OA11286A - 2-(4-Aryl or heteroaryl-piperazin-1-ylmethyl)-1h-indole derivatives interacting with the dopamine d4receptor. - Google Patents

Abstract

2(4-Aryl or Heteroaryl-piperazin-1-ylmethyl)-1H-Indole derivatives of formula (I) wherein a, T, V, X, Y, Z, R<1>, R<2>, R<3>, R<4>, R<5>, R<6>, R<7>, R<8> and R<9> are as defined above, their pharmaceutically acceptable salts and pharmaceutical compositions containing such compounds or their salts interacting with the dopamin D4 receptor.

Description

-1- 5 2~(4?ARYL Q-RHETE5OARYL-PIPERAZIN-1-YLMETHYL·- u 1 1 z

1H-INDOLE DERIVATIVES

Background of.the Invention

The présent invention relates to 2-(4-aryl or heteroaryl-piperazin-1-ylmethyl)-lH- 10 indole dérivatives possessing central dopaminergic activity. Such compounds areuseful in the treatment of Central Nervous Systems (CNS) disorders. This inventionalso relates to a methpd of using such compounds in the treatment of the abovedisorders in mammals, especially humaris, and the pharmaceutical compositions usefultherefor. 15 It is generally known that dopamine receptors seem to be important for many fonctions in the animal body. For example, altered fonctions of these receptorsparticipate in the genesis of psychosis, drug addiction, compulsive disorders, bipolardisorders, vision, emesis, sleep, feeding, leaming, memory, sexual behavior, régulationof immunological responses and blood pressure. Since these receptors control a great 20 number of pharmacological events, not ail of them are presently known, there is apossibility that compounds acting preferentially on D4 dopamine receptor may exert awide range of therapeutic effects in humans.

The 2-(4-aryl or heteroaryl-piperazin-1-ylmethyl)-1H-indole dérivatives of theprésent invention, including forms of tautomers, enantiomers and acceptable acid 25 addition salts, are centrally acting D4-dopamine receptor agonists and thus are usefulas cognition enhancers and treatment of CNS diseases, such as Parkinsons disease,ALzheimer’s disease, leaming and memory abnormalities. Another feature of thisinvention provides for the use of combinations'of compounds of the présent invention inconjunction with D1, D2, D3 or D5 dopamine receptor agonists, such as L- dopa and 30 D2 agonists, in treatment of CNS diseases, such as Parkinson’s disease, Alzheimer'sdisease, attention déficit disorder and leaming and memory abnormalities. -2-

Summarv of the Invention

The présent invention relates to a compound of the formula 011286 -

or the pharmaceutically acceptable sait thereof, wherein the broken linereprésente an optional double bond; a is 0 or 1, wherein when a is 0, X may form an optional double bond with thecarbon adjacent to V; V is CHR10 wherein R10 is hydrogen or (C-i-Cejalkyl; T is nitrogen or CH; X is nitrogen or CR11 wherein R11 is hydrogen, (CrC6)alkyl, (CrCejalkoxy,hydroxy or cyano; Y and Z are each independently nitrogen or CR12 wherein R12 is hydrogen,chloro, bromo, trifluoromethyl, trifluoromethoxy, cyano, (CrC6)alkoxy or (CrCejalkyi; R1 is hydrogen, fiuoro, chloro, bromo, trifluoromethyl, trifluoromethoxy, cyano or(CrC6)alkyl; . R2, R6, R7, R8 and R9 are each independently selected from hydrogen, fiuoro,chloro, bromo, trifluoromethyl, trifluoromethoxy, cyano, (CrC6)alkoxy and (C1-C6)alkyl; R3 and R4 are each independently hydrogen or (CrC6)alkyl; and R5 is hydrogen, (CrC6)alkoxy, trifluoromethyl, cyano, (C5-C6)alkyl or R13CO- wherein R13 is amino, (CrCejalkylamino, ((C-|-C6)alkyl)2amino, (CrC6)alkyl, (Cs-Cio)aryl; or when a is 1, R1 and R10 may be taken together with the carbons to which theyare attached to form a compound of the formula -3-

011286 wherein the broken lines represent optional bonds; T, X, Y, Z, R2, R3, R4, R5, R6, R7, R8 and R9 are defined as above;b is 0 or 1; and

A and B are each independently CH, CH2, oxygen, sulfur, NH or nitrogen;with the provïso that when X is nitrogen, the optional double bond between X and V does not exist; with the proviso that when b is 0, the optional double bond between A and Bdoes not exist; and with the proviso that when b is 1, A and B cannot both be oxygen or sulfur.

The term “alkyl”, as used herein, unless otherwise indicated, includes saturatedmonovalent hydrocarbon radicals having straight, branched or cyclic moieties orcombinations thereof.

The term “alkoxy’, as used herein, includes O-alkyl groups wherein “alkyl” isdefined above.

The term “treating”, as used herein, refers to reversing, alleviating, inhibiting theprogress of, or preventing the disorder or condition to which such term applies, or oneor more symptoms of such disorders or condition. The term “treatment", as usedherein, refers to the act of treating, as “treating” is defined immediately above.

The term "disorders of the dopamine System", as referred to herein, refers todisorders the treatment of which can be effected or facilitated by altering (i.e., increasingor decreasing) dopamine mediated neurotransmission.

The compounds in accordance with the présent invention, being ligands fordopamine receptor subtypes, especially the dopamine D4 receptor, within the body, areaccordingly of use in the treatment of disorders of the dopamine System.

The compound of formula I may hâve chiral centers and therefore exist in different enantiomeric forms. This invention relates to ail optical isomers and stereoisomers of the compounds of formula I and mixtures thereof. -4-

Preferred compounds of formula I include those wherein X is nitrogen.

Other preferred compounds of formula I include those wherein Y and 2 are eachCR12 wherein R12 is hydrogen or fluoro.

Other preferred compounds of formula I include those wherein R2 is hydrogen,fluoro or chloro.

Other preferred compounds of formula I include those wherein R3, R4 and R5 arehydrogen.

Other preferred compounds of formula I include those wherein R7 is fluoro or chloro.

Other preferred compounds of formula I include those wherein R9 is fluoro.chloro, bromo or alkoxy.

More preferred compounds of formula I include those wherein X is nitrogen; Yand 2 are each CR13 wherein R13 is hydrogen or fluoro; R2 is hydrogen fluoro or chloro;R3, R4 and R5 are hydrogen; R7 is fluoro or chloro; and R9 is fluoro, chloro, bromo oralkoxy.

Spécifie preferred compounds of formula I include the following: 2-[4-(3-T rifluoromethyl-phenyl)-piperazin-1 -yimethyl]-1 H-indole; 5-Fluoro-2-[4-(3-trifluoromethyl-phenyl)-piperazin-1-ylmethyl]-1H-indole; 5-Fluoro-2-[4-(4-fluoro-phenyl)-piperazin-1 -ylmethyl]-1 H-indole; 5-Fluoro-2-[4-(4-fluoro-phenyl)-piperazin-1 -yimethyl]-1 H-indole; 5-Fluoro-2-(4-pyridin-2-yl-piperazin-1 -ylmethyl)-1 H-indole; 2-[4-(6-Chloro-pyridazin-3-yl)-piperazin-1-ylmethyl]-5-fluoro-1 H-indole; 5-Fluoro-2-(4-[5'-fluoro]pyridin-2-yl-piperazin-1-ylmethyl)-1 H-indole; 2-(4-pyridin-2-yi-piperazin-1 -ylmethyl)-1 H-azaindole; 5-Fluoro-2-(4-pyridin-2-yl-piperazin-1-ylmethyl)-1 H-azaindole; and 2-(4-(4-fluoro-phenyl)-piperazin-1 -ylmethyl]-1 H-azaindole.

The présent invention also relates to a method for treating disorders of thedopamine System induding psychotic disorders (affective psychosis, schizophrenia, andschizoaffective disorders), movement disorders (extrapyramidal side effects fromneuroleptic agents, neuroleptic malignant syndrome, tardive dyskinesia, Gilles De LaTourette's syndrome, Parkinson's disease or Huntington’s disease), gastrointestinaldisorders (gastric acid sécrétion or emesis), Chemical abuse, Chemical dependencies,substance abuse, vascular and cardiovascular disorders (congestive heart failure and -5- 011286 hypertension), ocuiar disorders and sleep disorders in a mammal, comprisingadministering to said mammal an amount of a D4 dopamine receptor sélective compoundaccording to formula I, or a pharmaceutically acceptable sait thereof, that is effective intreating such disorder.

