CN1265660A

CN1265660A - 2-(4-aryl or heteroaryl-piperazin-1-ylmethyl)-1H-indole derivatives

Info

Publication number: CN1265660A
Application number: CN98807831A
Authority: CN
Inventors: 安东·F·J·弗里利; 马克·J·马吉科扎克; 帕特里西亚·A·西摩; 史蒂文·H·佐恩; 汉斯·罗尔马
Original assignee: Pfizer Products Inc
Current assignee: Pfizer Products Inc
Priority date: 1997-08-15
Filing date: 1998-08-05
Publication date: 2000-09-06
Also published as: WO1999009025A3; AU8457298A; HUP0003425A3; BG104069A; AP9801321A0; NO20000722L; CA2297486C; EP1003739A2; NO20000722D0; HRP980441A2; JP2002536291A; CA2297486A1; ID23803A; IL133960A0; OA11286A; WO1999009025A2; HUP0003425A2; EA200000023A1; PL338947A1; BR9811557A

Abstract

A compound of formula (I), a pharmaceutically acceptable salt thereof, and a pharmaceutical composition containing such compound or a salt thereof, wherein T, V, X, Y, Z, ^R1 , ^R2 , ^R3 , ^R4 , ^{R5, R6} ^, ^R7 , ^R8 , and ^R9 are defined as above.

Description

2-(4-aryl or heteroaryl-piperazine-1-ylmethyl)-1H-indole derivatives

Background of invention

The present invention relates to have central dopamine can active 2-(4-aryl or heteroaryl-piperazine-1-ylmethyl)-1H-indole derivatives.These compounds can be used for treating central nervous system (CNS) disorder.The invention still further relates to and use the particularly method of human above-mentioned disorder of these compounds for treating Mammalss, and relate to the medicinal compositions that is used for its purposes.

Common known Dopamine Receptors is very important for many functions of animal body.For example, the variation function of these acceptors participates in taking place psychosis, dopy, mandatory disorder, existing manic emotionality disorder, photis, vomiting, sleep, nursing, study, memory, sexual function, the adjusting of immune induced and the blood pressure that paralepsy is arranged again.Because these acceptors are controlled a large amount of pharmacology mechanism, and now its mechanism is not all understood, thereby possible preferential interaction can be to human relevant general result of treatment at the compound of D4 Dopamine Receptors.

2-of the present invention (4-aryl or heteroaryl-piperazine-1-ylmethyl)-1H-indole derivatives, the pattern that comprises tautomer, enantiomer and acceptable acid additive salt, it is a central action D4-dopamine-receptor stimulant, therefore can be used as identification enhanser and treatment CNS disease, unusual as Parkinson's disease, Alzheimer's, learning and memory.Another feature of the present invention provides compound of the present invention and D1, D2, D3 or D5 combination of dopamine agonists (as L-DOPA and the D2 agonist) purposes in treatment CNS disease (unusual as Parkinson's disease, Alzheimer's, learning and memory).

Summary of the invention

The present invention relates to the compound of following formula:

Or the acceptable salt of its medicine, wherein dotted line is represented a selectable pair of key;

A is 0 or 1, and wherein when a was 0, X formed optional two keys with the carbon of adjacency V;

V is CHR ¹⁰, R wherein ¹⁰Be hydrogen or (C ₁-C ₆) alkyl;

T is nitrogen or CH;

X is nitrogen or CR ¹¹, R wherein ¹¹Be hydrogen, (C ₁-C ₆) alkyl, (C ₁-C ₆) alkoxyl group, hydroxyl itself or cyano group;

Each is nitrogen or CR independently for Y and Z ¹², R wherein ¹²Be hydrogen, chlorine, bromine, trifluoromethyl, trifluoromethoxy, cyano group, (C ₁-C ₆) alkoxyl group or (C ₁-C ₆) alkyl;

R ¹Be hydrogen, fluorine, chlorine, bromine, trifluoromethyl, trifluoromethoxy, cyano group, or (C ₁-C ₆) alkyl;

R ², R ⁶, R ⁷, R ⁸And R ⁹Be independently selected from hydrogen, fluorine, chlorine, bromine, trifluoromethyl, trifluoromethoxy, cyano group, (C ₁-C ₆) alkoxyl group or (C ₁-C ₆) alkyl;

R ³And R ⁴Be hydrogen or (C independently ₁-C ₆) alkyl; With

R ⁵Be hydrogen, (C ₁-C ₆) alkoxyl group, trifluoromethyl, cyano group, (C ₁-C ₆) alkyl or R ¹³CO-, wherein R ¹³Be amino, (C ₁-C ₆) alkylamino, ((C ₁-C ₆) alkyl) ₂Amino, (C ₁-C ₆) alkyl, (C ₁-C ₆) aryl;

Or when a is 1, R ¹And R ¹⁰Carbon that can be coupled forms the compound of following formula together: Wherein dotted line is represented a selectable key; T, X, Y, Z, R ², R ³, R ⁴, R ⁵, R ⁶, R ⁷, R ⁸And R ⁹Definition as above; B is 0 or 1; Each is CH independently with A and B, CH ₂, oxygen, sulphur, NH or nitrogen; Condition is when X is nitrogen, does not have optional two keys between X and the V; With condition be when b is 0, do not have optional two keys between A and the B; With

Condition is when b is 1, and A and B can not be oxygen or sulphur.

Term used herein " alkyl ", except as otherwise noted, comprise have straight chain, the saturated univalence hydrocarbyl of side chain and circular part or its combination.

Term used herein " alkoxyl group " comprises the O-alkyl, and wherein " alkyl " definition as above.

Term used herein " treatment " refers to reverse, alleviate, suppress the disorder of this term indication or symptom or these disorders or symptom one or more symptoms development or prevent its generation.

Term used herein " treatment " refers to therapeutic action, and " treatment " defines as above.

Term used herein " disorder of Dopamine HCL system " refers to by the neurotransmission that changes (promptly increase or reduce) Dopamine HCL mediation can influence or alleviate disorder to its treatment.

Therefore be dopamine receptor subtype, be in particular the The compounds of this invention of dopamine d 4 receptor part, be used for the treatment of the disorder of Dopamine HCL system in vivo.

Formula I compound can have chiral centre, thereby has different enantiomorph patterns.The invention still further relates to all optical isomers and steric isomer and its mixture of formula I compound.

The preferred compound of formula I comprises that wherein X is a nitrogen compound.

Other preferred compound of formula I comprises wherein Y and Z, and each is CR ¹²Compound, R wherein ¹²Be hydrogen or fluorine.

Other preferred compound of formula I comprises wherein R ²It is the compound of hydrogen, fluorine or chlorine.

Other preferred compound of formula I comprises wherein R ³, R ⁴And R ⁵It is the compound of hydrogen.

Other preferred compound of formula I comprises wherein R ⁷It is the compound of fluorine or chlorine.

Other preferred compound of formula I comprises wherein R ⁹It is the compound of fluorine, chlorine, bromine or alkoxyl group.

The more preferably compound of formula I compound comprises that wherein X is a nitrogen; Each is CR for Y and Z ¹³Compound, R wherein ¹³Be hydrogen or fluorine; R ²Be hydrogen, fluorine or chlorine; R ³, R ⁴And R ⁵Be hydrogen; R ⁷It is fluorine or chlorine; R ⁹It is the compound of fluorine, chlorine, bromine or alkoxyl group.

The particularly preferred compound of formula I comprises following compound:

2-[4-(3-trifluoromethyl-phenyl)-piperazine-1-ylmethyl]-the 1H-indoles;

5-fluoro-2-[4-(3-trifluoromethyl-phenyl)-piperazine-1-ylmethyl]-the 1H-indoles;

5-fluoro-2-[4-(4-methyl fluoride-phenyl)-piperazine-1-ylmethyl]-the 1H-indoles;

5-fluoro-2-(4-pyridine-2-base-piperazine-1-ylmethyl]-the 1H-indoles;

2-[4-(6-chloro-pyridazine-3-yl)-piperazine-1-ylmethyl]-5-fluoro-1H-indoles;

5-fluoro-2-(4-[5 '-fluorine] pyridine-2-base-piperazine-1-ylmethyl]-the 1H-indoles;

2-(4-pyridine-2-base-piperazine-1-ylmethyl)-1H-indoles;

5-fluoro-2-(4-pyridine-2-base-piperazine-1-ylmethyl]-the 1H-azaindole; With

2-[4-(4-fluoro-phenyl)-piperazine-1-ylmethyl]-the 1H-azaindole.

The invention still further relates to the method for treatment Mammals disorders of dopamine system, this disorders of dopamine system comprises psychosis (alternating insanity, incoherence of speech and schizoaffective psychosis), mobility disorder (the extrapyramidal side effect that tranquilizer produces, the pernicious syndromes of tranquilizer, tardy dyskinesia, the Tourette's syndrome syndromes, Parkinson's disease, Huntington), gastrointestinal dysfunction (hydrochloric acid in gastric juice secretin or vomiting), chemical abuse disease, the chemical dependence syndrome, substance abuse disease, blood vessel and cardiovascular disorder (congestive heart failure and hypertension), eyes are disorderly and sleep disordered, and this method comprises gives said Mammals with the D4 dopamine 2 receptor alternative cpd or the acceptable salt dispenser of its medicine of effectively treating a certain amount of formula I of this disorder.

