ZA200307023B

ZA200307023B - Imidazo-pyrimidine derivatives as ligands for gaba receptors.

Info

Publication number: ZA200307023B
Application number: ZA200307023A
Authority: ZA
Inventors: Chambers Mark Stuart; Goodacre Simon Charles; Hallett David James; Andrew Jennings; Philip Jones; Lewis Richard Thomas; Moore Kevin William; Russell Michael Geoffrey Neil; Street Leslie Joseph; Szekeres Helen Jane
Original assignee: Merck Sharp & Dohme
Priority date: 2001-03-21
Filing date: 2003-09-09
Publication date: 2004-06-28
Also published as: GB0107134D0; JO2312B1

Description

IMIDAZO-PYRIMIDINE DERIVATIVES AS LIGANDS FOR GABA

RECEPTORS

‘ The present invention relates to a class of substituted imidazo- 3 pyrimidine derivatives and to their use in therapy. More particularly, this invention is concerned with imidazo[1,2-a]pyrimidine analogues which are substituted in the 3-position by a substituted phenyl ring. These compounds are ligands for GARA, 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: (1) GABAa receptors, which are members of the ligand-gated ion channel superfamily; and (2) GABAg 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 a subunits, four 8 subunits, three y subunits, one § subunit, one € 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 « subunit, a f subunit and ay subunit constitute the minimum requirement for forming a fully functional GABAA4 receptor expressed by transiently transfecting cDNAs into cells. As indicated above, 8, € 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 GABAAa receptor exists in pentameric form. The selection of at least one a, one B and one y subunit from a repertoire of seventeen allows for the possible existence of more than 10,000 pentameric subunit combinations. Moreover, this calculation overlooks the additional . permutations that would be possible if the arrangement of subunits around the ion channel had no constraints (i.e. there could be 120 possible : variants for a receptor composed of five different subunits).

Receptor subtype assemblies which do exist include, amongst many others, 01f2y2, a2Byl, a2p2/3y2, a:3py2/3, adps, 0abB3y2/3, abBy2 and a6Pd.

Subtype assemblies containing an ol subunit are present in most areas of the brain and are thought to account for vver 40% of GABAA receplors in the rat. Subtype assemblies containing 02 and a3 subunits respectively are thought to account for about 25% and 17% of GABAA receptors in the rat. Subtype assemblies containing an ob 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 GABAA4 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 GABA4 receptor comprising the a1 subunit in combination with a B subunit and y2. This is the most abundant GABAA receptor subtype, and is believed to represent almost half of all GABAA receptors in the brain. ) | Two other major populations are the 028vy2 and a3By2/3 subtypes.

Together these constitute approximately a further 35% of the total GABAA . receptor repertoire. Pharmacologically this combination appears to be equivalent to the BZ2 subtype as defined previously by radioligand binding, although the BZ2 subtype may also include certain o5-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 o18y2, 02py2 : or a3By2 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 al-selective GABAA receptor agonists alpidem and zolpidem are clinically prescribed as hypnotic agents, suggesting that at least some of the sedation associated with known anxiolytic drugs which act at the BZ1 binding site is mediated through GABAAa receptors containing the al subunit. Accordingly, it is considered that GABAA receptor agonists which interact more favourably with the a2 and/or a3 subunit than with ol will be effective in the treatment of anxiety with a reduced propensity to cause sedation. Moreover, agents which are inverse agonists of the ab subunit are likely to be beneficial in enhancing cognition, for example in subjects suffering from dementing conditions such as Alzheimer’s disease. Also, agents which are antagonists or inverse agonists at al might be employed to reverse sedation or hypnosis caused by al agonists.

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; 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 GABAA4 receptor.

The present invention provides a class of imidazo-pyrimidine derivatives which possess desirable binding properties at various GABA, receptor subtypes. The compounds in accordance with the present invention have good affinity as ligands for the a2 and/or a3 and/or ob subunit of the human GABA receptor. The compounds of this invention i may interact more favourably with the a2 and/or a3 subunit than with the : ol subunit; and/or may interact more favourably with the o5 subunit than . with the al subunit.

The compounds of the present invention are GABA4 receptor subtype ligands having a binding affinity (K;) for the «2 and/or a3 and/or ob 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 02 and/or a3 and/or 05 subunit relative to the al subunit.

However, compounds which are not selective in terms of their binding affinity for the 02 and/or a3 and/or 05 subunit relative to the al 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 al subunit and (i) a full or partial agonist profile at the a2 and/or a3 subunit, and/or (ii) an inverse agonist profile at the a5 subunit.

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

R' Ae N

Be J x . Y—Z ey wherein

X1 represents halogen, C16 alkyl, trifluoromethyl or Ci.¢ alkoxy;

X2 represents hydrogen or halogen; ’ Y represents a chemical bond, an oxygen atom, or a -NH- linkage;

Z represents an optionally substituted aryl or heteroaryl group;

R! represents hydrogen, hydrocarbon, a heterocyclic group, halogen, cyano, trifluoromethyl, nitro, -ORa, -SRe, -SOR?, -SOzR2, -SONR=2RP, -NR=Rb, -NR2CORP, -NR2CO2RP, -COR2, -COzR2, -CONR=RP or -CR2=NORb};

R? represents hydrogen or halogen; and

Ra and RP independently represent hydrogen, hydrocarbon or a . heterocyclic group.

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. Suitably, the group Z is unsubstituted or monosubstituted.

Typical substituents on the group Z include halogen, cyano, nitro, C16 alkyl, hydroxy, Cis alkoxy, oxy, Cig alkylsulphenyl, amine, aminocarbonyl, formyl, C26 alkoxycarbonyl and -CR2=NOR®P, wherein R2 and RP are as defined above. Illustrative substituents on the group Z : include halogen, cyano, nitro, C16 alkyl, Ci.6 alkoxy, amino, formyl, Cas alkoxycarbonyl and -CRa=NORP, wherein R2 and RP 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. alkyl, Ca. alkenyl, C26 alkynyl, Cs-7 , cycloalkyl, Csz.7 cycloalkyl(Ci¢)alkyl, indanyl, aryl and aryl(Ci-e)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 Ca 7 heterocycloalkyl, Ca heterocycloalkyl(Ci6)alkyl, heteroaryl and heteroaryl(Ci.¢)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, n-propyl, isopropyl, isobutyl, tert-butyl and 2,2-dimethylpropyl. Derived expressions such as “Ci alkoxy”, “Ci.6 alkylamino” and “Ci1.6 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 Ca.7 cycloalkyl(Ci.e)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(Ci-s)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, thienyl, benzthienyl, pyrrolyl, indolyl, pyrazolyl, indazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, benzimidazolyl, oxadiazolyl, thiadiazolyl, triazolyl and tetrazolyl groups.

