OXADIAZOLE DERIVATIVES AND THEIR USE AS NICOTINIC ACETYLCHOLINE RECEPTOR MODULATORS

The present invention relates to novel oxadiazole derivatives having pharmacological activity, processes for their preparation, compositions containing them and their use in the treatment of neurological, psychiatric disorders and gastrointestinal disorders.

Nicotinic acetylcholine receptors (nAChRs) are cation-specific, excitatory ligand-gated ion channels that are widely expressed throughout the central and peripheral nervous systems. To date, 16 mammalian nAChR subunit genes have been cloned: 5 encoding muscle receptor subunits, and 11 encoding neuronal receptor subunits. The nicotinic α7 receptor subunit is predominantly expressed in the mammalian central nervous system (CNS), where it is thought to assemble as a functional homopentameric complex, and is also expressed in peripheral tissues including the sympathetic nervous system, immune cells and the Gl tract. Activation of neuronal nicotinic α7 receptors by selective agonists or the endogenous ligand acetylcholine can modulate the release of various neurotransmitters including glutamate, GABA, dopamine, and noradrenaline and, thus, has the potential to modulate a range of neurological functions. Additionally, in vivo studies have shown that α7 nAChR agonists can modulate neurotransmitter release in brain areas such as the cortex and hippocampus that are relevant to cognition (Paterson D et al, (2000) Prog Neurobiol 61 :75-111.

A number of literature reports have demonstrated the cognitive enhancing properties of α7 nAChR agonists (e.g. GTS-21 (3-(2,4-dimethoxybenzylidene)anabaseine), AR-R 17779 ((-)- spiro[1-azabicyclo[2.2.2]octane-3,5'-oxazoldin-2'-one] 4-propyl-benzylidene anabaseine) and SSR-180771 (4-bromophenyl 1 ,4-diazabicyclo[3.2.2]nonane-4-carboxylate hydrochloride) in rodent and primate cognition models including the radial arm maze (Levin E. D. et al. (1999), Behavioural Pharmacology. 10(6-7):675-80), social recognition (Van Kampen M. et al. (2004) Psychopharmacology. 172(4):375-83), elevated plus maze/delayed matching-to-sample test (Briggs CA. et al. (1997) Pharmacology, Biochemistry & Behavior. 57(1-2):231-41 ), active avoidance and radial arm maze (Arendash G.W. et al. (1995) Brain Research. 674(2):252-9).

Consistent with these animal studies, recent data from small clinical trials demonstrates that the α7 nAChR partial agonist GTS-21 enhanced memory and attention in healthy volunteers (Kitagawa H. et al. (2003) Neuropsychopharmacology. 28(3):542-51 ). Furthermore, beneficial effects of nicotine on attention parameters have also been demonstrated in Alzheimer's disease (Potter A. and Levin E. D. (1997) Drugs & Aging. 11(3):206-28), age-associated memory impairments (White H. K. and Levin E. D. (2004), Psychopharmacology. 171(4):465-71) and attention deficit disorder (Levin E. D. et al. (1996) Psychopharmacology. 123(1):55-63). Activation of α7 nAChRs has also been reported to ameliorate sensory gating deficits in both preclinical (Simosky J. K. et al., (2001) Biological Psychiatry. 50(7):493-500) and small clinical studies. These data suggest that novel α7 nAChR agonists and/or partial agonists such as the current series could be useful for the treatment of cognitive impairments in neurological and

psychiatric disorders such as Alzheimer's disease, related neurodegenerative disorders and schizophrenia.

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

(I) wherein

R ¹ represents hydrogen, C _1-6 alkyl, C _1-6 alkoxy, halo, halo C _1-6 alkyl, or halo C _1-6 alkoxy;

R ² represents hydrogen, halo, methyl, CF ₃ , or OCF ₃ ;

R ³ and R ⁴ independently represent hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl; or R ³ and R ⁴ together with the nitrogen atom to which they are attached form a nitrogen containing heterocyclyl group which is unsubstituted or substituted with 1 , 2, or 3 substituents selected from methyl or fluoro;

Q represents -(CH ₂ ) _n - wherein n represents 0 or 1.

The term 'C _1-6 alkyl' as used herein as a group or a part of the group refers to a linear or branched saturated hydrocarbon group containing from 1 to 6 carbon atoms. Examples of such groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl or hexyl and the like. Unless a particular structure is specified, the terms propyl, butyl etc include all straight and branched chain forms having the appropriate number of carbon atoms e.g. propyl includes n-propyl and isopropyl.

The term 'C _1-6 alkoxy' as used herein refers to an -0-C _1-6 alkyl group wherein C _1-6 alkyl is as defined herein. C _1-6 alkoxy includes methoxy, ethoxy, propoxy, butoxy, pentoxy and hexoxy. As for alkyl unless a particular stucture is specified the terms propoxy, butoxy etc include all straight and branched chain forms having the appropriate number of carbon atoms e.g. propoxy includes n-propoxy and isopropoxy.

The term 'halo' as used herein refers to a fluorine, chlorine, bromine or iodine atom.

The term halo C _1-6 alkyl as used herein refers to a C _1-6 alkyl group substituted with one or more halogen groups, e.g CF _3, CF ₂ CH or CF ₃ CH ₂ .

The term halo Ci _-6 alkoxy as used herein refers to an -0-Ci _-6 alkyl group wherein Ci _-6 alkyl is as defined herein and substituted with one or more halogen groups, e.g. -0-CF ₃ .

The term 'C _3-6 cycloalkyl' as used herein refers to a saturated monocyclic hydrocarbon ring of 3 to 6 carbon atoms. C _3-6 cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.

The term "nitrogen containing heterocyclyl group" includes a 4-7 membered monocyclic saturated or partially unsaturated aliphatic ring system, a 6 -9 membered saturated or partially unsaturated bridged ring system or a 4-7 membered saturated or partially unsaturated aliphatic ring fused to a benzene ring containing a nitrogen atom in addition to 1 or 2 optional additional heteroatoms selected from oxygen, nitrogen or sulphur. Suitable examples of such monocyclic rings include pyrrolidinyl, azetidinyl, piperidinyl, piperazinyl, morpholinyl, hexahydroazepanyl, hexahydrodiazepanyl and homomorpholinyl. Examples of such bridged ring systems are azabicycloheptanyl and azabicyclononanyl. Suitable examples of benzofused heterocyclic rings include indolinyl, isoindolinyl, 2,3,4,5-tetrahydro-1H-3-benzazepinyl or tetrahydroisoquinolinyl.

In one embodiment, R ¹ represents hydrogen, Ci _-6 alkoxy, halo, or halo Ci _-6 alkyl, more particularly hydrogen, fluoro, chloro, -OCH ₃ , or CF ₃ .

In one embodiment, R ² represents hydrogen or halo, more particularly hydrogen or fluoro.

In one embodiment Q represents -(CH ₂ ) _n - wherein n is 1. In an alternative embodiment, Q represents -(CH ₂ ) _n - wherein n is 0.

In one embodiment, R ³ and R ⁴ together with the nitrogen atom to which they are attached form a nitrogen containing heterocyclyl group e.g. piperidinyl, morpholinyl, pyrrolidinyl wherein the heterocyclyl group is unsubstituted or substituted with 1 , 2, or 3 substituents selected from methyl or fluoro.

In one embodiment, R ³ and R ⁴ together with the nitrogen atom to which they are attached form a nitrogen containing heterocyclyl group e.g. piperidinyl, morpholinyl, pyrrolidinyl wherein the heterocyclyl group is unsubstituted. In a more particular embodiment, R ³ and R ⁴ together with the nitrogen atom to which they are attached form a nitrogen containing heterocyclyl group e.g. piperidinyl and pyrrolidinyl wherein the heterocyclyl group is unsubstituted.

