WO2010066658A1

WO2010066658A1 - Compounds which potentiate the ampa receptor and uses thereof in medicine

Info

Publication number: WO2010066658A1
Application number: PCT/EP2009/066476
Authority: WO
Inventors: Daniel Marcus Bradley; Francesca Cardullo; Howard Marshall; Paola Marzorati; Alfonso Pozzan; Simon E Ward
Original assignee: Glaxo Group Limited
Priority date: 2008-12-09
Filing date: 2009-12-07
Publication date: 2010-06-17
Also published as: GB0822425D0

Abstract

A compound of Formula (I) or a salt thereof are provided: wherein R is defined in the specification. Processes for preparation, pharmaceutical compositions, and uses thereof as a medicament, for example in the treatment of a disease or condition mediated by a reduction or imbalance in glutamate receptor function, such as schizophrenia or cognition impairment, are also disclosed.

Description

Compounds which potentiate the AMPA receptor and uses thereof in medicine

This invention relates to novel compounds which potentiate the glutamate receptor. The invention also relates to the use of the compounds in treating diseases and conditions mediated by potentiation of the glutamate receptor, compositions containing the derivatives and processes for their preparation.

Glutamate receptors, which mediate the majority of fast excitatory neurotransmission in the mammalian central nervous system (CNS), are activated by the excitatory amino acid, L-glutamate (for review see Watkins JC, Krogsgaard-Larsen P, Honore T (1990) Trends Pharmacol Sci 11 : 25-33).

Glutamate receptors can be divided into two distinct families. The G-protein or second messenger-linked "metabotropic" glutamate receptor family which can be subdivided into three groups (Group I, mGlui and mGlu5; Group II, mGlu2 and mGlu3; Group III, mGlu4, mGluθ, mGlu7, mGluδ) based on sequence homology and intracellular transduction mechanisms (for review see Conn PJ and Pinn JP (1997) Ann Rev Pharmacol Toxicol 37: 205-237). The "ionotropic" glutamate receptor family, which directly couple to ligand-gated cation channels, can be subdivided into at least three subtypes based on depolarizing activation by selective agonists, N-methyl-D-aspartate (NMDA), α-amino-3-hydroxy-5- methylisoxazole-4-propionic acid (AMPA) and kainic acid (KA) (for review see Dingledine R, Borges K, Bowie, Traynelis S (1999) 51 : 7-61 ).

Native AMPA receptors (AMPAR) exist as heterotetramers consisting of combinations of four different protein subunits (GIuRI -4) (for review see Bettler B and Muller C (1995) 34:

123-139.). Receptor subunit diversity is increased further as each subunit can undergo alternative splicing of a 38 amino acid sequence in the extracellular region just before the fourth membrane spanning domain M4. Such editing results in so-called 'flip' and 'flop' receptor isoforms which differ in kinetic and pharmacological properties (Sommer B, Keinanen K, Verdoon TA, Wisden W, Burnashev N, Herb A, Kohler M, Takagi T,

Sakmann B, Seeburg PH (1990) Science 249: 1580-1585).

Additionally, post-transcriptional editing of GluR2 mRNA changes a neutral glutamine to a positively charged arginine within M2. In normal humans >99% GluR2 is edited in this way. AMPAR containing such edited GluR2 subunit exhibit low calcium permeability (Burnachev N, Monyer H, Seeburg PH, Sakmann B (1992) Neuron 8: 189-198). There is a suggestion, however, that the number of AMPAR with high calcium permeability is elevated in certain disease-associated conditions (Weiss JH, and Sensi SL (2000) Trends in Neurosci 23: 365-371 ).

AMPAR depolarization removes voltage dependent Mg ²⁺ block of NMDA receptors which in turn leads to NMDA receptor activation, an integral stage in the induction of Long Term Potentiation ("LTP") (Bliss TVP, Collingridge GL (1993) Nature 361 : 31-9). LTP is a physiological measure of increased synaptic strength following a repetitive stimulus or activity, such as occurs during learning.

It has been reported that direct activation of glutamate receptors by agonists, in conditions where glutamate receptor function is reduced, increases the risk of excitotoxicity and additional neuronal damage. AMPAR positive allosteric modulators do not activate the receptor directly. However, when the ligand (L-glutamate or AMPA) is present AMPAR modulators increase receptor activity. Thus, AMPA receptor modulators enhance synaptic function when glutamate is released and is able to bind at post-synaptic receptor sites.

Compounds which act as AMPAR positive allosteric modulators have been shown to increase ligand affinity for the receptor (Arai A, Guidotti A, Costa E, Lynch G (1996) Neuroreport. 7: 221 1-5.); reduce receptor desensitization and reduce receptor deactivation (Arai AC, Kessler M, Rogers G, Lynch G (2000) 58: 802-813) and facilitate the induction of LTP both in vitro (Arai A, Guidotti A, Costa E, Lynch G (1996) 7: 2211-5.) and in vivo (Staubli U, Perez Y, Xu F, Rogers G, Ingvar M, Stone-Elander S, Lynch G (1994) Proc Natl Acad Sci 91 : 1 1158-1 1162). Such compounds also enhance the learning and performance of various cognitive tasks in rodent (Zivkovic I, Thompson DM, Bertolino M, Uzunov D, DiBeIIa M, Costa E, Guidotti A (1995) JPET 272: 300-309, Lebrun C, Pilliere E, Lestage P (2000) Eu J Pharmacol 401 : 205-212), sub-human primate (Thompson DM, Guidotti A, DiBeIIa M, Costa E (1995) Proc Natl Acad Sci 92: 7667-7671 ) and man (Ingvar M, Ambros-lngerson J, Davis M, Granger R, Kessler M, Rogers GA, Schehr RS, Lynch G (1997) Exp Neurol 146: 553-559). The efficacy of various AMPAR positive allosteric modulators in pre-clinical and clinical models of psychiatric disorders, such as schizophrenia, have been investigated (Morrow J A, Maclean J KF, Jamieson C (2006) Current Opinion in Drug Discovery and Development 9(5) 571-579). The ability of AMPAR positive allosteric modulators to improve pre-clinical and clinical cognitive task performance as well as the potential for efficacy in psychiatric disorders, such as schizophrenia, in man have been investigated (Morrow J A, Maclean J KF, Jamieson C (2006) Current Opinion in Drug Discovery and Development 9(5) 571-579).

Compounds which act as AMPAR positive allosteric modulators are known, for example in international patent application WO2006/015828. We have discovered novel compounds which potentiate the AMPA receptor.

In the first aspect, the present invention provides a compound of formula (I) or a salt thereof:

wherein R is selected from the group consisting of:

• pyrrolidinyl optionally substituted by oxo; • 1 ,2-dihydropyridyl optionally substituted by oxo;

• phenyl substituted by a group -CH₂-Z (wherein Z is pyrazolyl, morpholinyl or imidazolyl);

• pyridyl substituted by pyrrolidinyl; and

• thienyl or imidazolyl, both of which are fused with a 6- or 7-membered saturated carbocyclic ring, wherein one or two of the carbon atoms in the fused ring is optionally replaced by an oxygen atom; wherein the thienyl or imidazolyl group is further optionally substituted by a halogen.

In one embodiment, R is selected from the group consisting of : • pyrrolidinone;

• 1 ,2-dihydro-2-oxo-pyridyl;

• pyridyl subtitiuted by pyrrolidinyl; and • thienyl or imidazolyl, both of which are fused with a 6- or 7-membered saturated carbocyclic ring, wherein one or two of the carbon atoms in the fused ring is optionally replaced by an oxygen atom; wherein the thienyl or imidazolyl group is further optionally substituted by a halogen.

The term "halogen" refers to fluoro, chloro, bromo or iodo.

It will be appreciated that the present invention is intended to include compounds having any combination of the groups listed hereinbefore. It will be understood that, where appropriate, an embodiment described above for one part of the invention may be combined with an embodiment of another part of the invention.

In one embodiment, the compound is:

N-[(2S)-5-(2-oxo-1 (2H)-pyridinyl)-2,3-dihydro-1 H-inden-2-yl]-2-propanesulfonamide N-{(2S)-5-[3-(1 H-pyrazol-1 -ylmethyl)phenyl]-2,3-dihydro-1 H-inden-2-yl}-2- propanesulfonamide

N-{(2S)-5-[6-(1-pyrrolidinyl)-2-pyridinyl]-2,3-dihydro-1 H-inden-2-yl}-2-propanesulfonamide

N-{(2S)-5-[3-(1 H-imidazol-1-ylmethyl)phenyl]-2,3-dihydro-1 H-inden-2-yl}-2- propanesulfonamide N-[(2S)-5-(2-bromo-5_!6_!7_!8-tetrahydroimidazo[1 _!2-a]pyridin-3-yl)-2_!3-dihydro-1 H-inden-2- yl]-2-propanesulfonamide

N-[(2S)-5-(5_!6_!7_!8-tetrahydroimidazo[1 _!2-a]pyridin-3-yl)-2_!3-dihydro-1 H-inden-2-yl]-2- propanesulfonamide N-{(2S)-5-[3-(4-morpholinylmethyl)phenyl]-2,3-dihydro-1 H-inden-2-yl}-2- propanesulfonamide

N-[(2S)-5-(2_!3-dihydrothieno[3,4-b][1 _!4]dioxin-5-yl)-2,3-dihydro-1 H-inden-2-yl]-2- propanesulfonamide

N-[(2S)-5-(2-bromo-6_!7_!8_!9-tetrahydro-5H-imidazo[1 _!2-a]azepin-3-yl)-2,3-dihydro-1 H- inden-2-yl]-2-propanesulfonamide

N-[(2S)-5-(2-oxo-1-pyrrolidinyl)-2,3-dihydro-1 H-inden-2-yl]-2-propanesulfonamide or a salt thereof.

For the avoidance of doubt, unless otherwise indicated, the term "substituted" means substituted by one or more defined groups. In the case where groups may be selected from a number of alternative groups, the selected groups may be the same or different.

For the avoidance of doubt, the term "independently" means that where more than one substituent is selected from a number of possible substituents, those substituents may be the same or different.

In an embodiment there is provided a compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof.

Salts of compounds of formula (I) which are suitable for use in medicine are those wherein the counterion is pharmaceutically acceptable. However, salts having non- pharmaceutically acceptable counterions are within the scope of the present invention, for example, for use as intermediates in the preparation of other compounds of formula (I) and their pharmaceutically acceptable salts and/or for use in non-therapeutic, for example, in vitro, situations.

As used herein, the term "salt" refers to any salt of a compound according to the present invention prepared from an inorganic or organic acid or base, quaternary ammonium salts and internally formed salts. Pharmaceutically acceptable salts are particularly suitable for medical applications because of their greater aqueous solubility relative to the parent compounds. Such salts must clearly have a pharmaceutically acceptable anion or cation. Suitably pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts formed with inorganic acids such as hydrochloric, hydrobromic, hydroiodic, phosphoric, metaphosphoric, nitric and sulfuric acids, and with organic acids, such as tartaric, acetic, trifluoroacetic, citric, malic, lactic, fumaric, benzoic, formic, propionic, glycolic, gluconic, maleic, succinic, (1 R)-(-)-10-camphorsulphonic, (1 S)-(+)-10- camphorsulphonic, isothionic, mucic, gentisic, isonicotinic, saccharic, glucuronic, furoic, glutamic, ascorbic, anthranilic, salicylic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, pantothenic, stearic, sulfinilic, alginic, galacturonic and arylsulfonic, for example naphthalene-1 ,5-disulphonic, naphthalene-1 ,3-disulphonic, benzenesulfonic, and p-toluenesulfonic, acids; base addition salts formed with alkali metals and alkaline earth metals and organic bases such as N, N- dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumaine (N-methylglucamine), lysine and procaine; and internally formed salts. The salts may have any suitable stoichiometry. For example, a salt may have 1 :1 or 2:1 stoichiometry. Non-integral stoichiometry ratios are also possible.

