GB2448807A

GB2448807A - Substituted fused benzene and pyridine derivatives useful as ligands for GABAA receptors

Info

Publication number: GB2448807A
Application number: GB0807125A
Authority: GB
Inventors: Monique B Van Niel
Original assignee: Merck Sharp and Dohme Ltd
Current assignee: Organon Pharma UK Ltd
Priority date: 2007-04-27
Filing date: 2008-04-21
Publication date: 2008-10-29
Also published as: GB0807125D0; GB0708186D0

Abstract

Compounds of formula (I), or pharmaceutically acceptable salts thereof, wherein each of W, X, Y and Z is CR<9> or one of W, X, Y and Z is N and the others are CR<9>, each R<9> is independently H, hydroxy, cyano, halogen, C1-6alkyl, haloC1-6alkyl, C1-6alkoxy or haloC1-6alkoxy and A is a substituted imidazole or pyrrole residue. More specifically, A is substituted by an optionally substituted azetidinyl or 5, 6 or 7 membered saturated or partially saturated heterocycle containing 1, 2 or 3 items independently selected from N, O and S or such an azetidinyl or heterocycle forms a spiro ring attached to A. Preferred compounds include 1 ,3-dihydro-2H-benzimidazol-2-ones, benzimidazoles, indole-2(1H)-ones and indoles substituted by piperid-4-yl or spiro piperid-4-yl groups. The compounds are ligands for GABAA receptors and may therefore be useful for the treatment of neurological and psychiatric disorders.

Description

SUBSTITUTED FUSED BENZENE AND PYRIDINE DERIVATIVES AS LIGANDS FOR

GABAA RECEPTORS

The present invention relates to a class of substituted fused benzene and pyridine derivatives and to their use in therapy. These compounds are ligands for GABAA receptors and are therefore useful in the therapy of neurological and psychiatric disorders.

Receptors for the major inhibitory neurotransmitter, gamma-aminobutyric acid (GABA), are divided into two main classes: (1) GABAA receptors, which are members of the ligand-gated ion channel superfamily; and (2) GABAB receptors, which may be members of the G-protein linked receptor superfamily. To date there are 17 different GABAA subunits identified (a16, I-3.

71-3, P1-2, ô, c and 0).

Although knowledge of the diversity of the GABAA receptor gene family represents a huge step forward in our understanding of this ligand-gated ion channel, insight into the extent of subtype diversity is still at an early stage. It has been indicated that an a subunit, a 3 subunit and a subunit constitute the minimum requirement for forming a fully functional GABAA receptor expressed by transiently transfecting cDNAs into cells.

Studies of receptor size and visualisation by electron microscopy conclude that, like other members of the ligand-gated ion channel family, the native GABAA receptor exists in pentameric form. The selection of at least one a, one and one y subunit from a repertoire of seventeen allows for the possible existence of more than 10,000 pentameric subunit combinations.

Moreover, this calculation overlooks the additional permutations that would be possible if the arrangement of subunits around the ion channel had no constraints (i.e. there could be 120 possible variants for a receptor composed of five different subunits).

Receptor subtype assemblies which do exist include, amongst many others, a132'y2, a23y1, a2[2/3y2, a3fry2/3, a4, a42I3, a53'y2/3, a6fry2 and a63. Subtype assemblies * containing an al subunit are present in most areas of the brain and are thought to account for over 40% of GABAA receptors in the rat. Subtype assemblies containing a2 and a3 subunits respectively are thought to account for about 25% and 17% of GABAA receptors in the rat. a4 subunits comprise only a small percentage of neuronal subunits, concentrated in hippocampus, striatum, cerebral cortex, thalamus, and basal ganglia. They assemble with tv and 72 subunits in most areas of the brain but also with f3 and y subunits in olfactory bulb, dentate gyrus, and thalamus. Of the 20-27% of thalamic GABAA receptors that contain a4 subunits, approximately one-third contain 72 subunits, and two-thirds contain ö subunits. Subtype assemblies containing an a5 subunit are expressed predominantly in the hippocampus and cortex and are thought to represent about 4% of GABAA receptors in the rat.

A characteristic property of all known GABAA receptors is the presence of a number of modulatory sites, one of which is the benzodiazepine (BZ) binding site. The BZ binding site is the most explored of the GABAA receptor modulatory sites, and is the site through which anxiolytic drugs such as diazepam and temazepam exert their effect. Before the cloning of the GABAA receptor gene family, the benzodiazepine binding site was historically subdivided into two subtypes, BZI and BZ2, on the basis of radioligand binding studies. The BZ1 subtype has been shown to be pharmacologically equivalent to a GABAA receptor comprising the al subunit in combination with a subunit and y2. This is the most abundant GABAA receptor subtype, and is believed to represent almost half of all GABAA receptors in the brain.

Two other major populations are the a23'y2 and a3Ij2/3 subtypes. Together these constitute approximately a further 35% of the total GABAA receptor repertoire.

Pharmacologically this combination appears to be equivalent to the BZ2 subtype as defined previously by radioligand binding, although the BZ2 subtype may also include certain a5-containing subtype assemblies. The physiological role of these subtypes has hitherto been unclear because no sufficiently selective agonists or antagonists were known.

it is now believed that agents acting as BZ agonists at al fry2, a2fry2 or a3 fr'y2 subtypes will possess desirable anxiolytic properties. The al-selective GABAA receptor agonists alpidem and zolpidem are clinically prescribed as hypnotic agents, suggesting that at least some of the sedation associated with known anxiolytic drugs which act at the BZ1 binding site is mediated through GABAA receptors containing the al subunit. Accordingly, it is considered that GABAA receptor agonists which interact more favourably with the a2 and/or a3 subunit than with al will be effective in the treatment of anxiety with a reduced propensity to cause sedation. Moreover, agents which are inverse agonists of the a5 subunit are likely to be beneficial in enhancing cognition, for example in subjects suffering from dementing conditions such as Alzheimer's disease. Also, agents which are antagonists or inverse agonists at al might be employed to reverse sedation or hypnosis caused by al agonists.

