CN107586281A - Aralkyl heterocyclic derivative and its application in Mutiple Targets depression - Google Patents

Abstract

The invention discloses a class of arane heterocyclic compounds or pharmaceutically acceptable salts thereof, which have the following structure, The compound and the composition containing it all have activity on 5-HT reuptake, 5-HT _1A receptor and 5-HT ₇ receptor, and can be applied to the preparation of novel antidepressant drugs.

Description

Arane heterocyclic derivatives and their application in multi-target antidepressant

technical field

The invention belongs to the field of new drug design and synthesis, and specifically relates to an arane heterocyclic derivative and its application in multi-target antidepressant.

Background technique

Depression is a common clinical mental illness that seriously affects human health and quality of life. About 350 million people worldwide suffer from depression. It is estimated that by 2020, depression will become the second disease affecting the quality of human life.

To date, the mechanism of action of antidepressant drugs has not been fully elucidated. Drugs with clear curative effects basically act on the synaptic site of nerve endings, and exert therapeutic effects by regulating the level of neurotransmitters in the synaptic cleft. Biochemical studies of its etiology have shown that depression is mainly related to the central five-hydroxytryptamine (5-HT), norepinephrine (NA), dopamine (DA), acetylcholine (Ach) and γ-aminobutyric acid (GABA). Neurotransmitter related.

Antidepressants can be divided into two categories: early non-selective antidepressants and new selective reuptake inhibitors. Non-selective antidepressants mainly include monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants (TCAs); selective reuptake inhibitors mainly include (1) selective serotonin (5-HT) reuptake inhibitors (SSRIs), such as Fluoxetine, Paroxetine; (2) Norepinephrine (NA) reuptake inhibitors (NRIs), such as Reboxitine; (3) Norepinephrine (4) 5-HT and NA dual reuptake inhibitors (SNRIs), such as venlafaxine (Venlafaxine) and Duloxetine; (5) 5-HT reabsorption enhancers, such as Tianeptine and the like.

Due to the fact that most antidepressants currently used clinically have relatively large side effects, slow onset of effect, poor effectiveness and other deficiencies, resulting in many patients stopping medication during treatment. Therefore, the development of antidepressants is still a focus of new drug research, and many pharmaceutical industries have invested a large amount of funds for the development of safe and efficient therapeutic drugs.

In order to make up for the above defects, the strategy of simultaneously acting on 5-HT reuptake and 5-HT receptor subtypes is considered to be an effective method to shorten the onset time and improve drug efficacy. The marketed drug vilazodone has SSRI/5-HT _1A dual-target effects (J.Med.Chem.2004, 47, 4684-4692), and its antidepressant onset is accelerated and side effects are reduced, but there are still many deficiencies , such as low drug efficacy, can not improve the patient's cognitive impairment (Chin.J.Clin.Pharmacol.2014,30,862-864; J.Clin.Psychiatry,2011,72,1166–1173); currently marketed vortioxetine It is also a SSRI/5-HT _1A dual-target drug. Compared with vilazodone, it can improve the cognitive function of patients with depression. The reason is that it also affects 5-HT _1B , 5-HT _1D , 5- HT _3A , 5-HT ₇ and other subtypes have stronger effects (Pharmacology & Therapeutics, 2015, 145, 43-57; J. Med. Chem. 2011, 54, 3206–3221). However, vortioxetine will increase the suicidal tendency of adolescents in the initial treatment stage, while still causing sexual dysfunction in patients (Int.J.Clin.Pract.2014,68,60-82; Chin.J.Clin.Pharmacol.2015 , 31, 143-145). Therefore, more and more patients with depression need antidepressant drugs that have quick onset, improve cognitive function, reduce sexual dysfunction, and reduce suicidal tendencies. Safer and more effective antidepressant drugs are available. This is also the main focus of new antidepressant drug research at home and abroad. direction.

There are many 5-HT receptor subtypes associated with depression, and studies have shown that 5-HT ₇ receptor antagonists can produce antidepressant effects, and the onset time is faster than fluoxetine. The study also found that the 5-hydroxytryptamine reuptake inhibitor (SSRI) antidepressant citalopram combined with the 5-HT ₇ R antagonist SB269970 showed better activity in antidepressant animal models. It is also reported in the literature that vortioxetine, a marketed drug, can improve the cognitive impairment of patients, which may be related to its antagonistic effect on 5-HT ₇ receptors. In summary, the above studies suggest that, on the basis of the dual-target effect of SSRI/5-HT _1A , it also antagonizes the 5-HT ₇ receptor, which theoretically has the characteristics of strong antidepressant activity, rapid onset of action, and improvement of cognitive dysfunction. At present, there are few domestic and foreign research reports on new antidepressants with SSRI/5-HT _1A /5-HT ₇ triple-target effects. Therefore, drug research and development in this direction has great innovation and important scientific significance.

The present invention aims to obtain a series of novel antidepressant compounds with SSRI/5-HT _1A /5-HT ₇ triple-target effects by means of targeted drug molecule design and synthesis. After in vivo and in vitro activity and safety evaluation experiments, Obtain an antidepressant active structure with high efficiency, low toxicity and fast onset of action, so as to develop an ideal new antidepressant drug.

Contents of the invention

The invention discloses a class of arane heterocyclic derivatives (or called compounds) or pharmaceutically acceptable salts thereof, which have three target activities of 5-HT reuptake, 5-HT _1A and 5-HT ₇ Application in the preparation of antidepressants. The new derivatives can overcome the common defects of slow onset of action, low curative effect, large side effects and inability to improve cognitive impairment in existing antidepressant drugs, and meet the needs of depression treatment.

Specifically, the structure of the arane heterocyclic derivatives described in the present invention contains an aromatic group and a piperidinyl group or a piperazinyl group. More specifically, the arane heterocyclic compound or a pharmaceutically acceptable salt thereof according to the present invention is characterized in that it has the following general structural formula (I):

in:

Ar ₁ is selected from:

Ar is selected from _:

Ar ₁ selected from , the 2-position or 3-position of its five-membered heterocyclic ring is connected with the corresponding carbon chain in the formula (I);

Ar ₂ selected from When, it is connected with the corresponding nitrogen-containing six-membered ring in the formula (I), and its Z ring is in the combined position except for the positions occupied by R ₅ , R ₆ , and R ₇ on the adjacent benzene ring;

R ₁ is independently selected from hydrogen or hydroxyl;

R ₂ , R ₃ , R ₄ are each independently selected from hydrogen, halogen or cyano;

R ₅ , R ₆ , R ₇ are each independently selected from hydrogen, halogen, hydroxyl, methoxy, methylthio, acetyl, cyano, phenyl or substituted phenyl;

X is selected from C or N;

Y is selected from O, S or N;

Ring Z represents a five-membered or six-membered unsaturated ring containing one or more heteroatoms selected from O, S or N;

m is selected from 0, 1 or 2.

Preferably, the arane heterocyclic compound represented by formula (I) or _a pharmaceutically acceptable salt thereof provided by the present invention is characterized in that R is selected from hydroxyl;

Ar ₁ is selected from:

Ar is selected from _:

Ar ₂ selected from , it is connected with the corresponding nitrogen-containing six-membered ring in formula (I), and its Z ring is in the combined position except for R ₅ , R ₆ , and R ₇ on the adjacent benzene ring;

R ₂ , R ₃ , R ₄ are each independently selected from hydrogen, halogen or cyano;

R ₅ , R ₆ , R ₇ are each independently selected from hydrogen, halogen, hydroxyl, methoxy, methylthio, acetyl, cyano, phenyl or substituted phenyl;

X is selected from C or N;

Y is selected from O, S or N;

Ring Z represents a five-membered or six-membered unsaturated ring containing one or more heteroatoms selected from O, S or N;

m is selected from 1.

Preferably, the arane heterocyclic compound represented by the formula (I) provided by the present invention is characterized in that,

R ₁ is selected from hydroxyl;

Ar ₁ is selected from:

Ar is selected from _:

R ₂ , R ₃ , R ₄ are each independently selected from hydrogen, halogen or cyano;

R ₅ , R ₆ , R ₇ are each independently selected from hydrogen, halogen, hydroxyl, methoxy, methylthio, acetyl, cyano, phenyl or substituted phenyl;

X is selected from C or N;

m is selected from 1.

Preferably, the arane heterocyclic compound represented by the formula (I) provided by the present invention is characterized in that,

R ₁ is selected from hydrogen;

Ar ₁ is selected from:

Ar is selected from _:

Ar ₁ selected from , the 2-position or 3-position of its five-membered heterocyclic ring is connected with the corresponding carbon chain in the formula (I);

Ar ₂ selected from , it is connected with the corresponding nitrogen-containing six-membered ring in formula (I), and its Z ring is in the combined position except for R ₅ , R ₆ , and R ₇ on the adjacent benzene ring;

R ₂ , R ₃ , R ₄ are each independently selected from hydrogen, halogen or cyano;

R ₅ , R ₆ , R ₇ are each independently selected from hydrogen, halogen, hydroxyl, methoxy, methylthio, acetyl, cyano, phenyl or substituted phenyl;

X is selected from C or N;

Y is selected from O, S or N;

Ring Z represents a five-membered or six-membered unsaturated ring containing one or more heteroatoms selected from O, S or N;

m is selected from 0 or 1.

Preferably, the arane heterocyclic compound represented by the formula (I) provided by the present invention is characterized in that,

R ₁ is selected from hydrogen;

Ar ₁ is selected from: The 2-position or 3-position of its five-membered heterocyclic ring is connected with the corresponding carbon chain in the formula (I);

Ar is selected from _:

R ₂ , R ₃ , R ₄ are each independently selected from hydrogen, halogen or cyano;

R ₅ , R ₆ , R ₇ are each independently selected from hydrogen, halogen, hydroxyl, methoxy, methylthio, acetyl, cyano, phenyl or substituted phenyl;

X is selected from C or N;

Y is selected from O, S or N;

m is selected from 0.

Arane heterocyclic derivatives represented by formula (I) and pharmaceutically acceptable salts thereof provided by the present invention, wherein the halogen is selected from fluorine, chlorine, bromine or iodine, more preferably, the halogen is selected from from fluorine, chlorine or bromine.

Preferably, the present invention provides arane heterocyclic derivatives represented by formula (I) and pharmaceutically acceptable salts thereof; in the structural formula, X is selected from N.

