WO2009098455A1

WO2009098455A1 - 2- (9h-xanthen-9-yl) -oxazol derivatives as m3 muscarinic receptor antagonists for the treatment of asthma and chronic obstructive lung disease

Info

Publication number: WO2009098455A1
Application number: PCT/GB2009/000313
Authority: WO
Inventors: Richard James Bull; Nicholas Charles Ray
Original assignee: Astrazeneca Ab; Argenta Discovery Limited
Priority date: 2008-02-06
Filing date: 2009-02-05
Publication date: 2009-08-13

Abstract

The present invention relates to M3 antagonists of formula (I):wherein R1, R2, R3, R4, R5, R6, R8 and A are as defined herein; pharmaceutical compositions containing them; methods for their preparation; and their use in the treatment of diseases where enhanced M3 receptor activation is implicated.

Description

2- (9H-XANTHEN-9-YL) -OXAZOL DERIVATIVES AS M3 MUSCARINIC

RECEPTOR ANTAGONISTS FOR THE TREATMENT OF ASTHMA

AND CHRONIC OBSTRUCTIVE LUNG DISEASE

Field of the Invention

This invention relates to heterocyclic compounds, pharmaceutical compositions containing them, methods for their preparation, their use in the treatment of diseases where enhanced M3 receptor activation is implicated and their use in the treatment of diseases where compounds possessing muscarinic receptor antagonist activity are useful (such as in the treatment of asthma or COPD).

Background to the invention

Anti-cholinergic agents prevent the passage of, or effects resulting from the passage of, impulses through the parasympathetic nerves. This is a consequence of the ability of such compounds to inhibit the action of acetylcholine (Ach) by blocking its binding to the muscarinic cholinergic receptors.

There are five subtypes of muscarinic acetylcholine receptors (mAChRs), termed M1 -M5, and each is the product of a distinct gene and each displays unique pharmacological properties. mAChRs are widely distributed in vertebrate organs, and these receptors can mediate both inhibitory and excitatory actions. For example, in smooth muscle found in the airways, bladder and gastrointestinal tract, M3 mAChRs mediate contractile responses (reviewed by Caulfield, 1993, Pharmac. Ther., 58, 319 - 379).

In the lungs, muscarinic receptors M1 , M2 and M3 have been demonstrated to be important and are localized to the trachea, the bronchi, submucosal glands and parasympathetic ganglia (reviewed in Fryer and Jacoby, 1998, Am J Resp Crit Care Med., 158 (5 part 3) S 154 - 160). M3 receptors on airway smooth muscle mediate contraction and therefore bronchoconstriction. Stimulation of M3 receptors localised to submucosal glands results in mucus secretion.

Increased signalling through muscarinic acetylcholine receptors has been noted in a variety of different pathophysiological states including asthma and COPD. In COPD, vagal tone may either be increased (Gross et al. 1989, Chest; 96:984-987) and/or may provoke a higher degree of obstruction for geometric reasons if applied on top of oedematous or mucus-laden airway walls (Gross et al. 1984, Am Rev Respir Dis; 129:856-870). In addition, inflammatory conditions can lead to a loss of inhibitory M2 receptor activity which results in increased levels of acetylcholine release following vagal nerve stimulation (Fryer et al, 1999, Life ScL, 64, (6-7) 449-455). The resultant increased activation of M3 receptors leads to enhanced airway obstruction. Thus the identification of potent muscarinic receptor antagonists would be useful for the therapeutic treatment of those disease states where enhanced M3 receptor activity is implicated. Indeed, contemporary treatment strategies currently support regular use of M3 antagonist bronchodilators as first-line therapy for COPD patients (Pauwels et al. 2001 , Am Rev Respir Crit Care Med; 163:1256-1276)

Incontinence due to bladder hypercontractility has also been demonstrated to be mediated through increased stimulation of M3 mAChRs. Thus M3 mAChR antagonists may be useful as therapeutics in these mAChR-mediated diseases.

Despite the large body of evidence supporting the use of anti-muscarinic receptor therapy for treatment of airway disease states, relatively few anti-muscarinic compounds are in use in the clinic for pulmonary indications. Thus, there remains a need for novel compounds that are capable of causing blockade at M3 muscarinic receptors, especially those compounds with a long duration of action, enabling a once-daily dosing regimen. Since muscarinic receptors are widely distributed throughout the body, the ability to deliver anticholinergic drugs directly to the respiratory tract is advantageous as it allows lower doses of the drug to be administered. The design and use of topically active drugs with a long duration of action and that are retained on the receptor or in the lung would allow reduction of unwanted side effects that could be seen with systemic administration of the same drugs.

Tiotropium (Spiriva ™) is a long-acting muscarinic antagonist currently marketed for the treatment of chronic obstructive pulmonary disease, administered by the inhaled route.

Additionally ipratropium is a muscarinic antagonist marketed for the treatment of COPD.

Ipratropium

Chem. Pharm. Bull. 27(12) 3149-3152 (1979) and J. Pharm. Sci 69 (5) 534-537

(1980) describe furyl derivatives as possessing atropine-like activities.

Med. Chem. Res 10 (9), 615-633 (2001 ) describes isoxazoles and Δ²-isoxazolines as muscarinic antagonists.

WO97/30994 describes oxadiazoles and thiadiazoles as muscarinic receptor antagonists.

EP0323864 describes oxadiazoles linked to a mono- or bicyclic ring as muscarinic receptor modulators.

