CN116554145A - Aralkyl-4- (1H) indolylpiperazine derivative, preparation method and application thereof - Google Patents

Abstract

The invention relates to an aralkyl-4- (1H) indolyl piperazine derivative, a preparation method and application thereof. In particular, the present invention relates toA compound shown in a general formula (I), a preparation method thereof, a pharmaceutical composition containing the compound and application thereof in preparing medicines for preventing and/or treating central nervous system diseases related to mammal 5-hydroxytryptamine receptor and/or dopamine receptor.

Description

Aralkyl-4-(1H)indolylpiperazine derivatives, preparation methods and applications thereof

Technical Field

The present invention belongs to the field of pharmaceutical chemistry, and particularly relates to aralkyl-4-(1H)indolylpiperazine derivatives, and preparation methods and applications thereof.

Background Art

Parkinson’s disease (PD) is a neurodegenerative disease characterized by neurodegeneration of the nigrostriatal pathway. Its clinical features include resting tremor, muscle rigidity, bradykinesia and postural balance disorders, and may be accompanied by non-motor symptoms such as depression, constipation and sleep disorders.

Parkinson's disease is the second most common neurodegenerative disease in the world after Alzheimer's disease. It often occurs in the elderly. The incidence rate of elderly people over 65 years old in my country is 1.7% (Zhang Z X. The Lancet, 2005, 365 (9459): 595-597.). According to incomplete statistics, the number of Parkinson's patients in China is about 2.7 million, with an annual increase of 100,000 new patients, making it the "largest country for Parkinson's disease" (Pahwa R. American Journal of Managed Care, 2010 (4): S94.). Parkinson's disease not only has a high incidence rate, but is also a lifelong disease. There is currently no drug that can cure it. As the onset progresses, patients gradually lose their ability to live and work independently, and develop complications such as motor injuries and mental disorders, which seriously affect their quality of life. In addition, patients need to take medication for a long time, which brings a huge economic burden to their families.

Dopamine receptor agonists are important drugs for the clinical treatment of Parkinson's disease (PD). They can directly stimulate the postsynaptic dopamine receptors of the striatum to play a role. Because they do not compete with amino acids in the brain, metabolism does not produce free radicals and does not have oxidative stress reactions, and they may also have the function of protecting and repairing nerves. This type of drug can be administered alone to treat patients with milder PD symptoms, or it can be used in combination with compound levodopa to reduce the dose of levodopa and alleviate adverse reactions such as motor symptom fluctuations and dyskinesias (Guridi J.Parkinsons Dis, 2012, 2012: 1-15.). According to the classification of drug chemical structure, dopamine receptor agonists can be divided into ergot alkaloids (bromocriptine, pergolide, lisuride, etc.) and non-ergot alkaloids (ropinirole, pramipexole and cabergoline, etc.). Because the initial ergot drugs combined with levodopa will have heavier toxic and side effects, they are rarely used now and are gradually replaced by non-ergot novel selective dopamine receptor agonists. Representative drugs include: bromocriptine, pergolide, ropinirole, and pramipexole. Among them, pramipexole is a dopamine D ₂ , D ₃ , and D ₄ receptor agonist, and ropinirole is a dopamine D ₂ and D ₃ receptor agonist.

Selective dopamine receptor agonists remain the focus of Parkinson's disease drug research, and several drugs have entered the clinical trial stage, such as CQA-206-291 in clinical phase III, which is a _D2 receptor agonist developed by Novartis; Aplindore fumarate, BAM-1110 and Mesdopetam in clinical phase II also act on different dopamine receptors.

The 5-HT _1A receptor belongs to the transmembrane receptor or G protein-coupled receptor (GPCR) family. It is the first serotonin receptor subtype to be isolated and completely sequenced. It is mainly distributed in the raphe nucleus, hippocampus, amygdala and cortex in the central nervous system. It can control memory, cognition and improve mood.

The 5-HT _1A receptor in patients with Parkinson's disease (PD) is involved in levodopa-induced dyskinesias (LID), and therefore has attracted the attention of researchers. Studies have found that presynaptic 5-HT _1A receptors on serotonergic fibers can reduce abnormal dopamine release; postsynaptic 5-HT _1A receptors can reduce overactive cortical-striatal glutamate neurotransmission.

Studies have shown that selective 5-HT _1A receptor agonists are closely related to pharmacological effects such as movement disorders, improvement of cognitive impairment, and anti-anxiety and depression. Eltoprazine (eltoprazine), a new drug developed by Elto et al., is an oral small molecule 5HT _1A / _1B partial agonist. It has been granted orphan drug status by the FDA for the treatment of Parkinson's disease (PD) levodopa-induced movement disorders (PD-LID) and is currently in Phase 2b clinical trials. Currently, more than 680 subjects have taken Eltoprazine, which has shown good efficacy and safety in the treatment of cognitive and movement disorders. (Cabedo N. Journal of medicinal chemistry, 2001, 44 (11): 1794-1801.)

Befiradol, as a selective 5HT _1A agonist, was first used in clinical trials to treat neuropathic pain and is now used to treat Parkinson's disease (PD) induced dyskinesia (PD-LID). Literature reports (Noureddine ElAouad. European Journal of Medicinal Chemistry, 44 (11): 4616-4621.) show that Befiradol exhibits novel therapeutic properties, has significant anti-dyskinesia function without compromising the therapeutic properties of L-DOPA, and has an improvement effect on non-motor mental and emotional symptoms, such as anti-depression and antianxiety effects.

The anti-PD therapeutic effect of 5HT _1A agonists is expected to solve the movement disorders of Parkinson's disease, improve mood, and repair cognition, and has become a hot spot and difficulty in the global research and development of anti-PD drugs. With the in-depth study of PD pathogenesis and the rapid development of translational medicine, the development of drugs for the cause and clinical symptoms of anti-PD is accelerating.

In recent years, studies have found that dopamine neurotransmitters and 5-hydroxytryptamine neurotransmitters are involved in the brain's regulation of the motor system, and that there is a synergistic effect on motor regulation between the dopamine system and the 5-hydroxytryptamine system's related receptors. Related clinical trials have also confirmed the advantages of multi-target synergy in the treatment of PD. (Ricardo. Bioorganic & Medicinal Chemistry, 2003.)

Among them, Brilaroxazine was developed by Reviva Pharmaceuticals and is a multi-target partial agonist that acts on dopamine _D2 , _D3 receptors and 5- _HT1A receptors. It is clinically developed for indications including Parkinson's disease, anti-schizophrenia, bipolar disorder, etc., and is currently in Phase I and II clinical research. Brilaroxazine has anti-Parkinson's effects by increasing the release of cortical dopamine. At the same time, literature reports that Brilaroxazine has a significant improvement effect on the impairment of new object recognition induced by subchronic phencyclidine. These test results show that Brilaroxazine has obvious therapeutic anti-Parkinson's activity, as well as cognitive impairment improvement and recovery effects. (Grundt P. Bioorganic & Medicinal Chemistry Letters, 2007, 17 (3): 745-749.)

Bifeprunox, a new anti-PD drug in Phase III clinical development, is a 5-HT _1A receptor agonist and a D ₂ receptor partial agonist. Clinical trials have shown that it can improve motor symptoms and relieve depression, anxiety and other mental symptoms. (Wang, Q. Neuropharmacology, 2019, 148: 1-10.)

Pridopidine, a new anti-PD drug currently in Phase II clinical trials, acts on multiple receptor targets such as _D2 , 5- _HT1A , and sigma-1. It has shown good improvement in motor impairment in non-human primate models and has the effects of improving cognition and neuroprotection. (Chen X. Journal of Medicinal Chemistry, 2012, 55(16): 7141-7153.)

Pardoprunox (SLV-308) is a _D2 /D3 _partial agonist and a 5- _HT1A full agonist. It has anti-Parkinson's, antidepressant and antianxiety effects. (Jones CA. Eur Neuropsychopharmacol. 2010 Aug; 20(8): 582-93.) In addition, compared with other dopaminergic drugs, it has a lower tendency to cause side effects such as movement disorders. It has entered Phase III clinical trials for the treatment of Parkinson's disease. (Glennon, JC Synapse 2006, 60, 599-608.)

In addition, patent WO2001049680A1 discloses a new class of indole derivatives, among which the compound (1a) which is relatively similar to the compound of this patent has the following structure:

The compound has certain affinity activity for 5-HT _1A and D ₄ receptors and can be used to treat affective disorders such as depression, generalized anxiety disorder, panic disorder, obsessive-compulsive disorder, social phobia, eating disorders and neurological diseases such as mental disorders. Its IC ₅₀ values for inhibitory activity on 5-HT _1A and D ₄ receptor binding are 12nm and 92nm respectively.

Patent WO2003002552A1 discloses a new class of indole derivatives, some of which have valuable activity as serotonin reuptake inhibitors and have antagonistic effects on 5-HT _1A receptors, and some of which also have affinity for D ₃ and D ₄ receptors. The structure of the compound (1e) that is relatively similar to the compound of this patent is as follows:

The patent does not disclose any relevant activity data for the compound.

Patent WO2007026959A2 discloses a class of 4-piperazine-1-yl-4-benzo[B]thiophene derivatives, among which a compound (Example 40) having a structure similar to that of the present patent has the following structure:

The biological activity of this compound only shows affinity for _D2 and 5- _HT2A receptors (the receptor function is not disclosed, it may be agonist, antagonist or inverse agonist, etc.), and the receptor affinity Ki values are 3.1nm and 0.6nm respectively.

In summary, in view of the multi-target synergistic effects of dopamine _D2 , _D3 receptors and/or 5- _HT1A receptors, multi-target chemical small molecules with dopamine _D2 , _D3 receptors and/or 5- _HT1A receptor activity are expected to play a new clinical therapeutic role in overcoming movement disorders, improving cognitive impairment, and improving mental mood such as anxiety and depression while treating the main motor symptoms of Parkinson's disease. In particular, dopamine _D2 , _D3 and/or 5- _HT1A multi-target (partial) agonists have become an important direction for the development of new anti-Parkinson's, anti-depression, anti-schizophrenia and other new drugs in the world in terms of drug research and development and application. Research in this field is novel, creative and of great scientific value.

Summary of the invention

The technical problem to be solved by the present invention is to provide an aralkyl-4-(1H) indolyl piperazine derivative, a preparation method and application thereof, and in particular, by effectively acting on dopamine _D2 , _D3 receptors and/or 5- _HT1A receptors, the present invention can achieve the therapeutic characteristics of improving PD motor symptoms while overcoming movement disorders, improving cognitive impairment, and improving mental emotions such as anxiety and depression, so as to overcome the defects of the prior art.

The object of the present invention is to provide a compound represented by general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:

in:

M is selected from CR ₀ or N;

R ₀ is selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl or C _1-6 alkoxy, preferably halogen, cyano, C _1-6 alkyl or C _1-6 haloalkyl, more preferably halogen, cyano, C _1-3 alkyl or C _1-3 haloalkyl, further preferably cyano;

R ₁ is selected from halogen, hydroxyl, cyano, amino, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 alkoxy or -(CH ₂ ) _n1 NR _aa C(O)R _bb , preferably halogen, cyano, C _1-6 alkyl, C _1-6 haloalkyl or -(CH ₂ ) _n1 NR _aa C(O)R _bb , more preferably halogen, cyano, C _1-3 alkyl, C _1-3 haloalkyl or -NR _aa C(O)R _bb , further preferably fluorine, chlorine, bromine, cyano, methyl, trifluoromethyl or -NHC(O)CH ₃ ;

R _aa and R _bb are each independently selected from hydrogen, deuterium, C _1-6 alkyl, C _1-6 deuterated alkyl or C _1-6 haloalkyl, preferably hydrogen or C _1-6 alkyl, more preferably hydrogen or C _1-3 alkyl, further preferably hydrogen or methyl;

R ₂ is selected from hydrogen, deuterium, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, -(CH ₂ ) _n2 C(O)R _AA or -(CH ₂ ) _n2 S(O) ₂ R _AA , preferably hydrogen, C _1-6 alkyl, -(CH ₂ ) _n2 C(O)R _AA or -(CH ₂ ) _n2 S(O) ₂ R _AA , more preferably hydrogen, C _1-3 alkyl, -C(O)R _AA or -S(O) ₂ R _AA , further preferably hydrogen, methyl, -C(O)CH ₃ or -S(O) ₂ -Ph;

R _AA is selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, preferably C _1-6 alkyl or C _6-10 aryl, more preferably C _1-3 alkyl or phenyl, further preferably methyl or phenyl;

R ₃ is each selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl or C _1-6 alkoxy, preferably hydrogen, halogen, cyano or C _1-6 alkyl, more preferably hydrogen, halogen, cyano or C _1-3 alkyl, further preferably hydrogen, fluorine, chlorine, bromine, cyano or methyl;

n is an integer from 0 to 3;

n1 is an integer from 0 to 2; and

n2 is an integer from 0 to 2.