The présent invention also relates to a method for treating disorders of thedopamine System including psychotic disorders (affective psychosis, schizophrenia, andschizoaffective disorders), movement disorders (extrapyramidal side effects fromneuroleptic agents, neuroleptic malignant syndrome, tardive dyskinésie, Gilles De LaTourette's syndrome, Parkinson’s disease or Huntington's disease), gastrointestinaldisorders (gastric acid sécrétion or emesis), Chemical abuse, Chemical dependencies,substance abuse, vascular and cardiovascular disorders (congestive heart failure andhypertension), ocuiar disorders and sleep disorders in a mammal, comprisingadministering to said mammal an amount of a D4 dopamine receptor sélective compoundaccording to formula I, or a pharmaceutically acceptable sait thereof, in conjunction withone or more D1, D2, D3 or D5 dopamine receptor agonists, that is effective in treatingsuch disorder.

The présent invention also relates to a pharmaceutical composition for treatingdisorders of the dopamine System including psychotic disorders (affective psychosis,schizophrenia, and schizoaffective disorders), movement disorders (extrapyramidal sideeffects from neuroleptic agents, neuroleptic malignant syndrome, tardive dyskinesia,Gilles De La Tourette's syndrome, Parkinson’s disease or Huntington's disease),gastrointestinal disorders (gastric acid sécrétion or emesis), Chemical abuse, Chemicaldependencies, substance abuse, vascular and cardiovascular disorders (congestive heartfailure and hypertension), ocuiar disorders and sleep disorders in a mammal, comprisingadministering to said mammal an amount of a D4 dopamine receptor sélective compoundaccording to formula I, or a pharmaceutically acceptable sait thereof, that is effective intreating such disorder.

The présent invention also relates to a pharmaceutical composition for treatingdisorders of the dopamine System including psychotic disorders (affective psychosis,schizophrenia, and schizoaffective disorders), movement disorders (extrapyramidal sideeffects from neuroleptic agents, neuroleptic malignant syndrome, tardive dyskinesia,Gilles De La Tourette's syndrome, Parkinson’s disease or Huntington's disease),gastrointestinal disorders (gastric acid sécrétion or emesis), Chemical abuse, Chemical -6- 011286 5 dependencies, substance abuse, vascular and cardiovascular disorders (congestive heartfailure and hypertension), ocular disorders and sleep disorders in a mammal, comprisingadministering to said mammal an amount of a D4 dopamine receptor sélective compoundaccording to formula I, or a pharmaceutically acceptable sait thereof, in conjunction withone or more D1, D2, D3 or D5 dopamine receptor agonists, that is effective in treating 10 such disorder. -7- 011286 5 Detailed Description ofthe Invention

The following réaction Schemes illustrate the préparation of the compounds ofthe présent invention. Unless otherwise indicated a, T, V, X, Y, Z, R1, R2, R3, R4, R5, R6, R7, R8 and R9 in the reaction Schemes and the discussion that followare defined as above.

-8·

V 2

I -9- 011286

In reaction 1 of Scheme 1, the compounds of formula III and IV are coupled toform the corresponding compound of formula I by first treatîng III with O-, N- dimethylhydroxylamine hydrochloride, dicydohexylcarbodiimide and a base, such astriethylamine, in a polar aprotic solvent, such as methylene chloride. The hydroxamideintermediate so formed is reduced, using a reducing agent such as lithium aluminumhydride, in a polar aprotic solvent, such as tetrahydrofuran. The reductive amination ofthe aldéhyde intermediate so formed is accomplished by reacting the aldéhyde with thecompound of the formula IV in the presence of sodium triacetoxyborohydride and apolar aprotic solvent, such as dichloroethane, The reaction mixture is stirred, underinert atmosphère, at room température for a time period between about 40 hours toabout 56 hours, preferably about 48 hours.

In reaction 1 of Scheme 2, the compounds of formula VI, wherein L is a leavinggroup such as chloro, bromo, methoxy or any activated ester dérivative such as para-nitro phenyl ester, hydroxy benzotriazole ester, N-hydroxysuccinimide ester or hydroxy,and IV are coupled to form the corresponding methanone compound of formula III byreacting VI and IV in the presence of diisopropylethylamine, carbodiimide or adehydrating agent and a polar aprotic solvent, such as methylene chloride, or in form ofmixtures containing, if desired, combinations of organic solvents or water such ascombinations of cyclic and acyclic mono and dialkylamides, (CrC4) alcohols,halogenated solvents, or acyclic and cyclic alkylethers at températures ranging fromabout 0°C to about 150’C, preferabley about 0°C or the boiling point of the samesolvent mixture. Addition of an acid acceptor such as an alkalicarbonate, a tertiaryamine or a similar reagent may be useful.

In reaction 2 of Scheme 2. the methanone compound of formula V is convertedto the corresponding compound of formula I, wherein R3 and R4 are hydrogen, byreducing V with a reducing agent, such as lithium aluminum hydride or a boranedérivative, in the presence of a polar aprotic solvent, such as tetrahydrofuran, for a timeperiod between about 10 hours to about 14 hours, preferably about 12 hours.

In each of the above reactions, pressure is not critical. Pressures in th range of about 0.5 atmosphères to 3 atmosphères are suitable, and ambient pressure (generally, about one atmosphère) is preferred as a matter of convenience. Also, for those reactions where the preferred température varies with the particular compounds reacted, no preferred température is stated. For such reactions, preferred -10- 011286 températures for partîcular reactants may be determined by monitoring tbe reactionusing thin layer chromatography.

The novel compounds of the formula I and the pharmaceutically acceptable saltsthereof (herein "the therapeutic compounds of this invention") are usefol as dopaminergicagents, i.e., they possess the abiiity to alter dopamine mediated neurotransmission inmammals, induding humans. They are therefore able to fonction as therapeutic agents inthe treatment of a variety of conditions in mammals, the treatment or prévention of whichcan be effected or facilitated by an increase or decrease in dopamine mediatedneurotransmission.

The compounds of the formula I that are basic in nature are capable of forming awide variety of different salts with various inorganic and organic acids. Although such saltsmust be pharmaceutically acceptable for administration to animais, it is often désirable inpractice to initially isolate a compound of the formula I from the reaction mixture as apharmaceutically unacceptable sait and then simply convert the latter back to the freebase compound by treatment with an alkaline reagent and subsequently convert the latterfree base to a pharmaceutically acceptable acid addition sait. The acid addition salts ofthe base compounds of this invention are readily prepared by treating the base compoundwith a substantially équivalent amount of the chosen minerai or organic acid in anaqueous solvent medium or in a suitable organic solvent, such as methanol or éthanol.Upon carefol évaporation of the solvent, the desired solid sait is readily obtained. Thedesired acid sait can also be precipitated from a solution of the free base in an organicsolvent by adding to the solution an appropriate minerai or organic acid.

The therapeutic compounds of this invention can be administered orally,transdermally (e.g. through the use of a patch), parenterally or topically. Oraladministration is preferred. In general, these compounds are most desirably administeredin dosages ranging from about 0.1 mg up to about 1000 mg per day, or 1 mg to 1000 mgper day in some cases, although variations may occur depending on the weight andcondition of the person being treated and the particular route of administration chosen. Insome instances, dosage levels below the lower limit of the aforesaid range may be morethan adéquate, whiie in other cases still larger doses may be employed without causingany harmful side effect, provided that such larger doses are first divided into several smalldoses for administration throughout the day. -11- 011286 5 The therapeutic compounds of the invention may be administered alone or in combination with pharmaceuticaliy acceptable carriers or diluents by either of the tworoutes previously indicated, and such administration may be carried out in single ormultiple doses. More particuiarly, the novel therapeutic compounds of this invention canbe administered in a wide variety of different dosage forms, i.e., they may be combined 10 with various pharmaceuticaliy acceptable inert carriers in the form of tablets, capsules,lozenges, troches, hard candies, powders, sprays, creams, salves, suppositories, jeliies,gels, pastes, lotions, ointments, élixirs, syrups, and the like. Such carriers include soliddiluents or fillers, stérile aqueous media and various non-toxic organic solvents, forexample. Moreover, oral pharmaceutical compositions can be suitably sweetened and/or 15 flavored.

