WO2008119721A1

WO2008119721A1 - Compounds which have activity at m1 receptor and their uses in medicine

Info

Publication number: WO2008119721A1
Application number: PCT/EP2008/053601
Authority: WO
Inventors: Ian Thomson Forbes
Original assignee: Glaxo Group Limited
Priority date: 2007-03-29
Filing date: 2008-03-27
Publication date: 2008-10-09
Also published as: GB0706167D0; AR065864A1; PE20090553A1; TW200901979A; CL2008000865A1

Abstract

Compounds of formula (I) or a salt thereof are provided: (I) wherein R4, R5, R6, Q, n and R are as defined in the description. Uses of the compounds as medicaments and in the manufacture of medicaments for treating psychotic disorders and cognitive impairments are disclosed. The invention further discloses pharmaceutical compositions comprising the compounds.

Description

Compounds which have activity at M₁ receptor and their uses in medicine

This invention relates to novel compounds, pharmaceutical compositions containing them and their use in therapy, in particular as antipsychotic agents.

Muscarinic acetylcholine receptors are members of the G protein coupled receptor superfamily which mediate the actions of the neurotransmitter acetylcholine in both the central and peripheral nervous system. Five muscarinic receptor subtypes have been cloned, M₁ to M₅. The muscarinic M₁ receptor is predominantly expressed in the cerebral cortex and hippocampus, although it is also expressed in the periphery e.g. exocrine glands.

Muscarinic receptors in the central nervous system, especially M₁, play a critical role in mediating higher cognitive processing. Diseases associated with cognitive impairments, such as Alzheimer's disease, are 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 acetylcholinesterase inhibitors to prevent the breakdown of endogenous acetylcholine. These compounds have shown efficacy versus symptomatic cognitive decline in the clinic, but give rise to side effects resulting from stimulation of peripheral muscarinic receptors including disturbed gastrointestinal motility and nausea.

The dopamine hypothesis of schizophrenia suggests that excess dopaminergic stimulation is responsible for the positive symptoms of the disease, hence the utility of dopamine receptor antagonists to reduce psychotic symptoms. However, conventional dopamine receptor antagonists can cause extrapyramidal side effects (EPS) in patients, including tremor and tardive dyskinesias.

M₁ receptor agonists have been sought for the symptomatic treatment of cognitive decline. More recently, a number of groups have shown that muscarinic receptor agonists display an atypical antipsychotic-like profile in a range of pre-clinical paradigms. The muscarinic agonist, xanomeline, reverses a number of dopamine driven behaviours, including amphetamine induced locomotion in rats, apomorphine induced climbing in mice, dopamine agonist driven turning in unilateral 6-OH-DA lesioned rats and amphetamine- induced motor unrest in monkeys (without EPS liability). It also has been shown to inhibit A10, but not A9, dopamine cell firing and conditioned avoidance and induces c-fos expression in prefrontal cortex and nucleus accumbens, but not in striatum in rats. These data are all suggestive of an atypical antipsychotic-like profile. Xanomeline has also been shown to reduce psychotic symptoms such as suspiciousness, hallucinations and delusions in Alzheimer's patients. However, the relatively non-selective nature of the compound gives rise to dose-limiting peripheral cholinergic side effects.

Certain M₁ receptor agonists are known, for example in WO2007/036718, WO2007/036715, WO2007/03671 1 , WO2007/107566, WO2007/107567 and WO2007/107565. We have now found a novel group of compounds which are M₁ receptor agonists.

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

(I) wherein: R⁴ is selected from the group consisting of hydrogen and fluoro;

R⁵ is selected from the group consisting of hydrogen, cyano, halogen, C_1-6alkyl (optionally substituted with one or more fluorine atoms), and C_1-6alkoxy (optionally substituted with one or more fluorine atoms);

R⁶ is selected from the group consisting of hydrogen, halogen, cyano, C_1-6alkyl (optionally substituted with one or more fluorine atoms), C_1-6alkylsulfonyl, C_3-6cycloalkyl (optionally substituted with one or more fluorine atoms), and C_1-6alkoxy (optionally substituted with one or more fluorine atoms); n is selected from 2, 3 and 4;

Q is selected from the group consisting of hydrogen and C_1-6alkyl; and R is selected from the group consisting of C_1-6alkyl, C_3-6cycloalkyl, C₃-₆cycloalkylC_1-6alkyl and C₂-₆alkynyl, any alkyl or cycloalkyl group being optionally substituted by one or more fluorine atoms.

As used herein, the term "alkyl" refers to straight or branched hydrocarbon chains containing the specified number of carbon atoms. For example, C_1-6alkyl means a straight or branched alkyl containing at least 1 , and at most 6, carbon atoms. C_1-4alkyl means a straight or branched alkyl containing at least 1 , and at most 4, carbon atoms. C_1-2alkyl means a straight or branched alkyl containing at least 1 , and at most 2, carbon atoms

Examples of C_halky! groups include, but are not limited to, methyl, ethyl, n-propyl, n- butyl, n-pentyl, n-hexyl, isobutyl, isopropyl, t-butyl and 1 ,1-dimethylpropyl. As used herein, the term "alkoxy" refers to a straight or branched alkoxy group containing the specified number of carbon atoms. For example, Ci_-6alkoxy means a straight or branched alkoxy group containing at least 1 , and at most 6, carbon atoms. For example, C_1-4alkoxy means a straight or branched alkoxy group containing at least 1 , and at most 4, carbon atoms. For example, Ci_-2alkoxy means a straight or branched alkoxy group containing at least 1 , and at most 2, carbon atoms. Examples of "C-i-βalkoxy" as used herein include, but are not limited to, methoxy, ethoxy, propoxy, prop-2-oxy, butoxy, but-2- oxy, 1-methylethyl-oxy, 2-methylprop-1-oxy, 2-methylprop-2-oxy, pentoxy or hexyloxy.

As used herein, the term "cycloalkyl" refers to a non-aromatic hydrocarbon ring containing the specified number of carbon atoms. For example, C_3-6cycloalkyl means a non-aromatic carbocyclic ring containing at least three, and at most six, ring carbon atoms. Examples of "Cs-ecycloalkyl" as used herein include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

As used herein, the term "halogen" (or the abbreviated form "halo") refers to the elements fluorine (which may be abbreviated to "fluoro" or "F"), chlorine (which may be abbreviated to "chloro" or "Cl"), bromine (which may be abbreviated to "bromo" or "Br") and iodine (which may be abbreviated to "iodo" or "I"). Examples of halogens are fluorine, chlorine and bromine.

As used herein, the term "alkynyl" refers to a linear or branched hydrocarbon group containing one or more carbon-carbon triple bonds and the specified number of carbon atoms. For example, C₂-6alkynyl means a linear or branched hydrocarbon group containing one or more carbon-carbon triple bonds and at least two, and at most six, carbon atoms. Examples of "C₂-6alkynyl" as used herein include, but are not limited to, include ethynyl, propynyl, butynyl, pentynyl and hexynyl.

As used herein, the term "Ci_-6alkylsulfonyl" refers to a group SO₂-Ci_-6alkyl, wherein Ci- ₆alkyl is as defined above.

As used herein, the term "C_3-6cycloalkylCi.₆alkyr' as used herein refers to a group C_3- ₆cycloalkyl-Ci_-6alkyl wherein C_3-6cycloalkyl and Ci_-6alkyl are as defined above.

As used herein, the term "substituted" refers to substitution with the named substituent or substituents, multiple degrees of substitution being allowed unless otherwise stated. For example, there may be 1 , 2 or 3 substituents on a given substituted group. For example, if R⁵ is a Ci_-6alkyl group, it may be substituted by 1 , 2, 3 or 4 fluoro groups; and if R⁵ is a Ci_-6alkoxy group, it may be substituted by 1 , 2, 3 or 4 fluoro groups. In one embodiment, R⁶ is selected from the group consisting of hydrogen, halogen, cyano, C_1-6alkyl (optionally substituted with one, two or three fluorine atoms), C_1-6alkylsulfonyl, C_3- ₆cycloalkyl (optionally substituted with one, two or three fluorine atoms), and Ci_-6alkoxy (optionally substituted with one, two or three fluorine atoms).

In one embodiment, R⁶ is selected from halo and Ci_-6alkyl.

In one embodiment, R⁶ is selected from halo and C_1-4alkyl.

In one embodiment, R⁶ is selected from halo and

In one embodiment, R⁶ is selected from the group consisting of hydrogen, halogen, cyano, (optionally substituted with one or more fluorine atoms), C-i_-4alkylsulfonyl, C_3- ₆cycloalkyl (optionally substituted with one or more fluorine atoms), and C_1-4alkoxy (opitionally substituted with one or more fluorine atoms).

In one embodiment, R⁶ is selected from the group consisting of hydrogen, halogen, cyano, Ci_-2alkyl (optionally substituted with one, two or three fluorine atoms), Ci_-2alkylsulfonyl, C_3- βcycloalkyl (optionally substituted with one, two or three fluorine atoms), and

(optionally substituted with one, two or three fluorine atoms).

In one embodiment, R⁶ is selected from chloro, fluoro, methyl, methoxy, trifluoromethoxy, cyclopropyl and trifluoromethyl.

In one embodiment, R⁶ is selected from methyl, fluoro, chloro, methoxy and cyclopropyl.

In one embodiment, R⁶ is selected from fluoro, chloro, methyl and methoxy. In one embodiment R⁶ is selected from fluoro and methyl. In one embodiment, R⁶ is methyl. In one embodiment, R⁶ is fluoro.

In one embodiment, R⁵ is selected from the group consisting of hydrogen, cyano, halogen, C_1-6alkyl (optionally substituted with one, two or three fluorine atoms), and C_1-6alkoxy (optionally substituted with one, two or three fluorine atoms).

In one embodiment, R⁵ is selected from the group consisting of hydrogen, cyano, halogen, Ci_-4alkyl (optionally substituted with one or more fluorine atoms), and Ci_-4alkoxy (optionally substituted with one or more fluorine atoms).

In one embodiment, R⁵ is selected from the group consisting of hydrogen, cyano, halogen, (optionally substituted with one, two or three fluorine atoms), and

(optionally substituted with one, two or three fluorine atoms). In one embodiment, R⁵ is selected from H and halogen.

In one embodiment, R⁵ is selected from hydrogen, chloro, bromo, fluoro, methyl, ethyl, methoxy and trifluoromethyl.

In one embodiment, R⁵ is selected from hydrogen, chloro, fluoro and trifluoromethyl.

In one embodiment, R⁵ is selected from hydrogen, chloro and fluoro. In one embodiment, R⁵ is hydrogen.

In one embodiment, R⁴ is hydrogen.

In one embodiment, R⁴ is fluoro.

In an embodiment, Q is selected from hydrogen and C_halky!. In one embodiment, Q is selected from hydrogen and methyl. In one embodiment, Q is hydrogen. In one embodiment, Q is methyl.

In one embodiment, n is 2.

In one embodiment, R is C-i-βalkyl.

In one embodiment, R is Ci_-4alkyl.

In one embodiment, R is selected from methyl and ethyl. In one embodiment, R is methyl. In one embodiment R is ethyl.

In one embodiment, the invention provides a compound of formula (I') or a salt or solvate thereof:

(I¹) wherein:

- R⁴ is selected from the group consisting of hydrogen and fluoro; - R⁵ is selected from the group consisting of hydrogen, cyano, halogen, Ci_-6alkyl, Ci_-6alkyl substituted with one or more fluorine atoms, C_1-6alkoxy, and C_1-6alkoxy substituted with one or more fluorine atoms;

- R⁶ is selected from the group consisting of hydrogen, halogen, cyano, Ci_-6alkyl, Ci_-6alkyl substituted with one or more fluorine atoms, C_1-6alkylsulfonyl, C_3-6cycloalkyl, C_3-6cycloalkyl substituted with one or more fluorine atoms, Ci_-6alkoxy and Ci_-6alkoxy substituted with one or more fluorine atoms;

- n is 2, 3 or 4;

- Q is selected from the group consisting of hydrogen and Ci_-6alkyl; - R is selected from Ci_-6alkyl, C_3-6cycloalkyl, Cs-βcycloalkylCi-ealkyl and C₂-₆alkynyl, any alkyl or cycloalkyl group being optionally substituted by one or more fluorine atoms.

All features and embodiments for formula (I) apply to compounds of formula (I') mutatis mutandis. Hereinafter, all references to compounds of formula (I) include compounds of formula (I').

In one embodiment the salt of the compound of formula (I) is a pharmaceutically acceptable salt. In one embodiment, the invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof.

It will be appreciated that for use in medicine the salts of formula (I) should be pharmaceutically acceptable. Suitable salts will be apparent to those skilled in the art and include for example mono- or di- basic salts formed with inorganic acids e.g. hydrochloric, hydrobromic, sulfuric, nitric, sulfamic phosphoric, hydroiodic, phosphoric or metaphosphoric acid; and with organic acids, such as tartaric, acetic, trifluoroacetic, citric, malic, lactic, fumaric, benzoic, formic, propionic, glycolic, gluconic, maleic, succinic, (1 R)- (-)-IO-camphorsulphonic, (1 S)-(+)-10-camphorsulphonic, isothionic, mucic, gentisic, isonicotinic, saccharic, glucuronic, furoic, glutamic, ascorbic, anthranilic, salicylic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, pantothenic, stearic, sulfinilic, alginic, galacturonic and arylsulfonic, for example naphthalene-1 ,5- disulphonic, naphthalene-1 ,3-disulphonic, benzenesulfonic, and p-toluenesulfonic, acids. Other non-pharmaceutically acceptable salts e.g. oxalates, may be used, for example in the isolation of compounds of formula (I) and are included within the scope of this invention. The compounds of the present invention may be in the form of their free base or pharmaceutically acceptable salts thereof, particularly the monohydrochloride, monoformate or monotrifluoroacetate salts. Certain of the compounds of formula (I) may form acid addition salts with less than one (for example, 0.5 equivalent of a dibasic acid) or one or more equivalents of an acid. The present invention includes within its scope all possible stoichiometric and non-stoichiometric forms thereof.

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

The compounds of formula (I) may have the ability to crystallise in more than one form. This is a characteristic known as polymorphism, and it is understood that such polymorphic forms ("polymorphs") are within the scope of formula (I). Polymorphism generally can occur as a response to changes in temperature or pressure or both and can also result from variations in the crystallisation process. Polymorphs can be distinguished by various physical characteristics known in the art such as x-ray diffraction patterns, solubility, and melting point.

It will be appreciated by those skilled in the art that certain protected derivatives of compounds of formula (I), which may be made prior to a final deprotection stage, may not possess pharmacological activity as such, but may, in certain instances, be administered orally or parenterally and thereafter metabolised in the body to form compounds of the invention which are pharmacologically active. Such derivatives may therefore be described as "prodrugs". Further, certain compounds of the invention may act as prodrugs of other compounds of the invention. All protected derivatives and prodrugs of compounds of the invention are included within the scope of the invention. Examples of suitable protecting groups for the compounds of the present invention are described in Drugs of Today, Volume 19, Number 9, 1983, pp 499 - 538 and in Topics in Chemistry, Chapter 31 , pp 306 - 316 and in "Design of Prodrugs" by H. Bundgaard, Elsevier, 1985, Chapter 1 (the disclosures in which documents are incorporated herein by reference). It will further be appreciated by those skilled in the art, that certain moieties, known to those skilled in the art as "pro-moieties", for example as described by H. Bundgaard in "Design of Prodrugs" (the disclosure in which document is incorporated herein by reference) may be placed on appropriate functionalities when such functionalities are present within compounds of the invention. Suitable prodrugs for some compounds of the invention may include: esters, carbonate esters, hemi-esters, phosphate esters, nitro esters, sulfate esters, sulfoxides, amides, carbamates, azo-compounds, phosphamides, glycosides, ethers, acetals and ketals. Hereinafter, compounds of formula (I) (whether in solvated or unsolvated form) or their pharmaceutically acceptable salts (whether in solvated or unsolvated form) or prodrugs thereof defined in any aspect of the invention (except intermediate compounds in chemical processes) are referred to as "compounds of the invention".

The invention also includes all suitable isotopic variations of a compound of the invention. An isotopic variation of a compound of the invention is defined as one in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine and chlorine such as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N,

17, O, ¹⁸O, ³¹P, ³²P, ³⁵S, ¹⁸F and ³⁶CI, respectively. Certain isotopic variations of the invention, for example, those in which a radioactive isotope such as ³H or ¹⁴C is incorporated, are useful in drug and/or substrate tissue distribution studies. Tritiated, i.e., ³H, and carbon-14, i.e., ¹⁴C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with isotopes such as deuterium, i.e., ²H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements and hence may be preferred in some circumstances. Isotopic variations of the compounds of the invention can generally be prepared by conventional procedures such as by the illustrative methods or by the preparations described in the Examples hereafter using appropriate isotopic variations of suitable reagents.

It will be appreciated that compounds of formula (I) can exist in cis or trans isomeric forms (the O-(CH₂)_n-OR group on the cyclohexane ring in relation to the piperidine substituent).

It will be appreciated that the cis form may be drawn in the following different ways, although both represent the same isomeric form:

It will be appreciated that the trans form may be drawn in the following different ways, although both represent the same isomeric form:

The individual isomers {cis and trans) and mixtures of these are included within the scope of the present invention. The isomers may be separated one from the other by the usual methods or by methods detailed for the example compounds below. Any given isomer may also be obtained by stereospecific or asymmetric synthesis. The invention also extends to any tautomeric forms and mixtures thereof.

In one embodiment, the compounds of formula (I) are trans isomers.

In another embodiment, the compounds of formula (I) are cis isomers.

Mixtures of cis- and trans- compounds, or compounds in which the cis/trans conformation have not been determined, are drawn herein as shown below:

Compounds according to the invention include:

6-Methyl-1 -[1 -(frans-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-1 ,3-dihydro-2H- benzimidazol-2-one;

5-Fluoro-6-methyl-1-[1-(frans-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-1 ,3- dihydro-2H-benzimidazol-2-one;

5-Fluoro-6-methyl-1-[1-(c/s-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-1 ,3- dihydro-2H-benzimidazol-2-one; and salts thereof.

Further examples of compounds according to the invention include: 4,6-Difluoro-1-[1-(c/s-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-1 ,3- dihydro-2H-benzimidazol-2-one;

4,6-Difluoro-1-[1-(frans-1-methyl-4-{[2-(methyloxy)ethyl]oxy} cyclohexyl)-4-piperidinyl]-1 ,3- dihydro-2H-benzimidazol-2-one; 5-Chloro-6-methyl-1 -[1 -(frans-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-1 ,3- dihydro-2H-benzimidazol-2-one;

5-Chloro-6-methyl-1 -[1 -(c/s-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-1 ,3- dihydro-2H-benzimidazol-2-one;

1-[1-(frans-4-{[2-(Ethyloxy)ethyl]oxy}-1-methylcyclohexyl)-4-piperidinyl]-5-fluoro-6-methyl- 1 ,3-dihydro-2H-benzimidazol-2-one;

1-[1-(c/s-4-{[2-(Ethyloxy)ethyl]oxy}-1-methylcyclohexyl)-4-piperidinyl]-5-fluoro-6-methyl-

1 ,3-dihydro-2H-benzimidazol-2-one;

5-Fluoro-6-methyl-1-[1-(frans-1-methyl-4-{[2-(methyloxy)ethyl]oxy} cyclohexyl)-4- piperidinyl]-1 ,3-dihydro-2H-benzimidazol-2-one; and 5-Fluoro-6-methyl-1-[1-(c/s-1-methyl-4-{[2-(methyloxy)ethyl]oxy} cyclohexyl)-4-piperidinyl]-

1 ,3-dihydro-2H-benzimidazol-2-one; and salts thereof.

Specific examples of salts of the present invention include: 6-Methyl-1 -[1 -(frans-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-1 ,3-dihydro-2H- benzimidazol-2-one hydrochloride;

5-Fluoro-6-methyl-1-[1-(frans-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-1 ,3- dihydro-2H-benzimidazol-2-one hydrochloride; and

5-Fluoro-6-methyl-1 -[1 -(c/s-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-1 ,3- dihydro-2H-benzimidazol-2-one hydrochloride.

Further specific examples of salts of the present invention include:

4,6-Difluoro-1-[1-(c/s-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-1 ,3- dihydro-2H-benzimidazol-2-one hydrochloride; 4,6-Difluoro-1-[1-(frans-1-methyl-4-{[2-(methyloxy)ethyl]oxy} cyclohexyl)-4-piperidinyl]-1 ,3- dihydro-2H-benzimidazol-2-one hydrochloride;

5-Chloro-6-methyl-1 -[1 -(frans-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-1 ,3- dihydro-2H-benzimidazol-2-one hydrochloride;

5-Chloro-6-methyl-1 -[1 -(c/s-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-1 ,3- dihydro-2H-benzimidazol-2-one hydrochloride;

1-[1-(frans-4-{[2-(Ethyloxy)ethyl]oxy}-1-methylcyclohexyl)-4-piperidinyl]-5-fluoro-6-methyl-

1 ,3-dihydro-2H-benzimidazol-2-one hydrochloride;

1 ,3-dihydro-2H-benzimidazol-2-one hydrochloride; 5-Fluoro-6-methyl-1-[1-(frans-1-methyl-4-{[2-(methyloxy)ethyl]oxy} cyclohexyl)-4- piperidinyl]-1 ,3-dihydro-2H-benzimidazol-2-one hydrochloride; and 5-Fluoro-6-methyl-1-[1-(c/s-1-methyl-4-{[2-(methyloxy)ethyl]oxy} cyclohexyl)-4-piperidinyl]- 1 ,3-dihydro-2/-/-benzimidazol-2-one hydrochloride.

In one embodiment, the compound of formula (I) or a salt thereof is 4,6-difluoro-1-[1- (trans- 1-methyl-4-{[2-(methyloxy)ethyl]oxy} cyclohexyl)-4-piperidinyl]-1 ,3-dihydro-2H- benzimidazol-2-one hydrochloride.

Compounds of the invention may be prepared by methods known in the art of organic synthesis as set forth in part by the following synthesis schemes. In the following reaction schemes and hereafter, unless otherwise stated, all the groups are as defined in the first aspect. It is also recognised that in all of the schemes described below, it is well understood that protecting groups for sensitive or reactive groups are employed where necessary in accordance with general principles of chemistry. Protecting groups are manipulated according to standard methods of organic synthesis (T. W. Greene and P. G. M. Wuts (1991 ) Protecting Groups in Organic Synthesis, John Wiley & Sons). These groups are removed at a convenient stage of the compound synthesis using methods that are readily apparent to those skilled in the art. The selection of processes as well as the reaction conditions and order of their execution shall be consistent with the preparation of compounds of the invention.

In a further aspect, the invention provides a general process (A1 ) for preparing compounds of formula (I) in which Q =H, which process comprises:

coupling a compound of formula (II):

wherein R⁴ is a group R⁴ as defined for formula (I), or a group convertible to R⁴, R⁵ is a group R⁵ as defined for formula (I), or a group convertible to R⁵, R⁶ is a group R⁶ as defined for formula (I), or a group convertible to R⁶; with a compound of formula (III):

wherein n is as defined for formula (I), and R' is a group R as defined for formula (I), or a group convertible to R. The reaction is carried out under conditions suitable for reductive alkylation. The reductive alkylation reaction is typically carried out using sodium triacetoxyborohydride in dichloroethane, optionally in the presence of triethylamine, and optionally in the presence of titanium tetraisopropoxide. Alternatively sodium cyanoborohydride can be used as the reducing reagent in solvents such as methanol or ethanol, or the reductive alkylation can be effected under catalytic hydrogenation conditions using a palladium catalyst. In a further variation, the compounds (II) and (III) can be condensed under dehydrating conditions e.g. molecular sieves or magnesium sulfate, and the resultant imine or enamine reduced using for example sodium borohydride or by catalytic hydrogenation. This reaction can generate a mixture of cis and trans isomers which can be separated by chromatography or crystallisation.

A modification of general process (A1 ) is required where Q is C_1-6alkyl. Thus, in general process (A2), a compound of formula (II) as defined above is reacted with a compound of formula (III) as defined above, in the presence of a source of cyanide, e.g. acetone cyanohydrin, to form the cyano intermediate (XXXX) (wherein n is as defined for formula

(I) and R⁴ , R⁵ , R⁶ and R' are as defined above for formula (II) and (III)), and which can be reacted with an alkyl Grignard reagent, QMgX (wherein Q is

and X is bromo, iodo or chloro) to form compounds of formula (I) in which Q is C_1-6alkyl.

(XXXX)

This reaction can generate a mixture of cis and trans isomers which can be separated by chromatography or crystallisation.

In one aspect, the invention provides a compound of formula (XXXX) and salts thereof, wherein R⁴ , R⁵ , R⁶ , n and R' are as hereinbefore defined.

In a further aspect, the invention provides a general process (B) for preparing compounds of formula (I) which process comprises coupling a compound of formula (IV):

wherein n and Q are as defined for formula (I) and R⁴ , R⁵ , R⁶ and R' are as defined above for formula (II) and (III), with a compound of formula (V):

wherein X and Y both represent leaving groups. X and Y can be the same or different and examples are Cl, PhO, EtO and imidazole. When X and Y are both Cl, i.e. phosgene, this reagent can be generated in situ e.g. from diphosgene or triphosgene. The above reaction is carried out using standard methodology e.g. reacting the diamine (IV) with the reagent (V) in an inert solvent for example dichloromethane or toluene, optionally in the presence of a base such as triethylamine or potassium carbonate, and optionally with heating. It will be appreciated that compounds of formula (IV) can be cis or trans isomers, or a mixture of isomers. If necessary, separation of cis and trans isomers after the reaction with (V) can be achieved by chromatography or crystallisation.

In one aspect, the invention provides a compound of formula (IV) and salts thereof, wherein R⁴ , R⁵ , R⁶ , Q, n and R' are as hereinbefore defined.

In a further aspect, the invention provides a general process (C) for preparing compounds of formula (I) which process comprises treating a compound of formula (Vl):

wherein n and Q are as defined for formula (I) and R⁴ , R⁵ , R⁶ and R' are as defined above for formula (II) and (III), and Z is a leaving group such as bromo, iodo, chloro or triflate, with a palladium or copper catalyst (VII) to effect an intramolecular cyclisation. The cyclisation reaction can be carried out using a variety of palladium or copper reagents as described in the literature (JACS, 2003, 125, 6653; Tet. Lett., 2004, 45, 8535; or JACS, 2002, 124, 7421.) It will be appreciated that compounds of formula (Vl) can be cis or trans isomers, or a mixture of isomers. If necessary, separation of cis and trans isomers after the intramolecular cyclisation can be achieved by chromatography or crystallisation.

In one aspect the invention provides a compound of formula (Vl) and salts thereof, wherein R⁴ , R⁵ , R⁶ , Q, n, R' and Z are as hereinbefore defined.

In a further aspect, the invention provides a general process (D) for preparing compounds of formula (I) which process comprises coupling a compound of formula (VIII):

wherein R⁴ , R⁵ , and R⁶ are as defined above for formula (II), with a compound of formula

wherein n and Q are as defined for formula (I), R' is as defined for formula (III) and R^a is a Ci_-5alkyl group. The condensation and cyclisation reactions can be carried out under reaction conditions similar to those described in the literature for an analogous process (US 3161645) (for example heating in an inert solvent such as xylene) followed by reduction of the piperidine double bond using for example catalytic hydrogenation over palladium or Raney nickel. It will be appreciated that compounds of formula (IX) can be cis or trans isomers, or a mixture of isomers. If necessary, separation of cis and trans isomers after the intramolecular cyclisation can be achieved by chromatography or crystallisation.

In a further aspect, the invention provides a general process (E) for preparing compounds of formula (I) which process comprises reaction of a compound of formula (X):

wherein n and Q are as defined for formula (I) and R⁴ , R⁵ , R⁶ and R' are as defined above for formula (II) and (III), with diphenylphosphoryl azide or other reagent/combination of reagents to effect the Curtius rearrangement of compound (X), followed by intramolecular cyclisation. The Curtius rearrangement is typically carried out by mixing the two reactants in an inert solvent such as toluene, optionally with heating. It will be appreciated that compounds of formula (X) can be cis or trans isomers, or a mixture of isomers. If necessary, separation of cis and trans isomers after the intramolecular cyclisation can be achieved by chromatography or crystallisation.

In one aspect, the invention provides a compound of formula (X) and salts thereof, wherein R⁴ , R⁵ , R⁶ , Q, n and R' are as hereinbefore defined.

In a further aspect, the invention provides a general process (F) for preparing compounds of formula (I) which process comprises coupling a compound of formula (Xl):

wherein n and Q are as defined for formula (I) and R' is as defined above for formula and Z is hydroxy or a leaving group such as chloro, bromo or iodo, or alkyl/aryl sulfonate.

The alkylation reaction can be carried out under classical alkylation (Z = a leaving group) or Mitsunobu reaction (Z = OH) conditions. Using classical alkylation conditions, the benzimidazolone intermediate (Xl) can be deprotonated using a base such as sodium hydride in an inert solvent such as dimethylformamide, and then treated with the alkylating reagent (XII), optionally with heating. The Mitsunobu reaction with (XII) Z = OH can be carried out using standard conditions e.g. triphenylphosphine and diethylazodicarboxylate in an inert solvent such as dichloromethane or tetrahydrofuran at room temperature. It will be appreciated that compounds of formula (X) can be cis or trans isomers, or a mixture of isomers. If necessary, separation of cis and trans isomers after the intramolecular cyclisation can be achieved by chromatography or crystallisation.

Conversion of R⁶ to R⁶ or interconversions of R⁶ may be accomplished as indicated below. For example, when R⁶ is a halogen, it can be converted to an alkoxy or trifluoromethyl group by copper catalysed reaction, using an alcohol, or methyl fluorosulfonyl(difluoro)acetate, respectively. It may also be converted to an alkyl group with an organometallic reagent, for example an alkylstannane.

As another example, when R⁶ is hydroxy, it may be converted to an alkoxy group by reaction with an alkyl halide or sulfonate, or to trifluoromethoxy by conversion to the xanthate followed by oxidation in the presence of fluoride ion.

As a further example, when R⁶ is methyl, it may be converted to a trifluoromethyl group by chlorination or bromination followed by displacement of the introduced halogens with fluoride.

Similarly, conversion of R⁵ to R⁵ or interconversions of R⁵ may be accomplished as described for R⁶.

Conversion of R to R or interconversions of R may be accomplished as indicated below. For example when R' is benzyl, the benzyl group can be removed using standard methodology, e.g. catalytic hydrogenation over palladium on carbon, to provide the alcohol. Alkylation of the resultant alcohol using a strong base e.g. sodium hydride and a C-i-βalkylating agent e.g. methyl iodide or ethyl iodide or propyl iodide, will afford the desired product. It will be appreciated that protection of any NH functionality present in the molecule may be necessary

As another example, when R is methyl, the methyl group can be removed by treatment with a dealkylating agent such as boron tribromide to afford the alcohol intermediate, which can be alkylated in a similar manner to that described above.

Compounds of formula (II) are generally known in the literature or can be prepared by a range of different processes for example: (a) displacement of an ortho-fluoro or ortho-chloro nitrobenzene intermediate (XIII) with the amine (XIV), wherein R⁴ is a group R⁴ as defined for formula (I), or a group convertible to R⁴, R⁵ is a group R⁵ as defined for formula (I), or a group convertible to R⁵, R⁶ is a group R⁶ as defined for formula (I), or a group convertible to R⁶, and P represents a nitrogen protecting group (e.g. Boc, acetyl, trifluoroacetyl, ethoxycarbonyl, benzyloxycarbonyl), to give (XXIII), followed by reduction of the nitro group, cyclisation using phosgene or a phosgene equivalent, and deprotection of the piperidine nitrogen using standard literature conditions (Scheme 1 ).

Scheme 1.

Compounds of formula (XIII) are commercially available or can be prepared by standard methodology. The compound (XIV) in which P = Boc is commercially available.

(b) metal catalysed cyclisation of an intermediate (XV) followed by deprotection of the piperidine nitrogen, wherein R⁴ is a group R⁴ as previously defined, or a group convertible to R⁴, R⁵ is a group R⁵ as previously defined, or a group convertible to R⁵, R⁶ is a group R⁶ as previously defined, or a group convertible to R⁶, P represents a nitrogen protecting group (e.g. Boc, acetyl, trifluoroacetyl, benzyloxycarbonyl), and Z represents a leaving group such as bromo, iodo, chloro or triflate. Reaction conditions for the metal catalysed cyclisation are summarised in Process C. The urea (XV) can be prepared using any of the classical methods for urea formation as illustrated in Scheme 2. The starting materials for this process are commercially available or can be prepared using standard methodology.

Scheme 2.

(c) Curtius rearrangement of an intermediate (XVI), wherein R⁴ is a group R⁴ as previously defined, or a group convertible to R⁴, R⁵ is a group R⁵ as previously defined, or a group convertible to R⁵, R⁶ is a group R⁶ as previously defined, or a group convertible to R⁶, P represents a nitrogen protecting group (e.g. Boc, acetyl, trifluoroacetyl, benzyloxycarbonyl), and R^b represents H or a C_1-5alkyl group (e.g. methyl or ethyl), followed by intramolecular cyclisation and deprotection of the piperidine nitrogen (Scheme 3). The anthranilic acid or ester starting materials (XVII) are commercially available or can be made by standard methodology. The piperidone starting material (XVIII) (P = Boc or benzyl) is commercially available. The Curtius rearrangement can be effected using the conditions described under process E.

Scheme 3.

(d) Condensation of an orthophenylenediamine (VIII) with a 3-alkoxycarbonyl-4- piperidone (XX), wherein R⁴ is a group R⁴ as previously defined, or a group convertible to R⁴, R⁵ is a group R⁵ as previously defined, or a group convertible to R⁵, R⁶ is a group R⁶ as previously defined, or a group convertible to R⁶, P represents a nitrogen protecting group (e.g. Boc, acetyl, trifluoroacetyl, benzyloxycarbonyl) and R^b is a C_1-5alkyl group (Scheme 4), by heating in an inert solvent at elevated temperature, to afford the tetrahydropyridine intermediate (XXI). Hydrogenation of the double bond and deprotection of the piperidine nitrogen can be accomplished separately or concomitantly dependent on the precise nature of the protecting group P, to afford the desired product (II). Compounds of formula (VIII) are commercially available or can be prepared by standard methodology. Compounds of formula (XX) are commercially available or can be prepared by standard methodology.

Scheme 4.

(e) Reductive alkylation of an ortho nitroaniline (XXII) with an N-protected 4-piperidone (XVIII), wherein R⁴ is a group R⁴ as previously defined, or a group convertible to R⁴, R⁵ is a group R⁵ as previously defined, or a group convertible to R⁵, R⁶ is a group R⁶ as previously defined, or a group convertible to R⁶, and P represents a nitrogen protecting group (e.g. Boc, acetyl, trifluoroacetyl, benzyloxycarbonyl), using for example sodium triacetoxyborohydride to give the intermediate (XXIII). Reduction of the nitro group, followed by cyclisation and deprotection as described hereinbefore provides the desired product (II) (Scheme 5). Compounds of formula (XXII) and (XVIII) are commercially available or can be prepared by standard methodology.

Scheme 5.

(f) metal catalysed reaction between the amine (XIV) and a suitably substituted nitrobenzene compound (XXIV) wherein R⁴ is a group R⁴ as previously defined, or a group convertible to R⁴, R⁵ is a group R⁵ as previously defined, or a group convertible to R⁵, R⁶ is a group R⁶ as previously defined, or a group convertible to R⁶, P represents a nitrogen protecting group (e.g. Boc, acetyl, trifluoroacetyl, benzyloxycarbonyl), and Z represents a leaving group such as bromo, iodo, chloro or triflate (Scheme 6). This process generates intermediates of formula (XXIII) and subsequent reactions are similar to that for Scheme 5. Compounds of formula (XXIV) are commercially available or can be prepared by known methodology. The compound (XIV) in which P = Boc is commercially available

Scheme 6.

(g) metal catalysed reaction between the amine (XIV) and the protected aniline (XXV), wherein R⁴ is a group R⁴ as previously defined, or a group convertible to R⁴, R⁵ is a group R⁵ as previously defined, or a group convertible to R⁵, R⁶ is a group R⁶ as previously defined, or a group convertible to R⁶, P and P' independently represent a nitrogen protecting group (e.g. Boc, acetyl, trifluoroacetyl, benzyloxycarbonyl), and Z represents a leaving group such as bromo, iodo, chloro or triflate, to give the intermediate (XXVI) (Scheme 7). Deprotection of the aniline followed by the same reaction sequence as in Scheme 6 affords the desired intermediate (II). Compounds of formula (XXV) are commercially available or can be prepared by known methodology e.g. halogenation ortho to the optionally protected aniline group. The compound (XIV) in which P = Boc is commercially available

Scheme 7.

The compounds of formula (III) can be prepared by standard literature methodology.

Compounds of formula (IV) can be prepared by a number of different processes e.g.

(h) displacement of an ortho-fluoro or ortho-chloro nitrobenzene intermediate (XIII) with the amine (XXVII) wherein R⁴ is a group R⁴ as previously defined, or a group convertible to R⁴, R⁵ is a group R⁵ as previously defined, or a group convertible to R⁵, R⁶ is a group R⁶ as previously defined, or a group convertible to R⁶, R' is a group R as previously defined, or a group convertible to R, and n and Q are as previously defined, to afford compound (XXVIII) followed by reduction of the nitro group using standard conditions e.g. hydrogenation over palladium or Raney nickel (Scheme 8). Compounds of formula (XIII) are commercially available or can be prepared by standard methodology. It will be appreciated that separation of the cis and trans isomers can be achieved at any suitable stage in the synthesis.

Scheme 8.

(i) metal catalysed reaction of the amine (XXVII) with the ortho substituted nitrobenzene (XXIV), wherein R⁴ is a group R⁴ as previously defined, or a group convertible to R⁴, R⁵ is a group R⁵ as previously defined, or a group convertible to R⁵, R⁶ is a group R⁶ as previously defined, or a group convertible to R⁶, R' is a group R as previously defined, or a group convertible to R, and n and Q are as previously defined, to afford compound (XXVIII) (Scheme 9) followed by the same reactions as illustrated in Scheme 8. Compounds of formula (XXIV) are commercially available or can be prepared by standard methodology. It will be appreciated that separation of the cis and trans isomers can be achieved at any suitable stage in the synthesis.

Scheme 9.

(j) metal catalysed reaction of the amine (XXVII) with the protected aniline derivative

(XXV), wherein R is a group R as previously defined, or a group convertible to R 4 , ι R->5' is a group R⁵ as previously defined, or a group convertible to R⁵, R⁶ is a group R⁶ as previously defined, or a group convertible to R⁶, R' is a group R as previously defined, or a group convertible to R, and n and Q are as previously defined, and P' represents a nitrogen protecting group (such as acetyl, trifluoroacetyl, Boc, phthalimide), to afford compound (XXXI) (Scheme 10) followed by deprotection of the aniline group. Compounds of formula (XXV) are commercially available or can be prepared by standard methodology. It will be appreciated that separation of the cis and trans isomers can be achieved at any suitable stage in the synthesis.

Scheme 10.

(k) Reductive alkylation of an ortho nitroaniline (XXII) with the piperidone (XXXII) wherein R⁴ is a group R⁴ as previously defined, or a group convertible to R⁴, R⁵ is a group R⁵ as previously defined, or a group convertible to R⁵, R⁶ is a group R⁶ as previously defined, or a group convertible to R⁶, R' is a group R as previously defined, or a group convertible to R, and n and Q are as previously defined, using for example sodium triacetoxyborohydride in dichloroethane to give the intermediate (XXVIII) (Scheme 11 ). Reduction of the nitro group using, for example, palladium on carbon or Raney nickel affords the desired intermediate (IV). It will be appreciated that separation of the cis and trans isomers can be achieved at any suitable stage in the synthesis.

Scheme 11. CH₂J_n-OR-

(XXIl) (XXXIl) (XXVIII) OR-

Compounds of formula (V) are commercially available e.g. carbonyl diimidazole, phosgene, phosgene solution in toluene, diphosgene, triphosgene, phenyl chloroformate, diethyl carbonate.

Compounds of formula (Vl) can be prepared by a variety of processes e.g. urea formation can be achieved as shown in Scheme 12 by:

• combining the two amines (XXXIV) and (XXVII) with phosgene or a phosgene equivalent using standard conditions Phosgene equivalents include carbonyl diimidazole, diphosgene, triphosgene, phenyl chloroformate;

• reacting the amine (XXVII) with the isocyanate (XXXV); or

• reacting the amine (XXXIV) with the isocyanate (XXXVI).

Both isocyanates can be prepared from the corresponding amines using standard methodology for isocyanate formation.

It will be appreciated that separation of the cis and trans isomers can be achieved at any suitable stage in the synthesis.

Scheme 12.

(XXXIV) (XXXVl)

Palladium and copper catalysts (VII) are commercially available or can be prepared as described in the literature (see references in Process C).

Compounds of formula (VIII) are commercially available or can be prepared by known literature routes e.g. reduction of a mono or dinitrobenzene precursor.

Compounds of formula (IX) can be prepared by reductive alkylation of the 3- alkoxycarbonyl-4-piperidone with cyclohexanone.

Compounds of formula (X) can be prepared as shown in Scheme 13. Reductive alkylation of an anthranilic acid or ester (XVII) with the ketone (XXXII), followed if appropriate by hydrolysis of the ester group. It will be appreciated that separation of the cis and trans isomers can be achieved at any suitable stage in the synthesis.

Scheme 13.

Compounds of formula (Xl) are commercially available or can be prepared by literature processes.

Compounds of formula (XII) where Q = H can be prepared as shown in Scheme 14, by reductive alkylation of (XXXVII) where Z' represents Z or a group convertible to Z with the ketone (III). Conversion of a Z' = hydroxy group to Z = chloro or bromo can be accomplished using standard methodology e.g. treatment with thionyl chloride or triphenylphosphine/carbon tetrabromide. It will be appreciated that separation of the cis and trans isomers can be achieved at any suitable stage in the synthesis.

Scheme 14.

(XII)

The compound (XXVII) where Q = H can be prepared as shown in Scheme 15. Reductive alkylation of the commercially available amine (XXXVIII) with cyclohexanone (III) using for example sodium triacetoxyborohydride in dichloroethane provides the intermediate (XXXIX) which is deprotected using HCI in ethanol or trifluoroacetic acid to afford the primary amine (XXVII). It will be appreciated that separation of the cis and trans isomers can be achieved at any suitable stage in the synthesis.

Scheme 15.

The compound (XXVII) where Q = C_1-6alkyl can be prepared as in process A2, followed by deprotection.

In one embodiment, the group R⁴ in the above described processes is the group R⁴ as hereinbefore defined.

In one embodiment, the group R⁵ in the above described processes is the group R⁵ as hereinbefore defined.

In one embodiment, the group R⁶ in the above described processes is the group R⁶ as hereinbefore defined.

In one embodiment, the group R' in the above described processes is the group R as hereinbefore defined.

Compounds of the present invention are M₁ receptor agonists. Selective M₁ receptor agonists are said to be useful to ameliorate positive and cognitive symptoms of psychotic disorders such as schizophrenia, schizo-affective disorders, schizophreniform diseases, psychotic depression, mania, acute mania, paranoid and delusional disorders, and cognitive impairment including memory disorders such as Alzheimer's disease without peripheral cholinergic side effects mediated predominantly through M₂ and M₃ receptors. M₁ receptor agonists may also be suitable for combination with other typical and atypical antipsychotics and other actives such as mood stabilisers, antidepressants, anxiolytics, drugs for extrapyramidal side effects and cognitive enhancers, to provide improved treatment of psychotic disorders.

Thus in a further aspect, the invention provides a compound of formula (I) as hereinbefore described or a pharmaceutically acceptable salt thereof for use in therapy.

In another aspect, the invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of a condition wherein agonism of a muscarinic M₁ receptor would be beneficial.

The terms describing the indications used herein are classified in the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, published by the American Psychiatric Association (DSM-IV) and/or the International Classification of Diseases, 10th Edition (ICD-10). Treatment of the various subtypes of the disorders mentioned herein are contemplated as part of the present invention. Numbers in brackets after the listed diseases below refer to the classification code in DSM-IV. Within the context of the present invention, the term psychotic disorder includes Schizophrenia including the subtypes Paranoid Type (295.30), Disorganised Type (295.10), Catatonic Type (295.20), Undifferentiated Type (295.90) and Residual Type (295.60); Schizophreniform Disorder (295.40); Schizoaffective Disorder (295.70) including the subtypes Bipolar Type and Depressive Type; Delusional Disorder (297.1 ) including the subtypes Erotomanic Type, Grandiose Type, Jealous Type, Persecutory Type, Somatic Type, Mixed Type and Unspecified Type; Brief Psychotic Disorder (298.8); Shared Psychotic Disorder (297.3); Psychotic Disorder Due to a General Medical Condition including the subtypes With Delusions and With Hallucinations; Substance-Induced Psychotic Disorder including the subtypes With Delusions (293.81 ) and With Hallucinations (293.82); and Psychotic Disorder Not Otherwise Specified (298.9);

Other conditions wherein agonism of the M₁ receptor would be beneficial in their treatment include:

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

Anxiety disorders including 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- Injury 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);

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

Sleep disorders including primary sleep disorders such as Dyssomnias such as Primary Insomnia (307.42), Primary Hypersomnia (307.44), Narcolepsy (347), Breathing-Related Sleep Disorders (780.59), Circadian Rhythm Sleep Disorder (307.45) and Dyssomnia Not Otherwise Specified (307.47); primary sleep disorders such as Parasomnias such as Nightmare Disorder (307.47), Sleep Terror Disorder (307.46), Sleepwalking Disorder (307.46) and Parasomnia Not Otherwise Specified (307.47); Sleep Disorders Related to Another Mental Disorder such as Insomnia Related to Another Mental Disorder (307.42) and Hypersomnia Related to Another Mental Disorder (307.44); Sleep Disorder Due to a General Medical Condition; and Substance-Induced Sleep Disorder including the subtypes Insomnia Type, Hypersomnia Type, Parasomnia Type and Mixed Type;

Eating disorders such as Anorexia Nervosa (307.1 ) including the subtypes Restricting Type and Binge-Eating/Purging Type; Bulimia Nervosa (307.51 ) including the subtypes Purging Type and Nonpurging Type; Obesity; Compulsive Eating Disorder; and Eating Disorder Not Otherwise Specified (307.50);

Autistic Disorder (299.00); Attention-Deficit /Hyperactivity Disorder including the subtypes Attention-Deficit /Hyperactivity Disorder Combined Type (314.01 ), Attention-Deficit

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

/Hyperactivity Disorder Hyperactive-Impulse Type (314.01 ) and Attention-Deficit

/Hyperactivity Disorder Not Otherwise Specified (314.9); Hyperkinetic Disorder; Disruptive

Behaviour Disorders such as Conduct Disorder including the subtypes childhood-onset type (321.81 ), Adolescent-Onset Type (312.82) and Unspecified Onset (312.89),

Oppositional Defiant Disorder (313.81 ) and Disruptive Behaviour Disorder Not Otherwise

Specified; and Tic Disorders such as Tourette's Disorder (307.23); Personality Disorders including the subtypes Paranoid Personality Disorder (301.0), Schizoid Personality Disorder (301.20), Schizotypal Personality Disorder (301 ,22), Antisocial Personality Disorder (301.7), Borderline Personality Disorder (301 ,83), Histrionic Personality Disorder (301.50), Narcissistic Personality Disorder (301 ,81 ), Avoidant Personality Disorder (301.82), Dependent Personality Disorder (301.6), Obsessive-Compulsive Personality Disorder (301.4) and Personality Disorder Not Otherwise Specified (301.9); and

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

The compounds of formula (I) may also be useful for the enhancement of cognition, including both the treatment of cognitive impairment on its own and the treatment of cognition impairment in other diseases such as schizophrenia, bipolar disorder, depression, other psychiatric disorders and psychotic conditions associated with cognitive impairment. Where cognitive impairment results from a treatment of a disease, M₁ agonists may be beneficial. For example, when the treatment of epilepsy with anticonvulsants results in cognitive impairment, an M₁ agonist may be useful for the alleviation or treatment of the cognitive impairment.

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

Compounds of formula (I) or pharmaceutically acceptable salts thereof may also be used as memory and/or cognition enhancers in healthy humans with no cognitive and/or memory deficit.

In another aspect, the invention provides a compound of formula (I) as hereinbefore described or a pharmaceutically acceptable salt thereof for use in the treatment of a psychotic disorder. In one embodiment, the invention provides a compound of formula (I) as hereinbefore described or a pharmaceutically acceptable salt thereof for use in the treatment of schizophrenia.

The invention also provides a compound of formula (I) as hereinbefore described or a pharmaceutically acceptable salt thereof for use in the treatment of cognitive impairment.

In another aspect, the invention provides the use of a compound of formula (I) as hereinbefore described or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a condition wherein agonism of the M₁ receptor would be beneficial.

In another aspect, the invention provides the use of a compound of formula (I) as hereinbefore described or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a psychotic disorder. In one embodiment, the invention provides the use of a compound of formula (I) as hereinbefore described or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of schizophrenia.

In another aspect, the invention provides a compound of formula (I) as hereinbefore described or a pharmaceutically acceptable salt thereof in the treatment of a psychotic disorder. In one embodiment, the invention provides a compound of formula (I) as hereinbefore described or a pharmaceutically acceptable salt thereof for the treatment of schizophrenia.

The invention also provides the use of a compound of formula (I) as hereinbefore described or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of cognitive impairment.

The invention also provides a compound of formula (I) as hereinbefore described or a pharmaceutically acceptable salt thereof for the treatment of cognitive impairment. In another aspect, the invention provides a method of treating a condition where agonism of the M₁ receptor would be beneficial, which comprises administering to a mammal in need thereof an effective amount of a compound of formula (I) as hereinbefore described or a pharmaceutically acceptable salt thereof. In one embodiment, the mammal is a human.

In another aspect, the invention provides a method of treating a psychotic disorder which comprises administering to a mammal in need thereof an effective amount of a compound of formula (I) as hereinbefore described or a pharmaceutically acceptable salt thereof. In one embodiment, the invention provides a method of treating schizophrenia, which comprises administering to a mammal in need thereof an effective amount of a compound of formula (I) as hereinbefore described or a pharmaceutically acceptable salt thereof. In one embodiment, the mammal is a human.

The invention also provides a method of treating cognitive impairment, which comprises administering to a mammal in need thereof an effective amount of a compound of formula (I) as hereinbefore described or a pharmaceutically acceptable salt thereof. In one embodiment, the mammal is a human.

The compounds of formula (I) and pharmaceutically acceptable salts thereof may also be suitable for combination with other actives, such as typical and atypical antipsychotics, mood stabilisers, antidepressants, anxiolytics, drugs for extrapyrimidal side effects and cognitive enhancers to provide improved treatment of psychotic disorders.

The combination therapies of the invention are, for example, administered adjunctively. By adjunctive administration is meant the coterminous 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. Any and all treatment regimes in which a patient receives separate but coterminous or overlapping therapeutic administration of the compounds of formula (I) or a pharmaceutically acceptable salt thereof and at least one antipsychotic agent, a mood stabiliser, an antidepressant, an anxiolytic, a drug for extrapyrimidal side effects or a cognitive enhancer are within the scope of the current invention. In one embodiment of adjunctive therapeutic administration as described herein, a patient is typically stabilised on a therapeutic administration of one or more of the components for a period of time and then receives administration of another component. The compounds of formula (I) or a pharmaceutically acceptable salt thereof may be administered as adjunctive therapeutic treatment to patients who are receiving administration of at least one antipsychotic agent, a mood stabiliser, an antidepressant, an anxiolytic, a drug for extrapyrimidal side effects or a cognitive enhancer, but the scope of the invention also includes the adjunctive therapeutic administration of at least one antipsychotic agent, a mood stabiliser, an antidepressant, an anxiolytic, a drug for extrapyrimidal side effects or a cognitive enhancer to patients who are receiving administration of compounds of formula (I) or a pharmaceutically acceptable salt thereof.

The combination therapies of the invention may also be administered simultaneously. By simultaneous administration is meant a treatment regime wherein the individual components are administered together, either in the form of a single pharmaceutical composition or device comprising or containing both components, or as separate compositions or devices, each comprising one of the components, administered simultaneously. Such combinations of the separate individual components for simultaneous combination may be provided in the form of a kit-of-parts.

In a further aspect therefore, the invention provides a method of treatment of a psychotic disorder by adjunctive therapeutic administration of compounds of formula (I) or a pharmaceutically acceptable salt thereof to a patient receiving therapeutic administration of at least one antipsychotic agent. In a further aspect, the invention provides the use of compounds of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for adjunctive therapeutic administration for the treatment of a psychotic disorder in a patient receiving therapeutic administration of at least one antipsychotic agent. In a further aspect, the invention provides compounds of formula (I) or a pharmaceutically acceptable salt thereof for adjunctive therapeutic administration for the treatment of a psychotic disorder in a patient receiving therapeutic administration of at least one antipsychotic agent. The invention further provides compounds of formula (I) or a pharmaceutically acceptable salt thereof for use for adjunctive therapeutic administration for the treatment of a psychotic disorder in a patient receiving therapeutic administration of at least one antipsychotic agent.

In a further aspect, the invention provides a method of treatment of a psychotic disorder by adjunctive therapeutic administration of at least one antipsychotic agent to a patient receiving therapeutic administration of compounds of formula (I) or a pharmaceutically acceptable salt thereof. In a further aspect, the invention provides the use of at least one antipsychotic agent in the manufacture of a medicament for adjunctive therapeutic administration for the treatment of a psychotic disorder in a patient receiving therapeutic administration of compounds of formula (I) or a pharmaceutically acceptable salt thereof. In a further aspect, the invention provides at least one antipsychotic agent for adjunctive therapeutic administration for the treatment of a psychotic disorder in a pateient recieving therapeutic administration of compounds of formula (I) or a pharmaceutically acceptable salt thereof. The invention further provides at least one antipsychotic agent for adjunctive therapeutic administration for the treatment of a psychotic disorder in a patient receiving therapeutic administration of compounds of formula (I) or a pharmaceutically acceptable salt thereof.

In a further aspect, the invention provides a method of treatment of a psychotic disorder by simultaneous therapeutic administration of compounds of formula (I) or a pharmaceutically acceptable salt thereof in combination with at least one antipsychotic agent. The invention further provides the use of a combination of compounds of formula (I) or a pharmaceutically acceptable salt thereof and at least one antipsychotic agent in the manufacture of a medicament for simultaneous therapeutic administration in the treatment of a psychotic disorder. The invention further provides a combination of compounds of formula (I) or a pharmaceutically acceptable salt thereof and at least one antipsycotic agent for simultaneous therapeutic administration in the treatment of a psychotic disorder. The invention further provides the use of compounds of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for simultaneous therapeutic administration with at least one antipsychotic agent in the treatment of a psychotic disorder. The invention further provides compounds of formula (I) or a pharmaceutically acceptable salt thereof for use for simultaneous therapeutic administration with at least one antipsychotic agent in the treatment of a psychotic disorder. The invention further provides the use of at least one antipsychotic agent in the manufacture of a medicament for simultaneous therapeutic administration with compounds of formula (I) or a pharmaceutically acceptable salt thereof in the treatment of a psychotic disorder. The invention further provides at least one antipsychotic agent for simultaneous therapeutic administration with compounds of formula (I) or a pharmaceutically acceptable salt thereof in the treatment of a psychotic disorder.

In a further aspect, the invention provides a kit-of-parts for use in the treatment of a psychotic disorder comprising a first dosage form comprising compounds of formula (I) or a pharmaceutically acceptable salt thereof and one or more further dosage forms each comprising an antipsychotic agent for simultaneous therapeutic administration.

In another aspect, the invention provides a method of treatment of a psychotic disorder by adjunctive therapeutic administration of a compound of the present invention to a patient receiving therapeutic administration of an active ingredient selected from the group consisting of: a mood stabiliser, an antidepressant, an anxiolytic, a drug for extrapyrimidal side effects and a cognitive enhancer.

In a further aspect, the invention provides the use of a compound of the present invention in the manufacture of a medicament for adjunctive therapeutic administration for the treatment of a psychotic disorder in a patient receiving therapeutic administration of an active ingredient selected from the group consisting of: a mood stabiliser, an antidepressant, an anxiolytic, a drug for extrapyrimidal side effects and a cognitive enhancer. The invention also provides a compound of the present invention for adjunctive therapeutic administration for the treatment of a psychotic disorder in a patient receiving therapeutic administration of an active ingredient selected from the group consisting of: a mood stabiliser, an antidepressant, an anxiolytic, a drug for extrapyrimidal side effects and a cognitive enhancer.

The invention also provides the use of a compound of the present invention in adjunctive therapeutic administration for the treatment of a psychotic disorder in a patient receiving therapeutic administration of an active ingredient selected from the group consisting of: a mood stabiliser, an antidepressant, an anxiolytic, a drug for extrapyrimidal side effects and a cognitive enhancer.

The invention further provides the use of a compound of the present invention for use for adjunctive therapeutic administration for the treatment of a psychotic disorder in a patient receiving therapeutic administration of an active ingredient selected from the group consisting of: a mood stabiliser, an antidepressant, an anxiolytic, a drug for extrapyrimidal side effects and a cognitive enhancer.

In a further aspect, the invention provides a method of treatment of a psychotic disorder by adjunctive therapeutic administration of an active ingredient selected from the group consisting of: a mood stabiliser, an antidepressant, an anxiolytic, a drug for extrapyrimidal side effects and a cognitive enhancer to a patient receiving therapeutic administration of a compound of the present invention.

In a further aspect, the invention provides the use of an active ingredient selected from the group consisting of: a mood stabiliser, an antidepressant, an anxiolytic, a drug for extrapyrimidal side effects and a cognitive enhancer in the manufacture of a medicament for adjunctive therapeutic administration for the treatment of a psychotic disorder in a patient receiving therapeutic administration of a compound of the present invention.

The invention also provides an active ingredient selected from the group consisting of: a mood stabiliser, an antidepressant, an anxiolytic, a drug for extrapyrimidal side effects and a cognitive enhancer for adjunctive therapeutic administration for the treatment of a psychotic disorder in a patient receiving therapeutic administration of a compound of the present invention

The invention also provides the use of an active ingredient selected from the group consisting of: a mood stabiliser, an antidepressant, an anxiolytic, a drug for extrapyrimidal side effects and a cognitive enhancer for adjunctive therapeutic administration for the treatment of a psychotic disorder in a patient receiving therapeutic administration of a compound of the present invention In a further aspect, the invention provides a method of treatment of a psychotic disorder by simultaneous therapeutic administration of a compound of the present invention in combination with an active ingredient selected from the group consisting of: a mood stabiliser, an antidepressant, an anxiolytic, a drug for extrapyrimidal side effects and a cognitive enhancer.

The invention further provides the use of a combination of a compound of the present invention and an active ingredient selected from the group consisting of: a mood stabiliser, an antidepressant, an anxiolytic, a drug for extrapyrimidal side effects and a cognitive enhancer in the manufacture of a medicament for simultaneous therapeutic administration in the treatment of a psychotic disorder.

The invention further provides a combination of a compound of the present invention and an active ingredient selected from the group consisting of: a mood stabiliser, an antidepressant, an anxiolytic, a drug for extrapyrimidal side effects and a cognitive enhancer for simultaneous therapeutic administration for the treatment of a psychotic disorder.

The invention further provides the use of a combination of a compound of the present invention and an active ingredient selected from the group consisting of: a mood stabiliser, an antidepressant, an anxiolytic, a drug for extrapyrimidal side effects and a cognitive enhancer for simultaneous therapeutic administration in the treatment of a psychotic disorder.

The invention further provides the use of a compound of the present invention in the manufacture of a medicament for simultaneous therapeutic administration with an active ingredient selected from the group consisting of: a mood stabiliser, an antidepressant, an anxiolytic, a drug for extrapyrimidal side effects and a cognitive enhancer in the treatment of a psychotic disorder.

The invention further provides a compound of the present invention for simultaneous therapeutic administration with an active ingredient selected from the group consisting of: a mood stabiliser, an antidepressant, an anxiolytic, a drug for extrapyrimidal side effects and a cognitive enhancer for the treatment of a psychotic disorder.

The invention further provides the use of a compound of the present invention for simultaneous therapeutic administration with an active ingredient selected from the group consisting of: a mood stabiliser, an antidepressant, an anxiolytic, a drug for extrapyrimidal side effects and a cognitive enhancer in the treatment of a psychotic disorder. The invention further provides a compound of the present invention for use for simultaneous therapeutic administration with an active ingredient selected from the group consisting of: a mood stabiliser, an antidepressant, an anxiolytic, a drug for extrapyrimidal side effects and a cognitive enhancer in the treatment of a psychotic disorder.

The invention further provides the use of an active ingredient selected from the group consisting of: a mood stabiliser, an antidepressant, an anxiolytic, a drug for extrapyrimidal side effects and a cognitive enhancer in the manufacture of a medicament for simultaneous therapeutic administration with a compound of the present invention in the treatment of a psychotic disorder.

The invention further provides an active ingredient selected from the group consisting of: a mood stabiliser, an antidepressant, an anxiolytic, a drug for extrapyrimidal side effects and a cognitive enhancer for simultaneous therapeutic administration with a compound of the present invention for the treatment of a psychotic disorder.

The invention further provides the use of an active ingredient selected from the group consisting of: a mood stabiliser, an antidepressant, an anxiolytic, a drug for extrapyrimidal side effects and a cognitive enhancer for simultaneous therapeutic administration with a compound of the present invention in the treatment of a psychotic disorder.

In a further aspect, the invention provides a kit-of-parts for use in the treatment of a psychotic disorder comprising a first dosage form comprising a compound of the present invention and one or more further dosage forms each comprising an active ingredient selected from the group consisting of: a mood stabiliser, an antidepressant, an anxiolytic, a drug for extrapyrimidal side effects and a cognitive enhancer for simultaneous therapeutic administration.

In one embodiment, the patient is a human.

Examples of antipsychotic drugs that may be useful in the present invention include, but are not limited to: sodium channel blockers; mixed 5HT/dopamine receptor antagonists; mGluR5 positive modulators; D3 antagonists; 5HT6 angatonists; nicotinic alpha-7 modulators; glycine transporter GIyTI inhibitors; D2 partial agonist/D3 antanogist/H3 antagonists; AMPA modulators; NK3 antagonists such as osanetant and talnetant; an atypical antipsychotic, for example clozapine, olanzapine, risperidone, quetiapine, aripirazole, ziprasidone and amisulpride; butyrophenones, such as haloperidol, pimozide, and droperidol; phenothiazines, such as chlorpromazine, thioridazine, mesoridazine, trifluoperazine, perphenazine, fluphenazine, thiflupromazine, prochlorperazine, and acetophenazine; thioxanthenes, such as thiothixene and chlorprothixene; thienobenzodiazepines; dibenzodiazepines; benzisoxazoles; dibenzothiazepines; imidazolidinones; benzisothiazolyl-piperazines; triazine such as lamotrigine; dibenzoxazepines, such as loxapine; dihydroindolones, such as molindone; aripiprazole; and derivatives thereof that have antipsychotic activity.

Examples of tradenames and suppliers of selected antipsychotic drugs that may be suitable for use in the present invention are as follows : clozapine (available under the tradename CLOZARIL®, from Mylan, Zenith Goldline, UDL, Novartis); olanzapine (available under the tradename ZYPREXA®, from Lilly); ziprasidone (available under the tradename GEODON®, from Pfizer); risperidone (available under the tradename RISPERDAL®, from Janssen); quetiapine fumarate (available under the tradename SEROQUEL®, from AstraZeneca); sertindole (available under the tradename SERLECT®); amisulpride (available under the tradename SOLION®, from Sanofi- Synthelabo); haloperidol (available under the tradename HALDOL®, from Ortho-McNeil); haloperidol decanoate (available under the tradename HALDOL decanoate®); haloperidol lactate (available under the tradenames HALDOL® and INTENSOL®); chlorpromazine (available under the tradename THORAZINE®, from SmithKline Beecham (GSK)); fluphenazine (available under the tradename PROLIXIN®, from Apothecon, Copley, Schering, Teva, and American Pharmaceutical Partners, Pasadena); fluphenazine decanoate (available under the tradename PROLIXIN decanoate®); fluphenazine enanthate (available under the tradename PROLIXIN®); fluphenazine hydrochloride (available under the tradename PROLIXIN®); thiothixene (available under the tradename NAVANE®, from Pfizer); thiothixene hydrochloride (available under the tradename NAVANE®); trifluoperazine (10-[3-(4-methyl-1-piperazinyl)propyl]-2-

(trifluoromethyl)phenothiazine dihydrochloride, available under the tradename STELAZINE®, from SmithKline Beckman); perphenazine (available under the tradename TRILAFON®, from Schering); perphenazine and amitriptyline hydrochloride (available under the tradename ETRAFON TRILAFON®); thioridazine (available under the tradename MELLARIL®; from Novartis, Roxane, HiTech, Teva, and Alpharma); molindone (available under the tradename MOBAN®, from Endo); molindone hydrochloride (available under the tradename MOBAN®); loxapine (available under the tradename LOXITANE®; from Watson); loxapine hydrochloride (available under the tradename LOXITANE®); and loxapine succinate (available under the tradename LOXITANE®). Furthermore, benperidol (Glianimon®), perazine (Taxilan®) or melperone (Eunerpan®)) may be used.

Other suitable antipsychotic drugs include promazine (available under the tradename SPARINE®), triflurpromazine (available under the tradename VESPRIN®), chlorprothixene (available under the tradename TARACTAN®), droperidol (available under the tradename INAPSINE®), acetophenazine (available under the tradename TINDAL®;), prochlorperazine (available under the tradename COMPAZINE®), methotrimeprazine (available under the tradename NOZI NAN®), pipotiazine (available under the tradename PIPOTRIL®), iloperidone, pimozide and flupenthixol. The antipsychotic drugs listed above by Tradename may also be available from other suppliers under a different Tradename.

In one further aspect of the invention, suitable antipsychotic agents include olanzapine, risperidone, quetiapine, amisulpride, aripiprazole, haloperidol, clozapine, olanzepine, ziprasidone, talnetant and osanetant.

Mood stabilisers which may be used in the therapy of the present invention include lithium, sodium valproate/valproic acid/divalproex, carbamazepine, lamotrigine, gabapentin, topiramate, oxcarbazepine and tiagabine.

Antidepressant drugs which may be used in the therapy of the present invention include serotonin antagonists, CRF-1 antagonists, Cox-2 inhibitor/SSRI dual antagonists; dopamine/noradrenaline/serotonin triple reuptake inhibitors; NK1 antagonists; NK1 and NK2 dual antagonists; NK1/SSRI dual antagonists; NK2 antagonists; serotonin agonists (such as rauwolscine, yohimbine and metoclopramide); serotonin reuptake inhibitors (such as citalopram, escitalopram, fluoxetine, fluvoxamine, femoxetine, indalpine, zimeldine, paroxetine and sertraline); dual serotonin/noradrenaline reuptake inhibitors (such as venlafaxine, reboxetine, duloxetine and milnacipran); Noradrenaline reuptake inhibitors (such as reboxetine); tricyclic antidepressants (such as amitriptyline, clomipramine, imipramine, maprotiline, nortriptyline and trimipramine); monoamine oxidase inhibitors (such as isocarboxazide, moclobemide, phenelzine and tranylcypromine); 5HT3 antagonists (such as example ondansetron and granisetron); and others (such as bupropion, amineptine, radafaxine, mianserin, mirtazapine, nefazodone and trazodone).

Anxiolytics which may be used in the therapy of the present invention include V1 b antagonists, 5HT7 antagonists and benzodiazepines such as alprazolam and lorazepam.

Drugs for extrapyramidal side effects which may be used in the therapy of the present invention include anticholinergics (such as benztropine, biperiden, procyclidine and trihexyphenidyl), antihistamines (such as diphenhydramine) and dopaminergics (such as amantadine).

Cognitive enhancers which may be used in the therapy of the present invention include example cholinesterase inhibitors (such as tacrine, donepezil, rivastigmine and galantamine), H3 antagonists and muscarinic M₁ agonists (such as cevimeline).

For use in medicine, the compounds of the present invention are usually administered as a standard pharmaceutical composition. The present invention therefore provides in a further aspect a pharmaceutical composition comprising a compound of formula (I) as hereinbefore described or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. The pharmaceutical composition can be for use in the treatment of any of the conditions described herein. In a further aspect, the invention provides a process for preparing a pharmaceutical composition, the process comprising mixing a compound of formula (I) as hereinbefore described or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers. In a further aspect, the invention provides a pharmaceutical composition comprising a compound of formula (I) as hereinbefore described or a pharmaceutically acceptable salt thereof in combination with at least 1 antipsychotic, and one or more pharmaceutically acceptable carriers. In a further aspect, the invention provides a process for preparing a pharmaceutical composition, the process comprising mixing a compound of formula (I) as hereinbefore described or a pharmaceutically acceptable salt thereof, at least 1 antipsychotic, and one or more pharmaceutically acceptable carriers.

The compounds of the invention may be administered by any convenient method, for example by oral, parenteral (e.g. intravenous), buccal, sublingual, nasal, rectal or transdermal administration and the pharmaceutical compositions adapted accordingly.

The compounds of the invention which are active when given orally can be formulated as liquids or solids, for example syrups, suspensions or emulsions, tablets, capsules and lozenges.

A liquid formulation will generally consist of a suspension or solution of the compound or salt in a suitable liquid carrier(s) for example an aqueous solvent such as water, ethanol or glycerine, or a non-aqueous solvent, such as polyethylene glycol or an oil. The formulation may also contain a suspending agent, preservative, flavouring or colouring agent.

A composition in the form of a tablet can be prepared using any suitable pharmaceutical carrier(s) routinely used for preparing solid formulations. Examples of such carriers include magnesium stearate, starch, lactose, sucrose and cellulose.

A composition in the form of a capsule can be prepared using routine encapsulation procedures. For example, pellets containing the active ingredient can be prepared using standard carriers and then filled into a hard gelatin capsule; alternatively, a dispersion or suspension can be prepared using any suitable pharmaceutical carrier(s), for example aqueous gums, celluloses, silicates or oils and the dispersion or suspension then filled into a soft gelatin capsule.

Typical parenteral compositions consist of a solution or suspension of the compound or salt in a sterile aqueous carrier or parenterally acceptable oil, for example polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil. Alternatively, the solution can be lyophilised and then reconstituted with a suitable solvent just prior to administration.

Compositions for nasal administration may conveniently be formulated as aerosols, drops, gels and powders. Aerosol formulations typically comprise a solution or fine suspension of the active substance in a pharmaceutically acceptable aqueous or non-aqueous solvent and are usually presented in single or multidose quantities in sterile form in a sealed container, which can take the form of a cartridge or refill for use with an atomising device. Alternatively the sealed container may be a unitary dispensing device such as a single dose nasal inhaler or an aerosol dispenser fitted with a metering valve which is intended for disposal once the contents of the container have been exhausted. Where the dosage form comprises an aerosol dispenser, it will contain a propellant which can be a compressed gas such as compressed air or an organic propellant such as a fluorochloro- hydrocarbon. The aerosol dosage forms can also take the form of a pump-atomiser.

Compositions suitable for buccal or sublingual administration include tablets, lozenges and pastilles, wherein the active ingredient is formulated with a carrier such as sugar and acacia, tragacanth, or gelatin and glycerin.

Compositions for rectal administration are conveniently in the form of suppositories containing a conventional suppository base such as cocoa butter.

Compositions suitable for transdermal administration include ointments, gels and patches. The composition may be in unit dose form such as a tablet, capsule or ampoule.

Each dosage unit for oral administration contains, for example, from 1 to 250 mg (and for parenteral administration contains, for example, from 0.1 to 25 mg) of a compound of the formula (I) or a pharmaceutically acceptable salt thereof calculated as the free base.

It will be appreciated that the precise dose administered will depend on the age and condition of the patient and the frequency and route of administration and will be at the ultimate discretion of the attendant physician.

The antipsychotic agent component or components used in the adjunctive therapy of the present invention may also be administered in their basic or acidic forms as appropriate or, where appropriate, in the form of a pharmaceutically acceptable salt or other derivative. All solvates and all alternative physical forms of the antipsychotic agent or agents or their salts or derivatives as described herein, including but not limited to alternative crystalline forms, amorphous forms and polymorphs, are also within the scope of this invention. In the case of the antipsychotic agent or agents, the forms and derivatives are, for example, those which are approved for therapeutic administration as monotherapies, including those mentioned above, but all references to antipsychotic agents herein include all salts or other derivatives thereof, and all solvates and alternative physical forms thereof.

For adjunctive therapeutic administration according to the invention, compounds of formula (I) or pharmaceutically acceptable salts thereof and the antipsychotic agent or agents or their salts, derivatives or solvates may each be administered in pure form, but each of the components will, for example, be formulated into any suitable pharmaceutically acceptable and effective composition which provides effective levels of the respective component in the body. The choice of the most appropriate pharmaceutical compositions for each component is within the skill of the art, and may be the same form or different forms for each of the components. Suitable formulations include, but are not limited to tablets, capsules, powders, granules, lozenges, suppositories, reconstitutable powders, or liquid preparations such as oral or sterile parenteral solutions or suspensions.

For simultaneous administration as a combined composition of compounds of formula (I) and the antipsychotic agent or agents according to the invention, compounds of formula (I) or their pharmaceutically acceptable salts and the antipsychotic agent or agents and their salts, derivatives or solvates may be administered together in pure form, but the combined components will, for example, be formulated into any suitable pharmaceutically acceptable and effective composition which provides effective levels of each of the components in the body. The choice of the most appropriate pharmaceutical compositions for the combined components is within the skill of the art. Suitable formulations include, but are not limited to tablets, sub-lingual tablets, buccal compositions, capsules, powders, granules, lozenges, suppositories, reconstitutable powders, or liquid preparations such as oral or sterile parenteral solutions or suspensions.

In order to obtain consistency of adjunctive administration, the compositions of each of the components, or of the combination of the components is, for example, in the form of a unit dose.

The term "treatment" includes prophylaxis, where this is appropriate for the relevant condition(s).

Biological Test Methods

FLIPR experiments on M^ receptor to determine agonist/antagonist potency Assay A

Compounds of the invention were characterized in a functional assay to determine their ability to activate the intracellular calcium pathway in CHO cells with stable expression of human muscarinic receptors using FLIPR (Fluorometric Imaging Plate Reader) technology. Briefly, CHO-M1 cells were plated (20,000/well) and allowed to grow overnight at 37 degrees. Media was removed and 30μl_ loading buffer (HBSS with 2OmM HEPES, pH 7.4) containing FLIPR Calcium 3 dye (Molecular Devices Co., Sunnyvale, CA) was added according to manufacturer's instructions. After incubation at 37 degrees for 45-60 minutes, 10μL of the assay buffer (HBSS with 2OmM HEPES and 2.5 mM probenecid, pH 7.4) containing test compounds was added to each well on FLIPR instrument. Calcium response was monitored to determine agonism. Plates were then incubated for another 30 minutes before 10μL of assay buffer containing acetylcholine was added at an EC_8O, as the agonist challenge. Calcium response was then monitored again to determine compound's antagonism to acetylcholine. Concentration-response curves of both agonism and antagonism on M₁ receptors were performed for each compound. Results were imported into ActivityBase data analysis suite (ID Business Solution Inc., Parsippany, NJ) where the curves were analysed by non-linear curve fitting and the resulting pEC₅o/plC₅o were calculated. The intrinsic activities of agonist compounds were calculated as percentage of maximum FLIPR response induced by acetylcholine (i.e. using acetylcholine at EC₁00 as the control).

Assay B

Compounds of the invention were characterized in a functional assay to determine their ability to activate the intracellular calcium pathway in CHO cells with stable expression of human muscarinic receptors using FLIPR (Fluorometric Imaging Plate Reader) technology. Briefly, CHO-M1 cells were plated (15,000/well) and allowed to grow overnight at 37 degrees. Media was removed and 30μL loading buffer (HBSS with 2.5mM probenicid, 2μM Fluo-4, 500μM Brilliant Black, pH 7.4) was added. After incubation at 37 degrees for 90 minutes, 10μL of the assay buffer (HBSS with 2.5 mM probenecid, pH 7.4) containing test compounds was added to each well on the FLIPR instrument. Calcium response was monitored to determine agonism. Plates were then incubated for another 30 minutes before 10μL of assay buffer containing acetylcholine was added at an EC₈O, as the agonist challenge. Calcium response was then monitored again to determine compound's antagonism to acetylcholine. Concentration-response curves of both agonism and antagonism on M₁ receptors were performed for each compound. Results were imported into ActivityBase data analysis suite (ID Business Solution Inc., Parsippany, NJ) where the curves were analysed by non-linear curve fitting and the resulting pEC₅₀/fpK, were calculated. The intrinsic activities of agonist compounds were calculated as percentage of maximum FLIPR response induced by acetylcholine added as control on the same compound plates, and converted to a fraction between 0 and 1 (i.e. calculated using a 100% max response from a fitted acetylcholine standard curve, containing multiple concentrations, as control).

The example compounds below were tested in one or both of the above assays and were each found to have an average pEC₅o value of > 6.0 at the muscarinic M₁ receptor, and intrinsic activity > 50%. FLIPR experiments on M^ receptor to determine agonist intrinsic activity Assay A

To determine the intrinsic activities of M₁ agonist compounds, compounds of the invention were characterized in FLIPR experiments on U2OS cells with transient expression of human muscarinic M₁ receptors. Briefly, U2OS cells were transduced with M1 BacMam virus (Ames, R S; Fornwald, J A; Nuthulaganti, P; Trill, J J; Foley, J J; Buckley, P T; Kost, T A; Wu, Z and Romanos, M A. (2004) Use of BacMam recombinant baculoviruses to support G protein-coupled receptor drug discovery. Receptors and Channels 10 (3-4): 99- 109) in 2x10e5/mL cell suspension with 0.1% virus/cell ratio (v/v). The virus to cell ratio was determined in separate experiments by functional titration to be most appropriate to measure intrinsic activities of partial agonists. After mixing with virus in suspension, cells were then plated (10,000/well) and allowed to grow overnight at 37 degrees. FLIPR experiment was then carried out next day using the same protocol as described above for CHO-M1 cells. Results were imported into ActivityBase data analysis suite where the curves were analysed by non-linear curve fitting and the resulting pEC₅₀ values were calculated. The intrinsic activities of agonist compounds were calculated as percentage of maximum FLIPR response induced by acetylcholine added as control on the same compound plates, and converted to a fraction between 0 and 1 (i.e. calculated using a 100% max response from a fitted acetylcholine standard curve, containing multiple concentrations, as control).

Assay B

To determine the intrinsic activities of M₁ agonist compounds, compounds of the invention were characterized in FLIPR experiments on CHO cells with transient expression of human muscarinic M₁ receptors. Briefly, CHO cells were transduced with M1 BacMam virus (Ames, R S; Fornwald, J A; Nuthulaganti, P; Trill, J J; Foley, J J; Buckley, P T; Kost, T A; Wu, Z and Romanos, M A. (2004) Use of BacMam recombinant baculoviruses to support G protein-coupled receptor drug discovery. Receptors and Channels 10 (3-4): 99- 109) at a multiplicity of infection of 6. The virus to cell ratio was determined in separate experiments by functional titration to be most appropriate to measure intrinsic activities of partial agonists. After mixing with virus in suspension, cells were then plated (15,000/well) and allowed to grow overnight at 37 degrees. Alternatively, cells were then frozen in 1 ml vials at a concentration of 4.8x10e7 cells/ml in 90% dialysed Foetal Bovine Serum, 10% Dimethylsulphoxide at -140 degrees. Cells could then be thawed on the day prior to assay, plated (15,000/well) and allowed to grow overnight at 37 degrees.

The FLIPR experiment was carried out on the day following plating using the same protocol as described above for CHO-M1 cells. Results were imported into ActivityBase data analysis suite where the curves were analysed by non-linear curve fitting and the resulting pEC₅o values were calculated. The intrinsic activities of agonist compounds were calculated as percentage of maximum FLIPR response induced by acetylcholine added as control on the same compound plates, and converted to a fraction between 0 and 1 (i.e. calculated using a 100% max response from a fitted acetylcholine standard curve, containing multiple concentrations, as control).

The example compounds below were tested in one or both of the above assays, and were each found to have an average pEC₅₀ value of > 6.0 at the muscarinic M₁ receptor, and intrinsic activity of greater than or equal to 0.3.

FLIPR experiments on M_2-5 receptor to determine receptor subtype selectivity Assay A To determine selectivity of compounds of the invention against other muscarinic receptor subtypes, compounds were characterized in FLIPR experiments in CHO cells with stable expression of human muscarinic receptors, M₂, M₃, M₄ or M₅. In the case of M₂ and M₄ receptors, chimeric G-protein Gqi5 was also co-expressed to couple receptors to the calcium signaling pathway. Briefly, cells were plated (20,000/well) and allowed to grow overnight at 37 degrees. FLIPR experiment was then carried out next day using the same protocol as described above for CHO-M1 cells. Results were imported into ActivityBase data analysis suite where the curves were analysed by non-linear curve fitting and the resulting pEC₅o/plC₅o values were calculated.

Assay B

To determine selectivity of compounds of the invention against other muscarinic receptor subtypes, compounds were characterized in FLIPR experiments in CHO cells with stable expression of human muscarinic receptors, M₂, M₃, M₄ or M₅. In the case of M₂ and M₄ receptors, chimeric G-protein Gqi5 was also co-expressed to couple receptors to the calcium signaling pathway. Briefly, cells were plated (15,000/well) and allowed to grow overnight at 37 degrees. The FLIPR experiment was then carried out on the next day using the same protocol as described above for CHO-M1 cells. Results were imported into ActivityBase data analysis suite where the curves were analysed by non-linear curve fitting and the resulting pEC₅₀/fpK, values were calculated.

The example compounds below were tested in the above assay and were found to be selective for the M₁ receptor over M₂, M₃, M₄ and M₅ receptors, with typical selectivity (ratio of pEC₅₀'s) of >10-fold, and in certain cases > 100-fold.

The invention is further illustrated by the following non-limiting examples. In the procedures that follow, after each starting material, reference to a Description by number is typically provided. This is provided merely for assistance to the skilled chemist.

The starting material may not necessarily have been prepared from the batch referred to. SCX refers to a sulfonic acid ion exchange resin supplied by Varian. All reactions were either done under argon or can be done under argon, unless stated otherwise (for example hydrogenation reactions).

NMR spectra were run on either a Brucker DPX250A or DPX400B spectrometer at 250 or 400MHz frequency respectively at 295K and run as a dilute solution of d₆-DMSO unless otherwise stated. All NMR spectra were referenced to tetramethylsilane (TMS δH 0, δC 0). All coupling constants are reported in hertz (Hz) and multiplicities are labelled s (singlet), bs (broad singlet), d (doublet), t (triplet), q (quartet), dd (doublet of doublets), dt (doublet of triplets) and m (multiplet).

Mass spectra were recorded on an Agilent 1100 LCMS system using a Sunfire C18 3.5 micron reverse phase column eluted with acetonitrile - aqueous ammonium bicarbonate. Total ion current traces were obtained for electrospray positive and negative ionisation (ES+ / ES-) and/or atmospheric pressure chemical positive and negative ionisation (AP+ / AP-).

High pH MDAP purification was performed using either method A or B below.

High pH MDAP Method A

The HPLC analysis was conducted on an XBridge C18 column (150mm x 30mm i.d. 5μm packing diameter) at ambient temperature.

The solvents employed were:

A = 10 mM Ammonium Bicarbonate in water adjusted to pH 10 with Ammonia solution.

B = Acetonitrile.

The gradient employed was:

The UV detection was an averaged signal from wavelength of 210nm to 350nm and mass spectra were recorded on a mass spectrometer using alternate-scan positive and negative mode electrospray ionization.

High pH MDAP Method B

The solvents employed were:

B = Acetonitrile. The gradient employed was:

Starting materials, reagents and solvents were obtained from commercial suppliers and used without further purification unless otherwise stated. Unless otherwise stated, all compounds with chiral centres are racemic. Where reactions are described as having been carried out in a similar manner to earlier, more completely described reactions, the general reaction conditions used were essentially the same. Work up conditions used were of the types standard in the art, but may have been adapted from one reaction to another. The starting material may not necessarily have been prepared from the batch referred to. Compounds synthesised may have various purities ranging from for example 85% to 98%. However, calculations of number of moles and yield are generally not adjusted for this.

Abbreviations NMR Nuclear Magnetic Resonance

THF Tetrahydrofuran

DMSO Dimethylsulfoxide

DMF Dimethylformamide

DCM Dichloromethane EDC 1-ethyl-3-(dimethylaminopropyl)carbodiimide

HOBt 1 -hydroxybenzotriazole

MeCN /CH₃CN Acetonitrile

MDAP Mass-directed auto-preparation sat^d saturated nhex n-hexane

EtOAc ethyl acetate

LC/MS liquid chromatography/mass spectrometry

Rt room temperature

SM starting material RM reaction mixture DIPEA diisopropylethylamine

CV column volumes

Pd/C palladium on charcoal

PS polystyrenre

Description 1. (Methyloxy)acetaldehyde (D1).

A solution of 1 ,1 ,2-tris(methyloxy)ethane (4.66g, 38.8mmole) in HCI (0.08M) was stirred at 25⁰C for 16h. Sodium chloride was then added, the mixture the extracted using diethyl ether (20ml x 2) and the organic phase then dried (MgSO₄). The diethyl ether was then removed by distillation to afford a mixture of desired compound D1 (0.6g) and diethyl ether as a colourless liquid. 1H NMR δ (CDCI₃, 400 MHz): 3.46 (2H, d), 4.06 (3H, s), 9.73 (1 H, s)

Description 2. 2-(frans-4-{[2-(Methyloxy)ethyl]oxy}cyclohexyl)-1 H-isoindole-1 ,3(2H)- dione (D2).

To a solution of methoxyacetaldehyde D1 (0.5g, 6.67mmole) in acetonitrile (20ml) was added 2-(frans-4-{[(1 , 1-dimethylethyl)(dimethyl)silyl]oxy}cyclohexyl)-1 H-isoindole-1 ,3(2H)- dione (2.4g, 6.7mmole), triethylsilane (1.1 ml, 6.7mmole) and bismuth tribromide (300mg, 0.67mmole). The dark green reaction mixture was stirred at room temperature overnight and the solvent then removed by evaporation. The resultant residue was then taken up using ethyl acetate (30ml) and sodium bicarbonate followed by filtration through glass wool. The filtrate was then washed with brine (30ml) and the organic phase dried (MgSO₄) before solvents were removed by evaporation to afford crude material. The crude material was then purified on silica (0-50%, ethyl acetate/ hexane) to give D2 (440mg, 21%) as a white solid.

¹H NMR δ (CDCI₃, 400 MHz): 1.37-1.47 (2H, m), 1.76-1.80 (2H, m), 2.17-2.20 (2H, m), 2.26-2.36 (2H, m), 3.4 (3H, s), 3.37-3.43 (1 H, m), 3.54-3.56 (2H, m), 3.64-3.67 (2H, m), 4.09-4.18 (1 H, m), 7.68-7.72 (2H, m), 7.79-7.82 (2H, m)

Description 3. frans-4-{[2-(Methyloxy)ethyl]oxy}cyclohexanamine (D3).

To a solution of 2-(frans-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-1H-isoindole-1 ,3(2H)- dione D2 (440mg, 1.45mmole) in ethanol (15ml) was added hydrazine hydrate (0.21 ml,

4.3mmole) and the reaction brought to reflux at -8O⁰C for 3h. The mixture was then cooled, the white precipitate filtered-off and then volatiles removed by evaporation. The resultant residue was then taken up in diethyl ether and then filtered before solvents were removed under vacuum to afford the desired product D3 (100mg, 44%) as a colourless oil. ¹H NMR δ (CDCI₃, 400 MHz): 1.15-1.39 (4H, m), 1.87 (2H, m), 2.03 (2H, m), 2.16 (2H, m),

2.64-2.76 (1 H, m), 3.18-3.3 (1 H, m), 3.39 (3H, s), 3.53 (2H, m), 3.60 (2H, m).

Description 4. 1-(frans-4-{[2-(Methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinone (D4).

A stirred solution of the frans-4-{[2-(methyloxy)ethyl]oxy}cyclohexanamine D3 (110mg, 0.636mmole) in an ethanol/water (10ml/5ml) mixture was treated with potassium carbonate (10mg, 0.064mmole) followed by 1-ethyl-1-methyl-4-oxopiperidinium iodide (253mg, 0.954mmole) and the reaction heated at 8O⁰C under argon for 6hr. The reaction mixture was then cooled and then concentrated under vacuum. The resultant residue was treated with NaHCO₃ solution (30ml) and extracted with dichloromethane (3 x 50ml). The combined extract was dried (MgSO₄) and solvents removed by evaporation to afford the desired product D4 (160mg, 98%) as a yellow oil. 1H NMR δ(CDCI₃, 400 MHz): 1.18-1.37 (4H, m), 1.9 (2H, m), 2.13 (2H, m), 2.41-2.47 (4H, m), 2.49-2.53 (1 H, m), 2.82-2.85 (4H, m), 3.18 (1 H, m), 3.39 (3H, s), 3.53 (2H, m), 3.60 (2H, m).

Description 5. 1 -(frans-4-{[2-(Methyloxy)ethyl]oxy}cyclohexyl)-4-piperidin-amine (D5).

To a solution of 1-(frans-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinone D4 (160mg, 0.63mmole) in 2M NH₃/Me0H (15ml) was added 10% Pd/C (20mg) and the mixture shaken under a hydrogen atmosphere of initial pressure 55 psi for 72hr. The catalyst was the removed by filtration through Kieselguhr and the filtrate concentrated under vacuum to leave the title compound D5 (140mg, 88%) as a colourless oil. M⁺ + H = 257.

Description 6. Λ/-(5-Methyl-2-nitrophenyl)-1 -(frans-4-{[2-(methyloxy)ethyl] oxy}cyclohexyl)-4-piperidinamine (D6).

A solution of 3-fluoro-4-nitrotoluene (108mg, 0.695mmole) and 1 -(trans-4-{[2- (methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinamine D5 (70mg, 0.27mmole) in dimethylformamide (3ml) under argon was treated with diisopropylethylamine (0.17ml, 1 mmole) and the reaction mixture heated at 11 O⁰C for 20mins in a microwave reactor. The resulting mixture was then concentrated under vacuum, the residue treated using dil. NaHCO₃ solution (30ml) and then extracted using ethyl acetate (2x40ml). The combined extract was dried (MgSO₄) and concentrated under vacuum to give crude material as an orange residue. The residue was then chromatographed on silica eluting 0-10% methanol/dichloromethane to yield the title compound D6 (65mg, 61 %) as an orange oil. M⁺ + H = 392.

Description 7. (2-Amino-5-methylphenyl)[1 -(frans-4-{[2-(methyloxy)ethyl] oxy}cyclohexyl)-4-piperidinyl]amine (D7).

A stirred solution of the Λ/-(5-methyl-2-nitrophenyl)-1-(frans-4-{[2- (methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinamine D6 (65mg, 0.166mmole) in ethanol (1OmI) at room temperature under argon was treated with Raney Nickel (15mg), followed by hydrazine hydrate (80μl_, 1.66mmole). The reaction mixture left to stir for 2h when the initial yellow colour had disappeared. The catalyst was removed by filtration through Kieselguhr and the filtrate concentrated under vacuum to leave the diamine as an off- white solid D7 (51 mg, 88%). M⁺ + H = 362.

Description s. 1 ,4-Dioxaspiro[4.5]decan-8-ol (D8).

1 ,4-Dioxaspiro[4.5]decan-8-one (64 mmol, 10 g) was dissolved in ethanol (125 ml) and treated portionwise with NaBH₄ (1.2eq., 76.8 mmol, 2.9 g), at O⁰C and the mixture was stirred at room temperature for 1 hour. Reaction was quenched with NaOH (25 ml, 2N aqueous solution). The aqueous solution was extracted with dichloromethane. The organic extracts were combined, dried over Na₂SC>₄, filtered and the solvent was evaporated to afford the title compound, 8.3 g, 82%, as a colourless oil. 1H NMR δ (d⁶DMSO, 400 MHz) 1.44 (4H, m), 1.64 (4H, m), 3.54 (1 H, d broad), 3.82 (4H, m), 4.48 (1 H, d).

Description 9. 8-{[2-(Methyloxy)ethyl]oxy}-1,4-dioxaspiro[4.5]decane (D9).

1 ,4-dioxaspiro[4.5]decan-8-ol D8 (1g, 5.814mmole) was dissolved in dimethylformamide

(25ml) and sodium hydride 60% (0.2g, 8.72mmole) added portionwise at 0 ⁰C. The reaction mixture was stirred at this temperature for 10min before 1-bromo-2- (methyloxy)ethane (0.85ml, 8.72mmole) was added. The reaction was stirred at room temperature for 16h then quenched using methanol, before being partitioned between ethyl acetate and water. The aqueous phase was then extracted using ethyl acetate (x 2), organics combined, washed with brine, dried (MgSO₄), filtered and volatiles removed under vacuum to provide crude material. The crude compound was then purified on silica eluting (ethyl acetate/hexane, 0-50%) to afford D9 (250mg, 19%) colourless oil.

¹H NMR δ(CDCI₃, 400 MHz): 1.5-1.57 (2H, m), 1.68-1.87 (6H, m), 3.38 (3H, s), 3.40-3.46 (1 H, m), 3.52-3.56 (2H, m), 3.58-3.60 (2H, m), 3.90-3.97 (4H, m).

Description 9b. Scale-up preparation of 8-{[2-(methyloxy)ethyl]oxy}-1 ,4- dioxaspiro[4.5]decane (D9b)

D9b

1 ,4-dioxaspiro[4.5]decan-8-ol (D8) (1eq., 10 g, 58 mmol), was dissolved in 200 ml of dry DMF and NaH (1.01eq., 58.7 mmol, 2.3g, 60% in mineral oil), was added portion wise at 0 ⁰C. The mixture was stirred at the same temperature for 30 min and then 1-bromo-2- (methyloxy)ethane was added at 0 ⁰C (1.5eq., 87 mmol, 8.2 ml) followed by NaI (catalytic, 0.5g). The mixture was stirred at room temperature overnight then gently warmed to 40 ⁰C for one extra overnight. The mixture was subsequently quenched with MeOH, diluted with water and extracted with EtOAc (3x). Organic extracts were diluted with hexane and washed with brine and water (2x). The organic extracts were then dried over Na₂SO₄, filtered and the solvent was evaporated to afford 3.7g of crude product that was purified by silica chromatography (EtOAc-nhex, 40 M column) to afford the title compound, 12%, colourless oil, 1.6g.

¹H NMR (CDCI₃, 400 MHz) δ ppm: 1.51-1.69 (2H, m), 1.70-1.87 (6H, m), 3.39 (3H, s), 3.40-3.45 (1 H, m), 3.52-3.64 (4H, m), 3.94 (4H, s).

Description 10. 4-{[2-(methyloxy)ethyl]oxy}cyclohexanone (D10).

To a solution of 8-{[2-(methyloxy)ethyl]oxy}-1 ,4-dioxaspiro[4.5]decane D9 (250mg, 1.09mmole) in tetrahydrofuran (3ml) was added 5M HCI (5ml) and the reaction mixture left to stir at room temperature under argon overnight. The tetrahydrofuran was then removed by evaporation to leave an aqueous solution which was subsequently extracted using dichloromethane (30ml x 2). The organic phase was then separated, dried (phase separation cartridge) and volatiles removed under vacuum to yield ketone D10 (190mg, 41%) as a colourless oil.

¹H NMR δ(CDCI₃, 400 MHz): 1.93-1.99 (2H, m), 2.06-2.14 (2H, m), 2.23-2.29 (2H, m), 2.55-2.63 (2H, m), 3.4 (3H, s), 3.56-3.59 (2H, m), 3.66-3.68 (2H, m), 3.75-3.78 (1 H, m).

Description 10b. Scale-up preparation of 4-{[2-(methyloxy)ethyl]oxy}cyclohexanone (D10b).

8-{[2-(methyloxy)ethyl]oxy}-1 ,4-dioxaspiro[4.5]decane (D9b) (1.6g, 7 mmol), was dissolved in 20 ml of THF and HCI (25 eq., 35 ml) was added at room temperature. The mixture was stirred at room temperature for 5 hours, THF was evaporated and the aqueous layer was extracted with dichloromethane (2x). The organic extracts were washed once with water, dried over Na₂SO₄, filtered and the solvent was evaporated to afford 1.3 g of the title compound, complete conversion. 1H NMR (CDCI₃, 400 MHz) δ ppm: 1.96 (2H, m), 2.1 (2H, m), 2.27 (2H, m), 2.56 (2H, m), 3.41 (3H, s), 3.58 (2H, m), 3.84 (1 H, m). Description 11. 1,1-Dimethylethyl 4-[(4-fluoro-5-methyl-2-nitrophenyl)amino]-1- piperidine-carboxylate (D11).

1 ,4-Difluoro-2-methyl-5-nitrobenzene (1.5 mol, 260 mg) in dimethylformamide (10 ml.) was treated under argon at room temperature with commercially available 1 ,1- dimethylethyl 4-amino-1-piperidinecarboxylate (1.5 mmol, 300.5 mg, 1 eq) and diisopropylethylamine (1.5 mmol, 260 μl_, 1 eq) then stirred at 70-80 ⁰C for 38h. The mixture was concentrated under reduced pressure, treated with water and extracted twice with ether. The organic extracts were combined, dried over MgSO₄ and concentrated under reduced pressure to give a red-brown residue which was chromatographed (0-25% ethyl acetate/petrol ether) to give the title compound as a red solid (0.96 mmol, 340 mg, 64% yield). M+H-'Bu = 298.07, main fragment.

Description 12. 1,1-Dimethylethyl 4-[(2-amino-4-fluoro-5-methylphenyl)amino]-1- piperidinecarboxylate (D12).

1 ,1-Dimethylethyl 4-[(4-fluoro-5-methyl-2-nitrophenyl)amino]-1-piperidinecarboxylate

(D11 ) (0.96 mmol, 340 mg) in ethanol (10 ml.) was treated under argon at room temperature with Raney Nickel (50% in water, 0.5 ml.) then dropwise with hydrazine hydrate (9.6 mmol, 10 eq) in ethanol over 15min. The mixture was heated at 45°C for 50min. The Raney nickel was filtered off and washed with ethanol. The filtrate was concentrated under reduced pressure to give the title compound (0.88 mmol, 284 mg, 92% yield). M+H = 324.16

Description 13. 1,1 -Dimethylethyl 4-(5-fluoro-6-methyl-2-oxo-2,3-dihydro-1H- benzimidazol-1-yl)-1 -piperidine-carboxylate (D13).

1 ,1-Dimethylethyl 4-[(2-amino-4-fluoro-5-methylphenyl)amino]-1-piperidinecarboxylate (D12) (0.88 mmol, 284 mg) in tetrahydrofuran (5 ml.) was treated with N₁N'- carbonyldiimidazole (0.88 mmol, 141 mg, 1 eq) under argon and was stirred at room temperature for 3h then heated at 45 ⁰C for 45 min, then N,N'-carbonyldiimidazole (0.44 mmol, 70 mg, 0.5 eq) was added and allowed to react for 45 min. The mixture was concentrated, partitioned between 10% Na₂CO₃ aqueous solution and ethyl acetate. The organic extracts were dried over MgSO₄, concentrated and chromatographed to give the title compound (0.68 mmol, 239 mg, 77% yield). M-H = 348.3

Description 14. 5-Fluoro-6-methyl-1 -(4-piperidinyl)-1,3-dihydro-2H-benzimidazol-2- one hydrochloride (D14).

1 ,1-Dimethylethyl 4-(5-fluoro-6-methyl-2-oxo-2,3-dihydro-1 H-benzimidazol-1-yl)-1- piperidine-carboxylate (D13) (22 mmol, 7.6g) in dichloromethane (75 ml.) was treated under argon at room temperature with 4M hydrochloric acid/dioxane (25 ml.) and allowed to stir for 1 h. The mixture was then filtered to afford D14 (62 g, 100% yield). M+H = 250.2

Description 15. N-Boc 4-[(3,5-Difluoro-2-nitrophenyl)amino]-piperidine (D15).

A mixture of 2,4,6-trifluoronitrobenzene (2.0 g), N-Boc-4-aminopiperidine (2.0 g), diisopropylethylamine (2.2 ml), and DMF (25 ml) was stirred overnight at room temperature then diluted with ethyl acetate, washed three times with water, dried, evaporated, and purified by chromatography on silica gel (50 g), eluting with 0-25% ethyl acetate in hexane to give the title compound, (2.9g).

Description 16. N-Boc 4-[(3,5-Difluoro-2-aminophenyl)amino]-piperidine (D16).

A mixture of N-Boc 4-[(3,5-difluoro-2-nitrophenyl)amino]-piperidine (2.9 g) (D15), tin dichloride dihydrate (7.0 g), and ethanol (100 ml) was stirred at 80 ⁰C for 4h then cooled and partitioned between 1 M aqueous sodium hydroxide and diethyl ether. The organic layer was dried and evaporated then dissolved in dichloromethane and di-t-butyl dicarbonate (1.7 g) added. After 15 min at room temperature evaporation gave the title compound, (2.6g). [M-Boc]⁺=228

Description 17. 4,6-Difluoro-1 -(N-Boc-4-piperidinyl)-1 ,3-dihydro-2H-benzimidazol-2- one

A solution containing N-Boc 4-[(3,5-difluoro-2-aminophenyl)amino]-piperidine (2.6 g) (D16) in dichloromethane (50 ml) at O⁰C was treated with triphosgene (0.95 g) then diisopropylethylamine (2.7 ml). After 1 h at the same temperature the solution was washed with aqueous sodium bicarbonate, dried, evaporated, and purified by chromatography on silica gel, eluting with 0-10% 2M ammonia in methanol- dichloromethane to give the title compound, (0.7g), MH⁺=354 Description 18. 4,6-Difluoro-1-(4-piperidinyl)-1 ,3-dihydro-2H-benzimidazol-2-one hydrochloride (D18).

A mixture of 4,6-difluoro-1-(N-Boc-4-piperidinyl)-1 ,3-dihydro-2H-benzimidazol-2-one (D17) (700 mg), dichloromethane (10 ml), and 4M HCI in dioxane (10 ml) was stirred overnight at room temperature, then evaporated and the residue crystallised from diethyl ether to give the title compound, (600mg). MH⁺=254

Description 19. 1 -[4-(4,6-Difluoro-2-oxo-2,3-dihydro-1 H-benzimidazol-1 -yl)-1 - piperidinyl]-4-{[2-(methyloxy)ethyl]oxy}cyclohexanecarbonitrile (D19).

4,6-Difluoro-1-(4-piperidinyl)-1 ,3-dihydro-2H-benzimidazol-2-one monohydrochloride

(D18) (150 mg, 0.52 mmol) was combined with dimethylacetamide (2ml), 4-{[2- (methyloxy)ethyl]oxy}cyclohexanone (2eq., 1.04 mmol, 178 mg) (D10b), acetone cyanohydrin (2.2 eq., 1.14 mmol, 0.1 ml), MgSO₄ (3.5 eq., 1.82 mmol, 306 mg). Reagents were all heated to 60-70 ⁰C under a mild stream of argon for 2 days. The mixture was then cooled to room temperature and water and dichloromethane were added; the mixture was stirred vigorously at room temperature for 30 minutes. The two phases were separated and the aqueous phase was extracted with dichloromethane (2x). The organic extracts were combined , dried over Na₂SO₄, filtered and the solvent was evaporated to afford the crude product that was triturated with Et₂O to afford the title compound as a white solid (170 mg, 76%), MH+=435 Description 20. 1-Chloro-4-fluoro-2-methyl-5-nitrobenzene (D20).

1-Chloro-4-fluoro-2-methylbenzene (10 mmol, 1.44 g) was dissolved in concentrated sulphuric acid under argon and cooled to 0 ⁰C. KNO₃ (10 mmol, 1.01 g, 1 eq) was then added cautiously while keeping the temperature around 0⁰C. The mixture was then allowed to stir for 2h while warming up to room temperature, then poured cautiously onto ice and extracted twice with ether. The organic extracts were combined, dried over MgSO₄ and concentrated under reduced pressure to give an oil (9.1 mmol, 1.73 g, 91% yield), which was chromatographed (0-25% ethyl acetate/petrol ether) to give the title compound as a transparent oil (7 mmol, 1.3 g, 70% total yield). 1H NMR δ (CDCI₃): 8.09 (1 H, d), 7.19 (1 H, d), 2.46 (3H, s).

Description 21. 1,1-Dimethylethyl 4-[(4-chloro-5-methyl-2-nitrophenyl)amino]-1- piperidinecarboxylate (D21).

A solution of 1-chloro-4-fluoro-2-methyl-5-nitrobenzene (D20, 473mg, 2.5mmol) in DMF (7ml) was treated with diisopropylethylamine (49OuI, 2.75mmol) followed by addition of 1 ,1-dimethylethyl 4-amino-1-piperidinecarboxylate (500mg, 2.5mmol), then heated at 60 ⁰C under argon with stirring for 12 hours. The reaction mixture was concentrated under vacuum and the residue treated with NaHCO₃ solution (50ml) and extracted with dichloromethane (2 x 50ml). The combined extract was concentrated under vacuum and the residue purified by chromatography on silica gel eluting with dichloromethane to afford the title compound (808mg, 88%). 1H NMR δ (CDCI₃): 1.45-1.60 (13H, s + m), 2.02-2.08 (2H, m), 2.38 (3H, s), 3.02-3.12 (2H, m), 3.60-3.70 (1 H, m), 6.72 (1 H, s), 8.04 (1 H, br d), 8.18 (1 H, s).

Description 22. 1,1 -Dimethylethyl 4-[(2-amino-4-chloro-5-methylphenyl)amino]-1- piperidinecarboxylate (D22).

1 ,1-Dimethylethyl 4-[(4-chloro-5-methyl-2-nitrophenyl)amino]-1-piperidinecarboxylate

(D21 ) (850 mg, 2.3 mmol) was dissolved into EtOH (25 ml) and Raney-Ni (10% aqueous solution, 2.3 ml) was added at room temperature followed by hydrazine monohydrate ( 10 eq., 23 mmol, 0.7 ml). The mixture was heated to 40 ⁰C for 10 minutes then it was cooled to room temperature, filtered through celite and the solvent was evaporated to afford the title compound, (590mg, 76%). [M-BoC]⁺= 240

Description 23. 1,1-Dimethylethyl 4-(5-chloro-6-methyl-2-oxo-2,3-dihydro-1H- benzimidazol-1 -yl)-1 -piperidinecarboxylate (D23).

D23

1 , 1 -Dimethylethyl 4-[(2-amino-4-chloro-5-methylphenyl)amino]-1 -piperidinecarboxylate (D22) was dissolved in dichloromethane (10 ml) and DIPEA (2eq., 3.5 mmol, 0.6 ml) was added. The mixture was cooled to 0 ⁰C and triphosgene (0.4 eq., 0.7 mmol, 206 mg) was added at the same temperature portionwise. The mixture was then stirred at room temperature for one overnight. The mixture was then quenched with 5 ml of aqueous 2M NaOH, diluted with dichloromethane and aqueous saturated NaHCO₃, the two phases were separated and the aqueous phase was extracted with dichloromethane (1x). The organic extracts were combined, dried over Na₂SO₄, filtered and the solvent was evaporated to afford the crude product that was purified by silica chromatography to afford the title compound, (530 mg, 84%). [M-Boc]⁺=266

Description 24. 5-Chloro-6-methyl-1 -(4-piperidinyl)-1 ,3-dihydro-2H-benzimidazol-2- one monohydrochloride (D24).

D24

1 ,1-Dimethylethyl 4-(5-chloro-6-methyl-2-oxo-2,3-dihydro-1 H-benzimidazol-1-yl)-1- piperidinecarboxylate (D23) (530 mgs, 1.45 mmol), was dissolved into MeOH-DCM (5ml- 10ml) and HCI (13.8 eq., 5 ml) was added at room temperature. The mixture was stirred at room temperature for 48 hours, the solvent was then evaporated and the solid obtained was triturated with Et₂O to afford the title compound, (390mg, 90%). MH⁺= 266

Description 25. 8-{[2-(Ethyloxy)ethyl]oxy}-1,4-dioxaspiro[4.5]decane (D25).

A stirred solution of 1 ,4-dioxaspiro[4.5]decan-8-ol (D8, 3.Og, 0.019mol) in N, N- dimethylformamide (20ml) at O⁰C under argon was treated portionwise over 10 minutes with sodium hydride (0.92g of 60% oil dispersion, 0.023mol). Following addition, the reaction mixture was allowed to warm up to room temperature with good stirring. After 1 hour the mixture was treated with 2-bromoethyl ethyl ether (3.0ml, 0.027mol) and stirred at room temperature for 4 hours. The reaction mixture was treated with MeOH (1 ml) to destroy excess sodium hydride, then poured into water (200ml) and extracted with n- hexane (2 x 70ml). The combined extract was dried (Na₂SO₄) and concentrated under vacuum to leave a colourless oil (1.85g). The aqueous phase was further extracted with Et₂O (2 x 70ml) and these extracts combined, dried (Na₂SO₄) and concentrated under vacuum to give a second colourless oil (0.5g). The products from the n-hexane and Et₂O extracts were combined and then chromatographed on silica gel (2Og) eluting with 0-30% EtOAc/60-80 petrol ether to afford a colourless oil (1.25g). This still contained some starting alkyl bromide, so a solution in dichloromethane (20ml) was treated with PS- trisamine (1g of 3.71 mmol/g), stirred at room temperature for 18 hrs, then filtered through Kieselguhr and the filtrate concentrated under vacuum to afford the title compound as a colourless oil (1.2Og).

¹H NMR (CDCI₃, 400MHz) δ: 1.20 (3H, t), 1.50-1.60 (2H, m), 1.67-1.90 (6H, m), 3.40-3.48 (1 H, m), 3.5-3.68 (6H, m), 3.90-3.98 (4H, m).

Description 26. 4-{[2-(Ethyloxy)ethyl]oxy}cyclohexanone (D26).

D26

A stirred solution of 8-{[2-(ethyloxy)ethyl]oxy}-1 ,4-dioxaspiro[4.5]decane (D25, 1.2Og, 5.2mmol) in THF (5ml) at room temperature under argon was treated with 5M HCI acid (15ml) and stirred well for 18 hours. The solution was concentrated under vacuum to approx. 15ml volume to remove the THF and the remaining aqueous phase was extracted with DCM (2 x 20ml). The extract was dried (Na₂SO₄) and concentrated under vacuum at 25⁰C to afford the title compound as a colourless oil (0.95g, 98%). 1H NMR (CDCI₃, 400MHz) δ: 1.21 (3H, t), 1.90-2.00 (2H, m), 2.04-2.18 (2H, m), 2.20-2.30 (2H, m), 2.54-2.65 (2H, m), 3.50-3.70 (6H, m), 3.73-3.80 (1 H, m).

Description 27. 4-{[2-(Ethyloxy)ethyl]oxy}-1 -[4-(5-fluoro-6-methyl-2-oxo-2,3-dihydro- 1H-benzimidazol-1-yl)-1-piperidinyl]cyclohexanecarbonitrile (D27).

A sample of 5-fluoro-6-methyl-1-(4-piperidinyl)-1 ,3-dihydro-2H-benzimidazol-2-one hydrochloride (D14, 300mg, 1.05mmol) was converted to the free base by dissolving in a mixture of MeOH (2ml) and water (1 ml), loading on to a SCX cartridge (2g) and washing with MeOH, then eluting with 2M NH₃/MeOH. Concentration of the NH₃ solution afforded 5-fluoro-6-methyl-1-(4-piperidinyl)-1 ,3-dihydro-2H-benzimidazol-2-one as a brown gum. This gum was dissolved in N,N-dimethylacetamide (4ml) and treated with acetone cyanohydrin (180mg, 2.10mmol), 4-{[2-(ethyloxy)ethyl]oxy}cyclohexanone (D26, 390mg, 2.10mmol) and anhydrous magnesium sulphate (680mg), then heated at 6O⁰C for 4 days with a gentle flow of argon over the stirred mixture. The reaction mixture was allowed to cool, then treated with water (10ml) and extracted with DCM (2 x 20ml). The combined extract was washed with water (2 x 20ml), dried (Na₂SO₄) and concentrated under vacuum. The residue was crystallised from 4:1 mixture of Et₂O/EtOAc to afford the title compound as a white solid (230mg, 49%). This was a mixture of isomers.

¹H NMR (CDCI₃, 400MHz) δ: 1.20-1.28 (3H, m), 1.60-1.85 (3H, m), 1.85-2.13 (6H, m), 2.28-2.54 (8H, m), 3.25-3.34 (2H, m), 3.40 (approx. 0.33H, m), 3.50-3.65 (approx. 6.67H, m), 4.20-4.38 (1 H, m), 6.80 (1 H, d), 6.90 (approx. 0.33H, d), 6.97 (approx. 0.67H, d), 9.16 (approx. 0.33H, s), 9.25 (approx. 0.67H, s).

Description 28. 1-[4-(5-Fluoro-6-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)-1 - piperidinyl]-4-{[2-(methyloxy)ethyl]oxy}cyclohexanecarbonitrile (D28).

The free base (191.7 mg, 0.77 mmol) of 5-fluoro-6-methyl-1-(4-piperidinyl)-1 ,3-dihydro- 2H-benzimidazol-2-one monohydrochloride (D14) was dissolved in N, N- dimethylacetamide (6 ml.) at rt under argon. 4-{[2-(Methyloxy)ethyl]oxy}cyclohexanone (D10b) (283 mg, 1.65 mmol), magnesium sulphate (434 mg, 3.6 mmol) and acetone cyanohydrin (140 μl_, 1.53 mmol) were added and the reaction heated at 60-70 ⁰C under a gentle stream of argon, to remove acetone as it boiled off. The mixture was stirred for 2 h, during which time the reaction boiled dry so a portion of Λ/,Λ/-dimethylacetamide (10 ml.) was added. The reaction was heated overnight after which a further portion of N, N- dimethylacetamide (4 ml.) was added. The mixture was diluted with 1 :1 DCM:H₂O (20 ml.) and sonicated for 20 min. The two phases were separated by filtration through a hydrophobic cartridge. A second portion of DCM was added to the aqueous layer and the mixture was stirred vigorously for 10 min. The two phases were again separated by filtration through a hydrophobic cartridge and the combined organics concentrated by rotary evaporation to give a yellow/orange solid. This was triturated with Et₂O to give the title compound (D1 , 243 mg, 74%), as a mixture of cis and trans isomers, as a pale brown solid.

High pH LCMS: 2 peaks {cis and trans isomers) with [M-CN]⁺ = 404.

Example 1. 6-Methyl-1 -[1-(frans-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4- piperidinyl]-1,3-dihydro-2H-benzimidazol-2-one hydrochloride (E1).

A stirred solution of (2-amino-5-methylphenyl)[1-(frans-4-{[2-(methyloxy)ethyl] oxy}cyclohexyl)-4-piperidinyl]amine D7 (51 mg, 0.141 mmole) in dichloromethane (5ml) at 25⁰C under argon was treated with diisopropylethylamine (36μl_, 0.212mmole) followed by solid triphosgene (17mg, 0.0564mmole) and maintained at O⁰C for 1 h. The mixture was treated with dil. sodium bicarbonate solution (10ml) and extracted with dichloromethane (2 x 15ml). The combined extract was dried (MgSO₄) and concentrated under vacuum to afford a pale yellow solid E1 (50mg, 92%) as a free base.

¹H NMR (free base) δ(CDCI₃, 400 MHz): 1.02-1.03 (4H, m), 1.29-1.35 (5H, m), 1.83 (2H, d), 1.95 (2H, d), 2.15 (2H, d), 2.39 (3H, s), 3.06 (2H, d), 3.23 (1 H, m), 3.39 (3H, s) 3.54 (2H, t), 3.63 (2H, t), 4.34 (1 H, m), 6.85 (1 H, d), 6.96 (1 H, d), 7.12 (1 H, s), 9.36 (1 H, s).

The residue was dissolved in DCM then treated with 1 M HCI/diethyl ether (0.25ml) and solvents removed by evaporation to yield the hydrochloride salt as a white solid.

Example 2a. 5-Fluoro-6-methyl-1 -[1 -(frans-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4- piperidinyl]-1 ,3-dihydro-2H-benzimidazol-2-one hydrochloride (E2a)

and

Example 2b. 5-Fluoro-6-methyl-1 -[1 -(c/s-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4- piperidinyl]-1,3-dihydro-2H-benzimidazol-2-one hydrochloride (E2b).

A stirred suspension of 5-fluoro-6-methyl-1 ,3-dihydro-2H-benzimidazol-2-one hydrochloride D14 (156mg, 0.55mmole) in dichloromethane (10ml) was treated with 4-{[2- (methyloxy)ethyl]oxy}cyclohexanone D10 (95mg, 0.51 1 mmole) followed by portionwise addition of NaBH(OAc)₃ (529 mg, 2.5 mmol). After stirring overnight, polymer supported sodium cyanoborohydride (118mg) and sodium acetate (41 mg) were added and the reaction mixture was heated at 110 ⁰C for 2h in a microwave reactor. The polymer supported reagent was then removed by filtration and solvents removed by evaporation to afford a residue. This material was treated with sodium bicarbonate solution and the mixture extracted using ethyl acetate (50ml x 2). The organic extracts were combined, dried (MgSO₄), then solvents removed under vacuum to afford crude material. The crude material was then purified using a high pH MDAP method to provide the free base of both the trans E2a and cis E2b isomers.

¹H NMR (free base E2a) δ(CDCI₃, 400 MHz): 1.22-1.34 (4H, m), 1.84 (2H, m), 1.96 (2H, m), 2.17 (2H, m), 2.29 (3H, s), 2.42 (5H, m), 3.09 (2H, m), 3.21-3.24 (1 H, m), 3.40 (3H, s), 3.53-3.55 (2H, m), 3.62-3.64 (2H, m), 4.33 (1 H, m), 6.79 (1 H, d), 7.09 (1 H, s), 9.60 (1 H, s).

¹H NMR (free base E2b) δ(CDCI₃, 400 MHz): 1.4-1.47 (2H, m), 1.65 (2H, m) 1.69-1.77 (2H, m), 1.84 (2H, m), 2.03-2.05 (2H, m), 2.29 (3H, s), 2.45 (5H, m), 3.15 (3H, m), 3.40 (3H, s), 3.56-3.58 (4H, m), 4.36 (1 H, m), 6.80 (1 H, d), 7.12 (1 H, s), 9.89 (1 H, s)

Compound E2a was then treated with 1 M HCI/Et₂O (0.5 ml) and left to stir under argon for 1 h. Volatiles were then removed under vacuum to afford the hydrochloride salt (13mg, 5%) M⁺ + H = 406

Compound E2b was then treated with 1 M HCI/Et₂O (0.5 ml) and left to stir under argon for 1 h. Volatiles were then removed under vacuum to afford the hydrochloride salt (15mg, 6%) M⁺ + H = 406 Example 3a. 4,6-Difluoro-1 -[1 -(c/s-1 -methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)- 4-piperidinyl]-1 ,3-dihydro-2H-benzimidazol-2-one hydrochloride (E3a)

and

Example 3b. 4,6-Difluoro-1 -[1 -(trans-Λ -methyl-4-{[2-(methyloxy)ethyl]oxy} cyclohexyl)-4-piperidinyl]-1 ,3-dihydro-2H-benzimidazol-2-one hydrochloride (E3b).

E3a E3b

A cis/trans mixture of 1-[4-(4,6-difluoro-2-oxo-2,3-dihydro-1 H-benzimidazol-1-yl)-1- piperidinyl]-4-{[2-(methyloxy)ethyl]oxy}cyclohexanecarbonitrile (D19) (170 mgs, 0.39mmol) was dissolved into dry THF (5 ml) and MeMgI (5eq., 2mmol, 0.7 ml, from a 3M solution in Et₂O) was added at 0 ⁰C. The mixture was then left warming up to room temperature for one overnight and then it was quenched with NH₄CI (aq. saturated solution) and diluted with water. The aqueous mixture was extracted with EtOAc (2x), the organic extracts were combined, dried over Na₂SO₄, filtered and the solvent was evaporated to afford a cis/trans mixture of products, (150 mgs). The cis/trans mixture was purified by MDAP (high pH method) to afford the two separated isomers as free bases. The cis and trans free bases isomers (80mgs and 20mgs respectively) were subsequently converted to their corresponding HCI salts by treatment with a 1 M solution of HCI in Et₂O (0.47 mmol and 0.12 mmol respectively) to afford the title compounds (E3a), 62mgs, MH⁺=424 and (E3b), 20mgs, MH⁺=424.

¹H NMR (HCI salt E3a) (d₆-DMSO, 400 MHz) δ ppm: 1.34 (3H, s), 1.56 (2H, t), 1.73 (2H, d), 1.91 (6H, m), 2.74 (2H, q), 3.19 (3H, q), 3.27 (3H, s), 3.48 (5H, m), 3.67 (2H, d), 4.62 (1 H, m), 6.97 (1 H, t), 7.43 (1 H, dd), 9.47 (1 H, m br), 11.1 (1 H, s).

¹H NMR (HCI salt E3b) (d₆-DMSO, 400 MHz) δ ppm: 1.31 (5H, m), 1.81-2.00 (8H, m), 2.79 (2H, q), 3.14-3.25 (5H, m), 3.42 (2H, m), 3.55 (2H, m), 3.65 (2H, d), 4.62 (1 H, m), 6.70 (1 H, t), 7.53 (1 H, d), 9.95 (1 H, m br), 1 1.1 (1 H, s). Example 4a. 5-Chloro-6-methyl-1 -[1 -(frans-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)- 4-piperidinyl]-1,3-dihydro-2H-benzimidazol-2-one hydrochloride (E4a)

and

Example 4b. 5-Chloro-6-methyl-1 -[1 -(c/s-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4- piperidinyl]-1 ,3-dihydro-2H-benzimidazol-2-one hydrochloride (E4b).

E4a E4b

5-Chloro-6-methyl-1-(4-piperidinyl)-1 ,3-dihydro-2/-/-benzimidazol-2-one monohydrochloride (D24) (300 mgs, 1 mmol) was combined with dichloromethane (10 ml), PS-cyanoborohydride (3 eq., 3 mmol, 700 mg), sodium acetate (1.5 eq., 1.5 mmol, 123 mg), AcOH (1.5 eq, 1.5 mmol, 0.09 ml) and 4-{[2-(methyloxy)ethyl]oxy}cyclohexanone (D10) (2eq., 2mmol, 372 mg). The mixture was heated to 110 ⁰C by microwave for 30 minutes. The mixture was then filtered through hydrophobic filters, and it was purified by SCX (5g cartridge), to afford the crude product that was purified by amino column (25M cartridge, EtOAc-n-hex) first and by high pH MDAP second to afford the trans isomer (40 mg) and the cis isomer (65 mg) as free bases. Both isomers were subsequently dissolved into MeOH/dichloromethane (1 ml/1 ml) and treated with a 1 M solution of HCI (2 eq.). The resulting mixture was stirred at room temperature for 10 min; the solvent was evaporated to afford the title compounds (E4a), (38mg), MH⁺=422 and (E4b), (50mg), MH⁺=422.

¹H NMR (HCI salt E4a) (d₆-DMSO, 500 MHz) δ ppm: 1.20 (2H, m), 1.53 (2H, q), 1.88 (2H, d), 2.34 (3H, s), 2.82 (2H, q), 3.23 (7H, m), 3.41 (2H, m), 3.48-3.54 (4H, m), 4.55 (1 H, m), 7.00 (1 H, s), 7.66 (1 H, s), 10.4 (1 H, s br), 1 1.0 (1 H, s).

¹H NMR (HCI salt E4b) (d₆-DMSO, 500 MHz) δ ppm: 1.44 (2H, t), 1.68 (2H, q), 1.89 (4H, m), 1.99 (2H, d), 2.34 (3H, s), 2.84 (2H, q), 3.17-3.27 (6H, m), 3.45-3.55 (7H, m), 4.56 (1 H, m), 7.00 (1 H, s), 7.69 (1 H, s), 10.4 (1 H, s br), 11.0 (1 H, s). Example 5a. 1 -[1 -(frans-4-{[2-(Ethyloxy)ethyl]oxy}-1 -methylcyclohexyl)-4- piperidinyl]-5-fluoro-6-methyl-1 ,3-dihydro-2H-benzimidazol-2-one hydrochloride (E5a)

and

Example 5b. 1 -[1 -(c/s-4-{[2-(Ethyloxy)ethyl]oxy}-1-methylcyclohexyl)-4-piperidinyl]- 5-fluoro-6-methyl-1,3-dihydro-2H-benzimidazol-2-one hydrochloride (E5b).

E5a E5b

A stirred solution of 4-{[2-(ethyloxy)ethyl]oxy}-1-[4-(5-fluoro-6-methyl-2-oxo-2,3-dihydro- 1/-/-benzimidazol-1-yl)-1-piperidinyl]cyclohexanecarbonitrile (D27, 190mg, 0.43mmol) in THF (10ml) at room temperature under argon was treated with a 3M solution of methylmagnesium iodide in ether (0.43ml, 1.30mmol) and maintained for 30 minutes. As the reaction was only approx. 70% complete a further quantity of 3M solution of methylmagnesium iodide in ether (0.30ml) was added and the reaction maintained for further 1 hour. The mixture, containing a white precipitate, was cooled to O⁰C and treated dropwise with sat. aqueous NH₄CI solution (2ml), then the resulting mixture was diluted with water (10ml) and extracted with EtOAc (2 x 15ml). The combined extract was dried (Na₂SO₄) and concentrated under vacuum to leave a yellow solid. This was purified by high pH MDAP to separate the two isomers.

The faster running component was the trans isomer obtained as a colourless oil (65mg), which was converted to its HCI salt to afford title compound (E5a) as a white solid. MH⁺ 434. ¹H NMR (free base) (CDCI₃, 400MHz) δ: 0.97 (3H, s), 1.22 (3H, t), 1.45-1.62 (4H, m),

1.62-1.78 (2H, m), 1.78-2.00 (4H, m), 2.24-2.40 (7H, m), 3.16 (2H, d), 3.43-3.50 (1 H, m),

3.50-3.68 (6H, m), 4.20-4.30 (1 H, m), 6.82 (1 H, d), 6.99 (1 H, d), 10.15 (1 H, s).

The slower running component was the cis isomer obtained as a colourless oil (80mg), which was converted to its HCI salt to afford title compound (E5b) as a white solid.

MH⁺ 434.

¹H NMR (free base) (CDCI₃, 400MHz) δ: 0.90 (3H, s), 1.10-1.22 (2H, m), 1.24 (3H, t),

1.70-1.87 (6H, m), 2.00 (2H, br d), 2.22-2.34 (4H, m), 2.33 (3H, s), 3.08 (2H, br s), 3.29-

3.40 (1 H, m), 3.53-3.70 (6H, m), 4.20-4.35 (1 H, m), 6.83 (1 H, d), 6.99 (1 H, d), 9.84 (1 H, s).

Example 6a. 5-Fluoro-6-methyl-1 -[1 -(trans-Λ -methyl-4-{[2-(methyloxy)ethyl]oxy} cyclohexyl)-4-piperidinyl]-1 ,3-dihydro-2H-benzimidazol-2-one hydrochloride (E6a)

and

Example 6b. 5-Fluoro-6-methyl-1 -[1 -(c/s-1 -methyl-4-{[2-(methyloxy)ethyl]oxy} cyclohexyl)-4-piperidinyl]-1 ,3-dihydro-2H-benzimidazol-2-one hydrochloride (E6b).

Methylmagnesium iodide (1.9 ml_, 5.7 mmol, 3 M in Et₂O) was added to a suspension of 1-[4-(5-fluoro-6-methyl-2-oxo-2,3-dihydro-1 H-benzimidazol-1-yl)-1-piperidinyl]-4-{[2- (methyloxy)ethyl]oxy}cyclohexanecarbonitrile (D28, 240 mg, 0.56 mmol) in dry THF (5 ml.) at rt under argon. The reaction was stirred for 3 h before being cooled to 0 ⁰C and being quenched with saturated aqueous ammonium chloride (5 ml_). The mixture was partitioned between H₂O and EtOAc and the aqueous layer was extracted with EtOAc (2x). The combined organic extracts were dried (Na₂SO₄) and concentrated by rotary evaporation to give a pale brown solid. This crude residue was purified by high pH MDAP to give the free base of the trans isomer as a cream solid. HCI (0.5 ml_, 0.5 mmol, 1 M in Et₂O) was added to a solution of the trans freebase in 1 :2 MeOH:DCM (3 ml.) and stirred for 1 h. Et₂O was added causing the precipitation of a solid, which was isolated by filtration, washing with Et₂O (2x), to give the trans isomer of the title compound (E6a, 71 mg, 38%) as a white solid.

¹H NMR (HCI salt E6a) (d₆-DMSO): δ 1.30-1.35 (5 H, m), 1.86-1.91 (4 H, m), 1.96-2.00 (4 H, m), 2.24 (3 H, m), 2.87 (2 H, m), 3.18-3.23 (3 H, m), 3.25 (3 H, s), 3.43 (2 H, m), 3.55 (2 H, m), 3.64 (2 H, m), 4.57 (1 H, m), 6.79 (1 H, m), 7.64 (1 H, m), 10.10 (1 H, m), 10.93 (1 H, s). high pH LCMS: MH⁺ 420

The waste from the MDAP was purified by column chromatography (silica, NH₃-MeOH- DCM) to give a brown oil, which on standing solidified. This solid was triturated with Et₂O to give the free base of the cis isomer as an off-white solid. HCI (0.1 ml_, 0.1 mmol, 1 M in

Et₂O) was added to a suspension of the cis freebase in MeOH and the solution agitated for 5 min. The solvent was removed by rotary evaporation to give an oily solid which was triturated with Et₂O to give the cis isomer of the title compound (E6b, 19 mg, 7%) as a white solid.

¹H NMR (HCI salt E6b) (d₆-DMSO): δ 1.35 (3 H, s), 1.56 (2 H, m), 1.72 (2 H, m), 1.89 (6 H, m), 2.25 (3 H, s), 2.82 (2 H, m), 3.16 (2 H, m), 3.28 (3 H, s), 3.41-3.60 (5 H, m), 3.66 (2 H, m), 4.57 (1 H, m), 6.80 (1 H, d, J 9.6), 7.47 (1 H, d, J 6.4), 9.59 (1 H, m), 10.92 (1 H, s). high pH LCMS: MH⁺ 420

Claims

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

(I) wherein:

R⁴ is selected from the group consisting of hydrogen and fluoro;

R⁵ is selected from the group consisting of hydrogen, cyano, halogen, Ci_-6alkyl (optionally substituted with one or more fluorine atoms), and C_1-6alkoxy (optionally substituted with one or more fluorine atoms);

R⁶ is selected from the group consisting of hydrogen, halogen, cyano, Ci_-6alkyl (optionally substituted with one or more fluorine atoms), C_1-6alkylsulfonyl, C_3-6cycloalkyl (optionally substituted with one or more fluorine atoms), and C-i-βalkoxy (optionally substituted with one or more fluorine atoms); n is selected from 2, 3 and 4;

Q is selected from the group consisting of hydrogen and C_halky!; and R is selected from the group consisting of Ci_-6alkyl, C_3-6cycloalkyl, Cs-ecycloalkyld-ealkyl and C_2-6alkynyl, any alkyl or cycloalkyl group being optionally substituted by one or more fluorine atoms.

2. A compound as claimed in claim 1 wherein the salt is a pharmaceutically acceptable salt.

3. A compound as claimed in claim 1 or claim 2 wherein R⁶ is selected from halogen and Ci_-6alkyl.

4. A compound as claimed in any of claims 1-3 wherein R⁵ is selected from hydrogen and halogen.

5. A compound as claimed in any of claims 1-4 wherein Q is selected from hydrogen and Ci_-3alkyl.

6. A compound as claimed in any of claims 1-5 wherein n is 2.

7. A compound as claimed in any of claims 1-6 wherein R is Ci_-6alkyl.

8. A compound as claimed in claim 1 , which is selected from the group consisting of: 6-Methyl-1 -[1 -(frans-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-1 ,3-dihydro-2H- benzimidazol-2-one; 5-Fluoro-6-methyl-1-[1-(frans-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-1 ,3- dihydro-2H-benzimidazol-2-one;

5-Fluoro-6-methyl-1-[1-(c/s-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-1 ,3- dihydro-2H-benzimidazol-2-one;

4,6-Difluoro-1-[1-(c/s-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-1 ,3- dihydro-2H-benzimidazol-2-one;

4,6-Difluoro-1-[1-(frans-1-methyl-4-{[2-(methyloxy)ethyl]oxy} cyclohexyl)-4-piperidinyl]-1 ,3- dihydro-2H-benzimidazol-2-one;

5-Chloro-6-methyl-1 -[1 -(frans-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-1 ,3- dihydro-2H-benzimidazol-2-one; 5-Chloro-6-methyl-1 -[1 -(c/s-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-1 ,3- dihydro-2H-benzimidazol-2-one;

1 ,3-dihydro-2H-benzimidazol-2-one;

1-[1-(c/s-4-{[2-(Ethyloxy)ethyl]oxy}-1-methylcyclohexyl)-4-piperidinyl]-5-fluoro-6-methyl- 1 ,3-dihydro-2H-benzimidazol-2-one;

5-Fluoro-6-methyl-1-[1-(frans-1-methyl-4-{[2-(methyloxy)ethyl]oxy} cyclohexyl)-4- piperidinyl]-1 ,3-dihydro-2H-benzimidazol-2-one; and

5-Fluoro-6-methyl-1-[1-(c/s-1-methyl-4-{[2-(methyloxy)ethyl]oxy} cyclohexyl)-4-piperidinyl]-

1 ,3-dihydro-2H-benzimidazol-2-one; and salts thereof.

9. A compound as claimed in claim 8, wherein the salt is a pharamceutically acceptable salt.

10. A pharmaceutical composition comprising a compound as claimed in any of claims 2- 9 and a pharmaceutically acceptable carrier.

11. A compound as claimed in any of claims 2-9 for use in therapy.

12. A compound as claimed in any of claims 2-9 for use in the treatment of a condition wherein agonism of a muscarinic M₁ receptor may be beneficial.

13. A compound as claimed in any of claims 2-9 for use in the treatment of a psychotic disorder or cognitive impairment.

14. Use of a compound as claimed any of claims 2-9 in the manufacture of a medicament for the treatment of a condition wherein agonism of a muscarinic M₁ receptor would be beneficial.

15. Use of a compound as claimed in any of claims 2-9 in the manufacture of a medicament for the treatment of a psychotic disorder or cognitive impairment.

16. A compound as claimed any of claims 2-9 for the treatment of a condition wherein agonism of a muscarinic M₁ receptor would be beneficial.

17. A compound as claimed in any of claims 2-9 for the treatment of a psychotic disorder or cognitive impairment.

18. A method of treating a condition wherein agonism of a muscarinic M₁ receptor would be beneficial, which method comprises administering to a mammal in need thereof an effective amount of a compound as claimed in any of claims 2-9.

19. A method of treating a psychotic disorder or cognitive impairment, which method comprises administering to a mammal in need thereof an effective amount of a compound as claimed in any of claims 2-9.

20. A compound of formula (XXXX) or salts thereof:

(XXXX)

wherein: n is as defined in claim 1 ;

R⁴ is a group R⁴ as defined in claim 1 or a group convertible to R⁴;

R⁵ is a group R⁵ as defined in claim 1 or a group convertible to R⁵;

R⁶ is a group R⁶ as defined in claim 1 or a group convertible to R⁶; and R' is a group R as defined in claim 1 or a group convertible to R.

21. A compound of formula (IV) or salts thereof:

wherein: n is as defined in claim 1 ; Q is as defined in claim 1 ; R⁴ is a group R⁴ as defined in claim 1 or a group convertible to R⁴;

R is a group R as defined in claim 1 or a group convertible to R R⁶ is a group R⁶ as defined in claim 1 or a group convertible to R R' is a group R as defined in claim 1 or a group convertible to R.

22. A compound of formula (Vl) or salts thereof:

wherein: n is as defined in claim 1 ; Q is as defined in claim 1 ;

R⁴ is a group R⁴ as defined in claim 1 or a group convertible to R⁴;

R⁵ is a group R⁵ as defined in claim 1 or a group convertible to R⁵;

R⁶ is a group R⁶ as defined in claim 1 or a group convertible to R⁶;

R' is a group R as defined in claim 1 or a group convertible to R; and Z is a leaving group.

23. A compound of formula (X) or salts thereof:

wherein: n is as defined in claim 1 ; Q is as defined in claim 1 ;

R⁴ is a group R⁴ as defined in claim 1 or a group convertible to R⁴; R⁵ is a group R⁵ as defined in claim 1 or a group convertible to R⁵; R⁶ is a group R⁶ as defined in claim 1 or a group convertible to R⁶; and R' is a group R as defined in claim 1 or a group convertible to R.