MXPA04008190A - 5-heteroaryl substituted indoles. - Google Patents

Abstract

The present invention relates 5-heteroaryl substituted indoles having high affinity for alpha1-adrenoceptors. Accordingly, the compounds of the invention are considered useful for the treatment of diseases or disorders responsive to alpha1-adrenoceptor antagonists. Further, as some of the compounds are selective alpha1-adrenoceptor ligands they may be particularly useful as PET or SPECT ligands.

Description

INDOLES REPLACED WITH 5-HETEROARILLO The present invention relates to novel indoles substituted with 5-heteroaryl having high affinity for a, β-adrenoceptors. Accordingly, the compounds of the invention are considered useful for the treatment of diseases or disorders that respond to oti-adrenoceptor antagonists. In addition, since some of the compounds are ligands of selective α-adrenoceptors, they may be especially useful as PET or SPECT ligands.

BACKGROUND U.S. Patent No. 4,710,500 describes, in general, optionally optionally substituted 5-substituted derivatives having the general formula: The compounds can be substituted at the 5-position with a substituent selected from halogen, lower alkyl, lower alkoxy, hydroxy, cyano, nitro, lower alkylthio, CF3, lower alkylsulfonyl, amino, lower alkylamine and lower dialkylamino. The compounds are claimed to be potent and long-lasting dopamine antagonists, and in agreement, they are useful for the treatment of psychosis, and additionally they are said to be strong 5-HT antagonists which indicates effects in the treatment of negative symptoms of schizophrenia and depression and for the treatment of cardiovascular diseases. The use of sertindole that has the formula as an antisychotic is specifically claimed in EP-A2-0 392 959. This type of compound has also been shown to be useful for the treatment of a range of other disorders including anxiety (WO 92/00070), cognitive disorders (WO 92 / 15303), abuse (WO 92/15302) and hypertension (WO 92/15301). WO 92/15301 describes compounds that have affinity for the oti-adrenoceptor, however, the compounds described herein are not selective for the υi-adrenoceptor. WO 99/46259 and WO 01/21614 relate to the cti-adrenoceptor antagonists with respect to the compounds of the invention which, however, have very different substituents on the piperazine, piperidine and tetrahydropyridine ring. The compounds of WO 01/21614 are not substituted at the 5-position of the indole ring with a heteroaryl group. The interest in the development of antagonists of the oci-adrenoceptors has been centralized primarily in therapies for the treatment of cardiovascular diseases (Hieble and Col. Exp. Opin, Invest. Drugs, 1997, 6, 3657). Prazosin is the prototype of an α-adrenoceptor antagonist which has very potent peripheral effects. Prazosin has also indicated effects in the central nervous system in some animal models, although prazosin is considered to have poor CNS penetration. There is evidence that the blockade of the neurotransmission of a? -adrenoceptors could be beneficial in the treatment of psychoses. The most common antipsychotics including clozapine bind potently to a? -adrenoceptors labeled with [3H] prazosin or [3H] WB-4101. Some studies seem to indicate a central role of the ai component for the atypical profile of clozapine. (Baldessarini and Col. Br. J. Psychiatry, 1992, 160, 12-16 and Prinssen and Col. Eur. J. Pharmacol., 1994, 262, 167-170). Several lines of evidence indicate that blocking neurotransmission of ax-adrenoceptors alone could be beneficial in the treatment of schizophrenia. Metabolic studies and after death indicate noradrenergic system hyperactivity in psychotic patients (R. Baldessarini, D. Huston-Lyons, A. Campbell, E. Marsh, B. M. Cohen, Br J Psychiatry Suppl 12 (1992)). The detonating pattern of dopamine neurons in the midbrain in rats is modulated by the administration of prazosin (J. Grenhoff, TH Svensson, Eur J Pharmacol 233, 79 (1993)) and by electrical stimulation of noradrenergic neurons in the locus coeruleus (J. Grenhoff, M. Nisell, S. Ferre, G. Aston-Jones, T. H. Svensson, J Neural Transm Gen Sect 93, 11 (1993)). Additionally, prazosin reversed the interruption of inhibition of prepulsations of acoustic startle response at rates induced by phencyclidine (PCP) (VP Bakshi, MA Geyer, J Pharmacol Exp Ther 283, 666 (1997) and BS Carasso, VP Bakshi, MA Geyer, Neuropharmacology 37, 401 (1998)). In addition, the repeated co-administration of prazosin and haloperidol reduces the effect of haloperidol in the firing of dopamine neurons in nigrostriatal areas, suggesting that the combination would be effective as an antipsychotic treatment without producing extrapyramidal side effects (EPS) (Chiodo , and Col. J. Neurosci, 1985, 3, 2539-2544).

Co-administration of doses below the threshold of the dopamine D2 antagonist raclopride and the antagonist of the (Xi-adrenoceptor prazosin caused a significantly increased suppression of conditioned abstinence in rats without inducing catalepsy (L. Wadenberg and Col. J Neural Transm 107, 1229 (2000).) It was suggested that blockade of a? -adrenoceptors in the presence of low D2 receptor occupancy could improve antipsychotic efficacy and thereby improve the therapeutic window with respect to extrapyramidal side effects. It has also been suggested that antagonists of the centrally acting ci-adrenoceptors would have antimanic effects while the corresponding agonists would be beneficial for the treatment of depression (Lipinsky and Col. Life Sciences, 1987, 40, 1947-1963). antagonists of the centrally acting a? -adrenoceptors would also have an effect against Stress Disorder Post Traumatic (Raskind, .A .; Dobie, D J.; Kanter, E.D .; Petrie, E.C .; Thompson, CE; Peskind, E.R., J. Clin. Psychiatry, 2000, 61, 129-133 and Taylor, F.; Raskind, M.A., J. Clin Psychopharmacol. 2002, 22, 82-85) The labeled compounds of the present invention are considered PET (positron emission tomography) ligands and valuable SPECT ligands due to their selectivity for ai adrenoceptors.

Finally, it is well established that antagonists of peripherally acting α, β-adrenoceptors are useful for the treatment of benign prostatic hyperplasia, hypertension and cardiac arrhythmias and for the reduction of intraocular pressure.

The invention In accordance with the present invention, novel compounds having the formula are described wherein Het is a five or six membered aromatic, heterocyclic ring containing at least one nitrogen atom as a ring member, and optionally substituted with alkyl of N is 0 or 1; G is N, C or CH; the dotted line means a link when G is C, and the dotted line means no link when G is CH or N; Ar is phenyl optionally substituted with one or more substituents independently selected from halogen.

Ci_6alkyl Ci-6alkoxy, hydroxy, trifluoromethyl and cyano, or Ar is 2-thienyl, 3-thienyl, 2-furanyl, 3-furanyl, 2-thiazolyl, 2-oxazolyl, 2-imidazolyl, 2-pyridyl, 3-pyridyl or 4-pyridyl; R2, R3, R4 and R5 are independently selected from hydrogen, Ci-6 alkyl, Ci-6 alkoxy, hydroxy, halogen, trifluoromethyl, nitro, cyano, amino, Ci-6 alkylamino and Ci-6 dialkylamino; m is 1, 2 or 3; X is a bond, -CH2-, -0-, -S-, -NH-, -NHC0- or -C0NH-; and Y is cyano, Ci-6alkyloxy / Ci-6alkyl substituted with hydroxy, Ci-6alkoxy, or C 1-5 alkylcarbonyloxy or Y is phenyl which may be optionally substituted one or more times with substituents selected from halogen, Ci_6 alkyl, trifluoromethyl, hydroxy, Ci_6 alkoxy, Ci_6 alkylcarbonyloxy, nitro, cyano, amino, Ci-6 alkylamino, Ci-6 dialkylamino / methylenedioxy and ethylenedioxy, or Y is an aromatic, mono- or heterocyclic bicyclic containing only one heteroatom which may be optionally substituted one or more times with substituents selected from halogen, Ci-S alkyl, trifluoromethyl, hydroxy, Ci-6 alkoxy, Ci-6 alkylcarbonyloxy, nitro, cyano, amino , Ci-6 alkylamino and Ci-6 dialkylamino; provided that Y is not cyano when X is O, S, NH, NHCO or CONH; and Y is not C1-6 alkoxy when X is O, S or NH; or their pharmaceutically acceptable acid addition salts. In a particular embodiment of the invention, Het is optionally substituted triazolyl, pyrazolyl, pyrimidyl, pyridinyl or imidazolyl. Suitably, Het is 1-methyl-lH-1,2,4-triazol-3-yl, 2-methyl-2H-1,2, -triazol-3-yl, 3-methyl-3H-1, 2, 3 -triazol-4-yl, 1-methyl-lH-pyrazol-4-yl, 2-methyl-2H-pyrazol-3-yl, l-methyl-lH-imidazol-2-yl, pyrimidin-2-yl or pyridin-3-yl. In another embodiment, the invention relates to compounds of formula (I) wherein Y is cyano, Ci-6 alkyl substituted with hydroxy, Ci-6 alkoxy, or Ci or Y alkylcarbonyloxy is optionally substituted phenyl, in particular the a group of compounds wherein Y is Ci-6 alkyl substituted with hydroxy, Ci-s alkoxy or C 1-6 alkylcarbonyloxy or Y is optionally substituted phenyl. In a third embodiment, X is a bond, -CH2-, O or S, preferably O or S. In a fourth embodiment, Y is an aromatic, bicyclic, heterocyclic, optionally substituted ring containing only one heteroatom, such as for example indolyl, benzofuranyl or optionally substituted dihydro-1,4-benzodioxinyl. In a fifth mode, X is - HCO- or -CONH-.

In a sixth embodiment, Y is optionally substituted phenyl. In a seventh embodiment, the invention relates to compounds in which Y is Ci_6 alkyl substituted with hydroxy, Ci-6 alkoxy or Ci_6 alkylcarbonyloxy. Finally, the invention relates to the group of compounds wherein Y is cyano. The compounds of the invention are antagonists of the potent a? -adrenoceptors and the compounds are therefore useful for the treatment of disorders or diseases that respond to antagonism of the ci-adrenoceptor. Some of the compounds of the invention have a stronger affinity for the oti-adrenoceptor than for the otib-adrenoceptor and the a1 (j-adrenoceptor). Accordingly, in another aspect, the present invention relates to a pharmaceutical composition comprising at least a compound of formula I as defined above or its pharmaceutically acceptable acid addition salt and optionally a second pharmaceutically active ingredient in combination with one or more pharmaceutically acceptable carriers or diluents In a further aspect, the present invention relates to the use of a compound of formula I as defined above or its acid addition salt and optionally a second pharmaceutically active ingredient for the manufacture of a pharmaceutical medicament for the treatment of a disorder or disease responsive to antagonism of cii-adrenoceptor. , in yet another aspect, the present invention relates to use of a compound of formula I as in the above and optionally a second agent having antipsychotic activity for the preparation of a medicament for the treatment of psychosis. Diseases and disorders that respond to antagonism of the oci-adrenoceptors include psychosis, mania, benign prostatic hyperplasia, hypertension, post-traumatic stress disorder and cardiac arrhythmias. Antagonists of oti-adrenoceptors are also useful for the reduction of intraocular pressure. In a further aspect, the invention relates to a method for the treatment of a disorder or disease responsive to antagonism of the oci-adrenoceptors in a mammal comprising administering a compound of formula I as described above and optionally a second ingredient pharmaceutically active at such mammal. In still another aspect, the present invention relates to a method for the treatment of psychosis in a mammal comprising administering a compound of formula I as in the foregoing and optionally a second agent having antipsychotic activity to such a mammal.

