MXPA06006033A - Heterocyclic substituted indane derivatives and related compounds for the treatment of schizophrenia - Google Patents

Abstract

This invention relates to compounds of the formula (I) wherein J, M, G, m, X, R', R2, R4, R5, R6, R7, R8, R9, Y, n, z, and R"are defined as in the specification, pharmaceutical compositions containing them and their use in the treatment of central nervous system and other disorders.

Description

HETEROCICLES INDIVIDUAL DERIVATIVES SUBSTITUTED AND RELATED COMPOUNDS FOR THE TREATMENT OF SCHIZOPHRENIA BACKGROUND OF THE INVENTION This invention relates to substituted piperazines, pharmaceutical compositions containing them and their use for the treatment of schizophrenia and other disorders or affections of the central nervous system (CNS). The substituted heterocyclic piperazine derivatives of this invention exhibit activity as dopamine D2 receptor antagonists and serotonin 2A (5HT2A) receptors. In U.S. Patent 5,350,747, issued September 27, 1994, and in U.S. Patent 6,127,357, issued October 3, 2000, reference is made to other heterocyclic piperazine derivatives which are useful for treatment of schizophrenia. These patents are incorporated herein by reference in their entirety. Other piperazine and piperidine derivatives which have been reported to be useful as antipsychotic agents are those which are included in PCT patent publication WO 93/04684, published March 18, 1993 and in European patent application EP 402644A, published on December 19, 1990. These patent applications are incorporated herein by reference in their entirety. SUMMARY OF THE INVENTION The present invention relates to compounds of the formula 1 1A 1 B wherein J is S, SO, SO2, CH2 > O or NR 10, wherein R 10 is hydrogen, C 6 alkyl, C (= O) C 6 alkyl or C (= O) 0 C C 6 alkyl; M is CH or N; G is CH or N; m is an integer from one to six; X is O or NR3, wherein R3 is defined as defined R10 above, C (= O), CHOH, CHOR3, CH (halo) or CHNR3R12, wherein R12 is defined as defined R10 above; or X is absent; R1 is hydrogen, halogen, cyano, Ci-Cß alkyl optionally substituted by one to three fluorine atoms, C Cß alkoxy optionally substituted by one to three fluorine atoms or R1 forms a heterocyclic ring with R10; R2 is defined as R1 with the proviso that R2 can not form a heterocyclic ring when R1 is present; R4 and R5 are, independently, hydrogen, halogen, cyano, aminoalkyl CrC6, (alkyl CrC6) aminoalkyl C Cß, di (alkyl d- C C-aminoalkyl C C β, hydroxyalkyl C C β, alkoxy C C β or (alkoxy d-C 6) alkyl, wherein each of the alkoxy and alkyl moieties of the above groups R4 and R5 can be optionally substituted with one to three halo atoms, preferably with one to three fluorine atoms, R6, R7, R8 and R9 are, independently, hydrogen or C1-C6 alkyl optionally substituted with one to three fluorine atoms; and, when R11 is present, it is selected from O, NR13, wherein R13 is defined as defined above R10 or (CH2) W wherein is an integer of one or six, or Y, when R11 is absent, is selected from (= 0), hydroxy, NR13R14 in which R13 and R14 are defined as defined R10 above and (CH2) qCH3, in which that q is an integer from one to five, n is an integer from one to three, z is an integer from one to three, and R11 is hydrogen, CrC6 alkyl, -S02-CrC6 alkyl, -S02-aryl, aryl, arylalkyl Ci-Cß, heteroaryl, heteroarylalkyl CrC6, heterocyclyl, heterocyclylalkyl CrC4, COR15, C (0) OR15 or C (0) NR15R16, in those which R15 and R16 are independently selected from C?-C6 alkyl, aryl, heteroaryl, C?-C6 heteroarylalkyl, Ci-Cß arylalkyl, heterocyclyl and heterocyclylalkyl wherein said alkyl moieties in said R11 groups may be optionally substituted with one to three fluorine atoms and the aryl, heteroaryl and heterocyclyl moieties in said R11 groups may be optionally substituted, with one or more substituents, preferably from zero to two substituents , which are independently selected from CrC6 alkyl optionally substituted by one to three fluorine atoms, C-? -C6 alkoxy optionally substituted by one to three fluorine atoms, cyano, nitro, halo, amino, (CrC6 alkyl) amino and di ( alkyl CrC6) amino; or R11 is absent; with the proviso that the sum of n plus z can not exceed 3; and pharmaceutically acceptable salts of such compounds. The compounds of formulas 1A and 1B are collectively referred to collectively as compounds of formula 1. More specific embodiments of this invention relate to compounds of formula 1 and their pharmaceutically acceptable salts, wherein: it is sulfur and M is nitrogen; M is nitrogen and J is oxygen; G is nitrogen; m is 2; X is absent; X is CH (halo); X is CH (OH) X is CHNR3R12; X is C (= 0); X is CHOR13; X is NR3; X is oxygen; X is CHNR13R12; R1 and R2 are hydrogen; R1 and R2 are selected from hydrogen and fluorine; R1 and R2 are selected from hydrogen, methyl, methoxy, chloro and fluoro; R11 is absent; R11 is absent and Y is oxo; YR11 is NR13; YRi1 is acetamide; YR11 is an amide; And it is NR13R14; R13 is C (= 0) C6 alkyl; R14 is methyl; R4 is hydrogen and one or both of R2 and R3 are hydrogen; one or both of R2 and R3 are hydrogen; R4 and R5 are hydrogen; R1, R5, R6, R7 and R8 are independently selected from hydrogen and C1-C3 alkyl; R6, R7, R8 and R9 are hydrogen; R6, R7, R8 and R9 are methyl; R6 and R7 are methyl and R8 and R9 are hydrogen; R6 and R7 are hydrogen and R8 and R9 are methyl; or R6, R7, R8 and R9 are independently selected from hydrogen and methyl. DETAILED DESCRIPTION OF THE INVENTION The term "alkyl", unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight, branched or cyclic moieties or combinations thereof. Examples of "alkyl" groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl, pentyl, hexyl, heptyl, 3-ethylbutyl, cyclopropyl, cyclobutyl, cyclopentyl. , cyclohexyl, cycloheptyl, norbornyl and the like. The term "aryl", unless otherwise indicated, includes a heteroaromatic ring system without heteroatoms (e.g., phenyl or naphthyl). The term "alkoxy" unless otherwise indicated, means "alkyl-O-", wherein "alkyl" is as defined above. Examples of "alkoxy" groups include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy and pentoxy. The term "alkenyl", unless otherwise indicated, includes unsaturated hydrocarbon radicals having one or more double bonds connecting two carbon atoms, wherein said hydrocarbon radical may have linear, branched or cyclic moieties or combinations thereof. Examples of "alkenyl" groups include, but are not limited to, ethenyl, propenyl, butenyl, pentenyl. The term "heteroaryl", unless otherwise indicated, includes monocyclic aromatic heterocycles containing five or six ring members, of which 1 to 4 are heteroatoms which are independently selected from N, S and O and bicyclic aromatic heterocycles containing from eight to twelve members in the ring, of which from 1 to 4 are heteroatoms which are independently selected from N, S and O. Examples of heteroaryl groups include, but not limited to, furyl, thienyl, triazole, pyridyl, pyrimidinyl, pyrrolyl, imidazolyl, tetrazolyl, oxazolyl and isoxazolyl. The term "heterocyclyl" or "heterocyclic" refers to non-aromatic, saturated monocyclic or unsaturated ring systems containing 5 or 6 members in the ring, from 1 to 4 of which are heteroatoms that are independently selected from oxygen , sulfur and oxygen; and saturated or unsaturated nonaromatic ring systems containing from 10 to 12 members in the ring, of which from 1 to 4 are heteroatoms that are independently selected from oxygen, sulfur and nitrogen. Examples of heterocyclyl groups include the following: piperidinyl, piperazinyl, morpholinyl, tetrahydrofuryl and tetrahydropyranyl. The term "one or more substituents" refers to a number of substituents that equals from one up to the maximum number of substituents possible based on the number of available link sites.

The terms "halo" and "halogen", unless otherwise indicated, include fluorine, chlorine, bromine and iodine. The compounds of formula 1 and the pharmaceutically acceptable salts of these compounds are collectively referred to herein as "compounds of this invention" and "active compounds of this invention". This invention also relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula 1, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. Compounds of formula 1 that contain chiral centers and therefore may exist in different enantiomeric and diastereomeric forms. This invention relates to all optical isomers and all stereoisomers of the compounds of formula 1, both in the form of racemic mixtures and in the form of individual enantiomers and diastereomers of such compounds and mixtures thereof and to all pharmaceutical compositions and methods of treatment defined above that contain or employ them, respectively. Individual isomers can be obtained by known methods, such as optical resolution, fractional crystallization, optically selective reaction or chromatographic separation for the preparation of the final product or its intermediate. The individual enantiomers of the compounds of the formula 1 may have advantages, in relation to the racemic mixtures of these compounds, in the treatment of various disorders or conditions. Insofar as the compounds of formula 1 are basic compounds, they are all capable of forming a wide variety of different salts with various inorganic and organic acids. Although such salts must be pharmaceutically acceptable for administration to animals, it is often desirable in practice to initially isolate the basic compound from the reaction mixture in the form of a pharmaceutically unacceptable salt and then simply convert it to the free base compound by treatment with an alkaline reagent and thereafter converting the free base to a pharmaceutically acceptable acid addition salt. The acid addition salts of the basic compounds of this invention are readily prepared by treating the basic compound with a substantially equivalent amount of the chosen mineral or organic acid in an aqueous solvent or in a suitable organic solvent, such as methanol, ethanol, diethyl ether , dioxane, acetonitrile or tetrahydrofuran. By carefully evaporating the solvent, the desired solid salt is easily obtained. The acids which are used to prepare the pharmaceutically acceptable acid addition salts of the aforementioned basic compounds of this invention are those which form non-toxic acid addition salts, ie, salts containing pharmaceutically acceptable anions, such as hydrochloride salts , hydrobromide, hydrate, nitrate, sulfate or bisulfate, phosphate or acid phosphate, acetate, lactate, citrate p citrate acid, tartrate or bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate (i.e., 1-methylene-bis- (2-hydroxy-3-naphthoate) The present invention also includes isotopically-labeled compounds, which are identical to those of formula 1, except for the fact that one or more atoms are replaced by an atom that has an atomic mass or mass number different from the atomic mass or mass number that is usually found in Examples of isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as 2H, 3H, 13C, 11C, 14C, 15N, 180 , 170, 31 P, 32 P, 35 S, 18 F and 36 C, respectively. The compounds of the present invention, their prodrugs and pharmaceutically acceptable salts of said compounds or said prodrugs that contain the aforementioned isotopes and / or other isotopes of other atoms that are within the scope of this invention. Certain isotopically-labeled compounds of the present invention, for example those in which they incorporate radioactive isotopes such as 3 H and 14 C, are useful in drug and / or substrate tissue distribution assays. The tritiated isotopes, ie with 3H and carbon 14, ie 14C, are particularly preferred because of their ease of preparation and detection capability. In addition, replacement with heavier isotopes such as deuterium, ie 2H, may provide certain therapeutic advantages as a result of increased metabolic stability, for example, an increased live half-life or need for a lower dose and, therefore, they may be preferred in some circumstances. The isotopically-labeled compounds of formula 1 and the pharmaceutically acceptable salts and prodrugs thereof can generally be prepared by carrying out the procedures described in the Schemes and / or Examples below, substituting an isotopically non-labeled reagent for a reagent. experimentally labeled isotopically readily available. The compounds of formula 1 have useful pharmaceutical and medicinal properties. The term "treat" refers to investing, alleviatinginhibit the progress, or prevent the disorder or condition to which the term applies, or prevent one or more symptoms of such a condition or disorder. The term "treatment" refers to the act of treating, as defined "treat" immediately above. This invention also relates to a method for treating a disorder or condition that is selected from the group consisting of single or recurrent major depressive disorders, dysthymic disorders, depressive neurosis and neurotic depression, melancholic depression including anorexia, weight loss, insomnia, wakefulness at dawn or psychomotor retardation; atypical depression (or reactive depression) including increased appetite, hypersomnia, psychomotor agitation or irritability, seasonal affective disorder and pediatric depression; bipolar disorders or manic depression, for example, bipolar I disorder, bipolar II disorder and cyclothymic disorder; behavioral disorder; destructive behavioral disorder; hyperactivity disorder with attention deficit disorder (ADHD); behavioral disturbances associated with mental retardation, autistic disorder and conduct disorder; anxiety disorders such as panic disorder with or without agoraphobia, agoraphobia without a history of panic disorder, specific phobias, for example phobias to specific animals, social anxiety, social phobia, obsessive-compulsive disorder, stress disorders including post-traumatic stress disorder and acute stress disorder and generalized anxiety disorders; borderline personality disorder; schizophrenia and other psychotic disorders, for example, schizophreniform disorders, schizoaffective disorders, delusional disorders, brief psychotic disorders, shared psychotic disorders, psychotic disorders with delusions or hallucinations, psychotic episodes of anxiety, anxiety associated with psychosis, psychotic behavioral disorders such as major depressive behavioral disorders associated with psychotic disorders such as acute mania and depression associated with bipolar disorder; behavioral disorders associated with schizophrenia; delirium, dementia and amnestic disorders and other cognitive or neurodegenerative disorders, such as Parkinson's disease (PD), Huntington's disease (HD), Alzheimer's disease, senile dementia, Alzheimer's type dementia, memory disorders, loss of function performer, vascular dementia and other dementias, for example, due to HIV disease, brain trauma, Parkinson's disease, Huntington's disease, Pick's disease, Creutzfeldt-Jakob disease or due to multiple etiologies; movement disorders such as akinesias, dyskinesias, including paroxysmal familial dyskinesias, spasms, Guilles de la Tourette syndrome, Scott syndrome, paralysis and rigid akinetic syndrome; extrapyramidal movement disorders such as medication-induced movement disorders, eg, neuroleptic-induced parkinsonism, neuroleptic malignant syndrome, acute neuroleptic-induced dystonia, acute neuroleptic-induced akathisia, neuroleptic-induced tardive dyskinesia, and medication-induced postural tremor; dependencies and additions to chemical substances (eg dependencies or additions to alcohol, heroin, cocaine, benzodiazepines, nicotine or phenobarbitol) and behavioral additions such as pathological gambling; and ocular disorders such as glaucoma and ischemic retinopathy in a mammal, including a human being, comprising administering to a mammal in need of such treatment an amount of a compound of formula 1 or a pharmaceutically acceptable salt thereof, which is effective to treat such disorder or condition. This invention also relates to a pharmaceutical composition for treating a disorder or condition that is selected from the disorders and conditions as defined in the paragraph immediately above, in a mammal in need of such treatment, including a human being, which it comprises an amount of a compound of formula 1 or a pharmaceutically acceptable salt thereof, which is effective to treat such a disorder or condition and a pharmaceutically acceptable carrier. A more specific embodiment of this invention relates to the above method and composition in which the disorder or condition to be treated is selected from major depression, single depression, recurrent depression, depression induced by childhood abuse, postpartum depression, dysthymia , cyclothymia and bipolar disorder. Another more specific embodiment of this invention relates to the above method and composition in which the disorder or condition to be treated is selected from schizophrenia, schizoaffective disorder, delusional disorder, substance-induced psychotic disorder, brief psychotic disorder, shared psychotic disorder, psychotic disorder due to a general medical condition and schizophreniform disorder. Another more specific embodiment of this invention relates to the above method and composition in which the disorder or condition to be treated is selected from schizophrenia, schizophrenia with concomitant depression or schizophrenia with concomitant anxiety. Another more specific embodiment of this invention relates to the above method and composition in which the disorder or condition to be treated is selected from autism, pervasive developmental disorder and hyperactivity disorder with attention deficit. Another more specific embodiment of this invention relates to the above method and composition in which the disorder or condition to be treated is selected from generalized anxiety disorder, panic disorder, obsessive-compulsive disorder, post-traumatic stress disorder and phobias, including social phobia, agoraphobia and specific phobias. Another more specific embodiment of this invention relates to the above method and composition in which the disorder or condition to be treated is selected from movement disorders such as akinesias, dyskinesias, including paroxysmal familial dyskinesia, spasms, Guilles syndrome of the Tourette, Scott syndrome, paralysis and rigid akinetic syndrome; extrapyramidal movement disorders such as medication-induced movement disorders, for example, neuroleptic-induced parkinsonism, neuroleptic malignant syndrome, acute neuroleptic-induced dystonia, acute neuroleptic-induced akathisia, neuroleptic-induced tardive dyskinesia, and medication-induced postural tremor. Another more specific embodiment of this invention relates to the above method and composition in which the disorder or condition to be treated is selected from delirium, dementia and amnestic disorders and other cognitive or neurodegenerative disorders, such as Parkinson's disease (PD) , Huntington's disease (HD), Alzheimer's disease, senile dementia, Alzheimer's type dementia, memory disorder, vascular dementia and other dementias, for example, due to HIV disease, brain trauma, Parkinson's disease, Huntington, Pick disease, Creutzfeldt-Jakob disease or due to multiple etiologies. Another more specific embodiment of this invention relates to the above process and composition wherein the compound of formula 1 is administered to a human being for the treatment of any two or more comorbid conditions or disorders which are selected from the disorders and conditions referred to. in any of the above procedures. For the treatment of depression, anxiety, schizophrenia or any of the other disorders and conditions referred to above in the descriptions of the methods and pharmaceutical compositions of this invention, the compounds of this invention may be used in conjunction with one or more antidepressants. or different anti-anxiety agents. Examples of classes of antidepressants that may be used in combination with the active compounds of this invention include norepinephrine reuptake inhibitors, selective serotonin reuptake inhibitors (SSRIs), NK-1 receptor antagonists, monoamine oxidase (MAOI) inhibitors. , reversible monoamine oxidase inhibitors (RIMA), serotonin and noradrenaline reuptake inhibitors (SNRI), corticotropin releasing factor (CRF) antagonists, atypical antidepressant and adrenoreceptor antagonists. Suitable norepinephrine reuptake inhibitors include tricyclics of tertiary amines and tricyclics of secondary amines. Tricyclics of tertiary and tricyclic amines of suitable secondary amines include amitriptyline, clomipramine, doxepin, imipramine, trimipramine, dotiepin, butryipine, iprindol, lofepramine, nortriptyline, protriptyline, amoxapine, desipramine and maprotiline. Suitable selective serotonin reuptake inhibitors include fluoxetine, fluvoxamine, paroxetine and sertraline. Examples of suitable monoamine oxidase inhibitors include isocarboxazido, phenelzine and tranylcycloparamine. Suitable reversible monoamine oxidase inhibitors include moclobemide. Reversible monpamine oxidase inhibitors include moclobemide. Suitable serotonin and noradrenaline reuptake inhibitors for use in the present invention include venlafaxine. CRF antagonists include the compounds described in the international patent applications ne WO 94/13643, WO 94/13644, WO 94/13661, WO 94/13676 and WO 94/13677. Suitable atypical antidepressants include bupropion, lithium, nefazodone, trazodone and viloxazine. Suitable NK-1 receptor antagonists include those referred to in world patent publication WO 01/77100. Suitable classes of anxiolytic agents that can be used in combination with the active compounds of this invention include benzodiazepines and serotonin 1A (5-HT1A) agonists or antagonists, especially partial 5-HT? A agonists and corticotropin releasing factor antagonists ( CRF). Suitable benzodiazepines include alprazolam, chlordiazepoxide, clonazepam, clorazepate, diazepam, halazepam, lorazepam, oxazepam and prazepam. Suitable 5-HT-IA receptor agonists or antagonists include buspirone, flesinoxane, gepirone and ipsapirone. This invention also relates to a method for treating a disorder or condition that is selected from single or recurrent major depressive disorders, dysthymic disorders, depressive neurosis and neurotic depression, melancholic depression including anorexia, weight loss, insomnia, early morning wake-up or lateness psychomotor; atypical depression (or reactive depression) including increased appetite, hypersomnia, psychomotor agitation or irritability, seasonal affective disorder and pediatric depression; bipolar disorders or manic depression, for example, bipolar I disorder, bipolar II disorder and cyclothymic disorder; behavioral disorder; destructive behavioral disorder; hyperactivity disorder with attention deficit disorder (ADHD); behavioral disturbances associated with mental retardation, autistic disorder and conduct disorder; anxiety disorders such as panic disorder with or without agoraphobia, agoraphobia without a history of panic disorder, specific phobias, for example phobias to specific animals, social anxiety, social phobia, obsessive-compulsive disorder, stress disorders including post-traumatic stress disorder and acute stress disorder and generalized anxiety disorders; borderline personality disorder; schizophrenia and other psychotic disorders, for example, schizophreniform disorders, schizoaffective disorders, delusional disorders, brief psychotic disorders, shared psychotic disorders, psychotic disorders with delusions or hallucinations, psychotic episodes of anxiety, anxiety associated with psychosis, psychotic behavioral disorders such as major depressive behavioral disorders associated with psychotic disorders such as acute mania and depression associated with bipolar disorder; behavioral disorders associated with schizophrenia; delirium, dementia and amnestic disorders and other cognitive or neurodegenerative disorders, such as Parkinson's disease (PD), Huntington's disease (HD), Alzheimer's disease, senile dementia, Alzheimer's type dementia, memory disorders, loss of function performer, vascular dementia and other dementias, for example, due to HIV disease, brain trauma, Parkinson's disease, Huntington's disease, Pick's disease, Creutzfeldt-Jakob disease or due to multiple etiologies; movement disorders such as akinesias, dyskinesias, including paroxysmal familial dyskinesias, spasms, Guilles de la Tourette syndrome, Scott syndrome, paralysis and rigid akinetic syndrome; extrapyramidal movement disorders such as medication-induced movement disorders, eg, neuroleptic-induced parkinsonism, neuroleptic malignant syndrome, acute neuroleptic-induced dystonia, acute neuroleptic-induced akathisia, neuroleptic-induced tardive dyskinesia, and medication-induced postural tremor; dependencies and additions to chemical substances (eg dependencies or additions to alcohol, heroin, cocaine, benzodiazepines, nicotine or phenobarbitol) and behavioral additions such as pathological gambling; and ocular disorders such as glaucoma and ischemic retinopathy in a mammal in need of such treatment, including a human, which comprises administering to said mammal: (a) a compound of formula 1 or a pharmaceutically acceptable salt thereof; and (b) another pharmaceutically active compound which is an antidepressant or anxiolytic agent or a pharmaceutically acceptable salt thereof; wherein the compounds "a" and "b" are present in amounts that make the combination effective to treat a disorder or condition of. that guy. This invention also relates to a pharmaceutical composition for treating a disorder or condition that is selected from the disorders and conditions as defined in the paragraph immediately above, in a mammal in need of such treatment, including a human being, which comprises: (a) a compound of formula 1 or a pharmaceutically acceptable salt thereof; (b) another pharmaceutically active compound which is an anti-depressant or anxiolytic agent or a pharmaceutically acceptable salt thereof; and (c) a pharmaceutically acceptable carrier; wherein the compounds "a" and "b" are present in amounts that make the combination effective to treat such a disorder or condition. A more specific embodiment of this invention relates to the above method and composition in which the disorder or condition to be treated is selected from major depression, single depression, recurrent depression, depression induced by abuse in childhood, postpartum depression, dysthymia, cyclothymia and bipolar disorder. Another more specific embodiment of this invention relates to the above method and composition in which the disorder or condition to be treated is selected from schizophrenia, schizoaffective disorder, delusional disorder, substance-induced psychotic disorder, brief psychotic disorder, shared psychotic disorder , psychotic disorder due to a general medical condition and schizophreniform disorder. Another more specific embodiment of this invention relates to the above method and composition in which the disorder or condition to be treated is selected from schizophrenia, schizophrenia with concomitant depression or schizophrenia with concomitant anxiety. Another more specific embodiment of this invention relates to the above method and composition in which the disorder or condition to be treated is selected from autism, pervasive developmental disorder and attention deficit hyperactivity disorder. Another more specific embodiment of this invention relates to the above method and composition in which the disorder or condition to be treated is selected from generalized anxiety disorder, panic disorder, obsessive-compulsive disorder, post-traumatic stress disorder and phobias, including social phobia, agoraphobia and specific phobias. Another more specific embodiment of this invention relates to the above method and composition in which the disorder or condition to be treated is selected from movement disorders such as akinesias, dyskinesias, including paroxysmal familial dyskinesia, spasms, Guilles syndrome of the Tourette, Scott syndrome, paralysis and rigid akinetic syndrome; and extrapyramidal movement disorders such as medication-induced movement disorders, eg, neuroleptic-induced parkinsonism, neuroleptic malignant syndrome, acute neuroleptic-induced dystonia, acute neuroleptic-induced akathisia, neuroleptic-induced tardive dyskinesia, and medication-induced postural tremor. . Another more specific embodiment of this invention relates to the above method and composition in which the disorder or condition to be treated is selected from delirium, dementia and amnestic disorders and other cognitive or neurodegenerative disorders, such as Parkinson's disease (PD) , Huntington's disease (HD), Alzheimer's disease, senile dementia, Alzheimer's type dementia, memory disorder, vascular dementia and other dementias, for example, due to HIV disease, brain trauma, Parkinson's disease, Huntington, Pick disease, Creutzfeldt-Jakob disease or due to multiple etiologies. Another more specific embodiment of this invention relates to the above process and composition wherein the compound of formula 1 and the additional antidepressant or anxiolytic agent are administered to a human being for the treatment of any two or more comorbid conditions or conditions which are select from the disorders and conditions referred to in any of the above procedures. The active compounds of this invention can be prepared as described in the following reaction schemes. Unless otherwise indicated, Y, J, M, G, n, z, m, q, X and R1 to R16 in the reaction schemes and in the descriptions below are as defined above.

SCHEME A 1A (b) 1A (c) i) TFAA, Et3N, THF ii) Chloroacetyl chloride, AICI3, DCM iii) Et3SiH, IV TFA) Na2CO3, H2O, μl v) K2CO3, eOH vi) Acyl chloride, Et3N, THF Scheme A illustrates a process for synthesizing compounds of formula 1A wherein YR11 is amino (compounds of formula 1A (b)), trifluoroacetamide (compounds of formula 1A (a)) and NHC (O) R15 (compounds of Formula 1A (c)). Steps i, ii and iii of Scheme A are carried out as described in Preparations 1, 2 and 3 in the Experimental Examples section of this application. The compounds of formula 1A (a) can be prepared by reacting a compound of formula 5 with a compound of formula 6 in the presence of a base such as Na 2 CO 3, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, triethylamine, pyridine or any other organic or inorganic base which is suitable for inactivating acids, preferably sodium carbonate, in a polar solvent such as water, acetonitrile, tetrahydrofuran (THF), dimethylformamide (DMF), dioxane, dimethyl sulfoxide (DMSO) or a mixture of two or more of the above solvents, preferably in water, at a temperature from about 40 ° C to about 200 ° C, preferably at about 175 ° C with microwave intervention for about 10 to 180 minutes. This reaction can also be carried out at about 100SC using conventional heating for about 1-96 hours, preferably for about 24-48 hours. The compounds of the formula 1A (a) can be converted to the corresponding amines of the formula 1A (b) by reacting them with potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide or triethylamine, preferably potassium carbonate in a polar solvent such as water, ethanol, propanol or methanol or a mixture of water and methanol, at a temperature from about 25 ° C to about the reflux temperature of the solvent, preferably at about the reflux temperature. This reaction is preferably carried out in a mixture of water and methanol at about 60 ° C. The reaction of a compound of the formula 1A (b) with the appropriate acyl chloride or sulfonyl chloride or with isocyanate, in the presence of an inorganic base such as potassium carbonate or sodium carbonate or an organic base such as triethylamine (TEA), pyridine or diisopropylethylamine, in an ether solvent such as THF, dioxane, diglyme or ethyl ether or a chlorinated hydrocarbon solvent such as chloroform (CHCl3), dichloroethane or methylene chloride (CH2Cl2) at a temperature from about 09C to about the temperature of refluxing the reaction mixture, preferably at about room temperature, provides the corresponding compound of the formula 1A (c). Preferably, this reaction is carried out in THF in the presence of triethylamine at about room temperature. The compounds of the formula 1 A (a), 1A (b) and 1 A (c) in which Group K is replaced by Group L can be prepared using procedures analogous to those depicted in Scheme A, as is known to those skilled in the art, from the starting materials of formula 2 '. 2' Compounds of the formula 1B wherein YR11 is amino, trifluoroacetamide and NHC (O) R15 can be prepared using procedures analogous to those depicted in Scheme A, which will be available to a person skilled in the art, from the suitable starting materials of the formula 2 '. 2" SCHEME B 1A (c) 'i) MeOH / H2O, K2CO3 ii) Tartaric acid, classical resolution iii) (a) NaOH, Et2O; (b) Et3N, acyl chloride iv) Na2CO3, H2O Scheme B illustrates a process for preparing compounds of formula 1A (c) having the stereochemistry shown in Scheme B at the carbon to which YR11 is attached. Compounds of that type are hereinafter referred to as compounds of the formula 1A (c) \ Steps i, ii and iii of Scheme B are described in Preparations 7, 8 and 9 in the Experimental Examples section of this application. The preparation of the compounds of the formula 1A (c) 'from compounds of the formula 8 can be achieved using the method described above to prepare compounds of the formula 1A (a) from compounds of the formula in Scheme A. The compounds of the formula 1A (c) 'wherein the group K, as defined above, is replaced with the group L, as defined above, can be prepared using analogous procedures to which they are represented in Scheme B, from the appropriate initial materials, which will be known to one of skill in the art. Compounds of formula 1 B wherein YR11 is as defined for the compounds of formula 1A (c) 'in Scheme B, can be prepared using procedures analogous to those depicted in Scheme B, starting from of starting materials identical to those of formula 5, as depicted in Scheme B, but the trifluoroacetamide substituent on such compounds is bonded to a carbon atom adjacent to the benzo ring. The compounds of the formulas 1A (a) and 1A (b) wherein Y is NR13 and R13 is hydrogen can be converted into the corresponding compounds wherein Y is NR13 and R13 is other than hydrogen, by reacting the compounds of that type with the appropriate compound of the formula X1R13 wherein X1 is a leaving group such as halo, mesylate or tosylate, preferably iodine, in the presence of a base such as sodium hydride (NaH), potassium hydride (KH), sodium methoxide (NaOCH3) or potassium t-butoxide (KOt-Bu). This reaction is typically carried out in an ether solvent such as THF, ethyl ether, dioxane or diglyme at a temperature from about room temperature to about the reflux temperature of the reaction mixture. It is preferably carried out in THF, using KOt-Bu as the base, at the reflux temperature.

SCHEME C 1A (f) 1A (g) i) Chloroacetyl Chloride, AICI3, CH2Cl2 ü) K2CO3, Nal, CH3CN iii) NaBH4, MeOH, / -PrOH, 0 ° C iv) DAST, CH2Cl2, 0 ° C v) NaBH4 > MeOH, / -PrOH Scheme C illustrates a process that can be used to prepare compounds of formulas 1A and 1B in which R11 is absent, Y is oxo (= O) or hydroxy (OH) and X is C (= O) , CHOH or CH (halo). Although Scheme D represents this procedure for only a subgenus of compounds of formula 1A, analogous procedures can be used which will be available to a person skilled in the art to prepare all compounds of formulas 1A and 1B in which R11 is absent. , Y is (= O) or OH and X is C (= O), CHOH or CH (halo). Step i of Scheme C is carried out as described in Preparation 22 in the Experimental Examples section of this application.

The compounds of the formula 10 are reacted with the appropriate compounds of the formula 6 to form the corresponding compounds of the formula 1A (d). This reaction is typically carried out in a solvent such as acetonitrile, THF, dioxane, DMF, DMSO, dichloromethane, diethyl ether, methanol or ethanol, preferably in acetonitrile, in the presence of potassium carbonate, sodium carbonate, cesium carbonate, triethylamine, diethyl isopropylamine, pyridine or tert-butoxide and sodium iodide or potassium iodide, at a temperature from about 09C to about the reflux temperature of the reaction mixture. Preferably, the reaction is carried out in the presence of potassium carbonate and sodium iodide at about room temperature. The reduction of the compounds of the formula 1A (d) gives the corresponding compounds of the formula 1A (e). This reduction can be achieved using sodium borohydride (NaBH4) or lithium borohydride (LiBH4), preferably NaBH4, in a hydroxylated solvent such as a C6 alkanol or a mixture of such solvents, at a temperature between 0SC and room temperature. A mixture of methanol and isopropanol is the preferred solvent. The preferred temperature is approximately 09C. The corresponding compounds of the formula 1A (f) can be prepared by reacting the compounds of the formula 1A (e) formed in the previous step with diethylaminosulfur trifluoride (DAST) in a chlorinated hydrocarbon solvent such as chloroform, dichloroethane or methylene chloride , preferably in methylene chloride, at a temperature of about 0SC at about room temperature, preferably at about 09C. Reduction of the resulting compounds of formula 1A (f) using the procedures described above for step iii of Scheme C, gives the corresponding compounds of formula 1A (g).

SCHEME D 1A (i) 1A (j) Scheme D illustrates the synthesis of compounds of formula 1 wherein X is CH (halo) from the corresponding compounds wherein X is CH (OH) and the synthesis of the compounds of formula 1A wherein X is absent from the corresponding compounds in which X is CH (halo). Although these procedures are illustrated for a certain subgenus of compounds of formula 1A, they are applicable to all compounds of formula 1. Referring to Scheme D, the compounds of formula 1A (e) are reacted with Ts (halo) or Ms (halo), in which Ms is mesyl and Ts is tosyl, in a chlorinated hydrocarbon solvent such as chloroform (CHCl3), dichloroethane (DCE) or methylene chloride (CH2Cl2) or in an ether solvent such as diethyl ether, dioxane or THF, at a temperature from about 0 ° C to about room temperature, preferably at about room temperature, in the presence of a base, providing the corresponding compounds of the formula 1A (h). Suitable bases include tertiary organic bases such as triethylamine (TEA, Et3N), pyridine or diethylaminopyridine. Triethylamine is the preferred base. Methylene chloride is the preferred solvent. The resulting compounds of the formula 1A (h) can be converted to the corresponding compounds of the formula 1A (j) by reacting them with tributyltin hydride (Bu3SnH) in the presence of a catalyst which is a radical initiator such as benzoyl peroxide or azobisisobutyronitrile (AIBN), preferably AlBN, in an aromatic hydrocarbon solvent such as benzene, toluene or xylene, preferably toluene. Suitable reaction temperatures vary in the range from about room temperature to about the reflux temperature of the reaction mixture. The reflux temperature is preferred. Reduction of the compounds of the formula 1A (j), using the procedure described above to reduce compounds of the formula 1A (d) in Scheme C, provides the corresponding compounds of the formula 1A (i). Compounds of formula 1 wherein X is CH (halo) can be converted to the corresponding compounds of formula 1 wherein X is CHNR3R12 by reacting them with a compound of the formula NHR3R12 in an ether solvent such as THF, diglyme, diboxane, DMF, DMSO, acetonitrile or diethyl ether, at a temperature from about room temperature to the reflux temperature of the reaction mixture, preferably at about the reflux temperature.