Preferably, the present invention provides arane heterocyclic derivatives represented by formula (I) and pharmaceutically acceptable salts thereof; in the structural formula, m is selected from 0 or 1.

Preferably, the arane heterocyclic derivatives and pharmaceutically acceptable salts thereof provided by the present invention; in the structural formula, X is selected from N; Y is selected from O, S or N; m is selected from 0 or 1.

In the present invention, more preferred, but not limited to, the following compounds or chemical structures:

IV-1 3-(4-(1,2-Benzisothiazol-3-yl)-1-piperazin)yl-1-(3,4-dichlorophenyl)yl-propanol,

IV-2 3-(4-(6-fluoro-1,2-benzisothiazol-3-yl)-1-piperidinyl-1-(3,4-dichlorophenyl)yl-propanol,

IV-3 3-(4-([1,1'-biphenyl]-2-yl)-1-piperazin)yl-1-(3,4-dichlorophenyl)yl-propanol,

IV-4 3-(4-([1,1'-biphenyl]-3-yl)-1-piperazin)yl-1-(3,4-dichlorophenyl)yl-propanol,

IV-5 2-(4-(3-(3,4-dichlorophenyl)-3-hydroxy-propyl)-1-piperazinyl)-phenol,

IV-6 1-(3,4-dichlorophenyl)-3-(4-(2-methoxyphenyl)-1-piperazinyl)-propanol,

IV-7 1-(3,4-dichlorophenyl)-3-(4-(2-methylthiophenyl)-1-piperazinyl)-propanol,

IV-8 1-(2-(4-(3-(3,4-dichlorophenyl)-3-hydroxypropyl)-1-piperazinyl)-phenyl)-ethanone,

IV-9 3-(4-([1,1'-biphenyl]-2-yl)-1-piperazinyl)-1-(benzothiophen-3-yl)-propanol,

IV-10 3-(4-([1,1'-biphenyl]-3-yl)-1-piperazinyl)-1-(benzothiophen-3-yl)-propanol,

V-1 3-(3-(4-([1,1'-biphenyl]-2-yl)-piperazin-1-yl)-propyl)-5-fluoro-indole,

V-2 3-(3-(4-([1,1'-biphenyl]-3-yl)-piperazin-1-yl)-propyl)-5-fluoro-indole,

V-3 3-(2-(4-([1,1'-biphenyl]-2-yl)-piperazin-1-yl)-ethyl)-5-fluoro-indole,

V-4 3-(2-(4-([1,1'-biphenyl]-2-yl)-piperazin-1-yl)-ethyl)-5-cyano-indole,

V-5 3-(2-(4-([1,1'-biphenyl]-3-yl)-piperazin-1-yl)-ethyl)-5-cyano-indole,

V-6 1-([1,1'-biphenyl]-2-yl)-4-(2-(benzofuran-3-yl)-ethyl)-piperazine,

V-7 1-([1,1'-biphenyl]-3-yl)-4-(2-(benzofuran-3-yl)-ethyl)-piperazine,

V-8 1-([1,1'-biphenyl]-2-yl)-4-(2-(benzofuran-2-yl)-ethyl)-piperazine,

V-9 1-([1,1'-biphenyl]-2-yl)-4-(2-(benzothiophen-3-yl)-ethyl)-piperazine,

V-10 1-([1,1'-biphenyl]-2-yl)-4-(3,4-dichlorophenethyl)-piperazine,

and pharmaceutically acceptable salts of the aforementioned compounds.

The pharmaceutically acceptable salts of the arane heterocyclic derivatives described in the present invention are preferably hydrochloride, sulfuric acid, methanesulfonic acid or oxalate.

The pharmaceutically acceptable salts of the arane heterocycle derivatives described in the present invention can be formed through the acid-base salt formation reaction between the arane heterocycle derivatives and the above organic or inorganic acids.

The structural formulas of the above compounds are shown in Table 1.

Table 1. Structures of some target compounds:

Compounds of the present invention can be prepared using the following synthetic methods, comprising the following steps:

a), aryl haloketone (I) and the corresponding piperazine (pyridine) compound (II) undergo a substitution reaction to obtain an intermediate (III); b), the intermediate (III) undergoes a NaBH ₄ reduction reaction to obtain the final Product (IV); or c), intermediate (III) is reduced by HSiEt ₃ /CF ₃ COOH to obtain final product (V).

Wherein: Ar ₁ , Ar ₂ , R ₁ , m, X are the same as above; Y is selected from Cl or Br;

In the above-mentioned synthetic method, the experimental condition of each step is preferably:

a), organic base, appropriate solvent;

b), reducing agent, appropriate solvent;

c), reducing agent, appropriate solvent, 50°C;

In a preferred embodiment, the organic base in step a) is a common organic amine selected from Et ₃ N, EtN(i-Pr) ₂ and the like.

The reaction temperature in step a) is: 25-50°C.

The appropriate solvent used in step a) is selected from: CH ₃ CN or DMF; preferably CH ₃ CN.

In a preferred embodiment, the reducing agent in step b) is a boron reagent, preferably NaBH ₄ , KBH ₄ , etc.; more preferably NaBH ₄ .

The reaction temperature of the step b) is: 25-30°C.

The appropriate solvent used in step b) is selected from MeOH or EtOH; more preferably MeOH.

In a preferred embodiment, the reducing agent in step c) is preferably selected from HSiEt ₃ .

The reaction temperature of the step c) is: 40-70°C.

The reaction solvent in step c) is preferably: CF ₃ COOH;

The above-mentioned aryl halide ketone (I), piperazine or piperidine compound (II) can be prepared by commercial purchase and methods described in the examples.

The derivatives of the present invention can be administered orally, by injection, etc. in the form of compositions to patients in need of such treatment.

The composition includes a therapeutically effective amount of the above compound or a pharmaceutically acceptable salt thereof and a medically acceptable carrier.

The carrier referred to refers to a conventional carrier in the field of pharmacy, such as: diluents, excipients such as water, etc.; binders such as cellulose derivatives, gelatin, polyvinylpyrrolidone, etc.; fillers such as starch, etc.; disintegrating agents such as carbonic acid Calcium, sodium bicarbonate; In addition, other adjuvants such as flavoring and sweetening agents may also be added to the composition.

When used for oral administration, it can be prepared into conventional solid preparations such as tablets, powders or capsules, etc.; when used for injection, it can be prepared as injection solution.

Various dosage forms of the composition of the present invention can be prepared by conventional methods in the medical field, wherein the content of the active ingredient is 0.1% to 99.5% (weight ratio), more preferably, the content of the active ingredient is 20% to 80% ( weight ratio).

The present invention relates to the arane heterocyclic derivatives having activity on 5-HT reuptake, 5-HT _1A receptors and 5-HT ₇ receptors, having 5-HT reuptake/5-HT _1A /5- HT ₇ is a new compound with three targets.

The compound of the present invention or the pharmaceutically acceptable salt thereof has shown therapeutic effect on depression in animal experiments.

The compound of the present invention or a pharmaceutically acceptable salt thereof has shown a cognition-promoting effect in animal experiments, and may have the effect of improving cognitive dysfunction in patients with depression;

The compound of the present invention or its pharmaceutically acceptable salt has no effect on sexual function in animal experiments, and has no side effect of causing sexual dysfunction in depressed patients.

In summary, the antidepressant effect of the derivatives of the present invention is better than that of traditional antidepressants currently used clinically, such as antidepressants with a single mechanism of action, venlafaxine with 5-HT/NA dual reuptake inhibitors, and SSRI/5 Antidepressants such as vilazodone and vortioxetine, which have dual-target effects on HT _1A , have better curative effect, wider indications and less toxic side effects. The compound of the present invention is a novel 5-HT reuptake/5-HT _1A /5-HT ₇ triple-targeting new compound discovered for the first time, which has outstanding targeting novelty and has also achieved outstanding technology in terms of therapeutic effect Effective and substantial scientific progress.

Specific implementation method

The present invention will be further described by means of examples below, but the present invention is not limited to the scope of the examples, and the scope of protection claimed by the present invention is based on the claims. For the experimental methods that do not indicate specific conditions in the following examples, select according to conventional methods and conditions, or according to the commercial instructions.

General method one: preparation of aralkyl ketone amine intermediate (III)

Aryl haloketone (I) (0.1mol) and the hydrochloride (0.1mol) of piperazine (pyridine) compound (II) were dissolved in acetonitrile (100mL), diisopropylethylamine (0.2mol) was added, After reacting at room temperature for 12 h, TLC (dichloromethane:methanol=20:1) showed that the reaction of raw material (I) was complete. Concentrate the solvent to dryness, add dichloromethane (100mL) and saturated brine (40mL) and stir for 20min, and then separate the layers. The organic layer is dried over anhydrous MgSO4, filtered and concentrated, and purified by silica gel chromatography (eluent: dichloromethane/methanol =30:1) to obtain intermediate (III) with a yield of 60-85% (based on aryl haloketone I).

General Method 2: Preparation of Arkanolamine Compound (IV)

The aryl alkanone amine intermediate (III) (0.05mol) was dissolved in methanol (50mL), and sodium borohydride (0.05mol) was added in batches at room temperature, kept stirring at room temperature for 3h, TLC (dichloromethane:methanol=15 : 1) shows that the reaction of starting material (III) is complete. Concentrate the solvent to dryness, add dichloromethane (60mL) and saturated brine (30mL) and stir for 20min, and then separate the layers. ₄ After drying, filter and concentrate, the obtained crude product was dissolved in ethyl acetate (20 mL), and ethyl acetate hydrochloride was added to form hydrochloride to obtain the final product (IV), with a yield of 80-95%.

General Method 3: Preparation of Aralkylamine Compound (V)

Aralkanoneamine intermediate (III) (0.05mol) was dissolved in trifluoroacetic acid (50mL), cooled to 0°C, and HSiEt ₃ (0.15mol) was slowly added dropwise. Keep stirring at 0°C for 0.5h, then raise the temperature to 50°C for 3h, TLC shows (ethyl acetate:petroleum ether=1:15) that the reaction is complete. Concentrate the solvent to dryness, add dichloromethane (60mL) and saturated sodium bicarbonate (30mL) and stir for 20min, and then separate the layers. After drying over _MgSO4 , it was filtered and concentrated, and the obtained crude product was dissolved in ethyl acetate (20 mL), and ethyl acetate hydrochloride was added to form hydrochloride to obtain the final product (V), with a yield of 60-80%.

