WO1996004274A1

WO1996004274A1 - Azetidine, pyrrolidine and piperidine derivatives

Info

Publication number: WO1996004274A1
Application number: PCT/GB1995/001819
Authority: WO
Inventors: Raymond Baker; Sylvie Bourrain; Jose Luis Castro Pineiro; Mark Stuart Chambers; Alexander Richard Guiblin; Sarah Christine Hobbs; Richard Alexander Jelley; Andrew Madin; Victor Giulio Matassa; Austin John Reeve; Michael Geoffrey Neil Russell; Graham Andrew Showell; Francine Sternfeld; Leslie Joseph Street; Monique Bodil Van Niel
Original assignee: Merck Sharp & Dohme Limited
Priority date: 1994-08-02
Filing date: 1995-08-01
Publication date: 1996-02-15
Also published as: US5854268A; CA2195107A1; JPH10503768A; AU3182495A; EP0804434A1; AU699272B2

Abstract

A class of substituted azetidine, pyrrolidine and piperidine derivatives are selective agonists of 5-HT1-like receptors, being potent agonists of the human 5-HT1Dα receptor subtype whilst possessing at least a 10-fold selective affinity for the 5-HT1Dα receptor subtype relative to the 5-HT1Dβ subtype; they are therefore useful in the treatment and/or prevention of clinical conditions, in particular migraine and associated disorders, for which a subtype-selective agonist of 5-HT1D receptors is indicated, whilst eliciting fewer side-effects, notably adverse cardiovascular events, than those associated with non-subtype-selective 5-HT1D receptor agonists.

Description

AZETIDINE. PYRROLIDINE AND PIPERIDINE DERIVATIVES

The present invention relates to a class of substituted azetidine, pyrrolidine and piperidine derivatives which act on 5-hydroxytryptamine (5-HT) receptors, being selective agonists of so-called "5-HTι-like" receptors. They are therefore useful in the treatment of clinical conditions for which a selective agonist of these receptors is indicated.

It has been known for some time that 5-HTι-like receptor agonists which exhibit selective vasoconstrictor activity are of use in the treatment of migraine (see, for example, A. Doenicke et al., The Lancet, 1988, Vol. 1, 1309-11; and W. Feniuk and P.P.A. Humphrey, Drug Development Research, 1992, 26, 235-240).

The human 5-HTι-like or 5-HTID receptor has recently been shown by molecular cloning techniques to exist in two distinct subtypes. These subtypes have been termed 5-HTiDα (or 5-HTID-I) and 5-HTiDp (or 5-HTnw.), and their amino acid sequences are disclosed and claimed in WO-A-91/17174.

The 5-HTiDα receptor subtype in humans is believed to reside on sensory terminals in the dura mater. Stimulation of the 5-HTID,, subtype inhibits the release of inflammatory neuropeptides which are thought to contribute to the headache pain of migraine. The human 5-HTiDp receptor subtype, meanwhile, is located predominantly on the blood vessels and in the brain, and hence may play a part in mediating constriction of cerebral and coronary arteries, as well as CNS effects. Administration of the prototypical 5-HTID agonist sumatriptan

(GR43175) to humans is known to give rise at therapeutic doses to certain adverse cardiovascular events (see, for example, F. WiUett et al., Br. Med. J., 1992, 304, 1415; J.P. Ottervanger et al., The Lancet, 1993, 341, 861-2; and D.N. Bateman, The Lancet, 1993, 341, 221-4). Since sumatriptan barely discriminates between the human 5-HTiDα and 5-HTiDp receptor subtypes (cf. WO-A-91/17174, Table 1), and since it is the blood vessels with which the 5-HTiDp subtype is most closely associated, it is believed that the cardiovascular side-effects observed with sumatriptan can be attributed to stimulation of the 5-HTn_>p receptor subtype. It is accordingly considered (cf. G.W. Rebeck et al, Proc. Natl. Acad. Sci. USA, 1994, 91, 3666-9) that compounds which can interact selectively with the 5-HTiD_α receptor subtype, whilst having a less pronounced action at the 5-HTiDp subtype, might be free from, or at any rate less prone to, the undesirable cardiovascular and other side-effects associated with non-subtype- selective 5-HTID receptor agonists, whilst at the same time maintaining a beneficial level of anti-migraine activity.

The compounds of the present invention, being selective 5-HTι-like receptor agonists, are accordingly of benefit in the treatment of migraine and associated conditions, e.g. cluster headache, chronic paroxysmal hemicrania, headache associated with vascular disorders, tension headache and paediatric migraine. In particular, the compounds according to this invention are potent agonists of the human 5-HTID.. receptor subtype. Moreover, the compounds in accordance with this invention have been found to possess at least a 10-fold selective affinity for the 5-HTiDo receptor subtype relative to the 5-HTiDp subtype, and they can therefore be expected to manifest fewer side-effects than those associated with non-subtype-selective 5-HTID receptor agonists.

Several distinct classes of substituted five-membered heteroaromatic compounds are described in published European patent applications 0438230, 0494774 and 0497512, and published International patent applications 93/18029, 94/02477 and 94/03446. The compounds described therein are stated to be agonists of 5-HTι-like receptors, and accordingly to be of particular use in the treatment of migraine and associated conditions. None of these publications, however, discloses nor even suggests the substituted azetidine, pyrrolidine and piperidine derivatives provided by the present invention. Moreover, nowhere in the prior art available to date is there any disclosure of a subtype-selective 5-HTID receptor agonist having a 5-HTID__ receptor binding aff nity (ICso) below 50 nM and at least a 10-fold selective affinity for the 5-HTID_, receptor subtype relative to the 5-HTiDp subtype. The compounds according to the present invention are subtype- selective 5-HTID receptor agonists having a human 5-HTiDα receptor binding affinity (ICso) below 50 nM, typically below 10 nM and preferably below 1 nM; and at least a 10-fold selective affinity, typically at least a 50- fold selective affinity and preferably at least a 100-fold selective affinity, for the human 5-HTiDα receptor subtype relative to the 5-HTiDp subtype.

The present invention provides a compound of formula I, or a salt or prodrug thereof:

<D wherein Z represents an optionally substituted five-membered heteroaromatic ring selected from furan, thiophene, pyrrole, oxazole, thiazole, isoxazole, isothiazole, imidazole, pyrazole, oxadiazole, thiadiazole, triazole and tetrazole;

E represents a chemical bond or a straight or branched alkylene chain containing from 1 to 4 carbon atoms;

Q represents a straight or branched alkylene chain containing from 1 to 4 carbon atoms, optionally substituted in any position by a hydroxy group;

T represents nitrogen or CH; U represents nitrogen or C-R²;

V represents oxygen, sulphur or N-R³; R² and R³ independently represent hydrogen or Ci-β alkyl; M represents the residue of an azetLdine, pyrrolidine or piperidine ring;

R represents a group of formula -W-R¹; W represents a chemical bond or a straight or branched alkylene chain containing from 1 to 4 carbon atoms, optionally substituted in any position by a hydroxy group;

R¹ represents -OR¹, -SR^X, -SOR^x, -SO2R¹ or -NR*R^y; R¹ and R^y independently represent hydrogen, hydrocarbon or a heterocydic group; or R* and R? together represent a C2.6 alkylene group, which alkylene group may be optionally substituted by one or more substituents selected from Ci-β alkyl, aryl and hydroxy, or fused with a phenyl ring; and

R" represents hydrogen, hydroxy, hydrocarbon or a heterocydic group.

The present invention also provides compounds of formula I above wherein T represents CH; W represents a chemical bond or a straight or branched alkylene chain containing from 1 to 4 carbon atoms; R¹ represents -OR^x, -SR^X or -NR^xR^y; R^x and R* independently represent hydrogen, hydrocarbon or a heterocydic group, or R^x and R together represent a C2-6 alkylene group; and Z, E, Q, U, V, M and R' are as defined above.

The present invention further provides compounds of formula I above wherein Q represents a straight or branched alkylene chain containing from 1 to 4 carbon atoms; T represents CH; W represents a chemical bond or a straight or branched alkylene chain containing from 1 to 4 carbon atoms; R¹ represents -OR^x, -SR^X or -NR'-R-'; R^x and R* independently represent hydrogen, hydrocarbon or a heterocydic group, or R^x and R together represent a C2-6 alkylene group; R* represents hydrogen; and Z, E, U, V and M are as defined above. The present invention still further provides compounds of formula I above wherein Q represents a straight or branched alkylene chain containing from 1 to 4 carbon atoms; T represents nitrogen; U represents C-R²; V represents N-R³; W represents a chemical bond or a straight or branched alkylene chain containing from 1 to 4 carbon atoms; R¹ represents -OR^x, -SR^X or -NR*R^y; R^x and R^y independently represent hydrogen, hydrocarbon or a heterocydic group, or R^x and R^y together represent a C2-6 alkylene group; R* represents hydrogen; and Z, E, R², R³ and M are as defined above. The five-membered heteroaromatic ring Z in the compounds of formula I above may be optionally substituted by one or, where possible, two substituents. As will be appredated, where Z represents an oxadiazole, thiadiazole or tetrazole ring, only one substituent will be possible; otherwise, one or two optional substituents may be accommodated around the five-membered heteroaromatic ring Z.

Examples of suitable substituents on the five-membered heteroaromatic ring Z indude Ci-β alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cydoalkyl, aryl, aryl(Cw) alkyl, C37 heterocydoalkyl, heteroaryl,

Ci-β alkoxy, Ci-β alkylthio, amino, Ci-β alkylamino, di(Cκ)alkylamino, halogen, cyano or trifluoromethyl.

For use in medicine, the salts of the compounds of formula I will be pharmaceutically acceptable salts. Other salts may, however, be useful in the preparation of the compounds according to the invention or of their pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds of this invention indude add addition salts which may, for example, be formed by mixing a solution of the compound according to the invention with a solution of a pharmaceutically acceptable add such as hydrochloric add, sulphuric add, fumaric add, maleic add, succinic add, acetic add, benzoic add, oxalic add, dtric add, tartaric add, carbonic add or phosphoric add. Furthermore, where the compounds of the invention carry an addic moiety, suitable pharmaceutically acceptable salts thereof may indude alkali metal salts, e.g. sodium or potassium salts; alkaline earth metal salts, e.g. caldum or magnesium salts; and salts formed with suitable organic ligands, e.g. quaternary ammonium salts. The term "hydrocarbon" as used herein indudes straight-chained, branched and cyclic groups containing up to 18 carbon atoms, suitably up to 15 carbon atoms, and conveniently up to 12 carbon atoms. Suitable hydrocarbon groups indude Ci-e alkyl, C2-6 alkenyl, Cz alkynyl, C3-7 cydoalkyl, C37 cydoalkyl(Cι-β)alkyl, indanyl, aryl and ary Ci-β) alkyl. The expression "a heterocydic group" as used herein indudes cyclic groups containing up to 18 carbon atoms and at least one heteroatom preferably selected from oxygen, nitrogen and sulphur. The heterocydic group suitably contains up to 15 carbon atoms and conveniently up to 12 carbon atoms, and is preferably linked through carbon. Examples of suitable heterocydic groups indude C37 heterocydoalkyl, C3.7 heterocydoalkyl(Cι-β)alkyl, heteroaryl and heteroaryl(Cι^) alkyl groups.

Suitable alkyl groups indude straight-chained and branched alkyl groups containing from 1 to 6 carbon atoms. Typical examples indude methyl and ethyl groups, and straight-chained or branched propyl, butyl and pentyl groups. Particular alkyl groups are methyl, ethyl, n-propyl, isopropyl, isobutyl, t-butyl and 2,2-dimethylpropyl.

Suitable alkenyl groups indude straight-chained and branched alkenyl groups containing from 2 to 6 carbon atoms. Typical examples indude vinyl, allyl and dimethylallyl groups. Suitable alkynyl groups indude straight-chained and branched alkynyl groups containing from 2 to 6 carbon atoms. Typical examples indude ethynyl and propargyl groups.

Suitable cydoalkyl groups indude groups containing from 3 to 7 carbon atoms. Particular cydoalkyl groups are cydopropyl and cydohexyl. Typical examples of C3.7 cydoalkyl(Ci 6)alkyl groups indude cydopropylmethyl, cydohexylmethyl and cydohexylethyl.

Particular indanyl groups indude indan-1-yl and indan-2-yl. Particular aryl groups indude phenyl and naphthyl. Particular aryl(Ci<)alkyl groups indude benzyl, phenylethyl, phenylpropyl and naphthylmethyl.

Suitable heterocydoalkyl groups indude azetidinyl, pyrrolidyl, piperidyl, piperazinyl and morpholinyl groups.

Suitable heteroaryl groups indude pyridyl, quinolyl, isoquinolyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyranyl, furyl, benzofuryl, dibenzofuryl, thienyl, benzthienyl, pyrrolyl, indolyl, pyrazolyl, indazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, benzinudazolyl, oxadiazolyl, thiadiazolyl, triazolyl and tetrazolyl groups.

The expression "heteroaryl(Cι^) alkyl" as used herein indudes furylmethyl, furylethyl, thienylmethyl, thienylethyl, oxazolylmethyl, oxazolylethyl, thiazolylmethyl, thiazolylethyl, imidazolylmethyl, imidazolylethyl, oxadiazolylmethyl, oxadiazolylethyl, thiadiazolylmethyl, thiadiazolylethyl, triazolylmethyl, triazolylethyl, tetrazolylmethyl, tetrazolylethyl, pyridylmethyl, pyridylethyl, pyrimidinylmethyl, pyrazinylmethyl, quinolylmethyl and isoquinolylmethyl.

The hydrocarbon and heterocydic groups may in turn be optionally substituted by one or more groups selected from Ci-β alkyl, adamantyl, phenyl, halogen, Cι-6 haloalkyl, Cι-6 aminoalkyl, trifiuoromethyl, hydroxy, Cι-6 alkoxy, aryloxy, keto, C1.3 alkylenedioxy, nitro, cyano, carboxy, C2-6 alkoxycarbonyl, C24 alkoxycarbonyl(Cι-6)alkyl, C2-6 alkylcarbonyloxy, arylcarbonyloxy, aminocarbonyloxy, C26 alkylcarbonyl, arylcarbonyl, Cι-6 alkylthio, Ci-e alkylsulphinyl, Ci-β alkylsulphonyl, arylsulphonyl, -NR^VR^W, -NR'COR", -NR^vCO₂R^», -NR-SO∑R", -C^NR'SO∑R", -NHCONR'R*, -CONR^vR", -SO₂NR^vR^w and -CH₂SO2NR^vR^», in which R^v and R* independently represent hydrogen, Ci-β alkyl, aryl or aryl(Cι-6)alkyl, or R^v and R^w together represent a C26 alkylene group. When R^x and R^y, or R^v and R^w, together represent a C2-6 alkylene group, this group may be an ethylene, propylene, butylene, pentamethylene or hexamethylene group, preferably butylene or pentamethylene. When R^x and together represent a C2-6 alkylene group, this group may be unsubstituted or substituted by one or more substituents selected from Ci-e alkyl, aryl and hydroxy. Typical substituents indude methyl, phenyl and hydroxy.

Furthermore, when R^x and R^y together represent a C∑-β alkylene group, this group may optionally be fused with a phenyl ring. In this context, a typical group of formula -NR^xR^y as defined for the substituent R¹ is 1,2,3, 4-tetrahydroisoquinolinyl.

The term "halogen" as used herein indudes fluorine, chlorine, bromine and iodine, espedally fluorine. The present invention indudes within its scope prodrugs of the compounds of formula I above. In general, such prodrugs will be functional derivatives of the compounds of formula I which are readily convertible in υiυo into the required compound of formula I. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in Design of Prodrugs, ed. H. Bundgaard, Elsevier, 1985.

Where the compounds according to the invention have at least one asymmetric centre, they may accordingly exist as enantiomers. Where the compounds according to the invention possess two or more asymmetric centres, they may additionally exist as diastereoisomers. It is to be understood that all such isomers and mixtures thereof in any proportion are encompassed within the scope of the present invention.

In particular, where M represents the residue of a pyrrolidine ring, and the substituent R is attached to the 2 -position thereof, then the absolute stereochemical configuration of the carbon atom at the point of attachment of the moiety R is preferably as depicted in structure LA as follows:

<IA) wherein Z, E, Q, T, U, V, R and R" are as defined above.

Moreover, where M represents the residue of a pyrrolidine ring, and the substituent R is attached to the 3-position thereof, then the absolute stereochemical configuration of the carbon atom at the point of attachment of the moiety R is preferably as depicted in structure IB as follows:

(IB) wherein Z, E, Q, T, U, V, R and H- are as defined above.

The optionally substituted five-membered heteroaromatic ring Z in formula I is suitably a 1,3-oxazole, 1,3-thiazole, imidazole, 1,2,4- oxadiazole, 1,3,4-oxadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole, 1,2,3- triazole, 1,2,4-triazole or tetrazole ring. Preferably, the ring is a 1,3- oxazole, 1,3-thiazole, imidazole, 1,2,4-oxadiazole, 1,2,4-thiadiazole or 1,2,4-triazole ring, in particular an imidazol-1-yl, 1,2,4-triazol-l-yl or l,2,4-triazol-4-yl moiety.

Suitably, the five-membered heteroaromatic ring Z is unsubstituted. Examples of optional substituents which may typically be attached to the moiety Z indude methyl, ethyl, benzyl and amino. Where E, Q and W, which may be the same or different, represent straight or branched alkylene chains, these may be, for example, methylene, ethylene, 1-methylethylene, propylene, 2-methylprόpylene or butylene. In addition, Q and W may be substituted in any position by a hydroxy group giving rise, for example, to a hydroxymethyl-methylene, 2-hydroxypropylene or 2-hydroxymethyl-propylene linkage. Moreover, E and W may each independently represent a chemical bond. Where E represents a chemical bond, the moiety Z is attached directly to the central fused bicyclic heteroaromatic ring system containing the variables T, U and V. Similarly, where W represents a chemical bond, the substituent R¹ is attached directly to the azetidine, pyrrolidine or piperidine ring of which M is the residue.

Suitably, E represents a chemical bond or a methylene linkage.

Suitably, Q represents an ethylene or propylene linkage.

The compound of formula I in accordance with the present invention is suitably an indole, benzofuran or benzthiophene derivative of formula IC, an indazole derivative of formula ID, or a pyrrolo[2,3-c]- pyridine derivative of formula IE:

(ID)

wherein Z, E, Q, V, M, R, R^a, R² and R³ are as defined above. Preferably, the compounds according to the invention are indole or pyrrolo[2,3-c]- pyridine derivatives of formula IF:

OF⁾ wherein Z, E, Q, T, M, R, R^«, R² and R³ are as defined above, in particular wherein R² and R³ are both hydrogen.

Suitably, W represents a chemical bond or a methylene or hydroxymethyl-methylene linkage, in particular a chemical bond or a methylene linkage.

Suitably, R^x and R^y independently represent hydrogen, Ci-e alkyl, C2.6 alkenyl, C37 cydoalkyl(Cι^) alkyl, indanyl, aryl, aryl(Cκ)alkyl, heteroaryl or heteroaryl(Cκ)alkyl, any of which groups may be optionally substituted by one or more substituents selected typically from Ci-β alkyl, halogen, hydroxy, Ci-e alkoxy, aminocarbonyloxy, amino, C∑-β alkylcarbonylamino, Ci-e alkylsulphonylamino and Ci-β alkylaminosulphonylmethyl. Particular values of R^x and R^v indude hydrogen, methyl, hydroxyethyl, isobutyl, 2,2-dimethylpropyl, allyl, dimethylallyl, 1-cydohexylethyl, 2-cydohexylethyl, indanyl, hydroxy- indanyl, phenyl, benzyl, methyl-benzyl, fluorobenzyl, methoxy-benzyl, acetylamino-benzyl, 1-phenylethyl, 2-phenylethyl, 2-hydroxy-l- phenylethyl, 2-methoxy-l-phenylethyl, 2-aminocarbonyloxy-l- phenylethyl, l-(fluorophenyl)ethyl, l-(fluorophenyl)-2-hydroxyethyl, 1- (fluorophenyl)-2-methoxyethyl, l-(acetylamino-phenyl)ethyl, 2-^" (acetylamino-phenyl)ethyl, 2-hydroxy- 1-phenylprop- 1-yl, l-phenylprop-2- yl, 2-phenylprop-2-yl, l-hydroxy-l-phenylprop-2-yl, l-hydroxy-2- phenylprop-2-yl, l-hydroxy-3-phenylprop-2-yl, furylmethyl, thienylmethyl and pyridylmethyl.

In addition, where R^x and R together represent an optionally substituted or phenyl ring-fused C2-6 alkylene group, the substituent -NR^xRy as defined for R¹ may suitably represent 3,3-dimethylpiperidinyl, 2-phenylpiperidinyl, 3-hydroxy-2-phenylpiperidinyl or 1,2,3,4- tetrahydroisoquinolin-2-yl.

Suitable values for the substituent R¹ indude hydroxy, benzyloxy, methoxy-benzyloxy, pyridylmethoxy, benzylthio, fluorobenzyl-thio, phenylsulphinyl, benzylsulphinyl, fluorobenzyl-sulphinyl, fluorobenzyl- sulphonyl, amino, methylamino, indanylamino, hydroxyindanyl- amino, benzylamino, N-(methylbenzyl)-amino, N-(acetylamino-benzyl)-amino, N- (l-phenylethyl)-amino, N-(2-phenylethyl)-amino, N-(2-hydroxy-l- phenylethyl)- amino, N-(2-methoxy-l-phenylethyl)-amino, N-(2- aminocarbonyloxy- l-phenylethyl)-amino, N-[l-(fluorophenyl)ethyl]-amino, N-[l-(fluorophenyl)-2-hydroxyethyl]-amino, N-[l-(fluorophenyl)-2- methoxyethyl]-amino, N-[l-(acetylamino-phenyl)ethyl]-amino, N-[2- (acetylamino-phenyl)ethyl]-amino, N-(2-hydroxy- 1-phenylprop- 1-yl)- amino, N-(l-phenylprop-2-yl)-amino, N-(2-phenylprop-2-yl)-amino, N-(l- hydroxy- l-phenylprop-2-yl)-amino, Ν-(l-hydroxy-2-phenylprop-2-yl)- amino, N-(l-hydroxy-3-phenylprop-2-yl)-amino, N-(furylmethyl)-amino, N- (pyridylmethyl)-amino, dimethylamino, N-isobutyl-N-methylamino, N- (2,2-dimethylpropyl)-N-methylamino, N-allyl-N-methylamino, N-(3,3- dimethylprop-2-en-l-yl)-N-methylamino, N-(l-cydohexylethyl)-N- methylamino, N-benzyl-N-methylamino, N-methyl-N-(methylbenzyl)- amino, N-(fluorobenzyl)-N-methylamino, N-(acetylamino-benzyl)-iV- methylamino, N-methyl-N-(l-phenylethyl)-amino, N-methyl-N-(2- phenylethyl)-amino, N-(2-hydroxy-l-phenylethyl)-iV-methylamino, JV-(2- methoxy- l-phenylethyl)-N-methylamino, N-[2-(acetylamino-phenyl)ethyl]- iV-methyla ino, N«(furylmethyl)-N-met_hylamino, N-methyl-_?V- (thienylmethyl)-amino, _V-benzyl-N-(2-hydroxyethyl)-amino, N,N- bis(furylmethyl)-amino, 3,3-dimethylpiperidinyl, 2-phenylpiperidinyl, 3- hydroxy-2-phenylpiperidinyl and l,2,3,4-tetrahydroisoquinolin-2-yl. Particular values of the group R indude hydroxy, benzyloxy, benzyloxymethyl, methoxy-benzyloxy, pyridylmethoxy, benzylthio-methyl, fluorobenzylthio-methyl, phenylsulphinylmethyl, benzylsulphinylmethyl, fluorobenzyl-sulphinyl, fluorobenzyl-sulphinylmethyl, fluorobenzyl- sulphonylmethyl, indanylamino, indanylaminomethyl, hydroxyindanyl- amino, benzylamino, benzylaminomethyl, l-(N-benzylamino)-2- hydroxyethyl, j_V-(methylbenzyl)-aminomethyl, N-(acetylamino-benzyl)- amino, N-(acetylamino-benzyl)-aminomethyl, N-(l-phenylethyl)-amino, N- (l-phenylethyl)-aminomethyl, N-(2-phenylethyl)-aminomethyl, N-(2- hydroxy- l-phenylethyl)-amino, N-(2 -hydroxy- 1-phenylethyl)- aminomethyl, N-(2-methoxy-l-phenylethyl)-amino, N-(2- aminocarbonyloxy- l-phenylethyl)-amino, N-[l-(fluorophenyl)ethylj-amino, N-[l-(fluorophenyl)-2-hydroxyethyl]-amino, N-[l-(fluorophenyl)-2- methoxyethyl]-amino, N-[l-(acetylamino-phenyl)ethyl]-amino, N-[ l-(acetylamino-phenyl)ethyl]-aminomethyl, N-[2-(acetylamino- phenyl)ethyl] -amino, N-(2-hydroxy- 1-phenylprop- l-yl)-amino, N-(l- phenylprop-2-yl)-amino, N-(2-phenylprop-2-yl)-aminomethyl, N-(l- hydroxy- l-phenylprop-2-yl)-amino, N-(l-hydroxy-2-phenylprop-2-yl)- a ino, N-(l-hydroxy-3-phenylprop-2-yl)-amino, N-(furylmethyl)-amino, N- (furylmethyl)-aminomethyl, N-(pyridylmethyl)-aminomethyl, N-isobutyl- N-methyl-aminomethyl, N-(2,2-dimethylpropyl)-N-methyl-aminomethyl, N-allyl-Ν-methylamino, N-(3,3-d__methylprop-2-en-l-yl)-N-methylamino, N-(l-cydohexylethyl)-N-methyl-aminomethyl, N-benzyl-N-methylamino, N-benzyl-N-methyl-aminomethyl, N-methyl-N-(methylbenzyl)- aminomethyl, N-(fluorobenzyl)-N-methylamino, N-(acetylaminό-benzyl)- N-methyl-aminomethyl, N-methyl-N-(l-phenylethyl)-aminomethyl, N- methyl-N-(2-phenylethyl)-aminomethyl, N-(2-hydroxy-l-phenylethyl)-N- methylamino, N-(2-hydroxy-l-phenylethyl)-N-methyl-aminomethyl, N-(2- methoxy-l-phenylethyl)-N-methylamino, _N-[2-(acetylamino-phenyl)ethyl]- N-methylamino, N-(furylmethyl)-iV-methylam__no, N-methyl-N- (thienylmethyl)-amino, N-benzyl-N-(2-hydroxyethyl-aminomethyl, N,N- bis(furylmethyl)-amino, 3,3-dimethylpiperidinylmethyl, 2- phenylpiperidinyl, 2-phenylpiperidinylmethyl, 3-hydroxy-2- phenylpiperidinylmethyl and l,2,3,4-tetrahydroisoquinolin-2-yl.

Suitable values of R" indude hydrogen, hydroxy and benzyl, espedally hydrogen. Suitably, R² and R³ independently represent hydrogen or methyl, espedally hydrogen.

A particular sub-dass of compounds according to the invention is represented by the compounds of formula HA, and salts and prodrugs thereof:

⁽"A* wherein m is zero, 1, 2 or 3, preferably zero or 1; n is 2, 3 or 4, preferably 2 or 3; p is zero, 1 or 2; T represents nitrogen or CH; A represents nitrogen or CH;

B represents nitrogen or C-R^B;

R⁴ and R^B independently represent hydrogen, Cw alkyl, C2-6 alkenyl, C37 cydoalkyl, aryl, aryl(Cι*6)alkyl, C37 heterocydoalkyl, heteroaryl, heteroaryl(Cw)alkyl, Ci-β alkoxy, Cw alkylthio, amino, Ci-e alkylamino, di(Cι-6)alkylamino, halogen, cyano or trifiuoromethyl; and

Ri represents -X-R¹¹ or a group of formula (a) or (b):

(a) (b) in which R⁶ represents hydrogen or hydroxy;

X represents oxygen, sulphur, -SO-, -SO2- or N-R¹²; and R^u and R¹² independently represent hydrogen, Ci-e alkyl, d alkenyl, C3-7 cydoalkyl(Ci4)alkyl, indanyl, aryl, aryl(Cι_<)alkyl, heteroaryl or heteroaryl(Cι-6)alkyl, any of which groups may be optionally substituted.

Examples of suitable optional substituents on the groups R¹¹ and Rⁱ² indude Ci-β alkyl, halogen, cyano, trifiuoromethyl, hydroxy, C1.6 alkoxy, aminocarbonyloxy, C2-6 alkylcarbonyl, amino, Ci-e alkylamino, di(Cι-β) alkylamino, C2-6 alkylcarbonylamino, Ci-β alkylsulphonylamino and Ci-e alkylaminosulphonylmethyl.

Particular values of R⁴ and R⁵ indude hydrogen, methyl, ethyl, benzyl and amino, espedally hydrogen.

Particular values of Rⁿ and R¹² indude hydrogen, methyl, hydroxyethyl, isobutyl, 2,2-dimethylpropyl, allyl, dimethylallyl, 1- cydohexylethyl, 2-cydohexylethyl, indanyl, hydroxy-indanyl, phenyl, benzyl, methyl-benzyl, fluorobenzyl, methoxy-benzyl, acetylamino-benzyl, 1-phenylethyl, 2 -phenylethyl, 2 -hydroxy- 1-phenylethyl, 2-methoxy-l- phenylethyl, 2 -aminocarbonyloxy- 1-phenylethyl, l-(fluorophenyl)ethyl, 1- (fluorophenyl)-2-hydroxyethyl, l-(fluorophenyl)-2-methoxyethyl, 1- (acetylamino-phenyl)ethyl, 2-(acetylamino-phenyl)ethyl, 2 -hydroxy- 1- phenylprop-1-yl, l-phenylprop-2-yl, 2-phenylprop-2-yl, 1-hydroxy-l- phenylprop-2-yl, l-hydroxy-2-phenylprop-2-yl, l-hydroxy-3-phenylprop-2- yl, furylmethyl, thienylmethyl and pyridylmethyl.

In relation to formula HA, the variable p is preferably 1. Another sub-dass of compounds according to the invention is represented by the compounds of formula HB, and salts and prodrugs thereof:

wherein m, n, p, T, A, B, R⁴ and R¹⁰ are as defined with reference to formula HA above. In relation to formula HB, the variable p is suitably zero or 1.

A further sub-dass of compounds according to the invention is represented by the compounds of formula HC, and salts and prodrugs thereof:

(IIC) wherein R"^» represents hydrogen, hydroxy or aryl(Cι^)alkyl; and m, n, p, T, A, B, R⁴ and R¹⁰ are as defined with reference to formula HA above.

Suitable values of R^βa indude hydrogen, hydroxy and benzyl, espedally hydrogen.

In relation to formula IIC, the variable p is suitably zero or 1.

In one subset of the compounds of formula HC above, R" is hydrogen.

A still further sub-dass of compounds according to the invention is represented by the compounds of formula HD, and salts and prodrugs thereof:

am) wherein m, n, p, T, A, B, R⁴ and R¹⁰ are as defined with reference to formula HA above. In relation to formula HD, the variable p is suitably zero or 1.

The present invention also provides compounds of formula HA, IIB, HC and HD as defined above wherein T represents CH; R¹⁰ represents -X-R¹¹; X represents oxygen, sulphur or N-R¹²; Rⁿ and R¹² independently represent hydrogen, Ci-e alkyl, aryl, aryl(Cκ)alkyl, heteroaryl or heteroaryl(Cι-6)alkyl, any of which groups may be optionally substituted; and m, n, p, A, B and R⁴ are as defined above.

The present invention further provides compounds of formula HA, πB and IIC as defined above wherein T represents nitrogen; R¹⁰ represents -X-R"; X represents oxygen, sulphur or N-R¹²; R¹¹ and R¹² independently represent hydrogen, Ci-e alkyl, aryl, aryl(Cι β) alkyl, heteroaryl or heteroaryl(Cι^)alkyl, any of which groups may be optionally substituted; R" represents hydrogen; and m, n, p, A, B and R⁴ are as defined above.

Specific compounds within the scope of the present invention indude:

(3_R)-3-benzyloxy- l-[2-(5-(l,2,4-triazol-4-yl)- lH-indol-3- yl)ethyl]pyrro_Lidine;

(3_R)-3-(4-methoxyphenyl)methoxy-l-[2-(5-(l,2,4-triazol-4-yl)-l_f_^r-indol-3- yl)ethyl]pyrrolidine; (3B)-3-(pyridin-3-yl)methoxy- l-[2-(5-(l,2,4-triazol-4-yl)- lH-indol-3- yl)ethyllpyrrolidine;

(3_R)-3-benzyloxymethyl-l-[2-(5-(l,2,4-triazol-4-yl)-lH-indol-3- yl)ethyl]pyrrolidine;

(3S)-3-(N-benzyl-N-methyl)aminomethyl-l-[2-(5-(l,2,4-triazol-4-yl)-lH- indol-3-yl)ethyl]pyrrolidine;

(2S)-2-(N-benzyl-N-methyl)aminomethyl- l-[2-(5-(l,2,4-triazol-4-yl)- 1H- indol-3-yl)ethyl]pyrrolidine;

(3_S)-3-(N-benzyl)aminomethyl- l-[2-(5-(l,2,4-triazol-4-yl)- lH-indol-3- yl)ethyl]pyrrolidine; 4-(4-acetylammophenyl)methylamino-l-[3-(5-(l,2,4-triazol-4-yl)-lH-indol- 3-yl)propyl]piperidine;

4-benzylamino-l-[3-(5-(l,2,4-triazol-4-yl)-lH-indol-3-yl)propyl]piperidine; 4-(N-benzyl-N-methyl)amino- l-[3-(5-(l,2,4-triazol-4-yl)- lH-indol-3- yl)propyl]piperidine; 4-(N-benzyl)aminomethyl-l-[3-(5-(l,2,4-triazol-4-yl)-lH-indol-3- yl)propyl]piperidine;

(2S)-2-(N-benzyl-N-methylaminomethyl)-l-[2-(5-(l,2,4-triazol-l-yl)-lH- pyτrolo[2,3-c]pyridin-3-yl)ethyl]pyrroΗdine;

4-(N-benzyl-N-methyl)aminomethyl-l-[3-(5-(l,2,4-triazol-4-yl)-lH-indol-3- yl)propyl]piperidine; l-[3-(5-(l,2,4-triazol-4-yl)-lH-indol-3-yl)propyl]-4- (R)-a-

(methyl)benzylamino]piperidine; l-[3-(5-(l,2,4-triazol-4-yl)-lH-indol-3-yl)propyl]-4- (S)-α-

(methyl)benzylamino]piperidine; l-[3-(5-(l,2,4-triazol-4-yl)-li -indol-3-yl)propyl]-4- (S)-α-

(hydroxymethyl)benzylamino]piperidine; l-[3-(5-(l,2,4-triazol-4-yl)-l#-indol-3-yl)propyl]-4- (-R)-α-

(hydroxymethyl)benzylam__no]piperidine; l-[3-(5-U,2,4-triazol-4-yl)-l_ff-indol-3-yl)propyl]-4- (S)-(l-hydroxymethyl-

2-phenyl)ethylamino]piperidine; l-[3-(5-(l,2,4-triazol-4-yl)-lH-indol-3-yl)propyl]-4- (LR,2S)-(2-hydroxy-l- methyl-2-phenyl)ethylamino]piperidine; l-[3-(5-(l,2,4-triazol-4-yl)-lH-indol-3-yl)propyl]-4- (lS,2i2)-(2-hydroxy-l- methyl-2-phenyl)ethylamino]piperidine; l-[3-(5-(l,2,4-triazol-4-yl)-l/_f-indol-3-yl)propyl]-4- (LR,2i?)-(2-hydroxy-l- methyl-2-phenyl)ethylamino]piperidine; l-[3-(5-(l,2,4-triazol-4-yl)-l_ff-indol-3-yl)propyl]-4- 2-(4- acetylaminophenyl)ethylamino]piperidine; l-[3-(5-(l,2,4-triazol-4-yl)-l_ff-indol-3-yl)propyl]-4- (_R)-α-

(methyl)benzylamino]methylpiperidine; l-[3-(5-(l,2,4-triazol-4-yl)-lH-indol-3-yl)propyl]-4- (S)-α-

(methyl)benzylamino]methylpiperidine; l-[3-(5-(l,2,4-triazol-4-yl)-lH-indol-3-yl)propyl]-4- (S)-l-(4- acetylaminophenyl)ethylamino]methylpiperidine; l-[3-(5-(l,2,4-tri___zol-4-yl)-lH-indol-3-yl)propyl]-4- (fl)-l-(4- acetylanιinophenyl)ethylamino]methylpiperidine; l-[3-(5-(l,2,4-triazol-4-yl)-lH-indol-3-yl)propyl]-4- N-[(_R)-α-

(hydroxyπιethyl)benzyl]-N-methylam_Lno]piperidine; l-[3-(5-(l,2,4-triazol-4-yl)-lH-indol-3-yl)propyl]-4 N-[(S)-α- (hydroxymethyl)benzyl]-N-methylaminolpiperidine; l-[3-(5-(l,2,4-triazol-4-yl)-lH-indol-3-yl)propyl]-4-[N-(2-(4- acetylaπunophenyl)ethyl)-N-methylamino]piperidine; l-[3-(5-(l,2,4-triazol-4-yl)-lH-indol-3-yl)propyl]-4-[N-(4- acetylaminobenzyl)-N-methylamino]methylpiperidine; l-[3-(5-(l,2,4-triazol-4-yl)-lH-indol-3-yl)propyl]-4-[N-(thien-2-yl)methyl-N- methylamino]piperidine; l-[3-(5-(l ,2,4-triazol-4-yl)- lif-indol-3-yl)propyl]-4-[(_R)-α- (hydroxymethyl)benzylamino]methylpiperidine;

(3S)-3-(4-acetylaminobenzyl)aminomethyl- l-[2-(5-(l,2,4-triazol-4-yl)- 1H- indol-3-yl)ethyl]pyrrolidine;

(3Λ)-3-(N-benzyl)aminomethyl-l-[2-(5-(l,2,4-triazol-4-yl)-lH-indol-3- yl)ethyl]pyrrolidine;

(3S)-3-(pyridin-4-ylmethyl)aminomethyl-l-[2-(5-(l,2,4-triazol-4-yl)-l_ ι^τ- indol-3-yl)ethyl]pyrro_Lidine; 3-(N-benzyl)aminomethyl-l-[2-(5-(l,2,4-triazol-4-yl)-lH-indol-3- yl)ethyl] azetidine;

4-benzyl-4-hydroxy- l-[3-(5-(l,2,4-triazol-4-yl)- lif-indol-3- yl)propyl]piperidine;

3-(N-benzyl)aminomethyl- l-[3-(5-(l,2,4-triazol-4-yl)- lif-indol-3- yl)propyl] azetidine;

4-(N-benzyl)aminomethyl-4-hydroxy-l-[3-(5-(l,2,4-triazol-4-yl)-lH-indol-3- yl)propyllpip eridine ;

4-(N-benzyl-N-methyl)aminomethyl-4-hydroxy-l-[3-(5-(l,2,4-triazol-4-yl)- lH-indol-3-yl)propyl]piperidine; 3-(N-benzyl-N-methyl)aminomethyl-l-[2-(5-(l,2₍4-triazol-4-yl)-li_r-indol-3- yl)ethyl] azetidine;

(3S)-3-[N-(_R)-α-(methyl)benzyl]aminomethyl-l-[2-(5-(l,2,4-triazol-4-yl)- lH-indol-3-yl)ethyl]pyrrohdine;

(3S)-3-[N-(S)-α-(methyl)benzyl]aminomethyl-l-[2-(5-(l,2,4-triazol-4-yl)- lH-indol-3-yl)ethyl]pyrrolidine; (3S)-3-[N-(furan-3-yhnethyl)amino]methyl-l-[2-(5-(l,2,4-triazol-4-yl)-lH- indol-3-yl)ethyl]pyrrolidine;

(3S)-3-[N-(furan-2-ylmethyl)amino]methyl-l-[2-(5-(l,2,4-triazol-4-yl)-lH- indol-3-yl)ethyl]pyrrolidine; (3S)-3-[N-(Λ)-α-(hydroxymethyl)benzyl]aminomethyl-l-[2-(5-(l,2,4-triazol- 4-yl)- lH-indol-3-yl)ethyl]pyrroHdine;

(3S)-3-[N-(S)-α-(hydroxymethyl)benzyl]aminomethyl-l-[2-(5-(l,2,4-triazol- 4-yl)- l_ _T-indol-3-yl)ethyl]pyrrolidine;

(3S)-3-[N-benzyl-N-(2-hydroxy)ethyl]aminomethyl-l-[2-(5-(l,2,4-triazol-4- yl)-l_ _f-indol-3-yl)ethyl]pyrrolidine;

(3S)-3-[N-(2-phenylethyl)amino]methyl-l-[2-(5-(l,2,4-triazol-4-yl)-li/- indol-3-yl)ethyllpyrrolidine;

(3S)-3-[N-(2-phenyle l)-N-methylammo]methyl-l-[2-(5-(l,2,4-triazol-4-yl)-li7- indd-3-yl)ethyl]pyrrolidine; (3S)-3-(N-α-dimethylbenzyl)aminomethyl- l-[2-(5-(l,2,4-triazol-4-yl)- IH- indol-3-yl)ethyllpyrroHdine;

(3S)-3-[N-(S)-α-methylbenzyllaminomethyl-l-[2-(5-(l,2,4-triazol-l-yl)-lH- indol-3-yl)ethyl]pyrrolidine;

(3S)-3-[N-(Λ)-α-(hydroxymethyl)benzyllaminomethyl-l-[2-(5-(l,2,4-triazol- 1 -yl)- lH-indol-3-yl)ethyl]pyrrolidine;

(3S)-3-(N-benzyl)aminomethyl-l-[2-(5-(l,2,4-triazol-l-ylmethyl)-lH-indol-

3-yl)ethyl]pyrrolidine;

(3S)-3-[N-(S)-α-methylbenzyl]aminomethyl-l-[2-(5-(l,2,4-triazol-l- ylmethyl)-lH-indol-3-yl)ethyl]pyrroUdine; (3S)-3-[N-(_R)-α-(hydroxymethyl)benzyl]aminomethyl-l-[2-(5-(l,2,4-triazol- l-ylmethyl)-lH-indol-3-yl)ethyl]pyrrohdine;

(3S)-3-(N-benzyl-N-methyl)aminomethyl- l-[2-(5-(imidazol- 1-yl)- lH-indol-

3-yl)ethyl]pyrrohdine;

(3S)-3-(N-benzyl-N-methyl)aminomethyl-l-[2-(5-(l,2,4-triazol- l-ylmethyl)- lH-indol-3-yl)ethyl]pyrrolidine; (3_R)-3-[N-methyl-N-(S)-α-methylbenzyl]aminomethyl-l-[2-(5-(l,2,4- triazol- 1-ylmethyl)- lH-indol-3-yl)ethyl]pyrrolidine; (3_R)-3-[N-methyl-N-(_R)-α-hydroxymethylbenzyl]aminomethyl-l-[2-(5- (l,2,4-triazol-l-ylmethyl)-lH-indol-3-yl)ethyllpyrrolidine; (3_R)-3-[N-methyl-N-(S)-α-methylcydohexylmethyl]aminomethyl- 1-[2-(5- (l,2,4-triazol-l-ylmethyl)-li/-indol-3-yl)ethyl]pyrrolidine; (3Λ)-3-[3-(_R)-hydroxy-2-(_R)-phenylpiperidin-l-yl]methyl-l-[2-(5-(l,2,4- triazol- 1-ylmethyl)- lH-indol-3-yl)ethyl]pyrrolidine; (3i2)-3-[3-(_R)-hydroxy-2-(_R)-phenylpiperidin-l-yl]methyl-l-[2-(5-(l,2,4- triazol- 1 -yl)- 1 JY-indol-3-yl)ethyl]p yrrolidine;

4-hydroxy-4-(phenylsulfinyl)methyl-l-[3-(5-(l,2,4-triazol-4-yl)-lH-indol-3- yl)propyllpiperidine;

(3_R)-3-[2-(_R,S)-phenylpiperidin-l-yllmethyl-l-[2-(5-(l,2,4-triazol-l- y__methyl)-l_f_r-indol-3-yl)ethyllpyrrolidine; 4-(3,3-dimethylpiperidin-l-yl)methyl-4-hydroxy-l-[3-(5-(l,2,4-triazol-4-yl)- li/-indol-3-yl)propyl]piperidine;

4-hy droxy-4-( 1 ,2 ,3 ,4-tetrahydroisoquinolin-2-yl)methyl- 1-[3-(5-( 1 ,2 ,4- triazol-4-yl)-l_fi -indol-3-yl)propyl]piperidine;

4-hyd^oxy-4-(N--_sobutyl-N-met_hyl)aminomethyl-l-[3-(5-(l,2,4-triazol-4- yl)- lH-indol-3-yl)propyl]piperidine;

4- [N-benzyl-N-(2 -hy droxyethyl)amino]methyl-4-hy droxy- 1 -[3-(5-( 1 ,2 ,4- triazol-4-yl)-lH-indol-3-yl)propylJpiperidine;

4-[N-(2,2-dimethylpropyl)-N-methylamino]methyl-4-hydroxy-l-[3-(5-

(l,2,4-triazol-4-yl)-lH-indol-3-yl)propyl]piperidine; 4-[N-(_R)-α-hydroxymethylbenzyl-N-methylamino]methyl-4-hydroxy-l-[3-

(5-(l,2,4-triazol-4-yl)-lH-indol-3-yl)propyl]piperidine;

4-hydroxy-4-(2-pyridylmethyl)aminomethyl-l-[3-(5-(l,2,4-triazol-4-yl)-lH- indol-3-yl)propyl]piperidine;

4-hydroxy-4-(2-methylphenylmethyl)aminomethyl-l-[3-(5-(l,2,4-triazol-4- yl)- lH-indol-3-yl)propyl]piperidine; 4-hydroxy-4-[N-(2-methylphenylmethyl)-N-methylamino]methyl-l-[3-(5- ( 1 ,2 ,4-triazol-4-yl)- lH-indol-3-yl)propyl]piperidine; 3-(benzylamino)methyl-3-hydroxy-l-[3-(5-(l,2,4-triazol-4-yl)-l_ _ -indol-3- yl)propyl]pyrrolidine; 3-φenzylamino)methyl-3-hydroxy-l-[2-(5-(l,2,4-triazol-4-yl)-l/_T-indol-3- yl)ethyl]pyrrolidine; l-[3-(5-(l,2,4-triazol-4-yl)-li -indol-3-yl)propyl]-4-[(_R)-α-(carbamoyl- oxymethyl)benzylamino]piperidine; l-[3-(5-(l,2,4-triazol-4-yl)-li -indol-3-yl)propyl]-4-[(LR,2S)-2-hydroxy-l- phenylpropylamino]piperidine; l-[3-(5-(l,2,4-triazol-4-yl)-lH-indol-3-yl)propyl]-4-[(li2,2_R)-2-hydroxy-l- phenylpropylaminolpiperidine; l-[3-(5-(l,2,4-triazol-4-yl)-li/-indol-3-yl)propyl]-4-[(i2,S)-l-hydroxy-2- phenylprop-2-ylamino]piperidine; l-[3-(5-(l,2,4-triazol-4-yl)-l -indol-3-yl)propyl]-4-[(Λ)-2-hydroxy-l-(4- fluorophenyl)ethylamino]piperidine; l-[3-(5-(l,2,4-triazol-4-yl)-li/-indol-3-yl)propyll-4-l(LR,2_R)-2- hy droxyindan- 1 -ylamino)piperidine; l-[3-(5-(l,2,4-triazol-4-yl)-lH-indol-3-yl)propyl]-4-[(_R,S)-indan-l- ylaminolpiperidine; l-[3-(5-(l,2,4-triazol-4-yl)-l/ -indol-3-yl)propyl]-4-[(_R,S)-l-(4- fluorophenyl)ethylamino]piperidine; l-[3-(5-(l,2,4-triazol-4-yl)-lH-indol-3-yl)propyl]-4-[(_R)-l-phenylprop-2- ylamino]piperidine; l-[3-(5-(l,2,4-triazol-4-yl)-lH-indol-3-yl)propyl]-4-[N-(thien-3-ylmethyl)-N- methylamino]piperidine; l-[3-(5-(l,2,4-triazol-4-yl)-lH-indol-3-yl)propyl]-4-[N-(furan-3-ylmethyl)- N-methylamino]piperidine; l-[3-(5-(l,2,4-triazol-4-yl)-lH-indol-3-yl)propyl]-4-(furan-3- ylmethyl)aminopiperidine; l-[3-(5-(l,2,4-triazol-4-yl)-lH-indol-3-yl)propyl]-4-[N,N-di-(furan-3- ylmethyl)amino]piperidine; l-[3-(5-(l,2,4-triazol-4-yl)-lH-indol-3-yl)propyl]-4-[N-(3,3-dimethylallyl)- N-methylamino]pip eridine ; l-[3-(5-(l,2,4-triazol-4-yl)- li -indol-3-yl)propyl]-4-(N-allyl- - methylamino)piperidine; l-l3-(5-(l,2,4-triazol-4-yl)- lH-indol-3-yl)propyl]-4-(indan- 1- ylaminomethyl)piperidine; l-[3-(5-(l,2,4-triazol-4-yl)-lH-indol-3-yl)propyl]-4-[N-(_R)-α- (hydroxymethyl)benzyl-N-methylaminomethyllpiperidine;

(3_R)-3-(benzylthio)methyl-l-[2-(5-(l,2,4-triazol-4-yl)-lH-indol-3- yl)ethyl]pyrrolidine;

(±)-l-[3-(5-(l,2,4-triazol-4-yl)-lH-indol-3-yl)propyl]-4-(l-benzylamino-2- hy droxy ethyl)pip eridine ; l-[3-(5-(l,2,4-triazol- 1-yl)- lH-indol-3-yl)propyl]-4-[(_R)-α-

(hydroxymethyl)benzylaminolpiperidine; l-[3-(5-(imidazol- 1-yl)- lH-indol-3-yl)propyl]-4-[(_R)-α- (methyl)benzylamino]piperidine; l-[3-(5-(imidazol-l-yl)-lH-indol-3-yl)propyl]-4-[(_R)-α- (hydroxymethyl)benzylamino]piperidine; l-[3-(5-(l,2,4-triazol-l-ylmethyl)-lH-indol-3-yl)propyl]-4-[(i2)-α-

(hydroxymethyl)benzylamino]piperidine; l-[3-(5-(l,2,4-triazol-4-yl)-lH-indol-3-yl)propyl]-4-[(_R)-α-

(methoxymethyl)benzylamino]piperidine; l-[3-(5-(l,2,4-triazol-4-yl)-lH-indol-3-yl)propyl]-4-[N-(_R)-α-

(methoxymethyl)benzyl-N-methylamino]piperidine; l-[3-(5-(imidazol-l-yl)-lH-indol-3-yl)propyl]-4-[(i?)-α-

(methoxymethyl)benzylamino]piperidine; l-[3-(5-(l,2,4-triazol-l-ylmethyl)-lH-indol-3-yl)propyl]-4-[(_R)-l-(4- fluorophenyl)-2-methoxyethylamino]piperidine; l-[3-(5-(l,2,4-triazol- 1-ylmethyl)- lH-indol-3-yl)propyl]-4-[N-(4-fluorobenzyl)- N-methylamino]piperidine; l-[3-(5-(l,2,4-triazol-4-yl)-lH-indol-3-yl)propyl]-4-(2-phenylpiperidin-l- yl)piperidine; l-[3-(5-(l,2,4-triazol-4-yl)-lH-indol-3-yl)propyll-4-[(_R)-l-(4-fluorophenyl)- 2-methoxyethylamino]piperidine;

(3_R)-3-(benzylsulfinyl)methyl- l-[2-(5-(l,2,4-triazol-4-yl)- lH-indol-3- yl)ethyl]pyrrolidine;

(3_R)-3-(4-fluorobenzylthio)methyl-l-[2-(5-(l,2,4-triazol-l-ylmethyl)-li_r- indol-3-yl)ethyl]pyrrolidine;

(3-R)-3-(4-fluorobenzylsulfinyl)methyl-l-[2-(5-(l,2,4-triazol-l-ylmethyl)- l_f_r-indol-3-yl)ethyl]pyrrolidine;

(3_R)-3-(4-fluorobenzylsulfonyl)methyl-l-[2-(5-(l,2,4-triazol-l-ylmethyl)- l-f.f-indol-3 -yl)ethyl]p yrrolidine; 4-(4-fluorobenzylsulfinyl)-l-[3-(5-(l,2,4-triazol-4-yl)-lH-indol-3- yl)propyl]piperidine; and salts and prodrugs thereof.

