AU2003214018A1 - 5-heteroaryl substituted indoles - Google Patents

Description

WO 03/070723 PCT/DKO3/00105 5-Heteroaryl substituted indoles The present invention relates to novel 5-heteroaryl substituted indoles having high affinity for c adrenoceptors. Accordingly, the compounds of the invention are considered useful for the 5 treatment of diseases or disorders responsive to c-adrenoceptor antagonists. Further, as some of the compounds are selective a 1 -adrenoceptor ligands they may be particularly useful as PET or SPECT ligands. Background 10 US patent No. 4,710,500 discloses, in general, optionally 5-substituted indole derivatives having the general formula: A'

N-R

2 R N R 15 The compounds may be substituted in position 5 with a substituent selected from halogen, lower alkyl, lower alkoxy, hydroxy, cyano, nitro, lower alkylthio, CF 3 , lower alkylsulphonyl, amino, lower alkylamino and lower di-alklcyamino. The compounds are claimed to be potent and long lasting dopamine antagonists, and accordingly useful for the treatment of psychoses, and 20 additionally to be strong 5-HT antagonists indicating effects in the treatment of negative symptoms of schizophrenia and depression and for the treatment of cardiovascular diseases. The use of sertindole having the formula WO 03/070723 PCT/DKO3/00105 2 0 N NH C11 F as an antipsychotic is specifically claimed in EP-A2-0 392 959. This type of compounds has also been shown to be useful for the treatment of a range of other 5 disorders including anxiety (WO 92/00070), cognitive disorders (WO 92/15303), abuse (WO 92/15302) and hypertension (WO 92/15301). WO 92/15301 discloses compounds having affinity for the cx-adrenoceptor, however, the compounds disclosed herein are not selective for the aL-adrenoceptor. 10 WO 99/46259 and WO 01/21614 relate to ex-adrenoceptor antagonists related 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 in position 5 of the indole ring with a heteroaryl group. 15 Interest in the development of xL-adrenoceptor antagonists has primarily focused on therapeutics for the treatment of cardiovascular diseases (Hieble et al., Exp. Opin. Invest. Drugs, 1997, 6, 3657). Prazosin is the prototype of an cal-adrenoceptor antagonist which has very potent peripherally effects. Prazosin has also in some animal models indicated effects in the central 20 nervous system, although prazosin is considered to have poor CNS penetration. Evidence exists indicating that blockade of cu-adrenoceptor neurotransmission could be beneficial in the treatment of psychoses. Most classical antipsychotics including clozapine bind potently to ac-adrenoceptors labelled with [ 3 H]prazosin or [ 3 H]WB-4101. Some studies seem to indicate a 25 central role of the el-component for the atypical profile of clozapine. ( Baldessarini, et al., Br. J. Psychiatry, 1992, 160, 12-16 and Prinssen, et al., Eur. J Pharmacol., 1994, 262, 167-170).

WO 03/070723 PCT/DKO3/00105 3 Several lines of evidence indicate that blockade of el-adrenoceptor neurotransmission alone could be beneficial in the treatment of schizophrenia. Metabolic and post-mortem studies indicate hyperactivity of the noradrenergic system in psychotic patients (R.J. Baldessarini, D. Huston Lyons, A. Campbell, E. Marsh, B.M. Cohen, Br JPsychiatry Suppl 12 (1992)). The firing pattern 5 of midbrain dopamine neurons in rats is modulated by prazosin administration (J. Grenhoff, T.H. Svensson, Eur J Pharmnacol 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)). In addition, prazosin reversed the disruption of prepulse inhibition of acoustic startle response in rats induced by phencyclidine (PCP) (V.P. Bakshi, M.A. 10 Geyer, J Pharmacol Exp Ther 283, 666 (1997) and B.S. Carasso, V.P. Bakshi, M.A. Geyer, Neuropharmnacology 37, 401 (1998)). Further, repeated co-administration of prazosin and haloperidol was found to reduce the effect of haloperidol on the firing of dopamine neurons in nigrostriatal areas, suggesting that the 15 combination would be effective as antipsychotic treatment without producing extrapyramidal side effects (EPS) (Chiodo, et al., J. Neurosci. 1985, 3, 2539-2544). Co-administration of sub-threshold doses of the dopamine D 2 antagonist raclopride and the e.

adrenoceptor antagonist prazosin caused significantly enhanced suppression of conditioned 20 avoidance behaviour in rats without inducing catalepsy (M.L. Wadenberg, et al, JNeural Transm 107, 1229 (2000)). It was suggested that ca adrenoceptor blockade in the presence of a low Dz receptor occupancy might improve antipsychotic efficacy and thereby improve the therapeutic window with regard to extrapyramidal side effects. 25 It has also been suggested that centrally acting cl-adrenoceptor antagonists will have antimanic effects while corresponding agonists would be beneficial for the treatment of depression (Lipinsky, et al., Life Sciences, 1987, 40, 1947-1963). Centrally acting cxa-adrenoceptor antagonists may also have effect against Post Traumatic Stress 30 Disorder (Raskind, M.A.; Dobie, D.J.; Kanter, E.D.; Petrie, E.C.; Thompson, C.E.; Peskind, E.R., J. Clin. Psychiatry, 2000, 61, 129-133 and Taylor, F.; Raskind, M.A., J. Clin Psychopharmacol. 2002, 22, 82-85) Labelled compounds of the present invention are considered to be valuable PET (positron 35 emission tomography) ligands and SPECT ligands due to their selectivity for a 1 -adrenoceptors.

WO 03/070723 PCT/DKO3/00105 4 Finally, it is well established that cx-adrenoceptor antagonists acting peripherally are useful for the treatment of benign prostatic hyperplacia, hypertension and cardiac arrhytmias and for the reduction of intra ocular pressure. 5 The invention According to the present invention novel compounds having the formula

R

2 Het, (CH 2 )n G' N- (CH 2 )m- X-Y Het ( ) R N R A4 r (I) 10 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; 15 n is 0 or 1; G is N, C or CH; the dotted line meaning a bond when G is C, and the dotted line meaning no bond when G is CH or N; 20 Ar is phenyl optionally substituted with one or more substituents independently selected from halogen, C 1

-

6 -alkyl, Cl_ 6 -alkoxy, hydroxy, trifluoromnethyl 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; 25 R 2 , R, R 4 and R are independently selected from hydrogen, CI.

6 -alkyl, CI_ 6 -alkoxy, hydroxy, halogen, trifluoromethyl, nitro, cyano, amino, Cz_ 6 -alkylamino and CI- 6 -dialkylamnino; mis 1,2 or 3; 30 X is a bond, -CH 2 -, -0-, -S-, -NH-, -NHCO- or -CONHI-; and WO 03/070723 PCT/DKO3/00105 5 Y is cyano, C1.6-allcyloxy, C 1

_

6 -alkyl substituted with hydroxy, C 1

.

6 -alkoxy, or C-6 alkylcarbonyloxy or Y is phenyl which may optionally be substituted one or more times with substituents selected from halogen, C 1

.

6 -alkyl, trifluoromethyl, hydroxy, CI 6 -alkoxy, C1alklcylcarbonyloxy, nitro, cyano, amino, Ci 6 -alkylamino, C 1

.

6 -dialklcylamino, methylenedioxy and 5 ethylenedioxy, or Y is an aromatic mono- or bicyclic heterocyclic ring containing only one heteroatom which may optionally be substituted one or more times with substituents selected from halogen, C 1

-

6 -alkyl, trifluoromethyl, hydroxy, CI- 6 -alkoxy, Cl_ 6 -alkylcarbonyloxy, nitro, cyano, amino, C 1

-

6 -alkylamino and Cl_6-dialkylamino; provided Y is not cyano when X is O, S, NH, NHCO or CONH; and Y is not C 1 6 -alkoxy when X is O, S or NH; 10 or pharmaceutically acceptable acid addition salts thereof, is provided. 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, 15 2-methyl-2H-1,2,4-triazol-3-yl, 3-methyl-3HI-1,2,3-triazol-4-yl, 1-methyl-1H-pyrazol-4-yl, 2-methyl-2H-pyrazol-3-yl, 1-methyl-1H-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, C 1 _ 6 -alkyl substituted with hydroxy, C 1 6 -alkoxy, or C 1

.

6 -alkylcarbonyloxy or Y is optionally 20 substituted phenyl, in particular the group of compounds wherein Y is Cz 6 -alkyl substituted with hydroxy, Cl 6 -alkoxy, or C 1 6 -alkylcarbonyloxy or Y is optionally substituted phenyl In a third embodiment, X is a bond, -CH 2 -, O or S, preferably O or S. 25 In a fourth embodiment, Y is an optionally substituted, aromatic bicyclic heterocyclic ring containing only one heteroatom, such as for example optionally substituted indolyl, benzofuranyl or dihydro-l1,4-benzodioxinyl. In a fifth embodiment, X is -NHCO- or -CONH-. 30 In a sixth embodiment, Y is optionally substituted phenyl. In a seventh embodiment, the invention relates to compounds wherein Y is C 1 6 -alkyl substituted with hydroxy, CI 6 -alkoxy or C 1

.

6 -alkylcarbonyloxy 35 Finally, the invention relates to the group of compounds wherein Y is cyano.

WO 03/070723 PCT/DKO3/00105 6 The compounds of the invention are potent cx-adrenoceptor antagonists and the compounds are therefore useful for the treatment of disorders or diseases responsive to antagonism of the a, adrenoceptor. 5 Some of the compounds of the invention have stronger affinity to the O~al-adrenoceptor than the clb-adrenoceptor and the ald-adrenoceptor. Thus, in another aspect, the present invention relates to a pharmaceutical composition comprising at least one compound of formula I as defined above or a pharmaceutically acceptable acid 0 addition salt thereof 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 an acid addition salt thereof and optionally a second pharmaceutically active ingredient [5 for the manufacture of a pharmaceutical medicament for the treatment of a disorder or disease responsive to antagonism of c 1 -adrenoceptor. Thus, in still another aspect, the present invention relates to the use of a compound of formula I as above and optionally a second agent having antipsychotic activity for the preparation of a 20 medicament for the treatment of psychosis. Diseases and disorders responsive to antagonism of al-adrenoceptors includes psychosis, mania, benign prostatic hyperplacia, hypertension, post traumatic stress disorder and cardiac arrhytmias. Antagonists of a-adrenoceptors are also useful for the reduction of intra ocular pressure. 25 In a further aspect, the invention relates to a method for the treatment of a disorder or disease responsive to antagonism of aq -adrenoceptors in a mammal comprising administering a compound of formula I as above and optionally a second pharmaceutically active ingredient to said mammal. 30 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 above and optionally a second agent having antipsychotic activity to said mammal. 35 The above mentioned second pharmaceutically active ingredient may be another agent having antipsychotic activity, for example an agent having dopamine D 2 antagonistic effect. As WO 03/070723 PCT/DKO3/00105 7 mentioned above, evidence exists which indicate that such combinations may be advantageous for treatment of psychoses without causing extrapyramidal effects. Finally, the present invention relates to radio-labelled compounds of formula I and the use thereof 5 in various biological assays and PET- or SPECT studies. Detailed Description of the Invention When used herein halogen means fluoro, chloro, bromrno or iodo. 10 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. 15 The terms C 1 6 -alkoxy, C 1

.