In a further preferred embodiment of the present invention, the general formula (I) is further shown as the general formula (II):

in:

M, R ₁ , R ₂ and R ₃ are as described above.

In a further preferred embodiment of the present invention, the general formula (I) is further shown as the general formula (III):

in:

M is selected from CR ₀ or N;

R ₀ is selected from halogen, cyano, C _1-3 alkyl or C _1-3 haloalkyl, preferably cyano;

R ₁ is selected from halogen, cyano, C _1-3 alkyl, C _1-3 haloalkyl or -NR _aa C(O)R _bb , preferably fluorine, chlorine, bromine, cyano, methyl, trifluoromethyl or -NHC(O)CH ₃ ;

R _aa and R _bb are each independently selected from hydrogen or C _1-3 alkyl, preferably hydrogen or methyl;

R ₂ is selected from hydrogen, C _1-3 alkyl, -C(O) _RAA or -S(O) _{2 RAA} , preferably hydrogen, methyl, -C(O)CH ₃ or -S(O) ₂ -Ph;

R _AA is selected from C _1-3 alkyl or phenyl, preferably methyl or phenyl.

In a further preferred embodiment of the present invention, the general formula (I) is further shown as the general formula (IV):

in:

M is selected from CR ₀ or N;

R ₀ is selected from halogen, cyano, C _1-3 alkyl or C _1-3 haloalkyl, preferably cyano;

R ₁ is selected from halogen, cyano, C _1-3 alkyl, C _1-3 haloalkyl or -NR _aa C(O)R _bb , preferably fluorine, chlorine, bromine, cyano, methyl, trifluoromethyl or -NHC(O)CH ₃ ;

R _aa and R _bb are each independently selected from hydrogen or C _1-3 alkyl, preferably hydrogen or methyl;

R ₂ is selected from hydrogen, C _1-3 alkyl, -C(O) _RAA or -S(O) _{2 RAA} , preferably hydrogen, methyl, -C(O)CH ₃ or -S(O) ₂ -Ph;

R _AA is selected from C _1-3 alkyl or phenyl, preferably methyl or phenyl.

In a further preferred embodiment of the present invention, the general formula (I) is further selected from the following compounds:

In a further preferred embodiment of the present invention, the above-mentioned pharmaceutically acceptable salt is selected from hydrochloride, hydrobromide, sulfate, trifluoroacetate or methanesulfonate, preferably hydrochloride or hydrobromide.

The present invention further provides a method for preparing a compound represented by general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, comprising the following steps:

The compound represented by the general formula (I-1) reacts with the compound represented by the general formula (I-2) to generate the compound represented by the general formula (I-3), which is then subjected to a condensation reaction with the compound represented by the general formula (I-4) to prepare the compound represented by the general formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof;

or,

The compound represented by the general formula (I-1) is directly reacted with the compound represented by the general formula (I-5) to prepare the compound represented by the general formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof;

in:

_X1 and _X2 are halogen, each independently selected from fluorine, chlorine, bromine or iodine.

M, R ₁ , R ₂ , R ₃ and n are as described above.

The present invention further provides a method for preparing a compound represented by general formula (II), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, comprising the following steps:

The compound represented by the general formula (I-1) reacts with the compound represented by the general formula (II-2) to generate the compound represented by the general formula (II-3), which is then subjected to a condensation reaction with the compound represented by the general formula (I-4) to prepare the compound represented by the general formula (II), its stereoisomer or a pharmaceutically acceptable salt thereof;

or,

The compound represented by the general formula (I-1) is directly reacted with the compound represented by the general formula (II-5) to prepare the compound represented by the general formula (II), its stereoisomer or a pharmaceutically acceptable salt thereof;

in:

_X3 and _X4 are halogen, each independently selected from fluorine, chlorine, bromine or iodine.

M, R ₁ , R ₂ and R ₃ are as described above.

The present invention further provides a method for preparing a compound represented by general formula (III), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, comprising the following steps:

The compound represented by the general formula (III-1) reacts with the compound represented by the general formula (II-2) to generate the compound represented by the general formula (III-3), which is then subjected to a condensation reaction with the compound represented by the general formula (I-4) to prepare the compound represented by the general formula (III), its stereoisomer or a pharmaceutically acceptable salt thereof;

or,

The compound represented by the general formula (III-1) is directly reacted with the compound represented by the general formula (II-5) to prepare the compound represented by the general formula (III), its stereoisomer or a pharmaceutically acceptable salt thereof;

in:

_X3 and _X4 are halogen, each independently selected from fluorine, chlorine, bromine or iodine.

M, _R1 and _R2 are as described above.

The present invention further provides a method for preparing a compound represented by general formula (IV), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, comprising the following steps:

The compound represented by the general formula (IV-1) reacts with the compound represented by the general formula (II-2) to generate the compound represented by the general formula (IV-3), which is then subjected to a condensation reaction with the compound represented by the general formula (I-4) to prepare the compound represented by the general formula (IV), its stereoisomer or a pharmaceutically acceptable salt thereof;

or,

The compound represented by the general formula (IV-1) is directly reacted with the compound represented by the general formula (II-5) to prepare the compound represented by the general formula (IV), its stereoisomer or a pharmaceutically acceptable salt thereof;

in:

_X3 and _X4 are halogen, each independently selected from fluorine, chlorine, bromine or iodine.

M, _R1 and _R2 are as described above.

In the above-mentioned synthetic route, the raw material compounds involved can all be commercial products, and most of the key intermediates are directly purchased from commercial suppliers. Some intermediates can be prepared by the following two synthetic routes according to the methods reported in the literature (Zhou N. Bioorg Med Chem Lett. 2009 Mar 1; 19 (5): 1528-31.) (Kumar, A. S. J Chem Sci. 2018, 130, 72.) (Gu ZS. Bioorg Med ChemLett. 2017 Dec 15; 27 (24): 5420-5423.):

Route 1:

Route 2:

in:

_X5 and _X6 are halogen, each independently selected from fluorine, chlorine, bromine or iodine.

M, R ₁ , R ₂ , R ₃ and n are as described above.

The present invention further relates to a pharmaceutical composition comprising a therapeutically effective dose of any one of the compounds shown, its stereoisomers or pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable carriers.

In one embodiment of the present invention, the pharmaceutical composition can be prepared in a conventional manner using one or more pharmaceutically acceptable carriers. The carrier refers to a conventional carrier in the pharmaceutical field, for example: a diluent, an excipient such as water, etc.; a binder such as a cellulose derivative, gelatin, polyvinyl pyrrolidone, etc.; a filler such as starch, etc.; a disintegrant such as calcium carbonate, sodium bicarbonate; a lubricant such as calcium stearate or magnesium stearate, etc. In addition, other adjuvants such as flavoring agents and sweeteners can also be added to the composition. When used for oral administration, it can be prepared into conventional solid preparations such as tablets, powders, lozenges, capsules, suspensions, syrups, etc.; when used for injection, it can be prepared into an injection.

In one embodiment of the present invention, various dosage forms of the pharmaceutical composition can be prepared by conventional methods in the medical field, wherein the content of the active ingredient is 0.1% to 99.5% (by weight).

In one embodiment of the present invention, the pharmaceutical composition is administered to a patient in need of such treatment by oral administration, injection, etc. The dosage is generally 0.02-5 mg/kg (oral) or 0.01-2 mg/kg (injection), which can be determined by the physician based on the clinical test results and the patient's condition, age, etc.

The present invention further relates to the use of any of the compounds shown, their stereoisomers or pharmaceutically acceptable salts, or their pharmaceutical compositions in the preparation of drugs involving or regulating 5-hydroxytryptamine receptors and/or dopamine receptors, preferably in the preparation of drugs involving or regulating 5- _HT1A receptors, dopamine _D2 receptors and/or dopamine _D3 receptors.

The present invention further relates to the use of any of the compounds shown, their stereoisomers or pharmaceutically acceptable salts, or their pharmaceutical compositions in the preparation of drugs for treating central nervous system diseases.

The present invention further relates to a method for preparing a drug for treating central nervous system diseases using any of the compounds shown, their stereoisomers or pharmaceutically acceptable salts, or their pharmaceutical compositions.

The present invention also relates to a method for treating central nervous system diseases associated with mammalian 5-hydroxytryptamine receptors and/or dopamine receptors, which comprises administering to the mammal a therapeutically effective dose of any of the compounds shown, its stereoisomers or pharmaceutically acceptable salts, esters, prodrugs, solvates, hydrates or derivatives thereof, or a pharmaceutical composition thereof.

In some embodiments, the central nervous system diseases involved in the present invention are selected from one or more of Parkinson's disease PD, schizophrenia, bipolar disorder, depression, anxiety, mania, Huntington's disease HD, Alzheimer's disease, senile dementia, Alzheimer's dementia, memory impairment, loss of executive function, vascular dementia, neuropathic pain and functional disorders related to intelligence, learning or memory, preferably Parkinson's disease.

In some preferred embodiments, the central nervous system disease involved in the present invention is Parkinson's disease.

Detailed description of the invention

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood by those of ordinary skill in the art to which the invention belongs. If there is a conflict, the definition provided in the application shall prevail. When a trade name appears in this article, it is intended to refer to the corresponding commodity or its active ingredient. All patents, published patent applications and publications cited herein are incorporated herein by reference.

The term "hydrocarbon chain" refers to a chain group consisting of C and H. The hydrocarbon chain can be saturated or unsaturated, and in a preferred embodiment, the hydrocarbon chain is saturated. The hydrocarbon chain can be straight or branched, and in a preferred embodiment, the hydrocarbon chain is straight. The hydrocarbon chain may optionally contain one or more heteroatoms such as N, O and S. In the case of containing heteroatoms, the heteroatoms may be located on the main chain. In a preferred embodiment, the hydrocarbon chain may be straight or branched, and the hydrocarbon chain is saturated, and the hydrocarbon chain optionally contains one or more heteroatoms such as N, O and S on the main chain. When describing a hydrocarbon chain, whether or not it contains heteroatoms, it can be described by the number of C atoms without counting the number of heteroatoms. For example, C2 _{- C8} or _C2 - _C6 refers to a hydrocarbon chain containing 2-8 or 2-6 carbon atoms, which may optionally contain additional heteroatoms.

The term "alkyl" refers to a straight or branched saturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms, which is connected to the rest of the molecule by a single bond. "Alkyl" can have 1-8 carbon atoms, i.e. "C ₁ -C ₈ alkyl", such as C _1-4 alkyl, C _1-3 alkyl, C _1-2 alkyl, C ₃ alkyl, C ₄ alkyl, C _1-6 alkyl, C _3-6 alkyl. Non-limiting examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl, or 1,2-dimethylbutyl, or the like, or isomers thereof.

The above alkyl group may be optionally substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment. The substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, halogen, mercapto, hydroxyl, nitro, amino, cyano, carboxyl, oxo, cycloalkyl, heterocyclyl, aryl or heteroaryl.

The term "subunit" refers to a group derived from a carbon atom containing a free valence electron by removing a hydrogen atom, and having two attachment sites to the rest of the molecule. For example, "alkylene" or "alkyl subunit" refers to a saturated straight or branched chain divalent hydrocarbon group.

The term "alkylene", when used alone or in combination with other groups herein, refers to a straight or branched saturated divalent hydrocarbon group. For example, the term "C _1-8 alkylene" refers to an alkylene group having 1 to 8 carbon atoms, such as methylene, ethylene, propylene, butylene, pentylene, hexylene, 1-methylethylene, 2-methylethylene, methylpropylene or ethylpropylene, etc. Alkylene can be optionally substituted or unsubstituted, and when substituted, the substituent can be substituted at any available point of attachment, and the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, halogen, mercapto, hydroxyl, nitro, amino, cyano, carboxyl, oxo, cycloalkyl, heterocyclyl, aryl or heteroaryl.

The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl containing 3 to 20 carbon atoms, i.e. "C ₃ -C ₂₀ cycloalkyl", such as C _3-18 cycloalkyl, C _3-16 cycloalkyl, C _3-12 cycloalkyl, C _3-8 cycloalkyl, C _3-6 cycloalkyl, C _3-5 cycloalkyl, C _3-4 cycloalkyl, C _4-8 cycloalkyl, C _4-6 cycloalkyl, C _5-6 cycloalkyl, preferably C _3-8 cycloalkyl, C _3-6 cycloalkyl, C _3-5 cycloalkyl, C _3-4 cycloalkyl. Non-limiting examples of monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, etc.; polycyclic cycloalkyl includes cycloalkyl of spiro ring, condensed ring and bridged ring.