The expression “heteroaryl(Ci g)alky!l” as used herein includes furylmethyl, furylethyl, thienylmethyl, thienylethyl, 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 Cis alkyl, adamantyl, phenyl, halogen, C1. haloalkyl, Ci.6 aminoalkyl, trifluoromethyl, hydroxy,

C16 alkoxy, aryloxy, keto, Ci1.3 alkylenedioxy, nitro, cyano, carboxy, Coe alkoxycarbonyl, Co.s alkoxycarbonyl(Ci.e)alkyl, C26 alkylcarbonyloxy, arylcarbonyloxy, aminocarbonyloxy, Cos alkylcarbonyl, arylcarbonyl, Ci.6 alkylthio, C16 alkylsulphinyl, C16 alkylsulphonyl, arylsulphonyl, -NR'Rv, -NR*COR¥, -NR'CO2R¥, -NR"SO:R¥, -CH-NR'SQ:R¥, -NHCONRYR¥, -CONRYRv, -SO2NRVR¥ and -CH2SO2NRVRV, in which RY and R* independently represent hydrogen, Ci.¢ alkyl, aryl or aryl(Ci.s)alkyl.

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

The present invention includes within its scope prodrugs of the compounds of formula I above. In general, such prodrugs will be functional derivatives of the compounds of formula I which are readily convertible in vivo into the required compound of formula I. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in Design of Prodrugs, ed. H.

Bundgaard, Elsevier, 1985. - Where the compounds according to the invention have at least one asymmetric centre, they may accordingly exist as enantiomers. Where the compounds according to the invention possess two or more asymmetric centres, they may additionally exist as diastereoisomers. It is to be understood that all such isomers and mixtures thereof in any proportion are encompassed within the scope of the present invention.

Suitable values for the X! substituent include fluoro, chloro, methyl, trifluoromethyl and methoxy, especially fluoro.

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.

Selected values for the substituent Z include phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, thiazolyl, isothiazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl and tetrazolyl, any of which groups may be optionally substituted by one or more substituents.

Individual values for the substituent Z include phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, thiazolyl, isothiazolyl, pyrrolyl, imidazolyl, triazolyl and tetrazolyl, any of which groups may be optionally substituted by one or more substituents.

Representative values for the substituent Z include phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, thiazolyl, imidazolyl and triazolyl, any of which groups may be optionally substituted. Typical values of Z include phenyl, pyridinyl, pyridazinyl, pyrimidinyl and pyrazinyl, any of which groups may be optionally substituted. 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 or monosubstituted pyridin-2-yl, pyridin-3-yl or pyridin-4-yl.

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 individual substituents on the group Z include fluoro, chloro, cyano, methyl, hydroxy, methoxy, oxy, methanesulphonyl and aminocarbonyl.

Examples of typical substituents on the group Z include fluoro, chloro, cyano, nitro, methyl, methoxy, amino, formyl, methoxycarbonyl and -CH=NOH. Examples of particular substituents on the group Z include fluoro, cyano and methyl; especially fluoro or cyano; and more especially cyano.

Detailed values of Z include cyanophenyl, (cyano)(fluoro)phenyl, (chloro)(cyano)phenyl, nitrophenyl, methoxyphenyl, methanesulphonyl- phenyl, pyridinyl, fluoro-pyridinyl, difluoro-pyridinyl, (amino)(chloro)pyridinyl, cyano-pyridinyl, methyl-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, (chloro)(cyano)phenyl, methanesulphonyl-phenyl, pyridinyl, fluoro- pyridinyl, difluoro-pyridinyl, cyano-pyridinyl, methyl-pyridinyl, hydroxy- pyridinyl, methoxy-pyridinyl, oxy-pyridinyl, aminocarbonyl-pyridinyl, : pyridazinyl, pyrimidinyl, pyrazinyl, cyano-thienyl, aminocarbonyl-thienyl, thiazolyl, isothiazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl and methyl- tetrazolyl.

Suitable values of Z include cyanophenyl, (cyano)(fluoro)phenyl, (chloro)(cyano)phenyl, nitrophenyl, methoxyphenyl, methanesulphonyl-

phenyl, pyridinyl, fluoro-pyridinyl, difluoro-pyridinyl, (amino)(chloro)pyridinyl, cyano-pyridinyl, methyl-pyridinyl, hydroxy- pyridinyl, methoxy-pyridinyl, oxy-pyridinyl, pyridazinyl, pyrimidinyl, : pyrazinyl, cyano-thienyl, aminocarbonyl-thienyl, formyl-thienyl, methoxycarbonyl-thienyl, thienyl-CH=NOH, thiazolyl, isothiazolyl, pyrrolyl, imidazolyl, triazolyl and methyl-tetrazolyl.

Typical values of Z include cyanophenyl, (cyano)(fluoro)phenyl, (chloro) eyano)phenyl, methanesulphenyl-phenyl, pyridinyl, fluore- pyridinyl, difluoro-pyridinyl, cyano-pyridinyl, methyl-pyridinyl, hydroxy- pyridinyl, methoxy-pyridinyl, oxy-pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, cyano-thienyl, aminocarbonyl-thienyl, isothiazolyl, pyrrolyl, imidazolyl and methyl-tetrazolyl.

Illustrative values of Z include cyanophenyl, (cyano)(fluoro)phenyl, nitrophenyl, methoxyphenyl, pyridinyl, fluoro-pyridinyl, (amino)(chloro)pyridinyl, cyano-pyridinyl, methyl-pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, cyano-thienyl, formyl-thienyl, methoxycarbonyl- thienyl, thienyl-CH=NOH, thiazolyl, imidazolyl and triazolyl. Individual values of Z include cyanophenyl, (cyano)(fluoro)phenyl, pyridinyl, fluoro- pyridinyl, cyano-pyridinyl, methyl-pyridinyl, pyridazinyl, pyridimidinyl and pyrazinyl.

