WO2009124882A1

WO2009124882A1 - Novel piperidinyl-1,3-dihydro-benzoimidazol-2-ones as m1 agonists

Info

Publication number: WO2009124882A1
Application number: PCT/EP2009/053996
Authority: WO
Inventors: Benny Bang-Andersen
Original assignee: H. Lundbeck A/S
Priority date: 2008-04-09
Filing date: 2009-04-03
Publication date: 2009-10-15

Abstract

The present invention relates to novel M1 agonistic compounds of the present invention and their use in the treatment of cognitive impairment associated i.a. with schizophrenia and in the treatment of other diseases mediated by the muscarinic M1 receptor.

Description

Novel piperidinyl-l,3-dihydro-benzoimidazol-2-ones as Ml agonists

Field of the Invention The present invention provides compounds that are Ml agonists or partial agonists and as such are useful to treat cognitive impairment in connection with schizophrenia and other disorders or diseases involving the muscarinic Ml receptor. The present invention also provides pharmaceutical compositions comprising the compounds of the invention and methods of treating said disorders or diseases using the compounds of the invention.

Background of the Invention

Muscarinic acetylcholine receptors are members of the G protein coupled receptor super family, which mediate the action of the neurotransmitter acetylcholine in both the central and peripheral nervous system. Five muscarinic receptor subtypes (M1-M5) have been cloned; the muscarinic Ml receptor is predominantly expressed in the cerebral cortex and hippocampus, although it is also expressed in the periphery, e.g. in exocrine glands.

Muscarinic receptors in the central nervous system, especially Ml, play a critical role in mediating higher cognitive processing.

It has been suggested that muscarinic agonists may improve the symptoms of schizophrenia by acting directly at postsynaptic muscarinic receptors in cortical areas (Friedman et al, Biol Psychiatry 1999, 45 1-16). Recently, polymorphism of the Ml muscarinic receptor gene was shown to be associated with a poor cognitive function in subjects with schizophrenia (Liao et al, Neuropsychobiology 2003, 48, 72-76). Data from postmortem studies show a decrease in Ml receptor protein and mRNA levels in prefrontal cortices in human subjects with schizophrenia, which is confirmed by an in vivo brain imaging study in unmedicated subjects with schizophrenia. (Raedler et al, Molecular Psychiatry 2007, 12, 232-246). Altogether this suggests that there is a decrease in Ml receptors in the frontal cortex of schizophrenia which could result in an under activation of cholinergic pathways and that activating the Ml receptor would be a mechanism by which cognitive deficits could be reversed in schizophrenia. Alzheimer's disease, which is associated with cognitive impairment, is accompanied by loss of cholinergic neurons in the basal forebrain. Furthermore, in animal models, blockade or lesion of central cholinergic pathways results in profound cognitive deficits.

Cholinergic replacement therapy has largely been based on the use of acetylcholine esterase inhibitors to prevent the breakdown of endogenous acetylcholine. These compounds have shown to be efficient against symptomatic cognitive decline, but on the other hand give rise to side effects that come from stimulation of peripheral muscarinic receptors, including disturbed gastrointestinal motility and nausea.

In addition to schizophrenia and Alzheimer's Disease, cognitive impairment can be experienced in several patient groups, such as depressive or psychotic patients and patients with attention deficit hyperactivity disorder (ADHD), psychotic disorders, such as schizoaffective disorders, psychotic depression, mania, acute mania, Parkinson's disease, mild cognitive impairment (MCI), dementia, anxiety, age associated memory impairment, or posttraumatic stress disorder. Cognitive impairment can also be experienced in patients taking benzodiazepines or tricyclic antidepressants and in a range of neurodegenerative diseases in addition to Parkinson's Disease and Alzheimer's Disease.

Furthermore, there is a close link between cognitive impairment and unfavorable post- hospitalization rehabilitation outcomes, especially in elderly patients (SoIh et al., BMC Geriatr. 2006; 6: 12; Hershkovitz et al., Arch. Phys. Medicine and Rehab. 88 (7) 2007, 916- 921, such as postacute stroke rehabilitation (Massucci et al., Am. J. Phys. Medicine & Rehab. 85 (12), 2006 963-970).

Ml receptor agonists or partial agonists could potentially improve cognitive function in patients suffering from these disorders.

Ml receptor agonists may also be suitable for combination with typical and atypical antipsychotics and other drugs for the treatment of disorders or diseases in the central nervous system, such as mood stabilisers, antidepressants, anxiolytics, drugs for treatment of extrapyrimidal side effects and cognitive enhancers, to provide improved treatment of psychotic disorders. Moreover, the muscarinic family of receptors is the target for a number of pharmacological agents used for various other diseases, such as chronic obstructive pulmonary disease, asthma, urinary incontinence, glaucoma and pain, including acute pain, chronic pain and neuropathic pain states.

So far, the development of muscarinic Ml receptor agonists for the treatment of cognitive dysfunction or impairment has resulted in a variety of drug candidates, but many have been discontinued from development because of undesirable side effects, such as sweating, vomiting and nausea. Therefore, there is a need to develop better therapies to improve the cognitive impairment associated with these disorders and diseases.

Bridges, Thomas M et al, Poster COMC-082 at Frontiers in CNS and Oncology Medicinal Chemistry, ACS-EFMC, Siena, Italy, October 7-9 (2007) disclose certain N-benzyl- and N- benzoyl-[l,4']bipiperidinyl-4-yl)-l,3-dihydro-benzoimidazol-2-ones as Ml allosteric agonists. WO2007107565, WO2007107566 and WO2007107567 further disclose certain 4-alkoxy- cyclohexyl)-piperidin-4-yl]-l,3-dihydro-benzoimidazol-2-one as Ml receptor agonists, whereas WO2007036711, WO2007036715 and WO2007036718 disclose l-[l-(tetrahydro- pyran-4-yl)-piperidin-4-yl]-l,3-dihydro-benzoimidazol-2-one having effect on the Ml receptor. WO 2004/1089942 and WO 2003/028650 disclose benzimidazolidinone derivatives which increase acetylcholine signaling or effect in the brain, and which are highly selective muscarinic Ml and/or M4 receptor agonists.

None of these references discloses the l-(2-aryl-tetrahydro-pyran-4-yl)-substituted piperidin- 4-yl-l,3-dihydro-benzoimidazol-2-ones of the present invention.

Thus the compounds of the invention, which are muscarinic Ml receptor agonists, are believed to be useful in the treatment of cognitive impairment associated with schizophrenia, Alzheimer's disease, psychotic disorders such as schizoaffective disorders, psychotic depression, mania, acute mania and with affective disorders such as depression or or bipolar disorder, with memory disorders, and with other diseases mediated by muscarinic receptors, such as chronic obstructive pulmonary disease, asthma, urinary incontinence, glaucoma and pain, including acute pain, chronic pain and neuropathic pain states. Summary of the Invention

The present invention relates to novel piperidinyl-l,3-dihydro-benzoimidazol-2-ones which have been found to be highly active Ml agonists, and as such are ikely to be effective in the treatment of cognitive impairment and other diseases mediated by the muscarinic Ml receptor.

One object of the present invention is thus to provide novel compounds which are agonists at the Ml receptor.

The present invention is further directed to the use of a compound, alone or in combination with other antipsychotic agents or other drugs for the treatment of disorders or diseases in the central nervous system, for treating or preventing psychosis, such as a schizophrenic disorder or psychosis in Alzheimer's disease or bipolar disorder, for treatment of cognitive impairment associated with schizophrenia, Alzheimer's disease, psychotic disorders such as schizoaffective disorders, psychotic depression, mania, acute mania and with affective disorders such as depression or or bipolar disorder, with memory disorders, and with other diseases mediated by muscarinic receptors, such as chronic obstructive pulmonary disease, asthma, urinary incontinence, glaucoma and pain, including acute pain, chronic pain and neuropathic pain states. The present invention further provides a pharmaceutical composition comprising the compound accordin to the present invention and one or more pharmaceutically acceptable carriers, diluents or excipients for treating or preventing said disorders and diseases.

Furthermore, the present invention is also directed to a method for the treatment, control, amelioration or reduction of risk of a disease or disorder where abnormal oscillatory activity occurs in the brain, including depression, migraine, Parkinson's disease, psychosis and schizophrenia, as well as diseases or disorders where there is abnormal coupling of activity, particularly through the thalamus and with other diseases mediated by muscarinic receptors, such as chronic obstructive pulmonary disease, asthma, urinary incontinence, glaucoma and pain, including acute pain, chronic pain and neuropathic pain states.

Further objects of the invention will become apparent upon reading the present specification. Accordingly, in one aspect the present invention relates to compounds of formula I:

wherein

A is selected from CH₂ and O;

G is a phenyl, optionally substituted with one or two substituents individually selected from a Ci_6 alkyl group such as methyl, a C^ alkoxy group such as methoxy, or a halogen atom such as F or Cl,

or G is a 2- or 3-pyridyl group.

Rl and R3 are independently selected from H, cyano, halogen such as F or Cl, and Ci_6 alkoxy, such as methoxy,

R2 is selected from H and halogen, such as F or Cl,

and enantiomers, diastereomers, tautomers and pharmaceutically acceptable acid addition salts thereof, and polymorphic forms thereof.

The invention provides a compound of formula I, or a pharmaceutically acceptable acid addition salt thereof, for use as a medicament. In a further aspect the invention relates to a compound of formula I for use in the treatment of disorders associated with muscarinic receptors, such as cognitive impairment.

In another aspect, the invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I and one or more pharmaceutically acceptable carriers, diluents or excipients.

In another aspect, the invention provides a compound of formula I, or a pharmaceutically acceptable acid addition salt thereof, alone or in combination with one or more neuroleptic agents, for use in the treatment of schizophrenia.

The invention further provides the use of a compound of formula I, or a pharmaceutically acceptable acid addition salt thereof, for the preparation of a medicament for the treatment of disorders associated with muscarinic receptors, such as cognitive impairment.

The invention also provides the use of a compound of formula I, or a pharmaceutically acceptable acid addition salt thereof, for the preparation of a medicament for the treatment of cognitive impairment, such as mild cognitive impairment or cognitive impairment associated with schizophrenia.

The invention further provides a method of treating disorders selected from the group consisting of: cognitive disorders (including age-related cognitive disorder, mild cognitive impairment (MCI), cognitive impairment associated with schizophrenia, and chemotherapy- induced cognitive impairment), ADHD, mood disorders (including depression, mania, bipolar disorders), psychosis (in particular schizophrenia and schizophreniform disorder), dementia (including Alzheimer's disease, AIDS-induced dementia, vascular dementia, and dementia lacking distinctive histology), Parkinson's disease, Huntington's Chorea, pain (including acute pain and chronic pain such as neuropathic pain), xerostomia (dry mouth), Lewy body disease (including diffuse Lewy body disease), aphasia (including primary aphasia and primary aphasia syndromes), hypotensive syndromes, and chronic colitis (including Crohn's disease); the method comprising: administering to a mammal an effective amount of a compound of formula I. The present invention further provides use of a compound of formula I or a pharmaceutically acceptable acid addition salt thereof, or a pharmaceutical composition thereof, for the treatment of disorders associated with muscarinic receptors, such as cognitive impairment.

In separate embodiments of the invention, the compound is selected among the specific compounds disclosed in the Experimental Section herein.

Detailed Description of the Invention

Definition of Substitutents

As used in the context of the present invention, the expression "Ci_6 alkoxy" refers to a straight-chain or branched saturated alkoxy group having from one to six carbon atoms, inclusive, with the open valency on the oxygen. Examples of such groups include, but are not limited to, methoxy, ethoxy, n-butoxy, 2-methyl-pentoxy and n-hexyloxy.

The term "Ci_6 alkyl" refers to a straight-chain or branched saturated hydrocarbon having from one to six carbon atoms, inclusive. Examples of such groups include, but are not limited to, methyl, ethyl, 1 -propyl and 2-propyl, 1 -butyl, 2-butyl, 2-methyl-2-propyl, 2-methyl-l- butyl and n-hexyl.

The term "aryl group" refers to a phenyl group, optionally substituted with a Ci_6 alkyl group such as methyl or a Ci_6 alkoxy group such as methoxy, or a halogen atom such as F, Cl, Br or I. Typical examples, which should not be considered limiting, includeing phenyl, tolyl, methoxyphenyl, chlorophenyl and fluorophenyl.

The compounds of the present invention may have one or more asymmetric centers, and it is intended that any optical isomers (i.e. enantiomers or diastereomers), as separated, pure or partially purified optical isomers or any mixtures thereof, including racemic mixtures, are included within the scope of the invention.

Racemic forms may be resolved into the optical antipodes by known methods, for example by separation of diastereomeric salts thereof with an optically active acid, and liberation of the optically active amine compound by treatment with a base. Separation of such diastereomeric salts can be achieved, e.g. by fractional crystallization. The optically active acids suitable for this purpose may include, but are not limited to, d- or 1-tartaric, mandelic or camphorsulfonic acids. Another method for resolving racemates into the optical antipodes is based upon chromatography on an optically active matrix. The compounds of the present invention may also be resolved by the formation and separation, e.g. chromatographic separation, of diastereomeric derivatives from chiral derivatizing reagents, such as a chiral alkylating or acylating reagents, followed by cleavage of the chiral auxiliary. Additional methods for the resolution of optical isomers, known to those skilled in the art, may be used. Such methods include those discussed by J. Jaques, A. Collet and S. Wilen in "Enantiomers, Racemates, and Resolutions", John Wiley and Sons, New York (1981). Optically active compounds can also be prepared from optically active starting materials, or by stereoselective synthesis.

Furthermore, some of the compounds of the present invention may exist in different tautomeric forms, and it is intended that any such tautomeric forms are included within the scope of the present invention.

Some of the compounds of the present invention, including their pharmaceutically acceptable acid addition salts, may exist in different polymorphic forms, and it is intended that any such polymorphic forms are included within the scope of the present invention.

Definition of terms

The term "cognitive impairment" as used herein, refers to difficulties with attention, learning, memory and executive function (relevant reactions to external stimuli). These can include: deficits in attention, disorganized thinking, slow thinking, difficulty in understanding, poor concentration, impairment of problem solving, poor memory, difficulty in expressing thoughts and/or difficulty in integrating thoughts, feelings and behaviour and extinction of irrelevant thoughts as well as attention and vigilance, verbal learning and memory, visual learning and memory, speed of processing and social cognition.

The term "treatment" as used herein in connection with a disease or disorders such as cognitive impairment includes also prevention as the case may be. The term "therapeutically effective amount" as used herein shall mean that amount of a compound of formula I, or a pharmaceutically acceptable acid addition salt thereof, that will elicit the biological or medical response of a mammal that is being sought by a researcher or clinician. The therapeutically effective amount will depend on the condition to be treated, the route and duration of administration, the physical attributes of the mammal, including body weight, and whether other medications are being taken concurrently, and may be determined according to methods well known to those skilled in the art in light of the present disclosure.

The mammal treated in the present methods may be a human, male or female, in whom activation of muscarinic Ml receptor activity is desired. Although the present invention is applicable to both old and young people, in certain aspects such as in treating cognitive impairment associated with Alzheimer's disease, it would find greater application in elderly people.

Accordingly, the present invention includes within its scope the use of a compound of formula I, alone or in combination with other agents, for the treatment of diseases mediated by the muscarinic Ml receptor, such as cognitive impairment and neuropathic pain in a mammal.

The term "leaving group" as used herein, refers to a group that is displaced in a substitution or elimination reaction. Typical leaving groups include, but are not limited to, the chloride ion (Cl^"), bromide ion (Br^") and methanesulfonate ion (CH3SO3 ).

As used herein, the term "substantially pure enantiomer" refers to a substance containing between about 95% and 100% of one form (either R or S) and between about 5% and 0% of the other form, alternatively between about 99% and 100% of one form (either R or S) and between about 1% and 0% of the other form, or alternatively between about 99.9% and 100% of one form (either R or S) and about 0.1% and 0% of the other form.

As used herein, the term "substantially pure diastereomer" refers to a substance containing between about 95% and 100% of one diastereomeric form and between about 5% and 0% of the other form, alternatively between about 99% and 100% of one form and between about 1% and 0% of the other form, or alternatively between about 99.9% and 100% of one diastereomeric form and about 0.1% and 0% of the other form. As used herein, the term rac means a racemic mixture of enantiomers.

Accordingly, in one aspect the present invention relates to a compound of formula I:

wherein

A is selected from CH₂ and O;

G is a phenyl, optionally substituted with one or two substituents individually selected from a Ci_6 alkyl group such as methyl, a Ci_6 alkoxy group such as methoxy, or a halogen atom such as F or Cl,

or G is a 2- or 3-pyridyl group.

Rl and R3 are independently selected from H, cyano, halogen such as F or Cl, and Ci_6 alkoxy such as methoxy,

R2 is selected from H and halogen, such as F or Cl,

and enantiomers, diastereomers, tautomers and pharmaceutically acceptable acid addition salts thereof, and polymorphic forms thereof. In one embodiment of the invention, the group A is O. In another embodiment, A is CH₂.

In a further embodiment, the group G is phenyl. In another embodiment, G is a phenyl group substituted with a Ci_₆ alkyl group, such as methyl. In another embodiment, G is a phenyl group substituted with a Ci_6 alkoxy group, such as methoxy. In yet another embodiment, G is a phenyl group substituted with a halogen atom, such as F or Cl.

In a different embodiment, the group G is pyrid-2-yl, i.e. a pyridine ring attached via its 2- position. In another embodiment, the group G is pyrid-3-yl.

In a specific embodiment of the invention, Rl, R2 and R3 are all hydrogen. In another embodiment at least one of Rl, R2 and R3 is not hydrogen. In a further embodiment at least one of Rl, R2 and R3 is hydrogen. In another embodiment at least one of Rl, R2 and R3 is halogen such as F and Cl.

In a further embodiment of the invention, Rl is halogen, such as F or Cl. In another embodiment, R2 is halogen, such as F or Cl. In yet another embodiment, R3 is halogen, such as F or Cl.

In a further embodiment, R3 is Ci_6 alkoxy such as methoxy. In a different embodiment, R3 is cyano. In yet another embodiment of the invention, R2 and R3 are both halogen such as F and Cl.

It should be understood that the various aspects, embodiments, implementations or features of the invention mentioned herein can be used and may be claimed separately, or in any combination, which can be illustrated by the following non-limiting examples:

In a specific embodiment, Rl, R2 and R3 are all hydrogen, the group A is Oxygen and the group G is phenyl. In another specific embodiment, Rl and R2 are both hydrogen, R3 is selected from hydrogen, cyano, Ci_6 alkoxy such as methoxy or halogen such as F and Cl, the group A is Oxygen and the group G is phenyl. In a third specific embodiment, Rl, R2 and R3 are all hydrogen, the group A is CH₂, and the group G is phenyl. In an embodiment of the present invention, the compound of formula I possesses an EC50 for binding to the muscarinic Ml receptor of 1 μM or less as evaluated by the CellLux Muscarinic Calcium²⁺ flux assay. In another embodiment, the compound of formula I possesses an EC50 for binding to the muscarinic Ml receptor of 500 nM or less as evaluated by the CellLux Muscarinic Calcium²⁺ flux assay. In another embodiment, the compound of formula I possesses an EC50 for binding to the muscarinic Ml receptor of 100 nM or less as evaluated by the CellLux Muscarinic Calcium²⁺ flux assay assay. In another embodiment, the compound of formula I possesses an EC50 for binding to the muscarinic Ml receptor of 50 nM or less as evaluated by the CellLux Muscarinic Calcium²⁺ flux assay. In another embodiment, the compound of formula I possesses an EC50 for binding to the muscarinic Ml receptor of 10 nM or less as evaluated by the CellLux Muscarinic Calcium²⁺ flux assay.

In a separate embodiment of the invention, the compound of formula I is a substantially pure enantiomer. In another embodiment, the compound of formula I is a substantially pure diastereomer.

In separate individual embodiments of the invention, the compound of formula I is selected among the following specific compounds, either as the free base, tautomers thereof or as a pharmaceutically acceptable acid addition salt thereof:

1 -[ 1 -(2-Phenyl-tetrahydro-pyran-4-yl)-piperidin-4-yl]- 1 ,3-dihydro-benzoimidazol-2-one

6-Methoxy- 1 -[ 1 -(2-phenyl-tetrahydro-pyran-4-yl)-piperidin-4-yl]- 1 ,3-dihydro-benzoimidazol- 2-one

6-Chloro-5-fluoro- 1-[ 1 -(2-phenyl-tetrahydro-pyran-4-yl)-piperidin-4-yl]- 1 ,3-dihydro- benzoimidazol-2-one

(2S,4R)- 1-[ 1 -(2-Phenyl-tetrahydro-pyran-4-yl)-piperidin-4-yl]- 1 ,3-dihydro-benzoimidazol-2- one

1 -[ 1 -(3-Phenyl-cyclohexyl)-piperidin-4-yl]- 1 ,3-dihydro-benzoimidazol-2-one 2-Oxo-3-[l-(2-phenyl-tetrahydro-pyran-4-yl)-piperidin-4-yl]-2,3-dihydro-lH- benzoimidazo le-5 -carbonitrile

4-Fluoro- 1-[ 1 -(2-phenyl-tetrahydro-pyran-4-yl)-piperidin-4-yl]- 1 ,3-dihydro-benzoimidazol-2- one

1 -[ 1 -(2-Pyridin-3-yl-tetrahydro-pyran-4-yl)-piperidin-4-yl]- 1 ,3-dihydro-benzoimidazol-2-one

6-Fluoro- 1-[ 1 -(2-phenyl-tetrahydro-pyran-4-yl)-piperidin-4-yl]- 1 ,3-dihydro-benzoimidazol-2- one

5-Fluoro- 1-[ 1 -(2-phenyl-tetrahydro-pyran-4-yl)-piperidin-4-yl]- 1 ,3-dihydro-benzoimidazol-2- one

(2R,4S)- 1-[ 1 -(2-Phenyl-tetrahydro-pyran-4-yl)-piperidin-4-yl]- 1 ,3-dihydro-benzoimidazol-2- one

1 -[ 1 -(2-Pyridin-2-yl-tetrahydro-pyran-4-yl)-piperidin-4-yl]- 1 ,3-dihydro-benzoimidazol-2-one

5-Chloro- 1 -[ 1 -(2-phenyl-tetrahydro-pyran-4-yl)-piperidin-4-yl]- 1 ,3-dihydro-benzoimidazol-2- one

6-Fluoro- 1-[ 1 -(3-phenyl-cyclohexyl)-piperidin-4-yl]- 1 ,3-dihydro-benzoimidazol-2-one

5-Fluoro- 1-[ 1 -(3-phenyl-cyclohexyl)-piperidin-4-yl]- 1 ,3-dihydro-benzoimidazol-2-one

5-Chloro- 1 -[ 1 -(3-phenyl-cyclohexyl)-piperidin-4-yl]- 1 ,3-dihydro-benzoimidazol-2-one

6-Methoxy- 1 -[ 1 -(3-phenyl-cyclohexyl)-piperidin-4-yl]- 1 ,3-dihydro-benzoimidazol-2-one

6-Chloro-5-fluoro- 1-[ 1 -(3-phenyl-cyclohexyl)-piperidin-4-yl]- 1 ,3-dihydro-benzoimidazol-2- one 6-Methoxy- 1 -[ 1 -(2-pyridin-2-yl-tetrahydro-pyran-4-yl)-piperidin-4-yl]- 1 ,3-dihydro- benzoimidazol-2-one

6-Methoxy- 1 -[ 1 -(2-pyridin-3-yl-tetrahydro-pyran-4-yl)-piperidin-4-yl]- 1 ,3-dihydro- benzoimidazol-2-one

6-Methoxy- 1 -[ 1 -(2-pyridin-4-yl-tetrahydro-pyran-4-yl)-piperidin-4-yl]- 1 ,3-dihydro- benzoimidazol-2-one

Each of these compounds is considered a specific embodiment and may be made subject of individual claims.

Pharmaceutically Acceptable Salts

The present invention comprises pharmaceutically acceptable acid addition salts of the compounds of formula I. Such salts include salts of inorganic acids as well as organic acids.

Representative examples of suitable inorganic acids include hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric, sulfamic, nitric acids and the like. Representative examples of suitable organic acids include formic, acetic, trichloroacetic, trifluoroacetic, propionic, benzoic, cinnamic, citric, fumaric, glycolic, itaconic, lactic, methanesulfonic, maleic, malic, malonic, mandelic, oxalic, picric, pyruvic, salicylic, succinic, methane sulfonic, ethanesulfonic, tartaric, ascorbic, pamoic, bismethylene salicylic, ethanedisulfonic, gluconic, citraconic, aspartic, stearic, palmitic, EDTA, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, p-toluenesulfonic acids, theophylline acetic acids, as well as the 8- halotheophyllines, for example 8 -bromo theophylline and the like.

Furthermore, the compounds of this invention may exist in unsolvated as well as in solvated forms with pharmaceutically acceptable solvents such as water, ethanol and the like. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of this invention.

Pharmaceutical compositions

The present invention further provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I and a pharmaceutically acceptable carrier or diluent. The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of one of the specific compounds disclosed in the Experimental Section herein and a pharmaceutically acceptable carrier or diluent.

The compounds of the invention may be administered alone or in combination with pharmaceutically acceptable carriers, diluents or excipients, in either single or multiple doses. The pharmaceutical compositions according to the invention may be formulated with pharmaceutically acceptable carriers or diluents as well as any other known adjuvants and excipients in accordance with conventional techniques such as those disclosed in Remington: The Science and Practice of Pharmacy, 19^th Edition, Gennaro, Ed., Mack Publishing Co., Easton, PA, 1995.

The pharmaceutical compositions may be specifically formulated for administration by any suitable route such as oral, rectal, nasal, pulmonary, topical (including buccal and sublingual), transdermal, intracisternal, intraperitoneal, vaginal and parenteral (including subcutaneous, intramuscular, intrathecal, intravenous and intradermal) routes. It will be appreciated that the route will depend on the general condition and age of the mammal to be treated, the nature of the condition to be treated and the active ingredient.

Pharmaceutical compositions for oral administration include solid dosage forms such as capsules, tablets, dragees, pills, lozenges, powders and granules. Where appropriate, the compositions may be prepared with coatings such as enteric coatings or they may be formulated so as to provide controlled release of the active ingredient such as sustained or prolonged release according to methods well known in the art. Liquid dosage forms for oral administration include solutions, emulsions, suspensions, syrups and elixirs.

Pharmaceutical compositions for parenteral administration include sterile aqueous and nonaqueous injectable solutions, dispersions, suspensions or emulsions as well as sterile powders to be reconstituted in sterile injectable solutions or dispersions prior to use. Other suitable administration forms include, but are not limited to, suppositories, sprays, ointments, creams, gels, inhalants, dermal patches and implants. Typical oral dosages of a compound of formula I range from about 0.001 to about 100 mg/kg body weight per day, calculated as the free base. Typical oral dosages also range from about 0.01 to about 50 mg/kg body weight per day. Typical oral dosages further range from about 0.05 to about 10 mg/kg body weight per day. Oral dosages are usually administered in one or more dosages, typically, one to three dosages per day. The exact dosage will depend upon the frequency and mode of administration, the sex, age, weight and general condition of the mammal treated, the nature and severity of the condition treated and any concomitant diseases to be treated and other factors evident to those skilled in the art.

The formulations may also be presented in a unit dosage form by methods known to those skilled in the art. For illustrative purposes, a typical unit dosage form for oral administration may contain from about 0.01 to about 1000 mg, from about 0.05 to about 500 mg, or from about 0.5 mg to about 200 mg of a compound of formula I, calculated as the free base.

For parenteral routes such as intravenous, intrathecal, intramuscular and similar administration, typical doses are in the order of half the dose employed for oral administration.

The present invention also provides a process for making a pharmaceutical composition comprising admixing a therapeutically effective amount of a compound of formula I and at least one pharmaceutically acceptable carrier or diluent. In an embodiment of the present invention, the compound utilized in the aforementioned process is one of the specific compounds disclosed in the Experimental Section.

The compounds of this invention are generally utilized as the free base or as a pharmaceutically acceptable acid addition salt thereof. Such salts are prepared in a conventional manner by treating a solution or suspension of a free base of formula I with a molar equivalent of a pharmaceutically acceptable acid. Representative examples of suitable organic and inorganic acids are described above.

For parenteral administration, solutions of the compounds of formula I in sterile aqueous solution, aqueous propylene glycol, aqueous vitamin E or sesame or peanut oil may be employed. Such aqueous solutions should be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose. The aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. The compounds of formula I may be readily incorporated into known sterile aqueous media using standard techniques known to those skilled in the art.

Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solutions and various organic solvents. Examples of solid carriers include lactose, terra alba, sucrose, cyclodextrin, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and lower alkyl ethers of cellulose. Examples of liquid carriers include, but are not limited to, syrup, peanut oil, olive oil, phospholipids, fatty acids, fatty acid amines, polyoxyethylene and water. Similarly, the carrier or diluent may include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax. The pharmaceutical compositions formed by combining the compounds of formula I and a pharmaceutically acceptable carrier are then readily administered in a variety of dosage forms suitable for the disclosed routes of administration. The formulations may conveniently be presented in unit dosage form by methods known in the art of pharmacy.

Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules or tablets, each containing a predetermined amount of the active ingredient, and optionally a suitable excipient. Furthermore, the orally available formulations may be in the form of a powder or granules, a solution or suspension in an aqueous or non-aqueous liquid, or an oil- in- water or water-in-oil liquid emulsion.

If a solid carrier is used for oral administration, the preparation may be tabletted, placed in a hard gelatin capsule in powder or pellet form or it may be in the form of a troche or lozenge. The amount of solid carrier will vary widely but will range from about 25 mg to about 1 g per dosage unit. If a liquid carrier is used, the preparation may be in the form of a syrup, emulsion, soft gelatin capsule or sterile injectable liquid such as an aqueous or non-aqueous liquid suspension or solution.

The pharmaceutical compositions of the invention may be prepared by conventional methods in the art. For example, tablets may be prepared by mixing the active ingredient with ordinary adjuvants and/or diluents and subsequently compressing the mixture in a conventional tabletting machine prepare tablets. Examples of adjuvants or diluents comprise: corn starch, potato starch, talcum, magnesium stearate, gelatine, lactose, gums, and the like. Any other adjuvants or additives usually used for such purposes such as colorings, flavorings, preservatives etc. may be used provided that they are compatible with the active ingredients.

Treatment of Disorders

As mentioned above, the compounds of formula I are Ml receptor agonists and as such are useful for treating or reducing the severity of a Ml muscarinic receptor mediated diseases such as cognitive impairment and neuropathic pain.

The term "treating or reducing the severity of a Ml muscarinic receptor mediated disease" refers both to treatments for diseases that are directly caused by muscarinic activities and alleviation of symptoms of diseases not directly caused by muscarinic activities. Examples of diseases whose symptoms may be affected by muscarinic activity include, but are not limited to, CNS derived pathologies including cognitive disorders, Attention Deficit Hyperactivity Disorder (ADHD), obesity, Alzheimer's disease, various dementias such as vascular dementia, psychosis including schizophrenia, mania, bipolar disorders, pain conditions including acute and chronic syndromes such as neuropathic pain, Huntington's Chorea, Friederich's ataxia, Gilles de La Tourette's Syndrome, Down's Syndrome, Pick's disease, clinical depression, Parkinson's disease, peripheral disorders such as reduction of intraocular pressure in Glaucoma and treatment of dry eyes and dry mouth (xerostomia) including Sjogren's Syndrome, bradhycardia, gastric acid secretion, asthma, GI disturbances and wound healing.

The present invention thus provides a method of treating a mammal suffering from cognitive impairment, which comprises administering to the mammal a therapeutically effective amount of a compound of formula I.

This invention also provides a method of treating a mammal suffering from cognitive impairment associated with a psychiatric disorder, which comprises administering to the mammal a therapeutically effective amount of a compound of formula I. Examples of psychiatric disorders include, but are not limited to, schizophrenia, for example of the paranoid, disorganized, catatonic, undifferentiated, or residual type; schizophreniform disorder; schizoaffective disorder, for example of the delusional type or the depressive type; delusional disorder; substance-induced psychotic disorder, for example psychosis induced by alcohol, amphetamine, cannabis, cocaine, hallucinogens, inhalants, opioids, or phencyclidine; personality disorder of the paranoid type; and personality disorder of the schizoid type; and anxiety disorder selected from panic disorder; agoraphobia; a specific phobia; social phobia; obsessive-compulsive disorder; post-traumatic stress disorder; acute stress disorder; and generalized anxiety disorder.

The present invention provides a method of treating a mammal suffering from cognitive impairment associated with a cognition disorder, which comprises administering to the mammal a therapeutically effective amount of a compound of formula I. Examples of cognition disorders include, but are not limited to, Alzheimer's disease, multi-infarct dementia, alcoholic dementia or other drug-related dementia, dementia associated with intracranial tumors or cerebral trauma, dementia associated with Huntington's disease or Parkinson's disease, or AIDS-related dementia; attention deficits, delirium; amnestic disorder; post-traumatic stress disorder; mental retardation; a learning disorder, for example reading disorder, mathematics disorder, or a disorder of written expression; attention- deficit/hyperactivity disorder (ADHD); and memory impairment such as age associated memory impairment.

The compounds of formula I or pharmaceutically acceptable acid addition salts thereof may be used in combination with one or more other drugs in the treatment of diseases or conditions for which the compounds of the present invention have utility, where the combination of the drugs together are safer or more effective than either drug alone. Additionally, the compounds of the present invention may be used in combination with one or more other drugs that treat, prevent, control, ameliorate, or reduce the risk of side effects or toxicity of the compounds of the present invention. Such other drugs may be administered, by a route and in an amount commonly used therefore, contemporaneously or sequentially with the compounds of the present invention. Accordingly, the pharmaceutical compositions of the present invention include those that contain one or more other active ingredients, in addition to the compounds of the present invention. The combinations may be administered as part of a unit dosage form combination product, or as a kit or treatment protocol wherein one or more additional drugs are administered in separate dosage forms as part of a treatment regimen.

It has thus been found that the compounds of formula I or pharmaceutically acceptable acid addition salts thereof, may advantageously be administered in combination with at least one neuroleptic agent (which may be a typical or atypical antipsychotic agent) to provide improved treatment of schizophrenia. The combinations, uses and methods of treatment of the invention may also provide advantages in treatment of patients who fail to respond adequately or who are resistant to other known treatments.

The present invention thus provides a method of treating a mammal suffering from schizophrenia, which comprises administering to the mammal a therapeutically effective amount of a compound of formula I, either alone or as combination therapy with at least one neuroleptic agent.

The term "neuroleptic agent" as used herein, refers to drugs which have the effect on cognition and behaviour of antipsychotic agent drugs that reduce confusion, delusions, hallucinations, and psychomotor agitation in patients with psychoses. Also known as major tranquilizers and antipsychotic drugs, neuroleptic agents include, but are not limited to: typical antipsychotic drugs, including phenothiazines, further divided into the aliphatics, piperidines, and piperazines, thioxanthenes (e.g., cisordinol), butyrophenones (e.g., haloperidol), dibenzoxazepines (e.g., loxapine), dihydroindolones (e.g., molindone), diphenyl- butylpiperidines (e.g., pimozide), and atypical antipsychotic drugs, including benzisoxazoles (e.g., risperidone), sertindole, olanzapine, quetiapine, osanetant and ziprasidone.

The expression "co-administration of a neuroleptic agent" as used herein, refers to the administration of a compound as defined by formula I, or pharmaceutically acceptable acid addition salts thereof, in combination with at least one neuroleptic agent such as sertindole, olanzapine, risperidone, quetiapine, aripiprazole, haloperidol, clozapine, ziprasidone and osanetant.

Other examples of combinations of the compounds of formula I include combinations with anti-Alzheimer's Disease agents, for example beta-secretase inhibitors; alpha 7 nicotinic agonists, such as ABT089, SSRl 80711 and MEM63908; gamma-secretase inhibitors, such as LY450139 and TAK 070; tau phosphorylation inhibitors; blockers of Aβ oligomer formation; 5-HT4 agonists, such as PRX-03140; 5-HT6 antagonists, such as GSK 742467, SGS-518, FK- 962, SL- 65.0155, SRA-333 and xaliproden; 5-HT1 a antagonists, such as lecozotan; p25/CDK5 inhibitors; NKl /NK3 receptor antagonists; COX-2 inhibitors; HMG-CoA reductase inhibitors; NSAIDs including ibuprofen; vitamin E; anti-amyloid antibodies (including anti-amyloid humanized monoclonal antibodies), such as bapineuzumab, ACCOOl, CAD 106, AZD3102, Hl 2Al IVl; anti- inflammatory compounds such as (R)-flurbiprofen, nitroflurbiprofen, rosiglitazone, ND- 1251, VP-025, HT-0712 and EHT-202; CB-I receptor antagonists or CB-I receptor inverse agonists, such as AVE 1625; antibiotics such as doxycycline and rifampin; N-methyl-D-aspartate (NMD A) receptor antagonists, such as memantine, neramexane and EVTlOl ; cholinesterase inhibitors such as galantamine, rivastigmine, donepezil, tacrine, phenserine, ladostigil and ABT- 089; growth hormone secretagogues such as ibutamoren, ibutamoren mesylate, and capromorelin; histamine H3 receptor antagonists such as ABT-834, ABT 829, GSK 189254 and CEP 16795; AMPA agonists or AMPA modulators, such as CX-717, LY 451395, LY404187 and S- 18986; PDE IV inhibitors, including MEM1414, HT0712 and AVE8112; GABAA inverse agonists; GSK3β inhibitors, including AZD1080, SAR502250 and CEP16805; neuronal nicotinic agonists; selective Ml agonists; and microtubule affinity regulating kinase (MARK) ligands; or other drugs that affect receptors or enzymes that either increase the efficacy, safety, convenience, or reduce unwanted side effects or toxicity of the compounds of the present invention.

Examples of combinations of the compounds of formula I include combinations with agents for the treatment of pain, for example non-steroidal anti- inflammatory agents, such as aspirin, diclofenac, duflunisal, fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, naproxen, oxaprozin, piroxicam, sulindac and tolmetin; COX-2 inhibitors, such as celecoxib, rofecoxib, valdecoxib, 406381 and 644784; CB-2 agonists, such as 842166 and SAB378; VR-I antagonists, such as AMG517, 705498, 782443, PAC20030, Vl 14380 and A425619; bradykinin B 1 receptor antagonists, such as SSR240612 and NVPSAA164; sodium channel blockers and antagonists, such as VX409 and SPI860; nitric oxide synthase (NOS) inhibitors (including iNOS and nNOS inhibitors), such as SD6010 and 274150; glycine site antagonists, including lacosamide; neuronal nicotinic agonists, such as ABT 894; NMDA antagonists, such as AZD4282; potassium channel openers; AMPA/kainate receptor antagonists; calcium channel blockers, such as ziconotide and NMED 160; GABA-A receptor IO modulators (e.g., GABA- A receptor agonists); matrix metalloprotease (MMP) inhibitors; thrombolytic agents; opioid analgesics such as codeine, fentanyl, hydromorphone, levorphanol, meperidine, methadone, morphine, oxycodone, oxymorphone, pentazocine, propoxyphene; neutrophil inhibitory factor (NIF); pramipexole, ropinirole; anticholinergics; amantadine; monoamine oxidase B15 ("MAO-B") inhibitors; 5HT receptor agonists or antagonists; mGlu5 antagonists, such as AZD9272; neuronal nicotinic agonists, such as ABT894; NMDA receptor agonists or antagonists, such as AZD4282; NKI antagonists; with antidepressants, including SSRIs and SNRIs such as escitalopram, citalopram, fluoxetine, duloxetine paroxetine, and venlafaxine; tricyclic antidepressant drugs, norepinephrine modulators; lithium; valproate; gabapentin; pregabalin; rizatriptan; zolmitriptan; naratriptan and sumatriptan.

The compounds of the invention may also be administered in combination with compounds useful for enhancing sleep quality and preventing and treating sleep disorders and sleep disturbances, including e.g., sedatives, hypnotics, anxiolytics, antipsychotics, antianxiety agents, antihistamines, benzodiazepines, barbiturates, cyclopyrrolones, orexin antagonists, alpha- 1 antagonists, GABA agonists, 5HT-2 antagonists including 5HT-2A antagonists and 5HT-2A/2C antagonists, histamine antagonists including histamine H3 antagonists, histamine H3 inverse agonists, imidazopyridines, minor tranquilizers, melatonin agonists and antagonists, melatonergic agents, other orexin antagonists, orexin agonists, prokineticin agonists and antagonists, pyrazolopyrimidines, T-type calcium channel antagonists, triazolopyridines, and the like, such as: adinazolam, allobarbital, alonimid, alprazolam, amitriptyline, amobarbital, amoxapine, armodafmil, APD- 125, bentazepam, benzoctamine, brotizolam, bupropion, busprione, butabarbital, butalbital, capromorelin, capuride, carbocloral, chloral betaine, chloral hydrate, chlordiazepoxide, circadin, clomipramine, clonazepam, cloperidone, clorazepate, clorethate, clozapine, conazepam, cyprazepam, desipramine, dexclamol, diazepam, dichloralphenazone, divalproex, diphenhydramine, doxepin, EMD-281014, eplivanserin, estazolam, eszopiclone, ethchlorynol, etomidate, fenobam, flunitrazepam, flurazepam, fluvoxamine, fluoxetine, fosazepam, gaboxadol, glutethimide, halazepam, hydroxyzine, ibutamoren, imipramine, indiplon, lithium, lorazepam, lormetazepam, LY-156735, maprotiline, MDL-100907, mecloqualone, melatonin, mephobarbital, meprobamate, methaqualone, methyprylon, midaflur, midazolam, modafinil, nefazodone, NGD-2-73, nisobamate, nitrazepam, nortriptyline, oxazepam, paraldehyde, paroxetine, pentobarbital, perlapine, perphenazine, phenelzine, phenobarbital, prazepam, promethazine, propofol, pro tripty line, quazepam, ramelteon, reclazepam, roletamide, secobarbital, sertraline, suproclone, TAK-375, temazepam, thioridazine, tiagabine, tracazolate, tranylcypromaine, trazodone, triazolam, trepipam, tricetamide, triclofos, trifluoperazine, trimetozine, trimipramine, uldazepam, venlafaxine, zaleplon, zolazepam, zopiclone, Zolpidem, and salts thereof, and combinations thereof, and the like, or the compound of formula I may be administered in conjunction with the use of physical methods such as with light therapy or electrical stimulation.

The compounds of the invention may also be administered in combination with levodopa (with or without a selective extracerebral decarboxylase inhibitor such as carbidopa or benserazide), anticholinergics such as biperiden (optionally as its hydrochloride or lactate salt) and trihexyphenidyl (benzhexol) hydrochloride, COMT inhibitors such as entacapone, MOA-B inhibitors, antioxidants, A2a adenosine receptor antagonists, cholinergic agonists and dopamine receptor agonists such as alentemol, bromocriptine, fenoldopam, lisuride, naxagolide, pergolide and pramipexole.

The combination therapies of the invention are can be administered adjunctively. By adjunctive administration is meant the concurrent or overlapping administration of each of the components in the form of separate pharmaceutical compositions or devices. This regime of therapeutic administration of two or more therapeutic agents is referred to generally by those skilled in the art and herein as adjunctive therapeutic administration; it is also known as add- on therapeutic administration.

In a further aspect, the invention provides a method of treatment of schizophrenia by adjunctive therapeutic administration of a compound of formula I, or a pharmaceutically acceptable acid addition salt thereof, to a mammal in need thereof receiving therapeutic administration of at least one neuroleptic agent.

In specific embodiments, the present invention provides methods of treating disorders selected from the group consisting of: cognitive disorders (including age-related cognitive disorder, mild cognitive impairment, cognitive impairment associated with schizophrenia, and chemotherapy-induced cognitive impairment), ADHD, mood disorders (including depression, mania, bipolar disorders), psychosis (in particular schizophrenia and schizophreniform disorder), dementia (including Alzheimer's disease, AIDS-induced dementia, vascular dementia, and dementia lacking distinctive histology), Parkinson's disease, Huntington's Chorea, pain (including acute pain and chronic pain), xerostomia (dry mouth), Lewy body disease (including diffuse Lewy body disease), aphasia (including primary aphasia and primary aphasia syndromes), hypotensive syndromes, and chronic colitis (including Crohn's disease), comprising: administering to a mammal an effective amount of a compound of the present invention. That is, the present invention provides for the use of a compound of the present invention or pharmaceutical composition thereof for the treatment disorders associated with muscarinic receptors.

Of the disorders to be treated according to the present invention a number are particularly preferred. Particularly preferred disorders include the treatment of cognitive disorders (particularly mild cognitive impairment and cognitive impairment associated with schizophrenia), Alzheimer's disease, and psychosis, including schizophrenia.

The present invention will be better understood from the Experimental Section that follows. However, one skilled in the art will readily appreciate that the specific methods and results discussed therein are merely illustrative of the invention as described more fully in the claims that follow thereafter.

Experimental Section

General Methods

LC-MS, general: Solvent system: A = water/TFA (100:0.05) and B = water/acetonitrile/TFA (5:95:0.035). Retention times (RT) are expressed in minutes. MS instruments are from PESciex (API), equipped with APPI-source and operated in positive ion mode.

Method A: API 150EX and Shimadzu LCIOAD/SLC-IOA LC system. Column: 30 x 4.6 mm Waters Atlantis dC18 with 3 μM particles operated at 40 °C. Linear Gradient elution with 2% B to 100% B in 2.4 min and a flow rate of 3.3 ml/min. Method B: API 150EX and Shimadzu LC8/SLC-10A LC system. Column: 30 x 4.6 mm Waters Symmetry Cl 8 with 3.5 μM particles operated at 60 °C. Linear Gradient elution with 10% B to 100% B in 2.4 min and a flow rate of 3.3 ml/min.

SFC: Preparative SFC was performed on a Berger Multigram II system.

¹H NMR spectra were recorded at 500.13 MHz on a Bruker Avance AV500 instrument or at 250.13 MHz on a Bruker Avance DPX250 instrument. TMS was used as internal reference standard. Chemical shift values are expressed in ppm. The following abbreviations are used for multiplicity of NMR signals: s = singlet, d = doublet, t = triplet, q = quartet, qui = quintet, h = heptet, dd = double doublet, dt = double triplet, dq = double quartet, tt = triplet of triplets, m = multiplet, br s = broad singlet and br = broad signal.

Preparation of the compounds of the invention

The compounds of the invention may be prepared by the following general methods:

Reaction of a compound of formula II

II wherein Rl - R3 are as defined above, with a compound of formula III

wherein A and G are as defined above,

in the presence of a suitable reducing agent, such as sodium triacetoxy borohydride, in a suitable solvent, such as 1,2-DCE or THF, at a suitable temperature, such as room temperature, and in the presence or absence of a suitable acid, such as acetic acid.

Compounds of formula II are commercially available or may be prepared by standard procedures known to persons skilled in the art, as outlined below:

Deprotection of a compound of formula IV:

wherein Rl - R3 are as defined above and PG is a suitable protecting group, such as Boc or carbethoxy

Deprotection of compounds of formula IV may be accomplished using standard procedures known to the skilled person, such as treatment with a suitable acid, e.g. HCl or TFA, at a suitable temperature, such as room temperature, and in a suitable solvent, such as ether or methanol or dichloromethane (for Boc removal), or treatment with a suitable base, such as 6M NaOH (aq.), with a suitable co-solvent, such as MeOH, at a suitable temperature, such as reflux temperature (carbethoxy removal).

Compounds of formula IV may be prepared by standard procedures known to the skilled person. These include reaction of compounds of formula V

Wherein R1-R3 and PG are as defined above, with a suitable reagent VI

VI

wherein E and E' are leaving groups, such as chloride or trichloromethoxy or imidazole, and which leaving groups may be the same or different.

The reaction of compounds of formula V with compounds with formula VI may be accomplished using standard procedures known to the skilled person. These include reacting compounds of formula V with carbonyl diimidazole (E = E' = imidazole) in a suitable solvent, such as acetonitrile, at a suitable temperature, such as 20-80 °C; or reacting compounds of formula V with carbonic acid di-trichloromethyl ester "triphosgene" (E=E'= tricholoromethoxy) in a suitable solvent, such as 1,2-DCE, at a suitable temperature, such as 0-40 °C, in the presence of a suitable base, such as DIPEA.

Compounds of formula V may be prepared by standard procedures known to the skilled person. These include reduction of compounds of formula VII

wherein R1-R3 and PG are as defined above. The reduction of compounds of formula VII may be accomplished using standard procedures known to the skilled person. These include a reaction with hydrogen gas in the presence of a suitable catalyst, such as Pd, on charcoal in a suitable solvent, such as ethanol.

Compounds of formula VII may be prepared by standard procedures known to the skilled person. These include a) Reaction of compounds of formula VIII

wherein R1-R3 are as defined above. with a compound IX

IX wherein PG is a suitable protecting group, such as Boc or carbethoxy

Compounds of formula VIII are commercially available or may be prepared according to literature procedures.

Compounds with formula IX are commercially available.

Compounds of formula III were commercially available or may be prepared according to standard procedures known to the person skilled in the art, such as

a) oxidation of a compound with formula X

X

wherein A = O, and G is as described above.

Oxidation of a compound of formula X may be performed by standard procedures known to the skilled person, including reaction with a suitable oxidant, such as IBX, in a suitable solvent, such as THF or acetone, at a suitable temperature, such as reflux temperature, or in DMSO, at a suitable temperature, such as room temperature. Alternatively, oxidation of a compound of formula X may be accomplished by reaction with DMSO and oxalyl chloride in a suitable solvent, such as CH₂Cl₂, in the presence of a suitable base, such as DIPEA, and at a suitable temperature, such as -78 °C.

b) reduction of a compound of formula XI

XI wherein A = O, and G is as defined above.

Reduction of a compound of formula XI may be performed by standard procedures known to the skilled person, including hydrogenation in the presence of a suitable catalyst, such as Pd, on charcoal in a suitable solvent, such as ethanol, at a suitable temperature, such as between 15 and 70 °C.

Compounds with of formula X wherein A = O may be prepared according to standard procedures known to the person skilled in the art, such as

a) reaction of a compound XII

XII wherein G is as described above,

with 3-butenol in the presence of a suitable acid, such as concentrated sulfuric acid, at a suitable temperature, such as a temperature between 0°C and 30°C. b) saponification of a compound of formula XIII

XIII

wherein A = O and G is as described above

Saponification of compounds of formula XIII may be achieved according to standard procedures known to the person skilled in the art, such as reaction of compounds of formula XIII with a suitable base, such as LiOH, in a suitable solvent, such as MeOH, at a suitable temperature, such as a temperature between room temperature and reflux temperature.

Compounds of formula XIII me be prepared according to standard procedures known to the person skilled in the art, such as reaction of a compound XII as defined above with 3-butenol, in the presence of a suitable acid, such as trifluoroacetic acid, in a suitable solvent, such as 1,2-DCE, at a suitable temperature, such as room temperature.

Examples Preparation of intermediates

Preparation of the intermediates with structure II

The intermediates with structure II were either commercially available or synthesised according to procedures listed below.

The following intermediates with structure II can be prepared as described in WO2007/036711 : 1 : 6-Fluoro- 1 -prperidin-4-yl- 1 ,3-dihydro-benzoimidazol-2-one

2: 6-Methoxy- 1 -piperidin-4-yl- 1 ,3-dihydro-benzoimidazol-2-one

3 : 5-Fluoro- 1 -piperidin-4-yl- 1 ,3-dihydro-benzoimidazol-2-one

Prepared starting from 2,5-difluoro nitrobenzene:

¹H NMR (D₆-DMSO): 1.69 (m, 2H); 2.19 (m, 2H); 2.92 (br, 2H); 4.13 (m, 2H); 4.34 (m, IH); 6.76-6.86 (2H); 7.22 (m, IH); 11.01 (s, IH).

The following intermediate with structure II can be prepared as described in WO2007/036718: 4: 6-Chloro-5-fluoro-l-piperidin-4-yl-l,3-dihydro-benzoimidazol-2-one

4-Fluoro-l-piperidin-4-yl-l,3-dihydro-benzoimidazol-2-one:

5: 4-(3-Fluoro-2-nitro-phenylamino)-piperidine-l-carboxylic acid tert-butyl ester

l,3-Difluoro-2-nitro-benzene (31 mmol) and 4-amino-l-Boc piperidine (31 mmol) were dissolved in DMF (50 rnL) and K2CO3 (50 mmol) was added. The mixture was stirred at 70 °C for 6h, then it was cooled and poured into brine and extracted x3 with ethyl acetate. The combined organic phases were washed x3 with brine, dried on MgSO₄, filtered and evaporated. The crude product was used without further purification.

6: 4-(2-Amino-3-fluoro-phenylamino)-piperidine-l-carboxylic acid tert-butyl ester

4-(3-Fluoro-2-nitro-phenylamino)-piperidine-l-carboxylic acid tert-butyl ester (5) (31 mmol) was dissolved in EtOH (130 mL) and 5% Pd on charcoal (1.3g) was added. The mixture was hydrogenated on a Parr-apparatus under 3 atm. H₂ at room temperature for 5h. The catalyst was removed by filtration through a silica plug and the solvent was removed by evaporation. Yield = 83%

¹H NMR (CDCl₃): 1.50 (s, 9H); 2.04 (m, 2H); 2.97 (m, 2H); 3.34 (m, 2H); 4.06 (m, 2H); 6.43-6.58 (2H); 6.73 (m, IH). 7: 4-(4-Fluoro-2-oxo-2,3-dihydro-benzoimidazol-l-yl)-piperidine-l-carboxylic acid tert-butyl ester

4-(2-Amino-3-fluoro-phenylamino)-piperidine-l-carboxylic acid tert-butyl ester (6) (26 mmol) was dissolved in ethyl acetate (100 rnL) and added DIPEA (57mmol). The mixture was cooled to 0°C and triphosgene (26mmol) was added portion wise. The mixture was allowed to come to ambient temperature and was stirred over night. H₂O (100 mL) was added and the solvent volume was reduced by evaporation. The aqueous phase was extracted x3 with ethyl acetate and the combined organic phases were washed with brine, dried on MgSO₄, filtered and evaporated. Yield = 89%

¹H NMR (D₆-DMSO): 1.44 (s, 9H); 1.71 (m, 2H); 2.20 (m, 2H); 2.88 (m, 2H); 4.13 (m, 2H); 4.36 (m, IH); 6.83-7.10 (3H); 11.43 (s, IH).

8 : 4-Fluoro- 1 -prperidin-4-yl- 1 ,3-dihydro-benzoimidazol-2-one

4-(4-Fluoro-2-oxo-2,3-dihydro-benzoimidazol- 1 -yl)-piperidine- 1 -carboxylic acid tert-butyl ester (7) (23 mmol) was dissolved in MeOH (180 mL) and HCl in ether (2M) (100 mL) was added. Stirred at room temperature for 3h. The solvent was reduced by evaporation and ice water was added (100 mL) NH3 in water (ca.l2M) was added until pH was basic. The aqueous phase was extracted with ethyl acetate x3, the organic fractions were combined, dried on MgSO₄, filtered and evaporated. Yield ca. 100% ¹H NMR (D₆-DMSO): 1.59 (m, 2H); 2.18 (m, 2H); 2.57 (m, 2H); 3.07 (m, 2H); 2.24 (m, IH); 6.82-7.03 (2H); 7.15 (d, IH).

The following can be prepared analogously:

9: 2-Oxo-3-piperidin-4-yl-2,3-dihydro-lH-benzoimidazole-6-carbonitrile

Prepared starting from 3-fluoro-4-nitro-benzonitrile.

¹H NMR (D₆-DMSO): 1.67 (m, 2H); 2.28 (m, 2H); 2.65 (m, 2H); 3.14 (m, 2H); 4.35 (m, IH); 7.19 (d, IH); 7.51 (d, IH); 7.87 (s, IH).

10: 5-Chloro-l-piperidin-4-yl-l,3-dihydro-benzoimidazol-2-one

Prepared starting from 5-chloro-2-fluoro nitrobenzene 1H NMR (D₆-DMSO): 1.59 (m, 2H); 2.16 (m, 2H); 2.57 (m, 2H); 3.07 (m, 2H); 4.22 (s, IH); 6.98-7.06 (2H); 7.30 (d, IH).

Preparation of the intermediates with structure III

2-Phenyl-tetrahydro-pyran-4-one 11 : 2-Phenyl-tetrahydro-pyran-4-ol

Sulfuric acid (14 rnL) was added to a cooled (5 °C) mixture of 3-butenol (277 mmol) and benzaldehyde (141 mmol) (neat) and the mixture was stirred for 16 hours, during which time it was allowed to warm to room temperature. The mixture was poured onto crushed ice, neutralized by the addition of solid sodium bicarbonate and extracted with diethyl ether x2. The organic phases were combined, dried over Na₂SO₄, filtered and concentrated in vacuo. The oily residue was suspended in water and solid sodium sulfite was added to the point of saturation. The mixture was stirred at room temperature for 30 min, and extracted with diethyl ether x2. The organic phases were then combined, dried over Na₂SO₄, filtered and concentrated in vacuo. The product was purified by flash chromatography on silica gel using 50% ethyl acetate in petroleum ether as eluent. Yield = 60%

12 : 2-Phenyl-tetrahydro-pyran-4-one

DMSO (615 mmol) was added dropwise into a solution of (COCl)₂ (128 mmol) in CH₂Cl₂

(100 mL) at -78 ⁰C. The mixture was stirred at -78 ⁰C for 15 min, then 2-phenyl-tetrahydro- pyran-4-ol (11) (84 mmol) in CH₂Cl₂ (50 mL) was added dropwise. The mixture was stirred at -78 ⁰C for 30 min, then DIPEA (78 mL) was added dropwise at -78 ⁰C and the resulting mixture was stirred for additional 3h. Water (100 mL) and CH₂Cl₂ (200 mL) were added, and the reaction mixture was stirred at room temperature for 15 min. The layers were separated and the organic fraction was washed with water x2, dried with Na₂SO₄ and concentrated in vacuo. The product was purified by flash chromatography on silica gel using 50% ethyl acetate in petroleum ether as eluent to give the title compound. Yield = 72%

¹H NMR (D₆-DMSO): 2.44 (IH, d); 2.65 (IH, m); 2.66 (IH, t); 2.74 (IH, m); 3.85 (IH, dt); 4.44 (IH, m); 4.65 (IH, dd); 7.40-7.30 (m, 5H). The racemic 2-phenyl-tetrahydro-pyran-4-one was separated into the two enantiomers by preparative chiral SFC:

Method: Column: 250 x 21.2 mm Chiralcel OD-H with 5 μm particles operated at 40⁰C. Chromatography was carried out using 25% of 0.1% (v/v) diethylamine in isopropanol as modifier, a pressure of 120 bar and a flow rate 50 ml/min. Detection at 254 nm.

Upon evaporation of combined fractions containing a single enantiomer the enantiomeric excess was measured by analytical chiral SFC. Method: Column: 250 x 4.6 mm Chiralcel OD-H with 5 μm particles operated at 40⁰C. Chromatography was carried out using 20% of 0.1% (v/v) diethylamine in isopropanol as modifier, a pressure of 200 bar and a flow rate 3 ml/min. Detection at 210 nm.

This furnished: 13 : (5V2-Phenyl-tetrahydro-pyran-4-one ee > 97%, [α]_D = - 73.4° (C = 1.5, CHCl₃)

14 : (i?)-2-Phenyl-tetrahydro-pyran-4-one ee > 97%.

2-Pyridin-2-yl-tetrahydro-pyran-4-one

15: Trifluoro-acetic acid 2-pyridin-2-yl-tetrahydro-pyran-4-yl ester

2-pyridin-carboxaldehyde (43 mmol) was dissolved in 1,2-DCE (150 mL) and TFA (60 mL) was added followed by 3-butene-l-ol (43 mmol). The reaction mixture was stirred over night at room temperature, then it was poured into ice waster, the mixture was basicified with NaOH (2M). The phases were separated, and the aqueous phase was extracted x2 with ethyl acetate. The combined organic fractions were combined, dried on MgSO₄, filtered and the solvent removed by evaporation. The crude product was purified by chromatography on silica using 80% ethyl acetate in heptane as eluent. Yield = 11% 16: 2-Pyridin-2-yl-tetrahydro-pyran-4-ol

Trifluoro-acetic acid 2-pyridin-2-yl-tetrahydro-pyran-4-yl ester (15) (13 mmol) was dissolved in MeOH (100 mL) and LiOH (65 mmol) was added. Stirred at room temperature over night, then the solvent was removed by evaporation. Purified by chromatography on silica gel using ethyl acetate containing 5 v% triethylamine as eluent. Yield ca. 100 %

17: 2-Pyridin-2-yl-tetrahydro-pyran-4-one

2-Pyridin-2-yl-tetrahydro-pyran-4-ol (16) (14 mmol) was dissolved in THF (40 mL) and IBX

(14 mmol) was added. Re fluxed for 4h, then the reaction mixture was filtered and the solvent was removed in vacuo. The crude was purified by chromatography on silica using 80 % ethyl acetate in heptane containing 4 v% triethylamine as eluent. Yield = 59%

¹H NMR (CDCl₃): 2.42 (m, IH); 2.64-2.80 (3H); 3.87 (m, IH); 4.43 (m, IH); 4.74 (m , IH); 7.22 (m, IH); 7.45 (d, IH); 7.71 (dt, IH); 8.57 (m, IH).

The following may be prepared analogously: 18: 2-Pyridin-3-yl-tetrahvdro-pyran-4-one

Prepared starting from 3-pyridin-carboxaldehyde:

¹H NMR (D₆-DMSO): 2.46 (m, IH); 2.58-2.83 (3H); 3.87 (m, IH); 4.46 (m, IH); 4.71 (m, IH); 7.32 (m, IH); 7.26 (m, IH); 8.58 (m, IH); 8.63 (m, IH).

General procedures for the preparation of compounds of formula I

Examples:

19: l-[l-(2-Phenyl-tetrahvdro-pyran-4-yl)-piperidin-4-yll-l,3-dihydro-benzoimidazol-2-one

A solution of 2-phenyl-tetrahydro-pyran-4-one (12) (0.04 mmol) in 1,2-DCE (1 rnL) and acetic acid (0.12 mmol) was added to a mixture of l-piperidin-4-yl-l,3-dihydro- benzoimidazol-2-one (0.12 mmol) and NaBH(OAc)₃ (0.08 mmol).

The reaction was shaken over night at room temperature. MeOH (200 μL) was added and the mixture was shaken for 120 min. and concentrated by evaporation. The residue was dissolved in DMSO (200 μL) and purified by prep-LC-MS.

The purified fractions were combined and evaporated, then re-dissolved in MeOH (200 μL) and purified on an SCX column (The column was conditioned with 10% AcOH in MeOH). The solution of the compound in MeOH was added. The column was washed with MeOH and AcCN, and finally the product was eluted with 4M NH₃ in MeOH and evaporated. LC/MS: m/z = 378.6 (MH+); retention time = 1.05, method A

The following were prepared analogously:

20: 6-Methoxy- 1 -[ 1 -(2-phenyl-tetrahydro-pyran-4-yl)-piperidin-4-yll- 1 ,3-dihydro- benzoimidazo 1-2-one

Prepared from compounds 2 and 12

LC/MS: m/z = 408.4 (MH+); retention time = 1.06, method A

21 : β-Chloro-S-fluoro- 1 -[ 1 -(2-phenyl-tetrahydro-pyran-4-yl)-piperidin-4-yll- 1 ,3-dihydro- benzoimidazo 1-2-one

Prepared from compound 4 and 12

LC/MS: m/z = 430.1 (MH+); retention time = 1.21, method A 22: 4-Fluoro- 1 -[ 1 -(2-phenyl-tetrahydro-pyran-4-yl)-piperidin-4-yl^"|- 1 ,3-dihydro- benzoimidazol-2-one

Prepared from compound 8 and 12

LC/MS: m/z = 396.2 (MH+); retention time = 1.06, method A

23 : 2-Oxo-3-[ 1 -(2-phenyl-tetrahydro-pyran-4-yl)-piperidin-4-yll-2,3-dihydro- IH- benzoimidazo le-5 -carbonitrile

Prepared from compound 9 and 12

LC/MS: m/z = 403.3 (MH+); retention time = 1.06, method A

24: 6-Fluoro- 1 -[ 1 -(2-phenyl-tetrahydro-pyran-4-yl)-piperidin-4-yll- 1 ,3-dihydro- benzoimidazol-2-one

Prepared from compound 1 and 12

LC/MS: m/z = 396.3 (MH+); retention time = 1.09, method A

25: 5-Fluoro- 1 -[ 1 -(2-phenyl-tetrahydro-pyran-4-yl)-piperidin-4-yl^"|- 1 ,3-dihydro- benzoimidazol-2-one

Prepared from compound 3 and 12

LC/MS: m/z = 396.2 (MH+); retention time = 1.08, method A

26: 5-Chloro-l-[l-(2-phenyl-tetrahydro-pyran-4-yl)-piperidin-4-yll-l,3-dihydro- benzoimidazol-2-one

Prepared from compound 10 and 12

LC/MS: m/z = 412.4 (MH+); retention time = 1.17, method A 27: (2SAR)- 1 -\ l-(2-Phenyl-tetrahvdro-pyran-4-yl)-piperidin-4-yl1- 1.3-dihydro- benzoimidazo 1-2-one

l-Piperidin-4-yl-l,3-dihydro-benzoimidazo 1-2-one (2.7 mmol) and compound 13 were dissolved in THF (40 mL), and sodium triacetoxyborohydride (4.5 mmol) was added along with glacial acetic acid (6.8 mmol). The reaction mixture was stirred over night at room temperature. At this point, di-tertbutyl dicarbonate (2.3 mmol) was added followed by 15% NaOH (aq., 2 mL). Stirring was continued for 15 min., then H₂O (5 mL) and ethyl acetate (25 mL) was added. The volume was reduced to ca. 20 mL under reduced pressure, undissolved solids were removed by filtration, washed with ethyl acetate and dried. Yield = 35%

LC/MS: m/z = 378.6 (MH+); retention time = 1.03, method A

The following were prepared by analogous procedures:

28: l-ri-((2R.4S)-2-Phenyl-tetrahvdro-pyran-4-yl)-piperidin-4-yl1-1.3-dihvdro- benzoimidazo 1-2-one

Prepared from l-piperidin-4-yl-l,3-dihydro-benzoimidazo 1-2-one and compound 14 LC/MS: m/z = 378.6 (MH+); retention time = 0.72, method B 29: l-ri-(2-Pyridin-3-yl-tetrahvdro-pyran-4-yl)-piperidin-4-yll-l,3-dihydro-benzoimidazol-2- one

Prepared from l-piperidin-4-yl-l,3-dihydro-benzoimidazol-2-one and compound 18 LC/MS: m/z = 379.5 (MH+); retention time = 0.66, method A

30: 1 -[ 1 -(2-Pyridin-2-yl-tetrahydro-pyran-4-yl)-piperidin-4-yll- 1 ,3-dihydro-benzoimidazol-2- one

Prepared from l-piperidin-4-yl-l,3-dihydro-benzoimidazol-2-one and compound 17 LC/MS: m/z = 379.5 (MH+); retention time 0.70, method A

31: l-ri-(3-Phenyl-cvclohexyl)-piperidin-4-yll-l,3-dihydro-benzoimidazol-2-one

Prepared from l-piperidin-4-yl-l,3-dihydro-benzoimidazol-2-one and 2-phenyl cyclohexanone.

LC/MS: m/z = 376.4 (MH+); retention time = 1.16, method A

32: 6-Fluoro- 1 -I^" 1 -(3-phenyl-cvclohexyl)-piperidin-4-yll- 1 ,3-dihydro-benzoimidazol-2-one

Prepared from compound 1 and 2-phenyl cyclohexanone. LC/MS: m/z = 394.5 (MH+); retention time =1.29, method A

33 : 5-Fluoro- 1 -I^" 1 -(3-phenyl-cvclohexyl)-piperidin-4-yll- 1 ,3-dihydro-benzoimidazol-2-one

Prepared from compound 3 and 2-phenyl cyclohexanone. LC/MS: m/z = 394.5 (MH+); retention time = 1.28, method A 34: 5-Chloro-l-ri-(3-phenyl-cvclohexyl)-piperidin-4-yll-l,3-dihydro-benzoimidazol-2-one

Prepared from compound 10 and 2-phenyl cyclohexanone. LC/MS: m/z = 410.5 (MH+); retention time = 1.35, method A

35: 6-Methoxy- 1 -I^" 1 -(3-phenyl-cvclohexyl)-piperidin-4-yll- 1 ,3-dihydro-benzoimidazol-2-one

Prepared from compound 2 and 2-phenyl cyclohexanone. LC/MS: m/z = 406.7 (MH+); retention time 1.26, method A

36: ό-Chloro-S-fluoro- 1 -[ 1 -(3-phenyl-cyclohexyl)-piperidin-4-yll- 1 ,3-dihydro- benzoimidazol-2-one

Prepared from compound 4 and 2-phenyl cyclohexanone. LC/MS: m/z = 428.2 (MH+); retention time = 1.38, method A

Abbreviations:

Boc = tert-butyi carbonyloxy DMF = dimethyl formamid

DIPEA = Diisopropyl-ethyl amine DMSO = dimethylsulfoxide TFA = trifluoroacetic acid THF = tetrahydrofuran IBX = l-hydroxy-l,2-benziodoxol-3(lH)-one 1-oxide 1 ,2-DCE = 1 ,2-dichloroethane SFC = supercritical fluid chromatography SCX = strong cation exchange

Reagents used for the preparation of compounds 1-36

Name CAS no. Supplier Catalog no.

3-Fluoro-4-nitrobenzonitrile 218632-01-0 3B-Medical 3B-2884 2-Chloro-6-fluoronitrobenzene 64182-61-2 3B-Medical 3B-3442

Pharmacological Testing

Calcium²⁺ flux assay for human Ml-mACh receptor stably expressed in CHO-Kl cells. A. Stable cell lines.

Standard molecular cloning techniques (Maniatis et al. Molecular Cloning, A Laboratory

Manual (1989)) were used to generate a cell line of Chinese hamster ovary (CHO-Kl) cells stably expressing human muscarinic Ml receptor (Ml-mAChR). The cDNA encoding the Ml-mAChR corresponds to the sequence published in NCBI Genbank Nucleotide database, accession number Y00508. The cell line was grown in F-12 Kaighn's medium with L- Glutamine (Gibco), 10% FetalClone I serum (HyClone), 1% penicillin and streptavidine, and 0.5 μg/ml G418 (Gibco). B. Methods

CHO-Kl cells stably expressing human Ml-mAChR receptor were plated in growth medium at a density of 18.000 cells/well in clear-bottomed, cell-culture coated 96-well plates (Corning, Costar #3904) and grown for 48 hrs at 37°C in the presence of 5% CO₂. Before assay, the cells were washed with 2x100 μl of assay buffer (Hanks' balanced salt solution with Ca²⁺ and Mg²⁺(Gibco) containing 20 mM HEPES, pH 7.4. The cells were incubated with a calcium-sensitive fluorescent dye, Calcium assay kit R8033 (100 μl /well, half concentration relative to manufacturers instruction, Molecular Devices Inc) with 2.5 mM Probenecid (Sigma) for 50 minutes at 37°C and followed by 10 min at room temperature. Calcium flux was measured using a CellLux Cellular Fluorescence Workstation, a fluorometric plate reader (PerkinElmer Inc). The cells are excited by 480 nm light and emitted fluorescent light passed through an emission filter and detected by a CCD camera. The CellLux apparatus allows multiple liquid additions by computer-controlled liquid-handling hardware. Test compounds were diluted from 2 mM stock solutions in 100% DMSO in assay buffer, and then added to cells (25 μl to 100 μl in well). 10 different concentrations were tested for each compound. Fluorescence readout was measured for 5 minutes starting just prior to compound addition.

C. Data analysis

The fluorescence readout was calculated as max-min response, i.e. maximum fluorescence reading after and before liquid addition. The fluorescence max-min data were normalized to yield responses for no stimulation (buffer) and full stimulation (1 μM acetylcholine) of 0% and 100% stimulation, respectively. Data were collected from at least three independent experiments. Concentration-response data were fitted to the four-parameter logistic equation to estimate compound potency (EC50) and efficacy (E_max) (Motulsky and Christopoulos, 2004).

Harvey Motulsky, Arthur Christopoulos, Fitting Models to Biological Data Using Linear and Nonlinear Regression (A Practical Guide to Curve Fitting), ISBN: 0195171802, Oxford University, 2004.

Results of the experiments showed that the majority of the compounds of the invention had EC50 values of <50nM, many compounds <20nM and some had EC50 values <10nM. The majority of the tested compounds furthermore afforded E_max stimulation values of >80%, many even >95%.

Claims

1. A Compound of Formula I

wherein

A is selected from CH₂ and O;

G is a phenyl, optionally substituted with one or two substituents individually selected from a Ci_6 alkyl group, such as methyl, a Ci_6 alkoxy group, such as methoxy, or a halogen atom, such as F or Cl,

or G is a 2- or 3-pyridyl group,

Rl and R3 are independently selected from H, cyano, halogen, such as F or Cl, and Ci_6 alkoxy, such as methoxy,

R2 is selected from H and halogen, such as F or Cl,

2. The compound according to claim 1, in which A is O.

3. The compound according to claim 1, in which A is CH₂.

4. The compound according to any one of claims 1-3, in which G is phenyl.

5. The compound according to any one of claims 1-3, in which G is pyrid-2-yl.

6. The compound according to any one of claims 1-3, in which G is pyrid-3-yl.

7. The compound according to any one of 1-6, wherein Rl, R2 and R3 are all hydrogen.

8. The compound according to any one of 1-6, wherein at least one of Rl, R2 and R3 is not hydrogen.

9. The compound of any one of the claims 1-6, wherein at least one of Rl, R2 and R3 is halogen, such as F and Cl.

10. The compound according to any one of claims 1-6, wherein R3 is Ci_6 alkoxy, such as methoxy.

11. The compound according to any one of claims 1-6, wherein R3 is cyano.

12. The compound according to any one of claims 1-6, wherein R2 and R3 are both halogen, such as F and Cl.

13. The compound according to any one of the preceding claims, wherein at least one of Rl, R2 and R3 is hydrogen.

14. The compound according to claim 1, wherein the compound is selected from:

1 -[ 1 -(2-Phenyl-tetrahydro-pyran-4-yl)-piperidin-4-yl]- 1 ,3-dihydro-benzoimidazol-2-one 6-Methoxy- 1 -[ 1 -(2-phenyl-tetrahydro-pyran-4-yl)-piperidin-4-yl]- 1 ,3-dihydro-benzoimidazol- 2-one

1 -[ 1 -(3-Phenyl-cyclohexyl)-piperidin-4-yl]- 1 ,3-dihydro-benzoimidazol-2-one

2-Oxo-3-[l-(2-phenyl-tetrahydro-pyran-4-yl)-piperidin-4-yl]-2,3-dihydro-lH- benzoimidazo le-5 -carbonitrile

1 -[ 1 -(2-Pyridin-3-yl-tetrahydro-pyran-4-yl)-piperidin-4-yl]- 1 ,3-dihydro-benzoimidazol-2-one 6-Fluoro- 1-[ 1 -(3-phenyl-cyclohexyl)-piperidin-4-yl]- 1 ,3-dihydro-benzoimidazol-2-one

6-Chloro-5-fluoro- 1-[ 1 -(3-phenyl-cyclohexyl)-piperidin-4-yl]- 1 ,3-dihydro-benzoimidazol-2- one

6-Methoxy- 1 -[ 1 -(2-pyridin-2-yl-tetrahydro-pyran-4-yl)-piperidin-4-yl]- 1 ,3-dihydro- benzoimidazol-2-one

6-Methoxy- 1 -[ 1 -(2-pyridin-3-yl-tetrahydro-pyran-4-yl)-piperidin-4-yl]- 1 ,3-dihydro- benzoimidazol-2-one, and

or a pharmaceutically acceptable acid addition salt thereof.

15. A compound according to any one of claims 1 to 14, for use as a medicament.

16. A compound according to any one of claims 1 to 14, alone or in combination with one or more neuroleptic agents, for use in the treatment of schizophrenia.

17. A compound according to any one of claims 1 to 14, for use in the treatment of cognitive impairment, such as mild cognitive impairment and cognitive impairment associated with schizophrenia.

18. A compound according to any one of claims 1 to 14, for use in the treatment of cognitive impairment associated with a psychiatric disorder such as schizophrenia, for example of the paranoid, disorganized, catatonic, undifferentiated, or residual type; schizophreniform disorder; schizoaffective disorder, for example of the delusional type or the depressive type; affective disorders such as depression or anxiety, sleep disturbances, migraine, neuroleptic-induced parkinsonism, abuse disorders such as cocaine abuse, nicotine abuse, and alcohol abuse, bipolar disorder, delusional disorder; substance-induced psychotic disorder, for example psychosis induced by alcohol, amphetamine, cannabis, cocaine, hallucinogens, inhalants, opioids, or phencyclidine; personality disorder of the paranoid type; and personality disorder of the schizoid type; and anxiety disorder selected from panic disorder; agoraphobia; a specific phobia; social phobia; obsessive-compulsive disorder; post-traumatic stress disorder; acute stress disorder; and generalized anxiety disorder.

19. A compound according to any one of claims 1 to 14, for use in the treatment of cognitive impairment associated with a cognition disorder such as Alzheimer's disease, multi-infarct dementia, alcoholic dementia or other drug-related dementia, dementia associated with intracranial tumors or cerebral trauma, dementia associated with Huntington's disease or Parkinson's disease, or AIDS-related dementia; attention deficits, delirium; amnestic disorder; post-traumatic stress disorder; mental retardation; a learning disorder, for example reading disorder, mathematics disorder, or a disorder of written expression; attention-deficit/hyperactivity disorder (ADHD); and memory impairment such as age associated memory impairment.

20. Use of a compound according to any one of claims 1 to 14, for the manufacture of a medicament for the treatment of cognitive impairment, such as mild cognitive impairment and cognitive impairment associated with schizophrenia.

21. Use of a compound according to any one of claims 1 to 14, for the manufacture of a medicament for the treatment of schizophrenia.

22. Use of a compound according to any one of claims 1 to 14, for the manufacture of a medicament for the treatment of cognitive impairment associated with a condition or disease selected from the group consisting of a psychiatric disorder such as schizophrenia, for example of the paranoid, disorganized, catatonic, undifferentiated, or residual type; schizophreniform disorder; schizoaffective disorder, for example of the delusional type or the depressive type; affective disorders such as depression or anxiety, sleep disturbances, migraine, neuroleptic-induced parkinsonism, abuse disorders such as cocaine abuse, nicotine abuse, and alcohol abuse, bipolar disorder, delusional disorder; substance- induced psychotic disorder, for example psychosis induced by alcohol, amphetamine, cannabis, cocaine, hallucinogens, inhalants, opioids, or phencyclidine; personality disorder of the paranoid type; and personality disorder of the schizoid type; and anxiety disorder selected from panic disorder; agoraphobia; a specific phobia; social phobia; obsessive-compulsive disorder; post-traumatic stress disorder; acute stress disorder; and generalized anxiety disorder.

23. Use of a compound according to any one of claims 1 to 14, for the manufacture of a medicament for the treatment of cognitive impairment associated with a condition or disease selected from the group consisting of a cognition disorder such as Alzheimer's disease, multi- infarct dementia, alcoholic dementia or other drug-related dementia, dementia associated with intracranial tumors or cerebral trauma, dementia associated with Huntington's disease or Parkinson's disease, or AIDS-related dementia; attention deficits, delirium; amnestic disorder; post-traumatic stress disorder; mental retardation; a learning disorder, for example reading disorder, mathematics disorder, or a disorder of written expression; attention-deficit/hyperactivity disorder (ADHD); and memory impairment such as age associated memory impairment.

24. A method of treating a mammal suffering from schizophrenia, comprising administering a therapeutically effective amount of a compound of formula I as defined in any one of claims 1 to 14.

25. The method according to claim 24 wherein the compound of formula I is co-administered with a neuroleptic agent such as sertindole, olanzapine, risperidone, quetiapine, aripiprazole, haloperidol, clozapine, ziprasidone and osanetant.

26. A method of treating a mammal suffering from cognitive impairment, such as mild cognitive impairment and cognitive impairment associated with schizophrenia, which method comprises administering an effective amount of a compound according to any one of claims 1 to 14, or a pharmaceutically acceptable acid addition salt thereof.

27. A method of treating a mammal suffering from cognitive impairment associated with a condition or disease selected from the group consisting of a psychiatric disorder such as schizophrenia, for example of the paranoid, disorganized, catatonic, undifferentiated, or residual type; schizophreniform disorder; schizoaffective disorder, for example of the delusional type or the depressive type; affective disorders such as depression or anxiety, sleep disturbances, migraine, neuroleptic-induced parkinsonism, abuse disorders such as cocaine abuse, nicotine abuse, and alcohol abuse, bipolar disorder, delusional disorder; substance-induced psychotic disorder, for example psychosis induced by alcohol, amphetamine, cannabis, cocaine, hallucinogens, inhalants, opioids, or phencyclidine; personality disorder of the paranoid type; and personality disorder of the schizoid type; and anxiety disorder selected from panic disorder; agoraphobia; a specific phobia; social phobia; obsessive-compulsive disorder; post-traumatic stress disorder; acute stress disorder; and generalized anxiety disorder, which method comprises administering an effective amount of a compound according to any one of claims 1 to 14, or a pharmaceutically acceptable acid addition salt thereof.

28. A method of treating a mammal suffering from cognitive impairment associated with a condition or disease selected from the group consisting of a cognition disorder such as Alzheimer's disease, multi-infarct dementia, alcoholic dementia or other drug-related dementia, dementia associated with intracranial tumors or cerebral trauma, dementia associated with Huntington's disease or Parkinson's disease, or AIDS-related dementia; attention deficits, delirium; amnestic disorder; post-traumatic stress disorder; mental retardation; a learning disorder, for example reading disorder, mathematics disorder, or a disorder of written expression; attention-deficit/hyperactivity disorder (ADHD); and memory impairment such as age associated memory impairment, which method comprises administering an effective amount of a compound according to any one of claims 1 to 14, or a pharmaceutically acceptable acid addition salt thereof.

29. A pharmaceutical composition comprising a therapeutically effective amount of a compound as defined in any one of claims 1 to 14 and one or more pharmaceutically acceptable carriers, diluents and excipients.