Arylalkyl-4-(1H)indolylpiperazine derivatives, their preparation methods and uses

Abstract

The present invention relates to arylalkyl-4-(1H)-indolylpiperazine derivatives, a preparation method thereof and applications. In particular, the present invention relates to compounds represented by general formula (I), a preparation method thereof and a pharmaceutical composition containing the compounds, and their applications in the preparation of drugs for preventing and / or treating central nervous system diseases related to mammalian 5-hydroxytryptamine receptors and / or dopamine receptors.

Description

Technical Field

[0001] The present invention belongs to the field of medicinal chemistry, and particularly relates to arylalkyl-4-(1H) indolylpiperazine derivatives, their preparation methods and applications. Background Art

[0002] Parkinson's disease (PD) is a neurodegenerative disease of the nervous system mainly characterized by neurodegeneration in the nigrostriatal pathway. Its clinical features mainly include resting tremor, muscle rigidity, bradykinesia and postural balance disorders. At the same time, it can be accompanied by non-motor symptoms such as depression, constipation and sleep disorders.

[0003] Parkinson's disease is the second most common neurodegenerative disease in the world after Alzheimer's disease, and it often occurs in the elderly. The incidence rate of people over 65 years old in China is 1.7% (Zhang Z X. The Lancet, 2005, 365(9459):595 - 597.). According to incomplete statistics, the number of Parkinson's disease patients in China is about 2.7 million, and the number of newly diagnosed patients increases by 100,000 every year. China has become the "No. 1 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 also is a lifelong disease, and there is currently no drug that can cure it. As the disease progresses, patients gradually lose their ability to live and work independently, and complications such as sports injuries and mental disorders occur, seriously affecting the quality of life. And patients need to take medicine for a long time, bringing a huge economic burden to the family.

[0004] Dopamine receptor agonists are important drugs for the clinical treatment of Parkinson's disease (PD). They can directly stimulate the dopamine receptors postsynaptically in the striatum to play a role. Because they do not compete with amino acids in the brain, their metabolism does not produce free radicals and there is no oxidative stress response, and they may also have the function of protecting and repairing nerves. This type of drug can be administered alone to treat patients with mild PD symptoms, or it can be used in combination with compound levodopa, thereby reducing the dose of levodopa and alleviating adverse reactions such as motor symptom fluctuations and dyskinesia (Guridi J. Parkinsons Dis, 2012, 2012:1 - 15.). Classified by the chemical structure of the drug, 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 used in combination with levodopa would cause severe side effects, they are now rarely used and are gradually replaced by new non-ergot selective dopamine receptor agonists. Representative drugs include: bromocriptine, pergolide, ropinirole, pramipexole. Among them, pramipexole is dopamine D 2 、D 3 、D4 Receptor agonists, ropinirole is a dopamine D 2 、D 3 receptor agonist.

[0005] Selective dopamine receptor agonists remain a key research direction for Parkinson's drugs, and several drugs have entered the clinical trial stage. For example, CQA-206-291 in clinical phase III is a D 2 receptor agonist developed by Novartis; Aplindore fumarate, BAM-1110, and Mesdopetam in clinical phase II also act on different dopamine receptors.

[0006] 5-HT 1A receptors belong to the transmembrane receptor or G protein-coupled receptor (GPCR) family. It is the first subtype of the serotonin receptor subtype to be isolated and fully sequenced. It is mainly distributed in the raphe nucleus, hippocampus, amygdala, and cortex in the central nervous system and can control memory, cognition, and improve mood, etc.

[0007] The 5-HT 1A receptor in patients with Parkinson's disease (PD) is involved in levodopa-induced dyskinesias (LID), so it has attracted the attention of researchers. Studies have found that the presynaptic 5-HT 1A receptor on serotonergic fibers can reduce the release of abnormal dopamine; the postsynaptic membrane 5-HT 1A receptor can reduce the overactive cortico-striatal glutamate neurotransmission.

[0008] Studies have shown that selective 5-HT 1A receptor agonists are closely related to pharmacological effects such as dyskinesia, improving cognitive impairment, and anti-anxiety and depression. The new drug Eltoprazine developed by Elto et al. is an oral small molecule 5HT 1A / 1B partial agonist, which has obtained orphan drug qualification from the FDA and is used to treat Parkinson's disease (PD) levodopa-induced dyskinesia (PD-LID). Currently, it is in the phase 2b clinical trial stage. Currently, more than 680 subjects have taken Eltoprazine, and it has shown good efficacy and safety in the treatment of cognitive and motor disorders. (Cabedo N. Journal of medicinal chemistry, 2001, 44(11): 1794-1801.)

[0009] Befiradol as a selective 5HT 1AAgonists were first used to treat neuralgia in clinical trials and are now used to treat levodopa-induced dyskinesia (PD-LID) in Parkinson's disease (PD). Literature reports (Noureddine ElAouad. European Journal of Medicinal Chemistry, 44(11):4616-4621.) show that Befiradol exhibits novel therapeutic properties. Without compromising the therapeutic performance of L-DOPA, it has significant antidyskinetic function and can improve non-motor psychiatric and emotional symptoms such as antidepressant and antianxiety effects.

[0010] 5HT 1A The anti-PD therapeutic effects of agonists are expected to solve the dyskinesia in Parkinson's disease, improve mood, and repair cognition, etc., and have become the focus and difficulty in the research and development of anti-PD drugs globally. With the in-depth study of the pathogenesis of PD and the rapid development of translational medicine, the development of drugs for treating the causes and clinical symptoms of PD is accelerating.

[0011] In recent years, studies have found that dopamine neurotransmitters and 5-hydroxytryptamine neurotransmitters jointly participate in the regulation of the motor system by the brain, and there is a synergistic effect on motor regulation between the related receptors of the dopamine system and the 5-hydroxytryptamine system. Relevant clinical experiments have also confirmed the advantages of multi-target synergy in the treatment of PD. (Ricardo. Bioorganic&Medicinal Chemistry, 2003.)

[0012] Among them, Brilaroxazine was developed by Reviva Pharmaceuticals and acts on dopamine D 2 、D 3 receptors and 5-HT 1A receptor multi-target partial agonists. It is being clinically developed for indications including Parkinson's disease, antipsychosis, and bipolar disorder, and is currently in clinical studies Phase I and II. Brilaroxazine has an anti-Parkinson effect by increasing the release of cortical dopamine. At the same time, literature reports show that Brilaroxazine has a significant improvement effect on the damage of sub-chronic phencyclidine-induced novel object recognition. These experimental results indicate that Brilaroxazine has obvious anti-Parkinson activity, as well as the improvement and recovery effects on cognitive impairment. (Grundt P. Bioorganic&Medicinal Chemistry Letters, 2007, 17(3):745-749.)

[0013] The new anti-PD drug Bifeprunox in clinical Phase III is a 5-HT 1A receptor agonist, D 2Partial receptor 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.)

[0014] Pridopidine, a new anti-PD drug under clinical phase II, acts on D 2 , 5-HT 1A Drugs targeting multiple receptors, such as sigma-1, have shown good improvement in movement disorders in non-human primate models and have the effects of improving cognition and neuroprotection. (Chen X. Journal of Medicinal Chemistry, 2012, 55(16): 7141-7153.)

[0015] Pardoprunox (SLV-308) is a D 2 / D 3 Partial agonist, 5-HT 1A A full agonist with 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 dyskinesia. It has now entered Phase III clinical trials for the treatment of Parkinson's disease. (Glennon, JC Synapse 2006, 60, 599-608.)

[0016] 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:

[0017]

[0018] This compound has a certain 5-HT 1A and D 4 It has a strong affinity for 5-HT 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 psychosis. 1A and D 4 Receptor binding inhibitory activity IC 50 The values ​​are 12nm and 92nm respectively.

[0019] Patent WO2003002552A1 discloses a new class of indole derivatives, some of which have valuable activity as serotonin reuptake inhibitors and have the ability to antagonize 5-HT 1A receptors, some compounds also have D3 and D 4 The affinity for the receptor. Among them, the structure of the compound (1e) relatively close to the compound of this patent is as follows:

[0020]

[0021] This patent does not disclose any relevant activity data of this compound.

[0022] Patent WO2007026959A2 discloses a class of 4-piperazin-1-yl-4-benzo[b]thiophene derivatives, and the structure of the compound (Example 40) relatively close to the structure of this patent is as follows:

[0023]

[0024] The biological activity of this compound only shows an affinity for D 2 and 5-HT 2A receptors (the receptor function is not disclosed and may be agonist, antagonist or inverse agonist, etc.), and the receptor affinity Ki values are 3.1 nm and 0.6 nm respectively.

[0025] In summary, in view of the multi-target synergistic effect of dopamine D 2 , D 3 receptors and / or 5-HT 1A receptors, multi-target chemical small molecules with dopamine D 2 , D 3 receptors and / or 5-HT 1A receptor activity are expected to overcome movement disorders, improve cognitive impairment, and play new clinical treatment characteristics in improving mental emotions such as anti-anxiety and anti-depression while treating the main motor symptoms of Parkinson's disease. Especially, dopamine D 2 , D 3 and / or 5-HT 1A multi-target (partial) agonists have become an important direction in the research and development of new drugs for anti-Parkinson's, anti-depression, anti-schizophrenia, etc. globally, and the research in this field has novelty, creativity and important scientific value. Summary of the Invention

[0026] The technical problem to be solved by this invention is to provide an arylalkyl-4-(1H)indolylpiperazine derivative, its preparation method and application. In particular, by acting efficiently on dopamine D 2 , D 3 receptors and / or 5-HT 1A receptors, it achieves the treatment characteristics of improving the motor symptoms of PD, overcoming movement disorders, improving cognitive impairment, and playing a role in improving mental emotions such as anxiety and depression, so as to overcome the defects of the existing technology.

[0027] The object of the present invention is to provide a compound represented by the general formula (I), its stereoisomer or its pharmaceutically acceptable salt:

[0028]

[0029] Wherein:

[0030] M is selected from CR 0 or N;

[0031] 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;

[0032] 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 ;

[0033] 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;

[0034] R 2 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;

[0035] R AA Selected from hydrogen, deuterium, halogen, hydroxy, cyano, amino, C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, cycloalkyl, heterocyclic group, 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;

[0036] R 3 Each independently selected from hydrogen, deuterium, halogen, hydroxy, 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;

[0037] n is an integer from 0 to 3;

[0038] n1 is an integer from 0 to 2; and

[0039] n2 is an integer from 0 to 2.

[0040] In a further preferred embodiment of the present invention, the general formula (I) is further as shown in the general formula (II):

[0041]

[0042] Wherein:

[0043] M, R 1 , R 2 and R 3 are as described above.

[0044] In a further preferred embodiment of the present invention, the general formula (I) is further as shown in the general formula (III):

[0045]

[0046] Wherein:

[0047] M is selected from CR 0 or N;

[0048] R 0 is selected from halogen, cyano, C 1-3 alkyl or C 1-3 haloalkyl, preferably cyano;

[0049] 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 ;

[0050] R aa and R bb are each independently selected from hydrogen or C 1-3 alkyl, preferably hydrogen or methyl;

[0051] 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;

[0052] R AA is selected from C 1-3 alkyl or phenyl, preferably methyl or phenyl.

[0053] In a further preferred embodiment of the present invention, the general formula (I) is further as shown in the general formula (IV):

[0054]

[0055] Wherein:

[0056] M is selected from CR 0 or N;

[0057] R 0 is selected from halogen, cyano, C 1-3 alkyl or C 1-3 haloalkyl, preferably cyano;

[0058] 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 ;

[0059] R aa and R bb each independently is selected from hydrogen or C 1-3 alkyl, preferably hydrogen or methyl;

[0060] 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;

[0061] R AA is selected from C 1-3 alkyl or phenyl, preferably methyl or phenyl.