In one embodiment, R ³ and R ⁴ together with the nitrogen atom to which they are attached form a 4-7 membered monocyclic saturated or partially unsaturated aliphatic ring system containing a nitrogen atom in addition to 1 or 2 optional additional heteroatoms selected from oxygen, nitrogen or sulphur, wherein the monocyclic ring is unsubstituted or substituted with 1 , 2, or 3 substituents selected from methyl or fluoro. In a more particular embodiment, R ³ and R ⁴ together with the nitrogen atom to which they are attached form a 4-7 membered monocyclic

saturated or partially unsaturated aliphatic ring system containing a nitrogen atom in addition to 1 or 2 optional additional heteroatoms selected from oxygen, nitrogen or sulphur, wherein the monocyclic ring is unsubstituted.

In a further embodiment, R ³ and R ⁴ independently represent C _1-6 alkyl.

In a further embodiment, R ³ and R ⁴ represent ethyl.

Compounds of formula (I) include the compounds of Examples 1 to 59 and salts thereof.

In one embodiment, a compound of formula (I) or a salt thereof is selected from the compounds of Examples 1-21 , 23, 25, 26, 28-32, 37, 38, 40-59, or a salt thereof.

In one embodiment, R ¹ represents hydrogen, fluoro, chloro, -OCH ₃ , or CF ₃ , R ² represents hydrogen or fluoro, Q represents -(CH ₂ ) _n - wherein n is 0 or 1 , and R ³ and R ⁴ together with the nitrogen atom to which they are attached form a 4-7 membered monocyclic saturated or partially unsaturated aliphatic ring system containing a nitrogen atom in addition to 1 or 2 optional additional heteroatoms selected from oxygen, nitrogen or sulphur, wherein the monocyclic ring is unsubstituted.

In one embodiment, R ¹ represents hydrogen, fluoro, chloro, -OCH ₃ , or CF ₃ , R ² represents hydrogen or fluoro, Q represents -(CH ₂ ) _n - wherein n is 1 , and R ³ and R ⁴ together with the nitrogen atom to which they are attached form a nitrogen containing heterocyclyl group selected from piperidinyl, morpholinyl and pyrrolidinyl wherein the heterocyclyl group is unsubstituted.

In one embodiment, R ¹ represents hydrogen, fluoro, chloro, -OCH ₃ , or CF ₃ , R ² represents hydrogen or fluoro, Q represents -(CH ₂ ) _n - wherein n is 1 , and R ³ and R ⁴ represent ethyl.

In one embodiment, R ¹ represents hydrogen, fluoro, chloro, -OCH ₃ , or CF ₃ , R ² represents hydrogen or fluoro, Q represents -(CH ₂ ) _n - wherein n is 0, and R ³ and R ⁴ together with the nitrogen atom to which they are attached form a nitrogen containing heterocyclyl selected from piperidinyl and pyrrolidinyl wherein the heterocyclyl group is unsubstituted.

The present invention may also includes isotopically-labelled compounds, which are identical to the compounds of formula (I), except that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, iodine, and chlorine, such as ² H, ³ H, ¹¹ C, ¹⁴ C, ¹⁸ F, ³⁵ S, ¹²³ I and ¹²⁵ I. Compounds of formula (I) and salts of said compounds that contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of the present invention.

Isotopically-labelled compounds of the present invention, for example those into which

radioactive isotopes such as ³ H and/or ¹⁴ C are incorporated, are useful in drug and/or substrate tissue distribution assays. ³ H and ¹⁴ C are considered useful due to their ease of preparation and detectability. ¹¹ C and ¹⁸ F isotopes are considered useful in PET (positron emission tomography), and ¹²⁵ I isotopes are considered useful in SPECT (single photon emission computerized tomography), all useful in brain imaging. Substitution with heavier isotopes such as ² H may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, are considered useful in some circumstances. In one embodiment of the invention, the compounds of formula (I) are not isotopically labelled.

Certain compounds of formula (I) may be prepared in crystalline or non-crystalline form, and may exist as solvates such as hydrates. This invention includes with in its scope stoichiometric solvates as well as compounds containing variable amounts of solvate.

Because of the potential use of compounds of formula (I) in medicine, salts of compounds of formula (I) are preferably pharmaceutically acceptable.

Pharmaceutically acceptable salts include those described by Berge, Bighley and Monkhouse, J. Pharm. Sci., 1977, 66, 1-19. The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable acids, including inorganic and organic acids. Such acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, ethanedisulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, pamoic, pantothenic, phosphoric, propionic, succinic, sulfuric, tartaric, p-toluenesulfonic acid, and the like. In some circumstances some salts may be non-stoichiometric.

Compounds of formula (I) can be prepared as set forth in the following Schemes and in the Examples. The following processes form another aspect of the present invention.

The present invention also provides processes for the preparation of a compound of formula (I) or a salt thereof:

Process (a):

Compounds of formula (I) may be prepared in accordance with the following Scheme 1 :

Scheme 1

Step (a)

^H ₂ ^N -(3 ^" SCN

NR ³ R ⁴

(II) -CK NR°R'

(IN)

wherein Q, R ¹ , R ² , R ³ and R ⁴ are as defined for compounds of formula (I).

Step (a) typically comprises the use of a suitable reagent, such as 1 ,1-thiocarbonyldiimidazole or both carbon disulfide and a coupling agent such as dicyclohexylcarbodiimide in a suitable solvent such as tetrahydrofuran or DMF at a suitable temperature such as room temperature.

Step (b) comprises the reaction of a compound of formula (III) with a compound of formula (IV) in a suitable solvent such as DMF or THF at a suitable temperature such as room temperature. Step (a) and (b) may be combined or alternatively, intermediate (III) may be isolated.

Step (c) typically comprises treatment of a compound of formula (V) with a suitable reagent such as EDACHCI or dicyclohexylcarbodiimide in a suitable solvent such as DMF or THF. A suitable temperature, for example, would be 60 to 80 ⁰ C. Step (b) and (c) may be combined or alternatively, intermediate (V) may be isolated.

Compounds of formula (IV) may be prepared in accordance with the following Scheme 2:

Scheme 2

wherein R ¹ and R ² are as defined for compounds of formula (I).

Step (a) typically comprises the use of a suitable reagent, such as hydrazine monohydrate in the presence of a suitable solvent, such as methanol at a suitable temperature, e.g. from room temperature to reflux.

Step (b) typically comprises the reaction of a compound of formula (VII) with BocNHNH ₂ in a suitable solvent e.g. CH ₂ CI ₂ using a suitable coupling agent such as EDACHCI and optionally HOBt.

In Step (c) the Boc group can be removed by conventional means.

A compound of formula (VII) can typically be formed from hydrolysis of a compound of formula (Vl).

Compounds of formula (Vl) may be prepared in accordance with the following Scheme 3 using compound of formula (Xa) or (Xb):

Scheme 3

wherein R ¹ and R ² are as defined for compounds of formula (I) and L ³ represents a suitable leaving group, such as a halogen atom (e.g. a chlorine atom). Use of a compound of formula (Xb) should be accompanied by a coupling agent.

Step (a) typically comprises reaction of a compound of formula (IX) with a compound of formula (Xa) when L ³ is a leaving group such as halogen, in the presence of a suitable solvent, such as dichloromethane and a suitable base, such as N,N-diisopropylethylamine or triethylamine. Alternatively a compound of formula (IX) can be reacted with a compound of formula (Xb) in the presence of EDACHCI and optionally HOBt and optionally a suitable base.