Solvates of the compounds of formula (I) and solvates of the salts of the compounds of formula (I) are included within the scope of the present invention. As used herein, the term

"solvate" refers to a complex of variable stoichiometry formed by a solute (in this invention, a compound of formula (I) or a salt thereof) and a solvent. Those skilled in the art of organic chemistry will appreciate that many organic compounds can form such complexes with solvents in which they are reacted or from which they are precipitated or crystallized. Such solvents for the purpose of the invention may not interfere with the biological activity of the solute. Examples of suitable solvents include, but are not limited to, water, methanol, ethanol and acetic acid. Preferably the solvent used is a pharmaceutically acceptable solvent. Examples of suitable pharmaceutically acceptable solvents include, without limitation, water, ethanol and acetic acid. Most preferably the solvent used is water. Where the solvent used is water such a solvate may then also be referred to as a hydrate.

It will be appreciated by those skilled in the art that certain protected derivatives of compounds of formula (I), which may be made prior to a final deprotection stage, may not possess pharmacological activity as such, but may, in certain instances, be administered orally or parenterally and thereafter metabolised in the body to form compounds of the invention which are pharmacologically active. Such derivatives may therefore be described as "prodrugs". Further, certain compounds of the invention may be administered as prodrugs. Examples of pro-drug forms for certain compounds of the present invention are described in Drugs of Today, Volume 19, Number 9, 1983, pp 499 - 538 and in Topics in Chemistry, Chapter 31 , pp 306 - 316 and in "Design of Prodrugs" by H. Bundgaard, Elsevier, 1985, Chapter 1 (the disclosures in which documents are incorporated herein by reference). It will further be appreciated by those skilled in the art, that certain moieties, known to those skilled in the art as "pro-moieties", for example as described by H. Bundgaard in "Design of Prodrugs" (the disclosure in which document is incorporated herein by reference) may be placed on appropriate functionalities when such functionalities are present within compounds of the invention. Examples of prodrugs for certain compounds of the invention may include: amides, carbamates, azo-compounds, and phosphamides.

Hereinafter, compounds of formula (I) (whether in solvated or unsolvated form) or their pharmaceutically acceptable salts (whether in solvated or unsolvated form) or prodrugs thereof defined in any aspect of the invention (except intermediate compounds in chemical processes) are referred to as "compounds of the invention".

Also included within the scope of the invention are polymorphs of a compound of the invention.

The invention also includes all suitable isotopic variations of a compound of the invention. An isotopic variation of a compound of the invention is defined as one in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine and chlorine such as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁷O, ¹⁸O, ³¹P, ³²P, ³⁵S, ¹⁸F and ³⁶CI, respectively. Certain isotopic variations of the invention, for example, those in which a radioactive isotope such as ³H or ¹⁴C is incorporated, are useful in drug and/or substrate tissue distribution studies. Tritiated, i.e., ³H, and carbon-14, i.e., ¹⁴C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with isotopes such as deuterium, i.e., ²H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements and hence may be preferred in some circumstances. Isotopic variations of the compounds of the invention can generally be prepared by conventional procedures such as by the illustrative methods or by the preparations described in the Examples hereafter using appropriate isotopic variations of suitable reagents.

Compounds of the present invention are in the S enantiomeric form. The different forms (R and S) may be separated one from the other by the usual methods, or may be obtained by stereospecific or asymmetric synthesis. For the Example compounds of the present invention shown below, the chiral intermediate (2S)-5-bromo-2-aminoindane was first prepared:

using (1 /?)-(-)-10-camphorsulphonic acid as the resolving agent, as disclosed in Prashad et at, Adv. Synth. Catal. 2001 , 343, No. 5, pp 461-472 and also described in WO 2006/015828. The absolute configuration of (2S)-5-bromo-2-aminoindane (1 R)-(-)-10- camphorsulphonic acid salt so obtained was confirmed by single crystal X-ray analysis.

In one embodiment a compound of the invention has at least 80% e.e. In another embodiment, a compound of the invention has at least 90% e.e., for example at least 95% e.e. In another embodiment the isomer corresponds to at least 98% e.e, for example at least 99% e.e. Since the compounds of the invention are intended for use in pharmaceutical compositions it will readily be understood that they are each optionally provided in substantially pure form, for example at least 60% pure, for example at least 75% pure or at least 85%, or at least 98% pure (% are on a weight for weight basis). Impure preparations of the compounds may be used for preparing the more pure forms used in the pharmaceutical compositions; these less pure preparations of the compounds should contain at least 1%, or at least 5% or from 10 to 59% of a compound of the invention

Compounds of the invention may be prepared by methods known in the art of organic synthesis as set forth in part by the following synthesis schemes. In the following reaction schemes and hereafter, unless otherwise stated, all the groups are as defined in the first aspect. It is also recognised that in all of the schemes described below, it is well understood that protecting groups for sensitive or reactive groups are employed where necessary in accordance with general principles of chemistry. Protecting groups are manipulated according to standard methods of organic synthesis (T. W. Greene and P. G.

M. Wuts (1991 ) Protecting Groups in Organic Synthesis, John Wiley & Sons). These groups are removed at a convenient stage of the compound synthesis using methods that are readily apparent to those skilled in the art. The selection of processes as well as the reaction conditions and order of their execution shall be consistent with the preparation of compounds of the invention.

A compound of formula (Ib) shown below may be prepared from a compound of formula (II) by reaction with the appropriate heterocycle according to scheme 1. Typical reaction conditions comprise microwaving at a suitable temperature, for example 190 degC, a mixture of a compound of formula (II) and the required heterocycle, for example 2- hydroxypyridine, in the presence of a suitable copper reagent such as copper (I) iodide, a suitable ligand such as Λ/,Λ/-dimethylglycine, and a suitable base such as caesium carbonate in a suitable solvent such as dimethylsulphoxide for the required time, for example 30 minutes. Alternatively, the above mixture may be heated under argon using a heating block or oil bath for the appropriate time and temperature, for example 16 hours at 120 degC. The preparation of a compound of formula (II) where X equals Br is detailed in the experimental section. Compounds R₁R₂NH are commercially available or may be prepared by methods described in the literature.

Scheme 1

R₁R₂NH Z Cu reagent / ligand / base / solvent

X = leaving group such as Br R₁R₂NH = heterocycle A compound of formula (Ic) shown below may be prepared from a compound of formula (III) by reaction with the appropriate system R¹X according to scheme 2. Typical reaction conditions comprise heating under argon a mixture of a compound of formula (III) (where R is hydrogen, alkyl or the two R groups form a ring) and the required system R¹X, such as 1-[(3-iodophenyl)methyl]-1 H-pyrazole, in the presence of a suitable palladium reagent such as tetrakis(triphenylphosphine)palladium(0) and a suitable base such as sodium carbonate in a suitable solvent such as a 3:1 mixture of 1 ,4-dioxane and water at a suitable temperature such as 90 degC for the required time, for example 29 hours. The preparation of a compound of formula (III) where the pinacol ester of the boronic acid is used, is detailed in the experimental section. Compounds R¹X are commercially available or may be prepared by methods described in the literature.

Scheme 2

R¹X / Pd reagent / base / solvent

where X = leaving

group such as Br, I

R' = phenyl or heterocyclic system

A compound of formula (Ic) shown below may be prepared from a compound of formula (II) by reaction with the appropriate system (RO)₂BR' according to scheme 3. Typical reaction conditions comprise heating under argon a mixture of a compound of formula (II) with the appropriate boronic acid or boronate ester (RO)₂BR' (where R is hydrogen, alkyl or the two R groups form a ring) such as 4-{[3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl]methyl}morpholine, in the presence of a suitable palladium reagent such as tetrakis(triphenylphosphine)palladium(0) and a suitable base such as sodium carbonate in a suitable solvent such as a 3:1 mixture of 1 ,4-dioxane and water at a suitable temperature such as 90 degC for the required time, for example 16 hours. The preparation of a compound of formula (II) where X equals Br is detailed in the experimental section. Compounds (RO)₂BR' are commercially available or may be prepared by methods described in the literature.

Scheme 3

(RO) ₂BR' / Pd reagent / base / solvent

where X = leaving R' = phenyl or heterocyclic system group such as Br Salts may be prepared conventionally by reaction with the appropriate acid or acid derivative.

Compounds of formula (I) may be converted to other compounds of formula (I) using standard methods. For example, a compound of formula (I) wherein R is imidazolyl which is both fused with a saturated carbocyclic ring and also substituted by a halogen, may be dehalogenated using standard procedures to give a compound wherein R is imidazolyl fused with a saturated carbocyclic ring.

Further details for the preparation of compounds of formula (I) are found in the Examples section hereinafter.

The compounds of the invention may be prepared singly or as compound libraries comprising at least 2, for example 5 to 1 ,000 compounds, for example 10 to 100 compounds. Libraries of compounds of the invention may be prepared by a combinatorial 'split and mix' approach or by multiple parallel synthesis using either solution phase or solid phase chemistry, by procedures known to those skilled in the art. Thus according to a further aspect there is provided a compound library comprising at least 2 compounds of the invention.

Compounds of the invention have been found to potentiate the AMPA receptor, and are thus expected to be useful in the treatment of disease states which require potentiation of such receptors, such as in the enhancement of cognition, for example in the treatment of cognition impairment brought about by various diseases. The compounds are also expected to be useful in the treatment of psychotic conditions, including schizophrenia.

The present invention provides a compound of formula (I) or a salt thereof for use in medicine.

In one embodiment, the present invention provides a compound of formula (I) or a salt thereof for use in treating a disease or condition mediated by a reduction or imbalance in glutamate receptor function in a mammal.

The present invention also provides a pharmaceutical composition comprising a compound of formula (I) or a salt thereof and at least one carrier, diluent or excipient.

It will be appreciated that the invention includes the following further aspects. The embodiments described in respect of the first aspect apply equally to each of these further aspects: i) the use of a compound of formula (I) or a salt thereof in the manufacture of a medicament for treating a disease or condition mediated by a reduction or imbalance in glutamate receptor function in a mammal; ii) a compound of formula (I) or a salt thereof for use in treating a disease or condition mediated by a reduction or imbalance in glutamate receptor function in a mammal; iii) a method of treatment of a disease or condition mediated by a reduction or imbalance in glutamate receptor function in a mammal comprising administering an effective amount of a compound of formula (I) or a salt thereof; iv) a combination product of a compound of formula (I) or a salt thereof with an antipsychotic; v) a pharmaceutical composition comprising a combination product as defined in iv) above and at least one carrier, diluent or excipient; vi) the use of a combination product as defined in iv) above in the manufacture of a medicament for treating a disease or condition mediated by a reduction or imbalance in glutamate receptor function in a mammal; vii) a combination product as defined in iv) above for use in treating a disease or condition mediated by a reduction or imbalance in glutamate receptor function in a mammal; viii) a combination product as defined in iv) above for use as a medicament; ix) a method of treatment of a disease or condition mediated by a reduction or imbalance in glutamate receptor function in a mammal comprising administering an effective amount of a combination product as defined in iv) above.