Example 1

3-(4-(1,2-Benzisothiazol-3-yl)-1-piperazin)yl-1-(3,4-dichlorophenyl)yl-propanol (IV-1) hydrochloride preparation of

3-Chloro-1-(3,4-dichlorophenyl)-acetone (0.05mol), piperazine compound hydrochloride (0.05mol), diisopropylethylamine (0.2mol) dissolved in acetonitrile (100mL) According to the operation of General Method 1, 14.71 g of the intermediate (white solid) was obtained, and the yield was 70%. MS (m/z): 420.1 [M+1] ⁺ .

The above intermediate (10mmol), sodium borohydride (10mmol) in methanol (50mL), according to general method two operations, prepared 3-(4-(1,2-benzisothiazol-3-yl)-1- Piperazin)-1-(3,4-dichlorophenyl)-propanol hydrochloride (white solid) 4.13g, yield 90%. MS (m/z): 422.1 [M+1] ⁺ .

¹ H NMR (400MHz, DMSO) δ10.85(s, 1H), 8.12(t, J=7.7Hz, 2H), 7.64(dd, J=5.1, 3.2Hz, 2H), 7.60(dd, J=11.6 ,4.4Hz,1H),7.47(dd,J=11.6,4.4Hz,1H),7.39(dd,J=8.4,1.9Hz,1H),5.84(s,1H),4.75(d,J=5.0Hz ,1H),4.05(d,J=13.2Hz,2H),3.62(d,J=11.4Hz,2H),3.47(t,J=12.7Hz,2H),3.32–3.18(m,4H),2.18 –2.00(m,2H).

Example 2

3-(4-(6-fluoro-1,2-benzisothiazol-3-yl)-1-piperidinyl-1-(3,4-dichlorophenyl)yl-propanol (IV-2 ) preparation of hydrochloride

3-Chloro-1-(3,4-dichlorophenyl)-acetone (0.05mol), piperidine compound hydrochloride (0.05mol), diisopropylethylamine (0.2mol) dissolved in acetonitrile (100mL) According to the operation of General Method 1, 13.06 g of the intermediate (white solid) was obtained, and the yield was 62%. MS (m/z): 421.1 [M+1] ⁺ .

The above intermediate (10mmol), sodium borohydride (10mmol) in methanol (50mL), according to general method two operations, prepared 3-(4-(6-fluoro-1,2-benzisothiazol-3-yl )-1-piperidinyl-1-(3,4-dichlorophenyl)yl-propanol hydrochloride (white solid) 4.14g, yield 90%. MS (m/z): 423.2 [M+1] ⁺ .

¹ H NMR (400MHz,DMSO)δ10.85(s,1H),8.00(dd,J＝8.8,5.3Hz,1H),7.69(dd,J＝9.1,2.1Hz,1H),7.59(t,J =5.1Hz, 2H), 7.35(dd, J=8.3, 1.9Hz, 1H), 7.28(td, J=9.2, 2.2Hz, 1H), 5.70(s, 1H), 4.68(t, J=6.2Hz ,1H), 3.14(ddd,J=11.7,8.0,3.7Hz,1H),2.97(dd,J=17.9,11.5Hz,2H),2.41(t,J=6.5Hz,2H),2.13–1.99( m,4H),1.86–1.73(m,4H).

Example 3

3-(4-([1,1'-biphenyl]-2-yl)-1-piperazinyl-1-(3,4-dichlorophenyl)yl-propanol (IV-3) salt Salt preparation

3-Chloro-1-(3,4-dichlorophenyl)-acetone (0.05mol), piperazine compound hydrochloride (0.05mol), diisopropylethylamine (0.2mol) dissolved in acetonitrile (100mL) According to the operation of General Method 1, 13.18 g of the intermediate (white solid) was obtained, and the yield was 60%. MS (m/z): 439.2 [M+1] ⁺ .

The above intermediate (10mmol), sodium borohydride (10mmol) in methanol (50mL), according to general method two operations, prepared 3-(4-([1,1'-biphenyl]-2-yl)- 4.54 g of 1-piperazinyl-1-(3,4-dichlorophenyl)-propanol hydrochloride (white solid), yield 95%. MS (m/z): 441.2 [M+1] ⁺ .

¹ H NMR (400MHz, DMSO) δ10.85(s, 1H), 7.67–7.57(m, 4H), 7.45(t, J=7.6Hz, 2H), 7.37–7.30(m, 3H), 7.24(dd ,J=7.6,1.6Hz,1H),7.17–7.08(m,2H),4.68(s,1H),3.40(d,J=11.4Hz,2H),3.17–3.04(m,4H),3.00– 2.82(m,4H),2.09–1.91(m,2H).

Example 4

3-(4-([1,1'-biphenyl]-3-yl)-1-piperazinyl-1-(3,4-dichlorophenyl)yl-propanol (IV-4) salt Salt preparation

3-Chloro-1-(3,4-dichlorophenyl)-acetone (0.05mol), piperazine compound hydrochloride (0.05mol), diisopropylethylamine (0.2mol) dissolved in acetonitrile (100mL) According to the operation of General Method 1, 14.28 g of intermediate (white solid) was obtained, and the yield was 65%. MS (m/z): 439.3 [M+1] ⁺ .

The above intermediate (10mmol), sodium borohydride (10mmol) in methanol (50mL), according to general method two operations, prepared 3-(4-([1,1'-biphenyl]-3-yl)- 4.39 g of 1-piperazinyl-1-(3,4-dichlorophenyl)-propanol hydrochloride (white solid), yield 92%. MS (m/z): 441.2 [M+1] ⁺ .

¹ H NMR (400MHz, DMSO) δ10.85(s, 1H), 7.69–7.62(m, 4H), 7.45(t, J=7.6Hz, 2H), 7.41–7.32(m, 3H), 7.23(s ,1H),7.14(d,J=7.6Hz,1H),7.03–6.98(m,1H),5.55(s,1H),4.74(dd,J=8.3,3.7Hz,1H),3.93(d, J＝11.1Hz, 2H), 3.59(d, J＝10.4Hz, 2H), 3.28–3.06(m, 6H), 2.22–1.94(m, 2H).

Example 5

Preparation of 2-(4-(3-(3,4-dichlorophenyl)-3-hydroxy-propyl)-1-piperazinyl)-phenol (IV-5) hydrochloride

3-Chloro-1-(3,4-dichlorophenyl)-acetone (0.05mol), piperazine compound hydrochloride (0.05mol), diisopropylethylamine (0.2mol) dissolved in acetonitrile (100mL) According to the operation of General Method 1, 16.12 g of intermediate (white solid) was obtained, and the yield was 85%. MS (m/z): 379.1 [M+1] ⁺ .

The above intermediate (10mmol), sodium borohydride (10mmol) in methanol (50mL), according to general method two operations, prepared 2-(4-(3-(3,4-dichlorophenyl)-3-hydroxy -Propyl)-1-piperazinyl)-phenol hydrochloride (white solid) 3.34 g, yield 80%. MS (m/z): 381.2 [M+1] ⁺ .

¹ H NMR (400MHz, DMSO) δ10.85(s, 1H), 7.65–7.63(m, 2H), 7.39(dd, J=8.4, 1.8Hz, 1H), 6.89(t, J=7.8Hz, 2H ), 6.83(d, J=7.8Hz, 1H), 6.76(t, J=7.5Hz, 1H), 4.73(dd, J=8.4, 3.9Hz, 1H), 3.19(s, 6H), 3.00(t ,J＝11.6Hz,3H),2.16–1.97(m,3H).

Example 6

Preparation of 1-(3,4-dichlorophenyl)-3-(4-(2-methoxyphenyl)-1-piperazinyl)-propanol (IV-6) hydrochloride

3-Chloro-1-(3,4-dichlorophenyl)-acetone (0.05mol), piperazine compound hydrochloride (0.05mol), diisopropylethylamine (0.2mol) dissolved in acetonitrile (100mL) According to the operation of General Method 1, 14.75 g of the intermediate (white solid) was obtained, and the yield was 75%. MS (m/z): 393.1 [M+1] ⁺ .

The above intermediate (10mmol), sodium borohydride (10mmol) in methanol (50mL), according to general method two operations, prepared 1-(3,4-dichlorophenyl)-3-(4-(2-methanol) Oxyphenyl)-1-piperazinyl)-propanol hydrochloride (white solid) 3.97g, yield 92%. MS (m/z): 395.2 [M+1] ⁺ .

¹ H NMR (400MHz, DMSO) δ10.85(s, 1H), 7.64(dd, J=5.1, 3.1Hz, 2H), 7.39(dd, J=8.3, 1.8Hz, 1H), 7.06–6.87(m ,4H),4.73(dd,J＝8.6,3.7Hz,1H),3.79(s,3H),3.55(s,2H),3.47(d,J＝12.4Hz,2H),3.24–3.12(m, 4H), 3.05(t, J=11.7Hz, 2H), 2.09(ddd, J=23.6, 16.1, 11.0Hz, 2H).

Example 7

Preparation of 1-(3,4-dichlorophenyl)-3-(4-(2-methylthiophenyl)-1-piperazinyl)-propanol (IV-7) hydrochloride

3-Chloro-1-(3,4-dichlorophenyl)-acetone (0.05mol), piperazine compound hydrochloride (0.05mol), diisopropylethylamine (0.2mol) dissolved in acetonitrile (100mL) According to the operation of General Method 1, 13.92 g of the intermediate (white solid) was obtained, and the yield was 68%. MS (m/z): 409.1 [M+1] ⁺ .

The above intermediate (10mmol), sodium borohydride (10mmol) in methanol (50mL), according to general method two operations, prepared 1-(3,4-dichlorophenyl)-3-(4-(2-methanol) Thiophenyl)-1-piperazinyl)-propanol hydrochloride (white solid) 3.99g, yield 89%. MS (m/z): 411.2 [M+1] ⁺ .

¹ H NMR (400MHz, DMSO) δ10.85(s, 1H), 7.64(dd, J=5.1, 3.1Hz, 2H), 7.39(dd, J=8.4, 1.9Hz, 1H), 7.20–7.08(m ,4H),5.83(s,1H),4.72(s,1H),3.58(s,2H),3.25(dd,J＝20.1,6.6Hz,4H),3.11(d,J＝8.1Hz,4H) ,2.40(s,3H),2.06(ddd,J=37.3,17.8,10.8Hz,2H).