Compounds of formula (IX) can be prepared in accordance with the following Scheme 4:

Scheme 4

(XII)

wherein R ¹ is as defined for compounds of formula (I).

Step (a) is an esterification reaction which can be carried out under standard conditions e.g. with methanol in the presence of an acid e.g. H ₂ SO ₄ at a suitable temperature such as reflux.

Step (b) is an esterification reaction which can be carried out under standard conditions e.g. with a methanol in the presence of an acid e.g. H ₂ SO ₄ at a suitable temperature such as reflux.

Step (c) is a hydrogenation reaction which can be carried out under typical conditions, e.g. with stirring under an atmosphere of hydrogen in the presence of a Pd/C catalyst.

Compounds of formula (II) where Q is (CH ₂ ) _n and n is 1 may be prepared in accordance with the following Scheme 5:

Scheme 5

(XIV) (XV)

Step (b)

(H)

wherein R ³ and R ⁴ are as defined above for compounds of formula (I), Q in this instance represents (CH ₂ ) and P ¹ represents a suitable protecting group for example benzylcarbamate or fe/f-butylcarbamate (Boc).

Step (a) is a reductive amination with the appropriate amines and a suitable reducing agent, e.g. sodium triacetoxyborohydride. Step (a) takes place in a suitable solvent such as dichloroethane at a suitable temperature, for example room temperature.

In Step (b) the protecting group such as a Boc or benzylcarbamate group can be removed by conventional methods. Where the protecting group is benzylcarbamate, this may be removed by hydrogenation.

Compounds of formula (II) may also be prepared in accordance with the following Scheme 6:

Scheme 6

(XVI) (XV)

Step (b)

(N) wherein Q, R ³ and R ⁴ are as defined for compounds of formula (I) and P ¹ is a protecting group, for example a Boc group or benzylcarbamate.

Step (a) is an alkylation with an alkyl monohalide or alkyl dihalide in a suitable solvent, for example acetonitrile, in the presence of a suitable base such potassium carbonate. This reaction is generally carried out by heating to reflux, and then cooling to room temperature.

In Step (b) the protecting group such as a Boc or benzylcarbamate group can be removed by conventional methods. Where the protecting group is Boc, this can be removed by treatment with 4M HCI in dioxane.

Process (b):

Compounds of formula (I) may also be prepared by reacting a compound of formula (XVII) or (XVII) ^P

(XVII) ^P

wherein Q, R ¹ , R ³ and R ⁴ are as defined for compounds of formula (I), and P ¹ is a protecting group for example a Boc group, with a compound of formula (Xa) or (Xb)

(Xa) (Xb)

with R ² as defined for compounds of formula (I) and L ³ represents a suitable leaving group, such as a halogen atom (e.g. chlorine), and deprotecting if necessary.

Process (b) typically comprises an acylation reaction using a compound of formula (Xa) in the presence of a suitable solvent, such as dichloromethane and a suitable base, such as N, N-

diisopropylethylamine or triethylamine. Where compounds of formula (I) are prepared using a compound of formula (Xb), a suitable coupling reagent such as N-cyclohexylcarbodiimide N'- methyl polystyrene or EDACHCI in combination with N-hydroxybenzotriazole (HOBt) can be used. Deprotection of the product would then be required and for example where P ¹ is a Boc group, this could be achieved by using a reagent such as 4M HCI in dioxane or trifluoroacetic acid.

Compounds of formula (XVII) may be prepared in accordance with the following Scheme 7. Compounds of formula (XX) ^p are protected derivatives of compounds of formula (XX). Compounds of formula (XVII) ^p are protected derivatives of compounds of formula (XVII).

Scheme 7

Q, R ¹ , R ³ and R ⁴ are as defined above for compounds of formula (I) and P ¹ is a protecting group, for example Boc. It will be appreciated that compounds of formula (XX) can be protected as represented by compounds of formula (XX) ^P wherein P ¹ is a protecting group, for example a Boc protecting group.

Step (a) typically comprises the reaction of a compound of formula (XVIII) with a compound of formula (III) in the presence of a suitable solvent, such as N,N-dimethylformamide or THF at a suitable temperature, e.g. room temperature.

Step (b) typically comprises a cyclisation reaction using a suitable reagent, such as N- cyclohexylcarbodiimide N'-methyl polystyrene (P-DCC) or EDACHCI in the presence of a

suitable solvent, such as N,N-dimethylformamide at a suitable temperature, e.g. 8O ⁰ C. Alternatively Kl/I ₂ may be used.

Step (c) typically comprises protection of compound of formula (XX) with a suitable protecting group, such as Boc group under standard conditions.

Step (d) typically comprises a hydrogenation reaction according to standard procedures known in the art, for example with stirring under an atmosphere of hydrogen in the presence of Pd/C catalyst.

Process (c): Compounds of formula (I) may also be prepared by deprotecting a protected compound of formula (I).

Examples of protecting groups and the means for their removal can be found in T. W. Greene 'Protective Groups in Organic Synthesis' (J. Wiley and Sons, 3 ^rd Ed. 1999). Suitable amine protecting groups include acyl (e.g. acetyl, removed by hydrolysis), carbamates (e.g. 2',2',2'- trichloroethoxycarbonyl, removed with zinc in acetic acid; benzyloxycarbonyl, removed by acidolysis or hydrogenolysis; t-butoxycarbonyl, removed by acidolysis, e.g. using an acid such as HCI or TFA) and arylalkyl (e.g. benzyl, removed by hydrogenolysis) as appropriate. Other suitable amine protecting groups include trifluoroacetyl (-COCF ₃ ) which may be removed by base catalysed hydrolysis or a solid phase resin bound benzyl group, such as a Merrifield resin bound 2,6-dimethoxybenzyl group (Ellman linker), which may be removed by acid catalysed hydrolysis, for example with trifluoroacetic acid.

The term "protected compound of formula (I)" is used herein to refer to a compound which includes a protecting group, for example those referred to above.

Process (d): Compounds of formula (I) may also be prepared by interconversion of a compound of formula (I) to another compound of formula (I).

Process (d) may be performed using conventional interconversion procedures such as epimerisation, oxidation, reduction, alkylation, nucleophilic or electrophilic aromatic substitution or amide bond formation.

A further process of the invention is the preparation of pharmaceutically acceptable salts and solvates of compounds of formula (I).

Compounds of formula (Xa), (Xb), (Xl), (XII), (XIV) ₁ (XVI) and (XVIII) are either commercially available, or may be prepared by known methods.

Compounds of formula (I) and their pharmaceutically acceptable salts may have affinity for and be agonists at the nicotinic α7 receptor and are believed to be of potential use in the treatment of neurological diseases including Alzheimer's disease (particularly cognitive deficit of Alzheimer's disease), dementia (including Lewy body dementia and vascular dementia), age- related memory dysfunction, cognitive impairment as listed below, cognitive deficit especially cognitive deficit of schizophrenia, Parkinson's disease and Tourette's syndrome, psychiatric disorders including schizophrenia as listed below, attention deficit/hyperactivity disorder as listed below, depression as listed below, anxiety as listed below and addiction, pain related disorders including pain of neuropathic origin including neuralgias, neuritis and back pain, and inflammatory pain including osteoarthritis, rheumatoid arthritis, acute inflammatory pain and back pain, migraine; and other diseases including obesity, sepsis and gastro-intestinal disorders (including irritable bowel syndrome and inflammatory bowel disease). Further neurological diseases for which these compounds may be of potential use is epilepsy and learning & memory disorders.