Relevant diseases or conditions are: psychosis and psychotic disorders (including schizophrenia, schizo-affective disorder, schizophreniform diseases, brief reactive psychosis, child onset schizophrenia, "schizophrenia-spectrum" disorders such as schizoid or schizotypal personality disorders, acute psychosis, alcohol psychosis, drug- induced psychosis, autism, delerium, mania (including acute mania), manic depressive psychosis, hallucination, endogenous psychosis, organic psychosyndrome, paranoid and delusional disorders, puerperal psychosis, and psychosis associated with neurodegenerative diseases such as Alzheimer's disease); substance related disorders (including alcohol-related disorders and nicotine-related disorders); cognitive impairment (e.g. the treatment of impairment of cognitive functions including attention, orientation, memory (i.e. memory disorders, amnesia, amnesic disorders and age-associated memory impairment) and language function, and including cognitive impairment as a result of stroke, Alzheimer's disease, Aids-related dementia or other dementia states, as well as other acute or sub-acute conditions that may cause cognitive decline such as delirium or depression (pseudodementia states) trauma, aging, stroke, neurodegeneration, drug- induced states, neurotoxic agents), mild cognitive impairment, age related cognitive impairment, autism related cognitive impairment, Down's syndrome, cognitive deficit related to psychosis, post-electroconvulsive treatment related cognitive disorders; anxiety disorders (including generalised anxiety disorder, social anxiety disorder, agitation, tension, social or emotional withdrawal in psychotic patients, panic disorder, and obsessive compulsive disorder); neurodegenerative diseases (such as Alzheimer's disease, amyotrophic lateral sclerosis, motor neurone disease and other motor disorders such as Parkinson's disease (including relief from locomotor deficits and/or motor disability, including slowly increasing disability in purposeful movement, tremors, bradykinesia, hyperkinesia (moderate and severe), akinesia, rigidity, disturbance of balance and co-ordination, and a disturbance of posture), dementia in Parkinson's disease, dementia in Huntington's disease, neuroleptic-induced Parkinsonism and tardive dyskinesias, neurodegeneration following stroke, cardiac arrest, pulmonary bypass, traumatic brain injury, spinal cord injury or the like, and demyelinating diseases such as multiple sclerosis and amyotrophic lateral sclerosis); depression (which term includes bipolar (manic) depression (including type I and type II), unipolar depression, single or recurrent major depressive episodes with or without psychotic features, catatonic features, melancholic features, atypical features (e.g. lethargy, over-eating/obesity, hypersomnia) or postpartum onset, seasonal affective disorder and dysthymia, depression-related anxiety, psychotic depression, and depressive disorders resulting from a general medical condition including, but not limited to, myocardial infarction, diabetes, miscarriage or abortion); posttraumatic stress syndrome; attention deficit disorder; attention deficit hyperactivity disorder; drug-induced (phencyclidine, ketamine and other dissociative anaesthetics, amphetamine and other psychostimulants and ***e) disorders; Huntingdon's chorea; tardive dyskinesia; dystonia; myoclonus; spasticity; obesity; stroke; sexual dysfunction; sleep disorders and some forms of epilepsy.

Within the context of the present invention, the terms describing the indications used herein are classified in the Diagnostic and Statistical Manual of Mental Disorders, 4th

Edition, published by the American Psychiatric Association (DSM-IV) and/or the

International Classification of Diseases, 10th Edition (ICD-10). Treatment of the various subtypes of the disorders mentioned herein using a compound of the present invention is contemplated as part of the present invention. Numbers in brackets after the listed diseases below refer to the classification code in DSM-IV.

Within the context of the present invention, the term "psychotic disorder" includes :-

Schizophrenia including the subtypes Paranoid Type (295.30), Disorganised Type (295.10), Catatonic Type (295.20), Undifferentiated Type (295.90) and Residual Type

(295.60); Schizophreniform Disorder (295.40); Schizoaffective Disorder (295.70) including the subtypes Bipolar Type and Depressive Type; Delusional Disorder (297.1 ) including the subtypes Erotomanic Type, Grandiose Type, Jealous Type, Persecutory Type, Somatic

Type, Mixed Type and Unspecified Type; Brief Psychotic Disorder (298.8); Shared Psychotic Disorder (297.3); Psychotic Disorder Due to a General Medical Condition including the subtypes With Delusions and With Hallucinations; Substance-Induced Psychotic Disorder including the subtypes With Delusions (293.81 ) and With Hallucinations (293.82); and Psychotic Disorder Not Otherwise Specified (298.9).

Compounds of the invention may also be of use in the treatment of the following disorders:-

Depression and mood disorders including Major Depressive Episode, Manic Episode, Mixed Episode and Hypomanic Episode; Depressive Disorders including Major Depressive Disorder, Dysthymic Disorder (300.4), Depressive Disorder Not Otherwise Specified (31 1 ); Bipolar Disorders including Bipolar I Disorder, Bipolar Il Disorder (Recurrent Major Depressive Episodes with Hypomanic Episodes) (296.89), Cyclothymic Disorder (301.13) and Bipolar Disorder Not Otherwise Specified (296.80); Other Mood Disorders including Mood Disorder Due to a General Medical Condition (293.83) which includes the subtypes With Depressive Features, With Major Depressive-like Episode, With Manic Features and With Mixed Features), Substance-Induced Mood Disorder (including the subtypes With Depressive Features, With Manic Features and With Mixed Features) and Mood Disorder Not Otherwise Specified (296.90):

Anxiety disorders including Panic Attack; Panic Disorder including Panic Disorder without Agoraphobia (300.01 ) and Panic Disorder with Agoraphobia (300.21 ); Agoraphobia; Agoraphobia Without History of Panic Disorder (300.22), Specific Phobia (300.29, formerly Simple Phobia) including the subtypes Animal Type, Natural Environment Type, Blood-lnjection-lnjury Type, Situational Type and Other Type), Social Phobia (Social Anxiety Disorder, 300.23), Obsessive-Compulsive Disorder (300.3), Posttraumatic Stress Disorder (309.81 ), Acute Stress Disorder (308.3), Generalized Anxiety Disorder (300.02), Anxiety Disorder Due to a General Medical Condition (293.84), Substance-Induced Anxiety Disorder, Separation Anxiety Disorder (309.21 ), Adjustment Disorders with Anxiety (309.24) and Anxiety Disorder Not Otherwise Specified (300.00):

Substance-related disorders including Substance Use Disorders such as Substance Dependence, Substance Craving and Substance Abuse; Substance-Induced Disorders such as Substance Intoxication, Substance Withdrawal, Substance-Induced Delirium, Substance-Induced Persisting Dementia, Substance-Induced Persisting Amnestic Disorder, Substance-Induced Psychotic Disorder, Substance-Induced Mood Disorder, Substance-Induced Anxiety Disorder, Substance-Induced Sexual Dysfunction, Substance- Induced Sleep Disorder and Hallucinogen Persisting Perception Disorder (Flashbacks); Alcohol-Related Disorders such as Alcohol Dependence (303.90), Alcohol Abuse (305.00), Alcohol Intoxication (303.00), Alcohol Withdrawal (291.81 ), Alcohol Intoxication Delirium, Alcohol Withdrawal Delirium, Alcohol-Induced Persisting Dementia, Alcohol- Induced Persisting Amnestic Disorder, Alcohol-Induced Psychotic Disorder, Alcohol- Induced Mood Disorder, Alcohol-Induced Anxiety Disorder, Alcohol-Induced Sexual Dysfunction, Alcohol-Induced Sleep Disorder and Alcohol-Related Disorder Not Otherwise Specified (291.9); Amphetamine (or Amphetamine-I_ike)-Related Disorders such as Amphetamine Dependence (304.40), Amphetamine Abuse (305.70), Amphetamine Intoxication (292.89), Amphetamine Withdrawal (292.0), Amphetamine Intoxication Delirium, Amphetamine Induced Psychotic Disorder, Amphetamine-Induced Mood Disorder, Amphetamine-Induced Anxiety Disorder, Amphetamine-Induced Sexual Dysfunction, Amphetamine-Induced Sleep Disorder and Amphetamine-Related Disorder Not Otherwise Specified (292.9); Caffeine Related Disorders such as Caffeine Intoxication (305.90), Caffeine-Induced Anxiety Disorder, Caffeine-Induced Sleep Disorder and Caffeine-Related Disorder Not Otherwise Specified (292.9); Cannabis-Related Disorders such as Cannabis Dependence (304.30), Cannabis Abuse (305.20), Cannabis Intoxication (292.89), Cannabis Intoxication Delirium, Cannabis-lnduced Psychotic Disorder, Cannabis-lnduced Anxiety Disorder and Cannabis-Related Disorder Not Otherwise Specified (292.9); Cocaine-Related Disorders such as Cocaine Dependence (304.20), Cocaine Abuse (305.60), Cocaine Intoxication (292.89), Cocaine Withdrawal (292.0), Cocaine Intoxication Delirium, Cocaine-Induced Psychotic Disorder, Cocaine-Induced Mood Disorder, Cocaine-Induced Anxiety Disorder, Cocaine-Induced Sexual Dysfunction, Cocaine-Induced Sleep Disorder and Cocaine-Related Disorder Not Otherwise Specified (292.9); Hallucinogen-Related Disorders such as Hallucinogen Dependence (304.50), Hallucinogen Abuse (305.30), Hallucinogen Intoxication (292.89), Hallucinogen Persisting Perception Disorder (Flashbacks) (292.89), Hallucinogen Intoxication Delirium, Hallucinogen-Induced Psychotic Disorder, Hallucinogen-Induced Mood Disorder, Hallucinogen-Induced Anxiety Disorder and Hallucinogen-Related Disorder Not Otherwise Specified (292.9); Inhalant-Related Disorders such as Inhalant Dependence (304.60), Inhalant Abuse (305.90), Inhalant Intoxication (292.89), Inhalant Intoxication Delirium, Inhalant-Induced Persisting Dementia, Inhalant-Induced Psychotic Disorder, Inhalant- Induced Mood Disorder, Inhalant-Induced Anxiety Disorder and Inhalant-Related Disorder Not Otherwise Specified (292.9); Nicotine-Related Disorders such as Nicotine Dependence (305.1 ), Nicotine Withdrawal (292.0) and Nicotine-Related Disorder Not Otherwise Specified (292.9); Opioid-Related Disorders such as Opioid Dependence (304.00), Opioid Abuse (305.50), Opioid Intoxication (292.89), Opioid Withdrawal (292.0), Opioid Intoxication Delirium, Opioid-lnduced Psychotic Disorder, Opioid-lnduced Mood Disorder, Opioid-lnduced Sexual Dysfunction, Opioid-lnduced Sleep Disorder and Opioid- Related Disorder Not Otherwise Specified (292.9); Phencyclidine (or Phencyclidine-Like)- Related Disorders such as Phencyclidine Dependence (304.60), Phencyclidine Abuse (305.90), Phencyclidine Intoxication (292.89), Phencyclidine Intoxication Delirium, Phencyclidine-lnduced Psychotic Disorder, Phencyclidine-lnduced Mood Disorder, Phencyclidine-lnduced Anxiety Disorder and Phencyclidine-Related Disorder Not Otherwise Specified (292.9); Sedative-, Hypnotic-, or Anxiolytic-Related Disorders such as Sedative, Hypnotic, or Anxiolytic Dependence (304.10), Sedative, Hypnotic, or Anxiolytic Abuse (305.40), Sedative, Hypnotic, or Anxiolytic Intoxication (292.89), Sedative, Hypnotic, or Anxiolytic Withdrawal (292.0), Sedative, Hypnotic, or Anxiolytic Intoxication Delirium, Sedative, Hypnotic, or Anxiolytic Withdrawal Delirium, Sedative-, Hypnotic-, or Anxiolytic-Persisting Dementia, Sedative-, Hypnotic-, or Anxiolytic- Persisting Amnestic Disorder, Sedative-, Hypnotic-, or Anxiolytic-lnduced Psychotic Disorder, Sedative-, Hypnotic-, or Anxiolytic-lnduced Mood Disorder, Sedative-, Hypnotic-, or Anxiolytic- lnduced Anxiety Disorder Sedative-, Hypnotic-, or Anxiolytic-lnduced Sexual Dysfunction, Sedative-, Hypnotic-, or Anxiolytic-lnduced Sleep Disorder and Sedative-, Hypnotic-, or Anxiolytic-Related Disorder Not Otherwise Specified (292.9); Polysubstance-Related Disorder such as Polysubstance Dependence (304.80); and Other (or Unknown) Substance-Related Disorders such as Anabolic Steroids, Nitrate Inhalants and Nitrous Oxide:

Sleep disorders including primary sleep disorders such as Dyssomnias such as Primary Insomnia (307.42), Primary Hypersomnia (307.44), Narcolepsy (347), Breathing-Related Sleep Disorders (780.59), Circadian Rhythm Sleep Disorder (307.45) and Dyssomnia Not Otherwise Specified (307.47); primary sleep disorders such as Parasomnias such as Nightmare Disorder (307.47), Sleep Terror Disorder (307.46), Sleepwalking Disorder (307.46) and Parasomnia Not Otherwise Specified (307.47); Sleep Disorders Related to Another Mental Disorder such as Insomnia Related to Another Mental Disorder (307.42) and Hypersomnia Related to Another Mental Disorder (307.44); Sleep Disorder Due to a General Medical Condition, in particular sleep disturbances associated with such diseases as neurological disorders, neuropathic pain, restless leg syndrome, heart and lung diseases; and Substance-Induced Sleep Disorder including the subtypes Insomnia Type, Hypersomnia Type, Parasomnia Type and Mixed Type; sleep apnea and jet-lag syndrome:

Autism Spectrum Disorders including Autistic Disorder (299.00), Asperger's Disorder (299.80), Rett's Disorder (299.80), Childhood Disintegrative Disorder (299.10) and Pervasive Disorder Not Otherwise Specified (299.80, including Atypical Autism).

Attention-Deficit/Hyperactivity Disorder including the subtypes Attention-Deficit /Hyperactivity Disorder Combined Type (314.01 ), Attention-Deficit /Hyperactivity Disorder

Predominantly Inattentive Type (314.00), Attention-Deficit /Hyperactivity Disorder

Hyperactive-Impulse Type (314.01 ) and Attention-Deficit /Hyperactivity Disorder Not

Otherwise Specified (314.9); Hyperkinetic Disorder; Disruptive Behaviour Disorders such as Conduct Disorder including the subtypes childhood-onset type (321.81 ), Adolescent- Onset Type (312.82) and Unspecified Onset (312.89), Oppositional Defiant Disorder

(313.81 ) and Disruptive Behaviour Disorder Not Otherwise Specified; and Tic Disorders such as Tourette's Disorder (307.23):

Personality Disorders including the subtypes Paranoid Personality Disorder (301.0), Schizoid Personality Disorder (301.20), Schizotypal Personality Disorder (301 ,22),

Antisocial Personality Disorder (301.7), Borderline Personality Disorder (301 ,83),

Histrionic Personality Disorder (301.50), Narcissistic Personality Disorder (301 ,81 ), Avoidant Personality Disorder (301.82), Dependent Personality Disorder (301.6), Obsessive-Compulsive Personality Disorder (301.4) and Personality Disorder Not Otherwise Specified (301.9):

Enhancement of cognition including the treatment of cognition impairment in other diseases such as schizophrenia, bipolar disorder, depression, other psychiatric disorders and psychotic conditions associated with cognitive impairment, e.g. Alzheimer's disease: and

Sexual dysfunctions including Sexual Desire Disorders such as Hypoactive Sexual Desire Disorder (302.71 ), and Sexual Aversion Disorder (302.79); sexual arousal disorders such as Female Sexual Arousal Disorder (302.72) and Male Erectile Disorder (302.72); orgasmic disorders such as Female Orgasmic Disorder (302.73), Male Orgasmic Disorder (302.74) and Premature Ejaculation (302.75); sexual pain disorder such as Dyspareunia (302.76) and Vaginismus (306.51 ); Sexual Dysfunction Not Otherwise Specified (302.70); paraphilias such as Exhibitionism (302.4), Fetishism (302.81 ), Frotteurism (302.89), Pedophilia (302.2), Sexual Masochism (302.83), Sexual Sadism (302.84), Transvestic Fetishism (302.3), Voyeurism (302.82) and Paraphilia Not Otherwise Specified (302.9); gender identity disorders such as Gender Identity Disorder in Children (302.6) and Gender Identity Disorder in Adolescents or Adults (302.85); and Sexual Disorder Not Otherwise Specified (302.9).

All of the various forms and sub-forms of the disorders mentioned herein are contemplated as part of the present invention.

Within the context of the present invention, the term "cognitive impairment" includes for example the treatment of impairment of cognitive functions including attention, orientation, learning disorders, memory (i.e. memory disorders, amnesia, amnesic disorders, transient global amnesia syndrome and age-associated memory impairment) and language function; cognitive impairment as a result of stroke, Alzheimer's disease, Huntington's disease, Pick disease, Aids-related dementia or other dementia states such as Multiinfarct dementia, alcoholic dementia, hypotiroidism-related dementia, and dementia associated to other degenerative disorders such as cerebellar atrophy and amyotropic lateral sclerosis; other acute or sub-acute conditions that may cause cognitive decline such as delirium or depression (pseudodementia states) trauma, head trauma, age related cognitive decline, stroke, neurodegeneration, drug-induced states, neurotoxic agents, mild cognitive impairment, age related cognitive impairment, autism related cognitive impairment, Down's syndrome, cognitive deficit related to psychosis, and post- electroconvulsive treatment related cognitive disorders; and dyskinetic disorders such as Parkinson's disease, neuroleptic-induced parkinsonism, and tardive dyskinesias. In one embodiment, the present invention provides a compound of the invention for use in treating schizophrenia or impairment of cognition.

In one embodiment, the present invention provides a use of a compound of the invention in the manufacture of a medicament for treating schizophrenia or impairment of cognition.

In one embodiment, the present invention provides a method of treating schizophrenia or impairment of cognition in a human, comprising administering an therapeutically effective amount of a compound of the present invention, alone or combined with a pharmaceutically acceptable carrier, dilutent or excipient.

The compounds of the invention may be used in combination with one or more of the following agents to treat psychotic disorders: i) antipsychotics (such as olanzapine, risperidone, clozapine, ziprazidone, talnetant); ii) drugs for extrapyramidal side effects, for example anticholinergics (such as benztropine, biperiden, procyclidine, trihexyphenidyl), antihistamines (such as diphenhydramine), dopaminergics (such as amantadine); iii) antidepressants; iv) anxiolytics; v) cognitive enhancers for example cholinesterase inhibitors (such as tacrine, donepezil, rivastigmine,galantamine).

The compounds of the invention may be used in combination with antidepressants to treat depression and mood disorders.

The compounds of the invention may be used in combination with one or more of the following agents to treat bipolar disease: i) mood stabilisers; ii) antipsychotics; iii) antidepressants.

The compounds of the invention may be used in combination with one or more of the following agents to treat anxiety disorders: i) anxiolytics; ii) antidepressants.

The compounds of the invention may be used in combination with one or more of the following agents to improve nicotine withdrawal and reduce nicotine craving: i) nicotine replacement therapy, for example a sublingual formulation of nicotine beta-cyclodextrin and nicotine patches; ii) drugs for treating nicotine addition, for example bupropion.

The compounds of the invention may be used in combination with one or more of the following agents to improve alcohol withdrawal and reduce alcohol craving: i) NMDA receptor antagonists for example acamprosate; ii) GABA receptor agonists for example tetrabamate; iii) Opioid receptor antagonists for example naltrexone.

The compounds of the invention may be used in combination with one or more of the following agents to improve opiate withdrawal and reduce opiate craving: i) opioid mu receptor agonist/opioid kappa receptor antagonist for example buprenorphine; ii) opioid receptor antagonists for example naltrexone; Ni) vasodilatory antihypertensives for example lofexidine.

The compounds of the invention may be used in combination with one or more of the following agents to treat sleeping disorders: i) benzodiazepines for example temazepam, lormetazepam, estazolam, triazolam; ii) non-benzodiazepine hypnotics for example Zolpidem, zopiclone, zaleplon, indiplon; iii) barbiturates for example aprobarbital, butabarbital, pentobarbital, secobarbita, phenobarbital; iv) antidepressants; v) other sedative-hypnotics for example chloral hydrate, chlormethiazole.

The compounds of the invention may be used in combination with one or more of the following agents to treat anorexia: i) appetite stimulants for example cyproheptidine; ii) antidepressants; iii) antipsychotics; iv) zinc; v) premenstrual agents for example pyridoxine and progesterones.

The compounds of the invention may be used in combination with one or more of the following agents to treat bulimia: i) antidepressants; ii) opioid receptor antagonists; iii) antiemetics for example ondansetron; iv) testosterone receptor antagonists for example flutamide; v) mood stabilisers; vi) zinc; vii) premenstrual agents.

The compounds of the invention may be used in combination with one or more of the following agents to treat autism: i) antipsychotics; ii) antidepressants; iii) anxiolytics; iv) stimulants for example methylphenidate, amphetamine formulations, pemoline.

The compounds of the invention may be used in combination with one or more of the following agents to treat Attention Deficit Hyperactivity Disorder: i) stimulants for example methylphenidate, amphetamine formulations, pemoline; ii) non-stimulants for example norepinephrine reuptake inhibitors (such as atomoxetine), alpha 2 adrenoceptor agonists (such as clonidine), antidepressants, modafinil, cholinesterase inhibitors (such as galantamine and donezepil).

The compounds of the invention may be used in combination with one or more of the following agents to treat personality disorders: i) antipsychotics; ii) antidepressants; iii) mood stabilisers; iv) anxiolytics.

The compounds of the invention may be used in combination with one or more of the following agents to treat male sexual dysfunction: i) phosphodiesterase V inhibitors, for example vardenafil, sildenafil; ii) dopamine agonists/dopamine transport inhibitors for example apomorphine, buproprion; iii) alpha adrenoceptor antagonists for example phentolamine; iv) prostaglandin agonists for example alprostadil; v) testosterone agonists such as testosterone; vi) serotonin transport inhibitors for example serotonin reuptake inhibitors; v) noradrenaline transport inhibitors for example reboxetine; vii) 5-HT1A agonists, for example flibanserine.

The compounds of the invention may be used in combination with one or more of the following agents to treat female sexual dysfunction: i) the same agents specified for male sexual dysfunction, ii) an estrogen agonist such as estradiol.