SCHEME E 1A (|) 1A (k) 1A (I) Scheme E illustrates the synthesis of compounds of formula 1 in which YR 11 is NHCH 3 or N (CH 3) C (= O) CH 3. Referring to Scheme E, the compounds of formula 1A (k) can be prepared in the following manner. A compound of the formula 1A (j) is reacted with methylamine in the presence of a Lewis acid such as aluminum trichloride or titanium tetrachloride, preferably titanium tetrachloride. This reaction is carried out generally in an aromatic hydrocarbon solvent such as toluene, silene or benzene, preferably toluene, at a temperature of from about 80 ° C to about 150 ° C, preferably at about 150 ° C. The product of this reaction is then reacted with a reducing agent such as NaBH 4, L-BH 4, sodium cyanoborohydride (NaCNBH 3) or KBH 4, preferably NaBH 4, in a hydroxylated solvent such as a CrCβ alkanol or a mixture of two or more such solvents, at a temperature between 0 ° C and room temperature. A mixture of methanol and isopropanol is the preferred solvent. The preferred temperature is about 0 ° C. The resulting free base of the compound of the formula 1A (k) can be converted into the corresponding methanesulfonate salt by reacting it with methanesulfonic acid using procedures well known to those skilled in the art. Reaction of the compound of the formula 1A (k) with acetic anhydride or acetyl chloride provides the desired compound of the formula 1A (I). The reaction with acetic anhydride is typically carried out in a chlorinated hydrocarbon solvent such as methylene chloride, chloroform or dichloroethane or in an ether solvent such as THF, diglyme or diethyl ether, at a temperature from about 09C to about the temperature of reflux of the reaction mixture. Preferably, the reaction is carried out in a methylene chloride solvent at about room temperature.

SCHEME F NaBH eOH / i-PiOH iA (m) 1A (b) ' Scheme F represents a process for synthesizing compounds of formula 1 in which YR 11 is NHC (= O) CH 3. Although represented only for a subgenus of compounds of the formula 1A, analogous procedures can be used which will be available to a person skilled in the art to prepare all the compounds of the formula 1 wherein YR11 is NHC (= O) CH3. Referring to Scheme F, a compound of the formula 1A (j) is reacted with hydroxylamine hydrochloride (NH2OH • OH) in a basic tertiary amine solvent such as pyridine or triethylamine. Pyridine is preferred. Suitable reaction temperatures vary in the range from about room temperature to about the reflux temperature of the reaction mixture, with the reflux temperature being preferred. Treatment of the product of this reaction with titanium trichloride in an ether solvent such as dioxane, ethyl ether, diglyme or THF, preferably dioxane, at a temperature from about 0 ° C to about the reflux temperature of the reaction mixture, preferably at room temperature, provides the corresponding compound of formula 11. Reduction of the compound of formula 11 using the procedure described above to reduce compounds of formula 1A (d) in Scheme C, provides the corresponding compounds of the formula 1A (b) '. The compounds of the formula 1A (b) 'can be converted to the corresponding compounds of the formula 1A (m) using the procedure described above in Scheme E to prepare the free base of the compounds of the formula 1A (I).

SCHEME G 1A (j) 12 1A (b) 11. AcJO. Et N, CH2Cl2, 56% 2. CH3SO3H, 70% Msa, a3N CH2CI2 1A (n) 1A (m) ' The synthesis of compounds of formula 1 in which YR11 is NHSO2CH3 is shown in Scheme G. Although only a subgenre of compounds of formula 1A is shown in the Scheme, the synthetic procedures of Scheme G can be used to prepare all the compounds having the formula 1 in which YR 11 is NHSO 2 CH 3.

Referring to Scheme G, the compounds of formulas 12 and 11 can be prepared as described in Examples 110 and 111, respectively, in the Experimental Examples section of this application. Reduction of the compounds of the formula 11 using the procedure described above to reduce compounds of the formula 1A (d) in Scheme C provides the corresponding compounds of the formula 1A (b). The corresponding compounds of the formula 1A (b) can be converted to the corresponding compounds having the formula 1A (n) using the procedure described above to prepare compounds of the formula 1A (m) in Scheme F, except that the acyl derivative reagent is mesyl chloride instead of acetic anhydride or acetyl chloride.

SCHEME H 13 14 15 (inseparable) 16 (a) 16 (b) 0 (inseparable) 1A (o) 17 5 Scheme H represents an alternative method of synthesizing compounds of formula 1 in which YR11 is NHC (= O) R15. Referring to Scheme H, the procedures for preparing chemical intermediates 14, 15, 16 (a), 16 (b) and 17 are described in Preparations 30 to 33 of the Q experimental Examples section of this application. The compounds of the formula 1A (o) can be prepared using methods analogous to those described for the preparation of the compounds of the formula 1A (d) in Scheme O SCHEME I 1A (o) 1A (p) 1A (p) 1A (q) The compounds of the formulas 1A (p) and 1A (q) can be prepared as illustrated in Scheme I. Referring to Scheme I, a compound of the formula 1A (o) is reduced using a boron hydride such as diborane or lithium aluminum hydride, preferably diborane, giving the corresponding compounds of the formula 1A (p). Typically, this reaction is carried out in an ether solvent such as THF, diglyme, dioxane or ethyl ether, preferably in THF, at a temperature from about room temperature to about the reflux temperature of the reaction mixture, preferably at about reflux temperature. The formation of the methanesulfonate hydrate of the formula 1,7CH 3 S 3 H 2 H 2 O is described in Example 117 in the Experimental Examples section of this application. The reaction of the resulting compound of formula 1A (p) with acetic anhydride or acetyl chloride in a chlorinated hydrocarbon solvent such as CHCl3, CH2Cl2 or trichloroethane, preferably CH2Cl2 at a temperature from about 0 ° C to about the reflux temperature of the Reaction mixture, preferably at about room temperature provides the corresponding compound of formula 1A (q). The formation of the methanesulfonate hydrate of the formula 2CH3SO3H • 1.8H2O is described in Example 118 in the Experimental Examples section of this application. SCHEME J Scheme J illustrates the synthesis of exocyclic amidotetralin derivatives of formulas 1A (r), 1A (s) and 1A (t). Analogous compounds of formulas 1A and 1B in which J, M, G, X, Y, m and R1 to R11 have any of the meanings described above in the definition of the compounds of formulas 1A and 1B and in which one of n and z is one and the other is two, can be prepared using procedures that will be available to a person skilled in the art in view of the synthetic procedures described above and in Experimental Examples 1 to 172. Examples of the synthesis of tetralin derivatives of that type are described in Experimental Examples 121 to 172. Referring to Scheme J, the preparation of compound 19 is described in Preparation 34 in the Experimental Examples section of this application. The preparation of compounds 20, 21 and 22 is described, respectively, in Preparation 35, Preparation 36 and Example 121 in the Experimental Examples section of this application. The synthesis of compound 1A (r) is described in Example 122. Compound 1A (r) can also be prepared using procedures similar to those described above in Schemes C and D, starting with the appropriate analogue starting materials. The syntheses of compounds 1A (t) and 1A (s) are exemplified, respectively, in Examples 123 and 124. These compounds can also be prepared using procedures similar to those described in Scheme F, starting with the starting materials appropriate analogs. The preparation of other compounds of formula 1 not specifically described in the above experimental section can be achieved by using combinations of the reactions described above that will be apparent to those skilled in the art. In each of the reactions described or illustrated above, the pressure is not critical unless otherwise indicated. Pressures of about 0.5 atmospheres to 5 atmospheres are generally acceptable and ambient pressure, i.e. about 1 atmosphere, is preferred due to convenience. When microwave assisted heating is used, sealed reactors are indicated, which produces high pressure reactions up to 350 psi. The compounds of formula 1 and the intermediates shown in the above reaction schemes can be isolated and purified by conventional procedures, such as recrystallization or chromatographic separation. The compounds of formula 1 and their pharmaceutically acceptable salts can be administered to mammals orally, parenterally (such as by subcutaneous, intravenous, intramuscular, intrasternal and infusion techniques), rectal, buccal or intranasal. In general, these compounds of the most desirable form are administered in doses in the range of from about 3 mg to about 600 mg per day, in single or fractionated doses (ie, from 1 to 4 doses per day), although they will necessarily occur variations depending on the species, weight and condition of the patient being treated and the individual response of the patient to said medication, as well as the type of pharmaceutical formulation chosen and the period of time and interval with which said administration is performed. However, a dose level in the range of about 25 mg to about 100 mg per day is most desirably employed. In some cases, dose levels below the upper limit of the aforementioned range may be more than adequate, while in other cases even higher doses may be employed without causing any harmful side effects, provided that such dose levels are divide first into several small shots for administration during the day. The compounds of the present invention can be administered alone or in combination with pharmaceutically acceptable carriers or diluents by any of the routes indicated above and such administration can be carried out in single or multiple doses. More particularly, the therapeutic agents of this invention can be administered in a wide variety of different dosage forms, that is, they can be combined with several inert pharmaceutically acceptable carriers in the form of tablets, capsules, pills, tablets, hard candies, suppositories, gelatins, gels. , pastes, ointments, aqueous suspensions, injectable solutions, elixirs, syrups and the like. Such vehicles include diluents or solid fillers, sterile aqueous media and various non-toxic organic solvents, etc. In addition, the oral pharmaceutical compositions can be sweetened and / or flavored appropriately. In general, the weight ratio between the compounds of this invention and the pharmaceutically acceptable carrier will be in the range of from about 1: 6 to about 2: 1 and preferably from about 1: 4 to about 1: 1. For oral administration, tablets containing various excipients such as microcrystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate and glycine together with various disintegrants such as starch (and preferably corn starch) may be employed., potato or tapioca), alginic acid and certain complex silicates, together with granulation binders such as polyvinylpyrrolidone, sucrose, gelatin and gum arabic. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc for the formation of tablets are often very useful. Solid compositions of a similar type can also be used as fillers in gelatin capsules; Preferred materials in this regard also include lactose or milk sugar as well as high molecular weight polyethylene glycols. When aqueous suspensions and / or elixirs are desired for oral administration, the active ingredient can be combined with various sweetening or flavoring agents, colorants or dyes and, if desired, also emulsifying and / or suspending agents, together with diluents such as water, ethanol, propylene glycol, glycerin and various similar combinations thereof. For parenteral administration, solutions of a compound of the present invention in sesame or peanut oil or in aqueous propylene glycol can be employed. The aqueous solutions should be suitably buffered (preferably at pH above 8) if necessary and the liquid diluent made sotonic first. These aqueous solutions are suitable for intravenous injection purposes. Oleaginous solutions are suitable for intra-articular, intramuscular and subcutaneous injection purposes. The preparation of all these solutions under sterile conditions is easily accomplished by standard pharmaceutical techniques well known to those skilled in the art. This invention relates to methods for treating anxiety, depression, schizophrenia and the other disorders that are mentioned in the description of the methods of the present invention, in which a compound of this invention and another or other active agents mentioned above ( for example an NK1 receptor antagonist, tricyclic antidepressant, 5HT1 D receptor antagonist or serotonin reuptake inhibitor) are administered together as part of the same pharmaceutical composition, as well as to procedures in which such active agents are administered orally. separated as part of an appropriate dosing regimen designed to reap the benefits of polytherapy. The appropriate dosage regimen, the amount of each dose of active agent administered and the specific intervals between the doses of each active agent will depend on the subject being treated, the specific active agent being administered and the nature and severity of the disorder. or specific condition that is being treated. In general, the compounds of this invention, when used as a single active agent or combined with another active agent, will be administered to an adult human in an amount from about 3 mg to about 300 mg per day, in single or fractionated intakes, preferably from about 25 to about 100 mg per day. Such compounds can be administered at a dosage of up to 6 times a day, preferably 1 to 4 times a day, especially 2 times a day and more especially once a day. However, variations may occur depending on the species of animal being treated and its individual response to said medicament, as well as the type of pharmaceutical formulation chosen and the period of time and interval with which said administration is carried out. In some cases, dose levels below the lower limit of the aforementioned range may be adequate, while, in other cases, even higher doses may be employed, provided that such larger doses are first divided into several small doses for administration during the day. A proposed daily dose of 5HT reuptake inhibitor, preferably sertraline, in the methods and combined compositions of this invention, for oral, parenteral or buccal administration to the adult human medium for the treatment of the conditions mentioned above, is from about 0.1 to about 2000 mg, preferably from about 1 mg to about 200 mg of the 5HT reuptake inhibitor per unit dose, which could be administered, for example, 1 to 4 times a day. A proposed daily dose of a 5HT1 D receptor antagonist in the combined methods and compositions of this invention, for oral, parenteral, rectal or oral administration to the average adult human being for the treatment of the conditions mentioned above, is from about 0.01 to about 2000 mg, preferably from about 0.1 mg to about 200 mg of the 5HT1D receptor antagonist per unit dose, which could be administered, for example, 1 to 4 times a day. For intranasal administration or administration by inhalation, the compounds of the invention are conveniently administered in the form of a solution or suspension with a pump spray container that is tightened or pumped by the patient or in the form of an aerosol presentation. spray with a pressurized container or a nebulizer, using a suitable propellant, for example, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve for administering a dosed amount. The pressurized container or nebulizer may contain a solution or suspension of the active compound. Capsules and cartridges (composed, for example, of gelatin) can be formulated for use in an inhaler or insufflator containing a powder mixture of a compound of the invention and a suitable powder base such as lactose or starch. Formulations of the active compounds of this invention for the treatment of the conditions mentioned above in the average adult human are preferably prepared so that each dosed dose or "puff" of aerosol contains from 20 μg to 1000 μg of active compound. The total daily dose with an aerosol will be in the range of 100 μg to 10 mg. The administration can be several times a day, for example 2, 3, 4 or 8 times, providing for example 1, 2 or 3 doses each time. All compounds of the Examples were analyzed and at least one stereoisomer of each such compound showed binding affinity for the receptor. D2, measured as percent inhibition, at a concentration of 0.1 μm, not less than 14% and up to 100%. At least one stereoisomer of each such compound showed binding affinity for the 5HT2 receptor measured as percent inhibition, at a concentration of 0.1 μm, not less than 80% and up to 100%. The ability of the compounds of this invention to bind dopamine D2 and serotonin 2A (5HT2A) receptors can be determined using conventional radioligand binding assays to receptors. All receptors can be expressed heterologously in cell lines and experiments with membrane preparations of cell lines can be performed using the procedures described below. IC50 concentrations can be determined by non-linear regression of the concentration-dependent reduction of the specific binding. The Cheng-Prussoff equation can be used to convert the IC50 into Ki concentrations. Dopamine D2 receptor binding: Binding of [3 H] spiperone to a membrane preparation of CHO-hD2L cells is carried out in 250 μl of 50 mM Tris-HCl buffer containing 100 mM NaCl, 1 mM MgCl 2 and DMSO at 1% at pH 7.4. Duplicate samples are incubated containing (in order of addition) the test compounds, [3 H] 0.4 nM spiperone and about 12 μg of protein for 120 minutes at room temperature. The bound radioligand is removed by rapid filtration under reduced pressure through Whatman GF / B glass fiber filters previously treated with 0.3% polyethylenimine. The radioactivity retained in the filter is determined by liquid scintillation spectrophotometry. The title compounds of Examples 1-120 were analyzed using the above assay, in which it was determined that the specific binding in the presence of 1 mM haloperidol was 95%. All the title compounds of Examples 1-120 showed Ki values that were less than or equal to 1 μM. The title compound of Example 58 exhibited a Ki of 3 nM. The title compound of Example 56 exhibited a Ki of 5 nM. The title compound of Example 60 exhibited a Ki of 9 nM. Serotonin 2A binding: The binding of [3 H] ketanserin to Swiss-h5HT2A cell membranes can be carried out in 250 μl of 50 mM Tris-HCl buffer at pH 7,4. Duplicate samples are incubated containing (in order of addition) the test compounds, 1.0 nM [3H] quetanserin and about 75 μg of protein for 120 minutes at room temperature. The bound radioligand is removed by rapid filtration under reduced pressure through Whatman GF / B glass fiber filters previously treated with 0.3% polyethylenimine. The radioactivity retained in the filter is determined by liquid scintillation spectrophotometry. The title compounds of Examples 1-120 were analyzed using the above assay, in which it was determined that the specific binding in the presence of 1 mM quetanserin was 90%. All the title compounds of Examples 1-120 showed Ki values that were less than or equal to 1 μM. The title compound of Example 58 exhibited a Ki of 0.03 nM. The title compound of Example 56 exhibited a Ki of 0.55 nM. The title compound of Example 60 exhibited a Ki of 0.09 nM. The following Examples illustrate the preparation of the compounds of the present invention. The melting points are not corrected. The NMR data are expressed in parts per million and refer to the deuterium signal of the solvent in the sample. EXAMPLES PREPARATION 1 2.2.2-TRIFLUORO-N-INDAN-2-IL-ACETAMIDE To a solution of 2-aminoindane (7.89 g, 69.71 mmol, 1 equiv.) In anhydrous THF (100 mL) and triethylamine ( 19.43 ml, 139.42 mmol, 2.0 equiv.) To <59C (ice / acetone), a solution of trifluoroacetic anhydride (TFAA) (14.77 mL, 104.56 mmol, 1.5 equiv.) In anhydrous THF (20 mL) was added dropwise maintaining the reaction < 109C. After the addition of TFAA, the reaction was allowed to warm to rt (room temperature) and stirred for 30 minutes. The reaction was diluted with H20 (100 mL) / ethyl acetate (100 mL) and the phases were separated. The organic phases were washed with 2N HCl (2 x 100 ml), brine (100 ml), dried (MgSO 4) and concentrated to a dark liquid residue. The residue was dissolved in MeOH (75 ml) and the desired product was precipitated with water to give green / brown crystals. Upon vacuum drying at 60 ° C for 1 hour, the title product was obtained (13.56 g, 59.16 mmol, 85% yield). 1 H NMR (400 MHz, CDCl 3) d 7.30-7.15 (m, 4H), 6.44 (bs, 1 H), 4.81-4.71 (M, 1 H), 3.40 (d, J = 7.1 Hz, 1 H), 3.35 (d, J = 7.1 Hz, 1 H), 2.90 (d, J = 4.1 Hz, 1 H), 2, 86 (d, = 4.1 Hz, H H). PREPARATION 2 N-r5- (2-Chloroacetyl) INDAN-2-IL1-2,2,2-TRIFLUOROACETAMIDE To a solution of 2,2,2-trifluoro-N-indan-2-ylacetamide (11.75 g, 51 , 26 mmol, 1.0 eq.) In carbon disulfide (125 ml) was added aluminum trichloride (27.34 g, 205.04 mmol, 4.0 equiv.) At room temperature. To the stirred suspension, chloroacetyl chloride (6.12 ml, 76.90 mmol, 1.5 equiv.) Was added portionwise with marked HCl release. After stirring for 15 minutes at room temperature, the reaction was heated to reflux for 1.5 hours followed by cooling to room temperature. The solvent was decanted and the residue carefully quenched with cold water. The precipitate was removed by filtration and recrystallized from 2-propanol / water and dried under vacuum at 60 ° C to give the title product as an olive solid (13.43 g, 43.93 mmol, 86% yield). 1 H NMR (400 MHz, CDCl 3) d 7.84 (s, 1 H), 7.81 (d, J = 8.0 Hz, 1 H), 7.36 (d, J = 8.0 Hz, 1 H), 6.43 (bs, 1 H), 4.86-4.76 (m, 1 H), 4.66 (s, 2H), 3.46. (d, J = 7.2 Hz, 1 H), 3.42 (d, J = 7.2 Hz, 1 H), 2.98 (d, J = 4.5 Hz, 1 H), 2.94 (d) , J = 4.5 Hz, 1 H). PREPARATION 3 N-r5- (2-CHLOROETHYL) INPAN-2-ILr2.2,2-TRlFLUOROACETAMIPA To a solution of N- [5- (2-chloroacetyl) indan-2-yl] -2,2,2-trifluoroacetamide (13.43 g, 43.93 mmol, 1.0 eq.) In TFA (100 mL) was added triethylsilyl hydride (17.5 mL, 109.82 mmol, 2.5 equiv.) At room temperature. The reaction was heated to 60 ° C for 20 minutes The reaction was cooled and poured into cold water. The resulting solid was collected by filtration and crystallized from MeOH / H20 to provide the desired product in 87% yield. 1 H NMR (400 MHz, CDCl 3) d 7.19 (d, J = 7.6 Hz, 1 H), 7.11 (s, 1 H), 7.06 (d, J = 7.6 Hz, 1 H), 6.42 (bs, 1H), 4.83-3.73 (m, 1 H), 3.70 (t, J = 6.95, 2H), 3.40-3.30 ( m, 2H), 3.04 (t, J = 6.95 Hz, 1H), 2.87 (dd, Jt = 4.5 Hz, J2 = 4.9 Hz, 1 H), 2.83 (dd) , Ji = 4.4 Hz, J2 = 4.9 Hz, 1 H). EXAMPLE 1 N-f5-r2- (4-BENZ? RPllSOTIAZOL-3-ILPIPERAZIN-1-IL) ETIL1INDAN-2-ILV 2.2.2-TRIFLUOROACETAMIDE N- [5- (2-Chloroetyl) indan-2-yl ] -2,2,2-trifluoroacetamide (3.00 g, 10.28 mmol), 3-piperazin-1-yl-benzo [d] isothiazole hydrochloride (5.26 g, 20.57 mmol) and sodium carbonate (2.18 g, 20.57 mmol) in H20 (20mL) was subjected to 175eC for 10 minutes with microwave intervention using a MARS-5 CEM microwave. The reaction was diluted with H20 (50 mL) and EtOAc (100 mL). The phases were separated and the organic phases were washed with 4 N HCl (2 x 25 ml). The aqueous phase was basified and extracted with CH2Cl2 (3 x 50 ml). The organic phases were dried (MgSO 4), and concentrated to a solid residue. The residue was subjected to chromatography (3% MeOH / CH2Cl2). N-. { 5- [2- (4-Benzo [or isothiazol-3-ylpiperazin-1-yl] ethyl] indan-2-yl} -2,2,2-trifluoroacetamide (3.20 g), was isolated with a purity of 100% at 254 nm; EMCL (APCI): 475 [M + H] +. 1 H NMR (400 MHz, CDCl 3) d 7.90 (d, J = 8.2 Hz, 1 H), 7.80 (d, J = 8.2 Hz, 1 H), 7.46 (t, J = 7.4 Hz, 1 H), 7.34 (t, J = 7.4 Hz, 1 H), 7.17 (d, J = 7.4 Hz, 1 H), 7.12 (s, 1 H), 7.08 (d, J = 7.4 Hz, 1H), 6.46 (bs, 1 H), 4, 82-4.71 (m, 1 H), 3.63-3.55 (m, 4H), 3.40-3.29 (m, 2H), 2.90-2.80 (m, 4H) , 2.79-2.72 (m, 4H), 2.71-2.65 (m, 2H). EXAMPLE 2 SALT CHLORHYDRATE OF 5-G2- (4-BENZOGP1ISOTIAZOL-3-1LP1PERAZIN-1-IDETIL1INDAN-2-ILAMINE To a solution of N-. {5- [2- (4-benzo [d] isothiazole-3-) ilpiperazin-1-yl) ethylindan-2-yl.} -2,2,2-trifluoroacetamide (2.89 g, 6.09 mmol) in MeOH / H20 (100 mL, 1: 1), K2CO3 ( 2.17 g, 30 mmol) and the whole was heated at 60 ° C. for 2 hours.The organic phases were evaporated and the aqueous phase was extracted with dichloromethane (DCM) (4 x 50 ml) .The organic phases were dried (MgSO 4), concentrated and the residue was purified by chromatography (10% MeOH / DCM with 1% NH 4 OH) to provide the desired product (1.45 g, 3.83 mmol) The product was dissolved and treated with 1 N HCl in Et20 The HCl salt was isolated by filtration and dried under vacuum at 50 ° C with a purity of 100% at 254 nm; EMCL (APCI): 379 [M + H] +. 1 H NMR (400 MHz, DMSO-D6) d ppm 2.99 (d, = 8.40 Hz, 1 H), 3.09 (d, J = 16.80 Hz, 2H), 3.20 (m , 3H), 3.32 (d, J = 11, 92 Hz, 4H), 3.51 (s, 4H), 3.57 (s, 1 H), 3.62 (s, 2H), 3, 94 (dq, = 12.26, 6.14 Hz, 1 H), 4.05 (d, J = 13.29 Hz, 2H), 5.07 (s, 1 H), 7.09 (d, J = 7.62 Hz, 1 H), 7.20 (m, 2H), 7.44 (t, J = 7.42 Hz, 1 H), 7.57 (t, J = 7.52 Hz, 1 H), 8.10 (dd, J = 13.19, 8.30 Hz, 2H), 8.41 (s, 3H), 11, 71 (s, 1 H). EXAMPLE 3 N- (5-r2-f4-BENZ? R? LllSOTIAZOL-3-ILPIPERAZIN-1-IL) ETIL1INDAN-2-IDACETAMIDE To a solution of 5- [2- (4-benzo [c.sothiazole-3-] il-piperazin-1-yl) ethyl] -indan-2-ylamine (1.00 g, 2.41 mmol) and Et3N (1.08 mL, 7.23 mmol) in dry THF (10 mL) was added chloride of acetyl (0.26 ml, 3.61 mmol). The reaction was stirred at room temperature for 1 hour, then quenched with water (25 ml). The reaction was diluted with EtOAc (50 mL) and the phases were separated. The organic phases were dried (MgSO 4), concentrated and the residue was chromatographed (EtOAc) to give N-. { 6- [2- (4-Benzo [] isothiazol-3-ylpiperazin-1-yl) ethyl] indan-1-yl} acetamide (0.97 g, 2.30 mmol) with a purity of 100% at 254 nm; EMCL (IQPA) 421 [M + Hf. 1 H NMR (400 MHz, CHLOROFORM-D) d ppm 1.94 (s, 3H), 2.65-2.71 (m, 2H), 2.73-2.80 (m, 6H), 2, 81-2.87 (m, 2H), 3.28 (ddd, J = 16.04, 6.10, 5.92 Hz, 2H), 3.57-3.62 (m, 4H), 4, 69-4.76 (m, 1 H), 5.70 (d, J = 7.08 Hz, 1 H), 7.06 (d, = 7.81 Hz, 1 H), 7.11 (s) , 1H), 7.16 (d, J = 7.56 Hz, 1 H), 7.35 (ddd, J = 8.17, 7.08.1,10 Hz, 1H), 7.46 (ddd) , J = 8.11, 7.02, 1, 22 Hz, 1H), 7.81 (dt, J = 8.05, 0.85 Hz, 1H), 7.91 (dt, J = 8.30 , 0.98 Hz, 1H). EXAMPLE 4 N- (5-r2- (4-BENZ? RPllSOTIAZOL-3-ILPIPERAZIN-1-IL) ETIL1INDAN-2-IL-BUTIRAM1DA 5- [2- (4-Benzo [o] isothiazol-3-ylpiperazine- 1-yl) ethyl] indan-2-ylamine was diluted to 0.20 M with anhydrous dichloromethane, then introduced into an 8 ml vial by means of a pipette (0.20 mmol). PS-N-methylmorpholine (0.40 mmol): 0.20 M butyryl chloride was diluted with dichloromethane and added at room temperature (0.40 mmol) The solution was stirred overnight at room temperature. added resin to remove the polyamine (0.5 mmol) The solution was stirred overnight at room temperature, then filtered into an 8 ml vial The filtrate was evaluated by MS, then concentrated using a GeneVac HT- 12. The crude product was purified by HPLC (30 x 100 mm ODS-A C (18) 5u column) N-. {5- [2- (4-Benzo [o]] -thiazole-3-ylp perazin-1-yl) ethyl] indan-2-yl.} butyramide was isolated with a purity of 100% to 25%. 4 nm, EMCL (APCI) 449 [M + H] +. The amides of Examples 5-42 were synthesized in combinoteca format following the steps described in Example 1 at a 0.20 millimolar scale using 5- [2- (4-benzo [o] isothiazol-3-piperazine] 1-yl) ethyl] indan-2-ylamine with starting materials of appropriate acid chloride and N-methylmorpholine in polystyrene resin. The crude products were purified by HPLC (column 30 x 100 mm ODS-A C (18) 5u). fifteen twenty 12 N-. { 5- [2- (4-BENZO [D] ISOTIAZOL-3- Isolated with an ILPIPERAZIN-1-IL) ETHEL] INDAN-2-IL} -4- purity of 98% at CIANOBENZAMIDA 254 nm; EMCL (APCI) 508 [M + H] + 13 N-. { 5- [2- (4-BENZO [D] ISOTIAZOL-3- Isolated with an ILPIPERAZIN-1-IL) ETHYL] INDAN-2- purity of 100% ILJISOBUTIRAMIDE at 254 nm; EMCL (APCI) 449 [M + H] + 14 N-. { 5- [2- (4-BENZO [D] ISOTIAZOL-3- Isolated with one ILPIPERAZIN-1-IL) ETHEL] INDAN-2- 100% purity IL} FENILPROPIONAMIDE at 254 nm; EMCL (APCI) 511 [M + H] + 15 N-. { 5- [2- (4-BENZO [D] ISOTIAZOL-3- Isolated with an ILPIPERAZIN-1-IL) ETHEL] INDAN-2-IL} -4- purity of 100% METOXIBENZAMIDE at 254 nm; EMCL (APCI) 513 [M + H] + 16 N-. { 5- [2- (4-BENZO [D] ISOTIAZOL-3- Isolated with an ILPIPERAZIN-1-IL) ETHEL] INDAN-2-IL} -4- purity of 100% CHLOROBENZAMIDE at 254 nm; EMCL (APCI) 518 [M + H] + 17 N-. { 5- [2- (4-BENZO [D] ISOTIAZOL-3- Isolated with an ILPIPERAZIN-1-IL) ETHEL] INDAN-2-IL} -2- purity of 99% a (3,4-DlMETOXIFENIL) ACETAMID 254 nm; EMCL (APCI) 557 [M + H] + 25 18 N-. { 5- [2- (4-BENZO [D] ISOTIAZOL-3- Isolated with an ILPIPERAZIN-1-IL) ETHEL] INDAN-2-IL} -3- 100% purity (3-MEYLPIRAZZOL-1- at 254 nm; EMCL 10 fifteen twenty 10 fifteen twenty 10 fifteen twenty PREPARATION 4 2.2.2-TRIFLUORO-N-INDAN-1-ILACETAMIDE Starting with indan-1 -lamina (20.88 g, 156.77 mmol), trifluoroacetic anhydride (33.21 mL, 235.15 mmol) and triethylamine (2.0 equiv.) and following the procedure as described in Preparation 1, 33.75g of 2,2,2-trifluoro-N-indan-1-ylacetamide was isolated in 94% yield. 1 H NMR (400 MHz, CHLOROFORM-D) d ppm 1.91 (m, 1H), 2.65 (m, 1H), 2.92 (ddd, J = 16.00, 7.94, 7.82. Hz, 1H), 3.04 (ddd, J = 16.12, 8.79, 4.40 Hz, 1H), 5.49 (q, J = 7.57 Hz, 1H), 6.42 (s) , 1H), 7.27 (m, 4H). PREPARATION 5 N-r6-f2-Chloroacetyl) INDAN-1-ILl-2.2.2-TRIFLUOROACETAMIDE To a solution of 2,2,2-trifluoro-N-indan-1-ylacetamide (33.45 g, 145.94 mmol ) in DCM (300 ml) was added AICI3 (58.38 g, 437.82 mmol) in one portion followed by the addition of chloroacetyl chloride (21.5 ml, 218.91 mmol). The reaction was heated at 40 ° C for 1.5 hours, then cooled to room temperature. The reaction was poured into ice water and diluted with DCM. The phases were separated and the aqueous was washed with DCM (3 x 200 ml). The organic phases were washed with water (250 ml) brine (250 ml), dried (MgSO4) and concentrated to a solid mass. They were dissolved in hot IPA (500 ml) and recrystallized until the next morning. N- [6- (2-Chloroacetyl) indan-1-yl] -2,2,2-trifluoroacetamide was isolated by filtration as a cottony solid and dried under vacuum at 50 ° C until the next morning. NMR of H (400 MHz, CHLOROFORM-D) d ppm 2.00 (m, 1H), 2.72 (m, 1H), 2.98 (m, 1H), 3.09 (m, 1H), 3 , 13 (m, 1H), 4.62 (s, 2H), 5.53 (dd, J = 7.82, 16.37 Hz, 1 H, NOE with singlet at 7.81 ppm) 6.65 ( s, 1 H, NOE with singlet at 7.81 ppm) 7.39 (d, J = 7.81 Hz, 1H), 7.81 (s, 1 H, NOE with singlet at 6.65 ppm and dd in 5.53 ppm) 7.86 (dd, J = 8.06, 1.47 Hz, 2H). The above filtrate was chromatographed (20% EtOAc / Hexane) to give two compounds with Rf 0.2 and 0.17. The compound with Rf of 0.2 was determined to be the regioisomer N- [4- (2-chloroacetyl) indan-1-yl] -2,2,2-trifluoroacetamide. 1 H NMR (400 MHz, CHLOROFORM-D) d ppm 1.94 (m, 1 H), 2.68 (m, 1 H), 3.23 (ddd, J = 18.13, 8.00, 7.82 Hz, 1H), 3.46 (ddd, J = 18.19, 8.91, 4.40 Hz, 1H), 4.68 (d, J = 1.47 Hz, 2H), 5.53 (q , J = 7.90 Hz, 1H), 6.45 (s, 1H), 7.39 (t, J = 7.69 Hz, 1H), 7.54 (d, J = 7.57 Hz, 1H ), 7.76 (d, J = 7.81 Hz, 1H). The compound with Rf of 0.17 was recrystallized from EtOAc / Hexane to give N- [5- (2-chloroacetyl) indan-1-yl] -2,2,2-trifluoroacetamide. 1 H NMR (400 MHz, CHLOROFORM-D) d ppm 1.96 (m, 1H), 2.73 (m, 1H), 2.98 (m, 1H), 3.08 (m, 1H), 4 , 67 (s, 2H), 5.55 (q, J = 8.06 Hz, 1H), 6.50 (s, 1H), 7.39 (d, J = 8.06 Hz, 1 H), 7.82 (d, J = 7.81 Hz, 1 H), 7.85 (s, 1 H) PREPARATION 6 N-r6-f2-CHLOROETHYL) INDAN-1-IL1-2,2,2-TRIFLUOROACETAMIDE Starting with N- [6- (2-chloroacetyl) indan-1-yl] -2, 2,2-trifluoroacetamide (1.00 g, 3.275 mmoi) and following the procedure described in Preparation 3, (0.67 g, 2.29 mmol), N- [6- (2-chloroethyl) was isolated. ) Ndan-1-yl] -2,2,2-trifluoroacetamide. 1 H NMR (400 MHz, CHLOROFORM-D) d ppm 1.91 (m, 1H), 2.66 (m, 1H), 2.89 (ddd, J = 15.94, 7.88, 7.69 Hz, 1H), 3.00 (m, 1H), 3.05 (t, J = 7.20 Hz, 2H), 3.69 (t, J = 7.33 Hz, 2H), 5.48 ( q, J = 7.57 Hz, 1H), 6.39 (s, 1H), 7.13 (s, 1H), 7.15 (d, J = 7.81 Hz, 1H), 7.22 ( m, 1H). EXAMPLE 43 N- (6-G2- (4-BENZOGP1ISOTIAZOL-3-ILPIPERAZIN-1-IL-ETIL1INDAN-1-IL) -2,2,2-TRIFLUOROACETAMIDE Starting with N- [6- (2-chloroethyl) indan- 1-yl] -2, '2,2-trifluoroacetamide (6.35 g, 21.76 mmol) and 3-piperazin-1-ylbenzo [is isothiazole (11.13 g, 43.52 mmol) and following the procedure described in Example 1, (6.31 g, 13.30 mmol) of N-. {5- [2- (4-benzo [d] isothiazol-3-ylpiperazin-1-yl) ethyl were prepared ] indan-1-yl.} -2,2,2-trifluoroacetamide with a purity of 100% at 254 nm; EMCL (APCI) 475 [M + H] +. 1 H NMR (400 MHz, CHLOROFORM-D) d ppm 1.91 (m, 1H), 2.66 (m, 3H), 2.76 (m, 4H), 2.88 (m, 3H), 3 , 01 (ddd, J = 16.30, 8.73, 4.52 Hz, 1H), 3.59 (m, 4H), 5.49 (q, J = 7.82 Hz, 1H), 6, 41 (d, J = 8.55 Hz, 1H), 7.18 (m, 3H), 7.35 (ddd, J = 8.18, 7.08, 0.85 Hz, 1H), 7.46 (ddd, J = 8.06, 6.96, 1.10 Hz, 1H), 7.81 (d, = 8.30 Hz, 1H), 7.91 (d, J = 8.30 Hz, 1H ). EXAMPLE 44 6-r2- (4-BENZ? R0llSOTIAZOL-3-ILPIPERAZIN-1 -IDETILHNDAN-1-ILAMINE To a solution of N- { 5- [2- (4-benzo [o] isothiazol-3-ylpiperazin -1-yl) ethyl] -indan-1-yl.} -2,2,2-trifluoroacetamide (4.35 g, 9.17 mmol) in MeOH / H20 (3: 1) was added K2CO3 (6, 34 g, 45.85 mmol) The whole was subjected to microwave irradiation and heated at 100 ° C. for 15 minutes using the MARS-5 CEM microwave reactor.When cooling, the reaction was concentrated and diluted with EtOAc (200 ml). Water (100 ml) The phases were separated and the aqueous was extracted with EtOAc (100 ml) The combined organics were washed with water (2 x 50 ml), brine (50 ml), and dried (MgSO 4) and The residue was dissolved in 1,4-dioxane / Et20 (2: 1) followed by treatment with 1 N HCl in Et20.The precipitate was collected by filtration as a pale yellow solid and dried at 50 ° C under vacuum. elevated yielding 6- [2- (4-benzo [d] isothiazol-3-ylpiperazin-1-yl) -ethyl] indan-1 -lamin (3.371) g, 8.90 mmol) with a purity of 100% at 254 nm; EMCL (APCI) 379 [M + H] +. 1 H NMR (400 MHz, CHLOROFORM-D) d ppm 2.16 (m, 1 H), 2.51 (m, 1 H), 2.91 (m, 6H), 3.12 (ddd, J = 16,12, 8,43, 5,25 Hz, 1 H), 3,68 (s, 4H), 4,65 (t, = 6,59 Hz, 1 H), 7,05 (d, J = 7.82 Hz, 1 H), 7.11 (m, 1 H), 7.33 (ddd, J = 8.06, 7.08, 0.98 Hz, 1 H), 7.44 (td, J = 7.57, 0.98 Hz, 1 H), 7.63 (s, 1 H), 7.77 (d, = 8.06 Hz, 1 H), 7.84 (d, J = 8) , 30 Hz, 1 H). EXAMPLE 45 N-f6-r2-f4-BENZ? R0HSOTIAZOL-3-ILPIPERAZIN-1-IL) ETIL1INDAN-1- IL1ACETAMIDE To a solution of 6- [2- (4-benzo [jisothiazole-3-piperazine] 1-yl) ethyl] indan-1-amine (1.00 g, 2.41 mmol) and Et3N (1.08 mL, 7.23 mmol) in. Dry THF (10 mL) was added acetyl chloride (0.26 mL, 3.61 mmol). The reaction was stirred at room temperature for 1. one hour later it was inactivated with water (25 ml). The reaction was diluted with EtOAc (50 mL) and the phases were separated. The organic phases were dried (MgSO 4), concentrated and the residue was chromatographed (EtOAc) to give N-. { 6- [2- (4-Benzo [cG] isot-azole-3-ylpiperazin-1-yl) ethyl] indan-1-yl-acetamide (0.97 g, 2.30 mmol) with a purity of 100% at 254 nm; EMCL (APCI) 421 [M + H] +. 1 H NMR (400 MHz, CHLOROFORM-D) d ppm 1.71-1.83 (m, 1H), 2.04 (s, 3H), 2.52-2.63 (m, 1H), 2, 63-2.70 (m, 2H), 2.70-2.78 (m, 4H), 2.78-2.87 (m, 3H), 2.88-2.97 (m, 1H), 3.59-3.63 (m, 4H), 5.46 (dd, J = 7.73, 16.80 Hz, 1H), 5.65 (d, J = 8.79 Hz, 1H), 7 , 11 (d, J = 7.81 Hz, 1H), 7.16 (m, 2H), 7.35 (ddd, J = 8.12, 7.02, 0.98 Hz, 1H), 7, 46 (ddd, J = 8.06, 7.08, 0.98 Hz, 1H), 7.81 (d, J = 8.06 Hz, 1H), 7.91 (d, J = 8.06 Hz) , 1 HOUR). Examples 46-58 were synthesized in a parallel format following the steps described in Example 1 at a 0.12 millimolar scale using benzo [d] isothiazol-3-ylpiperazin-1-yl) ethyl] indane hydrochloride salt. 1 -amine (0.259 g, 0.624 mmol) with acid chloride (1.5 equiv.) Appropriate starting materials and Et3N (2 equiv.) In THF (5 ml). The crude products were purified by chromatography (50% EtOAc / Hexane).

