WO2004065388A1 - Fluoroimidazopyrimidines as gaba-a alpha 2/3 ligands for depression/anxiety - Google Patents

Abstract

The present invention provides a compound formula (I), or a pharmaceutically acceptable salt thereof: wherein W is phenyl or pyridyl; X1 represents hydrogen, halogen, C1-6 alkyl, trifluoromethyl or C1-6 alkoxy; X2 represents hydrogen or halogen; Y represents a chemical bond, an -NH- linkage or a group -OCnH2n-; Z represents an optionally substituted aryl or heteroaryl group; R1 represents hydrocarbon, a heterocyclic group, halogen, cyano, trifluoromethyl, nitro, -ORa, -SRa, -SORa, -SO2Ra, -SO2NRaRb, NRaRb, -NRaCORb, -NRaCO2Rb, -CORa, -CO2Ra, -CONRaRb or Cra=NORb; Ra and Rb independently represent hydrogen, hydrocarbon or a heterocyclic group; and n is zero, one, two or three; pharmaceutical compositions comprising it; its use in methods of treatment; use of it in the manufacture of medicaments to treat anxiety and/or depression; and methods of treatment for anxiety and/or depression using it.

Description

FLUOROIMIDAZOPY IMIDINES AS GABA-A ALPHA 2/3 LIGA DS

FOR DEPRESSION/ANXIETY

The present invention relates to a class of substituted imidazo- pyrimidine derivatives and to their use in therapy. More particularly, this invention is concerned with 8-fluoroimidazo[l,2-c]pyrimidine analogues which are substituted in the 3-position by a substituted phenyl ring. These compounds are ligands for GABAA receptors and are therefore useful in the therapy of deleterious mental states. Receptors for the major inhibitory neurotransmitter, gamma- aminobutyric acid (GABA), are divided into two main classes- (l) GABAA receptors, which are members of the ligand- ated ion channel superfamily! and (2) GABAB receptors, which may be members of the G-protein linked receptor superfamily. Since the first cDNAs encoding individual GABAA receptor subunits were cloned the number of known members of the mammalian family has grown to include at least six α subunits, four β subunits, three γ subunits, one δ subunit, one ε subunit and two p subunits.

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 α subunit, a β subunit and a γ subunit constitute the minimum requirement for forming a fully functional GABAA receptor expressed by transiently transfecting cDNAs into cells. As indicated above, δ, ε and p subunits also exist, but are present only to a minor extent in GABAA receptor populations.

Studies of receptor size and visualisation by electron microscopy conclude that, like other members of the ligand- gated ion channel family, the native GABA_A receptor exists in pentameric form. The selection of at least one α, one β and one γ 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, αlβ2γ2, cώβγl, α2β2/3γ2, α3βγ2/3, α4βδ, α5β3γ2/3, α6βγ2 and α6βδ. Subtype assemblies containing an αl 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 α2 and α3 subunits respectively are thought to account for about 25% and 17% of GABAA receptors in the rat. Subtype assemblies containing an α5 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, BZ1 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 αl subunit in combination with a β subunit and γ2. 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 α2βγ2 and α3βγ2/3 subtypes. Together these constitute approximately a further 35% of the total GABA_A 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 α5-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 αlβγ2, α2βγ2 or α3βγ2 subtypes will possess desirable anxiolytic properties. Compounds which are modulators of the benzodiazepine binding site of the GABAA receptor by acting as BZ agonists are referred to hereinafter as "GABAA receptor agonists". The αl-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 αl subunit. Accordingly, it is considered that GABAA receptor agonists which interact more favourably with the α2 and/or α3 subunit than with αl will be effective in the treatment of anxiety with a reduced propensity to cause sedation. Moreover, agents which are inverse agonists of the α5 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 αl might be employed to reverse sedation or hypnosis caused by αl agonists. 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 disorders of the central nervous system. Such disorders include 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; neurodegeneration arising from cerebral ischemia; attention deficit hyperactivity disorder; Tourette's syndrome; speech disorders, including stuttering; and disorders of circadian rhythm, e.g. in subjects suffering from the effects of jet lag or shift work.

Further disorders for which selective ligands for GABAA receptors may be of benefit include 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; urinary incontinence; and the effects of substance abuse or dependency, including alcohol withdrawal. Selective ligands for GABAA receptors may be beneficial in enhancing cognition, for example in subjects suffering from dementing conditions such as Alzheimer's disease; and may also be effective as pre-medication prior to anaesthesia or minor procedures such as endoscopy, including gastric endoscopy.

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.

WO 02/38569 describes a class of 3^_phβnylimidazo[l,2-dpyrimidine derivatives which are stated to be selective ligands for GABAA receptors, in particular having good affinity for the α2 and/or α3 subunit thereof, and hence to be of benefit in the treatment of adverse neurological conditions, including anxiety and convulsions. However, there is no disclosure nor any suggestion in that publication of substitution with a fluorine atom at the 8-position of the imidazo[l,2-c]pyrimidine ring system.

The present invention provides a class of imidazo-pyrimidine 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 α2 and/or α3 and/or α5 subunit of the human GABAA receptor. The compounds of this invention may interact more favourably with the α2 and/or α3 subunit than with the αl subunit; and/or may interact more favourably with the α5 subunit than with the αl subunit. The compounds of the present invention are GABAA receptor subtype ligands having a binding affinity (Ki) for the α2 and/or α3 and/or α5 subunit, as measured in the assay described hereinbelow, of 200 nM or less, typically of 100 nM or less, and ideally of 20 nM or less. The compounds in accordance with this invention may possess at least a 2-fold, suitably at least a 5-fold, and advantageously at least a 10-fold, selective affinity for the α2 and/or α3 and/or α5 subunit relative to the αl subunit. However, compounds which are not selective in terms of their binding affinity for the α2 and or α3 and/or α5 subunit relative to the αl subunit are also encompassed within the scope of the present invention; such compounds will desirably exhibit functional selectivity in terms of zero or weak (positive or negative) efficacy at the αl subunit and (i) a full or partial agonist profile at the α2 and/or α3 subunit, and/or (ii) an inverse agonist profile at the α5 subunit.

The present invention provides a compound of formula I, or a pharmaceutically acceptable salt thereof

(I)

wherein W is phenyl or pyridyl; X¹ represents hydrogen, halogen, Cι-6 alkyl, trifluoromethyl or Ci-β alkoxy;

X² represents hydrogen or halogen;

Y represents a chemical bond, an -NH- linkage, a group -CnH₂-r or a group -OCnH2n-;

Z represents an optionally substituted aryl or heteroaryl group;

R¹ represents hydrocarbon, a heterocyclic group, halogen, cyano, trifluoromethyl, nitro, -OR^a, -SR^a, -SOR^a, -S0₂R^a, -S0₂NR^aR^b, -NR^aR , -NR^aCOR^b, -NR^aC0₂R , -COR^a, -C0₂R^a, -CONR^aR^b or -CR^a=NOR^b; R^a and R^b independently represent hydrogen, hydrocarbon or a heterocyclic group; and n is zero, one, two or three.

In one embodiment the compounds are of formula LA:

(IA)

in which X¹, X², Z and R¹ are as defined above and Y represents a chemical bond, an oxygen atom, or an — NH- linkage.

The aryl or heteroaryl group Z in the compounds of formula I above may be unsubstituted, or substituted by one or more substituents.

Typically, the group Z will be unsubstituted, or substituted by one or two substituents. Z may be substituted by three substituents. Suitably, the group Z is unsubstituted or monosubstituted. Typical substituents on the group Z include halogen, cyano, nitro, Ci-β alkyl, hydroxy, Ci-β alkoxy, oxy, Cι-6 alkylsulphonyl, amino, aminocarbonyl, formyl, C2-6 alkoxycarbonyl and -CR^a=NOR^b, wherein R^a and R^b are as defined above.

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 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. quaternary ammonium salts.

The term "hydrocarbon" as used herein includes straight-chained, branched and cyclic groups containing up to 18 carbon atoms, suitably up to 15 carbon atoms, and conveniently up to 12 carbon atoms. Suitable hydrocarbon groups include Ci-β alkyl, C₂-β alkenyl, C₂-β alkynyl, C3-7 cycloalkyl, C3-7 cycloalkyl(Cι-6)alkyl, indanyl, aryl and aryl(Cι-6)alkyl.

The expression "a heterocyclic group" as used herein includes cyclic groups containing up to 18 carbon atoms and at least one heteroatom preferably selected from oxygen, nitrogen and sulphur. The heterocyclic group suitably contains up to 15 carbon atoms and conveniently up to 12 carbon atoms, and is preferably linked through carbon. Examples of suitable heterocyclic groups include C3-7 heterocycloalkyl, C3-7 heterocycloalkyl(Cι-6)alkyl, heteroaryl and heteroaryl(Cι-β)alkyl groups. Suitable alkyl groups include straight-chained and branched alkyl groups containing from 1 to 6 carbon atoms. Typical examples include methyl and ethyl groups, and straight-chained or branched propyl, butyl and pentyl groups. Particular alkyl groups are methyl, ethyl, 22-propyl, isopropyl, isobutyl, t.ar -butyl and 2,2-dimethylpropyl. Derived expressions such as "C₁-β alkoxy", "Cι-6 alkylamino" and "Cι-6 alkylsulphonyl" are to be construed accordingly.

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

Suitable alkynyl groups include straight-chained and branched alkynyl groups containing from 2 to 6 carbon atoms. Typical examples include ethynyl and propargyl groups.

Suitable cycloalkyl groups include groups containing from 3 to 7 carbon atoms. Particular cycloalkyl groups are cyclopropyl and cyclohexyl. Typical examples of C3-7 cycloalkyl(Cι-6)alkyl groups include cyclopropylmethyl, cyclohexylmethyl and cyclohexylethyl.

Particular indanyl groups include indan-1-yl and indan-2-yl. Particular aryl groups include phenyl and naphthyl, preferably phenyl.

Particular aryl(Cι-β) alkyl groups include benzyl, phenylethyl, phenylpropyl and naphthylmethyl.

Suitable heterocycloalkyl groups include azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl groups.

Suitable heteroaryl groups include pyridinyl, quinolinyl, isoquinolinyl, pyridazinyl, pyrimidinyl, pyrazinyl, furyl, benzofuryl, dibenzofuryl, thieny , benzthienyl, pyrrolyl, indolyl, pyrazolyl, indazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, benzimidazolyl, oxadiazolyl, thiadiazolyl, triazolyl and tetrazolyl groups.

The expression "heteroaryl(C-.-6)alkyl" as used herein includes furylmethyl, furylethyl, thienylmethyl, thiβnylethyl, oxazolylmethyl, oxazolylethyl, thiazolylmethyl, thiazolylethyl, imidazolylmethyl, imidazolylethyl, oxadiazolylmethyl, oxadiazolylethyl, thiadiazolylmethyl, thiadiazolylethyl, triazolylmethyl, triazolylethyl, tetrazolylmethyl, tetrazolylethyl, pyridinylmethyl, pyridinylethyl, pyrimidinylmethyl, pyrazinylmethyl, quinolinylmethyl and isoquinolinylmethyl.

The hydrocarbon and heterocyclic groups may in turn be optionally substituted by one or more groups selected from Ci-β alkyl, adamantyl, phenyl, halogen, Cι-6 haloalkyl, Ci-β aminoalkyl, trifluoromethyl, hydroxy, Cι-6 alkoxy, aryloxy, keto, C1-3 alkylenedioxy, nitro, cyano, carboxy, C2-6 alkoxycarbonyl, C2-6 alkoxycarbonyl(Cι-β) alkyl, C₂-β alkylcarbonyloxy, arylcarbonyloxy, aminocarbonyloxy, C₂-β alkylcarbonyl, arylcarbonyl, Cι-6 alkylthio, Ci-e alkylsulphinyl, Ci-β alkylsulphonyl, arylsulphonyl, -NR^VR^W, -N ^CO ^w, -NR^C0₂R^w, -NR^S0₂R^w, -CH₂NR^vS0₂R^w, -NHCONR^R^w, -CON ^vR^w -S0₂NR^vRw and -CH₂S0₂NR^vR^w, in which R^v and Rw independently represent hydrogen, C-.-6 alkyl, aryl or aryl(Cι-e)alkyl.

The term "halogen" as used herein includes fluorine, chlorine, bromine and iodine, especially fluoro or chloro.

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.