For oral administration, tablets containing various excipients such asmicrocrystaliine cellulose, sodium citrate, calcium carbonate, dicalcium phosphate andglycine may be employed along with various disintegrants such as starch (and preferabiycom, potato or tapioca starch), alginic acid and certain complex silicates, together with 20 granulation binders like polyvinyipyrrolidone, sucrose, geiatin and acacia. Addrtionally,lubricating agents such as magnésium stéarate, sodium lauryl sulfate and talc are oftenvery useful for tabletting purposes. Solid compositions of a simiiar type may also beemployed as fillers in geiatin capsules; preferred matériels in this connection also indudelactose or milk sugar as well as high molecular weight polyethyiene glycols. When 25 aqueous suspensions and/or élixirs are desired for oral administration, the activeingrédient may be combined with various sweetening or flavoring agents, coloring matteror dyes, and, if so desired, emulsifying and/or suspending agents as well, together withsuch diluents as water, éthanol, propylene glycol, glycerin and various like combinationsthereof. 30 For parentéral administration, solutions of a compound of the présent invention in either sesame or peanut oil or in aqueous propylene glycol may be employed. Theaqueous solutions should be suitably buffered if necessary and the liquid diluent firstrendered isotonie. These aqueous solutions are suitable for intravenous injectionpurposes. The oily solutions are suitable for intra-articuiar, intramuscular and 35 subeutaneous injection purposes. The préparation of ail these solutions under stérileconditions is readily accomplished by standard pharmaceutical techniques well known tothose skilled in the art. -12- 0112S6

Additionally, it is also possible to administer the compounds of the présentinvention topically when treating inflammatory conditions of the skin and this maypreferably be done by way of creams, jellies, gels, pastes, ointments and the like, inaccordance with standard pharmaceutical practice.

The ability of compounds to bind to mammalian dopamine receptors, and therelative ability of compounds of this invention to inhibit [3H]-spiperone binding to humandopamine D4 receptor subtypes expressed in clonal cell lines was measured using thefollowing procedure.

Dx Receptor Binding Ability

The détermination of D4 receptor binding ability has been described by Van Toi, etal. (Nature, 1991, 350, 610). Clonal cell lines expressing the human dopamine D4receptor are harvested and homogenized (polytron) in a 50 mM Tris.HCI (pH 7.4 at 4 °C)buffer containing 5 mM EDTA, 1.5 mM calcium chloride (CaCI2), 5 mM magnésiumchloride (MgCI2), 5 mM potassium chloride (KCI) and 120 mM sodium chloride (NaCI).The homogenates are centrifugated for 10-15 min. at 48,000 g, and the resulting pelletsresuspended in a buffer at a concentration of 150-250 mg/ml. For saturation experiments,0.75 ml aiiquots of tissue homogenate are incubated in triplicate with increasingconcentrations of ^HJ-spiperone (70.3 Ci/mmol; 10-3000 pM final concentration) for 30-120 minutes at 22 eC in a total volume of 1 ml. For compétition binding experiments,assays are initiated by the addition of 0.75 ml of membrane and incubated in duplicatewith the indicated concentrations of competing ligands (10'14-10‘3 M) and/or [3H]-spiperone (100-300 pM) for 60-120 min at 22°C. Assays are terminated by rapid filtrationthrough a Brandell cell harvester and the filters subsequently monitored for tritium asdescribed by Sunahara, R.K. et al. (Nature, 1990, 346, 76). For ail experiments, spécifief3H]spiperone binding is defined as that inhibited by 1-10 mM (+)-butaclamol. Binding dataare analyzed by non-linear least square curve-fitting. The compounds of the Exampleswere tested in this assay, and ail were found to hâve binding affintties (K,) for thedisplacement of [3H}-spiperone of less than 2 micromolar. -13- 011286

Human .04 receptor modulation of cAMP formationChinese hamster ovary (CHO) cells expressing the human D4.4 dopamine

receptor were obtained from Dr. H. Van Toi (Clarke Institute of Psychiatry, Toronto),and were grown to confluence in Minimal Essential Alpha Media (Gibco) supplementedwith 2.5% Fêtai Bovine Sérum (not heat inactivated), 2.5% Equine Sérum (heatinactivated), and 500 yg/ml Geneticin. Monolayers were disrupted and cells dislogedwith 5 mM ethylenediaminetetraacetic acid (EDTA) and resuspended in phosphatebuffered saline buffer containing 5 mM magnésium chloride, 30 mM hydroxyethylpiperazine-N-ethanesulfonic acid (HEPES), 300 μΜ 3-isobutyl-1 -methyl-xanthine (IBMX, a phosphodiesterase inhibitor), and 5.6 mM dextrose. Cells(approximately 200,000/tube) were exposed to 5 μΜ forskolin (an adenylate cyclaseactivator), forskolin plus test compounds or quinpirole (a D4 receptor agonist), orforskolin plus quinpirole plus antagonist for 11 minutes. In experiments withantagonists, cells were exposed to antagonists 11 minutes prior to agonist challenge.The effect of test compounds in the absence of the agonist quinpirole was used to judgeagonist activity. D4 agonists produce an inhibition of cAMP accumulation which can bereversed by D4 receptor antagonists. The reaction was terminated with the addition of6N perchloric acid, and samples neutraiized with 5N potassium hydroxide and 2M Trisbuffer. Cyclic AMP levels were measured using a commercially availabie compétitivebinding kit (Amersham). IC50 values were calculated by linear régression analysis ofthe concentration-response curves. Kj values were calculated using the équation: Kj =IC50/(1 + (agonist]/[agonist EC50]} (Minneman and Johnson, 1984).

The présent invention is illustrated by the following examples, but it is not limitedto the details thereof. EXAMP.LE 1 2-(4-(6-Chloro-pyridazin-3-yn-Diperazin-1-ylmethyn-5-fluoro-1H-indoleA mixture of 5 gm of 5-fluoro 2 indole carboxylic acid, 2.74 gm of O-, N-dimethyl hydroxylamine hydrochloride, 3.89 ml triethylamine and 5.76 gm of dicyclohexylcarbodiimide in 35 ml methylene chloride is stirred at ambient température until a tan precipitate is formed. The solid is removed by filtration, the residue concentrated and purified on SiO2 (25%) EtOAc in Hexane) obtained are 3.6 gm (64%) of the N-O-dimethyt 2 indole hydroxamide. -14- 0112S6 3.9 gm of N-O-dimethyl 2 indole hydroxylamide is added over a period of 5minutes to a cold suspension (-40 C) of 0.67 gm LÎA1H4 in 30 ml tetrahydrofuran. Themixture is stirre for an hour (-40 C-> -30 C) treated with a saturated aqueous solution ofsodium sulfate and warmed to ambient température. The solvent is separated afteraddition of solid sodiumsulfate and concentrated until a solid precipitate is formed (2.94gm of 5-fluoro 2-indolecarboxaldehyde. A mixture of 0.96 gm of 4-(5-chloro-phenyl)-piperazine, 1.0 gm of 5-Fluoro, 2-indolecarboxaldehyde and 1.2 gm of sodium triacetoxyborohydride in 50 mldichloroethane is stirred under nitrogen at ambient température for 48 hours. Thesolvent is removed and the residue portioned between 100 ml EtOAc and 20 ml NaOH(1N). The organic layer is washed with water (2x20ml) and brine (1x10 ml) andconcentrated. The residue is purified on Si02 (eluent: 5% methanol in methylenechloride) to yield 1.02 gm of a cream coiored solid which has a mp.: 204-205 C”). EXAMPLE 2 5-Fluoro-1H-indol-2-yn-t4-(3-tnfluoromethyl-phenyl)-oiperazin-1-yn-methanone A mixture of 1.0 mmol of 5-fluoro, 2-indole carboxylicacidchloride and 230 mg ofmeta-trifiuoromethylphenylpiperazine and 129 mg of diisopropylethylamine in 10 mlmethylenchloride is kept at ambient température for 12 hours. Water is added, theorganic layers separated, washed with wate, dried over sodium sulfate andconcentrated to yield 296 mg of the title compound. MP: 198°C. EXAM.PLE-3 5-Fluoro-2-{4-(3-trifluoromethyi-phenyn-piperazin-1-vlmethyll-1H-indole hydrochloride A solution of 275 mg of 5-Fluoro-1 H-indol-2-yl)-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]methanone in 5 ml anhydrous tetrahydrofurane is kept under an inert gasatmosphère and is treated at ambient température with 2.11 ml of a 1M solution ofLithiumaluminumhydride in tetrahydrofurane. After 12 hours the mixture is treated with78 pl 15% Sodium Hydroxide solution and again 234 μΙ water. After addition ofmagnesiumsulfate the organic layer is separated and concentrated to a yellow oil (240mg). This oil is disolved in ether and treated with an ether solution of hydrochloric aciduntil a precipitate is formed. The precipitate is collected, dried under vacuum.