The aforementioned second pharmaceutically active ingredient may be another agent having antipsychotic activity, for example an agent having a dopamine D2 antagonist effect. As mentioned above, there is evidence which indicates that such combinations may be advantageous for the treatment of psychoses without causing extra pyramidal effects. Finally, the present invention relates to radiolabelled compounds of formula I and their use in various biological assays and PET or SPECT studies.

Detailed Description of the Invention When used herein, halogen means fluoro, chloro, bromo or iodo. The term "C 1-6 alkyl" refers to a branched or unbranched alkyl group having from one to six carbon atoms inclusive, including groups such as methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2- butyl, 2-methyl-2-propyl and 2-methyl-1-propyl. The terms Ci-6 alkoxy, Ci-6 alkylamino, Ci-e dialkylamino, etc. designate such groups in which CI-G alkyl is as defined above. Het means an aromatic, heterocyclic, five-membered ring containing at least one nitrogen as a ring member, includes, but is not limited to, heterocyclic rings selected from pyrrol-1-yl, pyrrol-2-yl, pyrrole-3 -yl, imidazol-l-yl, imidazol-2-yl, imidazol-4-yl, pyrazol-l-yl, pyrazol-3-yl, 'pyrazol-4-yl, 1, 2, 3-triazol-1-yl, 1, 2, 3 triazol-2-yl, 1, 2, 3-triazol-4-yl, 1, 2,4-triazol-1-yl, 1, 2,4-triazol-3-yl, 1, 2,4-riazole - 5-yl, tetrazol-1-yl, tetrazol-2-yl, tetrazol-5-yl, oxazol-2-yl, oxazol-yl, oxazo-l-5-yl, isoxazol-3-yl, isoxazole-4 -yl, isoxazol-5-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, isothiazol-3-yl, isothiazol-yl, isothiazol-5-yl, 1, 2, 3 oxadiazol-4-yl, 1,2,3-oxadiazol-5-yl, 1, 2,4-oxadiazol-3-yl, 1, 2,4-oxadiazol-5-yl, 1. 3,4-oxadiazol-2-yl, 1,3,4-oxadiazol-5-yl, 1,2,3-thiadiazol-4-yl, 1,2,3-thiadiazol-5-yl, 1, 2, 4 - thiadiazol-3-yl, 1,2,4-thiazothiazol-5-yl, 1, 3, 4-thiadiazol-2-yl, 1,3,4-thiadiazol-5-yl, 1. 2.5-oxadiazol-3-yl, 1, 2, 5-thiadiazol-3-yl, oxatriazol-4-yl and thiatriazol-4-yl. Het means a six-membered aromatic heterocyclic ring containing at least one nitrogen as a ring member, including, but not limited to, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-2 - ilo, pyrimidin-4-yl and pyrimidin-5-yl. Y means an aromatic, mono- or bicyclic heterocyclic ring containing only one heteroatom includes, but is not limited to, rings such as pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, furan-2-yl, furan-3-yl, 2-thienyl, 3-thienyl, pyrrol-1-yl, pyrrol-2-yl, pyrrol-3-yl, indol-1-yl, indol-2-yl, indol-3-yl, indol-4-yl, indole-5-yl, indole-6-yl, indole-7-yl, benzofuran-2-yl, benzofuran-3-yl, benzofuran-yl, benzofuran-5-yl, benzofuran-6 -yl, benzofuran-7-yl, isobenzofuran-1-yl, isobenzofuran-3-yl, isobenzofuran-4-yl, isobenzofuran-5-yl, isobenzofuran-6-yl, isobenzofuran-7-yl, benzothien-2-yl , benzothien-3-yl, benzothien-4-yl, benzothien-5-yl, benzothien-6-yl, benzothien-7-yl, isobenzothien-1-yl, isobenzothien-3-yl, isobenzothien-4-yl, isobenzothien -5-yl, isobenzothien-6-yl, isobenzothien-7-yl, quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-5-yl, quinolin-6-yl, quinolin-7 -yl, quinolin-8-yl, isoquinolin-1-yl, isoquinolin-3-yl , isoquinolin-4-yl, isoquinolin-5-yl, isoquinolin-6-yl, isoquinolin-7-yl and isoquinolin-8-yl. The acid addition salts of the compounds of the invention are pharmaceutically acceptable salts formed with non-toxic acids. Examples of such organic salts are those with maleic, fumaric, benzoic, ascorbic, succinic, oxalic, bis-methylenesalicilic, methanesulfonic, ethanesulfonic, acetic, propionic, tartaric, salicylic, citric, gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, benzenesulfonic and acetic of theophylline, as well as the 8 -halotheophyllines, for example 8 -bromoteophylline. Examples of such inorganic salts are those with hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric and nitric acids. The selectivity of the compounds of the invention for the oci-adrenoceptor makes them particularly useful for the development of radiolabeled ligands useful in various biological assays and in PET and SPECT studies. The compounds of the invention "can be labeled by reacting precursor molecules not labeled with [11C] methyloduro, [1: LC] methyltriflate or other reagents labeled with [11C] carbon dioxide derivatives [" c]. The compounds can also be labeled with 18F, 1231 or 1251. The radiolabelling of the compounds of the present invention can also be carried out according to radiolabelling methods known and used in the prior art. For example, as stated in the specification, the compounds can be labeled by reaction of the appropriate precursors with radiolabelled reagents, including reagents marked with 1: LC such as [1XC] methyloduro and [1XC] methyltriflate. It is also within the knowledge of the person skilled in the art of radiopharmaceuticals the labeling of compounds with 18F or 123I. The compounds of the present invention radiolabeled with 18F can be prepared by nucleophilic aromatic substitution of a precursor molecule containing an appropriate leaving group (such as nitro, bromine, iodine or triflate) by reaction with [18F] F ~. For example, the compounds of the present invention can be radiolabelled with 18F at the 4-position of the phenyl group adhered to the indole N-1. The compounds can be prepared by aromatic nucleophilic substitution of a precursor molecule containing an appropriate leaving group (such as nitro, bromine, iodine or triflate) by reaction with [18F] F ~. After appropriate activation of the aromatic ring with one or two electron withdrawing groups, such as group or formyl groups. The formyl groups can be easily removed after radiofluorination by reaction with Wilkinson catalyst in dioxane at elevated temperature (Sobrio, F.; Amokhtari, M.; Gourand, F .; Dhilly, M.; Dauphin, F .; Barré, L., Bioorg. Med. Chem. 2000, 8, 2511-2518). Radiolabelling with 125I or 123I can be effected by halodemetallation of the corresponding tin (organotin) -replaced precursors, for example by treatment of an ethanolic solution of the organotin precursor with Na123I or Na125I in the presence of chloramine-T and aqueous hydrochloric acid in analogous to the procedure described by Foged and Col. (Foged, C; Halidin, C.; Hiltunen, J., - Braestrup, C.; Thomsen, C.; Hansen, HC; Suhara, T.; Pauli, S .; Swahn, CG; Karlsson, P .; Larsson, S. and Farde, L., Nucí, Med. Biol.1996, 23, 201-209). The organotin precursors of the compounds of the invention can be easily prepared from 5-heteroaryl-indoles substituted with 1- (4-bromophenyl) or 1- (4-iodophenyl) by reaction with n-butyllithium or tert-butyllithium in THF at low temperature, followed by reaction with a trialkyltin halide such as trimethyltin chloride or tributyltin chloride. Intermediates with magnesium metalation can also be used instead of lithium. Alternatively, the palladium catalyzed reaction with hexaalkyldistannanes can also give the corresponding organotin precursors. (Ali, H., Johan, and van Lier, J.E., Synthesis 1996, 423-445). Alternatively, 4- [18F] fluoreiodobenzene can be prepared as described in the literature (Shah, A.; iddowson, DA; Pike, VW, J. Labelled Compd. Radiopharm., 1997, 40, 65-67) and is reacted with N-unsubstituted indole to give the final radiolabelled compounds. The compounds of the present invention can be prepared according to the procedures described below: a) Reacting an indole derivative of the following formula wherein R2, R3, R4, R5, Ar, Het and n are as defined above, with a 4-piperidone of the formula wherein ra, X and Y are as defined above, A is an oxygen atom or a chain -0- (CH2) q-0-, where q is 2 or 3; b) reducing the tetrahydropyridine double bond in a compound of the formula as defined above; c) reacting a compound of the formula (V) in which R2, R3, R4, R5, m, X, Y, G, the dotted line, Het and n are as defined above, with a compound of the formula Ar-hal in which Ar are as defined above and "nal" is halogen, in the presence of a metal catalyst, d) reacting a compound of the formula wherein R2, R3, R4, Rs, G, dotted line, Ar, Het and n are as defined above, with a reagent of formula L- (CH2) mXY in which m, X, and Y are as defined above, and L is halogen, mesylate or tosylate e) reducing the carbonyl group of a compound of the formula where R2, R3, R4, R5, G, the dotted line, Ar, Het and n are as defined above, and R8 is (CH2) (mi) -XY, where m, X, and Y were defined previously f) decarboxylation of a compound of the formula. (CH2) n Het 'COOCH3 (VIII) wherein R2, R3, R4, Ar, Het and n are as defined above, followed by the reaction with a piperazine of the formula wherein m, X and Y are as defined above; g) alkylating the Het group in a compound of formula I wherein Het is unsubstituted in at least one nitrogen atom of the pyrrole type with an alkylating reagent, such as Ci-6-L alkyl, wherein L is chlorine, bromine , iodine, mesylate or tosylate. Accordingly, method g) can be used to introduce radio-labeled alkyl groups, such as [1: LC] methyloduro, [11C] methyltriflate, etc. Methods for the preparation of the starting materials used in the aforementioned processes are described in U.S. Patent No. 4,710,500, O 92/00070, O 99/46259 and Perregaard Col. J. Med. Chem. 1992 ( 35), 1092-1101, or can be prepared analogously to the methods described herein. Starting materials in which the Het group is tetrazol-5-yl can be prepared by reacting the corresponding 5-cyano indole with azide. Starting materials in which the group Het- (CH 2) n- is tetrazol-5-ylmethyl can be prepared in the same way from the corresponding indole containing a 5-cyanomethyl group by reaction with azide. The 5-cyanomethyl-indoles can be prepared by hydrolysis of the corresponding 5-cyano-indole, reduction of the functionality of the obtained carboxylic acid to hydroxymethyl, reaction with methanesulfonyl chloride to form the corresponding 5-chloromethyl-eneles followed by the reaction with a cyanide to form 5-cyanomethyl-indole. The 5-bromo-l-Ar-3-piperidinyl-lH-indole protected with N-Boc is prepared in three steps from 5-bromo-1-Ar-1H-indole. The reaction of 4-piperidin-2-one hydrochloride, hydrate with 5-bromo-Ar-fluorophenyl) -lH-indole using acidic conditions followed by catalytic hydrogenation analogously to published procedures (Perregaard and Col. J. Med. Chem. 1992, 35, 1092) results in the unsubstituted piperidyl compound. Finally, the reaction with boc-anhydride provides the desired starting material.