The above cycloalkyl groups can all be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring connected to the parent structure is a cycloalkyl group. The cycloalkyl group can be optionally substituted or unsubstituted, and when substituted, the substituent can be substituted at any available point of attachment, and the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, halogen, mercapto, hydroxyl, nitro, amino, cyano, carboxyl, oxo, cycloalkyl, heterocyclyl, aryl or heteroaryl.

The term "heterocyclyl" refers to a saturated or unsaturated monocyclic or polycyclic hydrocarbon substituent containing 3 to 20 ring atoms, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) _m (wherein m is an integer from 0 to 2), but excluding the ring portion of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon. That is, "3-20 membered heterocyclic group", for example, 3-18 membered heterocyclic group, 3-16 membered heterocyclic group, 3-12 membered heterocyclic group, 3-8 membered heterocyclic group, 3-6 membered heterocyclic group, 3-5 membered heterocyclic group, 3-4 membered heterocyclic group, 4-8 membered heterocyclic group, 4-6 membered heterocyclic group, 5-6 membered heterocyclic group, preferably 3-8 membered heterocyclic group, 3-6 membered heterocyclic group, 3-5 membered heterocyclic group, 3-4 membered heterocyclic group, 4-8 membered heterocyclic group, 4-6 membered heterocyclic group, 5-6 membered heterocyclic group, optionally containing 1-4 heteroatoms, 1-3 heteroatoms or 1-2 heteroatoms, wherein the heteroatom is optionally nitrogen, oxygen or S(O) _m (wherein m is an integer of 0 to 2). Non-limiting examples of monocyclic heterocyclic groups include oxetanyl, thietanyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, piperidinyl, piperazinyl, morpholinyl, 1,3-dioxolanyl, 2,2-difluoro-1,3-dioxolanyl or azepanyl, etc. Non-limiting examples of polycyclic heterocyclic groups include spirocyclic, condensed and bridged heterocyclic groups, wherein the spirocyclic, condensed and bridged heterocyclic groups are optionally connected to other groups through single bonds, or further connected to other cycloalkyl, heterocyclic, aryl and heteroaryl groups through any two or more atoms on the ring.

The above heterocyclic groups can all be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclic group. The heterocyclic group can be optionally substituted or unsubstituted, and when substituted, the substituent can be substituted at any available point of attachment, and the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, halogen, mercapto, hydroxyl, nitro, amino, cyano, carboxyl, oxo, cycloalkyl, heterocyclic, aryl or heteroaryl.

The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or condensed polycyclic group having a conjugated π electron system, preferably 6- to 12-membered, such as phenyl or naphthyl, more preferably phenyl.

The above-mentioned aryl group may be fused to a heteroaryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring, including benzo 5-10 membered heteroaryl, benzo 3-8 membered cycloalkyl and benzo 3-8 membered heterocyclic, preferably benzo 5-6 membered heteroaryl, benzo 3-6 membered cycloalkyl and benzo 3-6 membered heterocyclic. The aryl group may be optionally substituted or unsubstituted, and when substituted, the substituent may be substituted at any available connection point, and the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, halogen, mercapto, hydroxyl, nitro, amino, cyano, carboxyl, oxo, cycloalkyl, heterocyclic, aryl or heteroaryl.

The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen, etc. The heteroaryl group is preferably 5 to 12-membered, more preferably 5 to 6-membered, such as pyrrolyl, imidazolyl, furanyl, pyranyl, thienyl, thiazolyl, thiadiazolyl, pyrazolyl, oxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, etc.

The above heteroaryl groups may be fused to an aryl, cycloalkyl or heterocyclyl ring, wherein the ring connected to the parent structure is a heteroaryl ring. The heteroaryl group may be optionally substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, and the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, halogen, mercapto, hydroxyl, nitro, amino, cyano, carboxyl, oxo, cycloalkyl, heterocyclyl, aryl or heteroaryl.

The term "alkoxy" refers to -O-(alkyl) or -O-(unsubstituted cycloalkyl), wherein alkyl and cycloalkyl are as defined above. Non-limiting examples of alkoxy include: methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, etc. Alkoxy can be optionally substituted or unsubstituted, and when substituted, the substituent can be substituted at any available point of attachment, and the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, halogen, mercapto, hydroxyl, nitro, amino, cyano, carboxyl, oxo, cycloalkyl, heterocyclic radical, aryl or heteroaryl.

The term "alkylthio" refers to -S-(alkyl) or -S-(non-substituted cycloalkyl), wherein alkyl and cycloalkyl are as defined above. Non-limiting examples of alkylthio include: methylthio, ethylthio, propylthio, butylthio, cyclopropylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio, etc. Alkylthio can be optionally substituted or unsubstituted, and when substituted, the substituent can be substituted at any available point of attachment, and the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, halogen, sulfhydryl, hydroxyl, nitro, amino, cyano, carboxyl, oxo, cycloalkyl, heterocyclic radical, aryl or heteroaryl.

The term "alkylamino" refers to -NH-(alkyl or non-substituted cycloalkyl), or -N-(alkyl or non-substituted cycloalkyl)(alkyl or non-substituted cycloalkyl), wherein alkyl and cycloalkyl are as defined above. Non-limiting examples of alkylamino include: methylamino, ethylamino, propylamino, butylamino, cyclopropylamino, cyclobutylamino, cyclopentylamino, cyclohexylamino, etc. Alkylamino can be optionally substituted or unsubstituted, and when substituted, the substituent can be substituted at any available point of attachment, and the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, halogen, sulfhydryl, hydroxyl, nitro, amino, cyano, carboxyl, oxo, cycloalkyl, heterocyclic, aryl or heteroaryl.

The term "halo" or "halogen" or "halo" is understood to mean a fluorine (F), chlorine (Cl), bromine (Br) or iodine (I) atom, preferably a fluorine, chlorine or bromine atom.

The term "deuterated hydrocarbon chain" refers to a hydrocarbon chain substituted with one or more deuteriums, wherein the hydrocarbon chain is as defined above.

The term "deuterated alkyl" refers to an alkyl group substituted with one or more deuterium, wherein alkyl is as defined above.

The term "halogenated hydrocarbon chain" refers to a hydrocarbon chain substituted with one or more halogens, wherein the hydrocarbon chain is as defined above.

The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.

The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.

The term "alkenyl" refers to a chain alkenyl group, also known as an alkene group, wherein the alkene may be further substituted with other related groups.

The term "alkynyl" refers to (CH≡C-), wherein the alkynyl may be further substituted with other relevant groups.

"Hydroxyl" refers to -OH.

"Amino" refers to _-NH2 .

"Cyano" refers to -CN.

"Nitro" refers to _-NO2 .

"Mercapto" refers to -SH.

"Carbonyl" refers to -C(O)-.

"Carboxy" refers to -C(O)OH.

"Oxo" refers to =0.

The terms "include", "comprising", "having", "containing" or "involving" and other variations thereof herein are inclusive or open-ended and do not exclude other unlisted elements or method steps. Those skilled in the art will appreciate that the above terms such as "comprising" encompass the meaning of "consisting of".

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

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

Herein, "Z" and "-Z-" both represent the same specific group and can be used interchangeably.

The expression mn used herein refers to the range of m to n and the sub-ranges consisting of the individual point values therein and the individual point values. For example, the expression " _C2 - _C8 " or " _C2-8 " covers the range of 2-8 carbon atoms and should be understood to also cover any sub-ranges and each point value therein, such as C2 _{- C5} , _C3 - _C4 , _C2 - _C6 , _C3 - _C6 , _C4 - _C6 , _C4 - _C7 , _C4 - _C8 , _C2 - _C5 , etc., as well as _C2 , _C3 , _C4 , _C5 , _C6 , _C7 , _C8 , etc. For example, the expression " _C3 - _C10 " or " _C3-10 " should also be understood in a similar manner, e.g., may encompass any sub-ranges and point values contained therein, such as _C3 - _C9 , _C6 - _C9 , _C6 - _C8 , _C6 - _C7 , _C7 - _C10 , _C7 - _C9 , _C7 - _C8 , _C8 -C9 _, etc., as well as _C3 , _C4 , _C5 , _C6 , _C7 , _C8 , _C9 , _C10 , etc. For another example, the expression "C ₁ -C ₆ " or "C _1-6 " encompasses a range of 1-6 carbon atoms and should be understood to also encompass any subranges and individual point values therein, such as C ₂ -C ₅ , C ₃ -C ₄ , C ₁ -C ₂ , C ₁ -C ₃ , C ₁ -C ₄ , C ₁ -C ₅ , C ₁ -C ₆ , etc., as well as C ₁ , C ₂ , C ₃ , C ₄ , C ₅ , C ₆ , etc. For another example, the expression "three yuan to ten yuan" should be understood to include any sub-ranges therein and each point value, such as three yuan to five yuan, three yuan to six yuan, three yuan to seven yuan, three yuan to eight yuan, four yuan to five yuan, four yuan to six yuan, four yuan to seven yuan, four yuan to eight yuan, five yuan to seven yuan, five yuan to eight yuan, six yuan to seven yuan, six yuan to eight yuan, nine yuan to ten yuan, etc., as well as three, four, five, six, seven, eight, nine, ten yuan, etc. Other similar expressions in this document should also be understood in a similar manner.

The expressions "X is selected from A, B or C", "X is selected from A, B and C", "X is A, B or C", "X is A, B and C" and the like used herein all express the same meaning, that is, X can be any one or more of A, B and C.

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

The terms "substituted" and "substituted" refer to one or more (e.g., one, two, three, or four) hydrogens on the designated atom being replaced by a selection from the indicated group, provided that the normal valence of the designated atom in the current situation is not exceeded and the substitution forms a stable compound. Combinations of substituents and/or variables are permitted only when such combinations form stable compounds. When describing that a substituent does not exist, it should be understood that the substituent can be one or more hydrogen atoms, provided that the structure enables the compound to reach a stable state. When describing that each carbon atom in a group can be optionally replaced by a heteroatom, the condition is that the normal valence of all atoms in the group in the current situation is not exceeded and a stable compound is formed.

If a substituent is described as "optionally substituted with", the substituent may be unsubstituted or substituted. If an atom or group is described as optionally substituted with one or more of the substituent list, one or more hydrogens on the atom or group may be replaced with independently selected, optional substituents. When the substituent is oxo (i.e., =O), it means that two hydrogen atoms are replaced. Unless otherwise specified, as used herein, the point of attachment of a substituent may be from any suitable position of the substituent.

When a bond to a substituent is shown to pass through a bond connecting two atoms in a ring, then such substituent may be bonded to any ring atom in the substitutable ring.

When any variable (e.g., R), as well as variables with labels (e.g., R ₀ , R ₁ , R ₂ , R ₃ , R _AA , R _aa , R _bb, etc.) occurs more than once in a compound composition or structure, its definition at each occurrence is independent at each occurrence. For example, if a group is substituted with 0, 1, 2, 3, or 4 R substituents, then the group may be optionally substituted with up to four R substituents, and the options for each R substituent at each occurrence are independent of each other.

The term "substituted" means that one or more hydrogen atoms on a compound or group are replaced by other atoms or groups. The condition is that a stable valence state or compound is formed. The expression "non-substituted" can also be understood as "not substituted". It should be understood that when the substituent is hydrogen, this can also mean that the corresponding group is "non-substituted" or "not substituted".

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

The hydrogen atoms described in the present invention can all be replaced by their isotope deuterium, and the deuterium isotope content is at least greater than the natural deuterium isotope content. Any hydrogen atom in the embodiment compounds of the present invention can also be replaced by a deuterium atom.

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

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

The term "pharmaceutical composition" refers to a mixture containing one or more compounds of the present invention or their physiologically/pharmaceutically acceptable salts or prodrugs and other chemical components, as well as other components such as physiologically/pharmaceutically acceptable carriers or excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitate the absorption of the active ingredient, and thus exert biological activity.

The term "pharmaceutically acceptable carrier" refers to those substances that have no significant irritation to organisms and do not impair the biological activity and performance of the active compound. "Pharmaceutically acceptable carrier" includes, but is not limited to, glidants, sweeteners, diluents, preservatives, dyes/colorants, flavoring agents, surfactants, wetting agents, dispersants, disintegrants, stabilizers, solvents or emulsifiers.