6 -alkylamino, Cl_ 6 -dialkylamino etc. designate such groups in which CI_ 6 alkyl is as defined above. Het meaning a five-membered aromatic heterocyclic ring containing at least one nitrogen as a ring member, includes, but are not limited to, heterocyclic rings selected from pyrrol-l-yl, pyrrol-2-yl, 20 pyrrol-3-yl, imidazol-1-yl, imidazol-2-yl, imidazol-4-yl, pyrazol-l-yl, pyrazol-3-yl, pyrazol-4-yl, 1,2,3-triazol-l1-yl, 1,2,3-triazol-2-yl, 1,2,3-triazol-4-yl, 1,2,4-triazol-l1-yl, 1,2,4-triazol-3-yl, 1,2,4 triazol-5-yl, tetrazol-l1-yl, tetrazol-2-yl, tetrazol-5-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, thiazol-2-yl,, thiazol-4-yl, thiazol-5-yl, isothiazol-3 yl, isothiazol-4-yl, isothiazol-5-yl, 1,2,3-oxadiazol-4-yl, 1,2,3-oxadiazol-5-yl, 1,2,4-oxadiazol-3 25 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-thiadiazol-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 meaning a six-membered aromatic heterocyclic ring containing at least one nitrogen as a ring 30 member, includes, but are not limited to, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl and pyrimidin-5-yl. Y meaning an aromatic mono- or bicyclic heterocyclic ring containing only one heteroatom includes, but are not limited to, rings such as pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, furan-2-yl, 35 furan-3-yl, 2-thienyl, 3-thienyl, pyrrol-l-yl, pyrrol-2-yl, pyrrol-3-yl, indol-l-yl, indol-2-yl, indol 3-yl, indol-4-yl, indol-5-yl, indol-6-yl, indol-7-yl, benzofuran-2-yl, benzofuran-3-yl, benzofuran- WO 03/070723 PCT/DKO3/00105 8 4-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, isobensothien-6 5 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 10 formed with non-toxic acids. Exemplary of such organic salts are those with maleic, fumaric, benzoic, ascorbic, succinic, oxalic, bis-methylenesalicylic, methanesulfonic, ethanedisulfonic, acetic, propionic, tartaric, salicylic, citric, gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, and theophylline acetic acids, as well as the 8-halotheophyllines, for example 8-bromotheophylline. 15 Exemplary 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 al-adrenoceptor makes them particularly useful for the development of radiolabelled ligands useful in various biological assays 20 and in PET and SPECT studies. The compounds of the invention "can be labelled by reacting the unlabelled precursor molecules with ["C] methyl iodide, ["C] methyl triflate, or other ["C] labelled reagents derived from ["C] carbon dioxide. The compounds may also be labelled with "1F, 1231 or 1251. 25 Radiolabeling of compounds of the present invention may be performed according to radiolabeling methods known and used in the prior art. For example, as stated in the specification, compounds can be labelled by reaction of the appropriate precursors with radio labelled reagents, including "C-labelled reagents such as ["C]methyl iodide and ["C]methyl 30 triflate. It is also within the knowledge of a person skilled in the art of radiopharmaceuticals to label compounds with "F or 1231. Compounds of the present invention radiolabelled with "sF may be prepared by aromatic nucleophilic substitution of a precursor molecule containing an appropriate 35 leaving group (such as nitro, bromo, iodo or triflate) by reaction with ["F]F. For example, compounds of the present invention may be radiolabelled with "F in the 4-position of the phenyl WO 03/070723 PCT/DKO3/00105 9 group attached to the indole N-1. The compounds may be prepared by aromatic nucleophilic substitution of a precursor molecule containing an appropriate leaving group (such as nitro, bromo, iodo or triflate) by reaction with ['sF]F-. After appropriate activation of the aromatic ring with one or two electron withdrawing groups, such as formyl group(s). The formyl groups may 5 easily be removed after radioflourination by reaction with Wilkinson's catalyst in dioxane at elevated temperature (Sobrio, F.; Amokhtari, M.; Gourand, F.; Dhilly, M.; Dauphin, F.; Barr6, L., Bioorg. Med. Chemin. 2000, 8, 2511-2518). Radiolabelling with 1251 or 123I may be performed by halodemetalation of the corresponding tin 10 substituted (organotin) precursors, for example by treatment of an ethanolic solution of the organotin precursor with Na1 23 1 or Na 1 25 I in the presence of chloramine-T and aqueous hydrochloric acid analogously to the procedure described by Foged et al (Foged, C.; Halldin, C.; Hiltunen, J.; Braestrup, C.; Thomsen, C.; Hansen, H.C.; Suhara, T.; Pauli, S.; Swahn, C.-G.; Karlsson, P.; Larsson, S. and Farde, L., Nucl. Med. Biol. 1996, 23, 201-209). 15 The organotin precursors of the compounds of the invention can be readily prepared from 1-(4 bromophenyl) or 1-(4-iodophenyl) substituted 5-heteroaryl-indoles by reaction with n butyllithium or tert-butyllithium in THIF at low temperature, followed by reaction with a trialkyltin halide such as trimethyltin chloride or tributyltin chloride. Magnesium metalated 20 intermediates may also be used in place of lithium. Alternatively, palladium catalyzed reaction with hexaalkyldistannanes may also give the corresponding organotin precursors. (Ali, H.; Johan, and van Lier, J.E., Synthesis 1996, 423-445) Alternatively, 4-[' 8 F]flouroiodobenzene may be prepared as described in the literature (Shah, A.; 25 Widdowson, D. A.; Pike, V. W., J.Labelled Comnpd.Radiopharmn. 1997, 40, 65-67), and 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: 30 a) Reacting an indole derivative of the following formula WO 03/070723 PCT/DKO3/00105 10 R' (CH), Het 7

R

3 N R I R 5 R Ar (II) wherein R 2 , R 3 , R 4 , R s , Ar, Het and n are as defined above, with a 4-piperidone of the formula A N-(CH 2 )m-X-Y 5() wherein m, X and Y are as defined above, A is an oxygen atom or a -O-(CH 2 )q-O- chain, wherein q is 2 or 3; b) reducing the tetrahydropyridine double bond in a compound of the formula 10

(CH

2 )m-X-Y R 2 N'

(CH

2 )n Het R N Rs R4 Ar (IV) wherein R 2 , R 3 , R 4 , R s , m, X, Y, Ar, HIet and n are as defined above; 15 c) reacting a compound of the formula

(CH

2 )m-X-Y

R

2 N Het

R

3 N R4 , ol .. _M WO 03/070723 PCT/DKO3/00105 11 wherein R2, R', R 4 , R s , m, X, Y, G, the dotted line, Het and n are as defined above, with a compound of the formula Ar-hal wherein Ar is as defined above and "hal" is halogen, in the presence of a metal catalyst, 5 d) reacting a compound of the formula R 2 NH TG Het

(CH

2 ),n G I R' R4 R Ar (VI) wherein R2, R , R 4 , R s , G, the dotted line, Ar, Het and n are as defined above, with a reagent of 10 formula L-(CH 2 ),-X-Y wherein min, X, and Y are defined above and L is halogen, mesylate or tosylate e) reducing the carbonyl group of a compound of the formula 0 Ht(CH 2 )n GOR Het X N N R 4 1

R

4 Ar (VII) 15 wherein R2 , R 3 , R 4,

R

s , G, the dotted line, Ar, Het and n are as defined above and R 8 is

(CH

2 )(m-)-X-Y, wherein min, X, and Y are defined above f) decarboxylating a compound of the formula 20 WO 03/070723 PCT/DKO3/00105 12

R

2

(CH

2 ), OH Het R N COOCH3 4 Ar (VIII) wherein R 2 , R, R 4 , Ar, Het and n are as defined above, followed by reaction with a piperazine of the formula 5 HN N- (CH 2 )m X- Y (IX) wherein m, X and Y is as defined above; g) alklcylating the group Het in a compound of formula I wherein Het is unsubstituted on at least 10 one pyrrole-like nitrogen atom with an alkylating reagent, such as C 1 6 -alkyl-L, wherein L is chloro, bromo, iodo, mesylate or tosylate. Method g) may accordingly be used to introduce radiolabelled alkyl groups, such as ["C]methyl iodide, ["C]methyl triflate, etc. 15 Methods for the preparation of the starting materials used in the above processes are described in US patent No. 4,710,500, WO 92/00070, WO 99/46259 and in Perregaard et al., J.Med.Cheinm. 1992 (35), 1092-1101, or can be prepared analogously to the procedures described herein. 20 Starting materials wherein the group Het is tetrazol-5-yl may be prepared by reacting the corresponding 5-cyano-indole with azide. Starting materials wherein the group Het-(CH 2 )n- is tetrazol-5-ylmethyl may likewise be prepared from the corresponding indole containing a 5-cyanomethyl group by reaction with azide. The 5 25 cyanomethyl-indoles may be prepared by hydrolysis of the corresponding 5-cyano-indole, reduction of the carboxylic acid functionality obtained to hydroxymethyl, reaction with methanesulphonyl chloride to form the corresponding 5-chloromethyl-indoles followed by reaction with a cyanide to form the 5-cyanomethyl-indole.