Compared with other GABAA receptors, those containing a4 subunits differ in their rectification properties, affinity for GABA, and modulation by benzodiazepine. Receptors containing a4 and 3 subunits lack benzodiazepine binding sites entirely, and those containing (Li, f and 12 subunits have a benzodiazepine binding site that is atypical.

Transient expression of ternary GABAA receptors containing the 6 subunit is described in Wohlfarth et a!, J. Neuroscience, 22, 1541-9 (2002) and Belelli et a!, Neuropharmacology, 43, 65 1-61 (2002), and stable expression of the a436 receptor is described in Adkins eta!, J. Biol.

Chem., 276, 38934-9 (2001) and Brown eta!, British J. Pharmacol., 136, 965-74 (2002).

According to these papers, such receptors are likely to be involved in epilepsy, drug withdrawal and conditions associated with neurosteroid depletion, especially premenstrual syndrome.

WO 03/063845 discloes the use of ligands for the a26 receptor (e.g. gabapentin) for treatment of tinnitus.

Bauer and Brozoski, .J. Assoc. Res. Oto!arvngol., 2, 54-64 (2001) describe an animal model for testing the efficiency of prospective tinnitus therapies.

Gaboxadol (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridm-3-ol, also known as THIP) is reported (Brown et al, supra) to be a potent agonist at the u433 receptor. Previously, it had been claimed for use in treatment of sleep disorders (WO 97/02813), and subsequently it has been reported to be useful in the treatment of premenstrual syndrome (WO 02/40009; Gulinello et al, NeuroReport, 14, 43-6 (2003)).

The compounds of the present invention, being selective ligands for GABAA receptors, are therefore of use in the treatment and/or prevention of a variety of neurological and psychiatric disorders.

In addition, the compounds in accordance with the present invention may be useful as radioligands in assays for detecting compounds capable of binding to the human GABAA receptor.

The present invention provides a class of imidazo-pyridine derivatives which possess desirable binding properties at various GABAA receptor subtypes. The compounds in accordance with the present invention have good affinity as ligands for the human GABAA receptor which contains the a4 and ö subunits. The compounds of this invention interact more favourably with the a4133 receptor over the a4f337 The compounds of the present invention act as agonists at GABAA receptors which comprise an a4 subunit and a subunit.

The present invention provides compounds of formula I, or a pharmaceutically acceptable salt thereof: w x_'

II A z (I)

wherein: Ais: R' iR2 iR2 R' 1 R2 or R R' is azetidinyl or a 5, 6 or 7 membered saturated or a partially saturated heterocycle containing 1, 2 or 3 heteroatoms independently selected from N, 0 and S, optionally substituted by one, two or three groups independently selected from (CR6R1)aR8; R5 is hydrogen, hydroxy, halogen, C1a1kyl, C16alkoxy, haloC16aIkyl or haloCialkoxy; or R5 together with R' forms a Spiro ring selected from azetidine or a 5, 6 or 7 membered saturated or a partially saturated heterocycle containing 1, 2 or 3 heteroatoms independently selected from N, 0 and S, optionally substituted by one, two or three groups independently selected from (CR6R7)R8; R2 is hydrogen, hydroxy, cyano, halogen, CiaI1cyI, C 2.1oalkenyl, haloCi6alkyl, hydroxyC1..

6alkyl, C16a&oxy, haloCi6alkoxy, C31ocycloalkyl or C610ary1, any of which rings being optionally substituted by one, two or three groups independently selected from hydroxy, oxo, halogen, Ci 6alkyl, haloC1alkyl, C1a&oxy and haloC1a&oxy; R3 is hydrogen, hydroxy, halogen, CiaIkyl or haloC16alkyl; or R3 together with R2 represents oxo; R4 is hydrogen or Cjalkyl; either each of R6 and R7 independently represent hydrogen, hydroxy, halogen, C1aIkyl, haloCi6alkyl, Cisalkoxy, haloC1alkoxy or C6.ioaryl, any of which rings being optionally substituted by one, two or three groups independently selected from hydroxy, oxo, cyano, halogen, Cialkyl, haloCia&yl, Cia&oxy and haloC16alkoxy; or R6 together with R7 represents oxo; each R8 independently represents NRaR), N(SO2Ra)Rl, C610ary1, a 5 membered heteroaromatic ring containing 1. 2, 3 or 4 heteroatoms independently selected from N, 0 and S, not more than one heteroatom of which isO or S. a 6 membered heteroaromatic ring containing 1, 2 or 3 N atoms or a 7, 8, 9 or 10 membered unsaturated or partially saturated heterocyclic ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, 0 and S; any of which rings being optionally substituted by one, two or three groups independently selected from hydroxy, oxo, cyano, halogen, C1alkyl, ha1oCialkyl, C1aIkoxy and haloCia1koxy; aisO, 1, 2, 3, 4,5or6; Ra is hydrogen, Cialkyl or C6ioaiyl optionally substituted by one, two or three groups independently selected from hydroxy, oxo, cyano, halogen, Cialkyl, haloC1allcyl, C1..salkoxy and haloC1a&oxy; Rb is hydrogen or C1a1kyl; either each of W, X, Y and Z is CR9 or one of W, X, Y and Z is N and the others CR9; each R9 is independently hydrogen, hydroxy, cyano, halogen, C16alky1, haloC16alkyl, Ci 6alkoxy or haloC1alkoxy.