Antipsychotic drugs include Typical Antipsychotics (for example chlorpromazine, thioridazine, mesoridazine, fluphenazine, perphenazine, prochlorperazine, trifluoperazine, thiothixine, haloperidol, molindone and loxapine); and Atypical Antipsychotics (for example clozapine, olanzapine, risperidone, quetiapine, aripirazole, ziprasidone, amisulpride, ziprazidone and talnetant).

Antidepressant drugs include serotonin reuptake inhibitors (such as citalopram, escitalopram, fluoxetine, paroxetine and sertraline); dual serotonin/noradrenaline reuptake inhibitors (such as venlafaxine, duloxetine and milnacipran); Noradrenaline reuptake inhibitors (such as reboxetine); tricyclic antidepressants (such as amitriptyline, clomipramine, imipramine, maprotiline, nortriptyline and trimipramine); monoamine oxidase inhibitors (such as isocarboxazide, moclobemide, phenelzine and tranylcypromine); and others (such as bupropion, mianserin, mirtazapine, nefazodone and trazodone).

Mood stabiliser drugs include lithium, sodium valproate/valproic acid/divalproex, carbamazepine, lamotrigine, gabapentin, topiramate and tiagabine.

Anxiolytics include benzodiazepines such as alprazolam and lorazepam.

The compounds of the invention may be administered in conventional dosage forms prepared by combining a compound of the invention with standard pharmaceutical carriers or diluents according to conventional procedures well known in the art. These procedures may involve mixing, granulating and compressing or dissolving the ingredients as appropriate to the desired preparation.

The pharmaceutical compositions of the invention may be formulated for administration to mammals including humans. The compositions may be formulated for administration by any route. The compositions may be formulated for oral, topical, or parenteral administration, and may be in the form of tablets, capsules, powders, granules, lozenges, creams or liquid preparations, such as oral or sterile parenteral solutions or suspensions.

The topical formulations of the present invention may be presented as, for instance, ointments, creams or lotions, eye ointments and eye or ear drops, impregnated dressings and aerosols, and may contain appropriate conventional additives such as preservatives, solvents to assist drug penetration and emollients in ointments and creams.

The formulations may also contain compatible conventional carriers, such as cream or ointment bases and ethanol or oleyl alcohol for lotions. Such carriers may be present as from about 1 % up to about 98% of the formulation. More usually they will form up to about 80% of the formulation.

Tablets and capsules for oral administration may be in unit dose presentation form, and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate, talc, polyethylene glycol or silica; disintegrants, for example potato starch; or acceptable wetting agents such as sodium lauryl sulphate. The tablets may be coated according to methods well known in normal pharmaceutical practice. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives, such as suspending agents, for example sorbitol, methyl cellulose, glucose syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, oily esters such as glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and, if desired, conventional flavouring or colouring agents.

Suppositories will contain conventional suppository bases, e.g. cocoa-butter or other glyceride.

For parenteral administration, fluid unit dosage forms are prepared utilising the compound and a sterile vehicle, for example water. The compound, depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle. In preparing solutions the compound can be dissolved in water for injection and filter sterilised before filling into a suitable vial or ampoule and sealing.

Agents such as a local anaesthetic, preservative and buffering agents can be dissolved in the vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum. The dry lyophilised powder is then sealed in the vial and an accompanying vial of water for injection may be supplied to reconstitute the liquid prior to use. Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilisation cannot be accomplished by filtration. The compound can be sterilised by exposure to ethylene oxide before suspending in the sterile vehicle. A surfactant or wetting agent may be included in the composition to facilitate uniform distribution of the compound.

It will be recognised by one of skill in the art that the optimal quantity and spacing of individual dosages of a compound of the invention will be determined by the nature and extent of the condition being treated, the form, route and site of administration, and the particular mammal being treated, and that such optimums can be determined by conventional techniques. It will also be appreciated by one of skill in the art that the optimal course of treatment, i.e. the number of doses of a compound of the invention given per day for a defined number of days, can be ascertained by those skilled in the art using conventional course of treatment determination tests.

It is to be understood that "treatment" as used herein includes prophylaxis as well as alleviation of established symptoms. In one embodiment, the mammal to be treated is a human.

The invention is illustrated by the Examples described below.

Starting materials were obtained from commercial suppliers and used without further purification unless otherwise stated. Flash chromatography was carried out using prepacked lsolute Flash™ or Biotage™ silica-gel columns as the stationary phase and analytical grade solvents as the eluent unless otherwise stated.

NMR spectra were obtained at 298K, 303.2K or 300K, at the frequency stated using either a Bruker™ DPX400 or AV400 machine and run as a dilute solution of CDCI₃ unless otherwise stated. All NMR spectra were referenced to tetramethylsilane (TMS δ_H 0, δ_c 0). All coupling constants are reported in hertz (Hz), and multiplicities are labelled s (singlet), bs (broad singlet), d (doublet), t (triplet), q (quartet), dd (doublet of doublets), dt (doublet of triplets), td (triplet of doublets), ddd (double-double-doublet) and m (multiplet).

All quoted retention times are as measured using LC/MS (Liquid Chromatography/Mass Spectrometry). Where appropriate, these retention times were used as a guide for purification using mass-directed auto-purification (MDAP), which refers to purification by HPLC, wherein fraction collection is triggered by detection of the programmed mass ion for the compound of interest.

Total ion current traces were obtained for electrospray positive and negative ionisation (ES+ / ES-) and/or atmospheric pressure chemical positive and negative ionisation (AP+ / AP-). Where reactions are described as having been carried out in a similar manner to earlier, more completely described reactions, the general reaction conditions used were essentially the same. Work up conditions used were of the types standard in the art, but may have been adapted from one reaction to another. The starting material may not necessarily have been prepared from the batch referred to. Unless otherwise stated, all compounds with chiral centre(s) are racemic. Compounds synthesised may have various purities ranging from for example 85% to 98%. However, calculations of number of moles and yield are generally not adjusted for this. Abbreviations e.e. enantiomeric excess

TEA Triethylamine

TMS-CI Trimethylsilyl chloride ss saturated solution TFA Trifluoroacetic acid

DAD Diode Array Detector

CD Circular dichroism a/a% percentage by area unde the curve

LC/MS Liquid Chromatography / Mass Spectrometry NMR Nuclear Magnetic Resonance

SCX strong cationic exchange

THF Tetrahydrofuran

DMSO Dimethylsulfoxide

DMF Dimethylformamide DCM / MDC Dichloromethane / Methylene dichloride

CDI 1 ,1 '-Carbonyldiimidazole

LDA Lithium diisopropylamide

EDC 1-ethyl-3-(dimethylaminopropyl)carbodiimide

MsCI Methanesulfonyl chloride AcOH Acetic acid

HOAt 1 -hydroxy-7-azabenzotriazole

HOBt 1 -hydroxybenzotriazole

Pd on C Palladium on Charcoal

MeCN Acetonitrile MDAP Mass-directed auto-purification

ES electrospray min(s) minute(s)

PdCI₂(dppf) 1 ,1'-bis(diphenylphosphino)ferrocene palladium dichloride

DIAD diisopropyl azodicarboxylate degC degrees Celsius

Ph phenyl UPLC/MS ultra performance liquid chromatography / mass spectrometry Analytical chromatographic conditions

One of the following methods were used for the LC/MS analysis:

Method 1

Column: Waters Atlantis, 4.6mm x 50mm. The stationary phase particle size is

3um. Solvents: A : Aqueous solvent = Water + 0.05% Formic Acid;

B : Organic solvent = Acetonitrile + 0.05% Formic Acid Methods: 5 minute runtime.

Time / min %B

0 3

0.1 3

4 97

4.8 97

4.9 3

5.0 3

Flow rate: 3ml/min

Injection volume: 5μl

Column temperature: 30 degC

UV wavelength range: 220-330 nm

Method 1 - high pH version - as above, except:

- Column: Waters X-Bridge 4.6mm x 50mm. The stationary phase particle size is

3.5μm.

A : Aqueous solvent = 1OmM Ammonium Bicarbonate solution adjusted to pH 10 with ammonia solution.

B : Organic solvent = Acetonitrile.

Method 2

Column: Waters Acquity BEH UPLC C18, 2.1 mm x 50mm. The stationary phase particle size is 1.7μm.

Solvents

A : Aqueous solvent = Water + 0.05% Formic Acid

B : Organic solvent = Acetonitrile + 0.05% Formic Acid

Weak Wash = 1 :1 Methanol : Water

Strong Wash = Water

The generic method used has a 2 minute runtime.

• The above method has a flow rate of 1 ml/min.

• The injection volume for the generic method is 0.5μl

• The column temperature is 40degC

• The UV detection range is from 220 to 330nm

MDAP conditions

Column: Waters Atlantis, 19mm x 100mm (small scale) and 30mm x 100mm

(large scale). Stationary phase particle size = 5μm.

Solvents: A : Aqueous solvent = Water + 0.1% Formic Acid; B : Organic solvent = Acetonitrile + 0.1% Formic Acid. Make up solvent =

Methanol : Water 80:20. Needle rinse solvent = Methanol

Methods: There are five methods used depending on the analytical retention time of the compound of interest. They have a 13.5-minute runtime, which comprises of a 10-minute gradient followed by a 3.5 minute column flush and re-equilibration step.

Large/Small Scale 1.0-1.5 = 5-30% B

Large/Small Scale 1.5-2.2 = 15-55% B

Large/Small Scale 2.2-2.9 = 30-85% B

Large/Small Scale 2.9-3.6 = 50-99% B

Large/Small Scale 3.6-5.0 = 80-99% B (in 6 minutes followed by 7.5 minutes flush and re-equilibration)

Flow rate: 20mls/min (Small Scale) or 40mls/min (Large Scale).

High pH MDAP - as above, except for:

Column: Waters X-bridge, 30mm x 100mm. The stationary phase particle size is

5μm.

B : Organic solvent = Acetonitrile.

Make up solvent = Methanol : Water 80:20

Needle rinse solvent = Methanol

UPLC/MS conditions for Example 10: AcquityTM UPLC system coupled with a ZQ single quadrupole mass spectrometer (Waters - Micromass); operated in negative electrospray ionisation (ES-) mode. Column Acquity UPLCTM BEH C18, 1.7 μm, 2.1 x 50 mm; Column temperature 40 degC; Mobile phase: A: H₂O + 0.1% HCOOH; B: CH₃CN + 0.06% HCOOH Gradient: time=0 min 3% (B); time=0.05 min 6% (B); time=0.57 min 70% (B); time=1.06 min 99% (B); time=1.44 min 99% (B); time=1.45 min 3% (B); Stop time: 1.50 min. Flow rate: 1 ml/min; UV range: 210-350 nm; Sampling Rate: 20 points/sec, ZQ/MS Ionization: ES+; Mass range: 100-1000 amu; Scan/interscan: 0.10 sec/ 0.01 sec; Polarity mode interscan: 0.025 sec; DAD/MS data offset time: +0.01 min.

MDAP conditions for Example 10:

Column: XTerra Prep MS C₁₈, 30 x 150 mm. Stationary phase particle size =

10μm. Solvents: A : Aqueous solvent = NaHCO₃ 10 mM, pH 10 with NH₄OH; B :

Organic solvent = Acetonitrile Method:

Description 1 : Λ/-[(2S)-5-bromo-2,3-dihydro-1H-inden-2-yl]-2-propanesulfonamide

Λ/-[(2S)-5-bromo-2,3-dihydro-1 H-inden-2-yl]-2-propanesulfonamide was prepared following the method disclosed in WO 2006/015828.