WO 03/070723 PCT/DKO3/00105 13 N-Boc-protected 5-bromo-1-Ar-3-piperidinyl-lH-indole is prepared in three steps from 5-bromo 1-Ar-1H-indole. Reaction of 4-piperidin-2-one hydrochloride, hydrate with 5-bromo-Ar fluorophenyl)-1H-indole using acidic conditions followed by catalytic hydrogenation analogously to published procedures (Perregaard, et al. JMed Chemn 1992, 35, 1092) results in the 5 unsubstituted piperidyl compound. Finally, reaction with boc-anhydride affords the desired starting material. Introduction of heteroaryl groups in the 5-positions in the N-Boc-protected 5-bromo-1-Ar-3 piperidinyl-1H-indole is accomplished by two alternative methods A and B. 10 In Method A, the N-boc-protected 5-bromo-l-Ar-3-piperidinyl-lH-indole is treated with n butyllithium followed by transmetalation to the corresponding zinc chloride. Addition of the appropriate heteroaryl halide and 5 mol% tetraldkis(triphenylphosphine)palladium(0) affords the corresponding heteroaryl substituted intermediates. In the reverse method B deprotonation of the 15 heteroaryl derivatives or halogen/metal exchange of heteroaryl halides followed by transmetalation to the corresponding zinc chlorides and tetralkis(triphenylphosphine)palladium(0) catalysed cross-coupling with the N-boo-protected 5-bromo-l-Ar-3-piperidinyl-lH-indole results in the corresponding 5-heteroaryl-indoles. 20 The boc-protected derivatives obtained by Methods A and B is deprotected and used as starting materials for method d) described below. Starting materials for methods a), b), c) and e) may be prepared analogously using properly protected starting materials. 25 In method a), the reaction is performed under strong acidic conditions by heating. Trifluoroacetic acid or HC1 in ethanol are preferred as acidic catalysts. In method b), the reduction is preferably carried out at low hydrogen pressures (3 Ato.) in the 30 presence of platinum or palladium on carbon black. In method c), the arylation is preferably carried out at about 160-210 'C in aprotic polar solvents such as N-methyl-2-pyrrolodine or hexamethylphosphoric triamide with K 2

CO

3 as base and copper as a catalyst. 35 WO 03/070723 PCT/DKO3/00105 14 In method d), the alkylations are performed in a an aprotic solvent such as dimethylformamide or acetonitrile using an appropriate base such as potassium carbonate or diisopropyl ethyl amine at elevated temperatures (50-120 oC). 5 In method e), the reduction is preferably carried out with LiALH 4 in THF or diethylether or with diborane in THF. Method f), is a two step procedure in which compound VIII is first decarboxylated in the presence of an inorganic salt as e.g. LiC1 or MgC12 in a polar solvent as e.g. diglyme, 10 hexamethylphosphoric triamide or N-methyl-2-pyrolidone at elevated temperatures (120-150 oC). Finally, the appropriate piperazine is added and the temperature raised to about 200 'C and kept there until the corresponding indoxyle has disappeared according to TCL analysis. The compounds of Formula VIII are conveniently prepared according to the procedures reported by Unangst et al., J. Heterocyclic Chem. 1984, 21, 709. 15 In method g), the alkylation with alkyl iodides or bromides is performed by in aprotic solvents such as acetone or dimiethylformamide using an appropriate base such as potassium carbonate or diisopropyl ethyl amine at elevated temperatures (40-90 oC). 20 In the following, the invention is further illustrated by way of examples that, however, may not be construed as limiting. Examples 25 General. All reactions were carried out under a positive pressure of nitrogen or argon. Glassware for water sensitive reactions was dried in an oven at 150 'C over night. THIF was freshly distilled from sodium/benzophenone. DMF was sequentially dried and stored over 3 A molecular sieves. ZnC1 2 was flame dried in vacuo and dissolved to 1.0 M in dry THF after cooling to room temperature. Acetone and CH 3 CN for alkylation reactions were HPLC-grade. Saturated 30 HC1/MeOH solutions were prepared by saturation of MeOH with HC1 gas. For flash chromatography either silica gel of type Kieselgel 60, 230-400 mesh ASTM or Biotage Flash40 (50 or 100 g columns) were used. 1H NMR spectra were recorded of all novel compounds at 250 MHz on a Bruker AC 250 or at 500 MHIz on a Bruker Avance DRX500 instrument. Deuterated chloroform (99.8%D) or DMSO-d 6 (99.9%D) were used as solvents. TMS was used as internal 35 reference standard. Chemical shift values are expressed in ppm-values. The following abbreviations are used for multiplicity of NMR signals: s=singlet, d=doublet, t-triplet, q=quartet, WO 03/070723 PCT/DKO3/00105 15 dd=double doublet, dt-double triplet, tt=-triplet of triplets, m--multiplet. NMR signals corresponding to acidic protons are generally omitted. Melting points are reported uncorrected. Solvent residuals in elemental analysis samples were measured by Karl Fisher titration (H1120) or by Thermo Gravimetric Analysis (TGA) on a TA-instruments TGA 2950 with heating rate 10 oC 5 per min. The nature of the solvent was identified by 1 H-NMR. Solvent residuals are not reported in the NIVIR data. Analytical and preparative HPLC were run on a Shimadzu HPLC system with two Shimadzu LC-8A pumps. The UV trace was obtained using a Shimadzu SPD-10A detector operating at 254 nm. ELSD trace was obtained using a Sedere Sedex 55 detector operating at 42 'C and 2.3 bar. For analytical HPLC-MS a Perldkin Elmer API 150EX mass spectrometer equipped 10 with a Perldkin Elmer SCIEX Heated Nebulizer (APCI) ion source. The total ion current (TIC) was recorded in positive mode for m/z 100-1000 amiu. Analytical HPLC was run injecting 10 pLL to a Waters Symmetry C-18 (4.6x30 mm, 3.5 pim) column. 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 during 4 minutes, then isocratic A/B 90/10 during 1 15 minute. Flow was 2 mL/min throughout. Preparative HPLC-MS was run with 190 p L injections on a YMC RP18 (50x20 mm) column with a gradient of A/B 80/20 - 0/100 during 7 minutes, then isocratic 80/20 during one minute. The flow was 22.7 mL/min throughout and detection was performed using the MS (TIC) signal in a split system. The reported purities are based on integration of the peaks in the UV and ELSD spectrum. 20 Reagents: The following reagents were prepared according to published procedures: 3-(2 Chloroethyl)imidazolidin-2-one (Perregaard, et al. Med Chem 1992, 35, 1092 and Johnston, et al., JMed Chemin 1963, 6, 669), 3-(2-chloroethyl)-oxazolidin-2-one (Robinson, et al., JAm Chem 25 Soc 1972, 94, 7883), 3-(2-chloroethyl)-1l-methyl-2-pyrrolidin-2-one (Sucrow, et al., Chem. Ber. 1972, 105, 1621), 1-methyl-l,2,3-triazole (Begtrup, et al., Acta Chem Scand 1990, 44, 1050), 4 bromo-l-methyl-l,2,3-triazole (Hiittel, et al., Liebigs Ann Chem 1955, 593, 207), 2-bromo-1 methyl-1,3,4-triazole (Bernardini, et al., Soc Chim 1975, 5, 647), 5-bromo-l-methyl-1,2,4-triazole (Bemrnardini, et al., Soc Chim 1975, 5, 647) and 3-bromo-l-methyl-l,2,4-triazole, 7 3-Iodo-1 30 methylpyrazole (Balle, et al. Synthesis 2002, 1509-1512). Preparation of Starting Material 4-(5-Bromo-l-(4-fluorophenyl)-lH-indol-3-yl)-piperidine-l-carboxylic acid tert-butyl ester (1). A solution of 5-Bromo-l-(4-fluorophenyl)-3-(4-piperidinyl)-lH-indole (125 g, 0.33 mol) 35 (Prepared as described by Perregaard et al J Med Chem 1992, 35, 1092) and di-tert-butyl WO 03/070723 PCT/DKO3/00105 16 dicarbonate (260 g, 1.2 mol) in 1:1 THF/H 2 0 mixture (1 L) was stirred over night with K 2 CO3 (300 g, 2.2 mol) at 60 oC. EtOAc (1 L) was added. After separation of the two phases, the aqueous phase was extracted with EtOAc (3 x 0.5 L). The combined organic phases were washed with brine and dried over MgSO 4 . The crude product (115 g) was washed with cold MeOH to 5 yield 97 g of 1 as white crystals: Mp 160-162 'C (heptane); 1 H-NMR (CDC1 3 ): 1.49 (s, 9H), 1.65 (q, 2H), 2.04 (d, 2H), 2.85-3.00 (min, 3H), 4.25 (d, 2H), 7.03 (s, 1H), 7.15-7.35 (mn, 4H), 7.39-7.43 (min, 2H), 7.78 (s, 1H); MS m/z (relative intensity): 473 + 475 (MH+, 1%), 417+419 (40%), 373+375(100%); Anal. (C 24

H

26 BrFN 2 0 2 ): C, H, N. 10 Preparation of Intermediates (Method A) Cross-coupling of 4-(5-bromo-l-(4-fluorophenyl)-1H-indol-3-yl)-piperidine-l-carboxylic acid tert-butyl ester (1) with a heteroaryl halide 4-(5-Bromo-1l-(4-fluorophenyl)-1H-indol-3-yl)-piperidine-1l-carboxylic acid tert-butyl ester (1) (10 g, 21.1 mmol) in THF (20 mL) was added during 2 minutes to a solution of n-butyllithium 15 (39.6 mL, 63.4 mmol) in THF (210 inL) at -78 'C. After stirring for 3 minutes ZnCl, in THF (105.6 mL, 105.6 mmol) was added. The solution was stirred for further 30 minutes at -78 oC. The heteroaryl halide (amount specified below) was added together with Pd(PPh 3

)