The invention also provides pharmaceutical compositions comprising one or more compounds of this invention in assodation with a pharmaceutically acceptable carrier. Preferably these compositions are in unit dosage forms such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosol or liquid sprays, drops, ampoules, auto-injector devices or suppositories; for oral, parenteral, intranasal, sublingual or rectal administration, or for administration by inhalation or insufflation. For preparing solid compositions such as tablets, the prindpal active ingredient is mixed with a pharmaceutical carrier, e.g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic add, magnesium stearate, dicaldum phosphate or gums, and other pharmaceutical diluents, e.g. water, to form a solid prefoπnulation composition containing a homogeneous mixture of a compound of the present invention, or a pharmaceutically acceptable salt thereof. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing from 0.1 to about 500 mg of the active ingredient of the present invention. Typical unit dosage forms contain from 1 to 100 mg, for example 1, 2, 5, 10, 25, 50 or 100 mg, of the active ingredient. The tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials induding a number of polymeric adds and mixtures of polymeric adds with such materials as shellac, cetyl alcohol and cellulose acetate.

The liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection indude aqueous solutions, suitably flavoured syrups, aqueous or oil suspensions, and flavoured emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehides. Suitable dispersing or suspending agents for aqueous suspensions indude synthetic and natural gums such as tragacanth, acada, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone or gelatin. In the treatment of migraine, a suitable dosage level is about 0.01 to 250 mg/kg per day, preferably about 0.05 to 100 mg/kg per day, and espedally about 0.05 to 5 mg/kg per day. The compounds may be administered on a regimen of 1 to 4 times per day.

The compounds according to the invention wherein T represents

CH, U represents C-R² and V represents N-R³, corresponding to the indole derivatives of formula IC as defined above, may be prepared by a process which comprises reacting a compound of formula HI:

(III) wherein Z and E are as defined above; with a compound of formula IV, or a carbonyl-protected form thereof:

(IV) wherein R², Q, M, R and R^a are as defined above; followed, where required, by N-alkylation by standard methods to introduce the moiety R³. The reaction between compounds in and IV, which is an example of the well-known Fischer indole synthesis, is suitably carried out by heating the reagents together under mildly addic conditions, e.g. 4% sulphuric add at reflux.

Suitable carbonyl-protected forms of the compounds of formula IV indude the dimethyl acetal or ketal derivatives. Where the alkylene chain Q is substituted by a hydroxy group, this group may condense with the carbonyl moiety in compound IV whereby the carbonyl moiety is protected in the form of a cyclic hemiacetal.

The Fischer reaction between compounds III and IV may be carried out in a single step, or may proceed via an initial non-cyclising step at a lower temperature to give an intermediate of formula V:

(V) wherein Z, E, Q, R², M, and R' are as defined above; followed by cyclisation using a suitable reagent, e.g. a polyphosphate ester.

The intermediates of formula IV, or carbonyl-protected forms thereof, may be prepared by reacting a compound of formula VI, or a carbonyl-protected form thereof, with a compound of formula ^"VTI:

(VI) (VII) wherein Q, R², M, R and R* are as defined above, and L¹ represents a suitable leaving group. The leaving group L¹ is suitably a halogen atom, e.g. chlorine or bromine.

Where L¹ represents a halogen atom, the reaction between compounds VI and VH is conveniently effected by stirring the reactants under basic conditions in a suitable solvent, for example sodium carbonate or potassium carbonate in 1,2-dimethoxyethane or N.N-dimethyl- form amide, or triethylamine in tetrahydrofuran or acetonitrile, optionally in the presence of catalytic sodium iodide.

In an alternative procedure, the compounds according to the invention may be prepared by a process which comprises reacting a compound of formula VII as defined above with a compound of formula

VH!:

(VIII) wherein Z, E, Q, T, U and V are as defined above, and L² represents a suitable leaving group.

The leaving group L² is suitably _an alkylsulphonyloxy or arylsulphonyloxy group, e.g. methanesulphonyloxy (mesyloxy) orp- toluenesulphonyloxy (tosyloxy).

Where L² represents an alkylsulphonyloxy or arylsulphonyloxy group, the reaction between compounds VII and VIH is conveniently carried out in a suitable solvent such as isopropanol or 1,2-dimethoxy- ethane, typically in the presence of a base such as sodium carbonate or potassium carbonate, optionally in the presence of sodium iodide.

In one representative approach, the compounds of formula VEQ wherein T and U both represent CH, V represents NH and L² represents a mesyloxy or tosyloxy group may be prepared by the sequence of steps illustrated in the following reaction scheme (cf. Larock and Yum, J. Am. Chem. Soc, 1991, 113, 6689):

(IX)

wherein Z, E and are as defined above, L³ represents mesyloxy or tosyloxy, and TMS is an abbreviation for trimethylsilyl. In Step 1 of the reaction scheme, the aniline derivative IX is treated with iodine monochloride, advantageously in methanol in the presence of a base such as caldum carbonate, in order to introduce an iodine atom ortho to the amine moiety. Step 2 involves a palladium-mediated coupling reaction with the protected acetylene derivative TMS-C≤C-Q-OH, typically using palladium acetate and triphenylphosphine in the presence of lithium chloride and sodium carbonate, suitably in N,N-dimethyl- formamide at an elevated temperature. This is followed in Step 3 by removal of the TMS moiety, ideally in refluxing methanolic hydrochloric add; followed in turn by mesylation or tosylation, suitably by using mesyl chloride or tosyl chloride respectively in pyridine.

In another representative approach, the compounds of formula VHI wherein T and U both represent CH, V represents ΝH, Q represents a propylene chain and L² represents a mesyloxy or tosyloxy group may be prepared by reacting 3,4-dihydro-2H-pyran with a compound of formula HI as defined above or a salt thereof, under a variant of the Fischer reaction conditions as described above for the reaction between compounds IH and IV; followed by mesylation or tosylation of the 3- hydroxypropyl-indole derivative thereby obtained, typically by treatment with mesyl chloride or tosyl chloride under standard conditions.

The Fischer reaction with 3,4-d__hydro-2_fiT-pyran is suitably brought about by heating the hydrazine derivative in or an add addition salt thereof, typically the hydrochloride salt, in an inert solvent such as dioxan, advantageously in the presence of a mineral acid such as hydrochloric add or a Lewis add such as zinc chloride, at the reflux temperature of the solvent.

In a further procedure, the compounds according to the invention wherein T represents CH, U represents nitrogen and V represents Ν-R³, corresponding to the indazole derivatives of formula IB as defined above, may be prepared by a process which comprises cyclising a compound of formula X:

(X) wherein Z, E, Q, M, R and R^a are as defined above, and D¹ represents a readily displaceable group; followed, where required, by N-alkylation by standard methods to introduce the moiety R³.

The cyclisation of compound X is conveniently achieved in a suitable organic solvent at an elevated temperature, for example in a mixture of -xylene and 2,6-lutidine at a temperature in the region of 140^βC.

The readily displaceable group D¹ in the compounds of formula X suitably represents a Cι ₄ alkanoyloxy group, preferably acetoxy. Where D¹ represents acetoxy, the desired compound of formula X may be conveniently prepared by treating a carbonyl compound of formula XI:

(XI) wherein Z, E, Q, M, R and R^» are as defined above; or a protected derivative thereof, preferably the N-formyl protected derivative; with hydroxylamine hydrochloride, advantageously in pyridine at the reflux temperature of the solvent; followed by acetylation with acetic anhydride, advantageously in the presence of a catalytic quantity of 4-d___methylaminopyridine, in dichloromethane at room temperature. The N-formyl protected derivatives of the intermediates of formula

XI may conveniently be prepared by ozonolysis of the corresponding indole derivative of formula XH:

(XH) wherein Z, E, Q, M, R and R* are as defined above; followed by a reductive work-up, advantageously using dimethylsulphide.

The indole derivatives of formula XH may be prepared by methods analogous to those described in the accompanying Examples, or by procedures well known from the art. In a still further procedure, the compounds according to the invention wherein T represents CH, U represents C-R² and V represents oxygen or sulphur, corresponding to the benzofuran or benzthiophene derivatives of formula IA wherein V is oxygen or sulphur respectively, may be prepared by a process which comprises cyclising a compound of formula XHI:

(XIII) wherein Z, E, Q, R², M, R and R* are as defined above, and V¹ represents oxygen or sulphur. The cyclisation of compound XIH is conveniently effected by using polyphosphoric add or a polyphosphate ester, advantageously at an elevated temperature.

The compounds of formula XHI may be prepared by reacting a compound of formula XTV with a compound of formula XV:

(XIV) (XV) wherein Z, E, Q, R², V¹, M, R and R^a are as defined above, and Hal represents a halogen atom.

The reaction is conveniently effected in the presence of a base such as sodium hydroxide.

The hydroxy and mercapto derivatives of formula XTV may be prepared by a variety of methods which will be readily apparent to those skilled in the art. One such method is described in EP-A-049 512.

In a yet further procedure, the compounds according to the invention may be prepared by a process which comprises reducing a compound of formula XVI:

(XVI) wherein Z, E, T, U, V, M, R and R* are as defined above, and -Q--CH2- corresponds to the moiety Q as defined above. The reaction is suitably carried out by treating the compound of formula XVI with a reducing agent such as Uthium aluminium hydride in an appropriate solvent, e.g. diethyl ether, tetrahydrofuran or mixtures thereof.

The compounds of formula XVI above may suitably be prepared by reacting a compound of formula VH as defined above with the appropriate compound of formula XVH:

(XVII) wherein Z, E, T, U, V and Q¹ are as defined above, and Y represents a reactive carboxylate moiety.

Suitable values for the reactive carboxylate moiety Y indude esters, for example Cι-₄ alkyl esters; add anhydrides, for example mixed anhydrides with CM alkanoic adds; add halides, for example add chlorides; and acylimidazoles.

By way of example, the intermediates of formula XYTI above wherein Y is an add chloride moiety may be prepared by treating the corresponding carboxylic add derivative with thionyl chloride in toluene.

Similarly, the intermediates of formula XVII wherein Y is an acylimidazole moiety may be prepared by treating the corresponding carboxylic add derivative with 1,1 '-carbon yldϋmidazole. Alternatively, the reactive carboxylate moiety Y may be obtained by treating the corresponding compound wherein Y is carboxy with l-(3-dimethylam opropyl)-3-ethylcarbod-___mide hydrochloride and 1- hydroxybenzotriazole hydrate, optionally in the presence of triethylamine; the resulting activated carboxylate intermediate may then suitably be reacted in situ with the required compound of formula VII. The hydrazine derivatives of formula III above may be prepared by methods analogous to those described in WO-A-94/02477, EP-A-0438230 and EP-A-0497512, as also may the aniline derivatives of formula IX. Where they are not commerdally available, the starting materials of formula VI, VH, XV and XVII may be prepared by the methods described in the accompanying Examples, or by analogous procedures which will be apparent to those skilled in the art. It will be understood that any compound of formula I initially obtained from any of the above processes may, where appropriate, subsequently be elaborated into a further compound of formula I by techniques known from the art. For example, a compound of formula I wherein R^x is benzyl initially obtained may be converted into a compound of formula I wherein R^x is hydrogen typically by conventional catalytic hydrogen ation, or by transfer hydrogenation using a hydrogenation catalyst such as palladium on charcoal in the presence of a hydrogen donor such as ammonium formate. Moreover, a compound of formula I wherein R¹ is hydroxy initially obtained may be converted into the corresponding carbonyl compound (aldehyde or ketone) by treatment with a conventional oxidising agent such as sulphur trioxide-pyridine complex; the resulting carbonyl compound may then be converted in turn into a compound of formula I wherein R¹ represents -NHR^y, suitably by a standard reductive amination procedure which comprises treating the carbonyl compound with the appropriate amine of formula R^y-NH∑ in the presence of a suitable reducing agent, typically sodium cyanoborohydride. Alternatively, the carbonyl compound may be converted into a compound of formula I wherein R represents -CH2-SOR^x and R^β represents hydroxy by treatment of the carbonyl compound with the anion of CH3-SOR^x. Furthermore, a compound of formula I wherein R¹ represents -NHR initially obtained may be converted into a further compound of formula I wherein R¹ represents -NR^xR^y, in which R^x corresponds to the group -CH∑R¹, suitably by a reductive amination procedure which comprises treating the compound of formula I wherein R¹ represents -NHR^y with the appropriate aldehyde of formula R^l-CHO in the presence of a redudng agent such as sodium cyanoborohydride. In addition, a compound of formula I wherein R³ is hydrogen initially obtained may be converted into a compound of formula I wherein R³ represents Ci-e alkyl by standard alkylation techniques, for example by treatment with an alkyl iodide, e.g. methyl iodide, typically under basic conditions, e.g. sodium hydride in dimethylformamide, or triethylamine in acetonitrile.

Where the above-described processes for the preparation of the compounds according to the invention give rise to mixtures of stereoisomers, these isomers may be separated by conventional techniques such as preparative chromatography. The novel compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospedfic synthesis or by resolution. The novel compounds may, for example, be resolved into their component enantiomers by standard techniques such as preparative HPLC, or the formation of diastereomeric pairs by salt formation with an optically active add, such as (-)-di-p-toluoyl-d-tartaric add and/or (+)-di-p-toluoyl-l-tartaric add, followed by fractional crystallization and regeneration of the free base. The novel compounds may also be resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary. During any of the above synthetic sequences it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; and T.W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons,

1991. The protecting groups may be removed at a convenient subsequent stage using methods known from the art.

The following Examples illustrate the preparation of compounds according to the invention. The compounds in accordance with the present invention potently and selectively bind to the 5-HTID., receptor subtype, inhibit forskolin- stimulated adenylyl cydase activity, and stimulate [³⁵S]-GTPγS binding to membranes from donal cell lines expressing human doned receptors.

5-HTiDα/5-HTiDp Radioligand Binding

Chinese hamster ovary (CHO) donal cell lines expressing the human 5-HTiDα and 5-HTiDp receptors were harvested in PBS and homogenised in ice cold 50 mM Tris-HCl (pH 7.7 at room temperature) with a Kinematica polytron and centrifuged at 48,000g at 4°C for 11 min. The pellet was then resuspended in 50 mM Tris-HCl followed by a 10 min incubation at 37°C. Finally the tissue was recentrifuged at 48,000g, 4°C for 11 min and the pellet resuspended, in assay buffer (composition in mM: Tris-HCl 50, pargyline 0.01, CaCb 4; ascorbate 0.1%; pH 7.7 at room temperature) to give the required volume immediately prior to use (0.2 mg protein/ml). Incubations were carried out for 30 min at 37°C in the presence of 0.02-150 nM [³H]-5-HT for saturation studies or 2-5 nM [³H]-5-HT for displacement studies. The final assay volume was 1 ml. 5-HT (10 μM) was used to define non-specific binding. The reaction was initiated by the addition of membrane and was terminated by rapid filtration through Whatman GF/B filters (presoaked in 0.3% PEI/ 0.5% Triton X) followed by 2 x 4 ml washings with 50 mM Tris-HCl. The radioactive filters were then counted on a LKB beta or a Wallac beta plate counter. Binding parameters were determined by non-linear, least squares regression analysis using an iterative curve fitting routine, from which ICso (the molar concentration of compound necessary to inhibit binding by 50%) values could be calculated for each test compound. The ICso values for binding to the 5-HTID_<_ receptor subtype obtained for the compounds of the accompanying Examples were below 50 nM in each case. Furthermore, the compounds of the accompanying Examples were all found to possess a selective affinity for the 5-HTiDα receptor subtype of at least 10-fold relative to the 5-HTiDp subtype. 5-HTiDα/5-HTiDp Adenylyl Cydase Assay

Studies were performed essentially as described in J. Pharmacol. Exp. Ther., 1986, 238, 248. CHO donal cell lines expressing the human doned 5-HTiDα and 5-HTmp receptors were harvested in PBS and homogenised, using a motor driven teflon/glass homogeniser, in ice cold Tris HC1-EGTA buffer (composition in mM: Tris HCI 10, EGTA 1, pH 8.0 at room temperature) and incubated on ice for 30-60 min. The tissue was then centrifuged at 20,000g for 20 min at 4°C, the supernatant discarded and the pellet resuspended in Tris HC1-EDTA buffer (composition in mM: Tris HCI 50, EDTA 5, pH 7.6 at room temperature) just prior to assay. The adenylyl cydase activity was determined by measuring the conversion of α- PJ-ATP to [∞Pl-cyclic AMP. A 10 μl aliquot of the membrane suspension was incubated, for 10-15 min, in a final volume of 50 μl, at

30°C, with or without forskolin (10 μM), in the presence or absence of test compound. The incubation buffer consisted of 50 mM Tris HCI (pH 7.6 at room temperature), 100 mM NaCl, 30 μM GTP, 50 μM cyclic AMP, 1 mM dithiothreitol, 1 mM ATP, 5 mM MgCla, 1 mM EGTA, 1 mM 3-isobutyl-l- methylxanthine, 3.5 mM creatinine phosphate, 0.2 mg/ml creatine phosphokinase, 0.5-1 μCi α-f∞PJ-ATP and 1 nCi [³H]-cyclic AMP. The incubation was initiated by the addition of membrane, following a 5 min preincubation at 30°C, and was terminated by the addition of 100 μl SDS (composition in mM: sodium lauryl sulphate 2%, ATP 45, cyclic AMP 1.3, pH 7.5 at room temperature). The ATP and cyclic AMP were separated on a double column chromatography system (Anal. Biochem., 1974, 58, 541). Functional parameters were determined using a least squares curve fitting programme ALLFIT (Am. J. Physiol, 1978, 235, E97) from which Emaj (maximal effect) and ECso (the molar concentration of compound necessary to inhibit the maximal effect by 50%) values were obtained for each test compound. Of those compounds which were tested in this assay, the ECso values for the 5-HTiD_α receptor obtained for the compounds of the accompanying Examples were below 500 nM in each case. Moreover, the compounds of the accompanying Examples which were tested were all found to possess at least a 10-fold selectivity for the 5-HTID,, receptor subtype relative to the 5-HTiDp subtype.

5-HTiDα/5-HTn p GTPγS Binding

Studies were performed essentially as described in Br. J. Pharmacol., 1993, 109, 1120. CHO donal cell lines expressing the human doned 5-HTID., and 5-HTiDp receptors were harvested in PBS and homogenised using a Kinematica polytron in ice cold 20 mM HEPES containing 10 mM EDTA, pH 7.4 at room temperature. The membranes were then centrifuged at 40,000g, 4°C for 15 min The pellet was then resuspended in ice cold 20 mM HEPES containing 0.1 mM EDTA, pH 7.4 at room temperature and recentrifuged at 40,000g, 4°C for 15-25 minutes. The membranes were then resuspended in assay buffer (composition in mM: HEPES 20, NaCl 100, MgCb 10, pargyline 0.01; ascorbate 0.1%; pH 7.4 at room temperature) at a concentration of 40 μg protein/ml for the 5-HTiDo receptor transfected cells and 40-50 μg protein/ml for the 5-HTiDp receptor transfected cells. The membrane suspension was then incubated, in a volume of 1 ml, with GDP (100 μM for 5-HTiDα receptor transfected cells, 30 μM for the 5-HTiDp receptor transfected cells) and test compound at 30°C for 20 min and then transferred to ice for a further 15 min. [ SJ-GTPγS was then added at a final concentration of 100 pM and the samples incubated for 30 min at 30^βC. The reaction was initiated by the addition of membrane and was terminated by rapid filtration through Whatman GF/B filters and washed with 5 ml water. The radioactive filters were then counted on a LKB beta counter. Functional parameters were determined by a non-linear, least squares regression analysis using an iterative curve fitting routine, from which Em« (maximal effect) and ECso (the molar concentration of compound necessary to inhibit the maximal effect by 50%) values were obtained for each test compound. Of those compounds which were tested in this assay, the ECso values for the 5-HTiDα receptor obtained for the compounds of the accompanying Examples were below 500 nM in each case. Moreover, the compounds of the accompanying Examples which were tested were all found to possess at least a 10-fold selectivity for the 5-HTiDα receptor subtype relative to the 5-HTiDp subtype.

EXAMPLE 1

(3RV3-Benzyloxy-l-f2-(5-(1.2.4-triazol-4-ylVlH-indol-3- vDethvnpyrroIidine. Hydrogen Oxalate. Hemihvdrate.

1. Intermediate 1: 4'-(1.2.4-Triazol-4-yl)phenylhvdrazine

a) 4'-Aminoacetanilide

A solution of 4-nitroacetanilide (5.0g, 27.8mmol) in EtOH/EtOAc (160ml, 1:1), H₂O (15ml) and 5N HCI (5.6ml, 28.0mmol) was hydrogenated over 10% Pd-C (0.50g) at 50 psi for 0.25h. The catalyst was removed by filtration through celite and the solvents removed under vacuum. The free base was generated by dissolving the product in H2O, basifying with 2N NaOH and extracting into EtOAc. The combined extracts were dried (MgSO₄) and evaporated to give the ύύe-aniline (3.75g, 90%). δ (250MHz, CDCl3/d₄-MeOH) 2.10 (3H, s, Me), 6.68 (2H, d, J=8.8Hz, Ar-H), 7.27 (2H, d, J=8.8Hz, Ar-H).

b) 4'-(1.2.4-Triazol-4-yl)acetanilide

A mixture of the preceding aniline (3.52g, 23.4mmol), N.N-dimethylformamide azine (3.33g, 23.4mmol; J. Chem Soc. (C), 1967,

1664) and p-toluenesulphonic add monohydrate (0.223g, 1.17mmol), in anhydrous toluene (100ml) was heated at reflux for 17h. The beige coloured predpitate was filtered off and washed with toluene and CH2CI2 and dried under vacuum to give the desired triazole (4.29g, 91%), δ (250MHz, d₄-MeOH/dβ-DMSO) 2.14 (3H, s, CH3), 7.60 (2H, d, J=8.8Hz, Ar-H), 7.78 (2H, d, J=8.8Hz, Ar-H), 8.96 (2H, s, Ar-H).

c) 4'-( 1.2 ■4-Triazol-4-yl)aniline

A solution of the preceding acetamlide (4.9 lg, 24.3mmol) in 5N HCI (100ml) was heated at 125°C for 1.5h. The mixture was cooled to 0°C, basified with concentrated aqueous NaOH solution and extracted with CH2Cl2(x5). The combined extracts were dried (MgSO₄) and evaporated and the residue chromatographed on silica gel, eluting with CH2Cl2/MeOH/NH₃ (80:8:1), to give the title-αm-Zine (2.94g, 76%), δ (250MHz, CDCI3) 3.80 (2H, s, NH₂), 6.71 (2H, d, J=8.8Hz, Ar-H), 7.08 (2H, d, J=8.8Hz, Ar-H), 8.36 (2H, s, Ar-H).

d) 4' (1.2.4-Triazol-4-yl)phenylhvdrazine

To a solution of the preceding aniline (1.60g, 9.99mmol) in concentrated HCI/H2O (23ml and 3ml respectively) was added, at -21^CC, a solution of NaNO2 (0.69g, 9.99mmol) in H2O (8ml), at such a rate as to maintain the temperature below -10°C. The mixture was stirred for 0.3h and then filtered rapidly through a sinter, under vacuum. The filtrate was added to a cooled (-20°C) solution of SnCl2.2H2θ (9.02g, 40.0mmol) in concentrated HCI (17ml). The mixture was stirred at -20°C for 0.25h and then at room temperature for 1.25h. The resulting solid was filtered off, washed with Et∑O and dried under vacuum. The crude product was dissolved in H2O, basified with concentrated aqueous NaOH and extracted with EtOAc (x5). The combined extracts were dried (MgSO₄) and evaporated to afford the title-product (0.95g, 54%), δ (250MHz, CDCL>/d4-MeOH) 3.98 (3H, br s, NH and NH2), 6.97 (2H, d, J=12.0Hz, Ar-H), 7.25 (2H, d, J=12.0Hz, Ar-H), 8.48 (2H, s, Ar-H). 2. Intermediate 2: (3R)-4-(3-Benzyloxy)pyrroli in-1 -ylhu flnal dimethylacetal

a) (3RVN-ferf-Butyloxycarbonylpyrrohdin-3-ol

A mixture of (3R)-N-benzylpyrrolidin-3-ol (Aldrich; 5.00g, 28.2mmol), di-tert-butyldicarbonate (7.39g, 33.8mmol), Pearlmans catalyst (0.55g), methanol (200ml) and water (20ml) were hydrogenated at 40psi in a Parr apparatus for 2h. The catalyst was removed by filtration through celite and the solvents removed under vacuum. The crude product was chromatographed on silica gel eluting with ethyl acetate/hexane (1:1) to give the title-pyrrolidinol (4.55g, 86%), δ (250MHz, CDCls) 1.46 (9H, s, OC(Me)₃), 1.87-2.03 (2H, m, CH₂), 2.07 (1H, s, OH), 3.33-3.50 (4H, m, 2 of CH₂), 4.42-4.48 (1H, m,CH-OH).

b) (3R)-N-tβrt-Butyloxycarbonyl-3-benzyloχypyrrolidine

A solution of (3R)-N-tert-butyloxycarbonylpyrroHdin-3-ol (2.25g, 12.0mmol), in anhydrous THF (10ml) was added portion wise to a slurry of sodium hydride (60% dispersion in oil, 0.63g, 13.8mmol) in THF (35ml) and the mixture stirred for 0.3h at 0°C. A solution of benzyl bromide

(2.37g, 13.8mmol) in dry THF (2ml) was added and the mixture warmed to room temperature and stirred for 18h. Water (70ml) was added and the mixture extracted with ethyl acetate (3x 100ml). The combined extracts were washed with brine, dried (MgSO₄) and evaporated. The crude product was chromatographed on silica gel eluting with CH∑Cl∑/MeOH

(100:0→97:3) to give the desired product (2.53g, 76%), δ (250MHz, CDC ) 1.46 (9H, s, OC(Me)a), 1.87-2.11 (2H, m, CH₂), 3.42-3.50 (4H, m, 2 of CH₂), 4.10-4.16 (1H, m, CH-OBn), 4.53 (2H, s, OCH_Ar), 7.26-7.39 (5H, m, Ar). c) (3R)-N-fH)-3-BenzyloxypyrroIidine

A solution of the preceding N-Boc pyrrolidine (5.0g, lδ.Ommol) in 90% formic add (150ml) was stirred at 0°C for 0.3h and then atroom temperature for 2.5h. The solvents were removed under reduced pressure and the resulting residue was neutralised by addition of saturated K₂CO₃ solution. The aqueous was extracted with n-butanol (2 x 40ml), the solvent removed under vacuum and azeotroped with ethanol (x2). The product was chromatographed on silica^' gel eluting with CHzC-b/MeOH/NHa (80:8:1) to give the title-product (2.62g, 82%), δ (250MHz, CDCL.) 1.85-1.93 (2H, m, CH2), 2.79-2.89 (2H, m, CH2), 3.07- 3.17 (2H, m, CH2), 4.08-4.14 (IH, m, CH-OBn), 4.53 (2H, s, OCH2Ar), 7.24- 7.38 (5H, m, Ar-H).

d) (3R)-4-(3-Benzyloxy)pyrrolidin-l-ylbutanal dimethyl acetal A mixture of 4-chlorobutanal dimethyl acetal (J. Chem. Soc, Perkin

Trans. 1, 1981, 251-255; 2.29g, lδ.Ommol), (3R)-N-(H)-3- benzyloxypyrrolidine (2.60g, lδ.Ommol) and K2CO3 (2.23g, lβ.Ommol), in dry THF (40ml), was heated at reflux for 48h. The mixture was cooled to room temperature, water (70ml) added and extracted with ethyl acetate (3 x 70ml). The combined extracts were dried (MgSO₄) and evaporated and the residue chromatographed on silica gel eluting with MeOH/CH∑Cb (5:95) to give the title- dimethyl acetal (1.9g, 44%), δ (250MHz, CDCI3) 1.57-1.67 (4H, m, 2 of CH2), 1.84-1.96 (IH, m, CH of CH2), 2.03-2.17 (IH, m, CH of CH₂), 2.46-2.74 (5H, m, 2 of CH2 and CH of CH2), 2.89 (IH, dd, J=10.3 and 6.1Hz, CH of CH2), 3.31 (6H, s, CH(OMg)2), 4.10-4.18 (IH, m, CHOBn), 4.38 (IH, t, J=5.2Hz, CH(OMe)₂), 4.48 (2H, ABq, J=11.9Hz, CH₂OAr), 7.24-7.38 (5H, m, Ar). 3. (3RV3-Benzyloxy-l-r2-(δ-(1.2.4-triazol-4-yl)-lH-indol-3-v ethvn pyrrnli inp Hydrogen Oxalate. Hemihvdrate.

A solution of Intermediate 1 (1.2δg, 7.1mmol) and Intermediate 2 (1.90g, 6.48mmol) in 4% H2SO4 (2δml) was heated at reflux for 48h. The δ mixture was cooled to room temperature and basified with K2CO3. The product was extracted into ethyl acetate (x3), the combined extracts dried (MgSO₄) and the solvent removed under vacuum. The crude product was purified by chromatography on silica gel eluting with CH∑Cb/MeOH/NHs (90:8:1) to give the title-indole (O.δδg, 22%). The hydrogen oxalate 0 hemihydrate salt was prepared: mp 97-98°C. (Found: C, 61.76, H, δ*56,

N, 14.28. C23H2sNsO C2H2O₄ 0*5 H2O requires C, 61.72, H, δ.80, N, 14.39%), m/e 388 (M+l⁺), δ (360MHz, Dβ-DMSO) 1.96-2.22 (2H, m, CH2), 3.02-3.28 (4H, m, 2 of CH2), 4.24-4.28 (IH, m, CH-OBn), 4.δ0 (2H, s, CH2Ar), 7.29-7.38 (7H, m, Ar-H), 7.δl (IH, d, J=8.6Hz, Ar-H), 7.87 (IH, d, lδ J=1.8Hz, Ar-H), 9.02 (2H, s, Ar-H), 11.2δ (IH, s, NH).

EXAMPLE 2

(3RV3-(4-MethoxybenzyloxyVl-r2-(δ-(1.2.4-triazol-4-yl)-lH-indol-3- 20 vDethyl] pyrrolidine. 1.2 Oxalate. Hemihvdrate.

1. Intermediate 3: 2-fδ-(1.2.4-Triazol-4-yl)-lH-indol-3-vnethyl alcohol

a) 2-Iodo-4-( 1.2.4-triazol-4-yl)phenylaniline

25 A solution of iodine monochloride (22.3g, 137mmol) in methanol

(300ml) was added over 0.75h to a stirred suspension of 4-(l,2,4-triazol- 4-yl)phenylaniline (20.0g, 125mmol) and caldum carbonate (2δ.0g, 2δ0mmol) in methanol (800ml) at -30^CC under nitrogen. The mixture was allowed to warm to room temperature and stirred for 16h before filtering

30 through a pad of celite. The filtrate was evaporated in υacuo and the residue dissolved in EtOAc and washed with 50% w/w sodium bisulphite solution. The solid material was filtered off and the organic layer dried (MgSO ), evaporated in vacuo and combined with the solid material to give the title product (23.9g, 67%), δ (2δOMHz, dβ-DMSO) δ.δ4 (2H, br s, NH₂), 6.84 (IH, d, J=8.7Hz, Ar-H), 7.38 (IH, dd, J=2.6 and 8.7 Hz, Ar-H), δ 7.87 (IH, d, J=2.δHz, Ar-H), 8.92 (2H, s, Ar-H).

b) 2-rδ-(1.2.4-Triazol-4-ylV2-trimethylsilyl-lH-indol-3-vnethyl alcohol

A mixture of the preceding iodoa line (23.9g, 83.6mmol), 4-trimethylsilyl-3-butyn-l-ol (prepared by silylation of 3-butyn-l-ol) 0 (17.83g, 12δ.3mmol), lithium chloride (3.δ4g, 83.6mmol), sodium carbonate (44.24g, 417.8mmol) and triphenylphosphine (1.10g, 4.18mmol) in DMF (900ml) was degassed with nitrogen for O.δh at room temperature. Palladium (II) acetate (0.94g, 4.18mmol) was added in one portion and the mixture heated at 100°C under nitrogen for 6h. A second portion of lδ palladium (II) acetate (δg, 22.2mmol) was added and the mixture heated at 100°C for lh. The solvent was evaporated in vacuo and the residue partitioned between ethyl acetate (800ml) and water (1000ml) and filtered through celite. The aqueous layer was separated and re-extracted with ethyl acetate (3 x 800ml). The combined extracts were dried and

20 evaporated, and the crude product chromatographed on silica gel, eluting with CH₂Cl2 EtOH/NH₃ (80:8:1), to give the title product (8.δg, 34%), δ (2δOMHz, de-DMSO) 0.38 (9H, s, SiMes), 2.97 (2H, t, J=7.6Hz, CH₂), 3.δ8 (2H, m, CH₂), 4.69 (IH, t, J=δ.3Hz, OH), 7.30 (IH, dd, J=2.1 and 8.6 Hz, Ar-H), 7.48 (IH, d, J=8.7Hz, Ar-H), 7.78 (IH, d, J=2.1Hz, Ar-H), 9.03 (2H,

25 s, Ar-H), 10.83 (IH, br s, NH).

c) 2-r5-(1.2.4-Triazol-4-yl)-lH-indol-3-vnethyl alcohol

A solution of the preceding 2-trimethylsilyl-indole (8.5g, 28.3mmol) in methanol (68ml) and 5N HCI (57ml) was heated at 60°C for 16h. The 30 methanol was evaporated in vacuo and the residue neutralised with concentrated NH3 solution. The predpitate was filtered off, washed with Et2θ (2x100ml) and dried in vacuo to give the title alcohol (6.0g, 92%), δ (2δOMHz, dβ-DMSO), 2.88 (2H, t, J=7.2Hz, CH₂), 3.68 (2H, m, CH₂), 4.66 (IH, br s, OH), 7.23-7.32 (2H, m, Ar-H), 7.48 (IH, d, J=8.δHz, Ar-H), 7.81 (IH, d, J=2.1Hz, Ar-H), 9.03 (2H, s, Ar-H), 11.15 (IH, br s, NH).

2. Intermediate 4: (3R)-N-(HV3-(4-Methoxybenzyloxy) pyrrolidine

a) (3R)-N-tert-Butyloxycarbonyl-3-(¹4-methoxybenzyloxy)pyrrolidine A solution of (3R)-N-terf-butyloxycarbonylpyrrolidin-3-ol (2.00g, 10.7mmol) in anhydrous DMF (12ml) was added dropwise to a stirred slurry of sodium hydride (60% dispersion in oil, 0.465g, ll.βmmol) in DMF (25ml) at -10^βC under nitrogen and the mixture stirred at this temperature for 0.67h. 4-Methoxybenzyl chloride (1.52ml, 11.2 mmol) was added dropwise and the mixture warmed to 0°C over lh and then stirred at RT for 2h. Water was added and the mixture poured into ether and washed with water (x3). The ethereal layer was dried (MgSO₄), evaporated in vacuo and the crude product chromatographed on silica gel, eluting with ethyl acetate/hexane (30:70), to afford the title pyrrolidine (3.09g, 94%), δ (250MHz, CDCb) 1.46 (9H, br s, OC(Me)₃), 1.73-2.09 (2H, m, CH2), 3.40-3.46 (4H, m, 2 of CH2), 3.81 (3H, s, OMe), 4.12 (IH, m, CHOCH2Ar), 4.45 (2H, s, OCH.2Ar), 6.8δ-6.9l (2H, m, Ar-H), 7.23-7.27 (2H, m, Ar-H).

b) (3R)-N-(HV3-(4-MethoxybenzyloxyVpyrrolidine δ Prepared from the preceding N-Boc pyrrolidine as described for

Example 1, part 2c, δ (250MHz, CDCla) 1.85-1.93 (2H, m, CH₂), 2.81-2.91 (2H, m, CH2), 3.06-3.17 (2H, m, CH₂), 3.80 (3H, s, OMe), 4.10 (IH, m, CHOCH∑Ar), 4.41 (2H, s, OCHϊAr), 6.85-6.91 (2H, m, Ar-H), 7.23-7.27 (2H, m, Ar-H). 0 3. (3R)-3-(4-MethoxybenzyloxyVl-r2-(δ-(1.2.4-triazol-4-v -lH-indol-3- yDethyripyrrolidine. 1.2 Oxalate Hemihvdrate.

Methanesulphonyl chloride (0.20ml, 2.62mmol) was added dropwise to a stirred suspension of Intermediate 3 (400mg, 1.7δmmol) in pyridine δ (10ml) at -10°C under nitrogen. The mixture was warmed to, and stirred at, room temperature overnight and the solvent evaporated under high vacuum. The residue was partitioned between ethyl acetate and water and the aqueous layer extracted with ethyl acetate (x4). The combined extracts were dried (MgSO₄) and evaporated in vacuo. The residue

10 (33δmg) was taken with sodium carbonate (161mg, 1.07mmol) and sodium iodide (114mg, l.Oδmmol) in 1,2-dimethoxyethane (8ml) and a solution of Intermediate 4 (224mg, l.Oδmmol) in 1,2-dimethoxyethane (2ml) added. The mixture was heated at reflux under nitrogen for 2 lh in the dark. Water was added and the mixture extracted with ethyl acetate lδ (3 x 100ml). The combined extracts were dried (MgS0₄) and evaporated in vacuo, and the residue chromatographed on silica gel, eluting with CH₂Cl2/MeOH/NH3 (90:8:1), to give the title indole (87mg, 12%). The 1.2 oxalate hemihydrate salt was prepared. (Found: C, δ9.47, H, δ.49,

N, 12.99. C2₄H27Nsθ2 l.2(C2H2θ₄)*0.δ H₂O requires C, δ9.32, H, δ.73, 20 N, 13.10%), m/e (M+D 418, δ (360MHz, dβ-DMSO) 2.06 (IH, m, CH of CH₂), 2.18 (IH, m, CH of CH2), 3.07-3.11 (2H, m, CH₂), 3.20-3.42 (6H, m, 3 of CH₂), 3.74 (3H, s, OMe), 4.27 (IH, m, CHOCHjAr), 4.43 (2H, s, CHOCH2Ar), 6.89 (2H, d, J=8.7Hz, 2 of Ar-H), 7.2δ (2H, d, J=8.6Hz, 2 of Ar-H), 7.31 (IH, dd, J=2.1 and 8.4Hz, Ar-H), 7.35 (IH, s, Ar-H), 7.51 (IH, 25 d, J=8.4Hz, Ar-H), 7.81 (IH, d, J=2.0Hz, Ar-H), 8.89 (2H, s, Ar-H), 11.08 (IH, br s, NH).

30 EXAMPLE 3

(aT_>._-_-(PγriHin._-_.ylmethyloxy)-l-r2-(δ-(1.2.4-triazol-4-ylVlH-indol- 3-yl)ethvHpyrrolidine. Bisoxalate. 0.2δ Hydrate. δ a) (3R)-N-terf-Butyloxycarbonyl-3-(pyridin-3-ylmethyloxy)pyrrolidine

A suspension of 3-picolylchloride hydrochloride (1.84g, 11.2mmol) in DMF (50ml) was added to a stirred slurry of sodium hydride (60% dispersion in oil, 0.45g, 11.2mmol) in DMF at 0°C under nitrogen. The 0 mixture was stirred at 0°C for 0.2δh and then added to a mixture of

(3R)-N-tert-butyloxycarbonylpyrrolidin-3-ol (2.0g, 10.7mmol) and sodium hydride (60% dispersion in oil, 0.4δg, 11.2mmol) in DMF at 0°C under nitrogen (mixture stirred for 0.2h at 0°C prior to the addition). The reaction mixture was stirred at room temperature for 2.δh. Water (200ml) lδ was added and the mixture extracted with ethyl acetate (1 x 200ml), dried iazSOi) and evaporated in vαcuo. The crude product was chromatographed on silica gel, eluting with Et∑O/MeOH (9δ:δ), to give the desired product (1.63g, δδ%), δ (2δOMHz, d_ι-MeOH), 1.46 (9H, s, OC(Me)₃), 1.9δ-2.18 (2H, m, CH₂), 3.34-3.61 (4H, m, 2 of CH₂), 4.22 (IH,

20 m, CHOCH__Ar), 4.δ9 (2H, s, OCHzAr), 7.43 (IH, dd, J=4.7 and 7.8Hz, Ar-H), 7.48 (IH, d, J=7.9Hz, Ar-H), 8.4δ-8.δl (2H, m, 2 of Ar-H).

b) (3RVN-(HV3-(pyridin-3-ylmethyloxy)pyrrolidine

Prepared from the preceding N-Boc pyrrolidine as described for 25 Intermediate 2, part c, δ (250MHz, CDC ) 1.86-2.01 (2H, m, CH₂), 2.81- 2.91 (2H, m, CH₂), 3.07-3.18 (2H, m, CH₂), 4.13 (IH, m, CHOCH2Ar), 4.δ0 (2H, s, OCH__Ar), 7.28 (IH, m, Ar-H), 7.68 (IH, m, Ar-H), 8.74-8.98 (2H, m, 2 of Ar-H).

30 c) (3RV3-(Pyridin-3-ylmethyloxyVl-r2-(5-(1.2.4-triazol-4-yl)-lH-indol- 3-yl)ethyllpyrrolidine. Bisoxalate. 0.25 Hydrate.

Prepared from Intermediate 3 and the preceding N(H)-pγrrolidine using the procedure described for Example 2. The bisoxalate 0.25 hydrate 5 salt was prepared which crystallised out containing a small amount of ether; m.p. 87-89°C. (Found: C, 54.53, H, 5.08, N, 14.δ8.

C22H2 N6θ-2(C2H₂O₄) 0.2δ H₂O*0.04(C₄HιoO) requires C, 54.55, H, 5.06, N, 14.59%). m/e 389 (M+l⁺), δ (360MHz, dβ-DMSO) 2.08-2.30 (2H, m, CH₂), 3.10-3.15 (2H, m, CH₂), 3.38-3.δ0 (6H, m, CH₂), 4.37 (IH, br s, 10 CHOCH2Ar), 4.δ7 (2H, s, OCK Ar), 7.34-7.41 (3H, m, 3 of Ar-H), 7.δ3 (IH, d, J=8.7Hz, Ar-H), 7.78 (IH, br d, J=7.9Hz, Ar-H), 7.88 (IH, s, Ar-H), 8.δ0 (IH, m, Ar-H), 8.98 (IH, s, Ar-H), 9.02 (2H, s, Ar-H), 11.30 (IH, br s, NH).

EXAMPLE 4 lδ

(3RV3-Benzyloxymethyl-l-f2-(δ-(1.2.4-triazol-4-ylVlH-indol-3-yl) ethyl pyrrolidine. Hydrogen Oxalate Hemihvdrate.

a) (3R)-N-tert-Butyloxycarbonyl-3-hvdroxymethylpyττohdine 20 Prepared from (3R)-N-[(R)- l-phenylethyl]-3-(hydroxymethyl) pyrrolidine (J. Med. Chem., 1990, 33 (1), 71) as described for Example 1, part 2a, δ (2δOMHz, Dβ-DMSO) 1.39 (9H, s, OC(Me)₃), 1.31-1.64 (2H, m, CH₂), 1.79-1.88 (IH, m, CH), 2.19-2.31 (IH, m, CH of CH₂), 2.95 (IH, dd, J=10.7 and 7.0Hz, CH of CH₂), 3.11-3.35 (4H, m, 2 of CH₂), 4.67 (IH, t, 25 J=5.3Hz, OH).

b) (3R)-4-(3-Benzyloxymethyl)pyrrolidin-l-ylbutanal dimethyl acetal The title compound was prepared from (3R)-N-tert- butyloxycarbonyl-3-hydroxymethylpyrrolidine as described for Example 1, 30 parts 2b-d, δ (2δOMHz, DG-DMSO) 1.24-1.56 (6H, m, 3 of CH₂), 1.75-1.89 (IH, m, CH), 2.21-2.55 (6H, m, 3 of CH₂), 3.20 (6H, s, CH (QMe)₂). 3.30 (2H, d, J=7.1Hz, CJkOBn), 4.34 (IH, t, J=δ.3Hz, CH(OMe)₂), 4.4δ (2H, s, O£H__Ar), 7.24-7.39 (δH, m, Ar-H).

c) (3R)-3-Benzyloxymethyl-l-r2-(δ-(1.2.4-triazol-4-yl)-lH-indol-3- δ vDethyllpyrrolidine. Hydrogen Oxalate. Hemihvdrate.

A solution of Intermediate 1 (2.17g, 12.36mmol) and (3R)-4-(3- benzyloxymethyl)pyrrolidin-l-ylbutanal dimethyl acetal (3.80g, 12.36mmol) in 4% H₂SO₄ (30ml) was heated at reflux for 60h. The solution was cooled to room temperature and basified by addition of 0 4N NaOH solution and extracted with n-butanol (1 x 7δml). The solvent was removed under vacuum and the crude product chromatographed on silica eluting with C^CL/MeOH/NHs (80:8:1) to give the title-indole (0.4δg 10%). The hydrogen oxalate hemihydrate salt was prepared: mp 14δ^βC. (Found: C, 62.16; H, δ.97; N, 13.76. C24H27NsO*C2H2θ4- lδ 0.6 H₂O requires C, 62.16; H, 6.06; N, 13.94%), δ (360MHz, Dβ-DMSO) 1.64-1.78 (IH, m, CH of CH2), 2.04-2.16 (IH, m, CH of CH2), 2.60-2.72 (IH, m, CH), 3.04-3.δ0 (10H, m, δ of CH2), 4.49 (2H, s, OCH__Ar), 7.27-7.40 (7H, m, Ar-H), 7.δ2 (IH, d, J=8.6Hz, Ar-H), 7.90 (IH, d, J=2.0Hz, Ar-H), 9.04 (2H, s, Ar-H), 11.30 (IH, s, NH).

20

EXAMPLE 5

(3SV3-(N-Benzyl-N-methv aminomethyl-l-[2-(5-(1.2.4-triazol-4-yl)-lH- indol-3-yl)ethyllpyrrolidine Sesαuioxalate. 0.3 Hydrate.