W may be phenyl. W may be meta linked phenyl. W may be pyridyl. In one embodiment W is meta linked pyridyl.

Suitable values for the X¹ substituent include hydrogen, fluoro, chloro, methyl, trifluoromethyl and methoxy; in particular hydrogen or fluoro; and especially fluoro.

Typical values of X¹ include fluoro, chloro, methyl, trifluoromethyl and methoxy, especially fluoro. X¹ may be hydrogen.

Typical values of X² include hydrogen and fluoro, especially hydrogen.

In a preferred embodiment, Y represents a chemical bond. In another embodiment, Y represents an oxygen atom. In a further embodiment, Y represents a -NH- linkage. In another preferred embodiment, Y represents an -OCH2- group. In another preferred embodiment Y represents -CH₂- or -CH₂CH₂-. Selected values for the substituent Z include phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, furyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrrolyl, pyrazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl and tetrazolyl, any of which groups may be optionally substituted by one or more substituents. In one favoured embodiment, Z represents an optionally substituted phenyl group, in particular monosubstituted or disubstituted phenyl. In another favoured embodiment, Z represents optionally substituted pyridinyl, especially unsubstituted, monosubstituted or disubstituted pyridin-2-yl, pyridin-3-yl or pyridin-4-yl. Z may be trisubstituted. Examples of suitable substituents on the group Z include fluoro, chloro, cyano, nitro, methyl, hydroxy, methoxy, oxy, methanesulphonyl, amino, aminocarbonyl, formyl, methoxycarbonyl and -CH=NOH.

Examples of particular substituents on the group Z include fluoro and cyano. In another favoured embodiment Z represents a triazole, such as

1,2,4-triazole or 1,2,3-triazole optionally substituted by one or two substituents. Monosubstitution by Ci-salkyl such as methyl is preferred.

Detailed values of Z include cyanophenyl, (cyano) (fluorophenyl, (chloro) (cyano)phenyl, nitrophenyl, methoxyphenyl, methanesulphonyl- phenyl, pyridinyl, fluoro-pyridinyl, difluoro-pyridinyl,

(amino) (chloro)pyridinyl, cyano-pyridinyl, mβthyl-pyridinyl, hydroxy- pyridinyl, methoxy-pyridinyl, oxy-pyridinyl, aminocarbonyl-pyridinyl- pyridazinyl, pyrimidinyl, pyrazinyl, cyano-thienyl, aminocarbonyl-thienyl, formyl-thienyl, methoxycarbonyl-thienyl, thienyl- CH=NOH, thiazolyl, isothiazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl and methyl-tetrazolyl. Specific values of Z include cyanophenyl, (cyano) (fluoro)phenyl, pyridinyl, difluoro-pyridinyl and cyano-pyridinyl. Other specific values include (methyl)-l,2,3-triazolyl and (methyl)- 1,2,4-triazolyl.

In one embodiment, Z represents (cyano) (fluorophenyl. Typically, R¹ represents hydrocarbon, a heterocyclic group, halogen, cyano, trifluoromethyl, -COR^a, -C0₂R^a or -CR^a=NOR^b.

Typical values of R^a include hydrogen and Ci-β alkyl. Suitably, R^a represents hydrogen or methyl.

Typical values of R^b include hydrogen, Ci-β alkyl, hydroxy(Cι-6)alkyl and di(Cι-6)alkylamino(Cι-6)alkyl. Suitably, R^b represents hydrogen, methyl, ethyl, hydroxyethyl or dimethylaminoethyl. Particular values of R^b include hydrogen, hydroxyethyl and dimethylaminoethyl, especially hydrogen or dimethylaminoethyl.

Suitable values of R¹ include Ci-β alkyl, halo(Cι-6)alkyl, dihalo(Cι-6)alkyl, hydroxy(C_.-6)alkyl, dihydroxy(Cι-β)alkyl,

Ci-e alkoxy(Cι-6)alkyl, di(Cι-6)alkoxy(Cι-6)alkyl, cyano(Cι-β) alkyl, C₂-β alkoxycarbonyl(Cι-6)alkyl, C3-7 cycloalkyl, heteroaryl, Ci-β alkyHieteroaryl, heteroaryl(Cι-6)alkyl, halogen, cyano, trifluoromethyl, formyl, C₂-β alkylcarbonyl, C₂-β alkoxycarbonyl and -CR^a=NOR^b, in which R^a and R^b are as defined above.

Representative values of R¹ include halo(Cι-β)alkyl, hydroxy(Cι-β)alkyl and trifluoromethyl.

Individual values of R¹ include methyl, fluoromethyl, difluoromethyl, hydroxymethyl, methoxymethyl, dimethoxymethyl, hydroxyethyl (especially 1 -hydroxyethyl), fluoroethyl (especially

1-fluoroethyl), difluoroethyl (especially 1,1-difluoroethyl), dimethoxyethyl (especially 1,1 -dimethoxyethyl), isopropyl, hydroxypropyl (especially 2-hydroxyprop-2-yl), dihydroxypropyl (especially l,2-dihydroxyprop-2-yl), fluoropropyl (especially 2-fluoroprop-2-yl), cyanopropyl (especially 2- cyanoprop-2-yl), methoxycarbonylpropyl (especially 2- methoxycarbonylprop-2-yl), fertrbutyl, hydroxybutyl (especially 1-hydroxy- 2-methylprop-2-yl), cyclopropyl, pyridinyl, furyl, thienyl, oxazolyl, methylthiazolyl, methyloxadiazolyl, imidazolylmethyl, triazolylmethyl, chloro, cyano, trifluoromethyl, formyl, acetyl, methoxycarbonyl and -CR²=NOR³, in which R² represents hydrogen or methyl, and R³ represents hydrogen, hydroxyethyl or dimethylaminoethyl.

In a favoured embodiment, R¹ represents 2-hydroxyprop-2-yl. In another embodiment, R¹ represents 2-fluoroprop-2-yl. In an additional embodiment, R¹ represents trifluoromethyl. In another embodiment R¹ is hydroxyethyl. Suitably, R² is hydrogen.

Suitably, R³ represents hydrogen or dimethylaminoethyl, especially hydrogen.

A particular sub-class of compounds according to the invention is represented by the compounds of formula HA, and pharmaceutically acceptable salts thereof

12 X

(UA)

wherein Z is as defined above;

X¹¹ represents hydrogen, fluoro, chloro, methyl, trifluoromethyl or methoxy;

X¹² represents hydrogen or fluoro;

R¹¹ represents Ci-β alkyl, halo(C₁-6)alkyl, dihalo(Ci-6)alkyl, hydroxy(Cι-6)alkyl, dihydroxy(Cι-β)alkyl, Ci-β alkoxy(Cι-₆) alkyl, di(Cι-β)alkoxy(Cι-6)alkyl, cyano(Cι-6)alkyl, C₂-β alkoxycarbonyl(Cι-6)alkyl, C3-7 cycloalkyl, heteroaryl, Ci-β alkyl-heteroaryl, heteroaryl(Cι-6)alkyl, halogen, cyano, trifluoromethyl, formyl, C2-6 alkylcarbonyl, C2-6 alkoxycarbonyl or -CR⁴=NOR⁵; R⁴ represents hydrogen or Ci-β alkyl; and

R⁵ represents hydrogen, Ci-β alkyl, hydroxy(Cι-6)alkyl or di(Cι-6)alkylamino(Cι-6) alkyl.

Suitable values of X¹¹ include hydrogen and fluoro, especially fluoro.

Typical values of X¹¹ include fluoro, chloro, methyl, trifluoromethyl and methoxy.

A particular value of X¹¹ is fluoro.

In a favoured embodiment, X¹² represents hydrogen. In another embodiment, X¹² represents fluoro.

Suitably, R⁴ represents hydrogen or methyl, especially hydrogen. Suitably, R⁵ represents hydrogen, methyl, ethyl, hydroxyethyl or dimethylaminoethyl. Particular values of R⁵ include hydrogen, hydroxyethyl and dimethylaminoethyl. Typically, R⁵ represents hydrogen or dimethylaminoethyl, especially hydrogen.

Where R¹¹ represents heteroaryl, this group is suitably pyridinyl, furyl, thienyl or oxazolyl.

Where R¹¹ represents Ci-e alkyl-heteroaryl, this group is suitably methylthiazolyl (e.g. 2-methylthiazol-5-yl) or methyloxadiazolyl (e.g. 3- methyl-[l,2,4]oxadiazol-5-yl).

Where R¹¹ represents hetβroaryl(Cι-6)alkyl, this group is suitably imidazolylmethyl or triazolylmethyl.

Representative values of R¹¹ include hydroxy(Cι-6) alkyl, fluoro(Cι-6)alkyl and trifluoromethyl.

Individual values of R¹¹ include methyl, fluoromethyl, difluoromethyl, hydroxymethyl, methoxymethyl, dimethoxymethyl, hydroxyethyl (especially 1-hydroxyethyl), fluoroethyl (especially

1-fluoroethyl), difluoroethyl (especially 1,1-difluoroethyl), dimethoxyethyl (especially 1,1-dimethoxyethyl), isopropyl, hydroxypropyl (especially 2-hydroxyprop-2-yl), dihydroxypropyl (especially l,2-dihydroxyprop-2-yl), fluoropropyl (especially 2-fluoroprop-2-yl), cyanopropyl (especially 2- cyanoprop-2-yl), methoxycarbonylpropyl (especially 2- methoxycarbonylprop-2-yl), tertrhxxtyl, hydroxybutyl (especially 1-hydroxy- 2-methylprop-2-yl), cyclopropyl, pyridinyl, furyl, thienyl, oxazolyl, methylthiazolyl, methyloxadiazolyl, imidazolylmethyl, triazolylmethyl, chloro, cyano, trifluoromethyl, formyl, acetyl, methoxycarbonyl and -CR²=NOR³, in which R² and R³ are as defined above.

In a favoured embodiment, R¹¹ represents 2-hydroxyprop-2-yl. In another embodiment, R¹¹ represents 2-fluoroprop-2-yl. In an additional embodiment, R¹¹ represents trifluoromethyl.

One representative subset of the compounds of formula IIA above is represented by the compounds of formula IIB, and pharmaceutically acceptable salts thereof

(IIB)

wherein X¹¹, X¹² and R¹¹ are as defined above; and R⁶ represents hydrogen or fluoro.

In one embodiment, R⁶ is hydrogen.

In another embodiment, R⁶ is fluoro, in which case the fluorine atom R⁶ is favourably attached to the phenyl ring at the 3-, 4- or 6-position (relative to the cyano group at position 2). Another representative subset of the compounds of formula IIA above is represented by the compounds of formula IIC, and pharmaceutically acceptable salts thereof

(IIC)

wherein X¹¹, X¹² and R¹¹ are as defined above; and

R⁷ represents hydrogen, fluoro, cyano or methyl. In one embodiment, R⁷ is hydrogen. In an additional embodiment, R⁷ is fluoro.

In another embodiment, R⁷ is cyano. In a further embodiment, R⁷ is methyl.

A further representative subset of the compounds of formula IIA above is represented by the compounds of formula IID, and pharmaceutically acceptable salts thereof

(IID)

wherein X¹¹, X¹², R⁷ and R¹¹ are as defined above; and R⁸ represents hydrogen or fluoro. Suitably, R⁸ represents hydrogen.

In another embodiment, R⁸ represents fluoro.

In any of the above formulae IIA-IID, the phenyl group bearing X¹¹ and X¹² may be replaced by a pyridyl group bearing X¹¹ and X¹².

Specific compounds within the scope of the present invention include^

2',4-difluoro-5'-[8-fluoro-7-(l-hydroxy-l-methylethyl)imidazo[l,2- pyrimidin-3-yl]biphenyl-2-carbonitrile;

2',6-difluoro-5'-[8-fluoro-7-(l-hydroxy-l-methylethyl)imidazo[l,2- c pyrimidin- 3 -yl] biphenyl- 2-carbonitrile; 2',3-difluoro-5'-[8-fluoro-7-(l-hydroxy-l-methylethyl)imidazo[l,2- c] pyrimidin- 3 -yl] biphenyl- 2-carbonitrile ; and pharmaceutically acceptable salts thereof.