The title compounds of Examples 4- were prepared by a methods analogous tothat described in Example 1-3. -15- 011286 EXAMPLE 4 2-Î443Jj1fl.u.orQme.thvkpheny0-piperazin-1-ylmethyn-1H-indol-5-o| MP: 188-190’C; HRSMS 375.15. EXAMPLE 5 2-F4:f3-Trifl.UQro,methyl-PheDyl)-piP€razin-1-vlfnethyl)-1H-indoleMP: 192-194’C; HRSMS 359.15. EXAMELE-δ ilH-lndQl-2-vn-i4-f2-nitrc>-phenvl)-piperazin-1-vn-methanoneMP: 186-189’C. EXAMPLE·,7 f5-Eluorp-1 H-indol-2-yl)-[4-(2-nftrQ-phenvn-piperazin-1 -vil- methanoneMP: 184-188’C. EXAMPLE ..g (5-Fluoro-1 H-indol-2-yf)-f4-(3-trifïuoromethyl-pheny0-piperazin-1 - vH-methanone MP: 198’C.

EXAMSULS 3-(4-(1 H-tndol-2-vlmethyl)-piperazin-1-yH-benzofdjisothiazoleMP: 150-152’C; MRSMS 348.12. exameleliq 5-Fluoro-2-f4-(34rifluorpmethvl-phenyl)-piperazin-1 -ylmethyll-l H- indole MP: 196-197’C; HRSMS 377.148. EXAMELEJ1 2-(4-Naphthalen-1-yl-piperazin-1 -ylmethvB-1 H-indoleMP: 238-239°C; HRSMS 341.19. EXAMELEJ2 2-(4-(2-Nitro-phenyl)-piperazin-1 -ylmethvll-l H-indoleMP: 210-211"C; HRSMS 336.16. EXAMPLE J-3 5-Fluoro-2-f4-(2-nitro-phenyl)-piperazin-1 -vlmethyll-1 H-indoleMP: 236°C; HRSMS 354.14. -16- 011280 EXAMPLE.14 5-Fluorp-2-i4-naDhthalen-1-yi-Piperazin-1-vlmethvl)-1 H-indoleMP: 249-250°C; HRSMS 359.18.

EMMELEE 5-Fluoro-2-(4-pyndin-2-yl-piperazin-1 -ylmethyl)-1 H-indoleMP: 242°C; HRSMS 310.15. EXAMPLE-15 5-Fluoro-2-i4-(4-fluoroDhenvlVpiperazin-1 -ylm.ethyn-1 H-indoleMP. EXAMP-LEJL7 5-Fluoro-2-(4-pyrimidtn-2-vl-piperazin-1 -ylmethvO-1 H-indoleMP: 199°C; HRSMS 311.16. EXAMPLE 18 (5-Fluprp-1H-indol-2-yl)-(4-pyridin-2-yl-piperazin-1-yt)-methanoneMP: 214-218°C.

EXAMELEIS 2-(4-Pyridin-2-vl-piperazin-1 -ylmethyD-1 H-indoleMP:

EXAMP1E2.Q (1 H-lndol-2-y0-(4-pyridin-2-yl-piperazin-1 -vl)-methanoneMP: 198-200°C. EXAMPLE 21 2-(4-Pyridin-2-vt-piperazin-1 -vlmethyl)-1 H-indole13C NMR (CDCI3, 75 MHz) 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 (CDCI3, 250 MHz) 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, tR = 4.468 min., M+ = 292, (M-162) = 130. -17- 011286 EXAMELEL22 . (2‘α, 3’aB, 6:aD)-1-(4-FIUQ.rg-PhenvlM-f5,-phenvj-1,.2,.3.,.3,a.4,.6’a-hexahvdro-pentalen-2’_-yl)-piperazine dihydrochloride MP: 250-253°C. Analysis calculated for C24H27FN2*2 HCI»0.75 H2O: C, 66.28; H, 7.07; N, 6.44. Found: C, 66.18; H. 6.76; N. 6.56. EXAMPLE23 iZ'cx.O'aB. S'ct^S’aB^-S’^-ÎA-Fluoro-phenviy-Piperazin-l-vn^'-Dhenvl-octahvdro- pentalen^’-ol maleate MP: 206-207.5°C. Analysis calculated for C24H29FN2O«0.75 C4H4O4«0.75 H2O: C, 67.41; H, 7.02; N, 5.82. Found: C, 67.24; H. 6.77; N, 5.68. EXAMPLE 24 (2'α. 3’ap. 5’a. 6’apb1 -(4-FLuoro-ohenvl)-4-(5’-phenvl-octahvdro-pentalen-2’-vll· piperazine dihydrochloride MP: 255-256.5°C. Analysis calculated for C24H29FN2*2HCI*0.25 H2O: C, 65.23; H, 7.18; N, 6.34. Found: C, 65.40; H, 7.02; N, 6.38. EXAMPLE 25 f2’a. 3'aQ, 5’a, S’aB^-Fiuoro^-pf-fS’-hvdroxy-S’-phenvI-octahvdro-pentalen^1- yl)-piperazin-1-yl]-benzonitrile maleate MP: 207-207.5°C. Analysis calculated for Ο^Η^^Ο· C4H4O4: C, 66.78; H,6.18; N, 8.06. Found: C, 66.64; H, 6.06; N, 8.14. EXAMPLEJ5 (2’,g, .. m_5’tt, ^Κ:Ε1ν0Γς>-4-[4-(3’, 3‘a, 4’,_5’·. 6’, 6'a- hexahydrospirofisobenzofuran-1f3H). 2,('1’H)-pentalenI-5'-vlV1-piperazinvl]-benzonitriie maleate MP: 221-221.5®C. Analysis calculated for C26H28FN3O· C4H4O4*0.5 H2O: C,66.41; H, 6.13; N, 7.74. Found: C, 66.33; H, 6.26; N, 7.61. EXAMPLE 27 f2’g, 3'aB. 5’g, 6’a6)-5’-[4-(2-Methoxv-phenyB-piperazin-1-yl]-2’-phenyl- octabydro-pentalen-2,-ol maleate MP: 188-189°C. Analysis calculated for C^H^N^· C4H4O4: C, 68.48; H, 7.13; N, 5.51. Found: C, 68.64; H, 7.10; N, 5.81. -18- 011286

EXAMELE_2S (2’α. 3’aB. 5'α. 6,aS1-2-(4-nuoro-phenyh-5’-[4-(5-fluoro-Pvrimidin-2-vl)-pipera?in-1-yl1-octahvdro-pentalen-2’-ol maleate MP: 219.5-220°C. Analysis calculated for C22H26F2N4O· C^O^O.ô H2O: C,59.41; H, 5.94; N, 10.66. Found: C, 59.76; H, 5.89; N, 10.65. EXAMPLE 29 (2’a, 3IaB. 5’a. . 6,aB)-2-Fluoro-444-f5’-(4-fluoro-phenyn-5,-hydroxy-octahvdro-pentalen-Z-yn-piperazin-l -yB-benzonitrile maleate MP: 204-204.5°C. Analysis calculated for C25H27F2N3O· C4H4O4*H2O: C, 62.47;H. 5.97; N, 7.54. Found: C, 62.77; H, 5.74; N, 7.58.