The invention still further relates to the method for treatment Mammals disorders of dopamine system, this disorders of dopamine system comprises psychosis (alternating insanity, incoherence of speech and schizoaffective psychosis), mobility disorder (the extrapyramidal side effect that tranquilizer produces, the pernicious syndromes of tranquilizer, tardy dyskinesia, the Tourette's syndrome syndromes, Parkinson's disease, Huntington), gastrointestinal dysfunction (hydrochloric acid in gastric juice secretin or vomiting), chemical abuse disease, the chemical dependence syndrome, substance abuse disease, blood vessel and cardiovascular disorder (congestive heart failure and hypertension), eyes are disorderly and sleep disordered, this method comprises and will effectively treat D4 dopamine 2 receptor alternative cpd or the acceptable salt of its medicine of a certain amount of formula I of this disorder, in conjunction with one or more D1, D2, D3 or D5 dopamine-receptor stimulant dispenser together give said Mammals.

The invention still further relates to the pharmaceutical composition of treatment Mammals disorders of dopamine system, this disorders of dopamine system comprises psychosis (alternating insanity, incoherence of speech and schizoaffective psychosis), mobility disorder (the extrapyramidal side effect that tranquilizer produces, the pernicious syndromes of tranquilizer, tardy dyskinesia, the Tourette's syndrome syndromes, Parkinson's disease, Huntington), gastrointestinal dysfunction (hydrochloric acid in gastric juice secretin or vomiting), chemical abuse disease, the chemical dependence syndrome, substance abuse disease, blood vessel and cardiovascular disorder (congestive heart failure and hypertension), eyes are disorderly and sleep disordered, this methods of treatment comprises and will effectively treat D4 dopamine 2 receptor alternative cpd or the acceptable salt of its medicine of a certain amount of formula I of this disorder, in conjunction with one or more D1, D2, D3 or D5 dopamine-receptor stimulant dispenser together give said Mammals.

Detailed Description Of The Invention

The preparation of following reaction process explanation The compounds of this invention.Except as otherwise noted, a, T, V, X, Y, Z, R in reaction process and the following discussion ¹, R ², R ³, R ⁴, R ⁵, R ⁶, R ⁷, R ⁸And R ⁹Definition as above.

Flow process 1 Flow process 2

In the reaction 1 of flow process 1, at first in polar aprotic solvent such as methylene dichloride, use O-, N-dimethyl oxammonium hydrochloride, dicyclohexyl carbodiimide and alkali such as triethylamine are handled III, make the compound coupling of formula III and IV form the respective compound of formula I.At the azanol intermediate of polar aprotic solvent as forming as the lithium aluminium hydride reduction with reductive agent in the tetrahydrofuran (THF).Aldehyde and formula IV compound reaction in polar aprotic solvent such as ethylene dichloride in the presence of the triacetyl sodium borohydride is carried out reduction amination to the aldehyde intermediate of formation like this.Under inert atmosphere room temperature, stirred this reaction mixture about 40 hours-Yue 56 hours, preferred about 48 hours.

In the reaction 1 of flow process 2, at diisopropylethylamine, carbodiimide or dewatering agent exist down, in polar aprotic solvent such as methylene dichloride, or if need, the form of mixtures that is the combination that contains organic solvent or water, as ring and acyclic list and dialkyl amide, (C1-C4) alcohol, halogenated solvent, or combination acyclic or ring pass alkyl oxide, at about 0 ℃-Yue 150 ℃, under the boiling point of preferred about 0 ℃ or same solvent mixture, VI and IV react corresponding ketone (methanone) compound that just formula VI compound and IV coupling form formula III, and L is leavings group such as chlorine among the formula VI, bromine, methoxyl group or any activatory ester derivative such as p-nitrophenyl ester, oxybenzene and triazole ester, N-hydroxy-succinamide ester or hydroxyl.The acceptor of acid such as the addition of basic carbonate, tertiary amine or similar reagents are useful.

In the reaction 2 of flow process 2, in polar aprotic solvent such as tetrahydrofuran (THF), use reductive agent such as lithium aluminium hydride or boron derivative reduction V about 7 hours-Yue 14 hours, preferred about 12 hours, the methanone compounds of wushu V transformed the respective compound of accepted way of doing sth I, and wherein R3 and R4 are hydrogen.

In each above-mentioned reaction, pressure is not conclusive.About 0.5-3 atmospheric pressure suits, and normal pressure (about 1 normal atmosphere usually) is preferably pressure easily.In addition, for those reactions that preferred temperature wherein changes along with the particular compound of reaction, do not enumerate preferred temperature.For these reactions, can use thin-layer chromatography to monitor this and react the preferred temperature of measuring concrete reagent.

The new compound of formula I and the acceptable salt of its medicine (this paper " treatment compound of the present invention ") can be used as Dopamine HCL reagent, and promptly it has the ability that Mammals comprises the neurotransmission of human Dopamine HCL mediation that changes.Therefore, it can be as the therapeutical agent of treatment Mammals various diseases, this treatment or prevent from can to influence or alleviate by the neurotransmission that increases or reduce the Dopamine HCL mediation.

The formula I compound that is alkalescence can form various salt with various mineral acids and organic acid.Though these salt must be that medicine is acceptable to giving the Mammals administration, but usually wish that in fact initial gross separation formula I compound is as the acceptable salt of medicine from reaction mixture, by handling latter's simple conversion is returned the free basic cpd then, again the latter's free alkali is converted into the acceptable acid salt of medicine with alkaline reagents.By in water solvent medium or suitable organic solvent such as methyl alcohol or ethanol, handling this basic cpd, be easy to prepare the acid salt of basic cpd of the present invention with the selected inorganic or organic acid of equivalent in fact.Also can from the solution of this free alkali, precipitate required acid salt by in this solution, adding suitable inorganic or organic acid.

Treatment compound of the present invention can be oral, through skin (as using patch), parenteral or topical.The preferred oral administration.Usually wish most these compounds with every day about 0.1mg to the highest about 1000mg, or at the dosed administration of more every situation following every day of 1mg-1000mg, but but the patient's that the root a tree name is treated the body weight and the disease heart and selected concrete route of administration and changed.In some cases, the dosage that is lower than the lower limit of above-mentioned scope can be preferably, and in other cases, can use not cause the more heavy dose of of any harmful side effect, and condition is several low doses that these heavy doses at first are divided into a whole day dispenser.

Treatment compound of the present invention is can be by any of above-mentioned two kinds of approach individually dosed or with other pharmaceutical carrier or thinner administration, administration can single dose or multiple doses.More specifically, the new treatment compound of the present invention can various formulations be convenient to administration, promptly combines with tablet, capsule, lozenge, lozenge, hard candy, pulvis, spraying, emulsifiable paste, ointment, suppository, gelifying agent, frozen glue, paste, lotion, ointment, elixir, syrup etc. with various pharmaceutical carriers.Suitable pharmaceutical carrier for example comprises inert solid diluent or filler, aseptic aqueous solution and various organic solvent.In addition, suitably dulcification and/or flavoring of composition for oral liquid.

For oral, the tablet that contains various vehicle such as Microcrystalline Cellulose, Trisodium Citrate, lime carbonate, secondary calcium phosphate and glycine can use with various disintegrating agents such as starch (and being preferably corn, potato or tapioca (flour)), alginic acid and some composition silicate, and uses with granulation binders such as polyvinylpyrrolidone, sucrose, gelatin and gum arabic.In addition, lubricant such as Magnesium Stearate, sodium lauryl sulphate and talcum powder are also through being usually used in tablet.The solids composition of similar model also can be used as filler in the gelatine capsule of soft and rigid filling.Its preferred material comprises lactose or caramel and high-molecular weight polyoxyethylene glycol.When oral when needing waterborne suspension or elixir, necessary active constituent of the present invention can with various sweeting agents or correctives, tinting material or dyestuff, if necessary, emulsifying agent or suspension agent and thinner such as water, ethanol, propylene glycol, glycerine and the combination together of its mixture.

Through enteral administration, can use the solution of The compounds of this invention in sesame or peanut oil or aqueous solution of propylene glycol for non-.If desired, these aqueous solution should suitably be cushioned, and this liquid diluent at first with make its etc. ooze.These aqueous solution are suitable for intravenously, intramuscular, subcutaneous and intraperitoneal administration.The known standard method of the available those skilled in the art of the preparation of all these solution under aseptic condition and be easy to carry out.

In addition, when treatment during skin inflammation, but also topical of The compounds of this invention, but the pharmacy practice of its root a tree name standard is preferably undertaken by emulsifiable paste, gelifying agent, gel, paste, ointment etc.

With following method measure compound be attached to ability and The compounds of this invention on the Mammals Dopamine Receptors suppress [ ³H]-Spiperone is attached to the relative capacity on people's dopamine d 4 receptor subclass of expressing in cloned cell line.