Further specific compounds falling within the scope of the present invention include: 4-fluoro-2-{6-[8-fluoro-7-(l-hydroxy-l-methylethyl)imidazo[l,2-c]- pyrimidin-3-yl]pyridin-2-yl}benzonitrile;

4-fluoro-2-{3-fluoro-6-[8-fluoro-7-(l-hydroxy-l-methylethyl)imidazo[l,2- c]pyrimidin-3-yl]pyridin-2-yl}benzonitrile; 2-{3-[3-(3,5-difluoropyridin-2-yl)-4-fluorophenyl]-8-fluoroimidazo[l,2- c] pyrimidin- 7-yl}propan-2-ol;

2-{8-fluoro-3-[4-fluoro-3-(3-fluoropyridin-2-yl)phenyl]imidazo[l,2- c]pyrimidin-7-yl}propan-2-ol; 2',4,6-trifluoro-5'-[8-fluoro-7-(l-hydroxy-l-methylethyl)imidazo[l,2- c]pyrimidin-3-yl]-l,l'-biphenyl-2-carbonitrile;

2-{8-fluoro-3-[4-fluoro-3-(l-methyl-lH-[l,2,3]triazol-4-ylmethoxy)phenyl]- imidazo[l,2"c]pyrimidin-7-yl}propan-2-ol;

2-{8-fluoro-3-[4-fluoro-3-(3-methyl-3H-[l,2,3]triazol-4-ylmethoxy)phenyl]- imidazo[l,2-c]pyrimidin-7-yl}propan-2-ol;

2-{8-fluoro-3-[4-fluoro-3-(l-methyl-lH-[l,2,4]triazol-3-ylmethoxy)- phenyl]imidazo[l,2-c]pyrimidin-7-yl}propan-2-ol;

4,6,2'-trifluoro-3'-[8-fluoro-7-(l-hydroxy-l-methylethyl)imidazo[l,2- c]pyrimidin-3-yl]biphenyl-2-carbonitrile; 4,6-difluoro-3'-[8-fluoro-7-(l-hydroxy-l-methylethyl)imidazo[l,2- c] pyrimidin- 3 -yl] biphenyl- 2- carbonitrile;

6,2'-difluoro-3'-[8-fluoro-7-(l-hydroxy-l-methylethyl)imidazo[l,2- c]pyrimidin-3-yl]biphenyl-2-carbonitrile; and pharmaceutically acceptable salts thereof. Also provided by the present invention is a method for the treatment and/or prevention of anxiety which comprises administering to a patient in need of such treatment an effective amount of a compound of formula I as defined above or a pharmaceutically acceptable salt thereof. Further provided by the present invention is a method for the treatment and/or prevention of convulsions (e.g. in a patient suffering from epilepsy or a related disorder) which comprises administering to a patient in need of such treatment an effective amount of a compound of formula I as defined above or a pharmaceutically acceptable salt thereof.

The binding affinity (K_L) of the compounds according to the present invention for the α3 subunit of the human GABAA receptor is conveniently as measured in the assay described hereinbelow. The α3 subunit binding affinity (Ki) of the anxiolytic compounds of the invention is ideally 50 nM or less, preferably 10 nM or less, and more preferably 5 nM or less.

The anxiolytic compounds according to the present invention will ideally elicit at least a 40%, preferably at least a 50%, and more preferably at least a 60%, potentiation of the GABA EC20 response in stably transfected recombinant cell lines expressing the α3 subunit of the human GABAA receptor. Moreover, the compounds of the invention will ideally elicit at most a 30%, preferably at most a 20%, and more preferably at most a 10%, potentiation of the GABA EC20 response in stably transfected recombinant cell lines expressing the αl subunit of the human GABAA receptor.

The potentiation of the GABA EC₂o response in stably transfected cell lines expressing the α3 and αl subunits of the human GABAA receptor can conveniently be measured by procedures analogous to the protocol described in Wafford et al, Mol. Pharmacol, 1996, 50, 670-678. The procedure will suitably be carried out utilising cultures of stably transfected eukaryotic cells, typically of stably transfected mouse Ltk^" fibroblast cells.

The compounds according to the present invention may exhibit anxiolytic activity, as may be demonstrated by a positive response in the elevated plus maze and conditioned suppression of drinking tests (cf. Dawson et al., Psychopharmacology, 1995, 121, 109-117). Moreover, the compounds of the invention are likely to be substantially non-sedating, as may be confirmed by an appropriate result obtained from the response sensitivity (chain-pulling) test (cf. Bayley et al., J. Psychopharmacol., 1996, 10, 206-213).

The compounds according to the present invention may also exhibit anticonvulsant activity. This can be demonstrated by the ability to block pentylenetetrazole-induced seizures in rats and mice, following a protocol analogous to that described by Bristow et al. in J. Pharmacol. Exp. Ther., 1996, 279, 492-501. In another aspect, the present invention provides a method for the treatment and/or prevention of cognitive disorders, including dementing conditions such as Alzheimer's disease, which comprises administering to a patient in need of such treatment an effective amount of a compound of formula I as defined above or a pharmaceutically acceptable salt thereof. Cognition enhancement can be shown by testing the compounds in the Morris watermaze as reported by McNamara and Skelton, Psychobiology, 1993, 21, 101-108. Further details of relevant methodology are described in WO 96/25948. Cognitive disorders for which the compounds of the present invention may be of benefit include delirium, dementia, amnestic disorders, and cognition deficits, including age-related memory deficits, due to traumatic injury, stroke, Parkinson's disease and Down Syndrome. Any of these conditions may be attributable to substance abuse or withdrawal. Examples of dementia include dementia of the Alzheimer's type with early or late onset, and vascular dementia, any of which may be uncomplicated or accompanied by delirium, delusions or depressed mood; and dementia due to HIV disease, head trauma, Parkinson's disease or Creutzfeld- Jakob disease. 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 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 1 to 100 mg, for example 1, 2, 5, 10, 25, 50 or 100 mg, of the active ingredient. The tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials 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. The compounds in accordance with the present invention may be prepared by a process which comprises reacting a compound of formula III with a compound of formula IV:

(III) (IN)

wherein W, X¹, X², Y, Z and R¹ are as defined above, L¹ represents a suitable leaving group, and M¹ represents hydrogen, a boronic acid moiety -B(OH)₂ or a cyclic ester thereof formed with an organic diol, e.g. pinacol, 1,3-propanediol or neopentyl glycol, or M¹ represents -Sn(Alk)3 in which Alk represents a Ci-e alkyl group, typically irbutyl; in the presence of a transition metal catalyst.

The leaving group L¹ is typically a halogen atom, e.g. bromo or chloro.

The transition metal catalyst of use in the reaction between compounds III and IV is suitably tetrakis(triphenylphosphine)- palladium(θ), which may be present in the form of palladium (II) acetate and triphenylphosphine. The reaction is conveniently carried out at an elevated temperature in a solvent such as Λ -Vdimethylacetamide, 1,4- dioxane or tetrahydrofuran, advantageously in the presence of potassium phosphate, copperG) iodide, sodium carbonate or cesium carbonate. Alternatively, the transition metal catalyst employed may be dichloro[l,l'- bis(diphenyl-phosphino)ferrocene]palladium(II), in which case the reaction is conveniently effected at an elevated temperature in a solvent such as A -V-dimethylformamide, advantageously in the presence of potassium phosphate. In an alternative procedure, the compounds according to the present invention may be prepared by a process which comprises reacting a compound of formula V with a compound of formula VI:

(N)

(NI)

wherein W, X¹, X², Y, Z, R¹, L¹ and M¹ are as defined above? in the presence of a transition metal catalyst; under conditions analogous to those described above for the reaction between compounds III and IV. In another procedure, the compounds according to the present invention in which Y represents a chemical bond may be prepared by a process which comprises reacting a compound of formula VII with a compound of formula VIII:

(VII) (VIII)

wherein W, X¹, X², Z, R¹, L¹ and M¹ are as defined above; in the presence of a transition metal catalyst; under conditions analogous to those described above for the reaction between compounds III and IV.

In the compounds of formula VI and VII above, the leaving group L¹ is typically trifluoromethanesulfonyloxy (triflyloxy); or a halogen atom, e.g. bromo.

Alternatively, the compounds according to the present invention in which Y represents a chemical bond may be prepared by a process which comprises reacting a compound of formula IX with a compound of formula X:

(IX) (X)

wherein W, X¹, X², Z, R¹, L¹ and M¹ are as defined above; in the presence of a transition metal catalyst; under conditions analogous to those described above for the reaction between compounds III and IV.

In an additional procedure, the compounds according to the present invention in which Y represents an -OCJHb- group may be prepared by a process which comprises reacting a compound of formula XVIII with a compound of formula XI:

wherein W, X¹, X², R¹, Z and n are as defined above and L² is hydroxy or halogen such as chloro. When L² is hydroxy the reaction generally takes place in the presence of a catalyst such as triphenylphosphine and diethylazodicarboxylate generally in a solvent such as anhydrous tetrahydrofuran at about room temperature for several hours (Mitsunobu reaction). When L² is halogen the reaction can take place in a solvent such as DMF, in the presence of a base such as potassium carbonate, at about 50°C for several hours. In a further procedure, the compounds according to the present invention in which Y represents a -NH- linkage may be prepared by a process which comprises reacting a compound of formula X as defined above with a compound of formula XII:

(XII) wherein W, X¹, X² and R¹ are as defined above.

In relation to the reaction between compounds X and XII, the leaving group L¹ in the compounds of formula X may suitably represent fluoro.

The reaction between compounds X and XII is conveniently carried out by heating the reactants, typically at a temperature in the region of 120°C, in a solvent such as A^A^-dimethylformamide.

Where M¹ in the intermediates of formula IV and IX above represents a boronic acid moiety -B(OH)2 or a cyclic ester thereof formed with pinacol or neopentyl glycol, the relevant compound IV or IX may be prepared by reacting bis(pinacolato)diboron or bis(neopentyl glycolato)diborane respectively with a compound of formula VI or VII as defined above; in the presence of a transition metal catalyst. The transition metal catalyst of use in the reaction between bis(pinacolato)diboron or bis(neopentyl glycolato)diborane and compound VI or VII is suitably dichloro[l,l'-bis(diphenylphosphino)ferrocene]- palladiumdl). The reaction is conveniently carried out at an elevated temperature in a solvent such as 1,4-dioxane, optionally in admixture with dimethylsulf oxide, typically in the presence of 1, 1'- bis(diphenylphosphino)ferrocene and/or potassium acetate.

Where L¹ in the intermediates of formula VII above represents triflyloxy, the relevant compound VII may be prepared by reacting the appropriate compound of formula XI as defined above with triflic anhydride, typically in the presence of pyridine. Analogous conditions may be utilised for preparing a compound of formula VI wherein L¹ represents triflyloxy from the corresponding hydroxy precursor.

The intermediates of formula XI above may suitably be prepared from the appropriate benzyloxy- or methoxy-substituted precursor of formula XIII:

wherein W, X¹, X² and R¹ are as defined above and R²⁰ is methyl or benzyl; by treatment with boron tribromide, typically in chloroform or dichloromethane; or with hydrogen bromide, typically in acetic acid at reflux when R²⁰ is methyl; and by hydrogenation with hydrogen at about 45 psi on 10% palladium-carbon, for example in a Parr apparatus, for about 2 days when R²⁰ is benzyl.

The intermediates of formula XII and XIII above may be prepared by reacting a compound of formula III as defined above with the appropriate compound of formula XIV:

(XIV)

wherein W, X¹, X² and M¹ are as defined above, and Y¹ represents amino or methoxy; in the presence of a transition metal catalyst; under conditions analogous to those described above for the reaction between compounds III and IV. In particular, the transition metal catalyst of use in the reaction between compounds III and XIV is suitably tetrakis(triphenylphosphine)-palladium(θ), in which case the reaction is conveniently carried out at an elevated temperature in a solvent such as aqueous 1,2 -dimethoxy ethane, advantageously in the presence of sodium carbonate.

Where M¹ in the intermediates of formula V above represents -Sn(Alk)3 and Alk is as defined above, this compound may be prepared by reacting a compound of formula III as defined above with a reagent of formula (Alk)3Sn-Hal, in which Hal represents a halogen atom, typically chloro. The reaction is conveniently effected by treating compound III with isopropylmagnesium chloride, typically in a solvent such as tetrahydrofuran, with subsequent addition of the stannyl reagent (Alk)₃Sn-Hal.