25 a) (3R)-N-tβrt-Butyloxycarbonyl-3-methylsulphonyloxymethylpyrrohdine

A solution of methane sulphonyl chloride (3.37g, 29.39mmol) in CH2CI2 (30ml) was added dropwise to a solution of (3R)-N-terf- butyloxycarbonyl-3-hydroxymethylpyrrohdine (5.4g, 26.7mmol) and 30 anhydrous triethylamine (2.97g, 29.39mmol), in CH2CI2 (100ml), at -15°C. The mixture was warmed to room temperature and stirred for 16h before adding saturated K2CO3 solution (50ml) and diluting with CH2CI2 (100ml). The aqueous was separated and extracted further with CH2CI2 (2 x 100ml). The combined extracts were dried (Na2SO ) and evaporated to give the title-mesylate (7.5g, 100%), δ (2δOMHz, CDCI3) 1.46 (9H, s, δ OC(Me)₃), 1.62-1.84 (IH, m, CH of CH2), 2.00-2.14 (IH, m, CH of CH2), 2.58-2.72 (IH, m, CH), 3.04 (3H, s, Me), 3.08-3.62 (4H, m, 2 of CH2), 4.11- 4.33 (2H, m, CH₂OMs).

b) (3S)-N-tert-Butyloxycarbonyl-3-(N-benzyl-N-methyl) 0 aminomethylpyrrolidine

A solution of the preceding mesylate (7.46g, 26.72mmol) in N-benzylmethylamine (22.7g, 187.0mmol) was heated at 100°C for 4h. The solvent was removed under vacuum, ethyl acetate (lδOml) was added to the residue and the solution washed with water (100ml). The organic lδ phase was dried (Na2SO₄) and evaporated and the crude product chromatographed on silica gel eluting with CH∑C-b/MeOH (98:2) to give the title-N-methylbenzylamine (6.9g, 8δ%), δ (2δOMHz, CDCI3) 1.46 (9H, s, OC(Me)₃), 1.50-1.72 (2H, m, CH2), 1.90-2.02 (IH, m, CH), 2.21 (3H, s, NMe), 2.30-2.50 (2H, m, CH₂), 2.92-3.05 (IH, m, CH of CH2), 3.18-3.62

20 (2H, m, 2 of CH2 and CH of CH₂), 7.20-7.38 (5H, m, Ar-H).

c) (3S)-N(H)-3-(N-Benzyl-N-methyl)-aminomethylpyrrolidine

A solution of the preceding N-Boc pyrrolidine (6.9g, 22.7mmol) in trifluoroacetic add (30ml) and CH2CI2 (100ml) was stirred at room

2δ temperature for 16h. The solvents were removed under vacuum and the resulting residue was chromatographed on silica gel eluting with CH₂Cl2/MeOH/NH3 (60:8:1) to give the title-product (4.6g, 99%), δ (2δOMHz, Dβ-DMSO) 1.41-1.55 (IH, m, CH of CH2), 1.89-2.02 (IH, m, CH of CH2), 2.11 (3H, s, Me), 2.31 (2H, d, J=7.5Hz, CH_>NMe), 2.38-2.52

30 (IH, m, CH), 2.73 (IH, dd, J=11.3 and 6.9Hz, CH of CH2), 2.95-3.23 (5H, m, 2 of CH₂ and CH of CH₂), 3.46 (2H, ABq, J=13.4Hz, NCH__Ar), 7.19-7.36 (5H, m, Ar-H).

d) (3S)-4-(3-(N-Benzyl-N-methyl)aminomethyl)-pyrroUdin-l-ylbutanal 5 _ιiτn hγ1 ftf-fftfll

A mixture of the preceding N(H)-pyrrolidine (3.0g, 14.68mmol), 4-chlorobutanal dimethyl acetal (2.24g, 14.68mmol), Nal (2.42g, 16.15mmol) and NaaCOs (1.7 lg, 16.15mmol), in dimethoxyethane (δOml), was heated at reflux for 16h, in the absence of light. The solvent was 0 removed under vacuum and ethyl acetate (100ml), water (70ml) and saturated K2CO3 solution (10ml) were added to the residue. The aqueous was separated and further extracted with EtOAc (2 x 100ml). The combined extracts were dried and evaporated and the residue chromatographed on silica gel eluting with CHaCla/iPA/NH. (80:8: 1) to lδ give the title-acetal (2.06g, 44%), δ (2δOMHz, Dβ-DMSO) 1.23- l.δδ (5H, m, 2 of CH2 and CH), 1.75-1.89 (IH, m, CH of CH2), 2.09 (3H, s, Me), 2.14- 2.40 (9H, m, 4 of CH2 and CH), 3.20 (6H, s, (OMe)₂), 3.42 (2H, ABq, J= 13.3Hz NCH__Ar), 4.33 (IH, t, J=5.4Hz, CH(OMe)₂) 7.19-7.3δ (δH, m, Ar-H). 20 e) (3S)-3-(N-Benzyl-N-methyl)aminomethyl-l-r2-(δ-(1.2.4-triazol-4-yl)- lH-indol-3-yl)ethvnpyrrolidine Sesαuioxalate. 0.3 Hydrate.

Prepared from Intermediate 1 and the preceding acetal using the procedure described for Example 1. The sesquioxalate 0.3 hydrate salt 2δ was prepared; mp 116-117°C, (Found: C, 60.δ7; H, 6.47; N, 14.93.

C25H3oNG*l.δ(C2H2θ₄)*0.3 H2O requires C, 60.δ9; H, 6.10; N, lδ.14%); m/e 41δ (M+l⁺). δ (250MHz, CDCI3 on free base) 1.44-1.60 (IH, m, CH of CH2), 1.94-2.12 (IH, m, CH of CH₂), 2.20 (3H, s, Me), 2.31-3.01 (11H, , 5 of CH2 and CH), 3.48 (2H, ABq, J=13.2Hz, NCH__Ar), 7.15 (IH, dd, J=8.6 30 and 2.1Hz, Ar-H), 7.19 (IH, d, J=2.3Hz, Ar-H), 7.19-7.26 (5H, m, Ar-H), 7.47 (IH, d, J=8.6Hz, Ar-H), 7.57 (IH, d, J=2. lHz, Ar-H), 8.41 (IH, br s, NH), 8.47 (2H, s, Ar-H).

EXAMPLE 6

(2S)-2-(N-Benzyl-N-methyl)aminomethyl-l-r2-(5-(1.2.4-triazol-4-ylVlH- indol-3-yl)ethvnpyrrolidine. Sesquisucdnate. Sesquihvdrate. The title compound was preparedlrom (2S)-N-tert- butyloxycarbonyl-2-hydroxymethylpyrrolidine (L-prolinol from Aldrich) using the procedures described for the preparation of Example δ. The sesquisucdnate sesquihydrate salt was prepared, mp 70-72°C, (Found:

C, 61.4δ, H, 6.6δ, N, 13.9δ. C25H3oNβ l.δ(C₄H6θ₄) 1.5 H₂O requires C, 61.52, H, 6.75, N, 13.89%), δ (360MHz, D2O) 1.70-1.77 (IH, m, CH of CH2), 1.85-1.93 (IH, m, CH of CH2), 2.06-2.18 (IH, m, CH of CH2), 2.22 (3H, s, Me), 2.22-2.33 (IH, m, CH of CH2), 2.68-2.79 (2H, m, CH2), 3.12- 3.76 (9H, m, 4 of CH2 and CH), 7.01-7.03 (2H, m, Ar-H), 7.15-7.21 (3H, m, Ar-H), 7.32 (IH, dd, J=8.6 and 2.1Hz, Ar-H), 7.47 (IH, s, Ar-H), 7.64 (IH, d, J=2.1Hz, Ar-H), 7.67 (IH, d, J=8.6Hz, Ar-H), 8.70 (2H, s, Ar-H).

EXAMPLE 7

(3SV3-(N-Benzvnaminomethyl-l-r2-(5-(1.2.4-triazol-4-yl)-lH-indol-3- vDethyllpyrrolidine. 2.6 Hydrogen Oxalate. 0.1 Hydrate.

a) (3SVN(HV3-(N-Benzyl)aminomethylpyrrolidine Prepared from (3R)-N-ferf-butyloxycarbonyl-3- methylsulphonyloxvmethylpyrrolidine and benzylamine as described for Example 5, parts b and c, δ (2δOMHz, CDCI3) 1.38 (IH, m, CH), 1.90 (IH, m, CH), 2.24 (IH, qu, J=7.4Hz, CH), 2.64-2.62 (3H, m, CH₂ and CH of CH2), 2.83-2.99 (2H, m, CH2), 3.08 (IH, dd, J=7.6 and 1 l.OHz, CH of CH2). 3.80 (2H, s, CH∑Ar), 7.21-7.36 (δH, m, Ar-H). - -

b) (3S)-3-(N-Benzyl)aminomethyl-l-r2-(δ-(1.2.4-triazol-4-ylVlH-indol- 3-yl)ethyllpyrro1i inP! 2.6 Hydrogen Oxalate. O.l Hvdrate.

Prepared from Intermediate 3 and the preceding N(H)-pyrrolidine δ using the procedure described for Example 2. The 2.6 hydrogen oxalate,

0.1 hydrate salt was prepared, mp 228-230°C. (Found, C, δδ.16, H, δ.30,

N, 13.00. C24H2βN6-2.6(C2H₂θ4) 0.1 H2O requires C, 55.20, H, 5.29, N, 13.21%); m/e 401 (M+l^*), δ (360MHz, dβ-DMSO) 1.96 (IH, m, CH2), 2.10 (IH, m, CH₂), 2.76 (IH, m, CH of CH₂), 3.00-3.24 (5H, m, CH₂), 3.30- 0 3.60 (5H, m, CH*), 4.14 (2H, s, CH__Ar), 7.3δ-7.54 (8H, m, Ar-H), 7.91 (IH, s, Ar-H), 9.04 (2H, s, Ar-H), 11.30 (IH, br s, NH).

EXAMPLE 8

5 l-{3-f5-(1.2.4-Triazol-4-yl)-lH-indol-3-vnpropyll-4-r4-(acetylamino) benzylaminplpip^pridi-ne. 2.8δ Hydrogen Oxalate.

1. δ-Bromopentanal dimethyl acetal

To a solution of δ-bromovaleryl chloride (δOg, 0.25 lmol) in 0 anhydrous THF (500ml), at -78°C, was added lithium tτi-tert- butoxyaluminohydride (1.0M solution in tetrahydrofuran, 300ml; 0.30mol), keeping the temperture below 70°C. The solution was stirred at -78°C for 5h and then quenched by dropwise addition of 2M hydrochloric add (3δ0ml). The mixture was warmed to room temperature and stirred

2δ for 16h. Diethyl ether (500ml) was added, the aqueous phase separated and extracted further with ether (x2). The combined extracts were washed with saturated Na2COs solution (xl), water (xl) and brine (x2), dried (Na2SO₄) and evaporated to give 5-bromovaleraldehyde (37.5g, 91%). A solution of 5-bromovaleraldehyde (37.5g, 0.227mol) in methanol (2δ0ml)

30 and concentrated sulphuric add (O.δml) was stirred at room temperature for 3h. The solvent was removed under vacuum and to the residue was added K2CO3 solution (60ml) and diethyl ether (δOOml). The aqueous layer was separated and re-extracted with ether (x2). The combined extracts were washed with water and brine, dried (Na2SO₄) and evaporated. The crude product was chromatographed on silica eluting δ with diethyl ether hexane (1:9) to give the title-acetal (27.δg, 67%). δ (2δOMHz, CDCls) 1.43-1.67 (4H, m, 2 of CH2), 1.83-1.94 (2H, m, CH2), 3.38 (6H, s, CH(OMe)₂), 3.42 (2H, t, J=7Hz, CHuBr), 4.37 (IH, t, J=7Hz, CH(OMe)₂).

0 2. δ-(4-Hvdroxypiperidin-l-yl)pentanal dimethyl acetal

A mixture of δ-bromopentanal dimethyl acetal (3.34g, lδ.82mmol), anhydrous potassium carbonate (2.218g, 15.82mmol) and 4-hydroxypiperidine (2.0g, 19.77mmol) in anhydrous dimethylformamide (50ml) was stirred at 80-90°C for 3 hours under nitrogen. After cooling, 5 the mixture was diluted with water (lδOml), basified with saturated aqueous potassium carbonate and the product was extracted with ethyl acetate (3 x 250ml). The combined organic solutions were dried (Na_>SO ) and concentrated. Flash chromatography of the residue (silica gel, dichloromethane/methanol/ammonia, 90:10:1) gave 2.71g (74%) of the title 0 compound as a colourless oil, δ (250MHz, dβ-DMSO) 1.06-1.56 (8H, m), 1.62-1.75 (2H, m), 1.86-2.00 (2H, m), 3.20 (6H, s), 3.34-3.47 (IH, m), 4.31 (IH, t, J=5.7Hz), 4.53 (IH, d, J=4.2Hz), m/e (ES) 232 (M+l⁺).

3. l-{3-r5-Q.2.4-Triazol-4-ylVlH-indol-3-yllpropyl--4-

25 hvdroxypiperidine. 1.35 Hydrogen Oxalate.

A solution of the preceding dimethyl acetal (2.70g, 11.67mmol) and 4-(l,2,4-triazol-4-yl)phenylhydrazine (2.15g, 12.25mmol) in 4% sulphuric add (100ml) was refluxed for 9h. After cooling to room temperature, the reaction mixture was basified with saturated aqueous potassium

30 carbonate and products were extracted with ethyl acetate (3 x 250ml) and with a mixture of ethyl acetate and n-butanol (1:1, 2 x 250ml). The combined organic solutions were washed with brine (1 x 50ml), dried (Na2SO ) and concentrated. Flash chromatography of the residue (silica gel, dichloromethane/methanol/ammonia, 85:16:1.5) gave 1.96g.(51.6%) of the title compound free base as a pale yellow foam. The oxalate salt was 5 prepared and recrystallised from ethanol-diethyl ether, mp 102-105°C,

(Found: C, 56.76, H, 5.99, N, lδ.43. C.βH₂₃NδO-1.3δ(C₂H₂0₄) requires: C, 65.63, H, 5.80: N, 15.67%), δ (360MHz, D₂O) 7.31 (IH, dd, J=8.6 and 2.6Hz), 7.36 (IH, d, J=2.6Hz), 7.61 (IH, d, J=8.6Hz), 7.75 (IH, s), 8.87 (2H, s) among other signals, m/e (ES) 326 (M+l⁺). 0

4. l-(3-r5-(1.2.4-Triazol-4-ylVlH-indol-3-vnpropyl -4-ketopiperidine

To a stirred solution of the preceding alcohol free base (105mg, 0.322mmol) in a mixture of anhydrous dimethyl sulfoxide (3ml) and anhydrous triethylamine (314μl, 2.25mmol) was added portionwise, under lδ nitrogen, solid sulphur trioxide pyridine complex (18δmg, l.lβmmol) over 7 minutes. After 56 minutes of stirring at room temperature, the mixture was diluted with water (20ml), basified with saturated aqueous potassium carbonate and extracted with ethyl acetate (3 x 70ml). The organic phases were combined, washed with brine (1 x 20ml), dried (Na₂SO₄) and 20 concentrated. Flash chromatography of the residue (silica gel, dichloromethane/methanol/ammonia, 90:10:1) afforded 72mg (69%) of the title compound as a waxy solid, δ (250MHz, CDCb) 1.96 (2H, qn, J=7.3Hz), 2.42-2.62 (6H, m), 2.72-2.90 (6H, m), 7.13-7.19 (2H, m), 7.50 (IH, d, J=8.5Hz), 7.57 (IH, d, J=2.0Hz), 8.42 (IH, br s), 8.48 (2H, s), m/e 25 (ES) 324 (M+l⁺).

5. l-{3-f5-(1.2.4-Triazol-4-yl)-lH-indol-3-vnpropyU-4-f4- (acetylamino^')benzylamino .piperidine. 2.85 Hydrogen Oxalate.

To a stirred solution of the preceding ketone (lOOmg, 0.309mmol) 30 and 4-(acetylamino)benzylamine hydrochloride (111.5mg, 0.371mmol) in methanol (7ml) was added anhydrous triethylamine (51.7μl, 0.371mmol) followed by gladal acetic add (70.7μl, 1.236mmol). After 15 minutes, sodium cyanoborohydride (25mg) was added and stirring was continued at room temperature for 3.6 hours. Saturated aqueous potassium .carbonate (4ml) was added and the methanol was removed under vacuum. The aqueous residue was diluted with brine (25ml) and products were extracted with ethyl acetate (1 x 50ml), chloroform (2 x 50ml) and chloroform-n-butanol (1:2; 1 x 150ml). The combined organic extracts were dried (Na2SO₄) and concentrated.^' Flash chromatography of the residue (silica gel, dichloromethane/methanol/ammonia, 86:15:1.6) gave 95mg (65%) of the title compound free base. The oxalate salt was prepared and crystallised from ethanol-diethyl ether, mp 205-210°C,

(Found: C, 53.64, H, 5.26, N, 13.74. C₂7H3₃N7O*2.85(C₂H₂O₄) requires C, 53.94, H, 5.36, N, 13.46%), δ (360MHz, D₂O) 1.86-2.04 (2H, m), 2.10- 2.24 (2H, m), 2.17 (3H, s), 2.45 (2H, br d, J=13Hz), 2.90 (2H, t, J=7.0Hz), 3.04 (2H, t, J=12Hz), 3.14-3.24 (2H, m), 3.55 (IH, br t), 3.71 (2H, br d, J=13Hz), 4.27 (2H, s), 7.32-7.40 (2H, m), 7.46 (2H, d, J=8.6Hz), 7.49 (2H, d, J=8.6Hz), 7.64 (IH, d, J=8.7Hz), 7.80 (IH, s), 9.02 (2H, s), m/e (ES) 472

(M+r).

EXAMPLE 9

l-^3-r5-(1.2.4-Triazol-4-yl -lH-indol-3-vnpropyl.-4-(benzylamino) piperidine. Dihvdrogen Oxalate Dihvdrate

The title compound was prepared from l-{3-[5-(l,2,4-triazol-4-yl)- lH-indol-3-yl]propyl}-4-ketopiperidine and benzylamine using a similar procedure to that described for Example 8 (step 5), mp 233-234°C, (Found:

C, 55.49; H, 5.69; N, 13.26. C25H3oNβ*2(C₂H2θ₄)*2 H2O requires C, 55.23; H, 6.07; N, 13.33%). δ (360MHz, de-DMSO) 1.85-2.00 (2H, m), 2.01-2.11 (2H, m), 2.19-2.22 (2H, m), 2.73-2.90 (4H, m), 2.91-3.00 (2H, m), 3.16-3.25 (IH, m), 3.4-3.5 (2H, m), 4.14 (2H, s), 7.30-7.33 (2H, m), 7.40-7.42 (3H, m), 7.48-7.51 (3H, m), 7.80-7.81 (IH, m), 9.02 (2H, s), 11.20 (IH, s), m/e (ES) 415 (M+l⁺).

EXAMPLE 10

l-(3-r5-(1.2.4-Triazol-4-ylVlH-indol-3-vnpropyll-4-rN-benzyl-N- mp -hylanninolpiperidine. 1.5 Hydrogen Oxalate.

To a stirred solution of the preceding amine (Example 9) (164mg, 0.396mmol), formaldehyde (38% wt in H₂O, 32μL, 0.436mmol) and gladal acetic add (90mg, 1.584mmol) in methanol (10ml) was added sodium cyanoborohydride (27mg, 0.436mmol). Stirring was continued for 3h. Saturated aqueous potassium carbonate (4ml) was added and the methanol removed under vacuum. The aqueous residue was partitioned between ethyl acetate (30ml) and water (20ml). The organic layer was dried (Na__SO₄) and concentrated. Flash chromatography (silica gel, dichloromethane/methanol/ammonia, 90:10:1) gave 128mg (76%) of the title compound free base. The oxalate salt was prepared and crystallised from methanol-diethyl ether, mp 134-136°C; (Found: C, 59.39; H, 6.08;

N, 14.10. C26H32Nβ*1.5(C2H2θ₄)* 1.3 H₂O requires, C, 59.33, H, 6.46, N, 14.31%); δ (360xMHz, dβ-DMSO) 1.74-1.88 (2H, m), 1.90-2.08 (4H, m), 2.16 (3H, s), 2.70-2.84 (5H, m), 2.92-3.02 (2H, m), 3.36-3.46 (2H, m), 3.65 (2H, s), 7.20-7.36 (7H, m), 7.50 (IH, d, 8.6Hz), 7.80 (IH, s), 9.02 (2H, s), 11.18 (IH, s). m/e (ES^*) 429 (M+l⁺).

EXAMPLE 11

l-<3-r5-(1.2.4-Triazol-4-yl)-lH-indol-3-vnpropyll-4-[(Denzylamino^ methyl.piperidine. 2.5 Hydrogen Oxalate.

1. 4-f(Benzylamino)methvnpiperidine A solution of 4-(aminomethyl)piperidine (22.8g, 200mmol) and benzaldehyde (21.2g, 200mmol) in toluene (200ml) was refluxed for 5h, under nitrogen, using a Dean -Stark trap. After cooling, the toluene was removed under vacuum and the residual oil was dissolved in absolute ethanol (400ml) and cooled to 5°C. Sodium borohydride (6g, 158.7 mmol) was added portionwise to the above solution over 40 minutes, under nitrogen, and the mixture was stirred for a further 1 hour 15 minutes before excess borohydride was destroyed by dropwise addition of 5N hydrochloric add (150ml) (CAUTION: hydrogen evolution). The ethanol was removed under vacuum and the aqueous residue was basified and extracted with ethyl acetate (5 x 500ml). The combined organic solutions were dried (Na2SO ) and concentrated. Column chromatography (alumina, activity II-HI; dichloromethane/methanol/ammonia, 95:5:0.35) of the residue afforded 19.3g (47%) of the title compound as a pale yellow oil, δ (250MHz, dβ-DMSO) 1.13 (2H, dq, J=12 and 4.0Hz), 1.50-1.70 (IH, m), 1.78 (2H, br d, J=llHz), 2.47 (2H, d, J=6.6Hz), 2.56 (2H, dt, J=12 and 2.3Hz), 3.05 (2H, br d, J=12Hz), 3.83 (2H, s), 7.30-7.50 (5H, m), m/e (ES) 205 (M+l⁺).

2. 5- -f(Benzylamino)methvnpiperidin-l-vUpentanal dimethyl acetal The title compound was prepared in 58% yield from 5-bromo- pentanal dimethyl acetal and 4-[(benzylamino)methyl]piperidine using a similar method to that described for Example 8 (step 2). δ (250MHz, dβ-DMSO) 1.26-2.14 (13H, m), 2.49 (2H, t, J=7.0Hz), 2.63 (2H, d, J=6.6Hz), 3.04-3.14 (2H, m), 3.49 (6H, s), 3.95 (2H, s), 4.61 (IH, t, J=5.7Hz), 7.44-7.62 (5H, m), m/e (ES) 335 (M+l⁺).

3. l-!3-f5-(1.2.4-Triazol-4-ylVlH-indol-3-vnpropyll-4-

[(benzylamino)methyllpiperidine. 2.5 Hydrogen Oxalate. A solution of the preceding acetal (2.70g, 8.07mmol) and 4'-(l,2,4- triazol-4-yl)phenylhydrazine (1.50g, δ.δmmol) in 4% H2SO-, (100ml) was refluxed for 20 hours. After cooling, the mixture was basified with 4N sodium hydroxide and products were extracted with ethyl acetate (3 x 200ml). The combined organic solutions were washed with_brine (1 x 50ml), dried (Na_>SO₄) and concentrated. Flash chromatogrpahy of the residue (silica gel, dichloromethane/methanol/ammonia, 90:10:0.9) gave 1.63g (47%) of the title compound free base as a thick pale yellow oil. The oxalate salt was prepared and recrystallised from ethanol-methanol, mp 215-220°C, (Found: C, 56.78; H, 5.56; N, 12.82. C₂βH₃₂N6-2.5(C₂H₂θ4) requires: C, 56.96; H, 5.71; N, 12.86%). δ (360MHz, dβ-DMSO) 1.36-1.56 (2H, m), 1.86-2.12 (5H, m), 2.70-2.94 (6H, m), 2.98-3.08 (2H, m), 3.36-3.50 (2H, m), 4.12 (2H, s), 7.30-7.54 (8H, m), 7.80(1H, s), 9.02 (2H, s), 11.95 (IH, s), m/e (ES) 429 (M+l⁺).

EXAMPLE 12

l-(3-r5-(1.2.4-Triazol-4-vD-lH-indol-3-yllpropyl}-4-r(N-benzyl-N- methylamino)methvnnippri inp 2_Tfi5 Hydrogen Oxalate.

The title compound was prepared in 73% isolated yield from the product of Example 11 using a similiar procedure to that described for Example 10. The oxalate salt was prepared and recrystallised from ethanol, mp 131-134°C. (Found: C, 56.96; H, 5.84; N, 12.21.

C27H3₄Nβ*2.56(C2H2θ₄) requires: C, 56.95; H, 5.82; N, 12.34%), δ (360MHz, DMSO-dβ) 2.29 (3H, s), 3.72 (2H, s), 7.40-7.24 (7H, m), 7.50 (IH, d, J=8.6Hz), 7.81 (IH, d, J=1.9Hz), 9.02 (2H, s), 11.19 (IH, s) among other signals; m/e (ES) 443 (M^*+l).

Examples 13 - 20 were prepared from l-{3-[5-(l,2,4-triazol-4-yl)-lH-indol- 3-yl]propyl}-4-ketopiperidine and the corresponding commerdally available amines using a similar method to that described for Example 8 (step 5). EXAMPLE 13

l-(3-r5-(1.2.4-Triazol-4-yl)-lH-indol-3-vnpropyl -4-r(R>-α-(methvD

The oxalate salt was prepared from ethanol, mp 111-115°C.

(Found: C, 55.62; H, 5.82; N, 12.04. C26H₃₂Nβ-2.7(C₂H₂O₄) 0.4 HaO requires: C, 55.55; H, 5.67; N, 12.38%.) δ (360MHz, DMSO-dβ) 1.51 (3H, d, J=6.5Hz), 1.74-2.22 (6H, m), 2.64-2.96 (7H, m), 3.34-3.48 (2H, m), 4.42 (IH, br q, J=6.5Hz), 7.28-7.68 (8H, m), 7.78 (IH, d, J=2.0Hz), 9.01 (2H, s), 11.17 (IH, s); m/e (ES) 429 (M+l)⁺; [α]_D + 24 (c 0.52, MeOH).

EXAMPLE 14

l-(3-r5-(1.2.4-Triazol-4-yl)-lH-indol-3-vnpropyll-4-r(S)-α-(methyl) benzylaminolpiperidine. 2.7 Hydrogen Oxalate. 0.3 Hydrate.

The oxalate salt was prepared from ethanol, mp 12l-125°C.

(Found: C, 56.51; H, 5.86; N, 12.57. C2βH32N6-2.5(C2H₂O₄)*0.3 H2O requires: C, 56.49; H, 5.75; N, 12.75%). [α]_D - 23.9 (c 0.51, MeOH).

EXAMPLE 15

l-{3-f5-(1.2.4-Triazol-4-vn-lH-indol-3-vnpropyll-4-f(SVα- (hvdroxymethyl)benzylaminolpiperidine. 2.6 Hydrogen Oxalate. The oxalate salt was prepared from methanol-diethyl ether, mp 175-180°C. (Found: C, 54.92; H, 5.49; N, 12.59. C26H32Nβ-2.6(C2H₂O.) requires: C, 55.22; H, 5.53; N, 12.38%). δ (360MHz, DMSO-dβ) 1.62-1.84 (2H, m), 1.90-2.16 (4H, m), 2.60-2.96 (7H, m), 3.28-3.42 (2H, m), 3.63 (2H, br s), 4.19 (IH, m), 7.36-7.54 (8H, m), 7.78 (IH, d, J=2.0Hz), 9.01 (2H, s), 11.17 (IH, s); m/e (ES) 445 (M⁺+l). EXAMPLE 16

l-(3-r5-(1.2.4-Triazol-4-ylVlH-indol-3-vnpropyll-4-r(R)-α-(hvdroxymethvD benzylaminolpiperidine. 1.9 Hydrogen Oxalate. Monohvdrate.

The oxalate salt was prepared from methanol-diethyl ether, mp 154-157°C. (Found: C, 56.69; H, 6.20; N, 12.91.

C»Ha2NβO-1.9(C2H2θ4)-1.0 H₂O*0.15(C4HioO) requires: C, 56.63; H, 6.14; N, 13.03%).

EXAMPLE 17

l-{3-r5-(1.2.4-Triazol-4-yl)-lH-indol-3-vnpropyU-4-((S)-ri-hvdroxymethyl- 2-phenyllethylaminolpiperidine. 2.0 Hydrogen Oxalate. 1.4 Hvdrate. The oxalate salt was prepared from methanol-diethyl ether, mp 180-185°C. (Found: C, 56.14; H, 6.10; N, 12.83.

C27H3₄N6θ*2.0(C2H2θ4) 1.4 H2O requires: C, 56.08; H, 6.19; N, 12.66%). δ (360MHz, DMSO-dβ) 1.68-1.86 (2H, m), 1.94-2.18 (4H, m), 2.54-3.00 (8H, m), 3.24-3.40 (5H, m), 3.53 (IH, d, J=9.5Hz), 7.20-7.36 (7H, m), 7.49 (IH, d, J=8.6Hz), 7.80 (IH, d, J=2.0Hz), 9.02 (2H, s), 11.17 (IH, s); m/e (ES) 459 (M⁺ + 1).

EXAMPLE 18

l-{3-r5-(1.2.4-Triazol-4-yl)-lH-indol-3-yllpropyU-4-{(lR.2S)-r2-hvdroxy-l- methyl-2-phenyllethylamino-Piperidine. 2.3 Hydrogen Oxalate. Monohvdrate.

The oxalate salt was prepared from methanol-diethyl ether, mp

148- 152°C. (Found: C, 55.48; H, 6.16; N, 12.23. C2 H3_.N6O-2.3(C2H₂O₄)- 1.0 H2O. 0.15(C₄H.oO) requires: C, 55.66; H, 6.12; N, 12.10%). δ (360MHz, DMSO-de) 0.92 (3H, d, J=6.5Hz), 1.70-1.86 (2H, m), 1.90-2.04 (2H, m), 2.08-2.30 (2H, m), 2.52-2.86 (5H, m), 3.23-3.52 (5H, m), 5.07 (IH, s), 7.22- 7.44 (7H, m), 7.50 (IH, d, J=8.6Hz), 7.80 (IH, d, J=2.0Hz), 9.02 (2H, s), 11.17 (IH, s); m/e (ES) 459 (M⁺+l).

EXAMPLE 19

l- 3-r5-(1.2.4-Triazol-4-yl)-lH-indoI-3-vnpropyll-4-{(lS.2R)-r2-hvdroxy- l-methyl-2-phenyl]ethylamino}piperidine. 2.1 Hydrogen Oxalate. The oxalate salt was prepared from methanol-diethyl ether, mp 148-151°C. (Found: C, 56.36; H, 6.16; N, 12.58. Cn- NβO* 2.1(C2H₂O₄).0.1(C₄HιoO) requires: C, 56.39; H, 6.17; N, 12.49%). m/e (ES) 459 (M⁺+l).

EXAMPLE 20

l-(3-r5-(1.2.4-Triazol-4-ylVlH-indol-3-vnpropyll-4-^lR.2R)-r2-hvdroxy-l- methyl-2-phenyllethylaminolpiperidine. 2.4 Hydrogen Oxalate. 1.1 Hydrate.

The oxalate salt was prepared from methanol-diethyl ether, mp 125-128°C. (Found: C, 55.12; H, 6.47; N, 11.82. C27H34N6O.

2.4(C2H₂O₄) l.l H₂O 0.2(C₄HιoO) requires: C, 55.20; H, 6.11; N, 11.85%). δ (360MHz, DMSO-dβ) 0.94 (3H, d, J=6.6Hz), 1.76-2.24 (6H, ), 2.70-2.84 (4H, m), 2.86-2.98 (2H, m), 3.30-3.47 (4H, m), 4.51 (IH, d, J=9.0Hz), 7.28- 7.42 (7H, m), 7.50 (IH, d, J=8.6Hz), 7.81 (IH, d, J=2.0Hz), 9.03 (2H, s), 11.19 (IH, s); m/e (ES) 459 (M⁺+l).

EXAMPLE 21

l-{3-[5-(1.2.4-Triazol-4-vIVlH-indol-3-vnpropy -4-(f2-(4- acetylaminophenvDethyllaminolpiperidine. 2.4 Hydrogen Oxalate. Monohvdrate. a) 4-(Acetylamino^'_phenethylamine

To a cooled (0°C) and stirred solution of 4-aminobenzyl cyanide (2.38g, 18.04mmol) in anhydrous dichlorome thane (30ml) was added anhydrous triethylamine (7.54ml, 54.12mmol) followed by acetic anhydride (2.56ml, 27.06mmol) under nitrogen. The mixture was allowed to warm to room temperature and it was stirred for 18h before it was diluted with ethyl acetate (150ml) and -washed with 10% aqueous sodium bicarbonate (100ml), 2M hydrochloric add (50ml), brine (50ml), then dried (MgSO₄) and concentrated to give 4-(acetylamino)benzyl cyanide as an orange solid. The crude nitrile (2.8g) was dissolved in absolute ethanol (200ml) and chloroform (4ml) and it was hydrogenated at 50 psi over platinum (TV) oxide for 16h. The catalyst was filtered off, washed with ethanol and the filtrate was concentrated under vacuum. The residue was dissolved in 2M sodium hydroxide (30ml) and the product was extracted with dichloromethane (4 x 150ml), then dried (Na2SO₄) and concentrated. Flash chromatography of the residue (silica gel, dichloromethane/ methanol/ammonia, 85:15:1.5) gave 2.3g (80%) of the title compound as a yellow solid, δ (360MHz, CDCL.) 2.16 (3H, s), 2.71 (2H, t, J=6.8Hz), 2.94 (2H, t, J=6.8Hz), 7.14 (2H, d, J=8.3Hz), 7.26 (IH, br s), 7.41 (2H, d, J=8.3Hz).

b) l-{3-f5-(1.2.4-Triazol-4-vn-lH-indol-3-vnpropyl)-4-U2-(4- acetylaminophenvDethyllamino-Piperidine. 2.4 Hydrogen Oxalate. Monohvdrate.

The title compound was prepared from l-{3-[5-(l,2,4-triazol-4-yl)- lH-indol-3-yl]propyl}-4-ketopiperidine and 4-(acetylamino)phenylamine using a similar method to that described for Example 8 (step 5). Oxalate salt prepared from methanol-diethyl ether, mp 195-202°C. (Found: C, 54.87; H, 5.68; N, 13.83. C2₈H35N7O-2.4(C2H₂O4) 1.0 H₂O requires: C, 54.74; H, 5.85; N, 13.62%). δ (360MHz, DMSO-d₆) 1.70-1.86 (2H, m), 2.94-2.22 (5H, m and s), 2.60-2.94 (8H, m), 3.06-3.28 (3H, m), 3.34-3.44 (IH, m), 7.18 (2H, d, J=8.4Hz), 7.28-7.36 (2H, m), 7.46-7.56 (3H, m), 7.80 (IH, d, J=2.0Hz), 9.02 (2H, s), 9.92 (IH, s), 11.17 (IH, s); m/e (ES) 486 (M⁺+l).

EXAMPLE 22

l-<3-r5-(1.2.4-Triazol-4-yl)-lH-indol-3-vnpropyll-4-(r(R)-α-(methyl) benzylaminolmethyllpiperidine. Hydrogen Oxalate. 2.6 Hydrate.

a) 5-f4-(Hvdroxymethyl)piperidin-l-vnpentanal dimethyl acetal

To a cooled (0°C) and stirred suspension of isonipecotic add (25.83g, 200mmol), in anhydrous THF (100ml) was added lithium aluminium hydride (1M in THF; 200ml), under a nitrogen atmosphere. The reaction was allowed to attain room temperature and it was stirred for 18h, then refluxed for a further 4h. The reaction was quenched by sequential addition of water (7.5ml), 15% sodium hydroxide solution (7.5ml) and water (15ml). The reaction was filtered to remove a granular predpitate and the filtrate was concentrated under vacuum to give 11.24g of 4-(hydroxymethyl)piperidine as a colourless oil. The title compound was prepared from 5-chloropentanal dimethyl acetal (20.4g, 122mmol) and 4-(hydroxymethyl)piperidine (15.7g) using a similar method to that described for Example 8 (step 2). δ (360MHz, DMSO-dβ) 1.10 (2H, m), 1.28 (2H, m), 1.39 (2H, m), 1.48 (2H, m), 1.60 (2H, br d), 1.77 (2H, t). 2.20 (2H, t), 2.80 (2H, br d), 3.21 (8H, m), 4.31 (IH, t), 4.37 (IH, t).

b) l-{3-r5-(1.2.4-Triazol-4-ylVlH-indol-3-vnpropyl--4-(hvdroxymethyl) piperidine

The title compound was prepared from the preceding dimethyl acetal (18.64g, 76mmol) and 4'-(l,2,4-triazol-4-yl)phenyl hydrazine

(15.98g) using a similar method to that described for Example 8 (step 3). δ (250MHz, DMSO-dβ) 1.11 (2H, m), 1.30 (IH, m), 1.60 (2H, d), 1.80 (4H, m), 2.29 (2H, t), 2.70 (2H, t), 2.84 (2H, d), 3.22 (2H, t), 4.40 (IH, t), 7.26- 7.31 (2H, m), 7.46 (IH, d), 7.78 (IH, d), 9.02 (2H, s), 11.08 (lH, s).

c) l-(3-r5-(1.2.4-Triazol-4-yl)-lH-indol-3-vnpropyl}-4-(r(R)-α-

(methvDbenzylaminolmethyllpiperidine. Hydrogen Oxalate. 2.6 Hvdrate. To a solution of the preceding alcohol (0.5g, 1.48mmol) in a mixture of anhydrous dimethyl sulphoxide (20ml) and anhydrous triethylamine (755μl, 10.29mmol) was added portionwise, under nitrogen, sofid sulphur trioxide pyridine complex, (844mg, 5.3mmol). After 2 hours of stirring, the reaction was cooled to 0°C, quenched by dropwise addition of saturated aqueous potassium carbonate (5ml) and it was partitioned between water- butanol (30ml- 70ml). The organic phase was concentrated to 5ml under vacuum and diluted with methanol (10ml). Acetic add (506μl) and (R)- -methylbenzylamine (209μl, 1.62mmol) were added followed, after 10 minutes, by sodium cyanoborohydride (102mg). After 18h of stirring, the reaction was quenched with saturated aqueous potassium carbonate, volatiles removed in vacuo and the residue was partitioned between water- but an ol. The organic phase was concentrated and purified by flash chromatography (silica gel, dichloromethane/methanol ammonia, 92:8:1) to give 85mg of the title compound free base as a colourless solid. The oxalate salt was prepared and crystallised from methanol/diethyl/ether, mp 140°C. (Found: C, 59.86; H, 6.81; N, 14.37. C27H34N6*C__H2O-r2.6 H₂O requires: C, 59.90; H, 6.93; N, 14.45%). δ (360MHz, DMSO-dβ) 1.20 (2H, m), 1.39 (3H, d), 1.58 (IH, m), 1.76 (2H, brt), 1.92 (2H, m), 2.27-2.30(3H, m), 2.69- 2.72 (5H, m), 3.12-3.16 (2H, m), 3.97 (IH, d), 7.29-7.50 (8H,m), 7.78 (IH, d), 9.02 (2H, s), 11.16 (IH, s); m/e (ES) 443 (M⁺+l). HPLC analysis on a Chiralpak AD column, using hexane/ethanol diethylamine (25:75:0.1) as the mobile phase (UV detection at 280nm; flow lml/min; 40°C) showed the compound to have a retention time of 6.4min. EXAMPLE 23

l-(3-r5-(1.2.4-Triazol-4-ylVlH-indol-3-yllpropyl)-4-U(S)-α-(methyl) benzylaminolmethyllpiperidine. 1.5 Hydrogen Oxalate. Monohvdrate. The title compound was prepared using a similar procedure to that described for Example 22. The oxalate salt was prepared and recrystallised from methanol-diethyl ether, mp. 149-150°C. (Found:

C, 60.11; H, 6.92; N, 14.51. C27H₃4Ne l^'.5(C₂H₂O4) H₂0 requires: C, 60.49; H, 6.60; N, 14.11%). Other spectroscopic data identical to product from Example 22. HPLC analysis retention time = 8.3min (see Example 22 for conditions).

EXAMPLE 24

l-(3-r5-(1.2.4-Triazol-4-ylVlH-indol-3-vnpropyl}-4- (S)-l-(4- acetylaminophenvDethylaminolmethyllpiperidine. 2.0 Hydrogen Oxalate. 2.0 Hvdrate.

a) N-tβrf-Butyloxycarbonyl-(S)-l-(4-nitrophenyl)ethylamine To a suspension of (S)-l-(4-niμophenyl)ethylamine hydrochloride

(2.12g, 10.4mmol) in anhydrous dichloromethane (50ml) was added triethylamine (1.45ml). A solution of di-terf-butyldicarbonate (2.28g) in anhydrous dichloromethane (50ml) was added and the reaction allowed to stand for 18h. The reaction was washed with water, dried (MgSO₄), concentrated and purified by chromatography on silica gel using 1: 1 ethyl acetate:petroleum ether as eluant. The title compound was obtained as a yellow oil which crystallised slowly.

b) N-tert-Butyloxycarbonyl-(S)-l-(4-acetamidophenyl)ethylamine A solution of the product from above (2.96g) in ethyl acetate (100ml) was hydrogenolysed over PtO₂ (0.1 lg) at 15psi for 50 minutes in the presence of acetic anhydride (0.97ml). The catalyst was removed by filtration and washed with ethanol. The filtrate was concentrated to give the title compound, δ (250MHz, Dβ-DMSO) 1.26 (3H, d, J=10Hz), 1.35 (9H, s), 2.02 (3H, s), 4.54 (IH, m), 7.19 (2H, d, J=12.9Hz), 7.30 (IH, d, J=l 1.6Hz), 7.47 (2H, d, J=12.2Hz).

c) (SV l-(4-Acetamidophenyl)ethy1 am-jnp

The product from above (1.89g, β.βmmol) was dissolved in 90% formic add (5ml) and was stirred at room temperature, until all the starting material had reacted. The reaction was concentrated, basified with saturated potassium carbonate solution and extracted into butanol. The solvent was removed to give the title compound as a brown foam, which could be crystallised from methanol-ethyl acetate, δ (360MHz, Dβ-DMSO) 1.28 (3H, d, J=6.6Hz), 2.02 (3H, s), 4.03 (IH, m), 7.29 (2H, d, J=8.6Hz), 7.50 (2H, d, J=8.6Hz), 8.46 (2H, br s), 10.02 (IH, s).

d) l-<3-r5-(1.2.4-Triazol-4-ylVlH-indol-3-vnpropyl)-4-(r(S)-l-(4- acetylaminophenvDethylaminolmethyl-Piperidine. 2.0 Hydrogen Oxalate. 2.0 Hvdrate. The title compound was prepared from the amine described above using a similar procedure to that described in Example 22 (step 4). The oxalate salt was prepared and recrystallised from methanol-diethyl ether to give a hygroscopic solid; (Found: C, 55.41; H, 6.12; N, 13.38.

C29H37N₇O*2(C2H2O₄)*2 H₂O requires: C, 55.37; H, 6.33; N, 13.69%). δ (360MHz, Dβ-DMSO) 1.2-1.4 (2H, m), 1.44 (3H, d, J=6.7Hz), 1.8-2.0 (3H, m), 1.8-2.1 (5H, m), 2.37 (2H, m), 2.37-2.6 (2H, m), 2.7-2.9 (4H, m), 3.0-3.1 (2H, m), 3.3-3.5 (IH, m), 4.0-4.1 (IH, br s), 7.31-7.36 (4H, m,), 7.49-7.51 (IH, d, J=8.6Hz), 7.56-7.59 (2H, m), 7.80 (IH, s), 9.07 (2H, s), 10.01 (IH, s), 11.19 (IH, s); m/e (ES⁺) 450 (M+l)\ EXAMPLE 25

l-(3-r5-(1.2.4-Triazol-4-yl)-lH-indol-3-vnpropyn-4-(r(R)-l-(4- acetylaminophenv ethyllaminolpiperidine. 3.0 Hydrogen Oxalate. 1.2 Hvdrate.

The title compound was prepared from l-{3-[5-(l,2,4-triazol-4-yl)- lH-indol-3-yl]propyl}-4-ketopiperidine and (R)-l-(4-acetamidophenyl) ethylamine using a similar method to that decribed for Example 8 (step 5). The oxalate salt was prepared from methanol-diethyl ether, mp 135- 140°C. (Found: C, 52.51; H, 5.79; N, 12.59. C₂₈H₃₅N7θ*3.0(C₂H₂θ4)-

1.2 H₂O 0.2(C4HιoO) requires: C, 52.76; H, 5.78; N, 12.38%). δ (360MHz, Dβ-DMSO) 1.50 (3H, d, J=6.5Hz), 1.72-1.90 (2H, m), 1.92-2.20 (7H, m and s), 2.62-2.96 (7H, m), 3.32-3.44 (2H, m), 4.34-4.42 (IH, m), 7.29 (IH, s), 7.31 (IH, d, J=8.6Hz), 7.45 (2H, d, J=8.6Hz), 7.48 (IH, d, J=8.6Hz), 7.61 (2H, d, J=8.6Hz), 7.78 (IH, d, J=2.0Hz), 9.01 (2H, s), 10.6 (IH, s), 11.16 (IH, s); m/e (ES) 486 (M+l)⁺.

Examples 26-28 were prepared from the products of Examples 15, 16 and 21 using a similar method to that described for Example 10.

EXAMPLE 26

l-l3-r5-(1.2.4-Triazol-4-ylVlH-indol-3-vnpropyn-4-(N-r(RVα- (hvdroxymethyl)benzyll-N-methylamino-Piperidine. 2.0 Hydrogen Oxalate. 1.4 Hvdrate.

The oxalate salt was prepared from methanol-diethyl ether, mp 105-110°C. (Found: C, 56.13; H, 6.24; N, 12.34. C₂7H₃4N6θ*

2.0(C₂H2O₄) 1.4 H2O-O.KC.H10O) requires: C, 56.18, H, 6.28; N, 12.34%). δ (360MHz, DMSO-de) 1.78-2.08 (6H, m) 2.28 (3H, s), 2.70-3.06 (7H, m), 3.38-3.48 (2H, m), 3.72 (IH, dd, J=11.3 and 5.1Hz), 3.85 (IH, dd, J=11.3 and 6.1Hz), 4.01 (IH, m), 7.24-7.42 (7H, m), 7.49 (IH, d, J=8.5Hz), 7.79 (IH, d, J=2.0Hz), 9.01 (2H, s), 11.18 (IH, s); m/e (ES) 459 (M⁺ +1).

EXAMPLE 27

l-{3-r5-(1.2.4-Triazol-4-ylVlH-indol-3-vnpropyll-4-flSl-r(S)-α- (hvdroxymethyl)benzvn-N-metbγlaminolpipρridinp

2.9 Hydrogen Oxalate. Monohvdrate.

The oxalate salt was prepared from methanol-diethyl ether, mp 95-100°C. (Found: C, 53,37; H, 5.78, N, 11.49. C27H₃₄NβO* 2.9(C₂H₂O₄) 0.1(C4HιoO) requires: C, 53.52; H, 5.79; N, 11.28%). m/e (ES) 459 (M⁺ +1).

EXAMPLE 28

l-<3-r5-(1.2.4-Triazol-4-yl)-lH-indol-3-yllpropyll-4-(N-f2-(4- acetylaminophenyl)ethyl1-N-methylamino}piperidine. 3.0 Hydrogen Oxalate. 1.1 Hvdrate.

The oxalate salt was prepared from methanol-ether, mp 128-135°C. (Found: C, 53.36; H, 6.01; N, 12.19. C2βH3sN7θ*3.0(C2H2θ₄)* l.l H₂O- 0.2(C₄HιoO) requires: C, 53.45; H, 5.91; N, 12.19%). δ (360MHz, DMSO-dβ) 1.80-2.12 (9H, m), 2.62 (3H, s), 2.70-2.90 (6H, m), 2.91-3.01 (2H, m), 3.03-3.12 (2H, m), 3.18-3.30 (IH, m), 3.39-3.52 (2H, m), 7.16-7.22 (2H, m), 7.29-7.36 (2H, m), 7.46-7.54 (3H, m), 7.80 (IH, d, J=2.0Hz), 9.02 (2H, s) 9.89 (IH, s), 11.18 (IH, s); m/e (ES) 500 (M^* +1). EXAMPLE 29

l-^3-r5-(1.2.4-Triazol-4-ylVlH-indol-3-vnpropyll-4-{rN-(4- arptγ1aminobenzyl)-N-methylamino]methyllpiperidinp 3.7 Hydrogen Oxalate.

a) l-(3-r5-(1.2.4-Triazol-4-yl)-lH-indol-3-yllpropyll-4-r(N- ^Vι γ| ^τηiτι n)methvnpiperidine

A solution of the product from Example 12 (free base; 730mg) in absolute ethanol (60ml) was hydrogenated over 20% Pearlman's catalyst (500mg) for 24h at 4δpsi. The catalyst was filtered off, washed with ethanol (3 x 30ml) and the filtrate was concentrated under vacuum to give 573mg (99%) of the title compound as a yellow foam; m/e (ES) 363 (M^* +1).

b) l- -r5-(1.2.4-Triazol-4-ylVlH-indol-3-yllpropyU-4- rN-(4- acetylaminobenzylVN-methylaminolmethyllpiperidine. 3.7 Hydrogen Oxalate.

The title compound was prepared from the product of the preceding step and 4-acetamidobenzaldehyde using a similar method to that described for Example 10. The oxalate salt was prepared, mp lδ5-16δ°C.

(Found: C, 52.57; H, 5.47; N, 11.78. C29H₃ N7θ*3.7(C2H2θ₄) requires: C, 52.50; H, 5.37; N, 11.77%). δ (360MHz, DMSO-dβ) 1.23-1.42 (2H, m), 1.85-2.10 (8H, m and s), 2.39 (3H, s), 2.50-2.62 (2H, m), 2.72-2.96 (4H, m), 3.00-3.10 (2H, m), 3.36-3.54 (2H, m), 3.82 (2H, s), 7.28-7.36 (4H, m), 7.50 (IH, d, J=8.6Hz), 7.58 (2H, d, J=8.4Hz), 7.80 (IH, d, J=2.0Hz). 9.02 (2H, s), 10.01 (IH, s), 11.19 (IH, s); m/e (ES) 500 (M⁺ +1). EXAMPLE 30

l-(3-r5-(1.2.4-Triazol-4-yl)-lH-indol-3-vnpropyll-4-{N-r(thiophen-2- yl)methyll-N-methylaminolpiperidine. 2.0 Hydrogen Oxalate. δ Monohvdrate.

a) l-Benzyl-4-(N-ter^butyloxycarbonyl-N-methylaminotoineridinp

To a cooled (0°C) and stirred solution of l-benzyl-4-aminopiperidine (lOOg, 0.63mol) in anhydrous dichloromethane (500ml) was added a 0 solution of di-tert-butyldicarbonate (126g) in anhydrous dichloromethane (500ml). The reaction was allowed to attain room temperature and stirred overnight. Concentration and trituration with diethyl ether gave l-benzyl-4-(N-tert-butyloxycarbonylamino)piperidine.

