CN107793408B

CN107793408B - Piperidine amino derivatives and their use for the treatment of schizophrenia

Info

Publication number: CN107793408B
Application number: CN201610801391.6A
Authority: CN
Inventors: 李建其; 陈晓文; 李林; 孙媛媛; 阮乐军
Original assignee: Shanghai Institute of Pharmaceutical Industry; China State Institute of Pharmaceutical Industry
Current assignee: Shanghai Institute of Pharmaceutical Industry; China State Institute of Pharmaceutical Industry
Priority date: 2016-09-05
Filing date: 2016-09-05
Publication date: 2020-12-08
Anticipated expiration: 2036-09-05
Also published as: CN107793408A

Abstract

The invention discloses a piperidine amino compound and application thereof in resisting schizophrenia. Pharmacological experiment results show that the piperidine amino compound provided by the invention has good water solubility and can be used for treating dopamine D₂、D₃、5‑HT_1A、5‑HT_2AHigh affinity of the receptor for D₃/D₂The receptor selectivity is good. In vivo test results show that the preferred compound has good anti-schizophrenia effect, lower acute toxicity, higher safety and good pharmacokinetic property, and has development value as a novel high-efficiency low-toxicity anti-neuro-psychosis medicine. The piperidine amino compound is a compound shown as a structural general formula (I) or a salt or hydrate of the salt thereof:

Description

Piperidine amino derivatives and their use for the treatment of schizophrenia

Technical Field

The invention relates to a piperidine amino derivative with anti-schizophrenia activity or a pharmaceutically acceptable hydrate, salt or hydrate of salt thereof, a pharmaceutical composition containing the compound or the pharmaceutically acceptable hydrate, salt or hydrate of salt, a medicine box and application thereof in treating schizophrenia.

Background

Schizophrenia is a chronic persistent disease, is the most serious and most harmful one of mental diseases, affects the normal life of about 1% of the population in the world, and is the 7 th disease of the social burden, wherein the number of people in China exceeds 10,000,000. Schizophrenia is a complex disorder with symptoms often varying with the course of the disease. Schizophrenia symptoms mainly include positive symptoms such as delusions, hallucinations; negative symptoms, such as social withdrawal, apathy; cognitive dysfunction, such as three major symptoms of working memory loss.

The cause of schizophrenia is complex and is not clear up to now. There are several major hypotheses in academia, including the influence of neurodevelopmental hypothesis, neurobiochemical hypothesis, and genetic factor hypothesis, as well as social and environmental factors. The neurobiochemical hypothesis is accepted and approved by academia. Relevant basic research and clinical data of anti-schizophrenia medicines show that schizophrenia can have a plurality of neurotransmitter functional abnormalities, mainly Dopamine (DA) neuron hyperfunction, 5-hydroxytryptamine (5-HT) functional system loss and the like. The DA hypothesis states that schizophrenia symptoms result from an imbalance in dopamine activity in the mesocerebral-cortical pathway in schizophrenic patients. The 5-HT hypothesis states that alterations in the 5-HT energy mechanism of the patient's prefrontal cortex lead to an inability of the cerebral cortex to properly inhibit subcortical dopamine, leading to dopaminergic hyperactivity.

Currently, the commercially available and clinical anti-schizophrenia drugs are mainly atypical antipsychotics. The drugs mainly act on DA system and 5-HT system. Acting on dopamine D₂Receptors are a common mechanism for antipsychotics. D₂Receptors are widely distributed in the brain and are involved in numerous physiological functions and pathological conditions. D₂Receptor antagonists are widely used as antipsychotics. However, a large number of antagonisms of D₂D of receptors, especially of the nigro-striatal pathway₂The receptor causes the patient to develop extrapyramidal side Effects (EPS), etc. While acting simultaneously on the 5-HT system, e.g. antagonising 5-HT_2AReduced receptor capacity D₂The excessive inhibition of the receptor can reduce the side reaction of EPS, hyperprolactinemia and the like. Thus, non-classical antipsychotics may further treat negative symptoms, such as the marketed drugs risperidone, aripiprazole, ziprasidone, etc., in addition to maintaining the activity of anti-positive symptoms similar to those of classical antipsychotics. But with the depth of clinical practiceIn addition, the medicines have limited improvement on negative symptoms, cannot meet clinical requirements, interact with a plurality of receptors, and easily generate side effects of obesity, akathisia, insomnia, anxiety and the like. Meanwhile, clinical test results show that the existing antipsychotic has no obvious effect of improving cognitive impairment. Therefore, the search for novel anti-schizophrenia drugs with high efficiency, low toxicity and wide treatment spectrum is a common challenge for global pharmaceutical enterprises, and is also a hot spot of research on the drugs.

Clinical and animal test results show that the selective antagonism of dopamine D₃The receptors can reduce the occurrence of extrapyramidal side effects and improve the cognitive function of the patient. But with D₂Receptor comparison, D₃Receptor mRNA is less distributed in the brain, requiring the drug to act on D simultaneously₂、D₃And should have a certain D₃Receptor selectivity, i.e. for D₃Has a stronger affinity than for D₂The affinity of the receptor is 10 times or more, so as to exert physiological effects such as cognitive improvement. The results of clinical and preclinical tests show that D is too high₃Receptor selectivity, e.g. compound pair D₃Receptor affinity greater than D₂More than one hundred times of the receptor, or D₃/D₂At receptor selectivities greater than 100-fold or greater, the compounds fail to exhibit anti-schizophrenia activity, particularly against the positive symptoms of schizophrenia. In recent years, 5-HT_1AThe improvement effect of the receptor on reducing the side effect of the schizophrenia drug and improving the cognitive function is more and more accepted by academia. It has been shown that 5-HT_1ACan effectively reduce the cause D₂Excessive blocking of side effects such as EPS, and improving cognitive impairment of schizophrenia patients. Thus, selectively act on D₂、D₃、5-HT_1AAnd 5-HT_2AThe research and development of novel multi-target anti-schizophrenia medicines of receptors have wide prospects, and a novel anti-schizophrenia medicine Cariprazine (Cariprazine) belonging to the action mechanism is marketed in the United states in 2015 and 9 months.

The inventor notices that the series of compounds disclosed in Chinese patents CN1829703A, CN102159557A, CN103130737A and CN104140421A have the activity of treating mental and neurological diseases. The structures of the compounds all contain cyclohexyl amino fragments, but slight changes in the structures, such as the change of aryl groups connected with piperazine, different substituents on amino groups and intermediate connecting chains, cause the difference of physicochemical properties, pharmacokinetic parameters, in vitro receptor action characteristics, in vivo pharmacological activity and related side effects of the compounds to a great extent. The details are as follows.

1. Patent CN1829703A, which discloses the following structure as D₂And D₃Receptor dual modulators:

wherein

R₁And R₂Independently represents a substituent selected from hydrogen, alkyl, alkenyl, aryl, cycloalkyl, aroyl, or R₁And R₂May form a heterocyclic ring with the adjacent nitrogen atom;

x represents an oxygen or sulfur atom;

n is an integer of 1 to 2,

and/or geometric isomers and/or stereoisomers and/or diastereomers and/or salts and/or hydrates and/or solvates thereof.

2. Patent CN102159557A, which discloses the following structure as an alternative 5-HT_2AAnd D₃Receptor modulators:

wherein:

x independently of one another is halogen or C_1-6-an alkyl group;

n is 0, 1 or 2;

R¹is-COR²or-SO₂-C_1-6-an alkyl group;

R²is C_1-6Alkyl radical, C_1-6-haloalkyl group, C_1-6-hydroxy groupAlkyl radical, C_1-6-alkoxy, 3-to 10-membered cycloalkyl, 4-to 10-membered heterocycloalkyl or 5-to 10-membered heteroaryl, optionally substituted with one or more substituents selected from:

the halogen(s) are selected from the group consisting of,

a hydroxyl group(s),

C_1-6-an alkyl group,

C_1-6-a halogenated alkyl group,

C_1-6-a hydroxyalkyl group,

C_1-6-an alkoxy group,

optionally substituted by one or more R^aSubstituted C_1-6-alkoxy groups,

-S-C_1-6-an alkyl group,

-SO₂-C_1-6-an alkyl group,

-CONH₂，

CHO

optionally substituted by one or more R^aA substituted 3 to 10-membered cycloalkyl group,

optionally substituted by one or more R^aSubstituted 4 to 10 membered heterocycloalkyl and

optionally substituted by one or more R^aSubstituted 5 to 10 membered heteroaryl;

wherein R is^aSelected from:

halogen element

A hydroxyl group(s),

C_1-6-an alkyl group,

C_1-6-a hydroxyalkyl group,

C_1-6-haloalkyl and

C_1-6-alkoxy groups.

3. Patent CN 103130737A. It discloses the following structure as D₂、D₃、5-HT_1AReceptor modulators:

wherein:

r is

R₁，R₂，R₃Each represents hydrogen, trifluoromethyl, C₁～C₄Alkyl and substituted alkyl of (2), C₃～C₆Cycloalkyl and substituted cycloalkyl of (A), C₅～C₇The heterocycloalkyl and substituted heterocycloalkyl, phenyl and substituted phenyl, pyridyl and substituted pyridyl of (a);

R₄and R₅Independently represent hydrogen, C₁～C₄Alkyl and substituted alkyl of (2), C₃～C₆Cycloalkyl and substituted cycloalkyl of (A), C₅～C₇Heterocycloalkyl and substituted heterocycloalkyl of (A), R₄And R₅A pyrrolidine ring, unsubstituted or substituted piperazine, morpholine or unsubstituted or substituted piperidine formed with the adjacent nitrogen atom;

R₆and R₇Independently represent hydrogen, C₁～C₄Alkyl and substituted alkyl of (2), C₃～C₆Cycloalkyl and substituted cycloalkyl of (A), C₅～C₇Heterocycloalkyl and substituted heterocycloalkyl of (A), R₄And R₅A pyrrolidine ring, unsubstituted or substituted piperazine, morpholine or unsubstituted or substituted piperidine formed with the adjacent nitrogen atom;

R₈and R₉Independently represent hydrogen, C₁～C₄Alkyl and substituted alkyl of (2), C₃～C₆Cycloalkyl and substituted cycloalkyl of (A), C₅～C₇Heterocycloalkyl and substituted heterocycloalkyl of (A), R₄And R₅A pyrrolidine ring with an adjacent nitrogen atom, an unsubstituted or substituted piperazine, morpholine or an unsubstituted or substituted piperidine.

4. Patent CN104140421A, which discloses the following structure as D₂、D₃、5-HT_1A、5-HT_2AReceptor modulators:

wherein:

w is:

R₁、R₂each represents a heteroaryl group or a substituted heteroaryl group;

n is 0, 1, 2 or 3; m is 0, 1 or 2;

R₃represents C₁～C₄Alkyl, substituted C₁～C₄Alkyl of (C)₃～C₆Cycloalkyl, substituted C₃～C₆Cycloalkyl, phenyl, substituted phenyl, benzyl, substituted benzyl, heteroaryl, substituted heteroaryl, heteroarylmethyl or substituted heteroarylmethyl;

R₄is a hydrogen atom or C₁～C₄Alkyl groups of (a);

R₅is aryl or substituted aryl.

The differences in activity of the representative compounds in the above patents are exemplified by:

in summary, it is revealed that the change of the aryl group attached to piperazine and the different acyl substituents on cyclohexylamino group for the structure containing cyclohexylamino group fragment is completely different from the action of in vitro receptor or has larger activity difference.

In addition, the compounds represented in the patents also have the defects of poor solubility, unsatisfactory in vivo bioavailability, poor brain targeting and other drug-forming defects.

In the existing anti-schizophrenia drugs, metabolic side effects (such as obesity) and arrhythmia, constipation, somnolence, Extrapyramidal (EPS) side effects (such as catalepsy) and serious side effects are easy to generate, so that the compliance of patients is poor, and the cognitive disorder of the schizophrenia patients is not obviously improved. Therefore, it is necessary to research compounds with different structures or new compounds with different structures but good physicochemical properties to overcome the above-mentioned defects of the existing compounds.

The literature (Journal of Medicinal Chemistry,2013,56,9199-9221) reports that for G protein-coupled receptors such as dopamine D2, D3 and the like, the intermediate connecting chain of the compound, including the length, flexibility, configuration and the like thereof, influences the strength of the binding force between the compound and the receptor and the pharmacological activity, such as agonism and partial agonism, of the compound. In view of the specificity and specificity of central nervous system target, the change of the action of the receptor can lead the compound to show different pharmacological activities in vivo and larger difference of related side effects, and the influence of the compound on the action of the receptor and the activities in vitro and in vivo needs to be further proved by experiments.

The invention designs a piperidine amino derivative, the structure of which contains 1, 4-disubstituted piperidyl, compared with the 1, 4-disubstituted cyclohexyl in the prior art, the piperidine amino derivative has no cis/trans isomer, and the flexibility and the spatial configuration of the piperidine amino derivative are greatly different from those of the cyclohexyl; secondly, the "N" atom of the 1, 4-disubstituted piperidinyl group has a lone pair of electrons, with a greater difference in electron density from cyclohexyl. Thus, compounds having a 1, 4-disubstituted piperidinyl linker may differ significantly in the mode of binding to the receptor, the magnitude of the binding force, water solubility and pharmacological activity and safety compared to compounds containing a 1, 4-disubstituted cyclohexyl linker, but need to be confirmed experimentally.

Brief description of the invention

Aiming at the defects in the prior art, the invention discloses a piperidine amino derivative, which overcomes the defects of side effects such as obesity, high blood sugar rise and the like, side effects such as arrhythmia, EPS (e.g. catalepsy) and the like, poor treatment effect on negative symptoms and cognitive disorder and the like of the existing medicaments so as to meet the requirement of clinical medication.

Also disclosed are methods of using the above compounds in the treatment of schizophrenia. The invention also discloses the application of the compound in preparing broad-spectrum anti-schizophrenia and medicines for treating schizophrenia.

According to one aspect of the present application, there is provided a piperidinylamino derivative, which is a compound having the general structural formula (I):

wherein:

r is

R₂Is selected from C₁～C₃Alkyl of (C)₁～C₂Alkoxy group of (C)₃～C₆Cycloalkyl, phenyl, substituted phenyl or heteroaryl of (a);

R₃、R₄each independently represents hydrogen or C₁～C₃Alkyl of (C)₃～C₆Cycloalkyl, phenyl, benzyl or pyridyl;

or R₃、R₄Form a morpholine ring, a pyrrolidine ring or an azetidine with the attached N atom;

n is an integer of 0 to 1;

R₁is composed of

According to certain embodiments of the invention, the substituted phenyl is selected from halogen, cyano, methoxy or C₁～C₂Alkyl-substituted phenyl of (a).

According to certain embodiments of the invention, the heteroaryl group is selected from furyl, pyrrolyl, thienyl, pyridyl, 2-benzothienyl, 2-benzofuryl or 2-indolyl.

According to certain embodiments of the invention, the salt is a salt comprising a pharmaceutically acceptable anion.

According to certain embodiments of the invention, the salt of the pharmaceutically acceptable anion is preferably a hydrochloride, hydrobromide, sulfate, acetate, citrate, tartrate, maleate, fumarate, mesylate, p-toluenesulfonate, oxalate, trifluoroacetate salt.

According to certain embodiments of the present invention, the hydrate of the salt of the compound contains 0.5 to 3 molecules of water of crystallization.

According to certain embodiments of the invention, the salt in the hydrate of the salt of the compound is preferably a salt that is a hydrochloride, hydrobromide, trifluoroacetate, methanesulfonate or oxalate salt.

According to certain embodiments of the present invention, the piperidinylamino derivatives of the present invention may include, but are not limited to, the following preferred compounds:

I-1N- (4- (2- (4- (benzo [ d ] isothiazol-3-yl) piperazin-1-yl) ethyl) piperidin-1-yl) acetamide,

I-2N- (4- (2- (4- (benzo [ d ] isothiazol-3-yl) piperazin-1-yl) ethyl) piperidin-1-yl) butanamide,

I-3N- (4- (2- (4- (benzo [ d ] isothiazol-3-yl) piperazin-1-yl) ethyl) piperidin-1-yl) -2-methoxyacetamide,

I-4N- (4- (2- (4- (benzo [ d ] isothiazol-3-yl) piperazin-1-yl) ethyl) piperidin-1-yl) -2-ethoxyacetamide,

I-54- (2- (4- (benzo [ d ] isothiazol-3-yl) piperazin-1-yl) ethyl) piperidin-1-yl-carbamic acid ethyl ester

I-6N- (4- (2- (4- (benzo [ d ] isothiazol-3-yl) piperazin-1-yl) ethyl) piperidin-1-yl) cyclopropylcarboxamide,

I-7N- (4- (2- (4- (benzo [ d ] isothiazol-3-yl) piperazin-1-yl) ethyl) piperidin-1-yl) cyclohexylcarboxamide,

I-8N- (4- (2- (4- (benzo [ d ] isothiazol-3-yl) piperazin-1-yl) ethyl) piperidin-1-yl) benzamide,

I-9N- (4- (2- (4- (benzo [ d ] isothiazol-3-yl) piperazin-1-yl) ethyl) piperidin-1-yl) -4-fluorobenzamide,

I-10N- (4- (2- (4- (benzo [ d ] isothiazol-3-yl) piperazin-1-yl) ethyl) piperidin-1-yl) -4-cyanobenzamide,

I-11N- (4- (2- (4- (benzo [ d ] isothiazol-3-yl) piperazin-1-yl) ethyl) piperidin-1-yl) -4-methylbenzamide,

I-12N- (4- (2- (4- (benzo [ d ] isothiazol-3-yl) piperazin-1-yl) ethyl) piperidin-1-yl) nicotinamide,

I-13N- (4- (2- (4- (benzo [ d ] isothiazol-3-yl) piperazin-1-yl) ethyl) piperidin-1-yl) furan-2-carboxamide,

I-14N- (4- (2- (4- (benzo [ d ] isothiazol-3-yl) piperazin-1-yl) ethyl) piperidin-1-yl) pyrrole-2-carboxamide,

I-15N- (4- (2- (4- (benzo [ d ] isothiazol-3-yl) piperazin-1-yl) ethyl) piperidin-1-yl) thiophene-2-carboxamide,

I-16N- (4- (2- (4- (benzo [ d ] isothiazol-3-yl) piperazin-1-yl) ethyl) piperidin-1-yl) indole-2-carboxamide,

II-11- (4- (2- (4- (benzo [ d ] isothiazol-3-yl) piperazin-1-yl) ethyl) piperidin-1-yl) -3-methylurea,

II-23- (4- (2- (4- (benzo [ d ] isothiazol-3-yl) piperazin-1-yl) ethyl) piperidin-1-yl) -1, 1-dimethylurea,

II-31- (4- (2- (4- (benzo [ d ] isothiazol-3-yl) piperazin-1-yl) ethyl) piperidin-1-yl) -3-propylurea,

II-41-cyclopropyl-3- (4- (2- (4- (benzo [ d ] isothiazol-3-yl) piperazin-1-yl) ethyl) piperidin-1-yl) urea,