Where L¹ in the intermediates of formula III above represents bromo, this compound may be prepared by bromination of the corresponding compound of formula XV:

(XV)

wherein R¹ is as defined above; typically by treatment with bromine in acetic acid and/or methanol, in the presence of sodium acetate and optionally also potassium bromide. In a yet further procedure, the compounds according to the present invention wherein R¹ represents an aryl or heteroaryl moiety may be prepared by a process which comprises reacting a compound of formula XVI with a compound of formula XVII:

(XVI) (XVII)

wherein W, X¹, X², Y, Z and M¹ are as defined above, R^la represents an aryl or heteroaryl moiety, and L² represents a suitable leaving group; in the presence of a transition metal catalyst.

The leaving group L² is typically a halogen atom, e.g. chloro.

The transition metal catalyst of use in the reaction between compounds XVI and XVII is suitably tetrakis(triphenylphosphine)- palladium(θ), in which case the reaction is conveniently effected at an elevated temperature in a solvent such as AζA-dimethylacetamide, typically in the presence of potassium phosphate or in the presence of hthium chloride and copperCD iodide. Alternatively, the transition metal catalyst may suitably be tris(dibenzylideneacetone)dipalladium(θ), in which case the reaction is conveniently effected at an elevated temperature in a solvent such as 1,4-dioxane, typically in the presence of tri- fer^butylphosphine and cesium carbonate.

Where L² in the compounds of formula XVII above represents a halogen atom, these compounds correspond to compounds of formula I as defined above wherein R¹ represents halogen, and they may therefore be prepared by any of the methods described above for the preparation of the compounds according to the invention.

The compounds according to the invention in which Y represents a chemical bond and Z represents pyrrol- 1-yl may be prepared by reacting a compound of formula XII as defined above with 2,5-dimethoxy- tetrahydrofuran. The reaction is conveniently accomplished at an elevated temperature in a solvent such as acetic acid.

Furthermore, the compounds according to the invention may be prepared by a process which comprises reacting a compound of formula VI as defined above with a compound of formula XV as defined above in the presence of a transition metal catalyst.

The transition metal catalyst of use in the reaction between compounds VI and XV is suitably tetrakis(triphenylphosphine)- palladium(θ), in which case the reaction is conveniently effected at an elevated temperature in a solvent such as 1,4-dioxane, typically in the presence of cesium carbonate.

Compounds of formulae IV and VI can be made by coupling together aryl or heteroaryl groups using the methods described for the reaction between compounds of formulae III and IV. Subsequent transformations can be used to incorporate the desired groups L¹ and M¹ as defined above by routine methods as illustrated in the Examples.

Where they are not commercially available, the starting materials of formula IV, VI, VIII, X, XIV, XV, XVI and XVTII may be prepared by methods analogous to those described in the accompanying Examples, or by standard methods well known from the art.

It wjll be understood that any compound of formula I initially obtained from any of the above processes may, where appropriate, subsequently be elaborated into a further compound of formula I by techniques known from the art. For example, a compound of formula I wherein R¹ represents -C(0-Alk¹)₂R^a initially obtained, wherein Alk¹ is Ci-e alkyl, typically methyl or ethyl, may be converted into the corresponding compound of formula I wherein R¹ represents -COR^a by hydrolysis with a mineral acid, typically aqueous hydrochloric acid. A compound wherein R¹ represents formyl may be reduced with sodium triacetoxyborohydride to the corresponding compound wherein R¹ represents hydroxymethyl. A compound of formula I wherein R¹ represents C2-6 alkoxycarbonyl may be reduced with lithium aluminium hydride to the corresponding compound of formula I wherein R¹ represents hydroxymethyl. A compound of formula I wherein R¹ represents hydroxymethyl may be oxidised to the corresponding compound of formula I wherein R¹ represents formyl by treatment with manganese dioxide. The formyl derivative thereby obtained may be condensed with a hydroxylamine derivative of formula H₂N-OR^b to provide a compound of formula I wherein R¹ represents -CH=NOR^b. Furthermore, a compound of formula I wherein R¹ represents -CH=NOH may be treated with triethylamine in the presence of l,l'-carbonyldiimidazole to afford a corresponding compound of formula I wherein R¹ represents cyano. Alternatively, the compound of formula I wherein R¹ represents formyl may be reacted with a Grignard reagent of formula R^aMgBr to afford a compound of formula I wherein R¹ represents -CH(OH)R^a, and this compound may in turn be oxidised using manganese dioxide to the corresponding compound of formula I wherein R¹ represents -COR^a. The latter compound may then be condensed with a hydroxylamine derivative of formula H₂N-OR^b to provide a compound of formula I wherein R¹ represents -CR^a=NOR^b. A compound of formula I wherein R¹ represents -CH(OH)R^a may be converted into the corresponding compound of formula I wherein R¹ represents -CHFR^a by treatment with (diethylamino) sulfur trifluoride (DAST). Similarly, a compound of formula I wherein R¹ represents -COR^a may be converted into the corresponding compound of formula I wherein R¹ represents -CF₂R^a by treatment with DAST. A compound of formula I wherein R¹ represents amino may be converted into the corresponding compound of formula I wherein R¹ represents chloro by diazotisation, using sodium nitrite, followed by treatment with copperCD chloride. A compound of formula I wherein R¹ represents -COCH3 may be treated with thioacetamide in the presence of pyridinium tribromide to furnish the corresponding compound of formula I wherein R¹ represents 2- methylthiazol-5-yl. Moreover, a compound of formula I wherein R¹ is for yl may be treated with (/rtolylsulfonyOmethyl isocyanide (TosMIC) in the presence of potassium carbonate to afford the corresponding compound of formula I wherein R¹ represents oxazol-5-yl. A compound of formula I wherein R¹ represents hydroxymethyl may be treated with carbon tetrabromide and triphenylphosphine to afford the corresponding compound of formula I wherein R¹ represents bromomethyl, which may then be reacted (typically in situ) with the sodium salt of imidazole or 1-H- [l,2,4]triazole to provide a compound of formula I wherein R¹ represents imidazoM-ylmethyl or [l,2,4]triazoM-ylmethyl respectively; or with the sodium salt of lH-[l,2,3]triazole to provide a mixture of compounds of formula I wherein R¹ represents [l,2,3]triazol-l-ylmethyl and [l,2,3]triazol-2-ylmethyl; or with morpholine to provide a compound of formula I wherein R¹ represents morpholin-4-ylmethyl. A compound of formula I wherein Z is substituted with methoxy may be converted to the corresponding compound wherein Z is substituted with hydroxy by treatment with boron tribromide.

A compound initially obtained wherein the moiety W is substituted by a halogen atom, e.g. bro o, may be converted into the corresponding compound wherein the moiety W is substituted by an aryl or heteroaryl group, e.g. 2-cyanophenyl, 2-cyano-6-fluorophenyl or pyridin-3-yl, by treatment with the requisite aryl or heteroaryl boronic acid or cyclic ester thereof formed with an organic diol, e.g. 2-cyanophenylboronic acid, 3- fluoro- 2 - (4, 4, 5, 5 -tetr amet yl- [1,3,2] dioxaborolan- 2 -yl)beιιzonitrile or pyridine-3-boronic acid-l,3-propanediol cyclic ester, in the presence of a transition metal catalyst such as tetrakis(triphenylphosphine)palladium(θ), in which case the reaction is conveniently effected at an elevated temperature in a solvent such as N,N^m dimethylacetamide, aqueous 1,2-dimethoxyethane, aqueous 1,4-dioxane or aqueous tetrahydrofuran, typically in the presence of potassium phosphate, sodium carbonate or cesium carbonate; or by treatment with the appropriate stannyl reagent, e.g. 2-tributylstannylbenzonitrile, in the presence of a transition metal catalyst such as dichloro[l,l'- bis(diphenylphosphino)ferrocene]palladium(II), in which case the reaction is conveniently effected at a elevated temperature in a solvent such as A N^'-dimethylacetamide, typically in the presence of Hthium chloride and copperCD chloride; or by treatment with the appropriate stannyl reagent in the presence of a transition metal catalyst such as tetrakis(triphenylphosphine)palladium(θ), in which case the reaction is conveniently accomplished at an elevated temperature in a solvent such as tetrahydrofuran or 1,4-dioxane, typically in the presence of eopperCO iodide; or, where the moiety W is substituted by imidazol-1-yl, simply by treatment with imidazole in the presence of a strong base such as lithium hexamethyldisilazide (LiHMDS). A compound wherein the moiety W is substituted by pyridinyl may be converted into the corresponding compound wherein W is substituted by -V-oxypyridinyl by treatment with .mefø-chloroperbenzoic acid. A compound wherein W is substituted by a halogen atom, e.g. iodo, may be converted, by treatment with isopropylmagnesium chloride, into a Grignard reagent which may be reacted with an aldehyde such as acetaldehyde to afford a secondary alcohol, e.g. the 1 -hydroxyethyl derivative; and this compound may in turn be treated with an oxidising agent, e.g. Dess-Martin periodinane, to afford the corresponding compound wherein W is substituted by acetyl. The resulting acetyl derivative may be converted, by treatment with methylmagnesium chloride, into the corresponding compound wherein W is substituted by 2-hydroxyprop-2-yl; and this compound may in turn be treated with (diethylamino)sulfur trifluoride (DAST) to afford the corresponding compound of formula I wherein W is substituted by 2- fluoroprop-2-yl.

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-jrtoluoyl-d-tartaric acid and/or (+)-di-jrtoluoyl-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 following Examples illustrate the preparation of compounds according to the invention.

The compounds in accordance with this invention potently inhibit the binding of [³H] -flumazenil to the benzodiazepine binding site of human GABAA receptors containing the α2 and/or α3 and or α5 subunit stably expressed in Ltk^' cells. Reagents

• Phosphate buffered saline (PBS).

• Assay buffer: 10 mM KH₂P0₄, 100 mM KC1, pH 7.4 at room temperature.

• [³H]-Flumazenil (18 nM for αlβ3γ2 cells; 18 nM for α2β3γ2 cells; 10 nM for α3β3γ2 cells; 10 nM for α5β3γ2 cells) in assay buffer.

• Flunitrazepam 100 μM in assay buffer.

• Cells resuspended in assay buffer (l tray to 10 ml).

Harvesting Cells Supernatant is removed from cells. PBS (approximately 20 ml) is added. The cells are scraped and placed in a 50 ml centrifuge tube. The procedure is repeated with a further 10 ml of PBS to ensure that most of the cells are removed. The cells are pelleted by centrifuging for 20 min at 3000 rpm in a benchtop centrifuge, and then frozen if desired. The pellets are resuspended in 10 ml of buffer per tray (25 cm x 25 cm) of cells.

Assay

Can be carried out in deep 96-well plates or in tubes. Each tube contains: • 300 μl of assay buffer.

• 50 μl of [³H]-flumazenil (final concentration for αlβ3γ2: 1.8 nM; for α2β3γ2: 1.8 nM; for α3β3γ2: 1.0 nM; for α5β3γ2: 1.0 nM). o 50 μl of buffer or solvent carrier (e.g. 10% DMSO) if compounds are dissolved in 10% DMSO (total); test compound or flunitrazepam (to determine non-specific binding), 10 μM final concentration. o 100 μl of cells.

Assays are incubated for 1 hour at 40° C, then filtered using either a Tomtec or Brandel cell harvester onto GF/B filters followed by 3 x 3 ml washes with ice cold assay buffer. Filters are dried and counted by liquid scintillation counting. Expected values for total binding are 3000-4000 dpm for total counts and less than 200 dpm for non-specific binding if using liquid scintillation counting, or 1500-2000 dpm for total counts and less than 200 dpm for non-specific binding if counting with meltilex solid scintillant. Binding parameters are determined by non-linear least squares regression analysis, from which the inhibition constant Ki can be calculated for each test compound.

The compounds of the accompanying Examples were tested in the above assay, and all were found to possess a Ki value for displacement of [³H]-flumazenil from the α2 and/or α3 and/or α5 subunit of the human GABAA receptor of 100 nM or less.