To a cooled (-6°C) and stirred solution of lithium aluminium 5 hydride (IM in THF; 258ml) in anhydrous tetrahydrofuran (250ml) was added a solution of the above amine (50 g, 172mmol) in anhydrous tetrahydrofuran (750ml) over 20 minutes under nitrogen. The reaction mixture was then refluxed for 2.5 hours, cooled to room temperature and quenched by addition of water (10ml), 15% aqueous sodium hydroxide 0 (15ml) and water (30ml). The resulting mixture was filtered to remove a granular predpitate and the filtrate was cooled to 0°C before άi-tert- butyldicarbonate (41.3g) was added. After 2 hours at room temperature, the solvent was removed under vacuum and the residue was partitioned between 2N aqueous sodium hydroxide and dichloromethane. The organic 25 phase was washed with brine, dried (Na2SO₄) and concentrated. Flash chromatography of the residue (silica gel, dichloromethane/methanol ammonia, 89:10:1) gave the title compound, δ (250MHz, DMSO-dβ) 1.38- 1.49 (12H, m and s), 1.66 (2H, m), 1.94 (2H, m), 2.65 (3H, s), 2.90 (2H, br d), 3.44 (2H, s), 7.19-7.35 (5H, m). 30 b) 5-[4-(N-t6rf-Butyloxycarbonyl-N-methylamino)piperidin-l- yllpentanal dimethyl acetal

A solution of the preceding benzylic amine (δg, 16.4mmol) in methanol (100ml) was hydrogenolysed over 10% palladium hydroxide (lg) at 50psi for 18 hours. The catalyst was filtered off and the filtrate was concentrated to give 4-(N-ter<-butyloxycarbonyl-N-methylamino) piperidine as a colourless oil.

The title compound was prepared from the above amine and

6-bromopentanal dimethyl acetal using a similar method to that described for Example 8 (Step 2). δ (360MHz, CDCla) 1.34 (IH, m), 1.46-1.73 (19H, m and s), 1.98 (2H, m), 1.33 (2H, m), 2.73 (3H, s), 2.99 (2H, m), 3.31 (6H, s), 4.36 (IH, t).

c) l-{3-r5-(1.2.4-Triazol-4-ylVlH-indol-3-yllpropyll-4-(N- methylamino)piperidine

The preceding acetal was reacted in a similar manner to that described in Example 11 (Step 3) to give the title compound as a brown foam, δ (360MHz, DMSO-dβ) 1.16-1.24 (3H, m), 1.73-1.90 (6H, m), 2.25 (6H, m), 2.70 (2H, t), 2.78 (2H, m), 7.28 (2H, m), 7.46 (IH, d), 7.77 (IH, d), 9.01 (2H, s), 11.08 (lH, s).

d) l-(3-r5-(1.2.4-Triazol-4-ylVlH-indol-3-yllpropyU-4-(N-r(thiophen-2- vDmethvn-N-methylamino-Piperidine. 2.0 Hydrogen oxalate. Monohvdrate. To a solution of the preceding amine (390mg, 1. lδmmol), acetic add

(0.2ml) and thiophen-2-carboxaldehyde (0.12ml) in anhydrous ethanol (10ml) was added sodium cyanoborohydride (80mg). The reaction was allowed to stir under a nitrogen atmosphere for 18h. The reaction was quenched by addition of saturated aqueous K2CO3 solution, concentrated to remove the ethanol, and extracted with butanol. Concentration and purification of the residue by chromatography on silica gel using methanol dichloromethane/ammonia (10:90:1) as eluant gave the title compound free base (306mg). The oxalate salt was prepared and crystallised from methanol-diethyl ether, m.p. 132-135°C, (Found: C, 53.31; H, 5.64; N, 12.59. C24H3oNβS*2(C2H₂O₄)*H2θ*0.2(C₄HιoO) requires: C, 53.42; H, 5.91; N, 12.98%). δ (360MHz, D₂O) 2.00-2.20 (4H, m), 2.18-2.50 (2H, m), 2.82 (3H, s), 2.84-2.90 (2H, m), 3.0-3.10 (2H, m), 3.10-3.20 (2H, m), 3.60-3.80 (3H, m), 4.66 (2H, s), 7.16-7.18 (IH, m), 7.30- 7.36 (3H, m), 7.61-7.65 (2H, m), 7.75 (IH, s), 8.88 (2H, s); m/e (ES^*) 435

(M+ n*

EXAMPLE 31

l- 3-r5-(1.2.4-Triazol-4-vD-lH-indol-3-vnpropyl>-4- r(R)-α-(hvdroxymethyl) benzylamino]methyllpiperidine. 1.5 Hydrogen Oxalate. Dihvdrate. The title compound was prepared from l-{3-[5-(l,2,4-triazol-4-yl)- lH-indol-3-yl]propyl}-4-(hydroxymethyl)piperidine and (R)-2- phenylglycinol using a similar method to that described for Example 22 (Step 4). The oxalate salt was prepared and recrystallised from methanol- diethyl ether, mp 143-145°C. (Found: C, 56.83; H, 6.92; N, 13.49. C27H34N6O I.5 (C2H₂O₄)-2.0 H2O requires: C, 57.22; H, 6.56; N, 13.35%). δ (360MHz, DMSO-dβ) 1.26 (2H, m), 1.61 (IH, m), 1.73 (IH, m), 1.88 (IH, m), 1.97 (2H, m), 2.37 (IH, m), 2.49 (IH, m), 2.60 (2H, m), 2.74 (2H, t), 2.87 (2H, m), 3.25 (2H, m), 3.41 (IH, m), 3.50 (IH, m), 3.75 (IH, m), 7.26- 7.36 (7H, m), 7.49 (IH, d), 7.79 (IH, d), 9.01 (2H, s), 11.17 (IH, s); m/e (ES) 459 (M^* +1).

EXAMPLE 32

(3SV3-(4-(Acetylamino)benzylamino)methyl-l-f2-(5-(1.2.4-triazol-4-yl)-lH- indol-3-yr.ethyripyrrolidine. 2.6 Hydrogen Oxalate. 0.1 Hvdrate. a) (3SV3-Aminomethyl-l-f2-(5-(1.2.4-triazol-4-yl)-lH-indol-3- vDethvnpyrrolidine

A mixture of (3S)-3-(N-benzyl)aminomethyl-l-[2-(5-(l,2,4-triazol- 4-yl)-lH-indol-3-yl)ethyl]pyrrolidine (Example 7; 0.277g, 0.639mmol), ammonium formate (0.218g, 3.46mmol) and 10% Pd-C (0.28g), in anhydrous methanol (20ml) was stirred at 62°C for 0.75h. The mixture was cooled to 25°C and the catalyst removed filtration through celite. The solvent was removed under vacuum and the residue chromatographed on silica gel eluting with CHuCLz MeOH NHs (20:8: 1) to give the title compound (0.145g, 68%), δ (250MHz, CDCls) 1.48-1.59 (IH, m, CH of Clfc), 2.03-2.14 (IH, m, CH of CH₂), 2.29-2.41 (2H, m, 2 of CH), 2.63-3.02 (9H, m, 4 of CH2 and CH), 7.14 (IH, dd, J=2.1 and 8.6Hz, Ar-H), 7.21 (IH, s, Ar-H), 7.49 (IH, d, J=8.6Hz, Ar-H), 7.60 (IH, d, J=2.1Hz, Ar-H), 8.54 (2H, s, Ar-H).

b) (3S)-3-(4-Acetylamino)benzylamino)methyl-l-r2-(5-(1.2.4-triazol-4- yl)-lH-indol-3-yl)ethvnpyrrolidine. 2.6 Hydrogen Oxalate. 0.1 Hvdrate.

To a solution of the preceding aminomethyl pyrrolidine (0.14g, 0.452mmol) in ethanol (10ml) was added p-acetamidobenzaldehyde (0.074g, 0.452mmol) and the mixture stirred at 25°C for 16h. Sodium borohydride (17mg, 0.456mmol) was added and the solution stirred for lh. The solvent was removed under vacuum and the residue was taken up into H2O and addified with 2N HCI. The mixture was then basified with saturated K2CO3 solution and extracted with ethyl acetate (x4). The combined organic extracts were washed with brine, dried (Na2SO₄) and evaporated. The residue was chromatographed on silica gel eluting with CHjC MeOH/NHs (70:8: 1) to give the title product (73mg, 35%). The 2.6 hydrogen oxalate 0.1 hydrate salt was prepared, mp 197-199°C. (Found: C, 54.22, H, 5.50, N, 14.12. C2βH3iN7θ*2.6(C2H₂θ4) 0.1 H2O requires C, 54.04; H, 5.29; N, 14.14%), m/e 458 (M+l)^*. δ (250MHz, DcDMSO) 1.66-1.86 (IH, m, CH of CH₂), 2.05 (3H, s, NHAc), 2.12-2.26 (IH, m, CH of CH₂), 2.62-3.58 (11H, m, 5 of CH₂ and CH), 4.06 (2H, s, CHJNH), 7.34-7.42 (4H, m, Ar-H), 7.52 (IH, d, J=8.6Hz, Ar-H), 7.61 (2H, d, J=8.4Hz, Ar-H), 7.90 (IH, d, J=2.0Hz, Ar-H), 9.05 (2H, s, Ar-H), 10.08 (IH, s, NH), 11.30 (IH, s, NH).

EXAMPLE 33

(3RV3-(N-Benzyl)aminomethyl-l-f2-(5-(1.2.4-triazol-4-yl)-lH-indol-3- vDethyllpyrrc-lidin?. 2.5 Hydrogen Oxalate. 0.5 Etherate.

Prepared from (3S)-N-[(R)-l-phenethyl]-3-(hydroxymethyl)pyrrohdine (J. Med. Chem., 1990, 33 (1), 71) and Intermediate 3 using the procedures described for Examples 2 and 7. The 2.5 hydrogen oxalate 0.5 etherate salt was prepared, mp 230-232°C. (Found: C, 55.88; H, 6.02; N. 12.94. C₂₄H2βN6-2.5(C₂H₂θ4) 0.5(Et2θ) requires C, 56.18; H, 5.78; N, 12.68%), m/e 401 (M+D^*. δ (360MHz, Dβ-DMSO) 1.70-1.84 (IH, m, CH of CH∑), 2.14- 2.26 (IH, m, CH oi CHz), 2.68-3.60 (11H, m, 5 of CH₂ and CH), 4.13 (2H, s, CHjfin), 7.35-7.54 (8H, m, Ar-H), 7.90 (IH, s, Ar-H), 9.04 (2H, s, Ar-H), 11.30 (lH. s. NH).

EXAMPLE 34

(3SV3-(4-(Pyridyl)methyl')aminomethyl-l-r2-(5-(1.2.4-triazol-4-yl)-lH- indol-3-yl)ethyr|pyrrolidine. 3.0 Hydrogen Oxalate. 0.7 Hvdrate. 0.2 Etherate.

a) (3S)-N(H)-3-(4-(Pyridyl^')methyl)aminomethyl pyrrohdine

Prepared from (3R)-N-tert-butyloxycarbonyl-3- methylsulphonyloxymethylpyrrolidine and 4-aminomethyl pyridine using the procedures described for Example 5, parts b and c. δ (250MHz,

D..-MeOH) 1.33-1.46 (IH, m, CH of CH₂), 1.88-2.04 (IH, m, CH of CH₂), 2.21-3.05 (7H, m, 3 of CH₂ and CH), 3.83 (2H, s, CH₂-pyridyl), 7.42-7.45 (2H, m, Ar-H), 8.45-8.48 (2H, m, Ar-H).

b) (3S)-3-(4-(PyridvI)methyl)aminomethyl-l-f2-(5-(1.2.4-triazol-4-yl)- lH-indol-3-yl)ethvnpyrrohdi_ne, 3 0 Hydrogen Oxalate. 0.7 Hvdrate. 0.2 Etherate.

Prepared from Intermediate 3 and the preceding N(H)-pyrrolidine using the procedure described for Example 2. The 3.0 hydrogen oxalate 0.7 hydrate 0.2 etherate salt was prepared, mp 213-215° C. (Found: C, 51.00; H, 5.15; N, 13.73. C₂3H₂7N7-3.0(C₂H2O₄) 0.7 H₂O*0.2(Et2θ) requires C, 51.20; H, 5.25; N, 14.03%); m/e 402 (M+l)⁺. δ (360MHz, Dβ-DMSO) 1.70-1.84 (IH, m, CH of CH2), 2.14-2.26 (IH, m, CH of CH2), 2.66-2.80 (IH, m, CH of CH2), 2.94-3.62 (10H, m, 4 of CH2 and 2 of CH), 4.12 (2H, s, CH₂-pyridyl), 7.36 (IH, dd, J=1.8 and 8.6Hz, Ar-H), 7.40 (IH, s, Ar-H), 7.49 (2H, d, J=5.7Hz, Ar-H), 7.53 (IH, d, J=8.6Hz, Ar-H), 7.90 (IH, d, J=1.8Hz, Ar-H), 8.61 (2H, d, J=5.7Hz, Ar-H), 9.04 (2H, s, Ar-H), 11.30 (lH. s. NH).

EXAMPLE 35

3-(N-Benzv aminomethyl-l-f2-(5-(1.2.4-triazol-4-yl)-lH-indol-3- vDethyriazetidine. 2.0 Hydrogen Oxalate. Hemihvdrate.

a) N-te -Butyloxycarbonylazetidin-3-ol A suspension of azetidin-3-ol hydrochloride (J. Chem. Soc, Chem.

Commun., 1968, 93; 18.4g, 168.1mmol), (Boc)₂O (56g, 256.6 mmol) and NEts (52ml, 373mmol), in anhydrous THF (1000ml) was stirred at room temperature for 16h. The solvent was removed under vacuum and the residue partitioned between EtOAc (260ml) and H2O (200ml). The aqueous was further extracted with EtOAc (3 x 200ml). The combined extracted were dried (Na2S0₄) and evaporated and the crude product was chromatographed on silica gel eluting with CHj-C MeOH (95:5→90:10) to give the title product (16.9g, 58%). δ (250MHz, CDCls) 1.43 (9H, s, (Me)₃), 3.28 (IH, br s, OH), 3.77-3.83 (2H, m, CH₂), 4.10-4.17 (2H, m, CH₂), 4.50- 4.62 (IH, m, CH).

b) N-te^Butyloxycarbonyl-S-cvflnnflttp ft"*?

Methane sulphonyl chloride (4.7ml, 60mmol) was added slowly to a stirred solution of the preceding alcohol t7.0g, 40mmol) in dry pyridine (40ml) at +20°C. The mixture was stirred for 4h and the solvent then removed under vacuum. The residue was partitioned between EtOAc/H∑O and the aqueous was extracted with EtOAc (x2). The combined extracts were dried (Na₂SO4) and evaporated to give the desired mesylate (10.2g, 100%). A mixture of the mesylate (2.5g, lOmmol) and tetra-n- butylammonium cyanide (8.0g, 30mmol), in anhydrous toluene (80ml) was heated at reflux for 64h. The mixture was cooled to room temperature and partitioned between EtOAc H₂O. The aqueous was extracted with EtOAc (x2), the combined extracts dried (Na∑SO and evaporated and the residue chromatographed on silica gel eluting with 40% EtO Ac/petroleum ether to give the title nitrile (1.15g, 80%). δ (250MHz, CDCI3) 1.45 (9H, s (Me)₃), 3.33-3.46 (IH, m, CH), 4.11-4.25 (4H, m, 2 of CH2).

c) N-tert-Butyloxycarbonyl-3-formylazetidine

Dϋsobutyl aluminium hydride (39.8ml of a 1.0M solution in toluene, 39.8mmol) was added slowly to a stirred solution of the preceding nitrile (3.63g, 19.9mmol), in anhydrous THF (100ml), at 0°C. The mixture was allowed to warm to room temperature and stir for 2h. The reaction was quenched by addition of EtOAc (40ml) and aqueous NH4CI (40ml) and partitioned between EtOAc H2θ. The aqueous was further extracted with EtOAc (x3) and the combined extracts were dried (Na₂SO₄) and evaporated. The residue was purified by chromatography on silica gel eluting with 65% EtOAc/petroleum ether to give the desired aldehyde (1.35g, 37%). δ (250MHz, CDCI3) 1.45 (9H, s, (Me)₃), 3.30-3.42 (IH, m, CH), 4.05-4.17 (4H, m, 2 of CH2), 9.85 (IH, d, J=2.1Hz, CHO).

d) N-(lH)-3-(Benzylamino)methyl azetidine 5 Sodium cyanoborohydride (1.15g, 18.3mmol) was added to a solution of benzylamine (1.04ml, 9.5mmol) and gladal acetic add (2.10ml, 36.7mmol), in dry methanol (150ml), at room temperature. The solution was cooled to 0°C and a solution of the^'preceding aldehyde (1.35g, 7.3mmol), in methanol (50ml), was added. The mixture was warmed to 10 room temperature and stirred for 20h. The volatiles were removed in vacuo and the residue partitioned between EtOAc/aq. K2CO3. The aqueous was extracted with EtOAc (x3) and the combined extracts dried and evaporated. The crude product was chromatographed on silica gel eluting with CH∑C-U/MeOH (95:5→92:8) to give the desired N-benzylaminoazetidine lδ (l.δg, 73%). A mixture of formic add (99%, 18ml) and H₂O (2ml) was added to N-fert-butyloxycarbonyl-3-(benzylamino)methyl azetidine (l.δg, δ.3mmol) at 0°C. The mixture was warmed to room temperature, stirred for 16h, and the solvent then removed under vacuum. Saturated aqueous K2CO3 (25ml) was added to the residue and extracted with "BuOH 20 (5 x 25ml). The combined extracts were evaporated and the residue treated with CH2CI2 (50ml) and filtered to remove inorganics. The filtrate was dried (Na2SO ) and evaporated to give the title compound (0.512g, 55%). δ (360MHz, CDCI3) 2.85 (2H, s, CH2PI1), 3.36-3.39 (IH, m, CH), 3.57-3.72 (4H, m, 2 of CH2), 3.79 (2H, s, CH₂), 7.23-7.34 (5H, m, Ar-H). 25 e) 3-(N-Benzvnaminomethyl-l-f2-(5-(1.2.4-triazol-4-yl)-lH-indol-3- vDethyll azetidine. 2.0 Hydrogen Oxalate. Hemihvdrate.

Methane sulphonyl chloride (360μL, 4.65mmol) was added to a stirred suspension of 2-[5-(l,2,4-triazol-4-yl)-lH-indol-3-yl]ethyl alcohol 30 (Intermediate 3; 0.7g, 3.07mmol) in dry pyridine (17ml), at -20°C. The mixture was stirred at this temperature for 0.25h and then warmed to room temperature and stirred for 16h. The reaction mixture was quenched by addition of H2O (50ml) and then extracted with EtOAc (50ml) and CH2CI2 (2 x 50ml). The combined extracts were dried (Na_jSO4) and evaporated and the residue purified by chromatography on silica gel eluting with C^Cla/MeOH (9: 1) to give the desired mesylate (0.δ9g, 63%). The mesylate (0.39g, 1.2mmol) was added to a stirred suspension of N-(lH)-3-(benzylamino) methylazetidine (0.269g, 1.63mmol), K2CO3 (0.49g, 3.δ5mmol) and Nal (0.18g, 1.20inmol), in IPA (40ml). The mixture was heated at reflux for 18h, cooled to room temperature and the solvent removed in vacuo. The residue was partitioned between CH2CI2/H2O and the aqueous further extracted with CH₂C1_. (x3). The combined extracts were dried (Na2SO₄) and evaporated and the residue chromatographed on silica gel eluting with C^C MeOH/NHs (60:8:1) to give the title product (0.135g, 27%). The 2.0 hydrogen oxalate hemihydrate salt was prepared, mp 156-168°C. Found: C, 56.98; H, 5.50; N, 14.40.

0.5 H2O requires C, 56.34; H, 5.43; N, 14.60%); m e 387 (M+l)\ δ (360MHz, Dβ-DMSO) 2.80-3.22 (5H, m, 2 of CH₂ and CH), 3.36-3.44 (2H, m, CH2), 3.76-3.86 (2H, m, CH2), 3.98-4.08 (4H, m, 2 of CH2), 7.28-7.48 (7H, m, Ar-H), 7.52 (IH, d, J=8.7Hz, Ar-H), 7.89 (IH, d, J=1.8Hz, Ar-H), 9.04 (2H, s, Ar-H), 11.31 (IH, s, NH).

EXAMPLE 36

4-Benzyl-4-hvdroxy-l-r3-(5-(1.2.4-triazol-4-yl)-lH-indol-3- vDpropyl-piperidine. Hydrogen Oxalate.

a) 3-r5-(1.2.4-Triazol-4-yl)-lH-indol-3-yl1propan-l-ol

A solution of 4'-(l,2,4-triazol-4-yl)phenylhydrazine (25g, 143mmol) in dioxan (250ml) was treated with dihydropyran (24g, 286mmol) followed by IM hydrochloric add (150ml) and heated at reflux for 18h. The reaction mixture was evaporated, treated with toluene then re-evaporated. Inorganic solids were removed by treating the residue with a mixture of methanol and acetonitrile. The mother liquors were purified by column chromatography on silica using dichloromethane/methanol (9: 1=→4: 1) as the eluant. The compound was recrystallised from acetonitrile to afford the title compound as a colourless solid (10.24g, 30%); mp 205-207°C.

(Found: C, 64.37; H, 5.76; N, 22.83. C13H14N4O requires C, 64.45; H, 5.82; N, 23.13%.) δ (360MHz, dβ-DMSO) 1.81 (2H, q, J=7Hz, CH.), 2.75 (2H, t, J=8Hz, CH2), 3.46 (2H, dt, Jι=6, J₂=5Hz CH.), 4.43 (IH, t, J=5Hz, OH), 7.26 (IH, d, J=2Hz, Ar-H), 7.29 (IH, dd, Jι=9, J₂=2Hz, Ar-H), 7.47 (IH, d, J=9Hz, Ar-H), 7.77 (IH, d, J=2Hz, Ar-H), 9.01 (2H, s, triazole-H), 11.05 (IH, br s, indole NH). MS, CT, m z=243 for (M+H)⁺.

b) 4-Benzyl-4-hvdroxy- ir3-(5-(1.2.4-triazol-4-yl)- lH-indol-3-

A fine suspension of the preceding indole (300mg, 1.24mmol), stirred under a nitrogen atmosphere in anhydrous tetrahydrofuran (30ml) was treated with triethylamine (0.35ml, 2.48mmol) followed by methanesulphonyl chloride (0.2ml, 2.48mmol). The reaction mixture was stirred at ambient temperature for 1.5h, filtered, then evaporated to dryness. The residue was partitioned between dichloromethane (40ml) and water (30ml). The organic layer was separated, washed with water (30ml), then dried (sodium sulphate) and evaporated to dryness to give the mesylate as a dark yellow semi-solid. The mesylate was dissolved in propan-2-ol (70ml) then treated with potassium carbonate (514mg, 3.72mmol) and 4-benzyl-4-hydroxypiperidine (712mg, 3.72mmol) and heated at reflux, with stirring, for 24 hours. The reaction mixture was evaporated to dryness, the residue partitioned between dichloromethane (50ml) and water (30ml). The organic layer was separated, washed with water (30ml), dried (potassium carbonate) then evaporated to give an orange gum which was purified by column chromatography on silica using dichloromethane/methanol ammonia (20:1:0.1 to 8:1:0.1) to afford the title product free base as a viscous colourless gum (302mg, 59%). The hydrogen oxalate salt had mp 117-119°C (propan-2-ol ethanol (2:1)).

(Found: C, 62.05; H, 6.22; N, 12.17. C₂sH₂9N₆O 1.3(C₂H₂O )* 0.4(CH3)₂CHOH requires C, 62.15; H, 6.30; N, 12.58%.) δ (360MHz, dβ-DMSO) 1.55 (2H, d, J=12Hz, CHu), 1.74 (2H, dd, Jι=J₂=12Hz, CH2), 1.98-2.05 (2H, m, CH₂), 2.72-2.75 (4H, m, £H₂-indole and CIΪ2-phenyl), 2.96-3.10 (4H, m, 2 x CH₂), 3.20-3.32 (2H, m, CH₂), 7.20-7.33 (7H, m, Ar-H), 7.49 (IH, d, J=8Hz, Ar-H), 7.79 (iH, d, J=2Hz, Ar-H), 9.01 (2H, s, triazole-H), 11.19 (IH, s, indole-NH); MS, ES⁺, m/e=416 for (M+H)⁺ of free base.

EXAMPLE 37

3-(N-BenzvDaminomethyl- l-r3-(5-(1.2.4-triazol-4-ylV lH-indol-3- vDpropyll azetidine. 2.0 Hydrogen Oxalate. 0.1 Etherate. Monohvdrate. Prepared from 3-(5-[l,2,4-triazol-4-yll-lH-indol-3-yl)propan-l-ol and N-(lH)-3-(benzylamino)methyl azetidine as exemplified for Example 35. The 2.0 hydrogen oxalate 0.1 etherate monohydrate salt was prepared, mp 151-154°C. (Found: C, 56.61; H, 6.06; N, 13.57. C24H2βN6*2(C₂H₂O₄)*0.1(Et2θ) 1.0 HaO requires C, 56.29; H, 5.82;

N, 13.87%), m/e 401 (M+l)⁺. δ (360MHz, dβ-DMSO) 1.74-1.88 (2H, m, CH2), 2.75 (2H, t, J=7.5Hz, CH2), 2.98-3.14 (5H, m, CH and 2 of CH2), 3.77 (2H, t, J=7.5Hz, CH2), 3.96-4.06 (4H, m, 2 of CH2), 7.31-7.44 (7H, m, Ar-H), 7.50 (IH, d, J=8.5Hz, Ar-H), 7.80 (IH, d, J=1.6Hz, Ar-H), 9.02 (2H, s, Ar-H), 11.18 (lH. s. NH).

EXAMPLE 38

4-(Benzylamino)methyl-4-hvdroxy-l-f3-f5-(1.2.4-triazol-4-yl)-lH-indol-3- yllpropyllpiperidine a) l-Benzyl-4-hvdroxy-4-(terf-butyloxycarbonylamino)methyl piperidine

To a stirred solution of 4-aminomethyl-l-benzyl-4-hydroxy piperidine (Synth. Commun., 1994, 24 (10), 1483) (llg, 50mmol) in dichloromethane (300ml) was added di-tert-butyldicarbonate (llg,

50mmol). The solution was stirred overnight at ambient temperature, and then quenched with 10% aqueous potassium carbonate (150ml). The organic layer was decanted, dried (sodium sulphate) and evaporated under high vacuum. The residue was purified by column chromatography on silica, using dichloromethane/methanol as eluant, to afford the title compound (11.6g, 70%), mp 109-112°C. δ (250MHz, dβ-DMSO) 1.16-1.47 (4H, m, 2 of CH₂), 1.27 (9H, s, OC(Me)₃), 2.09-2.26 (2H, m, CH.), 2.29-2.44 (2H, m, CH*), 2.80 (2H, d, J=6Hz, CH₂), 3.25 (2H, s, CH₂), 4.09 (IH, s, OH), 6.49 (IH, t, J=6Hz, NH), 7.08-7.26 (5H, m, Ar-H). MS, m e=321 for (M+H)\

b) 4-Hvdroxy-4-(tert-butyloxycarbonylamino)methγ1 pipfriφ f

To a solution of the foregoing amine (12.5g, 39mmol) in methanol (300ml) was added 10% palladium on carbon (2.5g) in methanol (20ml), and ammonium formate (7g, llmmol). The suspension was stirred at ambient temperature for 3h, then the catalyst filtered off and washed with methanol. The solvent was evaporated in vacuo and the residue triturated with dichloromethane. The resulting solid was dissolved in saturated aqueous potassium carbonate and extracted with dichloromethane (12x). The combined organics were dried (sodium sulphate) and evaporated to give the required product as a solid (7g, 78%) mp 136-138°C. δ (360MHz, dβ-DMSO) 1.22-1.48 (4H, m, 2 of CH₂), 1.38 (9H, s, OC(Me)₃), 2.52-2.62 (2H, m, CH₂), 2.62-2.76 (2H, m, CH₂), 2.88 (2H, d, J=6Hz, CH₂), 4.12 (IH, s, OH), 6.49 (IH, t, J=6Hz, NH). MS, m/e=231 for (M+H)\ c) 4-(terf-Butyloxycarbonylamino)methyl-4-hvdroxy-l-f3-(5-(1.2.4- triazol-4-vD- lH-indol-3-yllpropyl piperidine

The title compound was obtained (2.7g, 60%) from the compounds in steps a and b, as described in Example 36; mp 86°C (sintered). (Found:

5 C, 60.43; H, 7.79; N, 16.95.

requires

C, 60.33; H, 7.81; N, 17.31%. δ (250MHz, dβ-DMSO) 1.26-1.56 (4H, m, 2 of CH*), 1.37 (9H, s, OC(Me)₃), 1.72-1.90 (2H, m, CH₂), 2.14-2.54 (6H, m, 3 of CH₂), 2.70 (2H, t, J=7Hz, CH₂), 2.89 (2H, d, J=6Hz, CH₂), 4.15 (IH, s, OH), 6.56 (IH, br t, NH), 7.25-7.32 (2H, m, Ar-H), 7.47 (IH, d, J=8Hz, Ar-H), 0 7.77 (IH, d, J=2Hz, Ar-H), 9.02 (2H, s, Ar-H), 11.08 (IH, s, NH); MS; m/e=455 for (M+H)⁺.

d) 4-Aminomethyl-4-hvdroxy-l-f3-f5-(1.2.4-triazol-4-yl)-lH-indol-3- yllpropyπpiperidine lδ To a solution of the preceding product (2.δg, δ.δmmol) in dichloromethane (50ml) was added trifluoroacetic add (4.2ml, δδmmol). The mixture was stirred overnight at ambient temperature then further trifluoroacetic add (4.2ml, δδmmol) was added and the mixture stirred 1.5 hours at 35°C. The solvent and excess reagent were evaporated 20 in vacuo, and the residue dissolved in a minimum of methanol and washed with diethyl ether (2 x 10ml). The methanol was evaporated in vacuo and the residue partitioned between 10% aqueous potassium carbonate and n-butanol. The aqueous was re-extracted with n-butanol (3x). The combined organics were evaporated to dryness and the low 25 melting solid used crude in the next reaction. MS, m/e=355 for (M+H)⁺. δ (250MHz, dβ-DMSO) 1.32-1.50 (4H, m, 2 of CH₂), 1.72-1.88 (2H, m, CH₂), 2.17-2.36 (4H, m, 2 of CH₂), 2.36-2.55 (2H, m, CH₂), 2.34 (2H, s, CH₂), 2.70 (2H, t, J=7Hz, CH₂), 7.24-7.32 (2H, m, Ar-H), 7.48 (IH, d, J=8Hz, Ar-H), 7.78 (IH, d, J=2Hz, Ar-H), 9.02 (2H, s, Ar-H), 11.21 (IH, s, NH). 30 e) 4-(Benzylamino)methyl-4-hvdroxy- 1 - [3- [5-(l .2.4-triazol-4-vD- 1H- indol-3-yllpropynpiperidine

To a stirred solution of the foregoing amine (400mg, l.lmmol) in methanol (10ml) was added benzaldehyde (lOOμl, lmmol), gladal acetic add (lOOμl, 1.7mmol) and sodium cyanoborohydride (69mg, l.lmmol). The yellow solution was stirred overnight at room temperature, then 10% aqueous potassium carbonate (5ml) was added. The mixture was evaporated in vacuo and the residue partitioned between 10% aqueous potassium carabonate and n-butanol. The aqueous was re-extracted once with n-butanol. The combined organics were evaporated to dryness to give a foam which was purified by column chromatography on silica using dichloromethane/methanol/ammonia as eluant, to afford the title compound (200mg, 41%); mp>60°C (sintered). (Found: C, 67.55; H, 7.04;

N, 17.75. C₂₆H37NβO*H₂O requires C, 67.51; H, 7.41; N, 18.17%. δ (360MHz, dβ-DMSO) 1.40-1.58 (4H, m, 2 of CH₂), 1.74-1.86 (2H, m, CH2), 2.20-2.55 (6H, m, 3 of CH₂), 2.39 (2H, s, CH₂), 2.70 (2H, t, J=7Hz, CH2). 3.71 (2H, s, CH₂), 4.01 (IH, s, OH), 7.17-7.32 (7H, m, Ar-H), 7.46 (IH, d, J=8Hz, Ar-H), 7.76 (IH, d, J=2Hz, Ar-H), 9.00 (2H, s, Ar-H), 11.05 (IH, s, NH). MS, m/e=445 for (M+H)⁺.

EXAMPLE 39

4-[(N-Benzyl-N-methyl)amino1methyl-4-hvdroxy-l-f3-f5-(1.2.4-triazol-4- yl)-lH-indol-3-vnpropyl .piperidine. 2.0 Hydrogen Oxalate. To a solution of 4-(benzylamino)methyl-4-hydroxy-l-[3-[5-(l,2,4- triazol-4-yl)-lH-indol-3-yl]propyl]piperidine (150mg, 0.34mmol) in methanol (8ml) were added 38% in water formaldehyde (27μl, 0.37mmol), gladal acetic add (85μl, 1.48mmol) and sodium cyanoborohydride (23mg, 0.37mmol). The solution was stirred overnight at room temperature, the 10% aqueous potassium carbonate (5ml) was added. The mixture was evaporated to dryness and the residue partitioned between 10% aqueous potassium carbonate and dichloromethane. The aqueous was re-extracted with dichloromethane (3x). The combined organics were dried (sodium sulphate) and evaporated to give the required product (130mg, 83%). The oxalate salt had mp>132°C (sintered). (Found: C, 57.17; H, 6.17; N, 12.59. C27H34N6O-2(CO2H)₂ 0.75 H₂O requires C, 57.09; H, 6.10;

N, 12.89%.) δ (360MHz, dβ-DMSO) 1.64-1.86 (4H, m, 2 of CH₂), 1.98-2.12 (2H, m, CH.), 2.31 (3H, s, CHs), 2.5 (2H, s, CH2), 2.76 (2H, br t, CHs), 3.0- 3.17 (4H, m, 2 of CH2), 3.23-3.40 (2H, m, CH..), 3.68 (2H, s, CH2), 7.20-7.40 (7H, m, Ar-H), 7.50 (IH, d, J=8Hz, Ar-H), 7.80 (IH, d, J=2Hz, Ar-H), 9.02 (2H, s, Ar-H), 11.19 (IH, s, NH). MS, m/e=459 for (M+H)⁺.

EXAMPLE 40

3-(N-Benzyl-N-methvDaminomethyl-l-r2-(5-(1.2.4-triazol-4-ylVlH-indol-3- vDethyll azetidine. 1.5 Hydrogen Oxalate. 1.5 Hvdrate.

The title compound was prepared from Example 35 and formaldehyde using the general reductive amination procedure. The 1.5 hydrogen oxalate 1.5 hydrate salt was prepared, mp 125-131°C.

(Found: C, 56.78; H, 6.15, N, 14.13. C24H2βNβ l.5(C2H2θ4) 1.5 H2O requires C, 56.48; H, 5.94; N, 14.36%, m/e 401 (M+l)⁺. δ (360MHz, dβ-DMSO) 2.13 (3H, s, Me), 2.71 (2H, d, J=7.6Hz, CH₂NMe), 2.90-3.08 (3H, m, CH and CH2), 3.36-3.46 (2H, m, CH2), 3.54 (2H, s, CH2PI1), 3.77 (2H, t, J=7.5Hz, CH2), 4.09 (2H, t, J=7.5Hz, CH2), 7.22-7.40 (7H, m, Ar-H), 7.53 (IH, d, J=8.7Hz, Ar-H), 7.88 (IH, s, Ar-H), 9.03 (2H, s, Ar-H), 11.29 (IH, s, NH).

EXAMPLE 41

(3S)-3-(N-rR1-α-Methylbenzyl)aminomethvI-l-f2-(5-(1.2.4-triazol-4-yl)- lH-indol-3-yl)ethvI1pyττolidine. 2.5 Hydrogen Oxalate. 0.5 Hvdrate. 0.2 Diethyl etherate. a) (3SVN(Η)-3-(N-rRl-α-Methylbenzyl)amino methyl pyrrnlidinp Prepared from (3R)-N-fert-butyloxycarbonyl-3-

(methylsulphonyloxymethyl)pyrroKdine and (R)-α-methyl benzylamine using the procedures described for Example 5, parts b and c. δ b) (3S)-3-(N-rR1-α-Methylbenzyl)aminomethyl- l-f2-(5- 1.2.4-triazol-4- ylV!H-:uidol-3-yl)ethyl1pyrrolidine. 2.5 Hydrogen Oxalate. O.δHvdrate. 0.2 Diethyl etherate.

Methane sulphonyl chloride (1.44g, 12.6mmol) was added to a 0 stirred suspension of Intermediate 3 (1.9 lg, 8.4mmol) in anhydrous pyridine (60ml), at -20°C. The mixture was warmed to room temperature and stirred for 2h. The pyridine was removed in vacuo, water (100ml) added and the mixture extracted with CH2CI2 (3 x 75ml). The combined extracts were dried (MgSO₄), the solvent removed under vacuum and the lδ residue chromatographed on silica gel eluting with MeOH/CH∑Cb (9:1) to give the desired mesylate (l.δOg, 60%). A mixture of the preceding mesylate (0.308g, l.Ommol), (3S)-N(H)-3-(N-[R]-α- methylbenzyl)aminomethyl pyrrolidine (0.35g, 1.71mmol) and K2CO3 (0.414g, 3.0mmol), in IPA (25ml), was heated at reflux for 4h. The solvent 20 was removed in vacuo and the residue taken up into CH2CI2 and washed with H2O (x3). The organic was dried (MgSO4) and evaporated and the residue chromatographed on silica gd eluting with CH∑C-b/MeOH/NHa (80:8:1) to afford the title product (0.206g, 50%). The 2.5 hydrogen oxalate 0.5 hydrate 0.2 diethyl etherate salt was prepared, mp 192-194°C;

25 (Found: C, 55.61; H, 5.84; N, 12.68. C2sH3oN₆*2.5(C2H2θ ) 0.5 H₂O* 0.2(Et₂O) requires C, 55.76; H, 5.77; N, 12.67%), m/e 415 (M+1V\

30 EXAMPLE 42

(^•3SV3-(N-rS1-α-Methylbenzyl)aminomethyl-l-r2-(5-(1.2.4-triazol-4-yl)-lH- indol-3-yl)ethyllpyrrolidine. 2.5 Hydrogen Oxalate 0.6Hvdrate 0.1 Diethyl etherate

Prepared from Intermediate 3 as described for Example 41, mp 191-193°C, (Found: C, 55.31; H, 5.69; N, 12.54.

0.6 H__O*0.1(Et₂O) requires C, 55.65; H, 5.68; N, 12.81%), m/e 415 (M+l)⁺.

EXAMPLE 43

(3S)-3-(N-Furan-3-ylmethyl'>aminomethyl-l-r2-(5-(1.2.4-triazol-4-yl)-lH- indol-3-yl)ethvnpyrrolidine. 2.5 Hydrogen Oxalate. 0.65 Diethyl etherate.

a) (3S)-N(H)-3-(N-Furan-3-ylmethv aminomethyl pyrrolidine Prepared from (3R)-N-tert-butyloxycarbonyl-3- (methylsulphonyloxymethyl)pyrrolidine and 3-furanmethylamine using the procedures described for Example 5, parts b and c.

b) (3SV3-(N-Furan-3-ylmethyl)aminomethyl-l-f2-(5-(1.2.4-triazol-4- yl)-lH-indol-3-yl)ethvπpyrτolidine. 2.5 Hydrogen Oxalate. 0.65 Diethyl etherate.

Prepared from Intermediate 3 and the preceding pyrrolidine as described for Example 41, (Found: C, 53.81; H, 5.97; N, 12.69. C22H26NO6 2.5(C2H₂θ4)*0.65(Et2θ) requires C, 53.56; H, 5.69, N, 12.66%). δ (360MHz, dβ-DMSO) 1.70-1.84 (IH, m, CH of CH2), 2.14-2.26 (IH, m, CH of CH2), 2.68-2.80 (IH, m, CH), 2.94-3.24 (5H, m, 2 of CH2 and CH of CH2), 3.26-3.58 (5H, m, 2 of CH2), 4.02 (2H, s, CH2), 6.65 (IH, s, Ar-H), 7.37 (IH, dd, J=2.1 and 8.7Hz, Ar-H), 7.40 (IH, s, Ar-H), 7.53 (IH, d, J=8.7Hz, Ar-H), 7.72 (IH, s, Ar-H), 7.81 (IH, s, Ar-H), 7.91 (IH, d, J=2.1Hz, Ar-H), 9.05 (2H, s, Ar-H), 11.31 (lH. s. NH). EXAMPLE 44

(3SV3-(N-Furan-2-ylmethyl)aminomethyl-l-r2-(5-(1.2.4-triazol-4-yl)-lH- indol-3-yl)ethvnpyrrolidine. 2.5 Hydrogen Oxalate. 0.5 Hvdrate.

Prepared as described for Example 43, (Found: C, 51.92; H, 5.28;

N, 13.32. C₂₂H₂βNβO*2.5(C₂H₂θ4) 0.δ H₂O requires C, 51.92; H, 5.16; N, 13.46%). δ (360MHz, dβ-DMSO) 1.70-1.84 (IH, m, CH of CH2), 2.12- 2.24 (IH, m, CH of CH₂), 2.64-2.78 (IH, m, CH), 2.98 (2H, d, J=6.8Hz, CH2), 3.04-3.58 (8H, m, 4 of CH₂), 4.16 (2H, s, CH₂), 6.61 (IH, dd, J=3.2 and 1.6Hz, Ar-H), 6.57 (IH, d, J=3.2Hz, Ar-H), 7.36 (IH, dd, J=2.1 and 8.7Hz, Ar-H), 7.40 (IH, s, Ar-H), 7.52 (IH, d, J=8.7Hz, Ar-H), 7.74 (IH, d, J=1.6Hz, Ar-H), 7.90 (IH, s, Ar-H), 9.04 (2H, s, Ar-H), 11.31 (IH, s, NH).

EXAMPLE 45

(3SV3-rN-(RVα-(Hvdroxymethyl)benzvnaminomethyl-l-r2-(5-(1.2.4- triazol-4-yl)-lH-indol-3-yl)ethyllpyrrolidine. 2.4 Hydrogen Oxalate. 0.1 Hvdrate.

(3S)-N(H)-3-r(R)-α-(Hvdroxymethyl)benzvnaminomethylpyrrohdine

a) (3S)-N-tβrt-Butyloxycarbonyl-3-(R)-α(hvdroxymethyl)benzvn aminomethylpyTTolidine δ A solution of (R)-(-)-phenylglycinol (2.20g, 16. lmmol) and (3R)-N- iert-butyloxycarbonyl-3-methylsulphonyloxymethylpyrrohdine (l.Og, 3. δδmmol), in toluene (20ml), was heated at 150°C for 6h in sealed pressure tube (Aldrich). The solvent was then removed under vacuum and the residue taken up into ethyl acetate (200ml) and washed with 0 water (x4). The organic was dried (MgSO₄) and evaporated and the crude product chromatographed on silica gel eluting with CH∑Cb/MeOH (97:3) to give the titie-α-(hydroxymethyl)benzylaminomethylpyrrolidine (l.Og, 87%), δ (360MHz, CDCb) 1.45 (9H, s, OC(Me)₃), 1.52-2.60 (5H, m, CH₂ and CH), 2.90-3.76 (7H, m, 3 of CH₂ and CH), 7.25-7.39 (5H, m, Ar-H).

b) (3S1-N (H)-3- f (RVα-HvdroxymethvDbenzvn amino b γlp γrr<->li ft n Prepared from the preceding N-Boc pyrrolidine using the procedure described for Example 5, part c, δ (250MHz, CDCb) 1.25-1.45 (IH, m, CH of CH₂), 1.83-1.97 (IH, m, CH of CH.), ?.14-2.61 (4H, m, 2 of CH₂), 2.80- 3.09 (3H, m, CH₂ and CH), 3.46-3.76 (3H, m, CH₂ and CH), 7.25-7.38 (5H, m, Ar-H).

2. (3S)-3-i -(RVα-(Hvdroxymethyl)benzvnaminomethyl-l-r2-(5-(1.2.4- triazol-4-yl)-lH-indol-3-yl)ethyl]pyrrolidine. 2.4 Hydrogen Oxalate. 0.1 Hvdrate Prepared from Intermediate 3 and the preceding pyrrolidine using the procedure described for Example 41, mp 158°C, (Found: C, 55.11;

H, 5.58; N, 12.85. C25H₃oNβO*2.4(C₂H₂θ4) 0.1H₂O requires C, 55.20; H, 5.44; N, 12.96%), m/e 431 (M+l)^*, δ (360MHz, Dβ-DMSO) 1.64-1.76 (IH, m, CH of CH2), 2.12-2.24 (IH, m, CH of CH₂), 2.64-2.76 (2H, m, CH2), 2.88- 2.94 (IH, m, CH), 3.04-3.14 (3H, m, CH₂ and CH of CH2), 3.30-3.42 (3H, m, CH2 and CH of CH₂), 3.46-3.56 (IH, m, CH of CH₂), 3.73 (2H, d, J=5.7Hz, CH2), 4.12-4.16 (2H, m, CH2), 7.34-7.54 (8H, m, Ar-H), 7.90 (IH, s, Ar-H), 9.04 (2H, s, Ar-H), 11.31 (IH, s, NH).

EXAMPLE 46

(3SV3-rN-(S)-α-(Hvdroxymethyl^')benzvnaminomethyl-l-f2-(5-(1.2.4-triazol- 4-yl)-lH-indol-3-yl)ethyllpyrrolidine. 2.4 Hydrogen Oxalate. 0.1 Hydrate.

a) (3S)-N(HV3-r(SVα-(Hvdroxymethyl)benzyl1aminomethylpyrroUdine Prepared from (S)-(+)-phenylglycinol and (3R)-N-tert- butyloxycarbonyl-3-methylsulphonyloxymethylpyrrohdine using the procedures described for Example 45, part la.

b) (3S)-3-rN-(SVα-(Hvdroxymethyl)benzvnaminomethyl-l-r2-(5-(1.2.4- triazol-4-yl)-lH-indol-3-yl)ethyl -pyrrolidine. 2.4 Hydrogen Oxalate. 0.1 Hvdrate.

Prepared from Intermediate 3 and the preceding pyrrolidine using the procedure described for Example 41, mp 155°C, (Found: C, 55.35; H, 5.71; N, 12.82. C₂₅H3oNeO*2.4(C₂H₂O4) 0.1 H2O requires C, 55.20; H, 5.44; N, 12.96%), m/e 431 (M+l)⁺.

EXAMPLE 47

(3SV3-rN-Benzyl-N-(2-hvdroxy)ethvnaminomethyl-l-f2-(5-(1.2.4-triazol-4- yl)-lH-indoI-3-yl)ethyllpyrrohdine. 2.4 Hydrogen Oxalate.

a) (3S)-N(H)-3-fN-Benzyl-N-(2-hvdroxy)ethyllaminomethylpyrrohdine Prepared from N-benzylethanolamine and (3R)-N-tert- butyloxycarbonyl-3-methylsulphonyloxymethylpyrrohdine using the procedures described for Example 5, parts b and c, δ (250MHz, CDCI3) 1.24-1.60 (2H, m, CH2), 1.82-1.94 (2H, m, CH2), 2.26-3.06 (9H, m, 4 of CH2 and CH), 3.56-3.60 (2H, m, CH₂), 7.20-7.36 (5H, m, Ar-H).

b) (3SV3-rN-Benzyl-N-(2-hvdroxy)ethyl1aminomethyl-l-.2-(5-(1.2.4- triazol-4-yl)-lH-indol-3-yl)ethyl]pyτroIidine. 2.4 Hydrogen Oxalate.

Prepared from Intermediate 3 and the preceding pyrrolidine using the procedure described for Example 41, mp 117°C, (Found: C, 55.93;

H, 5.39; N, 12.50.

requires C, 55.99; H, 5.61; N, 12.72%), m/e 445 (M+l)\ δ(360MHz, Dβ-DMSO) 1.56- 1.70 (IH, m, CH of CH₂), 2.04-2.16 (IH, m, CH of CH₂), 2.52-2.68 (7H, m. 3 of CH2 and CH), 3.04-3.12 (2H, m, CH₂), 3.28-3.52 (6H, m, 3 of CH₂), 3.68 (2H, ABq, J=14Hz, CH₂), 7.20-7.34 (5H, m, Ar-H), 7.38 (IH, dd, J=8.6 and 1.5Hz, Ar-H), 7.53 (IH, d, J=8.6Hz, Ar-H), 7.89 (IH, d, J=1.5Hz, Ar-HX 9.03 (2H, s, Ar-H), 11.31 (IH, s, NH).

EXAMPLE 48

(3S 3-(N-Phenethv aminomethyl-l-f -(5-(1.2.4-triazol-4-yl)-lH-indol-3- vDethyllpyrrolidine. 2.5Hvdrogen Oxalate. Hemihγdrat.^p

a) (3S)-N-(H)-3-(N-Phenethv am-_nomethylpyrrohdine

Prepared from phenethylamine and (3R)-N-tert-butyloxycarbonyl-3- methylsulphonyloxymethylpyrrolidine using the procedures described for Example 5, parts b and c.

b) (3S 3-(N-Phenethyl minomethyl- l-r2-(5-(1.2.4-triazol-4-ylV 1H- indol-3-yl)ethvnpyrrolidine. 2.5 Hydrogen Oxalate. Hemihvdrate.

Prepared from the preceding pyrrolidine and Intermediate 3 using the procedure described for Example 41, mp 189-190°C, (Found: C, 55.59; H, 5.55; N, 12.85. C₂5H3oNe-2.5(C₂H₂O ) H₂O requires C, 55.55; H, 5.59; N, 12.96%), m/e 415 (M+l)\ δ (360MHz, Dβ-DMSO) 1.74-1.86 (IH, m, CH of CH₂), 2.14-2.26 (IH, m, CH of CHa), 2.68-3.60 (lδH, m, CH and 7 of CHO, 7.22-7.40 (7H, m, Ar-H), 7.53 (IH, d, J=8.6Hz, Ar-H), 7.92 (IH, d, J=1.5Hz, Ar-H), 9.05 (2H, s, Ar-H), 11.30 (IH, s, NH).