4 (1.2 g, 5 mol %) and DMF (60 mL). The reaction mixture was stirred at 80 oC for 8 h. After cooling to room temperature, H20 (300 mL) and EtOAc (500 mnL) were added and the phases were separated. The 20 organic phase was washed with H 2 0 (200 mL) and saturated aqueous CaC12 (3 x 100 mL), dried over MgSO 4 and the solvent was removed in vacuo. The crude product was purified by flash chromatography. The amount of reagents and solvents were scaled according to the actual amount of 1 used. 25 The following derivatives were prepared according to Method A 4-(1-(4-Fluorophenyl)-5-(1-methylpyrazol-3-yl)-1H-indol-3-yl)-piperidine-l-carboxylic acid tert-butyl ester (2a). A solution of 1 (6.8 g, 14.4 mmol) in THF was reacted with 1-methyl-3 iodopyrazole (3.0 g, 14.4 mmol). The crude product was purified by flash chromatography (EtOAc/heptane 20/80 -> 50/50) to yield 4.31 g (63%) of 2a as white crystals: Mp. 145.3-145.6 30 oC (EtOAc/heptane); 'H-NMR (CDC1 3 ) 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 (min, 2H), 7.39 (d, J = 2.1 Hz, 1H), 7.42-7.52 (mn, 3H), 7.65 (d, J = 8.6 Hz, 1H), 8.08 (s, 1H); MS m/z: 475 (7%, MH+), 419 (100%), 375 (73%); Anal. (C 28

H

3 1

N

4

FO

2 ): C, H, N. 35 4-(1-(4-Fluorophenyl)-5-(1-methylpyrazol-4-yl)-1H-indol-3-yl)-piperidine-1-carboxylic acid tert-butyl ester (2b). A solution of 1 (10 g, 21.1 rnmol) in THF was reacted with 1-methyl-4- WO 03/070723 PCT/DKO3/00105 17 bromopyrazole (4.2 g, 31.7 mmol). The crude product was purified by flash chromatography (EtOAc/heptane 20/80 -+ 30/70) to yield 2.8 g (28%) of 2b as white crystals: Mp 133-136 'C (EtOAc/heptane); 'H-NMR (CDC1 3 ) 1.49 (s, 9H), 1.71 (q, 2H), 2.10 (d, 2H), 2.94 (t, 2H), 3.05 (t, 1H), 3.96 (s, 3H), 4.27 (s, broad, 2H), 7.04 (s, 1H), 7.20-7.25 (min, 2H), 7.34 (d, 1H), 7.41-7.50 (in, 5 3H), 7.63 (s, 1H), 7.71 (s, 1H), 7.79 (s, 1H); MS m/z: 475 (5%, MH), 419 (86%), 375 (100%); Anal. (C 28 sH 31

N

4

FO

2 ): C, H, N. 4-(1-(4-Fluorophenyl)-5-(1-methyl-1,2,4-triazo-3-yl)-1H-indo-3-yl)-piperidine-1-carboxylic acid tert-butyl ester (2c). A solution of 1 (20 g, 42 mmol) in THF was reacted with 3-bromo-1 10 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 crystallised from Et 2 0 to yield 8 g (40%) of 2c as white crystals: Mp 189-191 oC (Et 2 O); '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 (min, 2H), 7.40-7.52 (min, 3H), 8.00 (d, 1H), 8.08 (s, 1H), 8.42 (s, 1H); MS m/z: 476 (72%, 15 VMH), 420 (66%), 376 (100%); Anal. (C 2 7H3 0

NSFO

2 .2.17 % Et 2 0): C, H, N. 4-(1-(4-Fluorophenyl)-5-(1-methyl-1,3,4-triazol-2-yl)-IH-indol-3-yl)-piperidine-1-carboxylic acid tert-butyl ester (2d). A solution of 1 (10 g, 21.1 mmol) in THF was reacted with 2-bromo-1 methyl-1,3,4-triazole (2.8 g, 17.3 mmol). The crude product was purified by flash 20 chromatography (EtOAc/heptane/MeOH 30/70/0 -- > 100/0/0 -> 90/0/10) to yield 2.5 g (31%) of 2d as white crystals: Mp 156-158 'C (toluene/heptane 1:1); 'H-NMR (CDC13) 1.49 (s, 9H), 1.70 (q, 2H), 2.08 (d, 2H), 2.90 (t, 2H), 3.07 (t, 1H), 3.78 (s, 3H), 4.26 (s, broad, 2H), 7.13 (s, 1H1), 7.20-7.28 (min, 2H), 7.41- 7.50 (min, 3H), 7.53 (d, 1H), 8.05 (s, 1H), 8.21 (s, 1H); MS m/z: 476 (100%, MH+), 420 (51%), 376 (83%); Anal. (C 27

H

3 0 N5FO 2 ): C, H, N. 25 4-(1-(4-Fluorophenyl)-5-(l-methyl-1,2,4-triazol-5-yl)-lH-indol-3-yl)-piperidine-1-carboxylic acid tert-butyl ester (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 mnmol). The crude product was purified by flash chromatography (EtOAc/heptane/MeOH 30/70/0 -+ 100/0/0 -- 90/0/10) to yield 2.8 g (45%) of 2e as a pale 30 yellow foam: 'H-NMR (CDC1 3 ) 1.49 (s, 9H), 1.70 (q, 2H), 2.09 (d, 2H), 2.91 (t, 2H), 3.07 (t, 1H), 4.03 (s, 3H), 4.28 (s, broad, 2H), 7.13 (s, 1H), 7.20-7.30 (min, 2H), 7.42-7.50 (min, 3H), 7.52 (d, 1H), 7.96 (s, 1H), 8.02 (s, 1H); MS m/z: 476 (100%, MH+), 420 (33%), 376 (41%); Anal.

(C,

7 H3oNsFOz): C, H, N. 35 4-(1-(4-Fluorophenyl)-5-(pyrimidin-2-yl)-lH-indol-3-yl)-piperidine--carboxylic acid tert butyl ester (2f). A solution of 1 (18 g, 38 mmol rmol) in TIHF was reacted with 2- WO 03/070723 PCT/DKO3/00105 18 bromopyrimidine (10 g, 75 mmol). The crude product was purified by flash chromatography (EtOAc/heptane 10/90 -> EtOAc/MeOH 90/10) and crystallised from Et 2 O to yield 12 g (67%) of 2f as white crystals: Mp. 164-166 °C (Et20); 1 H-NMR (CDC1 3 ) 1.50 (s, 9H), 1.71 (q, 2H), 2.14 (d, 2H), 2.96 (t, 2H), 3.16 (t, 1H11), 4.27 (s, broad, 2H), 7.08 (s, 1H11), 7.13 (t, 1H1), 7.20-7.25 (min, 2H), 5 7.43-7.49 (min, 2H), 7.51 (d, 1H), 8.36 (d, 1H), 8.77-8.81 (min, 3H); MS m/z: 473 (11%, MH), 417 (100%), 373 (84%); Anal. (C 2 8H 2 9

N

4

FO

2 ): 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 TIF was reacted with 5-bromopyrimidine 10 (5g, 31.6 rmmol). Flash chromatography (EtOAc/heptane/NEt 3 30/70/4 - 70/30/4) gave 8.2 g which was recrystallised form toluene/heptane 1:1 to yield 5.0 g (50%) of 2g: Mp 144-146 oC (toluene/heptane 1:1); MS m/z: 473 (MH+, 3%), 417 (100%), 373 (33%); 'H-NMR (CDC1 3 ) 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 (min, 2H), 7.42 (dd, 1H), 7.43-7.50 (min, 2H) 7.57 (d, 1H), 7.85 (d, 1H), 9.02 (s, 2H), 9.19 15 (s, 1H); Anal. (C 28

H

29

FN

4 0 2 ): C, H, N. 4-(1-(4-Fluorophenyl)-5-(1-methyl-1,2,3-triazol-4-yl)-1H-indol-3-yl)-piperidine-1-carboxylic acid tert-butyl ester (2h). A solution of 1 (4.7 g, 10 mmol) in THF was reacted with 4-bromo-1 methyl-1,2,3-triazole (1.1 g, 6.8 mmol). The crude product was purified by flash chromatography 20 (EtOAc/heptane 20/80 -- 100/0) to yield 900 mg (28%) of 2h as a white foam: 1 H-NMR (CDC1 3 ) 1.50 (s, 9H), 1.69 (q, 2H), 2.12 (d, 2H), 2.94 (t, 21-H), 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 (in, 3H), 7.61 (d, 1H), 7.78 (s, 1H), 8.23 (s, 1H11); MS m/z: 476 (4%, MH), 420 (46%), 376 (100%); Anal.(C 27 H3oNsFO 2 -2.70 % EtOAc): C, H, N. 25 Preparation of Intermediates (Method B) Cross-coupling of a heteroarylzine chloride with 4-(5-bromo-1-(4-fluorophenyl)-1H-indol-3 yl)-piperidine-1-carboxylic acid tert-butyl ester (1) 4-(5-Bromo-1l-(4-fluorophenyl)-l1H-indol-3-yl)-piperidine-1l-carboxylic acid tert-butyl ester (1) (8.3 g, 16.9 mmol) was added to a solution of heteroarylzinc chloride in TIF (amount and 30 preparation specified below) with Pd(PPh 3

)

4 (5 mol%) and DMF (30% of the amount of THF). The solution was stirred at 80 'C for 8 h. Work up was performed as described in method A. The amounts of reagents and solvents were scaled according to the actual amount of 1 used. The following derivatives were prepared according to Method B: 35 4-(1-(4-Fluorophenyl)-5-(I-methylpyrazol-5-yl)-IH-indol-3-yl)-piperidine-1-carboxylic acid tert-butyl ester (3a). 1-Methylpyrazole (3.2 g, 39 mmol) in THF (200 mL) was cooled to - 78 oC.