Description 2: Λ/-[(2S)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H- inden-2-yl]-2-propanesulfonamide

A reaction mixture of Λ/-[(2S)-5-bromo-2,3-dihydro-1 H-inden-2-yl]-2-propanesulfonamide (5g, 15.7mmol), bis(pinacolato)diboron (4.4g, 17.3mmol), potassium acetate (4.62g, 47.1 mmol) and PdCI₂(dppf) (642mg) in DMSO (100ml) was heated at 9O⁰C, under an atmosphere of argon, for 24 hours. The mixture was allowed to cool before being partitioned between ethyl acetate and water. The organic solution was dried (MgSO₄) and evaporated under reduced pressure to yield the crude product which was purified by silica gel column chromatography, eluting with a gradient of 0 to 50% ethyl acetate in pentane. The title compound was obtained as a pale yellow solid (5.72g, 100%). LC/MS (ES): Found 366 (ES+), retention time 3.21 mins. C₁₈H₂₈BNO₄S requires 365.

Example 1 : Λ/-[(2S)-5-(2-oxo-1 (2H)-pyridinyl)-2,3-dihydro-1 H-inden-2-yl]-2- propanesulfonamide

A reaction mixture of Λ/-[(2S)-5-bromo-2,3-dihydro-1 H-inden-2-yl]-2-propanesulfonamide (100mg, 0.31 mmol, Description 1 ), 2-hydroxypyridine (31 mg, 0.32mmol), caesium carbonate (308mg, 0.94mmol), copper(l) iodide (66mg, 0.35mmol) and N, N- dimethylglycine (39mg, 0.38mmol) in DMSO (1.5ml) was heated in a microwave at 19O⁰C for 30 minutes. The mixture was then partitioned between dichloromethane and water, and the organic solution was dried and evaporated under reduced pressure to yield the crude product. The crude product was purified using MDAP. The resulting solution was diluted with saturated aqueous sodium bicarbonate solution and extracted with dichloromethane. The organic solution was dried (MgSO₄) and evaporated under reduced pressure to obtain the title compound as a white solid (40mg, 38%).

LC/MS (ES): Found 333 (ES+), retention time O.δOmins (2 minute run). Ci₇H₂₀N₂O₃S requires 332.

¹H NMR (400MHz, CDCI₃): δ 7.40 (1 H, ddd, J = 9, 7, 2 Hz), 7.31 (2H, m), 7.24 (1 H, m), 7.16 (1 H, dd, J = 8, 2 Hz), 6.66 (1 H, m), 6.24 (1 H, td, J = 7, 1 Hz), 4.58 (1 H, d, J = 9 Hz), 4.33 (1 H, m), 3.34 (2H, m), 3.19 (1 H, septet, J = 7 Hz), 2.94 (2H, m), 1.40, (6H, d, J = 7 Hz).

Example 2: Λ/-{(2S)-5-[3-(1H-pyrazol-1 -ylmethyl)phenyl]-2,3-dihydro-1H-inden-2-yl}- 2-propanesulfonamide

Under an inert atmosphere (Ar), Λ/-[(2S)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)- 2,3-dihydro-1 H-inden-2-yl]-2-propanesulfonamide (150 mg, 0.4 mmol, Description 2), 1- [(3-iodophenyl)methyl]-1H-pyrazole (139 mg, 0.5 mmol), Na₂CO₃ (93 mg, 0.9 mmol) and Pd(PPh₃)₄ (6.1 mg, 5.3 μmol) were combined in a 3:1 mixture of 1 ,4-dioxane and water (1.25ml_) and stirred at 90⁰C for 29 hours. The reaction mixture was allowed to cool, then partitioned between dichloromethane (25ml_) and water (25ml_) and the phases were separated using a phase separation filtration column. The remaining aqueous phase was further extracted with dichloromethane (2 x 15ml_) and the combined organic phases were concentrated in vacuo. This material was purified using an SCX column followed by MDAP. Further purification by column chromatography on silica (gradient elution: 100% pentane to 66% ethyl acetate in pentane) gave the title compound as a white oil (17 mg, 10%).

LC/MS (ES): Found 396 (ES+), retention time 3.19 mins. C₂₂H₂₅N₃O₂S requires 395. 1H NMR (400MHz, CDCI₃): δ 7.57-7.56 (1 H, m), 7.50-7.47 (1 H, m), 7.43-7.35 (5H, m), 7.27 (1 H, d, J = 7 Hz), 7.19-7.16 (1 H, m), 6.29 (1 H, t, J = 2 Hz), 5.38 (2H, s), 4.38-4.29 (2H, m), 3.39-3.32 (2H, m), 3.20 (1 H, septet, J = 7 Hz), 2.99-2.91 (2H, m), 1.40 (6H, d, J = 7 Hz).

Example 3: Λ/-{(2S)-5-[6-(1-pyrrolidinyl)-2-pyridinyl]-2,3-dihydro-1H-inden-2-yl}-2- propanesulfonamide

Under an inert atmosphere (Argon), Λ/-[(2S)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)-2,3-dihydro-1 H-inden-2-yl]-2-propanesulfonamide (150 mg, 0.4 mmol, Description 2), 2-bromo-6-(1-pyrrolidinyl)pyridine (102 mg, 0.5 mmol), Na₂CO₃ (IOO mg, 0.9 mmol) and Pd(PPh₃)₄ (3.8 mg, 3.3 μmol) were combined in a 3:1 mixture of 1 ,4-dioxane and water (1.25ml_) and stirred at 90⁰C for 29 hours. The reaction mixture was allowed to cool, then partitioned between dichloromethane (25ml_) and water (25ml_) and the phases were separated using a phase separation filtration column. The remaining aqueous phase was further extracted with dichloromethane (2 x 15ml_) and the combined organic phases were concentrated in vacuo. Purification by MDAP gave the title compound as a yellow oil (11 mg, 7%).

LC/MS (ES): Found 386 (ES+), retention time 2.29 mins. C₂₁H₂₇N₃O₂S requires 385. 1H NMR (400MHz, CDCI₃): δ 7.91 (1 H, s), 7.86-7.83 (1 H, m), 7.48 (1 H, dd, J = 8, 7 Hz), 7.26 (1 H, d, J = 8 Hz), 6.96 (1 H, d, J = 7 Hz), 6.30 (1 H, d, J = 8 Hz), 4.37-4.27 (2H, m), 3.57-3.52 (4H, m), 3.40-3.30 (2H, m), 3.19 (1 H, septet, J = 7 Hz), 2.99-2.90 (2H, m), 2.04- 2.00 (4H, m), 1.39 (6H, d, J = 7 Hz).

Example 4 : Λ/-{(2S)-5-[3-(1H-imidazol-1-ylmethyl)phenyl]-2,3-dihydro-1H-inden-2-yl}- 2-propanesulfonamide

Under an inert atmosphere (Ar), Λ/-[(2S)-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)- 2,3-dihydro-1 H-inden-2-yl]-2-propanesulfonamide (150 mg, 0.4 mmol, Description 2), 1- [(3-bromophenyl)methyl]-1 H-imidazole (1 19 mg, 0.5 mmol), Na₂CO₃ (90 mg, 0.8 mmol) and Pd(PPh₃)₄ (4.5 mg, 3.9 μmol) were combined in a 3:1 mixture of 1 ,4-dioxane and water (1.25ml_) and stirred at 90⁰C for 29 hours. Pd(PPh₃)₄ (4.2 mg, 3.6 μmol) was added and the mixture heated for a further 29 hours at 90⁰C. The reaction mixture was allowed to cool, then partitioned between dichloromethane (25ml_) and water (25ml_) and the phases were separated using a phase separation filtration column. The remaining aqueous phase was further extracted with dichloromethane (2 x 15ml_) and the combined organic phases were concentrated in vacuo. Purification using an SCX column followed by MDAP gave the title compound as a white solid (19 mg, 12%).

LC/MS (ES): Found 396 (ES+), retention time 2.08 mins. C₂₂H₂₅N₃O₂S requires 395. 1H NMR (400MHz, CDCI₃): δ 7.58-7.57 (1 H, m), 7.52-7.49 (1 H, m), 7.41 (1 H, t, J = 8 Hz), 7.38-7.26 (4H, m), 7.14-7.09 (2H, m), 6.94 (1 H, t, J = 1 Hz), 5.17 (2H, s), 4.58 (1 H, d, J = 9 Hz), 4.38-4.29 (1 H, m), 3.40-3.32 (2H, m), 3.20 (1 H, septet, J = 7 Hz), 3.00-2.92 (2H, m), 1.40 (6H, d, J = 7 Hz).

Example 5: Λ/-[(2S)-5-(2-bromo-5,6,7,8-tetrahydroimidazo[1 ,2-a]pyridin-3-yl)-2,3- dihydro-1H-inden-2-yl]-2-propanesulfonamide

Under an inert atmosphere (Ar), Pd(PPh₃)₄ (60 mg, 0.052 mmol) was added in one portion to a room temperature stirring mixture of Λ/-[(2S)-5-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)-2,3-dihydro-1 H-inden-2-yl]-2-propanesulfonamide (812 mg, 2.224 mmol, Description 2), 2,3-dibromo-5,6,7,8-tetrahydroimidazo[1 ,2-a]pyridine (766 mg, 2.74 mmol) and Na₂CO₃ (469 mg, 4.42 mmol) in degassed 1 ,4-dioxane/water (3:1 ) (8.0 ml_). This mixture was stirred at 90 ⁰C for 22.5 hours then cooled to room temperature. The crude mixture was partitioned between ethyl acetate (125 ml.) and water (125 ml_), and the aqueous phase was further extracted with DCM (125 ml_). The combined organic phase was dried (MgSO₄), and concentrated in vacuo, giving a yellow-brown oil (1.255 g). This resulting oil was further purified by column chromatography on silica (gradient elution from 100% pentane to 20%pentane/80% ethyl acetate and then with ethyl acetate only), giving the desired product (308 mg).

LC/MS (ES): Found 438, 440 (ES+), retention time 2.23 mins. C₁₉H₂₄BrN₃O₂S requires

437, 439.

¹H NMR (400MHz, CDCI₃): 5 7.30 (1 H, d, J = 8 Hz), 7.24 (1 H, s), 7.18-7.22 (1 H, m), 4.29-

4.46 (2H, m), 3.74-3.79 (2H, m), 3.32-3.41 (2H, m), 3.20 (1 H, septet, J = 7 Hz), 2.89-3.01

(4H, m), 1.90-1.97 (4H, m), 1.41 (6H, d, J = 7 Hz).