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

As used herein, the term "treat" includes alleviating, reducing or ameliorating a disease or symptom, preventing other symptoms, ameliorating or preventing the underlying metabolic factors of a symptom, inhibiting a disease or symptom, for example, preventing the development of a disease or symptom, alleviating a disease or symptom, promoting remission of a disease or symptom, or stopping the symptoms of a disease or symptom, and extends to include prevention. "Treatment" also includes achieving a therapeutic benefit and/or a prophylactic benefit. A therapeutic benefit refers to the eradication or improvement of the condition being treated. In addition, a therapeutic benefit is achieved by eradicating or improving one or more physiological signs associated with the underlying disease, and although the patient may still suffer from the underlying disease, an improvement in the patient's disease can be observed. A prophylactic benefit refers to the use of the composition by a patient to prevent the risk of a certain disease, or when a patient takes it when one or more physiological symptoms of a disease occur, although the disease has not yet been diagnosed.

The term "active ingredient", "therapeutic agent", "active substance" or "active agent" refers to a chemical entity that is effective in treating or preventing a target disorder, disease or condition. The term "neuropsychiatric disease" refers to a general term for neurological diseases and psychiatric diseases, including neurological diseases and/or psychiatric diseases.

With respect to a drug, drug unit or active ingredient, the term "effective amount", "therapeutically effective amount" or "prophylactically effective amount" refers to a sufficient amount of the drug or pharmaceutical agent that can achieve the desired effect with acceptable side effects. The determination of the effective amount varies from person to person, depending on the age and general condition of the individual and on the specific active substance. The appropriate effective amount in each case can be determined by a person skilled in the art based on routine experiments.

As used herein, "individual" includes human or non-human animals. Exemplary human individuals include human individuals (referred to as patients) suffering from diseases (e.g., diseases described herein) or normal individuals. "Non-human animals" in the present invention include all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, livestock and/or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).

The following detailed description of the invention is intended to illustrate non-limiting embodiments so that other technical personnel in the art can more fully understand the technical solutions, principles and practical applications of the present invention, so that other technical personnel in the art can modify and implement the present invention in many forms to best adapt it to the requirements of specific uses.

Beneficial Effects

The compounds of the present invention have novel structures, can act on 5-HT _1A receptors, dopamine D ₂ receptors and/or dopamine D ₃ receptors, and exhibit certain (partial) agonist activity. Some compounds exhibit (partial) agonist effects on at least two of the 5-HT _1A receptors, dopamine D ₂ and D ₃ receptors, and in particular, some compounds also exhibit triple (partial) agonist activity on 5-HT _1A receptors, dopamine D ₂ and D ₃ receptors, indicating that they have significant therapeutic effects on central nervous system disorders such as Parkinson's disease, and can be used to prepare drugs for treating central nervous system disorders.

DETAILED DESCRIPTION

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

Example

The embodiments of the present invention will be described in detail below in conjunction with examples, but those skilled in the art will appreciate that the following examples are only used to illustrate the present invention and should not be considered to limit the scope of the present invention. If specific conditions are not specified in the examples, they are carried out according to normal conditions or conditions recommended by the manufacturer. If the manufacturer is not specified for the reagents or instruments used, they are all conventional products that can be obtained commercially. If not otherwise specified, the ratios or percentages used herein are by weight.

The structures of the compounds of the present invention are determined by nuclear magnetic resonance (NMR) and/or liquid chromatography-mass spectrometry (LC-MS).

The nuclear magnetic resonance spectra were measured using a Unity Inova 400 or 600 nuclear magnetic resonance instrument. The chemical shift (δ) was given in parts per million (ppm). The solvents used were deuterated dimethyl sulfoxide (DMSO-d ₆ ) and heavy water (D ₂ O), and the internal standard was tetramethylsilane (TMS). The LC-MS/MS chromatography was measured using an Agilent 1946B ESI-MS mass spectrometer. The high-performance thin-layer chromatography silica gel plate was produced by Shanghai Haohong Biopharmaceutical Technology Co., Ltd., product number C10008, and the specification used by TLC was 2.5*5cm*0.25mm.

General method for synthesis of Examples 1-12:

Dissolve 4-(piperazine-1-yl)-1H-indole compound (6.46mmol) in acetone (20mL), add potassium carbonate (12.92mmol), 1-bromo-2-chloroethane (or 1-bromo-3-chloropropane) (12.92mmol), react at 60℃ for 8h, monitor by TLC until the aryl piperazine compound is completely converted or the raw material does not decrease with the increase of reaction time, stop the reaction, and filter to remove the remaining potassium carbonate. Take the filtrate and remove the solvent by rotary evaporation, add water (15mL), extract with dichloromethane (30mL*3), separate the organic phase, wash with saturated brine, dry with anhydrous sodium sulfate, filter and concentrate to obtain a crude product. The crude product is purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain a chloroalkyl 4-(piperazine-1-yl)-1H-indole compound.

Dissolve substituted chloroalkyl 4-(piperazine-1-yl)-1H-indole compound (1.80mmol, 1.0eq), substituted pyridinol (2.16mmol, 1.0eq), potassium carbonate (4.50mmol, 2.5-3.0eq), potassium iodide (1.80mmol, 1.0eq) in acetonitrile (15mL). Heat to reflux, stir at 85℃ for 5-12h. TLC monitors the reaction to be complete and stops heating. After cooling, filter to remove insoluble salts, and remove the solvent by vacuum distillation. Add water (10mL), extract with dichloromethane (20mL*3), combine the organic phases, wash with saturated brine, dry with anhydrous sodium sulfate, filter, and concentrate to obtain a crude product. The arylalkyl-4-(1H)indolylpiperazine compound was separated and purified by silica gel column chromatography (dichloromethane:methanol=50:1), dissolved in ethyl acetate (10 mL), and ethyl acetate hydrochloride (2N) was added dropwise to obtain arylalkyl-4-(1H)indolylpiperazine hydrochloride in a yield of 30-80%.

Example 1

Preparation of 4-(4-(3-((6-fluoropyridin-3-yl)oxy)propyl)piperazin-1-yl)-1H-indole hydrochloride

Dissolve 0.39 g (3.40 mmol, 1.2 eq) of 2-fluoro-5-hydroxypyridine, 0.78 g (2.8 mmol, 1.0 eq) of 4-(4-(3-chloropropyl)piperazine-1-yl)-1H-indole, 1.2 g (8.4 mmol, 3 eq) of K ₂ CO ₃ , and 0.47 g (2.80 mmol, 1.0 eq) of potassium iodide in 20 mL of acetonitrile, and stir under reflux for 8 h. After cooling, remove the insoluble salt by suction filtration, and remove the solvent by reduced pressure distillation. Add water (10 mL), extract with dichloromethane (20 mL*3), combine the organic phases, wash with saturated brine, and separate. Dry the organic phase with anhydrous sodium sulfate, filter, and concentrate the filtrate to obtain a crude product. The light yellow oil was purified by column chromatography, and 6 mL of ethyl acetate was added to dissolve it. 2M HCl/EtOAc was added dropwise to adjust the pH to <3. The solid precipitated, filtered, and dried in vacuo to obtain 0.60 g of the target product with a yield of 55.0%.

ESI-MS [M+H] ⁺ : m/z 355.2.

¹ H NMR (400MHz, DMSO) δ11.19(s,1H),10.51(s,1H),7.98(dd,J＝3.2,1.8Hz,1H),7.68(ddd,J＝9.5,6.6,3.2Hz ,1H),7.33(t,J＝2.8Hz,1H),7.20(dd,J＝8.9,3.4Hz,1H),7.14(d,J＝8.1Hz,1H),7.04(t ,J＝7.8Hz,1H),6.56(d,J＝7.4Hz,1H),6.49(t,J＝2.7Hz,1H),4.22(t,J＝6.0Hz,2H),3.76(d,J ＝12.8Hz,2H),3.70(d,J＝11.9Hz,2H),3.45-3.30(m,4H),3.17(t,J＝12.3Hz,2H),2.34-2.23(m,2H).

Example 2

Preparation of 7-(4-(3-((6-fluoropyridin-3-yl)oxy)propyl)piperazin-1-yl)-1H-indole hydrochloride

Dissolve 0.10 g (0.87 mmol, 1.2 eq) of 2-fluoro-5-hydroxypyridine, 0.20 g (0.72 mmol, 1.0 eq) of 7-(4-(3-chloropropyl)piperazine-1-yl)-1H-indole, 0.30 g (2.1 mmol, 3 eq) of K ₂ CO ₃ , and 0.12 g (0.72 mmol, 1.0 eq) of potassium iodide in 10 ml of acetonitrile, and stir under reflux for 8 h. After cooling, remove the insoluble salt by suction filtration, and remove the solvent by reduced pressure distillation. Add water (5 mL), extract with dichloromethane (15 mL*3), combine the organic phases, wash with saturated brine, and separate. Dry the organic phase with anhydrous sodium sulfate, filter, and concentrate the filtrate to obtain a crude product. The light yellow oil was purified by column chromatography, dissolved in 3 mL of ethyl acetate, and 2 M HCl/EtOAc was added dropwise to adjust the pH to <3. The solid precipitated, filtered, and dried in vacuo to obtain 0.15 g of the target product with a yield of 53.3%.

ESI-MS [M+H] ⁺ : m/z 355.1.

¹ H NMR (400MHz, DMSO) δ11.09(s,1H),10.51(s,1H),7.98(dd,J＝3.2,1.8Hz,1H),7.68(ddd,J＝9.4,6.6,3.1Hz ,1H),7.38(t,J＝2.8Hz,1H),7.31(d,J＝7.9Hz,1H),7.21(dd,J＝8.9,3.4Hz,1H),6.98(t,J ＝7.7Hz,1H),6.74(d,J＝7.5Hz,1H),6.48(dd,J＝3.1,1.8Hz,1H),4.23(t,J＝6.0Hz,2H),3.72(d,J =11.9Hz,2H),3.58(d,J=12.8Hz,2H),3.47-3.31(m,4H),3.17(t,J=12.0Hz,2H),2.33-2.23(m,2H).

Example 3

Preparation of 4-(4-(3-((6-(trifluoromethyl)pyridin-3-yl)oxy)propyl)piperazin-1-yl)-1H-indole hydrochloride

Dissolve 88mg (0.54mmol, 1.0eq) of 6-(trifluoromethyl)pyridin-3-ol, 150mg (0.54mmol, 1.0eq) of 4-(4-(3-chloropropyl)piperazine-1-yl)-1H-indole, 224mg (1.62mmol, 3.0eq) of K ₂ CO ₃ , and 90mg (0.54mmol, 1.0eq) of potassium iodide in 6mL of acetonitrile, and stir under reflux for 8h. After cooling, remove insoluble salts by suction filtration, and remove the solvent by reduced pressure distillation. Add water (5mL), extract with dichloromethane (15mL*3), combine the organic phases, wash with saturated brine, and separate. Dry the organic phase with anhydrous sodium sulfate, filter, and concentrate the filtrate to obtain a crude product. The light yellow oil was purified by column chromatography, dissolved in 3 mL of ethyl acetate, and 2 M HCl/EtOAc was added dropwise to adjust the pH to <3. The precipitated solid was filtered and dried in vacuo to obtain 81 mg of the target product with a yield of 34.0%.

ESI-MS [M+H] ⁺ : m/z 405.1.

¹ H NMR (400MHz, DMSO) δ11.21(s,1H),10.83(s,1H),8.52(d,J＝2.8Hz,1H),7.93(d,J＝8.8Hz,1H),7.68( dd,J＝8.8,2.9Hz,1H),7.34(t,J＝2.8Hz,1H),7.14(d,J＝8.1Hz,1H),7.04 (t,J＝7.8Hz,1H),6.57(d,J＝7.4Hz,1H),6.50(d,J＝2.8Hz,1H),4.34-4.21(m,3H),3.71(d,J＝ 16.5Hz, 3H), 3.37 (d, J = 12.8Hz, 3H), 3.22 (t, J = 12.1Hz, 2H), 2.43-2.24 (m, 3H).

Example 4

Preparation of 5-(3-(4-(1H-indol-4-yl)piperazin-1-yl)propoxy)-2-cyanopyridine hydrochloride

Dissolve 0.48g (3.89mmol, 1.2eq) of 2-cyano-5-hydroxypyridine, 0.90g (3.24mmol, 1.0eq) of 4-(4-(3-chloropropyl)piperazine-1-yl)-1H-indole, 1.12g (8.10mmol, 2.5eq) of K ₂ CO ₃ , and 0.54g (3.24mmol, 1.0eq) of potassium iodide in 20mL of acetonitrile, and stir under reflux for 6h. After cooling, remove insoluble salts by suction filtration, and remove the solvent by reduced pressure distillation. Add water (10mL), extract with dichloromethane (20mL*3), combine the organic phases, wash with saturated brine, and separate. Dry the organic phase with anhydrous sodium sulfate, filter, and concentrate the filtrate to obtain a crude product. The light yellow oil was purified by column chromatography, dissolved in 6 mL of ethyl acetate, and 2 M HCl/EtOAc was added dropwise to adjust the pH to <3. The solid precipitated, filtered, and dried in vacuo to obtain 0.85 g of the target product with a yield of 65.9%.