Particular values of Z include 2-cyanophenyl, 2-cyano-4- fluorophenyl, pyridinyl-2-yl, pyridin-3-vl and 3-cyanopyridin-2-yl.

In one embodiment, Z represents 2-cyano-4-fluorophenyl.

In another embodiment, Z represents pyridin-3-yl.

Typically, R! represents hydrogen, hydrocarbon, a heterocyclic group, halogen, cyano, trifluoromethyl, -CORz, -CO2R2 or -CR2=NOR?,

Typical values of R2 include hydrogen and Cis alkyl. Suitably, Ra represents hydrogen or methyl.

Typical values of RP include hydrogen, Ci alkyl, hydroxy(Ci-6)alkyl and di(Ci-¢)alkylamino(Cie)alkyl. Suitably, Rb represents hydrogen, methyl, ethyl, hydroxyethyl or dimethylaminoethyl. Particular values of

RP include hydrogen, hydroxyethyl and dimethylaminoethyl, especially hydrogen or dimethylaminoethyl.

Suitable values of R! include hydrogen, C16 alkyl, halo(Ci.¢)alkyl, : dihalo(Ci.¢)alkyl, hydroxy(Ci.e)alkyl, dihydroxy(Ci.6)alkyl,

C16 alkoxy(C1.6)alkyl, di(Ci.6)alkoxy(Ci-6)alkyl, cyano(Ci-6)alkyl, Ca.6 alkoxycarbonyl(Ci.e)alkyl, heteroaryl, Cis alkyl-heteroaryl, : heteroaryl(Ci.s)alkyl, halogen, cyano, trifluoromethyl, formyl, Cos alkylearhonyl, Cog alkoxyearbeny! and -CRa=NORbD, in which Ra and Rb are as defined above.

Representative values of R! include hydrogen, Ci.6 alkyl, halo(Ci.6)alkyl, dihalo(C1.6)alkyl, hydroxy(Ci.¢)alkyl, Cis alkoxy(Ci.6)alkyl, 'di(C1e)alkoxy(Cre)alkyl, heteroaryl, C16 alkyl-heteroaryl, heteroaryl(Ci.6)alkyl, halogen, cyano, trifluoromethyl, formyl, Cos alkylcarbonyl, C26 alkoxycarbonyl and -CR2=NORP, in which R2 and RP are as defined above.

Individual values of R! include hydrogen, 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 1,2-dihydroxyprop-2-yl), fluoropropyl (especially 2-fluoroprop-2-y1), cvancpropyl (especially 2- cyanoprop-2-yl), methoxycarbonylpropyl (especially 2- methoxycarbonylprop-2-yl), tert-butyl, hydroxybutyl (especially 1-hydroxy- 2-methylprop-2-yl), pyridinyl, furyl, thienyl, oxazolyl, methylthiazolyl, methyloxadiazolyl, imidazolylmethyl, triazolylmethyl, chloro, cyano, trifluoromethyl, formyl, acetyl, methoxycarbonyl and -CR3=NOR4, in which R3 represents hydrogen or methyl, and R#* represents hydrogen, hydroxyethyl or dimethylaminoethyl.

Itemised values of R! include hydrogen, 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), fluoropropyl (especially 2-fluoroprop-2-yl), tert-butyl, pyridinyl, furyl, thienyl, oxazolyl, methylthiazolyl, methyloxadiazolyl, imidazolylmethyl, triazolylmethyl, chloro, cyano, trifluoromethyl, formyl, acetyl, methoxycarbonyl and -CR3=NOR#%, in which R3 and R¢# are as defined ahave.

In one favoured embodiment, R! represents 2-hydroxyprop-2-yl. In another favoured embodiment, R! represents trifluoromethyl.

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

Suitably, R3 is hydrogen.

Suitably, R? represents hydrogen or dimethylaminoethyl, especially hydrogen.

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

RAN _N

OY x!

Z x2 (114) wherein

Z and R? are as defined above;

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

X12 represents hydrogen or fluoro;

R11 represents hydrogen, C1.6 alkyl, halo(C1.6)alkyl, dihalo(C1.¢)alkyl, hydroxy(Cie)alkyl, dihydroxy(Ci.e)alkyl, C1.6 alkoxy(Ci-¢)alkyl, di(Ci-¢)alkoxy(Cie)alkyl, cyano(Cis)alkyl, Co.6 alkoxycarbonyl(Ci.)alkyl, : heteroaryl, C16 alkyl-heteroaryl, heteroaryl(Ci.¢)alkyl, halogen, cyano, trifluoromethyl, formyl, C2. alkylcarbonyl, Cz.6 alkoxycarbonyl or -CR5=NORS,;

R5% represents hydrogen or C16 alkyl; and

R6 represents hydrogen, Cie alkyl, hydroxy(Ci g)alkyl or di(C1-¢)alkylamino(C1.¢)alkyl.

The present invention also provides a compound of formula IIA as depicted above, or a salt thereof or a prodrug thereof, wherein

R1! represents hydrogen, Ci.6 alkyl, halo(Ci.¢)alkyl, dihalo(Ci.¢)alkyl, hydroxy(Ci.6)alkyl, Cis alkoxy(Ci.6)alkyl, di(Ci.6)alkoxy(Ci.s)alkyl, heteroaryl, Ci.6 alkyl-heteroaryl, heteroaryl(Ci.6)alkyl, halogen, cyano, trifluoromethyl, formyl, Ca.6 alkylcarbonyl, Cs. alkoxycarbonyl or -CR5=NORS; and

Z,X1 X12 R2 RS and RS are as defined above.

A particular value of X!! is fluoro.

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

Suitably, R5 represents hydrogen or methyl, especially hydrogen.

Suitably, R6 represents hydrogen, methyl, ethyl, hydroxyethyl or dimethylaminoethyl. Particular values of R6 include hydrogen, hydroxyethyl and dimethylaminoethyl. Typically, RS represents hydrogen or dimethylaminoethyl, especially hydrogen.

