GB2448808A - Substituted imidazo[1,2-a]pyridines and their use as agonists at GABA-A receptors for treating or preventing neurological or psychiatric disorders - Google Patents

Abstract

Substituted imidazo[1,2-a]pyridines and their use as agonists at GABAA receptors for treating or preventing neurological or psychiatric disorders <EMI ID=1.1 HE=53 WI=58 LX=728 LY=603 TI=CF> <PC>wherein a is 0, 1, 2, 3, 4; R<1> is selected from an optionally substituted C6-10 aryl group, an optionally substituted 5-membered unsaturated heterocycle; R<2> is H or C<WC 1>1-6 alkyl; R<3> is C1-6 alkyl, C1-6 alkenyl, C1-6 alkynyl, an optionally substituted C1-6 alkoxy, or a ring system; R<4> is H or a substituent; X is a direct bond, C=O or SO2. Preferred compounds include those where X is C=O and R<1> is thiophenyl. The compounds of formula (I) act as agonists at GABAA receptors and are thus useful for treating or preventing neurological or psychiatric disorders.

Description

IMIDAZOPYRIDINE ANALOGUES AS LIGANDS FOR GABAA RECEPTORS

The present invention relates to a class of substituted imidazo-pyridine derivatives and to their use in therapy. More particularly, this invention is concerned with imidazo[ I,2-a]pyridine analogues. These compounds are ligands for GABAA receptors and are therefore useful in the therapy of neurological and psychiatric disorders.

Receptors for the major inhibitory neumtransmitter, ganirna-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 (a1.6, 71-3, P1-2, 6, 8 and 9).

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 subunit and a ? subunit constitute the mininunn 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 pentarneric form. The selection of at least one a, one 3 and one7 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, ccl a2f3ryl, cz22I372, a3fry2/3, a46, a42/36, a53y2/3, a6fry2 and a68. Subtype assemblies containing an a! 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. 04 subunits comprise only a small percentage of neuronal subunits, concentrated in hippocampus, striatum, cerebral cortex, thalamus, and basal ganglia. They assemble with and 72 subunits in most areas of the brain but also with Pv3 and y subunits in olfactory bulb, dentate gyrus, and thalamus. Of the 20-27% of thalamic GABAA receptors that contain 04 subunits, approximately one-third contain 72 subunits, and two-thirds contain 6 subunits. Subtype assemblies containing an aS 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

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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, BZ1 and BZ2, on the basis of radioligand binding studies. The BZI subtype has been shown to be pharmacologically equivalent to a GABAA receptor comprising the a! 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 a2y2 and a32/3 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, a2'y2 or cx3fry2 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 a! 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 uS subunit are likely to be beneficial in enhancing cognition, fur 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 fur GABA, and modulation by benzodiazepine. Receptors containing and 6 subunits lack benzodiazepine binding sites entirely, and those containing a4, and 72 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!, Neuropharrnaco!ogy, 43, 651-61(2002), and stable expression of the (X43ö receptor is described in Adkins et a!, J. Biol.

Cheni., 276, 38934-9 (2001) and Brown et a!, 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. Otolaryngol., 2, 54-64 (2001) describe an animal model for testing the efficiency of prospective tinnitus therapies. 3.

Gaboxadol (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol, also known as THIP) is reported (Brown et a!, supra) to be a potent agonist at the a433S receptor. Previously, it had been claimed for use in treatment of sleep disorders (WO 97/028 13), 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 subunits. The compounds of this invention interact more favourably with the a4f3ö receptor over the a433y 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 1, or a pharmaceutically acceptable salt thereof: (R4)a R'

X R3 (I)

wherein: aisO, 1,2,3or4; R' is C6. 1oaryl, a 5 membered unsaturated heterocycle containing 1, 2, 3 or 4 heteroatoms independently selected from N, 0 and S, but not more than one of which is 0 or S or a 6 membered unsaturated heterocycle containing 1, 2 or 3 N atoms; any of which rings being optionally substituted by one, two or three groups independently selected from hydroxy, oxo, cyano, halogen, C1 alkyl, C2. 1oatkenyl, haloC 1allcyl, C16aEkoxy and haloC 16alkoxy; R2 is hydrogen or C1.6alkyl; R3 is C1a1kyl, C210alkenyl, C210alkynyl, haloC1alkyl, hydmxyC1alkyl, C16alkoxy, haloC1.6alkoxy, C ocycloalkyl, C6. 1oaryl, C6. 1oarylC 1.6alkyl, a 5 membered unsaturated heterocycle containing 1,2,3 or 4 heteroatoms independently selected from N, 0 and S, but not more than one of which isO or S or a 6 membered unsaturated heterocycle containing 1,2 or 3 N atoms; any of which rings being optionally substituted by one, two or three groups independently selected from hydroxy, oxo, cyano, halogen, C1allcyl, C21oaIkenyl, haloC1a1ky1, C1alkoxy and haloC1.6alkoxy; each R4 is independently hydmxy, cyano, halogen, C1a1ky1, haloC1.6alkyl, C1aIkoxy, haloC16alkoxy, C14alkylcarbonyl, C1.6alkoxycarbonyl, C6..1oaryl, C610aryIC14aIkyl, C6.oaryloxy or C6.loarylCl.6alkoxy; and X is a direct bond, C-O or SO2.

In an embodiment a isO, 1 or 2.

In an embodiment R' is an optionally substituted ring selected from C6..1oaryl and a 5 membered unsaturated heterocycle containing 1,2, 3 or 4 heteroatoms independently selected from N, 0 and S, but not more than one of which isO or S. In another embodiment R' is an optionally substituted ring selected from phenyl, naphthalenyl or thiophenyl. Particularly R' is an optionally substituted thiophenyl.

In an embodiment R' is unsubstituted or substituted by one or two independently selected groups. In another embodiment R' is unsubstituted or monosubstituted.

In an embodiment the optional substituents on the R' ring are independently selected from halogen, C1alkyl, haloC1.4alkyl, C14alkoxy and haloC14alkoxy.

ParticuLarly R' is phenyl, naphthalenyl or thiophenyl optionally substituted by halogen or haloC1.4alkyl, particularly halogen.

Particular R' groups include thiophenyl, phenyl, fluorophenyl and naphthalenyl.

Specific R' groups include thiophen-2-yl, thiophen-3-yl, phenyl, 4-fluorophenyl and naphthalen-1-yl. In an embodiment R' is thiophen-2-yl.

In an embodiment R2 is hydrogen, methyl or ethyl.

Particularly R2 is hydrogen.

In an embodiment R3 is C1alkyl or an optionally substituted C1oary1 or C1oary1C1 ailcyL In another embodiment R3 is C1a1kyl or an optionally substituted phenyl.

In another embodiment R3 is an optionally substituted phenyi In an embodiment when R3 is a ring it is unsubstituted or substituted by one or two independently selected groups.

In an embodiment the optional substituents on the R3 ring are independently selected from halogen, C1alkyl, haloC1aIkyl, C1.6alkoxy and haloC1a1koxy.

Particularly R3 is butyl or phenyl optionally substituted by one or two groups independently selected from halogen, C1alkyl and haloC14alkoxy.

Particular R3 groups include dichlorophenyl, methylphenyl, chlorophenyl, methoxyphenyl, butyiphenyl, dimethoxyphenyl, phenyl and butyl.

Specific R3 groups include 2,4-dichiorophenyl, 4-methyiphenyl, 4-chlorophenyl, 3,4-dichlorophenyl, 4-methoxyphenyl, 4-tert-butylphenyl, 2,4-dimethoxyphenyl, phenyl and butyl.

In an embodiment R4 is halogen, C1a1kyl, ha1oC1aIkyl, CjaIkoxy, C14alkoxycarbonyl or C61oarylC1.6alkoxy.

Particular R4 groups are methyl, bromine, trifluoromethyl, methoxy, iso-propoxy, ethoxycarbonyl, benzyloxy and chlorine.

In an embodiment X is a direct bond or C=O. In another embodiment X is CO.

The present invention also provides compounds of formula II, or a pharmaceutically acceptable salt thereof: (R4)a iZiiiiri-ci) (II) wherein a, R2 and R4 are as defined above; R5 is C1oaryl, C6..1oarylCia1kyl, a 5 membered unsaturated heterocycle containing 1,2,3 or 4 heteroatoms independently selected from N, 0 and S. but not more than one of which isO or S or a 6 membered unsaturated heterocycle containing 1,2 or 3 N atoms, optionally substituted by one, two or three groups independently selected from halogen, C1alkyl, haloC1.a1kyl, C1..

6alkoxy and haloCiaIkoxy.

The preferred identities with reference to formula II are as defined previously mutatis nutandis.

In an embodiment R5 is C6.ioaryl optionally substituted by one or two groups independently selected from halogen, C1alkyl and haloC14aIkyL Particular R5 groups include dichlorophenyl, methyiphenyl, chlorophenyl, methoxyphenyl, butyiphenyl, dimethoxyphenyl and phenyl.

Specific R5 groups include 2,4-dichlorophenyl, 4-methyiphenyl, 4-chlorophenyl, 3,4-dichlorophenyl, 4-methoxyphenyl, 4-tert-butylphenyl, 2,4-dimethoxyphenyl and butyl.

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 fonned 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 carry 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 ammonium salts.

When any variable (e.g. R4) 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, flom 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,"C1.6alkyl" is defined to include groups having 1,2,3,4, 5 or 6 carbons in a linear or branched arrangement. For example,"Cl.6alkyl" 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 monocyc lie, 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 "C24alkenyl" 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 "C24alkynyl" 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 definitions 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 Cioaryloxy' can be construed analogously, and an example of this group is phenoxy.

The terms "haloC1alkyl" and "haloCialkoxy" mean a C14ky1 or Cia&oxy group in which one or more (in particular, 1 to 3) hydrogen atoms have been replaced by halogen atoms, especially fluorine or chlorine atoms. Preferred are fluoroCjaIkyl and fluomC1alkoxy groups, in particular fluoroC1..3aIkyl and fluomC1.3alkoxy groups, for example, CF3, CHF2, CH2F, CH2CH2F, CH2CHF2, CH2CF3, OCF3, OCHF2, OCH2F, OCH2CH2F, OCH2CHF2 or OCH2CF3, and most especially CF3, OCF3 and OCHF2.

As used herein, the term "hydmxyCialkyl" means a C1alkyl group in which one or more (in particular, 1 to 3) hydrogen atoms have been replaced by hydroxy groups. Preferred are CH2OH, CH2CHOH and CHOHCH3.

As used herein, the term "CL.aIkylcarbonyl" or "C1aIkoxycarbonyl" denotes a C1aIkyl or C1alkoxy radical, respectively, attached via a carbonyl (C=O) radical. Suitable examples of C1allcylcathonyl groups include methylcarbonyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl and tert-butylcarbonyl. Examples of C1.6alkoxycarbonyl include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl and tert-butoxycarbonyl. The term C1oarylcarbonyl' can be construed analogously, and an example of this group is benzoyl.

As used herein, "Coaryl" 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, fliryl, furazanyl, imidazolyl, indolinyl, indolyl, indolizinyl, indolinyl, isoindolinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthpyridinyl, oxadiazolyl, 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, hexahydroazepinyl, piperazinyl, piperidyl, pyridin-2-onyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrrolinyl, morpholinyl, thiomorpholinyl, dihydmbenzoimidazolyl, dihydrobenzofuranyl, dihydmbenzothiophenyl, dihydrobenzoxazolyl, dihydrofuranyl, dihydmimidazolyl, dihydroindolyl, dihydroisooxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dlhydmpyrrolyl, dihyciroquinolinyl, dihydroisoquinolinyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothienyl, dihydrotriazolyl, dihydmazetidinyl, dihydroisochromenyl, dihydrochromenyl, dihydroimidazolonyl, dihydrotriazolonyl, dihydrobenzodioxinyl, dihydrothiazolopyrimidinyl, dihydmimidazopyrazinyl, methylenedioxybenzoyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydroquinolinyl, thiazolidinonyl, imidazolonyl, isoindolinonyl, octahydroquinolizinyl, octahydroisoindolyl, imidazopyridinyl, azabicycloheptanyl, chromenonyl, triazolopyrimidinyl, dihydrobenzoxazinyl, thiazolotriazolyl, azoniabicycloheptanyl, azoniabicyclooctanyl, phthalazinyl, naphthyridinyl, pteridinyl, dihydmquinazolinyl, dihyclrophthalazinyl, benzisoxazolyl, tetrahydmnaphthyridinyl, dibenzo[b,d]furanyl, dihydrobenzothiazolyl, imidazothiazolyl, tetrahydroindazolyl, tetrahydrobenzothienyl, hexahydmnaphthyridinyl, tetrahydroimidazopyridinyl, tetrahydroimidazopyrazinyl, 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, imidazopyndinyl, benzothiazolyl, quinoxalinyl, benzothiadiazolyl, benzoxazolyl, dihydrobenzodioxinyl, benzotriazolyl, benzodioxolyl, dihydroisoindolyl, dihydroindolyl, tetrahydroisoquinolinyl, isoquinolinyl, benzoisothiazolyl, dihydroimidazopyrazinyl, benzothienyl, benzoxadiazolyl, thiazolotriazolyl, dihydrothiazolopyrimidinyl, dihydmbenzoxazinyl, dihydrobenzofiiranyl, benzimidazolyl, benzofuranyl, dihydmbenzoxazolyL dihydroquinazolinyl, dihydrophthalazinyl, indazolyl, benzisoxazolyl, tetrahydronaphthyridinyl, triazolopyrimidinyl, dibenzo[b,d]furanyl, naphthyridinyl, dihydroquinolinyl, dihydroisochromenyl, dihydmchromenyl, dihydrobenzothiazolyl, imidazothiazolyl, tetrahydmindazolyl, tetrahydrobenzothienyl, hexahydronaphthyridinyl, tetrahydroimidazopyridinyl, tetrahydroimidazopyrazinyl, pyrmlopyndinyl, 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: 2,4-Dichloro-N-(8-methyl-2-thiophen-2-yl-imidazO[ 1,2-a]pyridin-3-yl)-benzamide; 4-Methyl-N-(8-methyl-2-thiophen-2-yl-imidazo[ I,2-a]pyridin-3-yl)-benzamide; 4-Chloro-N-(8-methyl-2-thiophen-2-yl-imidazO[ 1,2-a]pyridin-3-yl)-benzamide; 4-Chloro-N-(2-thiophen-2-yl-imidazo[ 1,2-a]pyndin-3-yl)-benzamide; 4-Chloro-N-(6-methyl-2-thiophen-2-yl-imidazoE 1,2-a]pyridin-3-yI)-benzamide; N-(6-Bromo-8-methyl-2-thiophen-2-yl-imidazo[ I,2-a]pyridin-3-yl)-4-chloro-benzamide; 4-Chloro-N-(2-thiophen-2-yl-6-trifluoromethyl-imidazOEl,2-a]pyridin-3-yl) -benzamide; 4-Chloro-N-(6-methoxy-2-thiophen-2-yI-imidazo[ 1,2-a]pyridin-3-yl)-benzamide; 4Ch1oro-N-(6-isopropoxy-2-thiophen-2-yl-imid2ZO[l,2-a]pyridin-3-yl) -benzamide; 4-Chloro-N-(6,8-dibmmo-2-thiophen-2-yl-imidazO[ 1,2-a]pyridin-3-yl)-benzamide; 3(4-ch1oro-benzoy1amino)-2-thiophen-2-yl-imidazo[ 1,2-a]pyridine-6-carboxylic acid ethyl ester; 4-Methoxy-N-(2-thiophen-2-yl-imidazo[ 1,2-a]pyridin-3-yl)-benzamide; N-(8-Benzyloxy-2-thiophen-2-yl-imidazO[ 1,2-a]pyridin-3-yl)-4-chloro-benzamide, 4-tert-Butyl-N-(2-thiophen-2-yl-imidazO[ 1,2-a]pyridin-3-yl)-benzamide; 4-Chloro-N-(8-methyl-2-thiophefl-3-yl-imidazO[ 1,2-a]pyridin-3-yl)-benzamide; l,2-a]pyridin-3-yl)-benzamide; 4-Methyl-N-(2-thiophen-2-yl-imidaZO[ I,2-a]pyridin-3-yl)-benzamide; 4-Chloro-N-(6-chloro-2-thiophen-2-yl-itflidaZO[ I,2-a]pyridin-3-yl)-benzamide; N-(6-Chloro-2-thiophen-2-yl-imidazo[ 1,2-a]pyridin-3-yl)-4-methyl-benzamide; 2,4-Dimethoxy-N-(2-thiophen-2-yI-imidazo[ 1,2-a]pyridin-3-yl)-benzamide; N-(6,8-Dibromo-2-thiophen-2-yl-imidaZOE I,2-ajpyridin-3-yl)-4-methoxy-benzamide; 4-Chloro-N-(6-chloro-2-pheflyl-imidaZO[ 1,2-a]pyridin-3-yl)-benzamide; N-[6-chloro-2-(4-fluoro-phenyl)-imidazoE 1,2-ajpyridin-3-yl]-benzamide; Butyl-(2-naphthalen-1 -yl-imidazo[l,2-alpyridin-3-yl)-amine; 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 -10-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 I. The compounds of the present invention are 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 I 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; burette's syndrome; speech disorders, including stuttering; disorders of circadian rhythm, e.g. in subjects suffering from the effects of jet lag or shift worlq 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, fbr 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 mal 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 8 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 disorderssuch as Meniere's disease; benign paroxsysmal positional vertigo (BPPV), endolymphatic hydrops and mat de debarquement syndrome; attention deficit/hyperactivity disorder, intention tremor; and restless leg syndrome.

In a still further 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 -11 -medicament fbr 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 5 subunits together with a f3 subunit, such as the f33 subunit.

Preferably, the GABAA agonists of the present invention are selective for the a4f338 receptor over the rz4133y 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 fbr 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 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 fbnner. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and pennits 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.

-12 -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! 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.

Compounds of formula! can be prepared by a process which comprises reacting a compound of formula IA with a compound of formula IB: (R4)a L' X R3 NR2H (IA) (IB) wherein a, R', R2, R3, R4 and X are as defined above and L' is a leaving group such as halogen, for example chlorine. The reaction is generally carried out in solvents such as toluene and pyridine at about ambient temperature. The reaction may be carried out under a nitrogen atmosphere.

Compounds of formula IA wherein R2 is hydrogen can be prepared by reacting a compound of formula IC with a compound of formula ID: (R4)a iiiii" Na03\>.. R' (IC) (ID) wherein a, R' and R4 are as defined above, in the presence of a metal cyanide such as NaCN or KCN, particularly KCN, generally at about ambient temperature.

Compounds of formula ID can be prepared by reacting a compound of formula IE with NaHSO3: * 13-(IE) wherein R' is as defined above, generally in an aqueous solvent such as water at about ambient temperature.

Alternatively, compounds of formula I wherein R2 is hydrogen can be prepared by reacting compounds of formulae IC, IE and IF: NC X-R3 (IF) wherein R3 and X are as defined above, generally in the presence of a suitable catalyst such as scandium(III)trifiate, a solvent such as MeOH at about 160 C.

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 Imay be converted to other compounds of formula I by known methods or by methods described in the synthesis and Examples.

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-toluoyl-l-tartaric acid, 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, 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 a4f336 receptor as described by Brown et a! (supra) and Adkins et a! (supra).

In one suitable method for identii'ing such compounds, GABA-induced membrane potentials in the cells are measured in the presence and absence of putative agonists by fluorescence resonance energy transfer techniques, as described by Adkins et at (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 compound 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 eta! (supra). The Ki value at the a43& subunit of the GABAA receptor was less than lO5OnM.

The potentiation of the GABAA EC50 response in stably transfected cell lines expressing the a438 subunit of the GABAA receptor was measured by the procedure described in Brown et a! (supra). The EC50 value at the u41336 subunit of the GABAA receptor subunit is at least 50%.

EXAMPLE 1

2. 4-Dlchloro-N48-methvl-2-thionhen-2-vl-Imldazoll2-alnvrldln-3-vflbenzamlde Step 1: 8-Methyl-2-thlophen-2-yI-Imldazol 1,2-al pyrldln-3-ylamlne 2-Thiophene carboxyaldehyde (6.95g. 62mmol) was added to a solution of NaI4SO3 (6.36g) in H20 (80m1) at ambient temperature. After stirring for 30 minutes, 2-amino-3-methylpyridine (6.7g, 62mmol) was added and the reaction mixture was heated at 100 C for 2 hours. KCN (4.lg, 63mmol) was added and the reaction stirred at ambient temperature for 18 hours. The reaction was quenched with the addition of 2N NaOH (30m1). The precipitate was collected, washed with H20 and then triturated with ethyl acetate to afford the title compound as a dark yellow solid (l.lg). 1H NMR oH (500 MHz, d6 DMSO): 8 8.06 (1 H, d, J = 6.8 Hz), 7.54 (1 H, d, J = 2.8 Hz), --15 7.39(1 H, d, J = 5.0 Hz), 7.11 (1 H, dd, J = 3.6,5.0Hz), 6.86(1 H, d, J 6.7 Hz), 6.74(1 H, t, J = 6.8 Hz), 5.21 (2 H, s), 2.44 (3 H, s).

Step 2: 2,4-Dlchloro-N-(8-methyl-2-thlophen-2-yI-imidazoll,2-alpyridin-3-yJ) -benzamide 2,4-Dichlombenzoylchloride (0.32g. 1.5mmol) was added to a suspension of the product from above (O.32g, I.4mmol) in dry toluene (4m1) and pyridine (2m1) at ambient temperature under a nitrogen atmosphere. After stirring for 30 minutes the reaction was quenched with the addition of H20 and extracted with EtOAc2 (x2). The combined organic layers were washed with saturated NaHCO3, H20, dried over MgSO4 and concentrated to afford the crude product. Purification on the Biotage afforded the title compound as a white solid (25mg). IH NMR 814 (400 MHz, d6 DMSO): 6 10.85 (1 H, s), 8.03 (1 H, d, J = 6.7 Hz), 7.92 (1 H, d, J = 8.2Hz), 7.86 (1 H, d, J = 1.9 Hz), 7.67 (1 H, dd, J = 2.0, 8.2 Hz), 7.59 (2 H, t, J = 4.5 Hz), 7.17(2 H, t, J = 4.4 Hz), 6.95 (1 H, t, J = 6.8 Hz), 2.54 (3 H, s).

Examples 2 to 24 were prepared according to the procedure of Example 1.

EXAMPLE 2 4-Methyl-N-(8-methyl-2-1H NMR 8 (500 MHz, d thiophen-2-yl-DMSO): 6 10.54 (1 H, s), imidazo[1,2-a]pyridin-3-8.04(2 H, d, J = 8.1 Hz), 7.93 yl)-benzamide (1 H, d, J 6.7 Hz), 7.53 (1 H, d, J = 4.2 Hz), 7.48 (1 H, d, J = 3.5 Hz), 7.41 (2 H, d, 3 =8.OHz),7.15(1H,d,J 6.8 Hz), 7.11 (1 H, dd, J = 3.7, 4.9 Hz), 6.86 (1 H, t, J = 6.8 Hz), 2.55 (3 H, s), 2.43 (3 H, s).

EXAMPLE 3 4-Chloro-N-(8-methyl-2-1H NMR âH (400 MHz, d6 thiophen-2-yI-DMSO): 8 10.72 (1 H, s), imidazo[1,2-a]pyridin-3-8.15 (2 H, d, J = 8.6 Hz), 8.00 yl)-benzamide (1 H, d, J = 6.8 Hz), 7.70 (2 H, d, J = 8.5 Hz), 7.54 (1 H, dd, 3 = 1.0, 5.0 Hz), 7.49 (1 H, dd, J = 1.0, 3.6 Hz), 7.15 (1 H, d,J=6.9 Hz), 7.12 (1 H, dd, J = 3.6, 5.0 Hz), 6.86 (1 H, t, J = 6.8 Hz), 2.55 (3 H, s).

EXAMPLE 4 4-Chloro-N-(2-thiophen-1H NMR 8H (500 MHz, d6 2-yl-imidazo[1,2-DMSO): 8 10.72 (1 H, s), a]pyridin-3-yl)-benzamide 8.15 (3 H, m), 7.70 (2 H, d, i = 8.5 Hz), 7.61 (1 H, d, J = 9.0 Hz), 7.55 (1 H, d, J = 4.2 Hz), 7.49 (1 H, t, J = 1.7 Hz), 7.34 (1 H, t, J = 7.4 Hz), 7. 13 (1 H, dd, J = 3.7, 4.9 Hz), 6.95 (1 H, t, J = 6.4 Hz).

EXAMPLE 5 4-Chloro-N-(6-methyl-2-1H NMR 6 (500 MHz, d6 thiophen-2-yl-DMSO): 6 10.66 (1 H, s), imidazo[1,2-a]pyndin-3-8.16(2 H, d, J = 8.5 Hz), 7.98 yI-benzaniide (1 H, s), 7.70 (2 H, d, J = 8.5 Hz), 7.52 (2 H, m), 7.45 (1 H, dd, J = 0.9, 3.6 Hz), 7.20 (1 H, dd, J = 1.4, 9.1 Hz), 7.11 (1 H, dd, 3 = 3.6, 4.9 Hz), 2.30 (3 H, s).

EXAMPLE 6 N-(6-Bromo-8-methyl-2-IH NMR 8H (400 MHz, d6 thiophen-2-yl-DMSO): 8 10.71 (1 H, s), imidazo[1,2-a]pyridin-3-8.42 (1 H, s), 8.15 (2 H, d, 3 = yL)-4-chloro-benzamide 8.5 Hz), 7.68 (2 H, d, J = 8.5 Hz), 7.55 (1 H, d, J = 5.1 Hz), 7.49 (1 H, d, 3 = 3.5 Hz), 7.32 (1 H,s), 7.12 (1 H,dd,J= 3.7, 4.9 Hz), 2.55 (3 H, s).

EXAMPLE 7 3,4-Dichloro-N.-(8-1H NMR 8H (500 MHz, d6 methyl-2-thiophen-2-yl-DMSO): 6 10.82 (1 H, s), imidazo[1,2-a]pyridin-3-8.37 (1 H, d, J = 2.0 Hz), yl)-benzamide 8.09-8. 05 (2 H, m), 7.91 (1 H, d, J = 8.4 Hz), 7.54 (1 H, d, J = 4.2 Hz), 7.49 (1 H, dd, J = 1.0, 3.6 Hz), 7.17-7.11 (2 H, m), 6.86 (1 H, t, 3 = 6.8 Hz), 2.54 (3 H,s).

EXAMPLE 8 4-Chloro-N-(2-thiophen-1H NMR 6H (500 MHz, d6 2-yl-6-trifluoromethyl-DMSO): ó 10.78 (1 H, s), imidazo[1,2-a]pyridm-3-8.84 (1 H, s), 8.17 (2 H, d, 3 = yl)-benzamide 8.4 Hz), 7.81 (1 H, d, J = 9.3 Hz), 7.69(2 H, d, J = 8.4 Hz), 7.60(1 H, d, 3=5.0 Hz), 7.57 (1 H, d, 3 = 9.6 Hz), 7.54 (1 H,d,J3.6Hz),7.15(1 H,t, J4. 3 Hz).

EXAMPLE 9 4-Chloro-N-(6-methoxy-IH NMR 8H (500 MHz, d6 2-thiophen-2-yl-DMSO): 8 10.64 (1 H, s), imidazo[1,2-a]pyridin-3-8.17(2 H, d, J = 8.6 Hz), 7.71 yl)-benzamide (1 H, s) 7.70 (2 H, d, J = 8.6 Hz), 7.52 (2 H, dd, J = 9.7, 19.5 Hz), 7.41 (1 H, d, J = 2.7 Hz), 7.14-7.08 (2 H, m), 3.78 (3 H, s).

EXAMPLE 10 4-Chloro-N-(6-IH NMR 6H (400 MHz, d6 isopropoxy-2-thiophen-2-DMSO): ö 11.00 (1 H, s), yl-imidazo[1,2-a}pyridin-8.18(3 H, d, 3 = 8.6 Hz), 7.79 3-yl)-benzanude (2 H, t, 3 = 9.3 Hz), 7.72 (3 H, d, J = 8.6 Hz), 7.57 (1 H, d, 3 = 8.9 Hz), 7.23 (1 H, t, 3 = 4.3 Hz), 4.78-4.72(1 H, m), 1.29(6 H, d, J = 6.0 Hz).

EXAMPLE!! 4-Chloro-N-(6,8-1H NMR &H (400 MHz, d6 dibmmo-2-thiophen-2-yl-DMSO): 8 10.81 (1 H, s), imidazo[l,2-a]pyridin-3-8.72 (1 H, s), 8.15 (2 H, d, J = yI)-benzaniide 8.6 Hz), 7.90 (1 H, d, J = 1.4 Hz), 7.69 (2 H, d, J = 8.5 Hz), 7.60 (1 H, d, J = 5.0 Hz), 7.53 (1 H,d,33.1 Hz), 7.14(1 H, dd, 3.8, 5.0 Hz).

EXAMPLE 12 3-(4-Chloro-1H NMR 8H (400 MHz, d6 benzoylamino)-2-DMSO): 8 10.86 (1 H, s), thiophen-2-yl-8.65 (1 H, s), 8. 18 (2 H, d, J = imidazo[1,2-a]pyridine-6-8.5 Hz), 7.75-7.69 (4 H, m), carboxylic acid ethyl ester 7.60(1 H, d, 3= 5.0 Hz), 7.55 (1 H, d,J=3.4Hz), 7.15 (1 H, t, J = 4.3 Hz), 4.35 (2 H, q, J = 7.1 Hz), 1.31 (3 H, t, J = 7.1 Hz).

EXAMPLE 13 4-Methoxy-N-(2-1H NMR âH (500 MHz, d6 thiophen-2-yl-DMSO): 6 10.48 (1 H, s), imidazo[1,2-a]pyridin-3-8.12 (2 H, d, J = 8.8 Hz), 8.08 yI)-benzamide (1 H, t, 3 = 7.6 Hz), 7.60 (1 H, d, J = 9.0 Hz), 7.54 (1 H, d, J = 4.2 Hz), 7.48 (1 H, d, 3 = 3.5 Hz), 7.33 (1 H, t, J = 7.9 Hz), 7.15-7.11 (3 H, m), 6.94 (1 H, t, J = 6.7 Hz), 3.88 (3 H,d,J=4.2Hz).

EXAMPLE 14 N-(8-Benzyloxy-2-I H NMR 8H (400 MHz, d6 thiophen-2-yl-DMSO): 8 10.71 (1 H, s), imidazo[1,2-a]pyridin-3-8.14(2 H, d, J = 8.6 Hz), 7.77 yl)-4-chloro-benzamide (1 H, dd, J = 2.8, 4.8 Hz), 7.69 (2 H, d, 3 = 8.6 Hz), 7.57-7.37(7 H, m), 7.11 (1 H, * 19-dci, J 3.8, 5.0 Hz), 6.83 (2 H, dd, J = 0.0, 2.8 Hz), 5.36 (2 H, s).

EXAMPLE 15 4-tert-Butyl-N-(2-1H NMR 8H (400 MHz, d6 thiophen-2-yl-DMSO): 8 10.56 (1 H, s), imidazo[1,2-a}pyridin-3-8.09 (3 H, dd, J = 3.9, 5.8 yl)-benzamide Hz), 7.63 (2 H, d, J = 8.4 Hz), 7.60 (1 H, s), 7.54 (1 H, dd, J = 1.0, 5.0 Hz), 7.49 (1 H, dd, J = 1.0, 3.6 Hz), 7.35-7.3 1 (1 H, m), 7.12 (1 H, dd, J = 3.6, 5.0 Hz), 6.95 (1 H, t, J = 6.8 Hz), 1.36 (9 H, s).

EXAMPLE 16 4-Chloro-N-(8-methyl-2-1H NMR 8 (400 MHz, d6 thiophen-3-yl-DMSO): 6 10.71 (1 H, s), imidazo[1,2-a]pyridin-3-8.14(2 H, d, J = 8.5 Hz), 7.96 yl)-benzamide (1 H, d, 3 = 6.8 Hz), 7.86 (1 H, ci, J = 1.6 Hz), 7.68 (2 H, d, J = 8.5 Hz), 7.61 (2 H, t, J =3.8 Hz), 7.13 (1 H,d,J= 6.8 Hz), 6.84 (1 H, t, J = 6.8 Hz), 2.56 (3 H, s).

EXAMPLE 17 4-Methyl-N-(6-methyl-2-M+1 = 348 thiophen-2-yl- imidazo[ I,2-a]pyridm-3-yI)-benzamicie EXAMPLE 18 4-Methyl-N-(2-thiophen-M*+1 = 334 2-yl-imidazo[1,2-a]pyridin-3-yl)-benzamide EXAMPLE 19 4-Chloro-N-(6-chloro-2-M+1 = 388 thiophen-2-yl-imidazo[1,2-a]pyridin-3-yl)-benzamide EXAMPLE 20 N-(6-Chloro-2-thiophen-M-I-1 = 368 2-yl-imidazo[ 1,2-a]pyridin-3-yl)-4-methyl-benzamide EXAMPLE 21 2,4-Dimethoxy-N-(2-M+1 = 380 thiophen-2-yl- imidazo[ 1,2-a]pyridin-3-yl)-benzamide EXAMPLE 22 N-(6,8-Dibromo-2-M+ I = 508/510 thiophen-2-yl- imidazo[ 1,2-a]pyridin-3-yl)-4-methoxy-benzamide EXAMPLE 23 4-Chloro-N-(6-chloro-2-M+1 = 382 phenyt-imidazo[ 1,2-a]pyridin-3-yl)-benzamide EXAMPLE 24 N-[6-Chloro-2-(4-fluoro-M+1 = 366 phenyl)-imidazo[ 1,2-a]pyridin-3-yl]-benzaniide

EXAMPLE 25

Butvl-(2-naohthalen-1-vI-ImldazoFl.2-alDvridin-3-vfl-anilfle -21 -N-Butyl isocyanide was added to a solution of 2-ammopyridine and 1 -napthaldehyde in dry MeOH. Scandium(III)triflate was added and the reaction was heated in the microwave at 160 C fbr 30 minutes. The reaction was quenched with H20 and extracted with DCM (x2). The combined organic layers were washed with brine, dried over MgSO4 and concentrated to afford the crude product. Purification on the Agilent prep LC-MS system (low pH) afforded the title compound as a TFA salt (g). 1H NMR oH (500 MHz, d6 DMSO): 8 8.72 (1 H, d, J = 6.8 Hz), 8.16(1 H, d, J = 8.1 Hz), 8.09 (1 H, d, J = 8.2 Hz), 7.90 (1 H, d, J = 8.5 Hz), 7.85 (2 H, s), 7.79 (1 H, d, 3 = 6.0 Hz), 7.70 (1 H, t, J = 7.6 Hz), 7.65-7.57 (2 H, m), 7.51 (1 H, s), 2.69 (2 H, d, J = 4.7 Hz), 1.20-1.14 (2 H, m), 0.96-0.89 (2 H, m), 0.50 (3 H, t, J = 7.4 Hz). 22 -

Claims (8)

1. A compound of formula I, or a pharmaceutically acceptable salt thereof: (R4)a X/NR it3 (I) wherein: aisO, 1,2,3or4; R' is C61oaryl, a 5 membered unsaturated heterocycle containing 1,2,3 or 4 heteroatoms independently selected from N, 0 and S, but not more than one of which isO or S or a 6 membered unsaturated heterocycle containing 1,2 or 3 N atoms; any of which rings being optionally substituted by one, two or three groups independently selected from hydroxy, oxo cyano, halogen, C1.aIkyl, C2..1oalkenyl, haloC1aIkyl, C1alkoxy and haloC1aIkoxy; R2 is hydrogen or C1alkyl; R3 is C14alkyl, C2.10alkenyl, C2..10alkynyl, haloC1alkyl, hydmxyC1aIky1, C1alkoxy, haloC14alkoxy, C3..1ocycloalkyl, C6..1oaryl, C6.1oary1C1alkyl, a 5 membered unsaturated heterocycle containing 1,2,3 or 4 heteroatoms independently selected from N, 0 and S, but not more than one of which isO or S or a 6 membered unsaturated heterocycle containing 1,2 or 3 N atoms; any of which rings being optionally substituted by one, two or three groups independently selected from hydroxy, oxo, cyano, halogen, C1allcyl, C21oalkenyl, haloC1alkyl, C1allcoxy and haloC14alkoxy; each R4 is independently hydroxy, cyano, halogen, C1a1kyl, haloC1a1kyl, C1a1koxy, haloCi.6alkoxy, C1alkylcarbonyl, C1a&oxycarbonyl, C6.1oaryl, C6..joarylCi4kyl, C6..1oaryloxy or C410arylC1alkoxy; and X is a direct bond, C=0 or SO2.