II-51-cyclohexyl-3- (4- (2- (4- (benzo [ d ] isothiazol-3-yl) piperazin-1-yl) ethyl) piperidin-1-yl) urea,

II-61- (4- (2- (4- (benzo [ d ] isothiazol-3-yl) piperazin-1-yl) ethyl) piperidin-1-yl) -3-phenylurea,

II-73- (4- (2- (4- (benzo [ d ] isothiazol-3-yl) piperazin-1-yl) ethyl) piperidin-1-yl) -1-methyl-1-phenylurea,

II-81-benzyl-3- (4- (2- (4- (benzo [ d ] isothiazol-3-yl) piperazin-1-yl) ethyl) piperidin-1-yl) urea,

II-91- (4- (2- (4- (benzo [ d ] isothiazol-3-yl) piperazin-1-yl) ethyl) piperidin-1-yl) -3- (pyridin-3-yl) urea,

II-10N- (4- (2- (4- (benzo [ d ] isothiazol-3-yl) piperazin-1-yl) ethyl) piperidin-1-yl) morpholine-4-carboxamide,

II-11N- (4- (2- (4- (benzo [ d ] isothiazol-3-yl) piperazin-1-yl) ethyl) piperidin-1-yl) pyrrolidine-1-carboxamide,

II-12N- (4- (2- (4- (benzo [ d ] isothiazol-3-yl) piperazin-1-yl) ethyl) piperidin-1-yl) azetidine-1-carboxamide,

III-1N- (4- (2- (4- (6-fluorobenzo [ d ] isoxazol-3-yl) piperidin-1-yl) ethyl) piperidin-1-yl) acetamide,

III-2N- (4- (2- (4- (6-fluorobenzo [ d ] isoxazol-3-yl) piperidin-1-yl) ethyl) piperidin-1-yl) butanamide,

III-34- (2- (4- (6-Fluorobenzo [ d ] isoxazol-3-yl) piperidin-1-yl) ethyl) piperidin-1-yl-carbamic acid ethyl ester

III-4N- (4- (2- (4- (6-fluorobenzo [ d ] isoxazol-3-yl) piperidin-1-yl) ethyl) piperidin-1-yl) cyclopropylcarboxamide,

III-5N- (4- (2- (4- (6-fluorobenzo [ d ] isoxazol-3-yl) piperidin-1-yl) ethyl) piperidin-1-yl) cyclohexylcarboxamide,

III-6N- (4- (2- (4- (6-fluorobenzo [ d ] isoxazol-3-yl) piperidin-1-yl) ethyl) piperidin-1-yl) benzamide,

III-7N- (4- (2- (4- (6-fluorobenzo [ d ] isoxazol-3-yl) piperidin-1-yl) ethyl) piperidin-1-yl) -4-methoxybenzamide,

III-8N- (4- (2- (4- (6-fluorobenzo [ d ] isoxazol-3-yl) piperidin-1-yl) ethyl) piperidin-1-yl) -4-ethylbenzamide,

III-9N- (4- (2- (4- (6-fluorobenzo [ d ] isoxazol-3-yl) piperidin-1-yl) ethyl) piperidin-1-yl) nicotinamide,

III-10N- (4- (2- (4- (6-fluorobenzo [ d ] isoxazol-3-yl) piperidin-1-yl) ethyl) piperidin-1-yl) furan-2-carboxamide,

III-11N- (4- (2- (4- (6-fluorobenzo [ d ] isoxazol-3-yl) piperidin-1-yl) ethyl) piperidin-1-yl) pyrrole-2-carboxamide,

III-12N- (4- (2- (4- (6-fluorobenzo [ d ] isoxazol-3-yl) piperidin-1-yl) ethyl) piperidin-1-yl) thiophene-2-carboxamide,

III-13N- (4- (2- (4- (6-fluorobenzo [ d ] isoxazol-3-yl) piperidin-1-yl) ethyl) piperidin-1-yl) benzofuran-2-carboxamide,

III-14N- (4- (2- (4- (6-fluorobenzo [ d ] isoxazol-3-yl) piperidin-1-yl) ethyl) piperidin-1-yl) benzothiophene-2-carboxamide,

IV-13- (4- (2- (4- (6-fluorobenzo [ d ] isoxazol-3-yl) piperidin-1-yl) ethyl) piperidin-1-yl) -1, 1-dimethylurea,

IV-21-cyclopropyl-3- (4- (2- (4- (6-fluorobenzo [ d ] isoxazol-3-yl) piperidin-1-yl) ethyl) piperidin-1-yl) urea,

IV-31-cyclohexyl-3- (4- (2- (4- (6-fluorobenzo [ d ] isoxazol-3-yl) piperidin-1-yl) ethyl) piperidin-1-yl) urea,

IV-41- (4- (2- (4- (6-fluorobenzo [ d ] isoxazol-3-yl) piperidin-1-yl) ethyl) piperidin-1-yl) -3-phenylurea,

IV-51- (4- (2- (4- (6-fluorobenzo [ d ] isoxazol-3-yl) piperidin-1-yl) ethyl) piperidin-1-yl) -3- (pyridin-3-yl) urea,

IV-6N- (4- (2- (4- (6-fluorobenzo [ d ] isoxazol-3-yl) piperidin-1-yl) ethyl) piperidin-1-yl) morpholine-4-carboxamide,

IV-7N- (4- (2- (4- (6-fluorobenzo [ d ] isoxazol-3-yl) piperidin-1-yl) ethyl) piperidin-1-yl) pyrrolidine-1-carboxamide,

IV-8N- (4- (2- (4- (6-fluorobenzo [ d ] isoxazol-3-yl) piperidin-1-yl) ethyl) piperidin-1-yl) azetidine-1-carboxamide.

The structures of the preferred compounds are shown in the following table:

according to one aspect of the present invention, there is provided a pharmaceutical composition comprising a therapeutically effective amount of the piperidinylamino derivative, or a pharmaceutically acceptable hydrate, salt or hydrate of salt thereof, and a pharmaceutically acceptable carrier.

According to one aspect of the present invention, there is provided a kit comprising said piperidinylamino derivative, or a pharmaceutically acceptable hydrate, salt or hydrate of a salt thereof.

According to one aspect of the present invention, there is provided a method for treating schizophrenia by administering to a patient the piperidinylamino derivative, or a pharmaceutically acceptable hydrate, salt or hydrate of salt thereof.

According to one aspect of the invention, the invention provides the use of the piperidinylamino derivative, or a pharmaceutically acceptable hydrate, salt or hydrate of a salt thereof, for the manufacture of a medicament for the treatment of schizophrenia.

Detailed Description

Definition of

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

The term "halogen" or "halogen atom" refers to a fluorine (F) atom, a chlorine (Cl) atom, a bromine (Br) atom, or an iodine (I) atom. The term "halo" when used in front of a chemical group means that the substituent is substituted with one or more halo substituents. The term "haloalkyl" refers to an alkyl group as defined above wherein the hydrogen atom at one or more arbitrary positions is replaced by one or more halogen atoms which may be the same or different.

The term "cycloalkyl" refers to a monocyclic or polycyclic ring formed from carbon atoms, which may be saturated or partially saturated. In certain embodiments of the present application, the cycloalkyl group comprises a 3-6 membered (e.g., 3, 4, 5, or 6 membered) cycloalkyl, such as a 3 membered monocyclic ring, or a 5 membered monocyclic ring. Examples of cycloalkyl groups include cyclobutyl, cyclopentyl, and the like.

The term "aryl" refers to a carbocyclic aromatic ring comprising a single ring or multiple rings (e.g., 2,3, or 4 fused rings). In certain embodiments herein, examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthryl, phenanthryl, indenyl, and the like. In certain embodiments of the present application, the aryl group comprises a 5-9 membered (e.g., 5, 6, 7, 8, or 9 membered) aryl group.

The term "heteroaryl" means that one or more of the ring-forming carbon atoms in the above-mentioned aryl group is replaced by a heteroatom such as S, O or an N atom. The "heteroaryl" may be a monocyclic or polycyclic heteroaryl. Examples of such "heteroaryl" include, but are not limited to, furyl, pyridyl, pyrimidinyl, imidazolyl, indolyl, pyrrolyl, benzofuryl, benzothienyl, benzothiazolyl, isoxazolyl, pyrazolyl, purinyl, benzimidazolyl, and the like. In certain embodiments of the present application, the heterocycloalkyl group has 4 to 8 (e.g., 4, 5, 6, 7, or 8) carbon atoms.

The term "piperidinylamino" refers to

In certain embodiments of the present application, the cycloalkyl, aryl, heterocycloalkyl, or heteroaryl groups described above may be substituted or unsubstituted. In certain embodiments herein, the substituents may be one or more, independently selected from halogen, cyano, alkoxy, alkyl, and the like.

The compounds described herein include the anhydrate and hydrate forms of the compound. The hydrate may contain, for example, 0.5 to 3 water molecules, for example, 0.5, 1, 1.5, 2, 2.5 or 3 water molecules.

According to certain embodiments of the present application, the hydrate of the salt of the compound contains 0.5 to 3 molecules of water of crystallization, for example, 0.5, 1, 2,3 molecules of water of crystallization. According to certain embodiments of the present application, the salt of the compound is a hydrochloride, hydrobromide, trifluoroacetate, methanesulfonate or oxalate salt.

The term "pharmaceutical composition" means a mixture containing a therapeutically effective amount of one or more of the compounds and pharmaceutically acceptable hydrates or salts thereof, in admixture with other pharmaceutically acceptable carriers. The compounds are formulated into pharmaceutical compositions for more convenient administration to a subject.

The compounds of the present invention can be prepared into conventional pharmaceutical preparations by methods known in the art. For example, it may be a tablet, a capsule, an injection, etc.

According to some embodiments of the invention, the active ingredient is present in the formulation in an amount of 0.1% to 100% (by weight).

The compounds or pharmaceutical compositions described herein can be administered alone or in combination with other suitable agents.

The term "pharmaceutically acceptable carrier" is a pharmaceutically acceptable ingredient or vehicle, including but not limited to solvents, excipients, diluents, adjuvants, fillers, and the like.

The term "pharmaceutically acceptable salts" refers to acid addition salts formed by the compounds. The acid forming the acid addition salt may be an inorganic acid including, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, and the like, or an organic acid including, for example, acetic acid, oxalic acid, methanesulfonic acid, citric acid, and the like.

According to certain embodiments of the invention, the salt of the compound is a salt comprising a pharmaceutically acceptable anion.

The term "semi-Inhibitory Concentration (IC)₅₀) "or" half-inhibition "refers to the concentration of inhibitor when the activity of the target substance is half-inhibited during the inhibition of the target substance. Generally, the stronger the inhibitory potency of the inhibitor, the IC₅₀The lower. According to certain embodiments of the present application, the IC50 of the compounds described herein is when D₂、D₃、5-HT_1A、5-HT_2AThe compounds are effective when the receptor is inhibited by 50%And (4) concentration.

When "about" is used in this application to modify a numerical value, it is meant that the numerical value may fluctuate within a range of ± 10%, ± 9%, ± 8%, ± 7%, ± 6%, ± 5%, ± 4%, ± 3%, ± 2% or ± 1%.

General method of synthesis

The compounds of the present invention can be synthesized by the following two general synthetic methods.

The general method I comprises the following steps:

the method comprises the step of reacting raw material 1 and triethyl phosphonoacetate in tetrahydrofuran solution under the condition of potassium tert-butoxide to prepare an intermediate 2.2, carrying out palladium carbon hydrogenation reduction, ethyl ester reduction and mesylation, and condensing with an aryl piperazine fragment under an alkaline condition to obtain an important intermediate 6.6 removing protective group under the conditions of trifluoroacetic acid and dichloromethane, and preparing a compound 8 under the conditions of sodium nitrite and acetic acid. 8, reducing with zinc powder, and reacting with different acylating reagents to obtain the compounds I-1-I-16 and III-1-III-14. The specific description is as follows:

adding potassium tert-butoxide (720mmol)) into THF (600mL), dropwise adding a solution of triethyl phosphonoacetate (600mmol) in THF (120mL) at 5-10 ℃, stirring for 2h after addition, dropwise adding a solution of raw material 1(540mmol) in THF (100mL) at 5-10 ℃, reacting at room temperature for 2h after addition, stopping the reaction, dropwise adding water (100mL) to quench the reaction, extracting the reaction solution with ethyl acetate (200mL × 3), combining ethyl acetate layers, washing with water (100mL × 2) and saturated saline (100mL × 2) in sequence, drying over anhydrous sodium sulfate, filtering, and concentrating to obtain 130g of a white solid (intermediate 2) with a yield of 89%.

Adding the intermediate 2(500mmol) and 10% Pd/C, THF (1000mL) into a 1L hydrogenation kettle, reacting at the external temperature of 60 ℃ under the pressure of 2.0MPa for 10h, stopping the reaction, and filtering to obtain a THF solution of an intermediate 3. Adding lithium borohydride (1000mmol), carrying out reflux reaction for 21h, stopping the reaction, cooling to 5-10 ℃, sequentially adding 30% HCl aqueous solution (200mL) and 20% HCl aqueous solution (200mL), stirring for 1h, extracting with ethyl acetate (200mL × 3), combining ethyl acetate layers, sequentially washing with water (100mL × 2) and saturated saline (100mL × 2), drying with anhydrous sodium sulfate, filtering, and concentrating to obtain 108g of white solid (intermediate 4), wherein the yield of the two steps is 94% in total.

Adding the intermediate 4(480mmol), dichloromethane (400mL) and triethylamine (960mmol) into a 1000mL three-necked flask, dropwise adding a dichloromethane (100mL) solution of methanesulfonyl chloride (520mmol) at 0-5 ℃, reacting at room temperature for 3h, stopping the reaction, washing with a sodium carbonate aqueous solution (40mL multiplied by 2) and a saturated saline solution (100mL multiplied by 2) in sequence, drying with anhydrous sodium sulfate, filtering, and concentrating to obtain 126g of light yellow solid (intermediate 5) with the yield of 85%.

Adding the intermediate 5(360mmol), potassium carbonate (1080mmol), potassium iodide (2mmol), acetonitrile (2000mL) and aryl piperazine (325mmol) into a 5000mL four-neck bottle, carrying out reflux reaction for 24h, cooling to room temperature, stirring for 2h, filtering, washing a filter cake with acetonitrile (100mL multiplied by 2), and drying for 5h in an air drying oven (60 ℃) to obtain a white solid intermediate 6 with the yield of 76-80%.

Adding the intermediate 6(200mmol), trifluoroacetic acid (600mmol) and dichloromethane (1000mL) into a 2000mL single-neck flask, reacting at room temperature for 12h, adjusting the pH of the reaction solution to 10 with 20% sodium hydroxide, separating, washing the dichloromethane layer with water (200mL multiplied by 2) and saturated saline (150mL multiplied by 2) in sequence, drying with anhydrous sodium sulfate, filtering, and concentrating to obtain an off-white semisolid (intermediate 7) with the yield of 90-92%.

Adding the intermediate 7(160mmol), acetic acid (200mL), sodium nitrite (320mL) and water (100mL) into a 1000mL single-neck bottle, reacting for 6h at room temperature, concentrating the reaction solution, adding water (400mL), extracting with dichloromethane (200mL multiplied by 2), and concentrating the organic layer to obtain an off-white solid (intermediate 8) with the yield of 86-89%.

Adding the intermediate 8(100mmol), acetic acid (200mL) and zinc powder (300mmol) into a 500mL single-neck bottle, reacting at room temperature for 8h, filtering, concentrating the filtrate, adding water (400mL), extracting with dichloromethane (200mL multiplied by 2), and concentrating the organic layer to obtain a white solid (intermediate 9) with the yield of 78-80%.

Adding the intermediate 9(60mmol), dichloromethane (200mL) and triethylamine (50mmol) into a 500mL three-necked bottle, dropwise adding different acylating reagents (66mmol) at 0-5 ℃, reacting for 3h at room temperature, washing with water (200mL multiplied by 2) and saturated saline (120mL multiplied by 2) in sequence, drying with anhydrous sodium sulfate, filtering, concentrating to obtain a white solid, and crystallizing by using a 95% ethanol solution to obtain the white solid, namely the compounds I-1-I-16 and III-1-III-14, wherein the yield is 80-96%.

Putting the compounds I-1-I-16 and III-1-III-14 into 5% acid/ethanol for reflux dissolution, and cooling to separate out salts of the compounds I-1-I-16 and III-1-III-14, wherein the acid is hydrochloric acid, hydrobromic acid, sulfuric acid, acetic acid, citric acid, tartaric acid, maleic acid, fumaric acid, methanesulfonic acid, p-toluenesulfonic acid, oxalic acid or trifluoroacetic acid.

R in the above general method I₂The definitions of (a) are consistent with those in the aforementioned compounds, i.e.,

R₂is selected from C₁～C₃Alkyl of (C)₁～C₂Alkoxy group of (C)₃～C₆Cycloalkyl, phenyl, substituted phenyl or heteroaryl.

The general method II comprises the following steps:

adding the compound 9 (prepared by a general method I), substituted amine and triethylamine into a solvent dissolved with triphosgene to react to obtain the compounds II-1-II-12 and IV-1-IV-8. The specific description is as follows:

dissolving triphosgene (20mmol) in dichloromethane (100mL), dropwise adding a dichloromethane (100mL) solution of a compound 9(1.8mmol) and triethylamine (20mmol) at-0 ℃, keeping the temperature and stirring for 3h, dropwise adding a reaction solution into an isopropanol (200mL) solution of a substituted amine (100mmol) at-5-0 ℃, keeping the temperature and reacting for 5h, stopping the reaction, adding a saturated ammonium chloride solution (100mL), distributing, washing an organic phase with water (100mL multiplied by 2) and saturated saline (100mL multiplied by 2) in sequence, and drying with anhydrous sodium sulfate. Filtering, taking filtrate, concentrating under reduced pressure to obtain off-white or white solid, and recrystallizing or separating by a Flash column to obtain the compounds II-1-II-12 and IV-1-IV-8 of the invention with the yield of 80-88%. The preparation method of the salts of the compounds II-1 to II-12 and IV-1 to IV-8 and the used acid and the obtained salt form are the same as the one of the common method I.

R in the above general formula II₃、R₄The definitions of (a) are consistent with those in the aforementioned compounds, i.e.,

or R₃、R₄With the N atom to which it is attached, to form a morpholine ring, a pyrrolidine ring or an azetidine.

In addition, the invention synthesizes a representative compound 1 by referring to a method reported by a patent CN1829703A, synthesizes a marketed drug cariprazine (hydrochloride of the compound 1 reported by CN 1829703A) by referring to methods reported by patents WO2010070370 and WO2011073705, and synthesizes a representative compound 84 by referring to a method reported by a patent CN 102159557A; representative compound 84 was synthesized according to the method reported in patent CN102159557A, representative compound IV-2 was synthesized according to the method reported in patent CN103130737A, and representative compound I-1 was synthesized according to the method reported in patent CN 104140421A. The synthesized patent represents a compound, and is used as a control sample for in vivo and in vitro pharmacological screening and physicochemical property research of the compound.