EXAMPLS.3Q (2La^_3'aB^5’a,. 623gb2’-(4-FluQr(^phenvlï-5X4-(4-fluoro-phenvh-oiDerazin-1 -yll-octahydro-pentalen-2’-ol maleate MP: 209-209.5°C. Analysis calculated for C24H28F2N2O· C4H4O4: C, 65.36; H,6.27; N, 5.54. Found: C, 65.65; H, 6.25; N, 5.34. EXAMPLE .31. (2’a, 3^β, 6’aB)-5-Fluoro-2-[4-(5’-phenyl-1L2,.3’.3,a.4’.6’a-hexahydro-pentalen- 2,-vn-piperazin-1-yl}-pyrimidine maleate MP: 202-203°C. Analysis calculated for C22H25FN4· C4H4O4: C, 64.99; H, 6.08;N, 11.66. Found: C, 64.67; H, 6.00; N, 11.79. EXAMELEJ2 (2’a. 3’ap. 6'aBV2-Fluoro~4-î4-(5’-phenyl-1 ’^'.SVS’a^’.e’a-hexahydro-pentalen- 2'zy_l)-piperazin-1 -yl]-benzonitrile maleate MP: 172-173°C. Analysis calculated for C25H26FN3· C4H4O4: C, 69.17; H, 6.00; N, 8.34. Found: C, 69.06; H, 5.88; N, 8.57. EXAMPLE 33 (2’a. 3’aB, 5’a, 6,ap)-5-Fluoro-2-f4-(5’-phenyl-octahvdro-pentalen-2L-yl)- piperazin-1 -yl]-pyrimidine maleate MP: 211.5-212°C. Analysis calculated for C22H27FN4· C4H4O4: C, 64.72; H,6.48; N, 11.61. Found: C, 64.67; H, 6.43; N, 11.82. -19-

PC 011286 EZAMPLE-24 -3M-£&amp;5,9βν2-ΗυθΓο-4-ί4-(5’-ρΚ6ην!-οοΐ3ήνόΓο-ρβηΐ3ΐ6η-21-ν1)- piperazin-1 -vll-benzonitrile maleate MP: 195-196°C. Analysis calculated for C25H28FN3· C4H4O4: C, 68.89; H, 6.38;N, 8.31. Found: C, 68.99; H, 6.47; N, 8.30. EXAMPLÊ35 (2Ù2u_Sisft__6,ag)-2-Fluoro-4-{4-[5’-f2-trifluoromethvl-phenvn-octahvdro- pentalen-2’-y n-Pirerazin-1 -vl}-benzonitrile maleate MP: 192-193°C. Analysis calculated for C26H27F4N3· C4H4O4: C, 62.82; H, 5.45;N7.33. Found: C, 62.87; K, 5.22; N, 7.27. .EXAMPIE_3,5 (2’α, 3’aB. 6’ap1-2-Fluoro-4-{4-[5-(2-methoxy-DhenylM ’.Ζ’.^.β’ΒΛ’.θ’β- hexahvdro-pentalen-21-vl]-piperazin-1-vl)-benzonitrile maleate MP: 155-156°C. Analysis calculated for C26H28FN3O· C4H4O4*0.25H2O: C, 66.96; H, 6.09; N, 7.81. Found: C, 67.00; H.6.05; N, 7.82. emeiE.37. (2’g. _3'-aB, 5’a, 6’aB)-2-Fluoro-4-f4-[5’-(2-methoxy-Dhenvl)-octahvdro-pentalen- 2’-yl]-piperazin-1-yl}-benzonitrile maleate MP: 176-177°C. Analysis calculated for C26H30FN3O· C4H404»0.50H20: C, 66.16; H, 6.48; N, 7.71. Found: C, 66.20; H, 6.31; N, 7.69. EXAMPLE 38 (2’g 3’ap. 5’a, 6,aB)-2-Fluoro-4-f4-i5'-f1H-indol-3-vl)-octahvdro-pentaien-2,-vll- piperazin-1 -vl}-benzon?trile maleate MP: 226-227°C. Analysis calculated for C27H2gFN4· C4H4O4: C, 68.37; H, 6.11;N, 10.29. Found: C. 68.17; H, 6.24; N, 10.20. EXAMPLE 39 (2’a. 3’ap. S’a, 6,aBV2-Fluoro-4-{4-[5,-(2-pnethanesulfonyl-phenyl)-octahydro- pentalen-2’-yll-piperazin-1-ylkbenzonitrile maleate MP: 179-180°C. Analysis calculated for C26H30FN3O2S· C4H4O4*0.25 H2O: C, 61.25; H, 5.91; N, 7.14. Found: C, 61.26; H, 6.32; N, 6.76. -20- EXAMPLE 40 011286 IZsl_3'aB. 5'B. gaB^-rtuoro^ty, 3'a, 4’, 5', 6'. 6’a- hexahvdr-QSDJrQliS-Obenzofuran-l (3H). 2ï1’H)-pentalen]-5'-vlM-DiDerazinvll-benzonitrilemaiggig. MP >260°C. Analysis calculated for C^H^Fb^O· CH4O3S: C, 63.14; H, 6.27;10 N, 8.18. Found: C, 63.12; H, 6.66; N, 8.00. EXAMP.LE41 (2’g, 3'jap, 5’&amp;._6,a8)-2-Fluoro-4-{4-(3. 3', 3'a, 4, 4’, 5’, 6’, 6'a-hexahydrospirof2H- 1 -benzopyran-2.2'f 1 ’H)-pentalen]-5’-yn-1 -piperazinyQ-benzonitrile maleate MP: 176-177°C. Analysis calculated for C27H28FN3O2· C4H404»0.50 H2O: C, 16 65.25; H, 5.82; N, 7.36. Found: C, 65.52; H, 6.06; N, 7.19. EXAMPLE 42 f2’g. 3'aB. 5’B, 6'aB)-2-Fluoro-4-r4-(3. 3’. 3’a, 4.4’, 5'. 6', 6’a-hexahydrospiroi2H- 1-benzopyran-2.2ï1 'H^pentalen]- S’-yh-l-piperazinvII-benzonitrile maleate MP: 179-180°C. Analysis calculated for C27H28FN3O2· C4H4O4: C, 66.30; H, 20 5.74; N, 7.48. Found: C, 66.17; H, 6.07; N, 7.34. EXAMPLE 43 (2'g. 3’aB, 5’g, 6’ap,l-2-Fluoro-444-[5’-(2-trifluQrom_ethoxy-phenvn-octahvdro- pentalen-2'.-yn-piperazin-1 -ylFbenzonitrile maleate MP: 126-129°C. NMR DMSO d6 δ 7.70 (t, J=8.5 Hz, 1H), 7.52 (d, J=7.1 Hz,25 1H), 7.40-7.25 (m, 3H), 7.09 (d, J=13.6 Hz, 1H). 6.96 (d, J=9.0 Hz, 1H), 6.06 (s, 2H), 3.73-2.90 (br m, 10H), 2.65-2.54 (m, partially under DMSO, 1H), 2.46-2.18 (m, 4H), 1.63-1.42 (m,4H). EXAMPLE 44 (2’g. 3'aB, 5’g, 6’aB)-2-Fiuoro-4-{4-r5’-(2-ftuoro-phenvn-oçtahvdro-pentalen-2'-30 yl~|-piperazin-1 -vIFbenzonitrile maleate MP: 179-180.5°C. Analysis calculated for C25H27F2N3· 04Η404: C, 66.53; H,5.97; N, 8.03. Found: C, 66.62; H, 6.24; N, 7.98. -21- 011286 EXAMPLE 45 (2’α. 3'aS, 5’a.....6’aB)-2-Cyano-4-{4.-[5,-f2-fluoro-phenyn-octahydro-pentalen-2’- yl]zpipgrazifh.1.^,IH!aeDZQnttrile.maieate MP: 193-194°C. Analysis calculated for C26H27FN4· C4H404»0.50 H2O: C,66.78; H. 5.98; N, 10.38. Found: C, 66.99; H, 6.05; N, 10.34. EXAMPLE 46 (2’g. 3’aft_5’a,.....6,aB)-2-FLuojo-4-f4-f5,-pyridin-2-yl-octahydro-oentalen-2’-vn- piperazin-l-yll-beozonitrile dihydrochloride MP: 203-206°C. Analysis calculated for C24H27FN4· 2HCI*H2O: C, 59.88; H, 6.49; N, 11.63. Found: C, 59.55; H, 6.42; N, 11.47. EXAMPLE 47 (2’a, 3’ap, 5’α, 6’3βν5-ΡΙυοΓο-2-(4-[5’-(2-ηιβ^οχν-οΚβηνη-οοΐ3ΚνύΓθ-Ρ6ηΐ3ΐ8η- 2’-yl1-piperazin-1 -yl}-pyrimidine maleate MP: 183.5-184.5°C. Analysis calculated for C23H29FN4O· C4H4O4: C, 63.26; H, 6.49; N, 10.93. Found: C, 63.21; H, 6.71; N, 10.82. EXAMPLE.4.3 (2’α, 3’ap._5’a. 6’aB)-2-Fluoro-4-{4-f5,-i6-fluoro-2-oxo-2.3-dihydro- benzoimidazol-1 -yl)-octahydro-pentalen-2’-yn-piperazin-1 -yJLhenzonitrile dimesvlate MP: 219-222°C. Analysis calculated for C26H27FN5O· 2CH4O3S: C, 51.29; H, 5.38; N, 10.68. Found: C, 51.84; H, 5.57; N, 10.64. EXAMPLE 49 f2’g, 3’ap. 5’a, 6,aB)-2-Fluoro-4-f4-f5’-f6-fluoro-2-methylbenzoimidazol-1-yn- octahvdro-pentalen-2'-vl]-piperazin-1-vl}-benzonitrile dimesylate MP: >260°C. Analysis calculated for C27H29F2N5· 2CK403S*0.50 H2O: C, 52.56; H, 5.48; N, 10.57. Found: C, 52.64; H, 5.71; N, 10.57. EXAMPLE 50 (2‘q. 3'aB, _5’α._6’affl-5-Fluoro-2-f4-(3'· 3’a. 4\ 5'. 6', 6'a- hexahydrospiro[isobenzofuran-1 (3HL 2’( l'HVpentalenl-S'-ylVptperazin-l -vll-pvrimidine MP = 186°C. NMR CDCI3 δ 8.20 (s, 2H), 7.25-7.17 (m, 4H), 7.12-7.09 (m, 1 H), 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). -22- EXAMPLE,.,5.1. 011286 IZ&amp;_3'a6. 5’α. .β^δ-ΠυΡΓΟ-Σ^β·, 3'a. 4’. 5'. 6’, 6'a- bexahydrospirQfisobenzofuran-1 (3H), 2Ï1 ,H)-pentalenl-5’.-ylFpipgrazin-1-yl1-pynmidineMP: 186-187°C. NMR CDCI3 δ 8.18 (s, 2H),7.26-7.10 (m, 3H), 7.08-7.06 (m.lH), 5.00 (s, 2H), 3.78-3.76 (brs. 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). EXAMELE52 Î2’a, 3'aB. 5'a. e'aBM-PhenybATfS· 3’, 3'a. 4, 4’, 5', 6'. 6’a-hexahydrospiror2H-1- ί?^ηζ?ΡΥΓ9η-2.2,(1.,Η)-ρ9ΰΐ9.Ι?η]-·5’^!1-?,ιΥΐ)-ρίΡ^Τ.9Ζίπ§-ηΐ^5ΐ€ MP: 200-201 °C. Analysis calculated for C26H30N2O2· C4H4O4: C, 69.48; H, 6.61 ; N, 5.40. Found: C. 69.48; H, 6.80; N, 5.44. EXAMPLE53 (2’6, 3’ap. 5’a, 6’ap)-1-Phenyl-4rf3, 3’. 3’a, 4, 4’. 5', 6’, 6’a-hexahvdrospiro[2H-1- benzopyran-2.2‘(l 'H)-pentalen1-5’-yl]-5’-yn-piperazîne maleate MP: 220-221 °C. Analysis calculated for C26H30N2O2· C4H4O4: C, 69.48; H, 6.61; N. 5.40. Found: C, 69.28; H, 6.84; N, 5.33. EXAMPLE 54 (2’a, 3’a6, 5’a, 6’a6ï-3-(5'-(4-Phenyl-piperazin-1-yl)- octahydro-pentalen-2'-yl1- 1 H-indole maleate MP: 232-232.5°C. Analysis calculated for C^H^N-,· C4H4O4: C, 71.83; H, 7.03; N, 8.38. Found: C, 71.57; H, 7.38; N, 8.31. EXAMPLE 55 (2’a, 3'ap. 6'ap)-1 -Pl^eny^-4-f5,-phenyl-Γ.2,.3’3,a.4,6’a-hexahydro-pentalen-2,- vl)-piperazine dimaleate MP: 156-157°C. Analysis calculated for C26H3oN202*2C4H404: C, 66.65; H,6.29; N, 4.86. Found: C, 66.27; H, 6.57; N, 5.00. EXAMPLE 56 (2’a. 3’aB, 5’a. 6’aB)-1-Phenyl-4-(5'-phenyl-octahydro-pentalen-2’-yl)-piperazine. mâieaîe MP: 217-218°C. Anaiysis calculated for C24H30N2· C4H4O4: C, 72.70; H, 7.41; N. 6.06. Found: C, 72.28; H, 7.46; N, 6.01. -23-

EXAMEUL5Z ί2’α, 3^afi^5.^ 6’ag)-g-Fl.üorP-2-methvl-1 -r5’-(4:Phenvl-DiDerazin-l -vn-octahvdro-pentalen-2'-yl]-1 H-benzoimidazote dimaleate MP: 203-205°C. Analysis calculated for C26H31FN4· 2C4H404»0.50 H2O: C,61.90; H, 6.11; N, 8.49. Found: C, 61.96; H, 6.01; N, 8.58. EXAMPLE.. 59 Î22l_2j&amp;&amp;__6,aS)-1-r5,-f4-Fluoro-phenoxy)-octahydro-pentalen-2’-vlM- phenvl-piperazine maleate MP: 177-178°C. Analysis calculated for C24H29FN2O· C4H4O4: C, 67.72; H,6.70; N, 5.64. Found: C, 67.33; H, 6.82; N, 5.62. EXA.MP.LE.5.9 (2’a., 3'ap, 5’β. 6’aB1-2-r5'-f4-Phenyl-Diperazin-1-vn-octahydro-pentalen-2'-yn- isoindole-1.3-dione maleate MP: 235.5-236°C. Analysis calculated for C26H29N3O2*C4H4O4: C, 67.78; H,6.26; N, 7.90. Found: C, 67.71; H, 6.37; N, 7.94.

EXAMPLEJ5Q (2’a. . 3‘ap. 5'a, 6'ap)-N-(2-{5'-f4-(5-Fluoco-pyrimidin-2-y0-piperazin-1-yH- 00ΐ3ΐ^Γ0-Ρ6ηΐ8ΐ6η-2'-νΙ}-ρΙΐΘηνΠ-306ΐ3Π·^β maleate MP: 211.5-212°C. Analysis calculated for C24H30FN5O«C4H4O4: C, 62.33; H, 6.35; N, 12.98. Found: C, 62.07; H. 6.32; N, 12.87. EXAMPLE 61 (2’g. 3’8β, ‘5a._6‘ap)-N-(2-{5’-{4-(4-Cyano-3-fluoro-Dhenvl)-DiDerazin-1 vll- octahvdro-pentalen-2’-vl}-pher!vl)-3cetamide maleate MP: 197-199°C. Analysis calculated for C27H31FN4O*C4H404: C, 66.18; H. 6.27; N, 9.96. Found: C, 66.06; H,6.20; N, 9.89. EXAMPLE 62 (2’a, 3’aB. 5’a. 6'aB)-2-Fluoro-4-{4-f5’-(2-oxot2.3-dihydro-benzoimidazol-1-yl)- octahydro-pentalen-2,-yl]-pipe.razin-1 -yl}-benzonitrile mesvlate MP >260°C. Analysis calculated for C26H28FN50*CH403S«0.50 H2O: C, 58.89; H, 6.04; N. 12.72. Found: C, 59.01; H, 6.06; N, 12.71. -24- 011286