EXAMPLE 1 2' .4-Difluoro-5'- .8-fluoro-7-(l-hvdroχy- 1-methylethyl) imidazo[l,2-c]pyrimidin-3-yl]biphenyl-2-carbonitrile a) tert Butyl 2-chloro-5-fluoropyrimidin-4-ylcarbamate

To a stirred solution of 4-amino-2-chloro-5-fluoropyrimidine (4.22 g, 28.6 mmol) in anhydrous THF (60 ml) and anhydrous pyridine (8 ml) under nitrogen was added dropwise over 5 min a solution of di- -.ertrbutyl dicarbonate (15.60 g, 71.5 mmol) in THF (10 + 2 ml). The solution was stirred at room temperature under nitrogen for 22.25 h. More di- terfc utyl dicarbonate (3.12 g, 14.3 mmol) in THF (2 + 1 ml) was added and the solution was stirred for a further 3 days. The solvent was removed in vacuo and the residue was purified by flash chromatography, eluting with 15% EtOAc/isohexane, to leave 14.77 g of a 1:0.88 mixture of di-tør -butyl 2-chloro-5-fluoropyrimidin-4-yhmidodicarbonate and di-fer^-butyl dicarbonate as a white solid. This was dissolved in ethanol (400 ml) and 4N aqueous sodium hydroxide (21.5 ml, 86.0 mmol) was added. The mixture was stirred at room temperature for about 4 h, then left to stand overnight. The solvent was removed in vacuo and the residue was partitioned between water (100 ml) and dichloromethane (200 ml). The aqueous layer was extracted further with dichloromethane (9 x 200 ml). The pH of the aqueous layer was adjusted from >13 to 10 by adding 5N aqueous HC1 before extracting with more dichloromethane (3 x 200 ml). All organic extracts were combined, dried (Na₂S0 ) and evaporated in vacuo. The residue was purified by flash chromatography, eluting with 25% EtOAc/isohexane, to leave 5.63 g (79%) of the title compound as a white solid: δn (400 MHz, CDC1₃) 1.55 (9H, s), 7.15 (lH, br s), 8.30 (IH, d, J2.3 Hz). b) ter Butyl 2-chloro-5-fluoro-6-(l-hvdroxy- l-methylethyl)pyrimidin-4- ylcarbamate

To a stirred solution of 2,2,6,6-tetramethylpiperidine (11.5 ml, 68.2 mmol) in anhydrous THF (180 ml) at -74°C under nitrogen was added dropwise over 17 min butyllithium (1.6M solution in hexanes, 42.6 ml, 68.2 mmol), keeping the temperature below -70°C. The resulting yellow solution was stirred at <-70°C for 30 min, then a solution of the product of step a) (5.63 g, 22.7 mmol) in THF (60 + 5 ml) was added dropwise over 18 min, keeping the temperature below -70°C. The solution was stirred for a further 60 min, then acetone (6.7 ml, 91.2 mmol) was added dropwise over 15 min, keeping the temperature below -70°C. After stirring for 6 min, the cooling bath was removed and the mixture was allowed to warm to -10°C over 22 min then quenched with water (10 ml) and left to warm to room temperature. The mixture was then partitioned between ethyl acetate (300 ml) and water (300 ml). The aqueous layer was extracted further with ethyl acetate (2 x 300 ml). All organic extracts were combined, dried (Na₂S0₄) and evaporated in vacuo. The residue was purified by flash chromatography, eluting with 20-30% EtOAc/isohexane, to leave 6.19 g (89%) of the title compound as a white solid: δ_H (400 MHz, CDCI3) 1.55 (9H, s), 1.59 (6H, d, Jl.6 Hz), 4.36 (IH, s), 7.19 (IH, br s). c) 2-(6-Amino-2-chloro-5-fluoropyrimidin-4-yl)propan-2-ol

To a solution of the product of step b) (6.19 g, 20.2 mmol) in anhydrous dichloromethane (80 ml) under nitrogen was added trifluoroacetic acid (40.0 ml) and the solution was stirred at room temperature for 35 min. The mixture was quenched with methanol (40 ml) and the solvents were removed in vacuo. Methanol was added to the residue and this was removed in vacuo then left under high vacuum overnight to leave 4.26 g of the title compound as a white solid: δ_H (400 MHz, DMSO-cfe) 1.42 (6H, d, =71.2 Hz), 5.18 (lH, s), 7.64 (2H, s); m/z (ES⁺) 206/208 [M+Hh 188/190 [M H]⁺. d) 2-(5-Chloro-8-fluoroimidazo[l,2-c1pyrimidin-7-yl)propan-2-ol and 2-(5- bromo-8-fluoroimidazo[l,2-dpyrimidin-7-yl)propan-2-ol

A solution of bromoacetaldehyde diethyl acetal (6.00 ml, 39.9 mmol) in 48% hydrobromic acid (1.876 ml, 16.6 mmol) and water (1.876 ml) was stirred at 110°C for 30 min under nitrogen. This was allowed to cool for 5 min, then 2-propanol (8 ml) was added, followed by solid sodium hydrogen- carbonate (2.3693 g, 3.32 mmol) to bring the pH to 7. The mixture was then filtered into a flask containing the product of step c) (3.41 g, 16.6 mmol) in 2-propanol (41 ml), washing the solid with more 2-propanol (15 ml). This was then stirred at 80°C under nitrogen for 16 h. The solvent was evaporated in vacuo and the residue was dissolved in water (100 ml), brought to pH 7 by the addition of saturated aqueous sodium hydrogencarbonate (16 ml) and extracted with dichloromethane (5 x 100 ml). The combined organic extracts were dried (Na₂S0 ) and evaporated in vacuo. The residue was purified by flash chromatography, eluting with 70% EtOAc/isohexane, to leave 2.7155 g (67%) of a 2:1 mixture of the title compounds as a white solid: δ_H (400 MHz, CDCI3) 1.67-1.68 (6H, m), 3.90 and 3.94 (lH, two s), 7.73-7.76 (2H, m); mlz (ES⁺) 274/276 (52/53%), 254 (22%), 240 (19%), 230/232 (100/34%). e) 2-(8-Fluoroimidazo[l.2-g]pyrimidin-7-yl)propan-2-ol

The product of step d) (2.7077 g, 11.2 mmol), anhydrous sodium acetate (1.9348 g, 23.6 mmol) and 10% palladium on activated charcoal (281.1 mg) in ethanol (100 ml) was hydrogenated on the Parr apparatus at 50 psi for 1 h. The catalyst was removed by filtration through glass fibre paper, washing with ethanol, and the filtrate was evaporated in vacuo. The residue was partitioned between water (75 ml) and dichloromethane (100 ml) and the pH was adjusted to 7 with saturated aqueous NaHCOβ (~8 ml). The aqueous layer was separated and extracted further with dichloromethane (6 x 75 ml). All organic extracts were combined, dried (Na₂S0 ) and evaporated in vacuo. The residue was purified by flash chromatography, eluting with EtOAc, to leave 1.9172 g (88%) of the title compound as a white solid: δ_H (400 MHz, CDCI3) 1.67 (6H, d, «/1.8 Hz), 4.45 (IH, s), 7.72 (2H, m), 8.86 (lH, s); zπ ES⁺) 196 [M+H]⁺. f) 2-(3-Bromo-8-fluoroimidazo[l.2-clpyrimidin-7-yl)propan-2-ol

To a stirred solution of the product of step e) (0.1526 g, 0.784 mmol) and anhydrous sodium acetate (95.7 mg, 1.17 mmol) in glacial acetic acid (3.5 ml) was added dropwise over 4 min a solution of bromine (0.044 ml, 0.862 mmol) in glacial acetic acid (l + 0.5 ml). The solution was stirred at room temperature for 30 min. The solution was partitioned carefully between saturated aqueous sodium hydrogencarbonate (lOO ml) and ethyl acetate (80 ml). The aqueous layer (pH 8) was extracted further with ethyl acetate (80 ml). Both organic extracts were combined, dried (MgS0₄) and evaporated in vacuo. The residue was purified by flash chromatography, eluting with 70% EtOAc/isohexane, to leave 0.1933 g (90%) of the title compound as a white solid'- δπ (400 MHz, CDCI3) 1.67 (6H, d, J2.0 Hz), 4.39 (lH, s), 7.68 (lH, s), 8.84 (lH, d, Jl.2 Hz); mlz (ES⁺) 274/276 [M+H]⁺. g) 2^,,4-Difluoro-5^f-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)biphenyl-2- carbonitrile

A mixture of 5^,-bromo-2',4-difluorobiphenyl-2-carbonitrile (WO-A-0238568) (2.95 g, 10.0 mmol), dried potassium acetate (1.97 g, 20.1 mmol) and bis(pinacolato)diboron (2.93 g, 11.5 mmol) in 1,4-dioxane (24.5 ml) and dimethylsulfoxide (0.5 ml) was degassed by bubbling nitrogen through the mixture for 45 min. Dichloro[l,l'- bis(diphenylphosphino)ferrocene] -palladium(II) dichloromethane adduct (245.8 mg, 0.301 mmol) was added and the mixture was stirred at 85°C under nitrogen for 17 h. After allowing to cool, the mixture was filtered and the solid was washed with 1,4-dioxane. The combined filtrates were evaporated in vacuo and the residue was partitioned between water (50 ml) and diethyl ether (100 ml). The organic layer was washed with saturated aqueous NaCl (50 ml), filtered through glass fibre paper, dried (MgS0 ) and evaporated in vacuo to leave 4.24 g of the title compound as a dark brown solid. h) 2^,,4-Difluoro-5^,-[8-fluoro-7-(l-hvdroxy-l-methylethyl)imidazo[l.2- pyrimidin-3-yl]biphenyl-2-carbonitrile

A stirred mixture of the products of steps f) (0.0880 g, 0.321 mmol) and g) (0.2197 g, 0.644 mmol) and 2M aqueous sodium carbonate (0.642 ml, 1.28 mmol) in THF (5 ml) was degassed by bubbling nitrogen through for 20 min. Tetrakis(triphenylphosphine)palladium(θ) (0.0199 g, 0.0172 mmol) was then added and the mixture was degassed for a further 10 min before heating at 65° C for 18 h. The reaction mixture was partitioned between water (15 ml) and ethyl acetate (20 ml). The aqueous layer was extracted further with ethyl acetate (20 ml). Both organic extracts were combined, dried (Na₂S0 ) and evaporated in vacuo. The residue was purified by flash chromatography, eluting with 70% EtOAc/isohexane, to leave 0.1485 g of yellow oil. Recrystallisation from EtOAc-CH₂Cl₂- isohexane afforded 0.0973 g (74%) of the title compound as a white solid: mp 179-181°C; δ_H (400 MHz, CDC1₃) 1.68 (6H, d, 2.0 Hz), 4.47 (lH, s), 7.42-7.47 (2H, m), 7.55 (lH, dd, ^"7.8, 2.7 Hz), 7.60 (lH, ddd, 8.6, 5.5, 1.6 Hz), 7.64-7.68 (2H, m), 7.77 (lH, s), 9.12 (lH, d, Jl.2 Hz);

(E ⁺) 409 [M+H]⁺. Analysis Found: C, 64.67; H, 3.64; N, 13.56%. Required for C22H16F3N4O: C, 64.70; H, 3.70; N, 13.72%. EXAMPLE 2 2^,.6-Difluoro-5^,- 8-fluoro-7-(l-hvdroxyl-methylethyl) imidazo [ 1. - c] pyrimidin- 3 - yl] biphenyl- 2-carbonitrile a) 2^,,6-Difluoro-5'-(5.5-dimethyl-[l,3,2]dioxaborinan-2-yl)biphenyl-2- carbonitrile A mixture of 5'-bromo-2',6-difluorobiphenyl-2-carbonitrile

(WO-A-0238568) (12.81 g, 43.6 mmol), dried potassium acetate (8.55 g, 87.1 mmol) and bis(neopentyl glycolato)diboron (12.79 g, 56.6 mmol) in 1,4-dioxane (196 ml) and dimethylsulfoxide (4 ml) was degassed by bubbling nitrogen through the mixture for 40 min. Dichloro[l,l'- bis(diphenylphosphino)ferrocene]palladium(Il) dichloromethane adduct (1.07 g, 1.31 mmol) was added and the mixture was stirred at 85°C under nitrogen for 16 h. After allowing to cool, the mixture was diluted with diethyl ether (200 ml), filtered through glass fibre paper, and the solid was washed with a little more diethyl ether. The combined filtrates were evaporated in vacuo and the residue was dissolved in diethyl ether (450 ml) and extracted with 1M aqueous NaOH (2 x 200 ml). The combined aqueous extracts were acidified to pH 5 with concentrated hydrochloric acid, and the mixture was extracted with diethyl ether (2 x 400 ml). The combined organic extracts were washed with saturated aqueous NaCl (200 ml), dried (MgS0₄) and evaporated in vacuo to leave 16.26 g of the title compound as a brown solid. b) 2^f,6-Difluoro-5^f- [8-fluoro-7-(l -hydroxy l-methylethyl)imidazo[l, 2- c]pyrimidin-3-yl]biphenyl-2-carbonitrile