IL) ETHEL] INDAN-1- 3H), 1.73 (m, 3H), 2.18 (t J = 7.15 Hz, 2H), 2.53- IL} BUTIRAMIDE 2.63 (m, 1H), 2.64-2.71 (m, 2H), 2.73-2.88 (m, 6H), 2.92 (ddd, J = 15.87, 8, 79, 3.66 Hz, 1H), 3.54-3.65 (m, 4H), 5.47 (dd, J = 15.90, 7.73 Hz, 1H), 5.61 (d, J = 8.55 Hz, 1H), 7.09 (d, J = 7.60 Hz, 1H), 7.11 (s, 1H), 7.16 (d, J = 7.60 Hz, 1H), 7.34 (t, 8.06 Hz, 1H), 7.45 (t, J = 8.06 Hz, 1H), 7.79 (d, J = 8.06 Hz, 2H), 7.89 ( d, J = 8.06 Hz, 2H). 48 { 6- [2- (4- 100% purity at 254 nm; EMCL (IQPA) 447 BENZO [D] ISOTIAZOL-3- [M + H] +. 1 H NMR (400 MHz, ILPIPERAZIN-1- CHLOROFORM-D) d ppm 0.71-0.78 (m, 2H), IL) ETIL] INDAN-1- 0.99-1.06 (m, 2H), 1.27-1.36 (m, 1H), 1.79 (ddd, IL} AMID ACID J - 15.87, 12.94, 8.55 Hz, 1H), 2.53-2.63 (m, 1) CICLOPROPAN- 2.63-2.69 (m, 2H), 2.72- 2.78 (m, 4H), 2.78-2.87 CARBOXYLIC (m, 3H), 2.94 (ddd, J = 15.69, 8.85, 4.03 Hz, 1H), 3.54-3.61 (m, 4H), 5.48 (dd, J = 16.75, 7.57 Hz, 1H), 5.78 (d, J = 8.79 Hz, 1H), 7.10 (d, J = 8.79 Hz, 1H), 7.16 ( m, 2H), 7.34 (t, J = 8.18 Hz, 1H), 7.45 (t, J = 8.18 Hz, 1H), 7.79 (d, J = 8.06 Hz, 1H), 7.89 (d, J = 8.06 Hz, 1H). "49 | N- { 6- [2- (4- 100% purity at 254 nm; EMCL (IQPA) 449 BENZO [D] ISOTIAZOL-3- [M + H] +. 1 H NMR (400 MHz, ILPIPERAZIN-1- CHLOROFORM-D) d ppm 1.19 (dd, rotomeres, J IL) ETIL] INDAN-1- = 7.94, 6.96 Hz, 6H), 1.74 (ddd, J = 16.18, 12.88 IL.) ISOBUTIRAMLDA, 8.55 Hz, 1H), 2.36 (heptet, J = 6.85 Hz, 1H), 2.54-2.71 ( m, 3H), 2.71-2.79 (m, 4H), 2.79-2.88 (m, 3H), 2.91 (ddd, J = 16.00, 8.79, 3.54 Hz, 1H), 3.54-3.65 (m, 4H), 5.47 (dd, J = 16.51, 7.82 Hz, 1H), 5.59 (d, J = 8.30 Hz , 1H), 7.07-7.12 (m, 2H), 7.16 (d, J = 8.10 Hz, 1H), 7.34 (t, J = 8.06 Hz, 1H), 7 , 45 (t, J = 8.18 Hz, 1H), 7.79 (d, J = 8.06 Hz, 1H), 7.89 (d, J = 8.30 Hz, 1H). "50 [N- { 6- [2- (4- 100% purity at 254 nm; EMCL (IQPA) 517 BENZO [D] ISOTIAZOL-3- [M + H] +. 1 H NMR (400 MHz, ILPIPERAZIN-1- CHLOROFORM-D) d ppm 1.90 (ddd, J = 15.75, IL) ETIL] INDAN-1-IL} -4- 12.82, 8.30 Hz, 1H), 2.69 (m, 7H), 2.80-2.93 (m, CHLOROBENZAMIDE 3H), 2.99 (ddd, J = 15.94, 8.73, 3.91 Hz, 1H), 3.56 (m, 4H), 5.66 (dd, J = 15.79, 7.57 Hz, 1H), 6.25 (d, J = 8) , 30 Hz, 1 H), 7.13 (dd, J = 7.45, 1, 59 Hz, 1H), 7.20 (m, 2H), 7.33 (ddd, J = 8.12, 7 , 02, 0.98 Hz, 1H), 7.38 (m, 1H), 7.40 (m, 1H), 7.44 (ddd, J = 8.12, 7.02, 1.22 Hz, 1H), 7.71 (m, 1H), 7.73 (m, 1H), 7.79 (d, J = 8.06 Hz, 1H), 7.88 (d, J = 8.06 Hz, 1 HOUR).

PREPARATION 7 SALT (L) f +) - 5-IF2-CHLOROETH TARTRATE NDAN-2-ILAMONIUM (+/-) 2-lndanamine (4.4 g, 22.5 mmol) and L (+) - tartaric acid (3 , 4 g, 22.5 mmol) were dissolved in a reflux mixture of 50 ml of ethanol and 10 ml of water. After stirring for 6 hours, the mixture was allowed to cool to room temperature, the precipitate obtained was collected, rinsed with ethanol / water (5/1) and dried. The crystalline salt was recrystallized twice. The first 50 ml of ethanol / 15 ml of water and the second with 50 ml of ethanol and 20 ml of water. Salt (L) (+) - 5- (2-Chloroethyl) indan-2-ylammonium tartrate (0.94 g) was isolated with one ee. of 98% for the amine. 1 H NMR (200 MHz, Dβ-DMSO) d 2.80-3.10 (m, 4H), 3.15-3.40 (m, 2H), 3.8-4.1 (m, 4H) , 6.0-6.9 (bs, 3H), 7.0-7.3 (m, 3H). PREPARATION 8 SALT (D) f -) - 5- (2-CHLOROETHYL) INDAN-2-ILAMONIUM (+/-) 2-lndanamine (1 equiv.) And D (-) - tartaric acid (1 equiv.) TARTRATE was dissolved in a reflux mixture of 50 ml ethanol and 10 ml water. After stirring for 6 hours, while the mixture was allowed to cool to room temperature, the obtained precipitate was collected, rinsed with ethanol / water (5/1) and dried. The crystalline salt was recrystallized twice. The first 50 ml of ethanol / 15 ml of water and the second 50 ml of ethanol and 20 ml of water. Salt (D) (-) - 5- (2-cycloethyl) indan-2-ylammonium tartrate (0.94 g) was isolated with an ee. 95% for the amine. PREPARATION 9) -N-r5- (2-CHLOROETHYL) INDAN-2-I LACETAMIDE To a suspension of salt (L) (+) - 5- (2-Chloroethyl) indan-2-ylammonium tartrate (4.00 g , 11.58 mmol) in Et20 (150 mL) was added 2.5 N NaOH (100 mL). The suspension was sonicated, then diluted with Et20 (100 ml) and the phases were separated. The organic phases were washed with NaOH 2, 5 N (2 x 100 ml) and the aqueous phases were back extracted with Et20 (100 ml). The combined organics were washed with water (100 ml), brine (50 ml), dried (MgSO 4) and filtered. The ether solution was treated with Et3N (3.23 ml, 23.15 mmol) followed by the dropwise addition of acetyl chloride (0.91 ml, 12.74 mmol). After stirring for 1 hour, the reaction was quenched with water and the phases were separated. The organic phases were washed with 2N HCl (2 x 50 ml), water (50 ml), brine (50 ml), dried (MgSO 4) and concentrated to a solid in the form of (R) -N- [5 - (2-chloroethyl) indan-2-yl] acetamide (2.71 g, 11.58 mmol). 1 H NMR (400 MHz, CHLOROFORM-D) d ppm 1.92 (s, 3H), 2.75 (dt, J = 16.30, 4.55 Hz, 2H), 3.02 (t, J = 7.33 Hz, 2H), 3.23-3.30 (m, 2H), 3.68 (t, J = 7.45 Hz, 2H), 4.67-4.75 (m, 1 H) , 5.74 (s, 1 H), 7.02 (d, J = 7.57 Hz, 1 H), 7.07 (s, 1 H), 7.16 (d, J = 7.82 Hz , 1 HOUR). PREPARATION 10 (SV N-r5- (2-CHLOROETHL) INDAN-2-ILACETAMIPA Beginning with salt (D) (-) - 5- (2-Chloroethyl) indan-2-lamonium tartrate (4.00 g, 11 , 58 mmol) and acetyl chloride (1.5 equiv.) And following the procedure as described in Preparation 9, 2.29 g, 9.65 mmol of (S) -N- [5- ( 2-Chloroethyl) indan-2-yl] acetamide, 1 H NMR (400 MHz, CHLOROFORM-D) d ppm 1.93 (s, 3H), 2.75 (dt, J = 16.18, 4.61 Hz , 2H), 3.02 (t, = 7.33 Hz, 2H), 3.27 (dt, J = 16.18, 5.95 Hz, 2H), 3.69 (t, J = 7.33 Hz, 2H), 4.67-4.75 (m, 1 H), 5.69 (s, 1 H), 7.03 (d, J = 7.57 Hz, 1H), 7. 08 (s, 1 H), 7.16 (d, 'J = 7.81 Hz, 1H). PREPARATION 11 (R) -N-r5- (2-CHLOROETHYL) INDAN-2-IL1PROPIONAMIDE Starting with salt (L) (+) - 5- (2-Chloroethyl) indan-2-ammonium tartrate (2.00 g , 5.79 mmol) and proprionyl chloride (1.5 equiv.) And following the procedure as described in Preparation 9, 1.46 g, 5.79 mmol of (R) -N- [5 - (2-Chloroethyl) indan-2-yl] propionamide. 1 H NMR (400 MHz, CHLOROFORM-D) d ppm 1. 07 (t, J = 7.57 Hz, 3H), 2. 09 (q, = 7.65 Hz, 2H), 2.69 (dt, J = 16.30, 4.55 Hz, 2H), 2.97 (t, J = 7.45 Hz, 2H), 3 , 23 (dt, J = 16.12, 5.98 Hz, 2H), 3.64 (t, J = 7.45 Hz, 2H), 4.64-4.72 (m, 1 H), , 58 (s, 1H), 6.97 (d, J = 7.57 Hz, 1 H), 7.03 (s, 1H), 7.11 (d, J = 7.57 Hz, 1H). PREPARATION 12 (S) -N-r5- (2-CHLOROETHYL) INDAN-2-IL1PROPIONAMIPA Beginning with salt (D) (-) - 5- (2-Chloroethyl) indan-2-ylammonium tartrate (2.50 g, 7.24 mmol) and proprionyl chloride (1.5 equiv.) And following the procedure as described in Preparation 9, 1.64 g, 6.52 mmol of (S) -N- [5- (2-Chloroethyl) indan-2-yl] propionamide. 1 H NMR (400 MHz, CHLOROFORM-D) d ppm 1, 07 (t, J = 7.57 Hz, 3H), 2.09 (q, J = 7.57 Hz, 2H), 2.69 (dt) , J = 16.12, 4.64 Hz, 2H), 2.97 (t, J = 7.33 Hz, 2H), 3.23 (dt, J = 16.18, 5.95 Hz, 2H) , 3.64 (t, J = 7.33 Hz, 2H), 4.64-4.72 (m, 1 H), 5.58 (s, 1H), 6.97 (d, J = 7, 57 Hz, 1 H), 7.03 (s, 1 H), 7.11 (d, J = 7.81 Hz, 1 H). PREPARATION 13 r5- (2-CHLOROETHYL) INDAN-2-ILLAMIDE OF (R) -CICLOPROPANOCARBOXYLIC ACID Beginning with salt (L) (+) - 5- (2-chloroethyl) indan-2-ylammonium tartrate (3.10 g , 8.97 mmol) and cyclopropanecarbonyl chloride (1.5 equiv.) And following the procedure as described in Preparation 9, 2.36 g, 8.95 mmol of [5- (2-chloroethyl) indan were isolated. -2-yl] -amide of (R) -cyclopropanecarboxylic acid. 1 H NMR (400 MHz, CHLOROFORM-D) d ppm 0.61-0.67 (m, 2H), 0.88-0.92 (m, 2H), 1, 15-1, 23 (m, 1 H), 2.72 (dt, J = 16.18, 4.61 Hz, 2H), 2.98 (t, J = 7.45 Hz, 2H), 3.22 (ddd, J = 16.18 , 6.90, 4.52 Hz, 2H), 3.64 (t, J = 7.45 Hz, 2H), 4.64-4.72 (m, 1 H), 5.74 (s, 1 H), 6.98 (d, J = 7.82 Hz, 1 H), 7.04 (s, 1 H), 7.12 (d, J = 7.57 Hz, 1 H). PREPARATION 14 r5- (2-CHLOROETHYL) INDAN-2-lLAMIPA OF ACID IS) - CYCLOPROPANOCARBOXYLIC Starting with (D) (-) 5- (2-Chloroethyl) indan-2-ylammonium tartrate (3.08 g, 8 , 91 mmol) and cyclopropanecarbonyl chloride (1.5 equiv.) And following the procedure as described in Preparation 9, 2.09 g, 7.94 mmol of [5- (2-chloroethyl) indan- 2-yl] (S) -cyclopropanecarboxylic acid amide. 1 H NMR (400 MHz, CHLOROFORM-D) d ppm 0.67-0.72 (m, 2H), 0.96 (ddd, J = 7.08, 4.15, 3.91 Hz, 2H), 1, 19-1, 28 (m, 1 H), 2.78 (ddd, J = 15.94, 4.88, 4.58 Hz, 2H), 3.03 (t, J = 7.33 Hz , 2H), 3.28 (ddd, J = 16.18, 7.02, 4.88 Hz, 2H), 3.69 (t, J = 7.33 Hz, 2H), 4.64-4, 72 (m, 1 H), 5.80 (s, 1 H), 7.03 (d, J = 8.06 Hz, 1H), 7.09 (s, 1 H), 7.17 (d, J = 7.81 Hz, .1 H). PREPARATION 15 (RVN-r5- (2-CHLOROETHYL) INDAN-2-IL1BUTIRAMIDE Starting with salt (L) (+) - 5- (2-Chloroethyl) indan-2-ammonium tartrate (3.05 g, 8, 83 mmol) and butyryl chloride (1.5 equiv.) And following the procedure as described in Preparation 9, were isolated 2.34 g, 8.80 mmol of (R) -N- [5- (2 -chloroethyl) indan-2-yl] butyramide, 1 H-NMR (400 MHz, CHLOROFORM-D) d ppm 0.91 (t, J = 7.45 Hz, 3H), 1.63 (hexatet, J = 7, 39 Hz, 2H), 2.06-2.11 (m, 2H), 2.74 (dt, J = 16.12, 4.64 Hz, 2H), 3.03 (t, J = 7.45 Hz, 2H), 3.28 (ddd, J = 16.12, 6.84, 5.13 Hz, 2H), 3.69 (t, J = 7.33 Hz, 2H), 4.70-4 , 78 (m, 1 H), 5.61 (s, 1 H), 7.03 (d, J = 7.57 Hz, 1 H), 7.08 (s, 1 H), 7.16 ( d, J = 7.57 Hz, 1H) PREPARATION 16 (S) -N-r5- (2-CHLOROETHYL) INDAN-2-IL-BUTYRAMIDE Beginning with salt (D) (-) tartrate of 5- (2- chloroethyl) indan-2-y! ammonium (3.00 g, 8.83 mmol) and butyryl chloride (1.5 equiv.) and following the procedure as described in Preparation 9, 1.92 g were isolated. 7.24 mmol of (S) -N- [5- (2-chloroethe l) indan-2-yl] butyramide. 1 H NMR (400 MHz, CHLOROFORM-D) d ppm 0.91 (t, J = 7.33 Hz, 3H), 1, 57-1, 73 (m, 2H), 2.06-2.11 ( m, 2H), 2.74 (dt, J = 16.30, 4.55 Hz, 2H), 3.03 (t, J = 7.45 Hz, 2H), 3.28 (ddd, J = 16, 30, 6.90, 4.88 Hz, 2H), 3.69 (t, J = 7.45 Hz, 2H), 4.70-4.78 (m, 1 H), 5.62 (s, 1 H), 7.03 (d, J = 7.57 Hz, 1 H), 7.08 (s, 1 H), 7.16 (d, = 7.81 Hz, 1 H). PREPARATION 17 (R) -Nr-5- (2-CHLOROETHYL) INPAN-2-ILHSOBUTIRAMIDE Beginning with salt (L) (+) - 5- (2-Chloroethyl) indan-2-ylammonium tartrate (3.00 g, 8.68 mmol) and isobutyryl chloride (1.5 equiv.) And following the procedure as described in Preparation 9, 2.29 g, 8.62 mmol of (R) -N- [5- (2-Chloroethyl) indan-2-yl] isobutyramide. 1 H NMR (400 MHz, CHLOROFORM-D) d ppm 1.12 (d, J = 6.84 Hz, 6H), 2.25 (heptet, J = 6.88 Hz, 1 H), 2.73 ( dt, J = 16.30, 4.55 Hz, 2H), 3.03 (t, J = 7.45 Hz, 2H), 3.29 (ddd, J = 16.24, 6.96, 4, 88 Hz, 2H), 3.69 (t, J = 7.45 Hz, 2H), 4.70-4.78 (m, 1 H), 5.61 (s, 1 H), 7.03 ( d, J = 7.57 Hz, 1 H), 7.08 (s, 1 H), 7.16 (d, = 7.82 Hz, 1 H). PREPARATION 18 (S) -N-r5- (2-CHLOROETHYL) INDAN-2-IL1ISOBUTIRAMIDE Starting with salt (D) (-) - 5- (2-Chloroethyl) indan-2-ylammonium tartrate (3.00 g, 8.68 mmol) and isobutyryl chloride (1.5 equiv.) And following the procedure as described in Preparation 9, 1.99 g, 7.49 mmol of (S) were isolated. -N- [5- (2-Chloroethyl) indan-2-yl] isobutyramide. 1 H NMR (400 MHz, CHLOROFORM-D) d ppm 1.12 (d, J = 6.84 Hz, 6H), 2.25 (heptet, 6.88 Hz, 1H), 2.73 (ddd, J = 16.24, 4.64, 4.52 Hz, 2H), 3.03 (t, J = 7.33 Hz, 2H) ¡3.29 (ddd, = 16.24, 6.96, 4, 88 Hz, 2H), 3.69 (t, J = 7.33 Hz, 2H), 4.69-4.78 (m, 1 H), 5.61 (s, 1 H), 7.03 ( d, J = 7.57 Hz, 1 H), 7.08 (s, 1 H), 7.16 (d, J = 7.57 Hz, 1H). PREPARATION 19 r5- (2-CHLOROETHYL) INDAN-2-ACID ILLAMPY (RVLSOXAZOL-5-CARBOXYLIC Starting with salt (L) (+) - 5- (2-chloroethyl) indan-2-ylammonium tartrate (3.00 g, 8.68 mmol) and isobutyryl chloride (1.5 equiv.) and following the procedure as described in Preparation 9, 2.27, 7.81 mmol of [5- (2-chloroethyl) were isolated. indan-2-yl] (R) -isoxazole-d-carboxylic acid amide: 1 H NMR (400 MHz, CHLOROFORM-D) d ppm 2.91 (ddd, J = 16.24, 4.40, 4, 27 Hz, 2H), 3.04 (t, J = 7.45 Hz, 2H), 3.34-3.41 (m, 2H), 3.70 (t, J = 7.45 Hz, 2H) , 4.86-4.94 (m, 1 H), 6.76 (d, J = 6.59 Hz, 1 H), 6.90 (d, J = 1, 71 Hz, 1 H), 7 , 06 (d, J = 7.57 Hz, 1 H), 7.11 (s, 1 H), 7.20 (d, J = 7.81 Hz, 1 H), 8.30 (d, J = 1, 95 Hz, 1 H) PREPARATION 20 r5- (2-CHLOROETHYL) INDAN-2-IL1AMIPA OF ACID (S) -ISOXAZOL-5-CARBOXYLIC Starting with (D) (-) - tartrate salt of 5- ( 2-chloroethyl) indan-2-ylammonium (3.00 g, 8.68 mmol) and isobutyryl chloride (1.5 equiv.) And following the procedure as described in Preparation 9, 2.01, 6.93 mmol of [5- ( 2-Chloroethyl) indan-2-yl] -amide of (S) -isoxazole-5-carboxylic acid. 1 H NMR (400 MHz, CHLOROFORM-D) d ppm 2.91 (ddd, J = 16.24, 4.40, 4.27 Hz, 2H), 3.04 (t, J = 7.33 Hz, 2H), 3.38 (dt, J = 16.12, 5.98 Hz, 2H), 3.70 (t, J = 7.45 Hz, 2H), 4.86-4.94 (m, 1 H), 6.75 (s, 1H), 6.90 (d, J = 1.95 Hz, 1H), 7.06 (d, J = 7.57 Hz, 1H), 7.11 (s, 1H), 7.20 (d, J = 7.57 Hz, 1 H), 8.30 (d, J = 1.71 Hz, 1 H). EXAMPLE 59 (R) (-) - N-. { 5-r2- (4-BENZ? R0llSOTIAZOL-3-ILPIPERAZIN-1-IL) ETIL1lNDAN-2-IL) ACETAMID A suspension of (R) -N- [5- (2-chloroethyl) indan-2-yl] acetamide (2.00 g, 8.41 mmol), Na2C03 (1.5 equiv.) And 3-piperazin-1-ylbenzo [d] isothiazole hydrochloride (2.0 equiv.) In H20 (20 ml) was made react with microwave intervention using a MARS-5 CEM microwave reactor at 1759C for 10 minutes. Upon cooling, the reaction was diluted with EtOAc (250 mL), H20 (100 mL) and the phases were separated. The aqueous phase was extracted with EtOAc (2 x 50 ml). The organic phases were dried (MgSO 4), concentrated and the residue was purified by chromatography (EtOAc) to provide (R) (-) - N-. { 5- [2- (4-Benzo [s] isothiazol-3-ylpiperazin-1-yl) ethyl] indan-2-yl} acetamide (2.92 g, 6.94 mmol) with a purity of 100% at 254 nm; EMCL (APCI) 474 [M + H] +. [a] 25D 3.60 ° (c 5.5, CHCl3). 1 H NMR (400 MHz, CHLOROFORM-D) d ppm 1.94 (s, 3H), 2.65-2.71 (m, 2H), 2.73-2.80 (m, 6H), 2.81- 2.87 (m, 2H), 3.28 (ddd, J = 16.04, 6.10, 5.92 Hz, 2H), 3.57-3.62 (m, 4H), 4.69- 4.76 (m, 1H), 5.70 (d, J = 7.08 Hz, 1H), 7.06 (d, J = 7. 81 Hz, 1H), 7.11 (s, 1H), 7.16 (d, J = 7.56 Hz, 1H), 7.35 (ddd, J = 8.17, 7.08, 1.10. Hz, 1H), 7.46 (ddd, J = 8.11, 7.02, 1.22 Hz, 1H), 7.81 (dt, J = 8.05, 0.85 Hz, 1H), 7 , 91 (dt, J = 8.30, 0.98 Hz, 1H). Using the appropriate chloroethylindanes of Preparations 9-20, Examples 60-68 were reacted in parallel format according to the procedure described in Example 59. 3-ILPIPERAZIN-1- CHCI3). NMR of? (400 MHz, IL) ETHEL] INDAN-2- CHLOROFORM-D) d ppm 1.13 (t, J = IL.) PROPIONAMIDE 7.57 Hz, 3H), 2.15 (q, J = 7.57 Hz, 2H), 2.62-2.70 (m, 2H), 2.71-2.78 (m, 6H), 2.80-2.86 (m, 2H), 3.24-3, 32 (m, 2H), 3.57-3.61 (m, 4H), 4.70-4.78 (m, 1H), 5.59 (d, J = 7.06 Hz, 1H), 7 , 05 (d, J = 7.33 Hz, 1H), 7.10 (5.1H), 7.15 (d, J = 7.57 Hz, 1H), 7.34 (ddd, J = 8, 12, 7.02, 0.98 Hz, 1H), 7.46 (ddd, J = 8.18, 6.96, 0.98 Hz, 1H), 7.80 (dt, J = 8.12, 0.95 Hz, 1H), 7.90 (dt, J = 8.12, 0.95 Hz, 1H). 62 (S) (+) - N-. { 5- [2- (4- 100% purity at 254 nm; LCMS BENZO [D] ISOTIAZOL- (APCI) 435 [M + H] +. [α] 25D + 5.7 ° (c 6.3, 3-ILPIPERAZIN-1- CHCl3). 1 H NMR (400 MHz, IL) ETHEL] INDAN-2- CHLOROFORM-D) d ppm 1.12 (t, J = ILJPROPIONAMIDE 7.57 Hz, 3H), 2.14 (q, J = 7.57 Hz , 2H), 2.62-2.70 (m, 2H), 2.71-2.78 (m, 6H), 2.80-2.86 (m, 2H), 3.28 (ddd, J = 16.06, 6.23, 6.04 Hz, 2H), 3.56-3.61 (m, 4H), 4.70-4.77 (m, 1H), 5.64 (d, J = 7.33 Hz, 1H), 7.05 (d, J = 7.57 Hz, 1H), 7.10 ( s, 1H), 7.15 (d, J = 7.82 Hz, 1H), 7.34 (ddd, J = 8.12, 7.02, 0.98 Hz, 1H), 7.45 (ddd) , J = 8,12, 7,02, 1,22 Hz, 1H), 7,80 (ddd, J = 8,18, 0,85, 0,73 Hz, 1H), 7,90 (ddd, J = 8.18, 0.98, 0.85 Hz, 1H). 20 63 T5W 95% purity at 254 nm; LCMS (IQPA) BENZO [D] ISOTIAZOL- 447 [M + H] +. [a] 25D -2.8 ° (c 7.0, CHCl3). 3-ILPIPERAZIN-1-NMR of 1H (400 MHz, CHLOROFORM-IL) ETHEL] INDAN-2-D) d ppm 0.66-0.73 (m, 2H), 0.96 (ddd, JL.) AMINO OF ACID = 7.08, 4.15, 3.91 Hz, 2H), 1.20-1.28 (m, (RX 1H), 2.64-2.72 (m, 2H), 2 , 73-2.87 (m, CICLOPROPANE-8H), 3.27 (ddd, J = 16.06, 6.78, 5.01 Hz, CARBOXYLIC 2H), 3.54-3.63 (m, 4H), 4.71-4.79 (m, 1H), 5.83 (d, J = 8.44 Hz, 1H), 7.05 (d, J = 9.04 Hz, 1H), 7.11 (s, 1H), 7.16 (d, J = 7.82 Hz, 1H), 7.34 (ddd, J = 8.12, 7.02, 0.98 Hz, 1H), 7.46 (ddd, J = 8.12, 7.02, 0.98 Hz, 1H), 7.80 (d, J = 8.06 Hz, 1H ), 7.90 (d, J = 8.06 Hz, 1H). 64 100% purity at 254 nm; LCMS BENZO [D] ISOTIAZOL- (IQPA) 447 [M + H] +. 1 H NMR (400 3-ILPIPERAZIN-1-MHz, CHLOROFORM-D) d ppm 0,66-IL) ETHEL] INDAN-2-72 (m, 2H), 0.95 (ddd, J = 7, 02, 4.21, ACID ILJAMIDE 3.91 Hz, 2H), 1.21-1.28 (m, 1H), 2.77 (S) (+) - (ddd, J = 16.24, 3 , 79, 3.66 Hz, 2H), 2.84-CICLOPROPAN- 2.96 (m, 4H), 2.97-3.02 (m, 4H), 3.26 CARBOXYLIC (ddd, J = 16, 24, 6.96, 3.42 Hz, 2H ") 3.70-3.75 (m, 4H), 4.70-4.78 (m, 1H), 5.89 (d, J = 7, 33 Hz, 1H), 7.03 (d, J = 7.57 Hz, 1H), 7.09 (8, 1H), 7.16 (d, J = 7.57 Hz, 1H), 7.36 (ddd, J = 8.12, 7.02, 0.98 Hz, 1H), 7.47 (ddd, J = 8.12, 7.02, 1.22 Hz, 1H), 7.81 (d, J = 8.06 Hz, 1H), 7, 86 (d, J = 8.06 Hz, 1H). 65 (R) (-) - N-. { 5- [2- (4- 100% purity at 254 nm; LCMS BENZO [D] ISOTIAZOL- (APCI) 449 [M + H] +. [A] 25D -3.3 ° (c 7.1, 3-ILPIPERAZIN-1- CHCI3). 1 H NMR (400 MHz, IL) ETHL] INDAN-2-CHLOROFORM-D) d ppm 0.91 (t, J = ILJBUTIRAMIDE 7.33 Hz, 3H), 1.63 (hexatet, J = 7.42 Hz , 2H), 2.08 (t, J = 7.42 Hz, 2H), 2.62-2.73 (m, 3H), 2.74-2.78 (m, 5 H), 2.80 -2.86 (m, 2H), 3.24-3.32 (m, 2H), 3.56-3.61 (m, 4H), 4.71-4.78 (m, 1H), , 63 (d, J = 8.45 Hz, 1H), 7.05 (d, J = 7.57 Hz, 1H), 7.09 (s, 1H), 7.15 (d, J = 7.57 Hz, 1H), 7.34 (ddd, J = 8.12, 7.02, 0.98 Hz, 1H), 7.80 (d, J = 8.30 Hz, 1H), 7.90 (d, J = 8.30 Hz, 1 HOUR). 66 (S) (+) - N-. { 5- [2- (4- 100% purity at 254 nm; LCMS BENZO [D] ISOTIAZOL- (APCI) 449 [M + H] +. [A] 25D + 7.3 ° (c 6.0, 3-ILPIPERAZIN-1- CHCl3). 1 H NMR (400 MHz, IL) ETHEL] INDAN-2-CHLOROFORM-D) d ppm 0.91 (t, J = ILJBUTIRAMIDE 7.33 Hz, 3H), 1.64 (hextet, J = 7.42 Hz , 2H), 2.09 (t, J = 7.42 Hz, 2H), 2.65-2.74 (m, 3H), 2.74-2.78 (m, 5 H), 2.79. -2.86 (m, 2H), 3.28 (ddd, J = 16.30, 6.65, 5.37 Hz, 2H), 3.56-3.62 (m, 4H), 4.71 -4.78 (m, 1H), 5.62 (d, J = 7.63 Hz, 1H), 7.05 d (J = 7.57 Hz, 1H), 7.10 (s, 1H), 7.15 (d, J = 7.57 Hz, 1H), 7.34 (ddd, J = 8.18, 6.96, 0.98 Hz, 1H), 7.46 (ddd, J = 8, 06, 6.96, 1.10 Hz, 1H), 7.80 (d, J = 8.06 Hz, 1H), 7.90 (d, J = 8.06 Hz, 1H). I (R) (-) - N-. { 5- [2- (4- 95% purity at 254 nm; LCMS (IQPA) BENZOÍDjISOTIAZOL- 449 [M + H] +. [a] 25D -3.6 ° (c 7.7, CHCl3). 3-ILPIPERAZIN-1- 1 H NMR (400 MHz, CHLOROFORM-IL) ETHEL] INDAN-2-D) d ppm 1.12 (d, J = 6.84 Hz, 6H), 2.25 IL} ISOBUTIRAMIDE (heptet, J = 6.88 Hz, 1H), 2.62-2.73 (m, 3H), 2.73-2.79 (m, J = 4.40 Hz, 5 H), 2, 80-2.86 (m, 2H), 3.29 (ddd, J = 16.00, 6.23, 6.11 Hz, 2H), 3.56-3.62 (m, 4 H), 4 , 69-4.77 (m, 1H), 5.63 (d, J = 7.33 Hz, 1H), 7.05 (d, J = 7.82 Hz, 1H), 7.09 (s, 1H), 7.15 (d, J = 7.57 Hz, 1H), 7.34 (ddd, J = 8.12, 7.02, 0.98 Hz, 1H), 7.45 (ddd, J = 8.12, 7.02, 1.22 Hz, 1H), 7.80 (d, J = 8.30 Hz, 1H), 7.90 (d, J = 8.30 Hz, 1H).