In an embodiment of compounds of formula 1: R1 is piperidinyl optionally substituted by one, two or three groups independently selected from (CR6R7)aR8; R5 is hydrogen; or R5 together with R' forms a spiro-piperidine optionally substituted by one, two or three groups independently selected from (CR6R7)aR8; R2 is hydrogen or C61oaryl; R3 is hydrogen; or R3 together with R2 represents oxo; R4 is hydrogen or C1alkyl; each of R6 and R7 is independently selected from hydrogen, hydroxy, C16alkyl or C6.1oaryl optionally substituted by one or two groups independently selected from halogen, C16a1ky1, and haloCi6allcyl, or R6 and R7 together represent oxo; each R8 independently represents N(SO2Ra)Rb, C610ary1, a 6 membered heteroaromatic ring containing 1, 2 or 3 N atoms or a 8, 9 or 10 membered unsaturated or partially saturated heterocyclic ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, 0 and S; any of which rings being optionally substituted by one, two or three groups independently selected from halogen, C16a1kyl or haloC16allcyl; aisl,2,3,4or5 R' is hydrogen, C1alkyl or C610ary1 optionally substituted by one, two or three groups independently selected from hydroxy, oxo, cyano, halogen, C14alkyl, haloC1alkyl, C16alkoxy and haloC1oalkoxy; R' is hydrogen or C16a1ky1; and either each of W, X, Y and Z is CII or one is N and the others CH.

In an embodiment A is: R2 \R2 orR2.

In another embodiment A is: R1

IN kR2

NR R4

In another embodiment A is: /N R4 In another embodiment A is: In another embodiment A is: R2 In an embodiment R' is piperidinyl optionally substituted by one, two or three groups independently selected from (CR6R7)aR8.

In an embodiment R5 is hydrogen or C1a1kyl, particularly hydrogen.

In another embodiment R5 together with R' is spiro-piperidine optionally substituted by one, two or three groups independently selected from (CR6R7)aRS.

In an embodiment a is 1, 2, 3, 4 or 5. In another embodiment a is 2, 3 or 4.

In an embodiment either each of R6 and R7 is independently selected from hydrogen, hydroxy, Ci6allcyl or C6ioaryl optionally substituted by one or two groups independently selected from halogen, Ci6alkyl and haloC1a&yl, or R6 and R7 together represent oxo.

Particularly, one of R6 and R7 is hydrogen, and the other is hydrogen, hydroxy, CiaIkyl or CoioaryI optionally substituted by one or two halogen groups, or R6 and R7 together represent oxo.

Particular R6 groups arc hydrogen, hydroxy, methyl, chlorophenyl or fluorophenyl.

Specific R6 groups are hydrogen, hydroxy, methyl, 3-chlorophenyl and 4-fluorophenyl.

A particular R7 group is hydrogen In an embodiment R2 is hydrogen or C610ary1.

In an embodiment R3 is hydrogen.

In another embodiment R2 is hydrogen or C6..ioaryl and R3 is hydrogen.

In another embodiment R3 together with R2 represents oxo.

Particularly, R2 is hydrogen or phenyl and R3 is hydrogen; or R3 together with R2 represents oxo.

Particular R4 groups are hydrogen and methyl.

In an embodiment R8 is N(SO7Ra)Rb, C610ary1, a 6 membered heteroaromatic ring containing 1, 2 or 3 N atoms or a 8, 9 or 10 membered unsaturated or partially saturated heterocyclic ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, 0 and S; any of which rings being optionally substituted by one, two or three groups independently selected from halogen, CiaIkyl or haloC16alkyl.

In an embodiment R is C6ioaryl, particularly phenyl In an embodiment R" is Ciallcy1, particularly methyl Particularly, R8 is (benzenesulfonyl)(methyl)amino, phenyl, pyridinyl or benzoxadiazolyl, any of which rings being optionally substituted by one or two groups independently selected from fluorine and chlorine.

Particular R8 groups include (benzenesulfonyl)(methyl)amino, phenyl, fluorophenyl, pyridinyl and benzoxadiazolyl.

Specific R8 groups include (benzenesulfonyl)(methyl)amjno, phenyl, 4-fluorophenyl, pyridin-4-yl and 2,1,3-benzoxadiazol-5-yl.

In an embodiment either each of W, X, Y and Z is CH or one is N and the others CH.

In an embodiment each of W, X and Y is CH and Z is N or CH.

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 include acid 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 acid such as hydrochloric acid, sulphuric acid, methanesulphonic acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, oxalic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid. Furthermore, where the compounds of the invention cany an acidic moiety, suitable pharmaceutically acceptable salts thereof may include alkali metal salts, e.g. sodium or potassium salts; alkaline earth metal salts, e.g. calcium or magnesium salts; and salts formed with suitable organic ligands, e.g. quatemary ammoniurn salts.

When any variable (e.g. R6) occurs more than one time in any constituent, its definition on each occurrence is independent at every other occurrence. Also, combinations of substituents and variables are permissible only if such combinations result in stable compounds. Lines drawn into the ring systems from substituents represent that the indicated bond may be attached to any of the It is understood that substituents and substitution patterns on the compounds of the instant invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art, as well as those methods set forth below, from readily available starting materials. If a substituent is itself substituted with more than one group, it is understood that these multiple groups may be on the same carbon or on different carbons, so long as a stable structure results. The phrase "optionally substituted" should be taken to be equivalent to the phrase "unsubstituted or substituted with one or more substituents" and in such cases the preferred embodiment will have from zero to three substituents. More particularly, there are zero to two substituents. A substituent on a saturated, partially saturated or unsaturated heterocycle can be attached at any substitutable position.