Example 8

1-(2-(4-(3-(3,4-dichlorophenyl)-3-hydroxypropyl)-1-piperazinyl)-phenyl)-ethanone (IV-8) hydrochloride preparation of

3-Chloro-1-(3,4-dichlorophenyl)-acetone (0.05mol), piperazine compound hydrochloride (0.05mol), diisopropylethylamine (0.2mol) dissolved in acetonitrile (100mL) According to the operation of General Method 1, 13.17 g of the intermediate (white solid) was obtained, and the yield was 65%. MS (m/z): 405.1 [M+1] ⁺ .

The above intermediate (10mmol), sodium borohydride (10mmol) in methanol (50mL), according to general method two operations, prepared 1-(2-(4-(3-(3,4-dichlorophenyl)- 4.08 g of 3-hydroxypropyl)-1-piperazinyl)-phenyl)-ethanone hydrochloride (white solid), yield 92%. MS (m/z): 407.2 [M+1] ⁺ .

¹ H NMR (400MHz, DMSO) δ10.85(s, 1H), 7.64(dd, J=5.1, 3.1Hz, 2H), 7.53–7.47(m, 1H), 7.44(dd, J=7.6, 1.5Hz ,1H),7.39(dd,J=8.3,1.8Hz,1H),7.22–7.13(m,2H),4.74(dd,J=8.3,4.0Hz,1H),3.56(d,J=10.5Hz, 2H), 3.22(dd, J＝16.2, 11.9Hz, 8H), 2.58(s, 3H), 2.20–2.03(m, 2H).

Example 9

3-(4-([1,1'-biphenyl]-2-yl)-1-piperazinyl)-1-(benzothiophen-3-yl)-propanol (IV-9)hydrochloride salt preparation

1-(benzothiophen-3-yl)-3-chloro-acetone (0.05mol), piperazine compound hydrochloride (0.05mol), diisopropylethylamine (0.2mol) were dissolved in acetonitrile (100mL), According to General Method 1, 15.99 g of the intermediate (white solid) was obtained, with a yield of 75%. MS (m/z): 427.1 [M+1] ⁺ .

The above intermediate (10mmol), sodium borohydride (10mmol) in methanol (50mL), according to general method two operations, prepared 3-(4-([1,1'-biphenyl]-2-yl)- 4.37 g of 1-piperazinyl)-1-(benzothiophen-3-yl)-propanol hydrochloride (white solid), yield 94%. MS (m/z): 429.2 [M+1] ⁺ .

¹ H NMR (400MHz,DMSO)δ10.85(s,1H),8.02–7.91(m,2H),7.67–7.59(m,3H),7.45(t,J=7.6Hz,2H),7.42–7.28 (m,4H),7.24(dd,J=7.5,1.6Hz,1H),7.17–7.07(m,2H),5.03(dd,J=8.3,3.9Hz,1H),3.40(d,J=11.1 Hz,2H),3.25(dd,J＝13.0,7.6Hz,2H),3.08(d,J＝15.1Hz,2H),3.03–2.83(m,4H),2.28–2.07(m,2H).

Example 10

3-(4-([1,1'-biphenyl]-3-yl)-1-piperazinyl)-1-(benzothiophen-3-yl)-propanol (IV-10) hydrochloric acid salt preparation

1-(benzothiophen-3-yl)-3-chloro-acetone (0.05mol), piperazine compound hydrochloride (0.05mol), diisopropylethylamine (0.2mol) were dissolved in acetonitrile (100mL), According to General Method 1, 15.36 g of the intermediate (white solid) was obtained, with a yield of 72%. MS (m/z): 427.1 [M+1] ⁺ .

The above intermediate (10mmol), sodium borohydride (10mmol) in methanol (50mL), according to general method two operations, prepared 3-(4-([1,1'-biphenyl]-3-yl)- 4.42 g of 1-piperazinyl)-1-(benzothiophen-3-yl)-propanol hydrochloride (white solid), yield 95%. MS (m/z): 429.2 [M+1] ⁺ .

¹ H NMR (400MHz,DMSO)δ10.85(s,1H),8.04–7.96(m,2H),7.69–7.64(m,3H),7.48–7.32(m,6H),7.23(s,1H) ,7.14(d,J=7.7Hz,1H),7.00(dd,J=8.2,2.0Hz,1H),5.08(dd,J=8.5,3.8Hz,1H),4.78(s,1H),3.93( d,J=11.9Hz,2H),3.60(d,J=8.1Hz,2H),3.34(dd,J=13.0,7.7Hz,2H),3.27–3.09(m,4H),2.39–2.18(m ,2H).

Example 11

3-(3-(4-([1,1'-biphenyl]-2-yl)-piperazin-1-yl)-propyl)-5-fluoro-indole (V-1) sulfate preparation of

3-Chloro-1-(5-fluoro-1H-indol-3-yl)-acetone (I) (0.05mol), piperazine compound hydrochloride (0.05mol), diisopropylethylamine (0.2mol ) was dissolved in acetonitrile (100mL) and operated according to General Method 1 to obtain 14.96g of an intermediate (white solid) with a yield of 70%. MS (m/z): 428.2 [M+1] ⁺ .

The above intermediate (2 mmol) was dissolved in trifluoroacetic acid (10 mL), and HSiEt ₃ (6 mmol) was slowly added dropwise under ice-cooling. Stir at 0°C for 0.5h under controlled internal temperature, then raise the temperature to 50°C for 3h. According to General Method 3, the obtained crude product was dissolved in ethyl acetate (20 mL), and sulfuric acid was added to form a salt to obtain 3-(3-(4-([1,1'-biphenyl]-2-yl)-piperazine -1-yl)-propyl)-5-fluoro-indole sulfate (white solid) 0.56g, yield 60%. MS (m/z): 414.2 [M+1] ⁺ .

¹ H NMR (400MHz, DMSO) δ10.88(s, 1H), 7.61(d, J=7.3Hz, 2H), 7.42(t, J=7.6Hz, 2H), 7.34–7.17(m, 6H), 7.08(t, J=6.8Hz, 2H), 6.88(td, J=9.2, 2.4Hz, 1H), 2.79(s, 3H), 2.64(t, J=7.1Hz, 3H), 2.42–2.09(m ,4H),1.77(s,2H),1.24(d,J=5.9Hz,2H).

Example 12

3-(3-(4-([1,1'-biphenyl]-3-yl)-piperazin-1-yl)-propyl)-5-fluoro-indole (V-2) methanesulfonate Salt preparation

3-Chloro-1-(5-fluoro-1H-indol-3-yl)-acetone (I) (0.05mol), piperazine compound hydrochloride (0.05mol), diisopropylethylamine (0.2mol ) was dissolved in acetonitrile (100mL) and operated according to General Method 1 to obtain 14.11g of an intermediate (white solid) with a yield of 66%. MS (m/z): 428.2 [M+1] ⁺ .

The above intermediate (2 mmol) was dissolved in trifluoroacetic acid (10 mL), and HSiEt ₃ (6 mmol) was slowly added dropwise under ice-cooling. Stir at 0°C for 0.5h under controlled internal temperature, then raise the temperature to 50°C for 3h. According to General Method 3, the obtained crude product was dissolved in ethyl acetate (20 mL), and methanesulfonic acid was added to form a salt to obtain 3-(3-(4-([1,1'-biphenyl]-3-yl)- Piperazin-1-yl)-propyl)-5-fluoro-indole methanesulfonate (white solid) 0.65 g, yield 64%. MS (m/z): 414.2 [M+1] ⁺ .

¹ H NMR (400MHz, DMSO) δ10.72(s, 1H), 7.65(d, J=7.4Hz, 2H), 7.46(d, J=7.4Hz, 2H), 7.38–7.32(m, 4H), 7.27(s,1H),7.20(s,1H),7.12(d,J=6.3Hz,1H),6.99(d,J=8.4Hz,1H),6.91(dd,J=9.0,6.8Hz,1H ),3.86(dd,J＝36.5,12.3Hz,2H),3.59(d,J＝25.8Hz,2H),3.20–3.09(m,4H),2.72(t,J＝7.3Hz,2H),2.5 (s,3H),2.02(d,J=22.3Hz,2H),1.38–1.15(m,2H).

Example 13

3-(2-(4-([1,1'-biphenyl]-2-yl)-piperazin-1-yl)-ethyl)-5-fluoro-indole (V-3)oxalic acid salt preparation

2-Chloro-1-(5-fluoro-1H-indol-3-yl)-acetone (I) (0.05mol), piperazine compound hydrochloride (0.05mol), diisopropylethylamine (0.2mol ) was dissolved in acetonitrile (100mL) and operated according to General Method 1 to obtain 13.65g of an intermediate (white solid), with a yield of 66%. MS (m/z): 414.2 [M+1] ⁺ .

The above intermediate (2 mmol) was dissolved in trifluoroacetic acid (10 mL), and HSiEt ₃ (6 mmol) was slowly added dropwise under ice-cooling. Stir at 0°C for 0.5h under controlled internal temperature, then raise the temperature to 50°C for 3h. According to General Method 3, the obtained crude product was dissolved in ethyl acetate (20 mL), and oxalic acid was added to form a salt to obtain 3-(2-(4-([1,1'-biphenyl]-2-yl)-piperazine -1-yl)-ethyl)-5-fluoro-indole oxalate (white solid) 0.59 g, yield 60%. MS (m/z): 400.2 [M+1] ⁺ .

¹ H NMR (400MHz, DMSO) δ10.67(s, 1H), 7.66(d, J=7.3Hz, 2H), 7.50–7.40(m, 3H), 7.39–7.23(m, 5H), 7.16(t ,J=8.0Hz,2H),6.94(td,J=9.2,2.4Hz,1H),3.50(d,J=10.6Hz,2H),3.33–3.27(m,2H),3.18–2.90(m, 8H).

Example 14

3-(2-(4-([1,1'-biphenyl]-2-yl)-piperazin-1-yl)-ethyl)-5-cyano-indole (V-4) salt Salt preparation

3-(2-Chloroacetyl)-5-cyanindole (I) (0.05mol), piperazine compound hydrochloride (0.05mol), diisopropylethylamine (0.2mol) were dissolved in acetonitrile (100mL ), according to the general method one operation, the intermediate (white solid) 14.93g was obtained, and the yield was 71%. MS (m/z): 421.2 [M+1] ⁺ .