This was prepared in 94% yield using a similar method to that described in Example 1, step h, but using the product of step a) above: mp 212-214°C; δ_H (400 MHz, CBCI3) 1.69 (6H, d, J2.0 Hz), 4.48 (lH, s), 7.46 (IH, t, ^"8.6 Hz), 7.49 (lH, dt, 8.6, 1.2 Hz), 7.57 (lH, td, J8.6, 5.1 Hz), 7.64-7.68 (2H, m), 7.70 (lH, ddd, J8.6, 4.7, 2.3 Hz), 7.78 (lH, s), 9.12 (lH, d, Jl.2 Hz); m/z(ES⁺) 409 [M+H]⁺. Analysis Found: C, 64.82; H, 3.65; N, 13.46%. Required for C₂₂H₁₅F₃N4θ: C, 64.70; H, 3.70; N, 13.72%. EXAMPLE 3 2^,.3-Difluoro-5'-[8-fluoro-7-(l-hvdroχy-l-methylethyl) imidazo[l,2-c]pyrimidin-3-yl]biphenyl-2-carbonitrile This was prepared in 66% yield using a similar method to that described in Example 1, step h, but using 2',3-difluoro-5'-(5,5-dimethyl- [1,3,2] dioxaborinan-2-yl)biphenyl-2-carbonitrile (WO-A-02074773): mp 183-185°C; δ_H (400 MHz, CDC1₃) 1.68 (6H, d, J2.0 Hz), 4.46 (lH, s), 7.32 (IH, td, J8.6, 0.8 Hz), 7.39-7.48 (2H, m), 7.66-7.74 (3H, m), 7.77 (IH, s), 9.12 (IH, d, Jl.2 Hz); m/z(ES⁺) 409 [M+H]⁺. Analysis Found: C, 64.61; H, 3.68; N, 13.59%. Required for C₂₂Hι₅F₃N4θ: C, 64.70; H, 3.70; N, 13.72%.

EXAMPLE 4 4-Fluoro-2-{6-[8-fluoro-7-(l-hvdroχy-l-methylethyl) imidazo[l,2-c]-pyrimidin-3-yl]pyridin-2-yl}benzonitrile a) 4-Fluoro-2-(4.4.5,5-tetramethyl[l,3.2]dioxaborolan-2-yl)benzonitrile

A mixture of 4-fluoro-2-bromobenzonitrile (10.0 g, 50.0 mmol), potassium acetate (9.82 g, 100 mmoD, bis(pinacolato)diboron (14.0 g, 55.0 mmol) and dichloro[l, l'-bis(diphenylphosphino)ferrocene]palladium(II) CH₂C1₂ adduct (0.82 g, 1.0 mmol) in 1,4-dioxane (150 ml) and dimethylsulfoxide (3 ml) was degassed with nitrogen for 1 h then heated at 85°C for 20 h. The reaction was cooled to ambient temperature and then concentrated in vacuo. The residue was stirred with 2 N sodium hydroxide (250 ml) for 10 min then filtered. The filtrate was extracted with diethyl ether (300 ml) and the organics discarded. The aqueous component was cooled to 0°C then treated with 5 N hydrochloric acid, added dropwise over 15 min until the pH was 8. The aqueous phase was extracted with EtOAc (2 x 200 ml), the combined organics were dried over anhydrous sodium sulfate, filtered and evaporated to afford the title compound (10.9 g, 88%) as a pale brown solid: δ_H (360 MHz, CDCI3) 1.38 (12 H, s), 7.15-7.25 (l H, m), 7.53-7.60 (l H, m), 7.67-7.75 (l H, m). b) 2-(6-Bromopyridin-2-yl)-4-fluorobenzonitrile A stirred solution of 2,6-dibromopyridine (0.200g, 0.852 mmol) and the product of step a) (0.252 g, 1.02 mmol) in A -V-dimethylacetamide (4 ml) was degassed by bubbling nitrogen through for 15 min. Tetrakis(triphenylphosphine)palladium(θ) (0.049 g, 0.042 mmol) was added and the mixture was degassed for a further 5 min before heating at 65°C for 18 h. The reaction mixture was partitioned between water and EtOAc and the aqueous layer was extracted with EtOAc. Both organic extracts were combined, washed with brine, dried (MgSθ4) and evaporated in vacuo. The residue was purified by flash chromatography, eluting with 5% EtOAc/isohexane, to leave 0.104 g (44%) of the title compound as a white solid: δ_H (400 MHz, CDC1₃) 7.22 (l H, m), 7.59 (l H, dd, J7.8, 0.6 Hz), 7.65 (1 H, dd, 9.2, 2.6 Hz), 7.72 (l H, t, J7.8 Hz), 7.81 (l H, dd, J 8.6, 5.4 Hz), 7.85 (l H, dd, J7.8, 0.6 Hz). c) 4-Fluoro-2-{6-[8-fluoro-7-(l-hvdroxy-l-methylethyl)imidazo[l.2-c]- p yrimidin- 3 -yl] p yridiir 2 -yllbenzonitrile

A stirred mixture of the products of Example 1 step e) (0.0647 g, 0.331 mmol) and step b) above (0.101 g, 0.364 mmol), and potassium acetate (0.049 g, 0.497 mmol) in A -Vdimethylacetamide (1.5 ml) was degassed by bubbling nitrogen through for 15 min. Palladium acetate (0.0037g, 0.017 mmol) and triphenylphosphine (0.0043 g, 0.017 mmol) were added and the mixture degassed for a further 10 min before heating at 130°C for 5 h. The reaction mixture was partitioned between water (15 ml) and EtOAc (20 ml) and the aqueous layer was extracted further with EtOAc. Both organic extracts were combined, dried (MgS0₄) and evaporated in vacuo. The residue was purified by flash chromatography, eluting with 2% Me0H/CH₂Cl₂, to leave 0.102 g (79%) of the title compound as a white solid: mp 192-198°C (EtOAc/isohexane); δH (400

MHz, CDCI3) 1.70 (6 H, d, J1.7 Hz), 4.60 (l H, s), 7.31 (l H, m), 7.54 (1 H, dd, J9.0, 2.6 Hz), 7.67 (l H, dd, J7.7, 0.7 Hz), 7.91 (2 H, m), 7.99 (l H, t, J 7.9 Hz), 8.28 (1 H, s), 10.57 (l H, d, Jl.l Hz); m/z (ES⁺) 392 [M+H]⁺.

EXAMPLE S 4-Fluoro-2-{3-fluoro-6-[8-fluoro-7-(l-hvdroχy-l-methylethyl) imidazo [ 1.2-c] yrimidin- 3 - yl] pyridin- 2- yllbenzonitrile a) 4- Fluoro- 2 - (3 -fluorop yridin- 2 -yObenzonitrile

To a degassed solution of the product of Example 4, step a) (8.68 g, 35.1 mmol), 2-chloro-3-fluoropyridine (4.62 g, 35.1 mmol), potassium fluoride (6.74 g, 116 mmol) and έris(dibenzyhdeneacetone)dipa-ladium(θ) (1.28 g, 1.39 mmol) in THF (80 ml) and water (8 ml) was added tri-tertr butylphosphine (5.51 ml, 2.81 mmol) and the mixture heated at 70°C for 18 h. The reaction mixture was allowed to cool, then filtered and the filtrate diluted with EtOAc (400 ml) and washed with water (100 ml). The organic phase was separated, dried (MgS0₄) and evaporated in vacuo. The residue was purified by flash chromatography eluting with 10-30%

EtOAc/isohexane to leave 4.49 g (59%) of the title compound as pale yellow solid: δ_H (400 MHz, CDCls) 7.24-7.28 (l H, m), 7.45 (2 H, m), 7.61 (l H, t, J 9.1 Hz), 7.61 (1 H, dd, J8.6, 5.4 Hz), 8.61 (l H, d, -74.5 Hz). b) 4-Fluoro-2-(3-fluoro- l-Qxypyridin-2-yl)benzonitrile To a stirred solution of the product of step a) (4.49 g, 20.8 mmol) in

CH₂C1₂ (100 ml) was added 3-chloroperbenzoic acid (9.43 ml, 31.1 mmol) and the mixture was stirred at room temperature overnight. The mixture was cooled in an ice bath and quenched by the addition of saturated sodium sulfite solution (5 ml). The mixture was left stirring for 10 min and then washed with brine. The organic phase was dried (MgS0₄) and evaporated in vacuo. The residue was purified by flash chromatography eluting with 0-5% MeOH/CH2Cl2 to leave 3.35 g (70%) of the title compound as yellow crystals: δH (400 MHz, CDCI3) 7.22 (l H, m), 7.35 (3 H, m), 7.85 (1 H, dd, J8.7, 5.3 Hz), 8.26 (l H, dd, J1.8, 0.8 Hz). c) 2-(6-Chloro-3-fluoropyridin-2-yl)-4-fluorobenzonitrile

To a stirred slurry solution the product of step b) (3.35 g, 14.4 mmol) in chloroform (5 ml) was added phosphorous oxychloride (20 ml, 214 mmol) and the reaction was heated at 65°C for 3 h. The volatile materials were removed under vacuo and the residue treated with crushed ice (200 g) with external ice bath cooling. After stirring for 10 min the mixture was extracted with CH₂C1₂ (6 x 100 ml) and the organic phase was dried (MgS0₄) and evaporated. The residue was purified by flash chromatography eluting with 50-100% CH₂Cl₂/isohexane to leave 1.86 g (52%) of the title compound as a white solid: δ_H (400 MHz, CDC1₃) 7.25- 7.30 (1 H, m), 7.46 (2 H, m), 7.59 (l H, t, 8.6 Hz), 7.83 (l H, dd, J8.6, 5.3 Hz). d) 4-Fluoro-2-{3-fluoro-6-[8-fluoro-7-(l-hvdroxy-l-methylethyl)- imidazo [ 1.2-c] pyrimidin- 3 - yl] p yridin-2 -yllbenzonitrile

A stirred mixture of the products of Example 1 step e) (0.080 g, 0.410 mmol) and step c) above (0.113 g, 0.451 mmol), and potassium acetate (0.060 g, 0.615 mmol) in A A^-dimethylacetamide (2 ml) and water (0.060 ml) was degassed by bubbling nitrogen through for 15 min. Palladium acetate (0.0046 g, 0.020 mmol) and triphenylphosphine (0.0054 g, 0.020 mmol) were added and the mixture degassed for a further 10 min before heating at 130°C for 7 h. The reaction mixture was partitioned between water (20 ml) and EtOAc (40 ml) and extracted further with

EtOAc (3 x 40 ml). All organic extracts were combined, dried (MgS0₄) and evaporated in vacuo. The residue was purified by flash chromatography eluting with 50% isohexane/EtOAc to leave 0.079 g (49%) of the title compound as a white solid: H (400 MHz, CDCI3) 1.69 (6 H, d, Jl.7 Hz), 4.54 (1 H, s), 7.35 (l H, m), 7.50 (l H, m), 7.75 (l H, t, 8.9 Hz), 7.95 (2 H, m), 8.22 (1 H, s), 10.42 (l H, d, Jl.2 Hz); m/z (ES⁺) 410 [M+H] ⁺

EXAMPLE 8 2-{3-[3-(3,5-Difluoropyridin-2-yl)-4-fluorophenyl]-8- fluoroimidazo[l.2-c]pyrimidin-7-yllpropan-2-ol This was prepared in 68% yield using a similar method to that described in Example 5, step d, but using 2-(5-bromo-2-fluorophenyl)-3,5- difluoropyridine (WO-A- 02038568): δ_H (400 MHz, CDCI3) 1.69 (6 H, d. J 1.6 Hz), 4.43 (1 H, s), 7.39 (2 H, m), 7.65 (l H, m), 7.78 (l H, s), 7.81 (l H, dd, ^"6.5, 2.3 Hz), 8.50 (l H, d, ^"2.2 Hz), 9.00 (l H, s); m/z (E$⁺) 403 [M+H]⁺. EXAMPLE 7 2-{8-Fluoro-3-[4-fluoro-3-(3-fluoropyridin-2-yl)phenyl] imidazo l,2-c]pyrimidin-7-yl|propan-2-ol This was prepared in 64% yield using a similar method to that described in Example 5, step d, but using 2-(5-bromo-2-fluorophenyl)-3- fluoropyridine (WO-A-02038568): δ_H (400 MHz, CDC1₃) 1.69 (6 H, d , Jl.8 Hz), 4.45 (1 H, s), 7.41 (2 H, m), 7.58 (l H, m), 7.65 (l H, m), 7.78 (l H, s), 7.85 (1 H, dd, ,76.5, 2.4 Hz), 8.58 (l H, m), 9.01 (l H, d, =71.1 Hz); m/z (ES⁺) 385 [M+H]⁺.