(S) (+) - N-. { 5- [2- (4- 100% purity at 254 nm; LCMS BENZO [D] ISOTIAZOL- (IQPA) 449 [M + H] +. [a] 25D + 5.2 ° (c 5.4, 3-ILPIPERAZIN-1- CHCI3). 1 H NMR (400 MHz, IL) ETHEL] INDAN-2- CHLOROFORM-D) d ppm 1.12 (d, J = ILJISOBUTIRAMIDA 6.84 Hz, 6H), 2.25 (heptet, J = 6.84 Hz, 1H), 2.65-2.73 (m, 3H), 2.73-2.78 (m, 5 H) ), 2.80-2.86 (m, 2H), 3.25-3.33 (m, 2H), 3.56-3.62 (m, 4H), 4.69-4.77 (m , 1H), 5.63 (d, J = 7.57 Hz, 1H), 7.05 (d, J = 7.57 Hz, 1H), 7.09 (s, 1H), 7.15 (d , J = 7.57 Hz, 1H), 7.34 (ddd, J = 8.12, 7.02, 0.98 Hz, 1H), 7.46 (ddd, J = 8.12, 7.02 , 1.22 Hz, 1H), 7.80 (d, J = 8.06 Hz, 1H), 7.90 (d, J = 8.06 Hz, 1H).

EXAMPLE 69 SALT CHLORHYDRATE OF (R) (-) - N-f5-r2- (4-BENZ? R01ISOTIAZOL-3- ILPIPERAZIN-1-IL) ETIL1INDAN-2-IL) -N-METHYLACETAMIDE To a solution of (R) (-) - N-. { 5- [2- (4-Benzo [o] isothiazol-3-ylpiperazin-1-ylethyl] indan-2-yl}. Acetamide (0.504 g, 1.199 mmol) in dry THF (10 mL) was added. Potassium tert-butoxide (0.161 g, 1.439 mmol) was added at room temperature and the reaction was stirred for 10 minutes.to this stirring solution was added dropwise iodomethane (0.09 mL, 1.439 mmol) and the The reaction was stirred for 1 hour.The reaction was heated to reflux for 1 hour followed by cooling and quenching with water.The reaction was diluted with EtOAc and the phases were separated.The aqueous phase was washed with 4N HCl (3x) The aqueous acid was basified with KOH and extracted with DCM (3 x), dried (MgSO 4), concentrated and the residue was purified by chromatography (5% MeOH / DCM) .The free base was dissolved in 1, 4-dioxane and the HCl salt precipitated after treatment with 1 N HCl solution in Et20 yielding (R) (-) - N- { 5- [2- (4-benzo [a.sup.azol-3-] ilpiperazin-1-l) ethyl] indan-2-yl.}.-N-methylacetamide in the form of its to the hydrochloride, 100% purity at 254 nm; EMCL (APCI) 435 [M + H] +. [a] 25D -0.59s (c 6.7, CHCl3). 1 H NMR (400 MHz, CHLOROFORM-D) d ppm 2.09 (s, rotomer in CH 3, 2 H), 2.18 (s, rotomer in CH 3, 1 H), 2.74-2.88 (m, 5 H), 2.94-3.05 (m, 1 H), 3.07-3.21 (m, 7H), 3.22-3.32 (m, 3H), 3.47-3, 61 (m, 2H), 4.07-4.22 (m, 5 H), 4.68-4.78 (m, rotomer in CH, 0.4H), 5.54-5.64 (m, rotomere in CH, 0.6H), 7.01-7.08 (m, 1 H), 7.09-7.18 (m, 2H), 7.39 (t, J = 7.45 Hz, 1 H), 7.51 (t, J = 7.45 Hz, 1 H), 7.83 (t, J = 9.16 Hz, 2H), 13.31 (s, 1H). Anal. Cale, for .O HCl: C, 63.74; H, 6.63; N, 11, 89. Found: C, 63.76; H, 6.55; N, 11, 76. EXAMPLE 70 SALT CHLORHYDRATE (S) MN-re-r2- (4-BENZ? R? LlSOTIAZOL-3-ILPIPERAZIN-1-IL) ETIL1INDAN-2-IL) -N-METHYLACETAMIDE Starting with (S) (+) - N-. { 5- [2- (4-Benzo [] isothiazol-3-ylpiperazin-1-yl) ethyl] indan-2-yl} acetamide and iodomethane and following the procedure as described in Example 69, (S) (+) - N- was obtained. { 5- [2- (4-benzo [o] isothiazol-3-ylpiperazin-1-yl) ethyl] indan-2-yl} -N-methylacetamide in the form of its hydrochloride salt. 100% purity at 254 nm; EMCL (APCI) 435 [M + H] +. [a] 25D +3.59 (c 7.9, CHCl3). 1 H NMR (400 MHz, CHLOROFORM) d ppm 2.08 (s, rotomer in CH 3, 2 H), 2.17 (s, rotomer in CH 3, 1 H), 2.75 (s, rotomer in C (0) CH 3, 1 H), 2.79 (s, rotomer in C (0) CH 3, 2 H), 2.83 (ddd, J = 16.85, 6.47, 3.30 Hz, 1 H), 2, 98 (dd, J = 16.12, 6.11 Hz, 1 H), 3.07-3.21 (m, 6H), 3.22-3.30 (m, 2H), 3.50-3 , 58 (m, 2H), 4.07-4.19 (m, 4H), 4.65-4.80 (m, rotomer in CH, 0.35H), 5.48-5.63 (m, rotomere in CH, 0.65H), 7.00-7.07 (m, 1 H), 7.09-7.16 (m, 2H), 7.38 (t, J = 7.57 Hz, 1 H), 7.50 (t, = 7.57 Hz, 1 H), 7.82 (t, J = 8.79 Hz, 2H), 13.24 (s, 1 H). Anal. Cale, for C25H3oN4O? S1-1, 07 HCl: C, 63.40; H, 6.61; N, 11.83. Found: C, 63.15; H, 6.60; N, 11, 43 EXAMPLE 71 (R) -N-f5-r2- (4-BENZ? RP1ISOTIAZOL-3-lPIPERAZIN-1-IL) ETI llNDAN-2-ILT-N-ETHYLETAMIDE Starting with (R) -N-. { 5- [2- (4-Benzo [o] isothiazol-3-ylpiperazin-1-yl) ethyl] indan-2-yl} acetamide and iodoethane and following the procedure as described in Example 69, (R) -N- was obtained. { 5- [2- (4-Benzo [c] isothiazol-3-ylpiperazin-1-yl) ethyl] indan-2-yl} -N-methylacetamide in the form of its hydrochloride salt. 100% purity at 254 nm; EMCL (APCI) 449 [M + H] +. NMR of H (400 MHz, CHLOROFORM-D) d ppm 1, 11-1.21 (m, 3H), 1, 97-2.05 (bs, 3H), 2.12-2.22 (m, 3H) ), 3.00 (ddd, J = 15.78, 8.25, 3.71 Hz, 2H), 3.06-3.22 (m, 6H), 3.23-3.33 (m, 4H) ), 3.54 (d, J = 11, 14 Hz, 2H), 4.08-4.21 (m, 4H), 4.62-4.71 (m, rotomer in CH, 0.45H), 5.06-5.17 (m, rotomer in CH, 0.55H), 6.99-7.16 (m, 3H), 7.39 (t, J = 7.52 Hz, 1 H), 7 , 51 (t, J = 7.42 Hz, 1H), 7.83 (t, = 8.60 Hz, 2H), 13.26 (s, 1 H).