The above intermediate (2 mmol) was dissolved in trifluoroacetic acid (10 mL), and HSiEt ₃ (6 mmol) was slowly added dropwise under ice-cooling. Stir at 0°C for 0.5h under controlled internal temperature, then raise the temperature to 50°C for 3h. According to General Method 3, 3-(2-(4-([1,1'-biphenyl]-2-yl)-piperazin-1-yl)-ethyl)-5-cyano-ind Indole hydrochloride (white solid) 0.59g, yield 67%. MS (m/z): 407.2 [M+1] ⁺ .

¹ H NMR (600MHz, DMSO) δ10.85(s, 1H), 8.08(s, 1H), 7.62(d, J=7.1Hz, 2H), 7.50(d, J=8.4Hz, 1H), 7.42( dd,J＝17.9,7.6Hz,3H),7.35(s,3H),7.23(s,1H),7.15–7.08(m,2H),3.19–2.78(m,4H),2.73(s,4H) ,1.64(s,4H).

Example 15

3-(2-(4-([1,1'-biphenyl]-3-yl)-piperazin-1-yl)-ethyl)-5-cyano-indole (V-5) salt Salt preparation

3-(2-Chloroacetyl)-5-cyanindole (I) (0.05mol), piperazine compound hydrochloride (0.05mol), diisopropylethylamine (0.2mol) were dissolved in acetonitrile (100mL ), according to general method one operation, to obtain intermediate (white solid) 14.30g, yield 68%. MS (m/z): 421.2 [M+1] ⁺ .

The above intermediate (2 mmol) was dissolved in trifluoroacetic acid (10 mL), and HSiEt ₃ (6 mmol) was slowly added dropwise under ice-cooling. Stir at 0°C for 0.5h under controlled internal temperature, then raise the temperature to 50°C for 3h. According to General Method 3, 3-(2-(4-([1,1'-biphenyl]-3-yl)-piperazin-1-yl)-ethyl)-5-cyano-ind Indole hydrochloride (white solid) 0.57g, yield 64%. MS (m/z): 407.2 [M+1] ⁺ .

¹ H NMR (600MHz, DMSO) δ10.85(s, 1H), 8.11(s, 1H), 7.66(d, J=7.4Hz, 2H), 7.51(d, J=8.4Hz, 1H), 7.46( t,J=7.7Hz,2H),7.43–7.39(m,2H),7.36(dd,J=16.0,7.8Hz,2H),7.23(s,1H),7.14(d,J=7.6Hz,1H ),7.01(dd,J=8.2,2.1Hz,1H),3.93(d,J=12.8Hz,2H),3.54(d,J=11.4Hz,2H),3.23–3.07(m,2H),2.78 (t, J=7.4Hz, 2H), 1.79(dd, J=9.5, 6.1Hz, 2H), 1.74–1.65(m, 2H).

Example 16

Preparation of 1-([1,1'-biphenyl]-2-yl)-4-(2-(benzofuran-3-yl)-ethyl)-piperazine (V-6) hydrochloride

1-(benzofuran-3-yl)-2-chloroethanone (I) (0.05mol), piperazine compound hydrochloride (0.05mol), diisopropylethylamine (0.2mol) were dissolved in acetonitrile ( 100 mL), according to General Method 1, the intermediate (white solid) 15.46 g was obtained, and the yield was 78%. MS (m/z): 397.2 [M+1] ⁺ .

The above intermediate (2 mmol) was dissolved in trifluoroacetic acid (10 mL), and HSiEt ₃ (6 mmol) was slowly added dropwise under ice-cooling. Stir at 0°C for 0.5h under controlled internal temperature, then raise the temperature to 50°C for 3h. According to General Method 3, 1-([1,1'-biphenyl]-2-yl)-4-(2-(benzofuran-3-yl)-ethyl)-piperazine hydrochloride was obtained (White solid) 0.67g, yield 80%. MS (m/z): 383.2 [M+1] ⁺ .

¹ H NMR (400MHz, DMSO) δ10.85(s, 1H), 7.89(s, 1H), 7.77(d, J=7.2Hz, 1H), 7.66(d, J=7.1Hz, 2H), 7.58( d,J=8.0Hz,1H),7.46(t,J=7.6Hz,2H),7.38–7.24(m,5H),7.16(t,J=8.3Hz,2H),3.51(d,J=10.9 Hz, 2H), 3.44–3.36(m, 2H), 3.15(d, J=12.3Hz, 4H), 3.00(dt, J=21.9, 11.0Hz, 4H).

Example 17

Preparation of 1-([1,1'-biphenyl]-3-yl)-4-(2-(benzofuran-3-yl)-ethyl)-piperazine (V-7) hydrochloride

1-(benzofuran-3-yl)-2-chloroethanone (I) (0.05mol), piperazine compound hydrochloride (0.05mol), diisopropylethylamine (0.2mol) were dissolved in acetonitrile ( 100 mL), according to General Method 1, the intermediate (white solid) 15.07 g was obtained, and the yield was 76%. MS (m/z): 397.2 [M+1] ⁺ .

The above intermediate (2 mmol) was dissolved in trifluoroacetic acid (10 mL), and HSiEt ₃ (6 mmol) was slowly added dropwise under ice-cooling. Stir at 0°C for 0.5h under controlled internal temperature, then raise the temperature to 50°C for 3h. According to General Method 3, 1-([1,1'-biphenyl]-3-yl)-4-(2-(benzofuran-3-yl)-ethyl)-piperazine hydrochloride was obtained (White solid) 0.65g, yield 78%. MS (m/z): 383.2 [M+1] ⁺ .

¹ H NMR (400MHz,DMSO)δ10.85(s,1H),7.93(s,1H),7.81(d,J=6.9Hz,1H),7.70–7.65(m,2H),7.59(d,J =7.8Hz,1H),7.46(t,J=7.6Hz,2H),7.40–7.28(m,4H),7.26(s,1H),7.16(d,J=7.6Hz,1H),7.04(dd ,J=8.1,2.2Hz,1H),3.99(t,J=9.8Hz,2H),3.71(d,J=6.2Hz,2H),3.48(dd,J=13.0,8.3Hz,2H),3.31 –3.18(m,6H).

Example 18

Preparation of 1-([1,1'-biphenyl]-2-yl)-4-(2-(benzofuran-2-yl)-ethyl)-piperazine (V-8) hydrochloride

1-(benzofuran-2-yl)-2-chloroethanone (I) (0.05mol), piperazine compound hydrochloride (0.05mol), diisopropylethylamine (0.2mol) were dissolved in acetonitrile ( 100 mL), according to General Method 1, the intermediate (white solid) 15.86 g was obtained, and the yield was 80%. MS (m/z): 397.2 [M+1] ⁺ .

The above intermediate (2 mmol) was dissolved in trifluoroacetic acid (10 mL), and HSiEt ₃ (6 mmol) was slowly added dropwise under ice-cooling. Stir at 0°C for 0.5h under controlled internal temperature, then raise the temperature to 50°C for 3h. According to General Method 3, 1-([1,1'-biphenyl]-2-yl)-4-(2-(benzofuran-2-yl)-ethyl)-piperazine hydrochloride was obtained (White solid) 0.63g, yield 75%. MS (m/z): 383.2 [M+1] ⁺ .

¹ H NMR (600MHz, DMSO) δ10.85(s, 1H), 7.65(d, J=7.2Hz, 2H), 7.59(d, J=7.4Hz, 1H), 7.52(d, J=8.0Hz, 1H), 7.45(t, J＝7.7Hz, 2H), 7.36–7.32(m, 2H), 7.28–7.22(m, 3H), 7.14(dd, J＝18.1, 7.7Hz, 2H), 6.75(s ,1H),3.48(d,J=10.3Hz,4H),3.33–3.31(m,2H),3.13(d,J=12.3Hz,2H),3.04(t,J=12.0Hz,2H),2.96 (d,J=10.2Hz,2H).

Example 19

Preparation of 1-([1,1'-biphenyl]-2-yl)-4-(2-(benzothiophen-3-yl)-ethyl)-piperazine (V-9) hydrochloride

1-(benzothiophen-3-yl)-2-chloroethanone (I) (0.05mol), piperazine compound hydrochloride (0.05mol), diisopropylethylamine (0.2mol) were dissolved in acetonitrile ( 100mL), according to general method 1, the intermediate (white solid) 13.61g was obtained, and the yield was 66%. MS (m/z): 413.2 [M+1] ⁺ .

The above intermediate (2 mmol) was dissolved in trifluoroacetic acid (10 mL), and HSiEt ₃ (6 mmol) was slowly added dropwise under ice-cooling. Stir at 0°C for 0.5h under controlled internal temperature, then raise the temperature to 50°C for 3h. According to General Method 3, 1-([1,1'-biphenyl]-2-yl)-4-(2-(benzothiophen-3-yl)-ethyl)-piperazine hydrochloride was obtained (White solid) 0.61g, yield 70%. MS (m/z): 399.2 [M+1] ⁺ .

¹ H NMR (400MHz, DMSO) δ10.85(s, 1H), 7.99(d, J=7.2Hz, 1H), 7.85(d, J=7.2Hz, 1H), 7.65(d, J=7.2Hz, 2H), 7.52(s, 1H), 7.47–7.32(m, 6H), 7.25(dd, J＝7.5, 1.4Hz, 1H), 7.14(dd, J＝16.5, 7.9Hz, 2H), 3.42(s ,2H),3.06(q,J=11.6Hz,4H),2.87(t,J=7.3Hz,4H),2.13(dt,J=15.4,7.7Hz,2H).

Example 20

Preparation of 1-([1,1'-biphenyl]-2-yl)-4-(3,4-dichlorophenethyl)-piperazine (V-10) hydrochloride

2-Chloro-1-(3,4-dichlorophenyl)-ethanone (I) (0.05mol), piperazine compound hydrochloride (0.05mol), diisopropylethylamine (0.2mol) dissolved in Acetonitrile (100 mL) was operated according to General Method 1 to obtain 13.61 g of an intermediate (white solid) with a yield of 64%. MS (m/z): 425.2 [M+1] ⁺ .