As used herein, "alkyl" includes both branched and straight-chain aliphatic hydrocarbon groups having the specified number of carbon atoms. For example,"C1aIkyl" is defined to include groups having 1, 2, 3, 4, 5 or 6 carbons in a linear or branched arrangement. For example,"C1alkyl" specifically includes methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, i-butyl, pentyl, hexyl, and so on. Preferred alkyl groups are methyl and ethyl. The term "cycloalkyl" means a monocyclic, bicyclic or polycyclic saturated aliphatic hydrocarbon group having the specified number of carbon atoms. For example, "C3..7cycloalkyl" includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and so on.

As used herein, the term "C26aIkenyl" refers to a non-aromatic hydrocarbon radical, straight or branched, containing from 2 to 6 carbon atoms and at least one carbon to carbon double bond. Preferably one carbon to carbon double bond is present, and up to four non-aromatic carbon-carbon double bonds may be present. Alkenyl groups include ethenyl, propenyl and butenyl. Preferred alkenyl groups include ethenyl and propenyl.

As used herein, the term "C2aIkynyl" refers to a hydrocarbon radical straight or branched, containing from 2 to 6 carbon atoms and at least one carbon to carbon triple bond. Up to three carbon-carbon triple bonds may be present. Alkynyl groups include ethynyl, propynyl, butynyl and so on. Preferred alkynyl groups include ethynyl and propynyl "Alkoxy" represents an alkyl group of indicated number of carbon atoms attached through an oxygen bridge. "Alkoxy" therefore encompasses the defmitions of alkyl above. Examples of suitable alkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, cyclopropyloxy, cyclobutyloxy and cyclopentyloxy. The preferred alkoxy groups are methoxy and ethoxy. The term C6ioaryloxy' can be construed analogously, and an example of this group is phenoxy.

The terms "haloCialkyl" and "haloC16alkoxy" mean a CiaIkyl or Cioalkoxy group in which one or more (in particular, I to 3) hydrogen atoms have been replaced by halogen atoms, especially fluorine or chlorine atoms. Preferred are fluoroCialkyl and fluoroCi6alkoxy groups, in particular fluoroCi3allcyl and fluoroC13alkoxy groups, for example, CF3, CHF2, CH2F, CH2CH7F, CHCHF2, CH7CF3, OCF3, OCHF2, OCH2F, OCH2CH2F, OCH2CHF, or OCH7CF, and most especially CF3, OCF3 and OCHF2.

As used herein, the term "hydroxyC16alkyl" means a Ci6alkyl group in which one or more (in particular, I to 3) hydrogen atoms have been replaced by hydroxy groups. Preferred are CH2OH, CH7CHOH and CHOHCH3.

As used herein, the term "Cl6alkylcarbonyl" or "Cl6alkoxycarbonyl" denotes a Ci6alkyl or Cia&oxy radical, respectively, attached via a carbonyl (C=O) radical. Suitable examples of C1 oalkylcarbonyi groups include methylcarbonyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl and tert-butylcarbonyl. Examples of CisaIkoxycarbonyl include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl and tert-butoxycarbonyl. The term C6joarylcarbonyl' can be construed analogously, and an example of this group is benzoyl.

As used herein, "C6ioaryl" is intended to mean any stable monocyclic or bicyclic carbon ring of 6 to 10 atoms, wherein at least one ring is aromatic. Examples of such aryl elements include phenyl, naphthyl, tetrahydronaphthyl, indanyl and tetrahydrobenzo[7]annulene. The preferred aryl group is phenyl or naphthyl, especially phenyl.

Examples of particular heterocycles of this invention are benzimidazolyl, benzofurandionyl, benzofuranyl, benzofurazanyl, benzopyrazolyl, benzotriazolyl, benzothienyl, benzoxazolyl, benzoxazolonyl, benzothiazolyl, benzothiadiazolyl, benzodioxolyl, benzoxadiazolyl, benzoisoxazolyl, benzoisothiazolyl, chromenyl, chromanyl, isochromanyl, carbazolyl, carbolinyl, cinnolinyl, epoxidyl, fury!, furazanyl, imidazolyl, indolinyl, indolyl, indolizinyl, indolinyl, isoindolinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthpyridinyl, oxadiazoly!, oxazolyl, oxazolinyl, isoxazolinyl, oxetanyl, purinyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridopyridinyl, pyridazinyl, pyridinyl, pyrimidinyl, triazinyl, tetrazinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, quinolizinyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydroisoquinolinyl, tetrazolyl, tetrazolopyridyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, azetidinyl, 1,4-dioxanyl, hexahydroazepmy!, piperazinyl, piperidyl, pyridin-2-onyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrrolinyl, morpholinyl, thiomorpholiny!, dihydrobenzoiniidazolyl, dihydrobenzofuranyl, dihydrobenzothiopheny!, dihydrobenzoxazolyl, dihydrofuranyl, dihydroimidazolyJ, dihydroindoly!, dihydroisooxazoly!, dihydroisothiazolyl, dihydrooxadiazo!yl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl, dihydroisoquinolinyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl, dihydmisochromenyl, dihydrochromenyl, dihydroimidazolonyl, dihydrotriazolonyl, dihydrobenzodioxinyl, dihydrothiazolopyrinijdinyl, dihydroimidazopyrazinyl, methylenedioxybenzoyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydroquinolinyl, thiazolidinonyl, imidazolonyl, isOindolinonyl, octahydroquino!izjnyl, octahydroisoindolyl, -10 -imidazopyridinyl, azabicycloheptanyl, chromenonyl, triazolopyrimidinyl, dihydrobenzoxazinyl, thiazolotriazolyl, azoniabicycloheptanyl, azoniabicyclooctanyl, phthalazinyl, naphthyridinyl, pteridinyl, dihydroquinazolinyl, dihydrophthalazinyl, benzisoxazolyl, tetrahydronaphthyridinyl, dibenzo[b,d]furanyl, dihydrobenzothiazolyl, imidazothiazolyl, tetrahydroindazolyL, tetrahydrobenzothienyl, hexahydronaphthyridinyl, tetrahydroimidazopyridinyl, tetrahydroimidazopyrazjnyl, pyrrolopyridinyl, diazepanyl and N-oxides thereof. Attachment of a heterocyclyl substituent can occur via a carbon atom or via a heteroatom.