Pharmaceutical composition and kit

According to one aspect of the present invention, there is provided a process for preparing the pharmaceutical composition by mixing the piperidinylamino derivative, or a pharmaceutically acceptable hydrate, salt or hydrate of salt thereof, with a pharmaceutically acceptable carrier.

Pharmacological research

Acting on dopamine D₂Receptors are a common mechanism for classical and non-classical antipsychotic drugs. Antagonism of D₂The receptor can significantly treat the positive symptoms of patients with schizophrenia. At the same time, antagonize serotonin 5-HT_2AReduced receptor capacity D₂The excessive inhibition of the receptor can reduce the side reaction of EPS, hyperprolactinemia and the like. Selective antagonism of dopamine D₃The receptor can reduce the occurrence of extrapyramidal side effects and significantly improve cognitive deficits in schizophrenic patients. But with D₂Receptor comparison, D₃Receptor mRNA is less distributed in the brain, requiring that the drug have a certain D₃Receptor selectivity, i.e. for D₃Has a stronger affinity than for D₂The affinity of the receptor is 10 times or more, so as to exert physiological effects such as cognitive improvement. However, too high D₃Receptor selectivity, e.g. compound pair D₃Receptor affinity greater than D₂More than one hundred times of the receptor, or D₃/D₂At receptor selectivities greater than 100-fold or greater, the compounds fail to exhibit anti-schizophrenia activity, particularly against the positive symptoms of schizophrenia. 5-HT_1AThe improvement effect of the receptor on reducing the side effect of the schizophrenia drug and improving the cognitive function is more and more accepted by academia. Thus, selectively act on D₂、D₃、5-HT_1AAnd 5-HT_2AThe research and development of the novel multi-target anti-schizophrenia drug of the receptor have wide prospect

The results of in vitro pharmacological studies of the compounds of the invention show that:

1. the piperidine amino derivative (I) has strong affinity to drug effect targets of various neuropsychiatric diseases, such as dopamine D₂、D₃Receptor, serotonin 5-HT_1A、5-HT_2AReceptors, most of which are directed to 5-HT_2AThe receptor affinity is superior to that of the representative compound 1 in the patent CN 1829703A; most of the compounds of the pair D₂The receptor affinity is significantly better than that of CN102159557A (representing compound 84) andCN103130737A (representing compound IV-2).

2. The compounds of the invention have suitable dopamine D₃/D₂Receptor-selective, largely compound D₃/D₂The receptor selectivity is in the range of 5-60 fold, compared with CN1829703A (D)₃/D₂Receptor selectivity 5-200 times), CN102159557A (most of the compounds D)₃/D₂Receptor selectivity greater than 100-fold) and CN103130737A (majority of compound D)₃/D₂Receptor selectivity is more than 100 times) further proves that the compound has good cognitive impairment improving effect and is not easy to generate side effects such as extrapyramidal system (EPS) and the like.

3. Further receptor function test results show that part of compounds show certain D₂Partial receptor agonism, and meets the in vitro pharmacological model characteristics of the anti-schizophrenia drug on the market.

Animal in vivo model experiments show that:

the compound of the invention can obviously improve the related symptoms of a mouse apomorphine model and an MK-801 model, and the activity of part of the compound is better than that of the marketed drug Carilazine (see example 58). The action target and the animal model are closely related to nervous system diseases, particularly schizophrenia, caused by disorders of dopaminergic system and the like, so that the compound has a treatment effect on the schizophrenia.

The compound in vitro physicochemical experiment shows that:

the water solubility of the compound of the invention is obviously superior to that of the representative compounds in patents CN1829703A, CN102159557A, CN103130737A and CN104140421A (see example 59), so that the compound of the invention is more beneficial to preparation and research of preparations and prescriptions.

The pharmacokinetics experiment in the compound body shows that:

most of the compounds of the invention have high brain penetration rate (brain AUC/plasma AUC >8), good oral absolute bioavailability (more than 30%), and brain penetration rate and oral bioavailability are superior to the representative compounds in patents CN1829703A, CN102159557A, CN103130737A and CN104140421A (see example 60), which are related to good physicochemical properties of the compounds, so the compounds of the invention have good potential drug properties.

In summary, compared with the prior art, the compound of the invention has the following advantages and characteristics:

1. the compounds of the invention are not only p-D₂The receptor has partial agonism and also has D-agonism₃/D₂The receptor has proper selectivity and obvious action mechanism characteristics.

2. The compound of the invention has good anti-schizophrenia effect on various animal in vivo models, has broad-spectrum anti-schizophrenia effect, and is preferably stronger than a positive drug or a drug on the market.

3. The compound of the invention has low toxicity and low side effect.

4. The compound of the invention has strong brain targeting property, higher oral bioavailability, and drug-induced parameters conforming to the characteristics of central drugs, and has good drug-forming property.

5. Compared with the prior art, the compound of the invention has better water solubility and is more beneficial to the research of preparations and prescriptions.

Therefore, the compound has good effect characteristics on the drug effect target of schizophrenia, has definite anti-schizophrenia activity in animals, good water solubility and good pharmacokinetic property, and can be used for treating schizophrenia.

The piperidine amino derivative has the effects of improving and treating schizophrenia and can be used for treating schizophrenia. The schizophrenia refers to serious psychological disorder, and the mental activities of the patients, such as cognition, emotion, will, action and behavior, can all have lasting obvious abnormality; the normal study, work and life can not be realized; the action behavior is difficult to be understood by the ordinary people; under the control of pathological psychology, there are actions of suicide or attack, and harm to others.

In conclusion, compared with the cyclohexyl amino structure in the prior art, the compound has the piperidine amino structure, and the piperidyl and the cyclohexyl have essential differences in the aspects of chemical characteristics, such as water solubility, flexibility, configuration, electron density and the like, so that the piperidine amino derivative not only has novelty in chemical structure, but also has more advantages in the aspects of physicochemical properties, pharmacokinetic properties, in vivo and in vitro pharmacological activity, safety and the like, and embodies creative and substantial scientific progress.

All patents, patent applications, and references cited in this application are incorporated by reference into this application in their entirety to the same extent as if each individual reference were individually incorporated by reference. In the event of a conflict between the present application and the references provided herein, the present application shall control.

Detailed Description

The present invention will be further illustrated with reference to specific examples, but the scope of the present invention is not limited to these examples.

Example 1: n- (4- (2- (4- (benzo [ d ]))]Isothiazol-3-yl) piperazin-1-yl) ethyl) piperidin-1-yl) acetyl Preparation of amine (Compound I-1) and salts thereof

4- (2- (4- (benzo [ d ] isothiazol-3-yl) piperazin-1-yl) ethyl) piperidin-1-amine (9) (prepared according to general method one) (2.0g,5.8mmol), triethylamine (8.7mmol) were added to dichloromethane (20mL), a solution of acetyl chloride (0.5g,6.4mmol) in dichloromethane (10mL) was added dropwise, reacted for 3h, washed with water (40 mL. times.2) and saturated brine (20 mL. times.2) in this order, dried over anhydrous sodium sulfate, filtered, and concentrated to give a white solid, which was crystallized from a 95% ethanol solution to give 2.02g of a white solid in 90% yield.

¹HNMR(CDCl₃,:ppm):1.20-1.23(m,1H,A-H),1.35-1.38(m,2H,A-H),1.47-1.51(m,2H,A-H),1.54-1.57(m,2H,A-H),2.10(s,3H,A-H),2.42-2.44(m,2H,A-H),2.50(t,2H,J＝8.0Hz,N-CH₂),2.66(brs,4H,A-H),3.18-3.20(m,2H,A-H),3.54(brs,4H,A-H),7.12-7.14(m,1H,Ar-H),7.24-7.28(m,2H,Ar-H),7.32-7.34(m,1H,Ar-H).

ESI-MS:388[M+H⁺].

Preparation of Compound I-1 hydrochloride

Compound I-1(0.5g,1.3mmol) and 5% aqueous hydrochloric acid (1.35mmol) were added to ethanol (10mL), and the mixture was dissolved under reflux, cooled to precipitate a white solid, and filtered to obtain 0.5g of a white solid with a yield of 91%.

Elemental analysis: c₂₀H₂₉N₅OS & HCl (theoretical%: C56.65, H7.13, N16.52; experimental%: C56.52, H7.30, N16.41).

The difference between the theoretical and experimental values is within. + -. 0.3%, indicating that the salt or hydrate of the salt is obtained in this experiment. The theoretical values and experimental values in the following experiments have the same meaning.

Preparation of Compound I-1 mesylate hemihydrate

Compound I-1(0.5g,1.3mmol) and methanesulfonic acid aqueous solution (1.35mmol) were added to ethanol (10mL), and the mixture was dissolved under reflux, cooled to precipitate a white solid, and filtered to obtain 0.51g of a white solid with a yield of 80%.

Elemental analysis: c₂₀H₂₉N₅OS·CH₄O₃S·1/2H₂O (theoretical value%: C51.20, H6.69, N14.22; experimental value%: C51.33, H6.72, N14.19).

Preparation of Compound I-1 hydrobromide trihydrate

Compound I-1(0.5g,1.3mmol) and 5% aqueous hydrobromic acid (1.35mmol) were added to ethanol (10mL), dissolved under reflux, cooled to precipitate a white solid, which was filtered to give 0.56g of a white solid with a yield of 83%.

Elemental analysis: c₂₀H₂₉N₅OS·HBr·3H₂O (theoretical value%: C45.97, H6.94, N13.40; experimental value%: C45.81, H7.03, N13.29).

Preparation of Compound I-1 oxalate dihydrate

Compound I-1(0.5g,1.3mmol) and oxalic acid dihydrate (1.35mmol) were added to ethanol (10mL), and the mixture was dissolved under reflux, cooled to precipitate a white solid, and filtered to obtain 0.59g of a white solid with a yield of 89%.

Elemental analysis: c₂₀H₂₉N₅OS·C₂H₂O₄·2H₂O (theoretical value%: C51.45, H6.87, N13.64; experimental value%: C51.63, H6.68, N13.56).

Example 2: n- (4- (2- (4- (benzo [ d ]))]Isothiazol-3-yl) piperazin-1-yl) ethyl) piperidin-1-yl) butanoyl Preparation of amine (Compound I-2) and salts thereof

By using intermediate 9(5.6mmol) and butyryl chloride (6.2mmol) as raw materials and following the method for preparing compound I-1, 2.12g of the objective compound I-2 as a white solid was obtained with a yield of 91%.

¹HNMR(CDCl₃,:ppm):0.88(t,3H,J＝6.8Hz,A-H),1.21-1.24(m,1H,A-H),1.36-1.39(m,2H,A-H),1.48-1.52(m,2H,A-H),1.55-1.58(m,2H,A-H),1.64-1.66(m,2H,A-H),2.32(t,2H,J＝7.2Hz,A-H),2.43-2.45(m,2H,A-H),2.50(t,2H,J＝8.0Hz,N-CH₂),2.66(brs,4H,A-H),3.18-3.20(m,2H,A-H),3.54(brs,4H,A-H),7.10-7.12(m,1H,Ar-H),7.22-7.26(m,2H,Ar-H),7.31-7.32(m,1H,Ar-H).

ESI-MS:416[M+H⁺].

Preparation of Compound I-2 hydrobromic acid salt

Using compound I-2(4.0mmol) and 5% aqueous hydrobromic acid (4.1mmol) as starting materials, the procedure for the preparation of the hydrobromide salt of compound I-1 was used to give 1.69g of a white solid with a yield of 85%.

Elemental analysis: c₂₂H₃₃N₅OS & HBr (% of theory: C53.22, H6.90, N14.11; and% of experiment: C53.32, H6.81, N14.07).

Example 3: n- (4- (2- (4- (benzo [ d ]))]Isothiazol-3-yl) piperazin-1-yl) ethyl) piperidin-1-yl) -2-methyl Preparation of Oxoacetamide (Compound I-3) and salts thereof

The intermediate 9(5.6mmol) and 2-methoxyacetyl chloride (6.2mmol) were used as raw materials to obtain 2.06g of the target compound I-3 as a white solid in 88% yield according to the method for preparing the compound I-1.

¹HNMR(CDCl₃,:ppm):1.23-1.26(m,1H,A-H),1.38-1.41(m,2H,A-H),1.50-1.54(m,2H,A-H),1.57-1.60(m,2H,A-H),2.45-2.47(m,2H,A-H),2.52(t,2H,J＝7.8Hz,N-CH₂),2.68(brs,4H,A-H),3.20-3.22(m,2H,A-H),3.48(s,3H,A-H),3.55(brs,4H,A-H),4.44(s,2H,A-H),7.12-7.14(m,1H,Ar-H),7.24-7.28(m,2H,Ar-H),7.32-7.34(m,1H,Ar-H).

ESI-MS:418[M+H⁺].

Preparation of Compound I-3 fumarate

Using compound I-3(4.0mmol) and fumaric acid (4.1mmol) as starting materials, 1.73g of a white solid was obtained in a yield of 81% by the method for producing the compound I-1 hydrobromide.

Elemental analysis: c₂₁H₃₁N₅O₂S·C₄H₄O₄(theoretical values: C56.27, H6.61, N13.12; experimental values: C56.41, H6.85, N13.01).

Example 4: n- (4- (2- (4- (benzo [ d ]))]Isothiazol-3-yl) piperazin-1-yl) ethyl) piperidin-1-yl) -2-ethane Preparation of Oxoacetamide (Compound I-4) and salts thereof

The intermediate 9(5.6mmol) and 2-ethoxyacetyl chloride (6.2mmol) were used as raw materials to obtain 2.01g of the objective compound I-4 as a white solid in 83% yield according to the method for preparing the compound I-1.

¹HNMR(CDCl₃,:ppm):1.06(t,3H,J＝6.8Hz,A-H),1.28-1.40(m,3H,A-H),1.49-1.53(m,2H,A-H),1.56-1.59(m,2H,A-H),2.46-2.48(m,2H,A-H),2.51(t,2H,J＝7.8Hz,N-CH₂),2.69(brs,4H,A-H),3.21-3.23(m,2H,A-H),3.46(q,2H,J＝6.8Hz,A-H),3.56(brs,4H,A-H),4.21(s,2H,A-H),7.11-7.13(m,1H,Ar-H),7.23-7.27(m,2H,Ar-H),7.31-7.33(m,1H,Ar-H).

ESI-MS:432[M+H⁺].

Preparation of Compound I-4 succinate

By using the compound I-4(4.4mmol) and succinic acid (4.6mmol) as raw materials and adopting the preparation method of the compound I-1 hydrobromide, 2.23g of white solid is obtained with the yield of 92%.

Elemental analysis: c₂₂H₃₃N₅O₂S·C₄H₆O₄(theoretical values: C56.81, H7.15, N12.74; experimental values: C56.69, H7.01, N12.94).

Example 5: 4- (2- (4- (benzo [ d ]))]Isothiazol-3-yl) piperazin-1-yl) ethyl) piperidin-1-yl-carbamic acid Preparation of Ethyl ester (Compound I-5) and salts thereof

By using the intermediate 9(5.6mmol) and ethoxycarbonyl chloride (6.2mmol) as raw materials and according to the preparation method of the compound I-1, the target compound I-5 is obtained as a white solid 2.22g with a yield of 95%.

¹HNMR(CDCl₃,:ppm):1.25-1.40(m,6H,A-H),1.48-1.52(m,2H,A-H),1.54-1.57(m,2H,A-H),2.45-2.47(m,2H,A-H),2.53(t,2H,J＝7.8Hz,N-CH₂),2.68(brs,4H,A-H),3.20-3.22(m,2H,A-H),3.55(brs,4H,A-H),4.08(q,2H,J＝7.2Hz,A-H),7.10-7.12(m,1H,Ar-H),7.22-7.26(m,2H,Ar-H),7.30-7.32(m,1H,Ar-H).

ESI-MS:418[M+H⁺].

Preparation of Compound I-5 tartrate salt

Using compound I-5(4.0mmol) and tartaric acid (4.1mmol) as starting materials, 2.0g of a white solid was obtained in 88% yield by the method for producing the compound I-1 hydrobromide.

Elemental analysis: c₂₁H₃₁N₅O₂S·C₄H₆O₆(theoretical values: C52.90, H6.57, N12.34; experimental values: C52.68, H6.75, N12.49).

Example 6: n- (4- (2- (4- (benzo [ d ]))]Isothiazol-3-yl) piperazin-1-yl) ethyl) piperidin-1-yl) cyclopropane Preparation of benzamide (Compound I-6) and salts thereof

By using the intermediate 9(5.6mmol) and cyclopropylcarbonyl chloride (6.2mmol) as raw materials and following the preparation method of the compound I-1, 2.06g of the target compound I-6 as a white solid was obtained with a yield of 89%.

¹HNMR(CDCl₃,:ppm):0.68-0.79(m,4H,A-H),1.18-1.21(m,2H,A-H),1.32-1.35(m,2H,A-H),1.44-1.48(m,2H,A-H),1.51-1.54(m,2H,A-H),2.40-2.42(m,2H,A-H),2.47(t,2H,J＝8.0Hz,N-CH₂),2.63(brs,4H,A-H),3.15-3.17(m,2H,A-H),3.51(brs,4H,A-H),7.07-7.09(m,1H,Ar-H),7.19-7.23(m,2H,Ar-H),7.28-7.30(m,1H,Ar-H).

ESI-MS:414[M+H⁺].

Preparation of Compound I-6 hydrochloride

Using compound I-6(3.6mmol) and 5% aqueous hydrochloric acid (3.8mmol) as starting materials, 1.46g of a white solid was obtained in a yield of 90% by the method for producing the compound I-1 hydrobromide.

Elemental analysis: c₂₂H₃₁N₅OS & HCl (theoretical values: C58.71, H7.17, N15.56; experimental values: C58.92, H7.08, N15.69).

Example 7: n- (4- (2- (4- (2, 3-dichlorophenyl) piperazin-1-yl) ethyl) piperidin-1-yl) cyclohexanecarboxyl Preparation of amine (Compound I-7) and salts thereof

The intermediate 9(5.6mmol) and the cyclohexyl carbonyl chloride (6.2mmol) were used as raw materials to obtain the objective compound I-7 as a white solid 2.04g with a yield of 80% according to the preparation method of the compound I-1.

¹HNMR(CDCl₃,:ppm):1.21-1.23(m,1H,A-H),1.30-1.33(m,2H,A-H),1.38-1.50(m,10H,A-H),1.59-1.61(m,2H,A-H),1.75-1.78(m,2H,A-H),2.33(m,1H,A-H),2.41-2.43(m,2H,A-H),2.45(t,2H,J＝8.0Hz,N-CH₂),2.61(brs,4H,A-H),3.13-3.15(m,2H,A-H),3.50(brs,4H,A-H),7.06-7.08(m,1H,Ar-H),7.18-7.22(m,2H,Ar-H),7.29-7.31(m,1H,Ar-H).

ESI-MS:456[M+H⁺].

