AU2006303037A1 - Chromenones and their use as modulators of metabotropic glutamate receptors - Google Patents

Description

WO 2007/045876 PCT/GB2006/003888 CHROMENONES AND THEIR USE AS MODULATORS OF METABOTROPIC GLUTAMATE RECEPTORS FIELD OF THE INVENTION 5 The present invention is concerned with novel metabotropic glutamate receptor (mGluR) modulators, methods for their synthesis and the treatment and/or prevention of neurological disorders by administration of such substances. 10 BACKGROUND OF THE INVENTION Neuronal stimuli are transmitted by the central nervous system (CNS) through the interaction of a neurotransmitter released by a neuron, which neurotransmitter has a specific effect on a neuroreceptor of another neuron. 15 L-glutamic acid is considered to be the major excitatory neurotransmitter in the mammalian CNS, consequently playing a critical role in a large number of physiological processes. Glutamate-dependent stimulus receptors are divided into two main groups. The first group comprises ligand-controlled ion channels whereas the-econd cmp6rises -metabotropic glutamate receptors 20 (mGluR). Metabotropic glutamate receptors are a subfamily of G-protein coupled receptors (GPCR). There is increasing evidence for a peripheral role of both ionotropic and metabotropic glutamate receptors outside of the CNS e.g., in chronic pain states. 25 At present, eight different members of these mGluRs are known. On the basis of structural parameters such as sequence homology, the second messenger system utilized by these receptors and their different affinity to low-molecular weight compounds, these eight receptors can be divided into three groups: mGluR1 and mGluR5 belong to Group I which couple to 30 phospholipase C and their activation leads to intracellular calcium-ion mobilization. Both mGluR2 and mGluR3 belong to Group I and mGluR4, mGluR6, mGluR7 and mGluR8 belong to Group l1l, which couple to adenyl 1 WO 2007/045876 PCT/GB2006/003888 cyclase with their activation causing a reduction in second messenger cAMP and as such a dampening of the neuronal activity. Group I mGluR modulators have been shown to modulate the effects of the 5 presynaptically released neurotransmitter glutamate via postsynaptic mechanisms. Moreover, as these modulators can be both positive and/or negative Group I mGluR modulators, such modulators may increase or inhibit the effects of these metabotropic receptors. Since a variety of pathophysiological processes and disease states affecting the CNS are 10 thought to be related to abnormal glutamate neurotransmission, and Group I mGluRs are shown to be expressed in several areas of the CNS, modulators of these receptors could be therapeutically beneficial in the treatment of CNS diseases. 15 Therefore, group I mGluR modulators may be administered to provide neuroprotection in acute and chronic pathological conditions such as: AIDS related dementia, Alzheimer's disease, Creutzfeld-Jakob's syndrome, bovine spongiform encephalopathy (BSE) or other prion related infections, diseases involving mitochondrial dysfunction, diseases involving B-amyloid 20 and/or tauopathy such as Down's syndrome, hepatic encephalopathy, Huntington's disease, motor neuron diseases such as amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), olivoponto-cerebellar atrophy, post operative cognitive deficit (POCD), Parkinson's disease, Parkinson's dementia, mild cognitive impairment, dementia pugilistica, vascular and 25 frontal lobe dementia, cognitive impairment, eye injuries or diseases (e.g. glaucoma, retinopathy, macular degeneration), head and brain and spinal cord injuries / trauma, hypoglycaemia, hypoxia (e.g. perinatal), ischaemia (e.g. resulting from cardiac arrest, stroke, bypass operations or transplants), convulsions, epilepsy, temporal lope epilepsy, glioma and other tumours, 30 inner ear insult (e.g. in tinnitus, sound- or drug-induced), L-Dopa-induced and tardive dyskinesias. 2 WO 2007/045876 PCT/GB2006/003888 Other indications in this context include a symptomatological effect on the following conditions: abuse and addiction (nicotine, alcohol, opiate, cocaine, amphetamine, obesity and others), amyotrophic lateral sclerosis (ALS), anxiety and panic disorders, attention deficit hyperactivity disorder (ADHD), 5 restless leg syndrome, hyperactivity in children, autism, convulsions, epileptic convulsions, epilepsy, temporal lobe epilepsy, dementia (e.g. in Alzheimer's disease, Korsakoff syndrome, vascular dementia, HIV infections), major depressive disorder or depression (including that resulting from Borna virus infection) and bipolar manic-depressive disorder, drug 10 tolerance (e.g. to opioids), movement disorders, dystonia, dyskinesia (e.g. L Dopa-induced, tardive dyskinesia or in Huntington's disease), fragile-X syndrome, chorea, Huntington's chorea, irritable bowel syndrome (IBS), migraine, multiple sclerosis (MS), muscle spasms, pain (chronic and acute, e.g. inflammatory pain, neuropathic pain, allodynia, hyperalgesia, 15 nociceptive pain), Parkinson's disease, post traumatic stress disorder, schizophrenia (positive and negative symptoms), spasticity, tinnitus, Tourette's syndrome, urinary incontinence , vomiting, pruritic conditions (e.g. pruritis), sleep disorders, micturition disorders, neuromuscular disorder in the - lower urinary tract, gastroesophageal reflux disease (GERD), lower 20 esophageal sphincter (LES) disease, functional gastrointestinal disorders, dyspepsia, regurgitation, respiratory tract infection, bulimia nervosa, chronic laryngitis, asthma (e.g. reflux-related asthma), lung disease, eating disorders, obesity, obesity-related disorders, binge eating disorders, agoraphobia, generalized anxiety disorder, obsessive-compulsive disorder, 25 panic disorder, anxiety disorder, posttraumatic stress disorder, social phobia, substance-induced anxiety disorder, delusional disorder, schizoaffective disorder, schizophreniform disorder, substance-induced psychotic disorder and delirium. 30 Yet further indications for Group I mGluR modulators include those indications wherein a particular condition does not necessarily exist but wherein a particular physiological parameter may be improved through 3 WO 2007/045876 PCT/GB2006/003888 administration of the instant compounds, for example cognitive enhancement. Positive modulators may be particularly useful in the treatment of positive 5 and negative symptoms in schizophrenia and cognitive deficits in various forms of dementia and mild cognitive impairment. THE PRESENT INVENTION We have determined that certain chromenones are Group I mGluR 10 modulators. Therefore, these substances may be therapeutically beneficial in the treatment of conditions which involve abnormal glutamate neurotransmission or in which modulation of Group I mGluR receptors results in therapeutic benefit. These substances are preferably administered in the form of a pharmaceutical composition, wherein they are present 15 together with one or more pharmaceutically acceptable diluents, carriers, or excipients. OBJECTS OF THE INVENTION -It is an object of the present invention to provide- novel pharmaceutical 20 compounds which are chromenone Group I mGIuR modulators and pharmaceutical compositions thereof. It is a further object of the invention to provide a novel method of treating, eliminating, alleviating, palliating, or ameliorating undesirable CNS disorders which involve abnormal glutamate neurotransmission by employing a compound of the invention or a 25 pharmaceutical composition containing the same. An additional object of the invention is the provision of a process for producing the chromenone active principles. Yet additional objects will become apparent hereinafter, and still further objects will be apparent to one skilled in the art. 30 SUMMARY OF THE INVENTION What we therefore believe to be comprised by our invention may be summarized inter alia in the following words: 4 WO 2007/045876 PCT/GB2006/003888 A compound of Formula I R0 5 R R1 6 2 R R2 5 wherein

R

1 represents hydrogen, C1.

6 alkyl, aryl, heteroaryl or -C(=0)-Rlo

R

2 represents hydrogen, C1.

6 alkyl, aryl, heteroaryl, arylC1.

6 alkyl, heteroarylC 1

.

6 alkyl, cyano, nitro, halogen, hydroxy or C2.6 alkoxy; 10 or R 1 and R 2 together represent -W 1

-X

1

-Y

1

-Z

1 -, wherein W1 represents -a single bond, oxygen,-sulfur, -NR 7 -- or -CR 8 R-, and X1, Yi and Z' each independently represents oxygen, sulfur, -NR 7 - or 15 -CR"R 9 -;

R

3 represents hydrogen, C 1

.

6 alkyl, aryl, heteroaryl, nitro, amino, C 1

.

6 alkoxy, halogen, hydroxy, -C(=0)-Rl 0 , -N(R)-C(=0)-R 0 , -N(R11)SO2-R1O, -N(R")C(=0)OR11, -C(=0)N(R'1)2, -C1.ealkylene 20 C(=O)N(R'1)2, -N(R")C(=S)N(R")2, -N(R")C(=0)N(R'1)2,

C

1

.

6 alkylamino, di-C 1 . alkylamino, cycloC 3

-

1 2 alkylamino, cycloC 3 -12 alkylaminoC 1

-

6 alkyl, cycloC 3

-

1 2 alkyl-C 1 .ealkylamino, di-C 1

.

6 alkylaminoC1.

6 alkyl, C 1

.

6 alkoxy-C 2

-

6 alkylamino, arylamino, arylC1.6 alkylamino, N-cycloC 3

-

1 2 alkyl-N-C1.

6 alkylamino, N-aryl-N-C1.

6 25 alkylamino, N-arylC 1

-

6 alkyl-N-C 1

.

6 alkylamino, pyrrolidino, piperidino, 4-arylpiperidino, 4-heteroarylpiperidino, morpholino, morpholinoC 1

.

6 5 WO 2007/045876 PCT/GB2006/003888 alkyl, piperazino, 4-C 1

.

6 alkylpiperazino, 4-arylpiperazino, hexamethyleneimino, heteroarylamino or heteroarylC.6 alkylamino;

R

4 represents hydrogen, halogen, nitro, amino, hydroxy, -OR 12 , 5 -SO 3

CF

3 , C 1

.

6 alkyl, cycloC3-12alkyl, cycIoC31 2 alkyl-C.i6alkyl, C 2

-

6 alkenyl, C2- 6 alkynyl, aryl, biaryl, arylC 1

.

6 alkyl, arylC 2

-

6 alkenyl, aryIC2-6 alkynyl, heteroaryl, heteroarylC 1 .- alkyl, heteroaryC 2

-

6 alkenyl, heteroarylthio, 2,3-dihydro-1 H-indenyl, C 1

.

6 alkoxyC1.

6 alkyl, aryloxyarylC1.6alkoxy, C 1

.

6 alkylthio, C4.6 alkenylthio, CyCIOC3-12 10 alkylthio, cycloC 3 -1 2 alkyl-C1.

6 alkylthio, cycIoC 3 -12 alkyl-C 3

-

6 alkenylthio,

C

1

.

6 alkoxyC.

6 alkylthio, C1.

6 alkoxyC 3

-

6 alkenylthio, aryIC 3

-

6 alkenylthio, heteroaryC 1

.

6 alkylthio, C 1

.

6 alkylsulfonyl, CYCIOC3-12 alkyl-C 1

.

6 alkylsulfonyl, aryIC 1

.

6 alkylsulfonyl, C 1

.

6 alkylamino, di-C1.

6 alkylamino, cycloC 3

-

1 2 alkylamino, C1.

6 alkoxycycloC 3 -1 2 alkylamino, 15 CyCIOC3-12 alkylCI 1 -6 alkylamino, di-C 1 .alkylaminoC1.

6 alkyl, C 1

.

6 alkoxy C2-6 alkylamino, arylamino, arylC.

6 alkylamino, N-cycloC 3

-

12 alkyl-N

C

1

.

6 alkylamino, N-aryi-N-C 1

.

6 alkylamino, N-arylC1..alkyl-N-C1 alkylamino, 2-indanylamino, tetrahydrofuryl, pyrrolidino, piperidino, 4 arylpiperidino, 4-heteroarypiperidino, morpholino, piperazino, 4-C.-6 20 alkylpiperazino, 4-arylpiperazino, hexamethyleneimino, benzazepinyl, 1,3-dihydro-2H-isoindol-2-yl, heteroaryIC.6alkoxy, heteroarylamino, heteroarylCl-6 alkylamino, -N(R)C(=0)-Rl 0 , -N(R' 1 )S0 2

-R

10 , -N(R")C(=0)OR", -C(=0)N(R")2, -C1.6alkylene-C(=0)N(R'1)2, -S-C(=0)N(R'1)2 or -O-C(=0)-Rlo; 25

R

5 represents hydrogen, halogen, nitro, amino, hydroxy, C 1

.

6 alkoxy, C1.6 alkyl, C 1

.

6 alkylamino, hydroxyC.

6 alkoxy, aryl, heteroaryl, OCF 3 , -N(R")C(=0)-R1, -N(R11)SO2-R10, -N(R")C(=0)OR", -C(=0)N(R")2, -C1.6alkylene-C(=0)N(R'1)2, -N(R")C(=S)N(R'1)2, 30 -N(R 1 )C(=0)N(R) 2 , -O-SO 2

R

0 or -C(=0)R 0 ;

R

6 represents hydrogen, C 1

.

6 alkyl, aryl, heteroaryl, halogen, hydroxy or C 1

.

6 alkoxy; 6 WO 2007/045876 PCT/GB2006/003888

R

7 represents hydrogen, C 1

.

6 alkyl, aryl, heteroaryl, arylC 1

.

6 alkyl, C1.6 alkoxy, halogen, hydroxy, cyano, nitro, hydroxyC.

6 alkyl, CyClOC 3

..

2 alkoxy, C 1

.

6 alkylamino, di-C 1

.

6 alkylamino, cycloC 3

.

12 alkylamino, 5 cycloC 3

-

12 alkyl-C 1

.

6 alkylamino, di-C 1

.

6 alkylaminoC 1

.

6 alkyl, arylamino, arylC 1

.

6 alkyl, N-aryl-N-C 1

.

6 alkylamino, pyrrolidino, piperidino, 4-C 1

.

6 alkylpiperazino, morpholino, hexamethyleneimino, pyrrolidinylC.

6 alkyl, piperidinylC 1

.

6 alkyl, morpholinylC 1

.

6 alkyl, C 1

.

6 alkylsulfonyl, C1.6 alkylthio, C 1

.

6 alkylaminosulfonyl or di-C 1

.

6 alkylaminosulfonyl; 10

R

8 and R 9 each independently represent hydrogen, C 1

.

6 alkyl, aryl, heteroaryl, arylC.6 alkyl, C 1

.

6 alkoxy, halogen, hydroxy, cyano, nitro, amino or cycloC 3

.

1 2 alkyl; 15 R 10 represents hydrogen, C1.

6 alkyl, cycloC3- 2 alkyl (e.g. adamantyl), aryl, heteroaryl or carboxyC 1

.

6 alkyl; R" represents hydrogen, C 1

.

6 alkyl, cycloC 3

.

12 alkyl (e.g. adamantyl), aryl, heteroaryl, carboxyCi.

6 alkyl or C 1

.

6 alkylcarbonyl; 20

R

12 represents C 1

.

6 alkyl optionally substituted by one or more (e.g. 1, 2, 3, 4 or more) substituents selected from hydroxy, cycloC 3

.

12 alkyl, C1.6 alkylamino, di-C 1

.

6 alkylamino, morpholino, halogen, arylamino and -C(=O)R 1 3; heteroaryl; cycloC3- 12 alkyl; C 1

.

6 alkoxycycloC 3

-

1 2 alkyl; 25 arylC 1

.

6 alkyl; aryloxyaryC 1 .alkyl and C2-6 alkenyl; and

R

13 represents amino, pyrrolidino or piperidino; or if R 1 and R 2 represent -W 1

-X

1

-Y

1 -Zl- and W 1 does not represent a 30 single bond,

R

3 and R 4 , R 4 and R9 or R 5 and R 6 together with the carbon atoms to which they are attached may form a 5-6 membered ring which may be saturated or unsaturated, wherein the ring 7 WO 2007/045876 PCT/GB2006/003888 may optionally have 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, and wherein the ring may be optionally substituted by one or more (e.g. 1, 2, 3, 4 or more) substituents selected from hydrogen, C1-6 alkyl, cycloC 3

-

12 alkyl, aryl, 5 heteroaryl, arylC 1

.

6 alkyl, carboxyC 1

.

6 alkyl, alkylcarbonyl, arylcarbonyl, oxo, thioxo, C 1

.

6 alkoxy, C1.6 alkylthio, arylC 1

.

6 alkylthio, arylC 1

.

6 alkoxy, morpholino, C3-6 cycloalkylamino, pyrrolidino, piperidino, hexamethyleneimino, piperazinyl, N-C 1

.

6 alkylpiperazinyl and arylamino; 10 wherein the term "C 1

.

6 alkyl", unless otherwise specified, denotes straight or branched chain groups which may be unsubstituted or substituted by one or more (e.g. 1, 2, 3, 4 or more) fluorine, chlorine and/or bromine atoms; the term "C 1

.

6 alkoxy" denotes straight or 15 branched chain groups which may be unsubstituted or substituted by one or more (e.g. 1, 2, 3, 4 or more) fluorine, chlorine and/or bromine atoms; the term "cycloC3- 12 alkyl" denotes monocyclic, bicyclic or tricyclic groups which may be unsubstituted or substituted by one or more (e.g. 1, 2, 3, 4 or more) fluorine, chlorine and/or bromine atoms; 20 the term "aryl" denotes phenyl or naphthyl or phenyl substituted by one or more (e.g. 1, 2, 3, 4 or more) substituents, which may be the same or different, selected from C 1

.

6 alkyl, C 2

-

6 alkenyl, C 1

.

6 alkoxy, cycloC3-1 2 alkyl, hydroxy, halogen, cyano, nitro, C 1

.

6 alkoxycarbonyl, amino, C 1 .ealkylamino, di-C 1

.

6 alkylamino, N-cycloC 3 .. 1 2 alkyl-N 25 C 1

.

6 alkylamino, azetidinyl, pyrrolyl, piperidinyl, morpholinyl, 4-C1.6 alkylpiperazinyl, tetrazolyl, oxazolyl, furyl, thiophenyl, isoxazolyl, thiazolyl, imidazolyl, oxadiazolyl, pyridinyl, pyrimidyl and C1.6 alkylenedioxy; and the term "heteroaryl" denotes an aromatic 5-6 membered ring containing from one to four heteroatoms selected 30 from oxygen, sulfur and nitrogen, or a bicyclic group comprising a 5-6 membered ring containing from one to four heteroatoms selected from oxygen, sulfur and nitrogen fused with a benzene ring or a 5-6 membered aromatic ring containing from one to four heteroatoms 8 WO 2007/045876 PCT/GB2006/003888 selected from oxygen, sulfur and nitrogen, wherein the heteroaryl group may be optionally substitued by one or more (e.g. 1, 2, 3, 4 or more) substituents, which may be the same or different, selected from

C

1

.

6 alkyl, C 1

.

6 alkoxy, cycloC 3 -1 2 alkyl, hydroxy, halogen, cyano, nitro, 5 C 1

.

6 alkoxycarbonyl, amino, C.

6 alkylamino, di-C1.

6 alkylamino, N cycloC 3

..

1 2 alkyl-N-C 1

.

6 alkylamino, azetidinyl, pyrrolyl, piperazinyl, morpholinyl, 4-C 1

.

6 alkylpiperazinyl, tetrazolyl, oxazolyl, furyl, thiophenyl, isoxazolyl, thiazolyl, imidazolyl, oxadiazolyl, pyridinyl, pyrimidyl and phenyl; 10 and optical isomers, pharmaceutically acceptable salts, hydrates, solvates, and polymorphs thereof; with the proviso that the compounds of Formula I do not include: 15 chromen-2-one, 2-chloro-3-isopropoxy-7,8,9,1 0-tetrahydrobenzo[c]chromen-6-one, 3-(2-chlorobenzyloxy)-7,8,9,1 0-tetrahydrobenzo[c]chromen-6-one, 2-chloro-3-(2-chlorobenzyloxy)-7,8,9,1 0-tetrahydrobenzo[clchromen 6-one, 20 3-(1 -phenylethoxy)benzo[c]chromen-6-one, 8-hexyl-7-methoxy-2,3-dihydro-1 H-cyclopenta[c]chromen-4-one, 2-chloro-3-methoxy-7,8,9,1 0-tetrahydrobenzo[c]chromen-6-one, 3-hydroxy-4-piperidin-1 -ylmethyl-7,8,9,10 tetrahydrobenzo[c]chromen-6-one, 25 2-chloro-3-hydroxy-9-methyl-7,8,9,1 0-tetrahydrobenzo[c]chromen-6 one, 6-chloro-7-hydroxy-4-trifluoromethylchromen-2-one, 2-chloro-3-hydroxy-4-morpholin-4-ylmethyl-7,8,9,1 0-tetrahydro benzo[c]chromen-6-one, 30 2-chloro-4-dimethylaminomethyl-3-hydroxy-7,8,9,1 0-tetrahydro benzo[c]chromen-6-one, 2-ethyl-3-hydroxy-7,8,9,1 0-tetrahydrobenzo[c]chromen-6-one, 2,3-dimethoxy-7,8,9,1 0-tetrahydrobenzo[c]chromen-6-one, 9 WO 2007/045876 PCT/GB2006/003888 2-hydroxy-3-methoxy-7,8,9,1 0-tetrahydrobenzo[c]chromen-6-one, 2-chloro-3-(2-methylallyloxy)-7,8,9,1 0-tetrahydrobenzo[c]chromen-6 one, 3-allyloxy-2-chloro-7,8,9,1 0-tetrahydrobenzo[c]chromen-6-one, 5 2-chloro-3-hydroxy-7,8,9,1 0-tetrahydrobenzo[c]chromen-6-one, 2-hexyl-3-methoxy-7,8,9,1 0-tetrahydrobenzo[clchromen-6-one, 8-chloro-7-isopropoxy-2,3-dihydro-1 H-cyclopenta[c]chromen-4-one, 8-chloro-7-hydroxy-2,3-dihydro-1 H-cyclopenta[c]chromen-4-one, 3-(adamantane-1 -carbonyl)-6-methoxychromen-2-one, 10 3-(adamantane-1 -carbonyl)-6-bromochromen-2-one, 3-(adamantane-1 -carbonyl)chromen-2-one, 3-isopropoxy-7,8,9,1 0-tetrahydrobenzo[c]chromen-6-one, 2-chloro-3-(3-methylbut-2-enyloxy)-7,8,9,10 tetrahydrobenzo[c]chromen-6-one, 15 8-isopropoxy-1,2,3,4-tetrahydrochromeno[3,4-c]pyridin-5-one, 3-amino-7,8,9,1 0-tetrahydrobenzo(c]chromen-6-one, 3-isopropylamino-7,8,9,1 0-tetrahydrobenzo[c]chromen-6-one, 3-amino-2-chloro-7,8,9,1 0-tetrahydrobenzo[c]chromen-6-one, 6-chloro-3-imidazo[1,2-a]pyridin-2-ylchromen-2-one, 20 3-pyridin-2-yl-3,4,7,8,9,1 0-hexahydro-2H-1,5-dioxa-3-azachrysen-6 one or 6-chloro-3-imidazo[1,2-a]pyridin-2-ylchromen-2-one. Such a compound of Formula I wherein R' represents hydrogen or 25 -C(=O)-R 0 . Such a compound of Formula I wherein R 1 0 represents adamantyl. Such a compound of Formula I wherein R 2 represents hydrogen, aryl, heteroaryl or C 1

.

6 alkyl. 30 Such a compound of Formula I wherein R 2 represents phenyl or pyridyl. Such a compound of Formula I wherein R 1 and R 2 together represent 10 WO 2007/045876 PCT/GB2006/003888 -WI-xI-YI-zI-, wherein

W

1 represents a single bond or -CR 8 R9-, and X1, Y', and Z' each independently represent -CR 8

R

9 -, wherein R 8 and R 9 are each 5 independently selected from hydrogen, C 1

.

6 alkyl, aryl and heteroaryl. Such a compound of Formula I wherein R 8 represents hydrogen and R 9 represents hydrogen, C 1

.

6 alkyl, aryl or heteroaryl. 10 Such a compound of Formula I wherein R 9 represents hydrogen, methyl, ethyl, trifluoromethyl, t-butyl, phenyl or pyridyl. Such a compound of Formula I wherein R 9 represents hydrogen, methyl or trifluoromethyl. 15 Such a compound of Formula I wherein R 3 represents hydrogen, C 1

.

6 alkyl, morpholinoC 1

.

6 alkyl, amino, nitro, -N(R 1 )C(=0)N(R 1

)

2 , -N(R 1 1)S0 2

-R

10 , C1.6 alkylamino or -N(R 1

)C(=O)-R

1 0 . 20 Such a compound of Formula I wherein R 4 represents halogen, hydroxy,

OR

12 , -S-C(=O)N(R")2, -C(=O)N(R' 1 )2, C 1 .ealkylthio, C1.6 alkylsulfonyl, morpholino, pyrrolidino, arylC 1 .alkylamino, -N(R)C(=O)-Rl0, heteroarylthio, -O-C(=O)-Rl0, di-C 1

.

6 alkylamino or heteroaryl. 25 Such a compound of Formula I wherein R 4 represents halogen, OR 2 ,

-S-C(=O)N(R)

2 , -C(=O)N(R") 2 , C 1

.

6 alkylthio or di-C 1

.

6 alkylamino. Such a compound of Formula I wherein R 12 represents C 1

.

6 alkyl optionally substituted by one or more substituents selected from hydroxy, di-C.

6 30 alkylamino, morpholino, halogen, cycloC3.

12 alkyl, arylamino and -C(=0)R1 3 (e.g. as in CF 3 or CHF 2 ); cycloC 3 1 2 alkyl; C 1

.

6 alkoxycycloC 3

.

12 alkyl or heteroaryl. 11 WO 2007/045876 PCT/GB2006/003888 Such a compound of Formula I wherein R 4 represents bromo, methoxy, iso propoxy, -C(=O)N(R)2, isopropylsulfanyl, difluoromethoxy, dimethylamino or diethylamino. 5 Such a compound of Formula I wherein R" represents hydrogen or C 1

.

6 alkyl. Such a compound of Formula I wherein R" represents methyl. 10 Such a compound of Formula I wherein R9 represents hydrogen, nitro, halogen, C 1 .ealkyl, hydroxy C 1

.