EXAMPLE 49

(3S)-3-(N-Phenethyl-N-methyl)aminomethyl- l-12-(5-(l ,2.4-t_riazol-4-yl)- lH-indol- 3-vDethvnpyrrolidine. 2.5 Hydrogen Oxalate. 0.1 Diethyl etherate.

a) (3SVN(HV3-⁽N-Phenethyl-N-methvbaminomethylpyττohdine Prepared from N-phenethyl-N-methylamine and (3R)-N-tert- butyloxycarbonyl-3-methylsulphonyloxymethyl pyrrolidine using the procedures described for Example 5, parts b and c.

b) (3S)-3-(N-Phenethyl-N-methyl)aminomethyl-l-r2-(5-(1.2.4-triazol-4-yl)- lH-indol-3-yl)ethyl1pyrrohdine. 2.5 Hydrogen Oxalate. 0.1 Diethyl etherate.

Prepared from the preceding pyrrolidine and Intermediate 3 using the procedure described for Example 41, mp 168-170°C, (Found: C, 67.02; H, 5.71; N, 12.78. C₂6H32Nβ*2.5(C2H₂θ4) 0.1(Diethyl ether) requires C, 57.05; H, 5.79; N, 12.71%), m/e 429 (M+l)⁺.

EXAMPLE 50

(3S)-3-(N-α-Dimethylbenzyl)aminomethyl-l-r2-(5-(1.2.4-triazol-4-yl)-lH- indol-3-yl)ethvnpyτrolidine. 2.45 Hydrogen Oxalate. 0.1 Diethyl etherate. Prepared from Intermediate 3 and (3R)-N-ter*-butyloxycarbonyl-3- methylsulphonyloxymethylpyrrolidine using the general procedures, mp

172-174°C, (Found: C, 57.15; H, 5.94; N, 13.14. C2βN32N6*2.45(C2H2θ₄)* 0.1(Diethyl ether) requires C, 57.26; H, 5.82; N, 12.80%), m/e 429 (M+l)\ δ (360MHz, Dβ-DMSO) 1.61 (6H, s, 2 of CH₃), 1.61-1.70 (IH, m, CH of

CH₂), 2.10-2.21 (IH, m, CH of CH₂), 2.54-2.62 (3H, m, CH₂ and CH), 2.96- 3.48 (8H, m, 4 of CH2), 7.30-7.57 (8H, m, Ar-H), 7.84 (IH, d, J=1.8Hz, Ar-H), 8.92 (2H, s, Ar-H), 11.12 (IH, s, NH).

EXAMPLE 51

(3S)-3-(N-rSl-α-Methylbenzyl)aminomethyl-l-r2-(5-(1.2.4-triazol- l -yl)- lH- indol-3-yl)ethyl1pyrrolidine. 2.5 Hydrogen Oxalate. 0.2 Hydrate.

a) 2-.5-(1.2.4-Triazol-l-ylVlH-indol-3-yllethyl alcohol Prepared from 4-(l,2,4-triazol-l-yl)aniline (EP497512) as described for Intermediate 3, δ (250MHz, Dβ-DMSO) 2.89 (2H, t, J=7.2Hz, CH2), 3.64-3.74 (2H, m, CH₂), 4.67 (IH, t, J=5.3Hz, OH), 7.29 (IH, d, J=2.3Hz, Ar-H), 7.47 (IH, dd, J=8.7 and 1.5Hz, Ar-H), 7.53 (IH, dd, J=8.7 and 2.3Hz, Ar-H), 7.95 (IH, d, J=1.9Hz, Ar-H), 8.19 (IH, s, Ar-H), 9.19 (IH, s, Ar-H), 11.10 (lH. s. NH).

b) (3S)-3-(N-rSl-α-Methylbenzyl)ammomethyl-l-r2-(5-(1.2.4-triazol-l- yl)-lH-indol-3-yl)ethyl -pyrrolidine. 2.5 Hydrogen Oxalate. 0.2 Hvdrate Prepared from 2-[5-(l,2,4-triazol-l-yl)-lH-indol-3-yl]ethyl alcohol and (3S)-N(H)-3-(N-[S]-α-methylbenzyl)aminomethyl pyrrolidine as described for Example 41, mp 203-204°C, (Found: C, 55.95; H, 5.51; N, 13.11. C₂5H3oNβ*2.5(C2H2θ₄)*0.2 H₂O requires C, 56.02; H, 5.55; N, 13.07%), m/e 415 (M+l)⁺, δ (360MHz, Dβ-DMSO) 1.54 (3H, d, J=6.7Hz, CHs), 1.60-1.74 (IH, m, CH of CH2), 2.11-2.22 (IH, m, CH of CH2), 2.60- 3.56 (10H, m, 4 of CH2 and 2 of CH of CH.), 4.24-4.30 (2H, m, CH₂), 7.34- 7.56 (8H, m, Ar-H), 8.03 (IH, s, Ar-H), 8.19 (IH, s, Ar-H), 9.19 (IH, s, Ar-H), 11.28 (lH. s. NH).

EXAMPLE 52

(3SV3-rN-iR1-α(Hvdroxymethyl')benzvnaminomethyl-l-r2-(5-(1.2.4-triazol- l-yl)-lH-indol-3-yl)ethvnpyrroUdine. 2.0 Hydrogen Oxalate. 0.3 Hvdrate. Prepared from 2-[5-(l,2,4-triazol-l-yl)-lH-indol-3-yl]ethyl alcohol and (3S)-N(H)-3-[(R)-α-(hydroxymethyl)benzyl]aminomethyl pyrroUdine using the procedures described for Example 41, mp 173-174°C, (Found:

C, 56.57; H, 5.77; N, 13.57. C2sH3oN₆O*2.0(C2H2θ4) 0.3 H2O requires C, 56.54; H, 5.66; N, 13.64%), m/e 431 (M+l)⁺, δ (360MHz, Dβ-DMSO) 1.62-1.76 (IH, m, CH of CH2), 2.10-2.22 (IH, m, CH of CH₂), 2.56-2.72 (2H, m, CH and CH of CH2), 2.80-2.90 (IH, m, CH of CH₂), 3.02-3.52 (7H, m, 3 of CH₂ and CH), 3.64-3.70 (2H, m, CH₂), 4.02-4.06 (2H, m, CH₂), 7.32- 7.57 (8H, m, Ar-H), 8.03 (IH, s, Ar-H), 8.20 (IH, s, Ar-H), 9.18 (IH, s, Ar-H), 11.28 (IH, s, NH).

EXAMPLE 53

(3S)-3-(N-Benzyl)aminomethyl-l-r2-(5-(1.2.4-triazol-l-ylmethylVlH-indol- 3-yl)ethvnpyrrohdine. 2.4 Hydrogen Oxalate.

a) 2-r5-(1.2.4-Triazol- 1-ylmethylV lH-indol-3-vnethyl alcohol Prepared from 4-(l,2,4-triazol-l-ylmethyl)aniline (EP497512) as described for Intermediate 3, δ (250MHz, D₄-MeOH) 2.96 (2H, t, J=7.2Hz, CH₂), 3.80 (2H, t, J=7.2Hz, CH₂), 5.46 (2H, s, CH₂), 7.08 (IH, dd, J=1.7 and 8.6 Hz, Ar-H), 7.11 (IH, s, Ar-H), 7.33 (IH, d, J=8.6Hz, Ar-H), 7.58- 7.59 (IH, d, J=1.7Hz, Ar-H), 7.97 (IH, s, Ar-H), 8.44 (IH, s, Ar-H).

b) (3SV3-(N-BenzvDaminomethyl-l-f2-(5-Q.2.4-triazol-l-ylmethyl)- lH-indol-3-yl)ethvnpyrrolidine. 2.4 Hydrogen Oxalate.

Prepared from 2-[5-(l,2,4-triazol- 1-ylmethyl)- lH-indol-3-yl]ethyl alcohol and (3S)-N(H)-3-N-(benzyl)aminomethyl pyrroUdine as described for Example 41, mp 154-156°C, (Found: C, 56.92; H, δ.49; N, 13.40.

C25H3oNβ*2.4(C2H2θ4) requires C, δ6.76; H, δ.δ6; N, 13.33%), m/e 41δ (M+l)\ δ (360MHz, Dβ-DMSO) 1.72-1.86 (IH, m, CH of CH₂), 2.15-2.28 (IH, m, CH of CH₂), 2.70-2.84 (IH, m, CH), 3.00-3.62 (10H, m, 5 of CH₂), 4.16 (2H, s, CH₂), 5.44 (2H, s, CH₂), 7.07 (IH, d, J=8.6Hz. Ar-H), 7.27 (IH, s, Ar-H), 7.3δ (IH, d, J=8.6Hz, Ar-H), 7.40-7.54 (5H, m, Ar-H), 7.63 (IH, s, Ar-H), 7.9δ (IH, s, Ar-H), 8.64 (IH, s, Ar-H), 11.07 (IH, s, NH).

Examples 64 and 65 were prepared from 2-[5-(l,2,4-triazol- l-ylmethyl)- lH-indol-3-yl]ethyl alcohol and the appropriate pyrroUdine using the standard procedures. EXAMPLE 54

(3SV3-(N-rSl-α-Methylbenzyl)aminomethyl-l-f2-(5-(1.2.4-triazol-l- ylmethyl)-lH-indol-3-yl)ethvnpyrroUdine. 2.36 Hydrogen Oxalate. 0.1 Diethyl etherate. mp: 19δ-197°C, (Found: C, 56.99; H, 5.65; N, 13.16. CasHsuNβ- 2.35(C₂H₂O4) 0.3(H₂O) 0.1(diethyl ether) requires C, 57.21; H, 5.91; N, 12.87%), m/e 429 (M+l)⁺.

EXAMPLE 55

(3SV3-(N-rRl-α-(Hvdroxymethyl)benzvnaminomethyl-l-r2-(5-(1.2.4- triazol-l-ylmethyl)-lH-indol-3-yl)ethvnpyτroUdine. 2.25 Hydrogen Oxalate. mp: 102- 105°C, (Found: C, 56.60; H, 5.79; N, 13.02.

C₂6H32NβO-2.25(C₂H₂θ4) requires C, 56.61; H, 5.69; N, 12.99%), m/e 445 (M+l)⁺.

EXAMPLE 56

(3SV3-(N-Benzyl-N-methyl)aminomethyl- l-f2-(5-(imidazol- 1-ylV lH-indol- 3-yl)ethvnpyrroUdine. 2.0 Hydrogen Oxalate. Hemihvdrate.

a) 2-f5-αmidazol-l-v -lH-indol-3-yllethyl alcohol Prepared from 4-(imidazol-l-yl)aniUne (EP497512) as described for

Intermediate 3, δ (360MHz, Dβ-DMSO) 2.87 (2H, t, J=7.2Hz, CH₂), 3.64- 3.70 (IH. m, CH2-OH), 4.61 (IH, t, J=5.3Hz, OH), 7.08 (IH, s, Ar-H). 7.25- 7.27 (2H. m. Ar-H), 7.44 (IH, d, J=8.8Hz, Ar-H), 7.64 (IH, d, J=2.5Hz, Ar¬ il), 7.70 (IH. d, J=2.lHz, Ar-H), 8.11 (IH, s, Ar-H), 11.00 (IH, s, NH), m/e 228 (M+l)\ b) (3S)-3-(N-Benzyl-N-methv aminomethyl-l-f2-(δ-(imidazol-l-yl)-lH- indol-3-yl)ethvnpyrroUdine. 2.0 Hydrogen Oxalate. Hemihvdrate.

To a solution of (3S)-N(H)-3* N-meώyl-N-ben_tyl)aminomemy- yιrQhdine δ (0.2 lg, 1.02mmol) in anhydrous DMF (3ml) was added K2CO3 (0.114g, 0.83mmol) and, dropwise, a solution of the mesylate of the preceding alcohol (0.168g, O.δδmmol) in DMF (7ml). The mixture was heated at 50°C for lh and then at 70°C for 2h. After cooling, the solvent was removed under vacuum and the residue partitioned between CH2CI2 0 (3 x 25ml) and water (25ml). The combined organics were dried (NaaSO4) and evaporated and the residue chromatographed on siUca gel eluting with CH₂Cl2 MeOH/NH₃ (90:10:1) to give the desired product (0.134g, 59% from the alcohol). The 2.0 hydrogen oxalate hemihydrate salt was prepared, mp 92°C (dec), (Found: C, 59.53; H, 6.12; N, 11.83. 5 C2βH3iN 2(C2H2θ4>0.5 H2O requires C, 69.79; H, 6.02; N, 11.62%), m/e 414 (M+l)\ δ (360MHz, Dβ-DMSO) 1.60-1.74 (IH, m, CH of CH2), 2.09- 2.20 (IH, m, CH of CH2), 2.24 (3H, s, CH3), 2.54-3.68 (11H, m, 5 of CH2 and CH), 3.66 (2H, ABq, J=13.3Hz, CH2), 7.16 (IH, s, Ar-H), 7.26-7.39 (7H, m, Ar-H), 7.51 (IH, d, J=8.5Hz, Ar-H), 7.73 (IH, d, J=1.2Hz, Ar-H), 0 7.85 (IH, d, J=2.0Hz, Ar-H), 8.26 (IH, s, Ar-H), 11.24 (IH, s, NH).

EXAMPLE 57

(3SV3-(N-Benzyl-N-methvI)aminomethyl-l-f2-(5-(1.2.4-triazol-l- 25 ylmethyl)-lH-indol-3-yl)ethvnpyrroUdine. 2.5 Hydrogen Oxalate.

Prepared from 2-[5-(l,2,4-triazol-l-ylmethyl)-lH-indol-3-yl]ethyl alcohol and (3S)-N(H)-3-(N-methyl-N-benzyl)aminomethylpyrroUdine using the procedure described for Example 41. The 2.0 hydrogen oxalate hemihydrate salt was prepared, mp 154-155°C, (Found: C, 57.10; H, 5.95;

30 N, 12.66. C2GH3₂N6*2.5(C2H₂O ) requires C, 56.96; H, 5.70; N, 12.85%), m/e 429 (M+ir, δ (360MHz, Dc-DMSO) 1.60-1.72 (IH. m, CH of CH2). 2.08- 2.20 (IH, m, CH of CH₂), 2.26 (3H, s, CH₃), 2.52-3.60 (11H, m, 5 of CH₂ and CH), 3.69 (2H, ABq, J=13.4Hz, CH₂), 5.42 (2H, s, CH₂), 7.05 (IH, d, J=8.5Hz, Ar-H), 7.25-7.35 (7H, m Ar-H), 7.60 (IH, s, Ar-H), 7.92 (IH, s, Ar-H), 8.58 (IH, s, Ar-H), 11.02 (IH, s NH).

EXAMPLE 58

(3RV3-(N-Methyl-N-rSl-α-methylbenzyl)aminomethyl-l-r2-(5-(1.2.4- triazol-l-ylmethyl)-lH-indol-3-yl)ethyl1pyrroUdine. 2.0 Hydrogen Oxalate. 0.17 Diethyl etherate.

a) (3R)-N(H)-3-(N-Methyl-N-[Sl*<x-methylbenzyl)am omethylpyrrohdine

Gladal acetic add (0.9ml, 15.7mmol) and sodium cyanoborohydride (0.495g, 7.88mmol) were added successively to a stirred solution of (3S)-N- te^ butyloxycarbonyl-3-(N-[S]-α-methylbenzyl)aminomethylpvlτoHdine (1.92g, 6.31mmol) in methanol (150ml), at 0°C. A solution of formaldehyde (0.623g of a 38% w/v solution, 7.88mmol), in methanol (50ml), was added dropwise over O.lh. The mixture was stirred at 0°C for 4.5h and then at +2δ°C for 1.25h before adding saturated K2CO3 solution (2δml) and removing the solvent under vacuum. Ethyl acetate (100ml) was added to the residue and washed with water (xl), saturated K2CO3 solution (xl) and brine (xl), dried (MgSO ) and evaporated. The residue was chromatographed on siUca gel eluting with CH∑Cb/MeOH (95:6) to give (3R)-N-tert-butyloxycarbonyl-3-(N-[S]-α-methylbenzyl-N- methyl) aminometh yip yrroh dine (2.02g, 100%).

A solution of the preceding carbamate (2.01g, 6.32mmol) in 90% HCO2H (40ml) was stirred at 0°C for 2.75h and then at +25°C for 16h. The reaction was quenched by the addition of methanol and the solvents removed under vacuum. The residue was azeotroped with ethanol and then taken up into a small volume of water and basified with saturated K2CO3 solution. The aqueous was extracted with n-butanol (2 x 50ml), the combined extracts evaporated in vacuo and the inorganics removed by trituration with CHϋCL. and filtering. The filtrate was dried (MgSθ4) and evaporated and the residue chromatographed on siUca gel, eluting with CH₂Cl2 MeOH/NH₃ (15:8:1) to give the title pyrroUdine (1.25g, 89%), δ (250MHz, CDCls) 1.34 (3H, d, J=6.8Hz, CHs), 1.52-1.67 (IH, m, CH of CHa), 1.96-2.10 (IH, m, CH of CH₂), 2.17 (3H, s, CHa), 2.25-2.52 (3H, m, CH of ΕLm), 2.72 (IH, dd, J=11.3 and 7.3Hz, CH of Clfc), 3.10 (2H, dd, J=8.0 and 6.6Hz, CH of CH₂), 3.25 (IH; dd, J=11.3 and 7.3Hz, CH of CHa), 3.57 (IH, q, J=6.8Hz, CH), 5.97 (IH, br s, NH), 7.20-7.34 (5H, m, Ar-H).

b) (3R)-3-(N-Methyl-N-fS1-α-methylbenzv aminomethyl-l-r2-5-(1.2.4- triazol-l-ylmethyl)-lH-indol-3-yl)ethyllpyrroUdine. 2.0 Hydrogen Oxalate. 0.17 Diethyl etherate.

The title compound was prepared from the preceding pyrroUdine and the mesylate of 2-[5-(l,2,4-triazol- 1-ylmethyl)- lH-indol-3-yl]ethyl alcohol using the standard coupling procedure. The 2.0 hydrogen oxalate 0.17 diethyl etherate salt was prepared, mp 148-149°C, (Found: C, 59.82;

H, 6.58; N, 13.32. C27H34Nβ*2.0(C2H₂O₄)-0.17(diethyl ether) requires

C, 59.90; H, 6.30; N, 13.23%), m/e 443 (M+l)^*, δ (360MHz, Dβ-DMSO) 1.34 (3H, d, J=6.9Hz, CHs), 1.60-1.71 (IH, m, CH of CH₂), 2.06-2.16 (IH, m, CH of CH₂), 2.17 (3H, s, CH₃), 2.40-2.66 (3H, m, CH of CH₂), 2.92-3.09 (3H, m, CH₂ and CH of CH₂), 3.29-3.50 (5H, m, 2 of CH₂ and CH of CH₂), 3.73 (IH, q, J=6.9Hz, CH), 5.45 (2H, s. CH₂), 7.09 (IH, d, J=8.4Hz, Ar-H), 7.22-7.38 (7H, m, Ar-H), 7.59 (IH, s, Ar-H), 7.91 (IH, s, Ar-H), 8.51 (IH, s, Ar-H), 10.87 (IH, s, NH).

EXAMPLE 59

(3RV3-(N-Methyl-N-rR1-α-hvdroxymethylbenzyl>aminomethyl-l-f2-(5- (1.2.4-triazol-l-ylmethyl)-lH-indol-3-yl)ethyllpyrroUdine. 1.9 Hydrogen Oxalate. Hemihvdrate. 0.05 Diethyl etherate. The title compound was prepared from (3R)-N(H)-3-(N-methyl-N- [R]-α-hydroxymethylbenzyl)aminomethylpyrroUdine and the mesylate of 2-[5-(l,2,4-triazol- 1-ylmethyl)- lH-indol-3-yl)ethyl alcohol using-the general procedure. The 1.9 hydrogen oxalate hemihydrate 0.05 diethyl etherate salt was prepared, mp 154-155°C, (Found: C, 57.26; H, 6.26;

N, 12.75. C27H34NβO 1.9(C₂H₂θ4) 0.5 H₂O 0.05(diethyl ether) requires C, 57.25; H, 6.09; N, 12.92%), m/e 459 (M+l)\ δ (360MHz, Dβ-DMSO) 1.63-1.72 (IH, m, CH of CH₂), 2.04-2.14 (IH, m, CH of Clfc), 2.19 (3H, s, CHs), 2.51-2.68 (3H, m, CH and CH₂), 3.00-3.10 (3H, m, CH of CH₂ and CH₂), 3.30-3.50 (5H, 2 of CH₂ and CH of CH2), 3.63-3.89 (3H, m, CH and CH2), 5.43 (2H, s, CH2), 7.07 (IH, d, J=8.3Hz, Ar-H), 7.24-7.36 (7H, m, Ar-H), 7.58 (IH, s, Ar-H), 7.89 (IH, s, Ar-H), 8.50 (IH, s, Ar-H), 10.86 (IH, s, NH).

EXAMPLE 60

(3R 3-(N-Methyl -N- f S 1 -α-methylcvdohexylmethyl)aminomethyl- 1 - f2-(5- ( 1.2.4-triazol- 1-ylmethvD- lH-indol-3-yl)ethvnp yrrohdine. 2.26 Hydrogen Oxalate. 0.17 Diethyl etherate. Prepared from 2-[5-(l,2,4-triazol-l-ylmethyl)-lH-indol-3-yl)ethyl alcohol and (3R)-N(H)-3-(N-methyl-N-[S]-α-methylcydohexyUnethyl) aminomethylpyrroUdine using previously described procedures. The 2.26 hydrogen oxalate 0.17 diethyl etherate salt was prepared, mp 191-192°C,

Found: C, 58.13; H, 7.40; N, 12.80. C27H4oN6-2.25(C2H₂O₄)*0.17(diethyl ether) requires C, 58.22; H, 7.02; N, 12.66%), m/e 449 (M+l)^*, δ (360MHz, Dβ-DMSO) 0.82-0.93 (2H, m, CH₂), 0.91 (3H, d, J=6.6Hz, CHO, 1.09-2.40 (4H. m, 2 of CH₂), 1.56-1.74 (5H, m, 2 of CH∑ and CH of CH₂), 1.88-1.96 (IH, m, CH), 2.06-2.16 (IH, m, CH of CH2), 2.21 (3H, s, CHO, 2.36-2.44 (IH, m, CH), 2.48-2.62 (3H, m, CH2 and CH of CH₂), 3.00-3.10 (3H, m, CH2 and CH of CH₂), 3.28-3.48 (5H, m, 2 of CH₂ and CH), 5.43 (2H, s, CH2), 7.07 (IH, dd. J=1.6 and 8.4Hz, Ar-H), 7.24 (IH, d, J=1.6Hz, Ar-H), 7.3δ (IH, d, J=8.4Hz, Ar-H), 7.58 (IH, s, Ar-H), 7.89 (IH, s, Ar-H), 8.49 (IH, s, Ar-H), 10.85 (IH, s, NH).

EXAMPLE 61

(3R)-3-(3--R1-Hvdroxy-2-rR1-phenylpiperidin-l-yl)methyl-l-r2-(5-(1.2.4- triazol-l-ylmethvI)-lH-indol-3-yl)ethvnpyrroUdine. 2.35 Hydrogen Oxalate.

a) (3RVN(H)-3-(3-rR1-Hvdroxy-2-IR1-phenylpiperidin-l-yl) methylpyrroUdine A mixture of (3R)-N-terf-butyloxycarbonyl-3- (methylsulphonyloxymethyl)pyrroUdine (l.Og, 3.58mmol) and N(H)-3-[R]- hydroxy-2-[Rl-phenylpiperidine (3.17g, 17.92mmol), in toluene (12ml), was heated in a sealed tube at 150°C for 8h. The solvent was removed in vacuo and the residue partitioned between CH2CI2 (2 x 150ml) and water (30ml). The extracts were dried (Na__SO4) and evaporated and the residue chromatographed on siUca gel eluting with dkCL/MeOH (95:5) to give the desired 3-(piperidinyUnethyl)pyrroUdine (1.09g, 85%). To this material was added formic add (20ml) and the solution stirred at +25°C for 16h. The formic add was removed under reduced pressure and the residue basified with saturated K2CO3 solution. The aqueous was extracted with CH∑CL. (8 x 100ml), the combined extracts dried (Na2SO₄) and evaporated. The crude product was chromatographed on siUca gel eluting with CH∑Ck/MeOH/NHs (30:8:1) to give the title-pyrroUdine (0.79g, 100%).

b) (3R)-3-(3-rRl-Hvdroxy-2-rR1-phenylpiperidin-l-yl)methyl-l-f2-(5- (1.2.4-triazol-l-ylmethyl)-lH-indol-3-yl)ethyllpyrroUdine. 2.35 Hydrogen Oxalate. Prepared from the preceding pyrroUdine and the mesylate of 2-[5-

(l,2,4-triazol-l-ylmethyl)- lH-indol-3-yl]ethyl alcohol using the standard -Un¬

coupling procedure. The 2.35 hydrogen oxalate salt was prepared, mp 118°C, (Found: C, 58.24; H, 6.22; N, 11.82. C29H3βN6θ*2.35(C₂H₂O₄) requires C, 58.14; H, 5.89; N, 12.07%), m/e 485 (M+l)⁺, δ (360MHz, Dβ-DMSO) 1.52-3.72 (21H, m, 3 of CH and 9 of CH₂), 5.42 (2H, s, CH₂), 7.06 (IH, dd, J=1.5 and 8.6Hz, Ar-H), 7.21 (IH, d, J=1.5Hz, Ar-H), 7.25- 7.43 (6H, m, Ar-H), 7.57 (IH, s, Ar-H), 7.93 (IH, s, Ar-H), 8.58 (IH, s, Ar-H), 11.03 (IH, s, NH).

EXAMPLE 62

(3RV3-(3-rR1-Hvdroxy-2-rRl-phenylpiperidin-l-yl)methyl-l-f2-(5-(1.2.4- triazol-l-yl)-lH-indol-3-yl)ethyllpyrroUdine. Sesαuioxalate.

Prepared from (3R)-N(H)-3-(3-[R]-hydroxy-2-[R]-phenylpiperidin- l-yl)methylpyrroUdine and 2-[5-(l,2,4-triazol-l-yl)-lH-indol-3-yl]ethyl alcohol using the general procedure. The sesquioxalate salt was prepared, mp 192-193°C, (Found: C, 64.49; H, 6.30; N, 13.83.

C₂βH3₄N6θ*1.5(C₂H₂O₄) requires C, 61.48; H, 6.16; N, 13.87%), m/e 471 (M+l)⁺ , δ (250MHz, Dβ-DMSO) 1.40-3.60 (21H, 3 of CH and 9 of CH₂), 7.16-7.60 (8H, m, Ar-H), 7.99 (IH, s, Ar-H), 8.20 (IH, s, Ar-H), 9.17 (IH, s, Ar-H), 11.27 (IH, s, NH).

EXAMPLE 63

4-Hvdroxy-4-(phenylsulfinyl)methyl-l-(3-[5-(1.2.4-triazol-4-yl)-lH-indol-3- yllpropyl-piperidine. Hydrogen Oxalate.

To a stirred solution of methyl phenyl sulphoxide (0.1268g,

0.904mmol), in THF (2ml), cooled under nitrogen to -78°C, was added dropwise, over 5 minutes, a 1.0M solution of Uthium fais(trimethylsilyl)amide in THF (0.90ml, 0.900mmol), keeping the temperature below -77°C. The mixture was then stirred at -78°C for 30 minutes before adding by cannula, over 10 minutes, a stirred mixture of 4-keto-l-{3-[5-(l,2,4-triazol-4-yl)-lH-indol-3-yl]propyl}piperidine (0.1324g, 0.409mmol) in THF (2ml), cooled under nitrogen to -78°C. The reaction mixture was stirred at < -70°C for 2.25h, then allowed to warm :o +10°C over 10 minutes before quenching with saturated NH₄C1 solution (1ml). The mixture was then partitioned between ethyl acetate (25ml) and saturated K2CO3 solution (20ml). The aqueous layer was reextracted with more ethyl acetate (3 x 25ml) and the combined organic extracts were dried (Na₂SO₄) and evaporated in vacuo. The residue was purified by flash chromatography (silica gel, CHϋCWMeOH/NHa, 90:10:1), then alumina, 3-5% MeOH/C Cl.., then silica gel, CHϋCLj/MeOH/NHa, 92:8:0.8) to give 30.9mg (16%) of the title compound free base as a colourless oil. The oxalate salt was prepared in methanol-diethyl ether; mp 124°C (softens). (Found: C, 57.53; H, 5.84, N, 11.92.

C₂sH₂₉N5θ2S*(C2H2θ4)-0.18(C4HιoO)-0.6 H₂O requires: C, 57.62, H, 5.93; N, 12.12%). 5H (360MHz, DMSO-dβ) 1.74 (IH, m), 1.90-2.08 (5H, m), 2.77 (2H, m), 2.90-3.18 (8H, m), 7.32-7.35 (2H, m), 7.51 (IH, d, J=8.6Hz), 7.55- 7.62 (3H, m), 7.66-7.68 (2H, m), 7.81 (IH, s), 9.03 (2H, s), 11.18 (IH, s); m/e (ES) 464 (M^* +l).

EXAMPLE 64

(3RV3-(2-rR.Sl-Phenylpiperidin-l-yl)methyl-l-f2-(5-(1.2.4-triazol-l- ylmethyl)-lH-indol-3-yl)ethvnpyrroUdine. 1.8 Hydrogen Oxalate. 0.75 Hvdrate.

The title compound was prepared using the procedures described for Example 61. The 1.8 hydrogen oxalate 0.75 hydrate salt was prepared, mp 184- 185°C, (Found: C, 60.78; H, 6.67; N, 12.77.

0.75 H2O requires C, 60.78; H, 6.43; N, 13.05%); m/e 469 (M+l)^*. EXAMPLE 65

4-(r3.3-Dimethylpiperidin-l-yllmethyl)-4-hvdroxy-l-(3-r5-(1.2.4--triazol-4- yl)-lH-indol-3-vnpropyl)piperidine. Hydrogen Oxalate.

a) 6-Aza-6-benzyl-l-oxaspiror2.5-θctane

Dimethyl sulphoxide (50ml) was added dropwise to a stirred, cooled (10°C) mixture of sodium hydride (1.85g of a 55% oil dispersion, 0.0423mol) and trimethylsulphoxonium iodide (8.0g, 0.0423mol) under a nitrogen atmosphere. After addition the cooling bath was removed and the mixture stirred at room temperature for 30 minutes, then cooled to 7°C and treated with a solution of l-benzyl-4-piperidone (8.0g, 0.0423mol) in dimethyl sulphoxide (50ml). After addition the reaction mixture was stirred at room temperature for 15 minutes then at 50°C for 1 hour. The mixture was then stirred whilst cooling to room temperature then quenched with water (20ml). After stirring for a further 10 minutes the mixture was poured into water (250ml) and extracted with toluene (3 x 100ml). The combined organics were washed with water (200ml), dried (sodium sulphate) then evaporated to give the title compound as a pale yellow oil (7.4g, 86%). MS, ES⁺, m/z = 204 for (M+H)⁺; δ (360MHz,

Dβ-DMSO) 1.41-1.48 (2H, m) and 1.63-1.71 (2H, m, piperidine 3-CH₂ and 5-CH₂), 2.43-2.51 (4H, m, piperidine 2-CH2 and 6-CH2), 2.58 (2H, s, CH2O), 3.51 (2H, s, CH2PI1), 7.18-7.38 (5H, m, Ar-H).

b) l-Benzyl-4-(3.3-dimethylpiperi din- l-yl)methyl-4-hvdroxy piperidine A solution of 6-aza-6-benzyl-l-oxaspiro[2.5]octane (2.0g, 9.84mmol) and 3,3-dimethylpiperidine (6.7ml, 49.2mmol) in ethanol (20ml) was heated at reflux for 3 hours. The reaction mixture was evaporated and the residue partitioned between dichloromethane (20ml) and water (20ml). The organic layer was separated, washed with water (20ml) then extracted with 2M hydrochloric add (2 x 20ml). The combined aqueous was washed with Et∑O (20ml) then basified to pH=l2 with 40% sodium hydroxide solution and extracted with dichloromethane (4 x 20ml). The combined organics were dried (potassium carbonate) then evaporated to give the title compound as a colourless oil (2.16g, 69%). MS, ES⁺, m/z = 317 for (M+H)⁺; δ (250MHz, Dβ-DMSO) 0.90 (6H, s, 2 x CHs), 1.09-1.14 (2H, m, CH₂), 1.34-1.62 (6H, 3 x CH₂), 2.13 (4H, s, 2 x CHaN), 2.25-2.45 (6H, 3 x CHuN), 3.43 (2H, s, CHjPh), 3.80 (IH, s, OH), 7.19-7.34 (5H, m, Ar-H).

c) 4-(3.3-Dimethylpiperidin-l-yl)methyl-4-hvdroxypiperidine

The foregoing benzyl-pip eridine (2.03g, 6.42mmol) in methanol (60ml) was treated with formic add (90%, 1ml), ammonium formate (1.2 lg, 19.3mmol) then 10% palladium on carbon (500mg). The reaction mixture was stirred at room temperature for 18h, then filtered and evaporated. The residue was partitioned between dichloromethane

(80ml), methanol (10ml) and 10% potassium carbonate solution (20ml). The organic layer was separated and the aqueous extracted with dichloromethane (2 x 50ml). The combined organic layers were dried (potassium carbonate), then evaporated to give a gum which was purified using a short siUca column, eluting with dichloromethane/methanol/ ammonia (5:1:0.1) to give the title compound as a colourless oil which soUdified on standing (l.Og, 69%), mp 48-52°C; MS, ES⁺, m/z = 227 for (M+H)⁺; δ (250MHz, Dβ-DMSO) 0.90 (6H, s, 2 x CHs), 1.10-1.14 (2H, m, CH₂), 1.24-1.54 (6H, m, 3 x CH₂), 2.11 (2H, s, CH₂N), 2.11-2.13 (2H, m, CH∑N), 2.34-2.39 (2H, m, CH2N), 2.52-2.60 (2H, m, CH2N). 2.69-2.79 (2H, m, CH2N), 3.80 (IH, br s, OH).

d) 4-(f3.3-Dimethylpiperidin- 1 -yllmethyl)-4-hvdroxy- 1 -(3-f 5-( 1.2.4- triazol-4-yl^')-lH-indol-3-vnpropyl)piperidine. Hydrogen Oxalate. 3-[5-(1.2,4-Triazol-4-yl)-lH-indol-3-yl]propan- l-ol (300mg,

1.23mmol) was converted to the mesylate as previously described. This mesylate (343mg) in propan-2-ol (70ml) was treated with 4-(3,3- dimethylpiperidin-l-yl)methyl-4-hydroxypiperidine (315mg, 1.39mmol) and potassium carbonate (192mg, 1.39mmol) then heated at reflux, with stirring, for 20h. The reaction mixture was evaporated then the residue was partitioned between dichloromethane (40ml) and water (20ml). The organic layer was separated then the aqueous was re-extracted with dichloromethane (40ml). The combined organics were dried (potassium carbonate) then evaporated to give a yellow gum (512mg) which was purified by column chromatography on siUca using dichloromethane/methanol/ammonia (9: 1:0. l— 5: 1:0.1) to give the title compound free base as a colourless gum (130mg, 27%). The hydrogen oxalate salt had mp 125-132°C. δ (360MHz, Dβ-DMSO) 0.94 (6H, s, 2 x CHs), 1.19-1.27 (4H, m, 2 x CH₂), 1.55-1.59 (2H, m, CH₂), 1.64-1.70 (2H, m, CHu), 1.80-1.92 (2H, m, CH₂), 2.04-2.09 (2H, m, CH2CΗ_>CH₂), 2.38-2.62 (6H, m, 3 x CH2N), 2.78 (2H, t, J=7Hz, CH₂-indole), 3.00-3.18 (4H, m, 2 x CH2N), 3.34-3.40 (2H, m, CH-ΪN), 7.32-7.35 (2H, m, Ar-H), 7.51 (IH, d, J=8Hz, Ar-H), 7.82 (IH, d, J=2Hz, Ar-H), 9.03 (2H, s, triazole-H), 11.20 (IH, s, indole-NH). (Found: C, 54.43; H, 6.98; N, 11.25.

C26H38NβO*2.8(C2H2θ )*0.5(C2Hδ)2θ requires C, 54.55; H, 6.62; N, 11.36%). MS, ES\ m/z = 451 for (M+H)⁺.

EXAMPLE 66

4-Hvdroxy-4-(ri.2.3.4-tetrahvdroisoαuinoUn-2-vnmethyl)-l-(3-f5-(1.2.4- triazol-4-yl)-lH-indol-3-vnpropyl)piperidine. Hydrogen Oxalate.

a) l-Ben2^1*4-hvdroxy*4-(1.2.3.4-tetrahvdroisocιuinolin-2-yl)methylpiperidin

The title compound was obtained (2.3g, 82%) from 6-aza-6-benzyl-l- oxaspiro[2.5]octane and 1,2,3,4-tetrahydroisoquinoUne, mp 57-58°C. MS, ES^*, m/z = 337 for (M+H)^*. b) 4-Hvdroxy-4-(1.2.3.4-tetrahvdroisoQuinoUn-2-vDmethyl piperidine The title compound was obtained (1.0 lg, 69%) from the foregoing benzyl-piperidine, formic add, ammonium formate and 10% palladium on carbon in methanol, mp 92-93°C. MS, ES⁺, m/z = 247 for (M+H)⁺; δ (360MHz, Dβ-DMSO) 1.36-1.52 (4H, m, 2 x CH₂), 2.39 (2H, s, CHs.N),

2.55-2.62 (2H, m, CH2N), 2.72-2.78 (2H, m, CHϋN), 2.80 (4H, s, CHϋPh and CH__N), 3.69 (2H, s, NCH__Ph), 3.98 (IH, s, OH), 7.00-7.12 (4H, m, Ar-H).

c) 4-Hvdroxy-4-(fl.2.3.4-tetrahvdroisoαuinolin-2-vnmethyl)-l-(3-f5- (1.2.4-triazol-4-yl)-lH-indol-3-vnpropylpiperidine. Hydrogen Oxalate.

The title compound free base (191mg, 38%) was obtained from 4-hydroxy-4-(l,2,3,4-tetrahydroisoquinoUn-2-yl)methyl piperidine and the mesylate obtained from 3-[5-(l,2,4-triazol-4-yl)-lH-indol-3-yl]propan-l-ol. The hydrogen oxalate salt had mp 160-165°C. δ (360MHz, Dβ-DMSO) 1.66-1.94 (4H, m, 2 x CH₂), 1.98-2.10 (2H, m, CH₂£H₂CH₂), 2.58 (2H, br s, CHϋN), 2.77 (2H, t, J=7Hz, CH∑-indole), 2.83-2.87 (2H, m), 2.91-2.95 (2H, m), 3.00-3.18 (4H, m) and 3.30-3.40 (2H, m, 4 x CH∑N, CH₂-Ph), 3.82 (2H, s, N- CH₂-Ph), 7.00-7.16 (4H, m, Ar-H), 7.30-7.35 (2H, m, Ar-H), 7.51 (IH, d, J=8Hz, Ar-H), 7.80 (IH, s, Ar-H), 9.02 (2H, s, triazole-H), 11.19 (IH, s, indole-NH). (Found: C, 57.82; H, 5.81; N, 11.96. C28H34NβO*2.35(C2H2θ₄) requires C, 57.57; H, 5.72; N, 12.31%). MS, ES⁺, m/z = 471 for (M+H)⁺.

EXAMPLE 67

4-Hvdroxy-4-([N-isobutyl-N-methyl1aminomethyl)-l-(3-f5-(1.2.4-triazol-4- yl)-lH-indol-3-yl.propyDpiperidine

a) 6-Aza-6-t-butyloxycarbonyl-l-oxaspiro[2.51octane

Dimethyl sulphoxide (100ml) was added dropwise to a stirred, cooled (10°C) mixture of sodium hydride (3.70g of a 55% oil dispersion,

0.0846mol) and trimethylsulphoxonium iodide (18.6g, 0.0846mol) under a nitrogen atmosphere. After addition the cooling bath was removed and the mixture stirred at room temperature for 30 minutes, then cooled to 5°C and was treated with a solution of N-t-butoxycarbonyl-4-piperidone (16.86g, 0.0846mol) in dimethylsulphoxide (50ml). The cooling bath was removed and the reaction mixture stirred at room temperature for 15 minutes, then at 50°C for 1 hour. The mixture was stirred whilst cooling to room temperature then quenched with water (40ml) and stirred for a further 10 minutes. The reaction mixture was poured into water (600ml) and extracted with toluene (4 x 300ml). The combined organics were washed with water (300ml), dried (sodium sulphate) then evaporated to give an oil which was eluted through a short siUca column using ethyl acetate/n-hexane (1:1) to give a colourless soUd (lO.Og, 5δ%), mp 49-51°C; δ (360MHz, Dβ-DMSO) 1.35-1.40 (2H, m, CH₂), 1.41 (9H, s, C(CH3)₃), 1.60- 1.67 (2H, m, CH₂), 2.65 (2H, s, CH₂O), 3.33-3.41 (2H, m, CH₂), 3.46-3.54 (2H, m, CH₂). (Found: C, 61.88; H, 9.05; Ν, 6.42. C11H.9ΝO3 requires C, 61.95; H, 8.98; N, 6.57%). MS, ES⁺, m/z = 214 for (M+H)⁺.

b) l-t-Butyloxycarbonyl-4-hvdroxy-4-(rN-isobutyl-N- methyll aminomethylroiperidine A mixture of the preceding compound (3g, 0.0 Mmol) and isobutylamine (7ml, 0.0704mol) was heated in ethanol (30ml) at 60°C for 2h. The reaction mixture was evaporated to dryness and the residue eluted through a short silica column using dichloromethane/methanol ammonia (9:1:0.1) to give l-t-butyloxycarbonyl-4-hydroxy-4-(N- isobutylaminomethyl)piperidine (3.4g, 85%) as a colourless viscous gum, MS, ES^*, m/z = 287 for (M+H)\ This amine (3.3g, O.Ol lδmol) in methanol (30ml) was treated with formaldehyde (1.4ml of a 37% aqueous solution, 0.0173mol) and acetic add (3.3ml, 0.0575mol). After 5 minutes the solution was treated portion wise with sodium cyanoborohydride (1.09g, 0.0173mol) and the mixture was stirred at room temperature for 2h then quenched with saturated aqueous potassium carbonate (50ml). The methanol was evaporated and the aqueous extracted with dichloromethane (4 x 50ml). The combined organics were dried (potassium carbonate) then evaporated to give a yellow gum which was eluted through a short siUca column using dichloromethane/methanol (10:1) to give the title compound as a colourless gum (2.63g, 76%). δ (360MHz, Dβ-DMSO) 0.83 (6H, d, J=7Hz, 2 x CH₃), 1.35-1.48 (4H, m, 2 x CH₂) overlapped with 1.38 (9H, s, C(CHs)3), 1.61-1.69 (IH, m, CH), 2.11 (2H, d, J=7Hz, CH₂CH), 2.22 (3H, s, NCH₃), 2.23 (2H, s, CH₂N), 3.02-3.08 (2H, m, CHϋN), 3.60 (2H, d, J=13Hz, CH2N), 4.09 (IH, s, OH); MS, ES⁺, m/z = 301 for (M+H)\

c) 4-Hvdroxy-4-(rN-isobutyl-N-methvnaminomethyl)piperidine

The foregoing amine (2.55g, 8.49mmol) in dichloromethane (30ml) was treated with trifluoroacetic add (6.5ml, 84.9mmol) and the solution was left standing for 18h, then evaporated and partitioned between saturated aqueous potassium carbonate (15ml) and dichloromethane (40ml) containing methanol (2ml). The organic layer was separated and the aqueous re-extracted with dichloromethane (3 x 40ml). The combined organics were dried (potassium carbonate) then evaporated to give a pale yeUow gum (1.7g) which was eluted through a short siUca column using dichloromethane/methanol/ammonia (5:1:0.1) to give the title compound as a viscous colourless gum (1.44g, 85%). δ (360MHz, Dβ-DMSO) 0.84 (6H, t, J=7Hz, 2 x CHO, 1.31-1.47 (IH, m, CH), 2.11 (2H, d, J=7Hz, ΝCH₂CH), 2.21 (2H, s, CHJN), 2.23 (3H, s, NCH3), 2.57-2.63 (2H. m. CH2N), 2.73-2.80 (2H, m, CH2N); MS, ES⁺, m/z = 201 for (M+H)\

d) 4-Hvdroxy-4-(rN-isobutyl-N-methvnaminomethyl)-l-(3-f5-(1.2.4- triazol-4-yl)-lH-indol-3-yl-Propyl)piperidine

The title compound (230mg, 65%) was obtained from 4-hydroxy-4- ([N-isobutyl-N-methyl]aminomethyl)piperidine and the mesylate, obtained from 3-[5-(l,2,4-triazol-4-yl)-lH-indol-3-yl]propan- l-ol. in propan-2-ol using potassium carbonate as base, mp>60°C. δ (360MHz, Dβ- DMSO) 0.84 (6H, d, J=6.5Hz), 2 x CHs), 1.37-1.49 (2H, m, CH₂), 1.49-1.60 (2H, m, CH₂), 1.60-1.72 (IH, m, CH), 1.75-1.86 (2H, m, CH₂CH₂CH₂), 2.11 (2H, d, J=7Hz, £H₂CH), 2.21 (2H, s, CH2N), 2.22 (3H, s, NCH3), 2.20-2.35 (4H, m) and 2.37-2.52 (2H, m, 3 x CHsN), 2.71 (2H, t, J=7Hz, CHu-indole), 3.77 (IH, s, OH), 7.26 (IH, d, J=2Hz, Ar-H), 7.28 (IH, dd, Jι=2Hz, J₂=8Hz, Ar-H), 7.47 (IH, d, J=8Hz, Ar-H), 7.77 (IH, d, J=2Hz, Ar-H), 9.00 (2H, s, triazole-H), 11.05 (IH, s, indole-NH); MS, ES⁺, m/z = 425 for (M+H)⁺.

(Found: C, 66.38; H, 8.71; N, 18.90.

H2O requires C, 66.07; H, 8.62; N, 19.26%).

EXAMPLE 68

4-N-Benzyl-N-(2-hvdroxyethyl)aminomethvn-4-hvdroxy-l-(3-rδ-(1.2.4- triazol-4-yl)-lH-indol-3-vnpropyl)piperidine.

a) l^Butyloxy(3-ibσnyl-4-hvdιoxy-4^

The title compound was prepared from 6-aza-6-tert- butyloxycarbonyl-l-oxaspiro[2.δ]octane and ethanolamine. MS, ES^*, m/z = 275 for (M+H)⁺.

b) l-t-Butyloxycarbonyl-4-hvdroxy-4-(N-benzyl-N-[2-hvdroxyethyll aminomethvDpiperidine

The title compound was prepared (0.59g, 62%) from the foregoing piperidine. benzaldehyde, sodium cyanoborohydride and acetic add in methanol. MS, ES\ m/z = 365 for (M+H)^*, δ (360MHz, De-DMSO) 1.30- 1.45 (4H, m, 2 x CH2), 1.39 (9H, s, 3 x CHO, 2.48 (2H, s, CH2Ν). 2.54 (2H, t, J=6Hz, CH2N), 3.06 (2H, br s. 2 x CH), 3.44 (2H, q, J=6Hz, CH2O), 3.57 (2H, d, J=l3Hz, 2 x CH), 3.71 (2H. s. NCH₂Ph), 4.32 (IH, s, OH). 4.47 (IH, t, J=6Hz. OH), 7.22-7.36 (5H, m, Ar-H). c) 4-(N-Benzyl-N-f2-hvdroxyethyl1aminomethyl)-4-hvdroxypiperidine The title compound was obtained (0.44g, 100%) from the foregoing piperidine and trifluoroacetic add in dichloromethane. MS, ES^*, m/z = 265 for (M+H)⁺, δ (360MHz, Dβ-DMSO) 1.37-1.42 (4H, m, 2 x CH₂), 2.46 (2H, s, CHiΝ), 2.54-2.62 (2H, m, 2 x CH), 2.63 (2H, t, J=6Hz, CH₂Ν), 2.73- 2.81 (2H, m 2 x CH), 3.45 (2H, t, J=6Hz, CH₂0), 3.71 (2H, s, NCH^h), 4.14 (IH, br s, OH), 4.50 (IH, s, OH), 7.20-7.38 (5H, m, Ar-H).

d) 4-fN-Benzyl-N-(2-hvdroxyethyl)aminomethyll-4-hvdroxy-l-(3-fδ- (1.2.4-triazol-4-yl)- lH-indol-3-yriprop vDpiperidine

The title compound (lδδmg, 30%) was obtained from 4-(4-[N-benzyl- N-(2-hydroxyethyl)]aminomethyl)-4-hydroxypiperidine and the mesylate prepared from 3-[5-(l,2,4-triazol-4-yl)-lH-indol-3-yl]propan-l-ol in propan-2-ol using potassium carbonate as base, mp 75-78°C. δ (360MHz, Dβ-DMSO) 1.41-1.46 (4H, m, 2 x CH₂), 1.76-1.80 (2H, m, CH1.CH2CH2), 2.20-2.40 (6H, m, 3 x CH2N), 2.44 (2H, s, CHJN), 2.63 (2H, t, J=6Hz, CH2N), 2.69 (2H, t, J=7Hz, CH₂-indole), 3.43 (2H, q, J=6Hz, CH2O), 3.70 (2H, s, NCH2PI1), 4.04 (IH, s, OH), 4.45 (IH, t, J=6Hz, OH), 7.19-7.35 (7H. m), 7.46 (IH, d, J=8Hz) and 7.77 (9H, d, J=2Hz, 9 x Ar-H), 9.01 (2H, s, triazole-H), 11.05 (IH, s, indole-NH); MS, ES^*, m/z = 489 for (M+H)^*.

(Found: C, 68.41; H, 7.21; N, 16.29. C28H3βNβθ2 θ.2(C₄HιoO) requires C, 68.71; H, 7.60; N, 16.69%).