EXAMPLE 72 (S) -N- (5-r2- (4-BENZ? R0llSOTIAZOL-3-ILPIPERAZIN-1-IL) ETHYLNDAN-2-ID-N-ETHYLETHAMIDE Beginning with (S) -N- { [2- (4-benzo [cjisothiazol-3-ylpiperazin-1-yl] ethyl] indan-2-yl.} Acetamide and iodoethane and following the procedure as described in Example 69, (S ) -N- { 5- [2- (4-benzo [o] isothiazol-3-ylpiperazin-1-yl) ethyl] indan-2-yl}. -N-methylacetamide in the form of its hydrochloride salt, 100% purity at 254 nm, EMCL (IQPA) 449 [M + H] +. 1 H NMR (400 MHz, CHLOROFORM-D) d ppm 1, 02-1, 16 (m, rotomers in CH3, 3H), 2.08 (s, rotomere in C (0) CH3, 2H), 2.11 (s, rotomere in C (0) CH3,1H), 2.88-3.00 (m, 2H), 3.00-3.16 (m, 5 H), 3.18-3.28 (m, 4H), 3.44-3.52 (m, 2H), 3.64 (s, 3H), 4 , 03-4.17 (m, 4H), 5.54-5.69 (, rotomer in CH, 0.45H), 5.01-5.15 (m, rotomer in CH, 0.55H), 6, 95-7.12 (m, 3H), 7.35 (t, = 7.62 Hz, 1 H), 7.45 (t, J = 7.81 Hz, 1 H), 7.78 (t, J = 8.47 Hz, 2H), 13.24 (s, 1 H) EXAMPLE 73 (R) -N- {5-r2- (4-BENZ? R0llSOTIAZOL-3-ILPIPERAZIN-1-IL) ETIL1IN DAN-2-ID-N-CICLOPROPILMETILACETAMIDA Beginning with (R) -N-. { 5- [2- (4-Benzo [o] isothiazol-3-ylpiperazin-1-yl) ethyl] indan-2-yl} acetamide and bromomethylcyclopropane and following the procedure as described in Example 69, (R) -N- was obtained. { 5- [2- (4-benzo [alisothiazol-3-ylpiperazin-1-yl] ethyl] indan-2-yl} -N-cyclopropylmethylacetamide in the form of its hydrochloride salt. Purity of 100% at 254 rim; EMCL (APCI) 475 [M + H] +. 1 H NMR (400 MHz, CHLOROFORM-D) d ppm 0.01-0.05 (m, 2H), 0.26-0.34 (m, 1 H), 0.38-0.46 (m, 1 H), 0.69-0.88 (m, 1 H), 2.00 (s, rotomer in C (0) CH 3, 1.5 H), 2.04 (s, rotomere in C (0) CH3, 1.5 H), 2.90-3.06 (m, 10 H), 3.07-3.16 (m, 2H), 3.32-3.42 (m, 2H), 3, 93-4.07 (m, 4H), 4.49-4.59 (m, rotomer in CH, 0.5H), 4.72-4.82 (m, rotomer in CH, 0.5H), 6, 83-7.02 (m, 3H), 7.25 (t, J = 7.57 Hz, 1H), 7.36 (t, J = 7.69 Hz, 1H), 7.68 (dd, J = 10.50, 8.30 Hz, 2H), 13.15 (s, 1H). EXAMPLE 74 fS) -N-f5-r2- (4-BENZ? RP1ISOTIAZOL-3-ILPIPERAZIN-1-IL) ETIL1INDAN-2-ID-N-CICLOPROPYLLETHYLAMETAMIDE Beginning with (S) -N-. { 5- [2- (4-Benzo [cd] isot-azole-3-ylpiperazin-1-yl) ethyl] indan-2-yl} acetamide and bromomethylcyclopropane and following the procedure as described in Example 69, (S) -N- was obtained. { 5- [2- (4-Benzo [d] isothiazol-3-ylpiperazin-1-yl) ethyl] indan-2-yl} -N-cyclopropylmethylacetamide in the form of its hydrochloride salt. 100% purity at 254 nm; EMCL (APCI) 475 [M + H] +. 1 H NMR (400 MHz, CHLOROFORM-D) d ppm 0.01-0.05 (m, 2H), 0.26-0.34 (m, 1H), 0.39-0.46 (m, 1H ), 0.69-0.88 (m, 1H), 2.00 (s, rotomer in C (0) CH3, 2H), 2.04 (s, rotomere in C (0) CH3, 1 H), 2.90-3.08 (m, 10 H), 3.08-3.16 (m, 2H), 3.40 (d, J = 11, 33 Hz, 2H), 3.92-4.05 (m, 4H), 4.48-4.59 (m, rotomer in CH, 0.4H), 4.71-4.82 (m, rotomer in CH, 0.6H), 6.84-7, 02 (m, 3H), 7.24 (t, J = 7.52 Hz, 1H), 7.36 (t, = 7.42 Hz, 1H), 7.67 (t, J = 8.79 Hz , 2H), 13.05 (s, 1H). PREPARATION 21 1.1.3.3-TETRAMETILINPAN-2-ONA Registration number Beilstein 2048281; CAS registry number 5689-12-3, Star, J. E .; Eastman, R. H. J. Org. Chem. 1966, 37.1393. PREPARATION 22 5- (2-Chloroacetyl) -1, 1, 3,3-TETRAMETILINPAN-2-ONA In a 250 ml round bottom flask under N2 atmosphere, 1,1,3,3-tetramethylindanone (5, 00 g, 26.5 mmol), aluminum chloride (21.2 g, 159 mmol) and methylene chloride (65 mL). Chloroacetyl chloride (3.37 ml, 42.4 mmol) was added dropwise and the reaction was heated at 40 ° C for 5 hours. After cooling, the reaction mixture was poured into ice water (100 ml) while stirring. The mixture was diluted with methylene chloride (250 ml). The organic phase was separated, washed with saturated NaHCO 3, water, brine, dried over Na 2 SO 4 and evaporated. The residue was purified by chromatography (silica gel, hexanes / ethyl acetate 95: 5) to give 5- (2-chloroacetyl) -1, 1, 3,3-tetramethylindan-2-one (6.65 g, 95% ) in the form of a yellow solid: 1 H NMR (300 MHz, CDCl 3) d 7.93-7.89 (m, 2H), 7.40 (dd, J = 7.6, 0.9 Hz, 1H) , 4.73 (s, 2H), 1.38 (s, 6H), 1.37 (s, 6H). EXAMPLE 75 5-r2-f4-BENZ? RP1ISOTIAZOL-3-ILPlPERAZIN-1-IL) ACETYL1-1, 1, 3.3-TETRAMETILINDAN-2-ONA A mixture of 5- (2-chloroacetyl) -1, 1, 3,3-tetramethylindan-2-one (7.85 g, 29.6 mmol), hydrochloride 3- piperazin-1-yl-benzo [d] isothiazole (7.95 g, 31.1 mmol), potassium carbonate (13.5 g, 97.7 mmol), sodium iodide (4.50 g, 30.0 mmol) in acetonitrile (550 ml) was stirred at room temperature for 24 hours. The reaction was quenched with water (120 ml) and the acetonitrile was evaporated. The residue was extracted with methylene chloride (2 x 250 ml). The combined organic extracts were washed with water, brine, dried over Na 2 SO 4, evaporated and purified by chromatography (silica gel, hexanes / ethyl acetate 7: 3 to 6: 4) to give 5- [2- ( 4-Benzo [o] isothiazol-3-ylpiperazin-1-yl) acetyl] -1, 1, 3,3-tetramethylindan-2-one (11.2 g, 85%) as an off-white solid: NMR of 1H (300 MHz, CDCl 3) d 8.02 (dd, J = 8.0, 1.6 Hz, 1 H), 7.96 (s, 1 H), 7.91 (d, J = 8.0) Hz, 1 H), 7.83 (d, J = 8.0 Hz, 1 H), 7.47 (t, J = 7.0 Hz, 1 H), 7.38-7.34 (m, 2H), 3.94 (br s, 2H), 3.67-3.65 (m, 4H), 2.90-2.88 (m, 4H), 1.38 (s, 6H), 1, 37 (s, 6H). EXAMPLE 76 5-f2-l - (1 H-INDAZOL-3-1DPIPERAZIN-1-IL1ACETILI-1, 1.3.3-TETRAMETILINDAN-2-ONA Starting with 5- (2-chloroacetyl) -1, 1, 3.3 -tetramethylindan-2-one (3.00 g, 11.3 mmol) and 3-piperazin-1-yl-1 H-indazole hydrochloride (2.76 g, 11.6 mmol) and following the procedure described in Example 75, a residue was isolated and purified by chromatography (silica gel, EtOAc / hexanes 3: 2 to 4.1 with 0.5% Et3N) to give 5-. {2- 2- (1H- ndazol-3-yl) piperazin-1-yl] acetyl] -1, 1, 3,3-tetramethylindan-2-one (1.85 g, 37%) as a yellow solid: 1 H NMR ( 300 MHz, CDCl 3) d 9.13 (s, 1 H), 8.03 (dd, = 8.0, 1.6 Hz, 1 H), 7.97 (d, J = 1.4 Hz, 1 H ), 7.72 (d, J = 8.2 Hz, 1 H), 7.38-7.34 (m, 3H), 7.06 (m, 1 H), 3.92 (s, 2H) , 3.57 (m, 4H), 2.87 (m, 4H), 1, 39 (s, 6H), 1.37 (s, 6H); MS res. M / z 431 [C 26 H 30 N 4 O 2 + H] +. EXAMPLE 77 5-f2-r4- (BENZ? Rc? ISOTIAZOL-3-ILPIPERAZIN-1-IL) -1-HYDROXYETH1-1, 1.3.3-TETRAMETILINDAN-2-ONA To a suspension of 5- [2- (4 -benzo [d] isothiazol-3-ylpiperazin-1-yl) acetyl] -1, 1, 3,3-tetramethylindan-2-one (11.2 g, 25.0 mmol) in 2-propane (650 ml) and methanol (650 ml) was added NaBH 4 (0.99 g, 26 mmol) at 0 C. After stirring at 09 C for 8 hours, the reaction was quenched with the addition of acetone (50 ml). The solvent was removed in vacuo. The residue was dissolved in chloroform (1 L), washed with water, brine, dried over Na 2 SO 4, evaporated and purified by chromatography (silica gel, hexanes / EtOAc 7: 3 to 6: 4) to give 5- [ 2- (4-Benzo [d] isothiazol-3-ylpiperazin-1-yl) -1-hydroxyethyl] -1, 1, 3,3-tetramethylindan-2-one (8.50 g, 76%) in the form of a white solid: mp 189-191 C; 1 H NMR (300 MHz, CDCl 3) d 7.92 (d, J = 8.1 Hz, 1 H), 7.83 (d,, J = 8.1 Hz, 1 H), 7.48 (td) , J = 7.0, 1.0 Hz, 1H), 7.40-7.30 (m, 3H), 7.24 (s, 1 H), 4.83 (dd, J = 10.0, 3.8 Hz, 1 H), 4.03 (br s, 1 H), 3.63-3.57 (m, 4H), 3.06-2.99 (m, 2H), 2.77- 2.57 (m, 4H), 1.35 (s, 12H). EXAMPLE 78 5-r2-f4-BENZ? RP1ISOTIAZOL-3-ILPIPERAZIN-1-ILH-FLUOROETIL1-1.1.3.3-TETRAMETILINDAN-2-ONA To a solution of 5- [2- (4-benzo [d] isothiazole-3) -iIpiperazin-1-yl) -1- hydroxyethyl] -1, 1, 3,3-tetramethylindan-2-one (1.50 g, 3.34 mmol) in CH2Cl2 (300 mL) was added DAST (0.53 ml, 4.0 mmol) slowly at 09C. The mixture was stirred at 09 C for 30 minutes and then quenched with the addition of ice water (20 ml). The organic phase was separated and washed with H20, brine, dried over Na2SO4, filtered and the solvent was removed in vacuo. The residue was purified by flash chromatography (silica gel, hexanes / EtOAc 7: 3) to provide 5- [2- (4-benzo [] isothiazol-3-ylpiperazin-1-yl) -1-fluoroethyl] -1 , 1, 3,3-tetramethylindan-2-one (1.00 g, 67%) as a pale yellow solid: mp 64-739C; 1 H NMR (300 MHz, CDCl 3) d 7.92 (d, J = 8.1 Hz, 1 H), 7.83 (d, J = 8.1 Hz, 1H), 7.48 (dd, J = 7.8, 7.3 Hz, 1 H), 7.36 (dd, J = 7.8, 7.2 Hz, 1 H), 7.33-7.28 (m, 3H), 5, 75 (dd, J = 48.8, 8.6 Hz, 1 H), 3.64-3.61 (m, 4H), 3.12-2.70 (m, 6H), 1, 36 (s) , 6H), 1, 35 (6H); MSEs m / z 452 [C26H3QFN3OS + H] +; R 0.27 (Hexanes / EtOAc 7: 3); (AUC) 97.0% by HPLC (Method B), tR = 15.17 minutes. Anal. Cale, for C26H30FN3OS. 0.25H2O: C, 68.47; H, 6.74; N, 9.21. Found: C, 68.17; H, 6.65; N, 8.97. EXAMPLE 79 5-r2- (4-BENZ? R? PiSOTIAZOL-3-IPPERAZIN-1-IL) -1-FLUOROETIL1-1.1.3.3-TETRAMETILINDAN-2-OL To a suspension of 5- [2- (4-benzo [or isothiazol-3-ylpiperazin-1-yl) -1-fluoroethyl] -1, 1, 3,3-tetramethylindan-2-one (300 mg, 0.660 mmol) in 2-propanol (40 ml) and methanol (10 ml). ml) was added NaBH4 (62 mg, 1.6 mmol) at 09C. The reaction was allowed to stir at room temperature for 24 hours and quenched with the addition of acetone (10 ml). After evaporating the solvent, the residue was dissolved in chloroform (100 ml). The organic solution was washed with water, brine, dried over Na 2 SO 4, evaporated. The residue was purified by chromatography (silica gel, hexanes / ethyl acetate 7: 3) to give 5- [2- (4-benzo [s] isothiazol-3-ylpiperazin-1-yl) -1-fluoroethyl] -1 , 1, 3,3-tetramethylindan-2-ol (290 mg, 97%) as a white solid: mp 49-549C; 1 H NMR (300 MHz, CDCl 3) d 7.92 (d, = 8.1 Hz, 1 H), 7.83 (d, J = 8.1 Hz, 1 H), 7.45 (td, J = 7.2, 0.9 Hz, 1 H), 7.36 (td, J = 7.2, 0.9 Hz, 1 H), 7.24-7.16 (m, 3H), 5, 73 (dd, J = 49.3, 8.9 Hz, 1H), 3.85 (d, J = 8.2 Hz, 1H), 3.64-3.61 (m, 4H), 3.11 -2.67 (m, 6H), 1, 67 (d, J = 8.2 Hz, 1 H), 1.38 (s, 3H), 1, 37 (s, 3H), 1, 20 (s) , 3H), 1, 19 (s, 3H); MS APCI m / z 454 [C 26 H 32 FN 3 OS + H] +; R, 0.29 (Hexanes / EtOAc 3: 2); (AUC) > 99% by HPLC (Method B), t R = 14.24 minutes. Anal. Cale, for C26H32FN3OS. 0.25H2O: C, 68.17; H, 7.15; N, 9.17. Found: C, 68.03; H, 7.15; N, 8.86. EXAMPLE 80 5-G2- (4-BENZQG01ISOTIAZOL-3-ILPIPERAZIN-1 - | L) -1 -HIDROXIETIL1- 1.1.3.3-TETRAMETILINDAN-2-OL To a suspension of 5- [2- (4-benzo [o] isothiazol-3-ylpiperazin-1-yl) acetyl] -1, 1,3,3-tetramethylindan-2-one (500 mg, 1.12 mmol) in 2-propanol (70 ml) and methanol (20 ml) was added NaBH 4 (169 mg, 4.48 mmol) at 0SC. The reaction was allowed to stir at room temperature for 24 hours and was quenched with the addition of acetone. After evaporating the solvent, the residue was dissolved in chloroform (100 ml). The organic solution was washed with water, brine, dried over Na 2 SO 4, evaporated. The residue was purified by chromatography (silica gel, hexanes / EtOAc 6: 4) to give 5- [2- (4-benzo [o] isothiazol-3-ylpiperazin-1-yl) -1-hydroxyethyl] -1, 1,3,3-tetramethylindan-2-ol (450 mg, 89%) as a white solid: mp 88-97 sC; 1 H NMR (300 MHz, CDCl 3) d 7.91 (d, J = 8.1 Hz, 1 H), 7.83 (d, J = 8.1 Hz, 1H), 7.48 (td, J = 7.0, 1.0 Hz, 1H), 7.37 (td, J = 8.0, 1.0 Hz, 1H), 7.23-7.13 (m, 3H), 4.82 ( dd, J = 9.3, 4.3 Hz, 1H), 3.98 (br s, 1H), 3.83 (dd, J = 8.3, 1.8 Hz, 1 H), 3.66 -3.56 (m, 4H), 3.05-2.97 (m, 2H), 2.76-2.68 (m, 2H), 2.66-2.56 (m, 2H), 1 , 38 (s, 3H), 1.36 (s, 3H), 1, 19 (s, 3H), 1, 18 (s, 3H); Rf 0.35 (EtOAc / hexanes 3: 2); (AUC) > 99% by HPLC (Method B), t R = 13.51 minutes. Anal. Cale, for C 26 H 33 N 302 S: C, 69.15; H, 7.36; N, 9.30. Found: C, 68.79; H, 7.46; N, 8.92. EXAMPLE 81 5-f2-r4- (BENZ? R-7llSOTIAZOL-3-ILPIPERAZIN-1-IL) -1-CHLOROETHYL- 1.1.3.3-TETRAMETILINDAN-2-ONA To a solution of 5- [2- (4-benzo [or isothiazol-3-ylpiperazin-1-yl] -1-hydroxyethyl] -1,1,3-tetramethylindan-2-one (4.30 g, 9.56 mmol) in CH2Cl2 (300 mL) was added methanesulfonyl chloride (1.20 ml, 15.5 mmol), triethylamine (3.23 ml, 23.2 mmol) at 09C. The reaction mixture was allowed to stir at room temperature for 2 hours and then quenched with water. The organic phase was separated, washed with water, brine, dried over Na 2 SO 4 and evaporated. The residue was purified by chromatography (silica gel, hexanes / EtOAc 4: 1) to give 5- [2- (4-benzo [jisothiazol-3-ylpiperazin-1-yl] -1-chloroethyl] -1, 3 , 3-tetramethylindan-2-one (3.80 g, 85%) as a white solid: 1 H NMR (300 MHz, CDCl 3) d 7.90 (d, J = 8.1 Hz, 1 H) , 7.80 (d, J = 8.1 Hz, 1 H), 7.48 (dd, J = 8.0, 0.9 Hz, 1H), 7.38-7.22 (m, 4H) , 5.03 (dd, J = 8.1, 5.8 Hz, 1H), 3.58-3.55 (m, 4H), 3.12 (dd, J = 13.5, 8.1 Hz , 1H), 2.96 (dd, J = 13.5, 8.1 Hz, 1 H), 2.80-2.68 (m, 4H), 1.35 (s, 6H), 1, 34 (s, 6H); . EMES m / z 468 [C26H3oCIN3OS + Hf. EXAMPLE 82 5-G2- (4-BENZOGDHSOTIAZOL-3-ILPIPERAZIN-1 -IDETILM, 1.3.3- TETRAMETILINDAN-2-ONA A solution of 5- [2- (4-benzo [o] isothiazole-3-ylpiperazine] n-1-yl) -1-chloroethyl] -1,1, 3,3-tetramethylindan-2-one (2.00 g, 4.27 mmol) in toluene (120 ml) in a sealed flask was degassed by bubbling argon The solution was then treated with tri-n-butyltin hydride (1.73 ml, 6.40 mmol) and AIBN (105 mg, 0.640 mmol) and heated at 80 ° C. for 1 hour. and quenched with water, toluene was removed in vacuo and the residue was dissolved in chloroform (500 ml), the organic phase was separated, washed with water, brine, dried over Na 2 SO 4 and evaporated. chromatography (silica gel, hexanes / ethyl acetate 7: 3) to provide 5- [2- (4-benzo [o] isothiazol-3-ylpiperazin-1-yl) ethyl] -1, 1, 3,3-tetramethylindan-2 -one (1.65 g, 89%) as a white solid.The material was further purified by recrystallization. CH2Cl2 ion / hexanes giving white crystals: mp 122-1269C; 1 H NMR (300 MHz, CDCl 3) d 7.93 (d, = 8.1 Hz, 1 H), 7.82 (d, J = 8.1 Hz, 1 H), 7.47 (td, J) = 7.2, 0.9 Hz, 1 H), 7.36 (td, J = 7.2, 0.9 Hz, 1 H), 7.19 (m, 2H), 7.13 (s, 1 H), 3.63-3.60 (m, 4H), 2.94-2.70 (m, 8H), 1.34 (s, 6H), 1.33 (s, 6H); MSI m / z 434 [C 26 H 31 N 3 OS + H] +; Rf 0.25 (3: 2 hexanes / EtOAc); (AUC) > 99% by HPLC (Method B), tR = 15.04 minutes. Anal. Cale, for C26H31N3OS: C, 72.02; H, 7.21; N, 9.69. Found: C, 71, 67; H, 7.29; N, 9.45. EXAMPLE 83 5-G2- (4-BENZOG01ISOTIAZOL-3-1LPIPERAZ1N-1-IL) ETIL1-1.1.3.3-TETRAMETILINDAN-2-OL To a suspension of 5- [2- (4-benzo [o] isothiazole-3-) 1-piperazin-1-ii) ethyl] -1,1,3,3-tetramethylindan-2-one (520 mg, 1.20 mmol) in 2-propanol (70 ml) and methanol (20 ml) was added NaBH (113 mg, 3.00 mmol) at 09C. The reaction was allowed to stir at room temperature for 36 hours and was quenched with the addition of acetone. After evaporating the solvent, the residue was dissolved in chloroform (150 ml). The organic solution was washed with water, brine, dried over Na2SO4 and purified by chromatography (silica gel, hexanes / EtOAc 3: 2) to provide 5- [2- (4-benzo [o] isothiazol-3-ylpiperazine] -1-yl) etl] -1, 1, 3,3-tetramethylindan-2-ol (420 mg, 81%) as a white solid: mp 47-499C; 1 H NMR (300 MHz, CDCl 3) d 7.92 (d, J = 8.2 Hz, 1 H), 7.82 (d, J = 8.2 Hz, 1 H), 7.47 (td, J = 7.1, 0.8 Hz, 1 H), 7.36 (td, J = 7.1, 0.8 Hz, 1 H), 7.12-7.08 (m, 2H), 7 , 02 (s, 1H), 3.84 (d, J = 8.3 Hz, 1 H), 3.63-3.60 (m, 4H), 2.89-2.67 (m, 8H) , 1.65 (d, J = 8.3 Hz, 1 H), 1.37 (s, 3H), 1.36 (s, 3H), 1.19 (s, 3H), 1.18 (s) , 3H); MS APCI m / z 436 [C 26 H 33 N 3 OS + H] +; Rf 0.22 (hexanes / EtOAc 3: 2); 98.0% by HPLC (Method B) (AUC), tR = 14.16 minutes. Anal. Cale, for C26H33N3OS. 0.25H2O: C, 70.95; H, 7.67; N, 9.55. Found: C, 71, 22; H, 7.74; N, 9.37. EXAMPLE 84 5-r2- (4-BENZ? R0llSOTIAZOL-3-ILPIPERAZIN-1 -ID-1-METHYLAMINOETIL1-1.1.3.3-TETRAMETILINDAN-2-ONA A mixture of 5- [2- (4-benzo [or isothiazole-] 3-ylpiperazin-1-yl) -1- chloroethyl] -1, 1, 3,3-tetramethylindan-2-one (500 mg, 1.07 mmol) and methylamine (2 M in THF, 100 ml) in a vessel The mixture was heated at 100 ° C for 5 hours, after cooling, the solvent was evaporated under reduced pressure, the residue was dissolved in a mixture of ethyl acetate (150 ml) and saturated NaHCO 3 (20 ml). washed with brine, dried over Na2SO4 and evaporated to yield 5- [2- (4-benzo [o] isothiazol-3-ylpiperazin-1-yl) -1-methylaminoethyl] -1, 1, 3,3-tetramethylindan -2-one (500 mg, 100%) as a crude product: H-NMR (300 MHz, CDCl 3) d 7.91 (d, J = 8.1 Hz, 1H), 7.81 (d, J = 8.1 Hz, 1H), 7.47 (dt, J = 7.0, 1.0 Hz, 1H), 7.38 (dt, J = 7.0, 1.0 Hz, 1 H) , 7.28-7.21 (m, 3H), 3.74 (dd, J = 11, 3.3 Hz, 1 H), 3.64-3.54 (m, 4H), 2.88- 2.87 (m, 2H), 2.66-2.62 (m, 3H), 2.5 2-2.47 (m, 1 H), 2.37 (s, 3H), 1.34 (s, 12H). EXAMPLE 85 5-r2- (4-BENZ? R0llSOTIAZOL-3-ILPIPERAZIN-1-IL) -1-METHYLAMINOETILM, 1.3.3-TETRAMETILINDAN-2-OL To a suspension of 5- [2- (4-benzo [c] /] Sothiazol-3-ylpiperazin-1-yl) -1-methylaminoethyl] -1, 1, 3,3-tetramethyldan-2-one (500 mg, 1.08 mmol) in 2-propanol (40 ml) and methanol (40 ml) was added NaBH4 (102 mg, 2.70 mmol) at 0SC. The reaction was allowed to stir at room temperature for 36 hours and was quenched with the addition of acetone. After evaporating the solvent, the residue was dissolved in ethyl acetate (150 ml). The organic solution was washed with water, brine, dried over Na 2 SO 4 and purified by chromatography (silica gel, CH 2 Cl 2 / MeOH / Et 3 N 100: 5: 0.5) to give 5- [2- (4-benzo [c] Lysothiazol-3-ylpiperazin-1-yl) -1-methylaminoethyl] -1, 1, 3,3-tetramethylindan-2-ol (300 mg) as a white solid: mp 96-1019C; 1 H NMR (300 MHz, CDCl 3) d 7.91 (d, J = 8.1 Hz, 1 H), 7.82 (d, J = 8.1 Hz, 1H), 7.47 (td, J = 7, 1, 0.6 Hz, 1 H), 7.36 (t, J = 7.3 Hz, 1 H), 7.21-7.17 (m, 2H), 7.12 (d, J = 7 , 6 Hz, 1 H), 3.85 (d, J = 5.1 Hz, 1 H), 3.69 (dd, J = 10.9, 3.2 Hz, 4H), 3.59-3 , 53 (m, 4H), 2.90-2.84 (m, 2H), 2.66-2.42 (m, 5H), 2.34 (s, 1H), 1.69 (d, = 7.2 Hz, 1H), 1.38 (s, 3H), 1, 36 (s, 3H), 1, 19 (s, 6H); MSQ AP m / z 465 [C27H36N4OS + H] +; Rf 0 42 (chloroform / methanol 9: 1); (AUC) 97.3% by HPLG (Procedure B), tR = 13.44 minutes Anal Cale, for C27H36N4OS -0.375 H20: C, 68.79; , 7.86; N, 11, 88. Found: C, 68.99; H, 7.85; N, 11.53, EXAMPLE 86, 5-f 1 -HIPROXI-2-r4- (1 H-INDA ZOL-3-IDPIPERAZIN-1 -IDETID-1.1.3.3-TETRAMETILINPAN-2-OL To a suspension of 5-. { 2- [4- (1 H -indazol-3-yl) -piperazin-1-yl] -acetyl} -1, 1, 3,3-tetramethylindan-2-one (650 mg, 1.51 mmol) in 2-propanol (40 ml) and methanol (60 ml) was added NaBH 4 (228 mg, 6.04 mmol) to 09C. The reaction was allowed to stir at room temperature for 24 hours and was quenched with the addition of acetone. After evaporating the solvent, the residue was dissolved in ethyl acetate (200 ml). The organic solution was washed with water, brine, dried over Na 2 SO 4, evaporated. The residue was purified by chromatography (silica gel, CH2Cl2 / MeOH 20: 1) to give the 5-. { 1-hydroxy-2- [4- (1 H -indazol-3-yl) piperazin-1-yl-ethyl} -1,1,3,3-tetramethylindan-2-ol (486 mg, 74%) as a pale yellow solid: mp 104-110 ° C; 1 H NMR (300 MHz, CDCl 3) d 9.26 (s, 1 H), 7.72 (d, J = 8.1 Hz, 1H), 7.35-7.31 (m, 2H), 7 , 24-7.04 (m, 4H), 4.80 (dd, J = 9.0, 4.9 Hz, 1H), 4.07 (s, 1H), 3.84 (d, J = 7 , 0 Hz, 1H), 3.55-3.48 (m, 4H), 3.04-2.98 (m, 2H), 2.75-2.60 (m, 6H), 1.72 ( d, J = 8.2 Hz, 1 H), 1.37 (s, 3 H), 1, 36 (s, 3 H), 1, 19 (s, 3 H), 1, 18 (s, 3 H); MSI m / z 435 [C 26 H 34 N 402 + H] +; R { 0.20 (CH2Cl2 / Me0H 20: 1); 96.4% by HPLC (Method B) (AUC), t R = 12.50 minutes. Anal. Cale, for C26H34N402 • 0.25H2O: C, 71, 12; H, 7.92; N, 12.76. Found: C, 71, 18; H, 7.89; N, 12.57. EXAMPLE 87 5-r2- (4-BENZ? R / 1ISOXAZOL-3-ILPIPERAZIN-1-IL) ACETYLM.1.3.3-TETRAMETILINDAN-2-ONA A mixture of 5- (2-chloroacetyl) -1, 1, 3 , 3-tetramethylindan-2-one (9.20 g, 34.7 mmol), 3-piperazin-1-ylbenzo [o] isoxazole hydrochloride (8.33 g, 34.7 mmol), potassium carbonate (15, 8 g, 114 mmol), sodium iodide (5.17 g, 34.7 mmol) in acetonitrile (600 ml) was heated to reflux for 4 hours. The solvent was evaporated in vacuo and the residue was triturated with water (300 ml). The resulting precipitate was collected by filtration to give 5- [2- (4-Benzo [aJ, soxazol-3-ylpiperazin-1-yl) acetyl] -1, 1, 3,3-tetramethylindan-2-one (15.0 g, 100%) as a yellow solid: 1 H NMR (300 MHz, CDCl 3) d 8.00 (dd, J = 8.0, 1.6 Hz, 1 H), 7.95 (d, J = 1.3 Hz, 1 H), 7.70 (d, J = 8.0 Hz, 1 H), 7.50-7.47 (m, 2H), 7.37 (d, J = 7.9 Hz, 1 H), 7.25-7.20 (m, 1H), 3.92 (s, 2H), 3.72-3.66 (m, 4H), 2.87- 2.81 (m, 4H), 1.39 (s, 6H), 1.35 (s, 6H). EXAMPLE 88 5-G2- (4-BENZOGP1ISOXAZOL-3-ILPIPERAZIN-1-IL) -1-HYDROXYETH1-1.1.3.3-TETRAMETILINDAN-2-ONA A suspension of 5- [2- (4-benzo [o] isoxazole- 3-ylpiperazin-1-yl) -acetyl] -1,1,3,3-tetramethylindan-2-one (15.0 g, 34.7 mmol) in 2-propanol (800 mL) and methanol (800 mL) it was heated until the solution became clear. Then, the solution was cooled to 09C and treated with NaBH (1.38 g, 36.5 mmol). After stirring at 09C for 4 hours, the reaction is quenched with the addition of acetone. The solvent was removed in vacuo. The residue was dissolved in methylene chloride (800 ml), washed with water, brine, dried over Na 2 SO 4, evaporated and purified by chromatography (silica gel, hexanes / EtOAc 7: 3 to 6: 4) to give the compound 5- [2- (4-Benzo [d] isoxazol-3-ylpiperazin-1-yl) -1-hydroxyethyl] -1,3,1-tetramethylindan-2-one (12.3 g, 82%) in the form of a white solid: 1 H NMR (300 MHz, CDCl 3) d 7.70 (d, J = 8.0 Hz, 1 H), 7.51-7.46 (m, 2H), 7.33 -7.27 (m, 2H), 7.24-7.21 (m, 2H), 4.83 (dd, J = 9.8, 4.0 Hz, 1 H), 3.95 (s, 1H), 3.68-3.61 (m, 4H), 3.03-2.96 (m, 2H), 2.74-2.56 (m, 4H), 1.35 (s, 6H) , 1, 34 (s, 6H); MSI m / z 434 [C26H31N303 + H] +. EXAMPLE 89 5-G2- (4- (BENZOGP1ISOXAZOL-3-ILPIPERAZIN-1 -ILV1 -CLOROET1L1-1, 1.3.3-TETRAMETILINDAN-2-ONA To a solution of 5- [2- (4-benzo [of] isoxazole -3-ylpiperazin-1-yl) -1-hydroxyethyl] -1, 1,3,3-tetramethylindan-2-one (8.30 g, 19.2 mmol) in CH2Cl2 (400 mL) was added chloride of methanesultonyl (1.78 ml, 23.0 mmol), triethylamine (4.00 ml, 28.7 mmol) at 09 ° C. The reaction mixture was allowed to stir at room temperature for 1 hour and then quenched with water. Organic phase was separated, washed with water, brine, dried over Na 2 SO 4 and evaporated The residue was purified by chromatography (silica gel, hexanes / ethyl acetate 20: 3 to 20: 5) to give 5- [2- (4-benzo [d] isoxazol-3-ylpiperazin-1-yl) -1-chloro-eyl] -1, 1, 3,3-tetramethylindan-2-one (5.50 g, 64%) in the form of a pale yellow semisolid: 1 H NMR (300 MHz, CDCl 3) d 7.67 (d, J = 8.1 Hz, 1 H), 7.48-7.38 (m, 2H), 7.35 (d , J = 1, 7 Hz, 1 H), 7.30-7.19 (m, 4H), 5.04 (dd, J = 8.1, 5.8 Hz, 1 H), 3.58- 3 , 55 (m, 4H), 3.13 (dd, J = 13.6, 8.2 Hz, 1 H), 2.92 (dd, J = 13.6, 8.2 Hz, 1 H), 2.78-2.68 (m, 4H), 1.35 (s, 6H), 1.34 (s, 6H); MS res. M / z 452 [C26H30CIN3O2 + H] +. EXAMPLE 90 METHANOSULPHONATE OF 5-, 2- (4-BENZ? RgllSOXAZOL-3-ILPIPERAZIN-1-DETIL1-1.1.3.3-TETRAMETILINDAN-2-ONA A solution of 5- [2- (4-benzo [o] isoxazole- 3-ylpiperazin-1-yl) -1-chloroethyl] -1, 1, 3,3-tetramethylindan-2-one (4.90 g, 10.8 mmol) in toluene (150 ml) in a sealed flask was degassed bubbling N2 for 5 minutes The solution was then treated with tri-n-butyltin hydride (4.38 ml, 16.2 mmol) and AIBN (0.268 g, 1.63 mmol) and heated to 80 ° C for 1.5 minutes. The reaction was cooled and quenched with water, toluene was removed in vacuo and the residue was dissolved in methylene chloride (100 ml), the organic phase was separated, washed with water, brine, dried over Na2SO4, evaporated The residue was purified by chromatography (silica gel, hexanes / EtOAc 6: 4) to give 5- [2- (4-benzo [o]] soxazol-3-ylpiperazin-1-yl) ethyl] -1, 1, 3,3-tetramethylindan-2-one (4 , 30 g, 95%) in the form of a pale yellow solid. A solution of 5- [2- (4-Benzo [α-oxazol-3-ylpiperazin-1-yl] ethyl] -1, 1, 3,3-tetramethylindan-2-one (530 mg, 1.27 mmol) in ethyl acetate (10 ml) was treated with CH3S03H (2 M in Et20, 0.64 ml, 1.28 mmol). The reaction mixture was stirred at room temperature for 15 minutes. The precipitate was collected by filtration and dried in a vacuum oven at 55 ° C until the next morning to give 5- [2- (4-benzo [o] isoxazol-3-ylpiperazin-1-yl) ethyl methanesulfonate. ] -1, 1, 3,3-tetramethylindan-2-one (570 mg, 88%) as a white solid: mp 259-2619C; 1 H NMR (300 MHz, DMSO-d 6) d 9.94 (br s, 1 H), 8.08 (d, = 8.1 Hz, 1 H), 7.67-7.61 (m, 2H) ), 7.41-7.33 (m, 3H), 7.26 (dd, J = 7.8.1, 3 Hz, 1 H), 4.20 (d, = 12.7 Hz, 2H) , 3.73 (d, J = 11, 2 Hz, 2H), 3.49-3.33 (m, 6H), 3.11-3.05 (m, 2H), 2.35 (s, 3H) ), 1, 28 (s, 6H), 1, 26 (s, 6H); MSI m / z 418 [C26H3? N302 + H] +; Rf 0.22 (hexanes / EtOAc 3: 2); (AUC) > 99% by HPLC, t R = 14.76 minutes. Anal. Cale, for C26H3? N302. CH3S03H: C, 63.13; H, 6.87; N, 8.18. Found: C, 62.98; H, 6.89; N, 8.11. EXAMPLE 91 5-r2- (4-BENZ? R0llSOXAZOL-3-ILPIPERAZIN-1 -ID-1 -HIDROXYLETIL1- 1.1.3.3-TETRAMETILINDAN-2-OL To a suspension of 5- [2- (4-benzo [o]] isoxazol-3-ylpiperazin-1-yl) acetyl] -1, 1, 3,3-tetramethylndan-2-one (2.1 g, 4.85 mmol) in 2-propanol (100 ml) and methanol (100 ml) was added NaBH 4 (0.370 g, 9.70 mmol) .The reaction was allowed to stir at room temperature for 24 hours and was quenched with the addition of acetone.After evaporating the solvent, the residue was dissolved in methylene chloride (300 ml) The organic solution was washed with water, brine, dried over Na 2 SO 4 and evaporated to give 5- [2- (4-benzo [o] isoxazol-3-ylpiperazin-1-yl) -1 -hydroxylethyl] -1,1, 3,3-tetramethylindan-2-ol (2.00 g, 95%) as a pale yellow foam: 1 H NMR (300 MHz, CDCl 3) d 7.70 (d, = 8.1 Hz, 1H), 7.52-7.45 (m, 2H), 7.35-7.12 (m, 4H), 4.80 (dd, J = 8.5, 5.3 Hz, 1 H), 3.89-3.82 (m, 2H), 3.66-3.59 (m, 4H), 3.01-2.94 (m, 2H), 2.73-2 , 59 (m, 4H), 1, 72 (d, J = 8.2 Hz, 1 H), 1.37 (s, 3H), 1.35 (s, 3H), 1.19 (s, 3H), 1.17 (s, 3H); MSMEs m / z 436 [C 26 H 33 N 303 + H] +. EXAMPLE 92 5-r2- (4-BENZ? RPHSOXAZOL-3-ILPIPERAZIN-1-lU-1-CHLOROETIL1-1.1.3.3-TETRAMETILINDAN-2-OL To a solution of 5- [2- (4-benzo [d] isoxazol-3-ylpiperazin-1-yl) -1-hydroxyethyl] -1,1,3,3-tetramethylindan-2-ol (2.00 g, 4.59 mmsl) in CH 2 Cl 2 (80 ml) was added methanesulfonyl (0.36 ml, 4.59 mmol) and triethylamine (0.80 ml, 5.74 mmol) at 09 ° C. The reaction mixture was allowed to stir at 09 ° C. for 2 hours and then quenched with water. it was separated, washed with water, brine, dried over Na 2 SO 4 and evaporated The residue was purified by chromatography (silica gel, hexanes / EtOAc 5: 1) to give 5- [2- (4-benzo [a] isoxazole. -3-ylpiperazin-1-yl) -1-chloroethyl] -1, 1, 3,3-tetramethylndan-2-ol (600 mg, 29%) in the form of a pale yellow semisolid: 1 H NMR (300 MHz, CDCl 3) d 7.68 (d, J = 8.1 Hz, 1 H), 7.51-7.43 (m, 2H), 7.29-7.13 (m, 4H), 5, 02 (dd, J = 8.2, 5.6 Hz, 1 H), 3.84 (d, J = 8.2 Hz, 1 H), 3.59-3.55 (m, 4H), 3 , 11 (dd, J = 13.6, 8.3 Hz, 1H), 2 , 89 (dd, J = 13.6, 5.6 Hz, 1H), 2.76-2.73 (m, 4H), 1.37 (s, 3H), 1.36 (s, 3H), 1.19 (s, 3H), 1, 18 (s, 3H). EXAMPLE 93 METHANOSULPHONATE OF 5-r2- (4-BENZ? RPllSOXAZOL-3-ILPIPERAZIN-1-IDET1L1-1.1.3.3-TETRÁMETIHNDAN-2-OL A solution of 5- [2- (4-benzo [o] isoxazole-3 -ylpiperazin-1-yl) -1-chloroethyl] -1, 1, 3 (3-tetramethyldandan-2-ol (580 mg, 1.28 mmol) in toluene (50 ml) in a sealed flask was degassed by bubbling N2 for 10 minutes The solution was then treated with tri-n-butyltin hydride (0.52 ml, 1.92 mmol) and AIBN (31 mg, 0.19 mmol) and heated at 80 ° C. for 1.5 hours. The reaction was cooled and quenched with water, toluene was removed in vacuo and the residue was dissolved in methylene chloride (100 ml), the organic phase was separated, washed with water, brine, dried over Na 2 SO 4 and evaporated. The residue was purified by chromatography (silica gel, hexanes / EtOAc 6: 4) to give the free base of 5- [2- (4-benzo [o] isoxazol-3-ylpiperazin-1-yl) ethyl] - 1, 1, 3,3-tetramethylindan-2-ol (380 mg) as a white foam to a solution of 5- [2- (4-benzo [] isoxa] zol-3-ylpiperazin-1-yl) ethyl] -1, 1, 3,3-tetramethylindan-2-ol (free base, 380 mg, 0.910 mmol) in ethyl acetate (10 ml) was treated with CH3S03H (2 M in Et20, 0.45 ml, 0.90 mmol). The reaction mixture was stirred at room temperature for 20 minutes. The precipitate was collected by filtration and dried in a vacuum oven at 55 ° C until the next morning to give 5- [2- (4-benzo [o] isoxazol-3-ylpiperazin-1-yl) ethyl] -1 methanesulfonate, 1, 3,3-tetramethylindan-2-ol (400 mg, 61%) as a white solid: mp 245-2479C; 1 H NMR (300 MHz, DMSO-dβ) d 9.87 (br s, 1 H), 8.08 (d, J = 8.1 Hz, 1H), 7.65-7.60 (m, 2H) ), 7.38-7.33 (m, 1H), 7.15-7.09 (m, 3H), 5.08 (br s, 1 H), 4.19 (d, = 12.4 Hz , 2H), 3.72 (d, J = 11, 1 Hz, 2H), 3.65 (s, 1 H), 3.46-3.32 (m, 6H), 3.03-2.98 (m, 2H), 2.34 (s, 3H), 1, 27 (s, 3H), 1, 25 (s, 3H), 1, 07 (s, 3H), 1.05 (s, 3H); MS res. M / z 420 [C 26 H 33 N 302 + H] +; Rf 0.30 (hexanes / EtOAc 3: 2); (AUC) > 99% by HPLC, t R = 13.48 minutes. Anal. Cale, for C26H33N302. CH3SO3H: C, 62.89; H, 7.23; N, 8.15. Found: C, 62.57; H, 7.08; N, 8.04. EXAMPLE 94 METHANOSULPHONATE OF 5-r2- (4-BENZQr0llSOXAZOL-3-ILPIPERAZIN-1 -ID-1 -ETOXIETILM .1.3.3-TETRAMETILINDAN-2-ONA To a solution of 5- [2- (4-benzo [i? ] isoxazol-3-ylpiperazin-1-yl) -1-chloroethyl] -1, 1, 3,3-tetramethylindan-2-one (500 mg, 1.11 mmol) in ethanol (30 ml) was added palladium on carbon (50 mg, 10% Pd, 50% wet) and four drops of triethylamine The mixture was then hydrogenated at 30 psi until the next morning.The reaction mixture was filtered with a pad of Celite®. and the residue was purified by chromatography (silica gel, hexanes / EtOAc 6: 4) to provide 5- [2- (4-benzo [aj, isoxazol-3-ylpiperazin-1-yl-1-ethoxyethyl]] -1, 1, 3,3-tetramethylindan-2-one (free base, 400 mg) as a white solid.A solution of 5- [2- (4-benzo [o] isoxazol-3-ylpiperazin-1) -ii) - "I-ethoxyethyl] -1, 1, 3,3-tetramethylndan-2-one (free base, 400 mg, 0.87 mmol) in ethyl acetate (6 ml) was treated with CH3S03H ( 2 M in Et20, 0.43 ml, 0.87 mmol) The reaction mixture was stirred at room temperature for 10 minutes. The precipitate was collected by filtration and dried in a vacuum oven at 55 ° C. until the next morning to give 5- [2- (4-benzo [or isoxazol-3-ylpi] erazin-1-yl) -1-ethoxyethyl methanesulfonate. ] -1, 1, 3,3-tetramethylindan-2) na (430 mg, 66%) as a white solid: mp 219-2229C; 1 H NMR (300 MHz, CDCl 3) d 11.80 (br s, 1 H), 7.64 (d, J = 8.0 Hz, 1H), 7.59-7.50 (m, 2H), 7.37-7.25 (m, 4H), 5.24 (dd, J = 9.8, 8.5 Hz, 1 H), 4.21-3.91 (m, 5H), 3.66 (d, J = 12.5 Hz, 1 H), 3.54-3.42 (m, 2H), 3.35-3.12 (m, 4H), 2.90 (s, H), 1 , 34 (s, 6H), 1, 33 (s, 6H); EMES m / z 462 [C28H35N303 + Hf; Rf 0.32 (hexanes / EtOAc 3: 2); (AUC) of 97.2% by HPLC, tR = 15.72 minutes. Anal. Cale, for C28H35N303. CH3S03H: C, 62.45; H, 7.05; N, 7.53. Found: C, 62.29; H, 6.95; N, 7.17. PREPARATION 23 5- (3-CHLOROPROPIONIL) -1.1.3.3-TETRAMETILINDAN-2-ONA In a 250 mL round bottom flask under a N2 atmosphere, tetramethylindanone (7.00 g, 37.2 mmol), chloride was introduced. of aluminum (29.7 g, 223 mmol) and methylene chloride (90 ml). 3-Chloropropionyl chloride (5.68 ml, 59.5 mmol) was added dropwise and the reaction was heated at 40 ° C for 5 hours. After cooling, the reaction mixture was poured into ice water (150 ml) while stirring. The mixture was diluted with methylene chloride (500 ml). The organic phase was separated, washed with saturated NaHCO 3, water, brine, dried over Na 2 SO 4 and evaporated. The residue was purified by chromatography (silica gel, hexanes / ethyl acetate 93: 7 to 90:10) to give 5- (3-chloropropionyl) -1,1, 3,3-tetramethylindan-2-one (5.00 g, 48%) in the form of a yellow solid: 1 H NMR (300 MHz, CDCl 3) d 7.93-7.88 (m, 2H), 7.38 (dd, J = 7.9, 0.4 Hz, 1H), 3.95 (t, J = 6.8 Hz, 2H), 3.49 (t, J = 6.8 Hz, 2H), 1.38 (s, 3H), 1, 37 ( s, 6H); MS res. M / z 279 [C 16 H 19 Cl0 2 + H] +. EXAMPLE 95 5-G3- (4-BENZOGD11SOTIAZOL-3-ILPIPERAZIN-1 -IDPROPIONIL1-1.1.3.3-TETRAMETILINDAN-2-ONA A mixture of 5- (3-chloropropionyl) -1, 1, 3,3-tetramethylindan-2 -one (4.00 g, 14.4 mmol), 3-piperazin-1-yl-benzo [odisothiazole hydrochloride (3.81 g, 14.4 mmol), potassium carbonate (6.57 g, 47.5 g) mmol), sodium iodide (2.16 g, 14.4 mmol) in acetonitrile (250 ml) was stirred at room temperature for 24 hours, the reaction was quenched with water (120 ml) and the acetonitrile was evaporated. extracted with methylene chloride (2 x 250 ml) The combined organic extracts were washed with waterbrine, dried over Na 2 SO 4, evaporated. The residue was purified by chromatography (silica gel, hexanes / EtOAc 7: 3 to 1: 1) to provide 5- [3- (4-benzo [d] isothiazol-3-ylpiperazin-1-yl) propionyl] -1, 1, 3,3-tetramethylindan-2-one (4.60 g, 70%) as a pale yellow solid: 1 H NMR (300 MHz, CDCl 3) d 7.97-7.90 (m, 3H) , 7.82 (d, = 8.1 Hz, 1 H), 7.47 (dd, J = 7.1, 0.9 Hz, 1 H), 7.39-7.33 (m, 2H) , 3.58 (t, J = 4.8 Hz, 4H), 3.27 (t, J = 7.3 Hz, 2H), 2.97 (t, J = 7.3 Hz, 2H), 2 , 78 (t, J = 4.9 Hz, 4H), 1.38 (s, 6H), 1.37 (s, 6H); EMES m / z 462 [C27H3? N302S + H] +. PREPARATION 24 5-G3- (4-BENZOG01ISOTIAZOL-3-ILPIPERAZIN-1-IL) -1-HIDROXIPROPIL1- 1.1.3.3-TETRAMETILINDAN-2-ONA AND 5-G3- (4-BENZOGP1ISOTIAZOL-3-ILPIPERAZIN-1 -ID -1 -HIDROXIPROPIL-1.1.3.3-TETRAMETILINDAN-2-OL To a suspension of 5- [3- (4-benzo [o] isothiazol-3-ylpiperazin-1-yl) propionyl] -1, 1, 3.3 -tetramethylindan-2-one (3.30 g, 7.16 mmol) in 2-propanol (300 ml) and methanol (300 ml) was added NaBH4 (0.28 g, 7.5 mmol) at room temperature. After stirring at room temperature for 5 hours, the reaction was quenched with the addition of acetone, the solvent was removed in vacuo, the residue was dissolved in chloroform (1 L), washed with water, brine, dried over Na 2 SO, evaporated and chromatographed (silica gel, CH2Cl2 / MeOH 97: 3 to 95: 5) to give a mixture of the compounds 5- [3- (4-benzo [] isothiazol-3-ylpiperazin-1-yl) propionyl] -1, 1, 3,3-tetramethylindan-2-one, 5- [3- (4-benzo [o] isothiazol-3-ylpiperazin-1-yl) -1-hydroxypropyl] -1, 1, 3.3 -tetramethylindan-2-one and 5- [3 ( 4-benzo [o] sothiazol-3-ylpiperazin-1-yl) -1-hydroxypropyl] -1, 1, 3,3-tetramethylindan-2-ol (1.73 g, 3: 10: 4 by analysis by HPLC). 0.75 g of 5- [3- (4-benzo [o] isothiazol-3-ylpiperazin-1-yl) propionyl] -1, 1, 3,3-tetramethylindan-2-one was also recovered. EXAMPLES 96-97 5-r3- (4-BENZ? R0HSOTIAZOL-3-ILP) PERAZIN-1 -I-1-CLOROPROPIL1- 1.1.3.3-TETRAMETILINDAN-2-ONA AND 5-r3- (4-BENZ? RP11SOTIAZOL- 3- ILPIPERAZIN-1-IL) -1-CHLOROPROPIL1-1.1.3,3-TETRAMETILINDAN-2-OL The above mixture of 5- [3- (4-benzo [o] isothiazol-3-ylpiperazin-1-yl) propionyl] -1, 1, 3,3-tetramethylindan-2-one, 5- [3- (4 -benzo [ct] siathiazol-3-yl-piperazin-1-yl) -1-hydroxypropyl] -1, 1, 3,3-tetramethylindan-2-one and 5- [3 (4-benzo [o] isothiazole] 3-piperazin-1-yl) -1-hydroxypropyl] -1, 1, 3,3-tetramethylindan-2-ol (1.73 g, approximately 3.02 mmol) in CH 2 Cl 2 (60 mL) was treated with methanesulfonyl chloride (0.23 ml, 3.0 mmol) and triethylamine (0.52 ml, 3.8 mmol) at 0 ° C. The reaction mixture was allowed to stir at 09 C for 2 hours and then quenched with water. The organic phase was separated, washed with water, brine, dried over Na 2 SO 4 and evaporated. The residue was purified by chromatography (silica gel, hexanes / EtOAc 4: 1 to 3: 2) to provide the compound 5- [3- (4-benzo [or isothiazol-3-ylpperazin-1-yl] - 1-chloropropyl] -1, 1, 3,3-tetramethylindan-2-one (820 mg, 58%) and 5- [3- (4-benzo [or isothiazol-3-ylpiperazin-1-yl] -1- chloropropyl] -1, 1, 3,3-tetramethylindan-2-ol (360 mg, 25%). EXAMPLE 96 5-G3- (4-BENZOG01ISOTIAZOL-3-ILPIPERAZIN-1 -ID-1 -CLOROPROPIL1-1.1.3.3-TETRAMETILINDAN-2-ONA 1 H NMR (300 MHz, CDCl 3) d 7.90 (d, J = 8.1 Hz, 1 H), 7.82 (d, J = 8.1 Hz, 1H), 7.47 (td, J = 7.0, 1.0 Hz, 1H), 7.38-7.33 (m, 2H), 7.30-7.25 ( m, 2H), 5.10 (dd, J = 8.6, 5.8 Hz, 1 H), 3.57 (t, J = 4.9 Hz, 4H), 2.73-2.56 ( m, 8H), 2.40-2.22 (m, 2H), 1.35 (s, 6H), 1.34 (s, 6H). EXAMPLE 97 5-r3- (4-BENZ? RgllSOTIAZOL-3-ILPIPERAZIN-1-IL) -1-CHLOROPROPIL1- .1.3.3-TETRAMETILINDAN-2-OL 1 H NMR (300 MHz, CDCl 3) d 7.90 ( d, J = 8.1 Hz, 1H), 7.82 (d, J = 8.1 Hz, 1 H), 7.47 (td, J = 7.0, 1.0 Hz, 1H), 7 , 35 (td, J = 7.0, 1.0 Hz, 1 H), 7.30-7.27 (m, 1H), 7.17-7.13 (m, 2H), 5.07 ( dd, J = 8.0, 5.9 Hz, 1H), 3.84 (d, J = 7.2 Hz), 3.56 (t, J = 4.8 Hz, 4H), 2.72- 2.63 (m, 4H), 2.57 (t, J = 7.0 Hz, 2H), 2.38-2.22 (m, 2H), 1.66 (d, J = 8.3 Hz , 1H), 1.37 (s, 3H), 1.36 (s, 3H), 1.19 (s, 3H), 1.18 (s, 3H). EXAMPLE 98 METHANOSULPHONATE OF 5-r3- (4-BENZ? RflHSOTIAZOL-3-ILPIPERAZIN-1-IDPROPILM.1.3.3-TETRAMETILINDAN-2-ONA A solution of 5- [3- (4-benzo [o] isothiazole-3) -ylpiperazin-1-yl) -1-chloropropyl] -1,1,3,3-tetramethylindan-2-one (1.30 g, 2.70 mmol) in toluene (50 ml) in a sealed flask was degassed by bubbling N2 for 5 minutes, then the solution was treated with tri-n-butyltin hydride (1.10 ml, 4.00 mmol) and AIBN (66 mg, 0.40 mmol) and heated at 80 ° C. for 1 hour. The reaction was cooled and quenched with water, toluene was removed in vacuo and the residue was dissolved in methylene chloride (80 ml), the organic phase was separated, washed with water, brine, dried over Na 2 SO 4 and evaporated. The residue was purified by chromatography (silica gel, hexanes / EtOAc 6: 4) to give the free base of 5- [3- (4-benzo [o] isothiazol-3-ylpiperazin-1-yl) propyl] -1, 1, 3,3-tetramethylindan-2-one (1.13 g, 93%) in the form of a white foam, a solution of this free base 5- [3- (4-Benzo [tV] isothiazol-3-ylpiperazin-1-yl) propyl] -1, 1, 3,3-tetramethylindan-2-one (610 mg, 1.36 mmol) in ethyl acetate (10 ml) was treated with CH3S03H (2 M in Et20, 0.68 ml, 1.36 mmol). The reaction mixture was stirred at room temperature for 20 minutes, while the solution remained clear. Another portion of CH3S03H (3.00 ml) was added to the mixture, causing the onset of precipitation. Stirring was continued for 15 minutes. The precipitate was collected by filtration and dried in a vacuum oven at 55 ° C until the next morning to give 5- [3- (4-benzo [c (lysothiazol-3-ylpiperazin-li-propyl] .SS-tetramethylindan ^ methanesulfonate. -one (920 mg, 83%) as a white solid: mp 144-1479C; 1 H NMR (300 MHz, DMSO-d6) 89.67 (br s, 1H), 8.70 (br s, 2 , 2H), 8.15 (d, J = 8.2 Hz, 1H), 8.12 (d, J = 8.2 Hz, 1H), 7.63-7.58 (m, 1 H), 7.55-7.47 (m, 1 H), 7.34 (d, J = 7.8 Hz, 1H), 7.29 (s, 1 H), 7.21 (dd, J = 1, 5 Hz and 7.8 Hz, 1 H), 4.10 (d, = 10.2 Hz, 2H), 3.45-3.25 (m, 8H), 2.68 (t, J = 7, 8 Hz, 2H), 2.41 (s, 9.6H), 1, 28 (s, 6H), 1, 26 (s, 6H); EMES m / z 448 [C27H33N3OS + H] +, Rf 0 , 37 (CH2Cl2 / MeOH 40: 1); (AUC) > 99% by HPLC, t R = 15.62 minutes. Anal. Cale, for C27H33N3OS. 3.2CH3S03H: C, 48.03; H, 6.11; N, 5.56. Found: C, 48.25; H, 6.24; N, 5.42. EXAMPLE 99 METHANOSULPHONATE OF 5-r3- (4-BENZ? R0llSOTIAZOL-3-ILPIPERAZIN-1 -IDPROPIL1-1.1.3.3-TETRAMETILINDAN-2-OL Starting with 5- [3- (4-benzo [o] isot- azole- 3-ylpiperazin-1-yl) -1-chloropropyl] -1, 1, 3,3-tetramethylindan-2-ol (700 mg, 1.45 mmol) and following the procedure as described in Example 98, obtained the free base of 5- [3- (4-benzo [o] sot-azo-3-ylpiperazin-1-yl) propyl] -1, 1, 3,3-tetramethylindan-2-ol (400 mg) in the form of a white foam, a solution of this free base of 5- [3- (4-benzo [o] isot-azozol-3-ylpiperazin-1-yl) propyl] -1, 1, 3,3-tetramethylindan -2-ol (400 mg, 0.890 mmol) in ethyl acetate (10 ml) was treated with CH3S03H (2 M in Et20, 0.45 ml, 0.90 mmol) The reaction mixture was stirred at room temperature for 20 minutes The precipitate was collected by filtration and dried in a vacuum oven at 55 ° C until the next morning to give 5- [3- (4-benzo [t-isothiazol-3-ylpiperazin-1-yl] -propyl) methanesulfonate. ] -1, 1, 3,3-tetramethylindan-2-ol (475 mg, 60%) as a white solid: mp 223-2259C; 1 H NMR (300 MHz, DMSO-dβ) d 9.60 (br s, 1 H), 8.15 (d, J = 9.3 Hz, 1 H), 8.12 (d, J = 8, 7 Hz, 1H), 7.58 (m, 1H), 7.48 (dd, J = 7.3 and 7.1 Hz, 1H), 7.12-7.04 (m, 3H), 4, 10 (d, J = 9.6 Hz, 2H), 3.66-3.21 (m, 10H), 2.62 (t, J = 7.7 Hz, 2H), 2.33 (s, 3H) ), 1, 18-2.10 (m, 1 H), 1, 27 (s, 3H), 1, 25 (s, 3H), 1, 07 (s, 3H), 1, 05 (s, 3H) ); MSI m / z 450 [C27H35N3OS + H] +; Rf 0.24 (CH2Cl2 / MeOH 40: 1); (AUC) of 98.0% by HPLC, tR = 14.55 minutes. Anal. Cale, for C27H35N3OS. CH 3 SO 3 H - 0.5H 2 O: C, 60.62; H, 7.27; N, 7.57. Found: C, 60.88; H, 7.21; N, 7.31. EXAMPLE 100 5-G3- (4-BENZOGD1ISOXAZQL-3-ILPIPERAZIN-1 -ID-PROPIONILH .1, 3.3- TETRAMETILINDAN-2-ONA A mixture of 5- (3-chloropropionyl) -1, 1, 3,3-tetramethylindan -2-one (6.00 g, 21.6 mmol), 3-piperazin-1-yl-benzo [d] isoxazole hydrochloride (6.20 g, 21.9 mmol), potassium carbonate (9.84 g) 71. 2 mmol), sodium iodide (3.21 g, 21.6 mmol) in acetonitrile (400 ml) was heated to reflux for 4 hours The reaction was diluted with water (200 ml) and the acetonitrile was evaporated. The residue was extracted with ethyl acetate (2 x 250 ml) The combined organic extracts were washed with water, brine, dried over Na 2 SO, evaporated The residue was purified by chromatography (silica gel, hexanes / EtOAc 1: 1) providing 5- [3- (4-benzo [cQ] -oxazol-3-ylpiperazin-1-yl) propionyl] -1, 1, 3,3-tetramethylindan-2-one (4.00 g, 42% ) in the form of a pale yellow solid: 1 H NMR (300 MHz, CDCl 3) d 7.94 (dd, J = 8.0, 1.6 Hz, 1H), 7.90 (d, J = 1, 3 Hz, 1H), 7.70 (d, J = 8.1 Hz, 1H), 7 , 52-7.44 (m, 2H), 7.38 (d, J = 7.0 Hz, 1 H), 7.24-7.20 (m, 1 H), 3.61 (t, J) = 5.0 Hz, 4H), 3.26 (t, = 7.5 Hz, 2H), 2.94 (t, J = 7.5 Hz, 2H), 2.75 (t, J = 5, 0 Hz, 4H), 1.38 (s, 6H), 1.37 (s, 6H). EXAMPLE 101 5-G3- (4-BENZOGD11SOXAZOL-3-ILPIPERAZIN-1 -ID-1 -HIDROXIPROPIL1-1.1.3.3-TETRAMETILINDAN-2-ONA A suspension of 5- [3- (4-benzo [a] isoxazole-3 -ylpiperazin-1-yl) propionyl] -1, 1, 3,3-tetramethylindan-2-one (4.00 g, 8.98 mmol) in 2-propanol (250 ml) and methanol (250 ml) was heated While stirring until a clear solution formed, the mixture was then cooled to 09C and treated with NaBH4 (0.37 g, 9.9 mmol) After stirring at 09C for 7 hours, the reaction was quenched with the addition of acetone The solvent was removed in vacuo The residue was dissolved in methylene chloride (500 ml), washed with water, brine, dried over Na 2 SO 4, evaporated and chromatographed (silica gel, hexanes / EtOAc 2). : 3) yielding 5- [3- (4-benzo [o] isoxazol-3-ylpiperazin-1-yl) -1-hydroxypropyl] -1, 1, 3,3-tetramethylindan-2-one (3.00 g , 75%) as a white solid: 1 H NMR (300 MHz, CDCl 3) d 7.69 (d, J = 8.1 Hz, 1 H), 7.53-7.45 (m, 2H) , 7.32-7.14 (m, 4H), 6.29 ( br s, 1 H), 4.99 (dd, J = 8.6, 4.0 Hz, 1 H), 3.85-3.62 (m, 4H), 2.91-2.66 (m , 6H), 1, 99-1, 90 (m, 2H), 1, 35 (s, 6H), 1, 34 (s, 6H). EXAMPLE 102 5-G3- (4-BENZOGD1ISOXAZOL-3-ILPIPERAZIN-1-IL) -1-CHLOROPROPIL1-1.1.3.3-TETRAMETILINDAN-2-ONA A solution of 5- [3- (4-benzo [s] isoxazole- 3-ylpiperazin-1-yl) -1-hydroxypropyl] -1, 1, 3,3-tetramethylindan-2-one (3.00 g, 6.70 mmol) in CH2Cl2 (70 mL) was treated with methanesulfonyl chloride (0.67 ml, 8.7 mmol) and triethylamine (1.49 ml, 10.7 mmol) at 09C. The reaction mixture was allowed to stir at room temperature for 1 hour and then quenched with water. The organic phase was separated, washed with water, brine, dried over Na 2 SO 4 and evaporated. The residue was purified by chromatography (silica gel, hexanes / EtOAc 7: 3 to 3: 2) to provide 5- [3- (4-benzo [o] isoxazol-3-ylpiperazin-1-yl) -1-chloropropyl] -1, 1, 3,3-tetramethylindan-2-one (2.10 g, 68%) as a white foam: 1 H NMR (300 MHz, CDCl 3) d 7.69 (d, J = 8, 1 Hz, 1 H), 7.52-7.44 (m, 2H), 7.36 (dd, = 7.8, 1, 7 Hz, 1 H), 7.29-7.19 (m, 3H), 5.09 (dd, J = 8.6, 5.7 Hz, 1 H), 3.59 (t, J = 5.0 Hz, 4H), 2.70-2.63 (m, 4H), 2.61-2.55 (m, 2H), 2.38-2.21 (m, 2H), 1.35 (s, 6H), 1.34 (s, 6H); EMES m / z 466 [C27H32CIN302 EXAMPLE 103 METHANOSULPHONATE OF 5-r3- (4-BENZ? R0llSOXAZOL-3- ILPIPERAZIN-1 -IDPROPIL-1.1.3.3-TETRAMETILINDAN-2-ON A A solution of 5- [3- ( 4-Benzo [a [] isoxazol-3-ylpiperazin-1-yl) -1- chloropropyl] -1, 1, 3,3-tetramethylindan-2-one (2.10 g, 4.51 mmol) in toluene (75 ml) in a sealed flask was degassed by bubbling N2 for 5 minutes The solution was then treated with tri-n-butyltin hydride (1.82 ml, 6.77 mmol) and AIBN (112 mg, 0.680 mmol) and The reaction was cooled and quenched with water, toluene was removed in vacuo and the residue was dissolved in methylene chloride (100 ml), the organic phase was separated, washed with water brine, dried over Na 2 SO 4 and evaporated The residue was purified by chromatography (silica gel, hexanes / EtOAc 6: 4) to give the free base of 5- [3- (4-benzo [o] isoxazole- 3-ylpiperazin-1-yl) propyl] -1, 1, 3,3-tetramethylindan-2-one (1.80 g, 95%) in the form of a white semi-solid. A solution of 5- [3- (4-benzo [d] isoxazol-3-ylpiperazin-1-yl) propyl] -1, 1, 3,3-tetramethylindan-2-one (free base, 550 mg, 1, 27 mmol) in ethyl acetate (10 ml) was treated with CH3SO3H (2 M in Et20, 0.67 ml, 1.3 mmol). The reaction mixture was stirred at room temperature for 15 minutes. The precipitate was collected by filtration and dried in a vacuum oven at 55 ° C. until the next morning to provide the methanesulfonate compound of 5- [3- (4-benzo [] isoxazol-3-ylpiperazin-1-yl) propyl] -1 , 1, 3,3-tetramethylindan-2-one (540 mg, 81%) as a white solid: mp 200-203QC dec; 1 H NMR (300 MHz, DMSO-d 6) d 9.73 (br s, 1 H), 8.06 (d, J = 8.1 Hz, 1 H), 7.68-7.60 (m, 2H) ), 7.38-7.33 (m, 2H), 7.28 (s, 1 H), 7.21 (dd, J = 7.8, 1.4 Hz, 1H), 4.16 (d) , J = 12.8 Hz, 2H), 3.66 (d, J = 11.5 Hz, 2H), 3.44-3.28 (m, 6H), 2.68 (t, = 7.8) Hz, 2H), 2.35 (s, 3H), 2.35-1, 99 (m, 2H), 1.27 (s, 6H), 1.26 (s, 6H); EMES m / z 432 [CgyHssNsO;, + H] +; Rf 0.20 (Hexanes / EtOAc 3: 2); (AUC) > 99% by HPLC, tR = 15.15 minutes. Anal. Cale, for C27H33N302. . CH3S03H: C, 63.73; H, 7.07; N, 7.96. Found: C, 63.57; H, 7.20; N, 7.90. EXAMPLE 104 METHANOSULPHONATE OF 5-G3- (4-BENZOGD1ISOXAZOL-3-ILPIPERAZIN-1-IL) PROPILM.1.3,3-TETRAMETILINDAN-2-OL To a suspension of compound 5- [3- (4-benzo [o] isoxazole -3-ylpi? Erazin-1-yl) propyl] -1, 1,3,3-tetramethylindan-2-one (free base, 600 mg, 1.39 mmol) in 2-propanol (30 ml) and methanol ( 30 mL) was added NaBH4 (105 mg, 2.78 mmol) at 09C. The reaction mixture was allowed to stir at room temperature until the next morning and then quenched with the addition of acetone. The solvent was removed in vacuo. The residue was dissolved in methylene chloride (100 ml), washed with water, brine, dried over Na 2 SO, evaporated and chromatographed (silica gel, CH 2 Cl 2 / MeOH 93: 3), giving the free base of 5- [ 3- (4-benzo [c / | isoxazol-3 -? P¡perazin-1-yl) -propyl] -1,1,3,3-tetramethylindan-2-ol (510 mg, 85%) in the form of a white flexible solid. 5- [3- (4-Benzo [cd] -soxazol-3-ylpiperazin-1-yl) propyl] -1, 1, 3,3-tetramethylindan-2-ol (free base, 510 mg, 1.18 mmol) it was dissolved in ethyl acetate (10 ml) and then treated with CH3S03H (2 M in Et20, 0.62 ml, 1.22 mmol). The reaction mixture was stirred at room temperature for 10 minutes. The precipitate was collected by filtration and dried in a vacuum oven at 55 ° C until the next morning to give 5- [3- (4-benzo [d] isoxazol-3-ylpiperazin-1-yl) propyl] -1 methanesulfonate, 1,3,3-tetramethylindan-2-ol (601 mg, 95%) as a white solid: mp 240-2429C; 1 H NMR (300 MHz, DMSO-d 6) d 9.65 (br s, 1H), 8.05 (d, J = 8.1 Hz, 1H), 7.66-7.60 (m, 2H) , 7.38-7.33 (m, 1H), 7.11-7.04 (m, 3H), 5.05 (br s, 1H), 4.15 (d, J = 12.6 Hz, 2H), 3.67-3.64 (m, 3H), 3.45-3.23 (m, 6H), 2.61 (t, = 7.7 Hz, 2H), 2.33 (s, 3H), 2.05-1.91 (m, 2H), 1.26 (s, 3H), 1, 24 (s, 3H), 1.06 (s, 3H), 1.04 (s, 3H) ); MS res. M / z 434 [C27H35N302 + H] +; Rf 0.19 (EtOAc / hexanes 2: 3); (AUC) 98.8% by HPLC, t R = 13.82 minutes. Anal. Cale, for C27H35N302. CH3S03H 0.5H2O: C, 62.43; H, 7.48; N, 7.80. Found: C, 62.62; H, 7.45; N, 7.67. EXAMPLE 105 METHANOSULPHONATE OF (5-r2- (4-BENZ? RP1ISOXAZOL-3-ILPIPERAZIN-1 -IDETI tl-1.1.3.3-TETRAMETIL1NDAN-2-1DMETILAMIN A 5- [2- (4-benzoyl) was introduced into a sealed tube. [o] isothiazol-3-ylpiperazin-1-yl) ethyl] -1, 1, 3,3-tetramethylindan-2-one (500 mg, 1.15 mmol) and methylamine (2.0 M in THF, 8, 63 ml, 17.2 mmol) The mixture was cooled to 09 C and then titanium tetrachloride (2 M in CH 2 Cl 2, 4.61 ml, 9.22 mmol) was added.The mixture was diluted with toluene (15 ml) and it was heated at 150 ° C. for 2 hours.After cooling, the reaction mixture was diluted with methylene chloride (100 ml) The solid was removed by filtration through a layer of Celite.RTM .. The filtrate was concentrated to give a brown solid (670). mg, theoretical 513 mg) which was dissolved in a solution of 2-propanol (20 ml) and methanol (20 ml) The solution was then treated with NaBH 4 (284 mg, 7.50 mmol) at room temperature. The reaction mixture was allowed to stir at room temperature until the next morning and then quenched with the addition of acetone. The solvent was removed in vacuo. The residue was dissolved in methylene chloride (150 ml), washed with water, brine, dried over Na 2 SO 4, evaporated and chromatographed (silica gel, CH 2 Cl 2 / MeOH 20: 1) to give the free base. { 5- [2- (4-Benzo [o] isothiazol-3-ylpiperazin-1-yl) ethyl] -1, 1, 3,3-tetramethylindan-2-ylmethylamine (420 mg) as a semi-solid solid. This free base of. { 5- [2- (4-Benzo [c7 | sot-azo-3-ylpiperazin-1-yl] ethyl] -1, 1, 3,3-tetramethylindan-2-ylmethylamine (410 mg, 0.910 mmol) was dissolved in ethyl acetate (8 ml) and then treated with CH3S03H (2 M in Et20, 0.48 ml, 0.96 mmol). The reaction mixture was stirred at room temperature for 30 minutes. The precipitate was collected by filtration and dried in a vacuum oven at 55 ° C. until the next morning to give methane sulfonate. { 5- [2- (4-Benzo [c-isothiazol-3-ylpiperazin-1-yl] ethyl] -1, 1, 3,3-tetramethylindan-2-yichmethylamine (318 mg, 64%) as a white solid: mf 200-2039C dec; 1 H NMR (300 MHz, CDCl 3) d 7.91 (d, = 8.1 Hz, 1 H), 7.83 (d, J = 8.1 Hz, 1H), 7.48 (td, J = 7.1, 0.8 Hz, 1 H), 7.37 (td, J = 7.1, 0.8 Hz, 1H), 7.15 (dd, J = 7.8, 1.2 Hz, 1 H), 7.08 (d, J = 7.8 Hz, 1 H), 7.01 (s, 1 H), 3.68 (m, 4 H), 3.16 (s, 1 H), 3.03 (s, 3H), 2.95-2.77 (m, 12H), 1.56 (s, 3H), 1.55 (s, 3H), 1.40 (s, 3H), 1 , 39 (s, 3H); MS res. M / z 449 [C 27 H 36 N 4 S + H] +; R, 0.23 (CH2Cl2 / MeOH 20: 1); (AUC) > 99% by HPLC, t R = 10.99 minutes. Anal. Cale, for C27H36N4S - CH3SO3H. 0.25H2O: C, 61, 23; H, 7.43; N, 10.20. Found: C, 61, 25; H, 7.42; N, 10.09. EXAMPLE 106 METHANOSULPHONATE OF N- (5-r2- (4-BENZ? R0llSOTIAZOL-3-ILPIPERAZIN-1 -IDETIL1-1.1.3.3-TETRAMETILINDAN-2-ID-N-METHYLACETAMIDE To a solution of (5- [2- ( 4-benzo [o] isothiazol-3-ylpiperazin-1-yl.} Ethyl] -1,1, 3,3-tetramethylindan-2-yl.} Methylamine (free base, 900 mg, 2, 00 mmol) in methylene chloride (20 ml) was added acetic anhydride (0.75 ml, 8.0 mmol) and triethylamine (1.67 ml, 6.00 mmol) The mixture was stirred at room temperature for 5 hours and quenched with water The organic phase was separated, washed with water, brine, dried over Na 2 SO 4, evaporated and chromatographed (silica gel, CH 2 Cl 2 / MeOH 25: 1 with 0.5% Et 3 N) to provide the free base of N-. {5- [2- (4-benzo [/ jisothiazol-3-ylpiperazin-1-l) et] -1] -1, 1, 3,3-tetramethylindan-2-yl}. .N-methylacetamide (800 mg, 82%) as a pale yellow solid, N-. {5- [2- (4-Benzo [a] isothiazol-3-ylpiperazin-1-yl) ethyl] - 1, 1, 3,3-tetramethylindan-2-yl.}. -N-methylacetamide (free base, 792 mg, 1, 61 mmol) was dissolved in ethyl acetate (10 ml) and then treated with CH3S03H (2 M in Et20, 0.81 ml, 1.62 mmol). The reaction mixture was stirred at room temperature for 15 minutes. The precipitate was collected by filtration and dried in a vacuum oven at 55 ° C. until the next morning to give N-methanesulfonate. { 5- [2- (4-Benzo [o] isothiazol-3-ylpiperazin-1-yl) ethyl] -1, 1, 3,3-tetramethylindan-2-yl} -N-methylacetamide (809 mg, 87%) as a white solid: mp 248-2509C; 1 H NMR (300 MHz, CDCl 3, Note: mixture of two rotamers) d 11, 60 (br s, 1 H), 7.88-7.83 (m, 2 H), 7.53 (t, J = 7, 5 Hz, 1 H), 7.42 (t, J = 7.5 Hz, 1 H), 7.18-6.99 (m, 3H), 5.13 (s, 0.5 H), 4 , 19-3.96 (m, 4.5 H), 3.70-3.67 (m, 2H), 3.33-3.13 (m, 6H), 2.90 (s, 3H), 2.71 (s, 1, 5H), 2.67 (s, 1, 51-1), 2.22 (s, 1.5 H), 2.12 (s, 1.5 H), 1, 42 (s, 1, 5H), 1, 41 (s, 1, 5H), 1, 40 (s, 1, 5H), 1, 39 (s, 1.5H), 1, 33 (s, 1.5H) , 1, 32 (s, 1.5H), 1, 29 (s, 1, 5H), 1, 28 (s, 1, 5H); MS res. M / z 491 [C 29 H 38 N 4 OS + H] +; Rf 0.45 (CH2Cl2 / MeOH 20: 1); (AUC) > 98.1% by HPLC, tR = 14.00 minutes. Anal. Cale, for C29H38N4OS • CH3S03H: C, 61, 40; H, 7.21; N, 9.55. Found: C, 61, 28; H, 7.31; N, 9.52. EXAMPLE 107 5-r2- (4-BENZ? RP1ISOTIAZOL-3-ILPIPERAZIN-1 -IDETI 1-1.1.3.3-TETRAMETILINDAN-2-ILIDENAMINE A solution of 5- [2- (4-benzo [o] isothiazole-3-] ilpiperazin-1-yl) ethyl] -1,1,3-tetramethylindan-2-one (3.20 g, 7.66 mmol), hydroxylamine hydrochloride (1.60 g, 23.0 mmol) in pyridine (100 ml) was heated at 100 ° C. for 5 hours, then allowed to cool The solvent was removed in vacuo and the residue was partitioned between CH 2 Cl 2 (300 ml) and water (100 ml) The organic phase was separated, washed with water, brine, dried over Na2SO4, filtered and concentrated in vacuo to give the oxime (2.75 g, 80%) as a white solid: MSIs m / z 449 [C26H32N4OS + H] +. White solid (2.75 g, 6.14 mmol) was dissolved in dioxane (60 ml) The solution was treated with titanium trichloride (26.5 ml, -8.9% by weight in 30% HCl, , 4 mmol) and the reaction was allowed to stir under N2 at room temperature until the next morning.The reaction mixture was basified with NaO. H 5.8 N (75 ml), diluted with water (100 ml) and extracted with methylene chloride (300 ml once, then 2 x 100 ml). The combined organic extracts were washed with water, brine, dried over Na 2 SO 4, filtered and concentrated in vacuo. The crude residue was purified by chromatography on silica gel (EtOAc / hexanes 1: 1 to 4: 1) to provide 5- [2- (4-benzo [alisothiazol-3-ylpiperazin-1-yl] ethyl] -1 , 1, 3,3-tetramethylindan-2-ylideneamine (1.50 g, 57%) as a white foam: 1 H NMR (300 MHz, CDCl 3) d 9.40 (br s, 1 H), , 93 (d, J = 8.1 Hz, 1 H), 7.92 (d, J = 8.1 Hz, 1H), 7.50-7.45 (m, 1H), 7.39-7 , 34 (m, 1H), 7.20-7.12 (m, 2H), 7.10 (s, 1H), 3.63-3.60 (m, 4H), 2.92-2.70 (m, 8H), 1, 38 (s, 12H); MSI m / z 433 [C 26 H 32 N 4 S + H] +. EXAMPLE 108 5-r2-f4-BENZ? R0llSOTIAZOL-3-ILPIPERAZIN-1 -IL1ETIL1-1.1.3.3-TETRAMETILINDAN-2-ILAMINE To a solution of 5- [2- (4-benzo [d] isothiazol-3-ylpiperazine] -1 -yl) ethyl] -1,1, 3,3-tetramethylindan-2-ylideneamine (1.25 g, 2.89 mmol) in 2-proanol (20 ml) and methanol (20 ml) was added NaBH 4 (328 mg, 8.68 mmol) at 09C. The reaction mixture was allowed to stir at room temperature for 16 hours and then quenched with the addition of acetone. The solvent was removed in vacuo. The residue was dissolved in methylene chloride (250 ml), washed with water, brine, dried over Na 2 SO, evaporated and chromatographed (silica gel, CH 2 Cl 2 / MeOH 95: 5) to give 5- [2- ( 4-benzo [o] isothiazol-3-ylpiperazin-1-yl) ethyl] -1, 1, 3,3-tetramethylindan-2-ylamine (1.12 g, 90%) as a pale yellow semisolid: NMR of 1H (300 MHz, CDCl 3) d 7.93 (d, J = 8.1 Hz, 1 H), 7.82 (d, J = 8.1 Hz, 1H), 7.47 (td, J = 7.0, 1.0 Hz, 1H), 7.36 (td, J = 7.0, 1.0 Hz, 1H), 7.14-7.08 (m, 2H), 7.03 (s) , 1 H), 3.63-3.60 (m, 4H), 2.94-2.68 (m, 8H), 2.0-1, 0 (br s, 2H), 1.32 (s) , 3H), 1, 31 (s, 3H), 1, 11 (s, 3H) ,. 1, 10 (s, 3H); MS res. M / z 435 [C26H34N4S + H] +. EXAMPLE 109 N- (5-G2- (4-BENZOGD1ISOTIAZOL-3-ILPIPERAZIN-1 -IDETIL1-1.1, 3,3-TETRAMETILINDAN-2-IDACETAMIDE To a solution of 5- [2- (4-benzo [o] isothiazole] -3-ylpiperazin-1-yl) ethyl] -1,1,3-tetramethylindan-2-ylamine (595 mg, 1.14 mmol) in methylene chloride (20 ml) was added acetic anhydride (0.21). mi, 2.3 mmol) and triethylamine (0.63 mL, 4.5 mmol) The mixture was stirred at room temperature for 2 hours and quenched with water, the organic phase was separated, washed with water, brine, it was dried over Na 2 SO 4, evaporated and chromatographed (silica gel, CH 2 Cl 2 / MeOH 20: 1) to give N-. {5- [2- (4-benzo [] isothiazol-3-ylpiperazin-1 - il) ethyl] -1,1, 3,3-tetramethylindane-2-yl-acetamide (440 mg, 81%) as a white solid: mp 75-80 ° C; 1 H NMR (300 MHz, CDCl 3) d 8.01 (d, J = 8.1 Hz, 1H), 7.90 (d, J = 8.1 Hz, 1H), 7.58-7.53 (m, 1 H), 7.47-7.42 (m, 1 H), 7.21 -7.16 (m, 2H), 7.10 (s, 1 H), 5.63 (d, J = 10.7 Hz, 1 H), 4.50 (d, J = 10.7 Hz), 3.72-3.68 (m, 4H), 2.98-2.77 (m, 10H), 2.22 (s, 3H), 1.44 (s, 3H), 1, 43 (s, 3H), 1, 23 (s, 3H), 1.22 (s, 3H); MS res. M / z 477 [C28H36N4OS + H] +; Rf 0.44 (CH2Cl2 / MeOH 20: 1); (AUC) 96.2% by HPLC, tR = 13.47 minutes. Anal. Cale, for C28H36N4OS • 0.5H2O: C, 69.24; H, 7.68; N, 11, 54. Found: C, 68.90; H, 7.92; N, 11, 37. EXAMPLE 110 OXIMA OF 5-G2- (4-BENZOG 1ISOXAZOL-3-ILPIPERAZIN-1-IL) ETIL1-1, 1.3.3-TETRAMETILINDAN-2-ONA A solution of 5- [2- (4-benzo [d]] isoxazol-3-β-pperazin-1-yl) -1-chloroethyl] -1, 1, 3,3-tetramethylindan-2-one (2.30 g, 5.51 mmol), hydroxylamine hydrochloride ( 1.15 g, 16.5 mmol) in pyridine (80 ml) was heated at 100 ° C for 6 hours, then allowed to cool. The solvent was removed in vacuo and the residue was partitioned between CH2Cl2 (200 ml) and water (50 ml). The organic phase was separated, washed with water, brine, dried over Na 2 SO 4, filtered and concentrated in vacuo to give oxime of 5- [2- (4-benzo [o] isoxazol-3-yl? iperazin-1-yl) ethyl] -1, 1, 3,3-tetramethylindan-2-one (2.30 g, 97%) as a white solid: 1 H NMR (300 MHz, CDCl 3, note: mixture of E / Z isomers) d 7.74-7.70 (m, 2H), 7.49-7.46 (m, 2H), 7.25-7.30 (m, 3H), 3.68- 3.58 (m, 4H), 2.88-2.84 (m, 2H), 2.78-2.70 (m, 6H), 1.65 (s, 3H), 1.64 (s, 3H), 1.45 (s, 3H), 1.44 (s, 3H). EXAMPLE 111 5-r2- (4-BENZ? RD1ISOXAZOL-3-ILPIPERAZIN-1 -IDETI I-1.1, 3.3-TETRAMETILINDAN-2-ILIDENAMINE A solution of 5- [2- (4-benzo [or isoxazole-3] oxime. -ylpiperazin-1-yl) ethyl] -1, 1, 3,3-tetramethylindan-2-one (2.30 g, 5.32 mmol) in dioxane (120 ml) under N2 was treated with titanium trichloride ( Ill) (23 ml, 8.9% by weight and 30% HCl, 16 mmol) and the reaction was allowed to stir at room temperature until the next morning.The reaction mixture was basified with 5.8 N NaOH (45 mL). ml), diluted with water (60 ml) and extracted with methylene chloride (3 x 150 ml) The combined organic extracts were washed with waterbrine, dried over Na 2 SO 4, filtered and concentrated in vacuo to give 5- [2- (4-benzo [a]] -soxazol-3-ylpiperazin-1-yl) ethyl] -1, 1, 3, 3-tetramethylindan-2-ylidenamine (2.20 g, 99% crude) in the form of a tan solid. The crude 5- [2- (4-benzo [d] isoxazol-3-ylpiperazin-1-yl) ethyl] -1,1, 3,3-tetramethylndan-2-ylidenamine was used for the next step without additional purification. The analytical sample was obtained by purification of 5- [2- (4-benzo [ct] isoxazol-3-ylpiperazin-1-yl) ethyl] -1, 1, 3,3-tetramethylindan-2-ylidenamine by chromatography (gel silica, EtOAc / hexanes 4: 1 with 0.5% Et3N) in the form of a thick roasted oil: 1 H NMR (300 MHz, CDCl 3) d 9.35 (br s, 1 H), 7.71 ( d, J = 8.0 Hz, 1 H), 7.49-7.45 (m, 1 H), 7.25-7.09 (m, 4H), 3.64 (t, J = 5, 0 Hz, 4H), 2.90-2.85 (m, 2H), 2.77-2.67 (m, 6H), 1, 39 (m, 6H), 1.38 (s, 6H); MSI m / z 417 [C26H32N40 + H] +. EXAMPLE 112 5-G2- (4-BENZOGP1ISQXAZQL-3-ILP1PERAZIN-1-ILIET1L1-1.1.3,3-TETRAMETILINDAN-2-ILAMINE To a solution of 5- [2- (4-benzo [a] isoxazole-3-) 1-piperazin-1-yl) ethyl] -1,1, 3,3-tetramethylindan-2-ylidenamine (2.15 g, 5.17 mmol) in 2-proanol (45 mL) and methanol (45 mL). ml) was added NaBH4 (586 mg, 15.5 mmol) at room temperature The reaction mixture was allowed to stir at room temperature until the next morning and then quenched with the addition of acetone The solvent was removed in vacuo. The residue was dissolved in CH2Cl2 (200 ml).