6 alkoxy, -C(=O)-Rl 0 , -N(R)SO 2

-R

10 , -N(R")C(=O)-Rlo or C 1

.

6 alkylamino. Such a compound of Formula I wherein R 5 represents hydrogen, nitro, 15 chloro or ethyl. Such a compound of Formula I wherein R 6 represents hydrogen or C 1

.

6 alkyl. Such a-compound of Formula I wherein R 3 and R 4 together with the carbon 20 atoms to which they are attached form a 5-6 membered ring which may be saturated or unsaturated, wherein the ring has 1 or 2 heteroatoms selected from oxygen and nitrogen and may optionally be substituted by one or more substituents selected from C 1

.

6 alkyl, C..

6 alkylthio, C 1

.

6 alkoxy, oxo, arylC1.e alkyl, aryl, arylC 1

.

6 alkylthio and morpholino. 25 Such a compound of Formula I wherein R 4 and R 5 together with the carbon atoms to which they are attached form a 5-6 membered ring which may be saturated or unsaturated, wherein the ring has 1 or 2 heteroatoms selected from oxygen and nitrogen and may optionally be substituted by one or more 30 substituents selected from heteroaryl, piperazinyl, N-C 1

.

6 alkylpiperazinyl, arylamino, arylC 1

.

6 alkylthio, morpholino, C 1

.

6 alkylthio, oxo, thioxo, arylcarbonyl, aryl, C 1

.

6 Ealkoxy, arylC 1

.

6 alkyl and cycloC 3

-

1 2 alkyl. 12 WO 2007/045876 PCT/GB2006/003888 Such a compound of Formula I wherein R 5 and R 6 together with the carbon atoms to which they are attached form a 5-6 membered ring which may be saturated or unsaturated, wherein the ring has 1 or 2 heteroatoms selected from oxygen and nitrogen and may optionally be substituted by one or more 5 substituents selected from heteroaryl, oxo, thioxo, aryl, C1.alkyl and C1.6 alkoxy. Such a compound of Formula I selected from: N-acetyl-N-(2-chloro-3-isopropoxy-6-oxo-7,8,9,1 0-tetrahydro-6H 10 benzo[clchromen-4-yl)acetamide, N-(2-chloro-3-isopropxy-6-oxo-7,8,9, 1 0-tetrahydro-6H-benzo[c]chromen 4-yl)benzamide, N-(3-isopropxy-6-oxo-7,8,9,1 0-tetrahydro-6H-benzo[c]chromen-2 yl)isobutyramide, 15 N-(2-ch loro-3-isopropxy-6-oxo-7,8,9,1 0-tetrahydro-6H-benzo[c]chromen 4-yl)formamide, N-(2-chloro-3-isopropoxy-6-oxo-7,8,9,1 0-tetrahydro-6H benzo[c]chromen-4-yl)succinamic acid, dimethylthiocarbamic acid 6-oxo-7,8,9,10-tetrahydro-6H 20 benzo[c]chromen-3-yl ester, S-(N,N-dimethylcarbamoyl)-2-chloro-8-phenyl-3-thio-7,8,9,10 tetrahydrobenzo[c]chromen-6-one, 2-chloro-3-(pyridin-2-ylsulfanyl)-7,8,9,1 0-tetrahydrobenzo[c]chromen-6 one, 25 S-(N,N-d imethylcarbamoyl)-8-ethyl-2-chloro-6-oxo-3-thio-7,8,9,1 0 tetrahydro-6H-benzo[c]chromen-6-one, and 12-chloro-1 6-isopropylsulfanyl-1,2,3,4-tetrahydro-7,17-dioxa-1 5 azacyclopenta[a]phenanthren-6-one. 30 Such a compound of Formula I selected from: 3-(adamantane-1 -carbonyl)-7-methoxychromen-2-one, 3-(adamantane-1 -carbonyl)-7-dimethylaminochromen-2-one, 3-(adamantane-1 -carbonyl)-7-diethylaminochromen-2-one, 13 WO 2007/045876 PCT/GB2006/003888 3-(adamantane-1 -carbonyl)-7-bromochromen-2-one, 2-chloro-3-isopropoxy-9-methyl-7,8,9,1 0-tetrahydrobenzo[c]chromen-6 one, 2-chloro-3-isopropoxy-8-trifluoromethyl-7,8,9,10 5 tetrahydrobenzo[c]chromen-6-one, dimethylthiocarbamic acid S-(2-chloro-9-methyl-6-oxo-7,8,9,10 tetrahydro-6H-benzo[c]chromen-3-yl) ester, dimethylthiocarbamic acid S-(2-chloro-6-oxo-7,8,9,1 0-tetrahydro-6H benzo[c]chromen-3-yl) ester, 10 3-isopropoxy-2-nitro-7,8,9,1 0-tetrahydrobenzo[c]chromen-6-one, 2-chloro-3-isopropylsulfanyl-7,8,9,1 0-tetrahydrobenzo[c]chromen-6-one, 2-ethyl-3-isopropoxy-7,8,9,1 0-tetrahydrobenzo[c]chromen-6-one, 2-chloro-3-difluoromethoxy-7,8,9,1 0-tetrahydrobenzo[c]chromen-6-one, 7-isopropoxy-8-nitro-2,3-dihydro-1 H-cyclopenta[c]chromen-4-one, and 15 2-chloro-3-isopropoxy-7-methyl-7,8,9, 1 0-tetrahydrobenzo[c]chromen-6 one. Moreover, a compound of Formula I as hereinbefore defined or an optical isomer, pharmaceutically acceptable salt, ester, hydrate, solvate or 20 polymorph thereof, subject to the modified proviso that the compound of Formula I may additionally be 2-chloro-3-methoxy-7,8,9,10 tetrahydrobenzo[c]chromen-6-one, 2-chloro-3-isopropoxy-7,8,9, 10 tetrahydrobenzo[c]chromen-6-one or 8-chloro-7-isopropoxy-2,3-dihydro-1H cyclopenta[c]chromen-4-one, for use as a medicament. 25 Moreover, a pharmaceutical composition comprising as active ingredient a compound of the invention as hereinbefore defined, together with one or more pharmaceutically acceptable excipients or vehicles. 30 Moreover, use of a compound of the invention as hereinbefore defined but not subject to the foregoing proviso to Formula I as or in the manufacture of a medicament for prevention and/or treatment of a condition associated with 14 WO 2007/045876 PCT/GB2006/003888 abnormal glutamate neurotransmission or in which modulation of Group I mGluR receptors results in therapeutic benefit or for enhancing cognition. Furthermore, a method for treating or preventing a condition or disease 5 associated with abnormal glutamate neurotransmission or a method for modulating Group I mGluR receptors to achieve therapeutic benefit, or a method for enhancing cognition, such method comprising administering to a living animal, including a human, a therapeutically effective amount of a compound of the invention as hereinbefore defined but not subject to the 10 foregoing proviso to Formula 1. Such a use or method wherein the condition associated with abnormal glutamate neurotransmission, or wherein modulation of mGluR receptors results in therapeutic benefit, is selected from: AIDS-related dementia, 15 Alzheimer's disease, Creutzfeld-Jakob's syndrome, bovine spongiform encephalopathy (BSE) or other prion related infections, diseases involving mitochondrial dysfunction, diseases involving R-amyloid and/or tauopathy such as Down's syndrome, hepatic encephalopathy, Huntington's disease, motor neuron diseases such as amyotrophic lateral sclerosis (ALS), multiple 20 sclerosis (MS), olivoponto-cerebellar atrophy, post-operative cognitive deficit (POCD), Parkinson's disease, Parkinson's dementia, mild cognitive impairment, dementia pugilistica, vascular and frontal lobe dementia, cognitive impairment, eye injuries or diseases (e.g. glaucoma, retinopathy, macular degeneration), head and brain and spinal cord injuries / trauma, 25 hypoglycaemia, hypoxia (e.g. perinatal), ischaemia (e.g. resulting from cardiac arrest, stroke, bypass operations or transplants), convulsions, epileptic convulsions, epilepsy, temporal lobe epilepsy, glioma and other tumours, inner ear insult (e.g. in tinnitus, sound- or drug-induced), L-Dopa induced and tardive dyskinesias, abuse and addiction (nicotine, alcohol, 30 opiate, cocaine, amphetamine, obesity and others), anxiety and panic disorders, attention deficit hyperactivity disorder (ADHD), restless leg syndrome, hyperactivity in children, autism, convulsions / epilepsy, dementia (e.g. in Alzheimer's disease, Korsakoff syndrome, vascular 15 WO 2007/045876 PCT/GB2006/003888 dementia, HIV infections), major depressive disorder or depression (including that resulting from Borna virus infection) and bipolar manic depressive disorder, drug tolerance (e.g. to opioids), movement disorders, dystonia, dyskinesia (e.g. L-Dopa-induced, tardive dyskinesia or in 5 Huntington's disease), fragile-X syndrome, Huntington's chorea, chorea, irritable bowel syndrome (IBS), migraine, multiple sclerosis, muscle spasms, pain (chronic and acute, e.g. inflammatory pain, neuropathic pain, allodynia, hyperalgesia, nociceptive pain), Parkinson's disease, post traumatic stress disorder, schizophrenia (positive and negative symptoms), spasticity, 10 tinnitus, Tourette's syndrome, urinary incontinence, vomiting, pruritic conditions (e.g. pruritis), sleep disorders, micturition disorders, neuromuscular disorder in the lower urinary tract, gastroesophageal reflux disease (GERD), lower esophageal sphincter (LES) disease, functional gastrointestinal disorders, dyspepsia, regurgitation, respiratory tract 15 infection, bulimia nervosa, chronic laryngitis, asthma (e.g. reflux-related asthma), lung disease, eating disorders, obesity and obesity-related disorders, binge eating disorders, agoraphobia, generalized anxiety disorder, obsessive-compulsive disorder, panic disorder, anxiety disorder, posttraumatic stress disorder, social phobia, substance-induced anxiety 20 disorder, delusional disorder, schizoaffective disorder, schizophreniform disorder, substance-induced psychotic disorder, delirium, or for cognitive enhancement and/or neuroprotection. Such a use or method wherein the condition associated with abnormal 25 glutamate neurotransmission, or wherein modulation of mGluR receptors results in therapeutic benefit, is selected from: addiction, neuropathic pain, L-Dopa-induced and tardive dyskinesias, ALS, fragile-X syndrome, Parkinson's disease, anxiety disorders, epilepsy, positive and/or negative symptoms of schizophrenia, cognitive impairment, or for cognitive 30 enhancement and/or neuroprotection. Such a use or method wherein the condition associated with abnormal glutamate neurotransmission, or wherein modulation of mGluR receptors 16 WO 2007/045876 PCT/GB2006/003888 results in therapeutic benefit, is selected from: neuropathic pain, diabetic neuropathic pain (DNP), cancer pain, pain related to rheumathic arthritis, inflammatory pain, L-Dopa-induced and tardive dyskinesias, Parkinson's disease, anxiety disorders, Huntington's chorea and/or epilepsy. 5 Such a use or method wherein the compound is administered in the form of a pharmaceutical composition thereof comprising the compound of Formula I in combination with one or more pharmaceutically-acceptable diluents, excipients, or carriers. 10 Such a use or method wherein the compound of Formula I is selected from: 3-(adamantane-1 -carbonyl)-7-methoxychromen-2-one, 3-(adamantane-1 -carbonyl)-7-dimethylaminochromen-2-one, 3-(adamantane-1 -carbonyl)-7-diethylaminochromen-2-one, 15 3-(adamantane-1-carbonyl)-7-bromochromen-2-one, 2-chloro-3-isopro poxy-9-methyl-7,8,9,1 0-tetrahydrobenzo[c]chromen-6 one, 2-chloro-3-isopropoxy-8-trifluoromethyl-7,8,9,1 0-tetrahydro benzo[c]chromen-6-one, 20 dimethylthiocarbamic acid S-(2-chloro-9-methyl-6-oxo-7,8,9,10 tetrahyd ro-6H-benzo[c]chromen-3-yl) ester, dimethylthiocarbamic acid S-(2-chloro-6-oxo-7,8,9,10-tetrahydro-6H benzo[c]chromen-3-y) ester, 3-isopropoxy-2-nitro-7,8,9,1 0-tetrahydrobenzo[c]chromen-6-one, 25 2-chloro-3-isopropylsulfanyl-7,8,9,1 0-tetrahydrobenzo[c]chromen-6-one, 2-ethyl-3-isopropoxy-7,8,9,1 0-tetrahydrobenzo[c]chromen-6-one, 2-chloro-3-difluoromethoxy-7,8,9,1 0-tetrahydrobenzo[c]chromen-6-one, 7-isopropoxy-8-nitro-2,3-dihydro-1 H-cyclopenta[c]chromen-4-one, 2-ch loro-3-iso propoxy-7-methyl-7,8,9,1 0-tetrahydrobenzo[c]chromen-6 30 one, 2-chloro-3-isopropoxy-7,8,9,1 0-tetrahydrobenzo[clchromen-6-one, 2-chloro-3-methoxy-7,8,9,10-tetrahydrobenzo[c]chromen-6-one, and 8-chloro-7-isopropoxy-2,3-dihydro-1 H-cyclopenta[c]chromen-4-one. 17 WO 2007/045876 PCT/GB2006/003888 Specific compounds of Formula I within the present invention include but are not limited to: 5 6-chloro-7-(4-fluorobenzyloxy)-4-phenylchromen-2-one, 7-(3-phenoxybenzyloxy)-4-phenylchromen-2-one, 7-(4-fluorobenzyloxy)-4-phenylchromen-2-one, 6-chloro-7-isopropoxy-4-trifluoromethylchromen-2-one, 6-chloro-7-hydroxy-4-pyridin-2-ylchromen-2-one, 10 6-chloro-7-hydroxy-4-pyridin-3-ylchromen-2-one, 6-chloro-7-hydroxy-4-pyridin-4-ylchromen-2-one, 6-chloro-7-isopropoxy-4-pyridin-4-ylchromen-2-one, 6-chloro-7-isopropoxy-4-pyrid in-2-ylchro men-2-one, 6-chloro-7-isopropoxy-4-pyridin-3-ylchromen-2-one, 15 3-(adamantane-1 -carbonyl)-7-methoxychromen-2-one, 3-(adamantane-1 -carbonyl)-7-dimethylaminochromen-2-one, 3-(adamantane-1 -carbonyl)-7-diethylaminochromen-2-one, 3-(adamantane-1 -carbonyl)-7-oxazol-2-ylchromen-2-one, - 3-(adamantane-1-carbonyl)-7-bromochromen-2-one, 20 3-isopropoxy-7,8,9,1 0-tetrahydrobenzo[c]chromen-6-one, 3-hydroxy-2-nitro-7,8,9,1 0-tetrahydrobenzo[c]chromen-6-one, 3-isopropoxy-2-nitro-7,8,9,1 0-tetrahydrobenzo[c]chromen-6-one, 2-amino-3-isopropoxy-7,8,9,1 0-tetrahydrobenzo[c]chromen-6-one, 2,2-dimethylpropionic acid 6-oxo-7,8,9,10-tetrahydro-6H-benzo[c]chromen 25 3-yl ester, 2-chloro-3-(2-oxo-2-pyrrolidin-1 -ylethoxy)-7,8,9,1 0 tetrahydrobenzo[c]chromen-6-onene, 2-ch loro-3-(2-oxo-2-piperid in-1 -ylethoxy)-7,8,9,10 tetrahydrobenzo[c]chromen-6-onene, 30 2-chloro-3-isopropoxy-9-methyl-7,8,9,1 0-tetrahydrobenzo[c]chromen-6-one, 2-chloro-3-hydroxy-8-trifluoromethyl-7,8,9,1 0-tetrahydrobenzo[c]chromen-6 one, 18 WO 2007/045876 PCT/GB2006/003888 2-chloro-3-isopropoxy-8-trifluoromethyl-7,8,9,1 0-tetrahyd robenzo[c]chro men 6-one, 2-chloro-3-(2-hydroxyethoxy)-7,8,9,1 0-tetrahydrobenzo[c]chromen-6-one, dimethylthiocarbamic acid S-(2-chloro-9-methyl-6-oxo-7,8,9,1 0-tetrahydro 5 6H-benzo[c]chromen-3-y) ester, 2-chloro-3-(2-dimethylaminoethoxy)-7,8,9,1 0-tetrahydrobenzo[c]chromen-6 one, dimethylthiocarbamic acid S-(2-chloro-6-oxo-7,8,9,10-tetrahydro-6H benzo[c]chromen-3-yl) ester, 10 2-chloro-3-isopropylsulfanyl-7,8,9,1 0-tetrahydrobenzo[c]chromen-6-one, 2-chloro-3-methylsulfanyl-7,8,9,1 0-tetrahydrobenzo[c]chromen-6-one, 2-chloro-3-methanesulfonyl-7,8,9,1 0-tetrahydrobenzo[c]chromen-6-one, 2-chloro-3-(2-hydroxy-3-morpholin-4-ylpropoxy)-7,8,9,1 0-tetrahydro benzo[c]chromen-6-one, 15 2-chloro-3-isopropoxy-4-morpholin-4-ylmethyl-7,8,9,1 0-tetrahydro benzo[c]chromen-6-one, 2-chloro-3-(3-dimethylamino-2-hydroxypropoxy)-7,8,9,1 0-tetrahydro benzo[c]chromen-6-one, 2-chloro-3-(3-diethylamino-2-hydroxypropoxy)-7,8,9,10-tetrahydro 20 benzo[c]chromen-6-one, 2-chloro-3-(2-hydroxy-3-isopropylaminopropoxy)-7,8,9,1 0-tetrahydro benzo[c]chromen-6-one, 2-chloro-3-cyclobutylmethoxy-7,8,9,1 0-tetrahydrobenzo[cchromen-6-one, 2-ethyl-3-isopropoxy-7,8,9,1 0-tetrahydrobenzo[c]chromen-6-one, 25 2-(2-hydroxyethoxy)-3-methoxy-7,8,9,1 0-tetrahydrobenzo[c]chromen-6-one, 4-amino-3-isopropoxy-7,8,9, I 0-tetrahydrobenzo[c]chromen-6-one, 2-methoxy-3-isopropoxy-7,8,9,1 0-tetrahydro-6H-benzo[c]chromen-6-one, 2-chloro-3-(2-hyd roxy-3-isopropylaminopropoxy)-7,8,9,10 tetrahydrobenzo[c]chromen-6-one hydrochloride, 30 2-chloro-3-hydroxy-4-nitro-7,8,9,1 0-tetrahydrobenzo[c]chromen-6-one, 2-chloro-3-(3-chloro-2-hydroxypropoxy)-7,8,9,10 tetrahydrobenzo[c]chromen-6-one, 19 WO 2007/045876 PCT/GB2006/003888 1-(3-isopropoxy-6-oxo-7,8,9,1 0-tetrahydro-6H-benzo[c]chromen-4-yl)-3 phenylurea, 2-chloro-3-(2-hydroxy-3-phenylaminopropoxy)-7,8,9,1 0-tetrahydro benzo[c]chromen-6-one hydrochloride, 5 1-(2,4-dichlorophenyl)-3-(3-isopropoxy-6-oxo-7,8,9,1 0-tetrahydro-6H benzo[c]chromen-4-yl)thiourea, 3-isopropoxy-4-nitro-7,8,9,1 0-tetrahydrobenzo[c]chromen-6-one, N-tosyl-4-amino-3-isopropoxy-7,8,9,1 0-tetrahydrobenzo[c]chromen-6-one, 2-chloro-3-isopropoxy-4-nitro-7,8,9,1 0-tetrahydrobenzo[c]chromen-6-one, 10 4-amino-2-chloro-3-isopropoxy-7,8,9,1 0-tetrahydrobenzo[c]chromen-6-one, 2-difluoromethoxy-3-methoxy-7,8,9,1 0-tetrahydrobenzo[c]chromen-6-one, 2-chloro-3-difluoromethoxy-7,8,9,1 0-tetrahyd robenzo[c]ch romen-6-o ne, trifluoromethanesulfonic acid 2-chloro-6-oxo-7,8,9,10-tetrahydro-6H benzo[c]chromen-3-yl ester, 15 3-benzyl-8-isopropoxy-1,2,3,4-tetrahydrochromeno[3,4-c]pyridin-5-one, 2-acetyl-3-methoxy-7,8,9,1 0-tetrahydrobenzo[c]chromen-6-one, 3-isopropoxy-4-methylamino-7,8,9,1 0-tetrahydrobenzo[c]chromen-6-one, N-(3-isopropoxy-6-oxo-7,8,9,10-tetrahydro-6H-benzo[c]chromen-4-yl) methanesulfonamide 20 N-acetyl-N-(3-isopropoxy-6-oxo-7,8,9,1 0-tetrahydro-6H-benzo[c]chromen-4 yl)acetamide, 2-chloro-N-(3-isopropoxy-6-oxo-7,8,9,1 0-tetrahydro-6H-benzo[c]chromen-4 yl)acetamide, N-(3-isopropoxy-6-oxo-7,8,9,1 0-tetrahydro-6H-benzo[c]chromen-2 25 yl)methanesulfonamide, N-(3-isopropoxy-6-oxo-7,8,9,1 0-tetrahydro-6H-benzo[c]chromen-2-yl)-4 methylbenzenesulfonamide, 3-isopropoxy-4-nitro-7,8,9,1 0-tetrahydrobenzo[c]chromen-6-one, N-acetyl-N-(3-isopropoxy-6-oxo-7,8,9,1 0-tetrahydro-6H-benzo[c]dhromen-2 30 yl)acetamide, N-acetyl-N-(2-chloro-3-isopropoxy-6-oxo-7,8,9,1 0-tetrahydro-6H benzo[c]chromen-4-yl)acetamide, 20 WO 2007/045876 PCT1GB20061003888 2-ch lo ro-N-(3-iso pro poxy-6-oxo-7,8,9, I 0-tetrahydrobenzo[c]cromen-2 yI)acetamide, I -(3-isopropoxy-6-oxo-7,8,9, I 0-tetrahydro-6H-benzo[c]chromen-2-y)-3 phenyl urea, 5 N-(3-iso pro poxy-6-oxo-7,8,9, I 0-tetrahydro-6H-benzo[c]chromen-2 yI)succinamic acid, N-(3-isopropoxy-6-oxo-7,8,9, I 0-tetrahydro-6H-benzo[c]chromen-2 yI)formamide, 3-isopropoxy-2-methylamino-7,8,9, I 0-tetrahydrobenzo[c]chromen-6-one, 10 2-chloro-3-morpholin-4-yI-7,8,9, I 0-tetrahydrobenzo[cjchromen-6-one, 3-benzylamino-2-chloro-7,8,9, I 0-tetrahydrobenzo[c]chromen-6-one, N-(3-isopropoxy-6-oxo-7,8,9, I 0-tetrahydro-6H-benzo[c]-chromen-2 yI)benzamide, N-(3-isopropoxy-6-oxo-7,8,9, I 0-tetrahydro-6H-benzo~c]-chromen-4 15 yI)benzamide, N-(2-ch lo ro-3-iso pro pxy-6-oxo-7,8,9, I 0-tetrahydro-6H-benzo[c]chromen-4 yI)benzamide, N-(3-isopropoxy-6-oxo-7,8 ,9,1 0-tetrahyd ro-6H-benzo[c]ch romen-2 yI)isobutyra-mide, 20 N-isobutyryl-N-(3-isopropoxy-6-oxo-7,8,9, I 0-tetrahyd ro-6H benzo[c]chromen-2-yI)isobutyramide, N-(3-iso pro poxy-6-oxo-7,8 ,9, I 0-tetrahydro-6H-benzo[c]chromen-4 yI )isobutyram ide, N-(2-chloro-3-isopropoxy-6-oxo-7,8 ,9,1 I -tetrahydro-6H-benzo[c]chromen-4 25 yl)formamide, N-(2-ch lo ro-3-i so pro poxy-6-oxo-7,8,9, I 0-tetrahyd ro-6H-benzo[c]chromen-4 yi)-4-methylbenzesulfonamide, N-(2-ch lo ro-3-iso pro poxy-6-oxo-7,8,9, I 0-tetrahydro-6H-benzo[c]chromen-4 yI)succinamic acid, 30 N-(2-chloro-3-isopropoxy-6-oxo-7 ,8 ,9, I 0-tetrahydro-6H-benzo[c]chromen-4 yI)-acetamide, 2-chloro-3-pyrrolidin-1 -yi-7,8 ,9,1 I -tetrahydrobenzo[c]chromen-6-one, 21 WO 2007/045876 PCT/GB2006/003888 dimethylthiocarbamic acid 6-oxo-7,8,9,10-tetrahydro-6H-benzo[c]chromen-3 yl ester, acetic acid 2-chloro-6-oxo-7,8,9,10-tetrahydro-6H-benzo[c]chromen-3-y ester, 5 2-chloro-3-ethoxy-7,8,9,1 0-tetrahydrobenzo[c]chromen-6-one, 2-chloro-3-propoxy-7,8,9,1 0-tetrahydrobenzo[c]chromen-6-one, 2-(2-chloro-6-oxo-7,8,9,1 0-tetrahydro-6H-benzo[c]chromen-3 yloxy)acetamide, N-(2-chloro-6-oxo-7,8,9,1 0-tetrahydro-6H-benzo[c]chromen-3-yl)acetamide, 10 S-(N,N-dimethylcarbamoyl)-8-tert-butyl-2-chloro-6-oxo-3-thio-7,8,9,1 0 tetrahydro-6H-benzo[c]chromen-6-one, S-(N,N-dimethylcarbamoyl)-2-chloro-8-phenyl-3-thio-7,8,9,10 tetrahydrobenzo[c]chromen-6-one, 3-methoxy-2-pyridin-2-yl-7,8,9,1 0-tetrahydrobenzo[c]chromen-6-one, 15 3-(pyridin-2-yloxy)-7,8,9,1 0-tetrahyd robenzo[c]ch romen-6-one, 2-chloro-3-(pyridin-2-ylsulfanyl)-7,8,9,1 0-tetrahydrobenzo[c]chromen-6-one, S-(N,N-dimethylcarbamoyl)-8-ethyl-2-chloro-6-oxo-3-thio-7,8,9,10 tetrahyd ro-6H-benzo[c]chro men-6-one, S-(N,N-dimethylcarbamoyl)-10-methyl-2-chloro-6-oxo-3-thio-7,8,9,10 20 tetrahyd ro-6H-be nzo[c]chromen-6-one, 12-chloro-1 6-thioxo-1,2,3,4,15,16-hexahydro-7,1 7-dioxa-1 5 azacyclopenta[a]phenanthren-6-one, 2-chloro-3-(4-methoxycyclohexyloxy)-7,8,9,1 0-tetrahydrobenzo[c]chromen 6-one, mixture of cis and trans isomers, 25 2,2-dimethylpropionic acid 6-oxo-7,8,9,10-tetrahydro-6H-benzo[c]chromen 3-yl ester, 12-chloro-1 6-isopropylsulfanyl-1,2,3,4-tetrahydro-7,17-dioxa-1 5 azacyclopenta[a]phenanthren-6-one, 12-chloro-1 6-methylsulfanyl-1,2,3,4-tetrahydro-7,17-dioxa-1 5 30 azacyclopenta[a]phenanthren-6-one, 12-chloro-1 6-ethyl-1,2,3,4-tetrahydro-7,17-dioxa-1 5 azacyclopenta[a]phenanthren-6-one, 22 WO 2007/045876 PCT/GB2006/003888 12-chloro-1 6-methyl-1,2,3,4-tetrahydro-7,17-dioxa-I 5 azacyclopenta[a]phenanthren-6-one, 15-benzyl-1,2,3,4-tetrahydro-1 5H-7,17-dioxa-1 5 azacyclopenta[a]phenanthren-6,1 6-dione, 5 15-isopropyl-1,2,3,4-tetrahydro-155H-7,17-dioxa-15 azacyclopenta[a]phenanthren-6,16-dione, 15-methyl-1,2,3,4-tetrahydro-I 5H-7,17-dioxa-1 5 azacyclopenta[a]phenanthren-6,1 6-dione, 16-phenyl-1,2,3,4-tetrahydro-7,17-dioxa-I 5-azacyclopenta[a]phenanthren-6 10 one, 16-ethyl-1,2,3,4-tetrahydro-7,17-dioxa-1 5-azacyclopenta[a]phenanthren-6 one, 1,2,3,4-tetrahydro-1 5H-7,17-dioxa-1 5-azacyclopenta[a]phenanthrene-6,16 dione, 15 1,2,3,4-tetrahydro-7,17-dioxa-1 5-azacyclopenta[a]phenanthren-6-one, 16-benzylsulfanyl-1 2-chloro-1,2,3,4-tetrahydro-7,17-dioxa-1 5 azacyclopenta[a]phenanthren-6-one, 12-chloro-16-morpholin-4-y -1,2,3,4-tetrahydro-7,17-dioxa-15 azacyclopenta[a]phenanthren-6-one, 20 9-(6-hydroxypyridin-3yl)-1,2,3,4-tetrahydro-6,8-dioxa-1 0 azacyclopenta[b]phenanthren-5-one, 9-(4-methylpiperazin-1 -yl-1,2,3,4-tetrahydro-6,8-dioxa-1 0 azacyclopenta[b]phenanthren-5-one, 9-piperazin-1 -yl-1,2,3,4-tetrahydro-6,8-dioxa-1 0 25 azacyclopenta[blphenanthren-5-one, 9-phenylamino-1,2,3,4-tetrahydro-6,8-dioxa-1 0 azacyclopenta[blphenanthren-5-one, 9-benzylsulfanyl-1,2,3,4-tetrahydro-6,8-dioxa-1 0 azacyclopenta[b]phenanthren-5-one, 30 9-morpholin-4-y-1,2,3,4-tetrahydro-6,8-dioxa-1 0 azacyclopenta[b]phenanthren-5-one, 9-pyridin-3-yl-1,2,3,4-tetrahydro-6,8-dioxa-1 0-azacyclopenta[b]phenanthren 5-one, 23 WO 2007/045876 PCT/GB2006/003888 9-pyridin-4-yl-1,2,3,4-tetrahydro-6,8-dioxa-1 0-azacyclopenta[b]phenanthren 5-one, 9-methylsulfanyl-1,2,3,4-tetrahydro-6,8-dioxa-1 0 azacyclopenta[b]phenanthren-5-one, 5 1 0-thiophen-2-yl-1,2,3,4-tetrahydro-6,8-dioxa-1 1-azabenzo[a]anthracene 5,9-dione, 9-isopropylsulfanyl-1 ,2,3,4-tetrahydro-6,8-dioxa-10 azacyclopenta[b]phenanthren-5-one, 9-benzoyl-1,2,3,4-tetrahydro-6,8-dioxa-1 0-azacyclopenta[b]phenanthren-5 10 one, 9-thioxo-1,2,3,4,9,1 0-hexahydro-6,8-dioxa-1 0-azacyclopenta[b]phenanthren 5-one, 9-isopropyl-1,2,3,4-tetrahydro-6,8-dioxa-I 0-azacyclopenta [b]phenanthren-5 one, 15 9-phenyl-1,2,3,4-tetrahydro-6,8-dioxa-1 0-azacyclopenta[b]phenanthren-5 one, I 0-isopropyl-1,2,3,4-tetrahydro-1 OH-6,8-dioxa-1 0 azacyclopenta[b]phenanthrene-5,9-dione, 1,2,3,4-tetrahydro-lO1H-6,8-dioxa-1 0-azacyclopenta[bjphenanthrene-5,9 20 dine, 9-ethyl-1,2,3,4-tetrahydro-6,8-dioxa-1 0-azacyclopenta[b]phenanthren-5-one, 9-methyl-1,2,3,4-tetrahydro-6,8-dioxa-1 0-azacyclopenta[b]phenanthren-5 one, 9-ethoxy-1,2,3,4-tetrahydro-6,8-dioxa-1 0-azacyclopenta[b]phenanthren-5 25 one, 4-methoxy-2-thioxo-1,2,8,9,10,11 -hexahydro-3,6-dioxa-1 azacyclopenta[c]phenanthren-7-one, 12-chloro -1,2,3,4-tetrahydro-7,17-dioxa-15-azacyclopenta[a]phenanthren-6 one, 30 4-methoxy-2-phenyl- 8,9,10,11 -tetrahydro-3,6-dioxa-1 azacyclopenta[c]phenanthren-7-one, 5-methoxy-2-thiophen-2-yl-9,10,11,12-tetrahydro-4,7-dioxa-1 azabenzo[c]phenanthrene-3,8-dione, 24 WO 2007/045876 PCT/GB2006/003888 4-methoxy-2-methyl- 8,9,10,11 -tetrahydro-3,6-dioxa-1 azacyclopenta[clphenanthren-7-one, 4-methoxy-8,9,10,11 -tetrahydro-1 H-3,6-dioxa-1 azacyclopenta[clphenanthren-2,7-dione, 5 4-methoxy-2-methylsulfanyl- 8,9,10,11 -tetrahydro-3,6-dioxa-1 azacyclopenta[c]phenanthren-7-one, 2-ethoxy-4-methoxy- 8,9,10,11 -tetrahydro-3,6-dioxa-1 azacyclopenta[c]phenanthren-7-one, 2-chloro-3-pyridin-2-yl-7,8,9,1 0-tetrahydrobenzo[c]chromen-6-one, 10 3-acetyl-2-chloro-7,8,9,1 0-tetrahydrobenzo[c]chromen-6-one, 7-isopropoxy-8-nitro-2,3-dihydro-1 H-cyclopenta[c]chromen-4-one, 9-(4-dimethylaminobenzy)-1,2,3,4-tetrahydro-6,8-dioxa-10-aza cyclopenta[b]phenanthren-5-one, 4-methoxy-2-pyridin-2-yI-8,9,10,11 -tetrahydro-3,6-dioxa-1 -aza 15 cyclopenta[c]phenanthren-7-one, 9-pyridin-2-yl-1,2,3,4-tetrahydro-6,8-dioxa-1 0-aza cyclopenta[b]phenanthren-5-one, 2-chloro-3-isopropoxy-8-pyridin-2-yl-7,8,9,1 0-tetrahydrobenzo[c]chromen-6 one, 20 2-chloro-3-isopropoxy-8-pyridin-3-yl-7,8,9,1 0-tetrahydrobenzo[c]chromen-6 one, 10-(3,5-difluoropheny)-1,2,3,4-tetrahydro-6,8-dioxa-1 1 azabenzo[a]anthracene-5,9-dione, 4-(5,9-dioxo-1,3,4,5-tetrahydro-2H,9H-6,8-dioxa-1 1-azabenzo[a]anthracen 25 1 0-yl)benzonitrile, 9-phenyt-2,3-dihydro-1 H-5,7-dioxa-1 0-azacyclopenta [a]anthracene-4,8 dione, 1 0-phenyl-1,2,3,4-tetrahydro-6,8-dioxa-1 I -azabenzo[a]anthracene-5,9 dione, 30 10-(4-methoxyphenyl)-1,2,3,4-tetrahydro-6,8-dioxa-1 1 azabenzo[a]anthracene-5,9-dione, 10-(3,4-dimethoxyphenyl)-1,2,3,4-tetrahydro-6,8-dioxa-1 1 -aza benzo[a]anthracene-5,9-dione, 25 WO 2007/045876 PCT/GB2006/003888 10-(4-trifluoromethylphenyl)-1,2,3,4-tetrahydro-6,8-dioxa-1 1-aza benzo[a]anthracene-5,9-d ione, 9-adamantan-1 -yl-1,2,3,4-tetrahydro-6,8-dioxa-1 0-aza cyclopenta[b]phenanthren-5-one, 5 10-(4-dimethylaminophenyl)-1,2,3,4-tetrahydro-6,8-dioxa-1 1 -aza benzo[a]anthracene-5,9-d ione, 2-chloro-3-isopropoxy-7-methyl-7,8,9,1 0-tetrahydrobenzo[c]chromen-6-one, 2-chloro-3-isopropoxy-9-pyridin-2-yl-7,8,9,1 0-tetrahydrobenzo[c]chromen-6 one 10 and optical isomers, pharmaceutically acceptable salts, hydrates, solvates, and polymorphs thereof. DETAILED DESCRIPTION OF THE INVENTION 15 For the purpose of the present invention, the carbon atom content of various hydrocarbon-containing moieties is indicated by a prefix designating the minimum and maximum number of carbon atoms in the moiety, i.e., the prefix Cs; indicates a moiety of the integer "i" to the integer "j" carbon atoms, inclusive. Thus, for-example, CIa 3 alkyl refers to alkyl of-one to three carbon 20 atoms, inclusive, (i.e., methyl, ethyl, propyl, and isopropyl), straight and branched forms thereof. As used herein, the following definitions are applicable unless otherwise described. The term "C 1

.

6 alkyl" comprises straight or branched chain alkyl 25 groups having 1, 2, 3, 4, 5 or 6 carbon atoms. Said alkyl groups may be unsubstituted and include, e.g., methyl, ethyl, n-propyl, 2-propyl, n-butyl, tert butyl. Further, these alkyl groups may optionally be substituted by one or more fluorine, chlorine and/or bromine atoms. Examples of these halogenated alkyl moieties include -CF 3 , -C 2

F

5 , -CBr 3 , and -CC13; thus, for 30 example, groups such as R 2 , R 4 , R6 and R 7

-R

1 1 may represent e.g. trifluoromethyl. The term "C1.6 alkoxy" comprises straight or branched chain

-O-C

1

.

6 alkyl groups wherein "C1.e alkyl" is defined as given hereinbefore. 26 WO 2007/045876 PCT/GB2006/003888 Examples of "C1.

6 alkoxy" include methoxy, ethoxy, n-propoxy, i-propoxy. A

C

1

.

6 alkoxy group optionally may be substituted by one or more fluorine, chlorine and/or bromine atoms thereby forming, for instance, -OCF 3 and

-OC

2

F

5 . The term "cycloC 3

-

12 alkyl" represents monocyclic, bicyclic or tricyclic 5 alkyl groups having 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms and includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[2.2.1]heptyl and adamantyl. A cycloC 3

.

1 2 alkyl group optionally may be substituted with one or more fluorine, chlorine and/or bromine atoms. In the context of the present invention the term "di-C 1

.

6 alkylamino" refers to an amino moiety in 10 which the nitrogen atom of the amino group is substituted with two C1-6 alkyl groups, which may be the same or different, as defined above. Examples of di-C 1

.

6 alkylamino groups include dimethylamino, diethylamino and N-methyl N-isopropylamino. The term "N-cycloC 3

-

1 2 alkyl-N-C 1

.

6 alkylamino" comprises amino groups in which the nitrogen atom of the amino group is substituted 15 by one C 1

.

6 alkyl group and one N-cycloC 3 -1 2 alkyl group. Both the C 1

.

6 alkyl group and the N-cycloC 3

-

1 2 alkyl group are defined as given hereinbefore. The term "4-C 1

.

6 alkyl-piperazinyl" comprises piperazinyl radicals bearing a

C

1

.

6 alkyl moiety at the nitrogen atom in 4-position of the piperazine ring, said

"C

1

..

6 alkyl" having the same meaning as given hereinbefore. The term aryl 20 represents phenyl or naphthyl or phenyl substituted by one or more substituents, which may be the same or different, selected from C 1

.

6 alkyl, which is optionally substituted with one or more fluorine, chlorine or bromine atoms, C 2

-

6 alkenyl, C 1 .salkoxy, which is optionally substituted with one or more fluorine, chlorine or bromine atoms, cycloC3-1 2 alkyl, hydroxy, halogen, 25 cyano, nitro, C 1

.

6 alkoxycarbonyl, amino, C1.6 alkylamino, di-C 1

.

6 alkylamino, N-cycloC 3

-

1 2 alkyl-N-C1.

6 alkylamino, azetidinyl, pyrrolyl, piperidinyl, morpholinyl, 4-C 1

.

6 alkyl-piperazinyl, tetrazolyl, oxazolyl, furyl, thiophenyl, isoxazolyl, thiazolyl, imidazolyl, oxadiazolyl, pyridinyl, pyrimidyl, and C1.6 alkylenedioxy. The term "heteroaryl" represents an aromatic 5-6 membered 30 ring containing from one to four heteroatoms selected from oxygen, sulfur and nitrogen, or a bicyclic group comprising a 5-6 membered ring containing from one to four heteroatoms selected from oxygen, sulfur and nitrogen fused with a benzene ring or a 5-6 membered ring containing from one to 27 WO 2007/045876 PCT/GB2006/003888 four heteroatoms selected from oxygen, sulfur and nitrogen, wherein the heteroaryl group may be optionally substitued by one or more substituents, which may be the same or different, selected from C 1 ..alkyl, which is optionally substituted with one or more fluorine, chlorine or bromine atoms, 5 C1..

6 alkoxy, which is optionally substituted with one or more fluorine, chlorine or bromine atoms, cycloC 3

..

1 2 alkyl, hydroxy, halogen, cyano, nitro, C1.6 alkoxycarbonyl, amino, C 1

.

6 alkylamino, di-C1.

6 alkylamino, N-cycloC 3

-

1 2 alkyl

N-C

1

.

6 alkylamino, azetidinyl, pyrrolyl, piperazinyl, morpholinyl, 4-C.

6 alkyl piperazinyl, tetrazolyl, oxazolyl, furyl, thiophenyl, isoxazolyl, thiazolyl, 10 imidazolyl, oxadiazolyl, pyridinyl, pyrimidyl and phenyl. Representative heteroaryl groups include unsubstituted or appropriately substituted pyrroles, oxazoles, thiophens, furans, isoxazoles, imidazoles, oxazoles, oxadiazoles, thiazoles, imidazolines, pyrazoles, oxazolidines, isoxazolidines, thiazolidines, pyridines, pyridazines, pyrimidines, pyrazines, azepines. The 15 term "halogen" represents fluorine, chlorine, bromine and iodine. The compounds of the present invention are named according to the IUPAC or CAS nomenclature system. Abbreviations which are well known to one of ordinary skill in the art may be used (e.g. "Ph" for phenyl, "Me" for methyl, 20 "Et" for ethyl, "h" for hour or hours, and "rt" for room temperature). The term "analog" or "derivative" is used herein in the conventional pharmaceutical sense, to refer to a molecule that structurally resembles a reference molecule, but has been modified in a targeted and controlled 25 manner to replace one or more specific substituents of the reference molecule with an alternate substituent, thereby generating a molecule which is structurally similar to the reference molecule. Synthesis and screening of analogs (e.g., using structural and/or biochemical analysis), to identify slightly modified versions of a known compound which may have improved 30 or biased traits (such as higher potency and/or selectivity at a specific targeted receptor type, greater ability to penetrate mammalian blood-brain barriers, fewer side effects, etc.) is a drug design approach that is well known in pharmaceutical chemistry. 28 WO 2007/045876 PCT/GB2006/003888 In addition, using methods known to those skilled in the art, analogs and derivatives of the compounds of the invention can be created which have improved therapeutic efficacy in controlling neurological conditions including 5 dementia, i.e., higher potency and/or selectivity at a specific targeted receptor type, either greater or lower ability to penetrate mammalian blood brain barriers (e.g., either higher or lower blood-brain barrier permeation rate), fewer side effects, etc. 10 The phrase "pharmaceutically acceptable", as used in connection with compositions of the invention, refers to molecular entities and other ingredients of such compositions that are physiologically tolerable and do not typically produce untoward reactions when administered to a mammal (e.g., human). Preferably, as used herein, the term "pharmaceutically 15 acceptable" means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in mammals, and more particularly in humans. 20 Compounds of the present invention may be in the form of pharmaceutically acceptable salts. "Pharmaceutically acceptable salts" refers to those salts which possess the biological effectiveness and properties of the parent compound and which are not biologically or otherwise undesirable. The nature of the salt or isomer is not critical, provided that it is non-toxic and 25 does not substantially interfere with the desired pharmacological activity. It will be appreciated by those skilled in the art that compounds of the invention having a chiral center may exist in and be isolated in optically active and racemic forms. Some compounds may exhibit polymorphism. It is 30 to be understood that the present invention ecompasses any racemic, optically-active, polymorphic, tautomeric, or stereoisomeric form, or mixture thereof, of a compound of the invention, which possesses the useful properties described herein. 29 WO 2007/045876 PCT/GB2006/003888 The following Schemes describe the preparation of compounds of Formula I of the present invention. All of the starting materials are prepared by procedures described in these schemes, by procedures well known to one of 5 ordinary skill in organic chemistry or may be obtained commercially. All of the final compounds of the present invention are prepared by procedures described in this chart or by procedures analogous thereto, which would be well known to one of ordinary skill in organic chemistry. All of the variables used in the schemes are as defined in the specification, below or as in the 10 claims. It will be apparent to those skilled in the art that the described synthetic procedures are merely representative in nature and that alternative synthetic processes are known to one of ordinary skill in organic chemistry. 15 Chromenone 3A may be prepared by Pechmann condensation of a resorcinol I with a substituted p-ketoester 2 according to Scheme 1. Compound 4 may be prepared by Pechmann condensation of a mono 0 alkylated resorcinol 5 with a substituted 3-ketoester 2 or, alternatively, by 0 20 alkylation, arylation or acylation of chromenone 3A. 30 WO 2007/045876 PCT/GB2006/003888 Scheme I

R

3 R3 HO OH O 0 H 2

SO

4 HO O 0 + R OEt R R R6 2 R R R R 1 2 3A iPrBr(CI),

K

2 CO3 or iPrBr(Cl), Pd(OAc) 2 3

R

3 0 OH O0O H 2 SO4 + R2 OEt R R R R R R2 6 5R 2 4 5 Compound 6 may be prepared from compound 3B via reaction with an amine derivative (e.g., morpholine) and formaldehyde under acidic conditions (Scheme 2). Alkylation of compound 6 at oxygen with an alkyl bromide (e.g. isopropyl bromide) yields chromenone derivative 7. 31 WO 2007/045876 PCT/GB2006/003888 Scheme 2 N N HO 0 O iPrBr,

RCH

2 0,Hx__ HO 0 0 K 2

CO

3 R O O R5 R ~ I R I 6 2 R RD R R R R R 2

R

6

R

2 3B 6 Nitration of compound 3B yields nitrochromenone 8 (Scheme 3). Alkylation 5 of nitro derivative 8 at oxygen yields compound 9. Reduction of the nitro group of 9 provides aniline 10. The amino group of 10 may be mono- or bis alkylated, acylated, sulfonylated, and/or carbamoylated to yield compound 11. Alternatively, the nitro group in compound 8 may be reduced to yield aniline 12 with a free hydroxy group, the amino group of which may be 10 mono- or bis- acylated, sulfonylated, and/or carbamoylated in the presence of potassium carbonate to yield compound 11. Scheme 3 HO N 0 0 N2 NH 2

HNO

3 HO 0 0 H 2 , Pd/c HO 0 0 R ,R 51 1 #'' 1 6 2 R R R6 R R 6

R

2 R 6

R

2 3B iPrBr, 8 12

K

2

CO

3 O 0 NO 2 NH Ra HN 0 N 21P/ 0 0 0N R, RD R R 6#2 6 2 R R R 6 R 2 R R 9 10 11 Ra = H, iPr 15 32 WO 2007/045876 PCT/GB2006/003888 Nitration of compound 3C yields nitro chromenone 13 (Scheme 4). Alkylation of nitro derivative 13 at oxygen yields compound 14, the nitro group of which may be reduced to provide aniline 15. The amino group of aniline 15 may be mono- or bis-alkylated, acylated, sulfonylated, and/or 5 carbamoylated to yield compound 16. Alternatively, the nitro group of compound 13 may be reduced to yield aniline 17 with a free hydroxy group, the amino group of which may be mono- or bis- acylated, sulfonylated, and/or carbamoylated to yield compound 16. 10 Scheme 4 R 3 R3 R 3 HO 0 0 HO 0 0O0

HNO

3 H H 2 , Pd/c HO O O R O 2 N R H 2 N R R6 R 2 R R 2

R

6

R

2 3C 13 17 iPrBr,

K

2

CO

3 MeSO 2 Br(cl), K 2

CO

3 Ra R 3 Ra R 3 0 0 0 00 0 0 O O O H 2 ,Pd/c 0 Od 0 0 O 0 2 N R H2N R 1 HN R 6 2 HN6 2 R R R 6

R

2 'S=OR R 0 14 15 16 Ra = H, iPr Trifluorosulfonic acid ester 18 may be prepared from chromenone derivative 15 3A according to Scheme 5. Triflate 18 may be used to prepare stannyl derivative 19 which may be utilized in a palladium catalyzed coupling reaction with an aryl halide to prepare compound 20, or compound 19 may be coupled with an acyl chloride to prepare compound 21. 33 WO 2007/045876 PCT/GB2006/003888 Scheme 5 R3 R 3

R

3 HO 0 Tf 2 O, Py Tf OR Bu 3 SnSnBu 3 BuaSn O R R R R R 3A 18 ArBr, 19 CHac(O)CI R3 Pd(Ph 3 P0 R Pd 2 (dba)3 A r o 0 0 R X R 6 2 RD R Ar = aryl or heteroaryl R R R 6

R

2 20 21 5 Palladium catalyzed arylation of an amine with triflate 18 yields compound 22. N-Benzyl derivative 22 may be deprotected to yield aniline 23 (Scheme 6). Scheme 6 3 R 3

R

3 Rf N NH 2 ~ N BINAP, Pd(OAc) 2 H ,

H

2 , 10%PdC H 2 N 0 0 RR6 R 6 2R R 6 R 2 R 2 R R 10 18 22 23 Treatment of 7-hydroxychromenone 3A with NN-dimethylthiocarbamoyl chloride provides compound 24 which may be subjected to thermal 15 rearrangement to provide carbamoyl protected thiol 25 (Scheme 7). Cleavage of the carbamoyl group in compound 25 followed by alkylation or arylation at sulfur yields compound 26. This compound may be oxidized to sulfone 27. 34 WO 2007/045876 PCT/GB2006/003888 Scheme 7

R

3 Dimethyl Me 2 N fS R 3 HO 0 O thiocarbamoylchloride, 0 O O Et 3 N 200 0 C

R

6

R

2

R

6

R

2 3A 24 Me N 3R 3

R

3 R 1. MeONa R R 2 '# 0 0 2. iPrBr Oxone 2 6 R2 R R R2 R R 6R 2

R

6 R2 25 26 27 5 Amino phenol 17 may be condensed with a carboxylic acid to prepare oxazole 28 (Scheme 8). Condensation of amino phenol 17 with an a-keto carboxylic acid ester yields compound 29. Treatment of amino phenol 17 with carbonyldiimidazole provides oxazolidinone 30 which may be alkylated at nitrogen to give compound 31. Treatment of amino phenol 17 with 10 thiocarbonyldiimidazole provides oxazolidinethione 32 which may be - alkylated-at sulfur-to give- compound 33. Replacement -of sulfur with an amine in thione 32 provides compound 34 (wherein R 14 represents hydrogen, C1.

6 alkyl, cycloC3-1 2 alkyl, aryl, heteroaryl, carboxyC 1

.

6 alkyl, arylC 1

.

6 alkyl, alkylcarbonyl or CF 3 , and R 15 represents hydrogen, C 1

.

6 alkyl, 15 cycloC 3

-

12 alkyl, aryl, heteroaryl, arylC1.

6 alkyl, carboxyC1.salkyl, alkylcarbonyl,

CF

3 , C 1

.

6 alkyloxy, C 1

.

6 alkylthio, arylC1.

6 alkylthio, arylC 1

.

6 alkyloxy, morpholino, C 1

.

6 cycloamino, piperazinyl, N-C.alkylpiperazinyl or arylamino). 35 WO 2007/045876 PCT/GB2006/003888 Scheme 8 RR N R R 6 R2 28 0 0 Q0

R

1 5 C02H, O OEt R"' :hN R1 PPA R 6

R

2 29 HO 0 0 carbonyl 3

H

2 N R dilmidazole R R 1 o( i R 14 Br, K 2 , 3 17 N R R H 6 2 thiocarbonyl R 0 0 0 dilidazole 30 0oR R3 R14 R 6

R

2 0 R

R

1 4 Br, K 2 coa R N R 31 S < -~ 1 - 141$ < 1 N F- R R N R R R R R 32

R

1 4 Ri 4 NH 33

R

3 R 140 0 14p'\ R N R 6 2F R R 34 Amino phenol 12 may be condensed with a carboxylic acid to prepare 5 oxazole 35 (Scheme 9). Condensation of amino phenol 12 with an a-keto carboxylic acid ester yields compound 36. Treatment of amino phenol 12 with carbonyldiimidazole provides oxazolidinone 37 which may be alkylated at nitrogen to provide compound 38. Treatment of amino phenol 12 with thiocarbonyldiimidazole provides oxazolidinethione 39 which may be 10 alkylated at sulfur to provide compound 40. Replacement of sulfur with an 36 WO 2007/045876 PCT/GB2006/003888 amine in oxazolidinethione 39 yields compound 41 (wherein R 14 and R 1 5 are as previously defined). Scheme 9 R N o 0 0 R R R R 35

R

15

R

15 C0 2 H, PPA 0j 0 0 OEt 5

NH

2 6 2 t h R n carbonyl 6 2dilmidazole H ON RR R 12 0 0 0 thiocarbonylR R14Br, K2CO3 diimidazole

R

6

R

2 R 37 - 37 'N I - -~ s R4 R -- S H N O O R14Br, K2CO3 O O3O R FR 1R 5R1 R R R R2 39 R 1440 R141N R4 / R R R4 R 6 R 1 38

R

5 5 R 2 6. 21 6 2 R RR R 39 40 5 37 WO 2007/045876 PCT/GB2006/003888 Trifluorosulfonic acid ester 42 may be prepared from chromenone derivative 3D (Scheme 10). Triflate 42 may be used to prepare stannyl derivative 43 which may be utilized for palladium catalyzed coupling with an aryl halide to prepare compound 44, or compound 43 may be coupled with an acyl 5 chloride to prepare compound 45. Scheme 10

R

3

R

3

R

3 4 Bu 3 Sn~nBU 3 R4 0 0 HTf 2 , Py TR R 0BuS ) I U20 Py 0 0Pd(Ph 3

P)

4 I# R6 R2 R6 R2 6 R2 R R RG R R R 3D 42 ArBr, 43 Rc(O)cl N Pd 2 (dba) 3

R

3

R

3 R4 0 0 R4 0 0 Ar aryl or heteroaryl R 0 1 R 6 R2 R 10 R6 R2 44 45 10 Nitration of compound 3E yields nitrochromenone 46 (Scheme 11). Alkylation of nitro derivative 46 at oxygen yields compound 47, the nitro group of which may be reduced to yield aniline 48. The amino group in aniline 48 may be mono- or bis- alkylated, acylated, sulfonylated, and/or 15 carbamoylated to yield compound 49. Alternatively, the nitro group in compound 46 may be reduced to give aniline 50 with a free hydroxy group, the amino group of which may be mono- or bis- acylated, sulfonylated, and/or carbamoylated to give compound 49. 38 WO 2007/045876 PCT/GB2006/003888 Scheme 11 R 3 4R 3 4 R3 R O O HNO 3 R 0 H 2 ,Pd/C R# 00 11 H HO R HO R HO R2 2 2 NO 2 R NH 2 R 3E iPrBr, 46 50

K

2

CO

3 R R3O O4R 3

R

3

H

2 , Pd/C R0 0 R Os O R R

NO

2

R

2

NH

2

R

2 RNN R 2 47 48 49 Ra= H, iPr Amino phenol 50 may be condensed with a carboxylic acid to prepare 5 oxazole 51 (Scheme 12). Condensation of amino phenol 50 with an a-keto carboxylic acid ester yields compound 52. Treatment of amino phenol 50 with carbonyldiimidazole provides oxazolidinone 53 which may be alkylated at nitrogen to give compound 54. Treatment of amino phenol 50 with thiocarbonyldiimidazole provides oxazolidinethione 55 which may be 10 alkylated at sulfur to yield compound 56. Replacement of sulfur with an amine in thione 55 yields compound 57 (wherein R 14 and R 15 are as previously defined). 39 WO 2007/045876 PCT/GB2006/003888 Scheme 12

R

3 R 4 0 0 R R N R2 R 51

R

3

R

1 5 C0H, PPA R 4 0 0 2 OEt R R R3 R O N R 4 0 0 > R 15 R O O R 52 HO R diimidazole H2R R 5 R R 1 4 Br, K2CO thiocarbonyl NH R 4 O dmIdazoleR0 0 0 3 a R R-S S 54 -) 2, -- - N- NH R R -S s 55 56

R

14

R

1 4 NH R 3 R 4 O O R N R 2 R 1 '-N 14 RN \14 57 3-Acylchromenone derivative 60 may be prepared by piperidine catalysed condensation of 2-acylphenol 58 with p-ketoester 59 (Scheme 13). 5 40 WO 2007/045876 PCT/GB2006/003888 Scheme 13

R

3 R3 R 4 OH O O R 4 O O piperidine Rs / O Rlo" OEt R' /0 54 54.nz O 0 R6 R26 2 Rio R R R R2 R 58 59 60 EXPERIMENTAL PART 5 The compounds and their preparation of the present invention will be better understood in connection with the following examples, which are intended as an illustration of and not a limitation upon the scope of the invention. Hereinafter, "DMF" is defined as N,N-dimethylformamide, "HCl" as 10 hydrochloric acid, "DMSO" as dimethylsulfoxide and "TMS" as tetramethylsilane. Preparation I 3-Hydroxy-7,8,9,10-tetrahydro-benzo[c]chromen-6-one 15 HO 0 0 A mixture of resorcinol (1.45 g, 10 mmol) and ethyl 2-oxocyclohexane carboxylate (2.04 g, 12 mmol) is cooled in an ice bath and sulfuric acid (5 ml) is added dropwise. The reaction mixture is stirred for 2.5 h and diluted 20 with ice water (30 ml). The precipitate is collected on a filter and recrystallized from i-PrOH to give the title compound (1.44 g, 67% ) as colorless crystals. 41 WO 2007/045876 PCT/GB2006/003888 Physical characteristics are as follows: Mp 187-190 0C; 'H NMR (DMSO-d 6 , TMS) 8: 1.71, 2.37, 2.72, 6.68, 6.77, 7.52, 10.34; MS: 216 (M*). 5 Example I 6-Chloro-7-(4-fluoro-benzyloxy)-4-phenyl-chromen-2-one F ' O O O CI In analogy to the procedure described in Scheme 1, the title compound is obtained in moderate yield. 10 Example 2 7-(3-Phenoxy-benzyloxy)-4-phenyl-chromen-2-one 15 In analogy to the procedure described in Scheme 1, the title compound is obtained in moderate yield. 42 WO 2007/045876 PCT/GB2006/003888 Example 3 7-(4-Fluoro-benzyloxy)-4-phenyl-chromen-2-one F 0 0 0 in analogy to the procedure described in Scheme 1, the title compound is 5 obtained in moderate yield. Example 4 6-Chloro-7-isopropoxy-4-trifluoromethyl-chromen-2-one o 0 0 C 1 F F F 10 In analogy to the procedure described in Scheme 1, the title compound is obtained in moderate yield. Example 5 6-Chloro-7-hydroxy-4-pyridin-2-yl-chromen-2-one CI N 15 In analogy to the procedure described in Scheme 1, the title compound is obtained in moderate yield. 43 WO 2007/045876 PCT/GB2006/003888 Example 6 6-Chloro-7-hydroxy-4-pyridin-3-yi-chromen-2-one HO O 0 IN In analogy to the procedure described in Scheme 1, the title compound is 5 obtained in moderate yield. Example 7 6-Chloro-7-hydroxy-4-pyridin-4-yI-chromen-2-one HO 0 0 CI N 10 In analogy to the procedure described in Scheme 1, the title compound is obtained in moderate yield. Example 8 6-Chloro-7-isopropoxy-4-pyridin-4-y-chromen-2-one O 'N O CI N 15 In analogy to the procedure described in Scheme 1, the title compound is obtained in moderate yield. 44 WO 2007/045876 PCT/GB2006/003888 Example 9 6-Chloro-7-isopropoxy-4-pyridin-2-y-chromen-2-one S0 0 0 CI N In analogy to the procedure described in Scheme 1, the title compound is 5 obtained in moderate yield. Example 10 6-Chloro-7-isopropoxy-4-pyridin-3-yl-chromen-2-one C1 N 10 In analogy to the procedure described in Scheme 1, the title compound is obtained in moderate yield. Example 11 3-(Adamantane-1 -carbonyl)-7-methoxy-chromen-2-one 0 SN 0 0 0 15 In analogy to the procedure described in Scheme 13, the title compound is obtained in moderate yield. 45 WO 2007/045876 PCT/GB2006/003888 Example 12 3-(Adamantane-1-carbonyl)-7-dimethylamino-chromen-2-one 0 N WN 0 0 5 In analogy to the procedure described in Scheme 13, the title compound is obtained in moderate yield. Example 13 3-(Adamantane-1-carbonyl)-7-diethylamino-chromen-2-one 0 N~ N N o-O 10 In analogy to the procedure described in Scheme 13, the title compound is obtained in moderate yield. Example 14 15 3-(Adamantane-1-carbonyl)-7-oxazol-2-yi-chromen-2-one 0 0 0 N In analogy to the procedure described in Scheme 13, the title compound is obtained in moderate yield. 46 WO 2007/045876 PCT/GB2006/003888 Example 15 3-(Adamantane-1-carbonyl)-7-bromo-chromen-2-one 0 Br 0 In analogy to the procedure described in Scheme 13, the title compound is 5 obtained in moderate yield. Example 16 3-Hydroxy-2-nitro-7,8,9,1 0-tetrahydrobenzo[c]chromen-6-one HO 0 0 0 I I 0 10 3-Hydroxy-7,8,9,10-tetrahydro-benzo[c]chromen-6-one (Preparation 1) (1.0 g, 5.9 mmol) is dissolved in acetic acid (1.5 ml) and the mixture is cooled to 10 *C. Concentrated HNO 3 is added and the reaction mixture is stirred at r.t. for 0 h and diluted With water (15 ml). The precipitate is -collected -on a filter and recrystallized twice from MeOH to give the title compound (145 mg, 15 10%) as red crystals. Physical characteristics are as follows: Mp 208-210 0C; 1 H NMR (DMSO-d 6 , TMS) 6: 1.74, 2.41, 2.76, 6.97, 8.19, 11.77. 20 Example 17 3-isopropoxy-2-nitro-7,8,9,1 0-tetrahydrobenzo[c]chromen-6-one 47 WO 2007/045876 PCT/GB2006/003888 o N 0 2-Bromopropane (5 ml, 53 mmol) is added to a mixture of 3-Hydroxy-2-nitro 7,8,9,1 0-tetrahydrobenzo[c]chromen-6-one (Example 16) (4.15 g, 13.55 mmol) and K 2

CO

3 (5.6 g, 40 mmol) in DMFA (30 ml). The reaction mixture is 5 stirred at 500C for 24 h, cooled to r.t. and diluted with water (50 ml). The precipitate is collected on a filter and recrystallized from MeOH to give the title compound (154 mg, 30%) as colorless crystals. Physical characteristics are as follows: Mp 166-168 *C; 'H NMR (DMSO-d 6 , TMS9) 5: 1.32, 1.73, 2.41, 2.76, 4.95, 10 7.41, 8.19. Example 18 2-Amino-3-isopropoxy-7,8,9,10-tetrahydrobenzo[c]chromen-6-one o a o

H

2 N 15 3-Isopropoxy-2-nitro-7,8,9,10-tetrahydrobenzo[c]chromen-6-one (Example 17) (1.0 g, 3.3 mmol) is dissolved in EtOH (30 ml) and 10% Pd/C (280 mg) is added. Hydrogen pressure (7 bar) is applied for 6 h. The catalyst is filtered off and the solvent removed in vacuo. The residue is purified by flash chromatography on silica gel eluting with mixture of ethyl acetate and light 20 petroleum ether to give the title compound (0.68 g, 75%) as white crystals. Physical characteristics are as follows: 48 WO 2007/045876 PCT/GB2006/003888 Mp 95-97 0C; 'H NMR (DMSO-d 6 , TMS) 5: 1.30, 1.74, 2.38, 2.65, 4.69, 4.76, 6.85, 6.84. Example 19 5 2,2-Dimethyl-propionic acid 6-oxo-7,8,9,10-tetrahydro-6H benzo[c]chromen-3-yI ester 0 0 0 0 In analogy to the procedure described in Scheme 1, the title compound is obtained in moderate yield. 10 Example 20 2-Chloro-3-(2-oxo-2-pyrrolidin-1-yl-ethoxy)-7,8,9,10-tetrahydro benzo[c]chromen-6-onene 0 )t'-0 ~0 0 15 In analogy to the procedure described in Scheme 1, the title compound is obtained in moderate yield. Example 21 2-Chloro-3-(2-oxo-2-piperidin-1 -yl-ethoxy)-7,8,9,1 0-tetrahydro 20 benzo[c]chromen-6-onene 0 0 0 c4 49 WO 2007/045876 PCT/GB2006/003888 In analogy to the procedure described in Scheme 1, the title compound is obtained in moderate yield. Example 22 5 2-Chloro-3-isopropoxy-9-methyl-7,8,9,1 0-tetrahydro-benzo[c]chromen 6-one "T0 0 0 C! In analogy to the procedure described in Scheme 1, the title compound is obtained in moderate yield. 10 Example 23 2-Chloro-3-hydroxy-8-trifluoromethyl-7,8,9,1 0-tetrahydro benzo[c]chromen-6-one HO 50 0 C1 F F F 15 In analogy to the procedure described in Scheme 1, the title compound is obtained in moderate yield. 50 WO 2007/045876 PCT/GB2006/003888 Example 24 2-Chloro-3-isopropoxy-8-trifluoromethyl-7,8,9,1 0-tetrahydro benzo[c]chromen-6-one 0 0 0 F F F 5 In analogy to the procedure described in Scheme 1, the title compound is obtained in moderate yield. Example 25 2-Chloro-3-(2-hydroxy-ethoxy)-7,8,9,10-tetrahydro-benzo[c]chromen-6 10 one 0 0 HO I CI In analogy to the procedure described in Scheme 1, the title compound is obtained in moderate yield. 15 Example 26 Dimethyl-thiocarbamic acid S-(2-chloro-9-methyl-6-oxo-7,8,9,10 tetrahydro-6H-benzo[c]chromen-3-y) ester O N S 00O CI 51 WO 2007/045876 PCT/GB2006/003888 In analogy to the procedure described in Scheme 7, the title compound is obtained in moderate yield. Example 27 5 2-Chloro-3-(2-dimethylamino-ethoxy)-7,8,9,10-tetrahydro benzo[c]chromen-6-one 0 I 01 N 01 C1 In analogy to the procedure described in Scheme 1, the title compound is obtained in moderate yield. 10 Example 28 Dimethyl-thiocarbamic acid S-(2-chloro-6-oxo-7,8,9,10-tetrahydro-6H benzo[c]chromen-3-y) ester S N 0 CI 15 In analogy to the procedure described in Scheme 7, the title compound is obtained in moderate yield. 52 WO 2007/045876 PCT/GB2006/003888 Example 29 2-Chloro-3-isopropyisulfanyl-7,8,9,1 0-tetrahydro-benzo[c]chromen-6 one S 0 0 Cl 5 In analogy to the procedure described in Scheme 7, the title compound is obtained in moderate yield. Example 30 2-Chloro-3-methylsulfanyl-7,8,9,1 0-tetrahydro-benzo[c]chromen-6-one S 0 10 In analogy to the procedure described in Scheme 7, the title compound is obtained in moderate yield. Example 31 15 2-Chloro-3-methanesulfonyl-7,8,9,1 0-tetrahydro-benzo[c]chromen-6 one CI In analogy to the procedure described in Scheme 7, the title compound is 20 obtained in moderate yield. 53 WO 2007/045876 PCT/GB2006/003888 Example 32 2-Chloro-3-(2-hydroxy-3-morpholin-4-y-propoxy)-7,8,9,1 0-tetrahydro benzo[c]chromen-6-one 0 OH N 0 O 0 C1 5 In analogy to the procedure described in Scheme 1, the title compound is obtained in moderate yield. Example 33 2-Chloro-3-isopropoxy-4-morpholin-4-ylmethyl-7,8,9,1 0-tetrahydro 10 benzo[c]chromen-6-one 0 N O O O CI In analogy to the procedure described in Scheme 2, the title compound is obtained in moderate yield. 15 Example 34 2-Chloro-3-(3-dimethylamino-2-hydroxy-propoxy)-7,8,9,1 0-tetrahydro benzo[c]chromen-6-one i OH N O 0 0 Cl In analogy to the procedure described in Scheme 1, the title compound is 20 obtained in moderate yield. 54 WO 2007/045876 PCT/GB2006/003888 Example 35 2-Chloro-3-(3-diethylamino-2-hydroxy-propoxy)-7,8,9,10-tetrahydro benzo[c]chromen-6-one OH N O 0 O CI 5 In analogy to the procedure described in Scheme 1, the title compound is obtained in moderate yield. Example 36 10 2-Chloro-3-(2-hydroxy-3-isopropylamino-propoxy)-7,8,9,1 0-tetrahydro benzo[c]chromen-6-one H OH N 0 0 0 0 CI In analogy to the procedure described in Scheme 1, the title compound is obtained in moderate yield. 15 Example 37 2-Chloro-3-cyclobutylmethoxy-7,8,9,1 0-tetrahydro-benzo[c]chromen-6 one C1'0 0 0 CI 1 20 In analogy to the procedure described in Scheme 1, the title compound is obtained in moderate yield. 55 WO 2007/045876 PCT/GB2006/003888 Example 38 2-Ethyl-3-isopropoxy-7,8,9,1 0-tetrahydro-benzo[c]chromen-6-one 0 0 01 5 In analogy to the procedure described in Scheme 1, the title compound is obtained in moderate yield. Example 39 2-(2-Hydroxy-ethoxy)-3-methoxy-7,8,9,1 0-tetrahydro-benzo[c]chromen 10 6-one 0 0 0-OH In analogy to the procedure described in Scheme 1, the title compound is obtained in moderate yield. 15 Example 40 4-Amino-3-isopropoxy-7,8,9,10-tetrahydro-benzo[c]chromen-6-one

NH

2 0 00 In analogy to the procedure described in Scheme 3, the title compound is obtained in moderate yield. 56 WO 2007/045876 PCT/GB2006/003888 Example 41 2-Methoxy-3-isopropoxy-7,8,9,1 0-tetrahydro-6H-benzo[c]chromen-6 one o 0 0 0 5 In analogy to the procedure described in Scheme 1, the title compound is obtained in moderate yield. Example 42 10 2-Chloro-3-hydroxy-4-nitro-7,8,9,1 0-tetrahydrobenzo[c]chromen-6-one HO 0 0 ci In analogy to the procedure described in Scheme 3, the title compound is obtained in moderate yield. 15 Example 43 2-Chloro-3-(3-chloro-2-hydroxypropoxy)-7,8,9,1 0 tetrahyd robenzo[c]chromen-6-one OH cl o 0 0 Ci In analogy to the procedure described in Scheme 1, the title compound is 20 obtained in moderate yield. 57 WO 2007/045876 PCT/GB2006/003888 Example 44 1-(3-Isopropoxy-6-oxo-7,8,9,1 0-tetrahydro-6H-benzo[c]chromen-4-y)-3 phenylurea 0 HN 1 'k N H 0 0 0 5 In analogy to the procedure described in Scheme 3, the title compound is obtained in moderate yield. Example 45 2-Chloro-3-(2-hydroxy-3-phenylaminopropoxy)-7,8,9,1 0-tetrahydro 10 benzo[c]chromen-6-one hydrochloride N O 0 0 H OH I Ci In analogy to the procedure described in Scheme 1, the title compound is obtained in moderate yield. 15 Example 46 1-(2,4-Dichlorophenyl)-3-(3-isopropoxy-6-oxo-7,8,9,10-tetrahydro-6H benzo[c]chromen-4-yl)thiourea cl S cl NH 0 0 0 58 WO 2007/045876 PCT/GB2006/003888 In analogy to the procedure described in Scheme 3, the title compound is obtained in moderate yield. Example 47 5 3-Isopropoxy-4-nitro-7,8,9,1 0-tetrahydrobenzo[c]chromen-6-one N 0 0 0 In analogy to the procedure described in Scheme 3, the title compound is obtained in moderate yield. 10 Example 48 N-Tosyl-4-amino-3-isopropoxy-7,8,9,10-tetrahydrobenzo[c]chromen-6 one HN O1 0 15 In analogy to the procedure described in Scheme 3, the title compound is obtained in moderate yield. 59 WO 2007/045876 PCT/GB2006/003888 Example 49 2-Chloro-3-isopropoxy-4-nitro-7,8,9,1 0-tetrahydrobenzo[c]chromen-6 one cl 5 In analogy to the procedure described in Scheme 3, the title compound is obtained in moderate yield. Example 50 4-Amino-2-chloro-3-isopropoxy-7,8,9,1 0-tetrahydrobenzo[c]chromen-6 10 one

NH

2 o 0 0 C1 In analogy to the procedure described in Scheme 3, the title compound is obtained in moderate yield. 15 Example 51 2-Difluoromethoxy-3-methoxy-7,8,9,1 0-tetrahydrobenzo[c]chromen-6 one o-0 0 0 F F In analogy to the procedure described in Scheme 1, the title compound is 20 obtained in moderate yield. 60 WO 2007/045876 PCT/GB2006/003888 Example 52 2-Chloro-3-difluoromethoxy-7,8,9,1 O-tetrahydrobenzo[c]chromen-6-one F F o 0 ci In analogy to the procedure described in Scheme 1, the title compound is 5 obtained in moderate yield. Example 53 Trifluoromethanesulfonic acid 2-chloro-6-oxo-7,8,9,10-tetrahydro-6H benzo[c]chromen-3-yl ester F F o o CI 10 In analogy to the procedure described in Scheme 5, the title compound is obtained in moderate yield. Example 54 15 3-Benzyl-8-isopropoxy-1,2,3,4-tetrahydro-chromeno[3,4-c]pyridin-5-one 0 0 N In analogy to the procedure described in Scheme 1, the title compound is obtained in moderate yield. 61 WO 2007/045876 PCT/GB2006/003888 Example 55 2-Acetyl-3-methoxy-7,8,9,10-tetrahydro-benzo[c]chromen-6-one 000 0 o In analogy to the procedure described in Scheme 5, the title compound is 5 obtained in moderate yield. Example 56 3-Isopropoxy-4-methylamino-7,8,9,1 0-tetrahydrobenzo[c]chromen-6 one HN o 0 0 10 In analogy to the procedure described in Scheme 3, the title compound is obtained in moderate yield. Example 57 15 N-(3-isopropoxy-6-oxo-7,8,9,1 0-tetrahydro-6H-benzo[c]chromen-4-yI) methanesulfonamide o NH o 0 0 In analogy to the procedure described in Scheme 3, the title compound is obtained in moderate yield. 62 WO 2007/045876 PCT/GB2006/003888 Example 58 N-Acetyl-N-(3-isopropoxy-6-oxo-7,8,9,1 0-tetrahydro-6H benzo[c]chromen-4-yl)acetamide 0o N o 0 0 5 In analogy to the procedure described in Scheme 3, the title compound is obtained in moderate yield. Example 59 2-Chloro-N-(3-isopropoxy-6-oxo-7,8,9,1 0-tetrahydro-6H 10 benzo[c]chromen-4-yl)acetamide 0 Cl "NH o 0 0 In analogy to the procedure described in Scheme 3, the title compound is obtained in moderate yield. 15 Example 60 N-(3-Isopropoxy-6-oxo-7,8,9,1 0-tetrahydro-6H-benzo[c]chromen-2 yl)methanesulfonamide o 0 0 HN 0 63 WO 2007/045876 PCT/GB2006/003888 In analogy to the procedure described in Scheme 4, the title compound is obtained in moderate yield. Example 61 5 N-(3-Isopropoxy-6-oxo-7,8,9,1 0-tetrahydro-6H-benzo[c]chromen-2-yl)-4 methylbenzenesulfonamide o 0 0 HN 0 In analogy to the procedure described in Scheme 4, the title compound is obtained in moderate yield. 10 Example 62 N-Acetyl-N-(3-isopropoxy-6-oxo-7,8,9,1 O-tetrahydro-6H benzo[c]chromen-2-yl)acetamide 0 0 0 15 In analogy to the procedure described in Scheme 4, the title compound is obtained in moderate yield. 64 WO 2007/045876 PCT/GB2006/003888 Example 63 N-Acetyl-N-(2-chloro-3-isopropoxy-6-oxo-7,8,9,1 0-tetrahydro-6H benzo[c]chromen-4-yl)acetamide o 0 N CI 5 In analogy to the procedure described in Scheme 3, the title compound is obtained in moderate yield. Example 64 2-Chloro-N-(3-isopropoxy-6-oxo-7,8,9,1 0-tetrahydrobenzo[c]cromen-2 10 yl)acetamide 0 0 0 GCI - -"JN H In analogy to the procedure described in Scheme 4, the title compound is obtained in moderate yield. 15 Example 65 1-(3-Isopropoxy-6-oxo-7,8,9,1 0-tetrahydro-6H-benzo[c]chromen-2-yI)-3 phenylurea 0 0 0 N N H H 65 WO 2007/045876 PCT/GB2006/003888 In analogy to the procedure described in Scheme 4, the title compound is obtained in moderate yield. Example 66 5 N-(3-Isopropoxy-6-oxo-7,8,9,1 0-tetrahydro-6H-benzo[c]chromen-2 yl)succinamic acid 0 0 0 HN HO 0 0 In analogy to the procedure described in Scheme 4, the title compound is obtained in moderate yield. 10 Example 67 N-(3-Isopropoxy-6-oxo-7,8,9,1 0-tetrahydro-6H-benzo[c]chromen-2 yl)formamide 00 0 H N H 15 In analogy to the procedure described in Scheme 4, the title compound is obtained in moderate yield. 66 WO 2007/045876 PCT/GB2006/003888 Example 68 3-isopropoxy-2-methylamino-7,8,9,1 0-tetrahydrobenzo[c]chromen-6 one o 0 0 N H 5 In analogy to the procedure described in Scheme 4, the title compound is obtained in moderate yield. Example 69 2-Chloro-3-morpholin-4-yI-7,8,9,1 0-tetrahydrobenzo[c]chromen-6-one 0 N 0 0 CI 10 In analogy to the procedure described in Scheme 6, the title compound is obtained in moderate yield. Example 70 15 3-Benzylamino-2-chloro-7,8,9,1 0-tetrahydrobenzo[c]chromen-6-one H N 0 0 CI In analogy to the procedure described in Scheme 6, the title compound is obtained in moderate yield. 67 WO 2007/045876 PCT/GB2006/003888 Example 71 N-(3-Isopropoxy-6-oxo-7,8,9,1 0-tetrahydro-6H-benzo[c]-chromen-2 yl)benzamide o 0 0 0 1 H N 1 1 5 In analogy to the procedure described in Scheme 4, the title compound is obtained in moderate yield. Example 72 N-(3-lsopropoxy-6-oxo-7,8,9,1 0-tetrahydro-6H-benzo[c]-chromen-4 10 yl)benzamide o NH .0 0 - 0 In analogy to the procedure described in Scheme 3, the title compound is obtained in moderate yield. 68 WO 2007/045876 PCT/GB2006/003888 Example 73 N-(2-Chloro-3-isopropoxy-6-oxo-7,8,9,1 O-tetrahydro-6H 5 benzo[c]chromen-4-yl)benzamide O NH o 0 O Ci In analogy to the procedure described in Scheme 3, the title compound is obtained in moderate yield. 10 Example 74 N-(3-Isopropoxy-6-oxo-7,8,9,1 0-tetrahydro-6H-benzo[c]-chromen-2 yl)isobutyramide 0 0 0 0 1 N 'a H In analogy to the procedure described in Scheme 4, the title compound is 15 obtained in moderate yield. 69 WO 2007/045876 PCT/GB2006/003888 Example 75 N-Isobutyryl-N-(3-isopropoxy-6-oxo-7,8,9,1 O-tetrahydro-6H benzo[c]chromen-2-yl)isobutyramide 0 0 0 N 5 In analogy to the procedure described in Scheme 4, the title compound is obtained in moderate yield. Example 76 N-(3-Isopropoxy-6-oxo-7,8,9,1 0-tetrahydro-6H-benzo[c]-chromen-4 10 yl)isobutyramide 0 NH In analogy to the procedure described in Scheme 3, the title compound is obtained in moderate yield. 70 WO 2007/045876 PCT/GB2006/003888 Example 77 N-(2-Chloro-3-isopropoxy-6-oxo-7,8,9,1 O-tetrahydro-6H benzo[c]chromen-4-yl)formamide H o 0 0 C1 5 In analogy tothe procedure described in Scheme 3, the title compound is obtained in moderate yield. Example 78 N-(2-Chloro-3-isopropxy-6-oxo-7,8,9,1 O-tetrahydro-6H 10 benzo[c]chromen-4-yI)-4-methylbenzesulfonamide 0 NH -- 00- -0 C, In analogy to the procedure described in Scheme 3, the title compound is obtained in moderate yield. 71 WO 2007/045876 PCT/GB2006/003888 Example 79 N-(2-Chloro-3-isopropoxy-6-oxo-7,8,9,1 0-tetrahydro-6H benzo[c]chromen-4-yI)succinamic acid O OH NH OY 0 0 C1 5 In analogy to the procedure described in Scheme 3, the title compound is obtained in moderate yield. Example 80 N-(2-Chloro-3-isopropoxy-6-oxo-7,8,9,10-tetrahydro-6H 10 benzo[c]chromen-4-yl)-acetamide O NH O0 0 C1 In analogy to the procedure described in Scheme 3, the title compound is obtained in moderate yield. 72 WO 2007/045876 PCT/GB2006/003888 Example 81 2-Chloro-3-pyrrolidin-1-yl-7,8,9,10-tetrahydrobenzo[c]chromen-6-one N 0 0 CI In analogy to the procedure described in Scheme 6, the title compound is 5 obtained in moderate yield. Example 82 Dimethyl-thiocarbamic acid 6-oxo-7,8,9,10-tetrahydro-6H benzo[c]chromen-3-yi ester 0 0N S 0 10 In analogy to the procedure described in Scheme 7, the title compound is obtained in moderate yield. Example 83 15 Acetic acid 2-chloro-6-oxo-7,8,9,10-tetrahydro-6H-benzo[c]chromen-3 yl ester O O 0 0 Cl 73 WO 2007/045876 PCT/GB2006/003888 In analogy to the procedure described in Scheme 1, the title compound is obtained in moderate yield. Example 84 5 2-Chloro-3-ethoxy-7,8,9,1 0-tetrahydro-benzo[c]chromen-6-one o 0 0 Cl In analogy to the procedure described in Scheme 1, the title compound is obtained in moderate yield. 10 Example 85 2-Chloro-3-propoxy-7,8,9,1 0-tetrahydro-benzo[c]chromen-6-one 0 0 0 ci In analogy to the procedure described in Scheme 1, the title compound is obtained in moderate yield. 15 74 WO 2007/045876 PCT/GB2006/003888 Example 86 2-(2-Chloro-6-oxo-7,8,9,10-tetrahydro-6H-benzo[c]chromen-3-yloxy) acetamide 0 0 0 0

H

2 N O CI 5 In analogy to the procedure described in Scheme 1, the title compound is obtained in moderate yield. Example 87 N-(2-Chloro-6-oxo-7,8,9,10-tetrahydro-6H-benzo[c]chromen-3-yl) 10 acetamide H N 0 0 0 OCI In analogy to the procedure described in Scheme 6, the title compound is obtained in moderate yield. 15 Example 88 S-(N,N-Dimethylcarbamoyl)-8-tert-butyl-2-chloro-6-oxo-3-thio-7,8,9,1 0 tetrahydro-6H-benzo[c]chromen-6-one S 0 O Cl 75 WO 2007/045876 PCT/GB2006/003888 In analogy to the procedure described in Scheme 7, the title compound is obtained in moderate yield. Example 89 5 S-(N,N-Dimethylcarbamoyl)-2-chloro-8-phenyl-3-thio-7,8,9,10 tetrahydrobenzo[c]chromen-6-one 0 C1 In analogy to the procedure described in Scheme 7, the title compound is obtained in moderate yield. 10 Example 90 3-Methoxy-2-pyridin-2-yl-7,8,9,1 0-tetrahydro-benzo[c]chromen-6-one 0 0 o N In analogy to the procedure described in Scheme 10, the title compound is 15 obtained in moderate yield. 76 WO 2007/045876 PCT/GB2006/003888 Example 91 3-(Pyridin-2-yloxy)-7,8,9,1 0-tetrahydrobenzo[c]chromen-6-one N 0' 0 0 In analogy to the procedure described in Scheme 1, the title compound is 5 obtained in moderate yield. Example 92 2-Chloro-3-(pyridi n-2-ylsulfanyl)-7,8,9,1 0-tetrahyd robenzo[c]chromen-6 one Nq s 0 0 C1 10 In analogy to the procedure described in Scheme 7, the title compound is obtained in moderate yield. 77 WO 2007/045876 PCT/GB2006/003888 Example 93 S-(N,N-Dimethylcarbamoyl)-8-ethyl-2-chloro-6-oxo-3-thio-7,8,9,1 0 tetrahydro-6H-benzo[c]chromen-6-one oN CI 5 In analogy to the procedure described in Scheme 7, the title compound is obtained in moderate yield. Example 94 S-(N,N-Dimethylcarbamoyl)-1 0-methyl-2-chloro-6-oxo-3-thio-7,8,9,1 0 10 tetrahydro-6H-benzo[c]chromen-6-one S 0 0 CI In analogy to the procedure described in Scheme 7, the title compound is obtained in moderate yield. 78 WO 2007/045876 PCT/GB2006/003888 Example 95 12-Chloro-16-thioxo-1,2,3,4,15,16-hexahydro-7,17-dioxa-15 azacyclopenta[a]phenanthren-6-one S>/H o o a C1 5 In analogy to the procedure described in Scheme 9, the title compound is obtained in moderate yield. Example 96 2-Chloro-3-(4-methoxycyclohexyloxy)-7,8,9,1 0-tetrahydro 10 benzo[c]chromen-6-one, mixture of cis and trans isomers -o 0 0 C1 In analogy to the procedure described in Scheme 1, the title compound is obtained in moderate yield. 15 Example 97 2,2-Dimethyl-propionic acid 6-oxo-7,8,9,10-tetrahydro-6H benzo[c]chromen-3-yi ester 0 0 0 In analogy to the procedure described in Scheme 1, the title compound is 20 obtained in moderate yield. 79 WO 2007/045876 PCT/GB2006/003888 Example 98 12-Chloro-16-isopropyisulfanyl-1,2,3,4-tetrahydro-7,17-dioxa-15 azacyclopenta[a]phenanthren-6-one S

-

N ' N C1 5 In analogy to the procedure described in Scheme 9, the title compound is obtained in moderate yield. Example 99 10 12-Chloro-1 6-methylsulfanyl-1,2,3,4-tetrahydro-7,17-dioxa-1 5 azacyclopenta[a]phenanthren-6-one -s -N o o 0 Cl In analogy to the procedure described in Scheme 9, the title compound is obtained in moderate yield. 15 80 WO 2007/045876 PCT/GB2006/003888 Example 100 12-Chloro-1 6-ethyl-1,2,3,4-tetrahydro-7,17-dioxa-I 5 azacyclopenta[a]phenanthren-6-one -N o o o C1 5 In analogy to the procedure described in Scheme 9, the title compound is obtained in moderate yield. Example 101 12-Chloro-I 6-methyl-1,2,3,4-tetrahydro-7,17-dioxa-I 5 10 azacyclopenta[a]phenanthren-6-one -- N 0 0 0 CI In analogy to the procedure described in Scheme 9, the title compound is obtained in moderate yield. 81 WO 2007/045876 PCT/GB2006/003888 Example 102 15-Benzyl-1,2,3,4-tetrahydro-1 5H-7,17-dioxa-1 5 azacyclopenta[a]phenanthren-6,16-dione 090 N 0 0 5 In analogy to the procedure described in Scheme 9, the title compound is obtained in moderate yield. Example 103 15-Isopropyl-1,2,3,4-tetrahydro-1 5H-7,17-dioxa-1 5 10 azacyclopenta[a]phenanthren-6,1 6-dione 0 i-N 0 0 0 In analogy to the procedure described in Scheme 9, the title compound is obtained in moderate yield. 82 WO 2007/045876 PCT/GB2006/003888 Example 104 15-Methyl-1,2,3,4-tetrahydro-I 5H-7,17-dioxa-I 5 azacyclopenta[a]phenanthren-6,16-dione 0 N o 0 0 5 In analogy to the procedure described in Scheme 9, the title compound is obtained in moderate yield. Example 105 16-Phenyl-1,2,3,4-tetrahydro-7,17-dioxa-1 5 10 azacyclopenta[a]phenanthren-6-one -N 0 Q0 In analogy to the procedure described in Scheme 9, the title compound is obtained in moderate yield. 83 WO 2007/045876 PCT/GB2006/003888 Example 106 16-Ethyl-1,2,3,4-tetrahydro-7,17-dioxa-I 5 azacyclopenta[a]phenanthren-6-one -N 0 a0 5 In analogy to the procedure described in Scheme 9, the title compound is obtained in moderate yield. Example 107 1,2,3,4-Tetrahydro-1 5H-7,17-dioxa-1 5-azacyclopenta[a]phenanthrene 10 6,16-dione 0 N 0 0 a In analogy to the procedure described in Scheme 9, the title compound is obtained in moderate yield. 84 WO 2007/045876 PCT/GB2006/003888 Example 108 1,2,3,4-Tetrahydro-7,17-dioxa-15-azacyclopenta[a]phenanthren-6-one H N o o a In analogy to the procedure described in Scheme 9, the title compound is 5 obtained in moderate yield. Example 109 16-Benzylsulfanyl-1 2-chloro-1,2,3,4-tetrahydro-7,17-dioxa-1 5 azacyclopenta[a]phenanthren-6-one S S N 00 0I 10 In analogy to the procedure described in Scheme 9, the title compound is obtained in moderate yield. 85 WO 2007/045876 PCT/GB2006/003888 Example 110 12-Chloro-16-morpholin-4-yl -1,2,3,4-tetrahydro-7,17-dioxa-15 azacyclopenta[a]phenanthren-6-one 0 N

-

N o o 0 C 5 In analogy to the procedure described in Scheme 9, the title compound is obtained in moderate yield. Example 111 9-(6-Hydroxypyridin-3yl)-1,2,3,4-tetrahydro-6,8-dioxa-1 0 10 azacyclopenta[b]phenanthren-5-one N /, 0 HOI In analogy to the procedure described in Scheme 8, the title compound is obtained in moderate yield. 15 Example 112 9-(4-Methyl piperazin-1 -yl-1,2,3,4-tetrahydro-6,8-dioxa-1 0 azacyclopenta[b]phenanthren-5-one 0 0 0 -N -/N N N 86 WO 2007/045876 PCT/GB2006/003888 In analogy to the procedure described in Scheme 8, the title compound is obtained in moderate yield. Example 113 5 9-Piperazin-1-yl-1,2,3,4-tetrahydro-6,8-dioxa-10 azacyclopenta[b]phenanthren-5-one - 0 0 H-N N--\ N a In analogy to the procedure described in Scheme 8, the title compound is obtained in moderate yield. 10 Example 114 9-Phenylamino-1,2,3,4-tetrahydro-6,8-dioxa-1 0 azacyclopenta[b]phenanthren-5-one 0P 0 0 0 H N 15 In analogy to the procedure described in Scheme 8, the title compound is obtained in moderate yield. Example 115 9-Benzylsulfanyl-1,2,3,4-tetrahydro-6,8-dioxa-1 0 20 azacyclopenta[b]phenanthren-5-one / \0 0 N 87 WO 2007/045876 PCT/GB2006/003888 In analogy to the procedure described in Scheme 8, the title compound is obtained in moderate yield. Example 116 5 9-Morpholin-4-yl-1,2,3,4-tetrahydro-6,8-dioxa-1 0 azacyclopenta[b]phenanthren-5-one 0 0 0 N N In analogy to the procedure described in Scheme 8, the title compound is obtained in moderate yield. 10 Example 117 9-Pyridin-3-yl-1,2,3,4-tetrahydro-6,8-dioxa-1 0 azacyclopenta[b]phenanthren-5-one / \N 15 In analogy to the procedure described in Scheme 8, the title compound is obtained in moderate yield. Example 118 9-Pyridin-4-yl-1,2,3,4-tetrahydro-6,8-dioxa-1 0 20 azacyclopenta[b]phenanthren-5-one 0 0 N 88 WO 2007/045876 PCT/GB2006/003888 In analogy to the procedure described in Scheme 8, the title compound is obtained in moderate yield. Example 119 5 9-Methylsulfanyl-1,2,3,4-tetrahydro-6,8-dioxa-1 0 azacyclopenta[b]phenanthren-5-one 0 0 0 N In analogy to the procedure described in Scheme 8, the title compound is obtained in moderate yield. 10 Example 120 1 0-Thiophen-2-y-1,2,3,4-tetrahydro-6,8-dioxa-1 1 azabenzo[a]anthracene-5,9-dione o 0 0 0 N S 15 In analogy to the procedure described in Scheme 8, the title compound is obtained in moderate yield. Example 121 9-Isopropylsulfanyl-1,2,3,4-tetrahydro-6,8-dioxa-1 0 20 azacyclopenta[b]phenanthren-5-one 0 O 0 S \ N 89 WO 2007/045876 PCT/GB2006/003888 In analogy to the procedure described in Scheme 8, the title compound is obtained in moderate yield. Example 122 5 9-Benzoyl-1,2,3,4-tetrahydro-6,8-dioxa-1 0 azacyclopenta[b]phenanthren-5-one 0 0 0 0 N In analogy to the procedure described in Scheme 8, the title compound is obtained in moderate yield. 10 Example 123 9-Thioxo-1,2,3,4,9,10-hexahydro-6,8-dioxa-10 azacyclopenta[b]phenanthren-5-one O 0 S= N 15 In analogy to the procedure described in Scheme 8, the title compound is obtained in moderate yield. 90 WO 2007/045876 PCT/GB2006/003888 Example 124 9-isopropyl-1,2,3,4-tetrahydro-6,8-dioxa-1 0 azacyclopenta[b]phenanthren-5-one 0 0N. N 5 In analogy to the procedure described in Scheme 8, the title compound is obtained in moderate yield. Example 125 9-Phenyl-1,2,3,4-tetrahydro-6,8-dioxa-1 0-azacyclopenta[b]phenanthren 10 5-one C0 0 0 -oNo In analogy to the procedure described inScheme 8, the title compound is obtained in moderate yield. 15 Example 126 10-isopropyl-1,2,3,4-tetrahydro-1OH-6,8-dioxa-10 azacyclopenta[b]phenanthrene-5,9-dione 0zK 0 0 O= N In analogy to the procedure described in Scheme 8, the title compound is 20 obtained in moderate yield. 91 WO 2007/045876 PCT/GB2006/003888 Example 127 1,2,3,4-Tetrahydro-1 0H-6,8-dioxa-1 O-azacyclopenta[b] phenanthrene 5,9-dione 0 0 0 N 'X H 5 In analogy to the procedure described in Scheme 8, the title compound is obtained in moderate yield. Example 128 9-Ethyl-1,2,3,4-tetrahydro-6,8-dioxa-1 0-azacyclopenta[b]phenanthren-5 10 one N In analogy to the procedure described in Scheme 8, the title compound is obtained in moderate yield. 15 Example 129 9-Methyl-1,2,3,4-tetrahydro-6,8-dioxa-10-azacyclopenta[b]phenanthren 5-one 0 0 N In analogy to the procedure described in Scheme 8, the title compound is 20 obtained in moderate yield. 92 WO 2007/045876 PCT/GB2006/003888 Example 130 9-Ethoxy-1,2,3,4-tetrahydro-6,8-dioxa-1 0-azacyclopenta[b]phenanthren 5-one 0 0 0 N 5 In analogy to the procedure described in Scheme 8, the title compound is obtained in moderate yield. Example 131 4-Methoxy-2-thioxo-1,2,8,9,10,11-hexahydro-3,6-dioxa-1 10 azacyclopenta[c]phenanthren-7-one N R S H Inanalogy to the procedure described in Scheme 12, the title compound is obtained in moderate yield. 15 Example 132 12-Chloro -1,2,3,4-tetrahydro-7,17-dioxa-15 azacyclopenta[a]phenanthren-6-one /zN 0 o o CI In analogy to the procedure described in Scheme 9, the title compound is 20 obtained in moderate yield. 93 WO 2007/045876 PCT/GB2006/003888 Example 133 4-Methoxy-2-phenyl- 8,9,10,11 -tetrahydro-3,6-dioxa-1 azacyclopenta[c]phenanthren-7-one 0 5 In analogy to the procedure described in Scheme 12, the title compound is obtained in moderate yield. Example 134 5-Methoxy-2-thiophen-2-y-9,10,11,12-tetrahydro-4,7-dioxa-1 10 azabenzo[c]phenanthrene-3,8-dione 0 -N 0 S In analogy to the procedure described in Scheme 12, the title compound is obtained in moderate yield. 15 Example 135 4-Methoxy-2-methyl- 8,9,10,11 -tetrahydro-3,6-dioxa-1 azacyclopenta[c]phenanthren-7-one 1-1 0 0 o N 94 WO 2007/045876 PCT/GB2006/003888 In analogy to the procedure described in Scheme 12, the title compound is obtained in moderate yield. Example 136 5 4-Methoxy-8,9,10,11 -tetrahydro-1 H-3,6-dioxa-1 azacyclopenta[c]phenanthren-2,7-dione N -\H In analogy to the procedure described in Scheme 12, the title compound is obtained in moderate yield. 10 Example 137 4-Methoxy-2-methylsulfanyl- 8,9,10,11-tetrahydro-3,6-dioxa-1 azacyclopenta[c]phenanthren-7-one -s 15 In analogy to the procedure described in Scheme 12, the title compound is obtained in moderate yield. 95 WO 2007/045876 PCT/GB2006/003888 Example 138 2-Ethoxy-4-methoxy- 8,9,10,11 -tetrahydro-3,6-dioxa-1 azacyclopenta[c]phenanthren-7-one 1-10 0 0 O_ N \0 5 In analogy to the procedure described in Scheme 12, the title compound is obtained in moderate yield. Example 139 2-Chloro-3-pyridin-2-yl-7,8,9,1 0-tetrahydro-benzo[c]chromen-6-one 0 0 N I C 10 In analogy to the procedure -described in Scheme 5, the title compound is obtained in moderate yield. Example 140 15 3-Acetyl-2-chloro-7,8,9,1 0-tetrahydro-benzo[c]chromen-6-one 0 0 0 CI In analogy to the procedure described in Scheme 5, the title compound is obtained in moderate yield. 96 WO 2007/045876 PCT/GB2006/003888 Example 141 7-isopropoxy-8-nitro-2,3-dihydro-1 H-cyclopenta[c]chromen-4-one o 0 0 0 2 NX) 5 In analogy to the procedure described in Scheme 4, the title compound is obtained in moderate yield. Example 142 9-(4-Dimethylamino-benzyl)-1,2,3,4-tetrahydro-6,8-dioxa-1 0-aza 10 cyclopenta[b]phenanthren-5-one o0 0 N -N In analogy to the procedure described in Scheme 8, the title compound is obtained in moderate yield. 15 Example 143 4-Methoxy-2-pyridin-2-yl-8,9,10,11 -tetrahyd ro-3,6-d ioxa-1 -aza cyclopenta[c]phenanthren-7-one o 0 0 'N N 97 WO 2007/045876 PCT/GB2006/003888 In analogy to the procedure described in Scheme 12, the title compound is obtained in moderate yield. Example 144 5 9-Pyridin-2-yl-1,2,3,4-tetrahydro-6,8-dioxa-1 0-aza cyclopenta[b]phenanthren-5-one 00 0 \o o -N ~NI In analogy to the procedure described in Scheme 8, the title compound is obtained in moderate yield. 10 Example 145 2-Chloro-3-isopropoxy-8-pyridin-2-y-7,8,9,1 0-tetrahydro benzo[c]chromen-6-one Cl N_ 15 In analogy to the procedure described in Scheme 1, the title compound is obtained in moderate yield. Example 146 20 2-Chloro-3-isopropoxy-8-pyridin-3-yl-7,8,9,1 0-tetrahydro benzo[c]chromen-6-one 98 WO 2007/045876 PCT/GB2006/003888 CI N In analogy to the procedure described in Scheme 1, the title compound is obtained in moderate yield. 5 Example 147 10-(3,5-Difluoro-phenyl)-1,2,3,4-tetrahydro-6,8-dioxa-11-aza benzo[a]anthracene-5,9-dione 0 O 0 0 F N F In analogy to the procedure described in Scheme 8, the title compound is 10 obtained in moderate yield. Example 148 4-(5,9-Dioxo-1,3,4,5-tetrahydro-2H,9H-6,8-dioxa-1 1-aza benzo[a]anthracen-1 0-yl)-benzonitrile 15 0 00 0 N 99 WO 2007/045876 PCT/GB2006/003888 In analogy to the procedure described in Scheme 8, the title compound is obtained in moderate yield. Example 149 5 9-Phenyl-2,3-dihydro-1 H-5,7-dioxa-1 0-aza-cyclopenta[a]anthracene-4,8 dione o 01-110 0 0 N In analogy to the procedure described in Scheme 8, the title compound is 10 obtained in moderate yield. Example 150 1 0-Phenyl-1,2,3,4-tetrahydro-6,8-dioxa-1 1 -aza-benzo[a]anthracene-5,9 dione 15 o0 0 0 'N. N In analogy to the procedure described in Scheme 8, the title compound is obtained in moderate yield. 20 Example 151 10-(4-Methoxy-phenyl)-1,2,3,4-tetrahydro-6,8-dioxa-1I-aza benzo[a]anthracene-5,9-dione 100 WO 2007/045876 PCT/GB2006/003888 o0 0 0 N In analogy to the procedure described in Scheme 8, the title compound is obtained in moderate yield. 5 Example 152 10-(3,4-Dimethoxy-pheny)-1,2,3,4-tetrahydro-6,8-dioxa-11-aza benzo[a]anthracene-5,9-dione o "0 0 0 0 N 10 0 Iri analogy the procedure described in Scheme 8 the title compound is obtained in moderate yield. Example 153 15 10-(4-Trifluoromethyl-phenyl)-1,2,3,4-tetrahydro-6,8-dioxa-1 I -aza benzo[a]anthracene-5,9-dione o o 0 0 N F F F 101 WO 2007/045876 PCT/GB2006/003888 In analogy to the procedure described in Scheme 8, the title compound is obtained in moderate yield. Example 154 5 9-Adamantan-1 -yI-1,2,3,4-tetrahydro-6,8-dioxa-10-aza cyclopenta[b]phenanthren-5-one /U 0 0 0 N a In analogy to the procedure described in Scheme 8, the title compound is 10 obtained in moderate yield. Example 155 10-(4-Dimethylamino-phenyl)-1,2,3,4-tetrahydro-6,8-dioxa-11-aza benzo[a]anthracene-5,9-dione 15 o0 0 0 N I N6 In analogy to the procedure described in Scheme 8, the title compound is obtained in moderate yield. 102 WO 2007/045876 PCT/GB2006/003888 Example 156 2-Chloro-3-isopropoxy-7-methyl-7,8,9,1 0-tetrahydro-benzo[c]chromen 6-one 5 0 0 0 Cl~ In analogy to the procedure described in Scheme 1, the title compound is obtained in moderate yield. 10 Example 157 2-Chloro-3-isopropoxy-9-pyridin-2-yl-7,8,9,1 0-tetrahydro benzo[c]chromen-6-one 0 0 0 - N 15 In analogy to the procedure described in Scheme 1, the title compound is obtained in moderate yield. Pure stereoisomeric forms of the compounds and the intermediates of this invention may be obtained by the application of art-known procedures. 20 Diastereomers may be separated by physical separation methods such as 103 WO 2007/045876 PCT/GB2006/003888 selective crystallization and chromatographic techniques, e.g. liquid chromatography using chiral stationary phases. Enantiomers may be separated from each other by selective crystallization of their diastereomeric salts with optically active acids. Alternatively, enantiomers may be separated 5 by chromatographic techniques using chiral stationary phases. Said pure stereoisomeric forms may also be derived from the corresponding pure stereoisomeric form of appropriate starting materials, provided that the reaction occurs stereoselectively. Stereoisomeric forms of Formula I are obviously intended to be included within the scope of this invention. 10 ADDITION SALTS For therapeutic use, salts of the compounds of Formula I are those wherein the counterion is pharmaceutically acceptable. However, salts of acids and bases which are non-pharmaceutically acceptable may also find use, for 15 example, in the preparation and purification of pharmaceutically acceptable compounds. All salts whether pharmaceutically acceptable or not are included within the ambit of the present invention. The pharmaceutically acceptable salts as mentioned above are meant to comprise the therapeutically active non-toxic salt forms which the compounds of Formula I 20 are able to form. The latter can conveniently be obtained by treating the base form with such appropriate acids as inorganic acids, e.g. hydrohalic acids such as hydrochloric, hydrobromic and the like; sulfuric acid; nitric acid; phosphoric acid and the like; or organic acids such as acetic, propanoic, hydroxyacetic, 2-hydroxypropanoic, oxopropanoic, oxalic, 25 malonic, succinic, maleic, fumaric, malic, tartaric, 2-hydroxy-1,2,3 propanetricarboxylic, methanesulfonic, ethanesulfonic, benzenesulfonic, 4 methylbenzenesulfonic, cyclohexanesulfonic, 2-hydroxybenzoic, 4-amino 2-hydroxybenzoic and the like acids. Conversely, the salt form can be converted by treatment with alkali into the free base form. 30 PHARMACEUTICAL COMPOSITIONS The active ingredients of the invention, together with one or more conventional adjuvants, carriers, or diluents, may be placed into the form of 104 WO 2007/045876 PCT/GB2006/003888 pharmaceutical compositions and unit dosages thereof, and in such form may be employed as solids, such as coated or uncoated tablets or filled capsules, or liquids, such as solutions, suspensions, emulsions, elixirs, or capsules filled with the same, all for oral use; in the form of suppositories or 5 capsules for rectal administration or in the form of sterile injectable solutions for parenteral (including intravenous or subcutaneous) use. Such pharmaceutical compositions and unit dosage forms thereof may comprise conventional or new ingredients in conventional or special proportions, with or without additional active compounds or principles, and such unit dosage 10 forms may contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range to be employed. Tablets containing one (1) to one hundred (100) milligrams of active ingredient or zero point five (0.5) to five hundred (500) milligrams per tablet, are accordingly suitable representative unit dosage forms. 15 The term "carrier" applied to pharmaceutical compositions of the invention refers to a diluent, excipient, or vehicle with which an active compound is administered. Such pharmaceutical carriers can be sterile liquids, such as water, saline solutions, aqueous dextrose solutions, aqueous glycerol 20 solutions, and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences" by E.W. Martin, 18 th Edition. 25 METHOD OF TREATING Due to their high degree of activity and their low toxicity, together presenting a most favorable therapeutic index, the active principles of the invention may be administered to a subject, e.g., a living animal (including a human) body, in need thereof, for the treatment, alleviation, modulation, amelioration, 30 palliation, or elimination of an indication or condition which is susceptible thereto, or representatively of an indication or condition set forth elsewhere in this application, optionally concurrently, simultaneously, or together with one or more pharmaceutically-acceptable excipients, carriers, or diluents, 105 WO 2007/045876 PCT/GB2006/003888 and optionally in the form of a pharmaceutical composition thereof, whether by oral, rectal, or parental (including intravenous and subcutaneous) or in some cases even topical route, in an effective amount. Suitable dosage ranges are 1-1000 milligrams daily, 10-500 milligrams daily, and 50-500 5 milligrams daily, depending as usual upon the exact mode of administration, form in which administered, the indication toward which the administration is directed, the subject involved and the body weight of the subject involved, and the preference and experience of the physician or veterinarian in charge. 10 The term "therapeutically effective" applied to dose or amount refers to that quantity of a compound or pharmaceutical composition that is sufficient to result in a desired activity upon administration to a living animal body in need thereof. 15 The active agents of the present invention may be administered orally, topically, parenterally, or mucosally (e.g., buccally, by inhalation, or rectally) in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers. It is usually desirable to use the oral 20 route. The active agents may be administered orally in the form of a capsule, a tablet, or the like (see Remington: The Science and Practice of Pharmacy, 2 0 th Edition (2000), Philadelphia, PA). The orally administered medicaments may be administered in the form of a time-controlled release vehicle, including diffusion-controlled systems, osmotic devices, dissolution 25 controlled matrices, and erodible/degradable matrices. For oral administration in the form of a tablet or capsule, the active drug component can be combined with a non-toxic, pharmaceutically acceptable excipients such as binding agents (e.g., pregelatinized maize starch, 30 polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g., lactose, sucrose, glucose, mannitol, sorbitol and other reducing and non-reducing sugars, microcrystalline cellulose, calcium sulfate, or calcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talc, or silica, steric acid, 106 WO 2007/045876 PCT/GB2006/003888 sodium stearyl fumarate, glyceryl behenate, calcium stearate, and the like); disintegrants (e.g., potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulphate), coloring and flavoring agents, gelatin, sweeteners, natural and synthetic gums (such as acacia, tragacanth or 5 alginates), buffer salts, carboxymethylcellulose, polyethyleneglycol, waxes, and the like. For oral administration in liquid form, the drug components can be combined with non-toxic, pharmaceutically acceptable inert carriers (e.g., ethanol, glycerol, water), suspending agents (e.g., sorbitol syrup, cellulose derivatives or hydrogenated edible fats), emulsifying agents (e.g., lecithin or 10 acacia), non-aqueous vehicles (e.g., almond oil, oily esters, ethyl alcohol or fractionated vegetable oils), preservatives (e.g., methyl or propyl-p hydroxybenzoates or sorbic acid), and the like. Stabilizing agents such as antioxidants (BHA, BHT, propyl gallate, sodium ascorbate, citric acid) can also be added to stabilize the dosage forms. 15 The tablets can be coated by methods well known in the art. The compositions of the invention can be also introduced in microspheres or microcapsules, e.g., fabricated from polyglycolic acid/lactic acid (PGLA). Liquid preparations for oral administration can take the form of, for example, 20 solutions, syrups, emulsions or suspensions, or they can be presented as a dry product for reconstitution with water or other suitable vehicle before use. Preparations for oral administration can be suitably formulated to give controlled or postponed release of the active compound. 25 The active drugs can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines, as is well known. 30 Drugs of the invention may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled. Active drugs may also be coupled with soluble polymers as 107 WO 2007/045876 PCT/GB2006/003888 targetable drug carriers. Such polymers can include polyvinyl-pyrrolidone, pyran copolymer, polyhydroxy-propyl methacrylamide-phenol, polyhydroxy ethyl-aspartamide-phenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues. Furthermore, active drug may be coupled to a class of 5 biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polyhydropyrans, polycyanoacrylates, and cross-linked or amphipathic block copolymers of hydrogels. 10 For administration by inhalation, the therapeutics according to the present invention can be conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, 15 dichlorotetrafluoroethane, carbon dioxide, or other suitable gas. In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve to deliver a metered amount. Capsules and cartridges of, e.g., gelatin for use in an inhaler or insufflator can be formulated containing a powder mix oftthe compound and a suitable powder base such as lactose or starch. 20 The formulations of the invention can be delivered parenterally, i.e., by intravenous (i.v.), intracerebroventricular (i.c.v.), subcutaneous (s.c.), intraperitoneal (i.p.), intramuscular (i.m.), subdermal (s.d.), or intradermal (i.d.) administration, by direct injection, via, for example, bolus injection or 25 continuous infusion. Formulations for injection can be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. The compositions can take such forms as excipients, suspensions, solutions, or emulsions in oily or aqueous vehicles, and can contain formulatory agents such as suspending, stabilizing and/or dispersing 30 agents. Alternatively, the active ingredient can be in powder form for reconstitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use. 108 WO 2007/045876 PCT/GB2006/003888 Compositions of the present invention can also be formulated for rectal administration, e.g., as suppositories or retention enemas (e.g., containing conventional suppository bases such as cocoa butter or other glycerides). 5 The compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient, optionally at various dosage levels to act as a titration pack. The pack may, for example, comprise metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by 10 instructions for administration. Compositions of the invention formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition. As disclosed herein, the dose of, the components in the compositions of the 15 present invention is determined to ensure that the dose administered continuously or intermittently will not exceed an amount determined after consideration of the results in test animals and the individual conditions of a patient. A specific dose naturally varies depending on the dosage procedure, the conditions of a patient or a subject animal such as age, body 20 weight, sex, sensitivity, feed, dosage period, drugs used in combination, seriousness of the disease. The appropriate dose and dosage times under certain conditions can be determined by the test based on the above described indices but may be refined and ultimately decided according to the judgment of the practitioner and each patient's circumstances (age, general 25 condition, severity of symptoms, sex, etc.) according to standard clinical techniques. Toxicity and therapeutic efficacy of the compositions of the invention can be determined by standard pharmaceutical procedures in experimental animals, 30 e.g., by determining the LD 5 o (the dose lethal to 50% of the population) and the ED 5 o (the dose therapeutically effective in 50% of the population). The dose ratio between therapeutic and toxic effects is the therapeutic index and 109 WO 2007/045876 PCT/GB2006/003888 it can be expressed as the ratio ED 5 o/LD 50 . Compositions that exhibit large therapeutic indices are preferred. EXAMPLES OF REPRESENTATIVE PHARMACEUTICAL 5 COMPOSITIONS With the aid of commonly used solvents, auxiliary agents and carriers, the reaction products can be processed into tablets, coated tablets, capsules, drip solutions, suppositories, injection and infusion preparations, and the like and can be therapeutically applied by the oral, rectal, parenteral, and 10 additional routes. Representative pharmaceutical compositions follow. (a) Tablets suitable for oral administration which contain the active ingredient may be prepared by conventional tabletting techniques. (b) For suppositories, any usual suppository base may be employed for incorporation thereinto by usual procedure of the active ingredient, such 15 as a polyethyleneglycol which is a solid at normal room temperature but which melts at or about body temperature. (c) For parental (including intravenous and subcutaneous) sterile solutions, the active ingredient together with conventional ingredients in usual amounts are employed, such as for example sodium chloride and 20 double-distilled water q.s., according to conventional procedure, such as filtration, aseptic filling into ampoules or IV-drip bottles, and autoclaving for sterility. Other suitable pharmaceutical compositions will be immediately apparent to 25 one skilled in the art. FORMULATION EXAMPLES The following examples are again given by way of illustration only and are not to be construed as limiting. 110 WO 2007/045876 PCT/GB2006/003888 EXAMPLE 1 Tablet Formulation A suitable formulation for a tablet containing 10 milligrams of active ingredient is as follows: mg Active Ingredient 10 Lactose 61 Microcrystalline Cellulose 25 Talcum 2 Magnesium stearate 1 Colloidal silicon dioxide 1 5 EXAMPLE 2 Tablet Formulation Another suitable formulation for a tablet containing 100 mg is as follows: mg Active Ingredient 100 Polyvinylpyrrolidone, crosslinked 10 Potato starch 20 Polyvinylpyrrolidone 19 Magnesium stearate 1 Microcrystalline Cellulose 50 Film coated and colored. 111 WO 2007/045876 PCT/GB2006/003888 The film coating material consists of: Hypromellose 10 Microcryst. Cellulose 5 Talcum 5 Polyethylene glycol 2 Color pigments 5 EXAMPLE 3 Capsule Formulation 5 A suitable formulation for a capsule containing 50 milligrams of active ingredient is as follows: mg Active Ingredient 50 Corn starch 26 Dibasic calcium phosphate 50 Talcum 2 Colloidal silicon dioxide 2 filled in a gelatin capsule. 112 WO 2007/045876 PCT/GB2006/003888 EXAMPLE 4 Solution for injection A suitable formulation for an injectable solution is as follows: Active Ingredient mg 10 Sodium chloride mg q.s. Water for Injection mL add 1.0 5 EXAMPLE 5 Liquid oral formulation A suitable formulation for 1 liter of a an oral solution containing 2 milligrams of active ingredient in one milliliter of the mixture is as follows: mg Active Ingredient 2 Saccharose 250 Glucose 300 Sorbitol 150 Orange flavor 10 Colorant q.s. Purified water add 1000 mL EXAMPLE 6 Liquid oral formulation Another suitable formulation for 1 liter of a liquid mixture containing 20 15 milligrams of active ingredient in one milliliter of the mixture is as follows: 113 WO 2007/045876 PCT/GB2006/003888 G Active Ingredient 20.00 Tragacanth 7.00 Glycerol 50.00 Saccharose 400.00 Methylparaben 0.50 Propylparaben 0.05 Black currant-flavor 10.00 Soluble Red color 0.02 Purified water add 1000 mL EXAMPLE 7 Liquid oral formulation Another suitable formulation for 1 liter of a liquid mixture containing 2 5 milligrams of active ingredient in one milliliter of the mixture is as follows: G Active Ingredient 2 Saccharose 400 Bitter orange peel tincture 20 Sweet orange peel tincture 15 Purified water add 1000 mL 114 WO 2007/045876 PCT/GB2006/003888 EXAMPLE8 Aerosol formulation 180 g aerosol solution contain: G Active Ingredient 10 Oleic acid 5 Ethanol 81 Purified Water 9 Tetrafluoroethane 75 5 15 ml of the solution are filled into aluminum aerosol cans, capped with a dosing valve, purged with 3.0 bar. EXAMPLE 9 10 TDS formulation 100 g solution contain: G Active Ingredient 10.0 Ethanol 57.5 Propyleneglycol 7.5 Dimethylsulfoxide 5.0 Hydroxyethylcellulose 0.4 Purified water 19.6 115 WO 2007/045876 PCT/GB2006/003888 1.8 ml of the solution are placed on a fleece covered by an adhesive backing foil. The system is closed by a protective liner which will be removed before use. 5 EXAMPLE10 Nanoparticle formulation 10 g of polybutylcyanoacrylate nanoparticles contain: G Active Ingredient 1.00 Poloxamer 0.10 Butylcyanoacrylate 8.75 Mannitol 0.10 Sodium chloride 0.05 10-- Polybutylcyanoacrylate nanoparticles are prepared by emulsion polymerization in a water/0.1 N HCI/ethanol mixture as polymerizsation medium. The nanoparticles in the suspension are finally lyophilized under vacuum. 15 PHARMACOLOGY- SUMMARY The active principles of the present invention, and pharmaceutical compositions thereof and method of treating therewith, are characterized by unique and advantageous properties, rendering the "subject matter as a whole", as claimed herein, unobvious. The compounds and pharmaceutical 20 compositions thereof exhibit, in standard accepted reliable test procedures, the following valuable properties and characteristics: 116 WO 2007/045876 PCT/GB2006/003888 METHODS BINDING ASSAYS FOR THE CHARACTERIZATION OF MGLUR5 ANTAGONIST PROPERTIES

[

3 H]MPEP (2-methyl-6-(phenylethynyl)pyridine) binding to 5 transmembrane allosteric modulatory sites of mGluR5 receptors in cortical membranes Preparation of rat cortical membranes: Male Sprague-Dawley rats (200-250 g) are decapitated and their brains are removed rapidly. The cortex is dissected and homogenized in 20 volumes of 10 ice-cold 0.32 M sucrose using a glass-Teflon homogenizer. The homogenate is centrifuged at 1000xg for 10 min. The pellet is discarded and the supernatant centrifuged at 20,000xg for 20 min. The resulting pellet is re suspended in 20 volumes of distilled water and centrifuged for 20 min at 8000xg. Then the supernatant and the buffy coat are centrifuged at 15 48,000xg for 20 min in the presence of 50 mM Tris-HCI, pH 8.0. The pellet is then re-suspended and centrifuged two to three more times at 48,000xg for 20 min in the presence of 50 mM Tris-HCI, pH 8.0. All centrifugation steps are carried out at 4*C. After resuspension in 5 volumes of 50 mM Tris-HCI, -pH 8.0 the membrane- suspension is frozen rapidly at -80*C. 20 On the day of assay the membranes are thawed and washed four times by resuspension in 50 mM Tris-HCI, pH 8.0 and centrifugation at 48,000xg for 20 min. and finally re-suspended in 50 mM Tris-HCI, pH 7.4. The amount of protein in the final membrane preparation (250-500 pg/mL) is determined 25 according to the method of Lowry (Lowry 0. H. et al., 1951. J. Biol. Chem. 193, 256-275).

[

3 H]MPEP Assay Incubations are started by adding ( 3 H)-MPEP (50.2 Ci/mmol, 5nM, Tocris) to 30 vials with 125-250pg protein (total volume 0.5 ml) and various concentrations of the agents. The incubations are continued at room temperature for 60 min (equilibrium is achieved under the conditions used). 117 WO 2007/045876 PCT/GB2006/003888 Non-specific binding is defined by the addition of unlabeled MPEP (10 pM). Incubations are terminated using a Millipore filter system. The samples are rinsed twice with 4 mL of ice cold assay buffer over glass fibre filters (Schleicher & Schuell) under a constant vacuum. Following separation and 5 rinse, the filters are placed into scintillation liquid (5 mL Ultima Gold) and radioactivity retained on the filters is determined with a conventional liquid scintillation counter (Hewlett Packard, Liquid Scintillation Analyser). Characterization 10 Specific binding is extremely high i.e. normally > 85% and essentially independent of buffer (Tris or HEPES oth 50 mM) and pH (6.8-8.9). There is a clear saturable protein dependence and the chosen protein concentration used for subsequent assays (250-500 pg/mL) is within the linear portion of this dependence. Cold MPEP displaces hot ligand with an IC6 0 of 18.8 + 15 4.1nM. The Kd of ( 3 H)-MPEP of 13.6 nM is determined by Scatchard analysis and used according to the Cheng Prussoff relationship to calculate the affinity of displacers as Kd values (ICso of cold MPEP equates to a Ki of 13.7 nM). Bmax is 0.56 pm / mg protein. 20 FUNCTIONAL ASSAY OF MGLUR5 RECEPTORS Materials and Methods Astrocyte culture Primary astrocyte cultures are prepared from cortices of newborn rats as described by Booher and Sensenbrenner (1972). Briefly, Sprague-Dawley 25 rat pups (2 - 4 d old) are decapitated and neocortices are dissected, disintegrated with a nylon filter (poresize 80 pm) and carefully triturated. The cell suspension is plated on poly-D-lysine precoated flasks (Costar) and cultivated in Dulbecco's Modified Eagle's Medium (DMEM, InVitrogen) supplemented with 10% heat inactivated fetal calf serum (FCSi, Sigma), 4 30 mM glutamine (Biochrom) and 50 pg/mL gentamycin (Biochrom) at 37*C in a humidified atmosphere of 5% C0 2 /95% air for 7 d with exchanging the medium at day 2. 118 WO 2007/045876 PCT/GB2006/003888 After 7 DIV, cells are shaken overnight at 250 rpm to remove oligodendrocytes and microglia. The next day, astrocytes are rinsed twice with CMF-PBS, trypsinized and subplated on poly-o-lysine precoated 96-well plates (Becton Dickinson #6516 or #6640) at a density of 40,000 - 45,000 5 cells/well. 24 h after establishing the secondary culture the astrocytes are rinsed with PBS** and fed with astrocyte-defined medium (ADM) consisting of DMEM containing Ix G5-supplement (InVitrogen), 0.5 pg/mL heparan sulfate (Sigma), and 1.5 pg/ mL fibronectin (Sigma) (Miller et al., 1993). 3 d later the medium is exchanged and the cells incubated for another 2-3 d, so 10 that at the time of experiments astrocytes are 14-15 DIV. Immunocytochemistry Immunostaining is performed to confirm the presence of classical astrocytic markers such as GFAP as well the expression of mGluR5 receptors. 15 Accumulation of [ 3 H]-Inositol Phosphates After astrocytes are cultured for 12 d ADM is removed and inositol-free DMEM (MP Biomedicals) supplemented with [ 3 H]myo-inositol (0.5 pCi / well; PerkinElmer), and the ADM chemicals is added. After 48 h the medium is 20 replaced with 100 pL Locke's buffer (plus 20 mM Li*, pH 7.4) and incubated for 15 min at 370C before replacement with agonists / antagonists in Locke's buffer. The incubation (45 min at 37 0C) is terminated by replacing the Locke's solutions with 100 pL 0.1 M HCI (10 min on ice). The 96 well plates can be frozen at -20'C at this stage until further analysis. Home made resin 25 exchange columns (AG1-X8 Biorad, 140-14444) are used to separate labeled inositol phosphates by elution with 1 mL of 1 M ammonium formate / 0.1 M formic acid into 24-well visiplates (Perkin Elmer). Scintillation liquid (UltimaFlow AF, Perkin Elmer) is added, the plate sealed and vortexed before radioactivity is determined by conventional liquid scintillation counting 30 (Microbeta,Perkin Elmer) as disintegration per minute (DPM). Alternatively, on the day of assay, columns are washed with 1 mL of 0.1M formic acid followed by 1 mL of distilled water. The contents of each assay 119 WO 2007/045876 PCT/GB2006/003888 well are then added to one column and washed with 1 mL distilled water followed by 1 mL of 5 mM sodium tetraborate / 60 mM sodium formate. The retained radioactive inositol phosphates are then eluted with 2 X 1 mL of I M ammonium formate / 0.1 M formic acid into 24-well visiplates. Scintillation 5 liquid (UltimaFlow AF, Perkin Elmer) is added, the plate sealed and vortexed before radioactivity is determined by conventional liquid scintillation counting (Microbeta,Perkin Elmer) as disintegration per minute (DPM). Calcium FLIPR studies 10 Cultured astrocytes express mGluR5 receptors as shown by immunostaining. The increase of intracellular calcium after stimulation with the mGluR5 agonist DHPG or L-quisqualate is measured using the fluorometric imaging plate reader (FLIPR) and the Ca-Kit (both Molecular Devices, CA). Prior to addition of agonist or antagonist the medium is 15 aspirated and cells are loaded for 2 h at RT with 150 pL of loading buffer consisting of Ca-sensitive dye (MD # R8033) reconstituted in sodium chloride (123 mM), potassium chloride (5.4 mM), magnesium chloride (0.8 mM), calcium chloride (1.8 mM), D-glucose (15 mM), and HEPES (20 mM), pH 7.3. Subsequently, plates are transferred to FLIPR to detect calcium 20 increase with the addition of DHPG (300 pM) or L-quisqualate (100 nM) measured as relative fluorescence units (RFU). If antagonists are tested, these compounds are pre-incubated for 10 min at RT before addition of the respective agonist. 25 For positive modulators, concentration-response curves for quisqualate are performed in the presence and absence of 10 pM modulator to determine the extent of potentiation / agonist potency increase. Thereafter, concentration-response curves for the positive modulator are performed in the presence of a fixed concentration of quisqualate showing the biggest 30 window for potentiation (normally 10-30 nM). 120 WO 2007/045876 PCT/GB2006/003888 Data analysis The fluorescence signal increase after addition of agonist reflects the increase of intracellular calcium. Inconsistencies in the amount of cells per well are normalised by using the spatial uniformity correction of the FLIPR 5 software. The mean of replicated temporal data (n=5) is calculated and used for graphical representation. For the evaluation of the pharmacology, the calcium changes in response to different concentrations of agonist or antagonist are determined using a maximum minus minimum (MaxMin) calculation. 10 All responses (DPM- or RFU-values) are determined as percentage of control (= maximum response at 100 nM quisqualate).

EC

5 o and IC50 are calculated according the logistic equation using GraFit 5.0 (Erithacus Software). 15 FUNCTIONAL ASSAY OF mGluR1 RECEPTORS IN CEREBELLAR GRANULE CELLS - RADIOACTIVE ASSAY FOR CHANGES IN IP3 LEVELS Preparation of cerebellar granule cells 20 Cerebellar cortici are obtained from P8 postnatal Sprague Dawley rats, mechanically disrupted into small pieces with forceps and then transferred to Ca 2 + and Mg 2 + free Hank's buffered salt solution (HBSS-CMF) on ice. After three washes in HBSS-CMF, the tissue pieces are incubated at 370C for 8 minutes in the presence of 0.25% trypsin / 0.05% DNase. The enzymatic 25 reaction is stopped with 0.016% DNAase / 0.1% ovomucoid before centrifugation at 800 rpm for 5 minutes. The supernatant is replaced twice with NaHCO3/HEPES-buffered basal Eagle medium (BME) plus 20 mM KCl. Cells are mechanically dissociated in 2 ml of BME by trituration through three Pasteur pipettes of successively decreasing tip diameter and then 30 filtered through a 48 pM gauge filter. Cells are plated at a density of 150,000 cells in 50 pl in each well of poly-L-Lysin pre-coated 96 well plates (Falcon). The cells are nourished with BEM supplemented with 10% foetal calf serum, 2 mM glutamine (Biochrom), 20 mM KCI and gentamycin (Biochrom) and 121 WO 2007/045876 PCT/GB2006/003888 incubated at 36 0C with 5% C02 at 95% humidity. After 24 h, cytosine-B-D arabinofuranoside (AraC, 10 pM) is added to the medium. IP3 assay with [ 3 H]myo-inositol 5 After 6 DIV the culture medium is replaced completely with inositol free DMEM (ICN) containing [ 3 H]myo-inositol (Perkin Elmer) at a final concentration of 0.5 pCi / 100 pl / well and incubated for a further 48 hours. The culture medium in each well is replaced with 100 pL Locke's buffer (containing in (mM) NaCl (156), KCl (5.6), NaHCO 3 (3.6), MgCl 2 (1.0), CaCl 2 10 (1.3), Glucose (5.6), HEPES (10)) with additional (20 mM Li*, pH 7.4) and incubated for 15 min at 37*C. Locke's buffer is replaced with agonists / antagonists / putative mGluR1 ligands in Locke's buffer and incubated for 45 min. These solutions are then replaced by 100 pL 0.1M HCI in each well and incubated for a further 10 mins on ice. The 96 well plates can be frozen at 15 200C at this stage until further analysis. Home made resin exchange columns (AG1-X8 Biorad, 140-14444) are used to separate labeled inositol phosphates. On the day of assay, columns are washed with 1 ml of 0.1 M formic acid followed by 1 ml of distilled water. The contents of each assay well are- then added to one column and washed with 1 ml distilled water 20 followed by 1 ml of 5 mM sodium tetraborate / 60 mM sodium formate. The retained radioactive inositol phosphates are then eluted with 2 * 1 ml of 1 M ammonium formate / 0.1 M formic acid into 24-well visiplates. Scintillation liquid (UltimaFlow AF, Perkin Elmer) is added, the plate sealed and vortexed before radioactivity is determined by conventional liquid scintillation counting 25 (Microbeta,Perkin Elmer) as disintegration per minute (DPM). Chemicals Unless otherwise stated all chemicals are purchased from Sigma. 30 References Booher and. Sensenbrenner (1972) Neurobiology 2(3):97-105 Miller et al., (1993) Brain Res. 618(1):175-8 122 WO 2007/045876 PCT/GB2006/003888 Compounds of the present invention have a potency (ECo or IC50, respectively) range of about 0.5 nM to about 100 pM. CONCLUSIONS 5 In conclusion, from the foregoing, it is apparent that the present invention provides novel, valuable, and unpredictable applications and uses of the compounds of the present invention, which compounds comprise the active principle according to the present invention, as well as novel pharmaceutical compositions thereof and methods of preparation thereof and of treating 10 therewith, all possessed of the foregoing more specifically-enumerated characteristics and advantages. The high order of activity of the active agent of the present invention and compositions thereof, as evidenced by the tests reported, is indicative of 15 utility based on its valuable activity in human beings as well as in lower animals. Clinical evaluation in human beings has not been completed, however. It will be clearly understood that the distribution and marketing of any compound or composition falling within the scope of the present invention for use in human beings-will of course have to be predicated upon 20 prior approval by governmental agencies, such as the U.S. Federal Food and Drug Administration, which are responsible for and authorized to pass judgment on such questions. The instant chromenone derivatives represent a novel class of Group I 25 mGluR modulators. In view of their potency, they will be useful therapeutics in a wide range of CNS disorders which involve abnormal glutamate induced excitation. These compounds accordingly find application in the treatment of the 30 following disorders of a living animal body, especially a human: AIDS related dementia, Alzheimer's disease, Creutzfeld-Jakob's syndrome, bovine spongiform encephalopathy (BSE) or other prion related infections, 123 WO 2007/045876 PCT/GB2006/003888 diseases involving mitochondrial dysfunction, diseases involving B -amyloid and/or tauopathy such as Down's syndrome, hepatic encephalopathy, Huntington's disease, motor neuron diseases such as amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), olivoponto-cerebellar atrophy, post 5 operative cognitive deficit (POCD), Parkinson's disease, Parkinson's dementia, mild cognitive impairment, dementia pugilistica, vascular and frontal lobe dementia, cognitive impairment, eye injuries or diseases (e.g. glaucoma, retinopathy, macular degeneration), head and brain and spinal cord injuries / trauma, hypoglycaemia, hypoxia (e.g. perinatal), ischaemia 10 (e.g. resulting from cardiac arrest, stroke, bypass operations or transplants), convulsions, glioma and other tumours, inner ear insult (e.g. in tinnitus, sound- or drug-induced), L-Dopa-induced and tardive dyskinesias. These compounds also find application in the treatment of the following 15 disorders of a living animal body, especially a human: abuse and addiction (nicotine, alcohol, opiate, cocaine, amphetamine, obesity and others), amyotrophic lateral sclerosis (ALS), anxiety and panic disorders, attention deficit hyperactivity disorder (ADHD), restless leg syndrome, hyperactivity in children, autism, convulsions / epilepsy, dementia (e.g. in Alzheimer's 20 disease, Korsakoff syndrome, vascular dementia, HIV infections), major depressive disorder or depression (including that resulting from Borna virus infection) and bipolar manic-depressive disorder, drug tolerance (e.g. to opioids), movement disorders, dystonia, dyskinesia (e.g. L-Dopa-induced, tardive dyskinesia or in Huntington's disease), fragile-X syndrome, 25 Huntington's chorea, irritable bowel syndrome (IBS), migraine, multiple sclerosis, muscle spasms, pain (chronic and acute, e.g. inflammatory pain, neuropathic pain, allodynia, hyperalgesia, nociceptive pain), Parkinson's disease, post traumatic stress disorder, schizophrenia (positive and negative symptoms), spasticity, tinnitus, Tourette's syndrome, urinary incontinence, 30 vomiting, pruritic conditions (e.g. pruritis), sleep disorders, micturition disorders, neuromuscular disorder in the lower urinary tract, gastroesophageal reflux disease (GERD), lower esophageal sphincter (LES) disease, functional gastrointestinal disorders, dyspepsia, regurgitation, 124 WO 2007/045876 PCT/GB2006/003888 respiratory tract infection, bulimia nervosa, chronic laryngitis, asthma (e.g. reflux-related asthma), lung disease, eating disorders, obesity, obesity related disorders, agoraphobia, generalized anxiety disorder, obsessive compulsive disorder, panic disorder, posttraumatic stress disorder, social 5 phobia, substance-induced anxiety disorder, delusional disorder, schizoaffective disorder, schizophreniform disorder, substance-induced psychotic disorder, delirium, or for cognitive enhancement and/or neuroprotection. 10 These compounds also find application in the treatment of indications in a living animal body, especially a human, wherein a particular condition does not necessarily exist but wherein a particular physiological parameter may be improved through administration of the instant compounds, including cognitive enhancement. 15 The method-of-treating a living animal body with a compound of the invention, for the inhibition of progression or alleviation of the selected ailment therein, is as previously stated by any normally-accepted pharmaceutical- route, employing the selected dosage which is effective in 20 the alleviation of the particular ailment desired to be alleviated. Use of the compounds of the present invention in the manufacture of a medicament for the treatment of a living animal for inhibition of progression or alleviation of selected ailments or conditions, particularly ailments or 25 conditions susceptible to treatment with a Group I mGluR modulator is carried out in the usual manner comprising the step of admixing an effective amount of a compound of the invention with a pharmaceutically-acceptable diluent, excipient, or carrier, and the method-of-treating, pharmaceutical compositions, and use of a compound of the present invention in the 30 manufacture of a medicament. 125 WO 2007/045876 PCT/GB2006/003888 Representative pharmaceutical compositions prepared by admixing the active ingredient with a suitable pharmaceutically-acceptable excipient, diluent, or carrier, include tablets, capsules, solutions for injection, liquid oral formulations, aerosol formulations, TDS formulations, and nanoparticle 5 formulations, thus to produce medicaments for oral, injectable, or dermal use, also in accord with the foregoing. 10 The present invention is not to be limited in scope by the specific embodiments described herein. Indeed, various modifications of the invention in addition to those described herein will become apparent to those skilled in the art from the foregoing description. 15 All patents, applications, publications, test methods, literature, and other materials cited herein are hereby incorporated by reference. 126

Claims (24)

1. A compound selected from those of Formula I R 3 R R R6 R2 R R2 5 wherein R 1 represents hydrogen, CI. 6 alkyl, aryl, heteroaryl or -C(=0)-Rlo 10 R 2 represents hydrogen, C 1 .alkyl, aryl, heteroaryl, arylC1. 6 alkyl, heteroarylC 1 - 6 alkyl, cyano, nitro, halogen, hydroxy or C 2 - 6 alkoxy; or R and R 2 together represent -W'-X'-Yl-Z 1 -, wherein 15 W1 represents a single bond, oxygen, sulfur, -NR 7 - or -CR"R 9 - and X 1 , Y' and Z' each independently represent oxygen, sulfur, -NR- or CRR 9 -; R 3 represents hydrogen, C 1 . 6 alkyl, aryl, heteroaryl, nitro, amino, C1-6 20 alkoxy, halogen, hydroxy, -C(=O)-R 0 , -N(R)-C(=O)-R 0 , -N(R")S0 2 -R' 0 , -N(R")C(=0)OR, -C(=0)N(R' 1 ) 2 , -C 1 . 6 alkylene C(=0)N(R")2, -N(R")C(=S)N(R'1)2, -N(R")C(=0)N(R")2, C1.6 alkylamino, di-C 1 . 6 alkylamino, cycloC 3 - 1 2 alkylamino, cycloC 3 - 12 alkylaminoC,- 6 alkyl, cycloC3-12alkyl-C 1 .alkylamino, di-C 1 . 6 25 alkylaminoC 1 . 6 alkyl, C1..alkoxy-C2-ealkylamino, arylamino, arylC1.s alkylamino, N-cycloC 3 - 1 2 alkyl-N-C 1 . 6 alkylamino, N-aryl-N-C 1 . 6 127 WO 2007/045876 PCT/GB2006/003888 alkylamino, N-arylC 1 . 6 alkyl-N-C 1 . 6 alkylamino, pyrrolidino, piperidino,

4-arylpiperidino, 4-heteroarylpiperidino, morpholino, morpholinoC 1 . 6 alkyl, piperazino, 4-Cl.6alkylpiperazino, 4-arylpiperazino, hexamethyleneimino, heteroarylamino or heteroarylC 1 . 6 alkylamino; 5 R 4 represents hydrogen, halogen, nitro, amino, hydroxy, -OR, S0 3 CF 3 , CI.ealkyl, cycloC 3 .. 12 alkyl, cycloC 3 . 12 alkyl-C 1 . 6 alkyl, C 2 - 6 alkenyl, C2- 6 alkynyl, aryl, biaryl, arylC 1 . 6 alkyl, arylC 2 -ralkenyl, aryIC2- 6 alkynyl, heteroaryl, heteroaryC 1 l. 6 alkyl, heteroaryC 2 - 6 alkenyl, 10 heteroarylthio, 2,3-dihydro-11H-indenyl, CI. 6 alkoxyC1. 6 alkyl, aryloxyarylC 1 . 6 alkoxy, C1. 6 alkylthio, C4-6 alkenylthio, CYCIOC3.2 alkylthio, cycloC 3 . 1 2 alkyl-C 1 . 6 alkylthio, cycIoC 3 - 12 alkyl-C 3 - 6 alkenylthio, C 1 . 6 alkoxyC 1 . 6 alkylthio, CI.alkoxyC3- 6 alkenylthio, arylC 3 .alkenylthio, heteroarylC 1 . 6 alkylthio, C1. 6 alkylsulfonyl, cycIoC 3 - 12 alkyl-C1.e 15 alkylsulfonyl, arylC 1 - 6 alkylsulfonyl, Cl.6alkylamino, di-C 1 . alkylamino, cycIoC 3 - 12 alkylamino, C1.6alkoxy-cycloC 3 -Cl 2 alkylamino, cycloC 3 - 12 alkyl-C 1 . 6 alkylamino, di-CI 6 alkylaminoC 1 . 6 alkyl, C 1 .ealkoxy-C 2 - 6 alkylamino, arylamino, arylC 1 . 6 alkylamino, N-cycloC 3 -1 2 alkyl-N-C 1 - 6 -- alkylamino, N-aryl-N-C 1 . 6 alkylamino, N-arylC 1 .- 6 alkyl-N-C 1 . 6 alkylamino, 20 2-indanylamino, tetrahydrofuryl, pyrrolidino, piperidino, 4 arylpiperidino, 4-heteroarylpiperidino, morpholino, piperazino, 4-C1-6 alkylpiperazino, 4-arylpiperazino, hexamethyleneimino, benzazepinyl, 1,3-dihydro-2H-isoindol-2-yl, heteroarylC 1 . 6 alkoxy, heteroarylamino, heteroarylC 1 . 6 alkylamino, -N(R)C(=0)-R 1 0 , -N(R")S0 2 -R 1 ", 25 -N(R)C(=O)OR, -C(=O)N(R)2, -C 1 .ealkylene-C(=O)N(R")2, -S-C(=0)N(R")2 or -O-C(=O)-Rl 0 ; R 5 represents hydrogen, halogen, nitro, amino, hydroxy, C 1 . 6 alkoxy, C1.6 alkyl, C1. 6 alkylamino, hydroxyC 1 .ealkoxy, aryl, heteroaryl, OCF 3 , 30 -N(R 1 )C(=O)-Rl 0 , -N(Rll)S0 2 -R 1 0 , -N(R 1 )C(=O)OR, -C(=O)N(R)2, -C 1 . 6 alkylene-C(=O)N(R") 2 , -N(R")C(=S)N(R") 2 , -(R")C(=O)N(R") 2 , -O-SO2R10 or -C(=0)Rl0; 128 WO 2007/045876 PCT/GB2006/003888 R 6 represents hydrogen, C 1 . 6 alkyl, aryl, heteroaryl, halogen, hydroxy or C1. 6 alkoxy; R 7 represents hydrogen, C 1 . 6 alkyl, aryl, heteroaryl, aryIC1. 6 alkyl, C 1 - 6 5 alkoxy, halogen, hydroxy, cyano, nitro, hydroxyC 1 . 6 alkyl, CYCIOC3-12 alkoxy, C1. 6 alkylamino, di-C 1 . 6 alkylamino, cycloC3. 12 alkylamino, CYCIOC3-1 2 alkyl-C 1 . 6 alkylamino, di-C 1 . 6 alkylaminoC1. 6 alkyl, arylamino, arylC 1 . 6 alkyl, N-aryl-N-C 1 . 6 alkylamino, pyrrolidino, piperidino, 4-C1.6 alkylpiperazino, morpholino, hexamethyleneimino, pyrrolidinylC1.o 10 alkyl, piperidinylC1. 6 alkyl, morpholinylC 1 . 6 alkyl, C 1 . 6 alkylsulfonyl, C 1 . 6 alkylthio, C 1 .alkylaminosulfonyl or di-C 1 . 6 alkylaminosulfonyl; R 8 and R 9 each independently represent hydrogen, C 1 . 6 alkyl, aryl, heteroaryl, arylC 1 . 6 alkyl, C 1 . 6 alkoxy, halogen, hydroxy, cyano, nitro, 15 amino or cycIoC 3 . 1 2 alkyl; R 1 0 represents hydrogen, C 1 . 6 alkyl, cycloC 3 - 12 alkyl, aryl, heteroaryl or carboxyC1. 6 alkyl; 20 R 1 1 represents hydrogen, C 1 . 6 alkyl, cycloC 3 - 12 alkyl, aryl, heteroaryl, carboxyC 1.6 alkyl or C 1 . 6 alkylcarbonyl; R 12 represents C 1 . 6 alkyl optionally substituted by one or more substituents selected from hydroxy, cycloC 3 . 12 alkyl, C 1 . 6 alkylamino, di 25 C 1 . 6 alkylamino, morpholino, halogen, arylamino and -C(=O)R 13 ; heteroaryl; cycloC3.2 alkyl; C1. 6 alkoxycycloC3.1 2 alkyl; arylC 1 . 6 alkyl; aryloxyarylC1.ealkyl or C2-6 alkenyl; and R 13 represents amino, pyrrolidino or piperidino; 30 or if R 1 and R 2 represent -W 1 -X 1 -Y 1 -Zl- and W 1 does not represent a single bond, 129 WO 2007/045876 PCT/GB2006/003888 R 3 and R 4 , R 4 and R' or R 5 and R 6 together with the carbon atoms to which they are attached may form a 5-6 membered ring which may be saturated or unsaturated, wherein the ring may optionally have 1 to 4 heteroatoms selected from oxygen, 5 sulfur and nitrogen, and wherein the ring may be optionally substituted by one or more substituents selected from hydrogen, C 1 . 6 alkyl, cycloC 3 - 12 alkyl, aryl, heteroaryl, arylCI. 6 alkyl, carboxyC 1 . 6 alkyl, alkylcarbonyl, arylcarbonyl, oxo, thioxo, C 1 . 6 alkoxy, C. 6 alkylthio, arylC 1 . 6 alkylthio, arylC1. 6 alkoxy, 10 morpholino, C 3 - 6 cycloalkylamino, pyrrolidino, piperidino, hexamethyleneimino, piperazinyl, N-C 1 . 6 alkylpiperazinyl and arylamino; wherein the term "C. 6 alkyl", unless otherwise specified, denotes 15 straight or branched chain groups which may be unsubstituted or substituted by one or more fluorine, chlorine and/or bromine atoms; the term "C1.ealkoxy" denotes straight or branched chain groups which may be unsubstituted or substituted by one or more fluorine, chlorine and/or bromine atoms; the term "cycloC 3 -- 12 alkyl" denotes 20 monocyclic, bicyclic or tricyclic groups which may be unsubstituted or substituted by one or more fluorine, chlorine and/or bromine atoms; the term "aryl" denotes phenyl or naphthyl or phenyl substituted by one or more substituents, which may be the same or different, selected from C1.6alkyl, C 2 - 6 alkenyl, C1. 6 alkoxy, 25 cycloC 3 - 12 alkyl, hydroxy, halogen, cyano, nitro, C 1 - 6 alkoxycarbonyl, amino, C 1 .. 6 alkylamino, di-C1. 6 alkylamino, N-cycloC 3 - 1 2 alkyl-N Ci.alkylamino, azetidinyl, pyrrolyl, piperidinyl, morpholinyl, 4-C1.6 alkylpiperazinyl, tetrazolyl, oxazolyl, furyl, thiophenyl, isoxazolyl, thiazolyl, imidazolyl, oxadiazolyl, pyridinyl, pyrimidyl and C1.e 30 alkylenedioxy; and the term "heteroaryl" denotes an aromatic 5-6 membered ring containing from one to four heteroatoms selected from oxygen, sulfur and nitrogen, or a bicyclic group comprising a 5-6 membered ring containing from one to four heteroatoms selected 130 WO 2007/045876 PCT/GB2006/003888 from oxygen, sulfur and nitrogen fused with a benzene ring or a 5-6 membered aromatic ring containing from one to four heteroatoms selected from oxygen, sulfur and nitrogen, wherein the heteroaryl group may be optionally substitued by one or more substituents, 5 which may be the same or different, selected from C1. 6 alkyl, C1-6 alkoxy, cycloC 3 - 1 2 alkyl, hydroxy, halogen, cyano, nitro, C1.6 alkoxycarbonyl, amino, C 1 . 6 alkylamino, di-C1. 6 alkylamino, N-cycloC3- 1 2 alkyl-N-C 1 . 6 alkylamino, azetidinyl, pyrrolyl, piperazinyl, morpholinyl, 4 C1.6 alkylpiperazinyl, tetrazolyl, oxazolyl, furyl, thiophenyl, isoxazolyl, 10 thiazolyl, imidazolyl, oxadiazolyl, pyridinyl, pyrimidyl and phenyl; and optical isomers, pharmaceutically acceptable salts, hydrates, solvates, and polymorphs thereof; 15 with the proviso that the compounds of Formula I do not include: chromen-2-one, 2-chloro-3-isopropoxy-7,8,9,1 0-tetrahydrobenzo[c]chromen-6-one, 3-(2-chlorobenzyloxy)-7,8,9,1 0-tetrahydrobenzo[c]chromen-6-one, 2-chloro-3-(2-chlorobenzyloxy)-7,8,9,1 0-tetrahydrobenzo[c]chromen 20 6-one, 3-(1 -phenylethoxy)benzo[c]chromen-6-one,

8-hexyl-7-methoxy-2,3-dihydro-1 H-cyclopenta[c]chromen-4-one, 2-chloro-3-methoxy-7,8,9,1 0-tetrahydrobenzo[c]chromen-6-one, 3-hydroxy-4-piperidin-1 -ylmethyl-7,8,9,10 25 tetrahydrobenzo[c]chromen-6-one, 2-chloro-3-hydroxy-9-methyl-7,8,9,1 0-tetrahydrobenzo[c]chromen-6 one, 6-chloro-7-hydroxy-4-trifluoromethylchromen-2-one, 2-chloro-3-hydroxy-4-morpholin-4-ylmethyl-7,8,9,1 0-tetrahydro 30 benzo[c]chromen-6-one, 2-chloro-4-dimethylaminomethyl-3-hydroxy-7,8,9,1 0-tetrahydro benzo[c]chromen-6-one, 2-ethyl-3-hydroxy-7,8,9,1 0-tetrahydrobenzo[c]chromen-6-one, 131 WO 2007/045876 PCT/GB2006/003888 2,3-dimethoxy-7,8,9,1 0-tetrahydrobenzo[c]chromen-6-one, 2-hydroxy-3-methoxy-7,8,9,1 0-tetrahydrobenzo[c]chromen-6-one, 2-chloro-3-(2-methylailyloxy)-7,8,9,1 0-tetrahydrobenzo[c]chromen-6 one, 5 3-allyloxy-2-chloro-7,8,9,1 0-tetrahydrobenzo[c]chromen-6-one, 2-chloro-3-hydroxy-7,8,9,1 0-tetrahydrobenzo[c]chromen-6-one, 2-hexyl-3-methoxy-7,8,9,1 0-tetrahydrobenzo[c]chromen-6-one, 8-chloro-7-isopropoxy-2,3-dihydro-1 H-cyclopenta[c]chromen-4-one, 8-chloro-7-hydroxy-2,3-dihydro-1 H-cyclopenta[c]chromen-4-one, 10 3-(adamantane-1 -carbonyl)-6-methoxychromen-2-one, 3-(adamantane-1 -carbonyl)-6-bromochromen-2-one, 3-(adamantane-1 -carbonyl)chromen-2-one, 3-isopropoxy-7,8,9,1 0-tetrahydrobenzo[c]chromen-6-one, 2-chloro-3-(3-methylbut-2-enyloxy)-7,8,9,10 15 tetrahyd robenzo[c]ch romen-6-one, 8-isopropoxy-1,2,3,4-tetrahydrochromeno[3,4-c]pyridin-5-one, 3-amino-7,8,9,1 0-tetrahydrobenzo[c]chromen-6-one, 3-isopropylamino-7,8,9,1 0-tetrahydrobenzo[c]chromen-6-one, 3-amino-2-chloro-7,8,9,1 0-tetrahydrobenzo[c]chromen-6-one, 20 6-chloro-3-imidazo[1,2-a]pyridin-2-ylchromen-2-one, 3-pyridin-2-yl-3,4,7,8,9,1 0-hexahydro-2H-1,5-dioxa-3-azachrysen-6 one or 6-chloro-3-imidazo[1,2-a]pyridin-2-ylchromen-2-one. 25 2. A compound as claimed in Claim 1 wherein R' represents hydrogen or -C(=O)-R' 0 . 3. A compound as claimed in Claim 2 wherein R 10 represents adamantyl. 30 4. A compound as claimed in any of Claims 1 to 3 wherein R 2 represents hydrogen, aryl, heteroaryl or C1. 6 alkyl. 132 WO 2007/045876 PCT/GB2006/003888 5. A compound as claimed in Claim 4 wherein R 2 represents phenyl or pyridyl. 6. A compound as claimed in Claim 1 wherein R 1 and R 2 together 5 represent -Wi-xl-YI-zl-, wherein W1 represents a single bond or -CR 8 R 9 -, and X 1 , Y' and Z' each independently represent -CR 8 R 9 -, wherein R 8 and R 9 are each 10 independently selected from hydrogen, C1. 6 alkyl, aryl and heteroaryl. 7. A compound as claimed in Claim 6 wherein R 8 represents hydrogen and R 9 represents hydrogen, C 1 . 6 alkyl, aryl or heteroaryl. 15 8. A compound as claimed in Claim 7 wherein R 9 represents hydrogen, methyl, ethyl, trifluoromethyl, t-butyl, phenyl or pyridyl.

9. A compound as claimed in Claim 8 wherein R 9 represents hydrogen, methyl or trifluoromethyl. 20

10. A compound as claimed in any of Claims 1 to 9 wherein R 3 represents hydrogen, C1. 6 alkyl, morpholinoC1. 6 alkyl, amino, nitro, -N(R)C(=O)N(R' 1 )2, -N(R 11 )S0 2 -R 10 , C1. 6 alkylamino or -N(R")C(=0)-Rlo. 25 11. A compound as claimed in any of Claims I to 10 wherein R 4 represents halogen, hydroxy, OR 12 , -S-C(=0)N(R' 1 )2, -C(=0)N(R' 1 )2, C1.6 alkylthio, C 1 . 6 alkylsulfonyl, morpholino, pyrrolidino, arylC 1 . 6 alkylamino, -N(R)C(=O)-Rl 0 , heteroarylthio, -O-C(=O)-Rl 0 , di-C 1 . 6 alkylamino or heteroaryl. 30

12. A compound as claimed in Claim 11 wherein R 4 represents halogen, OR 12 , -S-C(=O)N(R' 1 )2, -C(=O)N(R' 1 )2, C 1 - 6 alkylthio or di-C 1 . 6 alkylamino. 133 WO 2007/045876 PCT/GB2006/003888

13. A compound as claimed in Claim 12 wherein R 1 2 represents C 1 . 6 alkyl optionally substituted by one or more substituents selected from hydroxy, di C 1 . 6 alkylamino, morpholino, halogen, cycloC 3 .. 12 alkyl, arylamino and -C(=O)R 13 ; cycloC 3 - 12 alkyl; C1. 6 alkoxycycloC 3 -1 2 alkyl or heteroaryl. 5

14. A compound as claimed in Claim 12 wherein R 4 represents bromo, methoxy, iso-propoxy, -C(=O)N(R 1 )2, isopropylthio, difluoromethoxy, dimethylamino or diethylamino. 10 15. A compound as claimed in Claim 12 wherein R" represents hydrogen or C1. 6 alkyl.

16. A compound as claimed in Claim 15 wherein R 1 1 represents methyl. 15 17. A compound as claimed in any of Claims 1 to 16 wherein R 5 represents hydrogen, nitro, halogen, C1..ealkyl, hydroxy C 1 ..alkoxy, -C(=O) R 1 0 , -N(Rll)S0 2 -R' 0 , -N(R)C(=O)-Rl 0 or C1. 6 alkylamino.

18. A compound as claimed in Claim 17 wherein R 5 represents hydrogen, 20 nitro, chloro or ethyl.

19. A compound as claimed in any of Claims 1 to 18 wherein R 6 represents hydrogen or C 1 .ealkyl. 25 20. A compound as claimed in Claim 1 wherein R 3 and R 4 together with the carbon atoms to which they are attached form a 5-6 membered ring which may be saturated or unsaturated, wherein the ring has 1 or 2 heteroatoms selected from oxygen and nitrogen and may optionally be substituted by one or more substituents selected from C 1 - 6 alkyl, C 1 -ealkylthio, 30 C 1 . 6 alkoxy, oxo, arylC 1 . 6 alkyl, aryl, arylCI. 6 alkylthio and morpholino.

21. A compound as claimed in Claim 1 wherein R 4 and R 5 together with the carbon atoms to which they are attached form a 5-6 membered ring 134 WO 2007/045876 PCT/GB2006/003888 which may be saturated or unsaturated, wherein the ring has 1 or 2 heteroatoms selected from oxygen and nitrogen and may optionally be substituted by one or more substituents selected from heteroaryl, piperazinyl, N-C1.6alkylpiperazinyl, arylamino, arylC1. 6 alkylthio, morpholino, 5 C 1 . 6 alkylthio, oxo, thioxo, arylcarbonyl, aryl, C 1 . 6 alkoxy, arylC1. 6 alkyl and cycloC 3 12 alkyl.

22. A compound as claimed in Claim 1 wherein R 5 and R 6 together with the carbon atoms to which they are attached form a 5-6 membered ring 10 which may be saturated or unsaturated, wherein the ring has 1 or 2 heteroatoms selected from oxygen and nitrogen and may optionally be substituted by one or more substituents selected from heteroaryl, oxo, thioxo, aryl, C 1 . 6 alkyl and C1. 6 alkoxy. 15

23. A compound as claimed in Claim 1 selected from: N-acetyl-N-(2-chloro-3-isopropoxy-6-oxo-7,8,9,1 0-tetrahydro-6H benzo[c]chromen-4-yl)acetamide, -N-(2-chloro-3-isopropxy-6-oxo-7,8,9,1 0-tetrahydro-6H-benzo[c]chromen 20 4-yl)benzamide, N-(3-isopropxy-6-oxo-7,8,9,1 0-tetrahydro-6H-benzo[c]-chromen-2 yl)isobutyramide, N-(2-chloro-3-isopropxy-6-oxo-7,8,9,1 0-tetrahyd ro-6H-benzo[c]chromen 4-yl)formamide, 25 N-(2-chloro-3-isopropoxy-6-oxo-7,8,9,1 0-tetrahydro-6H benzo[c]chromen-4-yl)succinamic acid, dimethylthiocarbamic acid 6-oxo-7,8,9,1 0-tetrahydro-6H benzo[c]chromen-3-yl ester, S-(N,N-dimethylcarbamoyl)-2-chloro-8-phenyl-3-thio-7,8,9,10 30 tetrahydrobenzo[c]chromen-6-one, 2-chloro-3-(pyridin-2-ylsulfanyl)-7,8,9,1 0-tetrahydrobenzo[c]chromen-6 one, 135 WO 2007/045876 PCT/GB2006/003888 S-(N,N-dimethylcarbamoyl)-8-ethyl-2-chloro-6-oxo-3-thio-7,8,9,1 0 tetrahydro-6H-benzo [c]chromen-6-one and 12-chloro-1 6-isopropylsulfanyl-1,2,3,4-tetrahydro-7,17-dioxa-1 5 azacyclopenta[a]phenanthren-6-one. 5

24. A compound as claimed in Claim 1 selected from: 3-(adamantane-1 -carbonyl)-7-methoxychromen-2-one, 3-(adamantane-1 -carbonyl)-7-dimethylaminochromen-2-one, 3-(adamantane-1 -carbonyl)-7-diethylaminochromen-2-one, 10 3-(adamantane-1 -carbonyl)-7-bromochromen-2-one, 2-chloro-3-isopropoxy-9-methyl-7,8,9,1 0-tetrahydrobenzo[c]chromen-6 one, 2-ch loro-3-isopropoxy-8-trifluoromethyl-7,8,9,10 tetrahydrobenzo[c]chromen-6-one, 15 dimethylthiocarbamic acid S-(2-chloro-9-methyl-6-oxo-7,8,9,10 tetrahyd ro-6 H-benzo[c]chromen-3-yl) ester, dimethylthiocarbamic acid S-(2-chloro-6-oxo-7,8,9,1 0-tetrahydro-6H benzo[c]chromen-3-yl) ester, 3-isopropoxy-2-nitro-7,4,9,1 0-tetrahydrobenzo[c]chromen-6-one, 20 2-chloro-3-isopropylsulfanyl-7,8,9,1 0-tetrahydrobenzo[c]chromen-6-one, 2-ethyl-3-isopropoxy-7,8,9,1 0-tetrahydrobenzo[c]chromen-6-one, 2-chloro-3-difluoromethoxy-7,8,9,1 0-tetrahydrobenzo[cjchromen-6-one, 7-isopropoxy-8-nitro-2,3-dihydro-1 H-cyclopenta[c]chromen-4-one and 2-chloro-3-isopropoxy-7-methyl-7,8,9, 10-tetrahydrobenzo[c]chromen-6 25 one.

25. A compound of Formula I as defined in claim 1 or an optical isomer, pharmaceuctically acceptable salt, hydrate, solvate or polymorph thereof, subject to the modified proviso that the compound of Formula I may 30 additionally be 2-chloro-3-methoxy-7,8,9,10-tetrahydrobenzo[c]chromen-6 one, 2-chloro-3-isopropoxy-7,8,9,1 0-tetrahydrobenzo[c]chromen-6-one or 8 chloro-7-isopropoxy-2,3-dihydro-1 H-cyclopenta[c]chromen-4-one, for use as a medicament. 136 WO 2007/045876 PCT/GB2006/003888

26. A pharmaceutical composition comprising as active ingredient a compound as claimed in any preceding claim, together with one or more pharmaceutically acceptable excipients or vehicles. 5

27. Use of a compound as defined in Claim 1 but not subject to the proviso thereof as or in the manufacture of a medicament for prevention and/or treatment of a condition associated with abnormal glutamate neurotransmission or in which modulation of Group I mGiuR receptors 10 results in therapeutic benefit or for enhancing cognition.

28. A method of treating a living animal body, including a human, afflicted with a condition associated with abnormal glutamate neurotransmission or in which modulation of Group I mGluR receptors results in therapeutic benefit, 15 comprising the step of administering to said body a compound as defined in Claim 1 but not subject to the proviso thereof in an amount which is effective for alleviation of the condition.

29. The use of Claim 27 or method of Claim 28 wherein the condition 20 associated with abnormal glutamate neurotransmission or in which modulation of Group I mGluR receptors results in therapeutic benefit is selected from: AIDS-related dementia, Alzheimer's disease, Creutzfeld Jakob's syndrome, bovine spongiform encephalopathy, prion related infections, diseases involving mitochondrial dysfunction, diseases involving 25 B-amyloid and/or tauopathy, Down's syndrome, hepatic encephalopathy, Huntington's disease, motor neuron diseases, amyotrophic lateral sclerosis, multiple sclerosis, olivoponto-cerebellar atrophy, post-operative cognitive deficit, Parkinson's disease, Parkinson's dementia, mild cognitive impairment, dementia pugilistica, vascular and frontal lobe dementia, 30 cognitive impairment, eye injuries, eye disorders, glaucoma, retinopathy, macular degeneration, head and brain and spinal cord injuries, trauma, hypoglycaemia, hypoxia, perinatal hypoxia, ischaemia, ischaemia resulting from cardiac arrest, stroke, bypass operations or transplants, convulsions, 137 WO 2007/045876 PCT/GB2006/003888 epileptic convulsions, epilepsy, temporal lobe epilepsy, glioma and other tumours, inner ear insult, inner ear insult in tinnitus, sound- or drug-induced tinnutis, L-Dopa-induced dyskinesias, tardive dyskinesias, abuse and addiction, nicotine addiction, nicotine abuse, alcohol addiction, alcohol 5 abuse, opiate addiction, opiate abuse, cocaine addiction, cocaine abuse, amphetamine addiction, amphetamine abuse, anxiety and panic disorders, attention deficit hyperactivity disorder, restless leg syndrome, hyperactivity in children, autism, dementia, dementia in Alzheimer's disease, dementia in Korsakoff syndrome, Korsakoff syndrome, vascular dementia, dementia 10 related to HIV infections, major depressive disorder, depression, depression resulting from Borna virus infection, bipolar manic-depressive disorder, drug tolerance, drug tolerance to opioids, movement disorders, dystonia, dyskinesias, L-Dopa-induced dyskinesias, tardive dyskinesias, dyskinesias in Huntington's disease, fragile-X syndrome, Huntington's chorea, chorea, 15 irritable bowel syndrome, migraine, multiple sclerosis, muscle spasms, pain, chronic pain, acute pain, inflammatory pain, neuropathic pain, allodynia, hyperalgesia, nociceptive pain, post traumatic stress disorder, schizophrenia, positive or cognitive or negative symptoms of schizophrenia, spasticity, tinnitus, Tourette's syndrome, urinary incontinence, vomiting, 20 pruritic conditions, pruritis, sleep disorders, micturition disorders, neuromuscular disorder in the lower urinary tract, gastroesophageal reflux disease, lower esophageal sphincter disease, functional gastrointestinal disorders, dyspepsia, regurgitation, respiratory tract infection, bulimia nervosa, chronic laryngitis, asthma, reflux-related asthma, lung disease, 25 eating disorders, obesity and obesity-related disorders, binge eating disorders, agoraphobia, generalized anxiety disorder, obsessive-compulsive disorder, panic disorder, posttraumatic stress disorder, social phobia, substance-induced anxiety disorder, delusional disorder, schizoaffective disorder, schizophreniform disorder, substance-induced psychotic disorder 30 and delirium.

30. The use of Claim 27 or method of Claim 28 wherein the condition associated with abnormal glutamate neurotransmission or in which 138 WO 2007/045876 PCT/GB2006/003888 modulation of Group I mGluR receptors results in therapeutic benefit is selected from: addiction, neuropathic pain, L-Dopa-induced and tardive dyskinesias, amyotrophic lateral sclerosis, fragile-X syndrome, Parkinson's disease, anxiety disorders, epilepsy, positive and/or negative symptoms of 5 schizophrenia and cognitive impairment.

31. The use of Claim 27 or method of Claim 28 wherein the condition associated with abnormal glutamate neurotransmission or wherein negative modulation of Group I mGluR receptors results in therapeutic benefit, is 10 selected from: neuropathic pain, diabetic neuropathic pain, cancer pain, pain related to rheumathic arthritis, inflammatory pain, L-Dopa-induced and tardive dyskinesias, Parkinson's disease, anxiety disorders, Huntington's chorea and epilepsy. 15 32. The use of Claim 27 or method of Claim 28 wherein the condition associated with abnormal glutamate neurotransmission or wherein positive modulation of Group I mGluR receptors results in therapeutic benefit, is selected from Alzheimer's disease, positive and/or negative symptoms of schizophrenia and cognitive impairment, or is for cognitive enhancement 20 and/or neuroprotection.

33. The use or method as claimed in any of Claims 27 to 32 wherein the compound as defined in Claim 1 but not subject to the proviso thereof is selected from: 25 3-(adamantane-1 -carbonyl)-7-methoxychromen-2-one, 3-(adamantane-1 -carbonyl)-7-dimethylaminochromen-2-one, 3-(adamantane-1 -carbonyl)-7-diethylaminochromen-2-one, 3-(adamantane-1 -carbonyl)-7-bromochromen-2-one, 2-chloro-3-isopropoxy-9-methyl-7,8,9,1 0-tetrahydrobenzo[c]chromen-6 30 one, 2-ch loro-3-isopropoxy-8-trifluoromethyl-7,8,9,10 tetrahydrobenzo[c]chromen-6-one, 139 WO 2007/045876 PCT/GB2006/003888 dimethylthiocarbamic acid S-(2-chloro-9-methyl-6-oxo-7,8,9,10 tetrahydro-6H-benzo[c]chromen-3-yl) ester, dimethylthiocarbamic acid S-(2-chloro-6-oxo-7,8,9,10-tetrahydro-6H benzo[c]chromen-3-yl) ester, 5 3-isopro poxy-2-nitro-7,8,9,1 0-tetrahydrobenzo[c]chromen-6-one, 2-chloro-3-isopropylsulfanyl-7,8,9,1 0-tetrahydrobenzo[c]chromen-6-one, 2-ethyl-3-isopropoxy-7,8,9,1 0-tetrahydrobenzo[c]chromen-6-one, 2-chloro-3-difluoromethoxy-7,8,9,1 0-tetrahydrobenzo[c]chromen-6-one, 7-isopropoxy-8-nitro-2,3-dihydro-1 H-cyclopenta[c]chromen-4-one, 10 2-chloro-3-isopropoxy-7-methyl-7,8,9,1 0-tetrahydrobenzo[c]chromen-6 one, 2-chloro-3-iso propoxy-7,8,9,1 0-tetrahydrobenzo[c]chromen-6-one, 2-chloro-3-methoxy-7,8,9,10-tetrahydrobenzo[c]chromen-6-one and 8-chloro-7-isopropoxy-2,3-dihydro-1 H-cyclopenta[c]chromen-4-one. 15

34. A method for treating or preventing a condition or disease associated with abnormal glutamate neurotransmission or a method for modulating Group I mGluR receptors to achieve therapeutic benefit, or a method for enhancing cognition, such method comprising administering to a living 20 animal, including a human, a therapeutically effective amount of a compound selected from those of Formula I R 3 R 4 O O R1R 1 R R 25 wherein 140 WO 2007/045876 PCT/GB2006/003888 R 1 represents hydrogen, C 1 . 6 alkyl, aryl, heteroaryl or -C(=0)-Rlo; R 2 represents hydrogen, C1. 6 alkyl, aryl, heteroaryl, arylC 1 . 6 alkyl, heteroarylC 1 . 6 alkyl, cyano, nitro, halogen, hydroxy or C 2 - 6 alkoxy; 5 or R 1 and R 2 together represent -W 1 -X'-Y 1 -Z'-, wherein W 1 represents a single bond, oxygen, sulfur, -NR 7 - or -CR 8 R 9 - and X 1 , Y' and Z' each independently represent oxygen, sulfur, -NR 7 - or 10 CR 8 R 9 -; R 3 represents hydrogen, C1. 6 alkyl, aryl, heteroaryl, nitro, amino, C1-6 alkoxy, halogen, hydroxy, -C(=O)-R 0 , -N(R)-C(=O)-R , -N(R11)SO2-R10, -N(R")C(=0)OR", -C(=0)N(R")2, -C1.ealkylene 15 C(=O)N(R' 1 ) 2 , -N(R')C(=S)N(R' 1 ) 2 , -N(R 1 )C(=O)N(R) 2 , C1.6 alkylamino, di-C 1 . 6 alkylamino, cycloC 3 -1 2 alkylamino, cycloC 3 - 12 alkylaminoC 1 - 6 alkyl, cycloC3.-2alkyl-C1. 6 alkylamino, di-C 1 . 6 alkylaminoC 1 . 6 alkyl, C1.6alkoxy-C 2 - 6 alkylamino, arylamino, arylC 1 . 6 alkylamino, N-cycloC 3 - 1 2 alkyl-N-C 1 . 6 alkylamino, N-aryl-N-Ce 6 20 alkylamino, N-arylC 1 . 6 alkyl-N-C 1 . 6 alkylamino, pyrrolidino, piperidino, 4-arylpiperidino, 4-heteroarylpiperidino, morpholino, morpholinoC 1 . 6 alkyl, piperazino, 4-C1. 6 alkylpiperazino, 4-arylpiperazino, hexamethyleneimino, heteroarylamino or heteroarylC 1 . 6 alkylamino; 25 R 4 represents hydrogen, halogen, nitro, amino, hydroxy, -OR, SO 3 CF 3 , C 1 . 6 alkyl, cycIoC3- 1 2 alkyl, cycloC 3 - 1 2 alkyl-C 1 . 6 alkyl, C2-6 alkenyl, C2- 6 alkynyl, aryl, biaryl, arylC 1 . 6 alkyl, arylC2- 6 alkenyl, aryC 2 - 6 alkynyl, heteroaryl, heteroarylC 1 . 6 alkyl, heteroaryC 2 - 6 alkenyl, heteroarylthio, 2,3-dihydro-1 H-indenyl, C 1 . 6 alkoxyC 1 . 6 alkyl, 30 aryloxyarylC1. 6 alkoxy, C1. 6 alkylthio, C4.6 alkenylthio, cycloC 3 - 12 alkylthio, cycloC 3 . 1 2 alkyl-C 1 . 6 alkylthio, cycloC 3 - 12 alkyl-C3- 6 alkenylthio, C1.6alkoxyC1.alkylthio, C1.6alkoxyC 3 -ealkenylthio, arylC3-6alkenylthio, heteroarylC 1 . 6 alkylthio, C1.6alkylsulfonyl, cycloC 3 - 12 alkyl-C. 6 141 WO 2007/045876 PCT/GB2006/003888 alkylsulfonyl, arylC 1 . 6 alkylsulfonyl, C1..alkylamino, di-C 1 . 6 alkylamino, CYcIOC3-1 2 alkylamino, C1.6alkoxy-cycloC 3 -Cl 2 alkylamino, cycloC 3 . 1 2 alkyl-C 1 - 6 alkylamino, di-C1. 6 alkylaminoCI.-alkyl, C 1 . 6 alkoxy-C 2 - 6 alkylamino, arylamino, arylC1. 6 alkylamino, N-cycloC 3 -1 2 alkyl-N-C 1 . 6 5 alkylamino, N-aryl-N-C. 6 alkylamino, N-aryl 1 . 6 alkyl-N-C 1 . 6 alkylamino, 2-indanylamino, tetrahydrofuryl, pyrrolidino, piperidino, 4 arylpiperidino, 4-heteroarylpiperidino, morpholino, piperazino, 4-C1.6 alkylpiperazino, 4-arylpiperazino, hexamethyleneimino, benzazepinyl, 1,3-dihydro-2H-isoindol-2-y, heteroarylC 1 . 6 alkoxy, heteroarylamino, 10 heteroarylC 1 . alkylamino, -N(R)C(=O)-Rl 0 , -N(R")S0 2 -Rlo, -N(R")C(=0)OR", -C(=0)N(R")2, -C1.ealkylene-C(=0)N(R'1)2, -S-C(=0)N(R")2 or -O-C(=O)-R 10 ; R 5 represents hydrogen, halogen, nitro, amino, hydroxy, C 1 . 6 alkoxy, 15 C1.6 alkyl, C 1 .alkylamino, hydroxyC 1 . 6 alkoxy, aryl, heteroaryl, OCF 3 , -N(R")C(=0)-R'O, -N(R11)SO2-R1O, -N(R")C(=O)OR", -C(=O)N(R")2, -C1.eaqlkylene-C(=0)N(R'1)2, -N(R")C(=S)N(R")2, -(R")C(=0)N(R'1)2, -O-S0 2 R 10 or -C(=0)Rl0; 20 R 6 represents hydrogen, C 1 . 6 alkyl, aryl, heteroaryl, halogen, hydroxy or C1. 6 alkoxy; R 7 represents hydrogen, C 1 . 6 alkyl, aryl, heteroaryl, aryC 1 . 6 alkyl, C1.6 alkoxy, halogen, hydroxy, cyano, nitro, hydroxyC 1 . 6 alkyl, cycloC 3 .. 12 25 alkoxy, C1. 6 alkylamino, di-C 1 . 6 alkylamino, cycloC 3 - 1 2 alkylamino, cycIoC 3 -. 1 2 alkyl-C 1 .ealkylamino, di-C.ialkylaminoC. 6 alkyl, arylamino, aryIl1 6 alkyl, N-aryl-N-C 1 . 6 alkylamino, pyrrolidino, piperidino, 4-C1.6 alkylpiperazino, morpholino, hexamethyleneimino, pyrrolidinyC 1 . 6 alkyl, piperidinylC 1 . 6 alkyl, morpholinylC 1 . 6 alkyl, C 1 . 6 alkylsulfonyl, C1.6 30 alkylthio, C1. 6 alkylaminosulfonyl or di-C1. 6 alkylaminosulfonyl; 142 WO 2007/045876 PCT/GB2006/003888 R 8 and R 9 each independently represent hydrogen, C1. 6 alkyl, aryl, heteroaryl, arylC 1 . 6 alkyl, C1.ealkoxy, halogen, hydroxy, cyano, nitro, amino or cycloC 3 - 1 2 alkyl; 5 R 10 represents hydrogen, C1. 6 alkyl, cycloC3- 12 alkyl, aryl, heteroaryl or carboxyC 1 . 6 alkyl; R" represents hydrogen, C1. 6 alkyl, cycloC 3 12 alkyl, aryl, heteroaryl, carboxyC 1 . 6 alkyl or Cl6alkylcarbonyl; 10 R 1 2 represents C1. 6 alkyl optionally substituted by one or more substituents selected from hydroxy, cycloC 3 - 12 alkyl, C 1 .alkylamino, di C1..alkylamino, morpholino, halogen, arylamino and -C(=O)R 13 ; heteroaryl; cycloC 3 . 1 2 alkyl; C1.6alkoxycycoC 3 -1 2 alkyl; arylC 1 . 6 alkyl; 15 aryloxyarylC 1 . 6 alkyl or C2-6 alkenyl; and R 1 3 represents amino, pyrrolidino or piperidino; or if R 1 and R 2 represent -W 1 -X 1 -Y 1 -Zl- and W 1 does not represent a 20 single bond, R 3 and R 4 , R 4 and R 5 or R 5 and R 6 together with the carbon atoms to which they are attached may form a 5-6 membered ring which may be saturated or unsaturated, wherein the ring may optionally have 1 to 4 heteroatoms selected from oxygen, 25 sulfur and nitrogen, and wherein the ring may be optionally substituted by one or more substituents selected from hydrogen, C 1 . 6 alkyl, cycloC 3 - 1 2 alkyl, aryl, heteroaryl, arylC 1 . 6 alkyl, carboxyC 1 . 6 alkyl, alkylcarbonyl, arylcarbonyl, oxo, thioxo, C1-.alkoxy, C 1 . 6 alkylthio, arylC 1 . 6 alkylthio, arylC 1 . 6 alkoxy, 30 morpholino, C3-6cycloalkylamino, pyrrolidino, piperidino, hexamethyleneimino, piperazinyl, N-C. 6 alkylpiperazinyl and arylamino; 143 WO 2007/045876 PCT/GB2006/003888 wherein the term "C1- 6 alkyl", unless otherwise specified, denotes straight or branched chain groups which may be unsubstituted or substituted by one or more fluorine, chlorine and/or bromine atoms; the term "C1. 6 alkoxy" denotes straight or branched chain groups 5 which may be unsubstituted or substituted by one or more fluorine, chlorine and/or bromine atoms; the term "cycloC 3 - 1 2 alkyl" denotes monocyclic, bicyclic or tricyclic groups which may be unsubstituted or substituted by one or more fluorine, chlorine and/or bromine atoms; the term "aryl" denotes phenyl or naphthyl or phenyl substituted by 10 one or more substituents, which may be the same or different, selected from C1.6alkyl, C 2 - 6 alkenyl, C 1 . 6 alkoxy, cycloC 3 -1 2 alkyl, hydroxy, halogen, cyano, nitro, C1- 6 alkoxycarbonyl, amino, CI-6alkylamino, di-C 1 . 6 alkylamino, N-cycloC 3 - 12 alkyl-N C1.6alkylamino, azetidinyl, pyrrolyl, piperidinyl, morpholinyl, 4-C1.6 15 alkylpiperazinyl, tetrazolyl, oxazolyl, furyl, thiophenyl, isoxazolyl, thiazolyl, imidazolyl, oxadiazolyl, pyridinyl, pyrimidyl and C1.6 alkylenedioxy; and the term "heteroaryl" denotes an aromatic 5-6 membered ring containing from one to four heteroatoms selected from oxygen, sulfur and nitrogen, or a bicyclic group comprising a 5-6 20 membered ring containing from one to four heteroatoms selected from oxygen, sulfur and nitrogen fused with a benzene ring or a 5-6 membered aromatic ring containing from one to four heteroatoms selected from oxygen, sulfur and nitrogen, wherein the heteroaryl group may be optionally substitued by one or more substituents, 25 which may be the same or different, selected from C 1 - 6 alkyl, C1-6 alkoxy, cycloC 3 .. 1 2 alkyl, hydroxy, halogen, cyano, nitro, C1.e alkoxycarbonyl, amino, C 1 . 6 alkylamino, di-C 1 - 6 alkylamino, N-cycloC3- 1 2 alkyl-N-C 1 . 6 alkylamino, azetidinyl, pyrrolyl, piperazinyl, morpholinyl, 4 C16- alkylpiperazinyl, tetrazolyl, oxazolyl, furyl, thiophenyl, isoxazolyl, 30 thiazolyl, imidazolyl, oxadiazolyl, pyridinyl, pyrimidyl and phenyl; and optical isomers, pharmaceutically acceptable salts, hydrates, solvates, and polymorphs thereof. 144