Preferred 5 or 6 membered saturated or partially saturated heterocycles are pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuran and thiomorpholinyl.

A preferred 7 membered saturated heterocycle is diazepanyl.

Preferred 5 membered heteroaromatic rings are thienyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, imidazolyl, thiadiazolyl, oxazolyl, oxadiazolyl, triazolyl, tetrazolyl, furyl and pyrrolyl.

Preferred 6 membered heteraromatic rings are pyridinyl, pyrimidinyL, pyridazinyl and pyrazinyl.

Preferred 7-10 membered partially saturated or unsaturated heterocyclic rings are tetrahydroquinolinyl, quinolinyl, indolyl, imidazopyridinyl, benzothiazolyl, quinoxalinyl, benzothiadiazolyl, benzoxazolyl, dihydrobenzodioxinyl, benzotriazolyl, benzodioxolyl, dihydroisoindolyl, dihydroindolyl, tetrahydroisoquinolinyl, isoquinolinyl, benzoisothiazolyl, dihydroimidazopyrazinyl, benzothienyl, benzoxadiazolyl, thiazolotriazolyl, dihydrothiazolopyrimidinyl, dihydrobenzoxazinyl, dihydrobenzofiiranyl, benzimidazolyl, benzofuranyl, dihydrobenzoxazolyl, dihydroquinazolinyl, dihydrophthalazinyl, indazolyl, benzisoxazolyl, tetrahydronaphthyridmyl, triazolopyrimidinyl, dibenzo[b,d]fliranyl, naphthyridinyl, dihydroquinolinyl, dihydroisochromenyl, dihydrochromenyl, dihydrobenzothiazolyl, imidazothiazolyl, tetrahydroindazolyl, tetrahydrobenzothieny[, hexahydronaphthyridinyl, tetrahydroimidazopyridinyl, tetrahydroimidazopyrazinyl, pyrrolopyridinyl, quinazolinyl and indolizinyl.

As used herein, the term "halogen" refers to fluorine, chlorine, bromine and iodine, of which fluorine and chlorine are preferred.

Particular compounds within the scope of the present invention are: 1 -[1 -(3-pyridin-4-ylpropyl)piperidin-4-yl]-I,3-dihydro-2FJ-imidazo[4,5b] pyrjdjn2one; 1 -[1 -(3-phenylpropyl)pipendin-4-yl]-I,3-dihydro-2H-benzimidazol-2-one; 1 -[1 -(3-phenylbutan)-I -piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one; 1 -[1 -(3-phenylpropan-2-ol)-1 -piperidin-4-yl]-I,3-dihydro-2H-benzimjdazol-2-one; 1-methyl-i -(4,4-bis(4-fluorophenyl)butan-I)-spiro[indole-3,4'-piperidin]-2( 1 H)-one; 1 -[2-(2, 1,3-benzoxadiazol-5-yl)ethyl].. I -methylspiro[indole-3,4'-piperidin]-2( 1 H)-one; 1 -(1 iperidin-4-yl)-I,3-dihydro- 2H-benzimidazol-2-one; 3-(3-phenylpropan-1 -piperidin-4-yl)-2-phenyl-I H-indole; 1 -(1 -(4-fluorophenyl)butan-1-one)-I -piperidin-4-yl-1,3-dihydro-2H-benzimidazol-2-one; I -(3-phenylpropyl)-3-methyl-I,3-dihydro-2H-benzjmidazol-2-one hydrochloride; I -[I -(3-pyridin-4-ylpropyl)piperidin4y1] I,3-dihydro-2H-benzimidazol-2-one; I -(3-pyridin-4-ylpropyl)-3-methyl-1,3-dihydro-2H-benzimjdazol-2-one; 1 -(3-phenylpropyl)spiro[indole-3,4'-pjperjd in]-2( I H)-one; 1 -[1 -(3-phenylpropyl)piperidin-4-yl]-1 H-benzimidazole; and pharmaceutically acceptable salts thereof.

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.

The compounds of the present invention can be used in a method of treatment of the human or animal body by therapy.

The invention provides the use of compounds of formula I for the manufacture of a medicament for the treatment or prevention of conditions which can be ameliorated by agonism of GABAA receptor.

The present invention also provides a method for the treatment or prevention of conditions which can be ameliorated by agonism of GABAA receptor, which method comprises administration to a patient in need thereof of an effective amount of a compound of formula I or a composition comprising a compound of formula 1.

The compounds of the present inventionare useful in the treatment or prevention of neurological or psychiatric disorders, such as anxiety disorders, such as panic disorder with or without agoraphobia, agoraphobia without history of panic disorder, animal and other phobias including social phobias, obsessive-compulsive disorder, stress disorders including post-traumatic and acute stress disorder, and generalized or substance-induced anxiety disorder; neuroses; convulsions; migraine; depressive or bipolar disorders, for example single-episode or recurrent major depressive disorder, dysthymic disorder, bipolar! and bipolar II manic disorders, and cyclothymic disorder; psychotic disorders including schizophrenia, epilepsy, Parkinson's disease and Huntington's disease; neurodegeneration arising from cerebral ischemia; attention deficit hyperactivity disorder; Tourette's syndrome; speech disorders, including stuttering; disorders of circadian rhythm, e.g. in subjects suffering from the effects ofjet lag or shift work; pain and nociception; emesis, including acute, delayed and anticipatory emesis, in particular emesis induced by chemotherapy or radiation, as well as motion sickness, and post-operative nausea and vomiting; eating disorders including anorexia nervosa and bulimia nervosa; premenstrual syndrome; muscle spasm or spasticity, e.g. in paraplegic patients; hearing disorders, including tinnitus and age-related hearing impairment, presbycusis and hyperacusis; urinary incontinence; the effects of substance abuse or dependency,including alcohol withdrawal; cognition disorders, -12 -for example in subjects suffering from dementing conditions such as Alzheimer's disease; sleep disorders such as insomnia; vestibular disorders such as Meniere's disease, benign paroxsysmal positional vertigo (BPPV), endolymphatic hydrops and ma! de debarquement syndrome; attention deficit/hyperactivity disorder; intention tremor; restless leg syndrome; and may also be effective as pre-medication prior to anaesthesia or minor procedures such as endoscopy, including gastric endoscopy.

In a particular embodiment of the invention, the condition is susceptible to amelioration by agonism of GABAA receptors comprising a4 and 6 subunits.

In a further embodiment of the invention, the disorder is selected from neurological or psychiatric disorders such as epilepsy, Parkinson's disease, schizophrenia and Huntington's disease; sleep disorders such as insomnia; premenstrual syndrome; hearing disorders such as tinnitus, age related hearing loss, presbycusis and hyperacusis; vestibular disorders such as Meniere's disease; benign paroxsysmal positional vertigo (BPPV), endolymphatic hydrops and ma! de debarquement syndrome; attention deficit/hyperactivity disorder; intention tremor; and restless leg syndrome.

In a still flirther embodiment of the invention, the disorder is a sleep disorder, in particular insomnia such as primary insomnia, chronic insomnia or transient insomnia. Within this embodiment is provided the use of the compounds of this invention for the manufacture of a medicament for increasing total sleep time, increasing non-REM (rapid eye movement) sleep time and/or decreasing sleep latency.

In a preferred embodiment, the compounds of the present invention are agonists at a GABAA receptor which comprises a4 and 6 subunits together with a J3 subunit, such as the 33 subunit.

Preferably, the GABAA agonists of the present invention are selective for the a4336 receptor over the a43'y receptor.

In order to elicit their behavioural effects, the compounds of the invention will ideally be brain-penetrant; in other words, these compounds will be capable of crossing the so-called "blood-brain barrier". Preferably, the compounds of the invention will be capable of exerting their beneficial therapeutic action following administration by the oral route.

The invention also provides pharmaceutical compositions comprising one or more compounds of this invention in association 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 principal active ingredient is mixed with a pharmaceutical carrier, e.g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical -13 -diluents, e.g. water, to form a solid preformulation 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 Ito 100 mg, for example 1, 2, 5, 10, 20, 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 including a number of polymeric acids and mixtures of polymeric acids 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 include 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 vehicles.

Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone or gelatin.

In the treatment of neurological disorders, 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 especially about 0.05 to 5 mg/kg per day. The compounds may be administered on a regimen of 1 to 4 times per day. A typical dose is in the range from about 5mg to about 50mg per adult person per day, e.g. 5mg, 10mg, 15mg, 20mg or 25mg daily.

Where the synthesis of intermediates and starting materials is not described, these compounds are commercially available or can be made from commercially available compounds by standard methods or by extension of the chemistry described in the synthesis above and

examples herein.

Compounds of formula I may be converted to other compounds of formula I by known methods or by methods described in the synthesis and Examples. For example, compounds of formula IA can be reacted with compounds of formula IB: -14 -Het w x o & RN'> Z H (CR6R7)aiR8 (IA) (IB) wherein a, R4, R6, R7, R8, W, X, Y and Z are as defined above and Het is azetidinyl or a 5, 6 or 7 membered heterocycle. The reaction is generally carried out in the presence of a catalyst such as acetic acid, reducing agent such as sodium tracetoxyborohydnde solvents such as Et3N and dichioroethane, at about ambient temperature.

Where a mixture of products is obtained from any of the processes described above for the preparation of compounds according to the invention, the desired product can be separated therefrom at an appropriate stage by conventional methods such as preparative HPLC; or column chromatography utilising, for example, silica and/or alumina in conjunction with an appropriate solvent system.

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 enantiospecific 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 acid, such as (-)-di-p-toluoyl-d_ tartaric acid and/or (+)-di-p-toluoyl4.tartanc acid, followed by fractional crystallization and regeneration of the free base. The novel compounds may also be resolved by formation of diastereomenc 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. McOmje, Plenum Press, 1973; and T.W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 3rd edition, 1999. The protecting groups may be removed at a convenient subsequent stage using methods known from the art.

The GABAA agonist activity of the compounds of the present invention can be determined using cells which express the receptor, such as mouse L (-tk) cells engineered to express the a4f33 receptor as described by Brown et a! (supra) and Adkins et a! (upra).

In one suitable method for identifying such compounds, GABA-induced membrane potentials in the cells are measured in the presence and absence of putative agonists by -15 -fluorescence resonance energy transfer techniques, as described by Adkins et a! (supra). In another suitable method, GABA-gated currents are measured in the presence and absence of putative agonists, e.g by patch clamp techniques as described by Brown et al (supra). Typically, the current or potential is measured in the presence of GABA at a concentration lower than that required to elicit the maximum GABA-induced response, e.g. 20% of that concentration. This current or potential represents a baseline signal, and elevation of this signal in the presence of a test compound indicates that the copipound in question is an agonist. The magnitude of the elevated signal (expressed as a percentage of the maximum GABA response) is a measure of potency. Compounds which elicit at least 50% of the maximum GABA response are preferred, and compounds which elicit 100% or more of the maximum GABA response are particularly preferred.