ESI-MS [M+H] ⁺ : m/z 362.1.

¹ H NMR (400MHz, DMSO) δ11.20 (s, 1H), 10.50 (s, 1H), 8.51 (d, J = 2.8Hz, 1H), 8.09 (d, J = 8.7Hz, 1H), 7.67 ( dd,J＝8.7,2.9Hz,1H),7.34(t,J＝2.8Hz,1H),7.14(d,J＝8.1Hz,1H),7.04(t,J＝7. 8Hz,1H),6.56(d,J＝7.5Hz,1H),6.49(t,J＝2.6Hz,1H),4.34(t,J＝5.9Hz,2H),3.77-3.70(m,2H), 3.70(d,J＝11.7Hz,2H),3.47-3.29(m,4H),3.17(t,J＝12.2Hz,2H),2.34-2.29(m,2H).

Example 5

Preparation of N-(5-(3-(4-(1H-indol-4-yl)piperazin-1-yl)propoxy)pyridin-2-yl)acetamide hydrochloride

Dissolve 0.13 g (0.87 mmol, 1.2 eq) of 2-acetylamino-5-hydroxypyridine, 0.20 g (0.72 mmol, 1.0 eq) of 4-(4-(3-chloropropyl)piperazine-1-yl)-1H-indole, 0.03 g (2.10 mmol, 3 eq) of K ₂ CO ₃ , and 0.12 g (3.24 mmol, 1.0 eq) of potassium iodide in 6 mL of acetonitrile, and stir under reflux for 8 h. After cooling, remove the insoluble salt by suction filtration, and remove the solvent by reduced pressure distillation. Add water (6 mL), extract with dichloromethane (15 mL*3), combine the organic phases, wash with saturated brine, and separate. Dry the organic phase with anhydrous sodium sulfate, filter, and concentrate the filtrate to obtain a crude product. The light yellow oil was purified by column chromatography, and 6 mL of ethyl acetate was added to dissolve it. 2M HCl/EtOAc was added dropwise to adjust the pH to <3. The solid precipitated, filtered, and dried in vacuo to obtain 0.17 g of the target product with a yield of 55.0%.

ESI-MS [M+H] ⁺ : m/z 394.2.

¹ H NMR (600MHz, D ₂ O) δ8.06 (d, J = 2.8 Hz, 1H), 7.66-7.58 (m, 2H), 7.42 (d, J = 3.2 Hz, 1H), 7.35 (d, J =8.2Hz,1H),7.22(t,J＝7.9Hz,1H),6.78(d,J＝7.5Hz,1H),6.58(dd,J＝3.3,0.9Hz,1H),4. 27(t,J＝5.7Hz,2H),3.91(d,J＝13.6Hz,2H),3.84(d,J＝12.2Hz,2H),3.54-3.49(m,2H),3.43(d,J ＝13.0Hz,2H),3.21(t,J＝12.6Hz,2H),2.39-2.31(m,2H),2.22(s,3H).

Example 6

Preparation of 4-(4-(3-((6-chloropyridin-3-yl)oxy)propyl)piperazin-1-yl)-1H-indole hydrochloride

Dissolve 0.28g (2.16mmol, 1.2eq) of 2-chloro-5-hydroxypyridine, 0.50g (1.80mmol, 1.0eq) of 4-(4-(3-chloropropyl)piperazine-1-yl)-1H-indole, 0.63g (4.50mmol, 2.5eq) of K ₂ CO ₃ , and 0.30g (1.80mmol, 1.0eq) of potassium iodide in 10mL of acetonitrile, and stir under reflux for 12h. After cooling, remove insoluble salts by suction filtration, and remove the solvent by reduced pressure distillation. Add water (5mL), extract with dichloromethane (15mL*3), combine the organic phases, wash with saturated brine, and separate. Dry the organic phase with anhydrous sodium sulfate, filter, and concentrate the filtrate to obtain a crude product. The light yellow oil was purified by column chromatography, and 6 mL of ethyl acetate was added to dissolve it. 2M HCl/EtOAc was added dropwise to adjust the pH to <3. The solid precipitated, filtered, and dried in vacuo to obtain 0.21 g of the target product with a yield of 28.6%.

ESI-MS [M+H] ⁺ : m/z 371.1.

¹ H NMR (400MHz, DMSO) δ11.18 (s, 1H), 10.47 (s, 1H), 8.20 (d, J = 3.0Hz, 1H), 7.56 (dd, J = 8.7, 3.1Hz, 1H), 7.51(d,J＝8.7Hz,1H),7.33(t,J＝2.8Hz,1H),7.14(d,J＝8.1Hz,1H), 7.04(t,J＝7.8Hz,1H),6.56(d,J＝7.4Hz,1H),6.52-6.46(m,1H),4.24(t,J＝5.9Hz,2H),3.80-3.66(m ,4H),3.40-3.31(m,4H),3.17(t,J＝12.2Hz,2H),2.33-2.23(m,2H).

Example 7

Preparation of 4-(4-(3-((6-methylpyridin-3-yl)oxy)propyl)piperazin-1-yl)-1H-indole hydrochloride

Dissolve 0.38g (3.48mmol, 1.2eq) of 3-hydroxy-6-methylpyridine, 0.80g (2.90mmol, 1.0eq) of 4-(4-(3-chloropropyl)piperazine-1-yl)-1H-indole, 1.00g (7.25mmol, 2.5eq) of K ₂ CO ₃ and 0.48g (2.90mmol, 1.0eq) of potassium iodide in 20mL of acetonitrile and stir under reflux for 11h. After cooling, remove insoluble salts by suction filtration and remove the solvent by reduced pressure distillation. Add water (10mL) and extract with dichloromethane (20mL*3). Combine the organic phases, wash with saturated brine and separate. Dry the organic phase with anhydrous sodium sulfate, filter and concentrate the filtrate to obtain a crude product. The light yellow oil was purified by column chromatography, and 6 mL of ethyl acetate was added to dissolve it. 2M HCl/EtOAc was added dropwise to adjust the pH to <3. The solid precipitated, filtered, and dried in vacuo to obtain 313 mg of the target product with a yield of 27.9%.

ESI-MS [M+H] ⁺ : m/z 351.1.

¹ H NMR (600MHz, D ₂ O) δ8.30 (d, J = 2.8 Hz, 1H), 8.07 (dd, J = 9.0, 2.9 Hz, 1H), 7.78 (d, J = 9.0 Hz, 1H), 7.42(t,J＝1.6Hz,1H),7.36(d,J＝8.1Hz,1H),7.22(t,J＝7.9Hz,1H),6.79(d,J＝7.6Hz, 1H),6.58(dd,J＝3.2,1.0Hz,1H),4.34(t,J＝5.7Hz,2H),3.94-3.78(m,5H),3.56-3.51(m,2H),3.48-3.43 (m,2H),3.24-3.21(m,2H),2.69(s,3H),2.44-2.36(m,2H).

Example 8

Preparation of 4-(4-(3-((6-bromopyridin-3-yl)oxy)propyl)piperazin-1-yl)-1H-indole hydrochloride

Dissolve 0.61g (3.48mmol, 1.2eq) of 2-bromo-5-hydroxypyridine, 0.80g (2.90mmol, 1.0eq) of 4-(4-(3-chloropropyl)piperazine-1-yl)-1H-indole, 1.00g (7.25mmol, 2.5eq) of K ₂ CO ₃ , and 0.48g (2.90mmol, 1.0eq) of potassium iodide in 20mL of acetonitrile, and stir under reflux for 11h. After cooling, remove insoluble salts by suction filtration, and remove the solvent by reduced pressure distillation. Add water (10mL), extract with dichloromethane (20mL*3), combine the organic phases, wash with saturated brine, and separate. Dry the organic phase with anhydrous sodium sulfate, filter, and concentrate the filtrate to obtain a crude product. The light yellow oil was purified by column chromatography, and 6 mL of ethyl acetate was added to dissolve it. 2M HCl/EtOAc was added dropwise to adjust the pH to <3. The solid precipitated, filtered, and dried in vacuo to obtain 0.50 g of the target product with a yield of 38.5%.

ESI-MS [M+H] ⁺ : m/z 415.0.

¹ H NMR (600MHz, D ₂ O) δ8.09 (d, J = 3.2 Hz, 1H), 7.59 (d, J = 8.8 Hz, 1H), 7.43-7.41 (m, 2H), 7.40 (d, J ＝3.2Hz,1H),7.38-7.34(m,1H),7.22(t,J＝7.9Hz,1H),6.79(d,J＝7.6Hz,1H),4.25(t,J＝5.7Hz,3H ),3.99-3.63(m,3H),3.54-3.48(m,3H),3.35-3.14(m,2H),2.50-2.24(m,3H).

Example 9

Preparation of 5-(3-(4-(1H-indol-4-yl)piperazin-1-yl)propoxy)-2-fluorobenzonitrile

Dissolve 0.12g (0.87mmol, 1.2eq) of 2-fluoro-5-hydroxybenzonitrile, 0.20g (0.72mmol, 1.0eq) of 4-(4-(3-chloropropyl)piperazine-1-yl)-1H-indole, 0.30g (2.1mmol, 2.5eq) of K ₂ CO ₃ and 0.12g (0.72mmol, 1.0eq) of potassium iodide in 6mL of acetonitrile and stir under reflux for 8h. After cooling, remove insoluble salts by suction filtration and remove the solvent by reduced pressure distillation. Add water (10mL) and extract with dichloromethane (20mL*3). Combine the organic phases, wash with saturated brine and separate the phases. Dry the organic phase with anhydrous sodium sulfate, filter and concentrate the filtrate to obtain a crude product. Purify by column chromatography to obtain 0.14g of the target product with a yield of 51.5%.

ESI-MS [M+H] ⁺ : m/z 423.0.

¹ H NMR (400MHz, DMSO) δ11.06 (s, 1H), 7.57 (dd, J = 5.1, 3.1Hz, 1H), 7.49 (t, J = 9.1Hz, 1H), 7.40 (ddd, J = 9.3 ,4.5,3.2Hz,1H),7.27(s,1H),7.05(d,J＝8.2Hz,1H),6.99(t,J＝7.7Hz,1H),6.47(d,J＝7.4Hz,1H ),6.40(s,1H),4.16-4.12(m,2H),3.21(s,1H),3.20(s,1H),3.18-3.07(m,4H),2.74-2.56(m,4H), 1.98-1.94(m,2H).

Example 10

Preparation of 4-(4-(3-((6-fluoropyridin-3-yl)oxy)propyl)piperazin-1-yl)-1-(phenylsulfonyl)-1H-indole hydrochloride

Sodium hydride (47 mg, 1.90 mmol) was mixed with THF (10 mL), cooled in an ice bath, and then a solution of Example 1 (230 mg, 0.65 mmol) in THF (5 mL) was added and stirred for 15 minutes. After benzenesulfonyl chloride (172 mg, 1.00 mmol) was added dropwise, the mixture was stirred at room temperature for 1 h. After the reaction was completed, ice water was added to quench the mixture, and ethyl acetate (15 mL*2) was used for extraction. The organic phases were combined, washed with saturated brine, and separated. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. A light yellow oil was obtained by column chromatography, dissolved in 3 mL of ethyl acetate, and 2M HCl/EtOAc was added dropwise to adjust the pH to <3. A solid was precipitated, filtered, and dried in vacuo to obtain 0.10 g of the target product with a yield of 29.0%.

ESI-MS [M+H] ⁺ : m/z 495.1.

¹ H NMR (400MHz, DMSO) δ10.50 (s, 1H), 8.05-7.99 (m, 2H), 7.96 (dd, J = 3.2, 1.8Hz, 1H), 7.86 (d, J = 3.8Hz, 1H) ),7.77-7.69(m,1H),7.69-7.60(m,4H),7.31(t,J＝8.1Hz,1H),7.19(dd ,J＝8.9,3.4Hz,1H),6.97(d,J＝3.8Hz,1H),6.85(d,J＝7.8Hz,1H),4.20(t,J＝6.0Hz,2H),3.63(t ,J＝13.5Hz,4H),3.44-3.26(m,4H),3.17(t,J＝11.9Hz,2H),2.27-2.23(m,2H).