Preparation of Compound I-7 hydrobromide

Using compound I-7(3.8mmol) and 5% aqueous hydrobromic acid (4.0mmol) as starting materials, the procedure for the preparation of compound I-1 hydrobromide gave 1.67g of a white solid in 82% yield.

Elemental analysis: c₂₅H₃₇N₅OS & HBr (theoretical%: C55.96, H7.14, N13.05; experimental%: C55.78, H7).36，N 13.18)。

Example 8: n- (4- (2- (4- (benzo [ d ]))]Isothiazol-3-yl) piperazin-1-yl) ethyl) piperidin-1-yl) benzyl Preparation of amide (Compound I-8) and salt thereof

By using the intermediate 9(5.6mmol) and benzoyl chloride (6.2mmol) as raw materials and following the preparation method of the compound I-1, the target compound I-8 was obtained as a white solid in an amount of 2.29g with a yield of 91%.

¹HNMR(CDCl₃,:ppm):1.24-1.27(m,1H,A-H),1.39-1.42(m,2H,A-H),1.51-1.55(m,2H,A-H),1.58-1.61(m,2H,A-H),2.46-2.48(m,2H,A-H),2.52(t,2H,J＝8.0Hz,N-CH₂),2.69(brs,4H,A-H),3.20-3.22(m,2H,A-H),3.57(brs,4H,A-H),7.12-7.14(m,1H,Ar-H),7.24-7.27(m,2H,Ar-H),7.31-7.33(m,1H,Ar-H),7.58-7.65(m,3H,Ar-H),7.94-7.97(m,2H,Ar-H).

ESI-MS:450[M+H⁺].

Preparation of Compound I-8 oxalate salt

1.2g of a white solid was obtained in a yield of 85% by using the compound I-8(4.8mmol) and oxalic acid dihydrate (5.0mmol) as raw materials and the method for producing the compound I-1 hydrobromide.

Elemental analysis: c₂₅H₃₁N₅OS·C₂H₂O₄(theoretical values%: C60.09, H6.16, N12.98; experimental values%: C60.31, H6.29, N12.75).

Example 9: n- (4- (2- (4- (benzo [ d ]))]Isothiazol-3-yl) piperazin-1-yl) ethyl) piperidin-1-yl) -4-fluoro Preparation of benzamide (Compound I-9) and salts thereof

By using the intermediate 9(5.6mmol) and 4-fluorobenzoyl chloride (6.2mmol) as raw materials and according to the preparation method of the compound I-1, 2.41g of the target compound I-9 white solid is obtained with the yield of 92%.

¹HNMR(CDCl₃,:ppm):1.28-1.31(m,1H,A-H),1.43-1.46(m,2H,A-H),1.55-1.59(m,2H,A-H),1.62-1.65(m,2H,A-H),2.50-2.52(m,2H,A-H),2.56(t,2H,J＝8.0Hz,N-CH₂),2.73(brs,4H,A-H),3.24-3.26(m,2H,A-H),3.61(brs,4H,A-H),7.16-7.18(m,1H,Ar-H),7.28-7.31(m,2H,Ar-H),7.35-7.39(m,3H,Ar-H),8.07-8.09(m,2H,Ar-H).

ESI-MS:468[M+H⁺].

Preparation of acetate salt of Compound I-9

2.02g of white solid was obtained in 87% yield from compound I-9(4.4mmol) and glacial acetic acid (4.6mmol) as raw materials by the method for preparing the compound I-1 hydrobromide.

Elemental analysis: c₂₅H₃₀FN₅OS·C₂H₄O₂(theoretical values: C61.46, H6.49, N13.27; experimental values: C61.29, H6.67, N13.45).

Example 10: n- (4- (2- (4- (benzo [ d ]))]Isothiazol-3-yl) piperazin-1-yl) ethyl) piperidin-1-yl) -4- Preparation of cyanobenzamide (Compound I-10) and salts thereof

The intermediate 9(5.6mmol) and 4-cyanobenzoyl chloride (6.2mmol) were used as raw materials to obtain the objective compound I-10 as a white solid (2.23 g) in 84% yield according to the method for preparing the compound I-1.

¹HNMR(CDCl₃,:ppm):1.30-1.33(m,1H,A-H),1.45-1.48(m,2H,A-H),1.57-1.61(m,2H,A-H),1.64-1.67(m,2H,A-H),2.52-2.54(m,2H,A-H),2.58(t,2H,J＝8.0Hz,N-CH₂),2.75(brs,4H,A-H),3.26-3.28(m,2H,A-H),3.63(brs,4H,A-H),7.18-7.20(m,1H,Ar-H),7.30-7.33(m,2H,Ar-H),7.36-7.40(m,1H,Ar-H),8.05-8.07(m,2H,Ar-H),8.17-8.19(m,2H,Ar-H).

ESI-MS:475[M+H⁺].

Preparation of Compound I-10 hydrochloride

Using compound I-10(4.6mmol) and 5% aqueous hydrochloric acid (4.8mmol) as starting materials, 1.86g of a white solid was obtained in a yield of 79% by the method for producing the compound I-1 hydrobromide.

Elemental analysis: c₂₆H₃₀N₆OS & HCl (theoretical%: C61.10, H6.11, N16.44; experimental%: C61.22, H6.38, N16.28).

Example 11: n- (4- (2- (4- (benzo [ d ]))]Isothiazol-3-yl) piperazin-1-yl) ethyl) piperidin-1-yl) -4- Preparation of methylbenzamide (Compound I-11) and salts thereof

The intermediate 9(5.6mmol) and 4-methylbenzoyl chloride (6.2mmol) were used as raw materials to obtain the objective compound I-11 as a white solid (2.18 g) in a yield of 84% according to the preparation method of the compound I-1.

¹HNMR(CDCl₃,:ppm):1.23-1.26(m,1H,A-H),1.38-1.41(m,2H,A-H),1.50-1.54(m,2H,A-H),1.57-1.60(m,2H,A-H),2.38(s,3H,A-H),2.45-2.47(m,2H,A-H),2.51(t,2H,J＝8.0Hz,N-CH₂),2.68(brs,4H,A-H),3.19-3.21(m,2H,A-H),3.56(brs,4H,A-H),7.11-7.13(m,1H,Ar-H),7.23-7.26(m,2H,Ar-H),7.30-7.32(m,1H,Ar-H),7.36-7.38(m,2H,Ar-H),7.85-7.87(m,2H,Ar-H).

ESI-MS:464[M+H⁺].

Preparation of compound I-11 maleate salt

Using compound I-11(4.2mmol) and maleic acid (4.4mmol) as starting materials, 1.06g of a white solid was obtained in 86% yield by the method for producing the compound I-1 hydrobromide.

Elemental analysis: c₂₆H₃₃N₅OS·C₄H₄O₄(theoretical values: C62.16, H6.43, N12.08; experimental values: C62.29, H6.56, N12.23).

Example 12: n- (4- (2- (4- (benzo [ d ]))]Isothiazol-3-yl) piperazin-1-yl) ethyl) piperidin-1-yl) nicotinoyl Preparation of amine (Compound I-12) and salts thereof

By using the intermediate 9(5.6mmol) and nicotinoyl chloride (6.2mmol) as raw materials and according to the preparation method of the compound I-1, 2.35g of the target compound I-12 as a white solid is obtained with a yield of 93%.

¹HNMR(CDCl₃,:ppm):1.29-1.32(m,1H,A-H),1.44-1.47(m,2H,A-H),1.56-1.60(m,2H,A-H),1.63-1.66(m,2H,A-H),2.51-2.53(m,2H,A-H),2.57(t,2H,J＝8.0Hz,N-CH₂),2.73(brs,4H,A-H),3.25-3.27(m,2H,A-H),3.62(brs,4H,A-H),7.17-7.19(m,1H,Ar-H),7.29-7.32(m,2H,Ar-H),7.35-7.39(m,1H,Ar-H),7.54-7.55(m,1H,Ar-H),8.18-8.21(m,2H,Ar-H),8.95-8.97(m,1H,Ar-H).

ESI-MS:451[M+H⁺].

Preparation of Compound I-12 mesylate

Using compound I-12(4.4mmol) and methanesulfonic acid (4.6mmol) as starting materials, 2.12g of a white solid was obtained in 88% yield by the method for producing the compound I-1 hydrobromide.

Elemental analysis: c₂₄H₃₀N₆OS·CH₄O₃S (theoretical values: C54.92, H6.27, N15.37; experimental values: C54.80, H6.13, N15.53).

Example 13: n- (4- (2- (4- (benzo [ d ]))]Isothiazol-3-yl) piperazin-1-yl) ethyl) piperidin-1-yl) furan Preparation of pyran-2-carboxamide (Compound I-13) and salts thereof

By using the intermediate 9(5.6mmol) and pyrrole-2 carbonyl chloride (6.2mmol) as raw materials and according to the preparation method of the compound I-1, 2.12g of the target compound I-13 as a white solid is obtained with the yield of 86%.

¹HNMR(CDCl₃,:ppm):1.25-1.28(m,1H,A-H),1.40-1.43(m,2H,A-H),1.52-1.56(m,2H,A-H),1.59-1.62(m,2H,A-H),2.47-2.49(m,2H,A-H),2.54(t,2H,J＝8.0Hz,N-CH₂),2.70(brs,4H,A-H),3.22-3.24(m,2H,A-H),3.58(brs,4H,A-H),6.49-6.50(m,1H,Ar-H),7.16-7.18(m,1H,Ar-H),7.34-7.37(m,1H,Ar-H),7.42-7.48(m,2H,Ar-H),7.81-7.91(m,2H,Ar-H).

ESI-MS:440[M+H⁺].

Preparation of Compound I-13 p-toluenesulfonate

Using compound I-13(4.8mmol) and p-toluenesulfonic acid (5.0mmol) as raw materials, 2.76g of a white solid was obtained in a yield of 94% by a method for producing a compound I-1 hydrobromide.

Elemental analysis: c₂₃H₂₉N₅O₂S·C₇H₈O₃S (theoretical values: C58.90, H6.10, N11.45; experimental values: C58.78, H6.33, N11.59).

Example 14: n- (4- (2- (4- (benzo [ d ]))]Isothiazol-3-yl) piperazin-1-yl) ethyl) piperidin-1-yl) pyridine Preparation of pyrrole-2-carboxamide (Compound I-14) and salts thereof

By using the intermediate 9(5.6mmol) and pyrrole-2 carbonyl chloride (6.2mmol) as raw materials and according to the preparation method of the compound I-1, 1.97g of the target compound I-14 white solid is obtained with the yield of 80%.

¹HNMR(CDCl₃,:ppm):1.24-1.27(m,1H,A-H),1.39-1.42(m,2H,A-H),1.51-1.55(m,2H,A-H),1.58-1.61(m,2H,A-H),2.46-2.48(m,2H,A-H),2.52(t,2H,J＝8.0Hz,N-CH₂),2.68(brs,4H,A-H),3.21-3.23(m,2H,A-H),3.57(brs,4H,A-H),4.96(brs,1H,NH-H),6.48-6.49(m,1H,Ar-H),7.14-7.16(m,1H,Ar-H),7.32-7.35(m,1H,Ar-H),7.39-7.43(m,2H,Ar-H),7.80-7.86(m,2H,Ar-H).

ESI-MS:439[M+H⁺].

Preparation of Compound I-14 citrate salt

Using compound I-14(3.6mmol) and citric acid (3.8mmol) as starting materials, 1.88g of a white solid was obtained in 83% yield by the method for producing the compound I-1 hydrobromide.

Elemental analysis: c₂₃H₃₀N₆OS·C₆H₈O₇(theoretical values: C55.22, H6.07, N13.32; experimental values: C56.44, H6.26, N13.45).

Example 15: n- (4- (2- (4- (benzo [ d ]))]Isothiazol-3-yl) piperazin-1-yl) ethyl) piperidin-1-yl) thia-nes Preparation of thiophene-2-carboxamides (Compound I-15) and salts thereof

The intermediate 9(5.6mmol) and thiophene-2 formyl chloride (6.2mmol) are used as raw materials, and the preparation method of the compound I-1 is adopted to obtain 2.30g of the target compound I-15 white solid with the yield of 90%.

¹HNMR(CDCl₃,:ppm):1.23-1.25(m,1H,A-H),1.38-1.41(m,2H,A-H),1.50-1.53(m,2H,A-H),1.57-1.60(m,2H,A-H),2.45-2.47(m,2H,A-H),2.51(t,2H,J＝8.0Hz,N-CH₂),2.68(brs,4H,A-H),3.20-3.22(m,2H,A-H),3.56(brs,4H,A-H),6.47-6.49(m,1H,Ar-H),7.13-7.15(m,1H,Ar-H),7.31-7.34(m,1H,Ar-H),7.38-7.42(m,2H,Ar-H),7.78-7.84(m,2H,Ar-H).

ESI-MS:456[M+H⁺].

Preparation of Compound I-15 hydrobromide

Using compound I-15(4.2mmol) and 5% aqueous hydrobromic acid (4.4mmol) as starting materials, the procedure for the preparation of compound I-1 hydrobromide gave 2.01g of a white solid with a yield of 89%.

Elemental analysis: c₂₃H₂₉N₅OS₂HBr (% of theory: C51.49, H5.64, N13.05; and% of experiment: C51.62, H5.78, N13.30).

Example 16: n- (4- (2- (4- (benzo [ d ]))]Isothiazol-3-yl) piperazin-1-yl) ethyl) piperidin-1-yl) indole Preparation of indole-2-carboxamides (Compound I-16) and salts thereof

By using the intermediate 9(5.6mmol) and indole-2 formyl chloride (6.2mmol) as raw materials and according to the preparation method of the compound I-1, 2.38g of a white solid of the target compound I-16 is obtained with the yield of 87%.

¹HNMR(CDCl₃,:ppm):1.22-1.24(m,1H,A-H),1.37-1.40(m,2H,A-H),1.49-1.52(m,2H,A-H),1.56-1.59(m,2H,A-H),2.44-2.46(m,2H,A-H),2.50(t,2H,J＝8.0Hz,N-CH₂),2.67(brs,4H,A-H),3.20-3.23(m,2H,A-H),3.54(brs,4H,A-H),6.45-6.48(m,1H,Ar-H),6.86-6.91(m,2H,Ar-H),7.12-7.14(m,1H,Ar-H),7.33(s,1H,Ar-H),7.36-7.40(m,4H,Ar-H),11.82(brs,1H,NH-H).

ESI-MS:489[M+H⁺].

Preparation of Compound I-16 hydrochloride

Using compound I-16(4.2mmol) and 5% aqueous hydrochloric acid (4.4mmol) as starting materials, 1.76g of a white solid was obtained in a yield of 80% by the method for producing the compound I-1 hydrobromide.

Elemental analysis: c₂₇H₃₂N₆OS & HCl (% of theory: C61.76, H6.33, N16.00; and% of experiment: C61.89, H6.12, N15.81).

Example 17: 1- (4- (2- (4- (benzo [ d ]))]Isothiazol-3-yl) piperazin-1-yl) ethyl) piperidin-1-yl) -3- Preparation of methylurea (Compound II-1) and salts thereof

Triphosgene (12.4mmol) is dissolved in dichloromethane (20mL), 4- (2- (4- (benzo [ d ] isothiazol-3-yl) piperazin-1-yl) ethyl) piperidin-1-amine (9) (prepared according to the general method I) (3.9g,11.2mmol) and triethylamine (12.4mmol) are added dropwise at-0 deg.C, a solution of dichloromethane (40mL) is stirred for 3h under heat preservation, the reaction solution is added dropwise to a solution of methylamine water (62mmol) in isopropanol (120mL) at-5-0 deg.C, the reaction is stopped under heat preservation for 5h, a saturated ammonium chloride solution (60mL) is added, the reaction is partitioned, and the organic phase is washed successively with water (60 mL. times.2) and saturated saline (60 mL. times.2), and dried over anhydrous sodium sulfate. Filtering, taking the filtrate, concentrating under reduced pressure to obtain off-white solid, and separating by a Flash column (dichloromethane: methanol: 100: 1) to obtain 4.0g of white solid with the yield of 88%.

¹HNMR(CDCl₃,:ppm):1.23-1.26(m,1H,A-H),1.38-1.41(m,2H,A-H),1.50-1.54(m,2H,A-H),1.57-1.60(m,2H,A-H),2.45-2.47(m,2H,A-H),2.53(t,2H,J＝8.0Hz,N-CH₂),2.68(brs,4H,A-H),2.71(s,3H,A-H),3.20-3.22(m,2H,A-H),3.56(brs,4H,A-H),5.95(brs,1H,NH-H),7.14-7.16(m,1H,Ar-H),7.26-7.30(m,2H,Ar-H),7.34-7.36(m,1H,Ar-H).

ESI-MS:403[M+H⁺].

Preparation of Compound II-1 sulfate

Compound II-1(1.0g,2.48mmol) and a 5% aqueous solution of sulfuric acid (2.60mmol) were added to ethanol (20mL), and the mixture was dissolved under reflux, cooled to precipitate a white solid, and filtered to obtain 1.12g of a white solid with a yield of 90%.

Elemental analysis: c₂₀H₃₀N₆OS·H₂SO₄(theoretical values: C47.98, H6.44, N16.79; experimental values: C47.76, H6.60, N16.91).

Preparation of compound II-1 trifluoroacetate monohydrate

Compound II-1(1.0g,2.48mmol) and a 5% aqueous trifluoroacetic acid solution (2.60mmol) were added to ethanol (20mL), and the mixture was dissolved under reflux, cooled to precipitate a white solid, and filtered to obtain 1.06g of a white solid with a yield of 80%.

Elemental analysis: c₂₀H₃₀N₆OS·CF₃COOH·H₂O (theoretical values: C49.43, H6.22, N15.72; experimental values: C49.61, H6.39, N15.58%)。

Example 18: 3- (4- (2- (4- (benzo [ d ]))]Isothiazol-3-yl) piperazin-1-yl) ethyl) piperidin-1-yl) -1, preparation of 1-dimethylurea (Compound II-2) and salts thereof

Using intermediate 9(5.6mmol) and dimethylamine (30.8mmol) as starting materials, 2.17g of the objective compound II-2 as a white solid was obtained in a yield of 93% according to the method for producing compound II-1.

¹HNMR(CDCl₃,:ppm):1.22-1.24(m,1H,A-H),1.37-1.40(m,2H,A-H),1.50-1.53(m,2H,A-H),1.56-1.59(m,2H,A-H),2.44-2.46(m,2H,A-H),2.52(t,2H,J＝8.0Hz,N-CH₂),2.67(brs,4H,A-H),3.14(s,6H,A-H),3.20-3.22(m,2H,A-H),3.57(brs,4H,A-H),7.13-7.15(m,1H,Ar-H),7.25-7.29(m,2H,Ar-H),7.33-7.34(m,1H,Ar-H).

ESI-MS:417[M+H⁺].

Preparation of Compound II-2 hydrochloride dihydrate

1.98g of a white solid was obtained in a yield of 81% by a method for producing a sulfate of compound II-1 using compound II-2(5.0mmol) and a 5% aqueous hydrochloric acid solution (5.2mmol) as raw materials.