The organic solution was washed with water, brine, dried over Na 2 SO 4 and evaporated. The residue was purified by chromatography (silica gel, MeOH gradient from 4 to 5% / CH 2 Cl 2) to give 5- [2- (4-benzo [d] isoxazol-3-ylpiperazin-1-yl) ethyl] -1,1, 3,3-tetramethylindan-2-ylamine (1.40 g, 65%) as a white foam: 1 H NMR (300 MHz, CDCl 3) d 7.71 (d, J = 8.0 Hz, 1 H), 7.49-7.47 (m, 2H), 7.25-7.20 (m, 1 H), 7.12-7.08 (m, 2H), 7.03 (s, 1 H), 3.65-3.62 (m, 4H), 2.94 (s, 1 H), 2.88-2.66 (m, 8H), 1.52 (br s, 2H), 1 , 32 (s, 3H), 1, 31 (s, 3H), 1, 11 (s, 3H), 1, 10 (s, 3H). EXAMPLE 113 METHANOSULPHONATE OF N-f5-r2- (4-BENZQrDllSOXAZOL-3- ILPIPERAZIN-1-IL) ETILH.1,3.3-TETRAMETILINDAN-2-IL) ACETAMIDE To a solution of 5- [2- (4-benzo [ or] isoxazol-3-ylpiperazin-1-yl) ethyl] -1, 1, 3,3-tetramethyl-indan-2-ylamine (700 mg, 1.67 mmol) in methylene chloride (20 ml) was added acetic anhydride (0.31 mL, 3.3 mmol) and triethylamine (0.93 mL, 6.7 mmol). The mixture was stirred at room temperature for 1 hour and quenched with water. The organic phase was separated, washed with water, brine, dried over Na 2 SO 4, evaporated and chromatographed [silica gel (Biotage), EtOAc in gradient from 50% to 100% / hexanes] to give the free base N-. { 5- [2- (4-Benzo [o] isoxazol-3-ylpiperazin-1-yl) ethyl] -1, 1, 3,3-tetramethyllindan-2-yl-acetamide (430 mg, 56%) in the form of a white solid. The free base of N-. { 5- [2- (4-Benzo [o] isoxazol-3-ylpiperazin-1-yl) ethyl] -1, 1, 3,3-tetramethylindan-2-yl-acetamide (430 mg, 0.93 mmol) was dissolved in ethyl acetate (6 ml) and then treated with CH3SO3H (2 M in Et20, 0.51 ml, 1.02 mmol). The reaction mixture was stirred at room temperature for 15 minutes, producing a gummy precipitate. The mixture was continued stirring for another 30 minutes. The precipitate was collected by filtration and dried in a vacuum oven at 55 ° C. until the next morning providing N- methanesultonate. { 5- [2- (4-Benzo [o] isoxazol-3-ylpiperazin-1-yl) ethyl] -1, 1, 3,3-tetramethylindan-2-yl} acetamide (400 mg, 70%) as a white solid: mp 197-2059C; 1 H NMR (300 MHz, DMSO-d 6) d 9.90 (br s, 1 H), 8.08 (d, J = 8.1 Hz, 1H), 7.65-7.60 (m, 3H) ), 7.38-7.34 (, 1 H), 7.20-7.12 (m, 3H), 4.28-4.18- (m, 3H), 3.72 (d, J = 10.9 Hz, 2H), 3.46-3.28 (m, 6H), 3.05-2.99 (m, 2H), 2.37 (s, 4.8 H), 2.00 ( s, 3H), 1, 21 (s, 3H), 1, 19 (s, 3H), 1, 09 (s, 3H), 1, 08 (s, 3H); MS res. M / z 461 [C28H36N402 + H] +; Rf 0.40 (CH2Cl2 / MeOH 20: 1); (AUC) > 99% by HPLC, t R = 12.86 minutes. Anal. Cale, for C28H36N402-1, 6CH3S03H: C, 57.87; H, 6.96; N, 9.12. Found: C, 58.01; H, 7, 11; N, 9.01. EXAMPLE 114 N-f5-r2-f4-BENZ? RD1ISOXAZOL-3-ILPIPERAZIN-1-IL) ETIL1-1.1, 3,3-TETRAMETILINPAN-2-IL1METANOSULFONAMIDE To a solution of 5- [2- (4-benzo [d ] isoxazol-3-ylpiperazin-1-yl) ethyl] -1, 1, 3,3-tetramethylindan-2-ylamine (330 mg, 0.789 mmol) in methylene chloride (8 ml) was added methanesultonyl chloride (0, 12 ml, 1.6 mmol) and triethylamine (0.44 ml, 3.2 mmol) at 09C. The mixture was stirred at room temperature for 1 hour and quenched with water. The mixture was diluted with methylene chloride (22 ml). The organic phase was separated, washed with brine, dried over Na 2 SO, evaporated and chromatographed (silica gel, EtOAc / hexanes 2: 3 to 3: 2) to give N-. { 5- [2- (4-benzo [aflisoxazol-3-ylpiperazin-1-yl] ethyl] -1, 1, 3,3-tetramethylindan-2-yl-methanesulfonamide (360 mg, 92%) as a white solid: mp 75 -809C; 1 H NMR (300 MHz, CDCl 3) d 7.71 (d, J = 8.1 Hz, 1 H), 7.49-7.46 (m, 2H), 7.25-7.19 (m, 1H), 7.13-7.09 (m, 2H), 7.02 (s, 1H), 4.61 (d, J = .10.8 Hz, 1 H), 3.70-3.61 (m, 5H), 3.12 (s, 3H), 2.88-2.66 (m, 8H), 1.41 (s, 3H), 1.40 (s, 3H), 1.17 ( s, 3H), 1, 16 (s, 3H); EMES m / z 497 [C27H36N403S + Hf; Rf 0.32 (EtOAc / hexanes 3: 2); (AUC) of 97.0% by HPLC, tR = 13.67 minutes. Anal. Cale, for C27H36N403S • 0.5H2O: C, 64.13; H, 7.38; N, 11, 08 Found: C, 64.27; H, 7.43; N, 10.86. PREPARATION 25 3-METHYL-3-PHENYLBUTYRIC ACID A 4-mouth, 12-I flask, equipped with a mechanical agitator, condenser and N2 admission, was charged via a cannula with 3-methyl-3-phenylpropylmagnesium chloride (0.5 M solution in ether) (1.6 mol, 3.2 I) and the The solution was cooled in a carbonic ice / acetone bath. An excess of carbonic ice was added in portions for 0.5 hours, forming a clear tan solution. The reaction mixture was allowed to warm to 09 C and the reaction mixture was quenched with cold aqueous HCl (200 ml of concentrated HCl was diluted to 1 L) while cooling in an ice-water bath. The transparent biphasic mixture was stirred for 1 hour. The organic phase was separated and the ether was removed with a rotovap. Aqueous NaOH (256 g of 50% NaOH diluted to 1 L) was added to the residual oil and the aqueous mixture was extracted twice with heptane. The heptane solution was re-extracted with aqueous NaOH (144 g of 50% NaOH was diluted to 1 L). The combined NaOH solutions were acidified with concentrated HCl to provide an oil that crystallized. After several minutes. The white solid was collected and dried in the air until the next morning. The crude acid was dissolved in EtOAc and the solution was washed with brine, dried (Na 2 SO 4) and the solvent was removed with a rotovap. The residual oil crystallized upon seeding providing 3-methyl-3-phenylbutyric acid in the form of a white solid with quantitative yield. Mp 53-549C. PREPARATION 26 3,3-DIMETILINDAN-1 -ONA A 5 L flask was charged with 3-methyl-3-phenylbutyric acid (343 g, 1.93 mol) followed by methanesulfonic acid (1.5 I). The reaction solution was slowly heated to 110 ° C for 1.25 hours. The heating mantle was turned off and the brown reaction solution was allowed to cool slowly to room temperature until the next morning. The reaction mixture was poured into 4.5 l of ice water with stirring. The aqueous mixture was extracted with heptane (2.5 L) followed by EtOAc (2 x 2 L). The combined organic solutions were washed with water (2 x 2 l), saturated NaHCO 3 (2 l), brine, then dried (Na 2 SO 4) and the solvent was removed in a rotovap to give 3,3-dimethylindan-1-one (260 g) in the form of a light brown oil. 1 H NMR (300 MHz, CDCl 3) d 7.7 (d, 1 H), 7.59 (t, 1 H), 7.45. (d, 1H), 7.30 (t, 1H), 2.59 (s, 2H), 1, 4 (s, 6H). PREPARATION 27 3,3-DIMETILINDAN-1 -OL To a 3 I flask was added a solution of NaOH (4.0 g of 50% in 225 ml of water) followed by NaBH 4 (0.444 mol, 16.8 g) and the reaction mixture was cooled to ~ 49C. A solution of 3,3-dimethylindan-1-one (129 g, 0.81 mol) in 500 ml of EtOH was added for 1 hour while the temperature was maintained at <59C. When the addition was complete, the reaction mixture was stirred 1 hour at < 59C, then allowed to warm to room temperature (1-2 ml of 50% NaOH were added periodically during the course of the reaction to maintain a pH> 9). After 2 hours, the TLC and EMCL showed that the reaction was complete. The reaction mixture was poured into 1.5 I of ice water and the aqueous mixture was extracted with EtOAc (3 x 600 mL). The organic solution was washed with water (2 x 1 L), brine, then dried (Na 2 SO 4) and the solvent was evaporated to give 3,3-dimethylindan-1-ol (127 g) as a yellowish brown oil. pale. 1 H NMR (300 MHz, CDCl 3) d 7.35 (d, 1 H), 7.1-7.30 (m, 3 H), 5.15-5.25 (m, 1 H), 2.30 (dd, 1 H), 1, 9 (bs, 1 H), 1, 79 (dd, 1 H), 1, 4 (s, 3H), 1, 2 (s, 3H). PREPARATION 28 1.1-DIMETHYL-1H-INDENOUS In a Kugelrohr distillation apparatus, a mixture of 3,3-dimethylindan-1-ol (63.2 g, 0.39 mol) and KHS04 (5.3 g, 0.039 mol) slowly at an oven temperature of 95-100 ° C, with vacuum from a Teflon vacuum pump (the receiving flask was cooled in a carbonic ice / acetone bath). Dehydration started at ~ 70QC. When the dehydration was complete, the distillate was warmed to room temperature, diluted with dichloromethane and water and separated. The organic solution was dried (Na2S04) and the solvent was slowly evaporated at ~409C followed by an additional hour at ~509C affording 1,1-dimethyl-1H-indene (53.2g) as a pale slightly yellow liquid. 1 H NMR (300 MHz, CDCl 3) d 7.25-7.35 (m, 2H), 7.15-7.25 (m, 2H), 6.6 (d, 1H), 6.35 (d , 1H), 1.30 (s, 6H). PREPARATION 29 1.1 -DIMETHYLLIN-2-ON A A 5 I flask was charged with 88% formic acid (385 ml) and 35% hydrogen peroxide (66 ml, 0.753 mol, 1.37 equiv.) And the mixture it was heated to 50SC. 1,1-Dimethyl-1H-indene (79.2 g, 0.55 mol) was added over 35 minutes while the temperature was maintained at 50-539C. When the addition was complete, the reddish orange reaction solution was heated to 55 ° C for 7 hours, then allowed to stand for a weekend. Solid NaHS03 (21.1 g, 0.202 mol, 0.37 equiv.) Was added and the reaction solution was concentrated to -1/3 of the volume. The concentrated reaction mixture was added with hot aqueous H 2 SO 4 (3 I of 7% by volume) and the mixture was steam distilled until 2.25 I of distillate was collected. The distillate was extracted with dichloromethane and the organic solution was washed with saturated NaHCO 3, brine, dried (Na 2 SO) and. The solvent was evaporated to yield 1,1-dimethylindan-2-one (72.1 g) as an orange liquid. This material was distilled through a short path distillation head providing 71.6 g of 1,1-dimethylindan-2-one as a pale yellowish orange liquid. 1 H NMR (400 MHz, CHLOROFORM-D) d ppm 1.31 (s, 6H), 3.58 (s, 2H), 7.24 (m, 2H), 7.29 (m, 2H). PREPARATION 30 OXYMES OF 1.1-DIMETILINDAN-2-ONA A solution of 1,1-dimethylindan-2-one (3.00 g, 18.7 mmol) and hydroxylamine hydrochloride (2.60 g, 37.5 mmol) in pyridine (50 ml) was heated at 80 ° C. for 6 hours, then allowed to cool. The solvent was removed in vacuo and the residue was partitioned between CH2Cl2 (200 ml) and water (50 ml). The organic phase was separated, washed with water, brine, dried over Na 2 SO 4, filtered and concentrated in vacuo to give a yellow oil which coevaporated with toluene and then chloroform to give 1, 1-dimethylindan-2-one oxime ( 3.20 g, 98%) as a yellow solid: 1 H NMR (300 MHz, CDCl 3) d 8.60 (br s, 1 H), 7.28-7.21 (m, 4H), 3 , 88 (s, 2H), 1, 47 (s, 6H); MSI m / z 176 [CuH13NO + H] +. PREPARATION 31 N- (1,1-Dimethylteran-2-IDACETAMIDE) To a solution of 1,1-dimethylindan-2-one oxime (10.0 g, 57.0 mmol) in ethanol (120 ml) was added Raney nickel (11 ml). , 0 g, 50% in H20) which had previously been washed with ethanol (4 x 15 ml) The mixture was then hydrogenated at 40 psi until the next morning.The reaction mixture was filtered with a pad of Celite® and the The residue was dissolved in CH 2 Cl 2 (220 ml) and the solution was dried over Na 2 SO 4, concentrated to give the amine (8.00 g, 87%, crude) as a brown liquid. above (8.00 g, 49.7 mmol) in methylene chloride (150 ml) was added acetic anhydride (12.0 ml, 127 mmol) and triethylamine (30.0 ml, 216 mmol) and the mixture was stirred at The reaction mixture was diluted with CH2Cl2 (150 ml), washed with water, brine, dried over Na2SO4 and evaporated, the residue was purified by chromatography (gel-free). lice, EtOAc gradient from 50 to 60% / hexanes) to give N- (1,1-dimethylindan-2-yl) acetamide as a brown oil (5.50 g, 55%): 1 H NMR (300 MHz , CDCl 3) d 7.25-7.13 (m, 4H), 5.55 (d, J = 7.6 Hz, 1H), 4.52 (m, 1 H), 3.29 (dd, J = 7.2, 7.0 Hz, 1 H), 2.67 (dd, J = 7.0, 7.0 Hz, 1 H), 2.02 (s, 3H), 1.31 (s, 3H), 1, 14 (s, 3H); MS res. M / z 204 [C13H17NO + H] +. PREPARATION 32 N-r5- (2-Chloroacetyl) -1.1-DIMETHYLINDAN-2-IL1ACETAMIDE AND N-F6- (2- CHLOROACEHYL-1,1-DIMETHYLINDAN-2-IL1ACETAMIDE) In a 250 ml round bottom flask under N2 introduced N- (1,1-dimethylindan-2-yl) acetamide (5.30 g, 26.0 mmol), aluminum chloride (20.8 g, 156 mmol) and methylene chloride (80 mL). dropwise chloroacetyl chloride (3.31 ml, 41.6 mmol) and the reaction was heated at 40 ° C. for 5 hours.After cooling, the reaction mixture was poured into ice water (300 ml) while stirring. The mixture was extracted with methylene chloride (2 x 200 ml) The combined organic extracts were washed with saturated NaHCOß, water, brine, dried over Na 2 SO and evaporated The residue was purified by chromatography (silica gel, gradient MeOH from 2 to 3% / CH2Cl2) providing an inseparable mixture of the regioisomers N- [5- (2-chloroacetyl) -1, 1-dimethylindan-2-yl] acetamide and N- [6- (2-chloroacetyl) - 1, 1-dimethylindan- 2-irjacetamide (5.15 g, 71%) as a pale yellow solid: 1 H NMR (300 MHz, CDCl 3) d 7.84-7.75 (m, 2 H), 7.32-7.24 (m, 1 H), 5.56 (d, J = 7.0 Hz, 1 H), 4.69 (s, 1 H), 4.67 (s, 1 H), 4.63-4.55 (m, 1 H), 3.37-3.29 (m, 1H), 2.75 (d, J = 7.6 Hz, 0.5H), 2.70 (d, J = 7.6 Hz , 0.5H), 2.04 (s, 3H), 1.36 (s, 1.5 H), 1.35 (s, 1.5 H), 1.17 (s, 1.5 H) , 1.16 (s, 1.5 H); . EMES m / z 280 [C? 5H? 8CIN02 + H; HPLC tR = 15.3 minutes, tR- = 15.5 minutes. PREPARATION 33 N-r5-. { 2-CHLOROETHYL) -1,1-DIMETHLINDAN-2-IL1ACETAMIDE AND N-f6- (2-CHLOROETHYL) -1,1-DIMETHYLINDAN-2-IL1ACETAMIDE In a sealed tube of 100 ml, the N- [5- (2-chloroacetyl) -1, 1-dimethylindan-2-yl] acetamide and N- [6- (2-chloroacetyl) -1,1-dimethylindan-2-yl] acetamide (3.90 g, 14 , 0 mmol), boron trifluoride diethyl etherate (10.6 ml, 83.8 mmol) and triethylsilane (13.5 ml, 83.8 mmol). The resulting mixture was introduced into an oil bath previously heated to 80 ° C for 2 hours. After cooling, the reaction was quenched by the addition of ice water (50 ml) and the mixture was extracted with CH2Cl2 (2 x 200 ml). The combined extracts were washed with saturated NaHCO 3, water, brine, dried over Na 2 SO 4 and evaporated. The residue was purified by chromatography (silica gel, 2.5% MeOH / CH2Cl2) and dried in a vacuum oven at 40 ° C to provide a mixture of inseparable regioisomers N- [5- (2-chloroethyl) -1, 1 -dimethylindan-2-yl] acetamide and N- [6- (2-chloroethyl) -1,1 -dimethylindan-2-yl] acetamide (3.30 g, 89%) in the form of a thick oil that solidified upon standing 1 H NMR (300 MHz, CDCl 3) d 7.15-6.99 (m, 3H), 5.56 (d, J = 8.8 Hz, 1H), 4.57-4.48 (m, 1 H), 3.73-3.68 (m, 2H), 3.30-3.22 (m, 1 H), 3.08-3.01 (m, 2H), 2.68-2, 59 (m, 1 H), 2.02 (s, 3H), 1, 304 (s, 1.5 H), 1, 300 (s, 1, 5H), 1, 14 (s, 1.5 H) ), 1, 13 (s, 1, 5 H); MS res. M / z 266 [C15H20CINO + H] +. EXAMPLES 115-116 N- (5-G2- (4-BENZOGPHSOTIAZOL-3-ILPIPERAZIN-1-ILIETIL1-1.1-DIMETYLINDAN-2-IDACETAMIDE AND N-. {6-G2- (4-BENZOG01ISOTIAZOL-3-ILPIPERAZIN- 1 -IDETILM. 1 -DIMETILINDAN-2-IDACETAMIDE A mixture of the compound N- [5- (2-chloroethyl) -1,1-dimethylindan-2-yl] -acetamide and N- [6- (2-chloroethyl) - 1, 1-dimethylindan-2-yl-acetamide (1.63 g, 6.15 mmol), 3-piperazin-1-yl-benzo [or -thiazole (1.96 g, 7.69 mmol), potassium carbonate hydrochloride (2.55 g, 18.4 mmol), sodium iodide (1.02 g, 6.76 mmol) in acetonitrile (120 mL) was stirred under reflux for 60 hours.After removing the solvent, the residue was fractionated between CH 2 Cl 2 / H 2 O (200 ml / 50 ml) The organic phase was separated and the aqueous phase was extracted with CH 2 Cl 2 (60 ml) The combined organic extracts were washed with water, brine, dried over Na 2 SO and evaporated. it was purified by chromatography (silica gel, MeOH gradient from 1 to 2% / EtOAc) to give two regioisomers N-. {5- [2- (4-be nzo [djisothiazol-3-ylpiperazin-1-yl) ethyl] -1,1-dimethylindan-2-yl} acetamide (655 mg) and N-. { 6- [2- (4-benzo [o] isothiazol-3-ylpiperazin-1-yl) ethyl] -1,1-dimethyl-2-yl} Acetamida (440 mg). EXAMPLE 115 N-. { 5-G2- (4-BENZOGP1ISOTIAZOL-3-ILPIPERAZIN-1 -IDETILM, 1-DIMETYLINDAN-2-ILYACETAMIDE (655 mg, 24%) as a pale yellow solid: mp 58-68eC; 1 H NMR (300 MHz , CDCl 3) d 7.92 (d, J = 8.1 Hz, 1 H), 7.82 (d, J = 8.1 Hz, 1H), 7.47 (td, J = 7.0, 0 , 9 Hz, 1 H), 7.36 (td, J = 8.0, 1.0 Hz, 1 H), 7.10-7.05 (m, 3H), 5.53 (d, J = 9.5 Hz, 1 H), 4.57-4.49 (m, 1 H), 3.61 (t, J = 4.8 Hz, 4H), 3.27 (dd, J = 7.3) , 7.2 Hz, 1 H), 2.87-2.61 (m, 9H), 2.02 (s, 3H), 1.30 (s, 3H), 1, 14 (s, 3H); EMES m / z 449 [C26H32N4OS + H] +, Rf 0.25 (CH2Cl2 / MeOH 40: 1); (AUC) 98.1% by HPLC, tR = 12.87 minutes Anal Cale, for C26H32N4OS - 0.5H2O: C, 68.24; H, 7.27; N, 12.24, Found: C, 68.12, H, 7.37, N, 12.13, EXAMPLE 116 N- (6-) r2-f4-BENZ? r £) 1-ITISTYAZOL-3-ILPIPERAZIN-1-IL) ETIL1-1,1-DIMETYLINDAN-2-IDACETAMIDE (440 mg, 16%) as a pale yellow solid: mp 62-72eC; 1 H NMR (300 MHz, CDCl 3) d 7.92 (d, = 8.1 Hz, 1 H), 7.82 (d, J = 8.1 Hz, 1 H), 7.47 (td, J = 7.0, 1.0 Hz, 1 H), 7.36 (td, J = 8.0, 1.0 Hz, 1 H), 7.13 (d, J = 7.6 Hz, 1 H ), 7.05 (d, J = 7.6 Hz, 1 H), 7.01 (s, 1 H), 5.53 (d, J = 9.5 Hz, 1 H), 4.57- 4.47 (m, 1 H), 3.61 (t, J = 4.8 Hz, 4H), 3.26 (dd, J = 7.2, 7.2 Hz, 1 H), 2.89 -2.59 (m, 9H), 2.02 (s, 3H), 1, 31 (s, 3H), 1.15 (s, 3H); MS res. M / z 449 [C 26 H 32 N 4 OS + H] +; Rf 0.29 (CH2Cl2 / MeOH 40: 1); (AUC) 96.1% by HPLC, tR = 12.63 minutes. Anal. Cale, for C26H32N4OS • 0.5H2O: C, 68.24; H, 7.27; N, 12.24. Found: C, 68.11; H, 7.50; N, 11, 96. EXAMPLES 115-116 AC N-f5-r2- (4-BENZ? RP1ISOTIAZOL-3-ILPIPERAZIN-1 -IDETIL1-1.1-DIMETHYLNDAN-2-IDACETAMIDE AND N-! 6-r2- (4-BENZ? R? 7llSOTIAZOL- 3-ILPIPERAZIN-1 -IL> ET1L1-1.1 -DIMETlLINDAN-2-lDACETAMlDA (RACEMATOS Y ENANTIÓMEROS (+ > Y (-)) A suspension of piperazinylbencisothiazole hydrochloride (16.50 g, 75.3 mmol), amidoindane as a mixture of regioisomers (10.00 g, 37.63 mmol) and Na2CO3 (5.98 g, 56.4 mmol) in water (180 mL) were divided equally into 6 microwave reactor vessels were heated at 1759C for 30 minutes with microwave intervention. Upon cooling, MS indicated only the desired product without the initial chloroethylamidoindane. The reactions were diluted with ethyl acetate and water and then combined. The phases were separated and the organic phases were washed with water (100 ml), dried (MgSO 4) and concentrated to a viscous residue. The regioisomers were separated by chromatography (30% ethyl acetate / Hexanes) and identified by 2D-NOE NMR, then each stereoisomer was separated using chiral HPLC from a portion of each racemate and finally isolated in the form of its HCl salt. The total conversion of the reaction was 95% based on the desired products recovered. EXAMPLE 115 TO N-. { 5-r2-f4-BENZ? RylylSOTIAZOL-3-ILPIPERAZIN-1-IL) ETIL1-1,1-DIMETYLINDAN-2-IL1ACETAMIDE 1 H NMR (400 MHz, DMSO-D6) d ppm 0.94 (s, 3H), 1, 16 (s, 3H), 1, 84 (s, 3H), 2.56 (m, 2H), 2.68 (q, J = 13.35 Hz, 7H), 2.95 ( dd, J = 15.63, 7.62 Hz, 1 H), 3.43 (s, 4H), 4.24 (q, J = 8.60 Hz, 1 H), 7.02 (s, 3H) ), 7.40 (t, J = 7.62 Hz, 1 H), 7.52 (t, J = 7.52 Hz, 1 H), 7.95 (d, J = 8.99 Hz, 1H ), 8.01 (dd, J = 8.21, 3.52 Hz, 2H), chiral HPLC: two enantiomers, retention time (tr) 9.78 and 19.73 minutes, ChiralCel OJ (250 x 4, 6 mm), hexane / EtOH 80:20; EMCL: Phenomenex Develosil Combi RP3 column 50 x 4.6 mm, 459C, H20 / MeCN 90-2% by weight / 0.1% HC02H for 3.5 minutes, maintaining 0.5 minutes, total test time 4.0 minutes Results: 100% purity at 254 nm, M + = 449, t.r. = 2.68 minutes. EXAMPLE 115 B (+) - N-f5-r2- (4-BENZ? RP1ISOTIAZOL-3-ILPIPERAZIN-1-IL) ETIL1-1, 1-DlMETLLINDAN-2-IDACETAMIDE 1 H NMR (400 MHz, DMSO-D6) d ppm 0.94 (s, 3H), 1.16 (s, 3H), 1.82 (s, 3H), 2.69 (dd, J = 15.75, 8.91 Hz, 1 H), 3.00 (m, J = 12.74, 12.74, 8.70, 6.23, 6.23 Hz, 3H), 3.30 (m, 4H), 3.49 (t, J = 11) , 96 Hz, 3H), 3.62 (d, J = 11, 23 Hz, 2H), 4.04 (d, J = 13.43 Hz, 2H), 4.25 (q, J = 8.79 Hz, 1 H), 7.07 (m, J = 7.93, 5.55, 4.36, 4.36 Hz, 3H), 7.42 (t, J = 7.32 Hz, 1H), 7.55 (t, J = 7.32 Hz, 1 H), 7.88 (d, J = 8.79 Hz, 1H), 8.06 (d, J = 8.06 Hz, 1 H), 8.10 (d, J = 8.06 Hz, 1H), 11.37 (s, 1 H), chiral HPLC: purity 100%, tr 9.66 minutes, ChiralCel OJ (250 x 4.6 mm), Hexane / EtOH 80:20; EMCL: Phenomenex Develosil Combi RP3 column 50 x 4.6 mm, 459C, H20 / MeCN 90-2% by weight / 0.1% HC02H for 3.5 minutes, maintaining 0.5 minutes, total test time 4.0 minutes Results: 100% purity at 254 nm, M + = 449, t.r. = 2.69 minutes; [a] 25/589 = +7.57. EXAMPLE 115 C (-) - N-f5-r2- (4-BENZ? RD1ISOTIAZOL-3-ILPIPERAZIN-1-IL) ETIL1-1.1-DIMETYLINDAN-2-IDACETAMIDE 1H NMR (400 MHz, DMSO-D6) d ppm 0.94 (s, 3H), 1, 16 (s, 3H), 1, 82 (s, 3H), 2.68 (dd, J = 15.87, 9.03 Hz, 1 H), 2, 99 (m, 3H), 3.30 (m, 4H), 3.47 (t, J = 12.09 Hz, 2H), 3.62 (d, J = 11, 47 Hz, 2H), 4, 05 (d, J = 13.67 Hz, 2H), 4.25 (q, J = 8.79 Hz, 1 H), 7.07 (d, = 7.87 Hz, 1 H), 7.09 (s, 1 H, NOE with m, 2.99 ppm, 3H and with m, 3.30 ppm, 4H), 7.11 (d, J = 7.11 Hz, 1 H, NOE with s, 0, 94 ppm, 3H and with s, 1, 16 ppm, 3H), 7.42 (tr J = 7.20 Hz, 1 H), 7.55 (t, J = 7.20 Hz, 1 H), 7 , 88 (d, J = 9.03 Hz, 1 H), 8.06 (d, J = 8.06 Hz, 1 H), 8.10 (d, J = 8.30 Hz, 1 H), 11, 22 (5.1 H), chiral HPLC: purity of 100%, tr 19.78 minutes, ChiralCel OJ (250 x 4.6 mm), Hexane / EtOH 80:20; EMCL: Phenomenex Develosil Combi RP3 column 50 x 4.6 mm, 459C, H20 / MeCN 90-2% by weight / 0.1% HC02H for 3.5 minutes, maintaining 0.5 minutes, total test time 4.0 minutes Results: 100% purity at 254 nm, M + = 449, t.r. = 2.69 minutes; [a] 25/589 = -9.04. EXAMPLE 116A Nf 6-r 2 - (4-BENZ? RffllSOTIAZOL-3-ILPlPERAZIN-1 -IDETILM, 1-DIMETHYLINDAN-2-ILIACETAMIDE 1 H NMR (400 MHz, DMSO-D6) d ppm 0.95 (s, 3H) , 1, 17 (s, 3H), 1, 84 (s, 3H), 2.56 (m, 2H), 2.69 (m, 7H), 2.94 (dd, J = 15.43, 8 , 01 Hz, 1 H), 3.42 (s, 4H), 4.25 (q, J = 8.66 Hz, 1 H), 6.98 (d, J = 7.46 Hz, 1H), 7.00 (s, 1 H, NOE with 1.17 ppm, s, 3H), 7.05 (d, J = 7.43 Hz, 1 H, NOE with 2.69 ppm, m, 7H), 7 , 40 (t, J = 7.72 Hz, 1 H), 7.52 (m, 1 H), 7.93 (d, J = 9.18 Hz, 1 H), 8.01 (d, J) = 8.21 Hz, 2H), chiral HPLC: two enantiomers tr 7.28 and 15.51 minutes, Chiralcel OJ (250 x 4.6 mm), Hexane / EtOH 80:20, EMCL: column Phenomenex Develosil Combi RP3 50 x 4.6 mm, 459C, 90-2% H20 / MeCN weight / 0.1% HC02H for 3.5 minutes, maintaining 0.5 minutes, total test time 4.0 minutes. 100% at 254 nm, M + = 449, tr = 2.64 minutes EXAMPLE 116B Í -) - N- (6-G2-Í4-BENZOGD1ISOTIAZOL-3-ILPIPERAZIN-1 -IDETIL1-1, 1-DIMETILINDAN-2 -ILTACETAMIDE 1 H NMR (400 MHz, DM SO-D6) d ppm 0.96 (s, 3H), 1.18 (s, 3H), 1.82 (s, 3H), 2.66 (dd, J = 15.75, 8.91 Hz, 1 H), 2.95 (dd, J = 15.75, 7.69 Hz, 1 H), 3.03 (dd, J = 10.50, 6.35 Hz, 2H), 3.33 (m , 4H), 3.46 (t, J = 13.06 Hz, 3H), 3.63 (d, J = 11, 72 Hz, 2H), 4.06 (d, J = 13.43 Hz, 2H ), 4.25 (dd, J = 16.80, 8.80 Hz, 1 H), 7.02 (dd, J = 11, 84, 4.27 Hz, 2H), 7.11 (d, J) = 7.57 Hz, 1 H), 7.43 (t, J = 7.20 Hz, 1 H), 7.55 (m, J = 5.55, 5.55, 4.03, 0.98 Hz, 1 H), 7.87 (d, J = 9.03 Hz, 1 H), 8.08 (dd, J = 13.43, 8.06 Hz, 2H), 11.05 (s, 1 H), Chiral HPLC: 100% purity, tr 7.28 minutes, ChiralCel OJ (250 x 4.6 mm), Hexane / EtOH 80:20; EMCL: Phenomenex Develosil Combi RP3 column 50 x 4.6 mm, 459C, H20 / MeCN 90-2% by weight / 0.1% HC02H for 3.5 minutes, maintaining 0.5 minutes, total test time 4.0 minutes Results: 100% purity at 254 nm, M + = 449, t.r. = 2.69 minutes; [a] 25/589 = +34.40 EXAMPLE 116C (-) - N-f6-r2- (4-BENZ? r0llSOTIAZOL-3-ILPIPERAZIN-1-IL) ETIL1-1,1-DIMETYLINDAN-2-IDACETAMIDE NMR of 1H (400 MHz, DMSO-D6) d ppm 0.96 (s, 3H), 1.18 (s, 3H), 1.82 (s, 3H), 2.66 (dd, = 15.87, 9.03 Hz, 1H), 2.95 (dd, J = 15.87, 7.57 Hz, 1H), 3.03 (dd, J = 10.74, 6.59 Hz, 2H), 3, 31 (m, J = 18.71, 10.50, 9.74, 8.42 Hz, 4H), 3.47 (t, J = 11, 96 Hz, 2H), 3.61 (s, 2H) , 4.05 (d, = .1.3.67 Hz, 2H), 4.25 (m, 1H), 7.01 (dd, J = 7.57, 1, 46 Hz, 1 H), 7.04 (s, 1H), 7.11 (d, J = 7.57 Hz, 1H), 7.43 (m, 1H), 7.55 (t, = 7.20 Hz, 1H), 7.87 ( d, J = 8.79 Hz, 1 H), 8.06 (d, J = 8.30 Hz, 1 H), 8.09 (d, J = 8.30 Hz, 1 H), 11, 10 (s, 1H), Chiral HPLC: 100% purity, tr 14.62 minutes, ChiralCel OJ (250 x 4.6 mm), Hexane / EtOH 80:20; EMCL: Phenomenex Develosil Combi RP3 column 50 x 4.6 mm, 459C, H20 / MeCN 90-2% by weight / 0.1% HC02H for 3.5 minutes, maintaining 0.5 minutes, total test time 4.0 minutes Results: 100% purity at 254 nm, M + = 449, t.r. = 2.65 minutes; [a] 25/589 = -29.05. EXAMPLE 117 METHANOSULPHONATE OF f5-r2- (4-BENZ? RP1ISOTIAZOL-3-ILPIPERAZIN-1-IL) ETIL1-1.1-DIMETHYLLIN-2-IL) ETHYLAMINE A solution of N-. { 5- [2- (4-Benzo [o] isothiazol-3-ylpiperazin-1-yl) ethyl] -1,1-dimethy! Indan-2-yl} Acetamide (650 mg, 1.45 mmol) in THF (20 ml) was treated dropwise with a solution of BH3 in THF (5.8 ml, 1.5 M, 8.7 mmol). The mixture was refluxed for 3 hours, allowed to cool. The reaction was quenched with 1 N HCl until the gas emission decreased. The mixture was refluxed for 1 hour, allowed to cool. Then the THF was removed in vacuo. The aqueous residue was basified with 6 N NaOH and extracted with CH2Cl2 (3 x 40 mL). The combined organic phases were dried over Na 2 SO 4, filtered and the solvent was removed in vacuo. The residue was purified by flash chromatography (silica gel, 5% MeOH / CH2Cl2 with 0.5% Et3N) providing the free base of. { 5- [2- (4-Benzo [o] isothiazol-3-ylp yperazin-1-yl) ethyl] -1,1-dimethylindan-2-yl} ethylamine (440 mg, 70%) as a colorless oil. . { 5- [2- (4-Benzo [o] isothiazol-3-ylpiperazin-1-yl) ethyl] -1,1-dimethylindan-2-yl} Ethylamine (free base, 440 mg, 1.01 mmol) was dissolved in ethyl acetate (10 ml) and then treated with CH3SO3H (2 M in Et20, 0.51 ml, 1.02 mmol). The reaction mixture was stirred at room temperature for 30 minutes. The precipitate was collected by filtration and dried in a vacuum oven at 60 ° C until the next morning to give methane sulfonate. { 5- [2- (4-Benzo [o] isothiazol-3-yl? I? Erazin-1-yl) ethyl] -1,1-dimethylindan-2-yl} ethylamine (350 mg, 38%) as a white solid: mp 115-125SC; 1 H NMR (300 MHz, CDCl 3) d 8.80 (br s, 1 H), 7.89 (d, J = 8.1 Hz, 1H), 7.83 (d, = 8.1 Hz, 1H ), 7.49 (t, J = 7.5 Hz, 1 H), 7.38 (t, J = 7.5 Hz, 1 H), 7.15-7.06 (m, 3H), 3 , 88-3.68 (m, 4H), 3.49 (t, J = 8.6 Hz, 1 H), 3.39-2.96 (m, 12.7 H), 2.77 (s) , 5.1 H), 1, 54-1, 49 (m, 6H), 1, 34 (s, 3H); MS res. M / z 435 [C 26 H 34 N 4 S + H] +; Rf 0.27 (CH2Cl2 / MeOH 10: 1); (AUC) of 97.9% by HPLC, tR = 10.87 minutes. Anal. Cale, for C26H34N4S-1, 7CH3S03H • 2H20: C, 52.47; H, 7, 13; N, 8.84. Found: C, 52.74; H, 7.01; N, 8.74. EXAMPLE 118 METHANOSULPHONATE OF N- (5-r2-f4-BENZ? R / 7IISOTIAZOL-3- ILPIPERAZIN-1-IL) ETI l-1,1-DIMETYLINDAN-2-IL) -N-ETHYLETHAMIDE To a solution of. { 5- [2- (4-Benzo [o] isothiazol-3-ylpiperazin-1-yl) ethyl] -1,1-dimethylindan-2-yl} Ethylamine (free base, 140 mg, 0.333 mmol) in methylene chloride (10 ml) was added acetic anhydride (66 mg, 0.64 mmol) and triethylamine (131 mg, 1.29 mmol). The mixture was stirred at room temperature until the next morning. The reaction mixture was washed with water, brine, dried over Na 2 SO 4, evaporated and chromatographed (silica gel, 3% MeOH / CH 2 Cl 2) to give N-. { 5- [2- (4-benzo [o] isothiazol-3-ylpiperazin-1-yl] ethyl] -1,1-dimethylindan-2-yl.} - N-ethylacetamide (base free, 142 mg, 92%) in the form of a white foam N-. {5- [2- (4-Benzo [o] isothiazol-3-ylpiperazin-1-yl) ethyl] -1, 1 -dimet Indan-2-yl.). N-ethylacetamide (free base, 142 mg, 0.300 mmol) was dissolved in ethyl acetate (6 ml) and then treated with CH3SO3H (2 M in Et20.0). 15 ml, 0.30 mmol) The reaction mixture was stirred at room temperature for 30 minutes and evaporated under reduced pressure The resulting solid was triturated with EtOAc, filtered and dried in a vacuum oven at 35 ° C. N-. {5- [2- (4-benzo [lysotoluzol-3-ylpiperazin-1-yl] ethyl] -1,1-dimethylandan-2-yl methanesulfonate} - N-ethylacetamide (130 mg, 57%) as a white solid: mp 60-70 ° C; 1 H NMR (300 MHz, CDCl 3) d 11.00 (br s, 1 H), 7, 86 (d, J = 8.7 Hz, 2H), 7.54 (t, J = 7.5 Hz, 1 H), 7.42 (t, J = 7.6 Hz, 1 H), 7, 21-7.05 (m, 3H), 5.11 (dd, J = 5.5.4.9 Hz, 0.5H), 4.35-4.11 (m, 6.5H), 3.96 (t, J = 12.6 Hz, 2H), 3.72 (d, J = 11.3 Hz, 2H), 3.49 -3.13 (m, 7H), 2.93 (s, 6H), 2.37 (s, 1.5 H), 2.33 (s, 1.5H), 1.28 (s, 1, 5H), 1, 27 (s, 1, 5H), 1, 24-1, 11 (m, 6H); MS res. M / z 477 [C28H36N4OS + H] +; Rf 0.34 (CH2Cl2 / MeOH 100: 3); (AUC) 97.0% by HPLC, t R = 13.78 minutes. Anal. Cale, for C26H34N4OS - 2CH3S03H. 1, 8H20: C, 51, 38; H, 6.84; N, 7.99. Found: C, 51, 60; H, 6.84; N, 7.64. EXAMPLE 119 METHANOSULPHONATE OF (6-r2- (4-BENZ? RZ7llSOTIAZOL-3-ILPIPERAZIN-1-IL) ETILl-1,1-DIMETILINPAN-2-IL) ETHYLAMINE A solution of N-. { 6- [2- (4-Benzo [or isothiazol-3-ylpiperazin-1-yl] ethyl] -1,1-dimethylindan-2-yl} Acetamide (630 mg, 1.40 mmol) in THF (15 ml) was treated dropwise with a solution of BH3 in THF (5.5 ml, 1.5 M, 5.5 mmol). The mixture was refluxed for 3 hours, allowed to cool. The reaction was quenched with 1 N HCl until the gas emission decreased. The mixture was refluxed for 1 hour, allowed to cool. The THF was then removed in vacuo. The residue aqueous residue was basified with 6 N NaOH and extracted with CH2Cl2 (2 x 50 mL). The combined organic phases were dried over Na 2 SO, filtered and the solvent removed in vacuo. The residue was purified by flash chromatography (silica gel, 5% MeOH / CH2Cl2 with 0.5% Et3N) to provide. { 6- [2- (4-Benzo [d] isothiazol-3-ylpiperazin-1-yl) ethyl] -1,1-dimethylindan-2-yl} ethylamine (free base, 438 mg, 72%) as a colorless oil. . { 6- [2- (4-Benzo [d] isothiazol-3-ylpiperazin-1-yl) ethyl] -1,1-dimethylindan-2-yl} Ethylamine (free base, 438 mg, 1.01 mmol) was dissolved in ethyl acetate (10 ml) and then treated with CH3SO3H (2 M in Et20, 1.0 ml, 2.0 mmol). The reaction mixture was stirred at room temperature for 30 minutes. The precipitate was collected by filtration and dried in a vacuum oven at 55 ° C. until the next morning to give methane sulfonate. { 6- [2- (4-Benzo [o] isothiazol-3-ylpiperazin-1-yl) ethyl] -1,1-dimethylndan-2-yl} ethylamine (305 mg, 38%) as a white solid: mp 125-135eC; 1 H NMR (300 MHz, CDCl 3) d 8.80 (br s, 1 H), 7.90 (d, J = 8.1 Hz, 1H), 7.83 (d, J = 8.1 Hz, 1 H), 7.49 (td, J = 7.5, 0.9 Hz, 1 H), 7.38 (td, J = 7.9, 0.9 Hz, 1 H), 7.14- 7.07 (m, 2H), 7.03 (s, 1H), 3.84-3.64 (m, 4H), 3.49 (t, J = 8.6 Hz, 1H), 3.39 -2.90 (m, 12.4H), 2.77 (s, 4.2H), 1, 56-1, 50 (m, 6H), 1.35 (s, 3H); MS res. M / z 435 [C 26 H 34 N 4 S + H] +; Rf 0.21 (20: 1 CH2Cl2 / MeOH); 98.4% by HPLC (AUC), t R = 10.78 minutes. Anal. Cale, for C26H34N4S -1, 4CH3S03H. 0.5H2O: C, 56.92; H, 7.08; N, 9.69. Found: C, 56.60; H, 7.22; N, 9.42. EXAMPLE 120 METHANOSULPHONATE OF N-f6-r2- (4-BENZQRP1ISOTIAZOL-3-ILPIPERAZIN-1 -IDETIL1-1.1-DIMETYLINDAN-2-ILVN-ETHYLETHAMIDE To a solution of. {6- [2- (4-benzo [a isothiazol-3-ylpiperazin-1-yl) ethyl] -1,1-dimethylindan-2-yl}. ethylamine (free base, 160 mg, 0.369 mmol) in methylene chloride (10 ml) was added acetic anhydride ( 75 mg, 0.74 mmol) and triethylamine (149 mg, 1.48 mmol) The mixture was stirred at room temperature until the next morning.The reaction mixture was washed with water, brine, dried over Na 2 SO 4, evaporated and chromatographed (silica gel, 3% MeOH / CH 2 Cl 2) to give N-. {6- [2- (4-Benzo [jisothiazol-3-ylpiperazin-1-yl] ethyl] -1,1-dimethyl} ndan-2-yl.} - N-ethylacetamide (free base, 158 mg, 92%) in the form of a white foam N-. {6- [2- (4-benzo [o] isothiazole-3-) ilpiperazin-1-yl) ethyl] -1,1 -dimethylindan-2-yl.} - N-ethylacetamide (free base, 158 mg, 0.330 mmol) was dissolved in ethyl acetate (8 ml) and then treated with CH3S03H (2 M in Et20, 0.17 ml, 0.34 mmol). The reaction mixture was stirred at room temperature for 30 minutes and evaporated under reduced pressure. The resulting solid was triturated with EtOAc, filtered and dried in a vacuum oven at 35 ° C. until the next morning to give N- methanesulfonate. { 6- [2- (4-benzo [o] isothiazol-3-yl-piperazin-1-yl) etii] -1, 1-dimethylindan-2-yl} -N-ethylacetamide (140 mg, 61%) as a white solid: mp 62-729C; NMR of H (300 MHz, CDCl 3) d 11.08 (br s, 1 H), 7.86 (d, J = 8.7 Hz, 2H), 7.54 (t, J = 7.7 Hz, 1 H), 7.42 (t, J = 7.7 Hz, 1 H), 7.22-7.05 (m, 3H), 5.13 (m, 0.5H), 5.00-4 , 55 (m, 4H), 4.33 (m, 0.5H), 4.18 (d, J = 4.7 Hz, 2H), 3.97 (t, J = 12.5 Hz, 2H) , 3.72 (d, J = 11, 8 Hz, 2H), 3.45-3.18 (m, 7H), 2.93 (s, 6H), 2.36 (s, 1.5 H) , 2.32 (s, 1, 5H), 1, 27 (s, 1, 5H), 1, 26 (s, 1, 5H), 1.20-1, 12 (m, 6H); MS res. M / z 477 [C28H36N4OS + H] +; Rf 0.34 (CH2Cl2 / MeOH 100: 3); (AUC) > 99% by HPLC, t R = 13.75 minutes. Anal. Cale, for C 26 H 34 N 4 OS-2 CH 3 S0 3 H -1, 5 H 20: C, 51, 78; H, 6.81; N, 8.05. Found: C, 51, 79; H, 6.89; N, 7.86. PREPARATION 34 ETHYL ESTER OF THE ACID (3 ', 4'-DIHYDRO-1? -SPIR? N, 31DIOXOLAN-2 2'-NAFTALEN-6'-ILACÉTICO A mixture of ethyl ester of the acid (6-oxo-5,6, 7,8-tetrahydronaphthalen-2-yl) acetic acid (500 mg, 2.15 mmol), prepared according to EP-430,459 A1, ethylene glycol (1.20 ml, 21.5 mmol) and a catalytic amount of p -TsOH in benzene (60 ml) was heated to reflux using a Dean-Stark trap to remove the water.After 4 hours, the reflux was stopped and the reaction mixture was diluted with EtOAc The organic phase was washed with aqueous solution saturated sodium bicarbonate, dried over magnesium sulfate, filtered and concentrated to a yellow oil (594 mg, 100%) which was used without further purification MS (APCI): (M + 1) + = 277. NMR of 1H (CDCl 3, d): 7.03 (m, 3H), 4.11 (q, 2H, J = 7.1, 7.3, 7.1 Hz), 4.00 (m, 4H), 3.52 (s, 2H), 2.94 (m, 4H), 1.93 (t, 2H, J = 6.6, 6.8 Hz), 1.23 (t, 3H, J = 7, 1, 7.3 Hz) PREPARATION 35 2- (3 ', 4'-DIHYDRO-1' H-SPIR OM .31DIOXOLAN-2 2'-NAFTALEN1-6'- IDETANOL To a solution of the title compound of Preparation 34 (594 mg, 2.15 mmol) in anhydrous THF (5 ml) under nitrogen, cooled to 0 ° C, 6.45 ml (6.45 mmol) of a 1.0 M solution of dussobutylaluminum hydride in THF (effervescence) were added dropwise. When the addition was complete, the reaction mixture was stirred at 09C for 1 hour and quenched by slowly adding MeOH. The mixture was partitioned between saturated, aqueous sodium potassium tartrate solution and EtOAc and the whole was stirred for 30 minutes. The aqueous phase was separated and washed with EtOAc and the organic phases were combined, dried (MgSO 4), filtered and concentrated to an oil, 471 mg (93%), which was used without further purification. MS (APCI): (M + 1) + = 235. 1 H NMR (CDCl 3, d): 6.98 (s, 3H), 4.01 (s, 4H), 3.81 (t, 2H, J = 6.4, 6.6 Hz), 2.94 (m, 4H) , 2.79 (t, 2H, J = 6.6, 6.6 Hz), 1.93 (t, 2H, J = 6.8, 6.8 Hz). PREPARATION 36 ESSTER S-ß '' -DIHIDRO-l 'H-SPIROPI .31DIOXOLAN-2.2'-NAFTALEN-6'-ID-ETHYLL OF TOLUENE-4-SULPHONIC ACID To a mixture of the title compound of Preparation 35 (471 mg, 2.01 mmol) and p-toluenesulfonyl chloride (421 mg, 2.21 mmol, recrystallized from hexanes) in anhydrous THF (10 mL) under nitrogen was added dropwise triethylamine (0.314 mL, 2.21 mmol). mmol, dried over NaOH). When the addition was complete, the reaction mixture was stirred at room temperature for 40 hours and fractionated between water and EtOAc. The organic phase was dried (MgSO 4), filtered and concentrated. The crude product was purified by eluting through a flash chromatography column (silica gel 60, 230-400 mesh, hexanes: EtOAc 7: 3) to give a clear oil, 531 mg (68%). MS (APCI): (M + 1) + = 389. 1 H NMR (CDCl 3, d): 7.65 (d, 2H, J = 8.3 Hz), 7.26 (d, 2H, J = 7 , 8 Hz), 6.85 (m, 3H), 4.13 (t, 2H, J = 7.1, 7.3 Hz), 4.01 (s, 4H), 2.90 (m, 6H ), 2.41 (s, 3H), 1.91 (t, 2H, J = 6.8, 6.8 Hz). EXAMPLE 121 S-H ^ -O '^' - DIHYDRO-l 'H-SPIROri.SIDlOXOLAN-S ^' - NAFTALENI-e'-IL) ETIL1PIPERAZIN-1 -IL} BENZOGP1ISOTIAZOL A mixture of 3- (piperazin-1-yl) benzo [cVjisothiazole hydrochloride (349 mg, 1.36 mmol) and the title compound of Preparation 36 (530 mg, 1.36 mmol) with anhydrous K2C03 (376 mg, 2.72 mmol) in acetonitrile (20 ml) was heated at reflux for 24 hours. The reaction mixture was filtered and the filtrate was concentrated. The crude product was purified by eluting through a flash chromatography column (silica gel 60, 230-400 mesh, hexanes: EtOAc 1: 1) to give a clear oil which crystallized upon standing, 497 mg (84%). MS (APCI): (M + 1) + = 436. 1 H NMR (CDCl 3, d): 7.89 (d, 1 H, J = 7.8 Hz), 7.80 (d, 1 H, J = 8.1 Hz), 7.46 (t, 1 H, = 7.3, 7. 3 Hz), 7.34 (t, 1 H, J = 7.3, 7.3 Hz), 6.98 (s, 3H), 4.01 (s, 4H), 3.58 (br s, 4H), 2.95-2.65 (m, 12H), 1.93 (t, 2H, J = 6.8, 6.8 Hz). CHN, cale, for C25H29N302S: C, 68.94%; H, 6.71%; N, 9.65%; Found: C, 68.75%; H, 6.70%; N, 9.54%. EXAMPLE 122 CHLORHYDRATE OF 6-r2- (4-BENZ? R3llSOTIAZOL-3-ILPIPERAZIN-1-IL) ETIL1-3,4-DIHYDRO-1H-NAFTALEN-2-ONA A solution of the title compound of Example 121 (451 mg , 1. 04 mmol) in acetone (20 ml) with 1.0 N aqueous HCl (2.0 ml) was heated to reflux for 2 hours (after the first 5 minutes at reflux, a white solid precipitated). Upon cooling to room temperature, the precipitated product was collected and washed with acetone to provide 429 mg (96%). MS (APCI): (M + 1) + = 392, (M-1) + = 390. 1 H NMR (DMSO-d 6, d): 8.08 (m, 2H), 7.57 (t, 1 H, = 7.3, 7.6 Hz), 7.44 (t, 1 H, = 7.8, 7.3 Hz), 7.18 (s, 1H), 7.11 (s, 2H) , 4.07 (br d, 2H, J = 13.7 Hz), 3.65 (br d, 2H, J = 12.2 Hz), 3.54 (s, 2H), 3.47-3, 35 (m, 6H), 3.04 (m, 2H), 2.98 (t, 2H, J = 6.6, 6.6 Hz), 2.40 (t, 2H, J = 6.6, 6.6 Hz). CHN, cale, for C23H25N3OS HCl: C, 64.55%; H, 6.12%; N, 9.82%; Found: C, 64.61%; H, 6.26%; N, 9.76%. EXAMPLE 123 6-r2- (4-BENZ? R0llSOTIAZOL-3-ILPIPERAZIN-1-Thyryl-1, 2,3,4-TETRAHYDROONAFTALEN-2-l LAMINE A mixture of the title compound of Example 122 (300 mg, , 70 mmol) with ammonium acetate (54 mg, 0.70 mmol) and sodium ethanoborohydride (102 mg, 1.6 mmol) in anhydrous MeOH (15 ml) was stirred at room temperature under nitrogen for 48 hours. The reaction was diluted with aqueous NaHCO 3 solution and extracted with dichloromethane, the organic extract was dried (MgSO 4), filtered and concentrated to give a white foamy solid, 222 mg (81%). MS (APCI): (M + 1) + = 393, (M + 2) + = 394. 1 H NMR (CDCl 3, d): 7.89 (d, 1 H, J = 8.3 Hz), 7.80 (d, 1 H, J = 8.3 Hz), 7.45 (t, 1 H, = 7.1, 7.1 Hz), 7.34 (t, 1H, J = 7.3, 7.1 Hz), 6, 99 (m, 3H), 3.60 (m, 4H), 3.32-2.41 (m, 15H), 2.15 (m, 1 H), 1.61 (, 1 H) EXAMPLE 124 {.6-r2- (4-BENZ? RP1lSOTIAZOL-3-ILPIPERAZIN-1 -IDETIL1-1.2.3,4-TETRAHIDRONAFTALEN-2-IL1METI LAMINA A mixture of the compound of t title of Example 122 (300 mg, 0.70 mmol) with methylamine hydrochloride (319 mg, 4.12 mmol) and sodium ethanoborohydride (51 mg, 7.0 mmol) in MeOH (10 mL) and the reaction mixture was stirred at room temperature for 4 days. The reaction mixture was diluted with water and extracted with dichloromethane. The organic extract was dried (MgSO 4), filtered and concentrated to a whitish, foamy solid, 244 mg (86%). MS (APCI): (M + 1) + = 407. 1 H NMR (CDCl 3, d): 7.90 (d, 1 H, J = 8.3 Hz), 7.80 (d, 1 H, J = 8.3 Hz), 7.46 (t, 1 H, J = 7.1, 7.1 Hz), 7.36 (t, 1 H, J = 7.1, 7.1 Hz), 7 , 03 (s, 2H), 6.98 (s, 1H), 3.62 (br s, 4H), 3.33-3.17 (m, 2H), 3.00-2.70 (m, 15H), 2.16 (br s, 1H), 1.95 (m, 1 H). EXAMPLE 125 N-re-r2- (4-BENZ? RP1ISOTIAZOL-3-ILPlPERAZIN-1 -IDETILM, 2.3.4-TETRAHYDRODONAFTALEN-2-ID-N-METHYLACETAMIDE To a solution of the title compound of Example 124 (242 mg, 0.60 mmol) and triethylamine (125 μl, 0.90 mmol, dried over NaOH), in anhydrous THF (5 ml) under nitrogen at room temperature was added dropwise acetyl chloride (64 μl, 0.90 mmol) was stirred vigorously.After 1 hour, the reaction mixture was partitioned between aqueous NaHCO 3 solution and dichloromethane.The organic phase was dried (MgSO 4) filtered and concentrated and the crude product was eluted through a chromatography column. ultrafast (silica gel 60, 230-400 mesh, 3% MeOH in EtOAc to 5% MeOH in EtOAc) to give the title compound as a glassy transparent solid, 140 mg (52%) .MS (IQPA) : (M + 1) + = 449. 1 H NMR (CDCl 3, d): 7.90 (d, 1 H, J = 8.1 Hz), 7.80 (d, 1 H, J = 8.1 Hz ), 7.45 (t, 1 H, J = 7.1, 8.3 Hz), 7.34 (t, 1 H, J = 7.8, 7.3 Hz), 6.97 (m, 3H), 4.88 (m, 1 H), 3.99 (m, 1 H), 3.58 (br s, 4H), 2.97-2 , 64 (m, 15H), 2.12 (d, 3H, J = 6.6 Hz), 1.97 (m, 1H), 1.86 (m, 1H). CHN, cale, for C26H32N4OS (0.4 mol of water): C, 68.51%; H, 7.25%; N, 12.29%; Found: C, 68.22%; H, 7.30%; N, 12.31%. The enantiomers of the title compound were isolated by eluting the racemate through a Chiralcel AD column (250 x 4.6 mm) with hexanes (0.2% TFA): EtOH 40:60 as eluent, flow rate = 0.80 ml / minute, test time 42 minutes. The (-) enantiomer exhibited a retention time of 6.17 minutes with an optical rotation of -289 (589 nm, c = 5, MeOH) and the (+) enantiomer preset a retention time of 6.77 minutes with a optical rotation of +32.89 (589 nm, c = 5, MeOH). EXAMPLE 126 N-f 6-G2- (4-BENZOGP1ISOTIAZOL-3-ILPIPERAZIN-1 -IDETILM .2.3.4-TETRAHYDROONAFTALEN-2-IDACETAMIDE To a solution of the title compound of Example 123 (220 mg, 0.56 mmol) and triethylamine (117 μl, 0.84 mmol, dried over NaOH), in anhydrous THF (5 ml) at room temperature under nitrogen atmosphere was added dropwise acetyl chloride (60 μl, 0.84 mmol) with vigorous stirring. After 1.5 hours, the reaction mixture was partitioned between saturated aqueous NaHCO3 and dichloromethane. The organic phase was dried (MgSO 4), filtered, concentrated and the crude product was purified by eluting through a flash chromatography column (silica gel 60, 230-400 mesh, 3% MeOH in EtOAc to 5% MeOH). % in EtOAc). The vitreous solid that was isolated was dissolved in dichloromethane and the solution was treated with 4.0 HCl solution. N in dioxane precipitating the HCl salt, 126 mg (48%). MS (APCI): (M + 1) + = 435, (M-1) + = 433. 1 H NMR (DMSO-d 6, d): 8.10 (m, 2H), 7.57 (t, 1 H, J = 7.3, 7.1 Hz), 7.45 (t, 1 H, J = 7.3, 7.3 Hz), 7.01 (m, 3H), 4.08 (br d , 2H, J = 12.5 Hz), 3.85 (m, 1 H), 3.65 (br d, 2H, J = 11, 2 Hz), 3.32 (m, 6H), 2.88 (m, 5H), 2.47 (s, 3H), 2.06 (m, 2H), 1.79 (m, 2H). CHN, cale, for C25H3oN4OS 1, 4 HCl: C, 61, 83%; H, 6.52%; N, 11, 54%; Found: C, 61, 43%; H, 6.58%; N, 10.74%. The enantiomers of the title compound were isolated by eluting the racemate through a Chiralpak AD column (250 x 4.6 mm) using hexanes (0.19 DEA): EtOH 3: 1 as eluent, flow rate = 0.50 ml / minute . The (+) enantiomer had a retention time of 20.1 minutes with an optical rotation of + 46s (589 nm, c = 1, CH2CI2) and the (-) enantiomer had a retention time of 22.8 minutes with a rotation optics of -369 (589 nm, c = 1, CH2Cl2). . The methodology described for the preparation of the Example 126 was applied appropriately to the preparation of Examples 127-130. EXAMPLE 127 N-f6-r2- (4-BENZ? RD1ISOTI AZOL-3-ILPIPERAZIN-1 -IDETI II .2.3.4-TETRAHYDROONAFTALEN-2-IL) PROPANAMIDE From the title compound of Example 123 (281 mg, , 72 mmol) and propionyl chloride (94 μl, 1.07 mmol). Isolated in the form of the HCl salt, 155 mg (44%). MS (APCI): (M + 1) + = 449, (M-1) + = 447. 1 H NMR (DMSO-dβ, d): 8.08 (m, 2H), 7.55 (t, 1 H, J = 7.6, 7.6 Hz), 7.42 (t, 1 H, J = 8.1, 7.1 Hz), 6.98 (m, 3H), 4.05 (br d , 2H, J = 13.2 Hz), 3.63 (br d, 2H, J = 11, 5 Hz), 3.29 (m, 12H), 2.80 (m, 5H), 2.02 ( m, 1 H), 0.94 (m, 2H). CHN, cale, for C26H32N4OS HCl: C, 64.38%; H, 6.86%; N, 11, 55%; Found: C, 64.28%; H, 6.77%; N, 10.76%. EXAMPLE 128 N-f6-r2- (4-BENZ? RP1ISOTIAZOL-3-ILPIPERAZIN-1 -IDETI 1-1.2.3.4-TETRAHYDROONAFTALEN-2-IL) BUTIRAMIDE From the title compound of Example 123 (200 mg, 0, 51 mmol) and butyryl chloride (80 μl, 0.77 mmol). Isolated in the form of the HCl salt, 104 mg (41%). MS (APCI): (M + 1) + = 463, (M-1) + = 461. 1 H NMR (DMSO-dβ, d): 8.10 (m, 2H), 7.57 (t, 1 H, = 7.6, 7.8 Hz), 7.45 (t, 1 H, J = 7.8, 7.3 Hz), 7.00 (m, 3H), 4.08 (br d, 2H, J = 12.0 Hz), 3.65 (br d, 2H, J = 12.0 Hz), 3.31 (m, 10H), 2.85 (m, 6H), 2.02 (t , 2H, J = 7.1, 7.3 Hz), 1.50 (q, 2H, J = 7.3, 7.3, 7.3 Hz), 0.85 (quintet, 3H, J = 7 , 3, 6.6, 7.1, 7.6 Hz). CHN, cale, for C27H34N4OS 1, 1 HCl: C, 64.50%; H, 7.04%; N, 11, 14%; Found: C, 64.60%; H, 6.92%; N, 10.57%. EXAMPLE 129 Nf 6-G2- (4-BENZOGD1ISOTIAZOL-3-ILPIPERAZIN-1 -IDETIL1-1.2.3,4-TETRAHIDRONAFTALEN-2-IL) -3-METHYLBUTIRAMIDE (13V. From the title compound of Example 123 (200 mg, 0.51 mmol) and isovaleryl chloride (94 μl, 0.77 mmol), isolated in the form of the HCl salt, 107 mg (41%). MS (APCI): (M + 1) + = 477. (M-1) + = 475. 1 H NMR (DMSO-de, 8): 8.10 (m, 2H), 7.57 (t, 1 H, J = 7.3, 7.8 Hz), 7.44 (t, 1 H, J = 8.1, 7.3 Hz), 7.00 (m, 3H), 4.08 (br d, 2H, J = 12.2 Hz), 3.65 (br d, 2H, J = 11, 2 Hz), 3.36 (m, 13H), 2.90 (m, 4H), 1.93 (m, 2H), 0.86 (m, 6H). CHN, cale, for C28H36N4OS 1.1 HCl: C, 65.08%; H, 7.24%; N, 10.84%; found: C, 64.68%; H, 7.06%; N, 10.35% EXAMPLE 130 f6-r2- (4-BENZ? RllllSOTIAZOL-3-ILPIPERAZIN-1 -IDETILM, 2.3.4- TETRAHYDRONAPHTHALEN-2-ILLAMIDE OF THE ACID Cyclopentane-cycloxylic Starting from the title compound of Example 123 (200 mg, 0.51 mmol) and cyclopentanecarbonyl chloride (100 μl, 0.77 mmol). Isolated in the form of the salt HCl, 37 mg (14%). MS (APCI): (M + 1) + = 489. 1 H NMR (DMSO-dβ, d): 8.08 (m, 2H), 7.55 (t, 1H, J = 7.6, 7, 6 Hz), 7.42 (t, 1H, J = 7.8, 7.6 Hz), 6.98 (m, 3H), 4.06 (br d, 2H, J = 12.7 Hz), 3.63 (br d, 2H, J = 10.2 Hz), 3.29 (m, 9H), 2.82 (m, 4H), 2.44 (m, 8H), 1.60 (m, 4H). CHN, cale, for C29H36N4OS 1, 2 HCl: C, 65.42%; H, 7.04%; N, 10.52%; Found: C, 64.94%; H, 6.89%; N, 10, 14%. EXAMPLE 131 f6-f2- (4-BENZ? RP1ISOTI AZOL-3-ILPIPERAZIN-1 -IDETIL1-1, 2,3,4-TETRAHIDRONAFTALEN-2-IDAMIDE OF ACID 1- METHYL CYCLOPROPANOCARBOXYLIC 6- [2- (4-benzo [o] isothiazol-3-ylpiperazin-1-yl) ethyl] -1,2,3,4-tetrahydronaphthalen-2-ylamine was diluted to 0.10 M with anhydrous dichloromethane, then introduced into an 8 ml vial by pipette ( 0.10 mmol). 1-Methylcyclopropanecarbonyl chloride was diluted to 1.0 M with anhydrous dichloromethane then added to the amine solution (0.20 mmol). PS-diisopropylethylamine (0.20 mmol) was added and the reaction the next morning the reaction was diluted with 1 ml of anhydrous dichloromethane, then the resin of PS-trisamine (0.20 mmol) was added for elimination, the reaction was stirred for 3 hours. At room temperature, the resin was filtered and washed with one ml of dichloromethane.The filtrate was concentrated by an HT-12 GeneVac.The crude product was purified by HPLC (column 30 x 100 mm ODS-A C (18) 5u). He recovered . { 6- [2- (4-benzo [clisothiazol-3-ylpiperazin-1-yl] etl] -1, 2,3,4-tetrahydronaphthalen-2-yl} 1-Methylcyclopropanecarboxylic acid amide with a purity of 90% at 214 nm, EMCL (IQPA) 475 [M + H] +. Examples 132-165 were synthesized in a combinoteca format following the steps described in Example 131 at a mi.10 molar scale using 6- [2- (4-benzo [c / | isothiazol-3-ylpiperazin-1-] il) ethyl] -1,2,3,4-tetrahydronaphthalen-2-ylamine with appropriate acid chloride or isocyanate starting materials and PS-diisopropylethylamine. The crude products were purified by HPLC (column 30 x 100 mm ODS-A C (18) 5u).