Example 6: Λ/-[(2S)-5-(5,6,7,8-tetrahydroimidazo[1 ,2-a]pyridin-3-yl)-2,3-dihydro-1 H- inden-2-yl]-2-propanesulfonamide, hydrochloride

A solution of Λ/-[(2S)-5-(2-bromo-5_!6_!7_!8-tetrahydroimidazo[1 _!2-a]pyridin-3-yl)-2_!3-dihydro- 1H-inden-2-yl]-2-propanesulfonamide (Example 5; 308 mg, 0.703 mmol) dissolved in methanol (14 ml) was continuously hydrogenated and recycled using the H-cube (10% Pd/C catcart cartridge) for 2 hours and then concentrated in vacuo giving yellow crystals (0.259 g). These crystals dissolved in methanol (14 ml) were hydrogenated a second time (without recycling) for 30 minutes and concentrated in vacuo giving yellow crystals. These were dissolved in methanol and purified by SCX giving a clear oil which was further purified by column chromatography on silica (gradient elution from 100% ethyl acetate to 80% ethyl acetate / 20% 1 M NH₃ in methanol) giving the desired product (188 mg). This was dissolved in methanol and DCM and 1 ml. of hydrochloric acid in Et₂O (1 M) was added in one portion. Concentration in vacuo gave the desired product as the hydrochloride salt (184 mg) as a white solid.

LC/MS (ES): Found 360 (ES+), retention time 1.47 mins. C₁₉H₂₅N₃O₂S requires 359.

¹H NMR free base (400MHz, CDCI₃): δ 7.26-7.17 (3H, m), 6.94 (1 H, s), 4.66-4.56 (1 H, m), 4.37-4.28 (1 H, m), 3.92-3.88 (2H, m), 3.38-3.31 (2H, m), 3.20 (1 H, septet, J = 7 Hz), 2.99- 2.92 (4H, m), 1.98-1.93 (4H, m), 1.41 (6H, d, J = 7 Hz).

Example 7: Λ/-{(2S)-5-[3-(4-morpholinylmethyl)phenyl]-2,3-dihydro-1H-inden-2-yl}-2- propanesulfonamide

A mixture of Λ/-[(2S)-5-bromo-2,3-dihydro-1 H-inden-2-yl]-2-propanesulfonamide (100 mg, 0.31 mmol, Description 1 ), 4-{[3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl]methyl}morpholine (114 mg, 0.38 mmol), Pd(PPh₃)₄ (3.6 mg, 3.1 umol), and Na₂CO₃ (67 mg, 0.63 mmol) in a 3:1 mixture of dioxane:water (2 ml) was stirred and refluxed at 90 ⁰C under argon for 16 hours. The mixture was allowed to cool and was then partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic solution was dried (MgSO₄) and evaporated under reduced pressure to yield the crude product as a yellow oil, which was purified using MDAP. The resulting material was partitioned between saturated aqueous sodium bicarbonate solution and dichloromethane. The organic solution was dried (MgSO₄) and evaporated under reduced pressure to yield the desired product as a white foam (81 mg, 62%). LC/MS (ES): Found 415 (ES+), retention time 0.74 mins (2 minute run). C₂₃H₃₀N₂O₃S requires 414.

¹H NMR (400MHz, CDCI₃): δ 7.51-7.53 (1 H, m), 7.41-7.47 (3H, m), 7.38 (1 H, t, J = 7 Hz), 7.27-7.32 (2H, m), 4.28-4.39 (2H, m), 3.70-3.74 (4H, m), 3.56 (2H, s), 3.33-3.42 (2H, m), 3.21 (1 H, septet, J = 7 Hz), 2.92-3.01 (2H, m), 2.46-2.50 (4H, m), 1.41 (6H, d, J = 7 Hz).

Example 8: Λ/-[(2S)-5-(2,3-dihydrothieno[3,4-fe][1 ,4]dioxin-5-yl)-2,3-dihydro-1H-inden- 2-yl]-2-propanesulfonamide

A reaction mixture of Λ/-[(2S)-5-bromo-2,3-dihydro-1H-inden-2-yl]-2-propanesulfonamide (100mg, 0.31 mmol, Description 1 ), 5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-2,3- dihydrothieno[3,4-fe][1 ,4]dioxin (102mg, 0.38mmol), tetrakis(triphenylphosphine)palladium(0) (3.6mg, 1 mol%) and sodium carbonate (67mg, 0.63mmol) in a 3:1 mixture of dioxane and water (2.0ml) was heated at 9O⁰C, under an atmosphere of argon, for 16 hours with stirring. The mixture was allowed to cool before being partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic solution was dried (MgSO₄) and evaporated under reduced pressure to yield the crude product. This crude product was purified using MDAP. The resulting solution was diluted with saturated aqueous sodium bicarbonate solution and extracted with dichloromethane. The organic solution was dried (MgSO₄) and evaporated under reduced pressure to obtain the title compound as a pale yellow solid (53mg, 45%).

LC/MS (ES): Found 380 (ES+), retention time 1.15mins (2 minute run). C₁₈H₂₁NO₄S₂ requires 379. 1H NMR (400MHz, CDCI₃) δ 7.57 (1 H, m), 7.52 (1 H, m), 7.20 (1 H, d, J = 8 Hz), 6.28 (1 H, s), 4.28 (6H, m), 3.32 (2H, m), 3.19 (1 H, septet, J = 7 Hz), 2.92 (2H, m), 1.40 (6H, d, J = 7 Hz).

Example 9: Λ/-[(2S)-5-(2-bromo-6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepin-3-yl)-2,3- dihydro-1H-inden-2-yl]-2-propanesulfonamide

Under an inert atmosphere (Ar), Λ/-[(2S)-5-bromo-2,3-dihydro-1 H-inden-2-yl]-2- propanesulfonamide (308 mg, 1.0 mmol, Description 1 ), bis(pinacolato)diboron (287 mg, 1.1 mmol), KOAc (273 mg, 2.8 mmol) and Pd(PPh₃)₄ (53 mg, 0.05 mmol) were combined in 1 ,4-dioxane (2.1 mL) and stirred at 100⁰C for 5 hours. 2,3-dibromo-6,7,8,9-tetrahydro- 5H-imidazo[1 ,2-a]azepine (360 mg, 1.2 mmol) was dissolved in dioxane (0.9ml_) and added to the reaction mixture, followed by the addition of aqueous K₂CO₃ (I M; 2.8ml_) and the reaction mixture was heated overnight. The reaction was allowed to cool and partitioned between ethyl acetate (5OmL) and water (5OmL). The separated aqueous layer was further extracted with ethyl acetate (2 x 25mL). The combined organic phase was dried (MgSO₄) and concentrated in vacuo. Purification by column chromatography on silica (gradient elution: 0-66% ethyl acetate in pentane) followed by purification by MDAP gave the title compound as a yellow oil (24 mg, 5%).

LC/MS (ES): Found 452, 454 (ES+), retention time 2.49 mins. C₂₀H₂₆BrN₃O₂S requires

451 , 453.

¹H NMR (400MHz, CDCI₃): 5 7.30 (1 H, d, J = 8 Hz), 7.17-7.15 (1 H, m), 7.14-7.11 (1 H, m),

4.76 (1 H, d, J = 9 Hz), 4.39-4.28 (1 H, m), 3.85-3.80 (2H, m), 3.40-3.32 (2H, m), 3.20 (1 H, septet, J = 7 Hz), 3.03-2.91 (4H, m), 1.91-1.84 (2H, m), 1.78-1.68 (4H, m), 1.40 (6H, d, J = 7 Hz).

Example 10: Λ/-[(2S)-5-(2-oxo-1 -pyrrolidinyl)-2,3-dihydro-1 H-inden-2-yl]-2-

Λ/-[(2S)-5-bromo-2,3-dihydro-1 H-inden-2-yl]-2-propanesulfonamide (50 mg, 0.16 mmol, Description 1 ), 2-pyrrolidinone (19 mg, 0.23 mmol), CuI (10 mg, 0.052 mmol), K₂CO₃ (44 mg, 0.32 mmol) and N,N'-dimethyl-1 ,2-ethanediamine (20 mg, 0.22 mmol) in dioxane (1.5 ml) were heated at 120 ⁰C for 16 hours. The reaction mixture was diluted with DCM and the organic layer was washed with saturated aqueous NH₄CI, concentrated under reduced pressure and the residue was purified by MDAP obtaining the title compound (5 mg).

UPLC/MS (ES): Found 321 (ES-), retention time 0.60 mins. Ci₆H₂₂N₂O₃S requires 322. 1 H-NMR (400MHz, CDCI₃): δ 7.51 (1 H, s), 7.28 (1 H, d, J = 8 Hz), 7.16 (1 H, d, J = 8 Hz), 4.27 (2H, m), 3.80 (2H, t, J = 7 Hz), 3.26 (2H, m), 3.14 (1 H, m), 2.86 (2H, m), 2.56 (2H, t, J = 8 Hz), 2.13 (2H, m), 1.36 (6H, d, J = 7 Hz).

The ability of the compounds of the invention to potentiate AMPA may be determined by the assays below. In the assays used and described herein, the compounds of the present invention were not necessarily from the same batch described above. A test compound from one batch may have been combined with other batch(es) for the assay(s).

1 ) Fluorescent calcium-indicator dye assays

1.1 ) Calcium Influx Fluorescence Assay 1 384 well plates were prepared containing confluent monolayer of HEK 293 cells either stably expressing or transiently transfected with human GluR2 flip (unedited) AMPA receptor subunit. These cells form functional homotetrameric AMPA receptors. The tissue culture medium in the wells were discarded and the wells were each washed three times with standard buffer (80 μl_) for the stable cell line

(145 mM NaCI, 5 mM KCI, 1 mM MgCI₂, 2 mM CaCI₂, 20 mM N-[2-hydroxyethyl]- piperazine-N-[2-ethanesulfonic acid (HEPES), 5.5 mM glucose, pH 7.3) or with a Na-free buffer for the transient transfected cells (145 mM N-methyl-glucamine instead of NaCI). The plates were then incubated for 60 minutes in the dark with 2 μM FLUO4-AM dye (20 μl_) (Molecular Probes, Netherlands) at room temperature to allow cell uptake of the FLUO-4AM, which was then converted to FLUO-4 by intracellular esterases which is unable to leave the cell. After incubation each well was washed three times with buffer (80 μl_) (30 μl_ of buffer remained in each well after washing).

Compounds of the invention (or reference compounds such as cyclothiazide) were dissolved in dimethylsulfoxide (DMSO) at a stock concentration of 10 mM. These solutions were further diluted with DMSO using a Biomek FX (Beckman Coulter) in a 384 compound plate. Each dilution (1 μl_) was transferred to another compound plate and buffer (50 μl_) added. An agonist stimulus (glutamate) plate was prepared by dissolving sodium glutamate in water to give a concentration of 100 mM. This solution was diluted with buffer to give a final concentration of 500 μM and dispensed into another 384-well plate (50μl_/well) using a Multidrop (Thermolabsystems).

The cell plate was then transferred into a fluorescence imaging plate based reader [such as the FLIPR384 (Molecular Devices)]. A baseline fluorescence reading was taken over a 10 to 240 second period, and then 10 μL from each plate containing a compound of the invention made up in standard buffer solution (in a concentration range from 100 μM to 10 pM) was added (to give a final concentration in the range

30 μM to 3 pM). The fluorescence was read over 5 minute period. 500 μM glutamate solution (10μl_) is added (to give a final concentration of 100 μM). The fluorescence was then read over a 4 minute period. The activities of the compounds of the invention and reference compounds were determined by measuring peak fluorescence after the last addition. The activity was also expressed relative to the fluorescence increase induced by cyclothiazide at their maximum response (i.e. greater than 30 μM).