Elemental analysis: c₂₁H₃₂N₆OS·HCl·3H₂O (theoretical values: C51.57, H7.63, N17.18; experimental values: C51.80, H7.46, N17.32).

Example 19: 1- (4- (2- (4- (benzo [ d ]))]Isothiazol-3-yl) piperazin-1-yl) ethyl) piperidin-1-yl) -3- Preparation of propylurea (Compound II-3) and salts thereof

By using the intermediate 9(5.6mmol) and n-propylamine (30.8mmol) as raw materials and according to the preparation method of the compound II-1, 2.15g of a white solid of the target compound II-3 was obtained with a yield of 89%.

¹HNMR(CDCl₃,:ppm):0.85(t,3H,J＝6.8Hz,A-H),1.21-1.23(m,1H,A-H),1.36-1.39(m,2H,A-H),1.49-1.52(m,2H,A-H),1.55-1.59(m,4H,A-H),2.43-2.45(m,2H,A-H),2.51(t,2H,J＝8.0Hz,N-CH₂),2.68(brs,4H,A-H),3.20-3.22(m,2H,A-H),3.33(t,2H,J＝6.8Hz,A-H),3.56(brs,4H,A-H),5.93(brs,1H,NH-H),7.12-7.14(m,1H,Ar-H),7.26-7.30(m,2H,Ar-H),7.32-7.34(m,1H,Ar-H).

ESI-MS:431[M+H⁺].

Preparation of Compound II-3 hydrobromide

Using compound II-3(4.4mmol) and 5% hydrobromic acid aqueous solution (4.6mmol) as starting materials, 1.78g of a white solid was obtained in 79% yield by the method for producing sulfate of compound II-1.

Elemental analysis: c₂₂H₃₄N₆OS & HBr (% of theory: C51.66, H6.90, N16.43; and% of experiment: C51.48, H6.70, N16.67).

Example 20: 1-cyclopropyl-3- (4- (2- (4- (benzo [ d ]))]Isothiazol-3-yl) piperazin-1-yl) ethyl) piperidine- Preparation of 1-yl) urea (Compound II-4) and salts thereof

By using the intermediate 9(5.6mmol) and cyclopropylamine (30.8mmol) as raw materials and following the method for the preparation of the compound II-1, 2.04g of the objective compound II-4 as a white solid was obtained with a yield of 85%.

¹HNMR(CDCl₃,:ppm):0.62-0.79(m,4H,A-H),1.21-1.23(m,1H,A-H),1.38-1.41(m,2H,A-H),1.51-1.54(m,2H,A-H),1.57-1.60(m,2H,A-H),2.43-2.45(m,2H,A-H),2.51(t,2H,J＝8.0Hz,N-CH₂),2.66(brs,4H,A-H),2.70(m,1H,A-H),3.21-3.23(m,2H,A-H),3.58(brs,4H,A-H),5.85(brs,1H,NH-H),7.14-7.16(m,1H,Ar-H),7.24-7.28(m,2H,Ar-H),7.30-7.32(m,1H,Ar-H).

ESI-MS:429[M+H⁺].

Preparation of compound II-4 hydrochloride monohydrate

1.83g of a white solid was obtained in 86% yield by a method for producing a sulfate of compound II-1 using compound II-4(4.4mmol) and a 5% aqueous hydrochloric acid solution (4.6mmol) as raw materials.

Elemental analysis: c₂₂H₃₂N₆OS·HCl·H₂O (theoretical values: C54.70, H7.30, N17.40; experimental values: C54.95, H7.17, N17.66).

Example 21: 1-cyclohexyl-3- (4- (2- (4- (benzo [ d ]))]Isothiazol-3-yl) piperazin-1-yl) ethyl) piperidine- Preparation of 1-yl) urea (Compound II-5) and salts thereof

By using the intermediate 9(5.6mmol) and cyclohexylamine (30.8mmol) as raw materials and according to the method for preparing the compound II-1, 2.22g of the target compound II-5 as a white solid was obtained with a yield of 84%.

¹HNMR(CDCl₃,:ppm):1.05-1.15(m,4H,A-H),1.23-1.25(m,1H,A-H),1.36-1.39(m,2H,A-H),1.48-1.54(m,6H,A-H),1.53-1.56(m,4H,A-H),2.45-2.47(m,2H,A-H),2.50(t,2H,J＝8.0Hz,N-CH₂),2.65(brs,4H,A-H),3.19-3.21(m,2H,A-H),3.49(m,1H,A-H),3.55(brs,4H,A-H),5.80(brs,1H,NH-H),7.11-7.13(m,1H,Ar-H),7.22-7.26(m,2H,Ar-H),7.30-7.32(m,1H,Ar-H).

ESI-MS:471[M+H⁺].

Preparation of Compound II-5 hydrobromide

Using compound II-5(4.4mmol) and 5% hydrobromic acid aqueous solution (4.6mmol) as starting materials, 2.18g of a white solid was obtained in a yield of 90% by a method for producing sulfate of compound II-1.

Elemental analysis: c₂₅H₃₈N₆OS & HBr (% of theory: C54.44, H7.13, N15.24; and% of experiment: C54.30, H7.29, N15.47).

Example 22: 1- (4- (2- (4- (benzo [ d ]))]Isothiazol-3-yl) piperazin-1-yl) ethyl) piperidin-1-yl) -3- Preparation of phenylurea (Compound II-6) and salts thereof

2.14g of a white solid of the objective compound II-6 was obtained in a yield of 82% by the method for producing the compound II-1 using the intermediate 9(5.6mmol) and aniline (30.8mmol) as starting materials.

¹HNMR(CDCl₃,:ppm):1.26-1.28(m,1H,A-H),1.41-1.44(m,2H,A-H),1.54-1.57(m,2H,A-H),1.59-1.62(m,2H,A-H),2.47-2.49(m,2H,A-H),2.55(t,2H,J＝8.0Hz,N-CH₂),2.70(brs,4H,A-H),3.24-3.26(m,2H,A-H),3.61(brs,4H,A-H),5.68(brs,1H,NH-H),7.14-7.17(m,2H,Ar-H),7.28-7.32(m,2H,Ar-H),7.36-7.39(m,3H,Ar-H),7.55-7.58(m,2H,Ar-H).

ESI-MS:465[M+H⁺].

Preparation of Compound II-6 hydrochloride

2.00g of a white solid was obtained in 83% yield by a method for producing a sulfate of compound II-1 using compound II-6(4.8mmol) and 5% aqueous hydrochloric acid (5.0mmol) as raw materials.

Elemental analysis: c₂₅H₃₂N₆OS & HCl (theoretical values: C59.92, H6.64, N16.77; experimental values: C59.78, H6.83, N16.92).

Example 23: 3- (4- (2- (4- (benzo [ d ]))]Isothiazol-3-yl) piperazin-1-yl) ethyl) piperidin-1-yl) -1- Preparation of methyl-1-phenylurea (Compound II-7) and salts thereof

The intermediate 9(5.6mmol) and N-methylaniline (30.8mmol) were used as raw materials to obtain 2.52g of the objective compound II-7 as a white solid in a yield of 94% according to the method for producing the compound II-1.

¹HNMR(CDCl₃,:ppm):1.25-1.27(m,1H,A-H),1.40-1.43(m,2H,A-H),1.53-1.56(m,2H,A-H),1.58-1.61(m,2H,A-H),2.46-2.48(m,2H,A-H),2.54(t,2H,J＝8.0Hz,N-CH₂),2.69(brs,4H,A-H),3.23-3.27(m,5H,A-H),3.60(brs,4H,A-H),7.13-7.16(m,2H,Ar-H),7.29-7.33(m,2H,Ar-H),7.35-7.38(m,3H,Ar-H),7.54-7.57(m,2H,Ar-H).

ESI-MS:479[M+H⁺].

Preparation of Compound II-7 hydrobromide

Using compound II-7(5.0mmol) and 5% hydrobromic acid aqueous solution (5.2mmol) as starting materials, 2.11g of a white solid was obtained in 82% yield by the method for producing sulfate of compound II-1.

Elemental analysis: c₂₆H₃₄N₆OS & HBr (% of theory: C55.81, H6.30, N15.02; and% of experiment: C55.96, H6.44, N15.29).

Example 24: 1-benzyl-3- (4- (2- (4- (benzo [ d ]))]Isothiazol-3-yl) piperazin-1-yl) ethyl) piperidin-1-one Preparation of the group) Urea (Compound II-8) and salts thereof

Using intermediate 9(5.6mmol) and benzylamine (30.8mmol) as starting materials, 2.15g of the objective compound II-8 as a white solid was obtained in a yield of 80% according to the method for producing compound II-1.

¹HNMR(CDCl₃,:ppm):1.23-1.25(m,1H,A-H),1.38-1.41(m,2H,A-H),1.51-1.54(m,2H,A-H),1.56-1.59(m,2H,A-H),2.44-2.46(m,2H,A-H),2.52(t,2H,J＝8.0Hz,N-CH₂),2.67(brs,4H,A-H),3.21-3.23(m,2H,A-H),3.58(brs,4H,A-H),4.19(s,2H,A-H),5.90(brs,1H,NH-H),7.11-7.14(m,2H,Ar-H),7.26-7.31(m,3H,Ar-H),7.33-7.35(m,4H,Ar-H).

ESI-MS:479[M+H⁺].

Preparation of Compound II-8 hydrochloride

1.86g of a white solid was obtained in a yield of 86% by a method for producing a sulfate of compound II-1 using compound II-8(4.2mmol) and a 5% aqueous hydrochloric acid solution (4.4mmol) as raw materials.

Elemental analysis: c₂₆H₃₄N₆OS & HCl (theoretical values: C60.62, H6.85, N16.31; experimental values: C60.49, H6.98, 16.40).

Example 25: 1- (4- (2- (4- (benzo [ d ]))]Isothiazol-3-yl) piperazin-1-yl) ethyl) piperidin-1-yl) -3- Preparation of (pyridin-3-yl) urea (Compound II-9) and salts thereof

The intermediate 9(5.6mmol) and pyridin-3-amine (30.8mmol) were used as starting materials to obtain 2.35g of the objective compound II-9 as a white solid in a yield of 90% according to the method for producing the compound II-1.

¹HNMR(CDCl₃,:ppm):1.25-1.30(m,1H,A-H),1.43-1.46(m,2H,A-H),1.56-1.59(m,2H,A-H),1.61-1.64(m,2H,A-H),2.49-2.51(m,2H,A-H),2.57(t,2H,J＝8.0Hz,N-CH₂),2.72(brs,4H,A-H),3.26-3.28(m,2H,A-H),3.63(brs,4H,A-H),5.95(brs,1H,NH-H),7.16-7.19(m,2H,Ar-H),7.31-7.36(m,3H,Ar-H),8.04-8.10(m,2H,Ar-H),8.87-8.89(m,1H,Ar-H).

ESI-MS:466[M+H⁺].

Preparation of Compound II-9 hydrobromide

Using compound II-9(4.6mmol) and 5% hydrobromic acid aqueous solution (4.8mmol) as starting materials, 2.06g of a white solid was obtained in 82% yield by a method for producing sulfate of compound II-1.

Elemental analysis: c₂₄H₃₁N₇OS & HBr (% of theory: C52.74, H5.90, N17.94; and% of experiment: C52.91, H5.72, N17.73).

Example 26: n- (4- (2- (4- (benzo [ d ]))]Isothiazol-3-yl) piperazin-1-yl) ethyl) piperidin-1-yl) morph Preparation of quinoline-4-carboxamide (Compound II-10) and salts thereof

Using intermediate 9(5.6mmol) and morpholine (30.8mmol) as raw materials, 2.39g of the objective compound II-10 as a white solid was obtained in a yield of 93% according to the method for producing the compound II-1.

¹HNMR(CDCl₃,:ppm):1.23-1.26(m,1H,A-H),1.38-1.41(m,2H,A-H),1.50-1.54(m,2H,A-H),1.57-1.60(m,2H,A-H),2.45-2.47(m,2H,A-H),2.51(t,2H,J＝8.0Hz,N-CH₂),2.68(brs,4H,A-H),3.20-3.25(m,6H,A-H),3.55(brs,4H,A-H),3.57-3.61(m,4H,A-H),7.14-7.16(m,1H,Ar-H),7.26-7.30(m,2H,Ar-H),7.34-7.36(m,1H,Ar-H).

ESI-MS:459[M+H⁺].

Preparation of Compound II-10 hydrochloride

2.00g of white solid was obtained in 88% yield by the method for producing a sulfate of compound II-1 using compound II-10(4.6mmol) and 5% aqueous hydrochloric acid (4.8mmol) as raw materials.

Elemental analysis: c₂₃H₃₄N₆O₂S & HCl (theoretical values: C55.80, H7.13, N16.98; experimental values: C55.61, H7.30, N17.11).

Example 27: n- (4- (2- (4- (benzo [ d ]))]Isothiazol-3-yl) piperazin-1-yl) ethyl) piperidin-1-yl) pyrrole Preparation of alkane-1-carboxamide (Compound II-11) and salts thereof

Using intermediate 9(5.6mmol) and pyrrolidine (30.8mmol) as raw materials, 2.11g of the objective compound II-11 as a white solid was obtained in a yield of 85% according to the method for producing the compound II-1.

¹HNMR(CDCl₃,:ppm):1.21-1.23(m,1H,A-H),1.36-1.39(m,2H,A-H),1.48-1.52(m,2H,A-H),1.55-1.58(m,2H,A-H),1.60-1.63(m,4H,A-H),2.43-2.45(m,2H,A-H),2.49(t,2H,J＝8.0Hz,N-CH₂),2.66(brs,4H,A-H),3.19-3.24(m,6H,A-H),3.53(brs,4H,A-H),7.12-7.14(m,1H,Ar-H),7.24-7.28(m,2H,Ar-H),7.32-7.34(m,1H,Ar-H).

ESI-MS:443[M+H⁺].

Preparation of Compound II-11 hydrobromide

Using compound II-11(4.6mmol) and 5% hydrobromic acid aqueous solution (4.8mmol) as starting materials, 2.19g of a white solid was obtained in 91% yield by a method for producing sulfate of compound II-1.

Elemental analysis: c₂₃H₃₄N₆OS & HBr (% of theory: C52.77, H6.74, N16.05; and% of experiment: C52.63, H6.96, N16.19).

Example 28: n- (4- (2- (4- (benzo [ d ]))]Isothiazol-3-yl) piperazin-1-yl) ethyl) piperidin-1-yl) azepines Preparation of cyclobutane-1-carboxamide (Compound II-12) and salts thereof

The intermediate 9(5.6mmol) and azetidine (30.8mmol) were used as starting materials to obtain the objective compound II-12 as a white solid (1.95 g, 81% yield) according to the method for producing the compound II-1.

¹HNMR(CDCl₃,:ppm):1.20-1.22(m,1H,A-H),1.35-1.38(m,2H,A-H),1.47-1.51(m,2H,A-H),1.54-1.57(m,2H,A-H),2.15-2.18(m,2H,A-H),2.42-2.44(m,2H,A-H),2.48(t,2H,J＝8.0Hz,N-CH₂),2.66(brs,4H,A-H),3.18-3.20(m,2H,A-H),3.51(brs,4H,A-H),3.73-3.76(m,4H,A-H),7.11-7.13(m,1H,Ar-H),7.23-7.27(m,2H,Ar-H),7.31-7.33(m,1H,Ar-H).

ESI-MS:429[M+H⁺].

Preparation of Compound II-12 hydrochloride

1.88g of white solid was obtained in 88% yield by the method for producing a sulfate of compound II-1 using compound II-12(4.6mmol) and 5% aqueous hydrochloric acid (4.8mmol) as raw materials.

Elemental analysis: c₂₂H₃₂N₆OS & HCl (theoretical values: C56.82, H7.15, N18.07; experimental values: C56.97, H7.34, N18.22).

Example 29: n- (4- (2- (4- (6-fluorobenzo [ d ]))]Isoxazol-3-yl) piperidin-1-yl) ethyl) piperidin-1-yl) Preparation of acetamide (Compound III-1) and salts thereof

4- (2- (4- (6-fluorobenzo [ d ] isoxazol-3-yl) piperidin-1-yl) ethyl) piperidin-1-amine (9-1) (prepared according to general procedure one) (2.0g,5.8mmol) and triethylamine (8.7mmol) were added to dichloromethane (20mL), a solution of acetyl chloride (0.5g,6.4mmol) in dichloromethane (5mL) was added dropwise, reacted for 3h, washed with water (40 mL. times.2) and saturated brine (20 mL. times.2) in this order, dried over anhydrous sodium sulfate, filtered and concentrated to give a white solid, which was crystallized from a 95% ethanol solution to give 2.01g of a white solid in 89% yield.

¹HNMR(CDCl₃,:ppm):1.25-1.28(m,1H,A-H),1.44-1.53(m,4H,A-H),1.64-1.67(m,2H,A-H),1.92-2.14(m,9H,A-H),2.39-2.45(m,4H,A-H),2.92-2.95(m,3H,A-H),3.11-3.14(m,2H,A-H),6.95-6.98(m,1H,Ar-H),7.12-7.16(m,2H,Ar-H).

ESI-MS:389[M+H⁺].

Preparation of compound III-1 hydrochloride

Compound III-1(5.0mmol) and 5% aqueous hydrochloric acid (5.2mmol) were added to ethanol (20mL), and the mixture was dissolved under reflux, cooled to precipitate a white solid, and filtered to obtain 1.95g of a white solid with a yield of 92%.

Elemental analysis: c₂₁H₂₉FN₄O₂HCl (% of theory: C59.36, H7.12, N13.18; in% of experiment: C59.52, H7.01, N13.31).

Example 30: n- (4- (2- (4- (6-fluorobenzo [ d ]))]Isoxazol-3-yl) piperidin-1-yl) ethyl) piperidin-1-yl) Preparation of butanamide (Compound III-2) and salts thereof

By using intermediate 9-1(5.6mmol) and butyryl chloride (6.2mmol) as raw materials and following the preparation method of compound III-1, 2.1g of the target compound III-2 as a white solid was obtained with a yield of 90%.

¹HNMR(CDCl₃,:ppm):0.83(t,3H,J＝7.2Hz,A-H),1.24-1.27(m,1H,A-H),1.43-1.52(m,4H,A-H),1.63-1.68(m,4H,A-H),1.91-2.13(m,6H,A-H),2.34-2.44(m,6H,A-H),2.91-2.94(m,3H,A-H),3.10-3.13(m,2H,A-H),6.94-6.97(m,1H,Ar-H),7.11-7.15(m,2H,Ar-H).

ESI-MS:417[M+H⁺].

Preparation of Compound III-2 hydrobromide

Using compound III-2(5.0mmol) and 5% aqueous hydrobromic acid (5.2mmol) as starting materials, the procedure for the preparation of hydrochloride of compound III-1 gave 2.06g of a white solid in 83% yield.

Elemental analysis: c₂₃H₃₃FN₄O₂HBr (% of theory: C55.53, H6.89, N11.26; and% of experiment: C55.81, H6.62, N11.42).