The following disease classification refer to the classification code in 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):

i) Psychotic disorders for example 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).

ii) cognitive impairment including 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, hypothyroidism-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.

iii) Depression and mood disorders for example Depressive Episodes (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 (311)); Bipolar Disorders (including Bipolar I Disorder, Bipolar Il Disorder (i.e. 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).

iv) Anxiety disorders for example Social Anxiety Disorder; Panic Attack; Agoraphobia, Panic Disorder; Agoraphobia Without History of Panic Disorder (300.22); Specific Phobia (300.29) (including the subtypes Animal Type, Natural Environment Type, Blood-lnjection-lnjury Type, Situational Type and Other Type); Social Phobia (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; and Anxiety Disorder Not Otherwise Specified (300.00).

v) 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).

A compound of formula (I) or a pharmaceutically acceptable salt thereof may be useful in the treatment or prophylaxis of pain. More particularly, a compound of formula (I) or a pharmaceutically acceptable salt thereof may be useful in the treatment of pain.

When used herein the term pain, includes pain of neuropathic origin including neuralgias, neuritis and back pain; acute pain, chronic pain, chronic articular pain, musculoskeletal pain, inflammatory pain including osteoarthritis, and rheumatoid arthritis, acute inflammatory pain and back pain, visceral pain, pain associated with cancer, pain associated with migraine, tension headache and cluster headaches, pain associated with functional gastrointestinal disorders, lower back and neck pain, pain associated with sprains and strains, sympathetically maintained pain; myositis, pain associated with influenza or other viral infections such as the common cold, pain associated with rheumatic fever, pain associated with myocardial ischemia, post operative pain, headache, toothache and dysmenorrhea.

In one embodiment a compound of formula (I) or a pharmaceutically acceptable salt thereof may be useful in the treatment or prophylaxis of chronic pain, post-operative pain, chronic lower back and neck pain, cancer pain, sprains and strains. More particularly, a compound of formula (I) or a pharmaceutically acceptable salt thereof may be useful in a treatment of these pain conditions. In the context of the present invention, treatment refers to symptomatic treatment.

Chronic articular pain conditions include rheumatoid arthritis, osteoarthritis, rheumatoid spondylitis, gouty arthritis and juvenile arthritis.

Pain associated with functional gastrointestinal disorders includes non-ulcer dyspepsia, non- cardiac chest pain and irritable bowel syndrome.

Thus the invention also provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, for use in therapy for example in the treatment or prophylaxis of the above disorders, in particular pain, neurological (e.g. cognitive deficit of Alzheimer's disease) and psychiatric disorders (e.g. cognitive deficit of schizophrenia). More particularly, a compound of formula (I) or a pharmaceutically acceptable salt thereof may be useful in the treatment or pain.

The invention further provides a method of treatment of the above disorders, in mammals including humans, which comprises administering to the sufferer a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

In another aspect, the invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the treatment or prophylaxis of the above disorders.

When used in therapy, a compound of formula (I) or a pharmaceutically acceptable salt thereof is usually formulated in a standard pharmaceutical composition. Such compositions can be prepared using standard procedures.

Thus, the present invention further provides a pharmaceutical composition for use in the treatment or prophylaxis of the above disorders which comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

The present invention further provides a pharmaceutical composition which comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

When used in the treatment of Alzheimer's disease, the compound of formula (I) or a pharmaceutically acceptable salt thereof may be used in combination with other medicaments indicated to be useful as either disease modifying or symptomatic treatments of Alzheimer's disease. Suitable examples of such other therapeutic agents may be agents known to modify cholinergic transmission such as 5-HT _1A antagonists, (e.g. lecozotan), 5-HT6 antagonists, M1 muscarinic agonists, M2 muscarinic antagonist, acetylcholinesterase inhibitors (e.g tetrahydroaminoacridine, donepezil or rivastigmine), or allosteric modulators, nicotinic receptor agonists or allosteric modulators, symptomatic agents such as 5-HT6 receptor antagonists, e.g. SB742457, H3 receptor antagonists e.g. GSK189254 and GSK239512, 5- HT4 receptor agonist, PPAR agonists, also NMDA receptor antagonists or modulators, also disease modifying agents such as β or γ-secretase inhibitors (e.g. R-flurbiprofen), also AMPA positive modulators and Glycine Transporter Reuptake inhibitors.

When used in the treatment of pain, the compound of formula (I) or a pharmaceutically acceptable salt thereof may be used in combination with other medicaments indicated to be

useful in the treatment of pain of neuropathic origin including neuralgias, neuritis and back pain, and inflammatory pain including osteoarthritis, rheumatoid arthritis, acute inflammatory pain, back pain and migraine. Such therapeutic agents include for example COX-2 (cyclooxygenase- 2 ) inhibitors, such as celecoxib, deracoxib, rofecoxib, valdecoxib, parecoxib, COX-189 or 2-(4- ethoxy-phenyl)-3-(4-methanesulfonyl-phenyl)-pyrazolo[1 ,5-b]pyridazine (WO99/012930); 5- lipoxygenase inhibitors; NSAIDs (non-steroidal anti-inflammatory drugs) such as diclofenac, indomethacin, nabumetone or ibuprofen; bisphosphonates, leukotriene receptor antagonists; DMARDs (disease modifying anti-rheumatic drugs) such as methotrexate; adenosine A1 receptor agonists; sodium channel blockers, such as lamotrigine; NMDA (N-methyl-D- aspartate) receptor modulators, such as glycine receptor antagonists or memantine; ligands for the α ₂ δ-subunit of voltage gated calcium channels, such as gabapentin and pregabalin; tricyclic antidepressants such as amitriptyline; neurone stabilising antiepileptic drugs; cholinesterase inhibitors such as galantamine; mono-aminergic uptake inhibitors such as venlafaxine; opioid analgesics; local anaesthetics; 5HT ₁ agonists, such as triptans, for example sumatriptan, naratriptan, zolmitriptan, eletriptan, frovatriptan, almotriptan or rizatriptan; nicotinic acetyl choline (nACh) receptor modulators; glutamate receptor modulators, for example modulators of the NR2B subtype; EP ₄ receptor ligands; EP ₂ receptor ligands; EP ₃ receptor ligands; EP ₄ agonists and EP ₂ agonists; EP ₄ antagonists; EP ₂ antagonists and EP ₃ antagonists; cannabinoid receptor ligands; bradykinin receptor ligands; vanilloid receptor ligand; and purinergic receptor ligands, including antagonists at P2X ₃ , P2X _2/3 , P2X ₄ , P2X ₇ or P2X _4/7 ,.

Additional COX-2 inhibitors are disclosed in US Patent Nos. 5,474,995, US5,633,272; US5,466,823, US6,310,099 and US6.291.523; and in WO 96/25405, WO 97/38986, WO 98/03484, WO 97/14691 , WO99/12930, WO00/26216, WO00/52008, WO00/38311 , WO01/58881 and WO02/18374.

When a compound of formula (I) or a pharmaceutically acceptable salt thereof is used in combination with another therapeutic agent, the compounds may be administered either sequentially or simultaneously by any convenient route.

The invention thus provides, in a further aspect, a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof together with a further therapeutic agent or agents.

The combinations referred to above may conveniently be presented for use in the form of a pharmaceutical formulation and thus pharmaceutical formulations comprising a combination as defined above together with a pharmaceutically acceptable carrier or excipient comprise a

further aspect of the invention. The individual components of such combinations may be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations.

When a compound of formula (I) or a pharmaceutically acceptable salt thereof is used in combination with a second therapeutic agent active the dose of each compound may differ from that when the compound is used alone. Appropriate doses will be readily appreciated by those skilled in the art.