WO 03/070723 PCT/DKO3/00105 19 n-butyllithium (43 mnL, 26.9 mmol) was added during 5 minutes. The solution was heated slowly to room temperature during 15 minutes and cooled again to -78 oC. ZnCl 2 in THF (120 mL, 120 mmol) was added and the solution was stirred at -78 oC for 30 minutes. Reaction with 1 (14.2 g, 30 nmiol) was performed following method B. Flash chromatography (EtOAc/heptane/NEt 3 5 30/70/5 -> 50/50/5) and recrystallisation from CH 2

C

2 afforded 11.5 g (80%) of 3a: Mp 166-168 C (CHzC1 2 ); 'H-NMR (CDCL 3 ): 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. (C 2 8

H

31

FN

4 0 2 ): C, H, N. 10 4-(1-(4-Fluorophenyl)-5-(1-methylimidazol-2-yl)-1H-indol-3-yl)-piperidine-1-carboxylic acid tert-butyl ester (3b). 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 during 2 minutes. The solution was stirred for 5 minutes at -78 'C and ZnC1 2 in THF (60 niL, 60 mmol) was added. After stirring at -78 'C for 1 h reaction with 1 (8.30 g, 16.9 mmol) was performed following method B. Flash 15 chromatography (EtOAc/heptane/NEt 3 30/70/4 - 70/30/4) afforded 6.77 g which was recrystallised from toluene/heptane 1:1 to give 4.73 g (59%): Mp 189-191 oC (toluene/heptane 1:1); 'H-NMR (CDCl 3 ) 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. (C 28

H

3 1

FN

4 0 2 ): C, H, N. 20 4-(1-(4-Fluorophenyl)-5-(1-methyl-1,2,3-triazol-5-yl)-IH-indol-3-yl)-piperidine-l-carboxylic acid tert-butyl ester (3c). 1-Methyl-l,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 miol) was added during 2 minutes and the solution was stirred for further 5 minutes before ZnC1 2 in THF (61.8 mL, 61.8 mmol) was 25 added. After 30 minutes at -78 oC reaction with 1 (9.75 g, 20.6 mmol) was performed following method B. Purification by flash chromatography (EtOAc/heptane/EtOH 30/70/2) gave 6.8 g which was recrystallised from toluene/heptane 1:2 to yield 4.3 g (44%) of 3c: Mp 137-141 oC (toluene/heptane 1:2); 'H-NMR (CDC1 3 ) 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), 30 7.45 (d, 1H), 7.69 (s, 1H), 7.74 (s, 1H); Anal. (C2 7

H

30

FN

5 0sO 2 ): C, H, N. 4-(1-(4-Fluorophenyl)-5-(pyridin-3-yl)-1H-indol-3-yl)-piperidine-1-carboxylic acid tert-butyl ester (3d). 3-Bromopyridine was lithiated as described by Fumeaux et al. Tetrahedron 1997, 53, 2915. THF (200 mL) was cooled to -100 oC (Et 2 0/liquid N 2 ) and n-butyllithium (19 mL, 30.4 35 mmol) was added. 3-Bromopyridine (4.00 g, 25.3 mmol) was added during 2 minutes. After 20 minutes at -100 'C ZnC1 2 in THF (60 mL, 60 mmol) was added. Hereby a white precipitate was WO 03/070723 PCT/DKO3/00105 20 formed. The temperature was shortly raised to -30 oC to dissolve the precipitate and thereafter stirred at -78 'C for 30 minutes. Reaction with 1 (10 g, 21.1 mmol) was performed following method B. Flash chromatography (EtOAc/heptane/NEt 3 30/70/5) afforded 8.3 g which was recrystallised from EtOAc/heptane 1:1 to yield 6.0 g (60%) of 3d: Mp 160-162 'C 5 (EtOAc/heptane 1:1); MS m/z: 472 (MH+, 3%), 416 (100%), 372 (37 %); 1 H-NMR (CDCl 3 ) 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 (min, 2H1), 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, 1H11), 8.91 (d, 1H11); Anal. (C 29

H

30

FN

3 0 2 ): C, H, N. 10 Preparation of Compounds of the Invention Deprotection and alkylation of 5-heteroaryl substituted 4-(1-(4-fluorophenyl)-1H-indol-3 yl)-piperidine-1-carboxylic acid tert-butyl esters (2a-h, 3a-d) Method C The 5-heteroaryl substituted 4-(1-(4-fluorophenyl)-1H-indol-3-yl)-piperidine-1-carboxylic acid tert-butyl ester (2a-h, 3a-d) (6.3 mmol) was dissolved in THF (20 mL) and HCI/MeOH (30 mL) 15 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. K 2

CO

3 (5 g, 36 mmol), KI (0.5 g, 3 mmol), 4-methyl-2-pentanone (100 mL) and an alklcyl halide (9.5 mmol if nothing else stated) were added and the solution was stirred under reflux for 8 h. The amounts of reagents and solvents were scaled according to the actual amount of 5-heteroaryl substituted 4-(1 20 (4-fluorophenyl)-1H-indol-3-yl)-piperidine-1l-carboxylic acid tert-butyl ester used. Work-up procedure 1: H20 (50 mL) was added to the warm mixture and the phases were separated. The aqueous phase was extracted with CH 2 C1 2 (100 mL). The combined organic phases were washed with H 2 0 and with saturated aqueous CaC1 2 , dried (MgSO 4 ) and the solvents were removed in vacuo. The resulting compound was purified by flash chromatography. 25 Work-up procedure 2: H20 (50 mnL) was added to the warm mixture and the phases were separated. The aqueous phase was extracted with CH 2 C1 2 (100 mL). Kieselgel was added to the combined organic phases and the solvents were removed in vacuo. The resulting compound adsorbed to kieselgel was purified using Biotage flash 40 equipped with a FZIM-0035 solid injection module. 30 3-{4-[1-(4-Fluoro-phenyl)-5-(1-methyl-1H-1,2,4-triazol-3-yl)-IH-indol-3-yl]-piperidin-1-yl} propionitrile-oxalate (4a). Reaction of 2c (1.2 g, 2.5 mmol) with 3-bromo-propionitrile (1. 1g, 8.2 mmol) was performed 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) 35 and precipitated with oxalic acid from EtOH to give 0.45 g (34 %) of the oxalate of 4a: Mp. 216 217 OC (EtOH); 1H-NMR (DMSO-d 6 ) 1.95 (qd, 2H11), 2.12 (d, 2H), 2.76 (t, 2H), 2.93 (t, 2H), 3.02- WO 03/070723 PCT/DKO3/00105 21 3.15 (m, 3H), 3.32 (d, 2H), 3.93 (s, 3H), 7.40-7.47 (m, 2H11), 7.48 (s, 1H), 7.54 (d, 1H11), 7.60-7.68 (mn, 2H), 7.89 (d, 1H), 8.32 (s, 1iH), 8.48 (s, 1H-); MS m/z: 429 (100%, MH+), 388 (12%), 241 (3%); Anal. (C 2 5 H2 5 FN6-C 2 H20 4 -0.55 % H20): C, H, N. 5 The following derivative was prepared accordingly from 2f: 3-{4-[1-(4-Fluoro-phenyl)-5-(pyrimidin-2-yl)-1H-indol-3-ylj]-piperidin-1-yl}-propionitrile (4b). The free base was recrystallised from EtOAc/CH 2

C

2 90/10 to give 0.96 g (63%) of 4b: Mp 182-183 'C (EtOAc/CH 2 C1 2 ); 'H-NMR (DMSO-d 6 ) 1.81 (q, 2H), 2.03 (d, 2H), 2.25 (t, 2H), 2.60 2.70 (s, broad, 2H11), 2.70-2.80 (m, 2H11), 2.83-2.95 (m, 1H11), 3.02 (d, 2H), 3.33 (s, 3H), 7.38 (t, 111), 10 7.41-7.48 (m, 211), 7.52 (s, 111), 7.58 (d, 1H), 7.62-7.70 (m, 2H) 8.31 (d, 1H), 8.77 (s, 1H11), 8.89 (d, 2H11); MS m/z: 426 (100%, MIH+), 384 (95%), 373 (95%); Anal. (C 2 6

H

24 FNs): C, H, N. 1-(4-Fluoro-phenyl)-3-{1-[2-(4-methoxyphenyl)-ethyl]-piperidin-4-yl}-5-(1-methyl-1H-1,2,4 triazol-3-yl)-1H-indole (4c). Reaction of 2c (1.0 g, 2.10 mmol) with 1-(2-chloroethyl)-4 15 methoxybenzene (0.75 g, 4.4 mmol) was performed according to method C followed by work-up procedure 2. Flash chromatography (EtOAc/heptane 70/30 -- EtOAc/MeOH/NEt 3 90/10/2) gave an oil (0.20 g) which was crystallised from EtOAc to give 0.13 g (12%) of compound 4c: Mp 152-153 oC (EtOAc); 'H-NMR (DMSO-d 6 ) 1.80 (qd, 2H), 2.00 (d, 2H11), 2.18 (t, 2H), 2.54 (t, 2H11), 2.73 (t, 2H), 2.80-2.90 (m, 1H), 3.07 (d, 211), 3.72 (s, 3H), 3.93 (s, 3H11), 6.84 (d, 2H11), 7.16 (d, 2H), 20 7.35-7.42 (mn, 2H), 7.47 (s, 1H), 7.53 (d, 1H), 7.60-7.70 (m, 2H), 7.86 (d, 111), 8.30 (s, 11), 8.49 (s, 1IH); MS m/z: 510 (100%, MH); Anal. (C 3 1 H11 32

FN

5 0sO): C, H, N. 1-(4-Fluoro-phlienyl)-5-(I-methyl-1H-1,2,4-triazol-3-yl)-3-[1-(2-phenylethyl)-piperidin-4-yl] lIH-indole (4d). Reaction of 2c (1.0 g, 2.10 mmol) with (2-bromo-ethyl)-benzene (0.81 g, 4.4 25 mmol) was performed according to method C followed by work-up procedure 2. flash chromatography (EtOAc/heptane 70/30 -. EtOAc/MeOH/NEt 3 90/10/2) gave 0.80 g which was recrystallised from EtOAc/heptane 1/3 to give 0.30 g (30%) of 4d: Mp 244-245 oC (EtOAc/heptane 1/3); 'H-NMR (DMSO-d 6 ) 1.90 (s, broad, 4H11), 2.10 (s, broad, 2H11), 2.51 (t, 2H), 2.90 (s, broad, 4H), 3.05 (s, broad, 1H1), 3.93 (s, 3H), 7.23 (t, 1H), 7.30 (t, 2H), 7.31 (d, 2H), 7.40 30 7.48 (m, 2H), 7.52 (s, broad, 111), 7.54 (d, 1IH), 7.62-6.68 (m, 2H), 7.90 (d, 111), 8.35 (s, 1H11), 8.50 (s, 1H); MS m/z: 480 (100%, MH+); Anal. (C 3 0H30FNs): C, H, N. 3-{4-[1-(4-Fluoro-phenyl)-5-(1-methyl-1H-[1,2,4]triazol-3-yl)-1H-indol-3-yl]-piperidin-1-yl} propan-1-ol (4e). Reaction of 2c (1.0 g, 2.10 mmol) with 3-bromo-1-propanol (0,34 g, 2.40 35 mmol) was performed according to method C followed by workup procedure 2. Flash chromatography EtOAc/MeOH/NEt3 (100/0/2 - 75/25/2) gave 500 mg of crude product which WO 03/070723 PCT/DKO3/00105 22 was crystallised from EtOAc/heptane (70/30) to give 250 mg of the title compound. Mp. 138-139 'C (EtOAc/heptane); 1 H-NMR (DMSO-d 6 ) 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 (mn, 2H), 7.45 (s, 1H), 7.52 (d, 1H), 7.49-7.55 (min, 2H), 7.88 (d, 1H), 8.30 (s, 1H), 8.50 (s, 1H). 5 Preparation of further Compounds of the Invention Each of the intermediates 2a-h and 3a-d (1 mmol) were dissolved in THF (30 mL) and reacted overnight with a saturated solution of HC1 in MeOH (15 mL) at room temperature. The solvents were removed in vacuo, H20 was added and pH adjusted to 10 by addition of aqueous ammonium 10 hydroxide (25%). The aqueous phase was extracted with CH2C 2 and the combined organic phases were dried over MgSO 4 . After evaporation of the solvent, stock solutions of the piperidinyl derivatives were prepared by dissolving to 0.2 M by addition of DMSO. Stock solutions of alkyl halides were prepared by dissolving the halides in as little DMF as possible. Solutions were subsequently diluted to 0.2 M by addition of CH 3 CN. Blocks (Multisyntech Microchem Blocks 15 (MultiSynTech GmnbH. 2002) containing 96 1.2 mL reactors fitted with fits were loaded with