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

Where R!! represents Ci. alkyl-heteroaryl, this group is suitably methylthiazolyl (e.g. 2-methylthiazol-5-yl) or methyloxadiazolyl (e.g. 3- methyl-[1,2,4]oxadiazol-5-yl).

Claims

CLAIMS:

1. A compound of formula I, or a salt or prodrug thereof: R! _N N Be N % = I X (D wherein X1 represents halogen, C16 alkyl, trifluoromethyl or Ci.¢ alkoxy; X2 represents hydrogen or halogen; Y represents a chemical bond, an oxygen atom, or a -NH- linkage; Z represents an optionally substituted aryl or heteroaryl group; R1 represents hydrogen, hydrocarbon, a heterocyclic group, halogen, cyano, trifluoromethyl, nitro, -ORa, -SRa, -SORe, -SO2R2, -SO:NR=2RP, -NR=Rb, -NR2CORP, -NRaCOzRP, -CORa, -COzR2, -CONR2R? or -CR2=NOR?; R2 represents hydrogen or halogen; and R2 and RP independently represent hydrogen, hydrocarbon or a heterocyclic group.

2. A compound as claimed in claim 1 represented by formula ITA, and salts and prodrugs thereof:

rR" NN rr

: . Zz x2 (11A) wherein Z and R? are as defined in claim 1; X11 represents fluoro, chloro, methyl, trifluoromethyl or methoxy; X12 represents hydrogen or fluoro; R11 represents hydrogen, Ci. alkyl, halo(Ci.e)alkyl, dihalo(Ci6)alkyl, hydroxy(Ci-s)alkyl, dihydroxy(Ci.e)alkyl, Ci. alkoxy(Ci-¢)alkyl, di(Ci.e)alkoxy(Ci.e)alkyl, cyano(Cie)alkyl, Cz.6 alkoxycarbonyl(Ci-6)alkyl, heteroaryl, Ci.¢ alkyl-heteroaryl, heteroaryl(Ci.s)alkyl, halogen, cyano, trifluoromethyl, formyl, Css alkylcarbonyl, Cz alkoxycarbonyl or -CR5=NORS,; R5 represents hydrogen or Ci alkyl; and RS represents hydrogen, C16 alkyl, hydroxy(Ci-¢)alkyl or di(C1-s)alkylamino(Cr.e)alkyl.

3. A compound as claimed in claim 2 represented by formula IIB, or a pharmaceutically acceptable salt thereof:

R'\_ _N ~ ~ ~N- - x12 (IL xH C] i" (IIB) wherein X11, X12 and R1! are as defined in claim 2; and RY" represents hydrogen, fluoro or chloro.

4. A compound as claimed in claim 3 wherein R7 represents fluoro.

5. A compound as claimed in claim 4 wherein R!! represents trifluoromethyl.

6. A compound as claimed in claim 2 represented by formula IIC, or a pharmaceutically acceptable salt thereof: 11 RUN v N NZ x1! = I CN } ANN 2 x i" (IIC)

-178 - PCT/GB02/0135 wherein X11, X12 and R!! are as defined in claim 2; and R7 is as defined in claim 3.

7. A compound as claimed in claim 2 represented by formula IID, or a pharmaceutically acceptable salt thereof: rR N N R vd — TT) XN x7 ~ °N xt (IID) wherein X11, X12 and R11 are as defined in claim 2; and R8 represents hydrogen, fluoro, cyano or methyl.

8. A compound as claimed in claim 7 wherein R® represents hydrogen.

9. A compound as claimed in claim 8 wherein R1! represents 2- hydroxyprop-2-yl.

10. A compound as claimed in claim 2 represented by formula IIE, or a pharmaceutically acceptable salt thereof:

RN v N : x _N J P Xx" “ x! NS ie (IIE) wherein X11, X12 and RY! are as defined in claim 2; R8 is as defined in claim 7; and R9 represents hydrogen or fluoro.

11. A compound as claimed in any one of claims 3 to 10 wherein X11 represents fluoro.

12. A compound as claimed in claim 11 wherein X12 represents hydrogen.

13. A compound selected from: 2'-fluoro-5’-(imidazo[1,2-a]pyrimidin-3-yl)biphenyl-2-carbonitrile; 2'-fluoro-5’-(7-methylimidazo[1,2-a]pyrimidin-3-yl)biphenyl-2-carbonitrile; 5’-(7-acetylimidazo[1,2-a]pyrimidin-3-y1)-2’-fluorobiphenyl-2-carbonitrile; 2'-fluoro-5’-(7-isopropylimidazo[1,2-a]pyrimidin-3-yDbiphenyl-2- carbonitrile; 2’ -fluoro-5’-(7-tert-butylimidazo[1,2-a]pyrimidin-3-yl)biphenyl-2- carbonitrile; ) 2’-fluoro-5'-[7-(1-hydroxy-1-methylethyl)imidazo[1,2-a]pyrimidin-3-yl]- biphenyl-2-carbonitrile; 2'-fluoro-5’-[7-(1-fluoro-1-methylethyl)imidazo[1,2-alpyrimidin-3-yl]- biphenyl-2-carbonitrile;

2’-fluoro-5’-(7-hydroxymethylimidazo[1,2-¢]pyrimidin-3-yl)biphenyl-2- carbonitrile; 2’-fluoro-5’-[7-( 1-hydroxyethylimidazo [1,2-alpyrimidin-3-yl]biphenyl-2- : carbonitrile; 2'-fluoro-5'-[7-(1-fluoroethyl)imidazo[1,2-a]pyrimidin-3-yl] biphenyl-2- carbonitrile; 2’-fluoro-5’-[7-(2-methylthiazol-5-yl)imidazo[1,2-a]pyrimidin-3-yl]- biphenyl-2-carbonitrile; 2’-fluoro-5’-(7-trifluoromethylimidazo([1,2-a]pyrimidin-3-yl)biphenyl-2- carbonitrile; 5’-[7-(1,1-difluoroethyl)imidazo[1,2-a]pyrimidin-3-y1]-2’-fluorobiphenyl-2- carbonitrile; 5-(7-chloroimidazol1,2-a] pyrimidin-3 -yD)-2’-fluorobiphenyl-2-carbonitrile; 5’-(7-difluoromethylimidazo(1,2-a]lpyrimidin-3-yl)-2’-fluorobiphenyl-2- carbonitrile; 2’-fluoro-5'-(7-methoxymethylimidazo[1,2-a]pyrimidin-3-yl)biphenyl-2- carbonitrile;