The above intermediate (2 mmol) was dissolved in trifluoroacetic acid (10 mL), and HSiEt ₃ (6 mmol) was slowly added dropwise under ice-cooling. Stir at 0°C for 0.5h under controlled internal temperature, then raise the temperature to 50°C for 3h. According to General Method 3, 1-([1,1'-biphenyl]-2-yl)-4-(3,4-dichlorophenethyl)-piperazine hydrochloride (white solid) 0.61 g, yield 68%. MS (m/z): 411.2 [M+1] ⁺ . ¹ H NMR (400MHz, DMSO) δ10.85(s, 1H), 7.63(d, J=7.5Hz, 2H), 7.56–7.51(m, 2H), 7.44(t, J=7.5Hz, 2H), 7.33(dd, J=14.6,7.3Hz,2H),7.23(d,J=7.4Hz,2H),7.11(dd,J=15.9,7.8Hz,2H),2.99–2.78(m,8H),2.60 (t,J=7.4Hz,2H),1.87(m,2H).

Antidepressant effect of compounds

Example 21. Inhibitory effect of compounds on 5-HT reuptake, 5-HT _1A and 5-HT ₇ receptor binding experiments:

Using the method of cell monoclonal technology and radioligand binding experiment to carry out in vitro screening research on new compounds with clear targets, this method can make the corresponding biological activity evaluation objectively, accurately and quickly.

Specifically, the in vitro activity screening of compounds was carried out using the research methods reported in (Biochem Phearmacol 2008, 75(9): 1835-1847 and Eur J Pharmacol, 2007, 576(1-3): 43-54). Simultaneously potent 5-HT reuptake/5-HT _1A /5-HT ₃ triple active vortioxetine and 5-HT reuptake/5-HT _1A dual active vilazodone (English name: Vilazodone) was used as a positive control substance to carry out 5-HT reuptake/5-HT _1A receptor/5-HT ₇ receptor binding experiments on the invented compound.

Methods as below:

1. Establishment of 5-HT transporter (hSERT) stable cell lines

HEK 293 cells were transfected with pcDNA3.0-hSERT vector plasmid. After 48 hours of transfection, G418 selective DMEM medium was added to culture the cells. After 3 weeks, the cells showing G418 resistance were serially diluted to obtain stably transfected monoclonal cells, and then expanded and cultured with G418-containing medium, and the 5-HT transporter was verified by 5-HT reuptake experiments in monoclonal cells. Finally, a stable cell line capable of stably expressing the 5-HT transporter protein was obtained.

2. 5-HT reuptake test

The test compound and the positive control drug (vortioxetine and vilazodone) were dissolved in DMSO to 0.01 mol/L, and then diluted to 100 μmol/L with deionized water. Take 50 μl of the compound to be tested (or positive drug) and add 430 μl of cells to the reaction test tube. After incubating in a water bath at 30°C for 10 minutes, add 20 μl of radioactive [ ³ H]-5-HT to make the compound to be tested (or positive drug) final. The concentration is 10 μmol/L. After incubating in a water bath at 30°C for 10 min, immediately move to an ice bath to terminate the reaction. On the BRANDEL 24-hole cell sample collector, quickly filter through GF/B glass fiber filter paper, wash with ice-cold washing buffer (50mM Tris, 5mM EDTA, pH 7.4) 3 times, dry the filter paper, and place in a 0.5ml centrifuge Add 500 μl of fat-soluble scintillation fluid to the tube, and measure the radiation intensity with a MicroBeta liquid scintillation counter. The experiment was divided into: total reuptake tube (blank control), non-specific reuptake tube (10 μmol/L positive drug), sample reuptake tube (10 μmol/L test compound). Duplicate tubes were assayed for each concentration and three independent experiments were performed. The reuptake inhibition percentage of each compound was calculated according to the following formula:

3. 5-HT _1A receptor binding assay

5-HT _1A cell transfection: In this experiment, the plasmid vector containing the 5-HT _1A receptor protein gene was used to transfect CHO cells, using the calcium phosphate transfection method, and from the transfected cells, passed through the culture medium containing G418 Cultivation, selection of cell monoclonals and radioactive culture combined experiments, and finally a stable cell line capable of stably expressing 5-HT _1A receptor protein was obtained. For cell culture, the cells were centrifuged at 1000 rpm for 5 minutes, the culture medium was discarded, the cells were collected, and stored in a -20°C refrigerator for later use. Resuspend with Tris-HCl reaction buffer (pH 7.7) during the experiment.

5-HT _1A receptor binding competition assay:

Add 10 μL of the test compound, positive control drugs (vortioxetine and vilazodone), and the radioisotope ligand [ ₃ H]8-OH-DPAT and 80 μL of the receptor protein into the reaction test tube, so that the test compound and the final concentration of the positive drug were

10 μmol/L, after incubating in a water bath at 37°C for 15 min, immediately move to an ice bath to terminate the reaction; filter quickly through GF/C glass fiber filter paper on the Millipore cell sample collector, and wash with the eluent (50 mM Tris-HCl, pH 7.7 ) 3mLX3 times, dried in a microwave oven for 8-9min, moved the filter paper to a 0.5mL centrifuge tube, and added 500μL of fat-soluble scintillation fluid. Stay away from light for more than 30 minutes, and count and measure the radioactive intensity with a Beckman LS-6500 multifunctional liquid scintillation counter. Duplicate tubes were assayed for each concentration and three independent experiments were performed. The percentage inhibition rate of each compound on isotopic ligand group binding was calculated with reference to the aforementioned formula.

4. 5-HT ₇ receptor binding assay

5-HT ₇ cell transfection: In this experiment, the plasmid vector containing the 5-HT ₇ receptor protein gene was used to transfect CHO cells, using the calcium phosphate transfection method, and from the transfected cells, passed through the culture medium containing G418 Cultivation, selection of cell monoclonals and radioactive culture combined experiments, and finally a stable cell line capable of stably expressing 5-HT ₇ receptor protein was obtained. For cell culture, the cells were centrifuged at 1000 rpm for 5 minutes, the culture medium was discarded, the cells were collected, and stored in a -20°C refrigerator for later use. Resuspend with Tris-HCl reaction buffer (pH 7.7) during the experiment.

5-HT ₇ receptor binding competition assay:

Add 10 μL of the test compound, positive control drugs (vortioxetine and vilazodone), and the radioisotope ligand [ ³ H]LSD and 80 μL of the receptor protein into the reaction test tube, so that the test compound and the positive drug are finally The concentration was 10 μmol/L. After incubating in a water bath at 37°C for 15 min, the reaction was immediately transferred to an ice bath to terminate the reaction; on the Millipore cell sample collector, it was quickly filtered through GF/C glass fiber filter paper, and the eluent (50 mM Tris-HCl , pH 7.7) 3mLX3 times, dried in a microwave oven for 8-9min, moved the filter paper to a 0.5mL centrifuge tube, and added 500μL of liposoluble scintillation fluid. Stay away from light for more than 30 minutes, and measure the radioactive intensity by counting with a Beckman LS-6500 multifunctional liquid scintillation counter. Duplicate tubes were assayed for each concentration and three independent experiments were performed. The percentage of inhibition (Inhibition) of each compound on the binding of the isotopic ligand group was calculated with reference to the aforementioned formula.

5. Results: Table 2 shows the 5-HT reuptake inhibitory effect, 5-HT _1A and 5-HT ₇ receptor binding test results of the compounds of the present invention.

Table 2 compound to 5-HT reuptake inhibition/5-HT _1A /5-HT ₇ receptor binding experiment

compound 5-HT (inhibition rate/%) 5-HT _1A (inhibition rate/%) 5-HT ₇ (inhibition rate/%) IV-1 109.0 97.3 97.8 IV-2 107.6 91.1 93.6 IV-3 107.3 99.1 102.2 IV-4 105.1 97.6 102.7 IV-5 98.9 98.9 101.5 IV-6 105.3 99.5 99.8 IV-7 109.3 92.3 101.9 IV-8 107.5 95.9 91.0 IV-9 102.3 99.0 93.4 IV-10 100.1 94.5 99.3 V-1 100.3 98.7 96.7 V-2 99.9 98.7 96.5 V-3 102.1 100.1 96.9 V-4 103.4 105.6 101.1 V-5 105.2 106.5 97.8 V-6 100.7 99.5 94.6 V-7 100.2 101.5 99.7 V-8 102.7 98.6 99.5 V-9 96.8 99.8 97.6 V-10 101.1 102.3 99.1 Vortioxetion 101.1 102.3 100.2 Vilazodone 102.1 99.9 23.4

It can be seen from the experimental results: under the same concentration of action, when the concentration of action of the tested product of the present invention and the selected positive control drug was 10 μmol/L, the above 20 compounds had no effect on the reuptake of 5-HT, 5-HT _1A and 5-HT. -Three receptors of HT ₇ are active, and its action strength is equivalent to that of Vortioxetine (Vortioxetion, 10 μmol/L) at the same concentration. Vilazodone (10 μmol/L) at the same concentration has stronger effects on 5-HT reuptake and 5-HT _1A receptors, but little effect on 5-HT ₇ receptors.

Embodiment 22, antidepressant result of compound in vivo

Using the mouse tail suspension test (tail suspension test) and the mouse forced swimming test (forced swimming test) in the "behavioral hopelessness model" and the learned helplessness model (learned helplessness), respectively, with vilazodone and vortixi Ting was used as a positive control drug to conduct a preliminary study on the in vivo antidepressant effect of compounds with 5-HT reuptake, 5-HT _1A and 5-HT ₇ triple activities.

1. Mouse tail suspension experiment

experimental method:

156 ICR mice, male, were randomly divided into 10 groups according to body weight balance: blank control group, positive drug group (choose vilazodone as positive control drug, invortioxetine is invalid in this model) (30.0mg/ kg), the compound test group (30.0mg/kg), was given intragastric administration at 10ml/kg, and the blank control group was given the same volume of normal saline. One hour after administration, the tail of the mouse was fixed with medical adhesive tape about 2 cm from the end, and the mouse was hung upside down in the tail-suspension box, with its head about 5 cm from the bottom of the box. After the mouse was suspended for 2 minutes, the observation was started immediately, and the observation lasted for 4 minutes, and the immobility time of the mouse within the 4 minutes was accumulated (the mouse stopped struggling in the air, or only had small limb movements). The improvement rate is calculated using the formula:

The results are shown in Table 3:

The influence of table 3 single oral administration of compound on mouse tail suspension test

*Compared with the blank group, P<0.05, there is a significant difference; **Compared with the blank group, P<0.01, there is a very significant difference. Note: P means statistical deviation.