EXAMPLE S 2'.4,6-Trifluoro-5'- [8-fluoro-7-(l-hvdroχy- 1-methylethyl) imida zo[l.2-c]pyrimidin-3-yl] -1, l'-biphenyl-2-carbonitrile a) 2-Bromo-3.5-difluorobenzonitrile

Dichloromethane (150 ml) was added to a slurry of 3,5- difluorobenzonitrile (10.0 g, 71.9 mmol) and l,3-dibromo-5,5- dimethylhydantoin (20.6 g, 71.9 mmol) in acetonitrile (11.8 g, 287 mmol). The mixture was cooled to 0°C then concentrated sulfuric acid (28.2 g, 287 mmol) was added dropwise to the solution over 30 min. On completion of the addition the mixture was allowed to warm to room temperature then heated at 50 °C for 4 h. 1 N Sodium sulfite solution (200 ml) and dichloromethane (300 ml) were added and the layers separated. The organic phase was washed with 1 N sodium sulfite solution (200 ml) and water (200 ml), dried over anhydrous sodium sulfate, filtered and evaporated to give 15.6 g (99%) of the title compound as an off white solid: δ_H (400 MHz, CDCI3) 7.22-7.14 (l H, m), 7.29 (l H, m). b) 2'.4,6-Trifluoro-l,l''biphenyl-2-carbonitrile

A suspension of the product of step a) (7.50 g, 34.4 mmol), 2- fluorophenylboronic acid (6.02 g, 43.0 mmol) and potassium phosphate (10.95 g, 51.6 mmol) were suspended in tetrahydrofuran (170 ml) and water (40 ml) and degassed with nitrogen for 30 min. Triεr (dibenzylidineacetone)dipalladium(O) (0.95 g, 1.0 mmol) and tri- te-rt butyl phosphine (10% w/w in hexane, 3.13 ml, 1.0 mmol) were added and the mixture was stirred at ambient temperature for 18 h. The mixture was diluted with diethyl ether (150 ml) and washed with 1 N sodium hydroxide solution (2 x 200 ml). The combined aqueous phase was extracted with diethyl ether (200 ml) and the organic layers were combined. The organic phase was washed with water (200 ml) and brine (100 ml) then evaporated. The oil was purified by flash column chromatography on silica eluting with 5% diethyl ether/isohexane to give 2.5 g (31%) of the title compound as a yellow oil which solidified on standing: δπ (400 MHz, CDC1₃) 7.17-7.42 (5H, m), 7.46-7.53 (l H, m). c) 5'-Bromo-2'.4,6-trifluoro-l.l'-biphenyl-2-carbonitrile

To a slurry of the product of step b) (2.50 g, 10.7 mmol) and 1,3- dibromo-5,5-dimethylhydantoin (3.07 g, 10.7 mmol) in acetonitrile (30 ml) was added concentrated sulfuric acid (0.93 ml, 16.1 mmol). The slurry was warmed to 50°C and the resulting solution stirred for 7 h then at ambient temperature for 18 h. Water (30 ml) was added dropwise to the solution over 15 min. The mixture was diluted with ethyl acetate (150 ml) and washed with 1 N sodium sulfite solution (2 x 100 ml), water (lOO ml) and brine (50 ml), dried over anhydrous sodium sulfate, filtered and evaporated onto silica. The compound was purified on the same, eluting with isohexane to give 1.44g (43%) of the title compound as a white solid: δ_H (360 MHz, CDCI3) 7.14 (l H, dd, J8.9, 8.9), 7.20-7.24 (lH, m), 7.33-7.37 (1 H, m), 7.51 (l H, dd, J6.2, 2.5), 7.58-7.63 (l H, m). d) 2',4 ,6'Trifluoro-5'- [8-fluoro-7-(l-hydroxy- l-methylethyl)imidazo[l,2- c] pyrimidin- 3 -yl] - 1. l'-biphenyl'2-carbonitrile The products of Example 1 step e) (0.20 g, 1.00 mmol), and step c) above (0.37 g, 1.20 mmol) and potassium acetate (0.16 g, 1.6 mmol) were dissolved in A -V-dimethylacetamide (4 ml) and degassed with nitrogen for 20 min. Palladium(Il) acetate (11.2 mg, 0.05 mmol) and triphenylphosphine (13.1 mg, 0.05 mmol) added and the mixture heated at 130°C for 2.5 h. The mixture was allowed to cool to ambient temperature, diluted with ethyl acetate (lOO ml) and washed with water (lOO ml) and brine (50 ml), dried over anhydrous sodium sulfate, filtered and evaporated to give yellow oil. The oil was purified on a silica cartridge eluting with 0-2 % MeOH/CH₂Cl2, then recrystallised from ethyl acetate/isohexane to give 172 mg (40%) of the title compound as a white solid: Mp 204-207°C; δ_H (500 MHz, CDCls) 1.68 (6 H, s), 4.46 (l H, s), 7.26 (1 H, m), 7.41 (1 H, d, ,77.3 Hz), 7.46 (l H, t, J8.8 Hz), 7.62 (l H, dd, J6Λ, 2.4 Hz), 7.70 (IH, ddd, 8.6, 4.8, 2.3 Hz), 7.78 (lH, s), 9.08 (l H, s); m/z (ES⁺) 427 [M+H]⁺. Analysis Found: C, 61.62; H, 3.40; N, 12.83%. Required for C₂2Hi4F₄N₄0: C, 61.97; H, 3.31. N, 13.14%.

EXAMPLE 9 2-{8-Fluoro-3-[4-fluoro-3-(l-methyl-lH-[l.2.3ltriazol-4- ylmethoxy)phenyl] -imidazo [ 1 , 2- c] pyrimidin- 7-yl|propan- 2 -ol a) 5-Bromo-2-fluorophenol

To a stirred solution of 4-bromo-l-fluoro-2-methoxybenzene (l.OO g, 4.88 mmol) in anhydrous CH₂C1₂ (20 ml) was added dropwise in an ice bath BBr3 (l M solution in CH₂C1₂, 9.75 ml, 9.75 mmol), and the mixture was stirred at room temperature overnight. The reaction was cooled in an ice bath and quenched by adding MeOH (1.0 ml) dropwise. The solvent was evaporated and the residue purified by flash chromatography eluting with isohexane/CH₂Cl₂/MeOH (70:20=10) to leave 0.802 g (86%) of the title compound: δ_H (400 MHz, CDCI3) 5.24 (l H, s), 6.96 (2 H, m), 7.16 (l H, dd, -77.7, 2.0 Hz). b) 2-Benzyloxy- l-bromo-4-fluorobenzene

To a solution of the product of step a) (0.802 g, 4.20 mmol) and benzyl bromide (0.755 ml, 6.30 mmol) in acetone (10 ml) was added potassium carbonate (1.16 g, 8.40 mmol) and the mixture was heated at reflux for 16 h at 60°C. The solid was filtered off washing with acetone and the filtrate evaporated. The residue was purified by flash chromatography eluting with 0-20% EtOAc/isohexane to leave 1.04 (88%) of the title compound as an oil that crystalhzed after cooling: δH (400 MHz, CDCI3) 5.08 (2 H, s), 6.98 (2 H, ), 7.13 (l H, dd, J7Λ, 2.2 Hz), 7.37 (5 H, m). c) 2-[3-(3-Benzyloxy-4-fluorophenyl)-8-fluoroimidazo[l.2-c]pyrimidin-7- yl]propan-2-ol

This was prepared in 72% yield using a similar method to that described in Example 5, step d, but using the product of step b) above: H (400 MHz, CDCls) 1.68 (l H, d, J1.8 Hz), 4.48 (l H, d, 5.4 Hz), 5.23 (2 H, s), 7.11 (2 H, m), 7.25-7.30 (l H, m), 7.41 (5 H, m), 7.66 (l H, s), 8.65 (l H, d, Jl.2 Hz). d) 2-Fluoro-5-[8-fluoro-7-(l-hydroxy-l-methylethyl)imidazo[l,2- cl yrimidin- 3 - yl] phenol To a solution of the product of step c) (0.626 g, 1.58 mmol) in

EtOAc (80 ml) was added 10% Pd-C (0.060 g) and the mixture hydrogenated on the Parr apparatus at 45 psi for 2 days. The catalyst was removed by filtration and the filtrate evaporated in vacuo. The residue was purified by flash chromatography eluting with 2-10% MeOH/CH2Cl₂ to leave 0.412 g (85%) of the title compound: δ_H (400 MHz, CDCI3) 1.68 (6 H, d, .71.80 Hz), 4.49 (l H, s), 6.42 (l H, br s), 7.04 (l H, m), 7.22-7.30 (2 H, m), 7.71 (1 H, s), 8.98 (l H, d, =71.2 Hz). e) 2-{8-Fluoro-3-[4-fluoro-3-(l-methyl-lH-[l.2.3ltriazol-4-ylmethoxy)- phenyl]imidazo[l,2-c]pyrimidin-7-yl|propan'2-ol To a solution of the product of step d) (0.080 g, 0.262 mmol), (l- methyl-li -[l,2,3]triazol-4-yl)methanol (prepared as described in Khim. Geterotsikl. Soedin. 1980, 12, 1688-9) (0.059 g, 0.521 mmol) and triphenylphosphine (0.137 g, 0.524 mmol) in anhydrous TΗF (2 ml), diethyl azodicarboxylate (0.091 ml, 0.577 mmol) was added dropwise over 5 min and the mixture was stirred overnight at room temperature. The solvent was evaporated in vacuo and the residue purified by flash chromatography eluting with 2% MeOΗ/CΗ₂Cl₂ to leave 0.110 g of the title compound: _mp 165°C (EtOAc/isohexane); δH (400 MHz, CDCI3) 1.69 (6 H, d, J1.7 Hz), 4.13 (3 H, s), 5.36 (2 H, s), 7.12 (l H, m), 7.23-7.27 (l H, m), 7.46 (1 H, dd, J7.8, 2.1 Hz), 7.69 (l H, s), 7.72 (l H, s), 9.07 (l H, d, ,71.2 Hz);

EXAMPLE 10 2-{8-Fluoro-3-[4-fluoro-3-(3-methyl-3H-[l,2.3]triazol-4-yl methoxy)phenyl1-imidazo[l,2-c]pyrimidin-7-yllpropan-2-ol This was prepared in 67% yield using a similar method to that described in Example, 9 step e, but using (3-methyl-3H-[l,2,3]triazol-4-yl)- methanol (WO-A-9804559): δ_H (400 MHz, CDC1₃) 1.69 (6 H, d, J1.7 Hz), 4.19 (3 H, s), 5.28 (2 H, s), 7.22 (2 H, m), 7.32 (l H, dd, Jll.O, 9.0 Hz), 7.72 (2 H, d, -74.8 Hz), 8.90 (l H, s); m/z(E$⁺) 401 [M+H]⁺.

EXAMPLE 11 2-{8-Fluoro-3-[4-fluoro-3-(l-methyl-lH-[l.2.4ltriazol-3-yl methoxy)-phenyl]imidazo[l,2-c]pyrimidin-7-yllpropan-2-ol To a solution of the product of Example 9 step d) (0.054 g, 0.177 mmol) and 3-chloromethyl-l-methyl-lH-[l,2,4]triazole hydrochloride (US-A-5985874) (0.033 g, 0.196 mmol) in DMF (2 ml) was added K₂C0₃ (0.146 g, 1.06 mmol) and the mixture stirred at 50°C overnight. The reaction mixture was allowed to cool and then azeotroped with xylene and evaporated in vacuo. The residue was partitioned between water and CΗ₂C1₂ and extracted further with CH₂C1₂ (2 x 20 ml). The organic extracts were combined, dried (MgS0 ) and evaporated in vacuo. The yellow residue was purified by flash chromatography eluting with isohexane/EtOAc/MeOH (60:30: 10) to leave 0.040 g (56%) of the title compound as a white solid: mp 178-180°C; δH (400 MHz, CDCI3) 1.69 (6 H, d, J1.7 Hz), 3.98 (3 H, s), 4.48 (l H, s), 5.30 (2 H, s), 7.12 (l H, m), 7.23- 7.27 (1 H, m), 7.51 (l H, dd, ,77.8, 2.1 Hz), 7.72 (l H, s), 8.07 (l H, s), 9.09 (1 H, d, Jl.2 Hz); m/ (ES⁺) 401 [M+H]⁺.