Embodiment 11

Preparation of 1-(4-(4-(3-((6-fluoropyridin-3-yl)oxy)propyl)piperazin-1-yl)-1H-indol-1-yl)ethan-1-one hydrochloride

Sodium hydride (37 mg, 0.92 mmol) was mixed with THF (10 mL), cooled in an ice bath, and then a solution of Example 1 (120 mg, 0.31 mmol) in THF (5 mL) was added and stirred for 15 minutes. Acetyl chloride (36 mg, 0.46 mmol) was added dropwise and stirred at room temperature for 1 h. After the reaction was completed, ice water was added to quench and ethyl acetate (15 mL*2) was used for extraction. The organic phases were combined, washed with saturated brine, and separated. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. A light yellow oil was obtained by column chromatography, dissolved in 3 mL of ethyl acetate, and 2M HCl/EtOAc was added dropwise to adjust the pH to <3. A solid was precipitated, filtered, and dried in vacuo to obtain 0.05 g of the target product with a yield of 37.3%.

ESI-MS [M+H] ⁺ : m/z 397.1.

¹ H NMR (600MHz, D ₂ O) δ8.15 (d, J = 8.3 Hz, 1H), 7.87 (dd, J = 3.2, 1.4 Hz, 1H), 7.73 (d, J = 3.9 Hz, 1H), 7.62(ddd,J＝9.3,6.4,3.2Hz,1H),7.41(t,J＝8.1Hz,1H),7.09(dd,J＝9.0,2.6Hz,1H), 7.04(d,J＝7.8Hz,1H),6.83(dd,J＝3.9,0.8Hz,1H),4.26(t,J＝5.7Hz,2H),3.91-3.70(m,4H),3.59-3.48 (m,2H),3.48-3.15(m,4H),2.70(s,3H),2.42-2.26(m,2H).

Example 12

Preparation of 4-(4-(3-((6-fluoropyridin-3-yl)oxy)propyl)piperazin-1-yl)-1-methyl-1H-indole hydrochloride

Dissolve 0.32g (1.50mmol, 1.0eq) of 1-methyl-4-(piperazine-1-yl)-1H-indole, 0.50g (1.5mmol, 1.0eq) of 3-((6-fluoropyridin-3-yl)oxy)propyl 4-methylbenzenesulfonate, and 0.60g (4.5mmol, 3.0eq) of K ₂ CO ₃ in 10ml of acetonitrile, and stir under reflux for 8h. After cooling, remove insoluble salts by suction filtration, and remove the solvent by reduced pressure distillation. Add water (10mL), extract with dichloromethane (20mL*3), combine the organic phases, wash with saturated brine, and separate. Dry the organic phase with anhydrous sodium sulfate, filter, and concentrate the filtrate to obtain a crude product. The light yellow oil was purified by column chromatography, and 3 ml of ethyl acetate was added to dissolve it. 2M HCl/EtOAc was added dropwise to adjust the pH to <3. The solid precipitated, filtered, and dried in vacuo to obtain 0.18 g of a white solid with a yield of 29.6%.

ESI-MS [M+H] ⁺ : m/z 369.2.

¹ H NMR (600 MHz, D ₂ O) δ7.87(dd,J＝3.2,1.4Hz,1H),7.62(ddd,J＝9.3,6.4,3.2Hz,1H),7.33-7.25(m,3H),7.09(dd,J＝9.0,2.6Hz,1H),6.80(dd,J＝7.4,1.0Hz,1H),6.55(dd,J＝3 .1,0.8Hz,1H),4.24(t,J＝5.7Hz,2H),3.91(d,J＝25.3Hz,3H),3.82(s,3H), 3.52-3.45(m,2H),3.46-3.32(m,3H),3.30-3.11(m,2H),2.37-2.29(m,2H) .

Comparative Example 1 (reference patent WO2001049680A1 compound 1a)

Preparation of 4-(4-(3-(2,4-difluorophenoxy)propyl)piperazin-1-yl)-1H-indole hydrochloride

Dissolve 75 mg (0.58 mmol, 1.0 eq) of 2,4-difluorophenol, 0.16 g (0.58 mmol, 1.0 eq) of 4-(4-(3-chloropropyl)piperazine-1-yl)-1H-indole, 0.24 g (1.7 mmol, 3 eq) of K ₂ CO _{3 and} 96 mg (0.58 mmol, 1.0 eq) of potassium iodide in 6 mL of acetonitrile and stir under reflux for 8 h. After cooling, remove the insoluble salt by suction filtration and remove the solvent by reduced pressure distillation. Add water (5 mL) and extract with dichloromethane (15 mL*3). Combine the organic phases, wash with saturated brine and separate the phases. Dry the organic phase with anhydrous sodium sulfate, filter and concentrate the filtrate to obtain a crude product. The light yellow oil was purified by column chromatography, dissolved in 3 mL of ethyl acetate, and 2 M HCl/EtOAc was added dropwise to adjust the pH to <3. The solid precipitated, filtered, and dried in vacuo to obtain 124 mg of the target product with a yield of 52.4%.

ESI-MS [M+H] ⁺ : m/z 372.2.

¹ H NMR (600MHz, DMSO-d6) δ11.21 (s, 1H), 11.13 (s, 1H), 7.31 (tt, J = 8.0, 4.1Hz, 2H), 7.25 (td, J = 9.4, 5.4Hz ,1H),7.13(d,J＝8.1Hz,1H),7.08-6.98(m,2H),6.56(d,J＝7.5Hz,1H),6.49(s,1H),4.17(t,J＝ 6.0Hz,2H),3.71(d,J＝12.6Hz,2H),3.66(d,J＝11.8Hz,2H),3.39-3.31(m,4H),3.30-3.23(m,2H),2.32- 2.24(m,2H).

Comparative Example 2 (reference patent WO2003002552A1 compound 1e)

Preparation of 4-(4-(2-((2-chloropyridin-3-yl)oxy)ethyl)piperazin-1-yl)-1H-indole hydrochloride

Dissolve 3.5mL 1-bromo-2-chloroethane, 0.55g 4-(piperazine-1-yl)-1H-indole and 0.5mL DIPEA in 6mL acetone and stir at 60℃ for 5h. After the reaction is complete, cool to room temperature, add 10mL water, extract with dichloromethane (15mL*3), combine the organic phases, wash with saturated brine, and separate the liquids. The organic phase is dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated to obtain a crude product. Purification by column chromatography gave 360mg of 4-(4-(3-chloroethyl)piperazine-1-yl)-1H-indole with a yield of 26.1%.

Dissolve 180 mg (1.4 mmol, 1.0 eq) of 2-chloro-3-hydroxypyridine, 0.36 g (1.4 mmol, 1.0 eq) of 4-(4-(3-chloroethyl)piperazine-1-yl)-1H-indole, 0.58 g (4.2 mmol, 3 eq) of K ₂ CO ₃ , and 0.23 g (1.4 mmol, 1.0 eq) of potassium iodide in 6 mL of acetonitrile, and stir under reflux for 12 h. After cooling, remove the insoluble salt by suction filtration, and remove the solvent by reduced pressure distillation. Add water (10 mL), extract with dichloromethane (20 mL*3), combine the organic phases, wash with saturated brine, and separate. Dry the organic phase with anhydrous sodium sulfate, filter, and concentrate the filtrate to obtain a crude product. The light yellow oil was purified by column chromatography, dissolved in 3 mL of ethyl acetate, and 2 M HCl/EtOAc was added dropwise to adjust the pH to <3. The solid precipitated, filtered, and dried in vacuo to obtain 92 mg of the target product with a yield of 16.7%.

ESI-MS [M+H] ⁺ : m/z 357.1.

¹ H NMR (600MHz, DMSO-d6) δ11.75(s,1H),11.24(s,1H),8.05(dd,J＝4.7,1.4Hz,1H),7.71(dd,J＝8.2,1.5Hz ,1H),7.46(dd,J＝8.2,4.6Hz,1H),7.32(t,J＝2.8Hz,1H),7.14(d,J＝8 .0Hz,1H),7.02(t,J＝7.8Hz,1H),6.61(d,J＝7.6Hz,1H),6.52(s,1H),4.68(t,J＝5.0Hz,2H),3.77 (d,J＝12.0Hz,2H),3.76-3.74(m,3H),3.74-3.70(m,3H),3.62-3.46(m,2H).

Comparative Example 3 (reference patent WO2007026959A2 Example 40)

Preparation of 1-(Benzo[b]thiophen-4-yl)-4-(3-((6-methylpyridin-3-yl)oxy)propyl)piperazine hydrochloride

After 1-(Benzo[b]thiophen-4-yl)piperazine hydrochloride was freed in a dichloromethane solution, 1-bromo-3-chloropropane was added and the general method was followed to obtain 1-(Benzo[b]thiophen-4-yl)-4-(3-chloropropyl)piperazine as a white solid in a yield of 61%.

Dissolve 371 mg 1-(Benzo[b]thiophene-4-yl)-4-(3-chloropropyl)piperazine (3.4 mmol, 1 eq) and 1 g 2-methyl-5-hydroxypyridine (3.4 mmol, 1 eq) in acetonitrile (50 mL). Add 1.4 g potassium carbonate (10.2 mmol, 3 eq) and 564 mg potassium iodide (3.4 mmol, 1 eq), and stir under reflux for 8 h. After cooling, remove insoluble salts by suction filtration, and remove the solvent by reduced pressure distillation. Add water (15 mL), extract with dichloromethane (25 mL*3), combine the organic phases, wash with saturated brine, and separate. Dry the organic phase with anhydrous sodium sulfate, filter, and concentrate the filtrate to obtain a crude product. The light yellow oil was purified by column chromatography, and 3 mL of ethyl acetate was added to dissolve it. 2M HCl/EtOAc was added dropwise to adjust the pH to <3. The solid precipitated, filtered, and dried in vacuo to obtain 530 mg of the target product with a yield of 38.6%.

ESI-MS [M+H] ⁺ : m/z 368.2.

¹ H NMR (400MHz, DMSO) δ10.96 (s, 1H), 8.47 (s, 1H), 7.92 (s, 1H), 7.82 (d, J = 5.6Hz, 1H), 7.75 (d, J = 8.1 Hz,1H),7.69(d,J＝8.6Hz,1H),7.54(d,J＝5.6Hz,1H),7.37(t,J＝7.9Hz,1H),7.0 2(d,J＝7.5Hz,1H),4.32(t,J＝6.0Hz,2H),3.70(d,J＝11.7Hz,2H),3.64-3.59(m,1H),3.59-3.56(m ,1H),3.41-3.37(m,4H),3.29(t,J＝12.1Hz,2H),2.62(s,3H),2.37-2.29(m,2H).

Biological test evaluation

The present invention is further described and explained below in conjunction with test examples, but these embodiments are not intended to limit the scope of the present invention.

Test Example 1: In vitro 5-HT _1A receptor function test of the compounds of the present invention

1.1 Experimental Materials

1.1.1 Cell information: HEK293/ _5HT1A , constructed in-house.

1.1.2 Experimental reagents and consumables:

1.1.3 Experimental instruments:

name supplier model Cell Counter Countstar BioTech EnVision Multi-Mode Plate Reader PerkinElmer 2105 Milli-Q Ultrapure Water Analyzer Millipore IQ 7000 Centrifuge Cence TDZ5-WS Picoliter Micro-Doser Tecan D300e

1.2 Experimental methods

(1) Compound preparation: The test compound and 5HT were diluted to 0.1 mM using stimulation buffer.

(2) Experimental buffer preparation: Dilute 5× stimulation buffer to 1× with ddH ₂ O, add IBMX to a final concentration of 0.5 mM, mix well and set aside.

(3) Digest the cells with trypsin, centrifuge after termination, resuspend the cell pellet in 10 mL of preheated HBSS, centrifuge, add 1 mL of stimulation buffer and resuspend, and take 20 μL for cell counting.

(4) Take an appropriate amount of cell suspension and dilute it to 0.6×10 ⁶ cells/mL. Add 5 μL of cell suspension to each well of the cell plate and centrifuge at 1000 rpm for 1 minute.

(5) Use bravo to dilute and transfer compounds: dilute the compounds 4-fold at 8 points on the compound plate; then use bravo to transfer the entire plate of diluted compounds to a 384 white plate and centrifuge at 1000 rpm for 1 minute.

(6) Block the test plate and incubate at room temperature for 15 minutes.

(7) Forskolin prepared in DMSO was added using Tecan D300e. The stock solution was 0.2 mM and the final concentration was 1 μM. The mixture was centrifuged at 1000 rpm for 1 min.