In the mouse tail suspension test, the above 10 compounds can significantly shorten the tail suspension time of mice, and the drug effects of 8 compounds such as IV-3, V-3, and V-10 at a dose of 30 mg/kg Compared with the positive drug vilazodone, the drug effect is stronger at the same dose, and there is a very significant difference compared with the blank group, indicating that the above compounds have strong antidepressant activity in vivo.

2. Mice forced swimming test

experimental method:

156 ICR mice, male, were randomly divided into 10 groups according to body weight balance: blank control group, vortioxetine group (20.0mg/kg), compound test group (20.0mg/kg), orally administered at 10ml/kg The blank control group was given the same volume of normal saline. Mice were pre-swimmed for screening the day before the experiment. The mice were put into a glass jar with a water depth of 10 cm (20 cm high and 14 cm in diameter), at a water temperature of 25° C., and allowed to swim for 6 minutes. Animals that stopped swimming for 70-160 seconds were selected for the formal experiment. The mice in each group were given corresponding drugs according to the group for one week. One hour after the last administration, the mouse swimming test was carried out, the animals were put into the above-mentioned environment to swim for 6 minutes, and the accumulated time for the mice to stop swimming within 4 minutes after 6 minutes was recorded. The data were statistically processed by t test. The results are shown in Table 4:

Table 4 The impact of one week of oral administration of compounds on mice forced swimming test

*Compared with the blank group, P<0.05, there is a significant difference; **Compared with the blank group, P<0.01, there is a very significant difference Note: P means statistical deviation.

In the forced swimming test of mice, the above-mentioned 8 compounds can significantly shorten the immobility time of mice swimming. The positive drug vortioxetine has a strong drug effect at the same dose, and there is a very significant difference compared with the blank group, indicating that the above compounds all have strong antidepressant activity in vivo.

3. Learned helplessness experiment

3.1 Principle

This model is an animal model of depression. When the animal is placed in an inescapable aversive stimulus environment, it will produce a desperate behavior, which is manifested as no longer avoiding the stimulus and interferes with the subsequent adaptive response. At this time, the level of catecholamines in the animal's brain is reduced, which is recognized as a state of depression, which can be combated by antidepressants. The learned helplessness model is sensitive to sub-long-term (3-7days) use of various antidepressants, including tricyclic antidepressants, monoamine oxidase inhibitors, monoamine reuptake inhibitors and atypical antidepressants.

3.2 Experimental method

Animals were divided into groups and preshocked animals were made on the first day by inescapable electric shock. Animals in pre-shock received 0.8mA x 15s foot electrical stimulation, once per minute, a total of 60 times. Rats in the control group were only placed in the box without electrical stimulation for the same time. Dosing started the next day. The administration components are positive drug group (vilazodone: 60mg/kg and gramfaxin: 30mg/kg), V-3: 10, 5, 2.5, 1.25mg/kg, VIII-2: 10mg/kg ( CN103420940B) continuous administration for one week. 24h after the last administration, the conditioned avoidance test was carried out. The measurement indicators are the number of successful evasions and the evasion latency.

Among them, VIII-2 in CN103420940 B is a new compound with the best comprehensive drug effect in this invention patent. In this experiment, it is used as the reference drug of the compound of the present invention, and its structure is:

3.3 Results

In the conditional avoidance experiment of the animals in the normal control group one week later, the escape latency was significantly shortened, and the number of successful avoidance was high; the animals in the model group showed obvious desperate behavior after the inescapable electric shock stimulation, and the escape latency was significantly prolonged. The number of avoidance successes was significantly reduced; vilazodone (60mg/kg), venlafaxine (30mg/kg) and V-3 at two doses (5mg/kg and 10mg/kg) all significantly shortened the escape latency , the number of evasion successes increased significantly; compound VIII-2 (CN103420940B) at a dose of 10 mg/kg failed to significantly shorten the escape latency, and the number of evasion successes did not increase significantly. It shows that V-3 can fight against this kind of depression state, its antidepressant activity is better than VIII-2, and the effective dose is lower than the marketed drugs vilazodone and venlafaxine (5-HT/NA dual reuptake inhibitor).

Table 5 Effect of V-3 on Rat Learned Helplessness Experiment (n=10)

*Compared with the blank group, P<0.05, there is a significant difference; **Compared with the blank group, P<0.01, there is a very significant difference Note: P means statistical deviation.

Example 23, compound in vivo 5-hydroxytryptophan-induced head shake experiment

Whether the compound has a 5-HT reuptake inhibitory effect in animals can be determined by head shaking experiments induced by 5-hydroxytryptophan (DL-5-HTP), and compound V-3 is selected for the experiment.

(1) Principle

With DL-5-HTP as the precursor of 5-HT, paxillin, an inhibitor of MAOs, can inhibit the enzymatic degradation of MAO. A characteristic symptom of mice - head shaking behavior can be observed.

(2) Experimental method

V-3 was divided into three dosage groups (20, 10, 5mg/kg), intraperitoneal injection of 0.2ml/10g, subcutaneous injection of paxillin 75mg/kg 30 minutes later, and intravenous injection of DL-5-HTP 90 minutes later. After 15 min, the head-shaking response of the mice was observed.

(3) Results

V-3 at 20, 10 and 5 mg/kg significantly enhanced the effect of 5-HTP, which showed obvious head-shaking response in mice, and this effect showed an obvious dose-effect relationship, indicating that V-3 can indeed inhibit 5-HTP in vivo Reuptake of 5-HT (consistent with in vitro results).

Table 6 V-3 enhances the effect of 5-hydroxytryptophan (DL-5-HTP) on mice

Blank vs V-3 20mg/kg: P<0.01, there is a very significant difference

Blank vs V-3 10mg/kg: P<0.01, there is a very significant difference

Blank vs V-3 5mg/kg: P<0.05, significant difference

Note: P means statistical deviation.

Example 24, compound in vivo cognition promoting experiment

mouse dark avoidance test

1.1 Principle

The device is designed based on the habit of mice or rats to avoid light and dark, half of which is a dark room and half of which is a light room, connected by a small hole in the middle. The bottom of the darkroom is covered with an electrified copper grid. Animals received electric shocks when they entered the dark chamber.

1.2 Method

Scopolamine replicated the model of memory acquisition impairment, and the experiment was divided into model group (scopolamine group), blank control group, V-3 group: 10, 5mg/kg, VIII-2 group: 10mg/kg (CN103420940B), respectively, in the abdominal cavity 20min before the experiment Scopolamine (3mg/kg), V-3, VIII-2 were injected, and the same amount of normal saline was injected intraperitoneally in the control group.

Mice with dark avoidance latency longer than 180s were discarded before the experiment. A 36v, 50Hz alternating current was applied to the copper grid at the bottom of the dark room of the dark room, and the mice were first put into the reaction box of the dark room for 3 minutes of training. After being shocked by the electric shock, the mice fled to the bright room. At the beginning of the formal test, the mice were placed in the bright room with their backs facing the hole, and the mice received electric shocks when they entered the dark room. To avoid the dark incubation period. Using the multiple measurement method, the training experiment started at 9:00 am on the first day, and was tested 3 times at 15:00 pm on the same day, 9:00 am on the next day and 9:00 am on the third day (48 hours after the training experiment), and recorded for 5 minutes The dark-avoidance latency and the number of mistakes of the inner mice, and the mean value of the three results were analyzed by t test.

1.3 Experimental results

The impact of table 7V-3 on mice avoiding the dark test (n=10)

*Compared with the control group, P<0.05, there is a significant difference; **Compared with the control group, P<0.01, there is a very significant difference Note: P means statistical deviation.

In the dark avoidance test of mice, the compound V-3 of the present invention can significantly prolong the dark avoidance latency of mice at two doses of 10 mg/kg and 5 mg/kg, specifically, V-3 at a dose of 10 mg/kg It is more effective than vortioxetine at a dose of 20 mg/kg, while only at a dose of 5 mg/kg it is as effective as vortioxetine at a dose of 20 mg/kg. Vilazodone (40 mg/kg) and VIII-2 (10 mg/kg) were ineffective in this model. It shows that the compound V-3 of the present invention has the effect of promoting learning and memory, can improve the cognitive dysfunction of patients with depression, and is significantly better than the drug effect of vortioxetine, which is already on the market, and the concentration of action is only a quarter of that of vortioxetine. one.

Example 25, compound in vivo sexual dysfunction evaluation experiment

Non-contact penile erection test in rats

1.1 Principle

Non-contact erections can be induced by the presence of estrous males with females. A representative method is to divide the observation room into two halves with a partition board with a hole. The female rats are placed on one side of the observation room, and the male rats in estrus are placed on the other side, and the penile erection times of the male rats are observed.

1.2 Method

Male Sprague-Dawley rats were mixed with sexually active female rats for one night to mate, and then the male rats were fed separately, and vilazodone (20mg/kg) was given by intragastric administration every day, Tioxetine (20mg/kg) and V-3 (10mg/kg), the control group was given the same amount of normal saline. 2 to 3 weeks after short-term, sub-long-term (7d) or long-term (14d) administration, observe the penis erection of male rats in the experimental area, the female rats mated before are allowed to exist in the experimental area, but no contact is allowed. Provide visual, auditory and olfactory stimuli only.

1.3 Experimental results

Table 8 The effect of compound V-3 of the present invention on the sexual function of rats (n=10)

*Compared with the control group, P<0.05, there is a significant difference; **Compared with the control group, P<0.01, there is a very significant difference Note: P means statistical deviation.

In the non-contact penile erection test of rats, at the same dose (20mg/kg), acute, sub-long-term, and long-term intragastric administration of vilazodone and compound V-3 of the present invention did not cause the number of penile erections in rats Significantly decreased, and vortioxetine can cause the number of penile erections in rats to be significantly reduced. It shows that compound V-3 of the present invention may not cause sexual dysfunction in patients with depression.

Embodiment 26, acute toxicity test:

Using the method reported in "Modern Pharmacological Experimental Methods" edited by Zhang Juntian, preliminary screening, and statistics by Bliss method, the LD ₅₀ of compound V-3 and V-10 mice were 1600mg/kg and 1400mg/kg, respectively. The LD ₅₀ of Compound VIII-2 (CN103420940B) administered to mice in a single administration was 1200 mg/kg.