EXAMPLE 170 f 6 > r2- (4-BENZ? rPHSOTIAZOL-3-ILPIPERAZIN-1 -IDETILM .2.3.4- TETRAHIPRONAFTALEN-2-IDMETILAMIDE OF THE ACID ETHANOSULPHONIC 6- [2- (4-Benzo [olisothiazol-3-ylpiperazin-1-yl] ethyl] -1,2,3,4-tetrahydronaphthalen-2-ylamine was diluted to 0.10 M with anhydrous pyridine, then introduced into an 8 ml vial by means of a pipette (0.10 mmol). Ethanesulfonyl chloride was diluted to 1.0 M with anhydrous pyridine and then added to the amine solution (0.20 mmol) and the reaction was stirred overnight at room temperature. The next morning the reaction was diluted with 1 ml of anhydrous pyridine. Then the PS-trisamine resin (0.20 mmol) was added for removal. The reaction was stirred for 3 hours at room temperature. The resin was filtered and washed with 1 ml of dichloromethane. The filtrate was concentrated by an HT-12 GeneVac. The crude product was purified by HPLC (column 30 x 100 mm ODS-A C (18) 5u). He recovered . { 6- [2- (4-benzo [c-isothiazol-3-ylpiperazin-1-yl] ethyl] -1,2,3,4-tetrahydronaphthalen-2-yl} ethanesulfonic methylamide with a purity of 97% at 214 nm, EMCL (APCI) 499 [M + H] +. Examples 171 and 172 were synthesized in a combinoteca format following the steps described in Example 170 at a 0.10 millimolar scale using 6- [2- (4-benzo [c] isothiazol-3-ylpiperazin-1-yl] ) ethyl] -1,2,3,4-tetrahydro-d-naphthalen-2-ylamine with appropriate sulfonyl chloride. The crude products were purified by HPLC (column 30 x 100 mm ODS-A C (18) 5u).