The introduction of the heteroaryl groups at the 5-positions into the 5-bromo-1-Ar-3-piperidinyl-1H-indole protected with N-Boc is achieved by two alternative methods A and B. In Method A, the 5 - Bromo-1-Ar-3-piperidinyl-1H-indole protected with N-Boc is treated with n-butyllithium followed by transmetallation to the corresponding zinc chloride. The addition of the appropriate heteroaryl halide and 5 mole% of tetrakis (triphenylphosphine) palladium (O) gives the corresponding heteroaryl substituted intermediates. In the reverse B method, the deprotonation of the heteroaryl derivatives or the halogen / metal exchange of heteroaryl halides followed by the transmetallation to the corresponding zinc chlorides and the cross coupling catalyzed with tetrakis (triphenylphosphine) palladium (O) with the 5-bromo-1 -Ar-3-piperidinyl-β-indole protected with N-Boc results in the corresponding 5 -heteroaryl -Indoles. The Boc-protected derivatives obtained by Methods A and B are deprotected and used as starting materials for method d) described below. The starting materials for methods a), b), c) and e) can be prepared analogously using appropriately protected starting materials. In method a), the reaction is carried out under strong acidic conditions by heating. Trifluoroacetic acid or HC1 in ethanol is preferred as acidic catalysts. In method b), the reduction is preferably carried out at low hydrogen pressures (3 Ato.) In the presence of platinum or palladium on carbon black. In method c), arylation is preferably carried out at about 160-210 ° C in polar aprotic solvents such as N-methyl-2-pyrrolidine or hexamethylphosphoric triamide with K2CO3 as base and copper as a catalyst. In method d), the alkylations are carried out in an aprotic solvent such as dimethylformamide or acetonitrile using an appropriate base such as potassium carbonate or diisopropylethylamine at elevated temperatures (50-120 ° C). In method e), the reduction is preferably carried out with LiALH4 in THP or diethyl ether or with diborane in THF. Method f) is a two-step process in which compound VIII is first decarboxylated in the presence of an inorganic salt such as for example LiCl or gCl 2 in a polar solvent such as diglyme, hexamethylphosphoric triamide or N-methyl-2 - pyrrolidone at elevated temperatures (120-150 ° C). Finally, the appropriate piperazine is added and the temperature is raised to approximately 200 ° C and maintained there until the corresponding indoxyl has disappeared according to the TLC analysis. The compounds of Formula VIII are conveniently prepared according to the methods reported by Unangst and Col. J. Heterocyclic Chem. 1984, 21, 709. In method g), alkylation with alkyl iodides or bromides is carried out by solvents. aprotic such as acetone or dimethylformamide using an appropriate base such as potassium carbonate or diisopropylethylamine at elevated temperatures (40-90 ° C). In the following, the invention is further illustrated by means of examples that, however, should not be considered as limiting.

General examples. All reactions were carried out under a positive pressure of nitrogen or argon. The glassware for water-sensitive reactions was dried in an oven at 150 ° C overnight. THF was recently distilled from sodium / benzophenone. The DMF was dried sequentially and stored in 3 A molecular sieves. The ZnCl2 was flame-dried under vacuum and dissolved to 1.0 M in dry THF after cooling to room temperature. The acetone and CH3CN for the alkylation reactions were brought to HPLC quality. The saturated HCl / MeOH solutions were prepared by saturating eOH with HCl gas. Flash chromatography was carried out using silica gel of the Kieselgel type 60, 230-400 mesh ASTM or Biotage Flash 40 (columns of 50 or 100 g). The "" H NMR spectra of all the novel compounds were recorded at 250 MHz on a Bruker AC 250 instrument or at 500 MHz on a Bruker Avance DRX500 instrument Deuterated chloroform (99.8% D) or DMSO-ds ( 99.9% D) TMS was used as the internal reference standard, the chemical deviation values are expressed in ppm values The following abbreviations are used for the multiplicity of NMR signals: s = singlet, d = doublet, t = triplet , q = quartet, dd = double doublet, dd = double triplet, tt = triplet of triplets, m = multiplet The NMR signals corresponding to the acidic protons are generally omitted, the melting points are reported uncorrected. The solvent in the samples of the analysis of elements were measured by Karl Fisher titration (H20) or by Thermo Gravimetric Analysis (TGA) in a TA TGA 2950 instrument with a heating index of 10 ° C per min. tified by LH NMR. Solvent residuals are not reported in the NMR data. Analytical and preparative HPLC were carried out in a Shimadzu HPLC system with two Shimadzu LC-8A pumps. The UV trace was obtained using a SPD-10A detector from Shimadzu operating at 254 nm. The ELSD trace was obtained using a Sedere Sedex 55 detector operating at 42 ° C and 2.3 bars. For the analytical HPLC-MS a Perkin Elmer API 150EX mass spectrometer equipped with an ion source of SCIEX Heated Nebulizer (APCI) from Perkin Elmer was used. The total ion current (TIC) was recorded in positive mode for m / z 100-1000 amu. Analytical HPLC was carried out by injecting 10 uL to a Waters Symmetry C-18 column (4.6x30 mm, 3.5 um). The sample was eluted with a gradient of the following solvent mixtures: A: water / TFA 100 / 0.05 and B: acetonitrile / water / TFA 95/5 / 0.035. Gradient: A / B 90/10? 0/100 for 4 minutes, then isocratic A / B 90/10 for 1 minute. The flow was 2 mL / min throughout the procedure. The preparative HPLC-MS was carried out with injections of 190 uL in. a YMC RP18 column (50x20 mm) with a 80/20 A / B gradient? 0/100 for 7 minutes, then 80/20 isocratic for one minute. The flow was 22.7 mL / min all the time and the detection was made using the MS signal (TIC) in a divided system. The purities reported are based on the integration of the peaks in the UV and ELSD spectrum.

Reagents: The following reagents were prepared according to published procedures: 3- (2-Chloroethyl) imidazolidin-2-one (Perregaard and Col. Med Chem 1992, 35, 1092 and Johnston and Col. J. Med. Chem. 1963 , 6, 669), 3- (2-chloroethyl) -oxazolidin-2-one (Robinson and Col. J Am Chem Soc 1972, 94, 7883), 3- (2-chloroethyl) -l-methyl-2-pyrrolidine -2-one (Sucrow and Col. Chem. Ber. 1972, 105, 1621), 1-methyl-1,2,3-triazole (Begtrup and Col. Acta. Chem Scand 1990, 44, 1050), 4-bromine -l-methyl-l, 2, 3-triazole (Hüttel and Col. Liebigs Ann Chem 1955, 593, 207), 2-bromo-l-methyl-1,3,4-triazole (Bernardini and Col. Soc Chim 1975 , 5, 647), 5-bromo-l-methyl-l, 2,4-triazole (Bernardini and Col. Soc Chim 1975, 5, 64.7) and 3-bromo-l-methyl-l, 2,4-triazole , 7 3 -Oodo- 1-methylpyrazole (Baile, EC al. Synthesis 2002, 1509-1512).

Preparation of Starting Material 4- (5-Bromo-1- (4-fluorophenyl) -lH-indol-3-yl) piperidine-l-carboxylic acid tert-butyl ester (I). A solution of 5-Bromo-l- (4-fluorophenyl) -3- (4-piperidinyl) -1-H-indole (125 g, 0.33 mol) (Prepared as described by Perregeard and Col. J Med Chem 1992, 35, 1092) and di-tert-butyl dicarbonate (260 g, 1.2 mol) in a 1: 1 mixture of THF / H20 (1 L) was stirred overnight with K2CO3 (300 g, 2.2 mol) at 60 ° C. EtOAc (1 L) was added. After separation of the two phases, the aqueous phase was extracted with EtOAc (3x0.5 L). The combined organic phases were washed with brine and dried over MgSO4. The crude product (115 g) was washed with cold MeOH to give 97 g of 1 as white crystals: Mp 160-162 ° C (heptane); XH RM (CDC13): 1.49 (s, 9H), 1.65 (q, 2H), 2.04 (d, 2H), 2.85-3.00 (m, 3H), 4.25 (d, 2H), 7.03 (s, lH), 7.15-7.35 (m, 4H), 7.39-7.43 (m, 2H), 7.78 (s, 1H); MS m / z (relative intensity): 473 + 475 (?? +, 1%), 417 + 419 (40%), 373 + 375 (100%); Anal. (C24H26BrFN202): C, H, N.

Preparation of Intermediaries (Method A) Cross coupling of 4- (5-bromo-l- (4-fluorophenyl) -lH-indol-3-yl) -piperidine-1-carboxylic acid tert-butyl ester with a heteroaryl halide The ter- butyl 4- (5-bromo-l- (4-fluorophenyl) -lH-indol-3-yl) -piperidine-l-carboxylic acid (I) (10 g, 21.1 mmol) in THF (20 mL) was added for 2 minutes to a solution of n-butyllithium (39.6 mL, 63.4 mmol) in THF (210 mL) at -78 ° C. After stirring for 3 minutes, ZnCl 2 in THF (105.6 mL, 105.6 mmol) was added. The solution was stirred for another 30 minutes at -78 ° C. The heteroaryl halide (amount specified below) was added together with Pd (PPh3) (1.2 g, 5 mol%) and DMF (60 ml). The reaction mixture was stirred at 80 ° C for 8 h. After cooling to room temperature, H20 (300 mL) and EtOAc (500 mL) were added and the phases were separated. The organic phase was washed with H20 (200 mL) and saturated aqueous CaCl2 (3x100 mL), dried over MgSO4 and the solvent was removed in vacuo. The crude product was purified by flash chromatography. The amount of reagents and solvents was measured according to the actual amount of 1 used.