K

2

CO

3 (40 mg, 0.3 mmol) and KI (10 mg, 0.06 mmol). From the stock solutions the piperidinyl derivatives (0.15 mL, 0.03 mmol), the alkyl halide (0.225 mL, 0.045 mmol) and CH 3 CN (0.3 mnL) were added and the reactors were closed and rotated in an oven at 70 oC for 14 h. After cooling to 50 'C isocyanate resin (30 mg, 1 nimol/g) was added and the reactors were again closed and 20 rotated at 50 'C for 2 h. After cooling to room temperature, solids were filtered off and washed with CH 3 CN (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 mL). The combined organic phases from the sample was added and washed with MeOH (3 mL) and CH 3 CN (3 mL). Finally, the sample was eluted with 25 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 diluted to 2 mM in DMSO. The identity and purity of the compounds was determined by HPLC/MS analysis with UV and ELSD detection. Compounds with a purity of 70% or above were submitted for biological evaluation. The remaining compounds were purified by preparative LC/MS (Zeng, et al., Comb Chem High 30 Throughput Screen JID - 9810948, 1998, 1, 101). The following alkylating agents were used for the preparation of the examples listed below: 3 bromo-propionitrile, 3-(2-chloroethyl)-oxazolidin-2-one, 3-(2-chloroethyl)-1H-quinazoline-2,4 dione, 3-(2-chloroethyl)-l-methylpyrolidin-2-one, 1-(2-Chloro-ethyl)-4-methoxy-benzene, 1-(2 Bromo-ethoxy)-2-methoxy-ethane, 3-Bromo-N-(2,5-dimethoxy-phenyl)-propionamide, 3-Bromo 35 N-(2,5-dimethoxy-phenyl)-propionamide, 5-(3-Bromo-propoxy)-2,3-dihydro-benzo[1,4]dioxine, WO 03/070723 PCT/DK03/00105 23 1 -(2-Chloro-ethoxy)-propane, 2-(3 -Bromo-propoxy)-benzonitrile, 1 -(3 -Bromo-propoxy)-4-fluoro 2-methoxy-benzene, 3-(2-Brorno-ethyl)-benzofuran, 3-(2-Bromo-ethyl)-1H-indole, 3 -(3 -Bromo propyl)-JH-indole 5 The following examples were prepared according to the general procedure d): 3-{4-[1-(4-Fluoro-pheny)-5-(2-methy-2H-pyrazo-3-y)-H-indo-3-yI-piperidin1yl} propionitrile (5aa): Rf = 2.02; Purity UV/ELSD: 97.2/99.8 10 3- [1-(2-Benzofuran-3-yl-ethyl)-piperidin-4-ylI-1-(4-fluoro-phenyl)-5-(2-metliyl-2H-pyrazol 3-yl)-1H-indole (5ab): Rf =2.47; Purity IJV/ELSD: 78.9/96.7 3-t1-(2-1H-indol-3-yI-etlhyl)-piperidin-4-y1-1-(4-fluoro-phenyl)-5-(2-methyl-2H-pyrazol-3 yI)-1H-indole (5ac): Rf = 2.3 8; Purity UV/ELSD: 99.0/100.0 15 3-{4-[1-(4-Fluoro-phenyl)-5-pyridin-3-yI-1H-indol-3-yl]-piperidiii-1-yl}-propionitrile (5 ad): Rf = 1.59; Purity UY/ELSD: 91.5/100.0 20 1-(4-Fluoro-phenyI)-3-{1-[2-(4-methoxy-pheny1)-ethy]-piperidin-4-yI}-5-pyridin-3-yI-IJI indole (Sac): Rf = 1.92; Purity UV/ELSD: 94.7/100.0 3- I1-(2-Benzofuran-3-y-ethy)-piperidin-4-y1-l-(4-fluoro-pheny)-5-pyridin-3-y-H-indoe (5afj): Rf = 2.04; Purity UV/ELSD: 95.0/99.1 25 3-11-(2-1H-indol-3-yl-ethyl)-piperidin-4-yll-l-(4-fluoro-phenyl)-5-pyridin-3-yl-lH-indole (5ag): Rf = 1.95; Purity UV/ELSD: 90.1/99.0 3-{1-[3-(2,3-Dihydro-1,4-benzodioxin-5-yloxy)-propylj-piperidin-4-y}-1-(4-fluoro-pieny)-5 30 (3-methyl-3H-1,2,3-triazol-4-yl)-1H-indole (5ah): Rf = 2.37; Purity UV/ELSD: 90.0/99.0 3- L1-(2-Benzofran-3-yl-ethyl)-piperidin-4-ylJ-1-(4-fluoro-pienyl)-5-(3-methyl-3H-1,2,3 triazol-4-yI)-1H-indole (Sai): Rf = 2.40; Purity UY/ELSD: 70.0/95.8 35 3- [1-(2-Benzofuran-3-yl-ethyl)-piperidin-4-yll-l-(4-fluoro-plienyl)-5-(1-methyl-IH-pyrazol 4-yl)-1H-indole (5aj): Rf = 2.47; Purity UV/ELSD: 70.0/95.5 WO 03/070723 PCT/DK03/00105 24 3-[l-(2-Benzofuran-3-yI-ethyl)-piperidin-4-ylJ-1-(4-fluoro-phenyl)-5-pyrimidin-2-yl-lH indole (5ak): Rf = 2.55; Purity UV/ELSD: 70.0/91.3 3-{4-[1-(4-Fluoro-plienyl)-5-(1-mctliyl-lH-imidazol-2-yl)-1H-indol-3-ylI-piperidin-1-yl 5 propionitrile (5a1): Rf = 1.46; Purity UV/ELSD: 90.0/100.0 3-{4-[1-(4-Fluoro-phenyl)-5-(2-metliyl-2H-1,2,4-triazol-3-yl)-1H-indol-3-yl-piperidin-1-yl propionitrile (5am): Rf = 1.76; Purity JV'/ELSD: 95.0/100.0 10 3-{4-[1-(4-Fluoro-phenyl)-5-(1-methyl-lH-1,2,4-triazol-3-yl)-lH-indol-3-ylJ-piperidin-1-yl propionitrile (5an): Rf = 1. 85; Purity UV/ELSD: 90.0/100.0 1-(4-Fluoro-phenyl)-3-{1-[2-(4-metlioxy-phenyl)-etliylj-piperidin-4-yl}-5-(l-netiyl-lH imidazol-2-yl)-1H-indole (5ao): Rf =1.78; Purity U\J/ELSD: 79.2/97.2 15 triazo1-3-y1)-II-indole (5ap): Rf = 2.28; Purity UV/ELSD: 70.0/97.5 20 1-(4-Fluoro-phenyl)-3-{1- [2-(2-methioxy-ethoxy)-ethyl]-piperidin-4-y}-5-2-methiy-2H-1,2,4 triazol-3-yl)-1H-indole (5aq): Rf =1.83; Purity IJV/ELSD: 78.0/99.2 1-(4-Fluoro-phenyl)-3-{1-[2-(2-metlioxy-ethoxy)-etliyll-piperidin-4-yl-5-(l-methyl-1H-1,2,4 triazol-3-yl)-1H-indole (5ar): Rf = 1.96; Purity UV/ELSD: 90.0/98.3 25 3-{1-[2-(2,3-Dihydro-1,4-beuzodioxin-5-yloxy)-ethyll-piperidin-4-y}-1-(4-fluoro-phenyl)-5 (2-metliyl-2H-1 ,2,4-triazol-3-yl)-1H-indole (5as): Rf 2.16; Purity UV/ELSD: 90.0/100.0 3-{1-[3-(2,3-Dihydro-1,4-benzodioxin-5-yloxy)-propylj-piperidin-4-y}-1-(4-fluoro-phenyl)-5 30 (2-methyl-2H-1,2,4-triazol-3-yl)-1H-indole (Sat): Rf = 2.18; Purity UVELSD: 80.0/98.3 2-(2-{4-[1-(4-Fluoro-phenyl)-5-(2-methyl-2H-1,2,4-triazol-3-y)-1H-indol-3-yl-piperidinyl}-ethoxy)-ethanol (5au): Rf =1.73; Purity UV/ELSD: 84.8/99.9 WO 03/070723 PCT/DK03/00105 25 2 -(2-{4-[1-(4-Fluoro-phenyl)-5-(-methyl-1H-1,2,4-triazol-3-yl)-H-indo3yllpiperidin-l yl}-etlioxy)-etlianol (5av): Rf = 1. 81; Purity UV/ELSD: 84.6/100.0 5 yl}-propoxy)-benzonitrile (Saw): Rf = 2.42; Purity UV/ELSD: 90.0/99.9 3-{1-[3-(4-Fluoro-2-methoxy-phefoxy)-propyl]-piperidin-4-yl-1-(4-fluoro-phenyl)-5-(2 rnetlhyl-2H-1,2,4-triazol-3-yl)-1H-indole (5ax): Rf = 2.30; Purity UV/ELSD: 71.0/98.7 10 1-(4-Fhioro-pheny)-3-{1-f2-(4-methoxy-pheny)-ethyJ-piperidin-4-y}-5-3-metiy-3H-1,2,3. triazol-4-yl)-1H-indole (5ay): Rf = 2.33; Purity UV/ELSD: 72.9/98.2 3-{1-[3-(4-Fluoro-2-methoxy-phenoxy)-propyI-piperidin-4-y}-1-4-fluoro-peny-5-(3 methyl-3H-1,2,3-triazol-4-yl)-1H-indole (5az): Rf = 2.4 1; Purity UV/ELSD: 70.8/97.3 15 3-{4-[1-(4-Fluoro-phenyl)-5-(3-methyl-3H-1,2,3-triazol-4-yl)-1H-indol-3-yl-piperidin-1-yl propionitrile (5ba): Rf = 1.96; Purity UV/ELSD: 85.1/99.2 3-{4-[1-(4-Fluoro-phenyl)-5-pyriniidin-2-yl-1H-inclol-3-yl]-piperidin-1-yl}-propionitrle 20 (5hb): Rf = 2. 10; Purity U-V/ELSD: 85.8/99.4 1-(4-Fluoro-phenyl)-3-{1-[2-(4-methoxy-phenyl)-ethyl]-piperidin-4-yl}-5-pyrimidin-2-yl-1H indole (5bc): Rf = 2.49; Purity UV/ELSD: 96.2/99.5 25 N-(2,5-Dirnethoxy-pheny)-3-{4-[1-(4-fluoro-pheny)-5-(2-methy-2H-1,2,4-triazo-3-y)-1H indol-3-ylJ-piperidin-1-yl}-propionainide (5bd): Rf 2.12; Purity TJV/ELSD: 93.3/99.6 3-{1-[3-(4-Fluoro-2-methoxy-phenoxy)-propyl-piperidin-4-y}-1-(4-fluoro-phenyl)-5-(1 methyl-1H-1,2,4-triazol-3-yl)-1H-indole (5be): Rf = 2.42; Purity UV/ELSD: 90.0/99.4 30 3- [l-(2-Benzofuran-3-yl-ethxyl)-piperidin-4-yl]-1-(4-fluoro-phenyl)-5-(2-methyl-2H-1,2,4 triazol-3-yI)-1H-indole (5b1): Rf = 2.29; Purity UTV/ELSD: 92.9/99.5 3- 11-(2-1H-incl-3-y-ethyl)-piperidin-4-ylI-1-(4-fluoro-phenyl)-5-(3-metliyl-3H-1,2,3-triazol 35 4.-yI)-1H-indole (5bg): Rf 2.37; Purity UV/ELSD: 99.0/99.1 WO 03/070723 PCT/DKO3/00105 26 3-[1-(2-1H-indol-3-yl-ethyl)-piperidin-4-yl]-1-(4-fluoro-phenyl)-5-(2-methyl-2H-1,2,4-triazol 3-yl)-lH-indole (5bh): Rrf = 2.20; Purity UV/ELSD: 80.3/98.3 3-[1-(3-1H-indol-3-yl-propyl)-piperidin-4-yl]-1-(4-fluoro-phenyl)-5-(3-methiyl-3H-1,2,3 5 triazol-4-yl)-IH-indole (5bi): Rf = 2.39; Purity UV/ELSD: 89.9/98.9 3-[1-(3-1H-indol-3-yl-propyl)-piperidin-4-yl]-1-(4-fluoro-phenyl)-5-(l-methyl-lH-pyrazol-4l.