The binding ability of D4 acceptor

People such as Van Tol have introduced the mensuration (Nature, 1991,350,610) of D4 receptor binding capacity.Containing 5mM EDTA, 1.5mM calcium chloride (CaCl2), 5mM magnesium chloride (MgCl2), the 50mM Tris of 5mM Repone K (KCl) and 120mM sodium-chlor (NaCl); Collection and homogenizing are expressed the clone cell of human dopamine d 4 receptor among the HCl (pH7.4 in the time of 4 ℃).48, under the 000g centrifugal homogenate 10-15 minute, and a granular substance that obtains is suspended in the buffer reagent that concentration is 150-250mG/ml.About saturation experiments, cumulative volume is 1ml, under 22 ℃, with concentration increase progressively [ ³H]-spiperone (70.3Ci/mmol; The 10-3000 ultimate density) cultivated the 0.75ml aliquot of tissue in triplicate 30-120 minute.About competition combination test, add the 0.75ml film also with the competition part (10 of indicating concentration ^-14-10 ^-13M) and/or [ ³H]-spiperone (100-300pM) cultivated 60-120 minute down at 22 ℃ in duplicate, began assessment.The tritium that filters, monitors then filtrate by the Brandell cell harvestor fast finishes assessment, as Sunahara, and people such as R.K. (Nature, 1990,346,76).For all experiments, specific [ ³H]-spiperone is in conjunction with being defined as the inhibition that is produced by 1-10mM (+) butaclamol.With nonlinear least square curve fitting analysis binding data.With the compound of this appraisal procedure test implementation example, all find to have less than 2 micromolar [ ³H]-the spiperone metathetical is in conjunction with affinity (Ki).

The human body D4 acceptor that cAMP forms is regulated

From Dr.H.Van Tol (Clarke Institute of Psychiatry, Toronto) obtain expressing Chinese hamster ovary (CHO) cell of human D4.4 Dopamine Receptors, and growth is paved with in the additional Minimal Essential Alpha Media (Gibco) of serum (not having hot deactivation), 2.5% horse serum (hot deactivation) and the 500 μ/ml Geneticin of 2.5% tire ox.Break unimolecular layer, make cell deposition with 5mM ethylenediamine tetraacetic acid (EDTA) (EDTA), and be suspended in once more in the physiological saline of the phosphate buffered that contains 5mM magnesium chloride, 30mM hydroxyethyl piperazine-N-ethylsulfonic acid (HEPES), 300 μ M3-isobutyl--1-methyl-xanthine (IBMX, phosphodiesterase inhibitor) and 5.6mM glucose.Cell (about 200,000/ pipe) is exposed to 5 μ M forskolins (forskolin) (adenylate cyclase enzyme activator), forskolin to be added test compound or quinpirole (D4 receptor stimulant) or forskolin and adds quinpirole and add in the antagonist 11 minutes.In the experiment of useful antagonist, before agonist is handled, cellular exposure in antagonist 11 minutes.Estimate the activity of agonist with the effect of the test compound that does not have agonist quinpirole.The D4 agonist has produced the cAMP accumulation to be suppressed, and it can reverse by the D4 receptor antagonist.Add 6N and cross the chloric acid termination reaction, and with in 5N potassium hydroxide and the 2M Tris buffer reagent and sample.Measure ring-type AMP amount with the competition binding reagents box (Amersham) that is purchased.IC is calculated in linear regression analysis by concentration-response curve ₅₀Value.Use equation: Ki=IC ₅₀/ (the 1+[antagonist]/[agonist EC ₅₀]) (Minneman and Johnson, 1984) calculating K i value.

The present invention illustrates the present invention with the following example, but is not limited to its details.Embodiment 1

2-[4-(6-chloro-piperazine-3-yl)-piperazine-1-ylmethyl]-5-fluoro-1H-indoles

At room temperature stir 5mg 5-fluorine 2 indole-carboxylic acids, 2.74mg O-, N-dimethyl oxammonium hydrochloride, 3.89ml triethylamine and 5.76mg dicyclohexyl carbodiimide mixture in the 35ml methylene dichloride is until forming the tawny precipitation.The solids removed by filtration thing, concentration residue and at SiO ₂(25%EtOAc is in hexane) goes up purifying.Obtain 3.6mg (64%) N-O-dimethyl 2 indoles azanols.

In 5 minutes, 3.9mg N-O-two-methyl 2 indoles azanols are joined 0.67mgLiAlH4 in the cold suspension (40 ℃) of 30ml tetrahydrofuran (THF).Stir the mixture of handling with the sodium sulfate saturated aqueous solution 1 hour (40 ℃-＞-30 ℃) and be warmed to room temperature.Separate solvent and be concentrated into formation brown precipitation (2.94mg 5-fluorine 2 indoles carboxylic aldehyde) after adding solid sodium sulfate.

Stirring 0.96mg 4-(5-chloro-phenyl)-piperazine, 1.0mg 5-fluorine 2 indoles carboxylic aldehyde and the solution of 1.2mg triacetyl sodium borohydride in the 50ml ethylene dichloride under the nitrogen room temperature.Except that desolvating and resistates being distributed among 100mlEtOAc and the 20mlNaOH (1N).(2 * 20ml) water and salt water washing organic layer also concentrate water.Resistates is at SiO ₂(eluent: 5% methyl alcohol is in methylene dichloride) gone up purifying and obtained the coloured solid of white shape, its mp.:204-205 ℃.Embodiment 2

5-fluoro-1H-indoles-2-base-[4-(3-trifluoromethyl-phenyl)-piperazine-1-yl]-ketone (methone)

1.0mmol 5-fluorine, 2-indole-carboxylic acid muriate and 230mg m-trifluoromethyl phenylpiperazine and the 129mg diisopropylethylamine mixture in the 10ml methylene dichloride kept at room temperature 12 hours.Add entry, separate organic layer, wash with water, dry and concentrate on sodium sulfate, obtain the title compound of 296mg.MP：198℃。Embodiment 3

5-fluoro-2-[4-(3-trifluoromethyl-phenyl)-piperazine-1-ylmethyl]

-1H-indole hydrochloride

275mg 5-fluoro-1H-indoles-2-base-[4-(3-trifluoromethyl-phenyl)-piperazine-1-yl]-ketone is remained in the inert atmosphere at the solution of anhydrous tetrahydro furan, and at room temperature use the solution-treated of the 1M lithium aluminium hydride of 2.11ml at tetrahydrofuran (THF).After 12 hours, this mixture is with 78 μ l, 15% sodium hydroxide solution and other 234 μ l water treatments.After adding lithium aluminium hydride, separate organic layer and concentrate obtaining yellow oil (240mg).This oil is dissolved in the ether and with the ethereal solution of hydrochloric acid and handles to forming precipitation.Collecting precipitation, vacuum-drying.

The title compound for preparing embodiment 4-by the method that is similar to embodiment 1-3.Embodiment 4

2-[4-(3-trifluoromethyl-phenyl)-piperazine-1-ylmethyl]-1H-indoles-5-alcohol

MP：188-190℃；HRSMS375.15。Embodiment 5

2-[4-(3-trifluoromethyl-phenyl)-piperazine-1-ylmethyl]-the 1H-indoles

MP：192-194℃；HRSMS359.15。Embodiment 6

(1H-indoles-2-yl)-[4-(2-nitro-phenyl)-piperazine-1-yl]-ketone

MP：186-189℃。Embodiment 7

(5-fluoro-1H-indoles-2-yl)-[4-(2-nitro-phenyl)-piperazine-1-yl]-ketone

MP：184-188℃。Embodiment 8

(5-fluoro-1H-indoles-2-yl)-[4-(3-trifluoromethyl-phenyl)-piperazine-1-yl]-ketone MP:198 ℃.Embodiment 9

3-[4-(1H-indoles-2-ylmethyl)-piperazine-1-yl]-benzo [d] isothiazole

MP：150-152℃；HRSMS348.12。Embodiment 10

5-fluoro-2-[4-(3-trifluoromethyl-phenyl)-piperazine-1-ylmethyl]-the 1H-indoles

MP：196-197℃；HRSMS377.148。Embodiment 11

2-(4-naphthalene-1-base-piperazine-1-ylmethyl)-1H-indoles

MP：238-239℃；HRSMS341.19。Embodiment 12

2-[4-(2-nitro-phenyl)-piperazine-1-ylmethyl]-the 1H-indoles

MP：210-211℃；HRSMS336.16。Embodiment 13

5-fluoro-2-[4-(2-nitro-phenyl)-piperazine-1-ylmethyl]-the 1H-indoles

MP：236℃；HRSMS354.14。Embodiment 14

5-fluoro-2-(4-naphthalene-1-base-piperazine-1-ylmethyl)-1H-indoles

MP：249-250℃；HRSMS359.18。Embodiment 15

5-fluoro-2-(4-pyridine-2-base-piperazine-1-ylmethyl)-1H-indoles

MP：242℃；HRSMS310.15。Embodiment 16

5-fluoro-2-[4-(4-fluoro-phenyl)-piperazine-1-ylmethyl]-the 1H-indoles

MP: embodiment 17

5-fluoro-2-(4-pyrimidine-2-base-piperazine-1-ylmethyl)-1H-indoles

MP：199℃；HRSMS311.16。Embodiment 18

(5-fluoro-1H-indoles-2-yl)-(4-pyridine-2-base-piperazine-1-yl)-ketone

MP：214-218℃。Embodiment 19

2-(4-pyridine-2-base-piperazine-1-ylmethyl)-1H-indoles

MP: embodiment 20

(1H-indoles-2-yl)-(4-pyridine-2-base-piperazine-1-yl)-ketone

MP：198-200℃。Embodiment 21

2-(4-pyridine-2-base-piperazine-1-ylmethyl)-1H-indoles

¹³C?NMR(CDCl ₃，75MHz)d?45.29，53.03，55.96，77.44，101.94，107.29，110.91，113.52，119.70，120.28，121.69，128.40，135.53，136.37，137.61，148.00，159.55.