The following derivatives were prepared according to Method A 4- (1- (4-fluorophenyl) -5- (l-methylpyrazol-3-yl) -lH-indol-3-yl) -piperidin ter -butyl ester - 1-carboxylic (2a). A solution of 1 (6.88 g, 14.4 mmol) in THF was reacted with l-methyl-3-iodopyrazole (3.0 g, 14.4 mmol). The crude product was purified by flash chromatography (EtOAc / heptane 20/80? 50/50) to give 4.31 g (63%) of 2a as white crystals: Mp. 145.3-145.6 ° C (EtOAc / heptane); XH-NMR (CDC13) 1.49 (s, 9H), 1.68 (q, 2H), 2.10 (d, 2H), 2.93 (t, 2H), 3.11 (t, 1H), 3.98 (s, 3H), 4.26 ( s, broad, 2H), 6.57 (d, J = 2.0 Hz, 1H), 7.04 (s, 1H), 7.17-7.24 (m, 2H), 7.39 (d, J = 2.1 Hz, 1H), 7.42-7.52 (m, 3H), 7.65 (d, J = 8.6 Hz, 1 H), 8.08 (s, 1 H); MS m / z: 475 (7%, MH +), 419 (100%), 375 (73%); Anal. (C28H3J, 4FO2): C, H, N. 4- (1- (4-fluorophenyl) -5- (1-methylpyrazol-4-yl) -lH-indol-3-yl) -piperidine-1-carboxylic acid tert-butyl ester (2b). A solution of 1 (10 g, 21.1 mmol) in THF was reacted with 1-methyl-4-bromopyrazole (4.2 g, 31.7 mmol). The crude product was purified by flash chromatography (EtOAc / heptane 20/80? 30/70) to give 2.8 g (28%) of 2b as white crystals: Mp 133-136 ° C (EtOAc / heptane); 1 H-NMR (CDCl 3) 1.49 (s, 9 H), 1.71 (q, 2 H), 2.10 (d, 2 H), 2.94 (t, 2 H), 3.05 (t, 1 H), 3.96 (s, 3 H), 4.27 ( s, broad, 2H), 7.04 (s, 1H), 7.20-7.25 (m, 2H), 7.34 (d, 1H), 7.41-7.50 (m, 3H), 7. 63 (s, 1H), 7.71 (s, 1H), 7.79 (s, 1H); MS m / z: 475 (5%, MH +), 419 (86%), 375 (100%); Anal. (C28H3i 4F02): C, H, N. 4- (1- (4-fluorophenyl) -5- (l-methyl-l, 2,4-triazol-3-yl) -lH-indol-3-1) -piperidin-1-tert-butyl ester carboxylic (2c). A solution of 1 (20 g, 42 mmol) in THF was reacted with 3-bromo-l-methyl-1,2,4-triazole (8.8 g, 55 mmol). The crude product was purified by flash chromatography (EtOAc / heptane / MeOH 50/50/0? 100/0/0? 90/0/10) and crystallized from Et20 to give 8 g (40%) of 2c in the form of white crystals: Mp 189-191 ° C (Et20); 1 H-NMR (CDC13) 1.50 (s, 9H), 1.70 (q, 2H), 2.12 (d, 2H), 2.95 (t, 2H), 3.13 (t, 1H), 4.00 (s, 3H), 4.28 ( s, broad, 2H), 7.06 (s, 1H), 7.15-7.28 (m, 2H), 7.40-7.52 (m, 3H), 8.00 (d, 1H), 8.08 (s, 1H), 8.42 (s, 1 HOUR); MS m / z: 476 (72%, MH +), 420 (66%), 376 (100%); Anal. (C27H30N5F02 »2.17% Et20): C, H, N. 4- (1- (4-fluorophenyl) -5- (1-methyl-1,3,4-triazol-2-yl) -lH-indol-3-yl) -piperidin-1-tert-butyl ester carboxylic (2d). A solution of 1 (10 g, 21.1 mmol) in THF was reacted with 2-bromo-l-methyl-1,3-triazole (2.8 g, 17.3 mmol). The crude product was purified by flash chromatography (EtOAc / heptane / MeOH 30/70/0? 100/0/0 - »90/0/10) to give 2.5 g (31%) of 2d as white crystals: Pf 156-158 ° C (toluene / heptane 1: 1); 1 H-NMR (CDCl 3) 1.49 (s, 9 H), 1.70 (q, 2 H), 2.08 (d, 2 H), 2.90 (t, 2 H), 3.07 (t, 1 H), 3.78 (s, 3 H), 4.26 ( s, broad, 2H), 7.13 (s, 1H), 7.20-7.28 (m, 2H), 7.41-7.50 (m, 3H), 7.53 (d, 1H), 8.05 (s, 1H), 8.21 (s, 1 HOUR); MS m / z: 476 (100%, MH +), 420 (51%), 376 (83%); Anal. (C27H30N5FO2): C, H,. N. 4- (1- (4-fluorophenyl) -5- (l-methyl-l, 2,4-triazol-5-yl) -lH-indol-3-yl) -piperidin-1-tert-butyl ester carboxylic (2e). A solution of 1 (7.5 g, 15.8 mmol) in THF was reacted with 5-bromo-1-methyl-1,2,4-triazole (2.1 g, 13 mmol). The crude product was purified by flash chromatography (EtOAc / heptane / MeOH 30/70/0 -OOO / O / O? 90/0/10) to give 2.8 g (45%) of 2e as a pale yellow foam: 1 H-NMR (CDCl 3) 1.49 (s, 9 H), 1.70 (q, 2 H), 2.09 (d, 2 H), 2.91 (t, 2 H), 3.07 (t, 1 H), 4.03 (s, 3 H), 4.28 ( s, broad, 2H), 7.13 (s, 1H), 7.20-7.30 (m, 2H), 7.42-7.50 (m, 3H), 7.52 (d, 1H), 7.96 (s, 1H), 8.02 (s, 1 HOUR); MS m / z: 476 (100%, MH +), 420 (33%), 376 (41%); Anal. (C27H30N5FO2): C, H, N. 4- (1- (4-fluorophenyl) -5- (pyrimidin-2-yl) -lH-indol-3-yl) -piperidine-1-carboxylic acid tert-butyl ester (2f).

A solution of 1 (18 g, 38 mmol) in THF was reacted with 2-bromo-pyrimidine (10 g, 75 mmol). The crude product was purified by flash chromatography (EtOAc / heptane 10/90? EtOAc / MeOH 90/10) and crystallized from Et20 to give 12 g (67%) of 2f as white crystals: Mp. 164-166 ° C (Et20); ^ -NMR (CDC13) 1.50 (s, 9H), 1.71 (q, 2H), 2.14 (d, 2H), 2.96 (t, 2H), 3.16 (t, 1H), 4.27 (s, broad, 2H), 7.08 (s, 1H), 7.13 (t, 1H), 7.20-7.25 (m, 2H), 7.43-7.49 (m, 2H), 7.51 (d, 1H), 8.36 (d, 1H), 8.77-8.81 ( m, 3H); MS m / z: 473 (11%, MH +), 417 (100%), 373 (84%); Anal. (C28H29N4FO;,): C, H, N. 4- (1- (4-Fluorophenyl) -5- (pyrimidin-5-yl) -lH-indol-3-yl) -piperidine-1-carboxylic acid tert-butyl ester (2g).

A solution of 1 (10 g, 21.1 mmol) in THF was reacted with 5-bromopyrimidine (5 g, 31.6 mmol). Flash chromatography (EtOAc / heptane / NEt3 30/70/4? 70/30/4) gave 8.2 g which was recrystallized from toluene / heptane 1: 1 to give 5.0 g (50%) of 2g: Pf 144- 146 ° C (toluene / heptane 1: 1); MS m / z: 473 (MH +, 3%), 417 (100%), 373 (33%); 1 H-NMR (CDC13) 1.49 (s, 9H), 1.75 (q, 2H), 2.13 (d, 2H), 2.95 (t, 2H), 3.08 (t, 1H), 4.28 (s, broad, 2H), 7.13 (s, 1H), 7.20-7.30 (m, 2H), 7.42 (dd, 1H), 7.43-7.50 (va, 2H) 7.57 (d, 1H), 7.85 (d, 1H), 9.02 (s, 2H) ), 9.19 (s, 1H); Anal. (C28H29FN402): C, H, N. 4- (1- (4-fluorophenyl) -5- (l-methyl-1,2,3-triazol-4-yl) -lH-indol-3-yl) -piperidin-1-tert-butyl ester carboxylic (2H). A solution of 1 (4.7 g, 10 mmol) in THF was reacted with 4-bromo-l-methyl-1,2,3-triazole (1.1 g, 6.8 mmol). The crude product was purified by flash chromatography (EtOAc / Heptane 20/80? 100/0) to give 900 mg (28%) of 2H as a white foam: aH-RM (CDC13) 1.50 (s, 9H), 1.69 (q, 2H), 2.12 (d, 2H), 2.94 (t, 2H), 3.09 (t, 1H), 4.18 (s, 3H), 4.28 (s, broad, 1H), 7.06 (s, 1H) , 7.17-7.24. (M, 2H), 7.40-7.55 (m, 3H), 7.61 (d, 1H), 7.78 (s, 1H), 8.23 (s, 1H); MS m / z: 476 (4%, MH +), 420 (46%), 376 (100%); Anal. (C27H3o 5F02 2.70% EtOAc): C, H, N.