EMMELEE f2a, yaB^S’a. 6’aS)-1 -f5l-f4-f5-Fluoro-Dyrimidin-2-vl)-piperazin-1-yll-octahydro-pentalen-2’-yft-1.3-dihydro-benzoimidazol-2-one mesvlate MP >260°C. Analysis calculated for C23H27FN6O*CH4O3S: C, 55.58; H, 6.04; N,16.20. Found: C, 55.48; H, 5.87; N, 16.41. EXAMP.IE54 _6la6)-2-{5’J4-f4-CYano-3-fluoro-phenyl)-Diperazin-l-yn- octahydro-pentalen-2’-yl}-benzamide maleate MP 198.5-200°C. Analysis calculated for C26H29FN4O· C4H404«0.50 H2O: C,64.62; H, 6.15; N, 10.05. Found: C, 64.84; H, 6.01; N, 10.03. EXAMPLLS5 (2'α, 3’ap, 5’g. 6,a6)-N-[5,-(4-Phenyl-piperazin-1-yl)-octahydrp-pentalen-2’-yn- benzamide maleate MP: 211-212.5°C. Analysis calculated for 025Η31Ν3Ο· C4H4O4*0.25 H2O: C,68.28; H, 7.01; N, 8.23. Found: C, 68.17; H, 6.94; N, 8.18. EXAMRLE66 (2’g, 3'aB, 5’B. β^Β^^-ΡΙυοΓΟ^^-Γδ’-ίΑ-ΑυοΓο-ρΚΒηοχνΙ-ο^ΚνόΓο-οβηίΒίΒη^’- yl)-piperazin-1 -yl}-benzonitrile maleate MP: 192-193°C. Analysis calculated for C25H27F2N3O· C4H4O4: C, 64.55; H,5.79; N, 7.79. Found: C, 64.50; H, 5.80; N, 7.71. EXAMPLE 67 (2’g, 3’aB, 5’β, 6’aB)-5-Fluoro-2-{4-r5,-(4-fluoro-phenoxvy-octabydro-pentalen-2’- vH-piperazin-l-vIV-pyrimidine maleate MP: 192-194°C. Analysis calculated for C22H26F2N4O· C4H4O4: C. 60.46; H,5.85; N, 10.85. Found: C, 60.30; H, 5.82; N, 10.78. EXAMRLE 6.8 (2’g, 3'ap. 5’β. 6’ap)-2-Fluorc>-4r{4-[5,-(2-oxo-2.3-dihydro-benzoimidazol-1-vl)- octahydro-pentalen-2,-yl]-piperazin-1 -yO-benzonitrile maleate MP: 170-177°C. NMR DMSO d6 δ 10.89 {s, 1H), 7.70 (t, J=8.4 Hz, 1H), 7.30- 7.23 (m, 1H), 7.11 (d, J=13.9 Hz, 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, 3,=12.4 Hz, J2=6.6 Hz, 2H), 1.58-1.34 (m, 2H). 4 -25- 011286 5 EXAMP.LE.69 f2’g. 31aB. 5’α, 6,aBl;2-Flu.orcH4-f4-f5'-f3-methoxy-phenyl)-octahydro-Dentalen- 2’-yl]-piperazin-1-yl}-benzonitrile maleate MP: 169-17Û°C. Analysis calculated for C26H30FN3O· C4H4O4: C, 67.27; H, 6.40; N, 7.85. Found: C, 67.18; H, 6.52; N, 7.87. 10 EXAMPLE 70 (2-ια^-·3ΐ3β, δία... 6,aB)--2-Fluoro=4rf445.,-f4_-methoxy-phenyh-octahydrp-pentalen- 2’-yl1-piperazin-1 -yl}-benzonitrile maleate MP: 186-186.5°C. Analysis calculated for C26H30FN3O· C4H4O4*0.25 H2O: C, 66.71; H, 6.44; N, 7.78. Found: C, 66.70; H, 6.60; N, 7.60. 15 EXAMPLE 71 IZ&amp;,_3'3g,~ _6'3βν2-ΡΙυθΓθ-4-(4-^5’-πι-1οΙνΙ-οοΐ3Κν0Γθ-Ρ6ηΐ3ΐβη-2'-νΙ')- piperazin-1-yl)-benzonitrile maleate MP: 198-198.5°C. Analysis calculated for C26H30FN3· C4H4O4: C, 69.35; H, 6.60; N, 8.09. Found: C, 69.48; H, 6.74; N, 8.14. 20 EXAMPLE 72 (2’g. 3’3β. 5’a. e'apï^-FluonM-W-ÎS'-p-tolyl-octahydro-pentalen^’-yll-piperaztn- 1-yl)-benzonitrile maleate MP: 194-195° C. NMR DMSO d6 δ 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, 11 H), 2.55-2.43 (m partially under 25 DMSO peak, 1 H), 2.40-2.23 (m with singlet @ 2.26,7H total), 1.63-1.32 (m,4H). ΕΧΔΜΡΙΕ.73 (2’β. 3’aB. 5’β. 6,aB)-1-(5,-(4-Fluoro-phenoxv)-octahvdro-pentalen-2,-yl1-4- phenyl-piperazine maleate MP: 174-175°C. Analysis calculated for C24H29FN2O· C4H4O4: C, 67.72; H, 30 6.70; N, 5.64. Found: C, 67.82; H, 6.83; N, 5.59. EXAMPLE 74 (2’g, 3’aB, 5’o, 6,ap>2-Fluoro-4-i4-(5,-o-tolyl-octahvdro-pentalen-2,-yn-piperazin- 1-yll-benzonitrile maleate MP: 198-199°C. Analysis calculated for C26H3oFN3· C4H4O4: C, 69.35; H, 6.60; 35 N, 8.09. Found: C, 69.13; H, 6.69; N, 8.12. -26- EXAMELEJ5 011286 (2’α, 3'aB, 5’α, .6,.9βΜ-Ρή^πνΙ-4-Ι5^ί3-ρνΓΓθΙΐάίΡ--1-νΙπιβΐΚνΙ-ρΚ6ηνΙ)-οοί3ήνάΓο-pentaLen-2’-yn-piD€razine dimaleate MP: 163.5-164°C. Analysis calculated for C29H39N3· 2C4H4O4: C, 67.15; H,7.16; N. 6.35. Found: C, 66.81; H, 7.22; N, 6.27. EÂAMPLE.7-6 (2'a. 3’aB. 5’a. 6^6)-5^11^0-244-(31. 3’a. 4’. 5’. 6'. e’a-hexahvdro-S'a.G’a-dimethytepiro[isobenzofuran-1 f 3H). 2 Y1 :Hï-pecitalenl-5'-vl)-1 -piperazinvll-pyrimidine mâlssîe MP: 224.5-225°C. Analysis calculated for C25H31FN4O· C4H4O4»0.25 H2O: C,64.13; H, 6.59; N, 10.32. Found: C, 64.25; H, 6.68; N, 10.14. EXAMPLE_7.7 (2'β. 3’ap, 5’α. 6'3β)-5-ΡΙυθΓθ-2-[4-(3’-. 3’a, .4’, 5'. 6’, 6'a-hexahvdro-3’a.6’a- dimethylspiro[isobenzofuran-l_(3H)._2 Y1 ’Hl-pentalenj-S’-yD-1 -piperazinvll-pyrimidine maleate MP: 222-223°C. NMR DMSO.d6 8 8.58 (s, 2H), 7.34-7.30 (m, 1H), 7.28-7.25 (m,3H), 6.04 (s, 2H), 4.94 (s, 2H), 3.65-2.75 (br m, 9H), 2.20-2.12 (m, 2H), 1.94 (ABquartet, Δν= 37.8Hz, J=13.2Hz, 4H), 1.54 (br t, J=11.7Hz, 2H), 1.21 (s, 6H). E&amp;MELEJ3 (2’g. 3’ap, 5'B, 6’ap)-4-{4-[5'-(1.3-Dioxo-1.3-dihvdro-isoindol-2-vl)-octahydro- pentalen-2’-yl1-piperazin-1 -yD-_2-fluoro-benzonitnle maleate MP: 224-224.5°C. Analysis calculated for C27H27FN4O2· C4H4O4: C, 64.80; H, 5.44; N, 9.75. Found: C, 64.85; H, 5.56; N, 9.74. EXAMPLE-79 (2'a. 3'ap. 5’β, S’aB^-fS’-tt-fS-Fluoro-pyrimidin^-yn-piperazin-l-yn-octahydro- pentalen-2’-yl}-isoindole;.1.3-dione maleate MP: 241.5-242°C. Analysis calculated for C24H26FN5O2· C4H4O4: C, 60.97; H, 5.48; N, 12.70. Found: C, 60.66; H, 5.55; N, 12.44. 4 -27- 011286 EJS&amp;UELEJÜ £21g^3iaB. j’cL,6’aB)-2-FlUQro-4-f4-(3, 3'. 3’a, 4, 4*. -5’· 6’, 6'a-hexahvdrospiroi2H- θ-ΑυοΓΟ-Ι^ΘΠζοονΓΒη^.Σ’ίΙΉΙ-ΡθΓ^ΙοηΙ-δ-’^ΙΙ-δ’-νΟ-Ι-piperazinyll-benzonitrile maleate MP: 219-220°C. Analysis calculated for C24H26F2N4O2· C4H404»0.50 H2O: C,59.46; H, 5.55; N, 9.90. Found: C, 59.86; H, 5.70; N, 9.40. ËXAMPLE 81 (2‘β, 3’ap, 5’a, 6'ap)-2-Fluoro-4-f4-(3, 3', 3'a, 4, 4’, 5’. 6’, 6'a-hexahydrospiror2H- 6-fluoro-1 -bgnzopvran-2.2’ri 'Hy-pcntalenj-S’-vlJ-S’-yQ-l -piperazinyll-benzonitrile maleate MP: 216.5-217°C. Analysis calculated for C24H26F2N4O2· C4H4O4: C, 60.43; H, 5.43; N, 10.07. Found: C, 60.39; H, 5.47; N, 9.90. EXAMPIE82 (2’g, 3’ap, 5’a, 6'aB)-5-Fluoro-2-f4-f5,-o-tolvl-octahydro-pentalen-2’-vl)-piperazin- 1-yn-pyrimidine maleate MP: 204-205°C. Analysis calculated for C23H29FN4· C4H4O4: C, 65.31; H, 6.70; N, 11.28. Found: C, 65.38; H, 6.77; N, 11.32. EXAMPLE.83 (2’β. 3'a6. 5’a, 6’aP)-1-{5’-[4-f4-Fluoro-phenyl)-piperazin-1-yl)-octahydro- pentalen-2’-ylV-1.3-dihydro-benzoimidazol-2-one maleate MP: 217-218°C. Analysis calculated for C25H29FN4O· C4H4O4: C, 64.91; H, 6.20; N, 10.44. Found: C, 64.57; H, 6.28; N, 10.18. EXAMPLE, $4 (2’β. 3’ap. 5’g. e'ap^-ÎS’-^-Phenyl-piperazin-l-yn-octahydro-pentalen^’-yloxy)- 1H-benzoimidazole maleate MP: 161-162°C. Analysis calculated for C25H30N4O· C4H4O4: C, 67.16; H, 6.61; N, 10.80. Found: C, 67.05; H, 6.66; N, 10.59. EXAMPLE 85 (2'a. 3’aB. 5’a. 6’aB)-5-Chloro-2-{4-[5,-(2-methoxy-phenyl)-octahydro-pentalen- 2’-yl]-piperazin-1-yl}-pyrimidine maleate MP: 199.5-200’C. Analysis calculated for C23H29CIN4O C4H4O4: C, 61.30; H, 6.29; N, 10.59. Found: C, 61.05; H, 6.31; N, 10.83. -28- EXAMPLE 86 011286 X2ÏL__6’aB)-5-Chloro-2-r4-f5,-o-tolyl-octahydro-pentalen-2,-ylj- piperazin-1-yl]-pyrimidine maleate MP: 200-200.5°C. Analysis calculated for C^HæClhL· C4H4O4: C, 63.21; H,6.48; N, 10.92. Found: C. 62.97; H, 6.33; N, 11.29. 10 EXAMPLE 87 O._3££._5!α, 6'aB)-2-{5’-f4-(3.4-Drfluoro-phenyl)-Diperazin-1-yn-octahvdro- pentalen-2*-yl>-isoindole-1 .3-dione maleate MP: 221.5-222°C. Analysis calculated for C26H27F2N3O2· C4H4O4: C, 63.48; H,5.51; N, 7.46. Found: C, 63.28; H, 5.51; N, 7.64. 15 EXAMPLE 88 2M&amp;&amp;6’aS)-2-<5’J4r(4-Flupro-phenyl)-piperazin-1-vn-octahydro- pentalen-2'-viy-isoindole-1.3-dione maleate MP: 209-210°C. Analysis calculated for C26H28FN3O2· C4H404*0.50H20: C. 64.51; H, 5.95; N, 7.52. Found: C, 64.47; H, 5.91; N, 7.66. 20 EXAMPLE 89 (2’B. 3'aB, 5’a, B’aB^HS’-H-O^-Drfluoro-phenyn-piperazin-l-yll-octahvdro- pentalen-2’-yiy-1.3-dihydro-benzoimidazol.-:2-one maleate MP: 201-202°C. Analysis calculated for C25H28F2N4O· C4H404«0.50H20: C, 61.80; H, 5.90; N, 9.94. Found: C, 62.10; H, 5.80; N, 9.56. 25

Claims (21)

1. -29- Claims

   011286
2. 2. A compound according to claim 1, wherein X is nitrogen.
3. 3. A compound according to daim 1, wherein Y and Z are each CR12wherein R12 is hydrogen or fluoro.
4. 4. A compound according to daim 1, wherein R2 is hydrogen, fluoro or chloro.
5. 5. A compound according to claim 1, wherein R3, R4 and R5 are hydrogen.
6. 6. A compound according to claim 1, wherein R7 is fluoro or chloro.
7. 7. A compound according to daim 1, wherein Rs is fluoro, chloro, bromo or alkoxy.
8. 8. A compound according to claim 1, wherein X is nitrogen; Y and Z areeach CR12 wherein R12 is hydrogen or fluoro; R2 is hydrogen fluoro or chloro; R3, R4 andR5 are hydrogen; R7 is fluoro or chloro; and R7 is fluoro, chloro, bromo or alkoxy.
9. 9. A compound according to daim 1, wherein said compound is selededfrom the group consisting of : 2-[4-(3-Trifluoromethyl-phenyl)-piperazin-1 -ylmethylJ-1 H-indole;
10. 10. Use of an amount of a D4 dopamine receptor sélective compoundaccording to claim 1, or a pharmaceutically acceptable sait thereof, for the manufactureof a médicament for treating a disorder of the dopamine System in a mammal.
11. 11. Use as claimed in claim 10 wherein disorders of the dopamine Systeminclude psychotic disorders, movement disorders, gastrointestinal disorders, Chemicalabuse, Chemical dependencies, substance abuse, vascular and cardiovascular disorders,ocular disorders and sleep disorders.
12. 12. Use of an amount of a D4 dopamine receptor sélective compoundaccording to claim 1, or a pharmaceutically acceptable sait thereof, in conjunction withone or more Dl, D2, D3 or D5 dopamine receptor agonists for the manufacture of amédicament for treating a disorder of the dopamine System in a mammal.
13. 13. Use as claimed in Claim 12 wherein disorders of the dopamine Systeminclude psychotic disorders, movement disorders, gastrointestinal disorders, Chemicalabuse, Chemical dependencies, substance abuse, vascular and cardiovascular disorders,ocular disorders and sleep disorders.
14. 14. Use as claimed in Claim 11, wherein psychotic disorders include affectivepsychosis, schizophrenia, and schizoaffective disorders.
15. 15. Use as claimed in Claim 11 wherein movement disorders includeextrapyramidal side effects from neuroleptic agents, neuroleptic malignant syndrome,tardive dyskinesia, Gilles De La Tourette’s syndrome, Parkinson’s disease orHuntington’s disease.
16. 16. Use as claimed in claim 11 wherein gastrointestinal disorders includegastric acid sécrétion or emesis.
17. 17. Use as claimed in claim 11, wherein vascular and cardiovascular disordersinclude congestive heart failure and hypertension. -32- < 011286
18. 18. A pharmaceutical composition for treating a disorder of the dopamine System in a mammal, comprising administering to said mammal an amount of a D4dopamine rèceptor sélective compound acconfing to claim 1, or a pharmaceutically acceptable sait thereof, that is effective in treating such disorder. ~ .
19. 19. A pharmaceutical composition according to daim 18, wherein disorders of * <the dopamine System indude psychotic disorders, movement disorders, gastrointestinaldisorders, Chemical abuse, Chemical dependencies, substance abuse, vascuiar andcardiovascular disorders, ocuiar disorders and sleep disorders.
20. 20. A pharmaceutical composition for treating a disorder of the dopamineSystem in a mammal, comprising administering to said mammal an amount of a D4dopamine receptor sélective compound according to daim 1, or a pharmaceuticallyacceptable sait thereof, in conjunction with one or more D1, D2, D3 or D5 dopaminereceptor agonists, that is effective in treating such disorder.
21. 21. A pharmaceutical composition according to daim 20, wherein disorders ofthe dopamine System indude psychotic disorders, movement disorders, gastrointestinaldisorders, Chemical abuse, Chemical dependendes, substance abuse, vascuiar andcardiovascular disorders, ocuiar disordrs and sleep disorders. f