2. A compound of claim 1 wherein R' is an optionally substituted ring selected from C1oaryl and aS membered unsaturated heterocycle containing 1,2,

3 or 4 hetematoms independently selected from N, 0 and S, but not more than one of which isO or S. 3. A compound of claim 1 of formula II, or a pharmaceutically acceptable salt thereof: (R4)a O/NR2 (LI) whereina,R2andR4areasdefinedinclaim 1; R5 is Coaryl, C6..1oarylC1allcyl, a 5 membered unsaturated heterocycle containing 1, 2, 3 or 4 heteroatoms independently selected from N, 0 and S. but not more than one of which isO or S or a 6 membered unsaturated heterocycle containing 1, 2 or 3 N atoms, optionally substituted by one, two or three groups independently selected from halogen, C1alkyl, haIoC16alkyl, Ci.

6alkoxy and haloC1aIkoxy.

4. A compound of claim 1 selected from: 2,4-Dichloro-N-(8-methyl-2-thiophen-2-yl-imidazo[ 1,2-a]pyridin-3-yl)-benzamide; 4-Methyl-N-(8-methyl-2-thiophen-2-yl-imidazo[ 1,2-a]pyridin-3-yl)-benzamide; 4-Chloro-N-(8-methyl-2-thiophen-2-yl-imidazo[ 1,2-a]pyridin-3-yl)-benzamide; 4-Chloro-N-(2-thiophen-2-yl-imidazo[ 1,2-a]pyridin-3-yl)-benzamide; 4-chloro-N-(6-methyl-2-thiophen-2-yl-imidazo[ 1,2-a]pyridin-3-yl)-benzamide; N-(6-Bromo-8-methyl-2-thiophen-2-yl-imidazo[1,2-a]pyridin-3-yl) -4-chloro-benzamide; 3,4-Dichloro-N-(8-methyl-2-thiophen-2-yl-imidazo[ l,2-a]pyridin-3-yl)-benzarnide; 4-Chloro-N-(2-thiophen-2-yl-6-trifluoromethyl-imidazo[ 1,2-a]pyridin-3-yI)-benzamide; 4-Chloro-N-(6-methoxy-2-thiophen-2-yl-imidazo[1,2-a]pyridin-3-yl) -benzamide; 4-Chloro-N-(6-isopropoxy-2-thiophen-2-yl-imidazo[ 1,2-a]pyridin-3-yl)-benzamide; 4-Chloro-N-(6,8-dibromo-2-thiophen-2-yl-imidazo[ I,2-a]pyridin-3-yl)-benzamide; 3-(4-Chloro-benzoylamino)-2-thiophen-2-yl-imidazo[ 1,2-a]pyridine-6-carboxylic acid ethyl ester, 4-Methoxy-N-(2-thiophen-2-yl-imidazo[ 1,2-a]pyridin-3-yl)-benzamide; N-(8-Benzyloxy-2-thiophen-2-yl-imidazo[ 1,2-a]pyridin-3-yl)-4-chloro-benzamide; 4-tert-ButyL-N-(2-thiophen-2-yl-imidazo[ 1,2-a]pyridin-3-yl)-benzamide; 4-Chloro-N-(8-methyl-2-thiophen-3-yl-imidazo[ 1,2-a]pyridin-3-yl)-benzamide; 4-Methyl-N-(6-methyl-2-thiophen-2-yl-imidazo[ 1,2-a]pyridin-3-yl)-benzamide; 4-Methyl-N-(2-thiophen-2-yl-imidazo[ 1,2-a]pyridin-3-yl)-benzamide; 4-Chloro-N-(6-chloro-2-thiophen-2-yl-imidazo[ 1,2-a]pyridin-3-yl)-benzamide; N-(6-Chloro-2-thiophen-2-yl-imidazo[ 1,2-a]pyridin-3-yl)-4-methyl-benzamide; 2,4-Dimethoxy-N-(2-thiophen-2-yl-imidazo[ 1,2-a]pyridin-3-yl)-benzamide; N-(6,8-Dibromo-2-thiophen-2-yl-imidazo[ 1,2-a]pyridin-3-yl)-4-methoxy-benzamide; 4-Chloro-N-(6-chloro-2-phenyl-iinidazo[ I,2-a]pyridin-3-yl)-benzamide; N-[6-Chloro-2-(4-fluoro-phenyl)-imidazo[ 1,2-a]pyridin-3-yl]-benzamide; Butyl-(2-naphthalen-l-yl-imidaz.o[l,2-a]pyridin-3-yl)-amine; and pharmaceutically acceptable salts thereof.

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

6. A compound of any one of claims I to 4, or a pharmaceutically acceptable salt thereof for use in therapy.

7. The use of a compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment or prevention of neurological or psychiatric disorders.

8. 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 I or a composition comprising a compound of formula I.