EXAMPLE 171 f6-i ~ 2- (4-BENZ? R0llSOTIAZOL-3-lPIPERAZIN-1-IDET1L1-1, 2,3,4- TETRAHLDRONAFTALEN-2-IL) PROPANIC-1- SULPHONIC ACID AMID Isolated with a purity of 99% at 214 nm; EMCL (IQPA) 499 [M + H] + EXAMPLE 172 Nf 6-G2- (4-BENZO, P1ISOTI AZOL-3-ILPIPERAZIN-1 -IDETIL1-1, 2,3,4- TETRAHYDRODONAFTALEN-2-IDBENCENOSULFONAMIDE Isolated with a purity of 90% at 214 nm; EMCL (IQPA) 533 M + H] +.

Claims (15)

CLAIMS A compound of formula 1 1A

1 B wherein J is S, SO, SO2, CH2, O or NR10, wherein R10 is hydrogen, C-Cß alkyl, C (= O) C?-C6 alkyl or C (= O) O-C Cß alkyl; M is CH or N; G is CH or N; m is an integer from one to six; X is O or NR3, wherein R3 is defined as defined R10 above, C (= 0), CHOH, CHOR3, CH (halo) or CHNR3R12, wherein R12 is defined as defined R10 above; or X is absent; R1 is hydrogen, halogen, cyano, CrCß alkyl optionally substituted with one to three fluorine atoms, CrCβ alkoxy optionally substituted with one to three fluorine atoms or R1 forms a heterocyclic ring with R10; R2 is defined as R1 with the proviso that R2 can not form a heterocyclic ring when R1 is present; R4 and R5 are independently hydrogen, halogen, cyano, aminoalkyl d-Css (alkyl CRC6) aminoalkyl CrCß, di (Cr C6) aminoalkyl d-Css, hydroxyalkyl CRC6, alkoxy CrCß or (alkoxy Cr C6) alkyl, wherein each of the alkoxy and alkyl moieties of the above groups R4 and R5 may be optionally substituted with one to three halo atoms, preferably with one to three fluorine atoms; R6, R7, R8 and R9 are, independently, hydrogen or CrC6 alkyl optionally substituted with one to three fluorine atoms; And, when R11 is present, it is selected from O, NR13, where R3 is defined as defined R0 above or (CH2) W in which w is an integer of one or six; or Y, when R11 is absent, it is selected from (= 0), hydroxy, NR13R14 where R13 and R14 are defined as defined R10 above and (CH2) qCH3, where q is an integer of one to five; n is an integer from one to three; z is an integer from one to three; and R1 is hydrogen, alkyl CrCß, CRC6 -S02-alkyl, -S02-aryl, aryl, arylalkyl CRC6, heteroaryl, heteroarylalkyl CrCß, heterocyclyl, heterocyclylalkyl C C4, COR15, C (0) OR15 or C (0) NR15R16, in those which R15 and R16 are independently selected from CrC6 alkyl, aryl, heteroaryl, heteroarylalkyl CrC6, arylalkyl CrC6, heterocyclyl and heterocyclylalkyl wherein said alkyl moieties in said R11 groups may be optionally substituted with one to three fluorine atoms and the aryl, heteroaryl and heterocyclyl moieties in said R11 groups may be optionally substituted, with one or more substituents, preferably from zero to two substituents which are independently selected from alkyl CRC6 optionally substituted with one to three fluorine atoms, alkoxy CrCß optionally substituted with one to three fluorine atoms, cyano, nitro, halo, amino, (CRC6) amino and di (C? - C6) amino; or R11 is absent; with the proviso that the sum of n plus z can not exceed 3; and pharmaceutically acceptable salts of such compounds.

2. A compound according to claim 1, wherein J is sulfur and M is nitrogen.

3. A compound according to claim 1, wherein G is N.

4. A compound according to claim 1, wherein m is two.

5. A compound according to claim 1, wherein X is absent.

6. A compound according to claim 1, wherein R6, R7, R8 and R9 are independently selected from hydrogen and methyl.

7. A compound according to claim 1, wherein YR11 is NR 13

8. A compound according to claim 1, wherein Y is NR13NR14.

9. A compound that is selected from the following compounds and their pharmaceutically acceptable salts:? / -. { 6- [2- (4-Benzo [o] isothiazol-3-ylpiperazin-1-yl) ethyl] indan-1-yl-acetamide; (S) (+) -? / -. { 5- [2- (4-Benzo [or isothiazol-3-ylpiperazin-1-yl] ethyl] indan-2-yl-acetamide; (R) (-) -? And-. { 5- [2- (4-Benzo [o] sot-azo-3-ylpiperazin-1-yl) ethyl] indan-2-yl-ylpropionamide; (S) (+) -? / -. { 5- [2- (4-Benzo [o] isothiazol-3-ylpiperazin-1-yl) ethyl] indan-2-yl-propionamide; . { 5- [2- (4-Benzo [d] isothiazol-3-ylpiperazin-1-yl) ethyl] indan-2-yl} amide of (S) (+) cyclopropanecarboxylic acid; (R) (-) -? And-. { 5- [2- (4-Benzo [o] isothiazol-3-ylpiperazin-1-yl) ethyl] indan-2-yl} -? / - methylacetamide; (S) (+) -? / -. { 5- [2- (4-Benzo [o] isothiazol-3-ylpiperazin-1-yl) ethyl] indan-2-yl} -? / - methylacetamide; . { 5- [2- (4-Benzo [o] isothiazol-3-ylpiperazin-1-yl) ethyl] -1, 1, 3,3-tetramethylindan-2-yl} methylamine; ? / -. { 5- [2- (4-Benzo [c / jisothiazo, -3-ylpiperazin-1-yl] ethyl] -1, 1, 3,3-tetramethylindan-2-yl} -? / - methylacetamide; ? / -. { 5- [2- (4-Benzo [o] isothiazol-3-ylpiperazin-1-yl) ethyl] -1, 1, 3,3-tetramethyldan-2-yl} acetamide; ? / -. { 5- [2- (4-Benzo [c-lysothiazol-3-ylpiperazin-1-yl] ethyl] -1,1-dimethylindan-2-yl] acetamide; (+) -? and-. { 5- [2- (4-Benzo [or isothiazol-3-ylpiperazin-1-yl] ethyl] -1,1-dimethylindan-2-yl} acetamide; (-) -? / -. { 5- [2- (4-Benzo [Gd] -thiazol-3-ylpiperazin-1-yl) ethyl] -1,1-dimethylindan-2-i ?} acetamide; ?Y-. { 6- [2- (4-Benzo [o] isothiazol-3-ylpiperazin-1-yl) ethyl] -1,1-dimethyl-indan-2-yl-acetamide; (+) -? / -. { 6- [2- (4-Benzo [o] isothiazol-3-ylpiperazin-1-yl) ethyl] -1,1-dimethylindan-2-yl} acetamide; Y (-)-?/-. { 6- [2- (4-Benzo [o] isothiazol-3-ylpiperazin-1-yl) ethyl] -1, 1-dimethylindan-2-yl} acetamide.

10. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 1 and a pharmaceutically acceptable carrier.

11. A method for treating a disorder or condition that is selected from single or recurrent major depressive disorders, dysthymic disorders, depressive neurosis and neurotic depression, melancholic depression including anorexia, weight loss, insomnia, early morning wakefulness or psychomotor retardation; atypical depression (or reactive depression) including increased appetite, hypersomnia, psychomotor agitation or irritability, seasonal affective disorder and pediatric depression; bipolar disorders or manic depression, for example, bipolar I disorder, bipolar II disorder and cyclothymic disorder; behavioral disorder; destructive behavioral disorder; hyperactivity disorder with attention deficit; behavioral disturbances associated with mental retardation, autistic disorder and conduct disorder; anxiety disorders such as panic disorder with or without agoraphobia, agoraphobia without a history of panic disorder, specific phobias, for example phobias to specific animals, social anxiety, social phobia, obsessive-compulsive disorder, stress disorders including post-traumatic stress disorder and acute stress disorder and generalized anxiety disorders; borderline personality disorder; schizophrenia and other psychotic disorders, for example, schizophreniform disorders, schizoaffective disorders, delusional disorders, brief psychotic disorders, shared psychotic disorders, psychotic disorders with delusions or hallucinations, psychotic episodes of anxiety, anxiety associated with psychosis, psychotic behavioral disorders such as major depressive behavioral disorders associated with psychotic disorders such as acute mania and depression associated with bipolar disorder; behavioral disorders associated with schizophrenia; delirium, dementia and amnestic disorders and other cognitive or neurodegenerative disorders, such as Parkinson's disease, Huntington's disease, Alzheimer's disease, senile dementia, Alzheimer's type dementia, memory disorders, loss of the executing function, vascular dementia and other dementias, for example, due to HIV disease, brain trauma, Parkinson's disease, Huntington's disease, Pick's disease, Creutzfeldt-Jakob disease or due to multiple etiologies; movement disorders such as akinesias, dyskinesias, including paroxysmal familial dyskinesias, spasms, Guilles de la Tourette syndrome, Scott syndrome, paralysis and rigid akinetic syndrome; extrapyramidal movement disorders such as medication-induced movement disorders, eg, neuroleptic-induced parkinsonism, neuroleptic malignant syndrome, acute neuroleptic-induced dystonia, acute neuroleptic-induced akathisia, neuroleptic-induced tardive dyskinesia, and medication-induced postural tremor; dependencies and additions to chemical substances (eg dependencies or additions to alcohol, heroin, cocaine, benzodiazepines, nicotine or phenobarbitol) and behavioral additions such as pathological gambling; and ocular disorders such as glaucoma and ischemic retinopathy in the mammal, which comprises administering to a mammal in need of such treatment an amount of a compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is effective to treat said disorder or condition.

12. A method according to claim 11, wherein the disorder or condition to be treated is selected from major depression, single depression, recurrent depression, depression induced by childhood abuse, postpartum depression, dysthymia, cyclothymia, and bipolar disorder .

13. A method according to claim 11, wherein the disorder or condition to be treated is selected from schizophrenia, schizoaffective disorder, delusional disorder, substance-induced psychotic disorder, brief psychotic disorder, shared psychotic disorder, psychotic disorder due to a general medical condition and schizophreniform disorder.

14. A method according to claim 11, wherein the compound according to claim 1 is administered to a human being for the treatment of two or more disorders or comorbid conditions that are selected from the disorders and conditions referred to in any of the previous procedures.

15. A method for treating a disorder or condition that is selected from single or recurrent major depressive disorders, dysthymic disorders, depressive neurosis and neurotic depression, melancholic depression including anorexia, weight loss, insomnia, early morning wakefulness or psychomotor retardation; atypical depression (or reactive depression) including increased appetite, hypersomnia, psychomotor agitation or irritability, seasonal affective disorder and pediatric depression; bipolar disorders or manic depression, for example, bipolar I disorder, bipolar II disorder and cyclothymic disorder; behavioral disorder; destructive behavioral disorder; hyperactivity disorder with attention deficit disorder (ADHD); behavioral disturbances associated with mental retardation, autistic disorder and conduct disorder; anxiety disorders such as panic disorder with or without agoraphobia, agoraphobia without a history of panic disorder, specific phobias, for example phobias to specific animals, social anxiety, social phobia, obsessive-compulsive disorder, stress disorders including post-traumatic stress disorder and acute stress disorder and generalized anxiety disorders; borderline personality disorder; schizophrenia and other psychotic disorders, for example, schizophreniform disorders, schizoaffective disorders, delusional disorders, brief psychotic disorders, shared psychotic disorders, psychotic disorders with delusions or hallucinations, psychotic episodes of anxiety, anxiety associated with psychosis, psychotic behavioral disorders such as major depressive behavioral disorders associated with psychotic disorders such as acute mania and depression associated with bipolar disorder; behavioral disorders associated with schizophrenia; delirium, dementia and amnestic disorders and other cognitive or neurodegenerative disorders, such as Parkinson's disease (PD), Huntington's disease (HD), Alzheimer's disease, senile dementia, Alzheimer's type dementia, memory disorders, loss of function performer, vascular dementia and other dementias, for example, due to HIV disease, brain trauma, Parkinson's disease, Huntington's disease, Pick's disease, Creutzfeldt-Jakob disease or due to multiple etiologies; movement disorders such as akinesias, dyskinesias, including paroxysmal familial dyskinesias, spasms, Guilles de la Tourette syndrome, Scott syndrome, paralysis and rigid akinetic syndrome; extrapyramidal movement disorders such as medication-induced movement disorders, eg, neuroleptic-induced parkinsonism, neuroleptic malignant syndrome, acute neuroleptic-induced dystonia, acute neuroleptic-induced akathisia, neuroleptic-induced tardive dyskinesia, and medication-induced postural tremor; dependencies and additions to chemical substances (eg dependencies or additions to alcohol, heroin, cocaine, benzodiazepines, nicotine or phenobarbitol) and behavioral additions such as gambling addiction; and ocular disorders such as glaucoma and ischemic retinopathy in a mammal, including a human, comprising administering to said mammal: (a) a compound according to claim 1 or a pharmaceutically acceptable salt thereof; and (b) another pharmaceutically active compound which is an antidepressant or anxiolytic agent or a pharmaceutically acceptable salt thereof; wherein the active agents "a" and "b" are present in amounts that make the combination effective to treat such disorder or condition.