yl)-1H-indole (5bj): Rf = 2.49; Purity UV/ELSD: 87.9/98.7 10 Pharmacological Testing The compounds of the invention have been tested using well-recognised and reliable methods. The tests are as follows: 15 INHIBITION OF 3 II-PRAZOSIN BINDING TO a-ADRENOCEPTORS IN RAT BRAIN IN VITRO By this method the inhibition by drugs of the binding of 3 H-prazosin (0.25 nM) to xi adi-enoceptors in membranes from rat brain is determined in vitro. Method and results in Hyttel 20 & 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 high affinity for the al-adrenoceptor. Most of the 25 compounds having an ICso value below 30 nM in this test. INHIBITION OF 3 H-PRAZOSIN BINDING TO CLONED ca, Clb, and ld, ADRENOCEPTORS 30 Cell lines: Cell lines expressing the bovine c,, rat ld receptors and the hamster al, receptor were used in the assays. In vitro binding assays: Briefly, the cells were homogenised in ice-cold 50 mM Tris, pH 7.7, using an Ultra-Turrax and the homogenates either kept on ice or stored at -80 oC until used. The assay buffer subsequently used contained 50 mM Tris, pH 7.7. Non-specific displacer was WB 35 4101 (1 [tM) for the (Xala, clb, and ald assays. All assays were incubated at 25 oC for 20 minutes.

WO 03/070723 PCT/DKO3/00105 27 All assays were terminated by vacuum filtration on GF/B filters and counted in a scintillation counter (Wallac Trilux). The radioligand used was [ 3 H]prazosin. It was found that some of the compounds of the invention have stronger affinity to the cla 5 adrenoceptor than the alb-adrenoceptor and the Ocld-adrenoceptor. Further, many of the compounds of the invention have much stronger affinity for the c, adrenoceptor compared to the D 2 and the 5-HT 2 receptor. 10 Pharmaceutical compositions The pharmaceutical compositions of this invention or those which are manufactured in accordance with this invention may be administered by any suitable route for example orally in the form of 15 tablets, capsules, powders, syrups, etc., or parenterally in the form of solutions for injection. For preparing such compositions, methods well Imown in the art may be used, and any pharmaceutically acceptable carriers, diluents, excipients or other additives normally used in the art may be used. 20 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 usually in the range of about 0.05 - 500 mg, and most preferably about 0.1 to 50 mg of the active compound of the invention. 25 Formulation Examples The pharmaceutical formulations of the invention may be prepared by conventional methods in the art. 30 Tablets may for example be prepared by mixing the active ingredient with ordinary adjuvants, carriers and/or diluents and subsequently compressing the mixture in a conventional tabletting machine. Examples of adjuvants, carriers or diluents comprise: corn starch, potato starch, talcum, magnesium stearate, gelatine, lactose, gums, and the like. Any other adjuvants or additives usually 35 used for such purposes such as colourings, flavourings, preservatives etc. may be used provided that they are compatible with the active ingredients.

WO 03/070723 PCT/DKO3/00105 28 Solutions for injections may be prepared by dissolving the active ingredient and possible additives in a part of the solvent for injection, preferably sterile water, adjusting the solution to desired volume, sterilisation of the solution and filling in suitable ampules or vials. Any suitable additive conventionally used in the art may be added, such as tonicity agents, preservatives, antioxidants, 5 etc.

Claims (22)

1. A compound having the general formula R2 (CH 2 )n G N- (CH 2 )m- X-Y Het R 3 N Rs 5 Ar I wherein Het is a five- or six-membered aromatic, heterocyclic ring containing at least one nitrogen atom as 10 a ring member, and optionally substituted with CI_ 6 -alkyl; n is 0 or 1; G is N, C or CIHI; the dotted line meaning a bond when G is C, and the dotted line meaning no 15 bond when G is CH or N; Ar is phenyl optionally substituted with one or more substituents independently selected from halogen, Cz- 6 -alkyl, C1. 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; 20 R 2, R 3, R 4 and R s are independently selected from hydrogen, C 1 . 6 -alkyl, C1. 6 -alkoxy, hydroxy, halogen, trifluoromethyl, nitro, cyano, amino, C 1 - 6 -alkCylamino and CI- 6 -dialkylamino; mis 1, 2 or3; 25 X is a bond, -CHI 2 -, -0-, -S-, -NH-, -NHCO- or -CONH-; and Y is cyano, CI.6-alkyloxy, CI_ 6 -alklcyl substituted with hydroxy, C 1 .6-alkoxy, or C16 alkylcarbonyloxy or Y is phenyl which may optionally be substituted one or more times with 30 substituents selected from halogen, C 16 -alkyl, trifluoromethyl, hydroxy, C 1 - 6 -alkoxy, C 1 6 alkylcarbonyloxy, nitro, cyano, amino, C 1 6 -alkylamino and C 1 6 -dialkylamino, methylenedioxy and ethylenedioxy, or Y is an aromatic mono- or bicyclic heterocyclic ring containing only one WO 03/070723 PCT/DKO3/00105 30 heteroatom which may optionally be substituted one or more times with substituents selected from halogen, CI_ 6 -alkyl, trifluoromethyl, hydroxy, C 1 . 6 -alkoxy, C 1 . 6 -alkylcarbonyloxy, nitro, cyano, amino, C 1 - 6 -alkylamino and Ci. 6 -dialkylamino; provided Y is not cyano when X is O, S, NH, NHCO or CONH; and Y is not C 1 . 6 -alkoxy when X is O, S or NH; 5 or a pharmaceutically acceptable acid addition salt thereof. 2. A compound according to claim 1, characterized in that Het is optionally substituted triazolyl, pyrazolyl, pyrimidyl, pyridinyl or imidazolyl. 10

3. A compound according to claim 2, characterized in that Het is 1-methyl-lH-1,2,4-triazol-3-yl, 2-methyl-2H-1,2,4-triazol-3-yl, 3-methyl-3H-1,2,3-triazol-4-yl, 1-methyl-1H-pyrazol-4-yl, 2-methyl-2H-pyrazol-3-yl, 1-methyl-lH-imidazol-2-yl, pyrimidin-2-yl or pyridin-3-yl. 15

4. A compound according to claims 1-3 wherein Y is C 1 . 6 -alkyl substituted with hydroxy, C 1 .6 alkoxy or Cl- 6 -alkylcarbonyloxy, or Y is optionally substituted phenyl.