3.(2"-cyano-6-fluorobiphenyl-3-yl)imidazo [1,2-a]pyrimidine-7-carbonitrile; 2’-fluoro-5-[7-(3-methyl-[1,2,4]Joxadiazol-5-yl)imidazo[1,2-a}pyrimidin-3- yllbiphenyl-2-carbonitrile; 2’-fluoro-5’-[7-(oxazol-5-yl)imidazo[1,2-a]pyrimidin-3-yl]biphenyl-2- carhonitrile; 2’-fluoro-5’-[7-(hydroxyiminomethyl)imidazo[1,2-a] pyrimidin-3-yl]- biphenyl-2-carbonitrile; 5-{7-11-(2-dimethylaminoethoxyimino)methyllimidazo[1,2-a} pyrimidin-3- yl}-2’-fluorobiphenyl-2-carbonitrile; 3'-(7-difluoromethylimidazol[1,2-a]pyrimidin-3-yl)-4’-fluorobiphenyl-2- - carbonitrile; 2’-fluoro-5’-(7-fluoromethylimidazo[1,2-a]lpyrimidin-3-yl)biphenyl-2- carbonitrile;

2'-fluoro-5'-[7-(furan-3-yl)imidazo[1,2-a] pyrimidin-3-yllbiphenyl-2- carbonitrile; 2'-fluoro-5'-[7-(thien-3-yl)imidazol1,2-a] pyrimidin-3-yllbiphenyl-2- . carbonitrile;

2’fluoro-5'-[7-(pyridin-2-yl)imidazo|1,2-a)pyrimidin-3-yl]biphenyl-2- carbonitrile; 2'-fluoro-5"-(6-fluoro-7-methylimidazo(1,2-alpyrimidin-3-ylbiphenyl-2- carbonitrile; 7-(1,1-difluoroethyl)-3-[4-fluoro-3-(pyridin-3-yl)phenyl)imidazo(1,2-

alpyrimidine; 2-[3-(4-fluoro-3-(pyridin-3-yl)phenyl)imidazo [1,2-a)pyrimidin-7-yllpropan- 2-0l; 3’-fluoro-5'-(7-trifluoromethylimidazo([1,2-a)pyrimidin-3-yl)biphenyl-2- carbonitrile;

3'-fluoro-5'-(7-hydroxymethylimidazo[1,2-a]pyrimidin-3-yl)biphenyl-2- carbonitrile;

9’ -fluoro-8'~(7-trifluoromethylimidazo[1,2-alpyrimidin-3-ylbiphenyl-2- carbonitrile; 3-[4-fluoro-3-(pyridin-2-yl)phenyl]-7-trifluoromethylimidazo[1,2-

alpyrimidine; 3-[4-fluoro-3-(pyridin-3-yl)phenyl}-7-trifluoromethylimidazo(1,2- alpyrimidine; 2 fluoro-5'-[7-([1,2,4]triazol-1-ylmethyl)imidazo[1,2-a]pyrimidin-3- ylibiphenyl-2-carbonitrile;

2'-fluoro-5'-[7-(imidazol-1-ylmethyl)imidazo(1,2-a]pyrimidin-3-yl}biphenyl- 2-carbonitrile;

9/-fluoro-5’-{7-([1,2,3]triazol-1-ylmethyl)imidazo[1,2-a]pyrimidin-3-yl]- . biphenyl-2-carbonitrile; 2 fluoro-5'-[7-([1,2,3}triazol-2-ylmethyl)imidazo[1,2-a] pyrimidin-3- | yllbiphenyl-2-carbonitrile;

3-[4-fluoro-3-(pyridin-4-yl)phenyl]-7-trifluoromethylimidazo(1,2- alpyrimidine; 3-[2,4-difluoro-3-(pyridin-3-yl)phenyl]-7-trifluoromethylimidazo[1,2- : a]pyrimidine;

3-[2,4-difluoro-3-(pyridin-2-yl)phenyl]-7-trifluoromethylimidazo[1,2- alpyrimidine; 2-[3-(4-fluoro-3-(pyridin-4-yl)phenyl)imidazo[1,2-a]pyrimidin-7-yl] propan- 2-0l; 3-[2-fluoro-3-(pyridin-3-yl)phenyl]-7-trifluoromethylimidazo[1,2-

a]pyrimidine; 2-13-(2-fluoro-3-(pyridin-3-yl)phenyl)imidazo[1,2-al pyrimidin-7-yl]propan- 2-0l; 3-[2-fluoro-3-(pyridin-4-yl)phenyl]-7-trifluoromethylimidazo[1,2- alpyrimidine 2-[3-(2-fluoro-3~(pyridin-4-yl)phenyl)imidazo[1,2-alpyrimidin-7-yl]propan- 2-ol 3-[2-fluoro-3-(pyridin-2-yl)phenyl]-7-trifluoromethylimidazo[1,2- alpyrimidine; 2-[3-(2-fluoro-3-(pyridin-2-yl)phenyl)imidazo[1,2-alpyrimidin-7-yl]propan- 2-ol; 3-[4-fluoro-3-(4-methylpyridin-2-yl)phenyl]-7-trifluoromethylimidazo[1,2- alpyrimidine; 3-[4-fluoro-3-(pyridazin-3-yl)phenyl]-7-trifluoromethylimidazo(1,2- alpyrimidine; 2-[2-fluoro-5-(7-trifluoromethylimidazo[1,2-a]pyrimidin-3-yl)phenyl]- nicotinonitrile; 3-[4-fluoro-3-(pyridin-2-yl)phenyllimidazo[1,2-a]pyrimidine; i 3,2’-difluoro-5’-(7-trifluoromethylimidazo[1,2-a¢]pyrimidin-3-yl)biphenyl-2- carbonitrile; 6,2’-difluoro-5'-(7-trifluoromethylimidazo[1,2-a] pyrimidin-3-yl)biphenyl-2- carbonitrile;