EXAMPLE 69

4-fN-(2.2-Dimethylpropyl)-N-methylaminomethyll-4-hydroxy- l-(3-[5- (1.2.4-triazol-4-yl)-lH-indol-3-yl]propyl)piperidine.

a) 4-fN-(2.2-Dimethylpropy aminomethvn-4-hvdroxy-l-(3-f5-(1.2.4- triazol-4-yl)-lH-indol-3-yllpropyl')piperidine The title compound was obtained (240mg, 75%) from 4-aminomethyl-4-hydroxy-l-(3-[5-(l,2,4-triazol-4-yl)-lH-indol-3- yllpropyl)piperidine, sodium cyanoborohydride, trimethylacetaldehyde and acetic add in methanol, mp>55°C. MS, ES^*, m/z = 425 for (M+H)^*; δ (360MHz, Dβ-DMSO) 0.85 (9H, s, 3 x CH₃), 1.40-1.52 (4H, , 2 x CKb), 1.75-1.86 (2H, m, CH₂CH₂CH₂), 2.27 (2H, s, CΕLzN), 2.20-2.35 (4H, m, 2 x CHaN), 2.39-2.50 (2H, m, CH2N), 2.42 (2H, s, CHJJSO, 2.71 (2H, t, J=7Hz, CH₂-indole), 4.00 (IH, s, OH), 7.26 (IH, d, J=2Hz, Ar-H), 7.29 (IH, dd, Jι=2Hz, J₂=8Hz, Ar-H), 7.47 (IH, d, J=8Hz, Ar-H), 7.77 (IH, d, J=2Hz, Ar-H), 9.00 (2H, s, triazole-H), 11.05 (lH, s, indole-NH).

b) 4-[N-(2.2-Dimethylpropyl)-N-methylaminomethyll-4-hvdroxy-l-(3- 5-(1.2.4-triazol-4-yl)-lH-indol-3-vnpropyl)piperidine.

The title compound was obtained (lOOmg, 74%) from the foregoing amine and formaldehyde in the presence of acetic add and sodium cyanoborohydride in methanol as solvent, mp>70°C. MS, ES^*, m/z = 439 for (M+H)^*; δ (360MHz, Dβ-DMSO) 0.86 (9H, s, 3 x CH3), 1.46-1.52 (4H, m, 2 x CH2), 1.76-1.86 (2H, m, CH2CH2CH2), 2.18 (2H, s, CH2Ν), 2.20-2.38 (6H, m, 3 x CH2N), 2.37 (3H, s, NCHs), 2.42-2.52 (2H, m, CH2N), 2.72 (2H, t, J=7Hz, indole-CH₂), 3.82 (IH, s, OH), 7.27 (IH, d, J=2Hz, Ar-H), 7.30 (IH, dd, Jι=2Hz, J₂=8Hz, Ar-H), 7.47 (IH, d, J=8Hz, Ar-H), 7.77 (IH, d, J=2Hz, Ar-H), 9.01 (2H, s, triazole-H), 11.06 (IH, s, indole-NH). (Found:

C, 67.40; H, 8.89; N, 18.62. C-aHwiNβO O.δ H2O requires C, 67.08; H, 8.78;

N, 18.77%).

EXAMPLE 70

4-(fN-(RVα-Hvdroxymethylbenzyl-N-methyl]aminomethyl)-4-hvdroxy-l- (3-[5-(1.2.4-triazol-4-yl)-lH-indol-3-yllpropyl.piperidine. a) l-f-Butyloxycarbonyl-4-hvdroxy-4-(fN-(R^')-α-hvdroxymethylbenzvn aminomethvDpjp eridine

The title compound was obtained (2g, 78%) from 6-aza-6--terf- butyloxycarbonyl-l-oxaspiro[2.5]octane and (R)-phenylglycinol.

b) 4-Hvdroxy-4(rN-(R)-α-hvdroxymethylben7γ11aminomethyl)pippri ine

The foregoing protected piperidine (1.9g, 5.4mmol) was stirred with trifluoroacetic add (5ml) in dichloromethane (10ml) for 3h. The solvent was evaporated and the residue azeotroped with toluene, then partitioned between water and dichloromethane and basified with saturated aqueous potassium carbonate. The organic layer was separated and the aqueous re-extracted with dichloromethane (x3). The combined organics were dried (sodium sulphate) then evaporated to give the product as a gum (600mg, 44%), δ (360MHz, Dβ-DMSO) 1.32-1.52 (4H, m, 2 x CHz), 2.56 (2H, s, CH2Ν), 2.47-2.52 (2H, m, tisN), 2.70-2.76 (2H, m, CH2N), 3.28 (IH, dd,

NCHPh), 3.42-3.47 (IH, m) and 3.59-3.63 (IH, m, CH2OH), 4.12 (IH, br s, OH), 4.94 (IH, br s, OH), 7.20-7.35 (5H, m, Ar-H).

c) 4-(fN-(RVα-Hvdroxymethylbenzyl1aminomethyl)-4-hvdroxy-l-(3-r5- (1.2.4-triazol-4-yl)-lH-indol-3-yl1propyl)piperidine

The title compound was prepared (290mg, 68%) from the foregoing piperidine and the mesylate prepared from 3-[5-(l,2,4-triazol-4-yl)-lH- indol-3-yl]propan-l-ol in propan-2-ol using potassium carbonate as base, mp>55°C. MS, ES^*, m/z = 475 for (M+H)^*. (Found: C, 66.73; H, 7.30; N, 16.87. C27H3-1N6O2 O.8 H2O requires C, 66.32; H, 7.34; N, 17.19%.

d) 4-(fN-(RVα-Hvdroxymethylbenzyl-N-methyllaminomethyl^')-4- hvdroxy- l-(3-f5-(1.2.4-triazol-4-yl)-lH-indol-3-vnpropyl)piperidine.

The title compound was obtained (140mg, 90%) from the foregoing benzylamine, formaldehyde, sodium cyanoborohydride and acetic add in methanol, mp>75°C. MS, ES^*, m/z = 489 for (M+H)^*; δ (360MHz, Dβ-DMSO) 1.40-1.56 (4H, m, 2 x CH₂), 1.72-1.88 (2H, m, CH2CH2CH2), 2.23 (3H, s, NCH3), 2.18-2.56 (6H, m, 3 x CH2N), 2.36 (2H, s, CH₂N), 2.72 (2H, t, J=7Hz, indole-CH₂), 3.58-3.70 (2H, m, CHO and CH-phenyl), 3.80- 3.88 (IH, m, CHO), 4.07 (IH, s, OH), 4.58 (IH, t, J=6Hz, OH), 7.20-7.33 (7H, m, Ar-H), 7.48 (IH, d, J=8Hz, Ar-H), 7.78 (IH, d, J=2Hz, Ar-H), 9.02 (2H, s, triazole-H), 11.07 (IH, s, indole-NH). (Found: C, 67.02; H, 7.60;

N, 15.89.

H₂O. 0.6(C2HβO) requires C, 67.00; H, 7.78; N, 16.05%).

EXAMPLE 71

4-Hvdroxy-4-(f2-Pyridylmethyllamino^')methyl-l-(3-r5-(1.2.4-triazol-4-yl)- lH-indol-3-vHpropylroiperidine.

The title compound was obtained using a procedure similar to

4-(benzylamino)methyl-4-hydroxy-l-(3-[5-(l,2,4-triazol-4-yl)-lH-indol-3- yl]propyl)piperidine, using 2-pyridinecarboxaldehyde in the final step. mp>55°C; δ (360MHz, Dβ-DMSO) 1.40-1.53 (4H, m, 2 x CH2), 1.72-1.87 (2H, m, CH2CH2CH2), 2.20-2.37 (6H, m, 3 x CH2N), 2.44 (2H, s, CH2NH), 2.71 (2H, t, J=7Hz, CH₂-indole), 3.80 (2H, s, NHCH2 pyridyl), 4.08 (IH, br s, OH), 7.20-7.32 (3H, m, Ar-H), 7.41 (IH, d, J=7Hz, Ar-H), 7.46 (IH, d, J=8Hz, Ar-H), 7.72 (IH, dd, Jι=2Hz, J₂=8Hz, Ar-H), 7.77 (IH, d, J=2Hz, Ar-H), 8.46 (IH, d, J=8Hz, Ar-H), 9.01 (2H, s, triazole-H), 11.05 (IH, s, indole-NH). MS. ES^*, m/z = 446 for (M+H)^*. (Found: C, 62.07; H, 7.19; N, 19.57. C25H31N7O I.I H₂O*0.3(CH₂Cl2) requires C, 61.91; H, 6.94; N, 19.97%).

EXAMPLE 72

4-Hvdroxy-4-([2-methylphenylmethyllamino)methyl- l-(3-f5-(1.2.4-triazol- 4-yl)-lH-indol-3-yllpropyl)piperidine. Hydrogen Oxalate. The title compound was obtained using a procedure similar to 4-(benzylamino)methyl-4-hydroxy-l-(3-[5-(l,2,4-triazol-4-yl)-lH-indol-3- yl]propyl)piperidine. The hydrogen oxalate salt had mp>138°C-(dec); δ (360MHz, Dβ-DMSO) 1.70-1.90 (4H, m, 2 x CH₂), 2.00-2.10 (2H, m, CH₂CH₂CH₂), 2.34 (3H, s, CHs), 2.70-2.80 (2H, m, CH₂-indole), 2.89 (2H, s, CHϋNH), 3.00-3.10 (4H, m) and 3.20-3.30 (2H, m, 3 x CΑi ), 4.06 (2H, s, NHCH∑Ar), 7.16-7.26 (3H, m, Ar-H), 7.30-7.35 (2H, m, Ar-H), 7.43-7.52 (2H, m, Ar-H), 7.80 (IH, d, J=2Hz, Ar-H), 9.01 (2H, s, triazole-H), 11.19 (IH, s, indole-NH). MS, ES⁺, m/z = 459 for (M+H)⁺. (Found: C, 55.89; H, 6.03; N, 11.50. C27H3₄N₆O*2.7(C2H₂O₄) requires C, 55.46; H, 5.66; N, 11.98%).

EXAMPLE 73

4-Hvdroxy-4-(fN-2-methylphenylmethyl-N-m^pt.hyl a^* ino)methyl-l-(3-f5- (1.2.4-triazol-4-yl)-lH-indol-3-yl]propyl)piperidine. Hydrogen Oxalate. The title compound was prepared (45mg, 64%) from the foregoing amine, using the procedure described for 4-([N-Benzyl-N-methyl] amino) methyl-4-hydroxy-l-(3-[5-(l,2,4-triazol-4-yl)-lH-indol-3-yl]propyl)piperidine. The hydrogen oxalate salt had mp>l 10°C (dec); δ (360MHz, Dβ-DMSO) 1.55-1.70 (4H, m, 2 x CH₂), 1.98-2.10 (2H, m, CH2CH2CH2), 2.32 (6H, s, 2 x CHO, 2.47 (2H, s, CH2N), 2.75 (2H, t, J=7Hz, CH₂-indole), 2.96-3.10 (4H, m) and 3.20-3.30 (2H, m, 3 x CH2N), 3.58 (2H, s, NCH__Ar), 7.05-7.20 (3H, m, Ar-H), 7.25-7.40 (3H, m, Ar-H), 7.50 (IH, d, J=8Hz, Ar-H). 7.80 (IH, d, J=2Hz, Ar-H), 9.01 (2H, s, triazole-H), 11.19 (IH, s, indole-NH). MS, ES^*, m/z = for 473 (M+H)^*. (Found: C, 56.93; H, 6.42; N, 11.97. C28H36N₆O*2(C2H₂O ) requires C, 56.55; H, 6.38; N, 12.36%). EXAMPLE 74

3-(Benzylamino)methyl-3-hvdroxy-l-(3-f5-(1.2.4-triazol-4-yl)- lH-indol-3- vnpropyDpyrroUdine.

a) l-Benzyl-3-(t-butyloxycarbonylamino)methyl-3-hvdroxypyrroUdine 3-Aminomethyl-l-benzyl-3-hydroxypyrroUdine was prepared from l-benzyl-3-pyrroUdinone using the procedure described in Synth. Commun., 1994, 24 (10), 1483. This crude amine (9.4g, 45mmol) in dichloromethane (200ml) was treated with di-t-butyl dicarbonate (lOg, 45mmol) and the reaction mixture was stirred at room temperature for 48h. The solvent was evaporated and the crude product was purified by column chromatography on siUca using methanol/dichloromethane (1:20). The title compound was obtained as a gum (2.3g, 17%). MS, ES^*, m/z = 307 for (M+H)^*; δ (250MHz, Dβ-DMSO) 1.37 (9H, s, 3 x CH , 1.52-1.62 (IH, m, CH), 1.76-1.87 (IH, m, CH), 2.27 (IH, d, J=10Hz, CHNH), 2.42- 2.64 (3H, m, CHNH, CH2N), 3.00-3.09 (2H, m, CH2N), 3.52 (2H, s, CH.iPh), 4.67 (IH, s, OH), 6.61 (IH, t, J=6Hz, NH), 7.18-7.33 (5H, m, Ar-H).

b) 3-(t-Butyloxycarbonylamino)methyl-3-hvdroxypyτroUdine A solution of the foregoing benzylamine (2.2g, 7.2mmol) in methanol (40ml) was treated with ammonium formate (l.lg) and 10% palladium on carbon (l.lg). The reaction mixture was stirred at room temperature for 4h, filtered, then evaporated. The residue was dissolved in water; basified with potassium carbonate then extracted with dichloromethane (x5). The combined organics were dried (sodium sulphate) then evaporated to give the required product as a gum (1.4g, 91%). δ (250MHz, Dβ-DMSO) 1.38 (9H, s, 3 x CHO, 1.48-1.69 (2H, m, CH2), 2.52 (IH, d, J=l 1Hz, CHNH), 2.62 (IH, d, J=l 1Hz, CHNH), 2.65- 2.94 (2H, m, CH2N), 3.06 (2H, d, J=6Hz, CH2N), 4.59 (IH, br s, OH), 6.66 (IH, t, J=6Hz, NHCO).

c) 3-(f-Butyloxycarbonylamino)methyl-3-hvdroxy-l-(3-f5-1.2.4-triazol- 4-yl)-lH-indol-3-vnpropy pyrroUdine

The title compound was prepared (300mg, 30%) from the foregoing amine and the mesylate prepared from 3-[5-(l,2,4-triazol-4-yl)-lH-indol- 3-yllpropan-l-ol in propan-2-ol using potassium carbonate as base, δ (250MHz, Dβ-DMSO) 1.35 (9H, s, 3 x CH3), 1.50-1.60 (IH, m, CH), 1.70- 1.84 (3H, m, CH and CH₂CH₂CH₂), 2.26 (IH, d, J=10Hz, CHNH), 2.38 (2H, t, J=8Hz, CHuN), 2.45-2.60 (2H, m, CH.^ , 2.58 (IH, d, J=10Hz, CHNH), 2.73 (2H, t, J=8Hz, CH₂-indole), 2.98-3.04 (2H, m, CH^, 4.64 (IH, s, OH), 6.60 (IH, t, J=6Hz, NHCO), 7.26-7.32 (2H, m, Ar-H), 7.46 (IH, d, J=8Hz, Ar-H), 7.78 (IH, d, J=2Hz, Ar-H), 9.02 (2H, s, triazole-H), 11.07 (IH, s, indole-NH).

d) 3-reenzylammo)methyl-3-hvdroxy- l-(3-r5-(1.2.4-triazol-4-yl)- 1H- indol-3-yllpropyl)pyrroUdine

The title compound was prepared from the foregoing t-butyloxycarbonyl-protected compound as described for

4-(benzylamino)methyl-4-hydroxy-l-(3-[5-(l,2,4-triazol-4-yl)-lH-indol-3- yl]propyl)piperidine. mp>61°C. MS, ES^*, m/z = 431 for (M+H)^*; δ (360MHz, Dβ-DMSO) 1.57-1.67 (IH, m, CH), 1.72-1.86 (3H, m, CH and CH2CH2CH2)), 2.31-2.65 (8H, m 4 x CH2N), 2.72 (2H, t, J=7Hz, CH₂-indole), 3.72 (2H, s, NHCH2PI1), 4.56 (IH, s, OH), 7.15-7.32 (7H, m. Ar-H), 7.47 (IH, d. J=8Hz, Ar-H), 7.77 (IH, d, J=2Hz, Ar-H), 9.00 (2H, s, triazole-H), 11.06 (IH, s, indole-NH). (Found: C, 68.40; H, 6.53; N, 18.73.

C2sH3oNβO*0.15(CH2Cl₂) requires C, 68.14; H, 6.89; N, 18.96%). EXAMPLE 75

3-(Benzylamino)methyl-3-hvdroxy-l-(2-r5-(1.2.4-triazol-4-yl)-lH-indol-3- yllethvDpyrroUdine. The title compound was prepared from 3-(t-butyloxycarbonylamino) methyl-3-hydroxypyrroUdine and l-chloro-2-[5-(l,2,4-triazol-4-yl)-lH- indol-3-yl]ethane (prepared from 2-[5-(l,2,4-triazol-4-yl)-lH-indol-3- yljethanol), followed by deprotection and fiinctionalisation as described for 4-(benzylamino)methyl-4-hy droxy- 1 -(3- [5-( 1 ,2 ,4-triazol-4-yl)- lH-indol-3- yl]propyl)piperidine. mp>56°C. MS, ES^*, m/z = 417 for (M+H)^*; δ (360MHz, Dβ-DMSO) 1.60-1.68 (IH, m, CH), 1.80-1.88 (IH, m, CH), 2.40- 2.76 (8H, m, 4 x CΕL2N), 2.84 (2H, t, J=7Hz, CH₂-indole), 3.72 (2H, s, NHCHjsAr), 4.56 (IH, s, OH), 7.17-7.36 (7H, m, Ar-H), 7.47 (IH, d, J=8Hz, Ar-H), 7.78 (IH, d, J=2Hz, Ar-H), 9.01 (2H, s, triazole-H), 11.07 (IH, s, indole-NH). (Found: C, 67.40; H, 6.68; N, 19.54. CwH∞NβO O.δ H₂O requires C, 67.74; H, 6.87; N, 19.75%).

EXAMPLE 76

l-<3-r5-(1.2.4-Triazol-4-ylVlH-indol-3-yllpropyU-4-<(R)- -f(carbamoyl) oxymethvHbenzylamino-Piperidine. 1.75 Hydrogen Oxalate.

1. (R)-α-f(carbamoyl)oxymethyl]benzylamine

To a stirred solution of N-tert-butyloxycarbonyl-(R)-2- phenylglydnol (500mg, 2.1mmol) in anhydrous dichloromethane (10ml) was added dropwise, under nitrogen, trichloroacetyl isocyanate (275μl, 2.31mmol) over 2 minutes. The resulting clear colourless solution was stirred at room temperature for 45 minutes before neutral alumina (activity III; 12g) was added and stirring was continued for a further 40 minutes. The mixture was filtered, and the alumina was washed with dichloromethane (1 x 25ml) and with dichloromethane-ethyl acetate (1:1, 3 x 25ml). The filtrate was concentrated under vacuum to leave a white soUd which was dissolved in dichloromethane-trifluoroacetic add (3:1, 40ml) and the solution was allowed to stand at room temperature for 36 minutes. Solvents were removed under vacuum and the residue was azeotroped with methanol (2 x 50ml). Flash chromatography of the residue (siUca gel, dichloromethane/methanol/ammonia, 90:10:1) gave 333mg (885) of the title compound as a white soUd: δH (360MHz, CDCla) 4.06 (IH, dd, J=11.8Hz and 9.5Hz), 4.21-4.28 (2H, m), 4.68 (2H, br s), 7.24-7.40 (5H, m); m/e (ES) 181 (M^*+l).

2. l-(3-r5-(1.2.4-Triazol-4-ylVlH-indol-3-yllpropyl)-4-((R)-α- f(carbamoyl) oxymethyllbenzylaminolpiperidine. 1.75 Hydrogen Oxalate.

The title compound was prepared in 65% yield from l-{3-[5-(l,2,4- triazol-4-yl)-lH-indol-3-yllpropyl}-4-ketopiperidine and (R)-α- [(carbamoyl) oxymethyl]benzylamine using a similar method to that described for Example 8 (step 5), mp 135-140°C (EtOH). (Found: C, 56.56; H, 5.89;

N, 15.34. C27H33N₇O₂- 1.75(C2H₂O₄) requires: C, 56.78; H, 5.70; N, 15.20%). δ_H (360MHz, DMSO-dβ; 353°K) 1.44-1.62 (2H, m), 1.74-1.82 (IH, m), 1.88-2.06 (3H, m), 2.55-2.68 (IH, m), 2.72-2.90 (4H, m), 2.91-3.00 (2H, m), 3.18-3.32 (2H, m), 3.92-4.06 (3H, m), 6.18 (2H, s,), 7.20-7.40 (7H, m), 7.48 (IH, d, J=8.6Hz), 7.73 (IH, d, J=2.0Hz), 8.87 (2H, s,), 10.97 (IH, s); m/e (ES) 488 (M^* +l).

EXAMPLE 77

l-<3-r5-(1.2.4-Triazol-4-yl)-lH-indol-3-yl1propyl)-4-{r(lR.2S)-2-hvdroxy- l- phenyl.propylamino.piperidine. 2.45 Hydrogen Oxalate.

The title compound was prepared from l-{3-[5-(l,2,4-triazol-4-yl)- lH-indol-3-yllpropyl}-4-ketopiperidine and (lR,2S)-l-amino-l-phenyl-2- propanol (Helv. Chim. Ada, 1983, 66, 2274) using a similar method to that described for Example 8 (step 5), mp 130- 135°C (EtOH-diethyl ether). (Found: C, 56.47; H, 5.82; N, 12.37. C2 H₃4N₆O-2.45(C2H2θ₄) requires: C, 56.41; H, 5.77; N, 12.37%). δ_H (360MHz, DMSO-dβ) 1.85 (3H, d, J=6.lHz), 1.68-1.84 (2H, m), 1.90-2.16 (4H, m), 2.60-2.96 (7H, m), 3.28- 3.42 (2H, m), 4.10-4.22 (2H, m), 7.26-7.42 (5H, m), 7.44-7.54 (3H, m), 7.78 (IH, d, J=1.9Hz), 9.01 (2H, s), 11.17 (IH, s); m/e (ES) 459 (M^* + l).

EXAMPLE 78

l-(3-r5-(1.2.4-Triazol-4-yl)-lH-indol-3-vnpropyU-4-(r(lR.2R)-2-hvdroxy-l- phenyllpropylaminolpiperidine. 2.45 Hydrogen Oxalate.

The title compound was prepared from l-{3-[5-(l,2,4-triazol-4-yl)- lH-indol-3-yl]propyl}-4-ketopiperidine and (1R.2R)- 1-amino- l-phenyl-2- propanol (Helv. Chim. Ada, 1983, 66, 2274) using a similar method to that described for Example 8 (step 5), mp 124-129°C (EtOH-diethyl ether). (Found: C, 56.40; H, 5.60; N, 12.50. C2 H34NβO*2.45(C2H2θ₄) requires: C, 56.41; H, 5.77; N, 12.37%). δ_H (360MHz, DMSO-dβ) 1.64-2.12 (6H, m), 2.60-2.78 (5H, m,), 2.80-2.92 (2H, m), 3.24-3.28 (2H, m), 3.87 (2H, br s), 7.26-7.50 (8H, m), 7.77 (IH, d, J=2.0Hz), 9.01 (2H. s), 11.16 (IH, s,); m/e (ES) 459 (M^* +l).

EXAMPLE 79

l-{3-r5-(1.2.4-Triazol-4-vD-lH-indol-3-yl1propyl}-4-U(R.S)-l-hvdroxy-2- phenylpropan-2-yllaminθ-Piperidine. 2.0 Hydrogen Oxalate. To a stirred solution of l-{3-[5-(l,2,4-triazol-4-yl)- lH-indol-3- yl]propyl}-4-ketopiperidine (0.133g, 0.41mmol) and (R,S)-2-amino-2- phenyl-1 -propanol (76mg, 0.50mmol) in anhydrous methanol (8ml), under nitrogen, was added gladal acetic add (94μl, 1.64mmol). After a further 30 minutes, sodium cyanoborohydride (32mg, O.δOmmol) was added and stirring was continued at room temperature for 2 days. Saturated aqueous potassium carbonate was added and the mixture was extracted with ethyl acetate (4 x 25ml). The combined organic extracts were dried (Na∑SO-O and evaporated in vacuo. The residue was purified by flash chromatography (siUca gel, dichloromethane/methanol/ammonia, 92:8:0.8) and the resulting oxazoUdine was dissolved in ethanol (8ml) and gladal acetic add (0.33ml, 5.76mmol) and sodium borohydride (0.58g, 15.2mmol) was added portionwise over 4 days whilst stirring at 20-80°C. The reaction mixture was then partitioned between water (75ml) and ethyl acetate (50ml). The aqueous layer was extracted with more ethyl acetate (3 x 30ml) and the combined organic extracts were dried (Na2SO₄) and evaporated in vacuo. Flash chromatography of the residue (siUca gel, dichloromethane/ methanol ammonia, 90:10:1 to 85:15:1.5) gave 12mg (7%) of the title compound free base. The oxalate salt was prepared in methanol-diethyl ether, mp 123-126°C. (Found: C, 56.47; H, 6.14;

N, 12.53. C₂7H3₄NβO-2(C₂H₂O₄) 1.2 H₂O*0.1(C₄HιoO) requires: C, 56.48; H, 6.25; N, 12.59%). δ_H (360MHz, DMSO-dβ) 1.56 (3H, s), 1.62-1.82 (4H, m), 1.95 (2H, m), 2.59-2.92 (7H, m), 3.25 (2H, m), 3.63 (2H, dd), 7.30-7.32 (3H, m), 7.38 (2H, t, J=7.5Hz), 7.49 (IH, d, J=8.6Hz), 7.55 (2H, d, J=7.4Hz), 7.77 (IH, d,), 9.01 (2H, s,), 11.16 (IH, s,); m/e (ES) 459 (M^* +1).

EXAMPLE 80

l-<3-r5-(1.2.4-Triazol-4-ylVlH-indoI-3-vnpropyl)-4-(f(RV2-hvdroxy-l-(4- fluorophenvDethyl aminolpiperidine. 2.0 Hydrogen Oxalate.

1. (RV2-Amino-2-(4-fluorophenv ethanol

To a stirred 1.0M solution of Uthium aluminium hydride in THF (23.5ml, 23.5mmol), cooled to 0°C under Ar, was added portionwise over lh 45min soUd (-)-4-fluoro-D-α-phenylglycine (1.98g, 11.7mmol). The reaction mixture was then stirred at room temperature overnight before carefuUy adding water (0.89ml), then 4N NaOH solution (0.89ml) and then water (2.68ml). The mixture was stirred for a few minutes, then filtered, and the filtrate was evaporated in vacuo. Flash chromatography of the residue (siUca gel, dichloromethane/methanol/ammonia, 90: 10:1) gave 1.499g (82%) of the title compound as a white soUd: δn (250MHz, CDCLO 3.52 (IH, dd, J=10.7 and 8.2Hz), 3.71 (IH, dd, J=10.7 and 4.4Hz), 4.06 (IH, dd, J=8.1 and 4.4Hz), 6.99-7.08 (2H, m), 7.28-7.34 (2H, m).

2. l-<3-r5-(1.2.4-Triazol-4-yl)-lH-indol-3-yllpropyl}-4-{r(R)-2-hvdroxy- l-(4-fluorophenyl)ethyl1amino}piperidine. 2.0 Hydrogen Oxalate.

This was prepared from l-{3-[5-(l,2,4-triazol-4-yl)-lH-indol-3- yl]propyl}-4-ketopiperidine and (R)-2-amino-2-(4-fluorophenyl)ethanol using a similar method to that described in Example 8 (step 5); mp 137°C

(softens). (Found: C, 54.92; H, 5.49; N, 12.51. C₂6H3iFNβO*2.0(C2H2θ₄)-

0.7 H2θ*0.15(CH₄O)*0.12(C4HιoO) requires C, 55.00; H, 5.76; N, 12.56%). 6H (360MHz, DMSO-dβ) 1.72 (2H, m), 1.90-2.05 (4H, m), 2.66-2.86 (5H, m), 2.94 (2H, m), 3.37 (2H, m), 3.61 (2H, m), 4.19 (IH, m), 7.23 (2H, t,

J=8.8Hz), 7.32-7.34 (2H, m), 7.49-7.55 (3H, m), 7.80 (IH, d), 9.02 (2H, s), 11.18 (IH, s); m/e (ES) 463 (M^* +l).

EXAMPLE 81

l-t3-f5-(1.2.4-Triazol-4-ylVlH-indol-3-yllpropyl.-4-(f(lR.2R)-2- hvdroxyindan- l-yllamino-piperidine. 2.0 Hydrogen Oxalate.

1. (lR.2R l-Amino-2-hvdroxyindan Racemic trans- l-amino-2-hydroxyindan was resolved into its individual enantiomers using a similar procedure to that described in the Uterature: J. Med. Chem., 1992, 35, 1685. The chiral purity of the individual enantiomers was assessed by HPLC analysis using a CrownPack CR(+) column (5% methanol in aqueous perchloric add, pH 1.8; lml min; 40°C; 210nm); retention time for (lR.2R)-enantiomer, 3.8min, 98.2% e.e. (retention time for (lS,2S)-enantiomer. 4.4min). 2. l-{3-r5-(1.2.4-Triazol-4-yl)-lH-indol-3-yl1propy -4-U(lR.2R)-2- hvdroxyindan-l-yl]amino}piperidine. 2.0 Hydrogen Oxalate.

The title compound was prepared from the product of the previous step and l-{3-[5-(l,2,4-triazol-4-yl)-lH-indol-3-yl]propyl}-4-ketopiperidine using a similar method to that described for Example 8 (step 5), mp 156- 158°C (methanol-diethyl ether). (Found: C, 58.17; H, 5.69;

N, 13.19. C₂7H₃₂N6O*2.0 (C₂H₂0₄) requires: C, 58.48; H, 5.70; N, 13.20%). δ_H (360MHz, DMSO-dβ) 1.78-2.00 (2H, m), 2.00-2.10 (2H, m), 2.10-2.20 (IH, m), 2.20-2.40 (IH, m), 2.70-2.90 (5H, m), 2.90-3.00 (2H, m), 3.20-3.35 (IH, m), 3.35-3.50 (3H, m), 4.35-4.50 (2H, m), 7.20-7.40 (5H, m), 7.40-7.55 (2H, m), 7.81 (IH, s), 9.03 (2H, s), 11.19 (IH, s); m/e (ES) 457 (M^* + l).

Examples 82-84 were prepared from l-{3-[5-(l,2,4-triazol-4-yl)-lH-indol-3- yllpropyl}-4-ketopiperidine and commerdally available amines using a similar method to that described for Example 8 (step 5).

EXAMPLE 82

l-J3-r5-(1.2.4-Triazol-4-yl H-indol-3-ylmropyl - (R.SVindan-l- yl]amino}piperidine. 2.55 Hydrogen Oxalate.

The oxalate salt was prepared from ethanol-diethyl ether, mp 122-128°C. (Found: C, 57.47; H, δ.5δ; N, 12.40.

C27H₃2N₆-2.55(C2H2θ4) requires: C. 57.53; H, 5.58; N, 12.54%). δ_H (360MHz, DMSO-dβ) 1.84-2.28 (7H, m), 2.38-2.50 (IH, m), 2.72-3.16 (8H, m), 3.30-3.52 (3H, m), 4.85 (IH, br t), 7.24-7.38 (5H, m), 7.50 (IH, d, J=8.6Hz), 7.58 (IH, d, J=7.5Hz), 7.82 (IH, s), 9.03 (2H, s), 11.20 (IH. s); m/e (ES) 441 (M^* +l). EXAMPLE 83

l-_3-r5-(1.2.4-Triazol-4-ylVlH-indol-3-vnpropyl}-4-{f(R.S)-l-(4- fluorophenyl)ethyl.amino}piperidine. 2.0 Hydrogen Oxalate. The oxalate salt was prepared in methanol-diethyl ether, mp 149°C

(softens). (Found: C, 57.44; H, 5.89; N, 13.33. C₂βH3iFNβ*2(C₂H₂0₄)* 0.17(C4HιoO) requires: C, 57.65; H, 5.79; N, 13.15%). δ_H (360MHz, DMSO-β)1.44 (3H, d, J=6.3Hz), 1.72 (2H, m), 1.91-2.13 (4H, m), 2.58-2.90 (7H, m), 3.30 (2H, m), 4.34 (IH, m), 7.25 (2H, t, J=8.8Hz), 7.31-7.33 (2H, m), 7.50 (IH, d, J=8.6Hz), 7.56 (2H, m), 7.79 (IH, d), 9.02 (2H, s), 11: 17 (IH, s). m/e (ES) 447 (M^* +1).

EXAMPLE 84

l--3-rδ-(1.2.4-Triazol-4-vD-lH-indol-3-yllpropyl^-4- f(R)-l-phenylpropan-2- yl-aminolpiperidine. 2.0 Hydrogen Oxalate.

The oxalate salt was prepared in methanol-diethyl ether; mp 14δ°C

(softens). (Found: C, δ9.42; H, 6.69; N, 13.11. C27H₃₄N6*2(C2H2O₄)*

0.3 H₂O 0.25(C₄HιoO) requires: C, 59.44; H, 6.41; N, 13.00%), δ_H (360MHz, DMSO-dβ) 1.07 (3H, d, J=6.6Hz), 1.72 (2H. m), 1.94 (2H. m), 2.06 (2H, m), 2.42 (IH, m), 2.δδ-2.77 (6H, m), 3.1δ-3.29 (4H, m), 3.44 (IH, m), 7.26-7.34 (7H, m), 7.δ0 (IH, d, J=8.6Hz), 7.80 (IH, d), 9.03 (2H, s), 11.16 (IH, s); m/e (ES) 443 (M^* +1).

EXAMPLE 85

l-{3-r5-(1.2.4-Triazol-4-yl)-lH-indol-3-yllpropy»-4-<N-Kthiophen-3- yl)methvn-N-methylamino}piperidine. 2.5 Hydrogen Oxalate. Di-hvdrate. The title compound was prepared using a similar method to that described for Example 30 (step 4). The oxalate salt was prepared and recrystalUsed from methanol-diethyl ether, mp 135- 137°C. (Found: C, 50.57; H, 5.43; N, 12.77. C24H3oN₆S-2.25(C2H₂θ )-2 H₂0 requires: C, 50.8δ; H, 5.76; N, 12.48%). δ_H (360MHz, DMSO-de) 1.35-1.50 (2H, m), 1.64-1.72 (2H, m), 1.72-1.84 (4H, m), 2.09 (3H, s), 2.22-2.34 (3H, m), 2.68- 2.72 (2H, m), 2.86-2.90 (2H, m), 3.53 (2H, s), 6.99-7.01 (IH, m), 7.24-7.30 (3H, m), 7.43-7.47 (2H, m), 7.77-7.78 (IH, m), 9.01 (2H. s), 11.05 (IH. s); m/e (ES) 435 (M^* +l).

EXAMPLE 86

l-(3-fδ-(1.2.4-Triazol-4-ylVlH-indol-3-yllpropyl}-4-<N-f(furan-3-yl)methvn- N-methylaminolpjperidine. 1.5 Hydrogen Oxalate. 2.2δ Hvdrate.

The title compound free base was prepared in a similar manner to that described in Example 30 (step 4). The oxalate salt was prepared and crystallised from methanol-diethyl ether, mp 128-130°C. (Found: C, δδ.OO; H, 6.74; N, 13.63. C24H₃oNβO l.δ(C2H2θ4)-2.δ H₂O*0.14(C4HιoO) requires: C, 64.76; H, 6.49; N, 13.90%). δ_H (2δOMHz, DMSO-dβ) 1.70-1.80 (2H, m), 1.80-2.10 (4H, m), 1.24 (3H, s), 2.60-2.80 (4H, m), 2.85-2.90 (2H, m), 3.30-3.40 (3H, m), 3.62 (2H, s), 6.46 (IH, s), 7.29-7.34 (2H, m), 7.48- 7.51 (IH, m), 7.63 (2H, s), 7.80 (IH, s), 9.02 (2H, s), 11.18 (IH, s).

EXAMPLE 87

l- .3-.5-(1.2.4-Triazol-4-yl H-indol-3-yl1propyl.-4-r(furan-3- vPmethylamino.piperidine. 2.0 Hydrogen Oxalate. 1.5 Hydrate. A mixture of the product from Example 9 (free base; 765mg), ammonium formate (349mg) and paUadium on carbon (10% w/w; 300mg) in anhydrous methanol (10ml) was refluxed. under nitrogen, for 3h. After cooUng, the soUds were filtered off and the filtrate was concentrated under vacuum. The residue was partitioned between water and n-butanol, and the organic layer was concentrated to Weld 544mg of l-J3-[5-(1.2.4-tnazol- 4-yl)- lH-indol-3-yl]propyl}-4-aminopιperidine as a white foam. δ_H (360MHz, DMSO-de) 1.20-1.40 (2H, m), 1.70-2.04 (6H, m), 2.35-2.41 (2H, m), 2.68-2.74 (2H, m), 2.89-2.94 (3H, m), 7.27-7.32 (2H, m), 7.47 (IH, d), 7.77 (IH, d), 9.02 (2H, s), 11.12 (IH, s).

A solution of the preceding amine (150mg, 0.46mmol), 3-furaldehyde (47mg, 0.49mmol), acetic add (160μl, 2.77mmol) and sodium cyanoborohydride (30mg, 0.49mmol) in methanol (20ml) was stirred at room temperature, under nitrogen, for 18h. Volatiles were removed under vacuum and the residue was partitioned between saturated aqueous potassium carbonate and ethyl acetate. The aqueous phase was extracted three times with ethyl acetate and the combined organic solutions were dried (Na2SO₄) and concentrated. Flash chromatography of the residue (siUca gel, dichloromethane/methanol ammonia, 9δ:5:0.δ to 90:10:1) gave 73mg of the dialkylated amine (see Example 88) and 43mg of the title compound free base, from which the oxalate salt was prepared, mp 150-152°C (methanol-diethyl ether).

(Found: C, 53.13; H, 5.48; N, 13.54. C23H28NβO*2.0(C2H2θ4)* 1.5 H₂O requires: C, 53.02; H, 5.77; N, 13.74%). δ_H (360MHz, DMSO-dβ) 1.60-1.70 (2H, m), 1.90-2.00 (2H, m), 2.05-2.10 (2H, m), 2.40-2.50 (5H. m), 2.70-2.80 (4H, m), 2.95-3.05 (IH, m), 3.15-3.20 (2H, m), 3.91 (2H, s), 6.57 (IH, s), 7.26-7.29 (2H, m), 7.47-7.49 (IH, m), 7.63 (IH, s), 7.70-7.73 (2H, m), 8.88 (2H, s), 10.95 (IH, s); m/e (ES) 405 (M^* +1).

EXAMPLE 88

l-.3-[5-(1.2.4-Triazol-4-yl)- lH-indoI-3-vnpropyl}-4-{N.N-rdi-furan-3- vDmethyllaminolpiperidine. Dihvdrogen oxalate hvdrate.

The title compound free base was isolated from the reaction described in Example 87. The oxalate salt was prepared and crystalUsed from methanol-diethyl ether, mp 119-121°C. (Found: C. 56.18; H. 5.69: N, 12.40. C2₈H3₂N6θ2-2(C₂H2θ ). H₂O requires: C, 56.30; H. 5.61:

N, 12.31%). διι (360MHz. DMSO-de) 1.70- 1.90 (4H. m). 2.02-2.10 (2H. m). 2.70-2.90 (5H, m), 2.95-3.05 (2H, m), 3.35-3.50 (2H, m), 3.49 (4H, s), 6.38 (2H, s), 7.27-7.30 (2H, m),7.47-7.53 (5H, m), 7.74-7.75 (IH, m), 8.88 (2H, s), 11.00 (IH, s); m/e (ES) 485 (M^* + l).

EXAMPLE 89

l-(3-r5-(1.2.4-Triazol-4-yl)-lH-indol-3-yllpropyl}-4-rN-(3 3-HimPtVιγl_an_γl). N-methylaminolpiperidine. 1.25 Hydrogen Oxalate. 1.5 Hvdrate.

A solution of l-{3-[5-(l,2,4-triazol-4-yl)-lH-indol-3-yl]propyl}-4- (N-methylamino)piperidine (417mg, 1.23mmol), prenylbromide (149μl, 1.29mmol) and potassium carbonate (170mg, 1.29mmol) in dimethylformamide (10ml) was heated to 80°C for 16h. The reaction was partitioned between water and ethyl acetate. The organic layer was dried (Na2SO ), concentrated and purified by chromatography using CH∑Ck/MeOH/NH-iOH (90: 10: 1) as eluant, to give the title compound free base. The oxalate salt was prepared and crystalUsed from methanol- diethyl ether, mp 128-130°C. (Found: C, 58.64; H, 7.44; N, 14.99.

C2₄H3₄Nβ l.25(C2H2θ4) 1.5 H2O requires: C, 58.28; H, 7.29; N, 15.39%). δ_H (360MHz, DMSO-de; free base) 1.30-1.50 (2H, m), 1.59 (3H, s), 1.60-1.67 (2H, m), 1.68 (3H, s), 1.78-1.84 (4H, m), 2.09 (2H, s), 2.24-2.31 (3H, m), 2.69-2.73 (2H, m), 2.86-2.89 (2H, m), 2.95-2.97 (2H, m), 5.10-5.14 (IH, m), 7.23 (IH. s), 7.25-7.28 (IH, m), 7.45-7.47 (IH, m), 7.75-7.76 (IH, m), 8.96 (2H, s), 11.02 (IH, s); m/e (ES) 407 (M^* +1).

EXAMPLE 90

l- .3-.5-(1.2.4-Triazol-4-yl,- lH-indol-3-yllpropyl. -4-(N-aUyl-N- methylamino)piperidine. 2.25 Hydrogen oxalate.

The title compound was prepared in a similar manner to that described in Example 89, using allyl bromide as the alkylating agent, mp 124- 126°C (methanol-diethyl ether). (Found: C. 54.97; H. 6.24: N, 14.11. C22H₃oN6-2.25(C₂H2θ4) requires: C, 54.77; H, 5.98; N, 14.46%). δ_H (360MHz, DMSO-dβ; free base) 1.34-1.45 (2H, m), 1.62-1.65 (2H, m), 1.77-1.84 (4H, m), 2.11 (3H, s), 2.27-2.31 (3H, m), 2.69-2.73 (2H, m), 2.86- 2.89 (2H, m), 3.02-3.03 (2H, m), 5.05-5.08 (IH, m), 5.12-5.17 (IH, m), 5.72- 5.82 (IH, m), 7.26-7.31 (2H, m), 7.46-7.48 (IH, m), 7.78-7.79 (IH, m), 9.01 (2H, s), 11.06 (IH, s); m/e (ES) 379 (M^* +l).

EXAMPLE 91

l- 3-f5-(1.2.4-Triazol-4-yl)-lH-indol-3-vnpropyl -4-Jr(indan-l- vDaminolmethyl-Piperidine. Dihvdrogen Oxalate. 0.5 Hvdrate.

The title compound was prepared in a similar manner to that described in Example 22 (step c), except that 1-aminoindan was used instead of (R)-α-methylbenzylamine. The oxalate was prepared and crystalUsed from methanol-diethyl ether, mp 140- 142°C. (Found:

C, 59.57; H, 6.11; N, 13.06. C28H3₄Nβ-2(C2H2θ₄)*0.5 H₂O requires: C, 59.71; H, 6.11; N, 13.06%). δ_H (360MHz, DMSO-dβ; free base) 1.26-1.33 (2H, m), 1.40-1.55 (IH, m), 1.75-1.79 (4H, m), 1.83-1.95 (4H, m), 2.35-2.42 (3H, m), 2.58-2.63 (2H, m), 2.75-2.84 (3H, m), 2.94-3.02 (3H, m), 4.20-4.24 (IH, m), 7.12-7.15 (2H. m), 7.18-7.22 (3H, m), 7.30-7.35 (IH, m), 7.45-7.48 (IH, m), 7.56 (IH, s), 8.50 (2H, s), 8.60 (IH, s); m/e (ES) 455 (M^* + l).

EXAMPLE 92

l--3-f5-(1.2.4-Triazol-4-yl)-lH-indol-3-vnpropyll-4-UN-f(R>-α-

(hvdroxymethyl)benzyll-N-methylaminolmethyl-piperidine.

2.0 Hydrogen Oxalate. 0.5 Hvdrate.

The title compound free base was prepared from the amine of

Example 31 using a similar method to that described for Example 10. The oxalate salt was prepared and crystalUsed from methanol-diethyl ether, mp 115-117°C. (Found: C. 57.96: H. 6.25: N. 12.6G. C28H3GN6O*2.0(C2H₂O4)-0.5 H₂O requires: C, 58.08; H, 6.24; N, 12.70%). δ_H (360MHz, CDC ; free base) 1.19-1.28 (2H, m), 1.68-1.95 (7H, m), 2.08- 2.14 (4H, m), 2.23-2.31 (IH, m), 2.38-2.44 (2H, m), 2.74-2.80 (2H, m), 2.91- 2.95 (2H, m), 3.59-3.65 (IH, m), 3.71-3.77 (IH, m), 3.92-4.00 (IH, m), 7.12- 7.17 (4H, m), 7.30-7.34 (3H, m), 7.45-7.48 (IH, m), 7.56-7.57 (IH, ), 8.32 (IH, s), 8.47 (2H, s); m/e (ES) 473 (M^* + l).

EXAMPLE 93

(3R)-3-(Benzylthio)methyl-l-(2-f5-(1.2.4-triazol-4-yl)-lH-indol-3- yllethyllpyrroUdine. Hydrogen Oxalate.

1. (3R)-3-(Benzylthio)methyl- 1 -(tert-butoxycarbonyl)pyτroUdine

To a stirred mixture of (3R)-l-(tert-butoxycarbonyl)-3-[(methane- sulfonyloxy)methyl]pyrroUdine (0.507 lg, 1.82mmol) and anhydrous potassium carbonate (0.3764g, 2.72mmol) in DMF (13ml), under argon, was added benzyl mercaptan (0.428ml, 3.65mmol) and the mixture was stirred overnight at room temperature, then at 60°C for 4h. The mixture was then partitioned between water (50ml) and diethyl ether (30ml). The aqueous layer was separated and reextracted with more diethyl ether (2 x 30ml). The combined organic layers were dried (MgSO₄) and evaporated in vacuo. The residue was purified by flash chromatography (siUca gel, 20% EtOAc/pet. ether) to give 0.5186 (93%) of the title compound as a colourless oil. δn (360MHz. CDCb) 1.45 (9H, s), 1.56 (IH, m), 1.99 (IH. m), 2.32 (IH, m), 2.45 (2H, t, J=6.4Hz), 2.97 (IH. m), 3.26 (IH. m), 3.61 (2H, m), 3.72 (2H, s), 7.22-7.40 (5H, m). m/e (ES+) 330 (M+Na)^~. 308

2. (3R)-3-[(Benzylthio')methvnpyrroUdine

To a stirred solution of (3R)-3-(benzylthio)methyl-l-(_.ert- butoxycarbonyl)pyrroUdine (0.2320g, 0.755mmol) in dichloromethane (3ml), under argon, was added trifluoroacetic add (1ml) and the mixture was stirred at room temperature for 65 minutes before quenching with anhydrous methanol (2ml) and evaporating in vacuo. More methanol (2ml) was added to the residue and removed in vacuo. The residual oil was then dissolved in dichloromethane (25ml) and washed with 2N NaOH solution (10ml). The aqueous layer was reextracted with more dichloromethane (15ml) and the combined dichloromethane extracts were washed with saturated NaCl solution (10ml), dried (Na2SO₄) and evaporated in vacuo. The residue was purified by flash chromatography (silica gel, CH₂Cl2 MeOH/NH₃, 85:15:1.5) to give 0.1210g (77%) of the title compound as a colourless oil. δn (250MHz,CDCl3) 1.41 (IH, m), 1.90-2.00 (IH, m), 2.24 (IH, m), 2.42-2.50 (2H, m), 2.57 (IH, dd, J=6.5 and 1 l.OHz), 2.82-2.99 (2H, m), 3.07 (IH, dd, J=7.3 and 1 l.OHz), 3.72 (2H, s), 7.20-7.36 (5H, m); m/e (ES) 208 (M^* +l).

3. (3RV3-(Benzylthio)methyl-l-(2-r5-(1.2.4-triazol-4-yl)-lH-indol-3- yllethv pyrrohdine. Hydrogen Oxalate.

To a stirred solution of 3-[2-(methanesulfonyloxy)ethyl]-5-(l,2,4- triazol-4-yl)-lH-indole (0.1147g, 0.374mmol) and sodium carbonate (59.6mg, 0.562mmol) in 2-propanol (8ml), under argon, was added a solution of (3R)-3[(benzylthio)methyl]pyrroUdine (0.1165g, 0.562mmol) in 2-propanol (5ml) and the mixture was heated at reflux for 2h. After cooling, the reaction mixture was filtered and the filtrate evaporated in vacuo. The residue was purified by flash chromatography (silica gel, CH₂Cl₂/MeOH/NH₃, 92:8:0.8) to give 0.1017g (65%) of the title compound free base as a colourless oil. The oxalate salt was prepared in methanol- diethyl ether; mp 79-9TC. (Found: C. 61.57; H, 5.94: N, 13.40.

C24H₂:N5S C2H₂θ4 θ.25(C HιoO) requires: C. 61.64: H, 6.03: N, 13.31%). δ_H (360MHz, DMSO-dβ) 1.63 (IH, m), 2.10 (IH, m), 2.53 (2H), 2.92 (IH, m), 3.05 (2H, m), 3.25 (4H, m), 3.38 (IH, m), 3.76 (2H, s), 7.25 (IH, m), 7.32-7.33 (5H, m), 7.37 (IH, dd, J=9.1 and 2.1Hz), 7.52 (IH, d, J=8.7Hz), 7.88 (IH, d, J=2.0Hz), 9.03 (2H, s,), 11.26 (IH, s), among other signals; m/e (ES⁺) 418 (M+H)^*.

EXAMPLE 94

(±Vl- 3-rδ-(1.2.4-Triazol-4-yl)-lH-indol-3-vnpropyU-4-(l-benzylamino-2- hvdroxyethvDpiperidine. 2.0 Hydrogen Oxalate. 2.0 Hvdrate,

1. (±)-2-f l-(te^Butyloxycarbonyl)piperidin-4-yl.glycine methyl ester.