[0062] In a further preferred embodiment of the present invention, the general formula (I) further includes the following compounds:

[0063]

[0064]

[0065]

[0066] In a further preferred embodiment of the present invention, the above pharmaceutically acceptable salts are selected from hydrochloride, hydrobromide, sulfate, trifluoroacetate or mesylate, preferably hydrochloride and hydrobromide.

[0067] The present invention further provides a method for preparing a compound represented by the general formula (I), its stereoisomers or its pharmaceutically acceptable salts, comprising the following steps:

[0068]

[0069] The compound represented by the general formula (I-1) reacts with the compound represented by the general formula (I-2) to form a compound represented by the general formula (I-3), and then undergoes a condensation reaction with the compound represented by the general formula (I-4) to prepare the compound represented by the general formula (I), its stereoisomers or its pharmaceutically acceptable salts;

[0070] Or,

[0071]

[0072] The compound represented by the general formula (I-1) directly reacts with the compound represented by the general formula (I-5) to prepare the compound represented by the general formula (I), its stereoisomers or its pharmaceutically acceptable salts;

[0073] Wherein:

[0074] X 1 and X 2 are halogens, each independently selected from fluorine, chlorine, bromine or iodine.

[0075] M, R 1 、R 2 、R 3 and n are as described above.

[0076] The present invention further provides a method for preparing a compound represented by the general formula (II), its stereoisomers or its pharmaceutically acceptable salts, comprising the following steps:

[0077]

[0078] The compound represented by the general formula (I-1) reacts with the compound represented by the general formula (II-2) to form a compound represented by the general formula (II-3), and then undergoes a condensation reaction with the compound represented by the general formula (I-4) to prepare the compound represented by the general formula (II), its stereoisomers or its pharmaceutically acceptable salts;

[0079] Or,

[0080]

[0081] The compound represented by the general formula (I-1) directly reacts with the compound represented by the general formula (II-5) to prepare the compound represented by the general formula (II), its stereoisomers or its pharmaceutically acceptable salts;

[0082] Wherein:

[0083] X 3 and X 4 are halogens, each independently selected from fluorine, chlorine, bromine or iodine.

[0084] M, R 1 , R 2 and R 3 are as described above.

[0085] The present invention further provides a method for preparing a compound represented by the general formula (III), its stereoisomers or its pharmaceutically acceptable salts, comprising the following steps:

[0086]

[0087] The compound represented by the general formula (III-1) reacts with the compound represented by the general formula (II-2) to form a compound represented by the general formula (III-3), and then undergoes a condensation reaction with the compound represented by the general formula (I-4) to prepare the compound represented by the general formula (III), its stereoisomers or its pharmaceutically acceptable salts;

[0088] Or,

[0089]

[0090] The compound represented by the general formula (III-1) directly reacts with the compound represented by the general formula (II-5) to prepare the compound represented by the general formula (III), its stereoisomers or its pharmaceutically acceptable salts;

[0091] Wherein:

[0092] X 3 and X 4 are halogens, each independently selected from fluorine, chlorine, bromine or iodine.

[0093] M, R 1 and R 2 are as described above.

[0094] The present invention further provides a method for preparing a compound represented by the general formula (IV), its stereoisomers or its pharmaceutically acceptable salts, comprising the following steps:

[0095]

[0096] The compound represented by the general formula (IV-1) reacts with the compound represented by the general formula (II-2) to form a compound represented by the general formula (IV-3), and then undergoes a condensation reaction with the compound represented by the general formula (I-4) to prepare the compound represented by the general formula (IV), its stereoisomers or its pharmaceutically acceptable salts;

[0097] Or,

[0098]

[0099] 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 its pharmaceutically acceptable salt;

[0100] Wherein:

[0101] X 3 and X 4 are halogens, each independently selected from fluorine, chlorine, bromine or iodine.

[0102] M, R 1 and R 2 are as described above.

[0103] In the above synthetic route, the raw material compounds involved can all be commercial products. Most of the key intermediates are obtained by direct commercial purchase. Some intermediates can be prepared by the methods reported in the references (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 Chem Lett. 2017 Dec 15; 27(24): 5420 - 5423.) through the following two synthetic routes:

[0104] Route 1:

[0105]

[0106] Route 2:

[0107]

[0108] Wherein:

[0109] X 5 and X 6 are halogens, each independently selected from fluorine, chlorine, bromine or iodine.

[0110] M, R 1 , R 2 , R 3 and n are as described above.

[0111] The present invention further relates to a pharmaceutical composition, which comprises a therapeutically effective dose of any of the shown compounds, its stereoisomer or its pharmaceutically acceptable salt and one or more pharmaceutically acceptable carriers.

[0112] In one embodiment of the present invention, the pharmaceutical composition can be formulated in a conventional manner using one or more pharmaceutically acceptable carriers. The carriers refer to the conventional carriers in the pharmaceutical field, such as diluents, excipients like water, etc.; binders like cellulose derivatives, gelatin, polyvinylpyrrolidone, etc.; fillers like starch, etc.; disintegrants like calcium carbonate, sodium bicarbonate; lubricants like calcium stearate or magnesium stearate, etc. Additionally, other adjuvants such as flavoring agents and sweetening agents can be added to the composition. For oral administration, it can be prepared into conventional solid preparations such as tablets, powders, lozenges, capsules, suspensions, syrups, etc.; for injection, it can be prepared into injection solutions.

[0113] 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% - 99.5% (by weight).

[0114] In one embodiment of the present invention, the pharmaceutical composition is administered to patients in need of such treatment by oral, injection, etc. The dosage is generally 0.02 - 5 mg / kg (oral) or 0.01 - 2 mg / kg (injection), and the specific dosage can be determined by a physician according to the results of clinical trials and the patient's condition, age, etc.

[0115] The present invention further relates to the use of any of the shown compounds, their stereoisomers or their pharmaceutically acceptable salts, or their pharmaceutical compositions in the preparation of drugs related to or modulating 5 - hydroxytryptamine receptors and / or dopamine receptors, preferably in the preparation of drugs related to or modulating 5 - HT 1A receptors, dopamine D 2 receptors and / or dopamine D 3 receptor drugs.

[0116] The present invention further relates to the use of any of the shown compounds, their stereoisomers or their pharmaceutically acceptable salts, or their pharmaceutical compositions in the preparation of drugs for treating central nervous system diseases.

[0117] The present invention further relates to a method for preparing drugs for treating central nervous system diseases using any of the shown compounds, their stereoisomers or their pharmaceutically acceptable salts, or their pharmaceutical compositions.

[0118] The present invention also relates to a method for treating central nervous system diseases related to mammalian 5 - hydroxytryptamine receptors and / or dopamine receptors, which comprises administering to the mammal a therapeutically effective dose of any of the shown compounds, their stereoisomers or their pharmaceutically acceptable salts, esters, prodrugs, solvates, hydrates or derivatives, or their pharmaceutical compositions.

[0119] In some embodiments, the central nervous system diseases related to the present invention are selected from one or more of Parkinson's disease (PD), schizophrenia, bipolar disorder, depression, anxiety disorder, mania, Huntington's disease (HD), Alzheimer's disease, senile dementia, Alzheimer's type dementia, memory disorder, loss of executive function, vascular dementia, neuropathic pain, and functional disorder diseases related to intelligence, learning or memory, preferably Parkinson's disease.

[0120] In some preferred embodiments, the central nervous disease related to the present invention is Parkinson's disease.

[0121] Detailed Description of the Invention

[0122] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In case of conflict, the definitions provided in this application shall prevail. When trade names appear herein, they are intended to refer to the corresponding goods or their active ingredients. All patents, published patent applications and publications cited herein are incorporated herein by reference.

[0123] The term "hydrocarbon chain" refers to a chain-like group composed 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-chain or branched, and in a preferred embodiment, the hydrocarbon chain is straight-chain. The hydrocarbon chain can optionally contain one or more heteroatoms such as N, O, and S. In the case of containing heteroatoms, the heteroatoms can be located on the main chain. In a preferred embodiment, the hydrocarbon chain can be straight-chain 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, C 2 -C 8 or C 2 -C 6 refers to a hydrocarbon chain containing 2 - 8 or 2 - 6 carbon atoms, which can optionally contain additional heteroatoms.

[0124] The term "alkyl" refers to a straight-chain or branched saturated aliphatic hydrocarbon group composed 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 3-6Alkyl. Non-limiting examples of alkyl 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, etc., or their isomers.

[0125] The above alkyl can be optionally substituted or unsubstituted. When substituted, the substituent can be substituted at any available connection point. The substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, halogen, mercapto, hydroxy, nitro, amino, cyano, carboxyl, oxo, cycloalkyl, heterocyclic group, aryl or heteroaryl.

[0126] The term "subunit" refers to a group obtained by removing one hydrogen atom from a carbon atom containing free valence electrons and having two connection sites connected to other parts of the molecule. For example, "alkylene" or "alkylidene" refers to a saturated straight-chain or branched-chain divalent hydrocarbon group.

[0127] The term "alkylene", when used alone or in combination with other groups herein, refers to a straight-chain or branched-chain saturated divalent hydrocarbon group. For example, the term "C 1-8 alkylene" refers to an alkylene having 1-8 carbon atoms, such as methylene, ethylene, propylene, butylene, pentylene, hexylene, 1-methylethylene, 2-methylethylene, methylpropylene or ethylpropylene, etc. The alkylene can be optionally substituted or unsubstituted. When substituted, the substituent can be substituted at any available connection point. The substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, halogen, mercapto, hydroxy, nitro, amino, cyano, carboxyl, oxo, cycloalkyl, heterocyclic group, aryl or heteroaryl.

[0128] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, and the cycloalkyl contains 3 to 20 carbon atoms, that is, "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, C4-8 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 spiro, fused and bridged cycloalkyl.

[0129] Any of the above cycloalkyl groups may be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring connected to the parent structure is cycloalkyl. The cycloalkyl group may be optionally substituted or unsubstituted. When substituted, the substituent may be substituted at any available attachment point. The substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, halogen, mercapto, hydroxy, nitro, amino, cyano, carboxyl, oxo, cycloalkyl, heterocyclic group, aryl or heteroaryl.

[0130] The term "heterocyclic group" refers to a saturated or unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing 3 to 20 ring atoms, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) m (where m is an integer from 0 to 2), but does not include the ring portion of -O-O-, -O-S- or -S-S-. The remaining ring atoms are carbon. That is, "3- to 20-membered heterocyclic group", such as 3- to 18-membered heterocyclic group, 3- to 16-membered heterocyclic group, 3- to 12-membered heterocyclic group, 3- to 8-membered heterocyclic group, 3- to 6-membered heterocyclic group, 3- to 5-membered heterocyclic group, 3- to 4-membered heterocyclic group, 4- to 8-membered heterocyclic group, 4- to 6-membered heterocyclic group, 5- to 6-membered heterocyclic group, preferably 3- to 8-membered heterocyclic group, 3- to 6-membered heterocyclic group, 3- to 5-membered heterocyclic group, 3- to 4-membered heterocyclic group, 4- to 8-membered heterocyclic group, 4- to 6-membered heterocyclic group, 5- to 6-membered heterocyclic group, which optionally contains 1-4 heteroatoms, 1-3 heteroatoms or 1-2 heteroatoms, and the heteroatoms are optionally nitrogen, oxygen or S(O) m (where m is an integer from 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 spiro, fused and bridged heterocyclic groups, and the spiro, fused and bridged heterocyclic groups involved are optionally connected to other groups by a single bond, or further fused to other cycloalkyl, heterocyclic, aryl and heteroaryl rings through any two or more atoms on the ring.