The binding affinity (Ki) of the exemplified compounds was measured in the assay described in Brown et a! (supra). The Ki value at the a4133ö subunit of the GABAA receptor was less than lO5OnM.

The potentiation of the GABAA EC50 response in stably transfected cell lines expressing the a4f3 subunit of the GABAA receptor was measured by the procedure described in Brown et a! (supra). The EC50 value at the a4f3ö subunit of the GABAA receptor subunit is at least 50%.

EXAMPLE 1

1-11 -(3-Dyridin-4-ylpropyl)piperidin4yl] 1 3-dihvdro-2H-imidazo[4.5-b]pyridin-2-one I -Piperidin-4-yl-1,3-dihydro-2H-imidazo[4,5b]pyndin2one (100mg, 0.46mmol), Et3N (0.O8mL, 0.S2mmol) and 3-pyridin-4-ylpropanal (93mg, 0.69mmol) were stirred in 3mL dichioroethane at ambient temperature for 30 minutes under a nitrogen atmosphere. Acetic acid (0.O3mL, 0.46mmol) was added followed by sodium triacetoxyborohydride (165mg, 0.78mmoI) and the reaction was stirred for 18 hours. The reaction was quenched with saturated NaHCO3 and extract with CH2CI2. The combined organic phase was washed with brine, dried over MgSO4 and concentrated. The reaction was purified using a Biotage Horizon preparative system using a 0- 10% methanol/dichioromethane gradient followed by crystallisation from EtOAc/hexanes to give the title compound as a pale yellow solid (27mg). 6H (400 MHz, d6 DMSO) IH NMR (500 MHz, CDCI3): 9.0 (br s, IH), 8.44 (2H, d, J 6.0), 7.95 (1H, d, J 5.2), 7.39 (1H, d, J 8.2), 7.07 (2H, d, J 5.8), 6.92 (IH, dd, J 5.2, 7.9), 4.32 (1H, s), 2.99 (2H, d, J 11.9), 2.61 (2H, t, J 7.6), 2.35 (2H, t, J 7.2), 2.25 (2H, t, J 12.6), 2.10-2.04 (2H, m), 1.79 (4H, d, J 8.0).

Examples 2 to 14 were prepared according to the procedures in Example 1.

EXAMPLE 2 1 -[ I -(3-phenylpropyl)piperidin-4-yl]-m/z 336 (M+ 1) I,3-dihydro-2H-benzjrnjdazol-2one EXAMPLE 3 1 -[1 -(3-phenylbutan)-1 -piperidin-4-mlz 350 (M+ 1) yl]-I,3-dihydro-2H-benzjmjdazol-2-one EXAMPLE 4 1 -[1 -(3-phenylpropan-2-ol)-I -mlz 352 (M+ 1) piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one EXAMPLE S 1-methyl-1'-(4,4-bis(4-m/z 461 (M+1) fluorophenyl)butan-I)-spiro[indole-3,4'-piperidin]-2( I H)-one EXAMPLE 6 1 -[2-(2, I,3-benzoxadiazol-5-m/z 363 (M+ 1) yl)ethyl}-. 1 -methylspiro[indoje-3,4'-piperidin]-2( 1 H)-one EXAMPLE 7 1-(1-N-[(2S)-2-(3-m/z 553 (M+1) chlorophenyl)butyl]-N-methylbenzenesulfonamidepipendjn 4-yI)-l,3-dihydro-2H-benzjmjdazol 2-one EXAMPLE 8 3-(3-pheny1propanIpiperidin4y1) m/z 395 (M+1) 2-phenyl-1 H-indole EXAMPLE 9 I-(l-(4-fluorophenyl)butan-1-one)I.. m/z 382 (M+1) piperidm-4-yI-1,3-dihydro-2H-benzimidazol-2-one * -17-EXAMPLE 10 l-(3-phenylpropyl)-3-methyl-1,3... IH NMR (ppm)(DMSO): 10.51 (1 dihydro-2H-benzimjdazol-2one H, s), 7.57 (1 H, d, J = 7.1 Hz), 7.33 hydrochloride (2 H, t, J = 7.5 Hz), 7.27-7.21 (3 H, m), 7.17 (1 H, t, J = 4.3 Hz), 7.11- 7.05 (2 H, m), 4.59 (1 H, t, J 12.1 Hz), 3.61 (2 H, d, J = 11.5 Hz), 3.35(3H, s), 3.20-3.08 (4 H, m), 2.80 (2 H, q, J = 12.1 Hz), 2.69-2.63 (2 H, m), 2.08(2 H, d, J = 8.5 Hz), 1.88(2 _____________ H, d, J = 12.2 Hz).

EXAMPLE 11 l-[l-(3-pyridin-4-ylpropyl)pipendin IH NMR (ppmXDMSO): 10.81 (1 4-yI]-1,3-dihydro2Hbenzjnijcjazo1 H, s), 8.45 (2 H, t, J = 3.0 Hz), 7.27 2-one (2 H, d, J = 5.8 Hz), 7.19 (1 H, t, J = 2.7 Hz), 6.98 (3 H, d, J = -0.0 Hz), 4.15-4.09 (1 H, m), 2.98 (2 H, d, J = 11.4 Hz), 2.65 (2 H, t, J = 7.6 Hz), 2.37-2.29 (4 H, m), 2.02 (2 H, t, J = 11.1 Hz), 1.82-1.74 (2 H, m), 1.63 (2 ___________ H,d,J= 10.0 Hz).

EXAMPLE 12 l-(3-pyridin-4-ylpropyI)3methy1 1H NMR (ppm)(DMSO): 8.46 (2 1,3-dihydro-2H-benzjmjdazol2one H, d, J = 5.8 Hz), 7.26 (3 H, dd, J = 5.9, 5.9 Hz), 7.14-7.12 (1 H, m), 7.07-7.03 (2 H, m), 4.20-4.13 (1 H, m), 2.98 (2 H, d, J = 11.5 Hz), 2.64 (2 H, t, J = 7.6 Hz), 2.38-2.30 (4 H, m), 2.03 (2 H, t, J = 11.1 Hz), 1.81- 1.75 (2 H, m), 1.64 (2 H, d, J = 9. 9 ______________________________ Hz).

-18--EXAMPLE 13 I'-(3-phenylpropyl)spiro[indole3,4' IH NMR (ppm)(DMSO): 10.47 (1 1 piperidrn]-2(1H)-one H, s), 7.33-7.19 (7 H, m), 6.98 (1 H, t, J = 7.3 Hz), 6.87 (1 H, d, J = 7.7 Hz), 2.8-3.4 (6H, m), 2.65 (2 H, t, J = 7.6 Hz), 1.91 (6 H, s).

EXAMPLE 14 l-[I-(3-phenylpropyl)piperidin4yl].. 1H NMR i (ppm)(CDCI3): 7.93 (1 H, 1H-benzjmjdazole s), 7.74 (1 H, dd, J = 3.5, 6.6 Hz), 7.36 (1 H, dd, J = 2.2, 5.6 Hz), 7.24- 7.18 (4 H, m), 7.12 (3 H, t, J = 8.3 Hz), 4.14 (1 H, t, J = 7.7 Hz), 3.05 (2 H, d, J = 3.8 Hz), 2.60 (2 H, t, J = 7.6 Hz), 2.38 (2 H, t, J = 7.5 Hz), 2.13- 2.06 (6 H, m), 1.83-1.77 (2 H, m).

Claims

-19 - CLAIMS

1. A compound of formula 1, or a pharmaceutically acceptable salt thereof: w x___

II A z (I)

wherein: Ais: R' R or R1 is azetidmyl or a 5, 6 or 7 membered saturated or a partially saturated heterocycle containing 1, 2 or 3 heteroatoms independently selected from N, 0 and S, optionally substituted by one, two or three groups independently selected from (CR6R7)aR8; R5 is hydrogen, hydroxy, halogen, C1aIkyl, Cia&oxy, haloCi6aIkyl or haloC16alkoxy; or R5 together with R' forms a Spiro ring selected from azetidine or a 5, 6 or 7 membered saturated or a partially saturated heterocycle containing 1, 2 or 3 heteroatoms independently selected from N, 0 and S, optionally substituted by one, two or three groups independently selected from (CR6R7)aR8; R2 is hydrogen, hydroxy, cyano, halogen, C1allcyl, C 2Ioalkenyl, haloC1a1kyl, hydmxyC1 6alkyl, Ci6alkoxy, haloC16alkoxy, C3locycloallcyl or C6ioaryl, any of which rings being optionally substituted by one, two or three groups independently selected from hydroxy, oxo, halogen, C1 6alkyl, haloC1aIkyl, Ci6alkoxy and haloCi6alkoxy; R3 is hydrogen, hydroxy, halogen, C1allcyl or haloC16alkyl; or R3 together with R2 represents oxo; R4 is hydrogen or Cialkyl; either each of R6 and R7 independently represent hydrogen, hydroxy, halogen, Ci6alkyl, haloC16alkyl, Ci6alkoxy, haloCialkoxy or C6ioaryl, any of which rings being optionally substituted by one, two or three groups independently selected from hydroxy, oxo, cyano, halogen, Ciallcyl, haloC1alkyl, Ci6aIkoxy and haloC16alkoxy; or R6 together with R7 represents oxo; each R8 independently represents NRaRb, N(SO2Ra)Rl, Coioaryl, a 5 membered heteroaromatic ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, 0 and S, not more than one heteroatom of which isO or S. a 6 membered heteroaromatic ring containing 1, 2 or 3 N atoms or a 7, 8, 9 or 10 membered unsaturated or partially saturated heterocyclic ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, 0 and S; any of which rings being optionally substituted by one, two or three groups independently selected from hydroxy, oxo, cyano, halogen, C1a1ky1, haloCiallcyl, C1a&oxy and haloCia&oxy; aisO, 1, 2, 3, 4,5 or 6; R is hydrogen, C1allcyl or C61oaryI optionally substituted by one, two or three groups independently selected from hydroxy, oxo, cyano, halogen, C16alkyl, haloC16alkyl, Ci6alkoxy and haloC16alkoxy; Rb is hydrogen or C1a1kyl; either each of W, X, Y and Z is CR9 or one of W, X, Y and Z is N and the others CR9; each R9 is independently hydrogen, hydroxy, cyano, halogen, Ci6aIkyl, haloC1alkyl, C1 6alkoxy or haloC1alkoxy.

2. A compound of claim 1 wherein A is: R2 S3orR.

3. A compound of claim 1 wherein A is: 5çR2 -21 -

4. A compound of claim 1 wherein A is:

5. A compound of claim 1 wherein A is:

6. A compound of claim I wherein A is: R2

7. A compound of any previous claim, or apharmaceutically acceptable salt thereof in association with a pharmaceutically acceptable carrier.

8. A compound of any one of claims I to 6, or a pharmaceutically acceptable salt thereof for use in therapy.

9. The use of a compound of any one of claims ito 6, or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment or prevention of neurological or psychiatric disorders.

10. A method for the treatment or prevention of neurological or psychiatric disorders, which method comprises administration to a patient in need thereof of an effective amount of a compound of formula! or a composition comprising a compound of formula I.