The title compound was prepared from l-(tert-butyloxycarbonyl)- 4-ketopiperidine and (±)-N-(benzyloxycarbonyl)-α-phosphonoglycine trimethyl ester using a similar procedure to that described by U. Schmidt et al. (Synthesis, 1992, 487; Synthesis, 1984, 53); δ_H (250MHz, CDC ) 1.19-1.78 (5H, m), 1.45 (9H, s), 2.60-2.74 (2H, m), 3.31 (IH, d, J=5.7Hz), 3.73 (3H, s), 4.08-4.18 (2H, m).

2. (±)-2-[l-(tβrt-Butyloxycarbonyl)piperidin-4-yllglycinol.

To a cooled (-78°C) solution of the ester from above (1.7g, 6.24mmol) in anhydrous tetrahydrofuran (50ml) was added Uthium aluminium hydride (1.0M in THF; 6.24ml). The mixture was stirred at -78°C for 3h and at room temperature for 18h before water was added to produce a granular precipitate, which was removed by filtration. Concentration of the filtrate foUowed by flash chromatography of the remaining residue (silica gel, dichloromethane/methanol/ ammonia, 90: 10: 1) afforded the title compound as a colourless oil; m/e (ES) 245 (M^* + 1). 3. (±)-l-(tert-Butyloxycarbonyl)-4-(l-ber_zylamino-2-hvdroxyethyl)piperidine.

A solution of the preceding glycinol (730mg, 2.99mmol), benzaldehyde (317mg, 2.99mmol), acetic add (2ml) and sodium cyanoborohydride (188mg, 2.99mmol) in methanol (20ml) was stirred at room temperature for 18h. Saturated potassium carbonate solution was added to pH>8 and the methanol was removed under vacuum. The residue was diluted with water (20ml) and products were extracted with ethyl acetate (δOml), dried (Na2SO₄) and concentrated. Flash chromatography (siUca gel, dichloromethane/methanol ammonia, 90:10:1) of the residue afforded 417mg (42%) of the title compound as a yellow oil; δ_H (360MHz, DMSO-dβ) 1.00-1.10 (IH, m), 1.38 (9H, s), 1.50-1.64 (2H, m), 1.64-1.78 (IH, m), 2.50-2.70 (2H, m), 3.31-3.34 (IH, m), 3.40-3.50 (IH, m), 3.60-3.80 (2H, m), 3.90-4.00 (2H, m), 4.40-4.43 (IH, m), 7.20-7.34 (5H, m).

4. (±)-4-(l-Benzylamino-2-hvdroxyethyl)piperidine

A solution of the product from step 3 (417mg, 1.25mmol) in a mixture of trifluoroacetic add and dichloromethane (1:10; 10ml) was stirred for 16h. The reaction was quenched by addition of saturated aqueous potassium carbonate and extracted with dichloromethane. The organic phase was dried (MgSO₄) and concentrated. Flash chromatography of the residue (siUca gel, dichloromethane/ methanol/ammonia, 90:9:1) gave the title compound as a colourless soUd; 6H (250MHz, DMSO-dβ) 1.20- 1.46 (2H. m), 1.56-1.76 (2H, m), 1.78-1.90 (IH, ), 2.20-2.30 (IH. m), 2.60- 2.76 (2H, m), 3.10-3.60 (4H, m). 3.65 (IH, d. J=l3.5Hz). 3.79 (IH, d, J=13.5Hz), 7.16-7.38 (5H, m).

5. (±)-l-{3-r5-(1.2.4-Triazol-4-yl H-indol-3-yllpronvn-4-π - benzylamino-2-hvdroxyethyl)piperidine. 2.0 Hydrogen Oxalate. 2.0 Hvdrate. The title compound was prepared from 3-[5-(l,2,4-triazol-4-yl)-lH- indol-3-yl]propan- l-ol and (±)-4-(l-benzylamino-2-hydroxyethyl)piperidine using a similar procedure to that described for Example 98 (step 3). The oxalate salt was prepared and crystalUsed from ethanol-diethyl ether; mp 125-127°C. (Found: C, 55.23; H, 6.37; N, 11.66. C2 H₃₄N₆σ2(C2H2θ4)-

2 H₂0*0.3(C₄HιoO) requires: C, 55.49; H, 6.51; N, 12.06%). δ_H (360MHz, DMSO-dβ) 1.50-1.70 (2H, m), 1.80-1.90 (2H, m), 1.90-2.10 (3H, m), 2.70- 2.95 (5H, m), 2.95-3.10 (2H, m), 3.40-3.50 (2H, m), 3.55-3.70 (IH, m), 3.70- 3.74 (IH, m), 4.04-4.19 (2H, m), 7.32-7.40 (6H, m), 7.48-7.52 (3H, m), 7.82 (IH, m), 9.03 (2H, s), 11.22 (IH, s); m/e (ES) 460 (M^* +l).

EXAMPLE 95

l-<3-r5-(1.2.4-Triazol-l-yl)-lH-indol-3-yllpropy -4-r(RV - (hvdroxymethyl)benzylamino .piperidine. 1.9 Hydrogen Oxalate.

1. l-{3-f5-(1.2.4-Triazol-l-yl)-lH-indol-3-vnpropyll-4-hvdroxypiperidine. The title compound was prepared from 4-(l,2,4-triazol-l-yl)- phenylhydrazine (EP497,512) and 5-(4-hydroxypiperidin-l-yl)pentanal dimethyl acetal using a similar method to that described for Example 8 (step 3). δ_H (250MHz, DMSO-dβ) 1.28-1.46 (2H, m), 1.64-2.04 (6H, m), 2.30 (2H, t, J=6.8Hz), 2.72 (4H, br t), 3.35-3.50 (IH. m), 4.53 (IH, d, J=4.2Hz), 7.25 (IH, d, J=2.2Hz), 7.44-7.54 (2H, m), 7.92 (IH, d, J=1.7Hz), 8.18 (IH, s), 9.18 (IH, s), 11.06 (IH, s); m e (ES) 326 (M^*+l).

2. l-{3-f5-(1.2.4-Triazol-l-yl)-lH-indol-3-yllpropyll-4-ketopiperidine. The title compound was prepared from the product of the previous step foUowing a similar procedure to that described in Example 8 (step 4): pale yellow soUd, mp 158- 161°C (ethyl acetate); δn (360MHz. CDC1.) 1.96 (2H, qn, J=7.3Hz), 2.46 (4H, t, J=6.1Hz), 2.55 (2H, t. J=7.2Hz). 2.75 (4H. t. J=6.lHz), 2.86 (2H, t, J=7.5Hz), 7.12 (IH. d. J=2.2Hz). 7.40-7.48 (2H. m), 7.88 (IH, s), 8.12 (IH, s), 8.20 (IH. br s). 8.53 (IH, s): m/e (ES) 324 (M^*+ l). 3. l-^3-r5-(1.2.4-Triazol-l-ylVlH-indol-3-yllpropyl}-4-r(R)-α- (hvdroxymethyl)benzylaminolpiperidine. 1.9 Hydrogen Oxalate.

The title compound was prepared from the product of the previous step and (R)-2-phenylglyάnol using a similar method to that described for Example 8 (step 5), mp 155-160°C (ethanol). (Found: C, 58.11; H, 6.04;

N, 13.44. C26H32NβO*1.9(C2H2θ4) requires: C, 58.14; H, 5.86; N, 13.65%). δ_H (360MHz, DMSO-dβ) 1.56-1.76 (2H, m), 1.84-2.12 (4H, m), 2.60-2.96 (7H, m), 3.24-3.38 (2H, m), 3.50-3.64 (2H, m),^'4.04-4.16 (IH, m), 7.26-7.56 (8H, m), 7.92 (IH, s), 8.18 (IH, s), 9.16 (IH, s), 11.14 (IH, s); m e (ES) 445 (M*+l).

EXAMPLE 96

l--3-r5-Qmidazol-l-yl)-lH-indol-3-yl1propyl.-4-r(R)-α- (methvDbenzylamino .piperidine. 2.6 Hydrogen Oxalate.

1. 4-(Imidazol- 1 -vDnitrobenzene.

To a stirred solution of imidazole (34. lg, O.δOmol) in DMF (300ml) under Ar, was added portionwise, over 23 minutes, 60% NaH in oil (20.02g, O.δOmol). The mixture was then stirred at room temperature for 18 minutes before adding dropwise, over 40 minutes, a solution of l-fluoro-4-nitrobenzene (70.62g, O.δOmol) in DMF (60ml). The mixture was then stirred at room temperature overnight. Water (600ml) was then added and the soUd was filtered off, washed with water, then stirred in boiling ethyl acetate (400ml), aUowed to cool and filtered, washing the soUd with more ethyl acetate (50ml), then petroleum ether (250ml). The filtrate, now containing more soUd, was refiltered and washed with petroleum ether. The combined soUds were dried in a vacuum dessicator overnight to give 90.14g (95%) of the title compound as a yeUow soUd. δ_H (360MHz, DMSO-dc) 9 (IH, t, J=l. lHz), 7.97-8.03 (3H, m). 8.38 (2H, d. J=9.2Hz), 8.52 (lH, t). 2. 4-(Imidazol- 1-vDaniUne. Dihvdrochloride.

A mixture of 4-(imidazol-l-yl)nitrobenzene (89.60g, 0.474mol) and 10% palladium on carbon (4.50g) in ethanol (1200ml) and 5N HCI (189ml) was hydrogenated in two batches at 40psi for 80 minutes. Water (450ml) was then added to dissolve the product and the catalyst was removed by filtration, washing with more water, and the combined filtrates were evaporated in vacuo, using finally a freeze drier, to give 10δ.4g (96%) of the title compound as a cream soUd. δri (250MHz, D2O) 7.22 (2H, d, J=8.8Hz), 7.3δ (IH, t, J=2.lHz), 7.44 (2H, d, J=9.0Hz), 7.69 (IH, t, J=1.8Hz), 8.89 (IH, t, J=1.5Hz).

3. 4-(Imidazol-l-yl)phenylhvdrazine. Dihvdrochloride.

To a cooled (-15°C) and stirred suspension of 4-(imidazol-l-yl)- dihydrochloride (20g, 86.16mmol) in concentrated hydrochloric add (100ml) was added dropwise, over 1 hour, a solution of sodium nitrite

(6.25g, 9.05mmol) in water (40ml). After a further 10 minutes of stirring at -12°C, the mixture was quickly filtered to remove a soUd, and the filtrate was added portionwise to a cooled (-20°C) and stirred solution of tin (ID chloride dihydrate (lOOg) in concentrated hydrochloric add (50ml) at such a rate as to maintain the internal temperature below -10°C (15 minutes). The mixture was aUowed to warm to 5°C over 30 minutes, and the soUd was coUected and washed with diethyl ether (4 x 100ml). The above soUd was suspended in water (200ml) and basified with 4N sodium hydroxide solution and extracted with ethyl acetate (5 x 500ml). The combined organic solutions were dried (Na∑SOj) and filtered. The filtrate was vigorously stirred while hydrogen chloride was being bubbled through the solution until a deep red mixture was obtained. Stirring was continued for a further 20 minutes to give a cream soUd which was coUected by filtration and dried over phosphorous pentoxide-potassium hydroxide under high vacuum to leave 12.7g (60%) of the title compound; δ_H (360MHz, DMSO-dβ) 7.20 (2H, d, J=9.0Hz), 7.73 (2H, d, J=9.0Hz), 7.91 (IH, t, J=1.5Hz), 8.23 (IH, t, J=1.7Hz), 9.71 (IH, t, J=1.3Hz).

4. l-.3-f5-(Imidazol-l-yl)-lH-indol-3-yl,propyl -ketopiperidine The title compound was prepared from 4-(imidazol-l-yl)- phenylhydrazine dihydrochloride and 5-(4-hydroxypiperidin-l-yl)- pentanal dimethyl acetal using a similar method to that described for Example 8 (steps 3 and 4); δ_H (250MHz, CDCLO 1.96 (2H, qn, d=7.5Hz), 2.46 (4H, t, J=6.lHz), 2.56 (2H, t, J=7.4Hz), 2.76 (4H, t, J=6.1Hz), 2.84 (2H, t, J=7.5Hz), 7.13 (IH, d, J=2.2Hz), 7.18-7.23 (2H, m), 7.30 (IH, t, J=1.2Hz), 7.44 (IH, d, J=8.5Hz), 7.58 (IH, d, J=2.1Hz). 7.84 (IH, t, J= l.OHz), 8.41 (IH, br s); m/e (ES) 323 (M^* + l).

5. l-{3-r5-αmidazol-l-yl)-lH-indol-3-yllpropyll-4-r(RVα- (methv benzylaminolpiperidine. 2.6 Hydrogen Oxalate.

This was prepared from l-{3-[5-(imidazol-l-yl)-lH-indol-3- yl]propyl}-4-ketopiperidine (0.20 lg, 0.62mmol) and (R)-(+)-α- methylbenzylamine (95.3μl, 0.75mmol) using a similar method to that described in Example 8 (step 5) to give 0.237g (89%) of the title compound, free base. The oxalate salt was prepared in methanol-diethyl ether, mp 130°C (softens). (Found: C, 58.63; H. 5.98; N, 10.33. C27H3₃N₅-

2.6(C₂H₂O4) 0.17(C4HioO) requires: C, 58.67; H, 5.96; N, 10.39%). δ_H (360MHz, DMSO-de) 1.50 (3H, d, J=6.6Hz), 1.75- 1.82 (2H, m), 1.92-2.06 (3H, m), 2.12-2.16 (IH, m), 2.73 (4H, m), 2.90 (3H, m), 3.38 (2H, m), 4.40 (IH, q), 7.13 (IH, s), 7.27-7.30 (2H, m), 7.37-7.47 (4H, m), 7.53 (2H, d, J=7.0Hz). 7.68 (IH. s), 7.70 (IH, d), 8.20 (IH, s), 11.09 (IH, s): m/e (ES) 428 (M^* + 1). EXAMPLE 97

l-^3-r5-αmidazol-l-yl)-lH-indol-3-yllpropyl}-4-f(RVα- (hvdroxymethyl)benzylaminolpiperidine. 3.0 Hydrogen Oxalate. The title compound was prepared from l-{3-[5-(Imidazol-l-yl)-lH- indol-3-yl]propyl}-4-ketopiperidine (0.127g, 0.40mmol) and (R)-2-phenylglycinol (6δmg, 0.48mmol) using a similar method to that described for Example 8 (step 5) to give 0.108g (62%) of the title compound, free base. The oxalate salt was prepared in methanol-diethyl ether; mp 99-102°C. (Found: C, 53.21; H, 6.45; N, 9.28.

C2 H₃3N₅0*3(C2H2θ4) 0.11(C HιoO)*1.8 H₂0 requires: C, 53.25; H, 5.84; N, 9.29%). δ_H (360MHz, DMSO-dβ) 1.80-2.17 (6H, m), 2.72-2.96 (7H, m), 3.42 (2H, m), 3.71 (2H, d, J=5.6Hz), 4.32 (IH, m), 7.19 (IH, s), 7.28-7.31 (2H, m), 7.40-7.48 (4H, m), 7.52 (2H, d, J=6.7Hz), 7.72 (2H, s), 8.31 (IH, s), 11.11 (IH, s); m/e (ES) 444 (M^* +l).

EXAMPLE 98

l-{3-r5-(1.2.4-Triazol-l-vDmethyl-lH-indol-3-yllpropyl}-4-r(RVα- ( vdroxymethyl)benzylamino.piperidine. 2.0 Hydrogen Oxalate. 1.5 Hvdrate.

1. 3-f 5-( 1.2 ,4-Triazo - 1 -yl imethyl- lH-indol-3-yl lpropan- 1 -ol

A mixture of pafladium acetate (0.78g), Uthium chloride (1.47g), sodium carbonate (18.49g), triphenylphosphine (1.8g), 5-triethylsilyl-4- pentyn-1-ol triethylsilyl ether (16.3g) and 2-iodo-4-[(l,2,4-triazol- l- yl)methyl]aniUne (10. Og) in degassed anhydrous dimethylformamide (400ml) was heated at 100°C for lOh, under nitrogen. After cooUng, the reaction was filtered, concentrated, and the residue was partitioned between water and ethyl acetate. The organic phase was dried (MgSO- , concentrated and the residue was treated with 5N hydrochloric acid/ methanol (1:3; 400ml) for 3h at room temperature. The methanol was removed under vacuum, the aqueous residue was basified with sodium carbonate solution and it was extracted with ethyl acetate. The combined organic extracts were dried (MgSO4) and concentrated. Flash chromatography of the residue (siUca gel, dichloromethane/methanol, 95:5) followed by trituration with petroleum ether, gave the title compound (56%) as a beige soUd. δ_H (360MHz, DMSO-dβ) 1.74-1.82 (2H, m), 2.66-2.70 (2H, m), 3.43-3.49 (2H, m), 4.41-4.44 (IH, m), 5.42 (2H, s), 7.01-7.04 (IH, m), 7.11-7.12 (IH, m), 7.28-7.30 (IH, m), 7.51 (IH, s), 7.93 (IH, s), 8.60 (IH, s), 10.79 (IH, s).

2. 4-f(R)-α-(Hvdroxymethyl)benzyllaminopiperidine.

To a stirred solution of N-terf-butyloxycarbonyl-4-piperidinone (2g, lOmmol), (R)-(-)-phenylglycinol (1.65g, 12mmol), and gladal acetic add (2.29ml, 40mmol) in methanol (200ml) was added sodium cyanoborohydride (754mg, 12mmol). After being stirred at room temperature, under nitrogen, for 16h, the mixture was basified with 4N sodium hydroxide and the methanol was removed under vacuum. The residue was diluted with water (35ml) and the product extracted with diethyl ether (2 x 200ml), washed with brine (1 x 40ml), dried (Na2SU ) and concentrated. Flash chromatography (siUca gel, dichloromethane/ methanol ammonia, 95:5:0.5) of the residue gave 2.91g (90.9%) of 1-tert- butyloxycarbonyl-4-[(R)-α-(hydroxymethyl)benzyl]aminopiperidine. A solution of the above BOC-protected piperidine (2.9g) in trifluoroacetic add (40ml) and dichloromethane (50ml) was aUowed to stand at room temperature for 16h. Solvents were removed under vacuum and the residue was azeotroped with toluene/ethanol (5: 1, 150ml). The residue was dissolved in 4N sodium hydroxide, extracted with dichloromethane (3 x 150ml) and the combined organic solutions were washed with brine (1 x 50ml), then dried (Na₂SO ) and concentrated. Crystallisation from ethyl acetate/hexane ( 1: 10, 200ml) afforded the title compound as white crystals (1.4g, 70.4%); δH (360MHz, DMSO-de) 0.96- 1.12 (2H, m), 1.52 (IH, d, J=12.0Hz), 1.78-2.06 (2H, br s and d, J=12.6Hz), 2.17-2.32 (3H, m), 2.76-2.90 (2H, m), 3.26 (IH, t, J=8.5Hz), 3.40 (IH, dd, J=10.5 and 4.5Hz), 3.83 (IH, dd, J=8.5 and 4.δHz), 4.82 (IH, br s), 7.27- 7.37 (5H, m); m/z (ES) 221 (M^* + 1).

3. l-(3-f5-(1.2.4-Triazol-l-v methyl-lH-indol-3-yllpropyn-4-r(RVα- (hvdroxymethyl)benzylaminolpiperidiήe. 2.0 Hydrogen Oxalate. 1.5 Hvdrate. A solution of the product from Step 1 (209mg, 8 lmmol) in THF

(10ml) was cooled to -40°C under nitrogen. Triethylamine (146μl) was added foUowed by methanesulfonyl chloride (75μl) and the reaction aUowed to attain room temperature. The reaction was filtered and solvent removed in vacuo. The residue was partitioned between water- dichloromethane and the organic phase dried (MgSU4) and concentrated. A solution of the mesylate in THF (20ml) with άusopropyl- ethylamine (310μl) and the amine from step 2 (231mg) was heated for 4h at 40°C and 6h at 60°C. Sodium iodide (150mg) was added and heating continued for 17h in a foil covered reaction vessel. Saturated sodium chloride was added, solvent removed in vacuo and the residue extracted into n-butanol. The organic phase was concentrated, and chromatographed using methanol/dichloromethane/ammonia (15:84: 1) as eluant, to give the title compound free base. The oxalate salt was prepared and crystalUsed from ethanol-diethyl ether. (Found: C, 58.97; H, 6.24; N, 13.56. C26H iN₅O₂-2(C₂H₂O4) 1.5 H₂O requires: C. 59.21;

H, 6.11; N, 13.54%.) διι (360MHz. DMSO-de) 1.60- 1.75 (2H. m), 1.85-2.10 (4H, m), 2.60-2.80 (4H, m), 2.80-2.95 (2H. m), 3.20-3.30 (2H, m), 3.50-3.60 (2H, m), 4.05-4.15 (IH, m), 5.42 (2H. s), 7.02-7.05 (IH, m), 7.16 (IH, m), 7.29-7.39 (4H, m), 7.44-7.50 (3H. m). 7.93 ( IH, s), 8.60 (IH. s). 10.90 (IH. s); m/e 459 (M^* + l). EXAMPLE 99

l-(3-r5-(1.2.4-Triazol-4-ylVlH-indol-3-yllpropyl. -4-r(R)-α- (methoxymethyl)benzylamino]piperidine. Dihvdrogen Oxalate. Hvdrate. 5 The title compound was prepared in a similar manner to that described in Example 8 (step 5) using (R)-(-)-l -amino- l-phenyl-2- methoxyethane (A.I. Meyers et al., J. Org. Chem., 1978, 43, 892); mp 138-140°C (methanol-diethyl ether). (Found: C, 56.65; H, 6.03;

N, 12.86. C27H3₄NβO*2(C2H2θ4)* 1.0 H2θ requires: C, 56.70; H, 6.14; 0 N, 12.80%.) δ_H (360MHz, DMSO-dβ) 1.60-1.80 (2H, m), 1.90-2.20 (4H, m), 2.65-2.90 (5H, m), 2.90-3.05 (2H, m), 3.27 (3H, m), 3.27-3.40 (2H, m), 3.50- 3.56 (2H, m), 4.20-4.30 (IH, m), 7.31-7.33 (δH, m), 7.46-7.51 (3H, m), 7.79 (IH, m), 9.02 (2H, s), 11.19 (IH, s); m/e (ES) 459 (M^* + l).

lδ EXAMPLE 100

l-<3-r5-(1.2.4-Triazol-4-yl)-lH-indol-3-vnpropyl}-4--N-f(R)-α- (methoxynethyl)benzvI.-N-methylaminθ-piperidine. 2.0 Hydrogen Oxalate. 0.6 Hvdrate. 20 The title compound was prepared from the product of Example 99 foUowing a similar method to that described for Example 10, mp 119-

121°C. (Found: C, 57.6δ; H, 6.33; N, 13.02. C∑βHseNβO ^•2.0(C₂H₂O4)- 0.6 H₂O requires: C, 57.93; H, 6.26; N, 12.67%). δn (360MHz, CDC ; free base) 1.60- 1.91 (10H, m), 2.25 (3H, s), 2.33-2.37 (2H. m), 2.45-2.48 (IH, 25 m), 2.72-2.77 (2H, m), 2.90-2.93 (2H, m), 3.29 (3H, s), 3.59-3.63 (2H, m), 3.69-3.73 (2H, m), 3.84-3.87 (2H, m), 7.11-7.14 (2H. m). 7.23-7.31 (6H. m), 7.44-7.47 (IH, m), 7.53-7.54 (IH, m), 8.40 (IH. s). 8.45 (2H. s); m/e (ES) 473 (M^* + 1).

30 EXAMPLE 101

l--3-r5-αmidazol-l-yl)-lH-indol-3-vnpropyl--4-r(RVα- (methoxymethyl)benzylaminolpiperidine. 2.0 Hydrogen Oxalate.

5 1.5 Hvdrate.

The title compound was prepared from l-{3-[δ-(imidazol-l-yl)-lH- indol-3-yl]propyl}-4-ketopiperidine and (R)-α-(methoxymethyl)benzylamine using a si lar procedure to that described for Example 8 (step δ); mp 128-130°C. (Found: C, δ7.72; H, 6.19; N, 10.3δ.

10 C2₈H35N₅O*2.0(C2H₂O₄) l.δ H₂O requires: C, 57.82; H, 6.37; N, 10.54%). δ_H (250MHz, DMSO-dβ) 1.55-1.80 (2H, m), 1.80-2.20 (4H, m), 2.60-2.85 (6H, m), 2.85-3.00 (2H, m), 3.23 (3H, s), 3.20-3.40 (2H, m), 3.40-3.60 (2H, m), 7.10 (IH, s), 7.24-7.46 (8H, m), 7.65-7.68 (2H, m), 8.18 (IH, s), 11.07 (IH, s); m/e (ES) 458 (M^* +l). lδ

EXAMPLE 102

l-(3-r5-(1.2.4-Triazol-l-yl)methyl-lH-indol-3-vnpropyll-4- .r(R)-l-(4- fluorophenyl⁾-2-methoxyethvπamino}^pi^peridine. 2.0 Hydrogen Oxalate 20 Hvdrate.

1. (R)-2-Amino-2-(4-fluorophenyl)-l-methoxy ethane. Hydrogen chloride.

A solution of (R)-2-amino-2-(4-fluorophenyl)ethanol (Example 80, step 1) (600mg, 3.9mmol) in anhydrous THF (5ml) was added dropwise to

25 a stirred suspension of sodium hydride (0.46g of 35% wt suspension in oil, washed with anhydrous pentane) in anhydrous THF (5ml). The reaction was stirred for 2h, treated with iodomethane (237μl) and aUowed to stand for 18h. The reaction was partitioned between diethyl-ether and saturated aqueous sodium chloride. The organic phase was dried

30 (MgSO4), concentrated, and redissolved in diethyl ether. The solution was treated with hydrogen chloride-diethyl ether ( 10ml) and concentrated to a yeUow soUd. RecrystalUsation from ethyl acetate gave colourless needles (δδlmg). δ_H (250MHz, DMSO-de) 3.32 (3H, s), 3.57-3.72 (2H, m), 4.48-4.53 (IH, m), 7.24-7.32 (2H, m), 7.56-7.61 (2H, m), 8.6 (3H, br s).

2. l-tβrf-Butyloxycarbonyl-4-r(R)-l-(4-fluorophenyl)-2- methoxyethyriaminopiperidine

The product from above (2δ0mg) and N-tert-butyloxycarbonyl- 4-ketopiperidine were reacted as described in Example 98 (step 2). The crude product was reacted as described below (step 3).

3. 4-[(R)- l-(4-Huorophenyl)-2-methoxyethyl1aminopiperidine hydrogen chloride

To a solution of the product from above (0.67g) in methanol (5ml) was added IN hydrogen chloride-diethyl ether (5ml). The reaction was concentrated and recrystallised from methanol -ethyl acetate to give a colourless soUd (367mg). 5H (250MHZ, αVmethanol) 2.08-2.44 (4H, m), 2.84- 3.08 (2H, m), 3.43 (2H, br s), 3.47 (3H, s), 3.76-3.96 (2H, m), 7.16-7.22 (2H, m), 7.61-7.66 (2H, m).

4. l- -3-r5-(1.2.4-Triazol-l-vDmethyl-lH-indol-3-yllpropyl -4-.ffR)- l-(4- fluorophenyl)-2-methoxyethyl1amino-piperidine. 2.0 Hvdrogen Oxalate Hvdrate.

The product from above (367mg) was reacted as described in Example 98 with the mesylate described in Example 98 (step 3) to give the title compound. (Found: C, 55.68; H, 6.12; N. 1 1.92.

C28H35FNeO*2(C2H₂O4) H₂O requires: C, 55.81; H, 6.00; N. 12.20%.) δn (360MHz, DMSO-de) 1.52- 1.70 (2H, m), 1.80- 1.90 (IH, m), 1.90-2.12 (3H, m), 2.56-2.74 (4H, m), 2.74-3.04 (4H, m). 3.24 (3H. s), 3.28-3.54 (3H, m), 4.20 (IH, br s), 5.43 (2H, s), 7.04-7.06 (IH. m), 7.17-7.22 (3H, m), 7.30- 7.33 (IH, m), 7.47-7.51 (3H, m), 7.94 (IH, s), 8.60 ( IH. s). 10.92 (IH. s); m/e (ES) 491 (M^* +l). EXAMPLE 103

l--3-f5-(1.2.4-Triazol-l-yl)methyl-lH-indol-3-vnpropyl}-4-rN-(4-fluorobenzylV δ N-methylaminolpiperidine. 2 Hydrogen Oxalate. Hvdrate.

1. l-terf-Butyloxycarbonyl-4-(4-fluorobenzyl)aminopiperidinp

4-Fluorobenzylamine (2.δg) and^'N-tert-butoxycarbonyl-4-piperidone (4g) were reacted as described in Example 98 (step 2), to give the title 10 product as a yeUow oil which crystalUsed (6.2g). OH (250MHz, CDCla)

1.22-1.37 (2H, m), 1.43 (9H, s), 1.82-1.94 (2H, m), 2.60-2.72 (IH, m), 2.74- 2.84 (2H, m), 3.80 (2H, s), 3.94-4.10 (2H, m), 6.97 (2H, m), 7.26-7.31 (2H, m).

lδ 2. l-tert-ButyloxycarbonvI-4-fN-(4-fluorobenzyl)-N- methylamino-Piperidine

The product from above (6.2g) was reacted using a similar procedure to that described in Example 10 to give the title product as a colourless oil (δ.66g). δ_H (250MHz, CDC ) 1.46 (9H, s), 1.46-1.57 (2H, m), 20 1.71-1.81 (2H, m), 2.17 (3H, s), 2.50-2.74 (3H, m), 3.53 (3H, s), 4.06-4.26

(2H, m), 6.95-7.02 (2H, m), 7.24-7.30 (2H, m).

3. 4-fN-(4-fluorobenzvI)-N-methylamino1piperidine

The product from above (2.73g) was deprotected using a similar 25 procedure to that described in Example 98 (step 2). The amine was obtained as a yeUow oil (1.81g). δ_H (360MHz, CDCb) 1.48- 1.59 (2H, m), 1.81-1.85 (2H, m), 2.18 (3H, s), 2.30-2.44 (2H, br s), 2.48-2.64 (3H, m), 3.16-3.20 (2H, m), 3.53 (2H, s), 6.96-7.00 (2H, m). 7.24-7.28 (2H, m).

30 4. l-{3-f5-(1.2.4-Triazol- l-yl)methyl- lH-indol-3-yllpropyll-4-rN-(4- fluorobenzyl)-N-methylaminolpiperidine. 2.0 Hydrogen Oxalate Hydrate. The title compound was prepared using a similar method to that described in Example 98 (step 3) using the product from above (642mg) and the mesylate from Example 98 (step 3). The oxalate salt was prepared and crystallised from methanol-diethyl ether; mp 180-181°C. (Found: C, 56.83; H, 5.79, N, 12.78. C27H33NβF*2(C2H2θ₄) H2θ requires C, 56.53; H, 5.97; N, 12.76%). δ_H (360MHz, DMSO-dβ) 1.80-1.95 (2H, m), 1.96-2.08 (4H, m), 2.24 (3H, s), 2.68-2.78 (2H, m), 2.80-2.98 (3H, s), 3.00- 3.10 (2H, m), 3.40-3.54 (2H, m), 3.77 (2H, s), 5.44 (2H, s), 7.06-7.07 (IH, m), 7.16-7.21 (3H, m), 7.32-7.34 (IH, m), 7.40-7.44 (2H, m), 7.54 (IH, s), 7.95 (IH, s), 8.6 (IH, s), 10.93 (IH, s); m/e (ES) 461 (M^* +1).

EXAMPLE 104

l-^3-r5-(1.2.4-Triazol-4-ylVlH-indol-3-yllpropyll-4-(2-phenylpiperidin-l- vDpiperidine. 2.6 Hydrogen Oxalate. 1.5 Hvdrate.

1. l-terf-Butyloxycarbonyl-4-f2-phenylpiperidin-l-vnpiperidine

N-tert-Butyloxycarbonyl-4-piperidone (5g), 2-phenylpiperidine (4.03g) and titanium isopropoxide (8.9ml) were stirred at room temperature under a nitrogen atmosphere for 3h. The resulting orange solution was diluted with methanol (40ml), treated with sodium cyanoborohydride (1.6g), and stirred for 20h. Water (50ml) was added to give a granular predpitate which was removed by filtration through ceUte. The filtrate was partitioned between water-ethyl acetate, the organic phase separated, dried (MgSO4) and concentrated. The residue was dissolved in ethyl acetate and washed with a saturated aqueous solution of dtric add. The aqueous phase was basified to pHlO using 4N sodium hydroxide, and extracted into ethyl acetate. The organic phase was dried (MgSO ) and concentrated. The residue was chromatographed using ethyl acetate-petroleum ether (20:80 to 50:50) to afford a partiaUy purified mixture, which was dissolved in ethyl acetate. The organic phase was washed with a saturated aqueous solution of dtric add. The aqueous phase was separated, basified to pHIO using 4N sodium hydroxide and extracted with ethyl acetate. The organic phase was dried (MgSO₄) and concentrated to give the product in 3% yield. δH (250MHz, CDCI3) 1.16- 1.79 (19H, m), 2.21-2.29 (2H, m), 2.41-2.50 (2H, m), 2.90-3.04 (IH, m), 3.36-3.44 (IH, ), 3.92-4.10 (2H, m), 7.16-7.40 (5H, m).

2. 4-(2-Phenylpiperidin-l-yl)piperidine

The product from above (245mg) was deprotected as described in Example 98 (step 2). The product was obtained as a yeUow soUd (170mg). δ_H (360MHz, CDCb) 1.29-1.83 (10H, m), 2.10-2.18 (IH, m), 2.25-2.45 (3H, m), 2.97-3.06 (3H, m), 3.39-3.42 (IH, m), 7.21-7.30 (5H, m).

3. l-!3-r5-(1.2.4-Triazol-4-ylVlH-indol-3-vnpropyI--4-(2- phenylpiperidip-l-vDpiperidine. 2.5 Hydrogen Oxalate. 1.5 Hvdrate.

The title compound was prepared from 3-[5-(l,2,4-triazol-4-yl)-lH- indol-3-yl]propan-l-ol and 4-(2-phenylpiperidin-l-yl)piperidine using a similar method to that described for Example 36 (step b). The oxalate salt was prepared and crystalUsed from methanol-diethyl ether; mp 126- 128°C. (Found: C, 56.42; H, 6.17; N, 11.56. C29H36Nβ-2.5(C2H2θ₄)*

1.5 H2O requires: C, 56.66; H, 6.15; N, 11.66%).δ_H (360MHz, DMSO-dβ, 353°K) 1.30-1.50 (IH, m), 1.52-2.06 (12H, m), 2.30-2.70 (4H, m), 2.71-2.75 (2H, m), 2.80-2.88 (2H, m), 3.00-3.14 (IH, m), 3.24-3.40 (2H, m), 3.60-3.70 (IH, m), 7.25-7.38 (7H, m), 7.47-7.50 (IH, m), 7.71-7.72 (IH, m), 8.86 (2H, m), 10.93 (IH, m); m/e (ES) 469 (M+l)^*.

EXAMPLE 105

l-(3-f5-(1.2.4-Triazol-4-yl)-lH-indol-3-yllpropyU-4-U(Η)- l -(4- fluorophenyl)-2-methoxyethyl]amino-piperidine. Hydrogen Oxalate. (R)-2-Amino-2-(4-fluorophenyl)-l-methoxy ethane (Example 102, step 1) (310mg) and l-{3-[5-(l,2,4-triazol-4-yl)-lH-indol-3-yl]propyl}-4- ketopiperidine (487mg) were reacted as described in Example 8.(step 5) to give the title compound. The oxalate salt was prepared and crystallised from methanol-diethyl ether. (Found: C, 54.75; H, 5.94; N, 12.47.

C27H3aFNβ-2(C2Haθ4)-1.2 H₂0 requires: C, 54.89; H, 5.86; N, 12.39%). 5_H (360MHz, DMSO-dβ) 1.56-1.70 (2H, m), 1.82-1.94 (IH, s), 1.94-2.20 (3H, m), 2.54-2.68 (IH, m), 1.68-1.90 (4H, m) 1.90-3.06 (2H, m), 3.25 (3H, s), 3.28-3.42 (2H, m), 3.42-3.56 (2H, m), 4.20-4.30 (IH, m), 7.17-7.22 (2H, m), 7.31-7.34 (2H, m), 7.48-7.51 (3H, m) 7.79-7.80 (IH, m), 9.01 (2H, s), 11.17 (lH, s).

EXAMPLE 106

(3RV3-(Benzylsulfinyl)methyl-l-{2-r5-(1.2.4-triazol-4-ylVlH-indol-3- yl]ethyl}pyrroUdine. Hydrogen Oxalate.

1. (3R)-3-(Benzylsulfinyl)methyl- 1 -(tert-butoxycarbon yl)p yrroUdine To a stirred solution of (3R)-3-(benzylthio)methyl-l-(terf- butoxycarbonyl)pyrroUdine (0.2553g, 0.830mmol) in ethyl acetate (15ml), under argon, cooled in a bath at ca. -40°C, was added portionwise 67-86% 3-chloroperoxybenzoic add (0.2094g). The mixture was then aUowed to warm to 0°C over 1.5h, before pouring into δ% NaHCOβ solution (15ml). The organic layer was separated and washed with more 5% NaHCO3 solution (15ml), then saturated NaCl solution (10ml), dried (MgSO₄) and evaporated in vacuo. The residue was purified by flash chromatography (siUca gel, 3% MeOH/CH₂Cl₂) to give 0.238 lg (89%) of the title compound as a colourless oil. δ_H (250MHz, CDCI3) 1.44 (9H. s), 1.61 (IH, m). 2.15 (IH, m), 2.52 (IH, m), 2.66 (2H, m). 3.00 (IH. m). 3.29 (IH. m). 3.43 (IH, m), 3.63 (IH, m), 3.96 (IH, d, J=12.9Hz), 4.07 (IH, d, J=12.9Hz), 7.28-7.30 (2H, m), 7.35-7.39 (3H, m). m/e (ES+) 324 (M+H)^*. 2. (3R)-3-f(Benzylsulfinyl)methvnpyrroUdine

Using a similar method to that described in Example 93, step 2, (3R)-3-(benzylsu nyl)methyl-l-(_:er_--butoxycarbonyl)pyrroUdine (0.2376g, 0.735mmol) was reacted with trifluoroacetic add (1ml) in dichloromethane (3ml) to give, after work up, 0.1543g (94%) of the title compound as a white soUd, which was used without further purification. δH (250MHz, CDCLO 1.47 (IH, m), 2.09 (IH, m), 2.52-2.72 (4H, m), 2.94 (2H, m), 3.19 (IH, m), 3.96 (IH, d, J=12.9Hz), 4.06 (IH, dd, J=12.9 and 3.6Hz), 7.27-7.43 (5H, m).

3. (3RV3-(BenzylsuffinvDmethyl-l-.2--5-(1.2.4-triazol-4-ylVlH-indol- 3-ylJethyllpyrroUdine. Hydrogen Oxalate.

Using a similar method to that described in Example 93, step 3, (3R)-3-[(benzylsulfinyl)methyl]pyrroUdine (O.lδOOg, 0.672mmol) was reacted with 3-[2-(methanesulfonyloxy)ethyl]-5-(l,2,4-triazol-4-yl)-lH- indole (0.1375g, 0.449mmol) and sodium carbonate (71.3mg, 0.673mmol) in 2-propanol (15ml) to give 93.8mg (48%) of the title compound free base as a colourless soUd. The oxalate salt was prepared in methanol-diethyl ether: mp 100-108°C. (Found: C, 57.77; H, 5.90; N, 12.36.

C₂₄H27N₅SO*C2H2θ4-0.18(C₄HιoO)*H2θ requires: C, 57.83; H, 5.96; N. 12.62%). δ_H (360MHz, DMSO-de) 1.80 (IH, m), 2.06 (IH, m). 2.79-2.86 (2H, m), 2.94 (IH, m), 3.09 (3H, m), 3.38 (4H, m). 3.62 (IH, m), 4.01 (IH, dd, J=3.4 and 12.7Hz). 4.18 (IH, dd, J=6.1 and 12.8Hz), 7.32-7.40 (7H, m), 7.52 (IH, d, J=8.6Hz), 7.89 (IH, s), 9.03 (2H, s), 11.29 (IH, s). m/e (ES+) 434 (M+H)^*.

EXAMPLE 107

(3RV3-r(4-Fluorobenzylthio)methvn- l-{2-(5-f(1.2.4-triazol- l-yl)methvIl- lH-indol-3-yl)ethyl.pyrroUdine. Hydrogen Oxalate. 1. (3R)-l-(tβrf-Butoxycarbonyl)-3-f(4-fluorobenzylthio)methyl1pyrroUdine Using a similar method to that described in Example 93, -step 1,

(3R)- l-(tert-butoxycarbonyl)-3- [(methanesulfonyloxy)methyl]pyrroUdine (1.5000g, 5.37mmol) was reacted with 4-fluorobenzyl mercaptan (1.551 lg, 10.91mmol) and potassium carbonate (1.1132g, 8.05mmol) in DMF (30ml) at room temperature for 24h to give 1.7507g (100%) of the title compound as a colourless oil. δ_H (360MHz, CDCls) 1.45 (9H, s), 1.60 (IH, m), 2.00 (IH, m), 2.44 (2H, m), 2.97 (IH, m), 3.28 (IH, m), 3.46 (2H, m), 3.69 (2H, s), 7.00 (2H, t, J=8.6Hz), 7.25-7.29 (2H, m). m/e (ES+) 348 (M+Na)^*, 326 M+H)^*, 270 (M-CMe₃+2H)^*.

2. (3R)-3-f(4-Fluorobenzylthio)methyllpyrroUdine A solution of (3R)-l-(iert-butoxycarbonyl)-3-[(4- fluorobenzylthio)methyl]pyrroUdine (0.5422g, 1.67mmol) in 90% formic add (5ml) was stirred at room temperature for 23h. The solvents were removed in vacuo and the residue was dissolved in dichloromethane (25ml) and washed with 2N NaOH solution (10ml). The aqueous layer was reextracted with more dichloromethane (25ml) and the combined organic extracts were washed with saturated NaCl solution (10ml), dried (Na2SO ) and evaporated in vacuo to leave 0.3903g of the title compound as an oil. δ_H (360MHz, CDCI3) 1.42 (IH, m), 1.94 (IH, m), 2.24 (IH, m). 2.45 (2H, m), 2.59 (IH, m), 2.92 (2H, m), 3.08 (IH, m), 3.69 (2H, s), 7.00 (2H, t. J=8.6Hz), 7.25-7.29 (2H, m).

3. (3RV3-r(4-Fluorobenzylthio)methyll-l-.2-(5-r(1.2.4-triazol-l- yl)methyl)-lH-indol-3-yl)ethyl}pyrrohdine. Hydrogen Oxalate.

To a stirred solution of 3-(2-hydroxyethyl)-5[(l,2,4-triazol- l- yl)methyl]-lH-indole (0.1425g, 0.588mmol) and triethylamine (0.107ml, 0.768mmol) in THF (10ml), cooled under argon in a bath at -40°C, was added dropwise methanesulfonyl chloride (56.0μl, 0.709mmol). The mixture was then stirred at room temperature for 1.5h before diluting with ethyl acetate (40ml) and washing with brine (20ml). The organic layer was dried (MgSO ) and evaporated in vacuo. The residue-was immediately dissolved in anhydrous 2-propanol (10ml) to which was added anhydrous potassium carbonate (0.1626g, 1.176mmol) foUowed by a solution of (3R)-3-[(4-fluorobenzylthio)methyl]pyrroUdine (0.1978g, 0.878mmol) in anhydrous 2-propanol (8ml). The mixture was then heated at reflux for 4h. After cooling, the solvents were removed in vacuo and the residue was partitioned between dichloromethane (25ml) and water (15ml). The aqueous layer was separated and reextracted with more dichloromethane (2 x 25ml). The combined organic layers were washed with saturated NaCl solution (20ml), dried (Na2SO₄) and evaporated in vacuo. The residue was purified by flash chromatography (siUca gel, CH₂Cl2 MeOH/NH3, 94:6:0.6), then by preparative t.l.c. (siUca gel, CH₂Cl2/MeOH/NH3, 92:8:0.8) to give 0.147g (56%) of the title compound, free base. The oxalate salt was prepared in methanol-diethyl ether; mp

68-71°C. (Found: C, 61.02; H, 5.65; N, 13.70. C25H28FN₅S*0.8(C₂H2θ4) requires: C, 61.25; H, 5.72; N, 13.43%). δ_H (360MHz, DMSO-dβ) 1.60 (IH, m), 2.07 (IH, m), 2.81 (IH, m), 2.96 (2H, m), 3.13 (4H, m), 3.27 (IH, m), 3.76 (2H, s), 5.43 (2H, s), 7.05 (IH, d, J=9.7Hz), 7.15 (2H. t, J=8.9Hz), 7.23 (IH, s), 7.32-7.39 (3H, m), 7.58 (IH, s), 7.94 (IH, s). 8.81 (IH, s), 10.97 (IH, s) among other signals, m/e (ES+) 450 (M+H) ^*.

EXAMPLE 108

(3R)-3-f(4-Fluorobenzylsu nyl)methyl)-l-{2-(5f(1.2.4-triazol- l-vnmethyll- lH-indol-3-yl)ethyl,pyrroUdine. Hydrogen Oxalate.

1. (3R)-l-(tgrt-Butoxy(^rbonyl)-3-f(4-fluorobenzylsulfinyl)ττ.pthvIlp\Υrolidine Using a similar procedure to that described in Example 107. step 1,

(3R)- l-(tert-butoxycarbonyl)-3-[(4-fluorobenzylthio)methyl]pyrrolidine (0.5818g, 1.79mmol) was reacted with 57-86% 3-chloroperoxybenzoic add (0.4477g) in ethyl acetate (35ml) to give 0.5233g (86%) of the title compound as a colourless oϋ δ_H (360MHz, CDCls) 1.45 (9H, s), 1.66 (IH, m), 2.15 (IH, m), 2.54-(lH, m), 2.63-2.71 (2H, m), 3.03 (IH, m), 3.31 (IH, m), 3.44 (IH, m), 3.65 (IH, m), 3.96 (2H, s), 7.08 (2H, t, J=8.6Hz), 7.25-7.29 (2H, m). m/e (ES+) 342 (M+H) ^*.

2. (3R)-3-K4-FluorobenzγlCTilfinγl)methyl]pyrmliHinp

Using a similar procedure to that described in Example 93, step 2, (3R)-1- (tert-butoxyca_d_K>nyl)-3-[(4-fluorob__nzy__^^ (0.5149g, 1.5 lmmol) was reacted with trifluoroacetic add (2ml) in dichloromethane (6ml) to give, after work up, 0.3447g (95%) of the title compound as a white soUd, which was used without further purification. 6H (360MHZ, CDCI3) 1.57 (IH, m), 2.13 (IH, m), 2.54-2.72 (4H, m), 3.05 (2H, m), 3.27 (IH, m), 3.96 (2H, m), 7.08 (2H, t, J=8.6Hz), 7.26-7.30 (2H, m).

3. (3RV3-f(4-Fluorobenzylsuu nyl)methyl)-l-(2-(5r(1.2.4-triazol-l- yl)methyl1-lH-indol-3-yl)ethyl}pyrroUdine. Hydrogen Oxalate.

Using a similar method to that described in Example 108, step 3, 3-(2- hydroxyethyl)-5-[(l,2,4-triazol-l-yl)methyl)-lH-indole (0.1200g, 0.495mmol) was reacted with methanesulfonyl chloride (58.7ul, 0.743mmol) and triethylamine (0.138ml, 0.990mmol) in THF (3ml), then with (3R)-3-[(4- fluorobenzylsuUinyl)methyl]pyrroUdine (0.1793g, 0.743mmol) and sodium carbonate (0.1048g, 0.989mmol) in 2-propanol (12ml) to give, after purification by flash chromatography (siUca gel, CH∑Cb/MeOH/NH., 92:8:0.8), then by preparative t.l.c. (siUca gel, CH∑C MeOH NHs, 90:10: 1), 70.1mg (30%), of the title compound, free base. The oxalate salt was prepared in methanol-diethyl ether: mp 72°C (softens). (Found: C, 57.68;

H, 5.85; N, 11.82.

H₂O requires: C, 57.65; H, 5.77; N. 12.04%). δ_H (360MHz. DMSO-de) 1.79 (IH, m), 2.25 (IH, m), 2.80 (2H, m), 2.92 (IH, m), 3.04 (3H. m), 3.35 (4H, m), 4.01 (IH. dd, J=2.9 and 12.9Hz), 4.21 (IH, dd, J=5.8 and 13.0Hz), 5.44 (2H, s), 7.07 (IH, d, J=8.4Hz), 7.23 (IH, t, J=8.8Hz), 7.26 (IH, s), 7.34-7.41 (3H, m), 7.61 (IH, s), 7.95 (IH, s), 8.81 (IH, s), 11.03 (IH, s) among other signals, m/e (ES+) 466 (M+H)⁺.

EXAMPLE 109

(3RV3-f(4-Fluorobenzylsulfonyl)methyl)-l-;2-(5r(1.2.4-triazol-l-yl)methyll- lH-indol-3-yl)ethyl>pyrroUdine. Hydrogen Oxalate.

1. (3R)-l-(terf-Butoxycarbonyl)-3-f(fluorobenzylsuUbnyl)methyllpyrrohdine To a stirred solution of (3R)-l-(tert-butoxycarbonyl)-3-[(4- fluorobenzylthio)methyllpyrroUdine (0.567 lg, 1.74mmol) in ethyl acetate (35ml), cooled under argon in a bath at -40°C, was added portionwise 57- 86% 3-chloroperoxybenzoic add (0.8780g). The mixture was aUowed to warm to +8°C over 1.5h, then stirred at this temperature for lh. The mixture was then poured into 5% NaHCOβ solution (30ml). The organic layer was separated and washed with more 5% NaHCOβ solution (30ml), then brine (20ml), dried (MgS0₄) and evaporated in vacuo. The residue was purified by flash chromatography (siUca gel, 1% MeOH/CH2θ2 and siUca gel, Et2θ) to give 0.612g (98%) of the title compound as a colourless oil. δ_H (360MHz, CDCls) 1.45 (9H, s), 1.68 (IH, m), 2.19 (IH, m), 2.73 (IH, m), 2.90 (2H, m), 3.01 (IH, dd, J=8.2 and 11.0Hz), 3.29 (IH. m), 3.45 (IH, m), 3.69 (IH, dd, J=7.2 and 10.9Hz), 4.21 (2H, s), 7.11 (2H, t, J=8.6Hz), 7.39 (2H, m). m/e (ES+) 358 (M+H)^*.