¹H?NMR(CDCl ₃，250MHz)d?2.6(m，4H)，3.6(m，4H)，3.7(s，2H)，6.4(s，1H)，6.7(m，2H)，7.1-7.6(m，4H)，8.2(m，1H)，8.7(br.s，1H).

GC-MS, t _R=4.468min., M ⁺=292, (M-162)=130. embodiment 22

(2 ' α, 3 ' α β, 6 ' α β)-1-(4-fluoro-phenyl)-4-(5 '-phenyl-1 ', 2 ', 3 ', 3 ' a, 4 ', 6 ' a '-six hydrogen-pentalene-2 '-yl)-piperazine dihydrochloride

MP:250-253 ℃. calculated value C ₂₄H ₂₇FN ₂2HCl0.75H ₂O:C, 66.28; H, 7.07; N, 6.44. measured value C, 66.18; H, 6.76; N, 6.56. embodiment 23

(2 ' α, 3 ' α β, 5 ' α, 6 ' α β)-5 '-[4-(4-fluoro-phenyl)-piperazine-1-yl]-2 '-phenyl-octahydro-pentalene-2 '-pure maleic acid salt

MP:206-207.5 ℃. calculated value C ₂₄H ₂₉FN ₂O0.75C ₄H ₄O ₄0.75H ₂O:C, 67.41; H, 7.02; N, 5.82. measured value C, 67.24; H, 6.77; N, 5.68. embodiment 24

(2 ' α, 3 ' α β, 5 ' α, 6 ' α β)-1-[4-(4-fluoro-phenyl)-4-(5 '-phenyl-six hydrogen-pentalene-2 '-yl)-piperazine dihydrochloride

MP:255-256.5 ℃. calculated value C ₂₄H ₂₉FN ₂2HCl0.25H ₂O:C, 65.23; H, 7.18; N, 6.34. measured value C, 65.40; H, 7.02; N, 6.38. embodiment 25

(2 ' α, 3 ' α β, 5 ' α, 6 ' α β)-2-fluoro-4-[4-(5 '-hydroxyl-5 '-phenyl-octahydro-pentalene-2 '-yl)-piperazine-1-yl)-the benzonitrile maleic acid salt

MP:207-207.5 ℃. calculated value C ₂₅H ₂₈FN ₃OC ₄H ₄O ₄: C, 66.78; H, 6.18; N, 8.06. measured value C, 66.64; H, 6.06; N, 8.14. embodiment 26

(2 ' α, 3 ' α β, 5 ' α, 6 ' α β)-2-fluoro-4-[4-(3 ', 3 ' a, 4 ', 5 ', 6 ', 6 ' a '-six hydrogen spiral [isobenzofuran-1 (3H), 2 ' (1 ' H)-pentalene]-5 '-yl)-the 1-piperazinyl]-the benzonitrile maleic acid salt

MP:221-221.5 ℃. calculated value C ₂₆H ₂₈FN ₃OC ₄H ₄O ₄0.5H ₂O:C, 66.41; H, 6.13; N, 7.74. measured value C, 66.33; H, 6.26; N, 7.61. embodiment 27

(2 ' α, 3 ' α β, 5 ' α, 6 ' α β)-5 '-[4-(2-methoxyl group-phenyl)-piperazine-1-yl]-2 '-phenyl-octahydro-pentalene-2 '-pure maleic acid salt

MP:188-189 ℃. calculated value C ₂₅H ₃₂N ₂O ₂C ₄H ₄O ₄: C, 68.48; H, 7.13; N, 5.51. measured value C, 68.64; H, 7.10; N, 5.81. embodiment 28

(2 ' α, 3 ' α β, 5 ' α, 6 ' α β)-2-(4-fluoro-phenyl)-5 '-[4-(5-fluoro-pyrimidine-2-base)-piperazine-1-yl]-octahydro-pentalene-2 '-pure maleic acid salt

MP:219.5-220 ℃. calculated value C ₂₂H ₂₆F ₂N ₄OC ₄H ₄O ₄0.5H ₂O:C, 59.41; H, 5.94; N, 10.66. measured value C, 59.76; H, 5.89; N, 10.65. embodiment 29

(2 ' α, 3 ' α β, 5 ' α, 6 ' α β)-2-fluoro-4-{4-[5 '-(4-fluoro-phenyl)-5 '-hydroxyl-octahydro-pentalene-2 '-yl]-piperazine-1-yl }-the benzonitrile maleic acid salt

MP:204-204.5 ℃. calculated value C ₂₅H ₂₇F ₂N ₃OC ₄H ₄O ₄H ₂O:C, 62.47; H, 5.97; N, 7.54. measured value C, 62.77; H, 5.74; N, 7.58. embodiment 30

(2 ' α, 3 ' α β, 5 ' α, 6 ' α β)-2 '-(4-fluoro-phenyl)-5 '-[4-(4-fluoro-phenyl)-piperazine-1-yl]-octahydro-pentalene-2 '-pure maleic acid salt

MP:209-209.5C. calculated value C ₂₄H ₂₈F ₂N ₂OC ₄H ₄O ₄: C, 65.36; H, 6.27; N, 5.54. measured value C, 65.65; H, 6.25; N, 5.34. embodiment 31

(2 ' α, 3 ' α β, 6 ' α β)-5-fluoro-2-[4-[5 '-phenyl-1 ', 2 ', 3 ', 3 ' a, 4 ', 6 ' a '-six hydrogen-pentalene-2 '-yl)-piperazine-1-yl }-the pyrimidine maleic acid salt

MP:202-203 ℃. calculated value C ₂₂H ₂₅FN ₄C ₄H ₄O ₄: C, 64.99; H, 6.08; N, 11.66. measured value C, 64.67; H, 6.00; N, 11.79. embodiment 32

(2 ' α, 3 ' α β, 6 ' α β)-2-fluoro-4-[4-[5 '-phenyl-1 ', 2 ', 3 ', 3 ' a, 4 ', 6 ' a '-six hydrogen-pentalene-2 '-yl)-piperazine-1-yl }-the benzonitrile maleic acid salt

MP:172-173 ℃. calculated value C ₂₅H ₂₆FN ₃C ₄H ₄O ₄: C, 69.17; H, 6.00; N, 8.34. measured value C, 69.06; H, 5.88; N, 8.57. embodiment 33

(2 ' α, 3 ' α β, 5 ' α, 6 ' α β)-5-fluoro-2-[4-[5 '-phenyl-octahydro-pentalene-2 '-yl)-piperazine-1-yl]-the pyrimidine maleic acid salt

MP:211.5-212 ℃. calculated value C ₂₂H ₂₇FN ₄C ₄H ₄O ₄: C, 64.72; H, 6.48; N, 11.61. measured value C, 64.67; H, 6.43; N, 11.82. embodiment 34

(2 ' α, 3 ' α β, 5 ' α, 6 ' α β)-2-fluoro-4-[4-[5 '-phenyl-octahydro-pentalene-2 '-yl)-piperazine-1-yl]-the benzonitrile maleic acid salt

MP:195-196 ℃. calculated value C ₂₅H ₂₈FN ₃C ₄H ₄O ₄: C, 68.89; H, 6.38; N, 8.31. measured value C, 68.99; H, 6.47; N, 8.30. embodiment 35

(2 ' α, 3 ' α β, 5 ' α, 6 ' α β)-2-fluoro-4-{4-[5 '-trifluoromethyl-phenyl)-octahydro-pentalene-2 '-yl]-piperazine-1-yl }-the benzonitrile maleic acid salt

MP:192-193 ℃. calculated value C ₂₆H ₂₇F ₄N ₃C ₄H ₄O ₄: C, 62.82; H, 5.45; N7.33. measured value C, 62.87; H, 5.22; N, 7.27. embodiment 36

(2 ' α, 3 ' α β, 6 ' α β)-2-fluoro-4-{4-[5-(2-methoxyl group-phenyl)-1 ', 2 ', 3 ', 3 ' a, 4 ', 6 ' a '-six hydrogen-pentalene-2 '-yl)-piperazine-1-yl }-the benzonitrile maleic acid salt

MP:155-156 ℃. calculated value C ₂₆H ₂₈FN ₃OC ₄H ₄O ₄0.25H ₂O:C, 66.96; H, 6.09; N, 7.81. measured value C, 67.00; H, 6.05; N, 7.82. embodiment 37

(2 ' α, 3 ' α β, 5 ' α, 6 ' α β)-2-fluoro-4-{4-[5 '-(2-methoxyl group-phenyl)-octahydro-pentalene-2 '-yl)-piperazine-1-yl }-the benzonitrile maleic acid salt

MP:176-177 ℃. calculated value C ₂₆H ₃₀FN ₃OC ₄H ₄O ₄0.50H ₂O:C, 66.16; H, 6.48; N, 7.71. measured value C, 66.20; H, 6.31; N, 7.69. embodiment 38

(2 ' α, 3 ' α β, 5 ' α, 6 ' α β)-2-fluoro-4-{4-[5 '-(1H-indol-3-yl)-octahydro-pentalene-2 '-yl)-piperazine-1-yl }-the benzonitrile maleic acid salt

MP:226-227 ℃. calculated value C ₂₇H ₂₉FN ₄C ₄H ₄O ₄: C, 68.37; H, 6.11; N, 10.29. measured value C, 68.17; H, 6.24; N, 10.20. embodiment 39

(2 ' α, 3 ' α β, 5 ' α, 6 ' α β)-2-fluoro-4-{4-[5 '-(2-methylsulfonyl-phenyl)-octahydro-pentalene-2 '-yl)-piperazine-1-yl }-the benzonitrile maleic acid salt

MP:179-180 ℃. calculated value C ₂₆H ₃₀FN ₃O ₂SC ₄H ₄O ₄0.25H ₂O:C, 61.25; H, 5.91; N, 7.14. measured value C, 61.26; H, 6.32; N, 6.76. embodiment 40

(2 ' α, 3 ' α β, 5 ' β, 6 ' α β)-2-fluoro-4-[4-(3 ', 3 ' a, 4 ', 5 ', 6 ', 6 ' a '-six hydrogen spiral [isobenzofuran-1 (3H), 2 ' (1 ' H)-pentalene]-5 '-yl)-the 1-piperazinyl]-the benzonitrile maleic acid salt

MP＞260 ℃. calculated value C ₂₆H ₂₈FN ₃OCH ₄O ₃S:C, 63.14; H, 6.27; N, 8.18. measured value C, 63.12; H, 6.66; N, 8.00. embodiment 41

(2 ' α, 3 ' α β, 5 ' α, 6 ' α β)-2-fluoro-4-[4-(3 ', 3 ' a, 4 ', 5 ', 6 ', 6 ' a '-six hydrogen spiral [2H-1-cumarone-2,2 ' (1 ' H)-pentalene]-5 '-yl)-the 1-piperazinyl]-the benzonitrile maleic acid salt

MP:176-177 ℃. calculated value C ₂₇H ₂₈FN ₃O ₂C ₄H ₄O ₄0.50H ₂O:C, 65.25; H, 5.82; N, 7.36. measured value C, 65.52; H, 6.06; N, 7.19. embodiment 42

(2 ' α, 3 ' α β, 5 ' β, 6 ' α β)-2-fluoro-4-[4-(3,3 ', 3 ' a, 4,4 ', 5 ', 6 ', 6 ' a '-six hydrogen spiral [2H-1-cumarone-2,2 ' (1 ' H)-pentalene]-5 '-yl)-the 1-piperazinyl]-the benzonitrile maleic acid salt

MP:179-180 ℃ of calculated value C ₂₇H ₂₈FN ₃O ₂C ₄H ₄O ₄: C, 66.30; H, 5.74; N, 7.48. measured value C, 66.17; H, 6.07; N, 7.34. embodiment 43

(2 ' α, 3 ' α β, 5 ' α, 6 ' α β)-2-fluoro-4-{4-[5 '-(2-trifluoromethoxy-phenyl)-octahydro-pentalene-2 '-yl)-piperazine-1-yl }-the benzonitrile maleic acid salt

MP:126-129 ℃ of .NMR DMSO d ₆δ 7.70 (t, J=8.5Hz, 1H), 7.52 (d, J=7.1Hz, 1H), and 7.40-7.25 (m, 3H), 7.09 (d, J=13.6Hz, 1H), 6.96 (d, J=9.0Hz, 1H), 6.06 (s, 2H), 3.73-2.90 (br m, 10H), and 2.65-2.54 (m, partially under DMSO, 1H), 2.46-2.18 (m, 4H), 1.63-1.42 (m, 4H). embodiment 44

(2 ' α, 3 ' α β, 5 ' α, 6 ' α β)-2-fluoro-4-{4-[5 '-(2-fluoro-phenyl)-octahydro-pentalene-2 '-yl)-piperazine-1-yl }-the benzonitrile maleic acid salt

MP:179-180.5 ℃. calculated value C ₂₅H ₂₇F ₂N ₃C ₄H ₄O ₄: C, 66.53; H, 5.97; N, 8.03. measured value C, 66.62; H, 6.24; N, 7.98. embodiment 45

(2 ' α, 3 ' α β, 5 ' α, 6 ' α β)-2-cyano group-4-{4-[5 '-(2-fluoro-phenyl)-octahydro-pentalene-2 '-yl)-piperazine-1-yl }-the benzonitrile maleic acid salt

MP:193-194 ℃. calculated value C ₂₆H ₂₇FN ₄C ₄H ₄O ₄0.50H ₂O:C, 66.78; H, 5.98; N, 10.38. measured value C, 66.99; H, 6.05; N, 10.34. embodiment 46

(2 ' α, 3 ' α β, 5 ' α, 6 ' α β)-2-fluoro-4-[4-(5 '-pyridine-2-octahydro-pentalene-2 '-yl)-piperazine-1-yl }-the benzonitrile dihydrochloride

MP:203-206 ℃. calculated value C ₂₄H ₂₇FN ₄2HClH ₂O:C, 59.88; H, 6.49; N, 11.63. measured value: C, 59.55; H, 6.42; N, 11.47. embodiment 47

(2 ' α, 3 ' α β, 5 ' α, 6 ' α β)-5-fluoro-2-{4-[5 '-(2-methoxyl group-phenyl)-octahydro-pentalene-2 '-yl)-piperazine-1-yl }-the pyrimidine maleic acid salt

MP:183.5-184.5 ℃. calculated value C ₂₃H ₂₉FN ₄OC ₄H ₄O ₄: C, 63.26; H, 6.49; N, 10.93 measured value C, 63.21; H, 6.71; N, 10.82. embodiment 48

(2 ' α, 3 ' α β, 5 ' α, 6 ' α β)-2-fluoro-4-{4-[5 '-(6-fluoro-2-oxo-2,3-dihydro-benzoglyoxaline-1-yl)-octahydro-pentalene-2 '-yl)-piperazine-1-yl }-benzonitrile diformazan sulphonyl hydrochlorate

MP:219-222 ℃. calculated value C ₂₆H ₂₇FN ₅O2CH ₄O ₃S:C, 51.29; H, 5.38; N, 10.68. measured value C, 51.84; H, 5.57; N, 10.64.

Embodiment 49

(2 ' α, 3 ' α β, 5 ' α, 6 ' α β)-2-fluoro-4-{4-[5 '-(6-fluoro-dimethylbenzimidazole-1-yl)-octahydro-pentalene-2 '-yl)-piperazine-1-yl }-benzonitrile diformazan sulphonyl hydrochlorate

MP:＞260 ℃. calculated value C ₂₇H ₂₉F ₂N ₅2CH ₄O ₃S0.50 H ₂O:C, 52.56; H, 5.48; N, 10.57. measured value C, 5 embodiment 50

(2 ' α, 3 ' α β, 5 ' α, 6 ' α β)-5-fluoro-2-[4-(3 ', 3 ' a, 4 ', 5 ', 6 ', 6 ' a '-six hydrogen spiral [isobenzofuran-1 (3H), 2 ' (1 ' H)-pentalene]-5 '-yl)-1-piperazine-1-yl]-pyrimidine

MP=186 ℃ of .NMR CDCl ₃δ 8.20 (s, 2H), 7.25-7.17 (m, 4H), 7.12-7.09 (m, 1H), 5.00 (s, 2H), 3.79-3.71 (m, 4H), 2.72-2.44 (m, 7H), 2.20-2.13 (m, 2H), 2.17-1.93 (m, 2H), 1.69-1.67 (s, 2H). embodiment 51

(2 ' β, 3 ' α β, 5 ' α, 6 ' α β)-5-fluoro-2-[4-(3 ', 3 ' a, 4 ', 5 ', 6 ', 6 ' a-, six hydrogen spirals [isobenzofuran-1 (3H), 2 ' (1 ' H)-pentalene]-5 '-yl)-1-piperazine-1-yl]-pyrimidine

MP:186-187 ℃ of .NMR CDCl ₃δ 8.18 (s, 2H), 7.26-7.10 (m, 3H), 7.08-7.06 (m, 1H), 5.00 (s, 2H), and 3.78-3.76 (br s, 4H), 2.78-2.73 (m, 2H), 2.66-2.54 (m, 5H), 2.32-2.22 (m, 4H), 1.74-1.69 (m, 2H), 1.38-1.29 (m, 2H). embodiment 52

(2 ' α, 3 ' α β, 5 ' α, 6 ' α β)-1-phenyl-4-(3,3 ', 3 ' a, 4,4 ', 5 ', 6 ', 6 ' a-, six hydrogen spirals [2H-1-cumarone-2,2 ' (1 ' H)-pentalene]-5 '-yl]-5 '-yl)-the piperazine maleic acid salt

MP:200-201 ℃. calculated value C ₂₆H ₃₀N ₂O ₂C ₄H ₄O ₄: C, 69.48; H, 6.61; N, 5.40. measured value C, 69.48; H, 6.80; N, 5.44. embodiment 53