[0131] Each of the above-mentioned heterocyclic groups may be fused to an aryl, heteroaryl or cycloalkyl ring, and the ring connected to the parent structure is a heterocyclic group. The heterocyclic group may be optionally substituted or unsubstituted. When substituted, the substituent may be substituted at any available connecting 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, hydroxy, nitro, amino, cyano, carboxyl, oxo, cycloalkyl, heterocyclic group, aryl or heteroaryl.

[0132] The term "aryl" refers to a 6- to 14-membered fully carbon monocyclic or fused polycyclic group having a conjugated π-electron system, preferably 6 to 12 members, such as phenyl or naphthyl, more preferably phenyl.

[0133] The above-mentioned aryl may be fused to a heteroaryl, heterocyclic or cycloalkyl ring, and the ring connected to the parent structure is an aryl ring, including benzo-5- to 10-membered heteroaryl, benzo-3- to 8-membered cycloalkyl and benzo-3- to 8-membered heterocyclic group, preferably benzo-5- to 6-membered heteroaryl, benzo-3- to 6-membered cycloalkyl and benzo-3- to 6-membered heterocyclic group. The aryl may be optionally substituted or unsubstituted. When substituted, the substituent may be substituted at any available connecting 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, hydroxy, nitro, amino, cyano, carboxyl, oxo, cycloalkyl, heterocyclic group, aryl or heteroaryl.

[0134] The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, where the heteroatoms are selected from oxygen, sulfur, nitrogen, etc. The heteroaryl is preferably 5 to 12 members, more preferably 5 to 6 members, such as pyrrolyl, imidazolyl, furyl, pyranyl, thienyl, thiazolyl, thiadiazolyl, pyrazolyl, oxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, etc.

[0135] The above-mentioned heteroaryl may be fused to an aryl, cycloalkyl or heterocyclic ring, and the ring connected to the parent structure is a heteroaryl ring. The heteroaryl may be optionally substituted or unsubstituted. When substituted, the substituent may be substituted at any available connecting 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, hydroxy, nitro, amino, cyano, carboxyl, oxo, cycloalkyl, heterocyclic group, aryl or heteroaryl.

[0136] The term "alkoxy" refers to -O-(alkyl) or -O-(unsubstituted cycloalkyl), where the definitions of alkyl and cycloalkyl are as described above. Non-limiting examples of alkoxy include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, etc. The alkoxy can be optionally substituted or unsubstituted. When substituted, the substituent can be substituted at any available attachment 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, hydroxy, nitro, amino, cyano, carboxyl, oxo, cycloalkyl, heterocyclic group, aryl or heteroaryl.

[0137] The term "alkylthio" refers to -S-(alkyl) or -S-(unsubstituted cycloalkyl), where the definitions of alkyl and cycloalkyl are as described above. Non-limiting examples of alkylthio include: methylthio, ethylthio, propylthio, butylthio, cyclopropylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio, etc. The alkylthio can be optionally substituted or unsubstituted. When substituted, the substituent can be substituted at any available attachment 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, hydroxy, nitro, amino, cyano, carboxyl, oxo, cycloalkyl, heterocyclic group, aryl or heteroaryl.

[0138] The term "alkylamino" refers to -NH-(alkyl or unsubstituted cycloalkyl), or -N-(alkyl or unsubstituted cycloalkyl)(alkyl or unsubstituted cycloalkyl), where the definitions of alkyl and cycloalkyl are as described above. Non-limiting examples of alkylamino include: methylamino, ethylamino, propylamino, butylamino, cyclopropylamino, cyclobutylamino, cyclopentylamino, cyclohexylamino, etc. The alkylamino can be optionally substituted or unsubstituted. When substituted, the substituent can be substituted at any available attachment 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, hydroxy, nitro, amino, cyano, carboxyl, oxo, cycloalkyl, heterocyclic group, aryl or heteroaryl.

[0139] The term "halo" or "halogen" or "halo-substituted" should be understood to mean a fluorine (F), chlorine (Cl), bromine (Br) or iodine (I) atom, preferably a fluorine, chlorine or bromine atom.

[0140] The term "deuterated hydrocarbon chain" refers to a hydrocarbon chain substituted with one or more deuteriums, where the hydrocarbon chain is defined as above.

[0141] The term "deuterated alkyl" refers to an alkyl substituted with one or more deuteriums, where the alkyl is defined as above.

[0142] The term "halogenated hydrocarbon chain" refers to a hydrocarbon chain substituted with one or more halogens, where the hydrocarbon chain is defined as above.

[0143] The term "haloalkyl" refers to an alkyl group substituted with one or more halogen atoms, wherein the alkyl group is as defined above.

[0144] The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogen atoms, wherein the alkoxy group is as defined above.

[0145] The term "alkenyl" refers to an alkenyl group, also known as an olefinic group, wherein the olefin can be further substituted with other relevant groups.

[0146] The term "alkynyl" refers to (CH≡C-), wherein the alkynyl group can be further substituted with other relevant groups.

[0147] "Hydroxy" refers to -OH.

[0148] "Amino" refers to -NH 2 。

[0149] "Cyano" refers to -CN.

[0150] "Nitro" refers to -NO 2 。

[0151] "Mercapto" refers to -SH.

[0152] "Carbonyl" refers to -C(O)-.

[0153] "Carboxyl" refers to -C(O)OH.

[0154] "Oxo" refers to =O.

[0155] The terms "comprises", "comprising", "has", "having", "includes", "including" or "relates to" and other variant forms thereof used herein are inclusive or open-ended and do not exclude other unrecited elements or method steps. Those skilled in the art should understand that the above terms such as "comprises" cover the meaning of "consisting of".

[0156] The term "one or more" or a similar expression "at least one" can represent, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more.

[0157] When the lower and upper limits of a numerical range are disclosed, any numerical value and any included range falling within that range are specifically disclosed. In particular, each range of values disclosed herein should be understood to represent every numerical value and range subsumed within the broader range.

[0158] In this document, both "Z" and "-Z-" represent the same specific group and can be used interchangeably.

[0159] As used herein, the expression m-n refers to the range from m to n, as well as the sub-ranges and individual point values composed of the respective point values therein. For example, the expression "C 2 -C 8 " or "C 2-8 " encompasses the range of 2 to 8 carbon atoms and should be understood to also encompass any sub-ranges and each point value therein, such as C 2 -C 5 、C 3 -C 4 、C 2 -C 6 、C 3 -C 6 、C 4 -C 6 、C 4 -C 7 、C 4 -C 8 、C 2 -C 5 etc., as well as C 2 、C 3 、C 4 、C 5 、C 6 、C 7 、C 8 etc. For example, the expression "C 3 -C 10 " or "C 3-10 " should also be understood in a similar manner, for example, it can encompass any sub-ranges and point values included therein, such as C 3 -C 9 、C 6 -C 9 、C 6 -C 8 、C 6 -C 7 、C 7 -C 10 、C 7 -C 9 、C 7 -C 8 、C 8 -C 9 etc. and C 3 、C 4 、C 5 、C 6 、C 7 、C 8 、C 9 、C 10 etc. Again, for example, the expression "C 1 -C 6 " or "C 1-6”covers the range of 1 to 6 carbon atoms and should be understood to also cover any sub-range and each point value 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., and C 1 、C 2 、C 3 、C 4 、C 5 、C 6 etc. Again, for example, the expression "from three to ten yuan" should be understood to cover any sub-range and each point value therein, such as from three to five yuan, from three to six yuan, from three to seven yuan, from three to eight yuan, from four to five yuan, from four to six yuan, from four to seven yuan, from four to eight yuan, from five to seven yuan, from five to eight yuan, from six to seven yuan, from six to eight yuan, from nine to ten yuan, etc., and three, four, five, six, seven, eight, nine, ten yuan, etc. Other similar expressions in this article should be understood in a similar manner.

[0160] The different expressions used in this article, such as "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", etc., all express the same meaning, that is, it means that X can be any one or several of A, B, and C.

[0161] The term "optionally" or "optionally" means that the subsequent described event or situation may or may not occur, and this description includes the occurrence and non-occurrence of the described event or situation. For example, "optionally (substituted) by an alkyl group cycloalkyl" means that the alkyl group may or may not be present, and this description includes the case where the cycloalkyl group is substituted by an alkyl group and the case where the cycloalkyl group is not substituted by an alkyl group.

[0162] The terms "substituted" and "substituting" mean that one or more (e.g., one, two, three, or four) hydrogens on the specified atom are replaced by a selection from the indicated groups, provided that the normal valence of the specified atom in the current case is not exceeded and the substitution forms a stable compound. Combinations of substituents and / or variables are permitted only if such combinations form stable compounds. When it is described that a certain substituent is absent, it should be understood that the substituent may be one or more hydrogen atoms, provided that the structure enables the compound to reach a stable state. When it is described that each carbon atom in a group may optionally be replaced by a heteroatom, the condition is that the normal valence of all atoms in the group in the current case is not exceeded and a stable compound is formed.

[0163] If a substituent is described as "optionally... substituted", the substituent may be unsubstituted or may be substituted. If an atom or group is described as optionally substituted by one or more from a list of substituents, one or more hydrogens on that atom or group may be replaced by independently selected optional substituents. When the substituent is oxo (i.e., =O), it means that two hydrogen atoms are replaced. Unless otherwise specified, as used herein, the point of attachment of a substituent may be from any suitable position of the substituent.

[0164] When the bond of a substituent is shown passing through a bond connecting two atoms in a ring, such a substituent may be bonded to any ring-forming atom in the ring that can be substituted.

[0165] When any variable (e.g., R), and variables with markings (e.g., R 0 、R 1 、R 2 、R 3 、R AA 、R aa 、R bb etc.) appear more than once in the composition or structure of a compound, their definitions in each case are independent at each occurrence. For example, if a group is substituted by 0, 1, 2, 3, or 4 R substituents, the group may optionally be substituted by up to four R substituents, and the options for each R substituent in each case are independent of each other.

[0166] 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 "unsubstituted" 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 "unsubstituted" or "not substituted".

[0167] The compounds of the present invention can 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, diastereoisomers, (D)-isomers, (L)-isomers, and their racemic mixtures and other mixtures, such as enantiomer- or diastereoisomer-enriched mixtures, all of which mixtures are within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and their mixtures are included within the scope of the present invention. In certain embodiments, preferred compounds are those isomeric compounds that exhibit superior biological activity. The purified or partially purified isomers and stereoisomers of the compounds of the present invention, or racemic mixtures or diastereoisomer mixtures, are also included within the scope of the present invention. The purification and separation of such substances can be achieved by standard techniques known in the art.

[0168] Any hydrogen atom described in the present invention can be replaced by its isotope deuterium, and the content of the deuterium isotope is at least greater than the natural deuterium isotope content. Any hydrogen atom in the exemplified compounds of the present invention can also be replaced by a deuterium atom.

[0169] The term "pharmaceutically acceptable" substance refers to a substance that, within the scope of normal medical judgment, is suitable for contact with the tissues of a patient without undue toxicity, irritation, allergic response, etc., has a reasonable benefit-risk ratio, and is effective for its intended use.

[0170] The term "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention that is safe and effective when used in mammals and has the desired biological activity.

[0171] 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 the pharmaceutical composition is to facilitate the administration to an organism, promote the absorption of the active ingredient, and thereby exert its biological activity.

[0172] The term "pharmaceutically acceptable carrier" refers to those substances that do not cause significant irritation to an organism and do not impair the biological activity and properties of the active compound. "Pharmaceutically acceptable carriers" include, but are not limited to, glidants, sweeteners, diluents, preservatives, dyes / colorants, flavoring agents, surfactants, wetting agents, dispersants, disintegrants, stabilizers, solvents, or emulsifiers.

[0173] The terms "administer" or "administration" etc. refer to methods that can enable a compound or composition to be delivered to a desired biological site of action. These methods include, but are not limited to, oral or parenteral (including intraventricular, intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular injection or infusion), topical, rectal administration, etc. In particular, injection or oral administration.