2. (3R)-3-f(4-FluorobenzylsuUbnyl)methyl)pyrroUdine

Using a similar method to that described in Example 93, step 2, (3R)-l-(tert-butoxycarbonyl)-3-[(4-fluorobenzylsulphonyl)- methyl]pyrroUdine (0.6465g, l.δlmmol) was reacted with trifluoroacetic add (2ml) in dichloromethane (6ml) to give, after work up, 0.4755g of the title compound as a white soUd, which was used without further purification. δ_H (360MHz, CDCls) 1.55 (IH, m), 2.15 (IH, m), 2.60-2.73 (2H, m), 2.90-3.00 (4H, m), 3.30 (IH, m), 4.21 (2H, s), 7.11 (2H, t, J=8.6Hz), 7.37-7.41 (2H, m).

δ 3. (3RV3-r(4-Fluorobenzylsulfonyl)methyl)-l-.2-(δr(1.2.4-triazol-l- yl)methyl.-lH-indol-3-yl)ethyl}pyrroUdine. Hydrogen Oxalate.

Using a similar method to that described in Example 108, step 3, 3-(2-hydroxyethyl)-δ-[(l,2,4-triazol- l-yl)methyl]- lH-indole (0.1480g, 0.6 llmmol) was reacted with methanesulfonyl chloride (72.4μl,

10 0.916mmol) and triethylamine (0.170ml, 1.22mmol) in THF (5ml), then with (3R)-3-[(4-fluorobenzylsulfonyl)methyl]pyrroUdine (0.2360g, 0.917mmol) and sodium carbonate (0.1295g, 1.22mmol) in 2-propanol (14ml) to give, after purification by flash chromatography (silica gel, CH₂Cl2/MeOH/NH3, 94:6:0.6), 48.7mg (17%) of the title compound, free lδ base. The oxalate salt was prepared in methanol-diethyl ether: mp 79°C

(softens). (Found: C, 63.86; H, 5.49; N, 10.64. C₂5H₂8FN₅O₂S-l.δ(C2H₂θ4)- 0.2(C4HιoO) 0.6 H2O requires: C, 53.86; H, 5.37; N, 10.90%). δ_H (360MHz, DMSO-dβ) 1.81 (IH, m), 2.16 (lH,.m), 2.87 (IH, m), 3.05 (2H. m), 3.30- 3.42 (4H, m), 4.66 (2H, s), 5.44 (2H, s), 7.07 (IH, d, J=8.6Hz), 7.25-7.29 20 (3H, m), 7.3δ (IH, d, J=8.3Hz). 7.45-7.49 (2H, m), 7.62 (IH, s), 7.95 (IH, s), 8.81 (IH, s), 11.04 (IH, s) among other signals, m/e (ES+) 482 (M+H) ^*.

EXAMPLE 110

25 4-(4-Fluorobenzylsu nyl)- l-<3-f5-(1.2.4-triazol-4-yl)- lH-indol-3- vllpropyUpiperidine. Hydrogen Oxalate.

1. l-(tert-Butoxycarbonyl)-4-(4-fluorobenzylthio)piperidine

To a stirred solution of 4-fluorobenzyl mercaptan (23.34g, 164mmol) in 30 DMF (150ml) under argon, cooled in a bath at -2°C. was added portionwise 60% NaH in oU (6.57g, 164mmol) over 12 minutes. The mixture was then stirred at room temperature for 15 minutes before recooling in bath at -2°C and adding by cannular, over 13 minutes, a solution of 4-bromo-l(tert- butoxycarbonyl)piperidine (10.84g, 41.0mmol) in DMF (50ml). The mixture was then stirred at room temperature for 24h before partitioning between δ water (δOOml) and diethyl ether (500ml). The aqueous layer was reextracted with more diethyl ether (500ml) and the combined organic extracts were dried (MgS0₄) and evaporated in vacuo. The residue was purified by flash chromatography (siUca gel, 10-15% EtOAc/hexane) to give 4.58g (34%) of the title compound as a colourless oil. 5H (360MHZ, CDCI3) 1.45 (9H, s), 1.49 (2H, 0 m), 1.86 (2H, m), 2.67 (IH, m), 2.88 (2H, m), 3.73 (2H, s), 3.92 (2H, m), 6.99 (2H, t, J=8.6Hz), 7.28 (2H, m). m/e (ES+) 326 (M+H) ^*.

2. l-(tert-Butoxycarbonyl)-4-(4-fluorobe"7.ylfiiilfinyl)pippridinp Using a similar method to that described in Example 107, step 1, 5 l-(tert-butoxycarbonyl)-4-(4-fluorobenzylthio)piperidine (1.506δg, 4.63mmol) was reacted with 57-86% 3-chloroperoxybenzoic add (1.0190g) in dichloromethane (100ml) to give 1.5287g (97%) of the title compound as a white soUd. δ_H (2δOMHz, CDCI3) 1.46 (9H, s), 1.64-1.82 (3H, m), 2.02 (IH, m), 2.63 (IH, m), 2.81 (2H, m). 3.88 (IH, d, J=13.2Hz), 3.98 (IH, d, J=13.2Hz), 0 4.21 (2H, m), 7.08 (2H, t, J=8.6Hz), 7.29 (2H, m); m/e (ES+) 683 (2M +H)^*, 342 (M+H)^*.

3. 4-(4-Fluorobenzylsιι1finyl-piperidine

Using a similar method to that described in Example 108. step 2, 5 l-(tert-butoxycarbonyl)-4-(4-fluorobenzylsulfinyl)piperidine (1.524g,

4.46mmol) was reacted with 90% formic add (15ml) to give 1.0276g (95%) of the title compound as a white soUd. διι (250MHz, CDCL) 1.47 (2H. m), 1.82 (2H, m), 2.49 (2H, m), 2.69 (IH, tt, J=4.0 and 11.8Hz), 3.03 (2H, m), 3.88 (IH. d, J=13.0Hz), 4.11 (IH, d, J=13.0Hz), 7.20 (2H, t, J=8.9Hz), 7.37 (2H. m). 30 m e (ES+) 242 (M+H) ^*. 4. 4-(4-FluorobenzylsulfinylVl- -r5-(1.2.4-triazol-4-ylVlH-indol-3- v propyUpiperidine. Hydrogen Oxalate.

Using a similar procedure to that described in Example 108, step 3, 3-(3-hydroxypropyl)-5-(l,2,4-triazol-4-yl)-lH-indole (0.1499g, 0.619mmol) was reacted with methanesulfonyl chloride (0.103ml, 1.30mmol) and triethylamine (0.183ml, 1.31mmol) in THF (20ml) at room temperature and then with 4-(4-fluorobenzylsuUιnyl)pipericiine (0.2376g, 0.985mmol) and anhydrous potassium carbonate (0.1822g, 1.32mmol) in anhydrous 2-propanol (20ml) at reflux overnight to give, after purification by flash chromatography (siUca gel, CH∑CWMeOH/NHj, 92:8:0.8) and preparative t c. (siUca gd, ClfeCla/MeOH/NHi, 90:10:1), 0.1159g (40%) of the title compound free base. The oxalate salt was prepared in ethanol-diethyl ether; mp 100°C (softens). (Found: C, 55.09, H, 5.35, N, 11.30.

C₂5H₂8FN5OS 1.5(C2H₂O₄)*0.6H2O requires: C, 55.00, H, 5.31, N, 11.45%). δ_H (360MHz, DMSO-dβ) 1.90 (2H, m), 2.00-2.16 (4H, m), 2.77 (2H, t, J=7.2Hz), 2.85 (IH, m), 2.90-3.06 (4H, m), 3.96 (IH, d, J=13.lHz), 4.17 (IH, d, J=13.lHz), 7.21 (2H, t, J=8.8Hz), 7.31-7.34 (2H, m), 7.39 (2H, m), 7.50 (IH, d, J=8.6Hz), 7.81 (IH, d, J=1.9Hz), 9.01 (2H, s), 11.18 (IH, s) among other signals, m e (ES+) 466 (M+H) ^*.

EXAMPLE 111

2S-2-(N-Benzyl-N-methylaminomethvn-l-f2-(5-(1.2.4-triazol-l-yl)-lH- pyrrolof2.3-clp\^rridin-3-yl)ethyllp\^rrroUdine oxalate

1. Intermediate δ: 2-(5-(1.2.4-Triazol- l-yl)-lH-pyrrolor2.3-clpyridin- 3-yl)acetonitrile

a) 4-Methyl-5-nitro-2-( 1.2.4-triazol-l-yl)pyri dine To a solution of 1.2.4-triazole (4.0g, 58mmol) in dry dimethyl formamide (20ml) was added potassium carbonate ( 12.0g, 87mmol) and 2-chloro-4-methyl-5-nitropyridine (lOg, δδmmol) and the mixture stirred at ambient temperature under nitrogen for 24h. Ethyl acetate (500ml) and water (250ml) were added to the mixture and the resulting predpitate was coUected by filtration to give the title compound (δ.08g, 43%) as a pale brown soUd. The filtrate was separated and the organic phase was washed with water (250ml) and brine (250ml), dried (MgSO4) and evaporated. The residue was triturated with ethyl acetate and the predpitate coUected by filtration to give the title compound as a brown soUd (4. llg, 35%, overaU yield 78%); mp 198-200°C. Η NMR (360MHz, CDCls) δ 2.72 (3H, s), 7.86 (IH, s), 8.07 (IH, s), 9.03 (IH, s), 9.15 (IH, s).

b) N.N-Dimethyl-2-(5-nitio-2-(1.2.4-triazol-l-yl)-pyridin-4-yl)ethenamine To a suspension of 4-methyl-δ-nitro-2-(l,2,4-triazol-l-yl)pyridine

(4.1g, 20mmol) in dry dimethylformamide (30ml) was added dimethylformamide dimethyl acetal (δ.9ml, 44mmol) and the mixture heated at 90°C for 20 min. The solvent was evaporated in vacuo using toluene as an azeotrope to give the title compound (5.2g, 100%) as a dark red soUd; mp 225-228°C. >H NMR (360MHz, CDC ) δ 3.10 (6H, s), 6.13 (IH, J=l3. lHz), 7.54 (IH, J=13.lHz), 7.81 (IH, s), 8.04 (IH, s), 8.92 (IH. s), 9.17 (IH. s).

c) 5-(1.2.4-Triazol-l-v -lH-pyrrolor2.3-clpyridine N,N-Dimethyl-2-(δ-nitro-2-(l,2,4-triazol-l-yl)pyridin-4- yl)ethenamine (8g, 31mmol) was hydrogenated over platinum oxide (1.6g) in ethanol (150ml) at 30psi of hydrogen for lh. The catalyst was removed by filtration and the solvent evaporated in vacuo. The residue was chromatographed on siUca eluting with ethyl acetate to afford an orange/brown soUd. This was triturated with ether and the precipitate coUected by filtration to give the title compound (2.89g, 51%) as a pink soUd; mp 203-205°C, ^»H NMR (360MHz, dβ-DMSO) δ 6.67 (IH. d, J=3.0Hz), 7.76 (IH, d, J=2.9Hz), 8.01 (IH, s), 8.23 (IH, s), 8.70 (IH, s), 9.25 (lH, s), 11.86 (lH. br s).

d) N.N-Dimethyl-15-( 1.2.4-triazol- 1-vD- lH-pyrrolof2.3-c1pyridin-3- yllmethylamine

To aqueous dimethylamine (40%, 0.35ml, 2.8mmol), was added acetic add (1.46ml, 26mmol) at 0°C. Aqueous formaldehyde solution (38%, 0.21ml, 2.8mmol) was added and the mixture was stirred at 0°C for 5 min. 5-(l,2,4-Triazol-l-yl)-lH-pyrrolo[2,3-c]pyridine (0.5g, 2.7mmol) was added in one portion and then the mixture was aUowed to warm to room temperature and then heated at 60°C for 18h. The reaction was cooled to 0°C and treated with NaOH (4M, 8ml) to basify. Water (20ml) was added, foUowed by dichloromethane (50ml). The soUd generated was removed by filtration and the two layers of the filtrate were separated. The aqueous phase was extracted with dichloromethane (5 x 50ml) and the combined organics were dried (Na∑SO-O and the solvent evaporated in vacuo. The residue was chromatographed on siUca eluting with 10% MeOH in DCM foUowed by a gradient of 90:10:1 to 80:20:1, DCM/MeOH/NHj to afford the title compound (0.58g, 87%) as a colourless soUd; mp 172-175°C. »H NMR (360MHz, de-DMSO) δ 2.16 (6H, s), 3.59 (2H, s), 7.6δ (IH, s), 8.04 (IH, s), 8.22 (IH, s), 8.64 (IH, s), 9.25 (IH, s), 11.69 (lH. br s).

e) N-(f5-(1.2.4-Triazol-l-yl)-lH-pyrrolof2^-c1pyridin-3-yllmethvn- N.N.N-trimethylammonium methyl sulphate

A mixture of dimethylsulphate (0.13ml, 1.4mmol) and dry THF (5ml) was cooled to 0°C under nitrogen and N,N-dimethyl-[5-(l,2,4-triazol- l-yl)-lH-pyrrolo[2,3-c]pyridin-3-yl]methylamine (0.15g, 0.62mmol) was added portionwise over a period of 5 min. The mixture was stirred at 0°C for 90 min. The resulting precipitate was coUected by filtration and washed with THF to afford the title compound (0.23g, 100%) as a colourless soUd; mp 182-185°C. Η NMR (250MHz, de-DMSO) δ 3.06 (9H, s), 3.38 (3H, s), 4.77 (2H, s), 8.08 (IH, s), 8.30 (IH, s), 8.38 (IH, s), 8.78 (IH, s), 9.31 (IH, s), 12.40 (IH, br s).

f) 2-(δ-(1.2.4-Triazol-l-yl)-lH-pyrrolor2.3-clpyridin-3-yl)acetonitrile

To a solution of N-([5-(l,2,4-triazol-l-yl)-lH-pyrrolo[2,3-c]pyridin-3- yl]methyl-N,N,N-trimethylammonium methylsulphate (0.56g, l.δmmol) in water (4ml) was added a solution of potassium cyanide (0.239g, 3.7mmol) in water (2ml). This mixture was heated at 70°C for 1 h. Further potassium cyanide (80mg, 1.2mmol) was added and the mixture heated for another hour at 70°C. Further potassium cyanide (80mg, 1.2mmol) was added and the mixture heated at 70°C for 1 hour and then at 100°C for 20 min , The mixture was then cooled in ice for 30 min. The precipitate was coUected by filtration and washed with water. The soUd was chromatographed on siUca eluting with 5% MeOH in DCM to afford the title compound (0.215g, 63%) as a colourless soUd; mp 218-220°C. Η NMR (250MHz, dβ-DMSO) δ 4.19 (2H, s), 7.78 (IH, s), 8.12 (IH, s), 8.26 (IH, s), 8.71 (IH, s), 9.29 (IH, s), 11.93 (IH, br s).

2. Intermediate 6: 2S-2-(N-Benzyl-N-methyl)aminomethylpyrroUdine

a) 2S-N-tert-Butyloxycarbonyl-2-hvdroxymethylpyrroUdine

To a solution of L-proUnol (15g, O.lδmol) in DCM (250ml) was added di-tert-butyl dicarbonate (36.5g, 0.163mol). The solution was stirred at ambient temperature for 18h. The solvents were evaporated in vacuo to give the title compound (30g, 100%) as a colourless oil. δ (250MHz, CDC ) 1.47 (9H, s). 1.57-2.10 (4H. m). 3.26-3.52 (2H. m), 3.55- 3.78 (3H, m), 3.86-4.00 (IH, m). b) 2_S-N-tert-Butyloxycarbonyl-2-methylsulphonylmethylpyrroUdine A solution of methanesulphonyl chloride (6.3g, 55mmol) in dichloromethane (25ml) was added dropwise to a solution of 2S-N-tert- butyloxycarbonyl-2-hydroxymethylpyrroUdine (lOg, 50mmol) and

5 triethylamine (5.53g, δδmmol) in dichloromethane (160ml) at -δ°C. The solution was stirred at 0°C for lh and then at ambient temperature for 17h. The mixture was diluted with dichloromethane (100ml) and washed with water (100ml) and brine (100ml). The organic layer was dried (Na2SO₄) and evaporated in vacuo to give the title compound (13.43g, 97%)

10 as a pale yeUow gum. δ (250MHz, CDC ) 1.47 (9H, s), 1.71-2.10 (4H, m), 3.01 (3H, s), 3.28-3.46 (2H, m), 3.90-4.36 (3H, m).

c) 2S-N-tert-Bu1yloxycaιbonyl-2-(N-benzyl-N-memyl)aminomethylpyι ohdine A solution of 2_S-N-<erf-butyloxycarbonyl-2-methylsulphonyUnethyl lδ pyrroUdine (2g, 7.2mmol) and N-benzylmethylamine (4.6ml, 36mmol) in dry DMF (δml) was stirred at ambient temperature for 2h and then heated at 100°C for 8h. The reaction mixture was partitioned between ether (50ml) and water (50ml). The organic phase was washed with brine (30ml), dried (Na2SO ) an evaporated in vacuo. The residue was

20 chromatographed on siUca eluting with EtOAc:Petrol (60/80) (1: 1) to give the title compound (1.07g, 49%) as an orange oil. δ (2δOMHz, CDC ) 1.46 (9H, s), l.δδ-2.04 (5H, m), 2.10-2.60 (4H, m), 3.19-3.42 (3H, m). 3.52-4.09 (2H, m), 7.18-7.40 (5H, m).

25 d) 2S-2-(N-Benzyl-N-methyl)aminomethyl)pyrroUdine

A solution of 2S-N-tert-butyloxycarbonyl-2-(N-benzyl-N- methyDaminomethylpyrroUdine (1.07g, 3.5mmol) and trifluoroacetic acid

(2ml) in dichloromethane (20ml) was stirred at room temperature for 16h. heated at reflux for 8h and then stirred at room temperature for a further 30 16h. The solvents were evaporated in vacuo and the residue was partitioned between ethyl acetate (50ml) and K₂CO_ (saturated. 50ml). The aqueous was extracted with ethyl acetate (3 x 25ml), dichloromethane (2 x 25ml) and butanol (2 x 25ml). The EtOAc and DCM layers were dried (Na2SO4) and combined with the butanol phases and evaporated. The residue was chromatographed on siUca with DCM/MeOH (98:2) foUowed by DCM/MeOH/NHs (90: 10: 1) to afford the title compound (0.62g, 86%) as a pale yeUow oil. δ (250MHz, CDCLO 1.38-1.50 (IH, m), 1.60-2.08 (3H, m), 2.27 (3H, s), 2.30-2.50 (2H, m), 2.77-2.87 (IH, m), 2.95-3.05 (IH, m), 3.36- 3.65 (3H, m), 4.85 (IH, br s), 7.23-7.36 (5H, m).

3. 2-(5-(1.2.4-Triazol-l-v -lH-pyrrolor2.3-clpyridin-3-yl)acetic acid (2S-2-(N-benzyl-N-methylaminomethyl)pyrroUdinyl)amide

To a suspension of Intermediate 5 (0.89g, 4.0mmol) in methanol (10ml) was added sodium hydroxide (2M, 25ml). This mixture was heated at 80°C for 16h. After cooling the mixture was neutraUsed (2M HCI) and the solvents evaporated. The residue was chromatographed on siUca eluting with a gradient of 90:10:1 to 80:20:2, DCM/MeOH/Acetic add foUowed by MeOH to afford 2-(5-(l,2,4-triazol-l-yl)-lH-pyrrolo[2,3-c] pyridin-3-yl)acetic add (3g) as a pale yeUow soUd. -H NMR (360MHz, de-DMSO) δ 3.53 (2H, s), 7.58 (IH, s), 7.98 (IH, s), 8.20 (IH, s), 8.60 (IH, s), 9.22 (IH, s), 11.68 (IH, br s). This was used without further purification in the next step.

To a suspension of 2-(5-(l,2,4-triazol-l-yl)-lH-pyrrolo[2,3-c]pyridin- 3-yl)acetic add (0.84g) in dry DMF (5ml) was added Intermediate 6 (0.262g, 1.3mmol), 1 -hydroxybenzotriazole (0.174 g, 1.3mmol), l-ethyl-3-[3- (dimethylamino)propyl]carbodnmide hydrochloride (0.247g, 1.3mmol) and triethylamine (0.18ml, 1.3mmol), and this mixture was stirred at room temperature under nitrogen for 64h. The mixture was neutraUsed (2M HCI) and the solvent evaporated in vacuo. The residue was triturated with DCM and the soUd removed by filtration. The filtrate was evaporated in vacuo and the residue chromatographed on siUca with 5% MeOH in DCM foUowed by a gradient of 95:5: 1 to 90: 10: 1 DCM MeOH/NH3 to afford the title compound (87mg) as a yeUow gum. Η NMR (360MHz, CDCb) δ 1.54-2.70 (10H, m), 3.28-3.92 (5H, m), 4.09- 4.16 and 4.34-4.44 (IH, 2xm), 7.16-7.41 (6H, m), 7.98 and 8.00 (IH, 2xs), 8.07 and 8.09 (IH, 2xs), 8.42 and 8.45 (IH, 2xs), 9.08 and 9.10 (IH, 2xs), δ 9.12-9.30 (lH. m).

4. 2_S-2-(N-Benzyl-N-methylaminomethyl)-l-r2-(δ-(1.2.4-triazol-l-ylV lH-pyrrolor2.3-c1pyridin-3-yl)ethyl]pyrroUdine oxalate

To a solution of LiAlH₄ in ether (1.0M, 0.6ml, 0.6mmol) and dry 0 THF (2ml) was added a solution of 2-(δ-( 1,2, 4-triazol- 1-yl)- 1H- pyrrolo[2,3-c]pyridin-3-yl)acetic add (2S-2-(N-benzyl-N-methyl- aminomethyl)pyrroUdinyl)amide (87mg, 0.2mmol) in dry THF (3ml) dropwise at ambient temperature under nitrogen. The mixture was heated at 50°C for lh. After cooling, water (24μL) was added, foUowed by 6 sodium hydroxide (4M, 24μL), foUowed by water (72μL). The soUd was removed by filtration and the solvent evaporated in vacuo. The residue was chromatographed on siUca eluting with a gradient of 5 to 10% MeOH in DCM foUowed by 90:10:1, DCM/MeOH/NH₃ to afford a yeUow gum. This was rechromatographed on siUca eluting with a gradient of 98:2:1 to 0 95:5: 1 DCM/MeOH/NH₃ to afford the free base (53mg, 63%) as a yeUow gum. The free base (40mg, O. lmmol) was dissolved in ether/MeOH (4: 1, 5ml) and treated dropwise with a solution of oxaUc add (8.7mg, O.lmmol) in ether (1ml). The predpitate formed was coUected by filtration to afford the title compound (30mg) as a beige soUd. mp 100°C (dec). Found: 5 C, 56.90; H, 6.22; N, 16.44. C24H29N7 1.75(CO₂H)₂ 0.6(H₂O) requires

C, 56.67; H, 5.82; N, 16.79%. >H NMR (360MHz, de-DMSO) δ 1.60- 1.74 (IH, m), 1.83-2.23 (6H, m), 2.50-2.60 (IH, m), 2.88-2.98 (IH, m). 3.12-3.42 (4H, m), 3.48-3.84 (5H, m), 7.16-7.38 (5H, m), 7.65 (IH, d. J=2.3Hz). 8.08 (IH, s), 8.23 (IH, s), 8.68 (IH, s), 9.25 (IH. s), 11.85 (IH. br s).

30

Claims

CLAIMS:

1. A compound of formula I, or a salt or prodrug thereof:

σ) wherein

Z represents an optionaUy substituted five-membered heteroaromatic ring selected from furan, thiophene, pyrrole, oxazole, thiazole, isoxazole, isothiazole, imidazole, pyrazole, oxadiazole, thiadiazole, triazole and tetrazole; E represents a chemical bond or a straight or branched alkylene chain containing from 1 to 4 carbon atoms;

Q represents a straight or branched alkylene chain containing from 1 to 4 carbon atoms, optionaUy substituted in any position by a hydroxy group; T represents nitrogen or CH;

U represents nitrogen or C-R²; V represents oxygen, sulphur or N-R³; R^z and R³ independently represent hydrogen or Ci-e alkyl; M represents the residue of an azetidine, pyrroUdine or piperidine ring;

R represents a group of formula -W-R¹;

W represents a chemical bond or a straight or branched alkylene chain containing from 1 to 4 carbon atoms, optionaUy substituted in any position by a hydroxy group; R¹ represents -OR*. -SR\ -SOR\ -SO₂R^> or -NR'R; R^x and R^y independently represent hydrogen, hydrocarbon or a heterocydic group; or R* and R^y together represent a C2.6 alkylene group, which alkylene group may be optionaUy substituted by one or more substituents selected from Ci-β alkyl, aryl and hydroxy, or fused with a phenyl ring; and

R* represents hydrogen, hydroxy, hydrocarbon or a heterocydic group.

2. A compound as daimed in daim 1 represented by formula HA, and salts and prodrugs thereof:

(IIA) wherein m is zero, 1, 2 or 3; n is 2, 3 or 4; p is zero, 1 or 2;

T represents nitrogen or CH;

A represents nitrogen or CH;

B represents nitrogen or C-R⁵;

R⁴ and R⁵ independently represent hydrogen, Ci-e alkyl, C_. c alkenyl, C37 cydoalkyl, aryl, aryl(C e)alkyl, C3 - heterocycloalkyl, heteroaryl, heteroaryl(C_-c)alkyl, Ci e alkoxy, Ci β alkylthio, amino, Ci c alkylamino, di(Cι-e)alkylamino, halogen, cyano or trifiuoromethyl; and

R¹⁰ represents -X-R¹¹ or a group of formula (a) or (b):

(a) (b) in which

R⁶ represents hydrogen or hydroxy;

X represents oxygen, sulphur, -SO-, -SO2- or N-R¹²; and R¹¹ and R¹² independently represent hydrogen, Ci β alkyl, C26 alkenyl, C37 cydoalkyl (Ci e) alkyl, indanyl, aryl, aryl(Ci 6)alkyl, heteroaryl or heteroaryl (Cι^)alkyl, any of which groups may be optionaUy substituted.

3. A compound as daimed in daim 1 represented by formula πB, and salts and prodrugs thereof:

(HB) wherein m, n, p, T, A, B, R⁴ and R¹⁰ are as defined in claim 2.

4. A compound as claimed in claim 1 represented by formula

IIC, and salts and prodrugs thereof:

(IIC) wherein

R" represents hydrogen, hydroxy or aryl(Cι β)alkyl; and m, n, p, T, A, B, R⁴ and R¹⁰ are as defined in claim 2.

5. A compound as daimed in daim 1 represented by formula IID, and salts and prodrugs thereof:

wherein m, n, p, T, A, B, R⁴ and R¹⁰ are as defined in daim 2.

6. A compound selected from: (3_R)-3-benzyloxy- l-[2-(5-(l,2,4-triazol-4-yl)-lH-indol-3- yl)ethyl]pyrroUdine;

(3i?)-3-(4-methoxyphenyl)methoxy- l-[2-(5-(1.2,4-triazol-4-yl)- lH-indol-3- yl)ethyl]pyrroUdine;

(3i?)-3-( yridin-3-yl)methoxy- l-[2-(5-(1.2,4-triazol-4-yl)-lH-indol-3- yl)ethyl]pyrroUdine;

(3/?)-3-benzyloxymethyl- l-[2-(5-(l,2,4-triazol-4-yl)- lH-indol-3- yl)ethyl]pyrroUdine; (3S)-3-(N-benzyl-N-methyl)aminomethyl-l-[2-(5-(l,2,4-triazol-4-yl)-lH- indol-3-yl)ethyl]pyrroUdine;

(2S)-2-(N-benzyl-N-methyl)aminomethyl-l-[2-(5-(l,2,4-triazol-4^"-yl)-lH- indol-3-yl)ethyl]pyrroUdine; (3S)-3-(N-benzyl)aminomethyl-l-[2-(δ-(l,2,4-triazol-4-yl)-lH-indol-3- yl)ethyl]pyrroUdine;

4-(4-acetylaminophenyl)methylamino- 1 - [3-(δ-( 1 ,2 ,4-triazol-4-yl)- lH-indol-

3-yl)propyl]piperidine;

4-benzylamino-l-[3-(5-(l,2,4-triazol-4-yl)-lH-indol-3-yl)propyl]piperidine; 4-(N-benzyl-N-methyl)amino-l-[3-(δ-(l,2,4-triazol-4-yl)-lH-indol-3- yl)propyl]piperidine;

4-(N-benzyl)aminomethyl-l-[3-(5-(l,2,4-triazol-4-yl)-lH-indol-3- yl)propyl]piperidine;

(2S)-2-(N-benzyl-N-methylaminomethyl)-l-[2-(5-(l,2,4-triazol-l-yl)- lH- pyrrolo[2,3-c]pyridin-3-yl)ethyl]pyrroUdine; and salts and prodrugs thereof.

7. A compound selected from:

4-(N-benzyl-N-methyl)aminomethyl-l-[3-(δ-(l,2,4-triazol-4-yl)-lH-indol-3- yl)propyl]piperidine; l-[3-(5-(l,2,4-triazol-4-yl)-lH-indol-3-yl)propyl]-4-[(i?)-α-

(methyl)benzylamino]piperidine; l-[3-(δ-(l,2,4-triazol-4-yl)-lH-indol-3-yl)propyl]-4-[(S)-α-

(methyl)benzylamino]piperidine; l-[3-(5-(l,2.4-triazol-4-yl)-lH-indol-3-yl)propyl]-4-[(S)-α-

(hydroxymethyl)benzylamino]piperidine; l-[3-(5-(l,2,4-triazol-4-yl)- lH-indol-3-yl)propyl]-4-[(i?)-α-

(hydroxymethyl)benzylamino]piperidine; l-I3-(5-(l,2.4-triazol-4-yl)- lH-indol-3-yl)propyl]-4-[(S)-(l-hydroxymethyl- 2-phenyl)ethylamino]piperidine; l-[3-(5-(l,2,4-triazol-4-yl)-lH-indol-3-yl)propyl]-4-[(l.R,2S)-(2-hydroxy-l- methyl-2-phenyl)ethylamino]piperidine; l-[3-(5-(l,2,4-triazol-4-yl)-lH-indol-3-yl)propyl]-4-[(lS,2Λ)-(2-hydroxy-l- methyl-2-phenyl)ethylamino]piperidine; l-[3-(5-(l,2,4-triazol-4-yl)-lH-indol-3-yl)propyl]-4-[(l_R,2i2)-(2-hydroxy-l- methyl-2-phenyl)ethylamino]piperidine; l-[3-(5-(l,2,4-triazol-4-yl)-lH-indol-3-yl)propyl]-4-[2-(4- acetylaminophenyl)ethylaminolpiperidine; l-[3-(δ-(l,2,4-triazol-4-yl)-lH-indol-3-yl)propyl]-4-[(_R)-α- (methyl)benzylamino]methylpiperidine; l-[3-(5-(l,2,4-triazol-4-yl)-lH-indol-3-yl)propyl]-4-[(S)-α- (methyl)benzylamino]methylpiperidine; l-[3-(δ-(l,2,4-triazol-4-yl)-lH-indol-3-yl)propyl]-4-[(S)-l-(4- acetylaminophenyl)ethylamino]methylpiperidine; l-[3-(5-(l,2,4-triazol-4-yl)-lH-indol-3-yl)propyl]-4-[(i?)-l-(4- acetylaminophenyl)ethylamino]methylpiperidine; l-[3-(δ-(l,2,4-triazol-4-yl)-lH-indol-3-yl)propyl]-4-[N-[(β)-α- (hydroxymethyl)benzyl]-N-methylamino]piperidine; l-[3-(5-(l,2,4-triazol-4-yl)-lH-indol-3-yl)propyl]-4-{N-[(S)-α- (hydroxymethyl)benzyl]-N-methylamino]piperidine; l-[3-(δ-(l,2,4-triazol-4-yl)-lH-indol-3-yl)propyl]-4-[N-(2-(4- acetylaminophenyl)ethyl)-N-methylamino]piperidine; l-[3-(5-(l,2,4-triazol-4-yl)-lH-indol-3-yl)propyl]-4-[N-(4- acetylaminobenzyl)-N-methylamino]methylpiperidine; l-[3-(5-(l,2,4-triazol-4-yl)-lH-indol-3-yl)propyl]-4-[N-(thien-2-yl)methyl-N- methylamino]piperidine; l-[3-(δ-(l,2,4-triazol-4-yl)-lH-indol-3-yl)propyl]-4-[(i?)-α-

(hydroxymethyl)benzylamino)methylpiperidine;

(3S)-3-(4-acetylaminobenzyl)aminomethyl- l-[2-(5-( l,2,4-tnazol-4-yl)-lH- indol-3-yl)ethyl]pyrroUdine; (3_R)-3-(N-benzyl)aminomethyl-l-[2-(5-(l,2,4-triazol-4-yl)-lH-indol-3- yl) ethyl] p yrroUdine ;

(3S)-3-(pvridin-4-yUnethyl)aminomethyl-l-[2-(5-(l,2,4-triazol-4-yl)-lH- indol-3-yl)ethyl]pyrroUdine; δ 3-(N-benzyl)aminomethyl-l-[2-(δ-(l,2,4-triazol-4-yl)-lH-indol-3- yl)ethyl] azetidine;

4-benzyl-4-hydroxy- l-[3-(δ-(l,2,4-triazol-4-yl)- lH-indol-3- yl)propyl]piperidine;

3-(N-benzyl)aminomethyl-l-[3-(5-(l,2,4-triazol-4-yl)-lH-indol-3- 10 yl)propyl] azetidine;

4-(N-benzyl)aminomethyl-4-hydroxy-l-[3-(δ-(l,2,4-triazol-4-yl)-lH-indol-3- yl)propyl]piperidine;

4-(N-benzyl-N-methyl)aminomethyl-4-hydroxy-l-[3-(5-(l,2,4-triazol-4-yl)- lΗ-indol-3-yl)propyl]piperidine; lδ 3-(N-benzyl-N-methyl)aminomethyl-l-[2-(5-(l,2,4-triazol-4-yl)-lH-indol-3- yl)ethyl] azetidine;

(3S)-3-[N-(i2)-α-(methyl)benzyl]aminomethyl-l-[2-(δ-(l,2,4-triazol-4-yl)- lH-indol-3-yl)ethyl]pyrroUdine;

(3S)-3-[N-(S -α-(methyl)benzyl]aminomethyl-l-[2-(δ-(l,2,4-triazol-4-yl)- 20 lH-indol-3-yl)ethyl]pyrroUdine;

(3S)-3-[N-(furan-3-yUnethyl)amino]methyl-l-[2-(δ-(l,2,4-triazol-4-yl)-lH- indol-3-yl)ethyl]pyrroUdine;

(3S)-3-[N-(furan-2-ylmethyl)amino]methyl- l-[2-(δ-(l,2,4-triazol-4-yl)-lH- indol-3-yl)ethyl]pyrroUdine; 25 and salts and prodrugs thereof.

8. A compound selected from: (3S)-3-[N-(_R)-α-(hydroxymethyl)benzyl]aminomethyl- l-[2-(5-(l,2,4-triazol- 4-yl)-lH-indol-3-yl)ethyl]pyrroUdine; (3S)-3-[N-(S)-α-(hydroxymethyl)benzyl]aminomethyl-l-[2-(5-(l,2,4-triazol- 4-yl)-lH-indol-3-yl)ethyl]pyrroUdine;

(3_5)-3-[N-benzyl-N-(2-hydroxy)ethyl]aminomethyl-l-[2-(δ-(l,2,4-triazol-4- yl)-lH-indol-3-yl)ethyl]pyrroUdine; δ (3S)-3-[N-(2-phenylethyl)amino]methyl-l-[2-(δ-(l,2,4-triazol-4-yl)-lH- indol-3-yl)ethyl]pyrroUdine; (3$-3-[N-(2-phenylethyl)-N-methyla_mino]methy^ indd-3-yl)ethyl]pyrrolidine;

(3S)-3-(N-α-dimethylbenzyl)aminomethyl-l-[2-(δ-(l,2,4-triazol-4-yl)-lH- 10 indol-3-yl)ethyl]pyrroUdine;

(3S)-3-[N-(S)- -methylbenzyl]aminomethyl-l-[2-(δ-(l,2,4-triazol-l-yl)-lH- indol-3-yl)ethyl]pyrroUdine;

(3S)-3-[N-(-R)-α-(hydroxymethyl)benzyl]aminomethyl-l-[2-(δ-(l,2,4-triazol- l-yl)-lH-indol-3-yl)ethyl]pyrroUdine; lδ (3_S)-3-(N-benzyl)aminomethyl-l-[2-(δ-(l,2,4-triazol-l-yUnethyl)-lH-indol- 3 -yl)ethyl] pyrroUdine ;

(3S)-3-[N-(S)-α-methylbenzyl]aminomethyl-l-[2-(δ-(l,2,4-triazol-l- ylmethyl)-lH-indol-3-yl)ethyl]pyrroUdine;

(3S)-3-[N-(i?)-α-(hydroxymethyl)benzyl]aminomethyl-l-[2-(δ-(l,2,4-triazol- 20 1-ylmethyl)- lH-indol-3-yl)ethyl]pyrroUdine;

(3S)-3-(N-benzyl-N-methyl)aminomethyl- l-[2-(δ-(imidazol- 1 -yl)- lH-indol-

3-yl)ethyl]pyrroUdine;

(35)-3-(N-benzyl-N-methyl)aminomethyl-l-[2-(5-(1.2,4-triazol-l-ylmethyl)- lH-indol-3-yl)ethyl]pyrroUdine; 25 (3i?)-3-[N-methyl-N-(S)-α-methylbenzyl]aminomethyl-l-[2-(5-(l, ,4- triazol- 1-ylmethyl)- lH-indol-3-yl)ethyl]pyrroUdine:

(3i?)-3-[N-methyl-N-(i?)-α-hydroxymethylbenzyl]amιnomethyl- l-[2-(5-

( 1 ,2 ,4-triazol- 1 -ylmethyl)- lH-indol-3-yl)ethyl]pyrroUdine:

(3i?)-3-[N-methyl-N-(S -α-methylcydohexylmethyl]amιnomethyl- l-[2-(5- 30 (l,2,4-triazol-l-ylmethyl)-lH-indol-3-yl)ethyl]pyrroΗdine; (3_R)-3-[3-(_R)-hydroxy-2-(_R)-phenylpiperidin-l-yl]methyl-l-[2-(δ-(l,2,4- triazol- 1 -ylmethyl)- lH-indol-3-yl)ethyl]pyrroUdine;

(3_R)-3-[3-(i?)-hydroxy-2-(i?)-phenylpiperidin-l-yl]methyl-l-[2-(5-(l,2,4- triazol- 1-yl)- li/-indol-3-yl)ethyl]pyrroUdine; 4-hydroxy-4-(phenylsulfinyl)methyl- l-[3-(δ-(l,2,4-triazol-4-yl)- lH-indol-3- yl)propyl]piperidine;

(3_R)-3-[2-(_R,S)-phenylpiperidin-l-yl]methyl-l-[2-(δ-(l,2,4-triazol-l- y__methyl)-lH- dol-3-yl)ethyl]pvrroUdine;

4-(3,3-dimethylpiperidin-l-yl)methyl-4-hydroxy-l-[3-(5-(l,2,4-triazol-4-yl)- l_f_T-indol-3-yl)propyl]piperidine;

4-hydroxy-4-(l,2,3,4-tetrahydroisoquinoUn-2-yl)methyl-l-[3-(δ-(l,2,4- triazol-4-yl)-lH-indol-3-yl)propyl]piperidine;

4-hydroxy-4-(N-isobutyl-N-methyl)aminomethyl-l-[3-(δ-(l,2,4-triazol-4- yl)-lH-indol-3-yl)propyl]piperidine; 4-[N-benzyl-N-(2-hydroxyethyl)amino]methyl-4-hydroxy-l-[3-(5-(l,2,4- triazol-4-yl)-lH-indol-3-yl)propyl]piperidine;

4-[N-(2,2-dimethylpropyl)-N-methylamino]methyl-4-hydroxy-l-[3-(δ-

(l,2,4-triazol-4-yl)-lH-indol-3-yl)propyl]piperidine;

4-[N-(_R)-α-hydroxymethylbenzyl-N-methylamino]methyl-4-hydroxy- l-[3- (5-(l,2,4-triazol-4-yl)-lH-indol-3-yl)propyl]piperidine;

4-hydroxy-4-(2-pyridylmethyl)aminomethyl-l-[3-(δ-(l,2,4-triazol-4-yl)-lH- indol-3-yl)propyl]piperidine;

4-hydroxy-4-(2-methylphenylmethyl)aminomethyl-l-[3-(5-(l,2,4-triazol-4- yl)- lH-indol-3-yl)propyl]piperidine; 4-hydroxy-4-[N-(2-methylphenylmethyl)-N-methylamino]methyl- l-[3-(5-

(l,2,4-triazol-4-yl)-lH-indol-3-yl)propyl]piperidine; 3-(benzylamino)methyl-3-hydroxy- l-[3-(5-(l,2,4-triazol-4-yl)- lH-indol-3- yl)propyl]pyrroUdine;

3-(benzylamino)methyl-3-hydroxy- l-[2-(5-(l,2,4-triazol-4-yl)- lH-indol-3- yl)ethyl]pyrroUdine; l-[3-(5-(l,2,4-triazol-4-yl)-lH-indol-3-yl)propyl -4-[(_R)-α-(carbamoyl- oxymethyl)benzylamino]piperidine; l-[3-(5-(l,2,4-triazol-4-yl)-lH-indol-3-yl)propyI -4-[(l_R,2S)-2-hydroxy-l- phenylpropylamino]piperidine; l-[3-(5-(l,2,4-triazol-4-yl)- lΗ-indol-3-yl)propyl -4-[(l_R,2_R)-2-hydroxy-l- phenylpropylamino]piperidine; l-[3-(5-(l,2,4-triazol-4-yl)-lH-indol-3-yl)propyl -4-[(i?,S)-l-hydroxy-2- phenylprop-2-ylamino]piperidine; l-[3-(5-(l,2,4-triazol-4-yl)-lH-indol-3-yl)propyl -4-[(i?)-2-hydroxy-l-(4- fluorophenyl)ethylamino]piperidine; l-[3-(5-(l,2,4-triazol-4-yl)-lH-indol-3-yl)propyl -4-[(LR,2_R)-2- hydroxyindan- l-ylamino)pip eridine; l-[3-(5-(l,2,4-triazol-4-yl)-lH-indol-3-yl)propyl -4-[(_R,S)-indan-l- ylamino]piperidine; l-[3-(5-(l,2,4-triazol-4-yl)-lH-indol-3-yl)propyI -4-[(i?,S)-l-(4- fluorophenyl)ethylamino]piperidine; l-[3-(5-(l,2,4-triazol-4-yl)-lH-indol-3-yl)propyl -4-[(i?)- l-phenylprop-2- ylamino]piperidine; l-[3-(5-(l,2,4-triazol-4-yl)-lH-indol-3-yl)propyl -4-[N-(thien-3-ylmethyl)-N- methylamino]piperidine; l-[3-(5-(l,2,4-triazol-4-yl)-lH-indol-3-yl)propyl -4-[N-(furan-3-ylmethyl)-

N-methylamino]piperidine; l-[3-(5-(l,2,4-triazol-4-yl)-lH-indol-3-yl)propyl -4-(furan-3- ylmethyl)aminopiperidine; l-[3-(5-(1.2,4-triazol-4-yl)-lH-indol-3-yl)propyl -4-[N,N-di-(furan-3- ylmethyl)amino]piperidine; l-[3-(5-(l,2,4-triazol-4-yl)- lH-indol-3-yl)propyl -4-[N-(3,3-dimethylallyl)-

N-methylamino]piperidine; l-[3-(5-(l,2,4-triazol-4-yl)-lH-indol-3-yl)propyl -4-(N-aUvl-N- methylamino)piperidine; l-[3-(δ-(l,2,4-triazol-4-yl)- lH-indol-3-yl)propyl]-4-(indan- 1- ylaminomethyl)piperidine; l-[3-(5-(l,2,4-triazol-4-yl)-lH-indol-3-yl)propyl]-4-[N-(_R)-α-

(hydroxymethyl)benzyl-N-methylaminomethyl]piperidine; δ (3_R)-3-(benzylthio)methyl-l-[2-(δ-(l,2,4-triazol-4-yl)-lH-indol-3- yl)ethyl]pyrroUdine;

(±)-l-[3-(5-(l,2,4-triazol-4-yl)-lH-indol-3-yl)propyl]-4-(l-benzylamino-2- hydroxyethyl)piperidine; l-[3-(δ-(l,2,4-triazol-l-yl)-lH-indol-3-yl)propyl]-4-[(Λ)-α- 10 (hydroxymethyl)benzylamino]piperidine; l-[3-(5-(imidazol- 1-yl)- lH-indol-3-yl)propyl]-4-[(_R)-c_-

(methyl)benzylamino]piperidine; l-[3-(5-(imidazol- 1-yl)- lH-indol-3-yl)propyl]-4-[(_R)-α-

(hydroxymethyl)benzylamino]piperidine; lδ l-[3-(δ-(l,2,4-triazol- 1-ylmethyl)- lH-indol-3-yl)propyl]-4-[(_R)-α-

(hydroxymethyl)benzylamino]piperidine; l-[3-(δ-(l,2,4-triazol-4-yl)-lH-indol-3-yl)propyl]-4-[(i?)-α-

(methoxymethyl)benzylamino]piperidine; l-[3-(5-(l,2,4-triazol-4-yl)-lH-indol-3-yl)propyl]-4-[N-(Λ)-α- 20 (methoxymethyl)benzyl-N-methylamino]piperidine; l-[3-(5-(imidazol- 1-yl)- lH-indol-3-yl)propyl]-4-[(_R)-α-

(methoxymethyl)benzylamino]piperidine; l-[3-(5-(l,2,4-triazol-l-ylmethyl)- lH-indol-3-yl)propyl]-4-[(_R)-l-(4- fluorophenyl)-2-methoxyethylamino]piperidine; 25 l-[3-(5-(l,2,4-triazol- 1-ylmethyl)- lH-indol-3-yl)propyl]-4-[N-(4-fluorobenzyl)-

N-methylamino]piperidine; l-[3-(5-(l,2,4-triazol-4-yl)- lH-indol-3-yl)propyl]-4-(2-phenylpiperidιn-l- yl)piperidine; l-[3-(5-(l,2,4-triazol-4-yl)-lH-indol-3-yl)propyl]-4-[(_R)- l-(4-fluorophenyl)- 30 2-methoxyethylamino]piperidine; (3i?)-3-(benzylsulfinyl)methyl- l-[2-(5-(l,2,4-triazol-4-yl)-lH-indol-3- yl)ethyl]pyrroUdine;

(3i?)-3-(4-fluorobenzylthio)methyl-l-[2-(5-(l,2,4-triazol-l-yhnethyl)- lH- indol-3-yl)ethyl]pyrroUdine; (3_R)-3-(4-fluorobenzylsulfinyl)methyl-l-[2-(5-(l,2,4-triazol-l-yUnethyl)- lH-indol-3-yl)ethyl]pyrroUdine;

(3Λ)-3-(4-fluorobenzylsuUOnyl)methyl-l-[2-(5-(l,2,4-triazol-l-yUnethyl)- lH-indol-3-yl)ethyl]pyrroUdine;

4-(4-fluorobenzylsulfinyl)-l-[3-(5-(l,2,4-triazol-4-yl)-lH-indol-3- yl)propyl]piperidine; and salts and prodrugs thereof.

9. A pharmaceutical composition comprising a compound as daimed in any one of the preceding claims in assodation with a pharmaceuticaUy acceptable carrier.

10. A compound as daimed in any one of claims 1 to 8 for use in therapy.

11. The use of a compound as daimed in any one of claims 1 to 8 for the manufacture of a medicament for the treatment and/or prevention of clinical conditions for which a subtype-selective agonist of 6-HTID receptors is indicated.

δ 12. A process for the preparation of a compound as claimed in any one of claims 1 to 8, which comprises:

(A) reacting a compound of formula III:

wherein Z and E are as defined in daim 1; with a compound of formula IV, or a carbonyl-protected form thereof:

(IV) wherein R², Q, M, R and R^a are as defined in daim 1; foUowed, where required, by N-alkylation by standard methods to introduce the moiety R³; or

(B) reacting a compound of formula VIH:

(VII) wherein M, R and R^a are as defined in claim 1; with a compound of formula VIII:

(VIII) wherein Z, E, Q, T, U and V are as defined in claim 1, and L² represents a suitable leaving group; or (C) cycUsing a compound of formula X:

(X) wherein Z, E, , M, R and R" are as defined in claim 1, and D¹ represents a readily displaceable group; foUowed, where required, by N-alkylation by standard methods to introduce the moiety R³; or

(D) cycUsing a compound of formula XIII:

(XIII) wherein Z, E, Q, R², M, R and R* are as defined in daim 1, and V represents oxygen or sulphur; or

(E) redudng a compound of formula XVI:

(XVI) wherein Z. E, T, U, V, M, R and R- are as defined in claim 1. and -Q'-CH.: corresponds to the moiety Q as defined in claim 1; and (F) subsequently, where required, converting a compound of formula I initiaUy obtained into a further compound of formula l by conventional methods.

12. A method for the treatment and/or prevention of clinical conditions for which a subtype-selective agonist of δ-HTm receptors is indicated, which method comprises administering to a patient in need of such treatment an effective amount of a compound as daimed in any one of claims 1 to 8.