Preparation of Intermediates (Method B) Cross-coupling of a heteroarilzinc chloride with 4- (5-bromo-l- (4-fluorophenyl) -lH-indol-3-yl) -piperidin-l-butyl ester -carboxylic acid (1) 4- (5-Bromo-l- (4-fluorophenyl) -lH-indol-3-yl) -piperidine-l-carboxylic acid tert-butyl ester (1) (8.3 g), 16.9 mmol) was added to a solution of heteroaryl zinc chloride in THF (amount and preparation specified below) with Pd (PPH3) 4 (5 mol%) and DMF (30% of the amount of or THF). The solution was stirred for 8 h at 80 ° C. The work-up was carried out as described in method A. The amounts of reagents and solvents were measured according to the actual amount of 1 used. The following derivatives were prepared according to Method B: 4- (1- (4-fluorophenyl) -5- (l-methylpyrazol-5-yl) -lH-indol-3-yl) -piperidine-l-carboxylic acid tert-butyl ester (3a). 1-methylpirazole (3.2 g, 39 mmol) in THF (200 mL) was cooled to -78 ° C. N-Butyllithium (43 mL, 26.9 mmol) was added over 5 minutes. The solution was slowly warmed to room temperature for 15 minutes and cooled again to -78 ° C. ZnCl2 in THF (120 mL, 120 mmol) was added and the solution was stirred at -78 ° C for 30 minutes. The reaction with 1 (14.2 g, 30 mmol) was carried out following method B. Flash chromatography (EtOAc / heptane / NEt3 30/70/5? 50/50/5) and recrystallization from CH2C12 gave 11.5 g ( 80%) of 3 *: Mp 166-168 ° C (CH2C12); ^ -NMR (CDCL3): 1.49 (s, 9H), 1.72 (q, 2H), 2.07 (d, 2H), 2.93 (t, 2H), 3.05 (t, 1H), 3.90 (s, 3H), 4.26 (s, broad, 2H), 6.32 (s, 1H), 7.10 (s, 1H), 7.20-7.30 (m, 3H), 7.40-7.47 (m, 2H), 7.50 (d, 1H), 7.54 (s) , 1H), 7.69 (s, 1H); Anal. (C2aH31FN402): C, H, N. 4- (1- (4-fluorophenyl) -5- (l-methylimidazol-2-yl) -lH-indol-3-yl) -piperidine-l-carboxylic acid tert-butyl ester (3b) The 1-methylimidazole (1.39 g, 16.9 mmol) in THF (195 mL) was cooled to -78 ° C. N-Butyllithium (14.7 mL, 23.5 mmol) was added over 2 minutes. The solution was stirred for 5 minutes at -78 ° C and ZnCl 2 in THF (60 mL, 60 mmol) was added. After stirring at -78 ° C for 1H the reaction was carried out with 1 (8.30 g, 16.9 mmol) following method B. Flash chromatography (EtOAc / heptane / NEt3 30/70/4? 70/30/4 ) gave 6.77 g which recrystallized from toluene / heptane 1: 1 to give 4.73 g (59%): mp 189-191 ° C (toluene / heptane 1: 1); ^ -NMR (CDCl3) 1.49 (s, 9H), 7.69 (q, 2H), 2.10 (d, 2H), 2.89 (t, 2H), 3.05 (t, 1H), 3.77 (s, 3H), 4.25 ( s, broad, 2H), 6.99 (s, 1H), 7.09 (s, 1H), 7.15 (s, 1H), 7.15-7.25 (m, 2H), 7.4-7.55 (m (4H), 7.97 (s, 1H); Anal. (C28H3iFN402): C, H, N. 4- (1- (4-fluorophenyl) -5- (l-methyl-l, 2,3-triazol-5-yl) -lH-indol-3-yl) -piperidin-1-tert-butyl ester carbid Ilic (3c). 1-Methyl-1, 2, 3-triazole (1.71 g, 20.6 mmol) was dissolved in THF (200 mL) and cooled to -78 ° C. N-Butyllithium (15.4 mL, 24.7 mmol) was added over 2 minutes and the solution was stirred for another 5 minutes before adding ZnCl 2 in THF (61.8 mL, 61.8 mmol). After 30 minutes at -78 ° C the reaction was carried out with 1 (9.75 g, 20.6 mmol) following method B. Purification by flash chromatography (EtOAc / heptane / EtOH 30/70/2) gave 6.8 g which recrystallized from toluene / heptane 1: 2 to give 4.3 g (44%) of 3c: Mp 137-141 ° C (toluene / heptane 1: 2); ^ -RMN (CDC13) 1.49 (s, 9H), 1.70 (q, 2H), 22.08 (d, 2H), 2.93 (t, 2H), 3.05 (t, 1H), 4.09 (s, 3H), 4.30 ( s, broad, 2H), 7.15 (s, 1H), 7.20-7.30 (m, 3H), 7.40-7.50 (m, 2H), 7.45 (d, 1H), 7.69 (s, 1H), 7.74 (s, 1 HOUR); Anal. (C27H3oF 502): C, H, N. 4- (1- (4-fluorophenyl) -5- (pyridin-3-yl) -lH-indol-3-yl) -piperidine-1-carboxylic acid tert-butyl ester (3d). 3-Bromopyridine was treated with lithium as described by Furneaux et al. Tetrahedron 1997. 53. 2915. The THF (200 mL) was cooled to -100 ° C (Et20 / N2 liquid) and n-butyllithium (19 mL, 30.4 mmol) was added. 3-Bromopyridine (4.00 g, 25.3 mmol) was added over 2 minutes. After 20 minutes at -100 ° C ZnCl 2 in THF (60 mL, 60 mmol) was added. By this method a white precipitate formed. The temperature was slightly elevated to -30 ° C to dissolve the precipitate and then stirred at -78 ° C for 30 minutes. The reaction was carried out with 1 (10 g, 21.1 mmol) following method B. Flash chromatography (EtOAc / heptane / NEt3 30/70/5) gave 8.3 g which was recrystallized from EtOAc / heptane 1: 1 to give 6.0 g (60%) of 3d: Mp 160-162 ° C (EtOAc / heptane 1: 1); MS m / z: 472 (MH +, 3%), 416 (100%), 372 (37%); XH-NMR (CDCl3) 1.49 (s, 9H), 1.74 (q, 2H), 2.14 (d, 2H), 2.93 (t, 2H), 3.10 (t, 1H), 4.29 (s, broad, 2H), 7.11 (s, 1H), 7.20-7.30 (m, 2H), 7.36 (dd, 1H), 7.40-7.50 (m, 3H), 7.55 (d, 1H), 7.85 (d, 1H), 7.95 (dt, 1H), 8.57 (dd, 1H), 8.91 (d, 1H); Anal. (C29H30FN3O2): C, H, N.

Preparation of Compounds of the Invention Deprotection and alkylation of the ter-butyl esters of 4- (1- (4-fluorophenyl) -lH-indol-3-yl) -piperidine-1-carboxylic acid substituted with 5-heteroaryl (2a- h, 3a-d) Method C The 4- (1- (4-fluorophenyl) -lH-indol-3-yl) -piperidine-1-carboxylic acid tert-butyl ester substituted with 5-heteroaryl (2a-h, 3a-d) (6.3 mmol) was dissolved in THF (20 mL) and HCl / eOH (30 mL) was added. The solution was stirred for 4 h, and the solvents were removed in vacuo. 4-Methyl-2-pentanone (30 ml) was added and the solvent was again removed in vacuo. K2C03 (5 g, 36 mmol), Kl (0.5 g, 3 mmol), 4-methyl-2-pentanone (100 mL) and an alkyl halide (9.5 mmol if indicated otherwise) were added and the solution was added. stirred under reflux for 8 h. The amounts of reagents and solvents were measured according to the actual amount of 4- (1 - (4-fluorophenyl) -lH-indol-3-yl) -piperidine-1-carboxylic acid tert-butyl ester substituted with 5- heteroaryl used. Preparation procedure 1: H20 (50 ml) was added to the hot mixture and the phases were separated. The aqueous phase is extracted with CH2C12 (100 ml). The combined organic phases were washed with H20 and with saturated aqueous CaCl2, dried (gS04) and the solvents were removed in vacuo. The resulting compound was purified by flash chromatography.

Preparation procedure 2: H20 (50 ml) was added to the hot mixture and the phases were separated. The aqueous phase was extracted with CH2C12 (100 mL). Kieselgel was added to the combined organic phases and the solvents were removed in vacuo. The resulting compound adsorbed on kieselgel was purified using Biotage flash 40 equipped with a solid injection module FZI M-0035.

Oxalate of 3-. { 4- [1- (4-Fluoro-phenyl) -5- (1-methyl-lH-1, 2,4-triazol-3-yl) -lH-indol-3-yl] -piperidin-1-yl} -propionitrile (4a). The reaction of 2c (1.2 g, 2.5 mmol) with 3-bromo-propionitrile (1.1 g, 8.2 mmol) was carried out according to method C followed by work-up procedure 2. The crude product was purified by flash chromatography (EtOAc / heptane 50/50? EtOAc / MeOH 90/10) and precipitated with oxalic acid from EtOH to give 0.45 g (34%) of the oxalate of 4a: Mp. 216-217 ° C (EtOH); ^ -RM (DMS0-d6) 1.95 (qd, 2H), 2.12 (d, 2H), 2.76 (t, 2H), 2.93 (t, 2H), 3.02-3.15 (m, 3H), 3.32 (d, 2H) ), 3.93 (s, 3H), 7.40-7.47 (m, 2H), 7.48 (s, 1H), 7.54 (d, 1H), 7.60-7.68 (m, 2H), 7.89 (d, 1H), 8.32 ( s, 1H), 8.48 (s, 1H); MS m / z: 429 (100%, MH +), 388 (12%), 241 (3%); Anal. (C25H25FN6 C2H204 0.55% H20): C, H, N.

The following derivative was prepared accordingly from 2f: 8.49 (s, 1H); E m / z: 510 (100%, MH +); Anal. (C3iH32FN50): C, H, N. 1- (4-Fluoro-phenyl) -5- (1-methyl-lH-1, 2,4-triazol-3-yl) -3- [1- (2-phenylethyl) -piperidin-yl] -lH-indole (4d) The reaction of 2c (1.0 g, 2.10 mmol) with (2-bromo-ethyl) -benzene (0.81 g, 4.4 mmol) was carried out according to method C followed by work-up procedure 2. Flash chromatography ( EtOAc / heptane 70/30? EtOAc / MeOH / Net3 90/10/2) gave 0.80 g which was recrystallized from EtOAc / heptane 1/3 to give 0.30 g (30%) of 4d: Mp 244-245 ° C (EtOAc / heptane 1/3); 1 H-NMR (DMSO-d 6) 1.90 (s, broad, 4H), 2.10 (s, broad, 2H), 2.51 - (t, 2H), 2.90 (s, broad, 4H), 3.05 (s, broad, 1H) ), 3.93 (s, 3H), 7.23 (t, 1H), 7.30 (t, 2H), 7.31 (d, 2H), 7.40-7.48 (m, 2H), 7.52 (s, broad, 1H), 7.54 ( d, 1H), 7.62-6.68 (m, 2H), 7.90 (d, 1H), 8.35 (s, 1H), 8.50 (s, 1H); MS m / z: 480 (100%, MH +); Anal. (C3oH3oFN5): C, H, N. 3-. { 4- [1- (4-Fluoro-phenyl) -5- (1-methyl-lH- [1,2,4] triazol-3-yl) -lH-indol-3-yl] -piperidin-1-yl } -propan-l-ol (4e). The reaction of 2c (1.0 g, 2.10 mmol) with 3-bromo-l-propanol (0.34 g, 2.40 mmol) was carried out according to method C followed by work-up procedure 2. Flash chromatography EtOAc / MeOH / NEt3 (100/0/2? 75/25/2) gave 500 mg of the crude product which was crystallized from EtOAc / heptane (70/30) to give 250 mg of the title compound. Mp. 138-139 ° C (EtOAc / heptane); 1H-RM (DMSO-d6) 1.65 (q, 2H), 1.80 (qd, 2H), 2.02 (d, 2H), 2.20 (t, 2H), 2.49 (d, 2H), 2.90 (t, 1H), 3.05 (d, 2H), 3.32 (s, broad, 1H), 3.49 (t, 2H), 3.92 (s, 3H), 7.39-7.43 (m, 2H), 7.45 (s, 1H), 7.52 (d, 1H), 7.49-7.55 (m, 2H), 7.88 (d, 1H), 8.30 (s, 1H), 8.50 (s, 1H).