A pharmaceutical composition of the invention, which may be prepared by admixture, suitably at ambient temperature and atmospheric pressure, is usually adapted for oral, parenteral or rectal administration and, as such, may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, reconstitutable powders, injectable or infusible solutions or suspensions or suppositories. Orally administrable compositions are generally preferred.

Tablets and capsules for oral administration may be in unit dose form, and may contain conventional excipients, such as binding agents, fillers, tabletting lubricants, disintegrants and acceptable wetting agents. 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 suspension, solutions, emulsions, syrups or elixirs, or may be in the form of a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, non-aqueous vehicles (which may include edible oils), preservatives, and, if desired, conventional flavourings or colorants.

For parenteral administration, fluid unit dosage forms may be prepared utilising a compound of the invention or pharmaceutically acceptable salt or solvate thereof and a sterile vehicle. 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 for injection and filter sterilised before filling into a suitable vial or ampoule and sealing. Advantageously, adjuvants such as a local anaesthetic, preservatives and buffering agents are dissolved in the vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum. Parenteral suspensions are prepared in a similar 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 suspension in a sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.

The composition may contain from 0.1% to 99% by weight, preferably from 10% to 60% by weight, of the active material, depending on the method of administration. The dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof used in the treatment of the aforementioned disorders will vary in the usual way with the seriousness of the disorders, the weight of the sufferer, and other similar factors. However, as a general guide suitable unit doses may be 0.05 to 1000 mg, more suitably 1.0 to 200 mg, and such unit doses may be administered more than once a day, for example two or three a day. Such therapy may extend for a number of weeks, months, years or even life.

A further aspect to the invention is a pharmaceutical composition comprising 0.05 to IOOOmg of a compound of formula (I) or a pharmaceutically acceptable salt thereof, and 0 to 3 g more suitably 0 to 2g of at least one pharmaceutically acceptable carrier.

All publications, including but not limited to patents and patent applications, cited in this specification are herein incorporated by reference as if each individual publication were specifically and individually indicated to be incorporated by reference herein as though fully set forth.

Abbreviations

DMF: N,N-dimethylformamide

THF: Tetrahydrofuran

EDACHCI: 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride

HOBt: 1 -Hydroxybenzotriazole

Boc: N-t-butoxycarbonyl

DCM: Dichloromethane h: Hour(s)

MDAP: Mass Directed Auto-Purification System

DMSO: Dimethyl sulfoxide

HEPES: 4-(2-hydroxyethyl)-1 -piperazineethanesulfonic acid

SCX Strong Cationic Exchange Resin

The following non-limiting Examples illustrate the preparation of pharmacologically active compounds of the invention.

Description 1 : frans-4-(1-Piperidinylmethyl)cyclohexanamine

A mixture of 1 ,1-dimethylethyl [frans-4-(aminomethyl)cyclohexyl]carbamate (1.00 g, 4.38 mmol), 1 ,5-diiodopentane (1.42 g, 4.38 mmol) and potassium carbonate (2.42 g, 17.5 mmol) in acetonitrile (10 ml.) was heated at reflux overnight and left to stand for 24 h. The solid was filtered off and washed with further acetonitrile. The filtrate was concentrated in vacuo to give a white solid. The crude material was suspended in 4M HCI in dioxane (5 ml.) and due to poor solubility methanol (2 ml.) was added. The reaction was stirred at room temperature overnight. The solvent was removed in vacuo and the residue added to an SCX cartridge, washed with methanol and eluted with 2M ammonia in methanol. The solvent was removed in vacuo to give the title compound as a white solid (328 mg, 1.67 mmol).

NMR: δH (MeOD, 400 MHz): 2.59 (1 H, tt), 2.40-2.35 (4H, m), 2.12 (2H, d), 1.85-160 (4H, m), 1.59 (4H, apparent quintet), 1.55-1.40 (3H, m), 1 ,14 (2H, qd), 0.98 (2H, qd) ppm.

The following compounds were also synthesised in a similar manner as in Description 1 : variations to the method included reaction time, work up of the first intermediate with ethyl acetate and aqueous sodium bicarbonate and/or trituration with ether. Instead of the SCX purification, frans-4-(1-piperidinyl)cyclohexanamine underwent an aqueous work up with ethyl acetate and sodium hydroxide whilst frans-4-(1-pyrrolidinyl)cyclohexanamine underwent trituration with ether in place of the SCX purification (providing the dihydrochloride salt).

Table 1 :

Description 2: Alternative synthesis of frans-4-(1-Piperidinylmethyl)cyclohexanamine:

(a): Phenylmethyl [frans-4-(1 -Piperidinylmethyljcyclohexyljcarbamate

Sodium triacetoxyborohydride (4.07 g, 19.4 mmol) was added to a stirred solution of phenylmethyl (frans-4-formylcyclohexyl)carbamate (2.50 g, 9.58 mmol) and piperidine (814 mg, 9.58 mmol) in dichloroethane (55 ml_). The reaction was stirred at room temperature for 1.5 h before the solution was poured onto a mixture of water (100 ml_), aqueous sodium hydroxide (100 ml.) and ice and the mixture stirred for 30 minutes. The organic layer was isolated and washed with water (100 ml.) and brine (100 ml_), dried (MgSO ₄ ) and the solvent evaporated in vacuo. The crude product was triturated with hexane to give the title compound as a white solid (2.56 g, 7.76 mmol).

LCMS (ES+ve): [M+H] ⁺ at m/z 331 (C ₂₀ H ₃₀ N ₂ O ₂ requires [M+H] ⁺ at m/z 331 ).

(b): frans-4-(1-Piperidinylmethyl)cyclohexanamine

Phenylmethyl [frans-4-(1-piperidinylmethyl)cyclohexyl]carbamate (2.56 g, 7.76 mmol) was dissolved in methanol (155 ml.) and hydrogenated using an H-Cube with a Pd/C cartridge at 1 ml_/min at 40 ⁰ C. The solvent was removed in vacuo to give the title compound as a white solid (1.48 g, 7.55 mmol).

The following compound was also synthesised in a similar manner as in Description 2.

Table 2:

Description 3: 1,1-Dimethylethyl [frans-4-(4-Morpholinylmethyl)cyclohexyl]carbamate

To a mixture of 1 ,1-dimethylethyl (frans-4-formylcyclohexyl)carbamate (2.0 g, 8.8 mmol) and morpholine (767 mg, 8.8 mmol) in dichloroethane (52 ml.) was added sodium triacetoxyborohydride (3.7 g, 17.8 mmol) and the reaction stirred at room temperature for 3 h. The reaction mixture was poured into a mixture of water (100 ml_), aqueous sodium hydroxide (2M, 100 ml.) and ice and the mixture stirred for 30 min. The organic layer was separated, washed with water (100 ml.) and brine (100 ml_), dried (MgSO ₄ ), filtered and the solvent removed in vacuo to give the title compound as a white solid (2.5 g, 8.4 mmol).

Description 4: [frans-4-(4-Morpholinylmethyl)cyclohexyl]amine dihydrochloride.

2HCI

1 ,1-Dimethylethyl [frans-4-(4-morpholinylmethyl)cyclohexyl]carbamate (2.5 g, 8.4 mmol) was stirred in 4M HCI in dioxane (50 ml.) at room temperature for 1 h and left to stand overnight. The solvent was removed in vacuo and the solid triturated with diethyl ether to give the title compound as a white solid (2.1 g, 7.7 mmol)

NMR: δH (MeOD, 400 MHz): 4.04 (2H, dd), 3.89 (2H, dd), 3.52 (2H, d), 3.20-3.05 (3H, m), 3.07 (2H, d), 2.18-2.07 (2H, m), 2.05-1.97 (2H, m), 2.00-1.90 (1 H, m), 1.49 (2H, qd), 1.23 (2H, qd) ppm.