(2 ' β, 3 ' α β, 5 ' α, 6 ' α β)-1-phenyl-4-(3,3 ', 3 ' a, 4,4 ', 5 ', 6 ', 6 ' a-, six hydrogen spirals [2H-1-cumarone-2,2 ' (1 ' H)-pentalene]-5 '-yl]-5 '-yl)-1-piperazine maleic acid salt

MP:220-221 ℃. calculated value C ₂₆H ₃₀N ₂O ₂C ₄H ₄O ₄: C, 69.48; H, 6.61; N, 5.40. measured value C, 69.28 embodiment 54

(2 ' α, 3 ' α β, 5 ' α, 6 ' α β)-3-[5 '-(4-phenyl-Piperazine-1-yl)-octahydro-pentalene-2 '-yl]-1H-indoles maleic acid salt

MP:232-232.5 ℃ of calculated value C ₂₆H ₃₁N ₃C ₄H ₄O ₄: C, 71.83; H, 7.03; N, 8.38. measured value C, 71.57; H, 7.38; N, 8.31. embodiment 55

(2 ' α, 3 ' α β, 6 ' α β)-1-phenyl-4-(5 '-phenyl-1 ', 2 ', 3 ', 3 ' a, 4 ', 6 ' a-, six hydrogen-pentalene]-2 '-yl)-piperazine two maleic acid salts

MP:156-157 ℃. calculated value C ₂₆H ₃₀N ₂O ₂2C ₄H ₄O ₄: C, 66.65; H, 6.29; N, 4.86. measured value C, 66.27; H, 6.57; N, 5.00. embodiment 56

(2 ' α, 3 ' α β, 5 ' α, 6 ' α β)-1-phenyl-4-(5 '-phenyl-octahydro-pentalene-2 '-yl)-the piperazine maleic acid salt

MP:217-218 ℃. calculated value C ₂₄H ₃₀N ₂C ₄H ₄O ₄: C, 72.70; H, 7.41; N, 6.06. measured value C, 72.28; H, 7.46; N, 6.01. embodiment 57

(2 ' α, 3 ' α β, 5 ' α, 6 ' α β)-6-fluoro-2-methyl isophthalic acid-[5 '-(4-phenyl-Piperazine-1-yl)-octahydro-pentalene-2 '-yl)-1H benzoglyoxaline two maleic acid salts

MP:203-205 ℃. calculated value C ₂₆H ₃₁FN ₄2C ₄H ₄O ₄0.50H ₂O:C, 61.90; H, 6.11; N, 8.49. measured value C, 61.96; H, 6.01; N, 8.58. embodiment 58

(2 ' α, 3 ' α β, 5 ' β, 6 ' α β)-1-[5 '-(4-fluoro-phenoxy group)-octahydro-pentalene-2 '-yl]-4-phenylpiperazine maleic acid salt

MP:177-178 ℃. calculated value C ₂₄H ₂₉FN ₂OC ₄H ₄O ₄: C, 67.72; H, 6.70; N, 5.64. measured value C, 67.33; H, 6.82; N, 5.62. embodiment 59

(2 ' α, 3 ' α β, 5 ' β, 6 ' α β)-2-[5 '-(4-phenyl-Piperazine-1-yl)-octahydro-pentalene-2 '-yl]-the isoindole maleic acid salt

MP:235.5-236 ℃. calculated value C ₂₆H ₂₉N ₃O ₂C ₄H ₄O ₄: C, 67.78; H, 6.26; N, 7.90. measured value C, 67.71; H, 6.37; N, 7.94. embodiment 60

(2 ' α, 3 ' α β, 5 ' α, 6 ' α β)-N-(2-{5 '-[4-(5-fluoro-pyrimidine-2-base)-piperazine-1-yl]-octahydro-pentalene-2 '-yl }-phenyl)-the ethanamide maleic acid salt

MP:211.5-212 ℃. calculated value C ₂₄H ₃₀FN ₅OC ₄H ₄O ₄: C, 62.33; H, 6.35; N, 12.98. measured value C, 62.07; H, 6.32; N, 12.87. embodiment 61

(2 ' α, 3 ' α β, 5 ' α, 6 ' α β)-N-(2-{5 '-[4-(4-cyano group-3-fluoro-phenyl)-piperazine-1-yl]-octahydro-pentalene-2 '-yl }-phenyl)-the ethanamide maleic acid salt

MP:197-199 ℃. calculated value C ₂₇H ₃₁FN ₄OC ₄H ₄O ₄: C, 66.18; H, 6.27; N, 9.96. measured value C, 66.06; H, 6.20; N, 9.89. embodiment 62

(2 ' α, 3 ' α β, 5 ' α, 6 ' α β)-2-fluoro-4-{4-[5 '-(2-oxo-2,3-dihydro-benzoglyoxaline-1-yl)-octahydro-pentalene-2 '-yl]-piperazine-1-yl }-benzonitrile methylsulfonyl hydrochlorate

MP＞260 ℃. calculated value C ₂₆H ₂₈FN ₅OCH ₄O ₃S0.50 H ₂O:C, 58.89; H, 6.04; N, 12.72. measured value C, 59.01; H, 6.06; N, 12.71. embodiment 63

(2 ' α, 3 ' α β, 5 ' α, 6 ' α β)-1-{5 '-[4-(5-fluoro-pyrimidine-2-base)-piperazine-1-yl]-octahydro-pentalene-2 '-yl }-1,3-dihydro-benzimidazolyl-2 radicals-ketone mesylate

MP＞260 ℃. calculated value C ₂₃H ₂₇FN ₆OCH ₄O ₃S:C, 55.58; H, 6.04; N, 16.20.Found:C, 55.48; H, 5.87; N, 16.41. embodiment 64

(2 ' α, 3 ' α β, 5 ' α, 6 ' α β)-2-{5 '-[4-(4-cyano group-3-fluoro-phenyl)-piperazine-1-yl]-octahydro-pentalene-2 '-yl }-the benzamide maleic acid salt

MP 198.5-200 ℃. calculated value C ₂₆H ₂₉FN ₄OC ₄H ₄O ₄0.50 H ₂O:C, 64.62; H, 6.15; N, 10.05. measured value C, 64.84; H, 6.01; N, 10.03. embodiment 65

(2 ' α, 3 ' α β, 5 ' α, 6 ' α β)-N-[5 '-(4-phenyl-Piperazine-1-yl)-octahydro-pentalene-2 '-yl]-the benzamide maleic acid salt

MP:211-212.5 ℃. calculated value C ₂₅H ₃₁N ₃OC ₄H ₄O ₄0.25H ₂O:C, 68.28; H, 7.01; N, 8.23. measured value C, 68.17; H, 6.94; N, 8.18. embodiment 66

(2 ' α, 3 ' α β, 5 ' β, 6 ' α β)-2-fluoro-4-{4-[5 '-(4-fluoro-phenoxy group)-octahydro-pentalene-2 '-yl]-piperazine-1-yl }-the benzonitrile maleic acid salt

MP:192-193 ℃. calculated value C ₂₅H ₂₇F ₂N ₃OC ₄H ₄O ₄: C, 64.55; H, 5.79; N, 7.79. measured value C, 64.50; H, 5.80; N, 7.71. embodiment 67

(2 ' α, 3 ' α β, 5 ' β, 6 ' α β)-5-fluoro-2-{4-[5 '-(4-fluoro-phenoxy group)-octahydro-pentalene-2 '-yl]-piperazine-1-yl }-the pyrimidine maleic acid salt

MP:192-194 ℃. calculated value C ₂₂H ₂₆F ₂N ₄OC ₄H ₄O ₄: C, 60.46; H, 5.85; N, 10.85. measured value C, 60.30; H, 5.82; N, 10.78. embodiment 68

(2 ' α, 3 ' α β, 5 ' β, 6 ' α β)-2-fluoro-4-{4-[5 '-(2-oxo-2,3-dihydro-benzoglyoxaline-1-yl)-octahydro-pentalene-2 '-yl)-piperazine-1-yl }-the benzonitrile maleic acid salt

MP:170-177 ℃ of .NMR DMSO d ₆δ 10.89 (s, 1H), 7.70 (t, J=8.4Hz, 1H), 7.30-7.23 (m, 1H), 7.11 (d, J=13.9Hz, 1H), 7.04-6.94 (m, 4H), 6.06 (s, 2H), 4.97-4.82 (m, 1H), 3.62-2.80 (br m, 10H), 2.75-2.63 (m, 2H), 2.60-2.50 (m partially under DMSOpeak, 1H), 2.48-2.36 (m, 2H), 1.60 (dd, J ₁=12.4Hz, J ₂=6.6Hz, 2H), 1.58-1.34 (m, 2H). embodiment 69

(2 ' α, 3 ' α β, 5 ' α, 6 ' α β)-2-fluoro-4-{4-[5 '-(3-methoxyl group-phenyl)-octahydro-pentalene-2 '-yl]-piperazine-1-yl }-the benzonitrile maleic acid salt

MP:169-170 ℃. calculated value C ₂₆H ₃₀FN ₃OC ₄H ₄O ₄: C, 67.27; H, 6.40; N, 7.85. measured value C, 67.18; H, 6.52; N, 7.87. embodiment 70

(2 ' α, 3 ' α β, 5 ' α, 6 ' α β)-2-fluoro-4-{4-[5 '-(4-methoxyl group-phenyl)-octahydro-pentalene-2 '-yl]-piperazine-1-yl }-the benzonitrile maleic acid salt

MP:186-186.5 ℃. calculated value C ₂₆H ₃₀FN ₃OC ₄H ₄O ₄0.25H ₂O:C, 66.71; H, 6.44; N, 7.78. measured value C, 66.70; H, 6.60; N, 7.60. embodiment 71

(2 ' α, 3 ' α β, 5 ' α, 6 ' α β)-2-fluoro-4-[4-(5 '--tolyl-octahydro-pentalene-2 '-yl)-piperazine-1-yl]-the benzonitrile maleic acid salt

MP:198-198.5 ℃. calculated value C ₂₆H ₃₀FN ₃C ₄H ₄O ₄: C, 69.35; H, 6.60; N, 8.09. measured value C, 69.48; H, 6.74; N, 8.14. embodiment 72

(2 ' α, 3 ' α β, 5 ' α, 6 ' α β)-2-fluoro-4-[4-(5 '-right-tolyl-octahydro-pentalene-2 '-yl)-piperazine-1-yl]-the benzonitrile maleic acid salt

MP:194-195 ℃ of .NMR DMSO d ₆δ 7.70 (t, J=8.5Hz, 1H), 7.16-7.09 (m, 5H), 6.96) d, J=8.7Hz, 1H), 6.06 (s, 2H), 3.75-2.85 (m, 11H), 2.55-2.43 (m, part is under the DMSO peak, 1H), 2.40-2.23 (m, Dan Feng @2.26,7H altogether), (m, 4H) embodiment 73 for 1.63-1.32

(2 ' α, 3 ' α β, 5 ' β, 6 ' α β)-1-[5 '-(4-fluoro-phenoxy group)-octahydro-pentalene-2 '-yl]-4-phenyl-Piperazine maleic acid salt

MP:174-175 ℃. calculated value C ₂₄H ₂₉FN ₂OC ₄H ₄O ₄: C, 67.72; H, 6.70; N, 5.64 measured value C, 67.82; H, 6.83; N, 5.59. embodiment 74

(2 ' α, 3 ' α β, 5 ' α, 6 ' α β)-2-fluoro-4-[4-(5 '-neighbour-tolyl-octahydro-pentalene-2 '-yl)-piperazine-1-yl]-the benzonitrile maleic acid salt

MP:198-199 ℃. calculated value C ₂₆H ₃₀FN ₃C ₄H ₄O ₄: C, 69.35; H, 6.60; N, 8.09. measured value C, 69.13; H, 6.69; N, 8.12. embodiment 75

(2 ' α, 3 ' α β, 5 ' α, 6 ' α β)-1-phenyl-4-[5 '-(3-tetramethyleneimine-1-ylmethyl-phenyl)-octahydro-pentalene-2 '-yl)-piperazine two maleic acid salts

MP:163.5-164 ℃. calculated value C ₂₉H ₃₉N ₃2C ₄H ₄O ₄: C, 67.15; H, 7.16; N, 6.35. measured value C, 66.81; H, 7.22; N, 6.27. embodiment 76

(2 ' α, 3 ' α β, 5 ' α, 6 ' α β)-5-fluoro-2-[4-(3 ', 3 ' a, 4 ', 5 ', 6 ', 6 ' a-, six hydrogen-3 ' a, 6 ' a-dimethyl spiral [isobenzofuran-1 (3H), 2 ' (1 ' H)-pentalene]-5 '-yl)-1-piperazine-1-yl]-the pyrimidine maleic acid salt

MP:224.5-225 ℃. calculated value C ₂₅H ₃₁FN ₄O C ₄H ₄O ₄0.25H ₂O:C, 64.13; H, 6.59; N, 10.32. measured value C, 64.25; H, 6.68; N, 10.14. embodiment 77

(2 ' β, 3 ' α β, 5 ' α, 6 ' α β)-5-fluoro-2-[4-(3 ', 3 ' a, 4 ', 5 ', 6 ', 6 ' a-, six hydrogen-3 ' a, 6 ' a-, two-methyl spiral [isobenzofuran-1 (3H), 2 ' (1 ' H)-pentalene]-5 '-yl)-the 1-piperazine]-the pyrimidine maleic acid salt

MP:222-223 ℃ of .NMR DMSO.d ₆. δ 8.58 (s, 2H), 7.34-7.30 (m, 1H), 7.28-7.25 (m, 3H) .6.04 (s, 2H), 4.94 (s, 2H), and 3.65-2.75 (br m, 9H), 2.20-2.12 (m, 2H), 1.94 (ABquartet, Δ=37.8Hz, J=13.2Hz, 4H), 1.54 (br t, J=11.7Hz, 2H), 1.21 (s, 6H). embodiment 78

(2 ' α, 3 ' α β, 5 ' β, 6 ' α β)-4-{4-[5 '-(1,3-dioxo-1,3-dihydro-isoindole-2-yl)-octahydro-pentalene-2 '-yl)-piperazine-1-yl }-2-fluoro-benzonitrile maleic acid salt

MP:224-224.5 ℃. calculated value C ₂₇H ₂₇FN ₄O ₂C ₄H ₄O ₄: C, 64.80; H, 5.44; N, 9.75. measured value C, 64.85; H, 5.56; N, 9.74. embodiment 79

(2 ' α, 3 ' α β, 5 ' β, 6 ' α β)-2-{5 '-[4-(5-fluoro-pyrimidine-2-base)-piperazine-1-yl]-octahydro-pentalene-2 '-yl }-isoindole-1,3-diketone maleic acid salt

MP:241.5-242 ℃. calculated value C ₂₄H ₂₆FN ₅O ₂C ₄H ₄O ₄: C, 60.97; H, 5.48; N, 12.70. measured value C, 60.66; H, 5.55; N, 12.44. embodiment 80

(2 ' α, 3 ' α β, 5 ' α, 6 ' α β)-2-fluoro-4-[4-(3,3 ', 3 ' a, 4,4 ', 5 ', 6 ', 6 ' a-, six hydrogen-spiral [2H-6-fluoro-1-cumarone-2,2 ' (1 ' H)-pentalene]-5 '-yl]-5 '-yl)-the 1-piperazine]-the benzonitrile maleic acid salt

MP:219-220 ℃. calculated value C ₂₄H ₂₆F ₂N ₄O ₂C ₄H ₄O ₄0.50H ₂O:C, 59.46; H, 5.55; N, 9.90. measured value C, 59.86; H, 5.70; N, 9.40. embodiment 81

(2 ' β, 3 ' α β, 5 ' α, 6 ' α β)-2-fluoro-4-[4-(3,3 ', 3 ' a, 4,4 ', 5 ', 6 ', 6 ' a-, six hydrogen-spiral [2H-6-fluoro-1-cumarone-2,2 ' (1 ' H)-pentalene]-5 '-yl]-5 '-yl)-1-piperazine-1-yl]-the benzonitrile maleic acid salt

MP:216.5-217 ℃. calculated value C ₂₄H ₂₆F ₂N ₄O ₂C ₄H ₄O ₄: C, 60.43; H, 5.43; N, 10.07. measured value C, 60.39; H, 5.47; N, 9.90. embodiment 82

(2 ' α, 3 ' α β, 5 ' α, 6 ' α β)-5-fluoro-2-[4-(5 '-neighbour-tolyl-octahydro-pentalene-2 '-yl)-piperazine-1-yl]-the pyrimidine maleic acid salt

MP:204-205 ℃. calculated value C ₂₃H ₂₉FN ₄C ₄H ₄O ₄: C, 65.31; H, 6.70; N, 11.28. measured value C, 65.38; H, 6.77; N, 11.32. embodiment 83

(2 ' β, 3 ' α β, 5 ' α, 6 ' α β)-1-{5 '-[4-(4-fluoro-phenyl)-piperazine-1-yl]-octahydro-pentalene-2 '-yl }-1,3-dihydro-benzimidazolyl-2 radicals-ketone maleic acid salt

MP:217-218 ℃. calculated value C ₂₅H ₂₉FN ₄OC ₄H ₄O ₄: C, 64.91; H, 6.20; N, 10.44. measured value C, 64.57; H, 6.28; N, 10.18. embodiment 84

(2 ' β, 3 ' α β, 5 ' α, 6 ' α β)-2-[5 '-(4-phenyl-Piperazine-1-yl]-octahydro-pentalene-2 '-Ji oxygen base]-1H-benzoglyoxaline maleic acid salt

MP:161-162 ℃. calculated value C ₂₅H ₃₀N ₄OC ₄H ₄O ₄: C, 67.16; H, 6.61; N, 10.80. measured value C, 67.05; H, 6.66; N, 10.59. embodiment 85

(2 ' α, 3 ' α β, 5 ' α, 6 ' α β)-5-chloro-2-{4-[5 '-(2-methoxyl group-phenyl)-octahydro-pentalene-2 '-yl]-piperazine-1-yl }-the pyrimidine maleic acid salt

MP:199.5-200 ℃. calculated value C ₂₃H ₂₉ClN ₄OC ₄H ₄O ₄: C, 61.30; H, 6.29; N, 10.59. measured value C, 61.05; H, 6.31; N, 10.83. embodiment 86

(2 ' α, 3 ' α β, 5 ' α, 6 ' α β)-5-chloro-2-[4-(5 '-neighbour-tolyl-octahydro-pentalene-2 '-yl)-piperazine-1-yl]-the pyrimidine maleic acid salt

MP:200-200.5 ℃. calculated value C ₂₃H ₂₉ClN ₄C ₄H ₄O ₄: C, 63.21; H, 6.48; N.10.92. measured value C, 62.97; H, 6.33; N, 11.29. embodiment 87

(2 ' β, 3 ' α β, 5 ' α, 6 ' α β)-2-{5 '-[4-(3,4-two fluoro-phenyl)-piperazine-1-yl]-octahydro-pentalene-2 '-yl }-isoindole-1,3-diketone maleic acid salt

MP:221.5-222 ℃. calculated value C ₂₆H ₂₇F ₂N ₃O ₂C ₄H ₄O ₄: C, 63.48; H, 5.51; N, 7.46. measured value C, 63.28; H, 5.51; N, 7.64. embodiment 88

(2 ' β, 3 ' α β, 5 ' α, 6 ' α β)-2-{5 '-[4-(4-fluoro-phenyl)-piperazine-1-yl]-octahydro-pentalene-2 '-yl }-isoindole-1,3-diketone maleic acid salt

MP:209-210 ℃. calculated value C ₂₆H ₂₈FN ₃O ₂C ₄H ₄O ₄0.50H ₂O:C, 64.51; H, 5.95; N, 7.52. measured value C, 64.47; H, 5.91; N, 7.66. embodiment 89

(2 ' β, 3 ' α β, 5 ' α, 6 ' α β)-1-{5 '-[4-(3,4-two fluoro-phenyl)-piperazine-1-yl]-octahydro-pentalene-2 '-yl }-1,3-dihydro-benzimidazolyl-2 radicals-ketone maleic acid salt

MP:201-202 ℃. calculated value C ₂₅H ₂₈F ₂N ₄OC ₄H ₄O ₄0.50H ₂O:C, 61.80; H, 5.90; N, 9.94. measured value C, 62.10; H, 5.80; N, 9.56

Claims

1. The compound of formula I

or a pharmaceutically acceptable salt thereof, wherein the dotted line represents an optional double bond;

a is 0 or 1, wherein when a is 0, X forms an optional double bond with the carbon adjacent to V;

V is CHR ¹⁰ , wherein R ¹⁰ is hydrogen or (C ₁ -C ₆ )alkyl;

T is nitrogen or CH;

X is nitrogen or CR ¹¹ , wherein R ¹¹ is hydrogen, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, hydroxy or cyano;

Y and Z are each independently nitrogen or CR ¹² , wherein R ¹² is hydrogen, chlorine, bromine, trifluoromethyl, trifluoromethoxy, cyano, (C ₁ -C ₆ )alkoxy or (C ₁ -C ₆ ) alkyl;

R ¹ is hydrogen, fluorine, chlorine, bromine, trifluoromethyl, trifluoromethoxy, cyano, or (C ₁ -C ₆ ) alkyl;

R ² , R ⁶ , R ⁷ , R ⁸ and R ⁹ are independently selected from hydrogen, fluorine, chlorine, bromine, trifluoromethyl, trifluoromethoxy, cyano, (C ₁ -C ₆ )alkoxy or (C ₁ -C ₆ )alkyl;

R ³ and R ⁴ are independently hydrogen or (C ₁ -C ₆ )alkyl; and

R ⁵ is hydrogen, (C ₁ -C ₆ ) alkoxy, trifluoromethyl, cyano, (C ₁ -C ₆ ) alkyl or R ¹³ CO-, wherein R ¹³ is amino, (C ₁ -C ₆ ) alkylamino, ((C ₁ -C ₆ ) alkyl) ₂ amino, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) aryl;

Or when a is ¹ , R and ^R together with the carbon to which they are attached form a compound of the formula:

where the dotted line represents an optional key;

T, X, Y, Z, R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ⁹ are as defined above;

b is 0 or 1; and

A and B are each independently CH, _CH2 , oxygen, sulfur, NH or nitrogen;

with the proviso that when X is nitrogen, there is no optional double bond between X and V; and

with the proviso that when b is 0, there is no optional double bond between A and B; and

The proviso is that when b is 1, A and B cannot both be oxygen or sulfur.

2. The compound of claim 1, wherein X is nitrogen.

3. The compound of claim 1, wherein Y and Z are each ^CR12 , wherein ^R12 is hydrogen or fluoro.

4. The compound of claim 1, wherein ^R2 is hydrogen, fluorine or chlorine.

5. The compound of claim 1, wherein ^R3 , ^R4 and ^R5 are hydrogen.

6. The compound of claim 1, wherein ^R7 is fluoro or chloro.

7. The compound of claim 1, wherein ^R9 is fluoro, chloro, bromo or alkoxy.

8. The compound of claim 1, wherein X is nitrogen; Y and Z are each a compound of CR ¹² , wherein R ¹² is hydrogen or fluorine; R ² is hydrogen, fluorine or chlorine; R ³ , R ⁴ and R ⁵ are hydrogen; R ⁷ is fluorine or chlorine; R ⁷ is fluorine, chlorine, bromine or alkoxy.

9. The compound of claim 1, wherein said compound is selected from the group consisting of:

2-[4-(3-Trifluoromethyl-phenyl)-piperazin-1-ylmethyl]-1H-indole;

5-Fluoro-2-[4-(3-trifluoromethyl-phenyl)-piperazin-1-ylmethyl]-1H-indole;

5-fluoro-2-[4-(4-fluoromethyl-phenyl)-piperazin-1-ylmethyl]-1H-indole;

5-Fluoro-2-(4-pyridin-2-yl-piperazin-1-ylmethyl]-1H-indole;

2-[4-(6-Chloro-pyridazin-3-yl)-piperazin-1-ylmethyl]-5-fluoro-1H-indole;

5-fluoro-2-(4-[5'-fluoro]pyridin-2-yl-piperazin-1-ylmethyl]-1H-indole;

2-(4-pyridin-2-yl-piperazin-1-ylmethyl)-1H-indole;

5-fluoro-2-(4-pyridin-2-yl-piperazin-1-ylmethyl]-1H-azindole; and

2-[4-(4-Fluoro-phenyl)-piperazin-1-ylmethyl]-1H-azindole.

10. A method for treating mammalian dopamine system disorders, comprising administering a certain amount of the D4 dopa receptor selective compound of formula I of claim 1 or a pharmaceutically acceptable salt thereof for effective treatment of this disorder to the subject Said mammals.

11. The method of claim 10, wherein the dopamine system disorder comprises psychosis, motility disorder, gastrointestinal disorder, chemical abuse disorder, chemical dependence disorder, substance abuse disorder, vascular and cardiovascular disorders, eye disorders, and sleep disorders.

12. A method for treating mammalian dopamine system disorder, comprising a certain amount of the D4 dopa receptor selective compound of formula I of claim 1 or a pharmaceutically acceptable salt thereof, combined with a or more D1, D2, D3 or D5 dopamine receptor agonists are administered together to said mammal.

13. The method of claim 12, wherein the dopamine system disorder comprises psychosis, motility disorder, gastrointestinal disorder, chemical abuse disorder, chemical dependence disorder, substance abuse disorder, vascular and cardiovascular disorders, eye disorders, and sleep disorders.

14. The method of claim 11, wherein the psychosis comprises affective psychosis, disorganized speech, and schizoaffective psychosis.

15. The method of claim 11, wherein the movement disorder comprises extrapyramidal side effects of antipsychotics, malignant syndrome of antipsychotics, tardive dyskinesias, Tourette's syndrome, Parkinson's disease, Huntington's chorea.

16. The method of claim 11, wherein the gastrointestinal disturbance comprises secretin or emesis.

17. The method of claim 11, wherein the vascular and cardiovascular disorders include congestive heart failure and hypertension.

18. A pharmaceutical composition for the treatment of mammalian dopamine system disorders, comprising administering a certain amount of the D4 dopa receptor selective compound of formula I of claim 1 or a pharmaceutically acceptable salt thereof to said mammal.

19. The pharmaceutical composition of claim 18, wherein the dopamine system disorder comprises psychosis, motility disorder, gastrointestinal disorder, chemical abuse disorder, chemical dependence disorder, substance abuse disorder, vascular and cardiovascular disorder, eye disorder and sleep disorder .

20. A pharmaceutical composition for the treatment of mammalian dopamine system disorders, comprising a certain amount of D4 dopa receptor selective compounds of formula I or pharmaceutically acceptable salts thereof, combined with one or more A D1, D2, D3 or D5 dopamine receptor agonist is administered to said mammal.

21. The pharmaceutical composition of claim 20, wherein the dopamine system disorder comprises psychosis, motility disorder, gastrointestinal disorder, chemical abuse disorder, chemical dependence disorder, substance abuse disorder, vascular and cardiovascular disorders, eye disorders, and sleep disorders .