Example 27, compound V-3, V-10 bacterial reverse mutation test

Strains: Salmonella murine histidine auxotrophic mutant strains TA ₉₇ , TA ₉₈ , TA ₁₀₀ and TA ₁₀₂ .

Test method: The method reported in the literature of Maron DM et al: (1983) Mutay Res.113, 173-216 was adopted.

Results: The experiment included two parts -S ₉ and +S ₉ , TA ₉₈ in the test system without S ₉ and TA ₉₇ 5000μg/dish in the test system with S ₉ had antibacterial effect. Other doses have no antibacterial effect on all strains, and the growth background is good. All test doses, no matter in the experimental system without S ₉ or with S ₉ , V-3 and V-10 did not cause any significant increase in the number of bacterial colonies, and the Ames test was negative. The experimental results indicated that compounds V-3 and V-10 had no mutation-inducing effect, and the risk of genotoxicity was low.

Example 28

Oral tablet, prescription:

Preparation method: mix the active ingredient (the compound of Examples 1-20) with sucrose and cornstarch, add water to moisten, stir evenly, dry, pulverize and sieve, add calcium stearate, mix evenly, and tablet. Each tablet weighs 200mg and contains 50mg of active ingredients.

Example 29

Injectable formulations, prescription:

Compound 20mg of Example 1-20

Water for injection 80mg

Preparation method: the active ingredient (the compound of Example 1-20) is dissolved in water for injection, mixed uniformly, filtered, and the obtained solution is subpackaged in ampoules under aseptic conditions, 10 mg per bottle, and the active ingredient content is 2mg/bottle.

Example 30

Capsules, prescription:

Compound 60mg of Example 1-20

Sucrose 20mg

Corn starch 20mg

Preparation method: mix active ingredients (compounds of Examples 1-20) with sucrose and cornstarch, add water to moisten, stir evenly, dry, pulverize and sieve, pack into hard gelatin capsules to obtain capsules, each capsule contains 60mg active ingredient.

The above-mentioned embodiment is a preferred embodiment of the present invention, but the embodiment of the present invention is not limited by the above-mentioned embodiment, and any other changes, modifications, substitutions, combinations, Simplifications should be equivalent replacement methods, and all are included within the scope of the present invention.

Claims (12)

1. aralkyl heterocycle compound or its pharmaceutically useful salt, it is characterised in that there is following general structure (I)：

Wherein：

Ar₁It is selected from:

Ar₂It is selected from:

Ar₁It is selected fromWhen, the 2- positions or 3- positions of its five-ring heterocycles are connected to corresponding carbochain in formula (I)；

Ar₂It is selected fromWhen, nitrogenous hexatomic ring corresponding to formula (I) is connected, and its Z ring, which is in adjacent phenyl rings, removes R₅, R₆, R₇Occupy outside place and and position；

R₁It is respectively selected from hydrogen or hydroxyl；

R₂, R₃, R₄It is each independently selected from hydrogen, halogen or cyano group；

R₅, R₆, R₇It is each independently selected from hydrogen, halogen, hydroxyl, methoxyl group, methyl mercapto, acetyl group, cyano group, phenyl or substituted benzene Base；

X is selected from C or N；

Y is selected from O, S or N；

Z rings are represented comprising one or more heteroatomic five yuan or hexa-atomic unsaturation rings including O, S or N；

M is selected from 0,1 or 2.

2. aralkyl heterocycle compound as claimed in claim 1, it is characterised in that

R₁Selected from hydroxyl；

Ar₁It is selected from：

Ar₂It is selected from:

Ar₂It is selected fromWhen, its nitrogenous hexatomic ring corresponding to formula (I) is connected, and its Z ring is in adjacent phenyl rings and removed R₅, R₆, R₇Occupy outside place and and position；

R₂, R₃, R₄It is each independently selected from hydrogen, halogen or cyano group；

R₅, R₆, R₇It is each independently selected from hydrogen, halogen, hydroxyl, methoxyl group, methyl mercapto, acetyl group, cyano group, phenyl or substituted benzene Base；

X is selected from C or N；

Y is selected from O, S or N；

Z rings are represented comprising one or more heteroatomic five yuan or hexa-atomic unsaturation rings including O, S or N；

M is selected from 1.

3. aralkyl heterocycle compound as claimed in claim 2, it is characterised in that

R₁Selected from hydroxyl；

Ar₁It is selected from：

Ar₂It is selected from:

R₂, R₃, R₄It is each independently selected from hydrogen, halogen or cyano group；

R₅, R₆, R₇It is each independently selected from hydrogen, halogen, hydroxyl, methoxyl group, methyl mercapto, acetyl group, cyano group, phenyl or substituted benzene Base；

X is selected from C or N；

M is selected from 1.

4. aralkyl heterocycle compound as claimed in claim 1, it is characterised in that

R₁Selected from hydrogen；

Ar₁It is selected from:

Ar₂It is selected from:

Ar₁It is selected fromWhen, the 2- positions or 3- positions of its five-ring heterocycles are connected to corresponding carbochain in formula (I)；

Ar₂It is selected fromWhen, its nitrogenous hexatomic ring corresponding to formula (I) is connected, and its Z ring is in adjacent phenyl rings and removed R₅, R₆, R₇Occupy outside place and and position；

R₂, R₃, R₄It is each independently selected from hydrogen, halogen or cyano group；

R₅, R₆, R₇It is each independently selected from hydrogen, halogen, hydroxyl, methoxyl group, methyl mercapto, acetyl group, cyano group, phenyl or substituted benzene Base；

X is selected from C or N；

Y is selected from O, S or N；

Z rings are represented comprising one or more heteroatomic five yuan or hexa-atomic unsaturation rings including O, S or N；

M is selected from 0 or 1.

5. aralkyl heterocycle compound as claimed in claim 1, it is characterised in that

R₁Selected from hydrogen；

Ar₁It is selected from:The 2- positions or 3- positions of its five-ring heterocycles are connected to corresponding carbochain in formula (I)；

Ar₂It is selected from:

R₂, R₃, R₄It is each independently selected from hydrogen, halogen or cyano group；

R₅, R₆, R₇It is each independently selected from hydrogen, halogen, hydroxyl, methoxyl group, methyl mercapto, acetyl group, cyano group, phenyl or substituted benzene Base；

X is selected from C or N；

Y is selected from O, S or N；

M is selected from 0.

6. the aralkyl heterocycle compound as described in claim 1-5 any one, it is characterised in that the halogen be selected from fluorine, Chlorine or bromine.

7. aralkyl heterocycle compound as claimed in claim 1, it is characterised in that X is selected from N.

8. aralkyl heterocycle compound as claimed in claim 1, it is characterised in that m is selected from 0 or 1.

9. aralkyl heterocycle compound as claimed in claim 1, it is characterised in that include but is not limited to chemical combination in detail below Thing：

IV-1 3- (4- (1,2- benzisothiazole -3- bases) -1- piperazines) base -1- (3,4- dichloro-benzenes) base-propyl alcohol,

IV-2 3- (4- (fluoro- 1, the 2- benzisothiazoles -3- bases of 6-) -1- piperidines) base -1- (3,4- dichloro-benzenes) base-propyl alcohol,

IV-3 3- (4- ([1,1 '-xenyl] -2- bases) -1- piperazines) base -1- (3,4- dichloro-benzenes) base-propyl alcohol,

IV-4 3- (4- ([1,1 '-xenyl] -3- bases) -1- piperazines) base -1- (3,4- dichloro-benzenes) base-propyl alcohol,

IV-5 2- (4- (3- (3,4- dichlorophenyl) -3- hydroxyl-propyls) -1- piperazinyls)-phenol,

IV-6 1- (3,4- dichlorophenyl) -3- (4- (2- methoxyphenyls) -1- piperazinyls)-propyl alcohol,

IV-7 1- (3,4- dichlorophenyl) -3- (4- (2- methyl mercaptos phenyl) -1- piperazinyls)-propyl alcohol,

IV-8 1- (2- (4- (3- (3,4- dichlorophenyl) -3- hydroxypropyls) -1- piperazinyls)-phenyl)-ethyl ketone,

IV-9 3- (4- ([1,1 '-xenyl] -2- bases) -1- piperazinyls) -1- (benzothiophene -3- bases)-propyl alcohol,

IV-10 3- (4- ([1,1 '-xenyl] -3- bases) -1- piperazinyls) -1- (benzothiophene -3- bases)-propyl alcohol,

V-1 3- (3- (4- ([1,1 '-xenyl] -2- bases)-piperazine -1- bases)-propyl group) fluoro- indoles of -5-,

V-2 3- (3- (4- ([1,1 '-xenyl] -3- bases)-piperazine -1- bases)-propyl group) fluoro- indoles of -5-,

V-3 3- (2- (4- ([1,1 '-xenyl] -2- bases)-piperazine -1- bases)-ethyl) fluoro- indoles of -5-,

V-4 3- (2- (4- ([1,1 '-xenyl] -2- bases)-piperazine -1- bases)-ethyl) -5- cyano-indols,

V-5 3- (2- (4- ([1,1 '-xenyl] -3- bases)-piperazine -1- bases)-ethyl) -5- cyano-indols,

V-6 1- ([1,1 '-xenyl] -2- bases) -4- (2- (benzofuran -3- bases)-ethyl)-piperazine,

V-7 1- ([1,1 '-xenyl] -3- bases) -4- (2- (benzofuran -3- bases)-ethyl)-piperazine,

V-8 1- ([1,1 '-xenyl] -2- bases) -4- (2- (benzofuran -2- bases)-ethyl)-piperazine,

V-9 1- ([1,1 '-xenyl] -2- bases) -4- (2- (benzothiophene -3- bases)-ethyl)-piperazine,

V-10 1- ([1,1 '-xenyl] -2- bases) -4- (3,4- dichlorophenethyl)-piperazine,

And the pharmaceutically useful salt of above-claimed cpd.

10. according to the aralkyl heterocycle compound described in claim any one of 1-9, it is characterised in that its pharmaceutically useful salt is Hydrochloride, sulfate, mesylate or oxalates.

11. pharmaceutical composition, it is characterised in that the aralkyl heterocycle described in the claim any one of 1-9 including therapeutically effective amount Class compound and pharmaceutically acceptable carrier.

12. the aralkyl heterocycle compound or its pharmaceutically useful salt described in claim any one of 1-9 are preparing antidepressant Application in thing.