The following compound was made by in a similar manner as in Description 3 and 4:

Table 3:

Description 5: Methyl 4-nitro-2-(trifluoromethyl)benzoate

Sulfuric acid (4.19 ml_, 42.8 mmol) was added dropwise to a suspension of 4-nitro-2-

(trifluoromethyl)benzoic acid (4.19 g, 17.8 mmol) in methanol (42 ml.) and the mixture heated to reflux over a weekend. After cooling to room temperature, the solvent was removed in vacuo and the crude product taken up in ethyl acetate and water (1 :1 ). Potassium carbonate was added until the solution was basic and the organic layer was separated, dried (MgSO ₄ ), filtered and the solvent removed in vacuo, to give the title compound as a white solid (3.95 g, 15.9 mmol).

NMR: δH (MeOD, 400 MHz): 8.62 (1 H, d), 8.58 (1 H, dd) 8.07 (1 H, d), 3.97 (3H, s) ppm.

Description 6: Methyl 4-amino-2-(trifluoromethyl)benzoate

Methyl 4-nitro-2-(trifluoromethyl)benzoate (3.95g, 15.9 mmol) was dissolved in ethanol (59 ml.) and Pd/C (395 mg) was added before stirring the reaction under an atmosphere of hydrogen overnight. The catalyst was removed by filtration and the solvent removed in vacuo to give the title compound as a yellow solid (3.41 g, 15.6 mmol).

LC/MS (ES +ve): [M+H] ⁺ at m/z 220 (C ₉ H ₈ F ₃ NO ₂ requires [M+H] ⁺ at m/z 220).

Description 7: Methyl 4-amino-2-fluorobenzoate

To a suspension of 4-amino-2-fluorobenzoic acid (3.00 g, 19.3 mmol) in methanol (30 ml.) was added concentrated sulphuric acid (3.0 ml.) dropwise and the solution heated to reflux overnight. The solvent was removed in vacuo and the crude product dissolved in ethyl acetate and water (1 :1 ) before addition of solid potassium carbonate until basic. The organic phase was

separated and then dried (phase separator) and concentrated in vacuo to give the title compound as a peach coloured solid (3.01 g, 17.8 mmol).

NMR: δH (MeOD, 400 MHz): 7.63 (1 H, t), 6.41 (1 H, dd), 6.31 (1 H, dd), 3.80 (3H, s) ppm.

The following compound was made in a similar manner as in Description 7.

Table 4:

Description 8: Methyl 4-{[(2-fluorophenyl)carbonyl]amino}benzoate

To a suspension of methyl 4-aminobenzoate (15.0 g, 99 mmol) in dichloromethane (120 ml.) at 0 ⁰ C under a flush of argon was added N,N-diisopropylethylamine (12.8 g, 99 mmol) followed by 2-fluorobenzoyl chloride (17.3 g, 109 mmol). After 5 min the cool bath was removed and the reaction stirred for 4 h, during which time a precipitate formed. The precipitate was removed by filtration and the filtrate washed with aqueous hydrochloric acid (2M, 100 ml. + 70 ml.) before the organic phase was isolated and dried (phase separator) and concentrated in vacuo to give the title compound as an off-white solid (24.6 g, 90 mmol)

LC/MS (ES +ve): [M+H] ⁺ at m/z 274 (C ₁₅ H ₁₂ FNO ₃ requires [M+H] ⁺ at m/z 274).

Description 9: Methyl 2-fluoro-4-{[(2-fluorophenyl)carbonyl]amino}benzoate

To a suspension of methyl 4-amino-2-fluorobenzoate

(5.10 g, 30.2 mmol) in dichloromethane (40 ml.) at 0 ⁰ C under a flush of argon was added N, N- diisopropylethylamine (3.90 g, 30.2 mmol) followed by 2-fluorobenzoyl chloride (5.27 g, 33.2 mmol). The reaction was stirred at room temperature over a weekend. Some of the title compound formed a precipitate as this stage, which was filtered off. The filtrate was washed with aqueous HCI (2M, 35 + 15 ml.) and further dichloromethane was added to aid dissolution. The organic phase was then isolated and dried (phase separator), concentrated in vacuo and combined with the first batch of solid to give the title compound as an orange/yellow solid (8.92 g, 30.2 mmol).

LC/MS (ES +ve): [M+H] ⁺ at m/z 292 (C ₁₅ H ₁₁ F ₂ NO ₃ requires [M+H] ⁺ at m/z 292).

Description 10: Methyl 4-{[(2-fluorophenyl)carbonyl]amino}-2-(methyloxy)benzoate

To a suspension of methyl 4-amino-2-methoxybenzoate (10.0 g, 55.0 mmol) in dichloromethane (75 ml.) at 0 ⁰ C under a flush of argon was added N,N-diisopropylethylamine (10.5 ml_, 60.7 mmol) followed by 2-fluorobenzoyl chloride (9.63 g, 60.7 mmol). The cool bath was removed and the reaction stirred overnight. The reaction mixture was diluted with DCM to 300 ml. and washed with aqueous hydrochloric acid (2M, 2 x 200 ml.) before the organic phase was isolated and dried (phase separator) and concentrated in vacuo to give the crude title compound as an off-white solid (17.7 g). This crude material was used without further purification.

LC/MS (ES +ve): [M+H] ⁺ at m/z 304 (C ₁₆ H ₁₄ FNO ₄ requires [M+H] ⁺ at m/z 304).

The following compounds were made in a similar manner as in Description 10. Variations to the method included reaction time and addition of extra acid chloride as required. Triethylamine has also been used instead of N,N-diisopropylethylamine.

Table 5:

Description 11 : 2-Fluoro-λ/-[4-(hydrazinocarbonyl)phenyl]benzamide

To a suspension of methyl 4-{[(2-fluorophenyl)carbonyl]amino}benzoate (24.6 g, 90 mmol) in methanol (400 ml.) was added hydrazine hydrate (31.5 g, 630 mmol) and the reaction heated to reflux overnight. Further hydrazine hydrate (15.8 g, 315 mmol) was then added and the reaction heated at reflux for a further 24 h. On cooling the solid precipitate was filtered off and

washed with methanol before drying in a vacuum oven to give the title compound (16.7 g, 61 mmol).

LC/MS (ES +ve): [M+H] ⁺ at m/z 274 (C ₁₄ H ₁₂ FN ₃ O ₂ requires [M+H] ⁺ at m/z 274).

Description 12: 2-Fluoro-λ/-[3-fl )phenyl]benzamide

Hydrazine monohydrate (14.9 ml_, 307 mmol) was added to a suspension of methyl 2-fluoro-4- {[(2-fluorophenyl)carbonyl]amino}benzoate (8.92 g, 30.2 mmol) in methanol and the mixture heated to reflux overnight. Further hydrazine monohydrate (4.46 ml_, 92.0 mmol) was added and the reaction heated for 2 h. The reaction was cooled to room temperature and the resultant precipitate filtered off and washed with methanol to give the title compound as a white solid (7.76 g, 26.7 mmol).

LC/MS (ES +ve): [M+H] ⁺ at m/z 292 (C ₁₄ H ₁₁ F ₂ N ₃ O ₂ requires [M+H] ⁺ at m/z 292).

Description 13: 2-Fluoro-λ/-[4-(hydrazinocarbonyl)-3-(methyloxy)phenyl]benz amide

Crude methyl 4-{[(2-fluorophenyl)carbonyl]amino}-2-(methyloxy)benzoate (17.7 g, 55 mmol) was dissolved in methanol (200 ml.) and hydrazine monohydrate (18.7 ml_, 385 mmol) was added. The reaction mixture was heated to reflux overnight. The product precipitated out of solution, so after addition of further methanol (150 ml_), the solid was filtered off and washed with methanol to give the title product as a white solid (13.9 g, 45.8 mmol).