5. A compound according to claim 4 wherein X is a bond, -CH 2 -, O or S. 20

6. A compound according to claim 5 wherein X is O or S.

7. A compound according to claims 1-3 wherein Y is an optionally substituted, aromatic bicyclic heterocyclic ring containing only one heteroatom. 25

8. A compound according to claim 7 wherein Y is indolyl, benzofuranyl or dihydro-l1,4 benzodioxinyl.

9. A compound according to claims 7-8 wherein X is a bond, -CH 2 -, O or S. 30

10. A compound according to claim 4 wherein X is -NHCO- or -CONH-.

11. A compound according to claim 10 wherein Y is optionally substituted phenyl.

12. A compound according to claims 1-3 wherein Y is cyano. 35

13. A compound according to claims 1 to 3, characterized in that it is selected from: WO 03/070723 PCT/DK03/00105 31 3- {4-[1 -(4-Fluoro-phenyl)-5-(1 -methyl-1H-1 ,2,4-triazol-3-yl)- 1H-indol-3-yl] -piperidin- l-yl} propionitrile; 3- {4-[1 -( 4 -Fluoro-plhenyl)-5-(pyrimidin-2y)4Hndop3-yllypiperidin-1-yl} -propion-itrile; 1 -(4-Fluoro-phenyl)-3- {11-[2-(4-methoxyphenyl)-ethyl]-piperidin-4-yl} -5-(1 -methyl-1H-1 ,2,4 5 triazol-3-yl)- 1H-indole; 1 -(4-Fluoro-phenyl)-5-(1 -methyl-1H- 1,2,4-triazol-3 -yl)-3-rl -(2-phenylethyl)-piperidin-4-yl]- 1H indole; 3- {4-[ 1 Fur-hny)5(-ehl-Hprzl3yl-Hidl3y -ieii--yl} propionitrile; 10 341 -( 2 -Benzofuran-3-yl-ethyl)-piperidin.4-yl]-1 -( 4 -fluoro-phenyl)-5-(2-methyl-2H-pyrazol-3 -yl) 1H-indole; 3-[1 -(2- 1H-indol-3 -yl-ethyl)-piperidin-4-yl] -1-( 4 -fluoro-phenyl)-5-(2-miethyl-2H-pyrazo[-3-y1) 1H-indole; 3- {4-I-(4-Fluoro-phienyl)-5-pyridin-3 -yl-1H-indol-3 -yl]-piperidin-1 -yl} -propionitrile; 15 1 -(4-Fluoro-phenyl)-3-{ 1 42-(4-methoxy-phenyl)-ethyl]-piperidini4-yl} -5-pyridin-3-yl- iN indole; 34 t -(2-Benzofuran-3 -yl-ethyl)-piperidin-4-yl] -1-(4-fluoro-phenyl)-5-pyridin-3-yl- 1H-indole; 3-[l -(2-1H-indol-3 -yl-ethyl)-piperidin-4-yl]- I-(4-fluoro-phenyl)-5-pyridin-3-yl- 1H-indole; 3-{i -[3-(2,3 -Dihydro-1 , 4 -benzodioxin-5-yloxy)-propyl]-piperidin-4yll -1-(4-fluoro-phenyl)-5-(3 20 methyl-3H- 1,2,3 -triazol-4-yl)-1H-indole; 3-[l -(2-Benzofuran-3-y-ethy)-piperidin4y1 -1-(4-fluoro-phenyl)-5-(3-methyl-3H-1,2,3-triazolp 4-yl)- 1H-indole; 3-[ 1-(2-Benzofuran-3-yl-ethyl)-piperidin-4-yl]1 -(4-fluoro-phenyl)-5-(1 -methyl- 1H-pyrazol-4-yl) 1H-indole; 25 3-[ 1-(2-Benzofurani-3-yl-ethyl)-piperidin-4-ylp 1 -( 4 -fluoro-pheny1)-5-pyrimidin-2-y1-lH-indole; 3- {4-[1 -(4-Fluoro-phenyl)-5 -(1 -methyl- 1H-imnidazol-2-yl)-1H-indol-3 -yl] -piperidin- i-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; 30 3- {4-[l1-(4-Fluoro-phenyl)-5-(1 -methyl-iN-i ,2,4-triazol-3-yl)- 1N-indol-3 -yl]-piperidin- l-yl} propionitrile; l-(4-Fluoro-phenyl) -3- { I-[2-(4-methoxy-phenyl)-ethyl]-piperidin4yl} -5-(1 -methyl- iH imidazol-2-yl)-iH-indole; 1 -(4-Fluoro-plienyl)-3-f { -[2-(4-methoxy-phenyi)-ethyll -piperidin-4-yl} -5-( i-methyl- iN-i,2,4 35 triazol-3-yl)-1H-indole; WO 03/070723 PCT/DK03/00105 32 1-(4-Fluoro-phen-yl)-3 -{ I-[ 2 -(2-methoxy-ethoxy)-ethyl-piperidin4yl} -5-(2-methyl-2-H-1 ,2,4 triazol-3 -yl)--1H-indole; l-(4-Fluoro-phenyl)-3- { 1 -[ 2 -( 2 -metlioxy-ethoxy)-ethyl]-piperidin4ylj -5-( 1-methiyl- 1H-1 ,2,4 triazol-3-yl)-1H-indole; 5 3-f 1 -[2-(2,3-Dihydro- 1,4-benzodioxin-5-yloxy)-ethyl]-piperidin4yl} -1-(4-fluoro-phenyl)-5-(2 methyl-2H-1I,2,4-ttiazol-3-yl)-1H-indole; 3-f{ 1[3 -(2,3-Dihydro-1 , 4 -benzodioxin-5-yloxy)-propy1]-piperidin-4y}-1 -(4-fluoro-phenyl)-5-(2 methyl-2H-1 ,2,4-triazol-3-yl)-1H-indole; 2-(2-{4-[l1-( 4 -Fluoro-pheny)-5-(2-methy1-2H1,2,4triazo13-yl> 1H-indol-3-yl] -piperidin-1 -yl} 10 ethoxy)-ethanol; 2-(2-{4-[ 1-(4-Fluoro-phenyl)-5 -(1 -methyl- 1H-1,2,4-triazol-3-yl)-1H-indol-3 -yl]-piperidini- -yl} ethoxy)-ethanol; 2-(3 -{4-[l1-(4-Fluoro-phenyl)-5-(l1-methyl-1H-1 , 2 , 4 -triazol-3-yl)-1H-indol-3-yl]-piperidin-1-yl} propoxy)-benzonitrile; 15 3-f{ 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)-1H-indole; 1 -(4-Fluoro-phenyl)-3- {l1-[ 2 -(4-methoxy-phenyl)-ethyl] -piperidin-4-yl} -5-(3 -methyl-3H- 1,2,3 triazol-4-yl)- 1H-ilidole; 3-f{ 1-[ 3 -( 4 -Fluoro-2-methoxy-phenoxy)-propylypiperidin-4yl} - -(4-fluoro-phenyl)-5-(3-methyl 20 3H-1 ,2,3-triazol-4-yl)-1H-indole; 3- {4-[ 1-(4-Fluoro-phenyl)-5-(3 -methyl-3H-1 ,2,3-triazol-4-yl)-1H-indol-3-yl] -piperidin-1 -yl} propionitrile; 3-{4-[-4F lur-hnl15prmdn- lI-ndl3y]ppeii- l-propionitrile; 1-(4-Fluoro-phenyl)-3- { I-[2-(4-methoxy-phenyl)-ethyll -piperidin-4-yl} -5-pyrimidin-2-yl-1H 25 indole; N-(2,5-Dimethoxy-phenyl)-3-{4-[ 1-( 4 -fluoro-phenyl)-5-(2-methyl-2H-1,2,4-triazo-3-yl) 1H indol-3 -yl] -piperidin- l-yl} -propionamide; 3- {11-[3 -( 4 -Fluoro-2-methoxy-phenoxy)-propyl]ypiperidin-4yl} -1-(4-fluoro-phenyl)-5-(1 -methyl 1H-1,2,4-friazol-3 -yl)-1H-indole; 30 3-fl -( 2 -Benzofuran-3-yl-ethyl)-piperidin4ylyl -(4-fluoro-phenyl)-5-(2-miethyl-2H- 1,2,4-triazol 3-yl)-1H-indole; 3-fl -(2-IT-indol-3 -yl-ethyl)-piperidin-4-yl]-1 -(4-fluoro-phenyl)-5-(3-methyl-3H- 1, 2 ,3-triazol-4 yl)- 1H-indole; 3-f 1-(2- 1H-indol-3 -yl-ethyl)-piperidin-4-yl]-1 -(4-fluoro-phenyl)-5-(2-methyl-2H-1 ,2,4-triazol-3 35 yl)-1H-indole; WO 03/070723 PCT/DKO3/00105 33 3-[1-(3- 1H-indol-3-yl-propyl)-piperidin-4-yl]-I-(4-fluoro-phenyl)-5-(3-methyl-3H-1,2,3-triazol-4 yl)-1H-indole and 3-[1-(3-1H-indol-3-y1-propyl)-piperidin-4-yl]-I-(4-fluoro-phenyl)-5-(l-methyl-1H-pyrazol-4-yl) 1H-indole, 5 3- {4-[1-(4-Fluoro-phenyl)-5-(1-methyl-1H-[1,2,4]triazol-3-yl)-1H-indol-3-yl]-piperidin-1-yl} propan- 1 -ol, or a pharmaceutically acceptable acid addition salt thereof.

14. A compound according to claims 1 to 3 which is radio-labelled. 10

15. A compound according to claim 14 which is radiolabelled with ["C]-methyl.

16. A compound according to claim 14 which is radiolabelled with 18 F, 1231 or 125.

17. A pharmaceutical composition comprising at least one compound according to claims 1 to 13 15 a pharmaceutically acceptable acid addition salt thereof and optionally a second pharmaceutically active ingredient in combination with one or more pharmaceutically acceptable carrier or diluents.

18. The use of a compound according to Claims 1 to 13 or an acid addition salt thereof and optionally a second pharmaceutically active ingredient for the preparation of a medicament for the 20 treatment of a disorder or disease responsive to antagonism of a-adrenoceptors.

19. The use of a compound according to claims 1 to 13 or an acid addition salt thereof and optionally a second agent having antipsychotic activity for the preparation of a medicament for the treatment of psychosis. 25

20. A method for the treatment of a disorder or disease responsive to antagonism of ca adrenoceptors in a mammal comprising administering a compound according to claims 1 to 13 or an acid addition salt thereof and optionally a second pharmaceutically active ingredient to said mammal. 30

21. A method for the treatment of psychosis in a mammal comprising administering a compound according to claims 1 to 13 or an acid addition salt thereof and optionally a second agent having antipsychotic activity to said mammal. 35

22. The use of a compound according to Claims 1 to 13 or an acid addition salt thereof for the preparation of a radio-labelled compound of the Formula I.