EXAMPLE 12 4,6.2'-Trifluoro-3'-[8-fluoro-7-(l-hvdroxy-l-methylethyl) imidazo[l,2-c]pyrimidin-3-yl]biphenyl-2-carbonitrile a) 2-Bromo-3-fluorobenzeneboronic acid zz-Butyl lithium (2.5 M, 36 ml) was added dropwise over 20 min to a cooled (-20°C) solution of 2,2,6,6-tetramethylpiperidine (31.3 g, 94.3 mmol) in tetrahydrofuran (225 ml). On complete addition the mixture was stirred for 10 min then cooled to -78°C. l-Bromo-2-fluorobenzene (15.0 g, 85.7 mmol) was added dropwise to the cooled solution over 20 min and stirring was continued for 3 h. Triisopropyl borate (18.5 g, 98.6 mmol) was added, the mixture stirred at -78°C for 30 min then allowed to warm to -40°C. 5 N Hydrochloric acid (150 ml) was added and the mixture allowed to warm to ambient temperature. A majority of the solvent was removed and the residue was partitioned between diethyl ether (200 ml) and 1 N hydrochloric acid (200 ml). The organic layer was washed with 2 N sodium hydroxide (200 ml) and the organics discarded. The aqueous phase was cooled in an ice bath and the pH adjusted to 4 by the addition of 5 N hydrochloric acid. The white solid was filtered, washed with water (30 ml) and dried under vacuum over phosphorus pentoxide to give the title compound as a white solid. b) 3'-Bromo-4.6,2'-trifluorobiphenyl-2-carbonitrile

The products of step a) (1.00 g, 4.57 mmol) and Example 8 step a) (1.00 g, 4.57 mmol) were suspended in 1,2 -dimethoxy ethane (20 ml) and 2 N sodium carbonate (10 ml) and the mixture degassed with nitrogen for 30 min. Tfeføa&iVtriphenylphosphine palladium(θ) (264 mg, 0.23 mmol) was added and the mixture was heated at 80°C for 18 h. The mixture was allowed to cool to ambient temperature, diluted with ethyl acetate (100 ml) and washed with 2 N sodium hydroxide solution (75 ml), water (50 ml) and brine (50 ml), dried over anhydrous sodium sulfate, filtered and evaporated to give a pale yellow oil. The oil was purified by flash column chromatography on silica eluting with 0—20 % EtOAc/isohexane to give

0.45 g (32%) of the title compound as a colourless oil: a (400 MHz, CDCI3) 7.14-7.29 (2 H, m), 7.32-7.37 (2 H, m), 7.69-7.73 (l H, m). c) 4.6.2'-Trifluoro-3'-[8-fluoro-7-(l-hvdroxy-l-methylethyl)imidazo[l.2- cl pyrimidin- 3 -yl] biphenyl- 2- carbonitrile This was prepared in 16% yield using a similar method to that described in Example 8, step d, but using the product of step b) above: δ_H (360 MHz, CDCls) 1.68 (6 H, d, -72.0 Hz), 4.50 (l H, s), 7.21-7.28 (l H, m), 7.38-7.42 (1 H, m), 7.47-7.61 (2 H, m), 7.67-7.72 (l H, m), 7.85 (l H, s), 8.82 (1 H, d, 1.3 Hz); m/z (ES⁺) 427 [M+H]⁺.

EXAMPLE 13 4.6-Difluoro-3'- [8-fluoro-7-(l-hvdroχy- 1-methylethyl) imidazo[l.2-c]pyrimidin-3-yl]biphenyl-2-carbonitrile a) 4.6-Difluoro-3'-nitrobiphenyl-2-carbonitrile

A suspension of the product of Example 8 step a) (4.36 g, 20.0 mmol), 3-nitrophenylboronic acid (4.17 g, 25.0 mmol) and potassium phosphate (6.37 g, 30.0 mmol) were suspended in tetrahydrofuran (100 ml) and water (25 ml) and degassed with nitrogen for 30 min. Tris- dibenzylidineacetone dipalladium(θ) (549 mg, 0.6 mmol) and tri- fe-rtr butyl phosphine (10% w/w in hexane, 1.82 ml, 0.6 mmol) was added and the mixture stirred at 50°C for 4 h. The mixture was allowed to cool to ambient temperature, diluted with diethyl ether (150 ml) and washed with 1 N sodium hydroxide solution (2 x 200 ml). The combined aqueous phase was extracted with diethyl ether (200 ml) and the organic layers combined. The organic phase was washed with water (200 ml) and brine (lOO ml) then evaporated. The oil was purified by flash column chromatography on silica eluting with 5% diethyl ether/isohexane to afford 5.2 g (99%) of the title compound as a yellow oil which solidified on standing: δπ (360 MHz, CDCI3) 7.26 (1 H, td, 8.2, 2.5 Hz), 7.37-7.43 (l H, m), 7.70-7.82 (2 H, m), 8.35-8.42 (2H, m).

b) 3'-Amino-4,6-difluorobiphenyl-2-carbonitrile

The product of step a) (5.20 g, 20.0 mmol) was suspended in ethyl acetate (30 ml) and ethanol (30 ml), platinum(IV) oxide (0.23 g, 1.0 mmol) added and the mixture was hydrogenated on a Parr apparatus at 40 psi for 45 min. The catalyst was filtered off through a glass fibre filter paper and the solvent was evaporated to give 4.6 g (99%) of the title compound as a brown oil: δ_H (360 MHz, CDC1₃) 3.80 (2 H, s), 6.71-6.82 (3 H, m), 7.12-7.17 (1 H, m), 7.19-7.30 (2 H, m). c) 3'-Bromo-4,6-difluorobiphenyl-2-carbonitrile A solution of the product of step b) (4.60 g, 21.7 mmol) in 1,4- dioxane (5 ml) was treated with 48% hydrobromic acid (50 ml). The mixture was then cooled to 0°C and a solution of sodium nitrite (1.50 g, 21.7 mmol) in water (3 ml) was added dropwise over 1 h maintaining the internal temperature below 3°C. The mixture was allowed to stir at 0°C for 2h then poured onto a 0°C solution of copper(ll) bromide (4.66 g, 32.5 mmol) in 48% hydrobromic acid (50 ml). The solution was stirred at 0°C for 10 min then warmed to 40°C for 1 h. The solution was allowed to cool to ambient temperature, diluted with water (200 ml) and extracted into ethyl acetate (2 x 150 ml). The combined organics were washed with 10% (v/v) 0.880 ammonia in water (2 x 75 ml), water (75 ml) and brine (50 ml), dried over anhydrous sodium sulfate, filtered and evaporated to give a brown oil. The oil was purified by flash chromatography on silica eluting with 5—20 % EtOAc/isohexane to give 3.8 g (60%) of the title compound as a pale yellow solid: δ_H (360 MHz, CDCI3) 7.16-7.22 (l H, ), 7.31-7.35 (l H, m), 7.38-7.40 (2 H, m), 7.59-7.65 (2 H, m). d) 4.6-Difluoro-3'-[8-fluoro-7-(l-hydroxy-l-methylethyl)imidazo[l.2- cl pyrimidin- 3 -yl] biphenyl- 2 - carbonitrile

This was prepared in 27% yield using a similar method to that described in Example 8, step d, but using the product of step c) above: δ_H (400 MHz, CDCI3) 1.68 (6 H, d, 2.0 Hz), 4.49 (1 H, s), 7.21-7.26 (l H, m), 7.36-7.40 (1 H, m), 7.57-7.61 (l H, m), 7.67-7.72 (3 H, m), 7.81 (l H, s), 9.15 (1 H, d, 1.3 Hz); m/z (ES⁺) 409 [M+H]⁺.

EXAMPLE 14 6.2'-Difluoro-3'-[8-fluoro-7-(l-hvdroχy-l-methylethyl) imidazo [ 1 , 2 -c] pyrimidin- 3 - yl] biphenyl- 2-carbonitrile a) 3'-Bromo-6.2'-difluorobiphenyl-2-carbonitrile

The product of Example 12 step a) (1.00 g, 4.57 mmol) and 2-bromo- 3-fluorobenzonitrile (0.91 g, 4.57 mmol) were suspended in 1,2- dimethoxyethane (20 ml) and 2 N sodium carbonate (10 ml) and the mixture degassed with nitrogen for 30 min. Tefraij-s-triphenylphosphine palladium (0) (211 mg, 0.18 mmol) was added and the mixture was heated at 80°C for 18 h. The mixture was allowed to cool to ambient temperature, diluted with ethyl acetate (100 ml) and washed with 2 N sodium hydroxide solution (75 ml), water (50 ml) and brine (50 ml), dried over anhydrous sodium sulfate, filtered and evaporated to give a pale yellow oil. The oil was purified by flash column chromatography on silica eluting with 0—15% EtOAc/isohexane to give 0.39 g (29%) of the title compound as a colourless oil which solidified on standing: δ_H (400 MHz, CDC1₃) 7.19 (l H, ddd, J 8.0, 8.0, 1.0), 7.34-7.38 (l H, m), 7.44 (l H, td, 9.0, 1.4), 7.50-7.56 (l H, m), 7.61 (1 H, ddd, J7.8, 1.0, 0.6), 7.68-7.72 (l H, m). b) 6,2'-Difluoro-3'-[8-fluoro-7-(l-hydroxy-l-methylethyl)imidazo[l,2- c]pyrimidin-3-yl]biphenyl-2-carbonitrile

This was prepared in 71% yield using a similar method to that described in Example 8, step d, but using the product of step a) above: δ_H (400 MHz, CDCI3) 1.68 (6 H, dd, -72.0, 2.0 Hz), 4.53 (l H, s), 7.49-7.72 (6 H, m), 7.85 (1 H, s), 8.85 (l H, d, 1.3 Hz); m/z (ES⁺) 409 [M+H]⁺.

Claims

1. A compound of formula I, or a pharmaceutically acceptable salt thereof-

(I)

wherein

W is phenyl or pyridyl; X¹ represents hydrogen, halogen, Ci-β alkyl, trifluoromethyl or Ci-β alkoxy;

X² represents hydrogen or halogen;

Y represents a chemical bond, an -NH- linkage or a group -OC_nH -; Z represents an optionally substituted aryl or heteroaryl group; R¹ represents hydrocarbon, a heterocyclic group, halogen, cyano, trifluoromethyl, nitro, -OR^a, -SR^a, -SOR^a, -S0₂R^a, -S0₂NR^aR^b, -NR^aR^b, -NR^aCOR^b, -NR^aC0₂R^b, -COR^a, -C0₂R^a, -CONR^aR^b or -CR^a=NOR^b;

R^a and R^b independently represent hydrogen, hydrocarbon or a heterocyclic group; and n is zero, one, two or three.

2. A compound according to claim 1 in which:

X¹ is hydrogen, fluoro, chloro, methyl, trifluoromethyl or methoxy; and X² is hydrogen or fluoro.

3. A compound according to claim 1 or 2 in which Z represents an optionally substituted triazolyl, phenyl or pyridinyl group wherein the optional substituents are chosen from fluoro, chloro, cyano, nitro, methyl, hydroxy, methoxy, oxy, methanesulphonyl, amino, aminocarbonyl, formyl, methoxycarbonyl and -CH=NOH.

4. A compound according to claim 1, 2 or 3 in which R¹ is halo(Cι-β) alkyl, hydroxy(Cι-6)alkyl or trifluoromethyl.

5. A compound according to claim 4 in which R¹ is 2-hydroxyprop-2-yl.

6. A compound according to any preceding claim in which W is nieta- linked to Z and the rest of the molecule.

7. A pharmaceutical composition comprising a compound of any preceding claim or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

8. A compound of any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof for use in a method of treatment of the human or animal body.

9. Use of a compound of any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating anxiety and or depression.

10. A method of treatment of a subject suffering from anxiety or depression which comprises administering to that subject a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.