LC/MS (ES +ve): [M+H] ⁺ at m/z 304 (C ₁₅ H ₁₄ FN ₃ O ₃ requires [M+H] ⁺ at m/z 304).

The following compounds were made in a similar manner as in Description 13. Variations to the method included the amount of hydrazine added and the reaction time to completion. In some instances purification by reverse phase chromatography or trituration with ethyl acetate was required.

Table 6:

Description 14: 1 -[(frans-4-lsothiocyanatocyclohexyl)methyl]pyrrolidine

frans-^i-Pyrrolidinylmethy^cyclohexanamine dihydrochloride (1.81 g, 7.10 mmol) was dissolved in water (10 ml_), basified with 2M sodium hydroxide and extracted with dichloromethane (3 x 25 ml_). The combined organic phase was dried (MgSO ₄ ), filtered and the solvent removed in vacuo to give the free base (1.2 g, 6.59 mmol). The resulting amine was dissolved in THF (10 ml_) and thiocarbonyldiimidazole (1.17 g, 6.59 mmol) was added. The reaction was stirred at room temperature for 2 h, then diluted with ethyl acetate (40 ml_), washed with water (2 x 20 ml_), dried (MgSO ₄ ), filtered and the solvent removed in vacuo to give the title compound as a yellow solid (1.48 g, 6.59 mmol). This was used without purification.

Description 15: λ/-Ethyl-λ/-[(frans-4-lsothiocyanatocyclohexyl)methyl]etha namine

The title compound was synthesised in a similar manner to Description 14. The trans-4- [(diethylamino)methyl]cyclohexanamine starting material was available as a free base and hence did not require the initial reaction with sodium hydroxide.

Example 1 : 2-Fluoro-λ/-[4-(5-{[frans-4-(1 -pyrrolidinylmethyl)cyclohexyl]amino}-1 ,3,4- oxadiazol-2-yl)phenyl]benzamide

i-Kfrans^-lsothiocyanatocyclohexyOmethylJpyrrolidine (1.48 g, 6.6 mmol) was dissolved in dimethylformamide (30 ml.) to give a stock solution. 3.0 ml. of the solution was added to 2- fluoro-λ/-[4-(hydrazinocarbonyl)phenyl]benzamide (180 mg , 0.66mmol) and the mixture stirred at room temperature for 18 h. 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (193 mg, 1.0 mmol) was added and the mixture heated at 80 ⁰ C for 3 h. The reaction mixture was then partitioned between ethyl acetate (25 ml.) and 2M sodium hydroxide (10 ml_). The organic phase was washed with water (3 x 15 ml_), dried (phase separator) and concentrated in vacuo. The residue was triturated with ethyl acetate, filtered and washed with acetone then diethyl ether to give the title compound (60 mg, 0.13 mmol).

LC/MS (ES +ve): [M+H] ⁺ at m/z 464 (C ₂₆ H ₃₀ FN ₅ O ₂ requires [M+H] ⁺ at m/z 464).

The following Examples were prepared in a similar manner as Example 1. Variations to the method include the number of equivalents of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and the subsequent reaction time. The method of purification also varied with one of the following methods used: MDAP followed by separation between ethyl acetate and aqueous sodium hydroxide and then drying the organic layer (MgSO ₄ ), filtration and trituration with ether or high pH MDAP followed by freeze-drying and trituration with ether.

Example 21 : 2-Fluoro-λ/-[3-(methyloxy)-4-(5-{[frans-4-(4- morpholinylmethyl)cyclohexyl]amino}-1,3,4-oxadiazol-2-yl)phe nyl]benzamide

To a solution of frans-4-(4-morpholinylmethyl)cyclohexanamine (1.00 g, 5.1 mmol) in dimethylformamide (70 ml.) was added 1 ,1-thiocarbonyldiimidazole (903 mg, 5.1 mmol) and the reaction stirred at room temperature overnight. 2-Fluoro-λ/-[4-(hydrazinocarbonyl)-3- (methyloxy)phenyl]benzamide (170 mg, 0.56 mmol) was added to 1/10 of the solution and the reaction stirred at room temperature overnight. 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (117 mg, 0.62 mmol) was added and the mixture heated to 60 ⁰ C for 4 h and then stirred at room temperature overnight. Further 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (117 mg, 0.62 mmol) was added and the reaction heated at 80 ⁰ C for 2 h then stirred at room temperature for 3 days. The reaction mixture was loaded onto an SCX cartridge, washed with methanol and eluted with 2M ammonia in methanol. The product containing fractions were concentrated and then partitioned between DCM:isopropyl alcohol (4:1 , 4 ml.) and aqueous sodium bicarbonate (4 ml_). The organic layer was dried (phase separator) and concentrated. Trituration with acetone did not purify the compound sufficiently so the material was purified by MDAP with the product trapped on SCX, washed with methanol and eluted with 2 M ammonia in methanol. The solvent was removed in vacuo to give the title compound as a white solid (23 mg, 0.05 mmol).

LC/MS (ES +ve): [M+H] ⁺ at m/z 510 (C ₂₇ H ₃₂ FN ₅ O ₄ requires [M+H] ⁺ at m/z 510).

Example 22: 2-Fluoro-λ/-[3-fluoro-4-(5-{[frans-4-(4-morpholinylmethyl)c yclohexyl]amino}- 1,3,4-oxadiazol-2-yl)phenyl]benzamide

To a solution of frans-4-(4-morpholinylmethyl)cyclohexanamine (1.00 g, 5.1 mmol) in dimethylformamide (70 ml.) was added 1 ,1-thiocarbonyldiimidazole (903 mg, 5.1 mmol) and the reaction stirred at room temperature overnight. 2-Fluoro-λ/-[3-fluoro-4- (hydrazinocarbonyl)phenyl]benzamide (163 mg, 0.56 mmol) was added to 1/10 of the solution and the reaction stirred at room temperature overnight. 1-Ethyl-3-(3-

dimethylaminopropyl)carbodiimide hydrochloride (117 mg, 0.62 mmol) was added and the mixture heated to 60 ⁰ C for 4 h and stirred at room temperature overnight. Further 1 -ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride (117 mg, 0.62 mmol) was added and the reaction heated at 80 ⁰ C for 2 h then stirred at room temperature for 3 days. The reaction mixture was loaded onto an SCX cartridge, washed with methanol and eluted with 2M ammonia in methanol. The product fractions were concentrated and then partitioned between DCM:isopropyl alcohol (4:1 , 4 ml.) and aqueous sodium bicarbonate (4 ml_). The organic layer was dried (phase separator) and concentrated. The crude material was triturated with acetone to give the title compound as a white solid (25 mg, 0.05 mmol).

LC/MS (ES +ve): [M+H] ⁺ at m/z 498 (C ₂₆ H ₃₀ F ₂ N ₅ O ₃ requires [M+H] ⁺ at m/z 498).