Preparation of other Compounds of the Invention Each of the intermediates 2a-h and 3a-d (1 mmol) was dissolved in THF (30 mL) and reacted overnight with a saturated solution of HCl in MeOH (15 mL) at room temperature. The solvents were removed in vacuo, H20 was added and the pH was adjusted to 10 by the addition of aqueous ammonium hydroxide (25%). The aqueous phase was extracted with CH2C12 and the combined organic phases were dried over MgSO4. After evaporation of the solvent, initial solutions of the piperidinyl derivatives were prepared by dissolving up to 0.2 M by the addition of DSO. Initial solutions of the alkyl halides were prepared by dissolving the halides in as little D F as possible. The solutions were subsequently diluted to 0.2 M by the addition of CH3CN. Blocks (Multisyntech Microchem Blocks (MultiSynTech GmbH, 2002) containing 96 1.2 ml reactors equipped with frits were loaded with K2C03 (40 mg, 0.3 mmol) and Kl (10 mg, 0.06 mmol). the piperidinyl derivatives (0.15 ml, 0.03 mmol), the alkyl halide (0.225 ml, 0.045 mmol) and CH3CN (0.3 ml) and the reactors were closed and rotated in an oven at 70 ° C for 14 h. to 50 ° C the isocyanate resin (30 mg, 1 mmol / g) was added and the reactors were closed again and rotated at 50 ° C for 2 h After cooling to room temperature, the solids were separated by filtration and washed with CH3CM (2 x 0.3 ml) The combined organic phases were purified using SCX ion exchange chromatography as follows: Columns (Varian Bond Elut-SCX 500 mg / 3 ml) were conditioned with acetic acid in methanol (10%). , 3 mi) The combined organic phases of the sample they were added and washed with MeOH (3 mL) and CH3CN (3 mL). Finally, the sample was eluted with ammonia in MeOH (3 ml, 4 M). Between each step, a slight air pressure was applied. The solvents were evaporated in vacuo and the solutions were diluted to 2 mM in DMSO. The identity and purity of the compounds were determined by HPLC / MS analysis with UV detection and ELSD. The compounds with a purity of 70% or higher were subjected to biological evaluation. The remaining compounds were purified by preparative LC / MS (Zeng, and Col. Comb. Chem. High Throughput ScreenJID-9810948.1998.1.101). The following alkylating agents were used for the preparation of the examples mentioned below: 3- bromo-propionitrile, 3- (2-chloroethyl) -oxazolidin-2-one, 3- (2-chloroethyl) -lH-quinazoline-2, 4 -dione, 3- (2-chloroethyl) -1-methylpyrrolidin-2-one, 1- (2-chloro-ethyl) -methoxy-benzene, 1- (2-bromo-ethoxy) -2-methoxy-ethane, 3- bromo-N- (2,5-dimethoxy-phenyl) propionamide, 3-bromo-N- (2,5-dimethoxy-phenyl) -propionamide, 5- (3-bromo-propoxy) -2,3-dihydro-benzo [ 1, 4] dioxin, 1- (2-chloro-ethoxy) propane, 2- (3-bromo-propoxy) -benzonitrile, 1- (3-bromo-propoxy) 4-fluoro-2-methoxy-benzene, 3 - (2-bromo-ethyl) -benzofuran, 3- (2-bromo-ethyl) -lH-indole, 3- (3-bromo-propyl) -lH-indole. The following examples were prepared according to general procedure d): 3-. { 4- [1- (4-Fluoro-phenyl) -5- (2-methyl-2H-pyrazol-3-yl) -lH-indol-3-yl] -piperidin-1-yl} -propionitrile (5aa): Rf = 2.02; UV / ELSD purity: 97.2 / 99.8 3- [1- (2-Benzofuran-3-yl-ethyl) -piperidin-4-yl] -1- (4-fluoro-phenyl) -5- (2-methyl-2H -pyrazol-3-yl) -lH-indole (5ab): R £ = 2.47; UV / ELSD purity: 78.9 / 96.7 3- [1- (2-lH-indol-3-yl-ethyl) -piperidin-4-yl] -1- (4-fluoro-phenyl) -5- (2-methyl) -2H-pyrazol-3-yl) -lH-indole (5ac): Rf = 2.38; UV / ELSD purity: 99.0 / 100.0 3-. { 4- [1- (4-Fluoro-phenyl) -5-pyridin-3-yl-1H-indol-3-yl] -piperidin-1-yl} -propionitrile (5ad): Rf = 1.59; UV / ELSD purity: 91.5 / 100.0 1- (4-Fluoro-phenyl) -3-. { l- [2- (4-methoxy-phenyl) -ethyl] -piperidin-4-yl} -5-pyridin-3-yl-lH-indole (5ae): Rf = 1.92; UV / ELSD Purity: 94.7 / 100.0 3- [1- (2-Benzofuran-3-yl-ethyl) -piperidin-4-yl] -1- (4-fluoro-phenyl) -5-pyridin-3-yl- 1H-indole (5af): Rf = 2.04; Purity UV / ELSD: 95.0 / 99.1 3- [1- (2-lH-indol-3-yl-ethyl) -piperidin-4-yl] -1- (4-fluoro-phenyl) -5-pyridin-3 il-lH-indole (5ag): Rf = 1.95; UV / ELSD purity: 90.1 / 99.0 3-. { l- [3 - (2,3-Dihydro-l, 4-benzodioxin-5-yloxy) -propyl] -piperidin-4-yl} -1- (4-fluoro-phenyl) -5- (3-methyl-3H-1,2,3-triazol-4-yl) -lH-indole (5aH): R £ = 2.37; UV / ELSD Purity: 90.0 / S9.0 3- [1- (2-Benzofuran-3-yl-ethyl) -piperidin-4-yl] -1- (4-fluoro-phenyl) -5- (3-methyl) -3H-1, 2, 3-triazol-4-yl) -lH-indole (5ai): Rf = 2.40; UV / ELSD purity: 70.0 / 95.8 3- [1- (2-Benzofuran-3-yl-ethyl) -piperidin-4-yl] -1- (4-fluoro-phenyl) -5- (l-methyl-lH -pyrazol-4-yl) -lH-indole (5aj): Rf = 2.47; UV / ELSD purity: 70.0 / 95.5 3- [1- (2-Benzofuran-3-yl-ethyl) -piperidin-4-yl] -1- (4-fluoro-phenyl) -5-pyrimidin-2-yl- lH-indole (5ak): Rf = 2.55; UV / ELSD purity: 70.0 / 91.3 3-. { 4- [1- (4-Fluoro-phenyl) -5- (1-methyl-1H-imidazol-2-yl) -lH-indol-3-yl] -piperidin-1-yl} -propionitrile (5al): RE 1.46; UV / ELSD purity: 90.0 / 100.0 3-. { 4- [1- (4-Fluoro-phenyl) -5- (2-methyl-2H-1,2,4-triazol-3-yl) -lH-indol-3-yl] -piperidin-1-yl} -propionitrile (5am): Rf = 1.76; UV / ELSD purity: 95.0 / 100. 3- . { 4- [1- (4-Fluoro-phenyl) -5- (1-methyl-lH-1,2,4-triazol-3-yl) -lH-indol-3-yl] -piperidin-1-yl} -propionitrile (5an): Rf = 1.85; UV / ELSD purity: 90.0 / 100.0 1- (4-Fluoro-phenyl) -3-. { l- [2- (4-methoxy-phenyl) -ethyl] -piperidin-4-yl} -5- (1-methyl-1H-imidazol-2-yl) -lH-indole (5ao): Rf = 1.78; UV / ELSD purity: 79.2 / 97.2 1- (4-Fluoro-phenyl) -3-. { l- [2- (4-methoxy-phenyl) -ethyl] -piperidin-4-yl} -5- (1-methyl-1H-1, 2,4-triazol-3-yl) -lH-indole (5ap): Rf = 2.28; UV / ELSD purity: 70.0 / 97.5 1- (4-Fluoro-phenyl) -3-. { l- [2- (2-methoxy-ethoxy) -ethyl] -piperidin-4-yl} -5- (2-methyl-2H-1,2,4-triazol-3-yl) -lH-indole (5aq): Rf = 1.83; UV / ELSD purity: 78.0 / 99.2 1- (4-Fluoro-phenyl) -3-. { l- [2- (2-methoxy-ethoxy) -ethyl] -piperidin-4-yl} -5- (1-methyl-1H-1, 2,4-triazol-3-yl) -lH-indole (5ar): R £ = 1.96; UV / ELSD purity: 90.0 / 98.3 3 -. { 1- [2 - (2,3-Dihydro-1,4-benzodioxin-5-yloxy) -ethyl] -piperidin-4-yl] -1- (4-fluoro-phenyl) -5- (2-methyl- 2H-1, 2,4-triazol-3-yl) -lH-indole (5as): Rf = 2.16; UV / ELSD purity: 90.0 / 100.0 3-. { l- [3- (2,3-Dihydro-l, 4-benzodioxin-5-yloxy) -propyl] -piperidin-4-yl} -1- (4-fluoro-phenyl) -5- (2-methyl-2H-1,2,4-triazol-3-yl) -IH-indole (5at): Rf = 2.18; UV / ELSD purity: 80.0 / 98.3 2- (2- { 4- [1- (4-Fluoro-phenyl) -5- (2-methyl-2H-1, 2, 4-triazol-3-yl) -1H-indol-3-yl] -piperidin-1-yl.}. -ethoxy) -ethanol (5au): Rf = 1.73; UV / ELSD purity: 84.8 / 99.9 2- (2- { 4- [l- (4-Fluoro-phenyl) -5- (1-methyl-1H-1, 2, 4-triazol-3-yl) -lH-indol-3-yl] -piperidin-1-yl.}. -ethoxy) -ethanol (5av): Rf = 1.81; UV / ELSD purity: 84.6 / 100.0 2- (3- { 4- [l- (4-Fluoro-phenyl) -5- (1-methyl-1H-1, 2,4-triazol-3-yl) -lH-indol-3-yl] -piperidin-1-yl} .propoxy) -benzonitrile (5aw): Rf = 2.42; Purity UV / ELSD: 90.0 / 99.9 3-. { l- [3- (4-Fluoro-2-methoxy-phenoxy) -propyl] -piperidin-4-yl} -l- (4-fluoro-phenyl) -5- (2-methyl-2H-1, 2,4-triazol-3-yl) -1H-indole (5ax): Rf = 2.30; UV / ELSD purity: 71.0 / 98.7 1- (4-Fluoro-phenyl) -3-. { l- [2- (4-methoxy-phenyl) -ethyl] -piperidin-4-yl} -5- (3-methyl-3H-1, 2, 3-triazol-yl) -lH-indole (5a): Rf = 2.33; UV / ELSD purity: 72.9 / 98.2 3-. { l- [3- (4-Fluoro-2-methoxy-phenoxy) -propyl] -piperidin-4-yl} -l- (4-fluoro-phenyl) -5- (3-methyl-3H-1, 2, 3-triazol-4-yl) -1H-indole (5az): Rf = 2.41; UV / ELSD purity: 70.8 / 97.3 3-. { 4- [1- (4-Fluoro-phenyl) -5- (3-methyl-3H-1, 2, 3-triazol-4-yl) -lH-indol-3-yl] -piperidin-1-yl} -propionitrile (5ba): Rf = 1.96; UV / ELSD purity: 85.1 / 99.2 3-. { 4- [1- (4-Fluoro-phenyl) -5-pyrimidin-2-yl-lH-indol-3-yl] -piperidin-1-yl} -propionitrile (5bb): Rf = 2.10; UV / ELSD purity: 85.8 / 99.4 1- (4-Fluoro-phenyl) -3-. { l- [2- (4-methoxy-phenyl) -ethyl] -piperidin-4-yl} -5-pyrimidin-2-yl-lH-indol (5bc): Rf = 2.49; UV / ELSD Purity: 96.2 / 99.5 N- (2,5-Dimethoxy-phenyl) -3-. { 4- [1- (4-fluoro-phenyl) -5- (2-methyl-2H-1, 2,4-riazol-3-yl) -lH-indol-3-yl] -piperidin-1-yl} -propionamide (5bd): Rf = 2.12; Purity UV / ELSD: 93.3 / 99.6 3-. { l- [3- (4-Fluoro-2-methoxy-phenoxy) -propyl] -piperidin-4-yl] -1- (4-fluoro-phenyl) -5- (1-methyl-1H-1, 2 , 4-triazol-3-yl) -1H-indole (5be): Rf = 2.42; UV / ELSD purity: 90.0 / 99.4 3- [1- (2-Benzofuran-3-yl-ethyl) -piperidin-4-yl] -1- (4-fluoro-phenyl) -5- (2-methyl-2H -l, 2, -triazol -3-yl) -lH-indole (5bf): Rf = 2.29; UV / ELSD purity: 92.9 / 99.5 3- [1- (2-lH-indol-3-yl-ethyl) -piperidin-4-yl] -1- (4-fluoro-phenyl) -5- (3-methyl) -3H-1 (2, 3-triazol-4-yl) -β-indole (5bg).-Rf = 2.37; UV / ELSD purity: 99.0 / 99.1 3- [1- (2-lH-indol-3 ethyl-ethyl) -piperidin-4-yl] -1- (4-fluoro-phenyl) -5- (2-methyl-2H-1, 2,4-riazol-3-yl) -lH-indole (5bh ): Rf = 2.20; UV / ELSD purity: 80.3 / 98.3 3- [1- (3-lH-indol-3-yl-propyl) -piperidin-4-yl] -1- (4-fluoro-phenyl) - 5- (3-methyl-3H-1, 2, 3-triazol-4-yl) -lH-indole (5bi): Rf = 2.39; UV / ELSD purity: 89.9 / 98.9 3- [1- (3-lH -indol-3-yl-propyl) -piperidin-4-yl -1- (4-fluoro-phenyl) -5- (l-methyl-lH-pyrazol-4-yl) -lH-indole (5bj): Rf = 2.49; UV Purity / ELSD: 87.9 / 98.7 Pharmacological Assay The compounds of the invention have been tested using well recognized and reliable methods.

INHIBITION OF 3H-PRAZ0SINA UNION A2-ADRANCERS IN RAT BRAIN IN VITRO This method determines in vitro the inhibition by drugs of the binding of 3H-prazosin (0.25 nM) to oci-adrenoceptors in rat brain membranes . The method and results in Hyttel & Larsen, J. Neurochem. 1985. 44. 1615-1622: Skarsfeldt & Hyttel, Eur. J. Pharmacol. 1986. 125. -323-340; Hyttel & Larsen, In: Research advances in New Psychopharmacological Treatments for Alcoholism (eds. Naranjo &Sellers). Elsevier 1985. pp.107-119. The compounds of the invention showed a high affinity with the oci-adrenoceptor. Most compounds have an IC 50 value below 30 nM in this assay.

INHIBITION OF THE 3H-PRAZOSINE UNION A aia / aib ald, CLONED ADRENOCEPTORS Cell lines: Cell lines expressing la, bovine, otia rat and hamster aib receptor were used in the assays.

In vitro binding assays: Briefly, the cells were homogenized in 50 mM Tris cooled with ice, pH 7.7, using an Ultra-Turrax and the homogenates were kept on ice or stored at -80 ° C until use. The test buffer subsequently used contained 50 mM Tris, pH 7.7. The non-specific displacer was WB-101 (1 uM) for the l3LI tests < xlb and ocia. All the assays were incubated at 25 ° C for 20 minutes. All tests were terminated by vacuum filtration on GF / B filters and counted in a scintillation counter (Wallac Trilux). The radioligand used was [3H] prazosin. It was found that some of the compounds of the invention have stronger affinity with the ia-adrenoceptor than with the cyc-adrenoceptor and the α-adrenoceptor. Additionally, many of the compounds of the invention have a much stronger affinity with the a? -adrenoceptor compared to the D2 receptor and 5-HT2 Pharmaceutical Compositions The pharmaceutical compositions of this invention or those that are manufactured in accordance with this invention can be administered by any suitable route for example orally in the form of tablets, capsules, powders, syrups, etc., or parenterally in the form of solutions for injection. To prepare such compositions, methods well known in the art can be used, and any carrier, diluent, excipient or other pharmaceutically acceptable additive commonly used in the art. Conveniently, the compounds of the invention are administered in unit dosage form containing said compounds in an amount of about 0.01 to 100 mg. The total daily dose is generally within the range of about 0.05-500 mg, and more preferably about 0.1 to 50 mg of the active compound of the invention.

Formulation Examples The pharmaceutical formulations of the invention can be prepared by methods conventional in the art. For example, tablets can be prepared by mixing the active ingredient with common adjuvants, carriers and / or diluents, and then compressing the mixture in a conventional tabletting machine. Examples of adjuvants, carriers or diluents comprise: corn starch, potato starch, talc, magnesium stearate, gelatin, lactose, rubbers and the like. Any other adjuvant or additive generally used for such purposes as colorants, flavors, preservatives etc. can be used. as long as it is compatible with the active ingredients. Injection solutions can be prepared by dissolving the active ingredient and possible additives in a portion of the solvent for injection, preferably sterile water, adjusting the solution to the desired volume, sterilizing the solution and loading into suitable ampoules or flasks. Any suitable additive conventionally used in the art can be added, such as tonicity agents, preservatives, anti oxidants, etc.

Claims (22)

1. CLAIMS compound that has the general formula wherein, Het is a five or six membered aromatic, heterocyclic ring containing at least one nitrogen atom as a ring member, and optionally substituted with Ci_6 alkyl; n is 0 or 1; G is N, C or CH; the dotted line means a link when G is C, and the dotted line means no link when G is CH or N; Ar is phenyl optionally substituted with one or more substituents independently selected from halogen, C 1-6 alkyl, C 1-6 alkoxy, hydroxy, trifluoromethyl and cyano, or Ar is 2-thienyl, 3-thienyl, 2-furanyl, 3- furanyl, 2-thiazolyl, 2-oxazolyl, 2-imidazolyl, 2-pyridyl, 3-pyridyl or 4-pyridyl; R2, R3, R4 and R5 are independently selected from hydrogen, Ci-6 alkyl, Ci-6 alkoxy, hydroxy, halogen, trifluoromethyl, nitro, cyano, amino, Ci-6 alkylamino and Ci-6 dialkylamino; m is 1, 2 or 3; X is a bond, -CH2-, -0-, -S-, -NH-, -NHCO- or -C0NH-; and Y is cyano, Ci-6alkyloxy. C 1-6 alkyl substituted with hydroxy, Ci-6-alkoxy alkylcarbonyloxy-Ci-6 or Y is phenyl which may be optionally substituted one or more times with substituents selected from halogen, Ci-6-alkyl. trifluoromethyl, hydroxy, alkoxy-Ci-6. alkylcarbonyloxy-Ci-g. nitro, cyano, amino, alkylamino-Ci_6 and dialkylamino-Ci-e. Methylenedioxy and ethylenedioxy, or Y is an aromatic, mono- or bicyclic heterocyclic ring containing only one heteroatom which may be optionally substituted one or more times with substituents selected from halogen, Ci_6 alkyl, trifluoromethyl, hydroxy, Ci-6-alkoxy , alkylcarbonyloxy-Ci_6, nitro, cyano, amino, alkylamino-Ci-6 and dialkylamino-C1-6; provided that Y is not cyano when X is O, S, H, NHCO or CONH; and Y is not C1-6 alkoxy when X is O, S or NH; or its pharmaceutically acceptable acid addition salt.
2. 2. A compound according to claim 1, characterized in that Het is optionally substituted triazolyl, pyrazolyl, pyrimidyl, pyridinyl or imidazolyl.
3. 3. A compound according to claim 2, characterized in that Het is 1-methyl-lH-l, 2,4-triazol-3-yl, 2-methyl-2H-l, 2, -triazol-3-yl, 3-methyl-3H-l, 2, 3-triazol-4-yl, l-methyl-lH-pyrazol-4-yl, 2-methyl-2H-pyrazol-3-yl, 1-methyl-lH-imidazole - 2-yl, pyrimidin-2-yl or pyridin-3-yl.
4. 4. A compound according to claims 1-3, wherein Y is Ci-6 alkyl substituted with hydroxy, Ci-6 alkoxy or Ci-6 alkylcarbonyloxy. or Y is optionally substituted phenyl.
5. 5. A compound according to claim 4, wherein X is a bond, -CH 2 -, O u is S.
6. 6. A compound according to claim 5 wherein X is O or S.
7. 7. A compound of according to the claims 1-3, wherein Y is an aromatic, bicyclic, heterocyclic, optionally substituted ring containing only one heteroatom.
8. 8. A compound according to claim 7 wherein Y is indolyl, benzofuranyl or dihydro-1,4-benzodioximyl.
9. 9. A compound according to claims 7-8, wherein X is a bond, -CH2-, O or S.
10. 10. A compound according to claim 4, wherein X is -NHCO- or -CO H -.
11. 11. A compound according to claim 10 wherein Y is optionally substituted phenyl.
12. 12. A compound according to claims 1-3, wherein Y is cyano.
13. 13. A compound according to the claims 1 to 3, characterized in that it is selected from: 3-. { 4- [1- (4-Fluoro-phenyl) -5- (1-methyl-1 H-1, 2,4-triazol-3-yl) -lH-indol-3-yl] -piperidin-1-yl} -propionitrile; 3- . { 4- [1- (4-Fluoro-phenyl) -5- (pyrimidin-2-yl) -lH-indol-3-yl] -piperidin-1-yl} -propionitrile; 1- (4-Fluoro-phenyl) -3-. { 1- [2- (4-methoxyphenyl) -ethyl] -piperidin-4-yl} -5- (l-methyl-lH-l, 2,4-triazol-3-yl) -lH-indole; 1- (4-Fluoro-phenyl) -5- (1-methyl-1H-1, 2,4-triazol-3-yl) -3- [1- (2-phenylethyl) -piperidin-4-yl] -lH -indol; 3- . { 4- [1- (4-Fluoro-phenyl) -5- (2-methyl-2H-pyrazol-3-yl) -1H-indol-3-yl] -piperidin-1-yl} -propionitrile; 3- [1- (2-Benzofuran-3-yl-ethyl) -piperidin-4-yl] -1- (4-fluoro-phenyl) -5- (2-methyl-2H-pyrazol-3-yl) - lH-indole; 3- [1- (2-lH-indole 3-yl-ethyl) -piperidin-4-yl] -1- (4-fluoro-phenyl) -5- (2-methyl-2H-pyrazol-3-yl) -lH-indole; 3 -. { 4- [1- (4-Fluoro-phenyl) -5-pyridin-3-yl-lH-indol-3-yl] -piperidin-1-yl} -propionitrile; 1- (4-Fluoro-phenyl) -3-. { 1- [2- (4-methoxy-phenyl) -ethyl] -piperidin-4-yl} -5-pyridin-3-yl-lH-indole; 3- [1- (2-Benzofuran-3-yl-ethyl) -piperidin-4-yl] -1- (4-fluoro-phenyl) -5-pyridin-3-yl-lH-indole; 3- [1- (2-1H-indol.-3-yl-ethyl) -piperidin-4-yl] -1- (4-fluoro-phenyl) -5-pyridin-3-yl-lH-indole; 3-. { 1- [3- (2,3-Dihydro-1, -benzodioxin-5-yloxy) -propyl] -piperidin-4-yl} -1- (4-fluoro-phenyl) -5- (3-methyl-3H-1, 2, 3-triazol-4-yl) -lH-indole; 3- [1- (2-Benzofuran-3-yl-ethyl) -piperidin-4-yl] -1- (4-fluoro-phenyl) -5- (3-methyl-3H-1, 2,3-triazole-4) -yl) -lH-indole; 3- [1- (2-Benzofuran-3-yl-ethyl) -piperidin-yl] -1- (4-fluoro-phenyl) -5- (l-methyl-lH-pyrazol-4-yl) -lH -indol; 3- [1- (2-Benzofuran-3-yl-ethyl) -piperidin-4-yl] -1- (4-fluoro-phenyl) -5-pyrimidin-2-yl-lH-indole; 3-. { 4- [1- (4-Fluoro-phenyl) -5- (1-methyl-lH-imidazol-2-yl) -lH-indol-3-yl] -piperidin-1-yl} -propionitrile; 3-. { 4- [1- (4-Fluoro-phenyl) -5- (2-methyl-2H-1,2,4-triazol-3-yl) -1H-indol-3-yl] -piperidin-1-yl} -propionitrile; 3- . { 4- [1- (4-Fluoro-phenyl) -5- (1-methyl-lH-1,2,4-triazol-3-yl) -lH-indol-3-yl] -piperidin-1-yl} -propionitrile; 1- (4-Fluoro-phenyl) -3-. { 1- [2- (4-Rethoxy-phenyl) -ethyl] -piperidin-4-yl} -5- (1-methyl-1H-imidazol-2-yl) -lH-indole; 1- (4-Fluoro-phenyl) -3-. { l- [2- (-methoxy-phenyl) -ethyl] -piperidin-4-yl} -5- (1-methyl-1H-1, 2,4-triazol-3-yl) -1H-indole; 1- (4-Fluoro-phenyl) -3-. { 1- [2 - (2-methoxy-ethoxy) -ethyl] -piperidin-4-yl} -5- (2-methyl-2H-l, 2,4-triazol-3-yl) -lH-indole; 1- (4-Fluoro-phenyl) -3-. { l- [2- (2-methoxy-ethoxy) -ethyl] -piperidin-4-yl} -5- (1-methyl-lH-l, 2,4-triazol-3-yl) -lH-indole; 3-. { l- [2- (2,3-Dihydro-1,4-benzodioxin-5-yloxy) -ethyl] -piperidin-4-yl} -1- (4-fluoro-phenyl) -5- (2-methyl-2H-l, 2,4-triazol-3-yl) -1H-indole; 3-. { l- [3 - (2,3-Dihydro-1,4-benzodioxin-5-yloxy) -propyl] -piperidin-4-yl} -l- (4-fluoro-phenyl) -5- (2-methyl-2H-1,2,4-triazole-3-yl) -1H-indolj 2- (2-. {4- [l- ( 4-Fluoro-phenyl) -5- (2-methyl-2H-1,2,4-triazol-3-yl) -lH-indol-3-yl] -piperidin-1-yl.} -ethoxy) - ethanol; 2- (2- { 4- [1- (4-Fluoro-phenyl) -5- (1-methyl-lH-l, 2,4-triazol-3-yl) -lH-indol-3-yl ] -piperidin-1-yl.} - ethoxy) -ethanol; 2- (3- { 4- [l- (4-Fluoro-phenyl) -5- (1-methyl-lH-l, 2,4-triazol-3-yl) -lH-indol-3-yl ] -piperidin-1-yl.} .propoxy) -benzonitrile; 3 - . { 1- [3 - (4-Fluoro-2-methoxy-phenoxy) -propyl] -piperidin-4-yl} -1- (4-fluoro-phenyl) -5- (2-methyl-2H-1,2,4-triazol-3-yl) -lH-indole; 1- (4-Fluoro-phenyl) -3-. { l- [2- (4-methoxy-phenyl) -ethyl] -piperidin-4-yl} -5- (3-methyl-3H-1, 2,3-triazol-4-yl) -1H-indole; 3- . { l- [3- (4-Fluoro-2-methoxy-phenoxy) -propyl] -piperidin-4-yl} -1- (4-fluoro-phenyl) -5- (3-methyl-3H-1, 2,3-triazol-yl) -1H-indole; 3-. { 4- [1- (4-Fluoro-phenyl) -5- (3-methyl-3H-1, 2, 3-triazol--yl) -lH-indol-3-yl] -piperidin-1-yl} -propionitrile; 3-. { 4- [1- (4-Fluoro-phenyl) -5-pyrimidin-2-yl-lH-indol-3-yl] -piperidin-1-yl} -propionitrile; 1- (4-Fluoro-phenyl) -3-. { l- [2- (4-methoxy-phenyl) -ethyl] -piperidin-4-yl} -5-pyrimidin-2-yl-lH-indole; N- (2,5-dimethoxy-phenyl) -3-. { 4- [1- (4-Fluoro-phenyl) -5- (2-methyl-2H-1,2,4-triazol-3-yl) -lH-indol-3-yl] -piperidin-1-yl} -propionamide; 3- . { 1- [3 - (4-Fluoro-2-methoxy-phenoxy) -propyl] -piperidin-4-yl} -1- (-fluoro-phenyl) -5- (1-met il-1H-1, 2,-riazol-3-yl) -lH-indole; 3- [1- (2-Benzofuran-3-yl-ethyl) -piperidin-4-yl] -1- (4-fluoro-phenyl) -5- (2-methyl-2H-1, 2,4-triazole -3-yl) -lH-indole; 3- [1- (2-lH-indol-3-yl-ethyl) -piperidin-4-yl] -1- (4-fluoro-phenyl) -5- (3-methyl-3H-1,2,3) -triazol-4-yl) -lH-indole; 3- [1- (2-lH-indol-3-ethyl-ethyl) -piperidin-4-yl] -1- (4-fluoro-phenyl) -5- (2-methyl-2H-1, 2, 4 - triazol -3-yl) -lH-indole; 3- [1- (3-lH-indol-3-yl-propyl) -piperidin-4-yl] -1- (4-fluoro-phenyl) -5- (3-methyl-3H-1, 2,3-triazole -4-yl) -lH-indole and 3- [1- (3-lH-indol-3-yl-propyl) -piperidin-4-yl] -1- (4-fluoro-phenyl) -5- (l -methyl-lH-pyrazol-4-yl) -lH-indole, 3-. { 4- [1- (4-Fluoro-phenyl) -5- (1-methyl-lH- [1,2,4] -triazol-3-yl) -lH-indol-3-yl] -piperidine-l- il} -propan-1-ol, or its pharmaceutically acceptable acid addition salt.
14. 14. A compound according to the claims 1 to 3 which is radio-labeled.
15. 15. A compound according to claim 14, which is radiolabelled with [1 C] -methyl.
16. 16. A compound according to claim 14, which is radiolabelled with 18F, 1231 or 51.
17. 17. A pharmaceutical composition comprising at least one compound according to claims 1 to 13, its pharmaceutically acceptable acid addition salt and optionally a second pharmaceutically active ingredient in combination with one or more pharmaceutically acceptable carriers or diluents.
18. 18. The use of a compound according to claims 1 to 13 or its acid addition salt and optionally a second pharmaceutically active ingredient for the preparation of a medicament for the treatment of a disorder or disease responsive to the antagonism of axons. -adrenoceptors.
19. 19. The use of a compound according to claims 1 to 13 or its acid addition salt and optionally a second agent having antipsychotic activity for the preparation of a medicament for the treatment of sycosis. A method for the treatment of a disorder or disease responsive to antagonism of cti-adrenoceptors in a mammal comprising administering a compound according to claims 1 to 13 or its acid addition salt and optionally a second ingredient pharmaceutically active at such mammal. 21. A method for the treatment of sycosis in a mammal comprising administering a compound according to claims 1 to 13 or its acid addition salt and optionally a second agent having antipsychotic activity to said mammal. 22. The use of a compound according to claims 1 to 13 or its acid addition salt for the preparation of a radiolabelled compound of Formula I.