5,2’-difluoro-5’-(7-trifluoromethylimidazo[1,2-alpyrimidin-3-yl)biphenyl-2- carbonitrile; 4,2’-difluoro-5'~(7-trifluoromethylimidazo[1,2-alpyrimidin-3-yl)biphenyl-2- carbonitrile; 2,6’-difluoro-3’-(7-trifluoromethylimidazo[1,2-alpyrimidin-3-yl)biphenyl-2- carbonitrile; 3-[4-fluoro-3-(pyrazin-2-yl)phenyl]-7-trifluoromethylimidazo[1,2- alpyrimidine; 3-[4-fluoro-3-(pyrimidin-2-yl)phenyl]-7-trifluoromethylimidazo(1,2- alpyrimidine; 3-[2-fluoro-5-(7-trifluoromethylimidazo{1,2-a]pyrimidin-3-yl)phenyl}- pyridine-2-carbonitrile; 3-[4-fluoro-3-(5-fluoropyridin-2-yl)phenyl]-7-trifluoromethylimidazo [1,2- alpyrimidine; 7-(1,1-difluoroethyl)-3-[4-fluoro-3-(pyridin-4-yl)phenyl}imidazo|[1,2- a]pyrimidine; 7-(1,1-difluoroethyl)-3-[2,4-difluoro-3-(pyridin-3-yl)phenyllimidazo[1,2- alpyrimidine; 3-[4-methyl-3-(pyridin-3-yl)phenyl]-7-trifluoromethylimidazo{1,2- a]pyrimidine; 3-[4-chloro-3-(pyridin-3-yl)phenyl]-7-trifluoromethylimidazo[1,2- a]pyrimidine; 3-[4-methoxy-3-(pyridin-3-yl)phenyl]-7-trifluoromethylimidazo[1,2- alpyrimidine; and salts and prodrugs thereof.

14. A compound selected from: 2-13-(2,4-difluoro-3-(pyridin-3-yl)phenyl)imidazo[1,2-a]pyrimidin-7-yl]- propan-2-ol; 1-[3-(4-fluoro-3-(pyridin-3-yl)phenyl)imidazo[1,2-a]lpyrimidin-7-yl]- ethanone;

3’-[7-(1-hydroxy-1-methylethyl)imidazo[1,2-a]pyrimidin-3-yl]-4,2",6’- trifluorobiphenyl-2-carbonitrile; 2-[3-(4-fluoro-3-(pyridin-3-yl)phenyl)imidazo[1,2-a]pyrimidin-7-yli- . propane-1,2-diol;

3-[2-fluoro-5-(7-trifluoromethylimidazo[1,2-a] pyrimidin-3-yl)phenyl}- thiophene-2-carbonitrile; 3-{2-fluoro-5-[7-(1-hydroxy-1-methylethyl)imidazo[1,2-alpyrimidin-3-yl]- phenyl}ithiophene-2-carbonitrile; 2-{3-[4-fluoro-3-(1-oxypyridin-3-yl)phenyllimidazo(1,2-al pyrimidin-7-yl}-

propan-2-ol; 3-{2,6-difluoro-3-[7-(1-hydroxy-1-methylethyl)imidazo[1,2-alpyrimidin-3- yllphenyl}thiophene-2-carbonitrile; 3-{2,6-difluoro-3-[7-(1-hydroxy-1-methylethyl)imidazo[1,2-a]pyrimidin-3- yllphenyl}thiophene-2-carboxylic acid amide;

3-[4-fluoro-3-(3-fluoropyridin-4-yl)phenyl]-7-trifluoromethylimidazo[1,2- alpyrimidine; 4-chloro-2’-fluoro-5'-(7-trifluoromethylimidazo(1,2-a}pyrimidin-3-yl)- biphenyl-2-carbonitrile; 3-[4-fluoro-3-(5-methylpyridin-3-yl)phenyl]-7-trifluoromethylimidazo[1,2-

alpyrimidine; 3-[2-fluoro-2’-(methanesulfonyl)biphenyl-5-yl]-7-trifluoromethyl- imidazo[1,2-alpyrimidine; 2-[3-(4-fluoro-3-(pyrazin-2-yl)phenyl)imidazo[1,2-a¢] pyrimidin-7-yl]propan- 2-ol;

2-[3-(4-fluoro-3-(5-fluoropyridin-2-yl)phenyl)imidazo[1,2-a]lpyrimidin-7- yllpropan-2-ol; 3-[4-fluoro-3-(3-fluoropyridin-2-yl)phenyl]-7-trifluoromethylimidazo[1,2- a]pyrimidine; 2-[3-(4-fluoro-3-(3-fluoropyridin-2-yl)phenyl)imidazo[1,2-a]pyrimidin-7-

yllpropan-2-ol;

3-[3-(8,5-difluoropyridin-2-yl)-4-fluorophenyl]-7-trifluoromethyl- imidazo[l,2-a]pyrimidine; 2-[3-(3-(3,5-difluoropyridin-2-yl)-4-fluorophenyl)imidazo[1,2-alpyrimidin-7- . yllpropan-2-ol; 3-[2,4-difluoro-3-(pyridin-4-yl)phenyl]-7-trifluoromethylimidazo[1,2- a]pyrimidine; 2-13-(2,4-difluoro-3-(pyridin-4-yl)phenyl)imidazo{1,2-a]pyrimidin-7- yllpropan-2-ol; : 4,2'-difluoro-5’-[7-(1-hydroxy-1-methylethyl)imidazo[1,2-a)pyrimidin-3-

yllbiphenyl-2-carbonitrile; 2'-fluoro-5'~(7-trifluoromethylimidazo[1,2-alpyrimidin-3-yl)biphenyl-3- carbonitrile; 2’ -fluoro-5'-(7-trifluoromethylimidazo(1,2-alpyrimidin-3-yl)biphenyl-4- carbonitrile;

4-fluoro-2"-methyl-3""/ trifluoromethylimidazo{1,2-alpyrimidin-3- y1)biphenyl-2-carbonitrile; 3-[2,4-difluoro-3-(pyridin-3-yl)phenyl]-7-(1-fluoro-1- methylethyl)imidazo[1,2-a]pyrimidine; 7-(1-fluoro-1-methylethyl)-8-[4-fluoro-3-(pyridin-3-yl)phenyllimidazo[1,2-

alpyrimidine; 9-[3-(2,4-difluoro-3-(pyridin-3-yl)phenyl)imidazo[1,2-alpyrimidin-7-yl]-2- methylpropionic acid methyl ester; 2-[3-(4-fluoro-3-(pyridin-3-yl)phenyl)imidazo(1,2-a]pyrimidin-7-yl}-2- methylpropionitrile; :