1.2) Calcium Influx Fluorescence Assay 2 384 well plates were prepared containing confluent monolayer of HEK 293 cells stably expressing human GluR2 flip (unedited) AMPA receptor subunit. On the day of the experiment, culture medium were discarded and the cells washed three times with standard buffer (145 mM NaCI, 5 mM KCI, 1 mM MgCI2, 2 mM CaCI2, 20 mM N-[2-hydroxyethyl]-piperazine-N-[2-ethanesulfonic acid (HEPES), 5.5 mM glucose, pH 7.3) and 20 μl_ of buffer remained in each well after washing. The plates were then incubated at room temperature for 60 minutes in the dark with 2 μM FLUO-4AM dye to allow cell uptake of the FLUO-4AM, which is then converted to FLUO-4 by intracellular esterases which is unable to leave the cells. After incubation cells were washed three times with buffer and 30 μl_ of buffer remained in each well after washing. Compounds of the invention were tested in a final assay concentration range from 100 μM to 1 nM.

Compounds of the invention (or reference compounds such as cyclothiazide) were dissolved in dimethylsulfoxide (DMSO) at a stock concentration of 10 mM. These solutions were further diluted with DMSO in a 384 compound plate and 1 μl_ of each dilution was transferred to another compound plate. Just prior to compound addition to the cells, 50 μl_ buffer was added to the 1 μl_ compound copy plate. An agonist stimulus 384-well plate containing 50μl_/well of 500 μM glutamate was prepared by diluting with buffer a 100 mM sodium glutamate stock solution prepared in water.

10 μl_ from each plate containing a compound of the invention made up in buffer solution was added and incubated with the loaded cells for 10 minute in the dark at room temperature.

The cell plate was then transferred into a fluorescence imaging plate based reader

(such as the FLIPR384 - Molecular Devices). A baseline fluorescence reading was taken over a 5 to 10 second period, and then 10 μL of 500 μM glutamate solution was added (to give a final concentration of 100 μM). The fluorescence was then read over a 4-5 minute period.

The activities of the compounds of the invention and reference compounds were determined by measuring peak fluorescence after the last addition. The activity was also expressed relative to the fluorescence increase induced by 150μM cyclothiazide at their maximum response.

1.3 Calcium Influx Fluorescence Assay 3

This was carried out in a similar manner as Assay 2 above, except that: a) the compounds of the invention were tested in a final assay concentration range from 50 μM to 50 nM; b) 50 μL pluronic buffer (standard buffer with 0.05% pluronic-F127 acid) was added to the 1 μL compound copy plate; c) an agonist stimulus 384-well plate containing 50μl_/well of 500 μM glutamate was prepared by diluting with pluronic buffer (standard buffer with 0.05% pluronic-F127 acid) a 100 mM sodium glutamate stock solution prepared in water; d) the reference compound was: Λ/-[(2/?)-2-(4'-cyano-4-biphenylyl)propyl]-

2-propanesulfonamide.

The assays described above are all believed to have an effective limit of detection of a pEC₅₀ in the region of 3.5-4.0 due to the limitations of compound solubility. The pEC₅₀ result is generally considered to be accurate +/- 0.3.

All the Example compounds were screened more than once using at least one of the assays described above. Each compound gave a pEC₅o of on average equal to or greater than 4.0 and/or demonstrated an activity of on average at least 10% that of the reference compound (cyclothiazide or Λ/-[(2/?)-2-(4'-cyano-4-biphenylyl)propyl]-2- propanesulfonamide, each at their maximal response).

2) Whole cell voltage-clamp electrophvsioloqy assays

2.1 ) Rat

The ability of the compounds of the invention to potentiate AMPA-subtype glutamate receptor-mediated response may also be determined by measuring AMPA-evoked current recorded from rat cultured hippocampal neurons.

This assay involved the electrophysiological characterisation of AMPA receptor positive modulators using rat cultured hippocampal neurons. The extracellular recording solution contains: 145 mM NaCI, 2.5 mM KCI, 1.2 mM MgCI₂, 1.5 mM CaCI₂, 10 mM N-[2-hydroxyethyl]-piperazine-N-[2-ethanesulfonic acid (HEPES), 10 mM D-glucose, pH 7.3 with NaOH. The intracellular solution contained: 80 mM CsCI, 80 mM CsF, 10 mM N-[2-hydroxyethyl]-piperazine-N-[2-ethanesulfonic acid

(HEPES), 10 mM ethylene glycol-bis(g-aminoethylether)-N,N,N',N,-tetra-acetic acid (EGTA), 14 mM MgATP, 14 mM DiTris Creatine Phosphate, 50 U/ml Creatine Phosphokinase pH 7.3 with CsOH. Recording electrodes were prepared from glass capillary tubes (Clark Electromedical GC120-F10) pulled into two equal lengths using a Zeitz Instruments DMZ Universal Puller, program 09, resulting in electrodes with a resistance of approximately 3-6 MOhms when measured in extracellular solution. Electrodes were back filled with internal recording solution. Positive pressure was applied to the electrode to prevent mixture of internal and external solutions and to assist in formation of high resistance seal when the electrode makes contact with the cell membrane. Glass coverslip fragment, bearing rat cultured hippocampal neurons, was placed in the recording chamber positioned on the stage of an inverted microscope. A tube at the edge of the chamber was used to apply extracellular solution to the bath. Rapid solution exchange used a fast step perfusion system (Biologic RSC160). Two outlet tubes attached together along their length were positioned close to a chosen cell so that the outflow from only one tube can pass directly over the cell surface. A motorized stepper could re-position the tubes such that the outflow from the second outlet tube flows over the cell allowing solution exchange at the cell membrane surface to occur within 10-20 ms. Excess bath solution was removed via a tube positioned at the edge of the chamber connected to a vacuum line.

A prospective cell was positioned in the centre of the microscope field of view.

Recording electrode was positioned directly above the cell membrane surface. Using fine manipulator control (Luigs and Neumann, SM-6) the electrode was lowered, while monitoring the change in electrode resistance during delivery of a 5 mV depolarizing pulse, until a high resistance seal (gigaseal) was achieved. Whole cell configuration was achieved by removing by suction a small fragment of cell membrane immediately beneath the recording electrode tip. The cell membrane potential was held at -70 mV (voltage-clamped) via the electrode (Axopatch 200B Integrating patch clamp amplifier, pClamp software, Axon Instruments). Test solutions were applied using the fast application system using the following protocol and changes in inward current are recorded and stored for off-line analysis.

1 ) Control current - exchange from extracellular solution to extracellular solution + 30 μM AMPA (2 s application time, 30 s interval between applications) repeated until measurements were stable. 2) Test current - exchange from extracellular solution + 10 nM of compound of invention to extracellular solution + 10 nM of compound of invention + 30 μM AMPA (2 s application time, 30 s interval between applications) repeated until measurements were stable.

All experiments were performed at ambient temperature (20 to 22 ⁰C).

The activity of a compound of the invention was determined by measuring the area under the curve (during 2 s period of application) for the 30 μM AMPA response in the presence of the compound of the invention and expressing it as % of potentiation of the 30 μM AMPA alone response (30 μM AMPA in the absence of the compound of the invention).

Examples 1 and 6 were tested in this assay. The mean responses at 1OnM was respectively 135% and 129% increase of response of 30 μM AMPA alone, and at 10μM was respectively 199% and 273% increase of response of 30 μM AMPA alone. 2.2) Human recombinant GluR2i homomeric AMPA receptors Response to 1 mM glutamate in the presence of compound was normalized against the response in the absence of compound that is considered 100%. Glutamate was applied for 2 seconds pulse every 30 seconds. Currents analysis was performed after data acquisition and using zero subtraction function (leak subtraction) measuring the net charge (time integration of the current) in the first 2000 ms from the onset of the peak and measuring the peak amplitude. If run-up or run-down was observed, extrapolation of control values is performed using pre and post drug control data. In the analysis the average of current amplitudes or charge transfer measurements was calculated considering only currents after the stabilization of the signal (when the equilibrium was reached). Potentiation of charge transfer and peak current amplitude was measured after application of 10OnM and 10 μM of the test compound. The activity of a compound of the invention was determined by measuring the area under the curve (during 2 s period of application) for the 1 mM glutamate challenge in the presence of the compound of the invention and expressing it as % of potentiation of the 1 mM glutamate challenge alone (1 mM glutamate in the absence of the compound of the invention).

Examples 1 and 6 were tested in this assay. The mean responses at 10OnM were respectively 109% and 191% potentiation of the 1 mM glutamate challenge alone, and mean reponses at 10μM were respectively 319% and 1761 % potentiation of the 1 mM glutamate challenge alone.

Claims

1. A compound of formula (I) or a salt thereof:

wherein R is selected from the group consisting of:

• pyrrolidinyl optionally substituted by oxo;

• 1 ,2-dihydropyridyl optionally substituted by oxo;

• pyridyl substituted by pyrrolidinyl; and

2. A compound as claimed in claim 1 , which is: N-[(2S)-5-(phenyloxy)-2,3-dihydro-1 H-inden-2-yl]-2-propanesulfonamide; N-{(2S)-5-[(2-pyridinylmethyl)oxy]-2,3-dihydro-1 H-inden-2-yl}-2-propanesulfonamide; N-{(2S)-5-[(6-methyl-3-pyridinyl)oxy]-2,3-dihydro-1 H-inden-2-yl}-2-propanesulfonamide;

N-[(2S)-5-(2-pyridinyloxy)-2,3-dihydro-1 H-inden-2-yl]-2-propanesulfonamide;

N-{(2S)-5-[(5-fluoro-2-pyridinyl)oxy]-2,3-dihydro-1 H-inden-2-yl}-2-propanesulfonamide;

N-{(2S)-5-[(2-methyl-3-pyridinyl)oxy]-2,3-dihydro-1 H-inden-2-yl}-2-propanesulfonamide;

N-((2S)-5-{[(2-methyl-3-pyridinyl)methyl]oxy}-2,3-dihydro-1 H-inden-2-yl)-2- propanesulfonamide;

N-{(2S)-5-[(4-methyl-3-pyridinyl)oxy]-2,3-dihydro-1 H-inden-2-yl}-2-propanesulfonamide;

N-((2S)-5-{[(6-methyl-3-pyridinyl)methyl]oxy}-2,3-dihydro-1 H-inden-2-yl)-2- propanesulfonamide;

N-{(2S)-5-[(3-pyridinylmethyl)oxy]-2,3-dihydro-1 H-inden-2-yl}-2-propanesulfonamide; or a salt or solvate thereof.

3. A compound as claimed in claim 1 or claim 2 for use as a medicament.

4. A compound as claimed in claim 1 or claim 2 for use in the treatment of a disease or condition caused by a reduction or imbalance in glutamate receptor function in a mammal.

5. A compound as claimed in claim 1 or claim 2 for use in the treatment of schizophrenia.

6. A pharmaceutical composition comprising a compound as defined in claim 1 or claim 2 and at least one pharmaceutically acceptable carrier or diluent.

7. A combination product comprising a compound as defined in claim 1 or claim 2 and an antipsychotic.

8. Use of a compound as defined in claim 1 or claim 2, or a composition as defined in claim 6, or a product as defined in claim 7, in the manufacture of a medicament for treating or preventing a disease or a condition caused by a reduction or imbalance in glutamate receptor function.

9. Use as claimed in claim 8 wherein the disease is schizophrenia.

10. A method of treating a disease or condition caused by a reduction or imbalance in glutamate receptor function in a mammal comprising administering an effective amount of a compound as defined in claim 1 or claim 2, or a composition as defined in claim 6, or a product as defined in claim 7.

11. A method as claimed in claim 10 wherein the disease is schizophrenia.