Example 31: 4- (2- (4- (6-fluorobenzo [ d ]))]Isoxazol-3-yl) piperidin-1-yl) ethyl) piperidin-1-yl-amino Preparation of Ethyl benzoate (Compound III-3) and salts thereof

The intermediate 9-1(5.6mmol) and ethoxycarbonyl chloride (6.2mmol) were used as raw materials to obtain 2.02g of the target compound III-3 as a white solid in 86% yield according to the preparation method of the compound III-1.

¹HNMR(CDCl₃,:ppm):1.27-1.30(m,1H,A-H),1.34(t,3H,J＝6.8Hz,A-H),1.46-1.55(m,4H,A-H),1.66-1.69(m,2H,A-H),1.94-2.16(m,6H,A-H),2.41-2.47(m,4H,A-H),2.94-2.97(m,3H,A-H),3.13-3.16(m,2H,A-H),4.18(q,2H,J＝6.8Hz,A-H),6.97-7.00(m,1H,Ar-H),7.14-7.18(m,2H,Ar-H).

ESI-MS:419[M+H⁺].

Preparation of compound III-3 hydrochloride

Using compound III-3(5.0mmol) and 5% aqueous hydrochloric acid (5.2mmol) as starting materials, 1.84g of a white solid was obtained in a yield of 81% by the method for producing hydrochloride of compound III-1.

Elemental analysis: c₂₂H₃₁FN₄O₃HCl (% of theory: C58.08, H7.09, N12.31; and% of experiment: C58.22, H7.31, N12.09).

Example 32: n- (4- (2- (4- (6-fluorobenzo [ d ]))]Isoxazol-3-yl) piperidin-1-yl) ethyl) piperidin-1- Yl) preparation of cyclopropylcarboxamide (Compound III-4) and salts thereof

By using the intermediate 9-1(5.6mmol) and cyclopropylcarbonyl chloride (6.2mmol) as raw materials and following the preparation method of the compound III-1, 2.14g of the target compound III-4 as a white solid was obtained with a yield of 92%.

¹HNMR(CDCl₃,:ppm):0.59-0.78(m,4H,A-H),1.20-1.25(m,2H,A-H),1.43-1.52(m,4H,A-H),1.62-1.65(m,2H,A-H),1.90-2.10(m,6H,A-H),2.37-2.43(m,4H,A-H),2.91-2.94(m,3H,A-H),3.10-3.13(m,2H,A-H),6.94-6.97(m,1H,Ar-H),7.11-7.15(m,2H,Ar-H).

ESI-MS:415[M+H⁺].

Preparation of Compound III-4 hydrobromide

Using compound III-4(5.0mmol) and 5% aqueous hydrobromic acid (5.2mmol) as starting materials, according to the method for producing hydrochloride of compound III-1, 2.13g of a white solid was obtained in 86% yield.

Elemental analysis: c₂₃H₃₁FN₄O₂HBr (% of theory: C55.76, H6.51, N11.31; and% of experiment: C55.54, H6.73, N11.12).

Example 33: n- (4- (2- (4- (6-fluorobenzo [ d ]))]Isoxazol-3-yl) piperidin-1-yl) ethyl) piperidin-1-yl) Preparation of Cyclohexylcarboxamide (Compound III-5) and salts thereof

The intermediate 9-1(5.6mmol) and the cyclohexyl carbonyl chloride (6.2mmol) were used as raw materials to obtain the target compound III-5 as a white solid 2.28g with a yield of 89% according to the preparation method of the compound III-1.

¹HNMR(CDCl₃,:ppm):1.24-1.27(m,1H,A-H),1.38-1.52(m,10H,A-H),1.61-1.66(m,4H,A-H),1.74-1.78(m,2H,A-H),1.91-2.13(m,6H,A-H),2.31-2.33(m,1H,A-H),2.38-2.44(m,4H,A-H),2.91-2.94(m,3H,A-H),3.09-3.12(m,2H,A-H),6.93-6.96(m,1H,Ar-H),7.10-7.14(m,2H,Ar-H).

ESI-MS:457[M+H⁺].

Preparation of compound III-5 hydrochloride

Using compound III-5(5.0mmol) and 5% aqueous hydrochloric acid (5.2mmol) as starting materials, 1.97g of a white solid was obtained in a yield of 80% according to the method for producing hydrochloride of compound III-1.

Elemental analysis: c₂₆H₃₇FN₄O₂HCl (% of theory: C63.34, H7.77, N11.36; in% of experiment: C63.12, H7.96, N11.51).

Example 34: n- (4- (2- (4- (6-fluorobenzo [ d ]))]Isoxazol-3-yl) piperidin-1-yl) ethyl) piperidin-1-yl) Preparation of benzamide (Compound III-6) and salts thereof

The intermediate 9-1(5.6mmol) and benzoyl chloride (6.2mmol) were used as raw materials to obtain the target compound III-6 as a white solid 2.1g with a yield of 83% according to the preparation method of the compound III-1.

¹HNMR(CDCl₃,:ppm):1.28-1.31(m,1H,A-H),1.47-1.56(m,4H,A-H),1.67-1.70(m,2H,A-H),1.95-2.11(m,6H,A-H),2.42-2.48(m,4H,A-H),2.96-2.99(m,3H,A-H),3.14-3.17(m,2H,A-H),6.98-7.01(m,1H,Ar-H),7.15-7.19(m,2H,Ar-H),7.58-7.63(m,3H,Ar-H),7.93-7.97(m,2H,Ar-H).

ESI-MS:451[M+H⁺].

Preparation of Compound III-6 hydrobromide

Using compound III-6(5.0mmol) and 5% aqueous hydrobromic acid (5.2mmol) as starting materials, 2.26g of a white solid was obtained in 85% yield according to the method for producing the hydrochloride of compound III-1.

Elemental analysis: c₂₆H₃₁FN₄O₂HBr (% of theory: C58.76, H6.07, N10.54; and% of experiment: C58.51, H6.28, N10.72).

Example 35: n- (4- (2- (4- (6-fluorobenzo [ d ]))]Isoxazol-3-yl) piperidin-1-yl) ethyl) piperidin-1- Preparation of yl) -4-methoxybenzamide (compound III-7) and salts thereof

By using the intermediate 9-1(5.6mmol) and 4-methoxybenzoyl chloride (6.2mmol) as raw materials and following the preparation method of the compound III-1, 2.18g of the target compound III-7 as a white solid was obtained with a yield of 81%.

¹HNMR(CDCl₃,:ppm):1.27-1.30(m,1H,A-H),1.46-1.55(m,4H,A-H),1.66-1.69(m,2H,A-H),1.94-2.10(m,6H,A-H),2.41-2.47(m,4H,A-H),2.95-2.98(m,3H,A-H),3.13-3.16(m,2H,A-H),3.78(s,3H,A-H),6.97-7.00(m,1H,Ar-H),7.12-7.18(m,3H,Ar-H),7.57-7.62(m,1H,Ar-H),7.85-7.88(m,2H,Ar-H).

ESI-MS:481[M+H⁺].

Preparation of compound III-7 hydrochloride

Using compound III-7(5.0mmol) and 5% aqueous hydrochloric acid (5.2mmol) as starting materials, 2.43g of a white solid was obtained in a yield of 94% according to the method for producing hydrochloride of compound III-1.

Elemental analysis: c₂₇H₃₃FN₄O₃HCl (% of theory: C62.72, H6.63, N10.84; and% of experiment: C62.85, H6.48, N10.67).

Example 36: n- (4- (2- (4- (6-fluorobenzo [ d ]))]Isoxazol-3-yl) piperidin-1-yl) ethyl) piperidin-1- Preparation of yl) -4-ethylbenzamide (compound III-8) and salts thereof

The intermediate 9-1(5.6mmol) and 4-ethylbenzoyl chloride (6.2mmol) were used as raw materials to obtain the target compound III-8 as a white solid 2.44g with a yield of 91% by the method for preparing the compound III-1.

¹HNMR(CDCl₃,:ppm):1.24-1.29(m,4H,A-H),1.45-1.54(m,4H,A-H),1.64-1.67(m,2H,A-H),1.93-2.09(m,6H,A-H),2.40-2.46(m,4H,A-H),2.54(q,2H,J＝6.8Hz,A-H),2.94-2.97(m,3H,A-H),3.12-3.15(m,2H,A-H),6.96-6.98(m,1H,Ar-H),7.11-7.17(m,3H,Ar-H),7.56-7.60(m,1H,Ar-H),7.84-7.87(m,2H,Ar-H).

ESI-MS:479[M+H⁺].

Preparation of Compound III-8 hydrobromide

Using compound III-8(5.0mmol) and 5% aqueous hydrobromic acid (5.2mmol) as starting materials, according to the method for producing hydrochloride of compound III-1, 2.35g of a white solid was obtained in 84% yield.

Elemental analysis: c₂₈H₃₅FN₄O₂HBr (% of theory: C60.11, H6.49, N10.01; true)The test value is as follows: c60.34, H6.56, N10.25).

Example 37: n- (4- (2- (4- (6-fluorobenzo [ d ]))]Isoxazol-3-yl) piperidin-1-yl) ethyl) piperidin-1-yl) Preparation of nicotinamide (compound III-9) and salts thereof

By using the intermediate 9-1(5.6mmol) and nicotinoyl chloride (6.2mmol) as raw materials and according to the preparation method of the compound III-1, 2.23g of the target compound III-9 white solid is obtained with the yield of 88%.

¹HNMR(CDCl₃,:ppm):1.30-1.33(m,1H,A-H),1.49-1.58(m,4H,A-H),1.69-1.72(m,2H,A-H),1.97-2.15(m,6H,A-H),2.44-2.50(m,4H,A-H),2.97-3.00(m,3H,A-H),3.16-3.19(m,2H,A-H),7.00-7.04(m,1H,Ar-H),7.17-7.21(m,2H,Ar-H),7.51-7.53(m,1H,Ar-H),8.16-8.18(m,2H,Ar-H),8.94-8.96(m,1H,Ar-H).

ESI-MS:452[M+H⁺].

Preparation of compound III-9 hydrochloride

Using compound III-9(5.0mmol) and 5% aqueous hydrochloric acid (5.2mmol) as starting materials, 2.32g of a white solid was obtained in a yield of 95% according to the method for producing hydrochloride of compound III-1.

Elemental analysis: c₂₅H₃₀FN₅O₂HCl (% of theory: C61.53, H6.40, N14.35; and% of experiment: C61.38, H6.61, N14.17).

Example 38: n- (4- (2- (4- (6-fluorobenzo [ d ]))]Isoxazol-3-yl) piperidin-1-yl) ethyl) piperidin-1-yl) Preparation of furan-2-carboxamide (Compound III-10) and salts thereof

The intermediate 9-1(5.6mmol) and furan-2 carbonyl chloride (6.2mmol) were used as raw materials to obtain the target compound III-10 as a white solid 2.07g with a yield of 84% according to the preparation method of the compound III-1.

¹HNMR(CDCl₃,:ppm):1.29-1.33(m,1H,A-H),1.48-1.57(m,4H,A-H),1.68-1.71(m,2H,A-H),1.96-2.18(m,6H,A-H),2.43-2.49(m,4H,A-H),2.96-2.99(m,3H,A-H),3.15-3.18(m,2H,A-H),6.42-6.44(m,1H,Ar-H),6.97-7.02(m,2H,Ar-H),7.16-7.19(m,1H,Ar-H),7.35-7.37(m,1H,Ar-H),7.67-7.69(m,1H,Ar-H).

ESI-MS:441[M+H⁺].

Preparation of Compound III-10 hydrobromide

Using compound III-10(5.0mmol) and 5% aqueous hydrobromic acid (5.2mmol) as starting materials, according to the method for producing hydrochloride of compound III-1, 2.37g of a white solid was obtained in 91% yield.

Elemental analysis: c₂₄H₂₉FN₄O₃HCl (% of theory: C55.28, H5.80, N10.74; in the experimental case%: C55.33, H5.62, N10.51).

Example 39: n- (4- (2- (4- (6-fluorobenzo [ d ]))]Isoxazol-3-yl) piperidin-1-yl) ethyl) piperidin-1-yl) Preparation of pyrrole-2-carboxamide (Compound III-11) and salts thereof

By using the intermediate 9-1(5.6mmol) and pyrrole-2 carbonyl chloride (6.2mmol) as raw materials and according to the preparation method of the compound III-1, 2.12g of the target compound III-11 white solid is obtained with the yield of 86%.

¹HNMR(CDCl₃,:ppm):1.28-1.32(m,1H,A-H),1.47-1.56(m,4H,A-H),1.67-1.70(m,2H,A-H),1.94-2.16(m,6H,A-H),2.41-2.47(m,4H,A-H),2.94-2.98(m,3H,A-H),3.14-3.17(m,2H,A-H),4.89(brs,1H,NH-H),6.40-6.42(m,1H,Ar-H),6.96-7.01(m,2H,Ar-H),7.15-7.17(m,1H,Ar-H),7.32-7.34(m,1H,Ar-H),7.64-7.66(m,1H,Ar-H).

ESI-MS:440[M+H⁺].

Preparation of compound III-11 hydrochloride

Using compound III-11(5.0mmol) and 5% aqueous hydrochloric acid (5.2mmol) as starting materials, 2.09g of a white solid was obtained in 88% yield according to the method for producing hydrochloride of compound III-1.

Elemental analysis: c₂₄H₃₀FN₅O₂HCl (% of theory: C60.56, H6.56, N14.71; and% of experiment: C60.67, H6.48, N14.93).

Example 40: n- (4- (2- (4- (6-fluorobenzo [ d ]))]Isoxazol-3-yl) piperidin-1-yl) ethyl) piperidin-1-yl) Process for preparing thiophene-2-carboxamides (compound III-12) and salts thereofPreparation of

The intermediate 9-1(5.6mmol) and thiophene-2 formyl chloride (6.2mmol) are used as raw materials, and the preparation method of the compound III-1 is adopted to obtain 2.41g of the target compound III-12 white solid with the yield of 94%.

¹HNMR(CDCl₃,:ppm):1.27-1.31(m,1H,A-H),1.46-1.55(m,4H,A-H),1.66-1.69(m,2H,A-H),1.93-2.14(m,6H,A-H),2.40-2.46(m,4H,A-H),2.92-2.96(m,3H,A-H),3.13-3.16(m,2H,A-H),6.39-6.41(m,1H,Ar-H),6.95-7.00(m,2H,Ar-H),7.13-7.15(m,1H,Ar-H),7.30-7.32(m,1H,Ar-H),7.63-7.65(m,1H,Ar-H).

ESI-MS:457[M+H⁺].

Preparation of Compound III-12 hydrobromide

Using compound III-12(5.0mmol) and 5% aqueous hydrobromic acid (5.2mmol) as starting materials, according to the method for producing hydrochloride of compound III-1, 2.18g of a white solid was obtained in a yield of 81%.

Elemental analysis: c₂₄H₂₉FN₄O₂S.HBr (% of theory: C53.63, H5.63, N10.42; and% of experiment: C53.88, H5.49, N10.68).

Example 41: n- (4- (2- (4- (6-fluorobenzo [ d ]))]Isoxazol-3-yl) piperidin-1-yl) ethyl) piperidin-1-yl) Preparation of benzofuran-2-carboxamide (Compound III-13) and salts thereof

The intermediate 9-1(5.6mmol) and benzofuran-2-carbonyl chloride (6.2mmol) were used as raw materials to obtain 2.28g of the objective compound III-13 as a white solid with a yield of 83% according to the preparation method of the compound III-1.

¹HNMR(CDCl₃,:ppm):1.29-1.33(m,1H,A-H),1.48-1.57(m,4H,A-H),1.68-1.71(m,2H,A-H),1.95-2.16(m,6H,A-H),2.42-2.48(m,4H,A-H),2.94-2.98(m,3H,A-H),3.15-3.18(m,2H,A-H),6.41-6.43(m,1H,Ar-H),6.97-7.02(m,2H,Ar-H),7.32-7.34(m,2H,Ar-H),,7.51(s,1H,Ar-H)7.61-7.66(m,2H,Ar-H).

ESI-MS:491[M+H⁺].

Preparation of compound III-13 hydrochloride

Using compound III-13(5.0mmol) and 5% aqueous hydrochloric acid (5.2mmol) as starting materials, 2.27g of a white solid was obtained in 86% yield according to the method for producing hydrochloride of compound III-1.

Elemental analysis: c₂₈H₃₁FN₄O₃HCl (% of theory: C63.81, H6.12, N10.63; in% of experiment: C63.67, H6.01, N10.82).

Example 42: n- (4- (2- (4- (6-fluorobenzo [ d ]))]Isoxazol-3-yl) piperidin-1-yl) ethyl) piperidin-1-yl) Preparation of benzothiophene-2-carboxamide (Compound III-14) and salts thereof

The intermediate 9-1(5.6mmol) and benzothiophene-2 carbonyl chloride (6.2mmol) were used as raw materials to obtain 2.56g of the target compound III-14 as a white solid with a yield of 90% according to the preparation method of the compound III-1.

¹HNMR(CDCl₃,:ppm):1.28-1.32(m,1H,A-H),1.47-1.56(m,4H,A-H),1.67-1.70(m,2H,A-H),1.94-2.14(m,6H,A-H),2.40-2.46(m,4H,A-H),2.93-2.97(m,3H,A-H),3.14-3.17(m,2H,A-H),6.40-6.42(m,1H,Ar-H),6.96-7.01(m,2H,Ar-H),7.31-7.33(m,2H,Ar-H),,7.46(s,1H,Ar-H)7.58-7.62(m,2H,Ar-H).

ESI-MS:507[M+H⁺].

Preparation of Compound III-14 hydrobromide

Using compound III-14(5.0mmol) and 5% aqueous hydrobromic acid (5.2mmol) as starting materials, 2.41g of an off-white solid was obtained in 82% yield according to the method for producing the hydrochloride salt of compound III-1.

Elemental analysis: c₂₈H₃₁FN₄O₂S & HBr (% of theory: C57.24, H5.49, N9.54; and% of experiment: C57.43, H5.27, N9.70).

Example 43: 3- (4- (2- (4- (6-fluorobenzo [ d ]))]Isoxazol-3-yl) piperidin-1-yl) ethyl) piperidin-1- Preparation of 1, 1-dimethylurea (Compound IV-1) and salts thereof

Using intermediate 9-1(5.6mmol) and dimethylamine (30.8mmol) as raw materials, the preparation method of compound II-1 was carried out to obtain 2.56g of the target compound IV-1 as a white solid with a yield of 80%.

¹HNMR(CDCl₃,:ppm):1.29-1.32(m,1H,A-H),1.48-1.57(m,4H,A-H),1.68-1.71(m,2H,A-H),1.96-2.16(m,6H,A-H),2.43-2.49(m,4H,A-H),2.96-2.99(m,3H,A-H),3.15-3.18(m,2H,A-H),3.15(s,6H,A-H),6.97-7.01(m,1H,Ar-H),7.15-7.19(m,2H,Ar-H).

ESI-MS:418[M+H⁺].

