a HEKA EPC-10 patch clamp amplifier and a PATCHMASTER acquisition system (HEKA Instruments Inc. D-67466 Lambrecht, Pfalz, Germany). All experiments were performed at room temperature (22-24°C).

[0236] The electrodes (BF150-110-10) were straightened using a P-97 microelectrode puller (Sutter Instrument Company, One Digital Drive, Novato, CA 94949). The inner diameter of the electrodes was 1-1.5 mm, and the water resistance after filling with the internal solution was 2-4 MΩ.

[0237] The electrophysiological stimulation protocol for hERG potassium channels is to first clamp the membrane voltage at -80 mV, then stimulate the cell with a voltage of +20 mV for 2 seconds to activate the hERG potassium channels. The cells are then repolarized to -50 mV for 5 seconds to generate an outward tail current. The stimulation frequency is once every 15 seconds. The current value is the peak tail current.

[0238] In the experiment, the whole-cell recording mode was used to record the channel current. First, the extracellular fluid was perfused (approximately 2 ml per minute) and the recording was continued, and the current was allowed to stabilize (the current decay (Run-Down) was less than 5% within 5 minutes). At this time, the peak value of the tail current was the control current value. Then the extracellular fluid containing the drug to be tested was perfused and the recording was continued until the inhibitory effect of the drug on the hERG current reached a stable state. At this time, the peak value of the tail current was the current value after drug addition. The standard of the stable state is judged by whether the three most recent consecutive current recording lines overlap. After reaching a stable state, if the hERG current recovers or approaches the size before the drug is added after flushing with extracellular fluid, the perfusion test of other concentrations or drugs can continue.

[0239] Experimental results:

[0240] Pemoserin hERG assay IC 50 The cardiotoxicity of compound 1 was 208 nM, which was less than that of pemoserine.

[0241] Table 3 In vitro hERG test results of compounds

[0242] Compound number hERG (nM) 1 404 Pemoserin 208

Claims

1. A compound represented by formula I-1 or a pharmaceutically acceptable salt thereof: in, R1 is H or a C1-C5 straight or branched chain alkyl group; R2 is a structure of formula II: R4 is an optionally substituted C1-C5 straight or branched alkyl group, wherein the substituent is selected from halogen; n1 is an integer of 1-3; R3 is a structure of formula III, In formula III, R5 is a substituted or unsubstituted phenyl or naphthyl group, and the substituent of the substituted phenyl or naphthyl group is selected from C1-C5 straight-chain or branched alkyl groups and halogen.

2. The compound represented by formula I-2 or a pharmaceutically acceptable salt thereof: in, R1 is H or a C1-C5 straight or branched chain alkyl group; R2 is a structure of formula II: R4 is an optionally substituted C1-C5 straight or branched alkyl group, wherein the substituent is selected from halogen; n1 is an integer of 1-3; R3 is a structure of formula III, In formula III, R5 is a substituted or unsubstituted phenyl or naphthyl group, and the substituent of the substituted phenyl or naphthyl group is selected from C1-C5 straight-chain or branched alkyl groups and halogen.

3. The compound of formula I-2 or a pharmaceutically acceptable salt thereof according to claim 2, characterized in that: The compound of formula I-2 is a compound of formula VI, R1 is H or a C1-C5 straight or branched chain alkyl group; R3 is a structure of formula III, In formula III, R5 is a substituted or unsubstituted phenyl or naphthyl group, and the substituent of the substituted phenyl or naphthyl group is selected from a C1-C5 straight chain or branched alkyl group, and a halogen; R4 is an optionally substituted C1-C5 straight or branched alkyl group, wherein the substituent is selected from halogen.

4. The compound of formula I-1 or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The compound of formula I-1 is a compound of formula V, R1 is H or a C1-C5 straight or branched chain alkyl group; R3 is a structure of formula III, In formula III, R5 is a substituted or unsubstituted phenyl or naphthyl group, and the substituent of the substituted phenyl or naphthyl group is selected from a C1-C5 straight chain or branched alkyl group, and a halogen; R4 is an optionally substituted C1-C5 straight or branched alkyl group, wherein the substituent is selected from halogen.

5. The compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, characterized in that: The C1-C5 straight-chain or branched alkyl group is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, n-butyl, pentyl, isopentyl, and neopentyl.

6. The compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, characterized in that: The R1 is selected from one of H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, n-butyl, pentyl, isopentyl, and neopentyl; R4 is selected from one of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, n-butyl, pentyl, isopentyl and neopentyl; R5 is a substituted or unsubstituted phenyl or naphthyl group, wherein the substituent is selected from methyl, ethyl, propyl, butyl, fluorine, chlorine, bromine and iodine.

7. The compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, wherein: The compound is selected from any one of the following compounds: 4-(5-benzyl-1-(4-isobutoxybenzyl)-1H-pyrazol-3-yl)-1-methylpiperidine; 4-(3-Benzyl-1-(4-isobutoxybenzyl)-1H-pyrazol-5-yl)-1-methylpiperidine; 4-(4-benzyl-1-(4-isobutoxybenzyl)-1H-pyrazol-3-yl)-1-methylpiperidine; 4-(4-benzyl-1-(4-isobutoxybenzyl)-1H-pyrazol-5-yl)-1-methylpiperidine; 4-(5-benzyl-1-(4-isobutoxybenzyl)-1H-pyrazol-3-yl)piperidine; 4-(3-Benzyl-1-(4-isobutoxybenzyl)-1H-pyrazol-5-yl)piperidine; 4-(5-(4-fluorobenzyl)-1-(4-isobutoxybenzyl)-1H-pyrazol-3-yl)-1-methylpiperidine; 4-(3-(4-fluorobenzyl)-1-(4-isobutoxybenzyl)-1H-pyrazol-5-yl)-1-methylpiperidine.

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

9. Use of the compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 8, in the preparation of a drug for treating mental illness.

10. The use according to claim 9, characterized in that The psychiatric disorders are schizophrenia, Parkinson's disease, dementia-related behavioral disorders and psychosis.

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