(8) Seal the plate and incubate at room temperature for 45 minutes.

(9) Preparation of cAMP standard curve: The starting concentration is 2848 nM, and 8 points of 4-fold serial dilution are performed. 10 μL is added to the experimental plate, and the highest point concentration is 712 nM.

(10) Add 5 μL of cAMP-d2 solution (the stock solution was diluted with lysis buffer at a ratio of 1:20) to the experimental plate and centrifuge at 1000 rpm for 1 min.

(11) Then, add 5 μL of Anti-cAMP-Cryptate solution (the stock solution was diluted with lysis buffer at a ratio of 1:20) to the experimental plate and centrifuge at 1000 rpm for 1 minute.

(12) The test plate was incubated at room temperature for 1 hour and centrifuged at 1000 rpm for 1 minute before reading.

(13) The plate was read using Envision. The excitation light was 320 nm, and the emission light was 620 nm and 665 nm. The exported data were analyzed and processed to calculate the maximum activation rate E _max and EC ₅₀ of the compound.

1.3 Experimental results: see Table 1.

Table 1 Results of the experimental study on the effect of the compounds of the present invention on the 5-HT _1A receptor function

1.4 Experimental conclusion:

According to the results in Table 1 above, it can be seen that the compounds of the present invention can act on 5-HT _1A receptors and exhibit good 5-HT _1A receptor (partial) agonist activity.

Test Example 2: In vitro dopamine _D2L receptor function test of the compound of the present invention

2.1 Experimental Materials

2.1.1 Cell information:

Cell Name supplier HEK293/D _2L GenScript Biotech Corporation

2.1.2 Experimental reagents and consumables:

2.1.3 Experimental instruments:

name supplier model Cell Counter Countstar BioTech EnVision Multi-Mode Plate Reader PerkinElmer 2105 Milli-Q Ultrapure Water Analyzer Millipore IQ 7000 Centrifuge Cence TDZ5-WS Picoliter Micro-Doser Tecan D300e

2.2 Experimental methods

(1) Compound preparation: The test compound and dopamine were diluted to 200 nM for later use.

(2) Experimental buffer preparation: Dilute 5× stimulation buffer to 1× with ddH ₂ O, add IBMX to a final concentration of 0.5 mM, mix well and set aside.

(3) Digest the cells with trypsin, centrifuge after termination, resuspend the cell pellet with 10 mL of preheated HBSS, centrifuge, and then add

Resuspend in 1mL stimulation buffer and take 20μL for cell counting.

(4) Take an appropriate amount of cell suspension and dilute it to 0.4×10 ⁶ cells/mL. Add 5 μL of cell suspension to each well of the cell plate and centrifuge at 1000 rpm for 1 minute.

(5) Use bravo to dilute and transfer compounds: dilute the compounds 4-fold at 8 points on the compound plate; then use bravo to transfer the entire plate of diluted compounds to a 384 white plate and centrifuge at 1000 rpm for 1 minute.

(6) Block the test plate and incubate at room temperature for 15 minutes.

(7) Forskolin prepared in DMSO was added using Tecan D300e. The stock solution was 0.2 mM and the final concentration was 0.25 μM. 25.1 nL of forskolin was added to each well and centrifuged at 1000 rpm for 1 min.

(8) Seal the plate and incubate at room temperature for 45 minutes.

(9) Preparation of cAMP standard curve: The starting concentration is 2848 nM, and 8 points of 4-fold serial dilution are performed. 10 μL is added to the experimental plate, and the highest point concentration is 712 nM.

(10) Add 5 μL of cAMP-d2 solution (the stock solution was diluted with lysis buffer at a ratio of 1:20) to the experimental plate and centrifuge at 1000 rpm for 1 min.

(11) Then, add 5 μL of Anti-cAMP-Cryptate solution (the stock solution was diluted with lysis buffer at a ratio of 1:20) to the experimental plate and centrifuge at 1000 rpm for 1 minute.

(12) The test plate was incubated at room temperature for 45 min and centrifuged at 1000 rpm for 1 min before reading.

(13) The plate was read using Envision. The excitation light was 320 nm, and the emission light was 620 nm and 665 nm. The exported data were analyzed and processed to calculate the maximum activation rate Emax and _EC50 of the compound.

2.3 Experimental results: see Table 2.

Table 2 Results of the experimental study on the function of the compounds of the present invention on _D2 receptors

2.4 Experimental conclusion:

According to the results in Table 2 above, it can be seen that the compounds of the present invention can act on dopamine _D2 receptors and show good dopamine _D2 receptor (partial) agonist activity.

Test Example 3: In vitro dopamine _D3 receptor function test of the compound of the present invention

3.1 Experimental Materials

3.1.1 Cell information: CHO-K1/D ₃ /CRE, constructed in-house.

3.1.2 Experimental reagents and consumables:

3.1.3 Experimental instruments:

name supplier model Cell Counter Countstar BioTech EnVision Multi-Mode Plate Reader PerkinElmer 2105 Milli-Q Ultrapure Water Analyzer Millipore IQ 7000 Centrifuge Cence TDZ5-WS Picoliter Micro-Doser Tecan D300e

3.2 Experimental methods

Day 1: Cell plating

(1) The cultured cells were digested with trypsin. After the digestion of the culture medium was terminated, the cell suspension was transferred to a centrifuge tube and centrifuged at 750

Centrifuge at rpm for 5 minutes.

(2) Discard the supernatant, resuspend the pellet in an appropriate amount of plating medium, and take 20 μL to count the cells using a cell counter.

(3) Take an appropriate amount of cell suspension and dilute it to 0.5×10 ⁶ cells/mL. Add 20 μL of cell suspension to each well of the cell plate (cell density is 10,000 cells/well).

(4) The cell plate was incubated overnight at 5% CO ₂ /37°C.

Day 2: Experimental testing

(1) The test compound was diluted to 0.2 mM using DMSO, and the reference compound Dopamine was diluted to 0.02 mM.

(2) Use Bravo to dilute the compounds (8 concentration points, 4-fold dilution), the starting concentration of the test compound is 5 μM, and the reference compound is 500 nM; then take 5 μL and add it to the cell plate, the final reaction concentration of the test compound is 1 μM, and the final reaction concentration of the reference compound is 100 nM. The positive control well is 100 nM Dopamine, and the negative control well is an equal volume of DMSO.

(3) Centrifuge at 1000 rpm for 1 minute and incubate at 5% CO ₂ /37°C for 30 minutes.

(4) Use Tecan-D300e to transfer 40 nL of 0.2 mM Forskolin DMSO solution to the cell plate, with a final concentration of 0.4 μM. Blank group: cells were added but no Forskolin was added.

(5) Centrifuge at 1000 rpm for 1 minute and incubate at 5% CO ₂ /37°C for 4 hours.

(6) Take out the lysis buffer 30 minutes in advance, thaw it in a room temperature water bath and return it to room temperature. Take out an appropriate amount of substrate and dilute it with the lysis buffer at a ratio of 1:50, mix well and set aside.

(7) Add 20 μL of detection reagent and centrifuge at 1000 rpm for 1 minute.

(8) After incubation at room temperature for 3 minutes, the plate was read using Envision. The ultrasensitive chemiluminescence detection program was selected. The exported data was analyzed and processed to calculate the maximum activation rate E _max and EC ₅₀ of the compound.

3.3. Experimental results: see Table 3.

Table 3 Results of the experimental study on the function of the compounds of the present invention on _D3 receptors

3.4 Experimental conclusion:

According to the results in Table 3 above, it can be seen that the compounds of the present invention can act on dopamine _D3 receptors and show good dopamine _D3 receptor (partial) agonist activity.

Based on the in vitro test results in Tables _1-3 above, _it is shown that the compounds of the present invention have the characteristics of acting on multiple targets of _D2 , _D3 and/or 5- _HT1A , and exhibit receptor (partial) agonist activity on _D2 , _D3 and/or 5- _HT1A receptors, among which Examples 1, 3-4, 6-9, 11-12 have agonist effects on at least two of the targets of D2, D3 and/or 5- _HT1A , and in particular, Examples 1, 4 and 11 exhibit triple (partial) agonist activity on 5- _HT1A receptor, dopamine _D2 and _D3 receptors.

Test Example 4: In vitro liver microsome experiment of the compound of the present invention

4.1 Experimental Purpose

The first-phase metabolic stability of the compounds of the present invention was evaluated in CD-1 mice, SD rats and human liver microsomes.

4.2 Experimental Materials

(1) Experimental reagents:

Reagents supplier model Potassium Hydrogen Phosphate Trihydrate Greagent 01031670 Potassium dihydrogen phosphate Greagent 01115129 Phosphoric acid Greagent 01113527 Testosterone Dr.E 01279087 Dimethyl sulfoxide Sigma D8418 Buspirone TRC B689850 Acetonitrile Fisher A9984 CD-1 mouse liver microsomes RILD LQDL LM-XS-02M SD rat liver microsomes RILD DMXD LM-DS-02M Human liver microsomes Corning 452117 NADP Aladdin N113163 G6P Shanghai Yuanye S11024 MgCl ₂ Greagent 01115966 G6PDH Shanghai Yuanye S10078

(2) Experimental instruments:

name supplier model Liquid Phase SCIEX Exion LC ^tm Mass spectrometry SCIEX Triple Qvad 5500 Centrifuge Thermo Fisher 75009915 Shaking machine Thermo Scientific 88882006

4.3 Experimental methods

(1) Preparation of buffer solution: Dissolve 73.21 g of potassium phosphate trihydrate and 10.78 g of potassium dihydrogen phosphate in 4000 mL of ultrapure water. Use 10% phosphoric acid or 1 M potassium hydroxide to adjust the pH value of the solution to 7.40 ± 0.10, with a final concentration of 100 mM.

(2) Solution preparation and dilution: Prepare a 10 mM stock solution of the test compound using dimethyl sulfoxide (DMSO), store it at 4°C, and dilute it with pure acetonitrile to a working solution concentration of 100 μM before use. Prepare a 10 mM stock solution of the control compound testosterone using DMSO, store it at -20°C, and dilute it with pure acetonitrile to a working solution concentration of 400 μM before use.

(3) Preparation of stop solution: The stop solution is acetonitrile containing internal standard buspirone. The prepared stop solution is stored in a refrigerator at 2-8°C.

(4) Preparation of liver microsome solution: Dilute microsomes of various species (CD-1 mouse, SD rat and human) into 20× working solution with 100 mM potassium phosphate buffer. The final concentration of microsomes in the reaction system is 0.5 mg/mL.

(5) Preparation of reduced nicotinamide adenine dinucleotide phosphate (NADPH) regeneration system: Weigh appropriate amounts of nicotinamide adenine dinucleotide phosphate (NADP), glucose-6-phosphate (G6P), magnesium chloride (MgCl ₂ ) and 6-phosphoglucose dehydrogenase (G6PDH) to prepare stock solutions with concentrations of 65.33 mM, 330 mM, 300 mM and 250 Units/mL, respectively. Add the above four stock solutions to an appropriate amount of buffer and gently mix them upside down. The final concentrations in the NADPH regeneration system are: 2.65 mM NADP, 10.2 mM G6P, 6.12 mM MgCl ₂ and 2.45 Units/mL G6PDH.

(6) Incubation process: The incubation was completed in a 96-well plate. Several incubation plates were prepared and named T0, T5, T10, T20, T40, T60, PB60 and NCF60. The reaction time points corresponding to the first 6 plates were 0, 5, 10, 20, 40 and 60 minutes, respectively. In the NCF60 plate, potassium phosphate buffer was used instead of NADPH regeneration system solution for incubation for 60 minutes. In the PB60 plate, potassium phosphate buffer was used instead of liver microsomes for incubation for 60 minutes. All condition samples were in triplicate.

Add 2 μL of the test compound or control compound and 100 μL of microsomal working solution (containing 1 mg/mL liver microsomal protein) to the T0, T5, T10, T20, T40, T60 and NCF60 plates, add 2 μL of the test compound and 100 μL of potassium phosphate buffer to the PB60 plate, and then place the above incubation plates in a 37°C water bath for preincubation for approximately 5 minutes.

After the pre-incubation, the T0 sample was first added with 600 μL of stop solution and then 98 μL of NADPH regeneration system working solution, the plate was sealed, and after shaking, it was waited for processing with subsequent samples. In addition to adding 98 μL of potassium phosphate buffer to each sample well of NCF60, 98 μL of NADPH regeneration system working solution was added to each sample well of other incubation plates to start the reaction. The final concentrations of the test compound and the control compound in the reaction system were 1 μM and 4 μM, respectively, the concentration of liver microsomes was 0.5 mg/mL, and the final concentrations of DMSO and acetonitrile in the reaction system were 0.01% (v/v) and 0.99% (v/v), respectively.

After incubation for an appropriate time (e.g., 5, 10, 20, 40, and 60 minutes), 600 μL of the stop solution containing the internal standard was added to each well of the test compound sample and the control compound to terminate the reaction, the plate was sealed, shaken, and centrifuged at 4°C, 4000×g for 15 minutes. The supernatant was taken into a 96-well sample receiving plate, diluted with an appropriate amount of pure water, shaken, and used for LC-MS/MS analysis. The software Analyst 7.1 (Sciex, Framingham, Massachusetts, USA) was used for data processing. 4.4 Experimental results: The results of the in vitro liver microsome stability test are shown in Table 4.

Table 4 In vitro liver microsome stability test results

Note: The clearance classification standards are shown in the following table:

4.5 Experimental conclusion:

The above data show that Example 1 of the present invention is cleared at a medium rate in the liver microsomes of SD rats and CD-1 mice, and at a low rate in the liver microsomes of humans; while Comparative Example 3 is cleared at a high rate in the liver microsomes of the three species. Based on the pharmacodynamic activity and pharmacological mechanism of this series of compounds, a slower metabolic rate is conducive to the compounds exerting their pharmacodynamic activity, so the compounds of the present invention are significantly better than the comparative example compounds in terms of metabolic rate.

Test Example 5: Effect of the Compound of the Invention on Tacrine-Induced Mandibular Tremor in Rats

5.1 Experimental Purpose:

The efficacy of the compounds of the present invention was evaluated by using a rat jaw tremor model induced by intraperitoneal injection of tacrine.

5.2 Experimental plan:

(1) Experimental materials:

Test compound: Compound of the present invention, homemade.

Positive control compound: rotigotine, TargetMoI, 153266.

Modeling drugs: tacrine, SIGMA, A3773-1G.

Solvent: Normal saline, Chenxin Pharmaceutical Co., Ltd., 2111060723.

DMSO: SIGMA, D2650-100ML.

(2) Main instruments:

(3) Experimental animals:

Experimental animals: Sprague Dawley rats, male, 6 rats/group, Shanghai Slake Laboratory Animal Co., Ltd.

(4) Medication information:

Drug preparation: Take the test compound, add the solvent and perform sonication.

Route and method of administration: administered by intraperitoneal injection.

Frequency and duration of administration: Single administration.

The animals were stratified by body weight and randomly divided into a model group, a drug-treated group, and a control group. Detailed drug administration information is shown in the following table:

(5) Experimental methods:

Rats were randomly divided into model group, drug group and control group according to body weight. Rats were trained for adaptation three days before the experiment. On the day of the experiment, the solvent or drug was injected intraperitoneally first, and 30 minutes later, 5 mg/kg (body weight) of tacrine was injected intraperitoneally. After drug administration, the rats were placed in a transparent observation box, and the mandibular tremor count was started 10 minutes later. The continuous counting time was 5 minutes, and the number of mandibular tremors of the rats within 5 minutes was recorded.

(6) Data processing and statistics:

Experimental data Inhibition rate % = 100% * (number of mandibular tremors in model group rats - number of mandibular tremors in drug-treated group rats) / number of mandibular tremors in model group rats

5.3 Experimental results: as shown in Table 5.

Table 5 Experimental results of the effects of the compounds of the present invention on the jaw tremor behavior induced by tacrine in rats

Group Inhibition rate@3mg/kg Inhibition rate@10mg/kg Example 1-A 99.9% - Rotigotine - 80.2%

5.4 Experimental conclusion:

Through the above scheme, it can be concluded that Example 1 of the present invention can significantly inhibit the jaw tremor of rats induced by tacrine, and compared with rotigotine, the compound of the present invention has a stronger efficacy and has a potential anti-Parkinson's effect.

Claims (11)

1. A compound represented by general formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof: in: M is selected from CR ₀ or N; R _O is selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl or C _1-6 alkoxy, preferably halogen , cyano, C _1-6 alkyl or C _1-6 haloalkyl, more preferably halogen, cyano, C _1-3 alkyl or C _1-3 haloalkyl, more preferably cyano; R ₁ is selected from halogen, hydroxyl, cyano, amino, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 alkoxy or -(CH ₂ ) _n1 NR _aa C(O)R _bb , preferably halogen, cyano, C _1-6 alkyl, C _1-6 haloalkyl or -(CH ₂ ) _n1 NR _aa C(O)R _bb , more preferably halogen, cyano , C _1-3 alkyl, C _1-3 haloalkyl or -NR _aa C(O)R _bb , more preferably fluorine, chlorine, bromine, cyano, methyl, trifluoromethyl or -NHC(O)CH ₃ ; R _aa and R _bb are each independently selected from hydrogen, deuterium, C _1-6 alkyl, C _1-6 deuterated alkyl or C _1-6 haloalkyl, preferably hydrogen or C _1-6 alkyl, more preferably hydrogen Or C _1-3 alkyl, more preferably hydrogen or methyl; R ₂ is selected from hydrogen, deuterium, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, -(CH ₂ ) _n2 C(O)R _AA or -(CH ₂ ) _n2 S(O) ₂ R _AA , preferably hydrogen, C _1-6 alkyl, -(CH ₂ ) _n2 C(O)R _AA or -(CH ₂ ) _n2 S(O) ₂ R _AA , more preferably hydrogen, C _1-3 alkyl, -C(O)R _AA or -S(O) ₂ R _AA , further preferably hydrogen, methyl, -C(O)CH ₃ or -S(O ) ₂ -Ph; _RAA is selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl, cycloalkyl, heterocyclyl, aryl Or heteroaryl, preferably C _1-6 alkyl or C _6-10 aryl, more preferably C _1-3 alkyl or phenyl, further preferably methyl or phenyl; _R is selected from hydrogen, deuterium, halogen, hydroxyl, cyano, amino, C _1-6 alkyl, C _1-6 deuterated alkyl, C _1-6 haloalkyl or C _1-6 alkoxy, preferably hydrogen , halogen, cyano or C _1-6 alkyl, more preferably hydrogen, halogen, cyano or C _1-3 alkyl, further preferably hydrogen, fluorine, chlorine, bromine, cyano or methyl; n is an integer from 0 to 3; n1 is an integer from 0 to 2; and n2 is an integer of 0-2. 2. the compound shown in general formula (I) according to claim 1, its stereoisomer or its pharmaceutically acceptable salt, it is characterized in that, general formula (I) is further described in general formula (II) Show: in: M, R ₁ , R ₂ and R ₃ are as described in claim 1. 3. according to the compound represented by general formula (I) described in claim 1 or 2, its stereoisomer or its pharmaceutically acceptable salt, it is characterized in that, general formula (I) is further as general formula (III) ) as shown: in: M is selected from CR ₀ or N; _R is selected from halogen, cyano, C _1-3 alkyl or C _1-3 haloalkyl, preferably cyano; R ₁ is selected from halogen, cyano, C _1-3 alkyl, C _1-3 haloalkyl or -NR _aa C(O)R _bb , preferably fluorine, chlorine, bromine, cyano, methyl, trifluoromethyl or -NHC(O) _CH3 ; R _aa and R _bb are each independently selected from hydrogen or C _1-3 alkyl, preferably hydrogen or methyl; R ₂ is selected from hydrogen, C _1-3 alkyl, -C(O)R _AA or -S(O) ₂ R _AA , preferably hydrogen, methyl, -C(O)CH ₃ or -S(O) ₂ -Ph; R _AA is selected from C _1-3 alkyl or phenyl, preferably methyl or phenyl. 4. according to the compound represented by general formula (I) described in claim 1 or 2, its stereoisomer or its pharmaceutically acceptable salt, it is characterized in that, general formula (I) is further as general formula (IV ) as shown: in: M is selected from CR ₀ or N; _R is selected from halogen, cyano, C _1-3 alkyl or C _1-3 haloalkyl, preferably cyano; R ₁ is selected from halogen, cyano, C _1-3 alkyl, C _1-3 haloalkyl or -NR _aa C(O)R _bb , preferably fluorine, chlorine, bromine, cyano, methyl, trifluoromethyl or -NHC(O) _CH3 ; R _aa and R _bb are each independently selected from hydrogen or C _1-3 alkyl, preferably hydrogen or methyl; R ₂ is selected from hydrogen, C _1-3 alkyl, -C(O)R _AA or -S(O) ₂ R _AA , preferably hydrogen, methyl, -C(O)CH ₃ or -S(O) ₂ -Ph; R _AA is selected from C _1-3 alkyl or phenyl, preferably methyl or phenyl. 5. according to the compound shown in the general formula (I) described in any one of claim 1-4, its stereoisomer or its pharmaceutically acceptable salt, it is characterized in that, be selected from following compound: 4-(4-(3-((6-fluoropyridin-3-yl)oxy)propyl)piperazin-1-yl)-1H-indole, 7-(4-(3-((6-fluoropyridin-3-yl)oxy)propyl)piperazin-1-yl)-1H-indole, 4-(4-(3-((6-(trifluoromethyl)pyridin-3-yl)oxy)propyl)piperazin-1-yl)-1H-indole, 5-(3-(4-(1H-indol-4-yl)piperazin-1-yl)propoxy)-2-cyanopyridine, N-(5-(3-(4-(1H-indol-4-yl)piperazin-1-yl)propoxy)pyridin-2-yl)acetamide, 4-(4-(3-((6-chloropyridin-3-yl)oxy)propyl)piperazin-1-yl)-1H-indole, 4-(4-(3-((6-methylpyridin-3-yl)oxy)propyl)piperazin-1-yl)-1H-indole, 4-(4-(3-((6-bromopyridin-3-yl)oxy)propyl)piperazin-1-yl)-1H-indole, 5-(3-(4-(1H-indol-4-yl)piperazin-1-yl)propoxy)-2-fluorobenzonitrile, 4-(4-(3-((6-fluoropyridin-3-yl)oxy)propyl)piperazin-1-yl)-1-(benzenesulfonyl)-1H-indole, 1-(4-(4-(3-((6-fluoropyridin-3-yl)oxy)propyl)piperazin-1-yl)-1H-indol-1-yl)ethan-1-one or 4-(4-(3-((6-fluoropyridin-3-yl)oxy)propyl)piperazin-1-yl)-1-methyl-1H-indole. 6. according to the compound represented by the general formula (I) described in any one of claim 1-5, its stereoisomer or its pharmaceutically acceptable salt, it is characterized in that, the pharmaceutically acceptable The salt is selected from hydrochloride, hydrobromide, sulfate, trifluoroacetate or methanesulfonate, preferably hydrochloride or hydrobromide. 7. A method for preparing a compound represented by the general formula (I) described in any one of claims 1-6, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that it comprises the following steps : The compound shown in general formula (I-1) reacts with the compound shown in general formula (I-2), generates the compound shown in general formula (I-3), then with the compound shown in general formula (I-4) Carrying out a condensation reaction to prepare a compound represented by general formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof; or, The compound represented by the general formula (I-1) is directly reacted with the compound represented by the general formula (I-5) to obtain the compound represented by the general formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof; in: _X1 and _X2 are halogen, each independently selected from fluorine, chlorine, bromine or iodine. M, R ₁ , R ₂ , R ₃ and n are as described in claim 1. 8. A pharmaceutical composition, comprising the compound represented by the general formula (I) described in any one of claims 1-6 in a therapeutically effective dose, its stereoisomer or its pharmaceutically acceptable salt and One or more pharmaceutically acceptable carriers. 9. according to the compound shown in the general formula (I) described in any one of claim 1-6, its stereoisomer or its pharmaceutically acceptable salt, or the pharmaceutical composition described in claim 8 in Application in the preparation of medicaments involving or regulating serotonin receptors and/or dopamine receptors, preferably in the preparation of medicaments involving or regulating 5-HT _1A receptors, dopamine _D receptors and/or dopamine _D receptors . 10. according to the compound shown in the general formula (I) described in any one of claim 1-6, its stereoisomer or its pharmaceutically acceptable salt, or the pharmaceutical composition described in claim 8 in Application in the preparation of medicines for treating diseases of the central nervous system. 11. purposes according to claim 10, is characterized in that, described central nervous system disease is selected from Parkinson's disease PD, schizophrenia, bipolar affective disorder, depression, anxiety disorder, mania, Huntington's disease HD, Alzheimer's disease, senile dementia, Alzheimer's type dementia, memory impairment, loss of executive function, vascular dementia, neuropathic pain and dysfunctional diseases related to intelligence, learning or memory One or more, preferably Parkinson's disease.