[0174] As used herein, the term "treatment" includes alleviating, reducing or improving a disease or symptom, preventing other symptoms, improving or preventing the underlying metabolic factors of a symptom, inhibiting a disease or symptom, e.g., preventing the development of a disease or symptom, alleviating a disease or symptom, promoting the remission of a disease or symptom, or arresting the signs 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 eradicating or improving the treated condition. 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 have the underlying disease, an improvement in the patient's disease can be observed. A prophylactic benefit means that a composition is used by a patient to prevent the risk of a certain disease, or is taken when the patient presents with one or more physiological conditions of a disease, although the disease has not yet been diagnosed.

[0175] The terms "active ingredient", "therapeutic agent", "active substance" or "active agent" refer to a chemical entity that can effectively treat or prevent a target disorder, disease or condition. The term "neuropsychiatric disease" refers to the general term for neurological diseases and psychiatric diseases, including neurological diseases and / or psychiatric diseases.

[0176] For a drug, drug unit or active ingredient, the terms "effective amount", "therapeutically effective amount" or "prophylactically effective amount" refer to a sufficient amount of the drug or agent that has acceptable side effects but can achieve the desired effect. The determination of the effective amount varies from person to person, depending on the age and general condition of the individual, and also depends on the specific active substance. In a particular case, the appropriate effective amount can be determined by those skilled in the art according to routine tests.

[0177] As used herein, "individual" includes human or non-human animals. Exemplary human individuals include human individuals suffering from a disease (such as the diseases described herein) (referred to as patients) or normal individuals. In the present invention, "non-human animals" include all vertebrates, such as non-mammals (such as birds, amphibians, reptiles) and mammals, such as non-human primates, domestic animals and / or domesticated animals (such as sheep, dogs, cats, cows, pigs, etc.).

[0178] The following detailed description of the invention is intended to illustrate non-limiting embodiments, enabling other technical personnel in the art to more fully understand the technical solutions of the present invention, its principles and its practical applications, so that other technical personnel in the art can modify and implement the present invention in many forms and adapt it optimally to the requirements of a specific use.

[0179] Advantageous Effects

[0180] The compounds of the present invention have novel structures and can act on 5-HT 1A receptors, dopamine D 2 receptors and / or dopamine D 3 receptors, and exhibit certain (partial) agonist activities. Some compounds exhibit (partial) agonist effects on at least two of the 5-HT 1A receptors, dopamine D 2 and D 3 receptors. In particular, some compounds also exhibit triple (partial) agonist activities on the 5-HT 1A receptors, dopamine D 2 and D 3 receptors, suggesting that they have significant efficacy for central nervous system disorders such as Parkinson's disease and can be used to prepare drugs for treating central nervous system disorders. Detailed implementation manners

[0181] The present invention will be further described below in conjunction with specific embodiments. It should be understood that these embodiments are only used to illustrate the present invention and not to limit the scope of the present invention. In addition, it should be understood that after reading the content taught by the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims of this application.

[0182] Examples

[0183] The embodiments of the present invention will be described in detail below in conjunction with the examples. However, those skilled in the art will understand that the following examples are only used to illustrate the present invention and should not be regarded as limiting the scope of the present invention. For those not specified in the examples, they are carried out under conventional conditions or the conditions recommended by the manufacturer. For reagents or instruments not specified for the manufacturer, they are all conventional products that can be obtained through commercial purchase. Unless otherwise specified, the ratios or percentages used herein are by weight.

[0184] The structures of the compounds of the present invention are determined by nuclear magnetic resonance (NMR) or / and liquid chromatography-mass spectrometry (LC-MS).

[0185] The nuclear magnetic resonance spectra are measured using a Unity Inova 400 or 600 nuclear magnetic resonance spectrometer. The chemical shifts (δ) are given in parts per million (ppm) units, and the solvents used for the measurement are deuterated dimethyl sulfoxide (DMSO-d 6 ) and heavy water (D 2O), with tetramethylsilane (TMS) as the internal standard; liquid chromatography-mass spectrometry was determined 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., with product number C10008, and the TLC specification used was 2.5 * 5 cm * 0.25 mm.

[0186] General synthetic method for Examples 1-12:

[0187] Dissolve the 4-(piperazin-1-yl)-1H-indole compound (6.46 mmol) in acetone (20 mL), add potassium carbonate (12.92 mmol), 1-bromo-2-chloroethane (or 1-bromo-3-chloropropane) (12.92 mmol), and react at 60 °C for 8 h. Monitor the reaction by TLC until the arylpiperazine compound is completely converted or the raw materials do not decrease with the increase of reaction time. Stop the reaction and filter to remove the remaining potassium carbonate. Take the filtrate and rotary evaporate to remove the solvent. Add water (15 mL), extract with dichloromethane (30 mL * 3), separate the organic phase, wash with saturated brine, dry with anhydrous sodium sulfate, filter and concentrate to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain the chloroalkyl 4-(piperazin-1-yl)-1H-indole compound.

[0188] Dissolve the substituted chloroalkyl 4-(piperazin-1-yl)-1H-indole compound (1.80 mmol, 1.0 eq), substituted pyridinol (2.16 mmol, 1.0 eq), potassium carbonate (4.50 mmol, 2.5 - 3.0 eq), and potassium iodide (1.80 mmol, 1.0 eq) in acetonitrile (15 mL). Heat to reflux and stir the reaction at 85 °C for 5 - 12 h. Monitor the reaction by TLC until it is complete, and then stop heating. After cooling, filter off the insoluble salts under reduced pressure and distill off the solvent. Add water (10 mL), extract with dichloromethane (20 mL * 3), combine the organic phases, wash with saturated brine and dry with anhydrous sodium sulfate, then filter and concentrate to obtain the crude product. Separate and purify by silica gel column chromatography (dichloromethane: methanol = 50:1) to obtain the aralkyl-4-(1H)-indolylpiperazine compound, dissolve it in ethyl acetate (10 mL), and dropwise add hydrochloric acid ethyl acetate (2N) to obtain the aralkyl-4-(1H)-indolylpiperazine hydrochloride, with a yield of 30 - 80%.

[0189] Example 1

[0190] Preparation of 4-(4-(3-((6-fluoropyridin-3-yl)oxy)propyl)piperazin-1-yl)-1H-indole hydrochloride

[0191] 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)piperazin-1-yl)-1H-indole, K 2 CO 3 1.2 g (8.4 mmol, 3 eq), and 0.47 g (2.80 mmol, 1.0 eq) of potassium iodide in 20 mL of acetonitrile, and stir the reaction under reflux for 8 h. After cooling, filter off the insoluble salts by suction, and distill off the solvent under reduced pressure. Add water (10 mL), extract with dichloromethane (20 mL × 3), combine the organic phases, wash with saturated brine, and separate the layers. Dry the organic phase over anhydrous sodium sulfate, filter, and concentrate the filtrate to obtain the crude product. Purify by column chromatography to obtain a pale yellow oil, dissolve it in 6 mL of ethyl acetate, adjust the pH < 3 by dropwise addition of 2 M HCl / EtOAc, precipitate a solid, filter, and dry in vacuo to obtain 0.60 g of the target product with a yield of 55.0%.

[0192] ESI-MS [M + H] + : m / z 355.2.

[0193] 1 H NMR (400 MHz, DMSO) δ 11.19 (s, 1H), 10.51 (s, 1H), 7.98 (dd, J = 3.2, 1.8 Hz, 1H), 7.68 (ddd, J = 9.5, 6.6, 3.2 Hz, 1H), 7.33 (t, J = 2.8 Hz, 1H), 7.20 (dd, J = 8.9, 3.4 Hz, 1H), 7.14 (d, J = 8.1 Hz, 1H), 7.04 (t, J = 7.8 Hz, 1H), 6.56 (d, J = 7.4 Hz, 1H), 6.49 (t, J = 2.7 Hz, 1H), 4.22 (t, J = 6.0 Hz, 2H), 3.76 (d, J = 12.8 Hz, 2H), 3.70 (d, J = 11.9 Hz, 2H), 3.45 - 3.30 (m, 4H), 3.17 (t, J = 12.3 Hz, 2H), 2.34 - 2.23 (m, 2H).

[0194] Example 2

[0195] Preparation of 7-(4-(3-((6-fluoropyridin-3-yl)oxy)propyl)piperazin-1-yl)-1H-indole hydrochloride

[0196] 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)piperazin-1-yl)-1H-indole, K 2 CO 30.30 g (2.1 mmol, 3 eq), potassium iodide 0.12 g (0.72 mmol, 1.0 eq) were dissolved in 10 ml of acetonitrile, and the mixture was stirred under reflux for 8 h. After cooling, the insoluble salts were removed by suction filtration, and the solvent was removed by distillation under reduced pressure. Water (5 mL) was added, and the mixture was extracted with dichloromethane (15 mL × 3). 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 the crude product. The crude product was purified by column chromatography to obtain a pale yellow oil. The oil was dissolved in 3 mL of ethyl acetate, and the pH was adjusted to <3 by dropwise addition of 2M HCl / EtOAc. A solid was precipitated, filtered, and dried under vacuum to obtain 0.15 g of the target product, with a yield of 53.3%.

[0197] ESI-MS [M + H] + : m / z 355.1.

[0198] 1 1H NMR (400 MHz, DMSO) δ 11.09 (s, 1H), 10.51 (s, 1H), 7.98 (dd, J = 3.2, 1.8 Hz, 1H), 7.68 (ddd, J = 9.4, 6.6, 3.1 Hz, 1H), 7.38 (t, J = 2.8 Hz, 1H), 7.31 (d, J = 7.9 Hz, 1H), 7.21 (dd, J = 8.9, 3.4 Hz, 1H), 6.98 (t, J = 7.7 Hz, 1H), 6.74 (d, J = 7.5 Hz, 1H), 6.48 (dd, J = 3.1, 1.8 Hz, 1H), 4.23 (t, J = 6.0 Hz, 2H), 3.72 (d, J = 11.9 Hz, 2H), 3.58 (d, J = 12.8 Hz, 2H), 3.47 - 3.31 (m, 4H), 3.17 (t, J = 12.0 Hz, 2H), 2.33 - 2.23 (m, 2H).

[0199] Example 3

[0200] Preparation of 4-(4-(3-((6-(trifluoromethyl)pyridin-3-yl)oxy)propyl)piperazin-1-yl)-1H-indole hydrochloride

[0201] 6-(Trifluoromethyl)pyridin-3-ol 88 mg (0.54 mmol, 1.0 eq), 4-(4-(3-chloropropyl)piperazin-1-yl)-1H-indole 150 mg (0.54 mmol, 1.0 eq), K 2 CO 3224 mg (1.62 mmol, 3.0 eq), potassium iodide 90 mg (0.54 mmol, 1.0 eq) were dissolved in 6 mL of acetonitrile, and the mixture was stirred under reflux for 8 h. After cooling, the insoluble salts were removed by suction filtration, and the solvent was removed by distillation under reduced pressure. Water (5 mL) was added, and the mixture was extracted with dichloromethane (15 mL × 3). 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 the crude product. The crude product was purified by column chromatography to obtain a pale yellow oil. The oil was dissolved in 3 mL of ethyl acetate, and the pH was adjusted to <3 by dropwise addition of 2 M HCl / EtOAc. A solid was precipitated, filtered, and dried in vacuo to obtain 81 mg of the target product, with a yield of 34.0%.

[0202] ESI-MS [M+H] + : m / z 405.1.

[0203] 1 1H NMR (400 MHz, DMSO) δ 11.21 (s, 1H), 10.83 (s, 1H), 8.52 (d, J = 2.8 Hz, 1H), 7.93 (d, J = 8.8 Hz, 1H), 7.68 (dd, J = 8.8, 2.9 Hz, 1H), 7.34 (t, J = 2.8 Hz, 1H), 7.14 (d, J = 8.1 Hz, 1H), 7.04 (t, J = 7.8 Hz, 1H), 6.57 (d, J = 7.4 Hz, 1H), 6.50 (d, J = 2.8 Hz, 1H), 4.34 - 4.21 (m, 3H), 3.71 (d, J = 16.5 Hz, 3H), 3.37 (d, J = 12.8 Hz, 3H), 3.22 (t, J = 12.1 Hz, 2H), 2.43 - 2.24 (m, 3H).

[0204] Example 4

[0205] Preparation of 5-(3-(4-(1H-indol-4-yl)piperazin-1-yl)propoxy)-2-cyanopyridine hydrochloride

[0206] 0.48 g (3.89 mmol, 1.2 eq) of 2-cyano-5-hydroxypyridine, 0.90 g (3.24 mmol, 1.0 eq) of 4-(4-(3-chloropropyl)piperazin-1-yl)-1H-indole, K 2 CO 31.12 g (8.10 mmol, 2.5 eq), potassium iodide 0.54 g (3.24 mmol, 1.0 eq) were dissolved in 20 mL of acetonitrile, and the mixture was stirred and reacted under reflux for 6 h. After cooling, the insoluble salts were removed by suction filtration, and the solvent was removed by distillation under reduced pressure. Water (10 mL) was added, and the mixture was extracted with dichloromethane (20 mL * 3). 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 the crude product. The crude product was purified by column chromatography to obtain a pale yellow oil. The oil was dissolved in 6 mL of ethyl acetate, and the pH was adjusted to < 3 by dropping 2 M HCl / EtOAc. A solid was precipitated, filtered, and dried in vacuo to obtain 0.85 g of the target product, with a yield of 65.9%.

[0207] ESI-MS [M + H] + : m / z 362.1.

[0208] 1 1H NMR (400 MHz, DMSO) δ 11.20 (s, 1H), 10.50 (s, 1H), 8.51 (d, J = 2.8 Hz, 1H), 8.09 (d, J = 8.7 Hz, 1H), 7.67 (dd, J = 8.7, 2.9 Hz, 1H), 7.34 (t, J = 2.8 Hz, 1H), 7.14 (d, J = 8.1 Hz, 1H), 7.04 (t, J = 7.8 Hz, 1H), 6.56 (d, J = 7.5 Hz, 1H), 6.49 (t, J = 2.6 Hz, 1H), 4.34 (t, J = 5.9 Hz, 2H), 3.77 - 3.70 (m, 2H), 3.70 (d, J = 11.7 Hz, 2H), 3.47 - 3.29 (m, 4H), 3.17 (t, J = 12.2 Hz, 2H), 2.34 - 2.29 (m, 2H).

[0209] Example 5

[0210] Preparation of N-(5-(3-(4-(1H-indol-4-yl)piperazin-1-yl)propoxy)pyridin-2-yl)acetamide hydrochloride

[0211] 0.13 g (0.87 mmol, 1.2 eq) of 2-acetamido-5-hydroxypyridine, 0.20 g (0.72 mmol, 1.0 eq) of 4-(4-(3-chloropropyl)piperazin-1-yl)-1H-indole, K 2 CO 30.03 g (2.10 mmol, 3 eq), potassium iodide 0.12 g (3.24 mmol, 1.0 eq) were dissolved in 6 mL of acetonitrile, and the reaction was stirred under reflux for 8 h. After cooling, the insoluble salts were removed by suction filtration, and the solvent was removed by distillation under reduced pressure. Water (6 mL) was added, and extraction was carried out with dichloromethane (15 mL × 3). 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 the crude product. The crude product was purified by column chromatography to obtain a pale yellow oil. The oil was dissolved in 6 mL of ethyl acetate, and 2 M HCl / EtOAc was added dropwise to adjust the pH < 3. A solid was precipitated, filtered, and dried in vacuo to obtain 0.17 g of the target product with a yield of 55.0%.

[0212] ESI-MS [M+H] + : m / z 394.2.

[0213] 1 H NMR (600 MHz, D 2 O) δ 8.06 (d, J = 2.8 Hz, 1H), 7.66 - 7.58 (m, 2H), 7.42 (d, J = 3.2 Hz, 1H), 7.35 (d, J = 8.2 Hz, 1H), 7.22 (t, J = 7.9 Hz, 1H), 6.78 (d, J = 7.5 Hz, 1H), 6.58 (dd, J = 3.3, 0.9 Hz, 1H), 4.27 (t, J = 5.7 Hz, 2H), 3.91 (d, J = 13.6 Hz, 2H), 3.84 (d, J = 12.2 Hz, 2H), 3.54 - 3.49 (m, 2H), 3.43 (d, J = 13.0 Hz, 2H), 3.21 (t, J = 12.6 Hz, 2H), 2.39 - 2.31 (m, 2H), 2.22 (s, 3H).

[0214] Example 6

[0215] Preparation of 4-(4-(3-((6-chloropyridin-3-yl)oxy)propyl)piperazin-1-yl)-1H-indole hydrochloride

[0216] 2-Chloro-5-hydroxypyridine 0.28 g (2.16 mmol, 1.2 eq), 4-(4-(3-chloropropyl)piperazin-1-yl)-1H-indole 0.50 g (1.80 mmol, 1.0 eq), K 2 CO 30.63 g (4.50 mmol, 2.5 eq), potassium iodide 0.30 g (1.80 mmol, 1.0 eq) were dissolved in 10 mL of acetonitrile, and the mixture was stirred and reacted under reflux for 12 h. After cooling, the insoluble salts were removed by suction filtration, and the solvent was removed by distillation under reduced pressure. Water (5 mL) was added, and the mixture was extracted with dichloromethane (15 mL × 3). 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. The crude product was purified by column chromatography to obtain a pale yellow oil. The oil was dissolved in 6 mL of ethyl acetate, and the pH was adjusted to <3 by dropwise addition of 2M HCl / EtOAc. A solid was precipitated, filtered, and dried in vacuo to obtain 0.21 g of the target product, with a yield of 28.6%.

[0217] ESI-MS [M+H] + : m / z 371.1.

[0218] 1 1H NMR (400 MHz, DMSO) δ 11.18 (s, 1H), 10.47 (s, 1H), 8.20 (d, J = 3.0 Hz, 1H), 7.56 (dd, J = 8.7, 3.1 Hz, 1H), 7.51 (d, J = 8.7 Hz, 1H), 7.33 (t, J = 2.8 Hz, 1H), 7.14 (d, J = 8.1 Hz, 1H), 7.04 (t, J = 7.8 Hz, 1H), 6.56 (d, J = 7.4 Hz, 1H), 6.52 - 6.46 (m, 1H), 4.24 (t, J = 5.9 Hz, 2H), 3.80 - 3.66 (m, 4H), 3.40 - 3.31 (m, 4H), 3.17 (t, J = 12.2 Hz, 2H), 2.33 - 2.23 (m, 2H).

[0219] Example 7

[0220] Preparation of 4-(4-(3-((6-methylpyridin-3-yl)oxy)propyl)piperazin-1-yl)-1H-indole hydrochloride

[0221] 0.38 g (3.48 mmol, 1.2 eq) of 3-hydroxy-6-methylpyridine, 0.80 g (2.90 mmol, 1.0 eq) of 4-(4-(3-chloropropyl)piperazin-1-yl)-1H-indole, K 2 CO 31.00 g (7.25 mmol, 2.5 eq), potassium iodide 0.48 g (2.90 mmol, 1.0 eq) were dissolved in 20 mL of acetonitrile, and the reaction was stirred under reflux for 11 h. After cooling, the insoluble salts were removed by suction filtration, and the solvent was removed by distillation under reduced pressure. Water (10 mL) was added, and extraction was carried out with dichloromethane (20 mL × 3). 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 the crude product. Purification by column chromatography gave a pale yellow oil, which was dissolved in 6 mL of ethyl acetate. 2M HCl / EtOAc was added dropwise to adjust the pH < 3, and a solid was precipitated. The solid was filtered and dried under vacuum to obtain 313 mg of the target product, with a yield of 27.9%.

[0222] ESI-MS [M + H] + : m / z 351.1.

[0223] 1 H NMR (600 MHz, D 2 O) δ 8.30 (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 = 1.6 Hz, 1H), 7.36 (d, J = 8.1 Hz, 1H), 7.22 (t, J = 7.9 Hz, 1H), 6.79 (d, J = 7.6 Hz, 1H), 6.58 (dd, J = 3.2, 1.0 Hz, 1H), 4.34 (t, J = 5.7 Hz, 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).

[0224] Example 8

[0225] Preparation of 4-(4-(3-((6-bromopyridin-3-yl)oxy)propyl)piperazin-1-yl)-1H-indole hydrochloride

[0226] 2-Bromo-5-hydroxypyridine 0.61 g (3.48 mmol, 1.2 eq), 4-(4-(3-chloropropyl)piperazin-1-yl)-1H-indole 0.80 g (2.90 mmol, 1.0 eq), K 2 CO 31.00 g (7.25 mmol, 2.5 eq), potassium iodide 0.48 g (2.90 mmol, 1.0 eq) were dissolved in 20 mL of acetonitrile, and the mixture was stirred and reacted under reflux for 11 h. After cooling, the insoluble salts were removed by suction filtration, and the solvent was removed by distillation under reduced pressure. Water (10 mL) was added, and the mixture was extracted with dichloromethane (20 mL × 3). 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 the crude product. The crude product was purified by column chromatography to obtain a pale yellow oil. The oil was dissolved in 6 mL of ethyl acetate, and the pH was adjusted to <3 by dropping 2 M HCl / EtOAc. A solid was precipitated, filtered, and dried in vacuo to obtain 0.50 g of the target product with a yield of 38.5%.

[0227] ESI-MS [M + H] + : m / z 415.0.

[0228] 1 H NMR (600 MHz, D 2 O) δ 8.09 (d, J = 3.2 Hz, 1H), 7.59 (d, J = 8.8 Hz, 1H), 7.43 - 7.41 (m, 2H), 7.40 (d, J = 3.2 Hz, 1H), 7.38 - 7.34 (m, 1H), 7.22 (t, J = 7.9 Hz, 1H), 6.79 (d, J = 7.6 Hz, 1H), 4.25 (t, J = 5.7 Hz, 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).

[0229] Example 9

[0230] Preparation of 5-(3-(4-(1H-indol-4-yl)piperazin-1-yl)propoxy)-2-fluorobenzonitrile

[0231] 0.12 g (0.87 mmol, 1.2 eq) of 2-fluoro-5-hydroxybenzonitrile, 0.20 g (0.72 mmol, 1.0 eq) of 4-(4-(3-chloropropyl)piperazin-1-yl)-1H-indole, K 2 CO 3 0.30 g (2.1 mmol, 2.5 eq), potassium iodide 0.12 g (0.72 mmol, 1.0 eq) were dissolved in 6 mL of acetonitrile, and the mixture was stirred and reacted under reflux for 8 h. After cooling, the insoluble salts were removed by suction filtration, and the solvent was removed by distillation under reduced pressure. Water (10 mL) was added, and the mixture was extracted with dichloromethane (20 mL × 3). 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 the crude product. The crude product was purified by column chromatography to obtain 0.14 g of the target product with a yield of 51.5%.

[0232] ESI-MS [M+H] + : m / z 423.0。

[0233] 1 H NMR (400 MHz, DMSO) δ 11.06 (s, 1H), 7.57 (dd, J=5.1, 3.1 Hz, 1H), 7.49 (t, J=9.1 Hz, 1H), 7.40 (ddd, J=9.3, 4.5, 3.2 Hz, 1H), 7.27 (s, 1H), 7.05 (d, J=8.2 Hz, 1H), 6.99 (t, J=7.7 Hz, 1H), 6.47 (d, J=7.4 Hz, 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)。

[0234] Example 10

[0235] Preparation of 4-(4-(3-((6-Fluoropyridin-3-yl)oxy)propyl)piperazin-1-yl)-1-(phenylsulfonyl)-1H-indole hydrochloride

[0236] Sodium hydride (47 mg, 1.90 mmol) was mixed with THF (10 mL) and cooled in an ice bath. Then a THF (5 mL) solution of Example 1 (230 mg, 0.65 mmol) was added and stirred for 15 minutes. After dropwise addition of phenylsulfonyl chloride (172 mg, 1.00 mmol), the mixture was stirred at room temperature for 1 h. After the reaction was completed, ice water was added to quench the reaction, and the mixture was extracted with ethyl acetate (15 mL × 2). 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. The crude product was purified by column chromatography to obtain a pale yellow oil, which was dissolved in 3 mL of ethyl acetate. 2M HCl / EtOAc was added dropwise to adjust the pH < 3, and a solid precipitated. The solid was filtered and dried under vacuum to obtain 0.10 g of the target product with a yield of 29.0%.

[0237] ESI-MS [M+H] + : m / z 495.1。

[0238] 11H NMR (400 MHz, DMSO) δ 10.50 (s, 1H), 8.05 - 7.99 (m, 2H), 7.96 (dd, J = 3.2, 1.8 Hz, 1H), 7.86 (d, J = 3.8 Hz, 1H), 7.77 - 7.69 (m, 1H), 7.69 - 7.60 (m, 4H), 7.31 (t, J = 8.1 Hz, 1H), 7.19 (dd, J = 8.9, 3.4 Hz, 1H), 6.97 (d, J = 3.8 Hz, 1H), 6.85 (d, J = 7.8 Hz, 1H), 4.20 (t, J = 6.0 Hz, 2H), 3.63 (t, J = 13.5 Hz, 4H), 3.44 - 3.26 (m, 4H), 3.17 (t, J = 11.9 Hz, 2H), 2.27 - 2.23 (m, 2H).

[0239] Example 11

[0240] Preparation of 1-(4-(4-(3-((6-Fluoropyridin-3-yl)oxy)propyl)piperazin-1-yl)-1H-indol-1-yl)ethan-1-one hydrochloride

[0241] Sodium hydride (37 mg, 0.92 mmol) was mixed with THF (10 mL) and cooled in an ice bath. Then a solution of Example 1 (120 mg, 0.31 mmol) in THF (5 mL) was added, and the mixture was stirred for 15 minutes. After dropwise addition of acetyl chloride (36 mg, 0.46 mmol), the mixture was stirred at room temperature for 1 h. After the reaction was completed, ice water was added to quench the reaction, and the mixture was extracted with ethyl acetate (15 mL × 2). 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. The crude product was purified by column chromatography to obtain a pale yellow oil, which was dissolved in 3 mL of ethyl acetate. 2M HCl / EtOAc was added dropwise to adjust the pH < 3, and a solid precipitated. The solid was filtered and dried in vacuo to obtain 0.05 g of the target product, with a yield of 37.3%.

[0242] ESI-MS [M + H] + : m / z 397.1.

[0243] 1 1H NMR (600 MHz, D 2O) δ 8.15 (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, 3.2 Hz, 1H), 7.41 (t, J = 8.1 Hz, 1H), 7.09 (dd, J = 9.0, 2.6 Hz, 1H), 7.04 (d, J = 7.8 Hz, 1H), 6.83 (dd, J = 3.9, 0.8 Hz, 1H), 4.26 (t, J = 5.7 Hz, 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).

[0244] Example 12

[0245] Preparation of 4-(4-(3-((6-Fluoropyridin-3-yl)oxy)propyl)piperazin-1-yl)-1-methyl-1H-indole hydrochloride

[0246] Dissolve 0.32 g (1.50 mmol, 1.0 eq) of 1-methyl-4-(piperazin-1-yl)-1H-indole, 0.50 g (1.5 mmol, 1.0 eq) of 3-((6-fluoropyridin-3-yl)oxy)propyl 4-methylbenzenesulfonate, and K 2 CO 3 0.60 g (4.5 mmol, 3.0 eq) in 10 ml of acetonitrile, stir the reaction under reflux for 8 h. After cooling, filter off the insoluble salts by suction, and distill off the solvent under reduced pressure. Add water (10 mL), extract with dichloromethane (20 mL * 3), combine the organic phases, wash with saturated brine, and separate the layers. Dry the organic phase over anhydrous sodium sulfate, filter, and concentrate the filtrate to obtain the crude product. Purify by column chromatography to obtain a pale yellow oil, dissolve it in 3 ml of ethyl acetate, add 2M HCl / EtOAc dropwise to adjust the pH < 3, precipitate the solid, filter, and dry in vacuo to obtain 0.18 g of a white solid, with a yield of 29.6%.

[0247] ESI-MS [M + H] + : m / z 369.2.

[0248] 1 H NMR (600 MHz, D 2O) δ 7.87 (dd, J = 3.2, 1.4 Hz, 1H), 7.62 (ddd, J = 9.3, 6.4, 3.2 Hz, 1H), 7.33 - 7.25 (m, 3H), 7.09 (dd, J = 9.0, 2.6 Hz, 1H), 6.80 (dd, J = 7.4, 1.0 Hz, 1H), 6.55 (dd, J = 3.1, 0.8 Hz, 1H), 4.24 (t, J = 5.7 Hz, 2H), 3.91 (d, J = 25.3 Hz, 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).

[0249] Comparative Example 1 (Compound 1a of Reference Patent WO2001049680A1)

[0250] Preparation of 4-(4-(3-(2,4-difluorophenoxy)propyl)piperazin-1-yl)-1H-indole hydrochloride

[0251]

[0252] 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)piperazin-1-yl)-1H-indole, K 2 CO 3 0.24 g (1.7 mmol, 3 eq), and 96 mg (0.58 mmol, 1.0 eq) of potassium iodide in 6 mL of acetonitrile, and stir the reaction under reflux for 8 h. After cooling, filter off the insoluble salts, and distill off the solvent under reduced pressure. Add water (5 mL), extract with dichloromethane (15 mL * 3), combine the organic phases, wash with saturated brine, and separate the layers. Dry the organic phase over anhydrous sodium sulfate, filter, concentrate the filtrate to obtain the crude product. Purify by column chromatography to obtain a pale yellow oil, dissolve it in 3 mL of ethyl acetate, add 2M HCl / EtOAc dropwise to adjust the pH < 3, precipitate the solid, filter, and dry in vacuo to obtain 124 mg of the target product, with a yield of 52.4%.

[0253] ESI-MS [M + H] + : m / z 372.2.

[0254] 11H NMR (600 MHz, DMSO-d6) δ 11.21 (s, 1H), 11.13 (s, 1H), 7.31 (tt, J = 8.0, 4.1 Hz, 2H), 7.25 (td, J = 9.4, 5.4 Hz, 1H), 7.13 (d, J = 8.1 Hz, 1H), 7.08 - 6.98 (m, 2H), 6.56 (d, J = 7.5 Hz, 1H), 6.49 (s, 1H), 4.17 (t, J = 6.0 Hz, 2H), 3.71 (d, J = 12.6 Hz, 2H), 3.66 (d, J = 11.8 Hz, 2H), 3.39 - 3.31 (m, 4H), 3.30 - 3.23 (m, 2H), 2.32 - 2.24 (m, 2H).

[0255] Comparative Example 2 (Compound 1e of Reference Patent WO2003002552A1)

[0256] Preparation of 4-(4-(2-((2-chloropyridin-3-yl)oxy)ethyl)piperazin-1-yl)-1H-indole hydrochloride

[0257]

[0258] Dissolve 3.5 mL of 1-bromo-2-chloroethane, 0.55 g of 4-(piperazin-1-yl)-1H-indole and 0.5 mL of DIPEA in 6 mL of acetone, and stir at 60 °C for 5 h. After the reaction is completed, cool to room temperature, add 10 mL of water, extract with dichloromethane (15 mL × 3), combine the organic phases, wash with saturated brine, and separate the layers. The organic phase is dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated to obtain the crude product. Purify by column chromatography to obtain 360 mg of 4-(4-(3-chloroethyl)piperazin-1-yl)-1H-indole, with a yield of 26.1%.

[0259] 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)piperazin-1-yl)-1H-indole, K 2 CO 30.58 g (4.2 mmol, 3 eq), potassium iodide 0.23 g (1.4 mmol, 1.0 eq) were dissolved in 6 mL of acetonitrile, and the reaction was stirred under reflux for 12 h. After cooling, the insoluble salts were removed by suction filtration, and the solvent was removed by distillation under reduced pressure. Water (10 mL) was added, and the mixture was extracted with dichloromethane (20 mL * 3). 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 the crude product. The crude product was purified by column chromatography to obtain a pale yellow oil. The oil was dissolved in 3 mL of ethyl acetate, and 2 M HCl / EtOAc was added dropwise to adjust the pH < 3. A solid precipitated, which was filtered and dried under vacuum to obtain 92 mg of the target product with a yield of 16.7%.

[0260] ESI-MS [M + H] + : m / z 357.1.

[0261] 1 1H NMR (600 MHz, DMSO-d6) δ 11.75 (s, 1H), 11.24 (s, 1H), 8.05 (dd, J = 4.7, 1.4 Hz, 1H), 7.71 (dd, J = 8.2, 1.5 Hz, 1H), 7.46 (dd, J = 8.2, 4.6 Hz, 1H), 7.32 (t, J = 2.8 Hz, 1H), 7.14 (d, J = 8.0 Hz, 1H), 7.02 (t, J = 7.8 Hz, 1H), 6.61 (d, J = 7.6 Hz, 1H), 6.52 (s, 1H), 4.68 (t, J = 5.0 Hz, 2H), 3.77 (d, J = 12.0 Hz, 2H), 3.76 - 3.74 (m, 3H), 3.74 - 3.70 (m, 3H), 3.62 - 3.46 (m, 2H).

[0262] Comparative Example 3 (Example 40 of Reference Patent WO2007026959A2)

[0263] Preparation of 1-(benzo[b]thiophen-4-yl)-4-(3-((6-methylpyridin-3-yl)oxy)propyl)piperazine hydrochloride

[0264]

[0265] After 1-(benzo[b]thiophen-4-yl)piperazine hydrochloride was liberated in dichloromethane solution, 1-bromo-3-chloropropane was added, and 1-(benzo[b]thiophen-4-yl)-4-(3-chloropropyl)piperazine was obtained according to the general method, as a white solid with a yield of 61%.

[0266] Dissolve 371 mg of 1-(benzo[b]thiophen-4-yl)-4-(3-chloropropyl)piperazine (3.4 mmol, 1 eq) and 1 g of 2-methyl-5-hydroxypyridine (3.4 mmol, 1 eq) in acetonitrile (50 mL). Add 1.4 g of potassium carbonate (10.2 mmol, 3 eq) and 564 mg of potassium iodide (3.4 mmol, 1 eq), and stir the reaction under reflux for 8 h. After cooling, filter off the insoluble salts by suction, and distill off the solvent under reduced pressure. Add water (15 mL), extract with dichloromethane (25 mL × 3), combine the organic phases, wash with saturated brine, and separate the layers. Dry the organic phase over anhydrous sodium sulfate, filter, and concentrate the filtrate to obtain the crude product. Purify by column chromatography to obtain a pale yellow oil. Dissolve it in 3 mL of ethyl acetate, add 2 M HCl / EtOAc dropwise to adjust the pH < 3, precipitate the solid, filter, and dry in vacuo to obtain 530 mg of the target product, with a yield of 38.6%.

[0267] ESI-MS [M + H] + : m / z 368.2.

[0268] 1 H NMR (400 MHz, DMSO) δ 10.96 (s, 1H), 8.47 (s, 1H), 7.92 (s, 1H), 7.82 (d, J = 5.6 Hz, 1H), 7.75 (d, J = 8.1 Hz, 1H), 7.69 (d, J = 8.6 Hz, 1H), 7.54 (d, J = 5.6 Hz, 1H), 7.37 (t, J = 7.9 Hz, 1H), 7.02 (d, J = 7.5 Hz, 1H), 4.32 (t, J = 6.0 Hz, 2H), 3.70 (d, J = 11.7 Hz, 2H), 3.64 - 3.59 (m, 1H), 3.59 - 3.56 (m, 1H), 3.41 - 3.37 (m, 4H), 3.29 (t, J = 12.1 Hz, 2H), 2.62 (s, 3H), 2.37 - 2.29 (m, 2H).

[0269] Biological Test Evaluation

[0270] The present invention will be further described and explained in combination with test examples below, but these examples do not mean to limit the scope of the present invention.

[0271] Test Example 1, 5-HT of the compound of the present invention in vitro 1A Receptor function test

[0272] 1.1 Experimental materials

[0273] 1.1.1 Cell information: HEK293 / 5HT 1A , internally constructed.

[0274] 1.1.2 Experimental reagents and consumables:

[0275]

[0276]

[0277] 1.1.3 Experimental instruments:

[0278] Name Supplier Model Cell Counter Countstar BioTech EnVision Multifunctional Microplate Reader PerkinElmer 2105 Milli-Q Ultrapure Water System Millipore IQ 7000 Centrifuge Cence TDZ5-WS Picoliter Upgrade Micropipette Tecan D300e

[0279] 1.2 Experimental methods

[0280] (1) Compound preparation: The compound to be tested and 5HT are diluted to 0.1 mM with stimulation buffer for standby.

[0281] (2) Preparation of experimental buffer: Dilute 5×stimulation buffer to 1× with ddH 2 O and add IBMX with a final concentration of 0.5 mM, mix well for standby.

[0282] (3) Digest cells with trypsin, centrifuge after termination, resuspend the cell pellet with 10 mL of pre-warmed HBSS, centrifuge, and then resuspend with 1 mL of stimulation buffer. Take 20 μL for cell counting.

[0283] (4) Dilute an appropriate amount of cell suspension to 0.6×10 6 cells / mL. Add 5 μL of cell suspension to each well in the cell plate and centrifuge at 1000 rpm for 1 minute.

[0284] (5) Use Bravo to dilute and transfer compounds: Dilute the compounds 4-fold at 8 points in the compound plate; then use Bravo to transfer the diluted compounds in the whole plate to a 384-well white plate and centrifuge at 1000 rpm for 1 minute.

[0285] (6) Seal the experimental plate and incubate at room temperature for 15 minutes.

[0286] (7) Use Tecan D300e to add forskolin prepared with DMSO. The stock solution is 0.2 mM and the final concentration is 1 μM. Centrifuge at 1000 rpm for 1 minute.

[0287] (8) Seal the plate and incubate at room temperature for 45 minutes.

[0288] (9) Preparation of cAMP standard curve: The starting concentration is 2848 nM, and it is serially diluted 4-fold at 8 points. Take 10 μL and add it to the experimental plate. The highest point concentration is 712 nM.

[0289] Add 5 μL of cAMP-d2 solution (the stock solution is diluted 1:20 with lysis buffer) to the assay plate and centrifuge at 1000 rpm for 1 minute.

[0290] (11) Then add another 5 μL of Anti-cAMP-Cryptate solution (the stock solution is diluted 1:20 with lysis buffer) to the assay plate and centrifuge at 1000 rpm for 1 minute.

[0291] (12) Incubate the assay plate at room temperature for 1 hour and centrifuge at 1000 rpm for 1 minute before reading.

[0292] (13) Read the plate using Envision. The excitation wavelength is 320 nm, and the emission wavelengths are 620 nm and 665 nm. Analyze and process the exported data to calculate the maximum activation rate E of the compound max and EC 50 .

[0293] 1.3 Experimental results: See Table 1.

[0294] Table 1 Experimental results of the compounds of the present invention on 5-HT 1A receptor function

[0295]

[0296] 1.4 Experimental conclusion:

[0297] According to the results in Table 1 above, the compounds of the present invention can act on 5-HT 1A receptor and exhibit good 5-HT 1A (partial) agonist activity.

[0298] Test Example 2 Functional experiment of the compounds of the present invention on dopamine D 2L receptor in vitro

[0299] 2.1 Experimental materials

[0300] 2.1.1 Cell information:

[0301] Cell Name Supplier <![CDATA[HEK293 / D 2L > GenScript Biotech Corporation

[0302] 2.1.2 Experimental reagents and consumables:

[0303]

[0304]

[0305] 2.1.3 Experimental instruments:

[0306] Name Supplier Model Cell Counter Countstar BioTech EnVision Multifunctional Microplate Reader PerkinElmer 2105 Milli-Q Ultrapure Water System Millipore IQ 7000 Centrifuge Cence TDZ5-WS Picoliter Upgrade Micropipette Tecan D300e

[0307] 2.2 Experimental methods

[0308] (1) Compound preparation: Dilute the compound to be tested and dopamine to 200 nM for standby.

[0309] (2) Preparation of experimental buffer: Dilute 5×stimulation buffer to 1× with ddH 2 O, and add IBMX with a final concentration of 0.5 mM, mix well for standby.

[0310] (3) Digest the cells with trypsin, centrifuge after termination, resuspend the cell pellet with 10 mL of pre-warmed HBSS, centrifuge, and then add

[0311] 1 mL of stimulation buffer to resuspend, and take 20 μL for cell counting.

[0312] (4) Take an appropriate amount of cell suspension and dilute it to 0.4×10 6 cells / mL. Add 5 μL of the cell suspension to each well in the cell plate and centrifuge at 1000 rpm for 1 minute.

[0313] (5) Use Bravo to dilute and transfer the compound: Dilute the compound 4-fold at 8 points in the compound plate; then use Bravo to transfer the diluted compound to the 384-well white plate as a whole plate and centrifuge at 1000 rpm for 1 minute.

[0314] (6) Seal the test plate and incubate at room temperature for 15 minutes.

[0315] (7) Use Tecan D300e to add forskolin prepared with DMSO. The stock solution is 0.2 mM, and the final concentration is 0.25 μM. Add 25.1 nL of forskolin to each well and centrifuge at 1000 rpm for 1 minute.

[0316] (8) Seal the plate and incubate at room temperature for 45 minutes.

[0317] (9) Preparation of cAMP standard curve: The starting concentration is 2848 nM, and it is serially diluted 4-fold at 8 points. Take 10 μL and add it to the experimental plate. The highest point concentration is 712 nM.

[0318] (10) Add 5 μL of cAMP-d2 solution (the stock solution is diluted 1:20 with lysis buffer) to the experimental plate and centrifuge at 1000 rpm for 1 minute.

[0319] (11) Then add another 5 μL of Anti-cAMP-Cryptate solution (the stock solution is diluted 1:20 with lysis buffer) to the experimental plate and centrifuge at 1000 rpm for 1 minute.

[0320] (12) The experimental plate was incubated at room temperature for 45 minutes and centrifuged at 1000 rpm for 1 minute before reading.

[0321] (13) Read the plate using Envision. The excitation wavelength was 320 nm, and the emission wavelengths were 620 nm and 665 nm. Analyze and process the exported data to calculate the maximum activation rate Emax and EC of the compound. 50 .

[0322] 2.3 Experimental results: See Table 2.

[0323] Table 2 Experimental results of the compounds of the present invention on D 2 receptor function

[0324]

[0325] 2.4 Experimental conclusion:

[0326] According to the results in Table 2 above, the compounds of the present invention can act on dopamine D 2 receptor and exhibit good dopamine D 2 (partial) agonist activity.

[0327] Test Example 3, dopamine D 3 receptor function experiment of the compounds of the present invention in vitro

[0328] 3.1 Experimental materials

[0329] 3.1.1 Cell information: CHO-K1 / D 3 / CRE, internally constructed.

[0330] 3.1.2 Experimental reagents and consumables:

[0331]

[0332]

[0333] 3.1.3 Experimental instruments:

[0334] Name Supplier Model Cell Counter Countstar BioTech EnVision Multifunctional Microplate Reader PerkinElmer 2105 Milli-Q Ultrapure Water System Millipore IQ 7000 Centrifuge Cence TDZ5-WS Picoliter Upgrade Micropipette Tecan D300e

[0335] 3.2 Experimental method

[0336] Day 1: Cell seeding

[0337] (1) The cultured cells were digested with trypsin. After terminating the digestion with the medium, the cell suspension was transferred to a centrifuge tube and centrifuged at 750

[0338] rpm for 5 minutes.

[0339] (2) Discard the supernatant, resuspend the precipitate with an appropriate amount of plating medium, and take 20 μL for counting with a cell counter.

[0340] (3) Dilute an appropriate amount of cell suspension to 0.5×10 6 cells / mL, and add 20 μL of the cell suspension to each well in the cell plate (cell density is 10,000 cells / well).

[0341] (4) Place the cell plate in 5% CO 2 incubate overnight at 37°C.

[0342] The next day: Experimental detection

[0343] (1) Dilute the test compound to 0.2 mM with DMSO, and dilute the reference compound Dopamine to 0.02 mM.

[0344] (2) Use Bravo to dilute the compounds (4-fold dilution at 8 concentration points). 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.

[0345] (3) Centrifuge at 1000 rpm for 1 minute, and incubate at 5% CO 2 for 30 minutes at 37°C.

[0346] (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. In the Blank group, add cells without adding Forskolin.

[0347] (5) Centrifuge at 1000 rpm for 1 minute, and incubate at 5% CO 2 for 4 hours at 37°C.

[0348] (6) Take out the lysis buffer 30 minutes in advance, melt it in a water bath at room temperature and restore it to room temperature. Take an appropriate amount of substrate and dilute it with the lysis buffer at a ratio of 1:50, and mix well for standby.

[0349] (7) Add 20 μL of the detection reagent and centrifuge at 1000 rpm for 1 minute.

[0350] (8) After incubating at room temperature for 3 minutes, use Envision to read the plate. Select the ultra-sensitive chemiluminescence detection program. Analyze and process the exported data, and calculate the maximum activation rate E max and EC 50 .

[0351] 3.3 Experimental Results: See Table 3.

[0352] Table 3 Experimental Results of the Compounds of the Invention on D 3 Receptor Function

[0353]

[0354] 3.4 Experimental Conclusion:

[0355] According to the results in Table 3 above, the compounds of the invention can act on dopamine D 3 receptor and exhibit good dopamine D 3 (partial) agonist activity.

[0356] Based on the in vitro test results in Tables 1 - 3 above, the compounds of the invention have the characteristics of acting on multiple targets of D 2 , D 3 and / or 5-HT 1A , and exhibit receptor (partial) agonist activity on D 2 , D 3 and / or 5-HT 1A receptors. Among them, Examples 1, 3 - 4, 6 - 9, 11 - 12 have agonist effects on at least two of the targets of D 2 , D 3 and / or 5-HT 1A . In particular, Examples 1, 4, and 11 exhibit triple (partial) agonist activity on 5-HT 1A receptor, dopamine D 2 and D 3 receptors.

[0357] Test Example 4: In Vitro Microsomal Experiment of the Compounds of the Invention

[0358] 4.1 Experimental Purpose

[0359] To evaluate the phase I metabolic stability of the compounds of the invention in CD-1 mice, SD rats, and human liver microsomes.

[0360] 4.2 Experimental Materials

[0361] (1) Experimental Reagents:

[0362] Reagent Supplier Model Dipotassium 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 <![CDATA[MgCl 2 > Greagent 01115966 G6PDH Shanghai Yuanye S10078

[0363] (2) Experimental Instruments:

[0364] Name Supplier Model Liquid Phase SCIEX <![CDATA[Exion LC tm > Mass Spectrometry SCIEX Triple Qvad 5500 Centrifuge Thermo Fisher 75009915 Plate Shaker Thermo Scientific 88882006

[0365] 4.3 Experimental Method

[0366] (1) Preparation of buffer solution: Dissolve 73.21 g of dipotassium hydrogen phosphate trihydrate and 10.78 g of potassium dihydrogen phosphate in 4000 mL of ultrapure water. Adjust the pH value of the solution between 7.40 ± 0.10 using 10% phosphoric acid or 1 M potassium hydroxide, and its final concentration is 100 mM.

[0367] (2) Preparation and dilution of solutions: Prepare a stock solution of the test compound with a concentration of 10 mM using dimethyl sulfoxide (DMSO), store it at 4°C, and dilute it to a working solution concentration of 100 μM with pure acetonitrile when in use. Prepare a stock solution of the control compound testosterone with a concentration of 10 mM using DMSO, store it at -20°C, and dilute it to a working solution concentration of 400 μM with pure acetonitrile when in use.

[0368] (3) Preparation of termination solution: The termination solution is acetonitrile containing the internal standard buspirone. The prepared termination solution is stored in a refrigerator at 2 - 8°C.

[0369] (4) Preparation of liver microsome solution: Dilute the microsomes of various species (CD-1 mice, SD rats, and humans) to a 20× working solution with 100 mM potassium phosphate buffer. The final concentration of microsomes in the reaction system is 0.5 mg / mL.

[0370] (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 glucose-6-phosphate dehydrogenase (G6PDH), and 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 up and down evenly. 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.

[0371] (6) Incubation process: The incubation is completed in a 96-well plate. Prepare several incubation plates, named T0, T5, T10, T20, T40, T60, PB60, and NCF60 respectively. The first 6 plates correspond to reaction time points of 0, 5, 10, 20, 40, and 60 minutes respectively. In the NCF60 plate, incubate for 60 minutes using potassium phosphate buffer instead of the NADPH regeneration system solution. In the PB60 plate, incubate for 60 minutes using potassium phosphate buffer instead of liver microsomes. All condition samples are in triplicate.

[0372] Add 2 μL of the test compound or control compound and 100 μL of microsome working solution (containing 1 mg / mL of liver microsome protein) to the T0, T5, T10, T20, T40, T60, and NCF60 plates respectively. Add 2 μL of the test compound and 100 μL of potassium phosphate buffer to the PB60 plate. Then place the above incubation plates in a 37 °C water bath for pre-incubation for about 5 minutes.

[0373] After the pre-incubation, the T0 sample is first added with 600 μL of the termination solution and then 98 μL of the NADPH regeneration system working solution. Seal the plate, shake it, and wait to be processed simultaneously with the subsequent samples. For each sample well in the incubation plates except NCF60, add 98 μL of the NADPH regeneration system working solution to initiate the reaction, while add 98 μL of potassium phosphate buffer to each sample well in the NCF60 incubation plate. The final reaction concentrations of the test compound and control compound in the reaction system are 1 μM and 4 μM respectively, the concentration of liver microsomes is 0.5 mg / mL, and the final concentrations of DMSO and acetonitrile in the reaction system are 0.01% (v / v) and 0.99% (v / v) respectively.

[0374] After incubation for an appropriate time (such as 5, 10, 20, 40, and 60 minutes), add 600 μL of the termination solution containing the internal standard to each well of the test compound sample and control compound to terminate the reaction. Seal the plate, shake well, and then centrifuge at 4 °C and 4000×g for 15 minutes. Take the supernatant and transfer it to a 96-well sample receiving plate. Dilute it with an appropriate amount of pure water, shake well, and use it for LC-MS / MS analysis. Use the software Analyst 7.1 (Sciex, Framingham, Massachusetts, USA) for data processing. 4.4 Experimental results: The results of the in vitro liver microsome stability test are shown in Table 4.

[0375] Table 4 Results of the in vitro liver microsome stability test

[0376]

[0377] Note: The clearance rate classification criteria are shown in the following table:

[0378]

[0379] 4.5 Experimental conclusion:

[0380] The above data show that Example 1 of the present invention belongs to medium-rate clearance in the liver microsomes of SD rats and CD-1 mice, and belongs to low-rate clearance in human liver microsomes; while Comparative Example 3 belongs to high-rate clearance in the liver microsomes of all three species. Based on the pharmacodynamic activity and pharmacological mechanism of this series of compounds, a slower metabolic rate is beneficial for the compound to exert its pharmacodynamic activity. Therefore, the compounds of the present invention are significantly superior to the comparative compounds in terms of metabolic rate.

[0381] Test Example 5. Test on the Effect of the Compound of the Present Invention on the Jaw Tremor Behavior of Rats Induced by Tacrine

[0382] 5.1 Experimental Purpose:

[0383] Evaluate the efficacy of the compound of the present invention through a rat jaw tremor model induced by intraperitoneal injection of tacrine.

[0384] 5.2 Experimental Scheme:

[0385] (1) Experimental Materials:

[0386] Test Compound: The compound of the example of the present invention, self-made.

[0387] Positive Control Compound: Rotigotine, TargetMoI, 153266.

[0388] Modeling Drug: Tacrine, SIGMA, A3773-1G.

[0389] Solvent: Normal saline, Chenxin Pharmaceutical Co., Ltd., 2111060723.

[0390] DMSO: SIGMA, D2650-100ML.

[0391] (2) Main Experimental Instruments:

[0392]

[0393]

[0394] (3) Experimental Animals:

[0395] Experimental Animals: Sprague Dawley rats, male, 6 rats / group, Shanghai Slac Laboratory Animal Co., Ltd.

[0396] (4) Administration Information:

[0397] Drug Preparation: Take the test compound, add the solvent and perform ultrasonic treatment.

[0398] Administration Route and Method: Intraperitoneal injection.

[0399] Administration Frequency and Duration: Single administration.

[0400] After stratifying the animals by body weight, randomly divide them into a model group, an administration group and a control group. The detailed administration information is shown in the following table:

[0401]

[0402] (5) Experimental method:

[0403] After stratifying the rats according to body weight, they were randomly divided into a model group, a drug administration group, and a control group. The rats were subjected to adaptation training three days before the experiment. On the day of the experiment, the rats were first intraperitoneally injected with a solvent or a drug. 30 minutes later, tacrine was intraperitoneally injected at 5 mg / kg (body weight). After administration, the rats were placed in a transparent observation box. 10 minutes later, the jaw tremor count was started, and the continuous counting duration was 5 minutes. The number of jaw tremors of the rats within 5 minutes was recorded.

[0404] (6) Data processing and statistics:

[0405] The experimental data are expressed as Inhibition rate % = 100% * (number of jaw tremors of rats in the model group - number of jaw tremors of rats in the drug administration group) / number of jaw tremors of rats in the model group

[0406] 5.3 Experimental results: As shown in Table 5.

[0407] Table 5 Test results of the effect of the compound of the present invention on tacrine-induced jaw tremor behavior in rats

[0408] Group Inhibition Rate @ 3 mg / kg Inhibition Rate @ 10 mg / kg Example 1-A 99.9％ - Rotigotine - 80.2％

[0409] 5.4 Experimental conclusion:

[0410] It is concluded from the above scheme that Example 1 of the present invention can significantly inhibit tacrine-induced jaw tremor in rats, and compared with rotigotine, the compound of the present invention has a stronger drug effect and has potential anti-Parkinson's effects.

Claims

1. An agonist compound of a serotonin receptor and / or a dopamine receptor represented by the general formula (II) or a pharmaceutically acceptable salt thereof: Wherein: M is selected from N; R 1 selected from halogen, cyano, C 1-3 alkyl, C 1-3 haloalkyl or -NR aa C(O)R bb ; R aa and R bb each independently selected from hydrogen or C 1-3 alkyl; R 2 selected from hydrogen, C 1-3 alkyl, -C(O)R AA or -S(O) 2 R AA ; R AA selected from C 1-3 alkyl or phenyl; R 3 Selected from hydrogen.

2. The agonist compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof according to claim 1, wherein, R 1 selected from fluorine, chlorine, bromine, cyano, methyl, trifluoromethyl or -NHC(O)CH 3 .

3. The agonist compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof according to claim 1, wherein, R 2 selected from hydrogen, methyl, -C(O)CH 3 or -S(O) 2 -Ph.

4. An agonist compound of a serotonin receptor and / or a dopamine receptor represented by the general formula (II) or a pharmaceutically acceptable salt thereof: Wherein: M is selected from CR 0 ; R 0 is selected from cyano; R 1 is selected from halogen; R 2 is selected from hydrogen; R 3 is selected from hydrogen.

5. The agonist compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof according to claim 1 or 4, wherein, The general formula (II) is further as shown in the general formula (III): Wherein: M, R 1 , R 2 As described in claim 1 or 4.

6. The agonist compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof according to claim 1 or 4, wherein, The general formula (II) is further as shown in the general formula (IV): Wherein: M, R 1 , R 2 As described in claim 1 or 4.

7. The agonist compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof according to claim 1 or 4, wherein, Selected from the following compounds: 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-(phenylsulfonyl)-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.

8. The agonist compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof according to claim 1 or 4, wherein, The pharmaceutically acceptable salt is selected from hydrochloride, hydrobromide, sulfate, trifluoroacetate or methanesulfonate.

9. The agonist compound of general formula (II) as claimed in claim 8 or a pharmaceutically acceptable salt thereof, characterized in that, the pharmaceutically acceptable salt is selected from hydrochloride or hydrobromide.

10. A method for preparing the agonist compound of general formula (II) as claimed in claim 1 or 4 or a pharmaceutically acceptable salt thereof, characterized in that, comprises the following steps: The compound of general formula (I-1) reacts with the compound of general formula (II-2) to form the compound of general formula (II-3), and then undergoes a condensation reaction with the compound of general formula (I-4) to prepare the agonist compound of general formula (II) or a pharmaceutically acceptable salt thereof; or, The compound of general formula (I-1) directly reacts with the compound of general formula (II-5) to prepare the agonist compound of general formula (II) or a pharmaceutically acceptable salt thereof; wherein: X 1 and X 2 is a halogen and is independently selected from fluorine, chlorine, bromine or iodine, M, R 1 , R 2 , R 3 As described in claim 1 or claim 4.

11. A pharmaceutical composition comprising a therapeutically effective dose of the agonist compound of general formula (II) as claimed in any one of claims 1-9 or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers.

12. Use of the agonist compound of general formula (II) as claimed in any one of claims 1-9 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition as claimed in claim 11 in the preparation of a drug related to or modulating 5-hydroxytryptamine receptor and / or dopamine receptor.

13. The use according to claim 12, characterized in that, The application is for use in the preparation of a drug involving or regulating 5-HT 1A receptor, dopamine D 2 receptor and / or dopamine D 3 receptor 14. Use of the agonist compound of general formula (II) as claimed in any one of claims 1-9 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition as claimed in claim 11 in the preparation of a drug for treating central nervous system diseases.

15. The use according to claim 14, characterized in that, the central nervous system diseases are selected from one or more of Parkinson's disease, schizophrenia, bipolar disorder, depression, anxiety, mania, Huntington's disease, Alzheimer's disease, memory disorder, loss of executive function, neuropathic pain and functional disorder diseases related to intelligence, learning or memory.

16. The use according to claim 14, characterized in that, the central nervous system disease is selected from Parkinson's disease.

17. The use according to claim 14, characterized in that, the central nervous system disease is selected from senile dementia.

18. The use according to claim 14, characterized in that, the central nervous system disease is selected from Alzheimer's type dementia.

19. The use according to claim 14, characterized in that, the central nervous system disease is selected from vascular dementia.

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