Preparation of Compound IV-1 hydrochloride

Using compound IV-1(5.0mmol) and 5% aqueous hydrochloric acid (5.2mmol) as starting materials, 2.07g of an off-white solid was obtained in a yield of 91% according to the method for producing hydrochloride of compound III-1.

Elemental analysis: c₂₂H₃₂FN₅O₂HCl (% of theory: C58.20, H7.33, N15.43; in% of experiment: C58.41, H7.19, N15.64).

Example 44: 1-cyclopropyl-3- (4- (2- (4- (6-fluorobenzo [ d ]))]Isoxazol-3-yl) piperidin-1-yl) ethyl) Preparation of piperidin-1-yl) urea (Compound IV-2) and salts thereof

The intermediate 9-1(5.6mmol) and cyclopropylamine (30.8mmol) were used as raw materials to obtain the desired compound IV-2 as a white solid (2.22 g, 92% yield) according to the method for producing the compound II-1.

¹HNMR(CDCl₃,:ppm):0.62-0.78(m,4H,A-H),1.26-1.29(m,1H,A-H),1.45-1.54(m,4H,A-H),1.65-1.68(m,2H,A-H),1.93-2.13(m,6H,A-H),2.40-2.46(m,4H,A-H),2.80(m,1H,A-H),2.93-2.96(m,3H,A-H),3.12-3.15(m,2H,A-H),5.83(brs,1H,NH-H),6.94-6.98(m,1H,Ar-H),7.12-7.16(m,2H,Ar-H).

ESI-MS:430[M+H⁺].

Preparation of Compound IV-2 hydrobromide

Using compound IV-2(5.0mmol) and 5% aqueous hydrobromic acid (5.2mmol) as starting materials, 1.98g of an off-white solid was obtained in 78% yield according to the method for producing hydrochloride of compound III-1.

Elemental analysis: c₂₃H₃₂FN₅O₂HBr (% of theory: C54.12, H6.52, N13.72; and% of experiment: C54).33，H 6.39，N 13.91)。

Example 45: 1-cyclohexyl-3- (4- (2- (4- (6-fluorobenzo [ d ]))]Isoxazol-3-yl) piperidin-1-yl) ethyl) Preparation of piperidin-1-yl) urea (Compound IV-3) and salts thereof

The intermediate 9-1(5.6mmol) and cyclohexylamine (30.8mmol) were used as raw materials to obtain the target compound IV-3 as a white solid in an amount of 2.46g in a yield of 93% by the method for producing the compound II-1.

¹HNMR(CDCl₃,:ppm):1.16-1.22(m,4H,A-H),1.28-1.31(m,1H,A-H),1.47-1.60(m,10H,A-H),1.67-1.70(m,2H,A-H),1.95-2.15(m,6H,A-H),2.41-2.47(m,4H,A-H),2.94-2.97(m,3H,A-H),3.13-3.16(m,2H,A-H),3.60-3.64(m,1H,A-H),5.85(brs,1H,NH-H),6.96-7.00(m,1H,Ar-H),7.12-7.16(m,2H,Ar-H).

ESI-MS:472[M+H⁺].

Preparation of Compound IV-3 hydrochloride

Using compound IV-3(5.0mmol) and 5% aqueous hydrochloric acid (5.2mmol) as starting materials, 2.06g of an off-white solid was obtained in a yield of 81% according to the method for producing hydrochloride of compound III-1.

Elemental analysis: c₂₆H₃₈FN₅O₂HCl (% of theory: C61.46, H7.74, N13.78; and% of experiment: C61.30, H7.92, N13.50).

Example 46: 1- (4- (2- (4- (6-fluorobenzo [ d ]))]Isoxazol-3-yl) piperidin-1-yl) ethyl) piperidin-1- Preparation of phenyl-3-phenylurea (Compound IV-4) and salts thereof

By using intermediate 9-1(5.6mmol) and aniline (30.8mmol) as raw materials and following the preparation method of compound II-1, the target compound IV-4 was obtained as a white solid 2.27g with a yield of 87%.

¹HNMR(CDCl₃,:ppm):1.32-1.36(m,1H,A-H),1.51-1.60(m,4H,A-H),1.71-1.74(m,2H,A-H),1.99-2.21(m,6H,A-H),2.46-2.52(m,4H,A-H),2.99-3.02(m,3H,A-H),3.18-3.21(m,2H,A-H),5.90(brs,1H,NH-H),6.45-6.47(m,1H,Ar-H),7.00-7.05(m,2H,Ar-H),7.24-7.26(m,1H,Ar-H),7.38-7.48(m,2H,Ar-H),7.66-7.70(m,2H,Ar-H).

ESI-MS:466[M+H⁺].

Preparation of Compound IV-4 hydrobromide

Using compound IV-4(5.0mmol) and 5% aqueous hydrobromic acid (5.2mmol) as starting materials, 2.32g of an off-white solid was obtained in 85% yield according to the method for producing hydrochloride of compound III-1.

Elemental analysis: c₂₆H₃₂FN₅O₂HBr (% of theory: C57.14, H6.09, N12.82; and% of experiment: C57.31, H6.24, N12.59).

Example 47: 1- (4- (2- (4- (6-fluorobenzo [ d ]))]Isoxazol-3-yl) piperidin-1-yl) ethyl) piperidin-1- Preparation of 3- (pyridin-3-yl) urea (Compound IV-5) and salts thereof

The intermediate 9-1(5.6mmol) and aniline (30.8mmol) were used as raw materials to obtain the target compound IV-5 as a white solid 2.33g with a yield of 89% according to the method for preparing the compound II-1.

¹HNMR(CDCl₃,:ppm):1.34-1.38(m,1H,A-H),1.53-1.62(m,4H,A-H),1.73-1.76(m,2H,A-H),2.01-2.23(m,6H,A-H),2.48-2.54(m,4H,A-H),3.01-3.04(m,3H,A-H),3.20-3.23(m,2H,A-H),5.94(brs,1H,NH-H),6.50-6.52(m,1H,Ar-H),7.04-7.09(m,2H,Ar-H),7.40-7.43(m,1H,Ar-H),8.14-8.18(m,2H,Ar-H),8.89-8.92(m,1H,Ar-H).

ESI-MS:467[M+H⁺].

Preparation of Compound IV-5 hydrochloride

Using compound IV-5(5.0mmol) and 5% aqueous hydrochloric acid (5.2mmol) as starting materials, 2.31g of an off-white solid was obtained in 92% yield according to the method for producing hydrochloride of compound III-1.

Elemental analysis: c₂₅H₃₁FN₆O₂HCl (% of theory: C59.69, H6.41, N16.71; and% of experiment: C59.84, H6.19, N16.48).

Example 48: n- (4- (2- (4- (6-fluorobenzo [ d ]))]Isoxazol-3-yl) piperidin-1-yl) ethyl) piperidin-1-yl) Preparation of morpholine-4-carboxamide (compound IV-6) and salts thereof

Using intermediate 9-1(5.6mmol) and morpholine (30.8mmol) as raw materials, the preparation method of compound II-1 was followed to obtain 2.14g of the target compound IV-6 as a white solid with a yield of 83%.

¹HNMR(CDCl₃,:ppm):1.26-1.30(m,1H,A-H),1.45-1.54(m,4H,A-H),1.65-1.68(m,2H,A-H),1.95-2.13(m,6H,A-H),2.40-2.46(m,4H,A-H),2.93-2.96(m,3H,A-H),3.12-3.15(m,2H,A-H),3.36-3.40(m,4H,A-H),3.70-3.74(m,4H,A-H),6.42-6.44(m,1H,Ar-H),6.96-7.01(m,2H,Ar-H).

ESI-MS:460[M+H⁺].

Preparation of Compound IV-6 hydrobromide

Using compound IV-6(5.0mmol) and 5% aqueous hydrobromic acid (5.2mmol) as starting materials, 2.32g of an off-white solid was obtained in 86% yield according to the method for producing hydrochloride of compound III-1.

Elemental analysis: c₂₄H₃₄FN₅O₃HBr (% of theory: C53.33, H6.53, N12.96; and% of experiment: C53.60, H6.27, N12.81).

Example 49: n- (4- (2- (4- (6-fluorobenzo [ d ]))]Isoxazol-3-yl) piperidin-1-yl) ethyl) piperidin-1-yl) Preparation of pyrrolidine-1-carboxamide (Compound IV-7) and salts thereof

The intermediate 9-1(5.6mmol) and pyrrolidine (30.8mmol) were used as raw materials to obtain the target compound IV-7 as a white solid 2.29g with a yield of 92% according to the method for preparing the compound II-1.

¹HNMR(CDCl₃,:ppm):1.24-1.28(m,1H,A-H),1.43-1.52(m,4H,A-H),1.63-1.66(m,2H,A-H),1.75-1.79(m,4H,A-H),1.93-2.11(m,6H,A-H),2.38-2.44(m,4H,A-H),2.91-2.94(m,3H,A-H),3.10-3.13(m,2H,A-H),3.28-3.32(m,4H,A-H),6.41-6.43(m,1H,Ar-H),6.94-6.99(m,2H,Ar-H).

ESI-MS:444[M+H⁺].

Preparation of Compound IV-7 hydrochloride

Using compound IV-7(5.0mmol) and 5% aqueous hydrochloric acid (5.2mmol) as starting materials, 2.14g of an off-white solid was obtained in 89% yield according to the method for producing hydrochloride of compound III-1.

Elemental analysis: c₂₄H₃₄FN₅O₂HCl (% of theory: C60.05, H7.35, N14.59; in the experimental case%: C60.27, H7.53, N14.40).

Example 50: n- (4- (2- (4- (6-fluorobenzo [ d ]))]Isoxazol-3-yl) piperidin-1-yl) ethyl) piperidin-1-yl) Preparation of azetidine-1-carboxamide (Compound IV-8) and salts thereof

The intermediate 9-1(5.6mmol) and azetidine (30.8mmol) were used as raw materials to obtain the target compound IV-8 as a white solid 2.02g with a yield of 84% according to the preparation method of the compound II-1.

¹HNMR(CDCl₃,:ppm):1.23-1.27(m,1H,A-H),1.42-1.51(m,4H,A-H),1.64-1.67(m,2H,A-H),1.94-2.12(m,6H,A-H),2.28-2.32(m,2H,A-H),2.37-2.43(m,4H,A-H),2.90-2.93(m,3H,A-H),3.11-3.14(m,2H,A-H),3.88-3.95(m,4H,A-H),6.42-6.44(m,1H,Ar-H),6.93-6.98(m,2H,Ar-H).

ESI-MS:430[M+H⁺].

Preparation of Compound IV-8 hydrobromide

Using compound IV-8(5.0mmol) and 5% aqueous hydrobromic acid (5.2mmol) as starting materials, 2.07g of an off-white solid was obtained in 81% yield according to the method for producing hydrochloride of compound III-1.

Elemental analysis: c₂₃H₃₂FN₅O₂HBr (% of theory: C54.12, H6.52, N13.72; and% of experiment: C54.28, H6.76, N13.54).

Example 51: preparation of tablets

This example is a tablet formulation of a compound of the present invention. In this example all compounds of the invention were prepared as tablets.

The components of the tablet are as follows:

compounds of the invention	5mg
		Sucrose	50mg
Corn starch	120mg
		Magnesium stearate	25mg

The preparation method comprises the following steps: mixing the active ingredients with sucrose and corn starch, moistening with water, stirring, drying, pulverizing, sieving, adding magnesium stearate, mixing, and tabletting. Each tablet weighs 200mg, and the content of active ingredients is 5 mg.

Example 52: preparation of injection

This example illustrates the preparation of an injection containing the compound of the present invention. In this example, all compounds of the present invention were prepared as injections.

The injection comprises the following components:

compounds of the invention	10mg
		Water for injection	90mg

The preparation method comprises the following steps: dissolving active ingredient in water for injection, mixing, filtering, and subpackaging the obtained solution in ampoule bottle under aseptic condition, wherein each bottle contains 10mg of active ingredient and 1.0mg of active ingredient.

₂Example 53: dopamine D receptor binding assay

In this example all compounds of the invention were subjected to dopamine D₂Receptor binding assays to detect the Compounds of the invention with dopamine D₂The affinity of the receptor.

1. Experimental Material

D₂Receptor isotope ligand [ alpha ], [ alpha³H]methyl-Spiperone (0.3nM), butalamol (10. mu.M), liposoluble scintillant, and recombinant (human recombiant) D₂HEK-293 cells that receive functional proteins. The new anti-schizophrenic drug on the market, cariprazine (cariprazine), served as a positive control drug.

2. Experimental methods

Reference is made to the methods of operation of Hall, D.A. and Strange, P.G (1997), Brit.J.Pharmacol, 121:731-736, using³H]methyl-Spiperone (0.3nM) as D₂Receptor isotope ligands in the expression of recombinant D of human origin₂Receptor protein on HEK-293 cells₂A receptor binding assay. Nonspecific binding was determined in the presence of 10 μ M butalamol (butaclad).

The inhibition rate was calculated by the following formula:

the inhibition (I%) (total bound tube cpm-compound cpm)/(total bound tube cpm-non-specific bound tube cpm) × 100%.

Compounds with inhibition greater than 95% were subjected to a series of receptor binding assays to determine the median inhibitory amount (IC)₅₀Inhibiting the expression of 50%³H]Methyl-spiroperimidezene and D₂Concentration of compound required for receptor binding). Two secondary tubes were measured per concentration and two independent experiments were performed for each compound.

The affinity of the drug for the receptor was calculated by the following formula:

Ki＝IC₅₀/(1+[L]K_D)

(Ki: affinity of drug to receptor, L: concentration of radioligand, K_D: affinity value of radioligand with receptor

Compounds of the invention and D₂The results of the receptor binding assay are shown in table 1. The test results in table 1 show that: the compound of the invention is p-dopamine D₂The receptor has a strong or moderate affinity.

₃Example 54: dopamine D receptor binding assay

In this example all compounds of the invention were subjected to dopamine D₃Receptor binding assays to detect the Compounds of the invention with dopamine D₃The affinity of the receptor.

1. Experimental Material

D₃Receptor isotope ligand [ alpha ], [ alpha³H]Methyl-spiro-piperdine (0.3nM), (+) butalamol (10. mu.M), liposoluble scintillation fluid, expression of human recombinant D₃CHO cells that receive functional proteins. Carilazine was used as a positive drug control.

2. Experimental methods

Reference is made to Mackenzie, R.G. et al (1994), Eur.J.Pharmacol, 266:79-85, methods of operation, using³H]methyl-Spirospiroperidine (0.3nM) as D₃Receptor isotope ligands in the expression of recombinant D of human origin₃Receptor protein CHO on cells for D₃A receptor binding assay. Nonspecific binding was determined in the presence of 10 μ M (+) butalamol.

The inhibition rate was calculated by the following formula:

Compounds with inhibition greater than 95% were subjected to a series of receptor binding assays to determine the median inhibitory amount (IC)₅₀Inhibiting the expression of 50%³H]Methyl-spiroperimidezene and D₃Concentration of compound required for receptor binding). Two secondary tubes were measured per concentration and two independent experiments were performed for each compound.

Ki＝IC₅₀/(1+[L]K_D)

Compounds of the invention and D₃The results of the receptor binding assay are shown in table 1. From Table 1, it can be seen that the compound pair D of the present invention₃The receptors have strong affinity and are equivalent to the positive drug Carilazine, and the compounds in the series have the results of example 53₃/D₂The acceptor is also suitably selective, i.e. between 10 and 60 fold selective.

_1AExample 55: 5-HT receptor binding assays

In this example all compounds of the invention were subjected to 5-HT_1AReceptor binding assays to detect the Compounds of the invention and 5-HT_1AThe affinity of the receptor.

1. Experimental Material

5-HT_1AReceptor isotope ligand [ alpha ], [ alpha³H]8-OH-DPAT (0.3nM), 8-OH-DPAT (10. mu.M), fat-soluble scintillation fluid and expression human recombinant 5-HT_1AHEK-293 cells that receive functional proteins. Carilazine was used as a positive drug control.

2. Experimental methods

Reference is made to the method of operation of Mulheron, J.G. et al (1994), J.biol.chem.,269:12954-³H]8-OH-DPAT (0.3nM) as 5-HT_1AReceptor isotope ligands in the expression of recombinant 5-HT of human origin_1A5-HT on HEK-293 cells of receptor proteins_1AA receptor binding assay. Nonspecific binding was determined in the presence of 10. mu.M 8-OH-DPAT.

Compounds with inhibition greater than 95% were subjected to a series of receptor binding assays to determine the median inhibitory amount (IC)₅₀Inhibiting the expression of 50%³H]8-OH-DPAT and 5-HT_1AConcentration of compound required for receptor binding). Two secondary tubes were measured per concentration and two independent experiments were performed for each compound.

Ki＝IC₅₀/(1+[L]K_D)

Compounds of the invention and 5-HT_1AThe results of the receptor binding assay are shown in table 1. The experimental results in Table 1 show that the compounds of the present invention are resistant to 5-HT_1AThe receptors all have strong affinity and are equivalent to the positive drug Carilazine.

_2AExample 56: 5-HT receptor binding assays

In this example all compounds of the invention were subjected to 5-HT_2AReceptor binding assays to detect the Compounds of the invention and 5-HT_2AThe affinity of the receptor.

1. Experimental Material

5-HT_2AReceptor isotope ligand [ alpha ], [ alpha³H]Ketanserin (0.5nM), Ketanserin (1 muM), liposoluble scintillant, and recombinant 5-HT expressed from human_2AHEK-293 cells that receive functional proteins. Carilazine was used as a positive drug control.

2. Experimental methods

Reference is made to Bonhaus, D.W. et al (1995), Brit.J.Pharmacol, 115:622-³H]Ketanserin (0.5nM) as 5-HT_2AReceptor isotope ligands in the expression of recombinant 5-HT of human origin_2A5-HT on HEK-293 cells of receptor proteins_2AA receptor binding assay. Nonspecific binding was determined in the presence of 1 μ M ketanserin.

Compounds with inhibition greater than 95% were subjected to a series of receptor binding assays to determine the median inhibitory amount (IC)₅₀Inhibiting the expression of 50%³H]Ketanserin and 5-HT_2AConcentration of compound required for receptor binding). Two secondary tubes were measured per concentration and two independent experiments were performed for each compound.

Ki＝IC₅₀/(1+[L]K_D)

Compounds of the invention and 5-HT_2AThe results of the receptor binding assay are shown in table 1. The results of the experiments in Table 1 show that the compounds of the present invention are active against 5-HT_2AThe receptors have strong affinity, and most of the compounds are resistant to 5-HT_2AThe affinity of the compound is stronger than that of the positive drug Carlinazine.

Table 1: affinity of Compounds for Each receptor (Ki values)

Thus, as can be seen from the results of Table 1, the compound pair D of the present invention₂、D₃、5-HT_1A、5-HT_2AThe receptors all have strong or moderate affinity, and in addition most compounds have a strong or moderate affinity for D₂/D₃The receptor has proper selectivity, the selectivity is between 10 and 60 times, and is better than that of the Carilazine (the selectivity is lower than 10 times). Most of the compounds are p-5-HT_2AThe receptor affinity is significantly better than that of the positive control drug. Therefore, the compounds have the potential effect of simultaneously improving cognitive impairment, low EPS side effect and the like.