Example 23: 2-Fluoro-λ/-[3-(methyloxy)-4-(5-{[frans-4-(1- piperidinylmethyl)cyclohexyl]amino}-1,3,4-oxadiazol-2-yl)phe nyl]benzamide

To a solution of frans-4-(1-piperidinylmethyl)cyclohexanamine (100 mg, 0.51 mmol) in dimethylformamide (8 ml.) was added 1 ,1-thiocarbonyldiimidazole (159 mg, 0.51 mmol) and the reaction stirred at room temperature overnight. To the resulting solution was added

2-fluoro-λ/-[4-(hydrazinocarbonyl)-3-(methyloxy)phenyl]benz amide (159 mg, 0.56 mmol) and the reaction stirred at room temperature for 5 h. 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (117 mg, 0.62 mmol) was added and the reaction stirred at room temperature for 3 days. The reaction mixture was heated at 60 ⁰ C for 2.5 h. Further 1 -ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride (117 mg, 0.62 mmol) was added and the reaction heated at 60 ⁰ C for 3 hours and then stirred at room temperature overnight, before being heated again at 60 ⁰ C for a further 4h before methanol was added and the product trapped on SCX cartridge, washed with methanol and eluted with 2M ammonia in methanol. The fractions were concentrated and the residue dissolved in 4:1 chloroform :isopropyl alcohol (40 ml.) and washed with aqueous sodium bicarbonate (2 x 40 ml_). The organic layer was dried (phase separator) and concentrated in vacuo. The crude product was purified by silica chromatography, eluting 5-20 % (2M ammonia in methanol) in DCM. The resultant product was triturated with DCIWMeOH to give an off-white solid (77 mg, 0.15 mmol).

LC/MS (ES +ve): [M+H] ⁺ at m/z 508 (C ₂₈ H ₃₄ FN ₅ O ₃ requires [M+H] ⁺ at m/z 508).

The following compounds were made in a similar manner as in Examples 21-23. Variations to the method included: the number of equivalents of hydrazinocarbonyl compound and 1 -ethyl-3- (3-dimethylaminopropyl)carbodiimide hydrochloride, the temperature of reaction after addition of these reagents (room temperature to 80 ⁰ C) and the time required for complete reaction. Work- up of the reaction may instead have been separation between ethyl acetate and aqueous sodium hydroxide with either filtration of the resultant solid or washing the ethyl acetate layer with further water, drying (MgSO ₄ ), filtering and concentration in vacuo. Purification of the compounds involved one or more of the following methods: filtering off as a solid after aqueous work-up, trituration with diethyl ether, ethyl acetate, a dichoromethane/methanol mixture or 1 :1 dimethylsulfoxide:water, MDAP, high pH MDAP or silica chromatography using a proportion of (2M ammonia in methanol) in dichloromethane as eluent.

Table 8:

MASS DIRECTED AUTO-PURIFICATION SYSTEM (MDAP)

Experimental: Hardware:

- Waters 2525 Binary Gradient Module

- Waters 515 Makeup Pump

- Waters Pump Control Module

- Waters 2767 Inject Collect

- Waters Column Fluidics Manager

- Waters 2996 Photodiode Array Detector

- Waters ZQ Mass Spectrometer

- Gilson 202 fraction collector

- Gilson Aspec waste collector

Software:

- Waters MassLynx version 4 SP2

Column:

Low pH: - Waters Atlantis, dimensions of which are 19mm x 100mm (small scale) and

30mm x 100mm (large scale). The particle size of the stationary phase was

5μm. High pH: - Waters X-bridge, dimensions of which are 30mm x 100mm. The particle size of the stationary phase was 5μm.

Solvents:

Low pH: The following two solvents were used: 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

High pH: The following two solvents were used:

A : Aqueous solvent = 10 mM Ammonium bicarbonate solution adjusted to pH 10 with ammonia solution.

B : Organic solvent = Acetonitrile

Make up solvent = Methanol : Water / 80:20

Needle rinse solvent = Methanol

Methods:

The following five methods were 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:

All of the above methods have a flow rate of either 20mls/min (Small Scale) or 40mls/min (Large

Scale).

The following gradients were used on the large scale column:

- Large 1.5 to 2.3 min = 13-29% B

- Large 1.9 to 2.3 min = 25-41% B

- Large 2.3 to 2.6 min = 37-53% B

- Large 2.6 to 3.1 min = 49-65% B

- Large 3.1 to 3.6 min = 61-77% B

ASSAYS FOR DETERMINING BIOLOGICAL ACTIVITY

α7 nAChR FLI PR® (Fluorometric Imaging Plate Reader) assay

Function of the heterologously expressed α7 nAChR was assessed by a FLIPR-Ca ²⁺ assay. Since nAChRs are non-selective cation channels with high permeability to Ca ²⁺ , these studies were carried out by measuring changes of intracellular Ca ²⁺ concentration using the Ca ²⁺ - chelating fluorescent dye Fluo-4 and FLI PR® (Fluorometric Imaging Plate Reader) technology.

GH4C1 cells (pituitary tumor, immortalized cell line) stably transfected with human α7 nAChR (Biocat ID 96986), were thawed, suspended in growth medium (Ham's Nutrient Mixture F10 - Ham's F10, Invitrogen 31550-023, 15% Horse Serum heat inactivated - Invitrogen 26050-047, 2.5% Foetal Bovine Serum - FBS, Gibco 10500-064, 200 μg/ml Hygromycin B - Invitrogen, 10687-010, 10 mg/L Phenol Red - Sigma, P 0290, 1 mM Glutamine - Invitrogen, 25030-024) and plated in 500 cm ² Triple Flask.

72 hours before an experiment, cells growing in suspension were harvested, centrifuged, resuspended in growth medium at a density of 1.8 x 10 ⁵ /mL and plated in coated clear bottom black 384 wells plates (Pierce) at 9000 cells/well. Cells were then incubated at 30 ⁰ C, 5% CO ₂ for 72 hours.

On the day of the experiment, cells were washed twice with Assay Buffer (AB) (145 mM NaCI, 5 mM KCI, 1 mM MgCI ₂ , 2 mM CaCI ₂ , 20 mM HEPES, 5.5 mM Glucose pH=7.3) containing 2.5 mM Probenecid. Changes in the intracellular Ca ²⁺ content of stably transfected cells were

measured using the Ca ²⁺ chelating dye Fluo-4 (Tef Labs 0152) in conjunction with a FLIPR® (Molecular Devices). The cell permeant dye Fluo-4 was prepared to a concentration of 1 mM in 100% DMSO and 10% Pluronic acid. The dye was then diluted with AB to a final concentration of 2 μM and placed on the cells. After 45-60 minutes dye loading incubation at 37°C, the unincorporated dye was removed from the cells by washing (80 μl_, 3 times) with AB, and a final volume of 30 μL/well of AB was left in each well.

Plates containing test compounds (dissolved in 100% DMSO at 2 mM and serially diluted with DMSO) were copied into "daughter" plates (1 μL/well dispensation). Just prior to starting the assay, the "daughter" plate was diluted with 50 μL/well of AB.

The plates were then placed in the FLIPR®, and cell fluorescence was determined before drug addition (30 seconds) and monitored (excitation 488 nm, emission 510-580 nm) immediately following exposure to compounds. Maximum fluorescence values were recorded and fitted for agonist EC50 calculations.

Results

The compounds of Examples 1-59 were tested in the α7 nAChR FLIPR® assay as free bases.

The results are expressed as pEC50 values. A pEC50 is the negative logarithm of the agonist EC50 calculation as determined in the α7 nAChR FLIPR® assay. Certain Examples have been tested more than once. Variations in pEC50 may arise between tests.

The compounds of Examples 1-59 exhibited a pEC50 value ≥ 6.

More particularly, the compounds of Examples 1-21 , 23, 25, 26, 28-32, 37, 38, 40-59 exhibited a pEC50 value ≥ 7.

The application of which this description and claims forms part may be used as a basis for priority in respect of any subsequent application. The claims of such subsequent application may be directed to any feature or combination of features described herein. They may take the form of product, composition, process, or use claims and may include, by way of example and without limitation the following claims: