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, as agents for the treatment of cognitive impairment associated with schizophrenia, and as agents for treatment of Alzheimer's Disease.

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, M₁to M₅. The muscarinic M₁receptor 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.

M₁receptor 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 and has subsequently been assessed in a small phase II trial in schizophrenic patients where it showed a trend to improvement in PANSS and separation from placebo in a cognitive readout. However, the relatively non-selective nature of the compound gives rise to dose-limiting peripheral cholinergic side effects.

Over-production of β amyloid is a critical pathogenic event in Alzheimer's Disease (AD) and data have been published showing that M₁receptor agonists modulate the processing of β-APP, the precursor of β amyloid, to increase the production of sAPPα (non-amyloidogenic). Subsequent studies have demonstrated that this event is accompanied by a decreased secretion of β amyloid (for review see Current Opinion in Investigational Drugs, 2002, 3 (11), 1633-1636). In addition, it has recently been reported that an M₁receptor agonist can affect APP processing toward the non-amyloidogenic pathway, in vivo (Neuron, 2006, 49, 671-682). Thus M₁selective agonists have potential for a preventative/disease modifying role in AD therapy.

Certain M₁receptor agonists are known, for example in PCT/EP2007/052640. We have now found a novel group of compounds which are M₁receptor agonists.

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

wherein:

- R⁴, R⁵and R⁶are independently selected from hydrogen, halogen, C_1-6alkyl, C_1-6alkyl substituted with one or more fluorine atoms, cyano, C_1-6alkylsulfonyl, C_1-6alkylsulfonyl substituted with one or more fluorine atoms, C_3-6cycloalkyl, C_1-6alkoxy, C_1-6alkoxy substituted with one or more fluorine atoms, C_1-6alkanoyl, —C(═NOC_1-6alkyl)C_1-6alkyl, —C_1-6alkoxyC_1-6alkyl, and —C(O)NR_aR_b;
- R_aand R_bare each independently H or C_1-6alkyl, or together with the nitrogen atom to which they are attached form a five or six membered ring;
- ring A represents a benzene ring, or a 6-membered aromatic heterocylic ring containing one or two nitrogen atoms;
- R is selected from C_3-6cycloalkylC_1-4alkyl, C_1-6alkyloxyC_1-6alkyl, C_3-6cycloalkyloxyC_1-6alkyl and C_3-6cycloalkylC_1-4alkyloxyC_1-6alkyl, wherein any alkyl or cycloalkyl group is optionally substituted by one or more fluorine atoms;
- Q is selected from hydrogen and C_1-6alkyl; and
- Y is selected from O, S, CF₂, CH₂CH₂, OCH₂, and CH₂O.

As used herein, the term “alkyl” refers to a straight or branched hydrocarbon chain 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. Examples of “C_1-6alkyl” include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, isobutyl, isopropyl, t-butyl and 1,1-dimethylpropyl. “C_1-4alkyl” means a straight or branched alkyl containing at least 1, and at most 4, carbon atoms. Examples of “C_1-4alkyl” include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, isobutyl, isopropyl, and t-butyl.

As used herein, the term “alkoxy” refers to the group “O-alkyl” where “alkyl” is as hereinbefore defined. For example, “C_1-6alkoxy” means a straight or branched alkoxy group containing at least 1, and at most 6, carbon atoms. Examples of “C_1-6alkoxy” 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 “C_3-6cycloalkyl” 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 “C_1-6alkylsulfonyl” refers to a group SO₂—C_1-6alkyl, wherein C_1-6alkyl is as hereinbefore defined. Examples of “C_1-6alkylsulfonyl” as used herein include, but are not limited to, methylsulphonyl, ethylsulphonyl, propylsulphonyl, butylsulphonyl, pentylsulphonyl and hexylsulphonyl.

As used herein, the term “C_1-6alkanoyl” refers to a group —C(O)C_1-6alkyl wherein C_1-6alkyl is as hereinbefore defined. Examples of “C_1-6alkanoyl” as use herein include, but are not limited to, methanoyl, ethanoyl, propanoyl, butanoyl, pentanoyl and hexanoyl.

As used herein, the term “C_1-6alkoxyC_1-6alkyl” refers to a group C_1-6alkyl-O—C_1-6alkyl wherein C_1-6alkyl is as hereinbefore defined. Examples of “C_1-6alkoxyC_1-6alkyl” as used herein include, but are not limited to, methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, methoxypentyl, methoxyhexyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, ethoxybutyl, ethoxypentyl, and ethoxyhexyl.

As used herein, the term “C_3-6cycloalkylC_1-4alkyl” refers to a group C_3-6cycloalkly-C_1-4alkyl wherein C_3-6cycloalkyl and C_1-4alkyl are as hereinbefore defined. Examples of “C_3-6cycloalkylC_1-4alkyl” as used herein include, but are not limited to, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclopropylethyl, cyclobutylethyl, cyclopentylethyl, and cyclohexylethyl.

As used herein, the term “C_3-6cycloalkyloxyC_1-6alkyl” refers to a group C_3-6cycloalkyl-O—C_1-6alkyl wherein C_3-6cycloalkyl and C_1-6alkyl are as hereinbefore defined. Examples of “C_3-6cycloalkyloxyC_1-6alkyl” as used herein include, but are not limited to cyclopropyloxymethyl, cyclobutyloxymethyl, cyclopentyloxymethyl, cyclohexyloxymethyl, cyclopropyloxyethyl, cyclobutyloxyethyl, cyclopentyloxyethyl, and cyclohexyloxyethyl.

As used herein, the term “C_3-6cycloalkylC_1-4alkyloxyC_1-6alkyl” refers to a group C_3-6cycloalkyl-C_1-4alkyl-O—C_1-6alkyl wherein C_3-6cycloalkyl, C_1-4alkyl and C_1-6alkyl are as hereinbefore defined. Examples of “C_3-6cycloalkylC_1-4alkyloxyC_1-6alkyl” as used herein include, but are not limited to, cyclopropylmethyloxymethyl, cyclobutylmethyloxymethyl, cyclopentylmethyloxymethyl, cyclohexylmethyloxymethyl, cyclopropylethyloxymethyl, cyclobutylethyloxymethyl, cyclopentylethyloxymethyl, and cyclohexylethyloxymethyl.

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 R⁶is a C_1-6alkyl group, it may be substituted by 1, 2, 3 or 4 fluoro groups; and if R⁶is a C_1-6alkoxy group, it may be substituted by 1, 2, 3 or 4 fluoro groups.

In one embodiment R⁴, R⁵and R⁶are independently selected from hydrogen, halogen, C_1-6alkyl optionally substituted with one or more fluorine atoms, cyano, C_1-6alkylsulfonyl, CF₃SO₂, C_1-6alkoxy optionally substituted with one or more fluorine atoms, and C_1-4alkoxyC_1-4alkyl. In a further embodiment R⁴, R⁵and R⁶are independently selected from hydrogen, halogen, C_1-4alkyl optionally substituted with one or more fluorine atoms, cyano, C_1-4alkylsulfonyl, and C_1-4alkoxy optionally substituted with one or more fluorine atoms. In a further embodiment R⁴, R⁵and R⁶are independently selected from hydrogen, halogen, C_1-2alkyl optionally substituted with one or more fluorine atoms, cyano, C_1-2alkylsulfonyl, and C_1-2alkoxy optionally substituted with one or more fluorine atoms. In a further embodiment R⁴, R⁵and R⁶are independently selected from hydrogen, fluorine, methyl, trifluoromethyl, cyano, methylsulfonyl, ethylsulfonyl, methoxy, difluoromethoxy, trifluoromethoxy, and methoxymethyl.

In one embodiment R⁴is selected from hydrogen, halogen, C_1-6alkyl (optionally substituted with one or more fluorine atoms), cyano, C_1-6alkylsulfonyl (optionally substituted with one or more fluorine atoms), C_1-6alkoxy (optionally substituted with one or more fluorine atoms), and C_1-4alkoxyC_1-4alkyl.

In one embodiment R⁴is selected from hydrogen, halogen, C_1-4alkyl (optionally substituted with one or more fluorine atoms), cyano, C_1-4alkylsulfonyl, and C_1-4alkoxy (optionally substituted with one or more fluorine atoms).

In one embodiment R⁴is selected from hydrogen, halogen, C_1-2alkyl (optionally substituted with one or more fluorine atoms), cyano, C_1-2alkylsulfonyl, and C_1-2alkoxy (optionally substituted with one or more fluorine atoms).

In one embodiment R⁴is selected from hydrogen, fluorine, methyl, trifluoromethyl, cyano, methylsulfonyl, ethylsulfonyl, methoxy, difluoromethoxy, trifluoromethoxy, and methoxymethyl.

In one embodiment R⁴is hydrogen or fluorine.

In one embodiment, R⁴is hydrogen.

In one embodiment R⁵is selected from hydrogen, halogen, C_1-6alkyl (optionally substituted with one or more fluorine atoms), cyano, C_1-6alkylsulfonyl (optionally substituted with one or more fluorine atoms), C_1-6alkoxy (optionally substituted with one or more fluorine atoms), and C_1-4alkoxyC_1-4alkyl.

In one embodiment R⁵is selected from hydrogen, halogen, C_1-4alkyl (optionally substituted with one or more fluorine atoms), cyano, C_1-4alkylsulfonyl, and C_1-4alkoxy (optionally substituted with one or more fluorine atoms).

In one embodiment R⁵is selected from hydrogen, halogen, C_1-2alkyl (optionally substituted with one or more fluorine atoms), cyano, C_1-2alkylsulfonyl, and C_1-2alkoxy (optionally substituted with one or more fluorine atoms).

In one embodiment R⁵is selected from hydrogen, fluorine, methyl, trifluoromethyl, cyano, methylsulfonyl, ethylsulfonyl, methoxy, difluoromethoxy, trifluoromethoxy, and methoxymethyl.

In one embodiment, R⁵is selected from hydrogen, fluorine and cyano.

In one embodiment, R⁵is hydrogen.

In one embodiment R⁶is selected from hydrogen, halogen, C_1-6alkyl (optionally substituted with one or more fluorine atoms), cyano, C_1-6alkylsulfonyl (optionally substituted with one or more fluorine atoms), C_1-6alkoxy (optionally substituted with one or more fluorine atoms), C_1-4alkoxyC_1-4alkyl, C_1-6alkanoyl, —C(═NOC_1-5alkyl)C_1-5alkyl and —C(O)NR_aR_b.

In one embodiment R⁶is selected from hydrogen, halogen, C_1-4alkyl (optionally substituted with one or more fluorine atoms), cyano, C_1-4alkylsulfonyl (optionally substituted with one or more fluorine atoms), C_1-4alkoxy (optionally substituted with one or more fluorine atoms), C_1-4alkoxyC_1-4alkyl, C_1-4alkanoyl, —C(═NOC_1-4alkyl)C_1-4alkyl and —C(O)NR_aR_b.

In one embodiment R⁶is selected from hydrogen, halogen, C_1-2alkyl (optionally substituted with one or more fluorine atoms), cyano, C_1-2alkylsulfonyl (optionally substituted with one or more fluorine atoms), C_1-2alkoxy (optionally substituted with one or more fluorine atoms), C_1-2alkoxyC_1-2alkyl, C_1-2alkanoyl, —C(═NOC_1-2alkyl)C_1-2alkyl and —C(O)NR_aR_b.

In one embodiment R⁶is selected from hydrogen, fluorine, methyl, trifluoromethyl, cyano, methylsulfonyl, ethylsulfonyl, trifluoromethylsulfonyl, methoxy, difluoromethoxy, trifluoromethoxy, —C(O)NH₂, —C(O)CH₃, —C(═NOCH₃)CH₃, and methoxymethyl.

In one embodiment R⁶is selected from methyl, trifluoromethyl, cyano, methylsulfonyl, —C(O)NH₂, —C(O)CH₃, —C(═NOCH₃)CH₃, and methoxymethyl.

In one embodiment, R⁶is cyano.

In one embodiment ring A represents a benzene ring or a pyridine ring.

In one embodiment ring A represents a benzene ring.

In one embodiment ring A represents a pyridine ring.

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

wherein R⁴, R⁵, R⁶, Y, Q and R are as hereinbefore defined for a compound of formula (I).

In one embodiment R is selected from C_3-6cycloalkylC_1-4alkyl and C_1-6alkyloxyC_1-6alkyl.

In one embodiment R is selected from C_3-6cycloalkylC_1-4alkyl and C_1-4alkyloxyC_1-4alkyl.

In one embodiment R is selected from C_3-6cycloalkylC_1-2alkyl and C_1-2alkyloxyC_1-2alkyl.

In one embodiment R is selected from cyclopropylmethyl and methoxyethyl.

In one embodiment R is C_1-6alkyloxyC_1-6alkyl.

In one embodiment R is C_1-4alkyloxyC_1-4alkyl.

In one embodiment R is C_1-2alkyloxyC_1-2alkyl.

In one embodiment R is methoxyethyl.

In one embodiment Q is selected from H and C_1-4alkyl.

In one embodiment, Q is selected from H and C_1-2alkyl.

In one embodiment, Q is H or methyl.

In one embodiment, Q is methyl.

In one embodiment, Q is H.

In one embodiment Y is selected from O, S, OCH₂, CH₂O and CH₂CH₂.

In one embodiment, Y is O.

In one embodiment, there is provided a compound of formula (I) or a salt thereof wherein:

R⁴is hydrogen or fluorine;

R⁵is selected from hydrogen, fluorine, cyano and methyl;

R⁶is selected from hydrogen, fluorine, methyl, trifluoromethyl, cyano, methylsulfonyl, ethylsulfonyl, trifluoromethylsulfonyl, methoxy, difluoromethoxy, trifluoromethoxy, —C(O)NH₂, —C(O)CH₃, —C(═NOCH₃)CH₃, and methoxymethyl;

A is a benzene ring or a pyridine ring;

R is selected from cyclopropylmethyl and methoxyethyl;

Q is H or methyl; and

Y is selected from O, S, OCH₂, CH₂O and CH₂CH₂.

In one embodiment, there is provided a compound of formula (I) or a salt thereof wherein:

R⁴is hydrogen or fluorine;

R⁵is selected from hydrogen, fluorine and cyano;

R⁶is selected from methyl, trifluoromethyl, cyano, methylsulfonyl, methoxy, —C(O)NH₂, —C(O)CH₃, —C(═NOCH₃)CH₃, and methoxymethyl;

A is a benzene ring or a pyridine ring;

R is selected from cyclopropylmethyl and methoxyethyl;

Q is H or methyl; and

Y is selected from O, S, OCH₂, CH₂O and CH₂CH₂.

In one embodiment, the compound of formula (I) is a compound of formula (Ia) wherein:

R⁴is hydrogen or fluorine;

R⁵is selected from hydrogen, fluorine, cyano and methyl;

R is selected from cyclopropylmethyl and methoxyethyl;

Q is H or methyl; and

Y is selected from O, S, OCH₂, CH₂O and CH₂CH₂.

In one embodiment, the compound of formula (I) is a compound of formula (Ia) wherein:

R⁴is hydrogen or fluorine;

R⁵is selected from hydrogen, fluorine and cyano;

R⁶is selected from methyl, trifluoromethyl, cyano, methylsulfonyl, methoxy, —C(O)NH₂, —C(O)CH₃, —C(═NOCH₃)CH₃, and methoxymethyl;

R is selected from cyclopropylmethyl and methoxyethyl;

Q is H or methyl; and

Y is selected from O, S, OCH₂, CH₂O and CH₂CH₂.

In one embodiment, there is provided a compound of formula (I) or a salt thereof wherein:

R⁴is hydrogen or fluorine;

R⁵is selected from hydrogen, fluorine, cyano and methyl;

A is a benzene ring or a pyridine ring;

R is selected from cyclopropylmethyl and methoxyethyl;

Q is H or methyl; and

Y is O.

In one embodiment, there is provided a compound of formula (I) or a salt thereof wherein:

R⁴is hydrogen or fluorine;

R⁵is selected from hydrogen, fluorine and cyano;

R⁶is selected from methyl, trifluoromethyl, cyano, methylsulfonyl, methoxy, —C(O)NH₂, —C(O)CH₃, —C(═NOCH₃)CH₃, and methoxymethyl;

A is a benzene ring or a pyridine ring;

R is selected from cyclopropylmethyl and methoxyethyl;

Q is H or methyl; and

Y is O.

In one embodiment, the compound of formula (I) is a compound of formula (Ia) wherein:

R⁴is hydrogen or fluorine;

R⁵is selected from hydrogen, fluorine, cyano and methyl;

R is selected from cyclopropylmethyl and methoxyethyl;

Q is H or methyl; and

Y is O.

In one embodiment, the compound of formula (I) is a compound of formula (Ia) wherein:

R⁴is hydrogen or fluorine;

R⁵is selected from hydrogen, fluorine and cyano;

R⁶is selected from methyl, trifluoromethyl, cyano, methylsulfonyl, methoxy, —C(O)NH₂, —C(O)CH₃, —C(═NOCH₃)CH₃, and methoxymethyl;

R is selected from cyclopropylmethyl and methoxyethyl;

Q is H or methyl; and

Y is O.

In one embodiment, the compound of formula (I) is a compound of formula (Ia) wherein:

R⁴is hydrogen, R⁵is hydrogen, R⁶iscyano, R is methoxyethyl, Q is methyl, and Y is O.

It will be appreciated that the present invention covers all combinations of features and embodiments described hereinbefore.

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

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.

In one embodiment, the invention provides a compound of formula (I) as the free base.

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, (1R)-(−)-10-camphorsulphonic, (1S)-(+)-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. 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.

The compounds of the present invention may be in the form of their free base or pharmaceutically acceptable salts thereof, particularly the hydrochloride, formate, trifluoroacetate, methanesulfonate, or 4-methylbenzenesulfonate salts.

In one embodiment, the pharmaceutically acceptable salt is a hydrochloride salt, a trifluoroacetate salt, or a formate salt.

In one embodiment the pharmaceutically acceptable salt is the hydrocholoride salt.

In one embodiment the pharmaceutically acceptable salt is the methanesulfonate salt.

In one embodiment the pharmaceutically acceptable salt is the 4-methylbenzenesulfonate salt.

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 compounds 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.

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. Possible prodrugs for some compounds of the invention include: esters, carbonate esters, hemi-esters, phosphate esters, nitro esters, sulfate esters, sulfoxides, amides, carbamates, azo-compounds, phosphamides, glycosides, ethers, acetals and ketals.

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.

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, ¹⁷O, ¹⁸O, ³¹P, ³²P, ³⁵S, ¹⁸F and ³⁶Cl, 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 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 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:

3-[1-(trans-1-Methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-2-oxo-2,3-dihydro-1,3-benzoxazole-5-carbonitrile;

3-[1-(cis-1-Methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-2-oxo-2,3-dihydro-1,3-benzoxazole-5-carbonitrile;

5-Methyl-3-[1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-2-oxo-2,3-dihydro-1,3-benzoxazole-6-carbonitrile;

5-Methyl-3-[1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-1,3-benzoxazol-2(3H)-one;

3-[1-(trans-1-Methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-5-(methyloxy)-1,3-benzoxazol-2(3H)-one;

3-(1-{trans-4-[(Cyclopropylmethyl)oxy]-1-methylcyclohexyl}-4-piperidinyl)-5-(methylsulfonyl)-1,3-benzoxazol-2(3H)-one;

3-[1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-5-(trifluoromethyl)-1,3-benzoxazol-2(3H)-one;

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

7-Fluoro-3-[1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-2-oxo-2,3-dihydro-1,3-benzoxazole-5-carbonitrile;

7-Fluoro-5-methyl-3-[1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-1,3-benzoxazol-2(3H)-one;

6-Fluoro-3-[1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-2-oxo-2,3-dihydro-1,3-benzoxazole-5-carbonitrile;

3-[1-(trans-1-Methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-5-(methylsulfonyl)-1,3-benzoxazol-2(3H)-one;

3-[1-(trans-1-Methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-5-[(methyloxy)methyl]-1,3-benzoxazol-2(3H)-one;

3-[1-(trans-1-Methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-2-oxo-2,3-dihydro-1,3-benzoxazole-5-carboxamide;

5-Acetyl-3-[1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-1,3-benzoxazol-2(3H)-one; and

3-[1-(trans-1-Methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-5-[N-(methyloxy)ethanimidoyl]-1,3-benzoxazol-2(3H)-one;

and salts thereof.

In one embodiment, the salt of a compound listed above is a pharmaceutically acceptable salt.

In one embodiment, the pharmaceutically acceptable salt is a hydrochloride salt, a trifluoroacetate salt, a methanesulfonate salt, a 4-methylbenzenesulfonate salt, or a formate salt.

In one embodiment, the pharmaceutically acceptable salt is a hydrochloride salt, a trifluoroacetate salt, or a formate salt.

In one embodiment the pharmaceutically acceptable salt is the hydrochloride salt.

In one embodiment, the compound of the present invention is selected from:

3-[1-(cis-1-Methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-2-oxo-2,3-dihydro-1,3-benzoxazole-5-carbonitrile hydrochloride;

5-Methyl-3-[1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-2-oxo-2,3-dihydro-1,3-benzoxazole-6-carbonitrile hydrochloride;

5-Methyl-3-[1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-1,3-benzoxazol-2(3H)-one hydrochloride;

3-[1-(trans-1-Methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-5-(methyloxy)-1,3-benzoxazol-2(3H)-one hydrochloride;

3-(1-{trans-4-[(Cyclopropylmethyl)oxy]-1-methylcyclohexyl}-4-piperidinyl)-5-(methylsulfonyl)-1,3-benzoxazol-2(3H)-one hydrochloride;

3-[1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-5-(trifluoromethyl)-1,3-benzoxazol-2(3H)-one hydrochloride;

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

7-Fluoro-3-[1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-2-oxo-2,3-dihydro-1,3-benzoxazole-5-carbonitrile hydrochloride;

7-Fluoro-5-methyl-3-[1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-1,3-benzoxazol-2(3H)-one hydrochloride;

6-Fluoro-3-[1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-2-oxo-2,3-dihydro-1,3-benzoxazole-5-carbonitrile hydrochloride;

3-[1-(trans-1-Methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-5-(methylsulfonyl)-1,3-benzoxazol-2(3H)-one hydrochloride;

3-[1-(trans-1-Methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-5-[(methyloxy)methyl]-1,3-benzoxazol-2(3H)-one hydrochloride;

3-[1-(trans-1-Methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-2-oxo-2,3-dihydro-1,3-benzoxazole-5-carboxamide hydrochloride;

5-Acetyl-3-[1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-1,3-benzoxazol-2(3H)-one hydrochloride; and

3-[1-(trans-1-Methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-5-[N-(methyloxy)ethanimidoyl]-1,3-benzoxazol-2(3H)-one hydrochloride.

In one embodiment, the compound of the present invention is selected from:

3-[1-(trans-1-Methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-2-oxo-2,3-dihydro-1,3-benzoxazole-5-carbonitrile;

3-[1-(trans-1-Methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-2-oxo-2,3-dihydro-1,3-benzoxazole-5-carbonitrile hydrochloride;

3-[1-(trans-1-Methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-2-oxo-2,3-dihydro-1,3-benzoxazole-5-carbonitrile 4-methylbenzenesulfonate; and

3-[1-(trans-1-Methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-2-oxo-2,3-dihydro-1,3-benzoxazole-5-carbonitrile methanesulfonate.

In one embodiment, the compound of the present invention is selected from 3-[1-(1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-2-oxo-2,3-dihydro-1,3-benzoxazole-5-carbonitrile and pharmaceutically acceptable salts thereof.

In one embodiment, the compound of the present invention is selected from 3-[1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-2-oxo-2,3-dihydro-1,3-benzoxazole-5-carbonitrile and pharmaceutically acceptable salts thereof.

In one embodiment, the compound of the present invention is 3-[1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-2-oxo-2,3-dihydro-1,3-benzoxazole-5-carbonitrile.

In one embodiment, the compound of the present invention is 3-[1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-2-oxo-2,3-dihydro-1,3-benzoxazole-5-carbonitrile hydrochloride.

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):

with a compound of formula (III)

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, for example, 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) can be reacted with a compound of formula (III) in the presence of a source of cyanide, e.g. acetone cyanohydrin, to form the cyano intermediate (IV) which can be reacted with an alkyl Grignard reagent QMgX to form compounds of formula (I) in which Q is C_1-6alkyl.

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

In a further aspect, the invention provides a general process (B) for preparing compounds of formula (I) in which Y═O or S, which process comprises:

coupling a compound of formula (V)

with a compound of formula (VI)

wherein R^6′ is a group R⁶as previously defined, or a group convertible to R⁶, R^5′ is a group R⁵as previously defined, or a group convertible to R⁵, R^4′ is a group R⁴as previously defined, or a group convertible to R⁴, ring A is as previously defined, R′ is a group R as previously defined, or a group convertible to R, Y is O or S, Q is as previously defined, and X and X′ both represent leaving groups. X and X′ can be the same or different and examples are Cl, PhO, EtO, and imidazole. When X and X′ are both Cl, i.e. (VI) is phosgene, this reagent can be generated in situ e.g. from diphosgene or triphosgene.

The above reaction can be carried out using standard methodology e.g. reacting the amine (V) with the reagent (VI) 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 (V) can be pure cis or trans isomers, or a mixture of isomers. If necessary, separation of pure cis and trans isomers after the reaction with (VI) can be achieved by chromatography or crystallisation.

In a further aspect, the invention provides a general process (C) for preparing compounds of formula (I) in which Y═CH₂CH₂, which process comprises:

hydrolysis and cyclisation of a compound of formula (VIII)

wherein R^6′ is a group R⁶as previously defined, or a group convertible to R⁶, R^5′ is a group R⁵as previously defined, or a group convertible to R⁵, R^4′ is a group R⁴as previously defined, or a group convertible to R⁴, ring A is as previously defined, R′ is a group R as previously defined, or a group convertible to R, Q is as previously defined, and R⁷represents C_1-6alkyl, benzyl, or other acid protecting group. Hydrolysis of the ester group CO₂R⁷can be accomplished using standard conditions, and cyclisation can be effected by activation of the acid group using for example EDC (1-ethyl-3-(dimethylaminopropyl)carbodiimide) and HOBT (1-hydroxybenzotriazole).

It will be appreciated that compounds of formula (VIII) can be pure cis or trans isomers, or a mixture of isomers. If necessary, separation of pure cis and trans isomers after the cyclisation of (VIII) can be achieved by chromatography or crystallisation.

In a further aspect, the invention provides a general process (D) for preparing compounds of formula (I) in which Y═OCH₂, which process comprises:

treatment of a compound of formula (IX) with a base, such as KO^tBu in an inert solvent for example THF, optionally with heating

It will be appreciated that compounds of formula (IX) can be pure cis or trans isomers, or a mixture of isomers. If necessary, separation of pure cis and trans isomers after the cyclisation of (IX) 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:

treatment of a compound of formula (X)

with a palladium or copper catalyst to effect an intramolecular cyclisation; wherein R^6′ is a group R⁶as previously defined, or a group convertible to R⁶, R^5′ is a group R⁵as previously defined, or a group convertible to R⁵, R^4′ is a group R⁴as previously defined, or a group convertible to R⁴, ring A is as previously defined, R′ is a group R as previously defined, or a group convertible to R, Y is O, S, CF₂, CH₂CH₂, OCH₂, or CH₂O, Q is as previously defined, and Z is a leaving group such as bromo, iodo, chloro or triflate.

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 (X) can be pure cis or trans isomers, or a mixture of isomers. If necessary, separation of pure 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 (F) for preparing compounds of formula (I) which process comprises:

coupling a compound of formula (XIII):

with a compound of formula (XIV)

wherein R^6′ is a group R⁶as previously defined, or a group convertible to R⁶, R^5′ is a group R⁵as previously defined, or a group convertible to R⁵, R^4′ is a group R⁴as previously defined, or a group convertible to R⁴, ring A is as previously defined, R′ is a group R as previously defined, or a group convertible to R, Y is O, S, CF₂, CH₂CH₂, OCH₂, or CH₂O, Q is as previously defined, 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 intermediate (XIII) can be deprotonated using a base such as sodium hydride in an inert solvent such as dimethylformamide, and then treated with the alkylating reagent (XIV), optionally with heating. The Mitsunobu reaction with (XIII) and (XIV) 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 (XIV) can be pure cis or trans isomers, or a mixture of isomers. If necessary, separation of pure cis and trans isomers after the displacement reaction can be achieved by chromatography or crystallisation.

Conversion of R^6′, R^5′ and R^4′ to R⁶, R⁵and R⁴respectively, or interconversions of and R⁴may be accomplished as illustrated below for R^6′

For example, when R^6′ is a halogen, it can be converted to an alkoxy, trifluoromethyl or methylsulphonyl group by copper catalysed reaction, using an alcohol, methyl fluorosulfonyl(difluoro)acetate or sodium methanesulphinate respectively. It may also be converted to an alkyl group with an organometallic reagent, for example an alkylstannane.

Alternatively, when R^6′ is a halogen, it can also be converted to a cyano group, for example, by palladium catalysed reaction using zinc cyanide.

As another example, when R^6′ is hydroxy, it may be converted to alkoxy 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 R^6′ is methyl, it may be converted to trifluoromethyl by chlorination or bromination followed by displacement of the introduced halogens with fluoride.

Conversion of a 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_1-6alkylating agent e.g. methyl iodide, ethyl iodide or propyl iodide, will afford the desired product.

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. Alternatively the alcohol intermediate can be converted to R=trifluoromethyl by conversion to the xanthate followed by oxidation in the presence of fluoride ion.

Compounds of formula (II) are generally known in the literature or can be prepared by a range of different processes, for example:

(a) reductive amination of the amine (XV) with the ketone (XVI), wherein R^6′ is a group R⁶as previously defined, or a group convertible to R⁶, R^5′ is a group R⁵aspreviously defined, or a group convertible to R⁵, R^4′ is a group R⁴aspreviously defined, or a group convertible to R⁴, ring A is as previously defined, Y′ is a group OH or SH or a group convertible to Y′, and P represents a nitrogen protecting group (e.g. Boc, acetyl, trifluoroacetyl, ethoxycarbonyl, benzyloxycarbonyl), to give (XVII), followed by deprotection of Y′ if necessary, and cyclisation using phosgene or a phosgene equivalent, and deprotection of the piperidine nitrogen using standard literature conditions (Scheme 1).

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

(b) metal catalysed cyclisation of an intermediate (XVIII) followed by deprotection of the piperidine nitrogen, wherein R^6′ is a group R⁶as previously defined, or a group convertible to R⁶, R^5′ is a group R⁵aspreviously defined, or a group convertible to R⁵, R^4′ is a group R⁴as previously defined, or a group convertible to R⁴, ring A is as previously defined, Y is O, S, CF₂, CH₂CH₂, OCH₂, or CH₂O, 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 F. The carbamate, thiocarbamate or amide intermediate (XVIII) can be prepared using any of the classical methods for formation of this functionality as illustrated in Scheme 2. Compounds of formula (XIX) and (XI) are commercially available or can be prepared by known methodology. The compound (XX) in which P=Boc is commercially available. The compound (LX) can be prepared from N-protected piperidine-4-carboxylic acid, for example by Curtius rearrangement using diphenylphosphoryl azide.

(c) metal catalysed reaction between the amine (XX) and a suitably substituted aromatic compound (XXI) wherein R^6′ is a group R⁶as previously defined, or a group convertible to R⁶, R^5′ is a group R⁵aspreviously defined, or a group convertible to R⁵, R^4′ is a group R⁴as previously defined, or a group convertible to R⁴, ring A is as previously defined, Y′ is OH or SH or a group convertible to Y′, 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 3). This process generates intermediates of formula (XXII) and subsequent reactions are similar to that for Scheme 1. Compounds of formula (XXI) are commercially available or can be prepared by known methodology. The compound (XX) in which P=Boc is commercially available.

(d) alkylation of the heterocycle (XIII) with the intermediate (XXIII) wherein R^6′ is a group R⁶as previously defined, or a group convertible to R⁶, R^5′ is a group R⁵as previously defined, or a group convertible to R⁵, R^4′ is a group R⁴as previously defined, or a group convertible to R⁴, ring A is as previously defined, Y is O, S or CF₂, P represents a nitrogen protecting group (e.g. Boc, acetyl, trifluoroacetyl, benzyloxycarbonyl), and Z represents a leaving group such as bromo, iodo, chloro, or mesylate, to give the intermediate (XXIV), followed by deprotection of the piperidine nitrogen (Scheme 4). Compounds of formula (XIII) are commercially available or can be prepared by known methodology. Compounds of formula (XXIII) are commercially available, or can be prepared using standard literature methodology.

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

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

(e) metal catalysed reaction of the amine (XXV) with the ortho substituted aromatic compound (XXI), wherein R^6′ is a group R⁶as previously defined, or a group convertible to R⁶, R^5′ is a group R⁵aspreviously defined, or a group convertible to R⁵, R^4′ is a group R⁴as previously defined, or a group convertible to R⁴, ring A is as previously defined, Y′ is OH or SH or a group convertible to Y′, R′ is a group R as previously defined, or a group convertible to R, Q is as previously defined, and Z represents a leaving group such as bromo, iodo, chloro or triflate (Scheme 5) followed by deprotection of Y′ if required.

Compounds of formula (XXI) are commercially available or can be prepared by standard methodology. Compounds of formula (XXV) can be prepared as shown in Schemes 11, 12, 13 and 14.

It will be appreciated that compounds of formula (XXV) can be pure cis or trans isomers, or a mixture of isomers. If necessary, separation of pure cis and trans isomers after the reaction with (XXI) can be achieved by chromatography or crystallisation.

(f) Reductive alkylation of the amine (XV) with the piperidone (XXVI) wherein R^6′ is a group R⁶as previously defined, or a group convertible to R⁶, R^5′ is a group R⁵as previously defined, or a group convertible to R⁵, R^4′ is a group R⁴as previously defined, or a group convertible to R⁴, ring A is as previously defined, Y′ is OH or SH or a group convertible to Y′, R′ is a group R as previously defined, or a group convertible to R, and Q is as previously defined, using for example sodium triacetoxyborohydride in dichloroethane to give the intermediate (XXVII), followed by deprotection of Y′ if required (Scheme 6). Compounds of formula (XXVI) can be prepared as shown in Schemes 12, 13 and 14. It will be appreciated that compounds of formula (XXVI) can be pure cis or trans isomers, or a mixture of isomers. If necessary, separation of pure cis and trans isomers after the reaction with (XV) can be achieved by chromatography or crystallisation.

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

Compounds of formula (VIII) can be prepared as illustrated in Scheme 7.

Wittig-Horner reaction of the aldehyde (XXXII) with the appropriate phosphono acetate (XXXIIb) using standard conditions provides the cinnamate (XXXIII). Reduction of the nitro group and double bond leading to the amine (XXXIV), can be followed by reductive alkylation with ketone (XXVI) to give amine (VIII) (Scheme 7), wherein R^6′ is a group R⁶as previously defined, or a group convertible to R⁶, R^5′ is a group R⁵as previously defined, or a group convertible to R⁵, R^4′ is a group R⁴as previously defined, or a group convertible to R⁴, ring A is as previously defined, R′ is a group R as previously defined, or a group convertible to R, and Q is as previously defined, and R⁷is a C_1-6alkyl group or other acid protecting group. Compounds of formula (XXXII) are commercially available, or can be prepared using standard literature methodology. Compounds of formula (XXXIIb) are commercially available.

It will be appreciated that compounds of formula (XXVI) can be pure cis or trans isomers, or a mixture of isomers. If necessary, separation of pure cis and trans isomers after the reaction with (XXXIV) can be achieved by chromatography or crystallisation.

Compounds of formula (IX) can be prepared as illustrated in Scheme 8.

Reductive alkylation of the amine (XXXV) with the ketone (XXVI) provides the intermediate (XXXVI), which can then be acylated with the appropriate acid chloride, using standard alkylation conditions to give (IX), wherein R^6′ is a group R⁶as previously defined, or a group convertible to R⁶, R^5′ is a group R⁵aspreviously defined, or a group convertible to R⁵, R^4′ is a group R⁴as previously defined, or a group convertible to R⁴, ring A is as previously defined, R′ is a group R as previously defined, or a group convertible to R, Q is as previously defined, and Z is a leaving group such as chloro or bromo. Compounds of formula (XXXV) are commercially available, or can be prepared by reduction of the respective commercially available nitrophenol.

It will be appreciated that compounds of formula (XXVI) can be pure cis or trans isomers, or a mixture of isomers. If necessary, separation of pure cis and trans isomers after the reaction with (XXXV) can be achieved by chromatography or crystallisation.

Compounds of formula (X) can be prepared by a variety of processes e.g. as illustrated in Scheme 9 by

- combining the alcohol/thiol (XIX) and the amine (XXV) with phosgene or a phosgene equivalent using standard conditions. Phosgene equivalents include carbonyl diimidazole, diphosgene, triphosgene, phenyl chloroformate;
  
  or
- reacting the alcohol/thiol (XIX) with the isocyanate (XXXVII)
  
  wherein R^6′ is a group R⁶as previously defined, or a group convertible to R⁶, R^5′ is a group R⁵as previously defined, or a group convertible to R⁵, R^4′ is a group R⁴as previously defined, or a group convertible to R⁴, ring A is as previously defined, R′ is a group R as previously defined, or a group convertible to R, Y is O or S, Z is a leaving group such as bromo, iodo, chloro or triflate, and Q is as previously defined.

The isocyanate (XXXVII) can be prepared from the corresponding amine (XXV) 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.

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

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

Compounds of formula (XIV) where Q=H can be prepared as shown in Scheme 10, by reductive alkylation of (XXXVIII) where Z′ represents Z or a group convertible to Z with the ketone (III), and R′ is as previously defined. Compounds of formula (XXXVIII) in which Z′ is OH can be prepared by reduction of an N-protected piperidone, followed by deprotection. 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.

The compound (XXV) where Q=H can be prepared as shown in Scheme 11. Reductive alkylation of the commercially available amine (XXXIX) with the cyclohexanone (III) using for example sodium triacetoxyborohydride in dichloroethane provides the intermediate (XL) which is deprotected using HCl in ethanol or trifluoroacetic acid to afford the primary amine (XXV). It will be appreciated that separation of the cis and trans isomers can be achieved at any suitable stage in the synthesis.

The compound (XXV) where Q=alkyl can be prepared from intermediates (XXXIX) and (III) using similar methodology as in process A2, followed by deprotection.

Alternatively the compounds (XXV) and (XXVI) where Q=H can be prepared as shown in Scheme 12. Reductive amination of cyclohexanone (III) using for example ammonia solution under catalytic hydrogenation conditions provides intermediate amine (XLI), which can be converted into piperidinone (XXVI) by reaction with quaternary piperidine salt (XLII). Reductive amination, for example using ammonia and catalytic hydrogenation, affords primary amine (XXV). It will be appreciated that separation of the cis and trans isomers can be achieved at any suitable stage in the synthesis. Compounds of formula (XXXIX) are commercially available.

Selective preparation of the cis and trans isomers of compound (XXV) where Q=H can be carried out via the process which is illustrated in Scheme 13 for the trans isomer. The commercially available amine (XLIII) is initially N-protected, for example by incorporation in a phthalimide ring, to give (XLIV), then the hydroxyl function converted into a silyl protected group, for example tert-butyldimethylsilyl, to give (XLV), which upon treatment with the appropriate aldehyde or ketone in the presence of triethylsilane and bismuth tribromide affords (XLVI), which after deprotection gives intermediate amine (XLI). Conversion of amine (XLI) to the piperidinone (XXVI) by reaction with the quaternary piperidine salt (XLII), followed by reductive amination, for example using ammonia and catalytic hydrogenation, affords primary amine (XXV).

The cis isomer of compound (XXV) can be prepared by a similar procedure from the appropriate cis isomer of the amine (XLIII).

A selective preparation of the trans isomer of compounds (XXV) and (XXVI) where Q=Me is shown in Scheme 14. A suitable ester of 4-hydroxycyclohexane carboxylic acid such as the methyl or ethyl ester (XLVII) wherein R″ is methyl or ethyl is protected as a silyl ether, for example the tert-butyldimethylsilyl ether, to give (XLVIII), which on treatment with the appropriate aldehyde or ketone in the presence of triethylsilane and bismuth tribromide affords ether (XLIX). Hydrolysis to acid (L) followed by alkylation using a base such as lithium diisopropylamide with iodomethane affords mixture of cis and trans 1-methylcyclohexane carboxylic acid (LI). The trans isomer (LII) can be isolated by conversion of the mixture to the acid chloride, for example with thionyl chloride, followed by selective hydrolysis of the products by treatment with weak aqueous base such as sodium hydrogen carbonate solution. The trans acid (LII) can be converted to the isocyanate (LIII) by Curtius rearrangement at elevated temperature of an intermediate azide prepared using for example diphenylphosphoryl azide, then the isocyanate hydrolysed to amine (LIV) under acidic conditions. Conversion of amine (LIV) to the piperidinone (XXVI) by reaction with quaternary piperidine salt (XLII) followed by reductive amination, for example using ammonia and catalytic hydrogenation, affords primary amine (XXV). Compounds of formula (XLVII) are commercially available.

An alternative preparation of the cis/trans acids (LI) is shown in Scheme 15.

Diels-Alder reaction of 2-(trimethylsilyloxy)buta-1,3-diene with a suitable ester of methacrylic acid (e.g. R″=iso-butyl) affords, after hydrolysis, the cyclohexanone (LVIII). Reductive alkylation using the appropriate alkoxy t-butyl dimethylsilane (R′OTBDMS), anhydrous ferric chloride and triethylsilane (see Iwanami et al, Synthesis 2005, 2669.). generates the ether (LIX) as a mixture of cis/trans isomers. Standard ester hydrolysis using for example aqueous sodium hydroxide leads to the formation of the acids (LI) as a cis/trans mixture. Further synthetic elaboration is as detailed in Scheme 15.

The cis isomer of (XXV) where Q=Me can be obtained as shown in Scheme 16. The mixture of acids (LI) is converted to a mixture of isocyanates (LV) via Curtius rearrangement of an intermediate azide at elevated temperature prepared using for example diphenylphosphoryl azide. The cis isomer (LVI) can be isolated from this mixture by chromatographic separation, then converted through to amine (XXV) using a similar procedure to that as shown for the trans isomer in Scheme 14 through intermediates (LVII) and (XXVI).

Compounds of the present invention are M₁receptor agonists. Selective M₁receptor 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 M₂and M₃receptors. M₁receptor 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.

M₁receptor agonists may also be suitable for treatment of the underlying pathology associated with Alzheimer's Disease, or in a preventative role.

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 M₁receptor 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 is contemplated as part of the present invention. Numbers in brackets after the listed diseases below refer to the classification code in DSM-IV.

Within the context of the present invention, the term psychotic disorder includes Schizophrenia including the subtypes Paranoid Type (295.30), Disorganised Type (295.10), Catatonic Type (295.20), Undifferentiated Type (295.90) and Residual Type (295.60); Schizophreniform Disorder (295.40); Schizoaffective Disorder (295.70) including the subtypes Bipolar Type and Depressive Type; Delusional Disorder (297.1) including the subtypes Erotomanic Type, Grandiose Type, Jealous Type, Persecutory Type, Somatic Type, Mixed Type and Unspecified Type; Brief Psychotic Disorder (298.8); Shared Psychotic Disorder (297.3); Psychotic Disorder Due to a General Medical Condition including the subtypes With Delusions and With Hallucinations; Substance-Induced Psychotic Disorder including the subtypes With Delusions (293.81) and With Hallucinations (293.82); and Psychotic Disorder Not Otherwise Specified (298.9);

Other conditions wherein agonism of the M₁receptor 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 (311); Bipolar Disorders including Bipolar I Disorder, Bipolar II 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-Injection-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-Like)-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-Induced Psychotic Disorder, Cannabis-Induced 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-Induced Psychotic Disorder, Opioid-Induced Mood Disorder, Opioid-Induced Sexual Dysfunction, Opioid-Induced 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-Induced Psychotic Disorder, Phencyclidine-Induced Mood Disorder, Phencyclidine-Induced 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-Induced Psychotic Disorder, Sedative-, Hypnotic-, or Anxiolytic-Induced Mood Disorder, Sedative-, Hypnotic-, or Anxiolytic-Induced Anxiety Disorder Sedative-, Hypnotic-, or Anxiolytic-Induced Sexual Dysfunction, Sedative-, Hypnotic-, or Anxiolytic-Induced 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);

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); and

Alzheimer's Type Dementia including Dementia of the Alzheimer's Type, With Early Onset, Without Behavioural Disturbance (294.10); Dementia of the Alzheimer's Type, With Late Onset, Without Behavioural Disturbance (294.10); Dementia of the Alzheimer's Type, With Early Onset, With Behavioural Disturbance (294.11); Dementia of the Alzheimer's Type, With Late Onset, With Behavioural Disturbance (294.11).

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, M₁agonists may be beneficial. For example, when the treatment of epilepsy with anticonvulsants results in cognitive impairment, an M₁agonist 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 accepatble 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.

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

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 for 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.

The invention also provides a compound of formula (I) as hereinbefore described or a pharmaceutically acceptable salt thereof for the treatment of Alzheimer's Disease.

In another aspect, the invention provides a method of treating a condition where agonism of the M₁receptor 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 invention also provides a method of treating Alzheimer's Disease, 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 patient 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 GlyT1 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 NAVAN E®); 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 NOZINAN®), 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 V1b 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 M₁agonists (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 of the invention 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.

The daily dosage contains suitably from 0.01mg/kg to 100 mg/kg of a compound of 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 M₁Receptors to Determine Agonist/Antagonist Potency

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 M₁receptors using FLIPR (Fluorometric Imaging Plate Reader) technology. Briefly, CHO-M₁cells were plated (15,000/well) and allowed to grow overnight at 37 degrees. Media were removed and 30 μl loading buffer (HBSS with 2.5 mM probenicid, 2 μM Fluo-4, 500 μM Brilliant Black, pH 7.4) was added. After incubation at 37 degrees for 90 minutes, 10 μL 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 10 μL of assay buffer containing acetylcholine was added at an EC₈₀, 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 M₁receptors were performed for each compound. Results were imported into ActivityBase data analysis suite (ID Business Solution Inc., Parsippany, N.J.) where the curves were analysed by non-linear curve fitting and the resulting pEC₅₀/fpKi were calculated. The maximum asymptotes of agonist compounds were calculated as percentage of maximum FLIPR response induced by carbamoylcholine chloride added as control on the same compound plates.

The example compounds below were tested in the above assay and were found to have average pEC₅₀values of >5.5 at the muscarinic M₁receptor, and intrinsic activity >50%.

FLIPR Experiments on M_2-5Receptor to Determine Receptor Subtype Selectivity

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, M₄or M₅. In the case of M₂and M₄receptors, chimeric G-protein Gqi5 was also co-expressed to couple receptors to the calcium signalling 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/fpKi values were calculated.

The example compounds below were tested in the M_2-5receptor assays and the majority of the examples were found to be selective for the M₁receptor over M₂, M₃, M₄and M₅receptors, with typical selectivity (ratio of pEC₅₀'s) of ≧10-fold, and in certain cases ≧100-fold.

FLIPR Experiments on M₁Receptor to Determine Agonist Intrinsic Activity

To determine the intrinsic activities of M₁agonist compounds, compounds of the invention were characterized in FLIPR experiments on CHO-K1 cells with transient expression of human muscarinic M₁receptors. Briefly, CHO-K1 cells were transduced with M₁BacMam 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). A functional titration was performed on each batch of cells continuously cultured ahead of experimentation to determine the appropriate multiplicity of infection ratio (MOI) for measuring intrinsic activities of test compounds. After mixing with virus in suspension, cells were plated (10,000/well) and allowed to adhere overnight at 37 degrees.

The FLIPR experiment was carried out on the day following plating using the same protocol as described above for CHO-M₁cells. Data was analysed by non-linear curve fitting using four-parameter logistics contained in XC50 version 2, and the resulting pEC₅₀values were calculated. The intrinsic activities of agonist compounds were measured 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).

Certain compounds below were tested in this assay, and were found to have average pEC₅₀values of >6.0 at the muscarinic M₁receptor, and intrinsic activity of greater than or equal to 0.3.

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 columns (including SCX, SCX-2, SCX-3) refer to sulfonic acid ion exchange resins supplied by Varian, IST and Radleys.

Amino-doped silica columns are supplied by Biotage

SPE-Si cartridges are silica solid phase extraction columns supplied by Varian.

Flash silica gel chromatography was carried out on, for example, silica gel 230-400 mesh (supplied by Merck AG Darmstadt, Germany) or over pre-packed Biotage silica cartridges (e.g. 12+M, or 65i) on Biotage Horizon, SP1 or SP4 machines.

For specified hydrogenation reactions, an H-cube was used. The H-cube is a continuous flow hydrogenator developed by Thales Nanotechnology. A solution of the sample to be hydrogenated is delivered to the reactor in a continuous stream using an HPLC pump. In the reactor it is mixed with hydrogen (generated from electrolysis of water), heated, and passed through a catalyst (e.g. palladium on charcoal) cartridge (up to 100° C. and 100 bar pressure) to produce a continuous flow of hydrogenated product.

NMR spectra were obtained at 298° K., at the frequency stated using either a Bruker™ DPX400 or an Oxford Instruments™ 250 MHz machine and run as a dilute solution of CDCl₃unless otherwise stated. All NMR spectra were reference to tetramethylsilane (TMS δ_H0, δ_C0). 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). NMR spectral data, where provided, were obtained for the title substance in each Description or Example (e.g. the hydrochloride salt, or the free base), unless otherwise stated.

Mass spectra (MS) were taken on a 4 II triple quadropole Mass Spectrometer (Micromass UK) or on a Agilent MSD 1100 Mass Spectrometer, operating in ES (+) and ES (−) ionization mode or on a Agilent LC/MSD 1100 Mass Spectrometer, operating in ES (+) and ES (−) ionization mode coupled with HPLC instrument Agilent 1100 Series [LC/MS—ES (+)]. Analysis was performed on a Waters Atlantis column (50×4.6 mm) with a stationary phase particle size of 3 μM. Mobile phase A (aqueous phase)=water+0.05% formic acid; mobile phase B (organic solvent)=acetonitrile+0.05% formic acid. Method as follows:

Time/min
% A
% B

0
97
3

0.1
97
3

4
3
97

4.8
3
97

4.9
97
3

5.0
97
3

The above method had a flow rate of 3 mL/min. The injection volume was 5 μL. The column temperature was 30° C. The UV detection range was from 220 to 330 nm.

MDAP (mass-directed auto-preparation) refers to purification by HPLC on a Waters machine, wherein fraction collection is triggered by detection of the programmed mass ion for the compound of interest. High pH separations refer to use of a water/acetonitrile/ammonium carbonate gradient.

MDAP was conducted using a Waters 2525 Binary Gradient Module, a Waters 515 Makeup Pump, a Waters Pump Control Module, a Waters 2767 Inject Collect, a Waters

Column Fluidics Manager, a Waters 2996 Photodiode Array Detector, a Waters ZQ Mass Spectrometer, a Gilson 202 fraction collector and a Gilson Aspec waste collector. For low pH, the column was a Waters Atlantis or Sunfire C18 column (19×100 mm or 30×100 mm, 5 μm packing diameter), solvent A was water plus 0.1% formic acid and solvent B was acetonitrile plus 0.1% formic acid. The gradient used was determined by LCMS retention time.

LCMS Rt
Gradient

1.0-1.5
5-30% B

1.5-2.2
15-55% B

2.2-2.9
30-85% B

2.9-3.6
50-99% B

3.6-5.0
80-99% B

For high pH, the column was an X Bridge C18 column (30×100 mm, 5 μm packing diameter), solvent A was 10 mM ammonium carbonate in water adjusted to pH 10 using ammonia solution and solvent B was acetonitrile. The gradient was determined by LCMS retention time:

LCMS Rt
Gradient

1.0-1.5
1-99% B

1.5-2.2
15-99% B

2.2-2.9
30-99% B

2.9-3.6
50-99% B

3.6-5.0
80-99% B

For reactions involving microwave irradiation, a Biotage Initiator was used.

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.

Where applicable, the ratio of cis/trans isomers was assessed by NMR integration. Characterisation of cis and trans was based on NMR shift data and coupling constants for the relevant H.

Abbreviations

NMR Nuclear Magnetic Resonance

THF tetrahydrofuran

DMSO dimethylsulfoxide

DMF dimethylformamide

DCM dichloromethane

DCE 1,2-dichloroethane

EDC 1-ethyl-3-(dimethylaminopropyl)carbodiimide

Et₂O diethyl ether

HOBt 1-hydroxybenzotriazole

MeCN/CH₃CN acetonitrile

MeOH methanol

DIPEA (Hunig's base)diisopropylethylamine

nhex n-hexane

c-hex cyclohexane

iso-hex iso-hexane

EtOAc ethyl acetate

Boc/BOC t-butyloxycarbonyl

MDAP Mass-Directed Auto-Preparation

TLC thin layer chromatography

aq aqueous

eq equivalents

sat^dsaturated

LC/MS liquid chromatography/mass spectrometry

Rt/rt/room temp room temperature

SM starting material

RM reaction mixture

FC flash chromatography

PS polymer supported

RB round bottomed

CV column volumes

Pd/C palladium on charcoal

Pd₂dba₃Tris(dibenzylideneacetone)dipalladium (0)

X-Phos 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl

BINAP 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl

mCPBA meta-chloroperoxybenzoic acid

NaI sodium iodide

Description 1. cis/trans-Ethyl 4-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}cyclohexanecarboxylate. (D1)

Chloro(1,1-dimethylethyl)dimethylsilane (115 g; 0.76 mol) was added in portions over 1 hour to a solution of commercially available ethyl 4-hydroxycyclohexanecarboxylate (118 g; 0.68 mol), imidazole (103 g; 1.52 mol) and dimethylformamide (400 mL) stirred under an atmosphere of argon. A small exotherm was observed resulting in the reaction mixture temperature increasing to ˜40° C. The mixture was stirred at room temperature overnight then poured into 10% citric acid solution (2 L) and extracted with diethyl ether (2×800 mL). The ether extracts were washed with water, brine and then dried (Na₂SO₄) and the solvent was removed to give the title compound as an oil (198.4 g)

¹H NMR δ (CDCl₃, 400 MHz): 0.01 (6H, m), 0.85 (9H, s), 1.2 (3H, m), 1.3-1.5 (2H, m), 1.6 (2H, m), 1.85-2 (3H, m), 2.15-2.3 (1H, m) 3.5 (0.4H, m) 3.86 (1H, m) 4.1 (1H, m).

Description 2. 1-Ethyl-1-methyl-4-oxopiperidinium iodide. (D2)

Iodomethane (65 mL; 1.00 mol) was added in portions to a solution of 1-ethyl-4-piperidone (100 g; 0.79 mol) in acetone (1 L) at 20-30° C. (internal, ice cooling). After stirring for 3 h more the title compound was obtained by filtration, and washing with acetone (189 g).

Description 3. cis/trans-Ethyl 4-(propyloxy)cyclohexanecarboxylate. (D3)

Propionaldehyde (6.4 g) in acetonitrile (50 mL) was added over 30 minutes to a solution of cis/trans ethyl 4-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}cyclohexanecarboxylate (D1, 25.2 g), bismuth tribromide (4.4 g) and triethylsilane (17.5 mL) in acetonitrile (300 mL) and the mixture was stirred for a further 1.5 hours. The solvent was partially removed then the residue was treated with ethyl acetate and saturated sodium bicarbonate solution. The organic layer was separated, washed with brine, dried with anhydrous sodium sulphate and the solvent was removed to give the title compounds contaminated with silicone residues (39.1 g).

Description 4. cis/trans-4-(Propyloxy)cyclohexanecarboxylic acid. (D4)

cis/trans-Ethyl 4-(propyloxy)cyclohexanecarboxylate (D3) (39.1 g), 40% w/w sodium hydroxide solution (150 mL), tetrahydrofuran (200 mL) and methanol (150 mL) was stirred for approx. 72 hours. The solvent was partially removed then the resulting mixture was treated with ethyl acetate and water. The aqueous layer was separated, acidified with concentrated hydrochloric acid and extracted with diethyl ether. The ether layer was washed with brine, dried with anhydrous sodium sulphate and the solvent was removed to give the title compounds as oil (15.42 g).

Description 5 cis/trans-1-Methyl-4-(propyloxy)cyclohexanecarboxylic acid. (D5)

A stirred solution of diisopropylamine (24 mL, 0.17 mol) in THF (300 mL) at −20° C. under argon was treated over 10 mins with 2.5M n-butyllithium in hexane (68 mL, 0.17 mol), then allowed to warm to 0° C. and stir for 15 mins. The mixture was re-cooled to −10° C. and treated over 10 mins with a solution of 4-(propyloxy)cyclohexanecarboxylic acid (D4, 13.8 g, 0.074 mol) in THF. The resulting yellow solution was heated at 50° C. for 2.5 hr, then cooled to 0° C. and treated with iodomethane (13.8 mL, 0.22 mol). The mixture was allowed to warm to room temperature and stir for 20 hr when a yellow precipitate had formed. The mixture was cooled to 10° C., treated with 10% citric acid solution (200 mL), then concentrated under vacuum to approx. 250 mL volume. The residual mixture was diluted with water (200 mL) and extracted with Et₂O (3×250 mL). The combined extract was dried (Na₂SO₄) and concentrated under vacuum to leave a yellow oil (15.0 g) which was approx. 60:40 mixture of cis:trans isomers.

Description 6. trans-1-Methyl-4-(propyloxy)cyclohexanecarboxylic acid. (D6)

cis/trans-1-Methyl-4-(propyloxy)cyclohexanecarboxylic acid (D5, 13 g, 0.070 mol) was added to stirred thionyl chloride (50 mL), 0.68 mol) at 10° C. and then allowed to warm to room temperature, followed by heating at 85° C. for 3 hr. The mixture was concentrated under vacuum and the residue concentrated twice with toluene to remove excess thionyl chloride. The residue was dissolved in THF (100 mL), treated with dil. NaHCO₃solution (250 mL) and stirred well at room temperature for 24 hr, followed by standing at room temperature for 3 days. The mixture from the same stage of a smaller scale reaction on 2 g of cis/trans-1-methyl-4-(propyloxy)cyclohexanecarboxylic acid was combined at this time. The combined mixture was concentrated under vacuum to approx. 300 mL and the aqueous residue washed with Et₂O (2×120 mL), then acidified with 2M HCl acid and extracted with EtOAc (2×150 mL). The combined extract was dried (Na₂SO₄) and concentrated under vacuum to leave the title compound as a pale yellow solid (5.1 g, 34%).

¹H NMR δ (CDCl₃, 400 MHz): 0.92 (3H, t), 1.24 (3H, s), 1.54-1.74 (8H, m), 1.78-1.88 (2H, m), 3.33-3.40 (3H, m). 1H not discernible from spectrum.

Description 7. trans-1-Isocyanato-1-methyl-4-(propyloxy)cyclohexane. (D7)

A stirred solution of trans-1-methyl-4-(propyloxy)cyclohexanecarboxylic acid (D6, 5.1 g, 0.027 mol) in toluene (120 mL) at room temperature under argon was treated with triethylamine (4.9 mL, 0.035 mol) and diphenylphosphoryl azide (5.8 mL, 0.027 mol) and heated at 85° C. for 1 hr. The mixture was allowed to cool to room temperature, then treated with 1M NaOH solution (200 mL) and extracted with Et₂O (2×150 mL). The combined extract was dried (Na₂SO₄) and concentrated under vacuum to leave the title compound as a yellow oil (5.0 g, 100%).

¹H NMR δ (CDCl₃, 400 MHz): 0.91 (3H, t), 1.36 (3H, s), 1.50-1.60 (4H, m), 1.65-1.80 (6H, m), 3.33 (2H, t), 3.46-3.52 (1H, m).

Description 8. [trans-1-Methyl-4-(propyloxy)cyclohexyl]amine hydrochloride. (D8)

A solution of trans-1-isocyanato-1-methyl-4-(propyloxy)cyclohexane (D7, 5.0 g, 0.027 mol) in THF (100 mL) was treated with 5M HCl acid (25 mL) and stirred at room temperature under argon for 20 hr, then concentrated under vacuum and the residue azeotroped with toluene to remove traces of water. The residual semi-solid was triturated with Et₂O (120 mL) to give a solid, which was filtered off, washed with Et₂O and dried at 50° C. under vacuum to afford the title compound as a white solid (4.5 g, 85%).

¹H NMR δ (CDCl₃, 400 MHz): 0.91 (3H, t), 1.47 (3H, s), 1-45-1.70 (4H, m), 1.75-2.00 (6H, m), 3.52 (2H, t), 3.40-3.48 (1H, m), 8.38 (3H, br s).

Description 9. 1-[trans-1-Methyl-4-(propyloxy)cyclohexyl]-4-piperidinone. (D9)

A stirred solution of [trans-1-methyl-4-(propyloxy)cyclohexyl]amine hydrochloride (D8, 4.5 g, 0.022 mol) in a mixture of ethanol (100 mL) and water (60 mL) at room temperature under argon was treated with potassium carbonate (3.31 g, 0.024 mol) followed by 1-ethyl-1-methyl-4-oxopiperidinium iodide (D9, 8.91 g, 0.033 mol), then heated at 80° C. for 2.5 hr. The mixture was allowed to cool, concentrated under vacuum to approx. 60 mL, then the aqueous residue was treated with sat. NaHCO₃solution and extracted with DCM (3×80 mL). The combined extract was dried (Na₂SO₄) and concentrated under vacuum to leave an orange oil (6.1 g), which was chromatographed on silica gel eluting with 0-10% MeOH/DCM to afford the title compound as a yellow oil (3.45 g, 63%).

¹H NMR δ (CDCl₃, 400 MHz): 0.93 (3H, s+3H, t), 1.48-1.72 (8H, m), 1.80-1.92 (2H, m), 2.41 (4H, t), 2.82 (4H, t), 3.35-3.45 (3H, t+m).

Description 10. 3-Amino-4-hydroxybenzonitrile. (D10)

4-Hydroxy-3-nitrobenzonitrile (0.5 g, 3.05 mmol) was dissolved in ethanol (20 mL) and methanol (10 mL), and Raney-Nickel (1 mL, 10% aqueous solution) was added at rt followed by hydrazine mono hydrate (0.296 mL, 6.09 mmol). The mixture was stirred at rt overnight. The mixture was then filtered through celite and concentrated by rotary evaporation. The residue was purified via chromatography (silica, n-hexane to ethyl acetate) to give 3-amino-4-hydroxybenzonitrile (D10, 200 mg, 49%) as an orange solid.

M+H⁺135

¹H NMR: δ (DMSO-d₆, 400 MHz) 4.99 (2H, br. s), 6.74 (1H, d, J 7.9), 6.82-6.89 (2H, m), 10.23 (1H, br. s).

Description 11. 1,1-Dimethylethyl 4-[(5-cyano-2-hydroxyphenyl)amino]-1-piperidinecarboxylate. (D11)

Polymer supported sodium cyanoborohydride (3531 mg, 7.20 mmol, 2.04 mmol/g) was added to a solution of 3-amino-4-hydroxybenzonitrile (D10, 477 mg, 3.56 mmol), 1,1-dimethylethyl 4-oxo-1-piperidinecarboxylate (709 mg, 3.56 mmol) and acetic acid (1 mL, 17.5 mmol) in tetrahydrofuran (10 mL). The mixture was heated by microwave at 100° C. for 30 min and then for a further 30 min before being filtered and concentrated by rotary evaporation to give 1,1-dimethylethyl 4-[(5-cyano-2-hydroxyphenyl)amino]-1-piperidinecarboxylate (D11, 982 mg, 3.09 mmol, 87% yield) as a yellow solid.

M−H⁺316

¹H NMR: δ (CDCl₃; 400 MHz) 1.32-1.53 (11H, m), 2.03 (2H, m), 2.86-3.14 (2H, m), 3.41 (1H, m), 4.03 (2H, m), 6.77 (1H, d, J 1.8), 6.82 (1H, d, J 8.0), 6.90 (1H, dd, J 8.0 and 1.8).

Description 12. 1,1-Dimethylethyl 4-(5-cyano-2-methylidene-1,3-benzoxazol-3(2H)-yl)-1-piperidinecarboxylate. (D12)

Hünig's base (1 mL, 5.73 mmol) was added to a solution of 1,1-dimethylethyl 4-[(5-cyano-2-hydroxyphenyl)amino]-1-piperidinecarboxylate (D11, 977 mg, 3.08 mmol) in dichloromethane (20 mL) at rt under argon. The reaction was cooled to 0° C. and triphosgene (373 mg, 1.26 mmol) was added. The reaction was then stirred for 30 min at 0° C. and quenched with saturated aqueous NaHCO₃(20 mL) before being partitioned between dichloromethane and water. The aqueous layer was extracted with dichloromethane (2×) and the combined organics were dried (Na₂SO₄) and concentrated by rotary evaporation to give a yellow oil. The crude residue was purified via chromatography (silica, Biotage 40+S column, dichloromethane to 0.5% ammonia/9.5% methanol/90% dichloromethane) to give 1,1-dimethylethyl 4-(5-cyano-2-methylidene-1,3-benzoxazol-3(2H)-yl)-1-piperidinecarboxylate (D12, 1.22 g, 92% yield, 82% purity by LC-MS) as a yellow oil.

[M-O^tBu] 270

¹H NMR: δ (CDCl₃; 400 MHz) 1.51 (9H, s), 1.93 (2H, m), 2.28 (2H, m), 2.92 (2H, m), 4.28-4.44 (3H, m), 7.35 (1H, d, J 8.8), 7.48-7.54 (2H, m).

Description 13. 2-Oxo-3-(4-piperidinyl)-2,3-dihydro-1,3-benzoxazole-5-carbonitrile monohydrochloride. (D13)

1,1-Dimethylethyl 4-(5-cyano-2-oxo-1,3-benzoxazol-3(2H)-yl)-1-piperidinecarboxylate (D12, 1.22 g, 2.84 mmol, 80% wt.) was dissolved in dichloromethane (20 mL) at rt to give a yellow solution and HCl (20 mL, 80 mmol, 4 M in 1,4-dioxane) was added whereupon the mixture turned orange. The reaction was stirred for 2 h (precipitate formed after 15 minutes). The reaction was diluted with diethyl ether (20 mL) and filtered. The solid was washed with diethyl ether (2×) and dried under high vacuum to give 2-oxo-3-(4-piperidinyl)-2,3-dihydro-1,3-benzoxazole-5-carbonitrile monohydrochloride (D13, 557 mg, 70% yield) as a pale pink solid.

[M+H]⁺244

¹H NMR δ (DMSO-d₆; 400 MHz) 2.01 (2H, m), 3.07 (2H, m), 3.44 (2H, m), 4.54 (1H, m), 7.59(1H, d, J 8.3), 7.70 (1H, dd, J 8.3 and 1.5), 8.07 (1H, d, J 1.5), 8.94 (2H, m). 2H obscured by solvent peak.

Description 14. 3-[1-(1-Cyano-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-2-oxo-2,3-dihydro-1,3-benzoxazole-5-carbonitrile. (D14)

2-Oxo-3-(4-piperidinyl)-2,3-dihydro-1,3-benzoxazole-5-carbonitrile monohydrochloride (D13, 254.4 mg, 0.909 mmol) was purified by SCX (5 g, eluting with MeOH followed by 2 M NH₃in MeOH) to give the free base (225 mg). The free base was then dissolved in N,N-dimethylacetamide (10 mL) at rt under argon. MgSO₄(560 mg, 4.66 mmol), 4-{[2-(methyloxy)ethyl]oxy}cyclohexanone (D21 259 mg, 1.51 mmol) and acetone cyanohydrin (0.17 mL, 1.86 mmol) were added and the reaction was heated at 70° C. overnight under a gentle stream of argon. The mixture was then cooled to rt, diluted with 1:1 dichloromethane:water (30 mL) and sonicated for 15 min. The phases were allowed to separate and the organic phase was dried by filtering through a hydrostatic cartridge. A further 10 mL of dichloromethane was added to the aqueous phase and the mixture stirred vigorously for 10 min. The 2 phases were again separated and the organic phase was dried by filtering through a hydrostatic cartridge. The combined organic layer was concentrated by rotary evaporation to give 3-[1-(1-cyano-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-2-oxo-2,3-dihydro-1,3-benzoxazole-5-carbonitrile (D14, 490 mg, 15% yield, 12% purity) as a yellow oil.

Isomer 1: [M-CN]⁺398; retention time 2.75.

Isomer 2: [M-CN]⁺398; retention time 2.85.

Description 15 and 16. 4-Hydroxy-3-{[1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]amino}benzonitrile. (D15) and
4-Hydroxy-3-{[1-(cis-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]amino}benzonitrile. (D16)

Methylmagnesium iodide (2.3 mL, 6.90 mmol, 3 M in diethyl ether) was added to a suspension of 3-[1-(1-cyano-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-2-oxo-2,3-dihydro-1,3-benzoxazole-5-carbonitrile (D14, 490 mg, 0.808 mmol, 70% wt.) in tetrahydrofuran (5 mL) at rt under argon. The reaction was diluted with a further portion of tetrahydrofuran (5.00 mL) and stirred for 2 h before being cooled to 0° C. and being quenched with saturated aqueous NH₄Cl (5 mL). The mixture was partitioned between ethyl acetate and water and the aqueous layer was extracted with ethyl acetate (2×). The combined organics were dried (Na₂SO₄) and concentrated by rotary evaporation to give an orange/yellow oil. The mixture was separated by high pH MDAP to give 4-hydroxy-3-{[1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]amino}benzonitrile (D15, 37.5 mg, 70% yield) as a colourless oil and 4-hydroxy-3-{[1-(cis-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]amino}benzonitrile (D16, 22.6 mg, 42% yield) as an off white solid.

Assignment of cis or trans geometry was by conversion to the benzoxazolone and then use of distinctive chemical shift

trans: [M+H]⁺388; Rt=5.61

cis: [M+H]⁺388; Rt=7.07

Description 15. Alternative Procedure. 4-Hydroxy-3-{[1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]amino}benzonitrile. (D15)

Polymer supported cyanoborohydride (908 mg, 3.90 mmol, 4.3 mmol/g) was added to a solution of 3-amino-4-hydroxybenzonitrile (D10, 265 mg, 1.98 mmol), 1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinone (D28, 526 mg, 1.95 mmol) and acetic acid (0.56 mL, 9.76 mmol) in THF (8 mL). The mixture was heated by microwave at 100° C. for 1 h and then for a further 1 hour. The reaction was then filtered and concentrated by rotary evaporation to give a yellow/brown oil which was purified via flash column chromatography (silica, Biotage 40+S column, DCM to 0.5% NH₃/9.5% MeOH/90% DCM) to give 4-hydroxy-3-{[1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]amino}benzonitrile (D15, 554 mg, 73%) as a cream solid.

LCMS: [M+H]⁺388

¹H NMR: δ (CDCl₃, 400 MHz) 1.04 (3H, s), 1.34-1.48 (2H, m), 1.50-1.77 (6H, m), 1.81-1.98 (2H, m), 2.05-2.16 (2H, m), 2.33-2.48 (2H, m), 3.04-3.29 (4H, m), 3.39 (3H, s), 3.51-3.61 (4H, m), 6.58 (1H, d, J 8.1), 6.70 (1H, d, J 1.9), 6.85 (1H, dd, J 8.1 and 1.9).

Description 17. 2-Fluoro-4-methyl-6-nitrophenol. (D17)

To 2-fluoro-4-methylphenol (500 mg, 3.96 mmol) in dichloromethane (5 mL) at room temperature was added dropwise nitric acid 70% (0.4 mL, 4.44 mmol) [exotherm observed]. After 15 min more washed with water, dried, evaporated to give 2-fluoro-4-methyl-6-nitrophenol (400 mg, 2.337 mmol, 59.0% yield) as a yellow solid.

Description 18. 2-Fluoro-4-methyl-6-aminophenol (D18)

A solution of 2-fluoro-4-methyl-6-nitrophenol D17 (400 mg, 2.337 mmol) (D41) in ethanol (50 mL) was hydrogenated using a Pd/C cartridge in the H-cube™ hydrogenator at 1 mL/min and full hydrogen. Evaporation gave 2-fluoro-4-methyl-6-aminophenol (250 mg, 1.771 mmol, 76% yield) as a fawn solid.

Description 19a. 1,4-Dioxaspiro[4.5]decan-8-ol. (D19)

1,4-Dioxaspiro[4.5]decan-8-one (64 mmol, 10 g) was dissolved in ethanol (125 mL) and treated with NaBH₄(1.2 eq., 76.8 mmol, 2.9 g), at 0° C. portionwise 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 (2×). The organics were combined, dried over Na₂SO₄, filtered and the solvent was evaporated to afford the title compound, 8.3 g, 82%, as a colourless oil.

¹H NMR δ (DMSO-d₆, 400 MHz) 1.44 (4H, m), 1.64 (4H, m), 3.54 (1H, d broad), 3.82 (4H, m), 4.48 (1H, d).

Description 19b. Scale-up procedure. 1,4-Dioxaspiro[4.5]decan-8-ol. (D19)

1,4-Dioxaspiro[4.5]decan-8-one (60 g, 384 mmol) was dissolved in methanol (600 mL) under Argon, then sodium borohydride (15.99 g, 423 mmol) was added portionwise (the addition was exothermic and a huge gas evolution was observed). The resulting mixture was stirred for 30 min. The reaction was quenched with water (200 mL) and stirred for 10 min. Solvent was removed under reduced pressure and the residue taken-up with DCM (600 mL) and water (300 mL). Phases were separated then the aqueous phase extracted with DCM (1×600 mL). Combined organic phases were dried on Na₂SO₄and concentrated under vacuum to obtain title material (58 g; 95%) as colourless oil.

¹H NMR δ (CDCl₃, 400 MHz): 1.64 (4H, m), 1.87 (4H, m), 3.83 (1H, m), 3.97 (4H, dt).

Description 20a. 8-{[2-(Methyloxy)ethyl]oxy}-1,4-dioxaspiro[4.5]decane. (D20)

1,4-Dioxaspiro[4.5]decan-8-ol (D19, 10 g, 58 mmol) was dissolved in 200 mL of dry DMF and NaH (60% dispersion in mineral oil, 1.01 eq., 58.7 mmol, 2.3 g) was added at 0° C. The mixture was stirred at the same temperature for 30 min and 1-bromo-2-(methyloxy)ethane (1.5 eq., 87 mmol, 8.2 mL) was added followed by NaI (cat, 500 mg) at 0° C. The mixture was stirred at Rt overnight. The mixture was then gently warmed to 40° C. and stirred overnight. The mixture was then quenched with MeOH, diluted with water and extracted with EtOAc (3×). Organics were diluted with hexane and extracted with brine and water respectively (2×). Organics were then dried over Na₂SO₄, filtered and the solvent was evaporated to afford 3.7 g of crude product that was purified by silica chromatography (40 M column, EtOAc-nhex) to afford 1.6 g of the title compound, 12%.

¹H NMR δ (CDCl₃, 400 MHz): 1.51-1.56 (2H, m), 1.69-1.87 (6H, m), 3.40 (3H,s), 3.43 (1H, m), 3.54 (2H, m), 3.59 (2H, m), 3.93 (4H, m).

Description 20b. Scale-up procedure. 8-{[2-(Methyloxy)ethyl]oxy}-1,4-dioxaspiro[4.5]decane. (D20)

Two different batches of material were reacted separately and then worked up together. In a 1 L round-bottomed flask 1,4-dioxaspiro[4.5]decan-8-ol D19 (45 g, 284 mmol) was dissolved in dimethyl sulfoxide (DMSO) (320 mL) to give a colourless solution. Potassium hydroxide (64 g, 1138 mmol) was added and the mixture was allowed to stir under argon for 20 minutes then a catalytic amount of sodium iodide was added. 2-Bromoethyl methyl ether (106 mL, 1138 mmol) was added dropwise keeping the internal temperature below +35° C. and the mixture was allowed to stir at room temperature overnight. The reaction was 80% complete by TLC after 5 hours. A further 32 g of potassium hydroxide and 54 mL of 2 bromoethyl methyl ether were added consequently and the reaction was allowed to stir at room temperature for 72 h.

In a similar way, in a 2 L round-bottomed flask 1,4-dioxaspiro[4.5]decan-8-ol D19 (65.6 g, 415 mmol) was dissolved in dimethyl sulfoxide (DMSO) (400 mL) to give a colourless solution. Potassium hydroxide (93.3 g, 1659 mmol) was added and the mixture was allowed to stir under argon for 20 minutes then a catalytic amount of NaI was added. 2-bromoethyl methyl ether (156 mL, 1659 mmol) was added dropwise keeping the internal temperature below +35° C. and the mixture was allowed to stir at room temperature overnight. After 5 h, reaction was 80% complete by TLC. Potassium hydroxide (46.7 g) and 2-bromoethyl methyl ether (78 ml) were added and the reaction allowed to stir at rt for a further 72 h.

The two reaction mixtures were combined and the overall resulting mixture was carefully portionwise added to a well stirred mixture of 1 L of water and 2 L of diethyl ether. The aqueous layer was back extracted with diethyl ether (2×500 mL). The organic phase was dried over anhydrous Na₂SO₄, filtered and concentrated to obtain 210 g of an oil residue that was purified via Biotage® 75 L SiO₂column eluting with 8/2 c-hex/EtOAc. Collected fractions were evaporated under vacuum to afford title material (155.3 g; 102% uncorrected) as yellow oil.

¹H NMR δ (CDCl₃, 400 MHz): 1.55 (2H, m), 1.80 (6H, m), 3.40 (3H, s), 3.44 (1H, m), 3.62-3.53 (4H, m), 3.95 (4H, d t).

Description 21a. 4-{[2-(Methyloxy)ethyl]oxy}cyclohexanone. (D21)

8-{[2-(Methyloxy)ethyl]oxy}-1,4-dioxaspiro[4.5]decane (D20) (1.6 g, 7 mmol), was dissolved in 20 mL of THF and HCl (25 eq., 5M, 35 mL) was added at Rt. The mixture was stirred at Rt for 5 hr. THF was then evaporated and the aqueous was extracted with dichloromethane (2×). Organics were washed once with water, dried over Na₂SO₄, filtered and the solvent was evaporated to afford the title compound, 1.3 g, complete conversion as a pale yellow oil.

¹H NMR δ (CDCl₃, 400 MHz): 1.92-2.00 (2H, m), 2.10-2.14 (2H, m), 2.23-2.30 (2H, m), 2.55-2.63 (2H, m), 3.41 (3H, s), 3.58 (2H, m), 3.64 (2H, m), 3.76 (1H, m).

Description 21b. Scale-up procedure. 4-{[2-(Methyloxy)ethyl]oxy}cyclohexanone. (D21).

In a 10 L round-bottomed flask 8-{[2-(methyloxy)ethyl]oxy}-1,4-dioxaspiro[4.5]decane D20 (151 g, 700 mmol) was dissolved in tetrahydrofuran (THF) (3000 mL) to give a colourless solution. 3M hydrochloric acid (2333 mL, 7000 mmol) was added. Reaction was allowed to stir at room temperature overnight. The organic solvent was partially evaporated under vacuum and then the aqueous layer was back extracted with DCM (3×500 mL). The organic phase was dried over Na₂SO₄, filtered and concentrated to obtain 121 g of crude material as yellow oil. The crude product was purified by Biotage® 75 L SiO₂column eluting with c-hex/EtOAc 8/2 to get title material (76 g; 63%).

¹H NMR δ (CDCl₃, 400 MHz): 1.98 (2H, m), 2.11 (2H, m), 2.28 (2H, m), 2.60 (2H, m), 3.41 (3H, s), 3.59 (2H, m), 3.68 (2H, m), 3.77 (1H, m).

Description 22. 2-Methylpropyl 1-methyl-4-oxocyclohexanecarboxylate. (D22)

2-(Trimethylsilyloxy)buta-1,3-diene (40 g, 281 mmol) was weighed into a Teflon™ microwave container. Isobutyl methacrylate (50.8 mL, 317 mmol) was added followed by 4,4′-methylenebis(2,6-di-tert-butylphenol) (0.5 g, 1.177 mmol), finally 1-butyl-3-methylimidazolium hexafluorophosphate (0.5 mL) was added, the vessel transferred to the Advancer microwave and heated for 4 hr (normal absorption, no fixed hold time, 190° C.). After 1 hr 20 min an error message was seen for the temperature probe, the error was cleared and heating was continued for a further hour. At this time the software had frozen forcing a shutdown at the mains. The reaction mixture was allowed to cool to RT. Tetrahydrofuran (THF) (200 mL) was added and the solution transferred to a round bottomed flask. 2M HCl was added and the reaction mixture left to stir overnight. DCM was added to the reaction mixture, whereupon an emulsion formed. An attempt to filter this was unsuccessful, and the mixture was left to stand overnight. The organic layer was separated, dried (Na₂SO₄) and evaporated to give a sticky oil. Flash column chromatography, eluting with ethyl acetate/isohexane gave 2-methylpropyl 1-methyl-4-oxocyclohexanecarboxylate as a yellow oil (12.74 g, 60.0 mmol, 21.35% yield).

Description 23. Isobutyl 1-methyl-4-(2-methoxyethoxy)cyclohexanecarboxylate.

A solution of isobutyl 1-methyl-4-oxocycylohexanecarboxylate (D22, 12.7 g, 59.8 mmol), t-butyl dimethyl 2-methoxyethoxy silane (11.4 g, 59.9 mmol), and anhydrous ferric chloride (250 mg, 1.541 mmol) in acetonitrile (150 mL) at 0° C. was treated with triethylsilane (12 mL, 75 mmol). The mixture was stirred for 1 h at room temperature, then partitioned between saturated sodium bicarbonate and dichloromethane, and the organic layer was dried and evaporated to give isobutyl 1-methyl-4-(2-methoxyethoxy)cyclohexanecarboxylate (27 g, 49.6 mmol, 83% yield) as a cis/trans mixture containing one equivalent of t-butyldimethyl triethyl siloxane.

Description 24. 1-Methyl-4-(2-methoxyethoxy)cyclohexanecarboxylic acid. (D24)

A mixture of isobutyl 1-methyl-4-(2-methoxyethoxy)cyclohexanecarboxylate (D23, 27 g, 49.6 mmol), 1,4-dioxane (100 mL) and 3M aqueous sodium hydroxide (100 mL, 300 mmol) was heated at 100° C. for 18 h then cooled and partitioned between water and diethyl ether. The aqueous phase was acidified and extracted with ethyl acetate to give the desired product. Unreacted starting material remained in the ether wash, so the ether was evaporated and the residue dissolved in a mixture of THF (100 mL), methanol (100 mL), and 6M aqueous sodium hydroxide (100 mL) and heated at 65° C. for 18 h then worked up as before to give additional product, which was combined to give 1-methyl-4-(2-methoxyethoxy)cyclohexanecarboxylic acid (9.5 g, 43.9 mmol, 89% yield) as a pale yellow oil.

Description 25. trans 1-Methyl-4-(2-methoxyethoxy)cyclohexanecarboxylic acid. (D25)

A solution containing 1-methyl-4-(2-methoxyethoxy)cyclohexanecarboxylic acid (D24, 9.5 g, 43.9 mmol), thionyl chloride (50 mL, 685 mmol), and toluene (25 mL) was heated at 90° C. for 4 h then cooled and evaporated. The residue was stirred with aqueous sodium bicarbonate for 30 min then washed with diethyl ether. Acidification and extraction with ethyl acetate gave trans 1-methyl-4-(2-methoxyethoxy)cyclohexanecarboxylic acid (3.2 g, 14.80 mmol, 33.7% yield) as an oil.

Description 26. trans 1-Methyl-4-(2-methoxyethoxy)cyclohexyl isocyanate. (D26)

A mixture of trans 1-methyl-4-(2-methoxyethoxy)cyclohexanecarboxylic acid (D25, 3.3 g, 15.26 mmol), diphenylphosphoryl azide (3.4 mL, 15.75 mmol), triethylamine (4.0 mL, 28.6 mmol), and toluene (50 mL) was heated at 100° C. for 1 h, then cooled and washed with water to give trans 1-methyl-4-(2-methoxyethoxy)cyclohexyl isocyanate (3.2 g, 15.00 mmol, 98% yield) as a mobile oil.

Description 27. trans 1-Methyl-4-(2-methoxyethoxy)cyclohexylamine hydrochloride. (D27)

A mixture of trans 1-methyl-4-(2-methoxyethoxy)cyclohexyl isocyanate (D26, 3.2 g, 15.00 mmol), 5M hydrochloric acid (50 mL, 250 mmol), and THF (50 mL) was stirred at room temperature for 18 h then evaporated to give trans 1-methyl-4-(2-methoxyethoxy)cyclohexylamine hydrochloride (3.5 g, 15.64 mmol, 104% yield) as a pale brown foam.

Description 28. 1-(trans-1-Methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinone. (D28)

A solution of trans 1-methyl-4-(2-methoxyethoxy)cyclohexylamine hydrochloride (D27, 3.5 g, 15.64 mmol) in ethanol (80 mL) and water (40 mL) was treated with potassium carbonate (3.0 g, 21.71 mmol). The mixture was heated to 80° C. and then a solution of 1-ethyl-1-methyl-4-oxopiperidinium iodide (D2, 7.0 g, 26.0 mmol) in ethanol (20 mL) and water (10 mL) added. After 2 h at the same temperature the reaction was partitioned between aqueous sodium bicarbonate and dichloromethane. Chromatography on silica (20 g), eluting with 0-10% 2M ammonia in methanol—dichloromethane, gave 1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinone (1.9 g, 7.05 mmol, 45.1% yield) as a straw coloured oil.

Description 29. 1,1-Dimethylethyl 4-[bis(phenylmethyl)amino]-1-piperidinecarboxylate. (D29)

1,1-Dimethylethyl 4-amino-1-piperidinecarboxylate (100 g, 499 mmol) was dissolved in 1,2-dichloroethane (DCE) (1000 mL), 55 mL (1.1 eq) of benzaldehyde were added and finally 127 g (1.2 eq.) of sodium triacetoxyborohydride were added portionwise.

The suspension was stirred overnight, then further 55 mL (1.1 eq) of benzaldehyde were added and 127 g (1.2 eq.) of sodium triacetoxyborohydride were added portionwise and stirred for 5 h, then further 28 mL (0.55 eq) of benzaldehyde were added and finally 64 g (0.6 eq.) of sodium triacetoxyborohydride were added portionwise and stirred overnight.

The reaction was treated with 3 L of NaHCO₃saturated solution until pH was basic, resulting mixture was diluted with water (500 mL) and DCM (1.5 L). Phases were separated, the organic layer was washed with brine (2×1 L), dried over Na₂SO₄and concentrated under vacuum. The residue was triturated with methanol (700 mL). The suspension was filtered through sintered glass funnel and the solid washed with methanol (100 mL). Obtained white solid was dried under vacuum to give title material (161 g; 85%).

¹H NMR δ (CDCl₃, 400 MHz): 1.47 (9H, s), 1.56 (2H, m), 1.82 (2H, m), 2.72-2.50 (3H, m), 3.66 (4H, m), 4.17 (2H, bs), 7.23 (2H, m), 7.31 (4H, m), 7.38 (4H, m).

Description 30. N,N-bis(Phenylmethyl)-4-piperidinamine. (D30)

1,1-Dimethylethyl 4-[bis(phenylmethyl)amino]-1-piperidinecarboxylate D29 (160 g, 420 mmol) was dissolved in dichloromethane (DCM) (1 L) and TFA (188 mL, 2443 mmol) was added dropwise at room temperature. The resulting mixture was stirred for 3 h then further 100 mL of TFA was added and stirred for 2 h. The mixture was concentrated under reduced pressure and the residue treated with saturated solution NaHCO₃(1.5 L) and NaOH (3M solution; 200 mL) to basic pH. The aqueous phase was extracted with DCM (2×1.5 L). Combined organic layers were diluted with ethyl acetate (100 mL), washed with water (1×1 L) and brine (1×1 L) then dried on Na₂SO₄and concentrated to obtain title material (118 g; 100%).

¹H NMR δ (CDCl₃, 400 MHz): 1.56 (2H, qd), 1.83 (2H, m), 2.49 (2H, td), 2.60 (1H, tt), 3.12 (2H, d), 3.66 (4H, s), 7.22 (2H, m), 7.30 (4H, t), 7.38 (4H, d).

Description 31. 1-(trans-1-Methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-N,N-bis(phenylmethyl)-4-piperidinamine. (D31)

In a 4000 mL round-bottomed flask 4-{[2-(methyloxy)ethyl]oxy}cyclohexanone D21 (78.7 g, 457 mmol) was dissolved in 1,2-dichloroethane (DCE) (2000 mL) to give a colourless solution. N,N-bis(phenylmethyl)-4-piperidinamine D30 (96.3 g, 343 mmol) was added, then titanium (IV) isopropoxide (174 mL, 584 mmol) was added and the mixture was stirred at room temperature. After 22 h cyano(diethyl)aluminium 1M in toluene (650 mL, 650 mmol) was added and the mixture was allowed to stir at room temperature for 20 h. The reaction was quenched by dropwise addition of 1.5 L of saturated sodium bicarbonate solution under mechanical stirring; the resulting mixture was filtered over a Celite® pad washing the panel with 800 mL of DCM. The organic layer was dried over anhydrous sodium sulphate and finally concentrated to dryness to afford 151.4 g of a crude oil that was dissolved in tetrahydrofuran (THF) (1500 mL) in a 4 L pear flask to give a colourless solution. The solution was chilled to 0° C. and methylmagnesium bromide 3M in diethyl ether solution (601 mL, 1804 mmol) was added dropwise. The reaction was allowed to stir at room temperature.

The day after, the work up was performed in the following way: the mixture was chilled to 0° C. and quenched by dropwise addition of 300 mL of water (strong gas evolution, salt precipitation was observed). The resulting mixture was diluted with 1.5 L of diethyl ether. The suspension was filtered and the solid was washed with 2×400 mL of DCM. The two organic phases were combined and dried over anhydrous sodium sulphate and finally concentrated under vacuum to afford 129 g of a crude white solid. The crude product was added to a silica gel column (1400 g) and was eluted with DCM/MeOH/NH₃2M in methanol from 2000/0/0 to 2000/150/0 ending with 2000/150/30. Collected fractions were evaporated under vacuum to give cis,trans-[1′-methyl-4′-{[2-(methyloxy)ethyl]oxy}-1,1-bi(cyclohexyl)-4-yl]bis(phenylmethyl)amine mixture (120.4 g, yield=77% considering cis/trans mixture) as white solid. 119 g of this material were purified by preparative HPLC. Evaporation of collected fraction afforded title material (35.6 g; 30% considering only preparative HPLC separation step) as white solid.

Preperative HPLC conditions:

Preparative instrument: Hipersep LC110 lab unit and Novasep LC50 mm DAC column.

Column: Kromasil Silica 10 um 60 angstrom (50 mm×27 cm)

Mobile phase: 50% C7: 50% MTBE with 0.25% v/v DEA

Flow rate: 200 mL/min

Main Pump stroke length: 5 mm

Sample pump stroke length: 2 mm

Mixer valve: 60 mm

UV detection wavelength: 254 nm

Overall run time: 6 mins

Sample preparation: 50 g/L cis/trans mixture dissolved in DCM

Sample load: 2 g.

¹H NMR δ (CDCl₃, 400 MHz): 0.86 (3H, s), 1.44 (4H, m), 1.61 (4H, m), 1.84 (4H, m), 1.97 (2H, t), 2.47 (1H, t), 3.00 (2H, d), 3.37 (1H, m), 3.39 (3H, s), 3.55 (4H, m), 7.20 (2H, t), 7.30 (4H, t), 7.37 (4H, d).

Description 32. 1-(trans-1-Methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinamine. (D32)

1-(trans-1-Methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-N,N bis(phenylmethyl)-4-piperidinamine D31 (42.5 g, 94 mmol) was dissolved in dry methanol (425 mL). Pd/charcoal 10% w/w (16.05 g, 15.09 mmol) and ammonium formate (59.5 g, 943 mmol) were added (caution, flammable; operation carried out under Argon) and the mixture heated at 80° C. for 1 h. Reaction mixture was cooled down to room temperature and filtered, washing with MeOH. Volatiles were evaporated to dryness under reduced pressure to afford title compound (25.2 g, 93 mmol, yield=99%) as pale grey oil.

¹H NMR δ (DMSO-d₆, 400 MHz): 0.79 (3H, s), 1.13 (2H, m), 1.44 (8H, m), 1.69 (4H, m), 2.00 (2H, dt), 2.43 (1H, m), 2.79 (2H, d), 3.25 (3H, s), 3.53-3.34 (5H, m).

MH⁺=271.0

Description 33. 3-Bromo-4-[(phenylmethyl)oxy]benzonitrile. (D33)

To a solution of 3-bromo-4-hydroxybenzonitrile (60 g, 303 mmol) in acetone (600 mL) under nitrogen, potassium carbonate (62.8 g, 455 mmol) was added followed by potassium iodide (0.503 g, 3.03 mmol). To the mixture benzyl chloride (49.3 mL, 424 mmol) was added dropwise and the mixture was heated at 50° C. (48° C. internal temp) for 16 h. Reaction mixture was cooled down to room temperature, taken up with water (500 mL)/Et₂O (1 L). Phases were separated and the aqueous phase back extracted with Et₂O (2×500 mL). Combined organics were washed with NaHCO₃saturated solution (400 mL), then with 1M HCl solution (400 mL) and brine. Crude solution was then dried over Na₂SO₄and evaporated under reduced pressure to give crude material (110 g) as brown solid that was triturated with c-hex (500 mL) for 30 min. The solid was collected by filtration and washed with c-hex/EtOAc 9/1 (200 mL). Evaporation of residual solvents under high vacuum afforded title material (75.5 g;261 mmol; 86%) as pale brown solid.

¹H NMR δ (CDCl₃, 400 MHz): 5.25 (2H, s), 6.99 (1H, d), 7.43 (5H, m), 7.58 (1H, dd), 7.88 (1H, d).

Description 34. 3-{[1-(trans-1-Methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]amino}-4-[(phenyl methyl)oxy]benzonitrile. (D34)

To a solution of 1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinamine D32 (26.8 g, 99 mmol) and 3-bromo-4-[(phenylmethyl)oxy]benzonitrile D33 (26 g, 90 mmol) in dry toluene (520 mL) under argon, sodium tert-butoxide (13.01 g, 135 mmol) and BINAP (5.62 g, 9.02 mmol) were added at room temperature. The resulting slurry was degassed (vacuum/Argon) 3 times, then Pd₂dba₃(4.13 g, 4.51 mmol) was added and the mixture heated at 70° C. for 3 h. Slurry was cooled down to room temperature, then taken up with EtOAc (500 mL)/water (500 mL). Phases were separated and the aqueous one was back extracted with EtOAc (2×500 mL). Combined organics were dried over Na₂SO₄then evaporated to dryness to get crude material as brown orange oil 62 g, which was purified by SiO₂FC eluting with DCM/MeOH 98/2 to 95/5 to get title material (42 g, 88 mmol; yield 97%) as thick yellow oil.

¹H NMR δ (CDCl₃, 400 MHz): 0.94 (3H, s), 1.46 (6H, m), 1.67 (2H, m), 1.86 (2H, m), 2.05 (2H, m), 2.28 (2H, m), 2.95 (2H, m), 3.26 (1H, m), 3.41 (4H, bs), 3.58 (4H, m), 4.37 (1H, d), 5.13 (2H, s), 6.79 (1H, d), 6.82 (1H, d), 6.94 (1H, dd), 7.40 (5H, m).

MH⁺=478.17

Description 35. (Alternative procedure for preparation of D15)
4-Hydroxy-3-{[1-(trans-1-methyl-4-{[2(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]amino}benzonitrile. (D35)

To a solution of 3-{[1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]amino}-4-[(phenylmethyl)oxy]benzonitrile D34 (37 g, 77 mmol) in ethyl acetate (555 mL) under a nitrogen atmosphere, palladium on carbon 10% w/w (9.25 g, 8.69 mmol) was carefully added. The resulting slurry was hydrogenated at atmospheric pressure and room temperature for 15 h. Reaction mixture was filtered over Sterimat® under an Argon atmosphere, washing the solid with EtOAc. Solvent was evaporated under vacuum to give crude material, (33 g) as yellow foam that was purified by SiO₂FC eluting with DCM/MeOH/NH₄OH from 95/5/0 to 9/1/0 to 90/10/0.5 to 90/10/1 to 85/15/2. Evaporation of volatiles afforded title material (26.33 g, 67.9 mmol, yield 88%) as off white foamy solid.

¹H NMR δ (CDCl₃, 400 MHz): 1.07 (3H, s), 1.46 (2H, m), 1.65 (4H, m), 1.76 (2H, m), 1.94 (2H, m), 2.13 (2H, m), 2.43 (2H, m), 3.13 (3H, m), 3.28 (3H, m), 3.42 (3H, s), 3.59 (4H, m), 6.64 (1H, d), 6.75 (1H, d), 6.90 (1H, dd).

MH⁺=388.14

Description 36. 5-Hydroxy-2-methylbenzonitrile. (D36)

Concentrated sulfuric acid (5 mL, 94 mmol) was added to H₂O (10 mL) (causing an exotherm). While the diluted acid was still hot, 5-amino-2-methylbenzonitrile (826 mg, 6.25 mmol) was added giving a clear solution. This was cooled to 15° C. (during which time a precipitate occurred) and 8 g of ice was added. As soon as the temperature was below 5° C., a solution of sodium nitrite (522 mg, 7.57 mmol) in H₂O (5 mL) was added from a syringe (with the needle extended below the surface of the liquid) keeping the internal temperature below 5° C. The solution went clear after 5 min of stirring and then cold H₂O (5 mL), urea (59 mg, 0.97 mmol) and ice (5 g) were added sequentially. In a separate flask H₂O (5 mL) was added to sodium sulfate (4.75 g, 33.4 mmol) under an atmosphere of argon. Concentrated sulfuric acid (10 mL) was cautiously added and the reaction heated to reflux. The diazonium species was added to the refluxing mixture in portions and the heating continued for 2 h (NOTE: Blast shield used during heating). The mixture was cooled to rt and extracted with Et₂O (2×). The combined organics were washed with H₂O and 10% Na₂CO₃solution before being extracted with 10% NaOH solution. The NaOH solution was acidified with concentrated HCl and then extracted with Et₂O (2×). The combined organics from this second extraction were dried (Na₂SO₄) and concentrated by rotary evaporation to give a light brown solid which was purified via flash column chromatography (silica, DCM to 0.5% NH₃/9.5% MeOH/90% DCM) to give 5-hydroxy-2-methylbenzonitrile (D36, 476 mg, 52%) as an orange solid.

LCMS: [M−H]⁻132

Description 37. 5-Hydroxy-2-methyl-4-nitrobenzonitrile. (D37)

5-Hydroxy-2-methylbenzonitrile (D36, 475 mg, 3.57 mmol) was dissolved in DCM (5 mL) and 70% nitric acid (1 mL, 22 mmol) was added dropwise to the reaction. The mixture was stirred for 45 min before the addition of H₂O (15 mL). The two phases were separated and the aqueous phase was extracted with DCM (2×). The combined organics were dried (Na₂SO₄) and concentrated by rotary evaporation to give a yellow solid. The crude residues were purified by flash column chromatography (silica, 10% EtOAc/90% iso-hexane to 50% EtOAc/50% iso-hexane) to give 5-hydroxy-2-methyl-4-nitrobenzonitrile (D37, 186 mg, 26%) as a yellow solid.

LCMS: [M−H]⁻177

Description 38. 4-Amino-5-hydroxy-2-methylbenzonitrile. (D38)

5-hydroxy-2-methyl-4-nitrobenzonitrile (D37, 185 mg, 1.04 mmol) was dissolved in EtOH:EtOAc (24 mL, 1:1) and was reduced using an H-Cube (full H₂mode, 25° C., 1 mL/min). The reaction was concentrated by rotary evaporation to give 4-amino-5-hydroxy-2-methylbenzonitrile (D38, 152 mg, 95%) as a pale yellow solid.

LCMS: [M+H]⁺149

Description 39. 5-Hydroxy-2-methyl-4-{[1-(trans-1-methyl-4-{[2-(methyloxy)-ethyl]oxy}cyclohexyl)-4-piperidinyl]amino}benzonitrile. (D39)

Polymer supported cyanoborohydride (199 mg, 0.86 mmol, 4.3 mmol/g) was added to a solution of 4-amino-5-hydroxy-2-methylbenzonitrile (D38, 65 mg, 0.44 mmol), 1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinone (D28, 117 mg, 0.43 mmol) and acetic acid (0.12 mL, 2.17 mmol) in THF (2.5 mL). The mixture was heated by microwave at 100° C. for 1 h and then for a further 2 h. An extra 50 mg of polymer supported cyanoborohydride was added and the reaction heated by microwave at 100° C. for 2×1 h. The reaction was then filtered and concentrated by rotary evaporation to give a yellow oil, which was purified via high pH MDAP to give 5-hydroxy-2-methyl-4-{[1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]amino}benzonitrile (D39, 62 mg, 36%) as a green oil.

LCMS: [M+H]⁺402

Description 40. 4-Methyl-2-{[1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]amino}phenol. (D40)

1-(trans-1-Methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinone (D28, 60 mg, 0.223 mmol) was dissolved in DCM (1.25 mL) and acetic acid (0.125 mL) and 2-amino-4-methylphenol (32.9 mg, 0.267 mmol) was added, followed by macroporous triethylammonium methylpolystyrene cyanoborohydride (193 mg, 0.445 mmol). The reaction mixture was heated in a microwave reactor at 100° C. for 10 min. The reaction mixture was filtered and evaporated to dryness. The crude product was purified by flash column chromatography on a pre-packed silica cartridge (column size 10 g), eluting with 5-10% 0.2 M ammonia in methanol in DCM to afford the desired compound as a colourless oil (56 mg). (M +H)⁺=377.

Description 41. 2-{[1-(trans-1-Methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]amino}-4-(methyloxy)phenol. (D41)

1-(trans-1-Methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinone (D28, 55 mg, 0.204 mmol) was dissolved in DCM (1.25 mL) and acetic acid (0.125 mL) and 2-amino-4-methoxyphenol (37 mg, 0.266 mmol) was added, followed by macroporous triethylammonium methylpolystyrene cyanoborohydride (177 mg, 0.408 mmol). The reaction mixture was heated in a microwave reactor at 100° C. for 10 min. The reaction mixture was filtered and evaporated to dryness. The crude product was purified by flash column chromatography on a pre-packed silica cartridge (column size 10 g), eluting with 5-10% 0.2 M ammonia in methanol in DCM to afford the desired compound as a yellow oil (12 mg). Due to the poor recovery, the remaining fractions were combined and evaporated to give a yellow oil (20 mg). The yellow oils were combined to give the desired product as a crude yellow oil (31 mg). The material was carried forward without further purification.

¹H NMR δ (CDCl₃): 1.26 (3H, s), 1.40 (3H, br. m), 1.88 (6H, br. m), 2.04 (4H, m), 2.24 (2H, br. m), 2.83 (2H, br.m), 3.30 (2H, br. m), 3.38 (3H, s), 3.42 (3H, br. m), 3.53 (2H, m), 3.60 (2H, m), 3.72 (2H, br. m), 6.18 (1H, m), 6.72 (1H, m).

Description 42. Ethyl 4-[(cyclopropylmethyl)oxy]cyclohexanecarboxylate. (D42)

Triethylsilane (10 mL, 63 mmol) was added to a solution of ethyl 4-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}cyclohexanecarboxylate (D1, 13.6 g, 47.4 mmol), bismuth tribromide (923 mg, 2.06 mmol) and cyclopropanecarbaldehyde (4.25 mL, 56.8 mmol) in acetonitrile (60 mL) at rt under Ar. A black precipitate and an exotherm occurred on the addition of the triethylsilane. The mixture was stirred for 1 h before being poured on to sat. NaHCO₃(200 mL). The reaction was extracted with EtOAc (2×) and the combined organics were washed (sat. NaCl), dried (Na₂SO₄) and concentrated by rotary evaporation to give a mixture of cis and trans ethyl 4-[(cyclopropylmethyl)oxy]cyclohexanecarboxylate (D42, 20.8 g, 97%, contained silyl residues) as a colourless oil.

¹H NMR δ (CDCl₃, 400 MHz) mixture of approx. 1:1 cis:trans 0.15-0.20 (2H, m), 0.47-0.54 (2H, m), 1.02 (1H, m), 1.20-1.28 (3H, m), 1.39-2.10 (8H, m), 2.23 (0.5 H, m), 3.17-3.30 (2.5H, m), 3.45 (0.5H, m), 4.06-4.15 (2H, m).

Description 43. 4-[(Cyclopropylmethyl)oxy]cyclohexanecarboxylic acid. (D43)

Ethyl 4-[(cyclopropylmethyl)oxy]cyclohexanecarboxylate (D42, 20.8 g, 45.8 mmol) was taken up in THF (50 mL)/methanol (50 mL). Sodium hydroxide (20 mL, 250 mmol, concentrated) was added to the solution which was left to stir o/n. The THF/methanol was evaporated and the crude residue washed with Et₂O. The aqueous layer was acidified with 5 M HCl and extracted with EtOAc (2×). The EtOAc organics were combined, dried (Na₂SO₄) and the solvent evaporated to give a mixture of cis and trans 4-[(cyclopropylmethyl)oxy]cyclohexanecarboxylic acid (D43, 9.47 g, 94%) as a yellow oil.

¹H NMR δ (CDCl₃, 400 MHz) mixture of approx. 1:1 cis:trans 0.12-0.19 (2H, m), 0.45-0.53 (2H, m), 0.95-1.06 (1H, m), 1.19-1.32 (1H, m), 1.38-1.69 (3.5H, m), 1.72-1.83 (1H, m), 1.84-2.10 (2.5H, m), 2.27 (0.5H, m), 2.38 (0.5H, m), 3.17-3.29 (2.5H, m), 3.44 (0.5H, m), 10.85 (1H, br. s).

Description 44. 4-[(Cyclopropylmethyl)oxy]-1-methylcyclohexanecarboxylic acid—mixture of cis and trans. (D44)

Diisopropylamine (15 mL, 105 mmol) in THF (100 mL) was cooled to 0° C. under Ar. n-Butyllithium (38 mL, 95 mmol, 2.5M in hexane) was added dropwise over 10 min. The reaction mixture was left to stir for 15 min at 0° C. A solution of 4-[(cyclopropylmethyl)oxy]cyclohexanecarboxylic acid (D43, 9.47 g, 43.0 mmol) in THF (50 mL) was added and the resulting yellow solution was heated at 50° C. for 2 h. The reaction mixture was cooled to 0° C. and iodomethane (8 mL, 128 mmol) was added dropwise, the reaction was then allowed to warm to rt and left to stir for 3 days. 10% Citric acid (200 mL) was then added and the reaction mixture was concentrated by rotary evaporation. The residual mixture was diluted with H₂O and extracted with Et₂O (2×). The organics were combined, dried (Na₂SO₄) and concentrated by rotary evaporation to give a mixture of cis and trans 4-[(cyclopropylmethyl)oxy]-1-methylcyclohexanecarboxylic acid (D44, 10.0 g, 93%) as a brown oil.

¹H NMR δ (DMSO-d₆, 400 MHz) mixture of approx. 1:1 cis:trans 0.09-0.17 (2H, m), 0.39-0.47 (2H, m), 0.83-2.03 (12H, m), 3.16-3.24 (2H, m), 3.33 (0.5H, m), 3.60 (0.5H, m), 12.12 (1H, br. s).

Description 45. trans-4-[(Cyclopropylmethyl)oxy]-1-methylcyclohexanecarboxylic acid. (D45)

4-[(Cyclopropylmethyl)oxy]-1-methylcyclohexanecarboxylic acid—mixture of cis and trans (D44, 10.0 g, 40.0 mmol) was azeotroped with PhMe (2×) to remove any trace H₂O and then dissolved in toluene (50 mL). Thionyl chloride (50 mL, 685 mmol) was added and the reaction heated at 90° C. for 4 h. Excess thionyl chloride was removed by rotary evaporation and the residue was azeotroped with toluene to remove the final traces. THF (50 mL) was added and the solution poured on to 5% Na₂CO₃solution (200 mL). The mixture was stirred vigorously for 20 min before being washed with Et₂O (2×). The aqueous layer was then acidified with concentrated HCl and extracted with EtOAc (2×). The combined EtOAc organics were dried (Na₂SO₄) and concentrated by rotary evaporation to give a brown oil. This residue was purified by being divided into 4 roughly equal portions, each of which was purified via flash column chromatography (silica, 5% EtOAc/95% iso-hexane to 25% EtOAc/75% iso-hexane). The desired fractions were combined to give trans-4-[(cyclopropylmethyl)oxy]-1-methylcyclohexanecarboxylic acid (D45, 893 mg, 10%) as a colourless oil.

¹H NMR δ (CDCl₃, 400 MHz) 0.16-0.23 (2H, m), 0.49-0.56 (2H, m), 1.05 (1H, m), 1.25 (3H, s), 1.60-1.87(8H, m), 3.26(2H, d, J6.8), 3.40 (1H, m).

Description 46. trans-4-[(Cyclopropylmethyl)oxy]-1-isocyanato-1-methylcyclo-hexane. (D46)

trans-4-[(Cyclopropylmethyl)oxy]-1-methylcyclohexanecarboxylic acid (D45, 890 mg, 4.19 mmol) was dissolved in toluene (25 mL) and triethylamine (0.760 mL, 5.45 mmol) was added, followed by diphenyl phosphoryl azide (0.903 mL, 4.19 mmol). The reaction mixture was heated at 85° C. for 2 h, then allowed to cool to room temperature overnight. The reaction mixture was treated with 1 M aq. sodium hydroxide (75 mL), then extracted with diethyl ether (3×50 mL). The combined organics were dried (MgSO₄) and evaporated to afford the desired product (D46) as a colourless oil (934 mg).

¹H NMR δ (CDCl₃): 0.18 (2H, m), 0.52 (2H, m), 1.03 (1H, m), 1.37 (3H, s), 1.54 (2H, m), 1.74 (6H, m), 3.23 (2H, d, J=6.8 Hz), 3.53 (1H, br. s).

Description 47. trans-4-[(Cyclopropylmethyl)oxy]-1-methylcyclohexanamine hydrochloride. (D47)

trans-4-[(Cyclopropylmethyl)oxy]-1-isocyanato-1-methylcyclohexane (D46, 877 mg, 4.19 mmol) was dissolved THF (25 mL) and 5 M hydrochloric acid (0.127 mL, 4.19 mmol) was added. The reaction mixture was stirred at room temperature for 3 h in an argon atmosphere. The reaction mixture was evaporated to dryness, redissolved in THF and evaporated. This was repeated until a white solid was obtained. This solid was triturated with ethanol and dried in a vacuum oven to afford the desired product (D47, 700 mg, 76% yield).

¹H NMR δ (CD₃OD): 0.20 (2H, m), 0.51 (2H, m), 1.01 (1H, m), 1.37 (3H, s), 1.59 (4H, m), 1.87 (4H, m), 1.32 (2H, d, J=5.2 Hz), 3.42 (1H, m).

Description 48. 1-{trans-4-[(Cyclopropylmethyl)oxy]-1-methylcyclohexyl}-4-piperidinone. (D48)

To a solution of trans-4-[(cyclopropylmethyl)oxy]-1-methylcyclohexanamine hydrochloride (D47, 700 mg, 3.19 mmol) in ethanol (20 mL) was added a solution of potassium carbonate (572 mg, 4.14 mmol) in water (10 mL), followed by 1-ethyl-1-methyl-4-oxopiperidinium iodide (D2, 1500 mg, 5.57 mmol). The reaction mixture was heated at 80° C. for 3 h. The reaction mixture was evaporated to dryness and partitioned between DCM and saturated sodium bicarbonate (25 mL of each). The aqueous layer was extracted with further DCM (2×25 mL). The combined organics were dried (MgSO₄) and evaporated to give an orange oil. The crude product was purified by flash column chromatography on a Biotage SP4 (column size 24+S), eluting with 0-10% methanol in DCM to afford the product (D48) as an orange oil (340 mg).

¹H NMR δ (CDCl₃): 0.20 (2H, m), 0.53 (2H, m), 0.94 (3H, s), 1.05 (1H, m), 1.48-1.61 (4H, m), 1.69 (2H, m), 1.86 (2H, m), 2.41 (4H, t, J=6 Hz), 2.82 (4H, t, J=6 Hz), 3.27 (2H, d, J=6.4 Hz), 3.44 (1H,m).

Description 49. 2-[(1-{trans-1-Methyl-4-[(2-methyl butyl)oxy]cyclohexyl}-4-piperidinyl)amino]-4-(methylsulfonyl)phenol. (D49)

1-{trans-4-[(Cyclopropylmethyl)oxy]-1-methylcyclohexyl}-4-piperidinone (D48, 170 mg, 0.641 mmol) was dissolved in THF (5 mL) and 2-amino-4-(methylsulfonyl)phenol (120 mg, 0.641 mmol) was added, followed by acetic acid (0.158 mL, 2.75 mmol) and macroporous triethylammonium methylpolystyrene cyanoborohydride (555 mg, 1.281 mmol). The reaction mixture was heated in a microwave reactor at 100° C. for 90 minutes. The reaction filtered, washing with methanol to dissolve a precipitate which formed. The collected solution was evaporated to give an orange oil-solid mixture. This was triturated with THF to give the desired product (D49) as a white solid (85 mg). (M+H)⁺=437.

Description 50. 2-{[1-(trans-1-Methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]amino}-4-(trifluoromethyl)phenol. (D50)

2-Amino-4-(trifluoromethyl)phenol (65.8 mg, 0.371 mmol), 1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinone (D28) (100 mg, 0.371 mmol), PS-CNBH₃(354 mg, 0.817 mmol) were placed in a 5 mL microwave tube, AcOH (0.13 mL, 2.271 mmol) and dichloromethane (DCM) (2.5 mL) were added. The tube was sealed and heated to 100° C. for 15 min, fixed hold time. The reaction mixture was filtered and the filtrate evaporated to give a clear oil. The oil was purified on a 10 g silica column, eluent —NH3/MeOH/DCM. This gave a clear oil 2-{[1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]amino}-4-(trifluoromethyl)phenol (109 mg, 0.253 mmol, 68.2% yield).

¹H NMR δ (CDCl₃, 400 MHz) 0.9 (3H,s), 1.4-1.6 (6H, br m), 1.7 (3H, br m), 1.9 (2H, br m), 2.1 (2H, br m), 2.35 (2H, t, J=12.0 Hz), 3.05 (2H, d, J=12.0 Hz), 3.25 (2H, br m), 3.4 (3H, s), 3.55 (4H, m), 4.5 (1H, br s), 6.70 (1H, d, J=8.0 Hz), 6.76 (1H, s), 6.82 (1H, d, J=8.0 Hz).

Description 51. 2-Fluoro-4-methyl-6-nitrophenol. (D51) (Scale-up preparation of D17)

2-Fluoro-4-methylphenol (2.6 g, 20.61 mmol) was dissolved in dichloromethane (DCM) and placed in a 100 mL RB flask. Nitric acid, 70% (1.576 mL, 24.74 mmol) was added dropwise (exotherm observed). The reaction mixture was left to stir for ˜1 hr, washed with water, the organic dried and evaporated to give a yellow solid, 2-fluoro-4-methyl-6-nitrophenol (3.276 g, 19.14 mmol, 93% yield).

¹H NMR δ (CDCl₃, 400 MHz) 2.35 (3H,s), 7.26 (1H, d, J=1.0 Hz), 7.71 (1H, d, J=1.0 Hz), 10.3 (1H, s).

Description 52. 2-Fluoro-4-methyl-6-aminophenol. (D52) (Scale-up preparation of D18)

2-Fluoro-4-methyl-6-nitrophenol (D51, 3.276 g, 19.14 mmol) was dissolved in ethanol (100 mL). 10% Pd/C (0.323 g, 0.304 mmol) was added and the reaction mixture hydrogenated for ˜18 hr. Catalyst was filtered off and the filtrate evaporated to dryness. TLC showed only a small amount of material had been reduced. Solid was redissolved in 350 mL ethanol, 150 mL of this solution was passed down the H-cube at 1 mL/min with full hydrogen. After ˜2 hr the cartridge had been exhausted. A new cartridge was used and the reaction mixture was left recycling through the instrument for ˜4 hr. ˜30% of nitro compound was still remaining. The reaction mixture was evaporated to dryness. Redissolved in EtOH and passed through the H-cube with a new cartridge to give fully reduced material 2-fluoro-4-methyl-6-aminophenol (907 mg, 6.43 mmol, 33.6% yield) as a brown solid. The remaining nitro compound was passed down the H-cube at 1 mL/min with full hydrogen—still only 58% conversion. Redissolved in EtOH and passed through the H-cube with a new cartridge. Evaporated to dryness redissolved in MeOH and loaded onto an SCX-2 cartridge (50 g) washed with MeOH and eluted with 1M NH₃/MeOH, evaporated to dryness to give a brown solid batch 2 (1.319 g, 9.35 mmol, 48.8% yield).

¹H NMR δ (CDCl₃, 400 MHz) 2.18 (3H,s), 3.5 (2H, br s), 6.33 (2H, br m), 7.47 (1H, s).

Description 53. [4-({[4-(Methyloxy)phenyl]methyl}oxy)-3-nitrophenyl]methanol. (D53)

To a solution of 4-(hydroxymethyl)-2-nitrophenol (2.20 g, 13.01 mmol) in DMF (60 mL) was added cesium carbonate (8.48 g, 26.0 mmol) followed by the portionwise addition of 4-methoxybenzyl chloride (3.06 g, 19.51 mmol). After stirring at rt for 45 mins additional 4-methoxybenzyl chloride (2.037 g, 13.01 mmol) was added followed by tetrabutylammonium iodide (2.402 g, 6.50 mmol). The reaction mixture was stirred at rt for 18 hr and then diluted with EtOAc (200 mL) and washed successively with water, 10% aq. K₂CO₃, water and finally brine, dried (MgSO₄), filtered and concentrated to dryness in vacuo. The residue was purified by silica gel chromatography eluting with 10-50% EtOAc in isohexane to afford the title compound as a cream solid, 2.17 g, 57.7% .

¹H NMR δ (CDCl₃): 1.81 (1H, t, J=5.6 Hz), 3.81 (3H, s), 4.67 (2H, d), 5.15 (2H, s), 6.90 (2H, d), 7.10 (1H, d), 7.37 (2H, d), 7,50 (1H, m), 7.85 (1H, d).

Description 54. 4-[(Methyloxy)methyl]-1-({[4-(methyloxy)phenyl]methyl}oxy)-2-nitrobenzene. (D54)

To a solution of [4-({[4-(methyloxy)phenyl]methyl}oxy)-3-nitrophenyl]methanol D53 (2.16 g, 7.47 mmol) in THF (100 mL) was added iodomethane (0.700 mL, 11.20 mmol) followed by the portionwise addition of a 0.5M solution of potassium hexamethyldisilazide (22.40 mL, 11.20 mmol) in toluene. After stirring at rt for 2 hr the mixture was diluted with EtOAc (150 mL) and washed with water (2×50 mL) and brine (2×50 mL). The organic phase was dried (MgSO₄) filtered and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 10-40% EtOAc in isohexane to afford the title compound as a pale orange oil which solidified on standing, 1.57 g, 69.3%.

¹H NMR δ (CDCl₃): 3.39 (3H, s), 3.81 (3H, s), 4.41 (2H, s), 5.16 (2H, s), 6.92 (2H, d), 7.10 (1H, d, J=8.0 Hz), 7.38 (2H, d), 7,45 (1H, m), 7.82 (1H, d).

Description 55. 2-Methyl-4-[(methyloxy)methyl]phenol. (D55)

To a solution of 4-[(methyloxy)methyl]-1-({[4-(methyloxy)phenyl]methyl}oxy)-2-nitrobenzene D54 (1.57 g, 5.18 mmol) in DCM (80 mL) was added trifluoroacetic acid (3.99 mL, 51.80 mmol). After 1 hr the mixture was washed with water (3×25 mL) and then extracted with 10% aq potassium carbonate solution (3×20 mL). The combined extracts were back washed with diethyl ether (20 mL) and then the pH was adjusted to 1 with 2N HCl, the mixture was extracted with DCM (3×25 mL), the combined extracts were washed with water (25 mL) and brine (25 mL), dried(MgSO₄), filtered and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 5-40% EtOAc in isohexane to afford the title compound as a bright yellow oil. 0.72 g, 76% ¹H NMR δ (CDCl₃): 3.41 (3H, s), 4.42 (2H, d), 7.15 (1H, d, J=8.4 Hz), 7.56 (1H, m), 8.08 (1H, d).

Description 56. 2-Amino-4-[(methyloxy)methyl]phenol. (D56)

A mixture of 4-[(methyloxy)methyl]-2-nitrophenol D55 (0.72 g, 3.93 mmol) and platinum (IV) oxide (0.089 g, 0.393 mmol) in ethanol (15 mL) was stirred under an atmosphere of hydrogen for 16 hr. The catalyst was removed by filtration through celite and the filtrate concentrated to dryness in vacuo to afford the title compound as a green/brown solid 0.51 g, 85%.

¹H NMR δ (CDCl₃): 3.35 (3H, s), 3.7-4.5 (2H, br s +2H, s), 6.62 (2H, m), 6.74 (1H, d).

Description 57. 2-{[1-(trans-1-Methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]amino}-4-[(methyloxy)methyl]phenol. (D57)

A mixture of 2-amino-4-[(methyloxy)methyl]phenol (D56) (37.5 mg, 0.245 mmol),1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinone (D28, 60 mg, 0.223 mmol), Polymer supported cyanoborohydride (185 mg, 0.445 mmol) and acetic acid (0.064 mL, 1.114 mmol) in THF (3 mL) was heated to 100° C. for 40 mins (2×20 mins) in a microwave reactor. The mixture was diluted with EtOAc (5 mL) washed with dilute aq potassium bicarbonate, water and brine, dried (MgSO₄) and concentrated to dryness in vacuo. The reside was purified by silica gel chromatography eluting with DCM to 20% of 1:10 2M NH₃in MeOH/DCM to yield the title compound as a thick pale yellow oil. 58 mg, 57.6%

¹H NMR δ (CDCl₃): 1.35-1.61 (8H, m), 1.66-1.71 (2H, m), 1.86-1.91 (2H, m), 2.23-2.40 (2H, m), 2.89-2.98 (2H, m), 3.21 (1H, m), 3.37 (3H, s), 3.43 (3H, s), 3.49 (3H, s), 3.53-3.66 (5H, m), 4.34 (2H, s), 6.55 (1H, br s), 6.67 (1H, br s).

LC/MS 407(MH+), 405(M−H).

Description 58. 4-Hydroxy-3-nitrobenzamide. (D58)

A mixture of methyl 4-hydroxy-3-nitrobenzoate (1.00 g, 5.07 mmol) and concentrated aq ammonia (10.0 mL, 162 mmol) was heated to 100° C. for 90 mins (3×30 mins) in a microwave reactor. The mixture was poured into water (70 mL), acidified with 6N HCl and extracted with EtOAc (4×25 mL). The combined extracts were dried (MgSO₄) and concentrated in vacuo. The residue was triturated with DCM (20 mL) filtered and washed with DCM before drying under vacuum to afford the crude title compound as a yellow solid 0.49 g, 53.0%

¹H NMR δ (DMSO-d₆, 400 MHz): 7.15 (1H, d), 7.36 (1H, s), 8.00-8.05 (2H, m), 8.42 (1H, s), 11.75 (IH, br s)

Description 59. 3-Amino-4-hydroxybenzamide. (D59)

A mixture of 4-hydroxy-3-nitrobenzamide D58 (0.49 g, 2.69 mmol), cyclohexene (1.105 g, 13.45 mmol) and 10% palladium on carbon (0.143 g, 0.135 mmol) in ethanol (20 mL) was heated to reflux under argon for 3 hr. The cooled mixture was filtered through celite and the filtrate concentrated to dryness in vacuo to afford a yellow/brown solid. The product was purified by silica gel chromatography eluting with 0-15% 2M ammonia in MeOH/DCM. The title compound was isolated as a pale brown powder, 0.26 g, 57.2%.

¹H NMR δ (d⁶DMSO, 400 MHz): 4.36 (2H, br s), 6.63 (1H, d), 6.89 (1H, s), 6.96 (1H, m), 7.13 (1H, d), 7.53 (1H, s), 9.50 (IH, br s)

Description 60. 4-Hydroxy-3-{[1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]amino}benzamide. (D60)

A mixture of 3-amino-4-hydroxybenzamide (D59) (33.9 mg, 0.223 mmol),1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinone (60 mg, 0.223 mmol), polymer supported cyanoborohydride (185 mg, 0.445 mmol) and acetic acid (0.064 mL, 1.114 mmol) in THF (3 mL) was heated to 100° C. for 40 mins (2×20 mins) in a microwave reactor. The mixture was filtered, diluted with EtOAc (5 mL) washed with dilute aq potassium bicarbonate, water and brine, dried (MgSO₄) and concentrated to dryness in vacuo. The residue was purified by silica gel chromatography eluting with 0-10% 2M NH₃in MeOH/DCM. The title compound was isolated as a colourless solid 29 mg, 28.9%.

¹H NMR δ (CDCl₃): 1.49-1.70 (10H, m), 1.85-1.91 (4H, m), 2.23-2.32 (4H, m), 3.14 (2H, m), 3.40-3.54 (5H, m), 3.56 (4H, dd), 4.10 (1H, m), 4.47 (2H, s), 7.04 (1H, d), 7.15 (2H, m).

LC/MS 406(MH+), 404(M−H).

Description 61. 4-(2-Methyl-1,3-dioxolan-2-yl)-2-nitrophenol. (D61)

A stirred mixture of 1-(4-hydroxy-3-nitrophenyl)ethanone (3.00 g, 16.56 mmol), ethylene glycol (1.385 mL, 24.84 mmol) and p-toluenesulfonic acid monohydrate (0.158 g, 0.828 mmol) in toluene (60 mL) was heated to reflux for 18 hr in a 250 mL round bottom flask fitted with a Dean-Stark apparatus. The mixture was cooled and diluted with EtOAc (80 mL) and then washed with water (3×30 mL) and brine (20 mL), dried (Na₂SO₄) and concentrated to dryness in vacuo to afford a thick brown oily residue. This was purified by silica gel chromatography eluting with 5-50% Et₂O in isohexane. The title product was isolated as a yellow oil (2.41 g, 64.6%).

¹H NMR δ (CDCl₃, 400 MHz): 1.64 (3H, s), 3.83 (4H, q), 4.06 (4H, q), 7.14 (1H, d), 7.69 (1H, d), 8.23 (1H, d), 10.57 (1H, s).

Description 62. 2-Amino-4-(2-methyl-1,3-dioxolan-2-yl)phenol. (D62)

A stirred mixture of 4-(2-methyl-1,3-dioxolan-2-yl)-2-nitrophenol D61 (2.40 g, 10.66 mmol), cyclohexene (4.38 g, 53.3 mmol) and 10% palladium on carbon (0.227 g, 0.213 mmol) in ethanol (75 mL) was heated to reflux for 6 hr under argon. The mixture was cooled to rt and the catalyst was removed by filtration through celite. The filtrate was concentrated to dryness in vacuo and the reside dissolved in 10% MeOH in DCM (20 mL) and passed through a SCX-2 cartridge (25 g) which was then eluted with further 10% MeOH in DCM to wash through any unreacted starting material and then with 2M ammonia in MeOH. The basic eluate was concentrated under vacuum to give the title compound as a yellow-brown solid (1.58 g, 76%).

¹H NMR δ (DMSO-d₆, 400 MHz) 2.44 (3H, s), 3.44 (4H, s) (note: partly obscured by water signal), 3.74 (2H, br s), 6.69 (1H, d), 7.53 (1H, s), 7.12 (1H, d), 7.21 (1H, s), 9.30 (1H, br s)

Description 63. 1-(4-Hydroxy-3-{[1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}-cyclohexyl)-4-piperidinyl]amino}phenyl)ethanone. (D63)

A mixture of 2-amino-4-(2-methyl-1,3-dioxolan-2-yl)phenol D62 (43.5 mg, 0.223 mmol), 1(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinone (D28, 60 mg, 0.223 mmol), polymer supported cyanoborohydride (185 mg, 0.445 mmol) and acetic acid (0.019 mL, 0.334 mmol) in THF (3 mL) was heated in a microwave reactor to 100° C. for 60 mins (3×20 mins). The cooled mixture was diluted with EtOAc (5 mL) and washed with dilute aq potassium carbonate and brine, dried (MgSO₄), then concentrated to dryness in vacuo. The residue was subjected to chromatography on silica gel eluting with DCM to DCM/MeOH/NH₄OH (90/9/1). The crude title product was isolated as a sticky brown gum (32 mg, 32.0%), the product was taken forward to the next step in the synthesis without further purification.

LC/MS 405(MH)⁺, 403(M−H)⁺.

Description 64. 1-(3-Amino-4-hydroxyphenyl)ethanone O-methyloxime. (D64)

A mixture of O-methylhydroxylamine hydrochloride (535 mg, 6.40 mmol), 2-amino-4-(2-methyl-1,3-dioxolan-2-yl)phenol D62 (250 mg, 1.28 mmol) and potassium carbonate (442 mg, 3.20 mmol) in ethanol (10 mL) was heated to reflux for 2 hr. The mixture was cooled to rt and concentrated to dryness under vacuum and the residue partitioned between DCM and water. The organic phase was separated washed with brine, dried (MgSO₄) and concentrated to dryness in vacuo. The residue was purified using silica gel chromatography eluting with 0 to 10% MeOH in DCM. The title product was isolated as a pale brown solid, 224 mg, 97%.

¹H NMR δ (CDCl₃, 400 MHz): 2.03 (3H, s), 3.84 (3H, s), 4.61 (2H, br s), 6.62 (1H, d), 6.69 (1H, d), 6.89 (1H, d), 9.33 (1H, br s).

Description 65. 1-(4-Hydroxy-3-{[1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]amino}phenyl)ethanone O-methyloxime. (D65)

A mixture of 1-(3-amino-4-hydroxyphenyl)ethanone O-methyloxime (D64) (33 mg, 0.183 mmol), 1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinone (D28, 49.3 mg, 0.183 mmol), polymer supported cyanoborohydride (152 mg, 0.366 mmol) and acetic acid (0.052 mL, 0.916 mmol) in dichloromethane (DCM) (3 mL) was heated to 100° C. for 30 mins in a microwave reactor. The mixture was washed with dilute aq potassium carbonate dried (MgSO₄) and concentrated to dryness under vacuum. The residue was purified by silica gel chromatography eluting with DCM/MeOH/NH₄OH (90:9:1). The title product was isolated as a v pale yellow gum, 40 mg, 50.4%.

LC/MS 434(MH)⁺, 432(M−H)⁺.

Description 66. 2-Fluoro-4-hydroxy-5-nitrobenzonitrile. (D66)

Nitric acid (0.326 mL, 7.29 mmol) 70% was added dropwise to a stirred solution of 2-fluoro-4-hydroxybenzonitrile (1 g, 7.29 mmol) in acetic acid (20 mL). The resulting solution was warmed to 40° C. for 24 hr. Solvent removed under reduced pressure to afford a yellow solid. Recrystallisation from EtOH (˜15 mL) afforded 2-fluoro-4-hydroxy-5-nitrobenzonitrile (401 mg, 2.202 mmol, 30.2% yield) as a yellow solid.

¹H NMR δ (CDCl₃): 7.04 (1H, d, J=9.6 Hz), 8.52 (1H, d, J=6.4 Hz), 11.10 (1H, s).

Description 67. 5-Amino-2-fluoro-4-hydroxybenzonitrile. (D67)

A solution of 2-fluoro-4-hydroxy-5-nitrobenzonitrile (D66; 270 mg, 1.483 mmol) in ethanol (35 mL) was passed through an H-Cube flow hydrogenator at room temperature and atmospheric pressure on full H₂mode, with a flow rate of 1 mL min⁻¹and using a CatCart30 (approx. 140 mg catalyst). The residual solution was diluted with further ethanol (8 mL) to ensure maximum recovery of material. The collected product solution was evaporated to dryness to give the desired product as a tan solid (215 mg).

¹H NMR δ (CD₃OD): 6.58 (1H, dd, J=7.6, 3 Hz), 6.85 (1H, d, J=6.8 Hz).

EXAMPLE 1a
3-[1-(trans-1-Methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-2-oxo-2,3-dihydro-1,3-benzoxazole-5-carbonitrile hydrochloride. (E1a)

Diisopropylethylamine (0.04 mL, 0.229 mmol) was added to a solution of 4-hydroxy-3-{[1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]amino}benzonitrile (D15, 37.5 mg, 0.097 mmol) in dichloromethane (2.5 mL) at rt under argon. The reaction was cooled to 0° C. and triphosgene (13.6 mg, 0.046 mmol) was added. The mixture was stirred for 1 h at 0° C. The reaction was quenched with saturated aqueous NaHCO₃(5 mL) and partitioned between dichloromethane and water. The aqueous layer was extracted with dichloromethane (2×) and the combined organics were dried (Na₂SO₄) and concentrated by rotary evaporation to give a pale yellow solid. The residue was purified via chromatography (silica, Biotage 12S column, dichloromethane to 0.5% ammonia/9.5% methanol/90% dichloromethane) to give the free base of the title compound as a colourless oil. HCl (0.1 mL, 0.1 mmol, 1 M in diethyl ether) was added to a solution of the free base in dichloromethane (0.5 mL) and the solvent removed by rotary evaporation. The resulting residue was triturated with diethyl ether (2×) to give 3-[1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-2-oxo-2,3-dihydro-1,3-benzoxazole-5-carbonitrile hydrochloride (E1a, 11.2 mg, 24% yield) as a cream solid.

¹H NMR δ (DMSO-d₆, 400 MHz) 1.25-1.40 (5H, m), 1.84 (2H, m), 1.96-2.12 (6H, m), 2.74 (2H, m), 3.13-3.29 (6H, m), 3.42 (2H, m), 3.55 (2H, m), 3.69 (2H, m), 4.59 (1H, m), 7.59 (1H, d, J 8.4), 7.69 (1H, dd, J 8.4 and 1.6), 8.22 (1H, d, J 1.6), 9.95 (1H, m).

M+H⁺414.

Example 1b
3-[1-(trans-1-Methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-2-oxo-2,3-dihydro-1,3-benzoxazole-5-carbonitrile free base. (E1b)

N.B. free base was also isolated en route to the HCl salt produced in E1a.

Hunig's Base (0.5 mL, 2.86 mmol) was added to a solution of 4-hydroxy-3-{[1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]amino}benzonitrile (D15—alternative procedure, 554 mg, 1.43 mmol) in DCM (10 mL) at rt under Ar. The reaction was cooled to 0° C. and triphosgene (180 mg, 0.61 mmol) was added. The mixture was stirred for 2 h at 0° C. The reaction was quenched with sat. NaHCO₃(10 mL) and partitioned between DCM and H₂O. The aqueous layer was extracted with DCM (2×) and the combined organics were dried (Na₂SO₄) and concentrated by rotary evaporation to give a yellow solid. The residues were purified via flash column chromatography (silica, Biotage 40+S column, DCM to 0.5% NH₃/9.5% MeOH/90% DCM) to give 3-[1-(trans-1-methyl-4-{[2 (methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-2-oxo-2,3-dihydro-1,3-benzoxazole-5-carbonitrile free base (E1b, 421 mg, 64%) as an off-white solid.

¹H NMR δ (DMSO-d₆, 400 MHz) 0.87 (3H, s), 1.36-1.59 (6H, m), 1.73-1.86 (4H, m), 2.12-2.24 (4H, m), 3.00-3.07 (2H, m), 3.26 (3H, s), 3.40-3.51 (5H, m), 4.07 (1H, m), 7.54 (1H, d, J 8.3), 7.65 (1H, dd, J 8.3 and 1.5), 7.97 (1H, d, J 1.5).

LCMS: [M+H]⁺414.

Example 1c
3-[1-(trans-1-Methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-2-oxo-2,3-dihydro-1,3-benzoxazole-5-carbonitrile hydrochloride. (E1c)

HCl (1.3 mL, 1.3 mmol, 1 M in Et₂O) was added to a solution of 3-[1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-2-oxo-2,3-dihydro-1,3-benzoxazole-5-carbonitrile free base (E1b, 270 mg, 0.65 mmol) in DCM (3 mL) at rt. The reaction was stirred for 5 min, then the solvent was removed by rotary evaporation and the residue triturated with Et₂O to give 3-[1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-2-oxo-2,3-dihydro-1,3-benzoxazole-5-carbonitrile hydrochloride (E1c, 265 mg, 81%) as an off-white solid.

¹H NMR δ (DMSO-d₆, 400 MHz) 1.27-1.39 (5H, m), 1.78-1.89 (2H, m), 1.95-2.12 (6H, m), 2.68-2.81 (2H, m), 3.12-3.28 (6H, m), 3.40-3.45 (2H, m), 3.53-3.58 (2H, m), 3.65-3.73 (2H, m), 4.60(1H, m), 7.59(1H, d, J 8.4), 7.70 (1H, dd, J 8.4 and 1.4), 8.22 (1H, d, J 1.4), 9.95 (1H, m).

LCMS: [M+H]⁺414.

Example 1d
3-[1-(trans-1-Methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-2-oxo-2,3-dihydro-1,3-benzoxazole-5-carbonitrile free base. (E1d)

To a solution of 4-hydroxy-3-{[1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]amino}benzonitrile (D35) (26.33 g, 67.9 mmol) in dry dichloromethane (DCM) (400 mL), DIPEA (23.73 mL, 136 mmol) was added at room temperature under argon. The reaction was chilled at 0° C. and then triphosgene (8.67 g, 29.2 mmol) was added portionwise. Reaction mixture was allowed to stir at 0° C. for 1 h then at room temperature for an additional hour. Reaction mixture was quenched with saturated solution NaHCO₃(200 mL), phases were separated and the aqueous one back extracted with DCM (2×300 mL). Combined organics were dried over Na₂SO₄and evaporated to dryness to give crude material, 31 g, as pale yellow semisolid. Further 3.4 g of crude material were obtained in a similar way starting from 3.24 g of 4-hydroxy-3-{[1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]amino}benzonitrile. The two crude batches were combined and purified by SiO₂FC eluting with DCM/MeOH/NH₄OH from 98/2/05 to 96/4/0.5 to 90/10/1. Evaporation of volatiles afforded title material (E1d, 27 g; 85%) as white crystalline solid.

¹H NMR δ (CDCl₃, 400 MHz): 0.95 (3H, s), 1.58 (4H, m), 1.68 (2H, m), 1.89 (4H, m), 2.23 (4H, m), 3.18 (2H, d), 3.41 (3H, s), 3.50 (1H, m), 3.57 (2H, m), 3.62 (2H, m), 4.13 (1H, m), 7.29 (1H, d), 7.47 (1H, dd), 7.47 (1H, s).

MH⁺=414.1.

Example 1e
3-[1-(trans-1-Methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-2-oxo-2,3-dihydro-1,3-benzoxazole-5-carbonitrile hydrochloride. (E1e)

To a solution of 3-[1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-2-oxo-2,3-dihydro-1,3-benzoxazole-5-carbonitrile (E1d) (10 g, 24.18 mmol) in dichloromethane (DCM) (100 mL), cooled at 0° C. under an Argon atmosphere, HCl 1M in Et₂O (48.4 mL, 48.4 mmol) was added dropwise. The slurry was left stirring 30 min at 0° C. then 30 min. at room temperature. White solid precipitation occurred. Slurry was then cautiously evaporated under reduced pressure with no bath heating. Obtained solid was triturated with Et₂O (100 mL) for 20 minutes and collected by filtration over a sintered glass filter. Product was dried at high vacuum overnight at room temperature then for 30 min at 40° C. under vacuum to get title material (E1e, 10.58 g, 97% yield) as white solid.

¹H NMR δ (DMSO-d₆, 400 MHz): 1.32 (2H, m) 1.34 (3H, s), 1.98 (8H, m), 2.79 (2H, m), 3.21 (3H, m), 3.25 (3H, s), 3.43 (2H, m), 3.56 (2H, m), 3.68 (2H, m), 4.61 (1H, m), 7.59 (1H, d), 7.62 (1H, dd), 8.30 (1H, d), 10.19 (1H, m).

MH⁺=414.1.

Example 1f
3-[1-(trans-1-Methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-2-oxo-2,3-dihydro-1,3-benzoxazole-5-carbonitrile 4-methylbenzenesulfonate. (E1f)

p-Toluenesulfonic acid monohydrate (11 mg, 0.06 mmol) was added to a solution of 3-[1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-2-oxo-2,3-dihydro-1,3-benzoxazole-5-carbonitrile free base (23 mg, 0.06 mmol) in DCM (0.5 mL):Et₂O (0.5 mL) at rt. The reaction was stirred for 3 h before the addition of Et₂O (10 mL) which caused the precipitation of a white solid. The solid was isolated by filtration, washing with Et₂O (2×) and EtOAc (2×) to give 3-[1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-2-oxo-2,3-dihydro 1,3-benzoxazole-5-carbonitrile 4-methylbenzenesulfonate (E1f, 27 mg, 74%) as a white solid.

¹H NMR δ (DMSO-d₆, 400 MHz) 1.28-1.40 (5H, m), 1.60-1.70 (2H, m), 1.96-2/06 (4H, m), 2.09-2.17 (2H, m), 2.29 (3H, s), 3.10-3.28 (6H, m), 3.40-3.46 (2H, m), 3.52-3.59 (2H, m), 3.66-3.75(2H, m), 4.57 (1H, m), 7.11 (2H, d, J 8.0), 7.47 (2H, d, J 8.0), 7.60 (1H, d, J 8.3), 7.71 (1H, dd, J 8.3 and 1.2), 7.84 (1H, d, J 1.2), 8.71 (1H, m), Note: 2H not visible in NMR spectrum as obscured by solvent or water.

LCMS: [M+H]⁺414.

Example 1g
3-[1-(trans-1-Methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-2-oxo-2,3-dihydro-1,3-benzoxazole-5-carbonitrile methanesulfonate. (E1g)

Methanesulfonic acid (4 μl, 0.06 mmol) was added to a solution of 3-[1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-2-oxo-2,3-dihydro-1,3-benzoxazole-5-carbonitrile free base (24 mg, 0.06 mmol) in DCM (1 mL) at rt. The reaction was stirred for 30 min before the addition of Et₂O (10 mL) which caused the precipitation of a white solid. The solid was isolated by filtration, washing with Et₂O (2×) and EtOAc (2×) to give 3-[1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-2-oxo-2,3-dihydro-1,3-benzoxazole-5-carbonitrile methanesulfonate (E1g, 9.6 mg, 31% yield) as a white solid.

¹H NMR δ (DMSO-d₆, 400 MHz) 1.27-1.41 (5H, m), 1.61-1.73 (2H, m), 1.96-2.19 (6H, m), 2.30(3H, s), 3.11-3.29(6H, m), 3.53-3.59(2H, m), 3.67-3.76(2H, m), 4.57 (1H, m), 7.60 (1H, d, J 8.2), 7.71 (1H, d, J 8.2), 7.86 (1H, s), 8.80 (1H, m). Note: 4H not visible in NMR spectrum as obscured by solvent or water.

LCMS: [M+H]⁺414.

Example 2
3-[1-(cis-1-Methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-2-oxo-2,3-dihydro-1,3-benzoxazole-5-carbonitrile hydrochloride. (E2)

Diisopropylethylamine (0.02 mL, 0.115 mmol) was added to a solution of 4-hydroxy-3-{[1-(cis-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]amino}benzonitrile (D16, 22.6 mg, 0.058 mmol) in dichloromethane (2.5 mL) at rt under argon. The reaction was cooled to 0° C. and the triphosgene (9 mg, 0.03 mmol) was added. The mixture was stirred for 30 min at 0° C. The reaction was quenched with saturated aqueous NaHCO₃(5 mL) and partitioned between dichloromethane and water. The aqueous layer was extracted with dichloromethane (2×) and the combined organics were dried (Na₂SO₄) and concentrated by rotary evaporation to give a pale yellow solid. The residue was purified via chromatography (silica, dichloromethane to 0.5% ammonia/9.5% methanol/90% dichloromethane) to give the free base of the title compound as a pale yellow solid. HCl (0.1 mL, 0.1 mmol, 1 M in diethyl ether) was added to a solution of the free base in dichloromethane (0.5 mL) and the solvent removed by rotary evaporation. The resulting residue was triturated with diethyl ether (2×) to give 3-[1-(cis-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-2-oxo-2,3-dihydro-1,3-benzoxazole-5-carbonitrile hydrochloride (E2, 14.8 mg, 53.6% yield) as a pale yellow solid.

¹H NMR δ (DMSO-d₆, 400 MHz) 1.33 (3H, s), 1.52-1.63 (2H, m), 1.75 (2H, m), 1.82-1.96 (4H, m), 2.09 (2H, m), 2.65 (2H, m), 3.16 (2H, m), 3.27 (3H, s), 3.43-3.58 (5H, m), 3.71 (2H, m), 4.60 (1H, m), 7.60 (1H, d, J 8), 7.71 (1H, dd, J 8 and 1.2), 8.37 (1H, d, J 1.2), 9.30 (1H, m).

M+H⁺414.

Example 3
5-Methyl-3-[1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-2-oxo-2,3-dihydro-1,3-benzoxazole-6-carbonitrile hydrochloride. (E3)

Hunig's Base (0.06 mL, 0.34 mmol) was added to a solution of 5-hydroxy-2-methyl-4-{[1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]amino}benzonitrile (D39, 62 mg, 0.16 mmol) in DCM (3 mL) at rt under Ar. The reaction was cooled to 0° C. and the triphosgene (21 mg, 0.07 mmol) was added. The mixture was stirred for 2 h at 0° C. The reaction was quenched with sat. NaHCO₃(5 mL) and partitioned between DCM and H₂O. The aqueous layer was extracted with DCM (2×) and the combined organics were dried (Na₂SO₄) and concentrated by rotary evaporation to give a yellow oil. The crude residues were purified via flash column chromatography (silica, DCM to 0.5% NH₃/9.5% MeOH/90% DCM) to give the free base of the title compound as a colourless oil. HCl (0.2 mL, 0.2 mmol, 1 M in Et₂O) was added to a solution of the free base in DCM (0.5 mL) and the solvent was removed by rotary evaporation. The resulting solid was triturated with Et₂O to give 5-methyl-3-[1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-2-oxo-2,3-dihydro-1,3-benzoxazole-6-carbonitrile hydrochloride (E3, 49 mg, 64%) as a beige solid.

¹H NMR δ (DMSO-d₆, 400 MHz) 1.26-1.39 (5H, m), 1.82-1.93 (2H, m), 1.94-2.10 (6H, m), 2.53 (3H, s), 2.72-2.85 (2H, m), 3.12-3.28 (6H, m), 3.40-3.45 (2H, m), 3.53-3.58 (2H, m), 3.62-3.72 (2H, m), 4.58 (1H, m), 7.87 (1H, s), 7.99 (1H, s), 10.09 (1H, m).

LCMS: [M+H]⁺428.

Example 4
5-Methyl-3-[1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-1,3-benzoxazol-2(3H)-one hydrochloride. (E4)

4-Methyl-2-{[1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-amino}phenol (D40, 56 mg, 0.149 mmol) was dissolved in DCM (3 mL) and DIPEA (0.052 mL, 0.297 mmol) was added. The reaction mixture was cooled to 0° C. and triphosgene (33 mg, 0.111 mmol) was added. The reaction mixture was stirred for 1.5 h. LC/MS analysis showed the reaction to be incomplete. An additional 0.75 eq. of triphosgene (33 mg) was added and the reaction mixture stirred for 42 h. The reaction mixture was treated with saturated sodium bicarbonate solution (2 mL) and stirred for 15 min. The reaction mixture was diluted with DCM and water (6 mL of each) and the layers separated using a phase separator cartridge. The organic layer was evaporated to dryness to give a colourless oil. The crude product was purified by flash column chromatography on a pre-packed silica cartridge (column size 10 g), eluting with 3-7% 2 M ammonia in methanol in DCM to afford the product as a colourless oil. This was treated with 2 M HCl in diethyl ether to afford the HCl salt E4 as a white solid (38 mg).

(M +H)⁺=403.

¹H NMR δ (CD₃OD): 1.43-1.51 (1H, m), 1.47 (3H, s), 1.83 (2H, m), 2.15 (6H, m), 2.42 (3H, s), 2.80 (2H, m), 3.24-3.40 (7H, m), 3.53 (2H, m), 3.65 (2H, m), 3.83 (2H, m), 4.51 (1H, m), 6.98 (1H, d, J=8.4 Hz), 7.13 (1H, d, J=8.0 Hz), 7.33 (1H, s).

Example 5
3-[1-(trans-1-Methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-5-(methyloxy)-1,3-benzoxazol-2(3H)-one hydrochloride. (E5)

2-{[1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]amino}-4-(methyloxy)phenol (D41, 31 mg, 0.079 mmol) was dissolved in DCM (3 mL) and DIPEA (0.043 mL, 0.246 mmol) was added. The reaction mixture was cooled to 0° C. and triphosgene (37 mg, 0.125 mmol) was added. The reaction mixture was stirred for 64 h, warming to room temperature. The reaction mixture was treated with saturated sodium bicarbonate solution. The reaction mixture was diluted with DCM and water (6 mL of each) and the layers separated with a phase separator cartridge. The organic layer was evaporated to dryness. The crude product was purified by flash column chromatography on a pre-packed silica cartridge (column size 10 g), eluting with 2-5% 0.2 M ammonia in methanol in DCM to afford the desired product as a colourless oil. This was treated with 2 M HCl in diethyl ether to afford the HCl salt E5 as a white solid (10 mg).

(M+H)⁺=419.

¹H NMR δ (CD₃OD): 1.45-1.48 (2H, m), 1.46 (3H, s), 1.89 (2H, m), 2.15 (6H, m), 2.85 (2H, m), 3.29 (2H, m), 3.37 (4H, m), 3.52 (2H, m), 3.64 (2H, m), 3.82 (1H, s), 3.85 (3H, s), 4.55 (1H, m), 6.70 (1H, m), 7.15 (2H, m). Note: 1 H not visible in NMR spectrum as obscured by solvent or water.

Example 6
3-(1-{trans-4-[(Cyclopropylmethyl)oxy]-1-methylcyclohexyl}-4-piperidinyl)-5-(methylsulfonyl)-1,3-benzoxazol-2(3H)-one hydrochloride. (E6)

2-[(1-{trans-4-[(Cyclopropylmethyl)oxy]-1-methylcyclohexyl}-4-piperidinyl)amino]-4-(methylsulfonyl)phenol (D49, 80 mg, 0.183 mmol) was suspended in DCM (5 mL) and DIPEA (0.065 mL, 0.372 mmol) was added. The reaction mixture was cooled to 0° C. and triphosgene (35.9 mg, 0.121 mmol) was added. The reaction mixture was stirred at 0° C. for 1 h, then allowed to warm to room temperature. The reaction mixture was treated with saturated sodium bicarbonate solution (4 mL) and stirred for 10 min. The reaction mixture was diluted with DCM and water (10 mL each) and the layers separated. The aqueous layer was extracted with DCM (2×10 mL) and the combined organics were dried (MgSO₄) and evaporated. The crude product was purified by flash column chromatography on a pre-packed silica cartridge (column size 10 g), eluting with 3-6% 0.2 M ammonia in methanol in DCM, to afford the desired product as a colourless oil. This was treated with 2 M HCl in diethyl ether to afford the desired product E6 as an HCl salt (72 mg).

(M +H)⁺=463.

¹H NMR δ (CD₃OD): 0.21 (2H, m), 0.50 (2H, m), 1.02 (1H, m), 1.45 (5H, m), 1.85 (2H, m), 2.12 (4H, m), 2.25 (2H, m), 2.85 (2H, m), 3.21 (3H, s), 3.32 (5H, m), 3.85 (2H, m), 4.65 (1H, m), 7.50 (1H, d, J=8.4 Hz), 7.81 (1H, m), 8.07 (1H, s).

Example 7
3-[1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-5-(trifluoromethyl)-1,3-benzoxazol-2(3H)-one hydrochloride. (E7)

2-{[1-(trans-1-Methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]amino}-4-(trifluoromethyl)phenol (D50, 109 mg, 0.253 mmol) was dissolved in dichloromethane (DCM) (5 mL) and cooled to 0° C. in an ice bath. DIPEA (0.15 mL, 0.859 mmol) was added followed by triphosgene (50 mg, 0.168 mmol). The reaction mixture was left to stir for 30 min at 0° C. and 30 min at RT. The mixture was washed with aqueous sodium bicarbonate, passed through a phase separation cartridge and evaporated to give a clear oil. Purified by column (10 g) eluting with 0-10% 2M NH₃/MeOH/DCM to give a clear oil. Treated with 4M HCl in dioxan, evaporated to dryness to give a white solid 3-[1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-5-(trifluoromethyl)-1,3-benzoxazol-2(3H)-one hydrochloride (E7, 96.9 mg, 0.197 mmol, 78% yield).

¹H NMR δ (DMSO-d₆, 400 MHz) 1.23-1.35 (5H, m), 1.87-2.08 (6H, m), 2.79-2.88 (2H, m), 3.17-3.24 (5H, m), 3.32 (3H, s), 3.41-3.43 (2H, m), 3.54-3.59 (2H, m), 3.66-3.73 (2H,m), 4.59-4.65 (1H, m), 7.52-7.68 (2H, m), 8.14 (1H, s), 10.4 (1H, m).

m/z (M+H)⁺457.

Example 8
6-Fluoro-5-methyl-3-[1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]-oxy}cyclohexyl)-4-piperidinyl]-1,3-benzoxazol-2(3H)-one hydrochloride. (E8)

The title compound was prepared from the compound of Description 28 and 2-amino-5-fluoro-4-methylphenol using the methods of Description 50 and Example 7.

¹H NMR δ (DMSO-d₆, 400 MHz) 1.23-1.32 (5H, m), 1.82-2.02 (6H, m), 2.27 (3H, s), 2.81-2.90 (2H, m), 3.15-3.24 (5H, m), 3.32 (3H, s), 3.40-3.43 (2H, m), 3.53-3.59 (2H, m), 3.64-3.71 (2H,m), 4.52-4.58 (1H, m), 7.34-7.36 (1H, d, J=8.0 Hz)), 7.96-4.0 Hz)), 10.5 (1H, m).

m/z (M+H)⁺421.

Example 9
7-Fluoro-3-[1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-2-oxo-2,3-dihydro-1,3-benzoxazole-5-carbonitrile hydrochloride. (E9)

The title compound was prepared from the compound of Description 28 and 3-amino-5-fluoro-4-hydroxybenzonitrile (see WO 2005074603 for synthesis) using the methods of Description 50 and Example 7.

¹H NMR δ (MeOH-d₄, 400 MHz) 0.87-0.96 (2H, m), 1.12-1.46 (6H, m), 1.83-1.88 (2H, t) 2.12-2.15 (3H, m), 2.25-2.51 (2H, m), 2.76-2.85 (2H, m), 3.18-3.37 (6H, m), 3.51-3.56 (2H, m), 3.63-3.65 (2H, m), 4.57-4.67 (1H, m), 7.51-7.42 (1H, d), 7.82 (1H, s).

m/z (M+H)⁺432.

Example 10
7-Fluoro-5-methyl-3-[1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-1,3-benzoxazol-2(3H)-one hydrochloride. (E10)

The title compound was prepared from the compounds of Description 28 and Description 52 using the methods of Description 50 and Example 7.

¹H NMR δ (DMSO-d₆, 400 MHz) 1.25-1.36 (5H, m), 1.91-2.03 (6H, m), 2.35 (3H, s), 2.81-2.90 (2H, m), 3.15-3.24 (5H, m), 3.32 (3H, s), 3.40-3.49 (2H, m), 3.53-3.59 (2H, m), 3.64-3.71 (2H,m), 4.52-4.59 (1H, m), 6.92-6.95 (1H, d), 7.70 (1H, s), 10.51 (1H, m).

m/z (M+H)⁺421.

Example 11
6-Fluoro-3-[1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-2-oxo-2,3-dihydro-1,3-benzoxazole-5-carbonitrile hydrochloride. (E11)

The title compound was prepared from the compound of Description 28 and 5-amino-2-fluoro-4-hydroxybenzonitrile (D67) using the methods of Description 50 and Example 7.

¹H NMR δ (MeOH-d₄, 400 MHz) 1.39-1.50 (3H, m), 1.86-1.98 (2H, m), 2.12-2.0 (3H, m), 2.23-2.34 (2H, m), 2.76-2.82 (2H, m), 3.24-3.36 (9H, m), 3.63-3.65 (2H, m), 3.82-3.85 (2H, m), 4.57-4.67 (1H, m), 7.43-7.45 (1H, d), 7.91-7.93 (1H, m).

m/z (M+H)⁺432.

Example 12
3-[1-(trans-1-Methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-5-(methylsulfonyl)-1,3-benzoxazol-2(3H)-one hydrochloride. (E12)

The title compound was prepared from the compound of Description 28 and 2-amino-4-(methylsulfonyl)phenol using the methods of Description 50 and Example 7.

¹H NMR δ (MeOH-d₄, 400 MHz) 1.5 (2H, m), 1.75 (2H, m), 2.2 (4H, m), 2.25 (2H, m), 2.75 (2H, m), 3.15 (3H, s), 3.3 (6H, s and m, obscured by MeOH peak), 3.4 (3H, s), 3.55 (2H, m), 3.65 (2H, m), 3.85 (2H, m), 4.6 (1H, m), 7.5 (1H, d J=6.0 Hz), 7.8 (1H, d J=6.0 Hz), 7.95 (1H, s).

m/z (M+H)⁺467.

Example 13
3-[1-(trans-1-Methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-5-[(methyloxy)methyl]-1,3-benzoxazol-2(3H)-one hydrochloride. (E13)

To a stirred mixture of 2-{[1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]amino}-4-[(methyloxy)methyl]phenol D57 (58 mg, 0.143 mmol), and DIPEA (0.050 mL, 0.285 mmol) in dichloromethane (DCM) (5 mL) cooled to 0° C. under argon was added, in portions, triphosgene (16.93 mg, 0.057 mmol). After stirring at 0° C. for 1 hr the reaction was quenched with dilute aq potassium bicarbonate (5 mL). The organic phase was separated, dried (MgSO₄) and concentrated to dryness in vacuo. The reside was subjected to silica gel chromatography using a Biotage Horizon with a 12+M cartridge and eluting with 0-10% MeOH/DCM over 12 CVs. The product 53 mg, was isolated as a thick colourless oil, which was dissolved in dichloromethane (DCM) (5 mL) and treated with 1M HCl (0.2 mL) after stirring for 20 mins the mixture was concentrated to dryness under vacuum and the residue triturated in diethyl ether to afford the title compound E13 as a colourless solid 44 mg, 65.8%.

¹H NMR δ (DMSO-d₆, 400 MHz) 1.33 (3H, m), 1.79-2.05 (8H, m), 2.87 (2H, q), 3.11-3.23 (5H, m), 3.25 (3H, s), 3.29 (3H, s), 3.41 (2H, m), 3.50-3.67 (5H, m), 4.43 (1H, s), 4.55 (1H, t), 7.10 (1H, d), 7.31 (1H, d), 7.86(1H, s), 10.28(1H, m).

M+H⁺433.

Example 14
3-[1-(trans-1-Methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-2-oxo-2,3-dihydro-1,3-benzoxazole-5-carboxamide hydrochloride. (E14)

To a stirred mixture of 4-hydroxy-3-{[1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]-oxy}cyclohexyl)-4-piperidinyl]amino}benzamide D60 (27 mg, 0.061 mmol), and DIPEA (0.021 mL, 0.122 mmol) in dichloromethane (DCM) (5 mL) at room temp under argon was added, in small portions, triphosgene (7.25 mg, 0.024 mmol). After stirring for 1 hr the reaction was quenched with dilute aq potassium bicarbonate (5 mL). The organic phase was separated, dried (MgSO₄) and concentrated to dryness in vacuo. The reside was subjected to silica gel chromatography using a Biotage Horizon with a 12+M cartridge and eluting with 0-10% MeOH/DCM over 12 CVs. The product was isolated as a thick colourless oil which was dissolved in dichloromethane (DCM) (5 mL) and treated with 1M HCl (0.2 mL) after stirring for 20 mins the mixture was concentrated to dryness under vacuum and the residue triturated in diethyl ether to give the title compound E14 as a colourless solid (17 mg, 56.5%).

¹H NMR δ (DMSO-d₆, 400 MHz) 1.24-1.34 (6H, m), 1.87-2.09 (9H, m), 2.87 (2H, q), 3.25 (5H, m), 3.55 (2H, m), 3.70 (3H, m), 4.64 (1H, m), 7.43 (1H, d, J=6.8 Hz), 7.53 (1H, s), 7.79 (1H, d, J=6.8 Hz), 8.16 (1H, s), 8.46 (1H, s), 10.08 (1H, m).

LC/MS 402 (MH+).

Example 15
5-Acetyl-3-[1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-1,3-benzoxazol-2(3H)-one hydrochloride. (E15)

To a stirred solution of 1-(4-hydroxy-3-{[1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]amino}phenyl)ethanone D63 (30 mg, 0.074 mmol) and DIPEA (0.026 mL, 0.148 mmol) in dichloromethane (DCM) (3 mL) at 0° C. under argon was slowly added triphosgene (8.80 mg, 0.030 mmol). After stirring at 0° C. for 20 mins the mixture was allowed to warm to rt. After 2 hr the mixture was washed with dilute aq. potassium carbonate solution (4 mL), dried and evaporated to dryness in vacuo. The residue was purified by MDAP which afforded the free base as a colourless gum, after a basic work up. This was dissolved in DCM (1 mL) and 1M HCl in diethyl ether (0.2 mL), after stirring for 20 mins the mixture was concentrated to dryness under vacuum to yield the title compound E15 as a cream powder (8 mg, 21.95%).

¹H NMR δ (CDCl₃, 400 MHz) (free base) 1.47-1.58 (4H, m), 1.64-1.69 (5H, m) 1.86-1.92 (4H, m), 2.21-2.38 (4H, m), 2.63 (3H, s), 3.17 (2H, d), 3.41 (3H, s), 3.46 (1H, m), 3.52-3.82 (4H, m), 4.11 (1H, s), 7.24 (1H, d), 7.74 (1H, d), 7.81 (1H, s).

LC/MS 431 (MH+).

Example 16
3-[1-(trans-1-Methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-5-[N-(methyloxy)ethanimidoyl]-1,3-benzoxazol-2(3H)-one hydrochloride. (E16)

To a stirred solution of 1-(4-hydroxy-3-{[1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]amino}phenyl)ethanone O-methyloxime (D65) (40 mg, 0.092 mmol) and triethylamine (0.019 mL, 0.138 mmol) in dichloromethane (DCM) (3 mL) cooled to 0° C. was slowly added triphosgene (10.95 mg, 0.037 mmol). After stirring at 0° C. for 15 mins the cooling bath was removed and the mixture allowed to reach rt and was stirred for another 2 hr. The mixture was washed with dilute aq potassium carbonate solution and brine, dried (MgSO₄) concentrated to dryness under vacuum. The residue was subjected to silica gel chromatography using a Biotage Horizon with a 12+M column eluting with 0-5% MeOH in DCM. A pale yellow solid was isolated, which was dissolved in DCM (3 mL) and treated with 1M HCl (0.1 mL) in diethyl ether, after stirring for 30 mins the mixture was concentrated to dryness under vacuum and the residue triturated in diethyl ether to afford the title compound E16 as a pale yellow solid (9 mg, 17.70%).

¹H NMR δ (DMSO-d₆, 400 MHz) 1.27-1.33 (5H, m), 1.88-2.07 (8H, m), 2.28 (3H, s), 2.86 (2H, m), 3.19-3.24 (6H, m), 3.41 (2H, m), 3.55 (2H, m), 3.65 (2H, d), 3.92 (3H, s), 4.59 (1H, m), 7.36 (1H, d), 7.43 (1H, d), 7.91 (1H, s), 10.31 (1H, br s).

LC/MS 460 (MH+).

The compound 5-methyl-3-[1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-2-oxo-2,3-dihydro-1,3-benzoxazole-4-carbonitrile hydrochloride can be made in a similar manner to the Examples above. 5-Methyl-3-[1-(trans-1-methyl-4-{[2-(methyloxy)ethyl]oxy}cyclohexyl)-4-piperidinyl]-2-oxo-2,3-dihydro-1,3-benzoxazole-4-carbonitrile hydrochloride was not tested for activity.

Number	Date	Country	Kind
0718419.5	Sep 2007	GB	national
08/14902.3	Aug 2008	GB	national

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

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