₂ ³Example 57: [ H ] for intrinsic agonistic activity of dopamine D receptor]Adenosine uptake test face

In this example all compounds of the invention were subjected to dopamine D₂Of intrinsic agonistic activity of a receptor³H]Adenosine was taken to test the face. Aripiprazole is a positive control drug.

Experimental methods

Cells were serum removed by washing twice with 200 μ Ι _ of serum free medium, 90 μ Ι _ of serum free medium was added to each well, plates were incubated for 2-3 h. 10 μ of serum-containing medium as a positive control, vehicle (serum-free medium), negative control (antagonist, haloperidol) or test compound and standard (quinpirole, 10 μ L of 10 μ M solution at a final concentration of 1 μ M) in serum-free medium were added to each well. The plate is returned to the incubator.

After 18h, add [ 2 ]³H]Adenosine (0.5. mu. Ci/well) was in 10. mu.L serum free medium and the plates were returned to the incubator. After 4h, membrane protease (0.25%) (100. mu.L/well) was added. The plate is again returned to the incubator. After 1h, a rapid filtration termination test was performed by passing through a Whatman GF/B glass fiber filter. For example, using a Brandel MLR-96T cell harvester, the filter is washed with 500mL of 50mM Tris-HCl pH 7.0 buffer. For example, retained radioactivity (50% effective amount) on the filter was assessed using a Wallac 1205Betaplate liquid scintillation counter. Intrinsic activity was defined as total uptake (l μ M quinpirole) minus serum free medium and test compounds were compared to l μ M quinpirole (full DA receptor agonist) classified as 100% intrinsic activity. All assays are preferably performed in triplicate, with each drug in a complete column in each plate.

TABLE 2 having D according to the invention₂Compound results of partial receptor agonism

The test result shows that: the compounds I-5, I-7, I-12, I-15, I-16, II-2, II-6, II-9, II-12, III-2, III-3, III-5, III-6, III-13, IV-2, IV-4, IV-6 and IV-8 of the invention have the structure D₂Partial receptor agonism.

Example 58: in vivo anti-schizophrenic activity assay of the compounds of the invention

In this exampleSelection D₂/D₃Receptor selectivity of 10-60 times, and D₂/D₃/5-HT_1A/5-HT_2ACompounds with strong receptor affinity were tested for anti-schizophrenic activity.

1. Apomorphine model

(1) Test method

The experiment used an acute dosing mode.

Experimental mice were randomized into groups, and the stereotypic motor model was induced by intraperitoneal injection of apomorphine (5mg/kg) 30 minutes after gavage of either control or test compound. Observations record that within 70 minutes after administration of the apomorphine solution to the mice, the following symptoms appear every first 30 seconds of 10 minutes (0-10 minutes, 11-20 minutes, 21-30 minutes, 31-40 minutes, 41-50 minutes, 51-60 minutes, 61-70 minutes) and are scored according to the following criteria:

1)4 min, continuously biting;

2)3 min, biting the cage cover at least once during observation;

3)2 min, licking the cage bottom plate or the cage wall at least once during observation;

4)1 minute, compulsive sniffing and head lowering activities occur;

5) score 0, no such activity occurred.

The total score of the mice showing the above behavior within 70 minutes was calculated, and the improvement rate was calculated according to the following formula. Data are expressed as Mean ± SEM, plotted using GraphPad Prism software, and analyzed using the t-test, with significant differences being considered when P < 0.05.

(2) Experimental grouping and drug administration design

The C57BL/6 mice were randomly divided into 6 groups of at least 9 mice, each of which was a model control group (apomorphine, in saline), a cariprazine (positive control drug) and a compound of the invention.

(3) Administration and post-administration observation

The invention claimsThe compound and the positive drug Carilazine are administered in gradient dosage of 0.05, 0.10, 0.40, 0.60, 1.20 mg/kg^-1(oral gavage). During the experiment, the clinical response symptoms of the animals were recorded.

(4) Statistical method

All data to

Show that the two samples were compared in mean t-test and one-way anova with P, processed with 11.5 software statistical package<0.05 is a significant difference.

(5) Results of the experiment

The specific experimental results are shown in table 3.

Table 3: inhibition of apo. induced gross stereotypical movements (ED) in the mouse schizophrenic model by a single oral administration of compound I-5₅₀)

The test result shows that: compared with the positive control drug Carilazine, the compounds of the invention can obviously improve the stereotypy of mice, and the apomorphine-induced schizophrenia model is a classic model of schizophrenia, so the series of compounds of the invention have good anti-schizophrenia effect. Improvement of stereotypy behavior (ED) of mouse by Compounds I-5, I-13, II-2, II-6, III-5, IV-8₅₀) Is superior to the positive control drug Carilazine.

2. MK-801 induced spontaneous locomotion experiment in mice

(1) Test method

The experiment used an acute dosing mode. Experimental mice were randomly grouped and acclimated in a spontaneous activity box for 5-10 minutes prior to the experiment. After the animals receive the intragastric administration for 10 minutes, MK-801(0.5mg/kg) is injected into the abdominal cavity, the animals are placed back to the spontaneous activity box to start infrared monitoring, and videos of the animal activities are continuously collected for 90 minutes. And (4) analyzing the video file by using an SPSS 11.5 software statistical package after the experiment is finished to obtain the total activity distance within 90 minutes. Data are expressed as Mean ± SEM, plotted using GraphPad Prism software, and analyzed using the t-test, with significant differences being considered when P < 0.05.

(2) Experimental grouping and drug administration design

57BL/6 mice were randomly divided into 6 groups of at least 12 mice each, a placebo control group, a model control group (MK-801, in physiological saline), a cariprazine group, and a preferred compound group of the invention. Carilazine as a positive drug control, MK-801 as a molding tool drug.

(3) Results of the experiment

The specific results are shown in Table 4.

Table 4: effect of a Single oral administration on MK-801 induced Total distance to open field movement in a mouse model of schizophrenia (ED)₅₀)

The test result shows that: the kalilazine group and the compound of the invention can obviously improve the total distance of field movement of mice, and the MK-801 induced field movement model is a common model of schizophrenia negative symptoms, so the series of compounds of the invention have good effect of resisting the schizophrenia negative symptoms. The improvement rate of the compounds I-5, I-13, II-2, II-6, III-5 and IV-8 on the mouse open field movement is better than that of positive drug control Carlinazine, which indicates that the activity of the compounds I-5, I-13, II-2, II-6, III-5 and IV-8 in the model is better than that of Carlinazine.

Example 59: determination of Water solubility of Compounds

This example selects 18 compounds according to the invention and 4 compounds from the prior art (PR-1: CN1829703A, compound 1 according to example 3 on page 17 of the description; PR-2: CN102159557A, compound 84 according to example 84 on page 86 of the description; PR-3: CN103130737A, compound IV-2 according to example 44 on page 41 of the description; PR-4: CN104140421A, compound I-1 according to example 1 on page 15 of the description) for the determination of the water solubility test.

1. The instrument comprises the following steps: waters e2695 high performance liquid chromatograph, SHA-B water bath constant temperature oscillator.

2. The method comprises the following steps: adding excessive raw materials into water of certain volume to obtain saturated solution, shaking in a constant temperature (37 deg.C) shaking instrument for 2 hr, standing, collecting supernatant, filtering with 0.45 μm filter membrane to sample injection vial, and sampling for determination.

3. Dissolution rate measuring instrument

(1) The instrument comprises the following steps: ZRD-14 intelligent dissolution instrument, Waters e2695 high performance liquid chromatograph.

4. Dissolution medium: 900mL of a hydrochloric acid solution having a pH of 1.0 and water were used as dissolution media, respectively.

The method comprises the following steps: method for measuring dissolution rate and release rate of 0931 general rule of preparation in Chinese pharmacopoeia 2015 year edition by a second method.

Rotating speed: 75 revolutions per minute.

Sampling points are as follows: respectively passing through 5, 10, 15, 20, 30, 45, and 60min, collecting 10mL of eluate, filtering with 0.45 μm filter membrane, and measuring by sample injection.

5. Results of the experiment

The water solubility test was carried out as described above for 18 compounds according to the invention (compounds I-5, I-7, I-12, I-13, I-16, II-2, II-6, II-9, II-12, III-2, III-3, III-5, III-6, III-13, IV-2, IV-4, IV-6, and IV-8) and for 4 compounds according to the prior art (PR-1: CN1829703A, page 17, Compound 1 of example 3 of the description, page 17, PR-2: CN102159557A, page 86, Compound 84 of example 84 of the description, PR-3: CN103130737A, page 41, Compound IV-2 of example 44 of the description, page 4: CN104140421A, page 15, Compound I-1 of example 1 of the description). The specific experimental results are shown in table 5.

Table 5: water solubility of compounds

The test result shows that: the water solubility of the compounds of the present invention is significantly superior to that of representative compounds in the patent literature. Therefore, the compound of the invention is more beneficial to the preparation and research of preparations and prescriptions.

Example 60: compound rat in vivo drug test

This example selects 11 compounds according to the invention (compounds I-5, I-12, I-13, II-2, II-6, II-9, III-3, III-5, III-13, IV-6 and IV-8) and 4 prior art compounds (PR-1: CN1829703A, Compound 1 of example 3, page 17 of the description, PR-2: CN102159557A, Compound 84, example 84, page 86 of the description, PR-3: CN103130737A, Compound IV-2, example 44, page 41 of the description, PR-4: CN104140421A, Compound I-1, example 1, page 15 of the description) and Carilazine for carrying out in vivo pharmacological tests in rats.

1. Test protocol

1.1 test animals

Healthy male SD rats were 48, divided into two groups of 24 rats each. All rats were aged 10-12 weeks in the week and weighed 250-290 g.

1.2 methods of administration

Different groups of rats used different modes of administration. The compound of the present invention was administered intravenously at a dose of 0.5mg/kg and in a volume of 5 mL/kg. The dose for oral administration was 2mg/kg, and the volume for administration was 10 mL/kg. The drug is respectively administered by tail vein puncture and oral gavage. Fasting was overnight before dosing and four hours after dosing.

1.3 sample Collection

CO at each time point 0.083, 0.25, 0.5, 1, 2, 4, 8 and 24 hours post-administration₂3 rats were inhaled euthanasia, blood was collected by cardiac puncture (about 1mL) into an EDTA-K2 anticoagulation tube (Bofeimei, product No. CLS-11131), brain tissue was taken and weighed, blood samples were centrifuged at 6000rpm for 8min (wet ice before centrifugation) within 1 hour, and supernatant, i.e., plasma, was taken, and the plasma and brain tissue were cryopreserved at-20 ℃ for LC-MS/MS analysis.

1.4 analytical methods and assays

In the experiment, the contents of the compound of the invention in a plasma sample and a brain tissue sample in a rat PK experiment are respectively measured by adopting a liquid chromatography-mass spectrometry method. And (3) establishing two standard curves for each analysis batch, calculating the concentration of the substance to be detected in the samples of the analysis batch, and controlling the samples along with the quality. The accuracy of the concentration points above 3/4 in the standard curve is within 80% -120%. Each analysis batch was set with quality control samples (QC) at different concentrations, high, medium, and low, each concentration being in parallel with a double sample. And (3) calculating the concentration of the quality control samples according to the standard curve of each analysis batch, wherein the quantity of the quality control samples is more than or equal to 5% of the quantity of each batch of samples.

1.5 preparation of quality control samples

Taking 95 mu L of rat blank plasma, respectively adding 5 mu L of the test object standard solution with the concentration of 40, 20, 10, 2, 1, 0.2, 0.04 and 0.02 mu g/mL, and uniformly mixing to obtain standard curve samples with the concentrations of 2000, 1000, 500, 100, 50, 10, 2 and 1 ng/mL. Taking 95 mu L of rat blank plasma, respectively adding 5 mu L of standard solutions of the test substances with the concentrations of 32, 16, 0.8 and 0.06 mu g/mL, and uniformly mixing to obtain Quality Control (QC) samples with the concentrations of 1600, 800, 40 and 3 ng/mL.

2. Chromatographic conditions

High-performance liquid phase system: shimadzu LC-30AD column: thermo, C18, 2.1X 50mm, 5 μm

Flow rate: 0.4mL/min

3. Mass spectrometric detection mode

ESI，MRM(+)

4. Data computation and processing

The raw data in the experiment were collected and calculated by AB Sciex Mass spectrometer software Analyst 1.6.1, the standard curve was linear regression, and the weight coefficient was 1/X2.

The data and charting were processed using the computer program Microsoft Office Excel 2007 (Microsoft corporation, usa). Pharmacokinetic parameters were calculated using DAS (version 2.1.1) processing software statistical moment method.

5. Test results

In vivo pharmacological tests were carried out in rats using 11 compounds of the invention (compounds I-5, I-12, I-13, II-2, II-6, II-9, III-3, III-5, III-13, IV-6 and IV-8) and 4 prior art compounds (PR-1: CN1829703A, Compound 1 of example 3, page 17 of the description, PR-2: CN102159557A, Compound 84 of example 84, page 86 of the description, PR-3: CN103130737A, Compound IV-2 of example 44, page 41 of the description, PR-4: CN104140421A, Compound I-1 of example 1, page 15 of the description) and Carilazine (positive control) as described above. The specific experimental results are shown in table 6.

Table 6: brain penetration rate and bioavailability of the compound of the invention in male SD rats

The test result shows that: the compound of the invention has high brain penetration rate and conforms to the pharmacological characteristics of central drugs.

In addition, the tested compounds have good absolute bioavailability (greater than 20%) when orally taken, which indicates that the compounds of the invention have good potential druggability.

Example 61: examination of side effects of catalepsy in Compounds

In this example, 6 compounds (compounds I-5, I-13, II-2, II-6, III-5 and IV-8) of the present invention, as well as cariprazine (positive control drug) and risperidone (positive control drug) were selected to perform a test for examining the side effects of catalepsy.

1. Laboratory animal

SD rats, male, available from chengzhou kavens laboratory animals llc.

2. Laboratory apparatus

A 9mm diameter wooden stick, placed horizontally, and 11cm high.

3. Design of experiments

The rat forelimb was placed on a wooden stick to start timing and stopped when its posture was changed. The Catalepsy test time was 60 seconds and if exceeded, was recorded as 60 seconds. Compound dose design ED tested with apomorphine₅₀Values are standard, and 10, 50 and 200 times doses are given. Compounds were administered orally and tested for catallepsy after 30, 60 and 120 minutes, respectively.

3. Results of the experiment

6 compounds of the invention, as well as cariprazine and risperidone were selected to perform compound catalepsy side effect investigation experiments as described above. The specific experimental results are shown in Table 7.

Table 7: the compound causes catalepsy

Experimental results show that the compounds such as I-5 and the like have low incidence rate of catalepsy and low EPS side effect, and are superior to risperidone.

Example 62: acute toxicity test of Compounds

In this example, 11 compounds (I-5, I-12, I-13, II-2, II-6, II-9, III-3, III-5, III-13, IV-6 and IV-8) according to the present invention and Carilazine (positive control drug) were selected for acute toxicity test.

(1) Experimental protocol

Firstly, toxicity symptoms and death situations of animals are observed after the animals are orally administered with ICR mouse Carilazine and the compound such as I-5 of the invention, and the acute toxicity is compared.

Preparing a solvent: weighing a proper amount of Tween-80, and diluting with deionized water to a concentration of 5% (g/v) Tween-80.

③ administration preparation: the required test samples were weighed out separately and formulated with 5% Tween 80 solutions to 6.25, 12.50, 25.00, 50.00 and 100.00mg/mL (corresponding to 125, 250, 500, 1000, 2000mg/kg, respectively) suspensions.

Fourthly, the administration route: the test article and the vehicle control group (0.5% Tween-80) were administered orally.

Fifthly, administration frequency: single administration, with fasting overnight before dosing.

Sixthly, administration volume: 20 mL/Kg.

General symptom observation: the day of administration was observed 1 time about 0.5, 1, 2, 4, 6 hours after the first administration; the observation period is 2-6 days, 2 times per day, 1 time in the morning and afternoon.

Observations include, but are not limited to: general condition, behavioral activity, gait posture, eye, mouth, nose, gastrointestinal tract, dermal hair, urogenital tract.

(2) Statistical analysis

Body weight data are expressed as mean ± standard deviation and are compared between groups using the Levene's test and one-way analysis of variance, and if differences are indicated, the Dunnet test is followed.

(3) Results of the experiment

11 compounds of the invention were selected, and cariprazine (positive control) was used for acute toxicity experiments as described above. The results are shown in Table 8.

In the MTD test, the tolerance of the animals to the drugs is considered, and the dosage is up to the time when the animals die frequently, namely the maximum tolerance.

Table 8: test results of acute toxicity of compounds such as I-5 and positive Carilazine by single oral administration

Note: maximum tolerated MTD.

The results show that: the MTD (maximum tolerance) of the compounds I-13, II-2, II-6 and III-5 in the test object is more than 2000mg/kg, and the acute toxicity is far lower than that of the kalilazine; the MTD values of the compounds I-5, I-12, II-9, III-3, III-13, IV-6 and IV-8 are all more than 400mg/kg, and the safety is better than that of the kalilazine.

Claims

1. A piperidine amino derivative, characterized by having a compound represented by the general structural formula (I) or a pharmaceutically acceptable salt thereof:

wherein:

r is

n is an integer of 0 to 1;

R₁is composed of

The substituted phenyl is selected from halogen, cyano, methoxy or C₁～C₂Alkyl-substituted phenyl of (a);

the heteroaryl is selected from furyl, pyrrolyl, thienyl, pyridyl, 2-benzothienyl, 2-benzofuryl or 2-indolyl.

2. Piperidinylamino derivative according to claim 1, wherein said salt is a salt comprising a pharmaceutically acceptable anion selected from the group consisting of hydrochloride, hydrobromide, sulfate, acetate, citrate, tartrate, maleate, fumarate, methanesulfonate, p-toluenesulfonate, oxalate, trifluoroacetate.

3. A piperidinylamino derivative, characterized by:

I-54- (2- (4- (benzo [ d ] isothiazol-3-yl) piperazin-1-yl) ethyl) piperidin-1-yl-carbamic acid ethyl ester,

III-34- (2- (4- (6-fluorobenzo [ d ] isoxazol-3-yl) piperidin-1-yl) ethyl) piperidin-1-yl-carbamic acid ethyl ester,

4. A pharmaceutical composition comprising a therapeutically effective amount of a piperidinylamino derivative of any one of claims 1-3, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

5. A process for preparing a pharmaceutical composition according to claim 4, wherein said process is carried out by mixing said piperidinylamino derivative or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable carrier.

6. A kit comprising a piperidinylamino derivative according to any one of claims 1-3, or a pharmaceutically acceptable salt thereof.

7. Use of a piperidinylamino derivative according to any one of claims 1-3, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment of schizophrenia.