2-[3-(4-fluoro-3-(pyridin-3-yl)phenyl)imidazo[1,2-a]pyrimidin-7-yl]-2-

methylpropan-1-ol; 3-[4-fluoro-3-(6-methoxypyridin-3-yl)phenyl]-7-trifluoromethyl- . | imidaze[1,2-a]pyrimidine; 5- [2-fluoro-5-(7-trifluoromethylimidazo[1,2-a]pyrimidin-3- ylphenyllpyridin-2-ol;

3-[4-fluoro-3-(4-fluoropyridin-3-yl)phenyl]-7-trifluoromethylimidazo(1,2- alpyrimidine;

3-[4-fluoro-3-(pyrrol-1-yl)phenyl]-7-trifluoromethylimidazol1,2- a]pyrimidine;

3-[4-fluoro-3-(pyridin-3-yl)phenyllimidazo(l,2-a]pyrimidine; 3-[4-fluoro-3-(5-fluoropyridin-2-yl)phenyl}imidazo[1,2-alpyrimidine; 3-[2,4-difluoro-3-(pyridin-3-yl)phenyllimidazo{1,2-alpyrimidine; 3-[4-chloro-3-(pyridin-3-yl)phenyllimidazoll,2-alpyrimidine; 3-[56-fluoro-3-(pyridin-3-yl)phenyl]-7-trifluoromethylimidazo{1,2-

alpyrimidine; 3-[4-fluoro-3-(4-fluoropyridin-3-yphenyl]-7-trifluoromethylimidazo(1,2- alpyrimidine; 3-[2-fluoro-5-(pyridin-3-yl)phenyl]-7-trifluoromethylimidazo(1,2- alpyrimidine; 3- [4-fluoro-3-(pyridazin-4-yl)phenyl] -7-trifluoromethylimidazo[1,2- alpyrimidine; 3-[4-fluoro-3-(imidazol-1-yl)phenyl]-7-trifluoromethylimidazo{1,2- alpyrimidine; 3-[4-fluoro-3-(isothiazol-4-yl)phenyl]-7-trifluoromethylimidazo[1,2-

alpyrimidine; 3-[4-fluoro-3-(pyrimidin-5-yl)phenyl]-7-trifluoromethylimidazo[1,2- alpyrimidine; 3-[4-fluoro-3-(5-methoxypyridin-3-yl)phenyl}-7-trifluoromethylimidazo[1,2- a}pyrimidine;

3-[4-fluoro-3-(2-methylpyridin-3-yl)phenyl]-7-trifluoromethylimidazo[1,2- alpyrimidine; 3-[4-fluoro-3-(2-methyltetrazol-5-yl)phenyl]-7-trifluoromethylimidazo[1,2- : alpyrimidine; 3-[4-fluoro-3-(1-methyltetrazol-5-yl)phenyl]-7-trifluoromethylimidazo[1,2-

alpyrimidine; .

and salts and prodrugs thereof.

15. A compound selected from: 3-{4-fluoro-3-(6-methoxypyridin-2-yl)phenyl]-7-trifluoromethyl- imidazo[1,2-a}pyrimidine; 3-(4-fluoro-3-(4-methoxypyridin-2-yl)phenyl})-7-trifluoromethyl- imidazo[1,2-a]pyrimidine; 3-[4-fluoro-3-(thiazol-2-yl)phenyl}-7-trifluoromethylimidazo[1,2- alpyrimidine; 2-{2-fluoro-5-[7-(1-hydroxy-1-methylethyl)imidazo[1,2-a]pyrimidin-3-yl}-

phenyl}nicotinonitrile; 4-[2-fluoro-5-(7-trifluoromethylimidazo(1,2-a]pyrimidin-3-yl)phenyl]- nicotinonitrile; 4-{2-fluoro-5-[7-(1-hydroxy-1-methylethyl)imidazo[1,2-a]pyrimidin-3-yl}- phenylinicotinonitrile;

3-[2-fluoro-5-(7-trifluoromethylimidazo[1,2-a]pyrimidin-3-yl)phenyl]- isonicotinonitrile; 3-[2-fluoro-5-(7-trifluoromethylimidazo|[1,2-alpyrimidin-3-yl)phenyl]- isonicotinamide; 3-{2-fluoro-5-[7-(1-hydroxy-1-methylethyl)imidazo(1,2-a]pyrimidin-3-yli]-

phenyllisonicotinamide; 2-[3-(4-fluoro-3-(pyridazin-3-yl)phenyl)imidazo(1,2-alpyrimidin-7-yl}- propan-2-ol; 2-[3-(4-fluoro-3-(pyridazin-4-yl)phenyl)imidazo|1,2-a]pyrimidin-7-yl]- propan-2-ol;

3-[4-fluoro-3-(pyrazol-1-yl)phenyl}-7-trifluoromethylimidazo[1,2- alpyrimidine;

’ 2-[3-(4-fluoro-3-(pyrazol-1-yl)phenyl)imidazol1,2-a]pyrimidin-7-yl]propan- 2-ol; 3-[4-fluoro-3-({1,2,4]triazol-1-yl)phenyl]-7-trifluoromethylimidazo(1,2-

alpyrimidine;

2-[3-(4-fluoro-3-([1,2,4]triazol-1-yl)phenyl)imidazo[1,2-alpyrimidin-7-yl]- propan-2-ol; : 2-[2-fluoro-5-(7-trifluoromethylimidazol1,2-e}pyrimidin-3-yl)phenyl)- : nicotinamide; 2-{3-[4-fluoro-3-(5-fluoropyridin-3-yl)phenyllimidazo(1,2-alpyrimidin-7- ylipropan-2-ol; and salts and prodrugs thereof.

16. A pharmaceutical composition comprising a compound of formula I as defined in claim 1, or a pharmaceutically acceptable salt thereof or a prodrug thereof, in association with a pharmaceutically acceptable carrier.

17. The use of a compound of formula I as defined in claim 1, or a pharmaceutically acceptable salt thereof or a prodrug thereof, for the manufacture of a medicament for the treatment and/or prevention of adverse neurological conditions.

18. A process for the preparation of a compound as claimed in claim 1, which comprises: (A) reacting a compound of formula III with a compound of formula IV: 1 M'

RA. _N_ nN LR £1 rr NN X : L' Y—2z X (11) aw wherein X1, X2 Y, Z, R! and R? are as defined in claim 1, L1 represents a suitable leaving group, and M! represents a boronic acid moiety -B(OH); or a cyclic ester thereof formed with an organic diol, or M! represents -Sn(Alk)s in which Alk represents a Ci alkyl group, in the presence of a transition metal catalyst; or E : (B) reacting a compound of formula V with a compound of formula VIL L} SE Be ed pd IG F ) gig M Y—1z X V) (VI) wherein X3, X2, Y, Z, R! and R?2 are as defined in claim 1, and L! and M? 1 are as defined above; in the presence of a transition metal catalyst; or (C) reacting a compound of formula VII with a compound of formula VIII: R\__N_ N z hi Be N J M— 2 x! 1 o 1. (VID) (VIII) wherein X!, X2, Z Rt and R? are as defined in claim 1, and L! and M! are as defined above; in the presence of a transition metal catalyst; or (D) reacting a compound of formula IX with a compound of formula X:

RAN __N = N . Be 7 L'—7Z . xt x’ M (IX) X) wherein X1, X2, Z, R! and R? are as defined in claim 1, and L! and M! are as defined above; in the presence of a transition metal catalyst; or (E) reacting a compound of formula X as defined above with a compound of formula XI: R' _N Ne N IT J R?

x! . OH <° XD wherein X1, X2, R! and R? are as defined in claim 1; or (F) reacting a compound of formula X as defined above with a compound of formula XII: 1 R NNER x! 2 NH, X (XID)

wherein X1, X2 R! and R? are as defined in claim 1; or (GQ) reacting a compound of formula XVI with a compound of formula XVII: Li_ CHO

R._ __N. _NH, | Ps Or t—, a 2 yz (XVI) (XVID) wherein X1, X2, Rl, R2, Y and Z are as defined in claim 1, and L3 represents a suitable leaving group; or (H) reacting a compound of formula XXI with a compound of formula XXII: LY N “ he ~ NZ Rr? R*® — M: Y—2 (XXI) (XXII) wherein Y, Z and R? are as defined in claim 1, M?® is as defined above, R12 represents an aryl or heteroaryl moiety, and L* represents a suitable leaving group; in the presence of a transition metal catalyst; or (J) reacting a compound of formula XII as defined above with 2,5- dimethoxytetrahydrofuran; and

(K) where appropriate, converting a compound of formula I initially obtained into a further compound of formula I by standard methods.

19. A compound of formula I as defined in claim 1 or a pharmaceutically acceptable salt thereof or a prodrug thereof for use in the treatment and/or prevention of adverse neurological conditions.

20. 2-18-(4-Fluoro-3-(pyridin-3-yl)phenylimidazol1,2-alpyrimidin. 7-yllpropan-2-ol, or a pharmaceutically acceptable salt thereof.

21. The bis-hydrochloride salt of 2-[3-(4-fluoro-3-(pyridin-3- ylphenylimidazo[1,2-alpyrimidin-7-yllpropan-2-o].

22. A pharmaceutical composition comprising 2-[3-(4-fluoro-3- (pyridin-3-ylphenylimidazol1,2-alpyrimidin-7-yllpropan-2-l, ora pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier.

23. A pharmaceutical composition comprising the bis- hydrochloride salt of 2-13-(4-fluoro-3-(pyridin-3-yl)phenylimidazo[1,2- : alpyrimidin-7-yllpropan-2-ol in association with a pharmaceutically acceptable carrier.

24. The use of 2-{8-(4-fluoro-3-(pyridin-3-ybphenylimidazo(1,2- alpyrimidin-7-yl]propan-2-ol, ora pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment and/or prevention of anxiety. AMENDED SHEET

25. The use of the bis-hydrochloride salt of 2-[3-(4-fluoro-3- (pyridin-3-yl)phenyl)imidazo(1,2-a]pyrimidin-7-yllpropan-2-ol for the manufacture of a medicament for the treatment and/or prevention of anxiety.

26. 2-[3-(4-fluoro-3-(pyridin-3-yl)phenyl)imidazo[1,2-a] pyrimidin-7- yl]propan-2-ol, or a pharmaceutically acceptable salt thereof for use in the treatment and/or prevention of anxiety.

27. The bis-hydrochloride salt of 2-[3-(4-fluoro-3-(pyridin-3- ylphenyl)imidazo[1,2-a]pyrimidin-7-yl] propan-2-ol for use in the treatment and/or prevention of anxiety. -

28. 4,2"-Difluoro-5"~(7-trifluoromethylimidazo(1,2-a]pyrimidin-3- yDbiphenyl-2-carbonitrile.

29. A pharmaceutical composition comprising 4,2'-difluoro-5'-(7- trifluoromethylimidazo(1,2-a]pyrimidin-3-yl)biphenyl-2-carbonitrile in association with a pharmaceutically acceptable carrier.

30. The use of 4,2’-difluoro-5’«(7-trifluoromethylimidazo[1,2- alpyrimidin-3-yl)biphenyl-2-carbonitrile for the manufacture of a medicament for the treatment and/or prevention of anxiety.

31. 4,2-difluoro-5'~(7-trifluoromethylimidazol[1,2-a]pyrimidin-3- yl)biphenyl-2-carbonitrile for use in the treatment and/or prevention of anxiety. AMENDED SHEET

-193A -

32. A compound as claimed in any one of claims 1, 19, 26, 27 or 31, substantially as herein described and exemplified.

33. A pharmaceutical composition as claimed in any one of claims 16, 22, 23 or 29, substantially as herein described and exemplified.

34. Use as claimed in any one of claims 17, 24, 25 or 30, substantially as herein described and exemplified.

35. A process as claimed in claim 18, substantially as herein described and exemplified. AMENDED SHEET