Summary of the Invention

According to the present invention, there is provided a compound of formula (I):

wherein (i) R¹ is C_rC₆-alkyl; and R² is a group -(Z)_p-R⁷, -Z-Y-R⁷, -Z-CO-NR⁹R¹⁰, or -Z-C(O)- R⁷; and R³ is a lone pair or R³ is d-Ce-alkyl, in which case the nitrogen to which they are attached is quaternary and carries a positive charge; or (ii) R¹ and R³ together with the nitrogen to which they are attached form a heterocycloalkyl ring, and R² is a group -(Z)_p-R⁷, -Z-Y-R⁷, -Z-CO-NR⁹R¹⁰, or -Z-C(O)-R⁷, in which case the nitrogen to which they are attached is quaternary and carries a positive charge; or

(iii) R¹ and R² together with the nitrogen to which they are attached form a heterocycloalkyl ring, said ring being substituted by a group -R⁷, -Y-R⁷, -Z-Y-R⁷, -Z-CO-NR⁹R¹⁰ or -Z-C(O)-R⁷; and R³ is a lone pair or R³ is C_rC₆-alkyl, in which case the nitrogen to which they are attached is quaternary and carries a positive charge;

p is 0 or 1 ;

R⁴ and R⁵ are joined together to form a tricyclic ring so that the group R⁴R⁵R⁶C-

represents the group , where R^b is -OH, C_rC₆-alkyl, C₁- C₆-alkoxy or a hydrogen atom, Q is an oxygen atom, -CH₂-, -CH₂CH₂- or a bond, R¹⁴ and R¹⁵ are independently selected from halo, CrC₆-alkyl and C_rC₆-alkoxy, and a and b are, independently, O or 1 ;

A is oxygen or sulfur;

X is a CrC₁₂-alkylene, C₂-C₁₂-alkenylene or C₂-C₁₂-alkynylene group;

R⁷ is an CrC_θ-alkyl, CrCe-alkenyl, aryl, aryl-fused-cycloalkyl, aryl-fused- heterocycloalkyl, heteroaryl, ary^d-Cs-alkyl)-, heteroary^CrCs-alkyl)-, cycloalkyl or heterocycloalkyl group;

Z is a CrC^-alkylene, C₂-C₁₆-alkenylene or C₂-C₁₆-alkynylene group;

Y is an oxygen atom, a group -S(O)_n, C(O)O, OC(O), N(R¹²)S(O)₂ or S(O)₂N(R¹²);

n is O, 1 or 2; R⁹ and R¹⁰ are independently a hydrogen atom, Ci-C₆-alkyl, aryl, aryl-fused- heterocycloalkyl, aryl-fused-cycloalkyl, heteroaryl, aryl(CrC₆-alkyl)-, or heteroaryl(Cr C₆-alkyl)- group; or R⁹ and R¹⁰ together with the nitrogen atom to which they are attached form a heterocyclic ring of 4-8 atoms, optionally containing a further nitrogen or oxygen atom;

R⁸, R¹¹, R¹² and R¹³ are, independently, hydrogen atom or CVCValkyl group;

or a pharmaceutically acceptable salt thereof;

wherein, unless otherwise specified, each occurrence of alkyl, alkenyl, heterocycloalkyl, aryl, aryl-fused-heterocycloalkyl, heteroaryl, cycloalkyl, alkoxy, alkylene, alkenylene, alkynylene or aryl-fused-cycloalkyl may be optionally substituted; and wherein each alkenylene chain may contain, where possible, up to 2 carbon-carbon double bonds and each alkynylene chain may contain, where possible, up to 2 carbon-carbon triple bonds.

In another aspect, the present invention provides a prodrug of a compound of formula (I) as herein defined, or a pharmaceutically acceptable salt thereof.

In yet another aspect, the present invention provides an N-oxide of a compound of formula (I) as herein defined, or a prodrug or pharmaceutically acceptable salt thereof.

In a further aspect, the present invention provides a solvate (such as a hydrate) of a compound of formula (I) as herein defined, or an N-oxide, prodrug or pharmaceutically acceptable salt thereof.

In one aspect, the present invention provides a compound of formula (I) wherein each alkyl, heterocycloalkyl, aryl, aryl-fused-heterocycloalkyl, heteroaryl, cycloalkyl, alkoxy, alkylene, alkenylene, alkynylene or aryl-fused-cycloalkyl group is unsubstituted.

In one aspect, the present invention provides a compound of formula (I) wherein R¹, R² and R³ are not all C₁-C₆ alkyl. In another aspect, the present invention provides a compound of formula (I) wherein R¹, R² and R³ are not all unsubstituted C₁-C₆ alkyl. In yet another aspect, the present invention provides a compound of formula (I) wherein R¹, R² and R³ do not all represent CH₃. In a further aspect, the present invention provides a compound of formula (I) wherein R³ is a lone pair and R¹ and R² do not both represent CH₃.

In another aspect, the present invention provides a compound of formula (I) wherein R¹ and R³ are, independently, C₁-C₆-SIkVl; and R² is a group -Z-Y-R⁷; and Y, Z and R⁷ are as defined herein.

In yet another aspect, the present invention provides a compound of formula (I) wherein R¹ and R³ are, independently, C₁-C₆-SIkVl; and R² is a group -(Z)_p-R⁷; and Z, p and R⁷ are as defined herein.

In a further aspect, the present invention provides a compound of formula (I) wherein R² is a group -(Z)_p-R⁷; and Z, p and R⁷ are as defined herein.

In one aspect, the present invention provides a compound of formula (I) wherein Y is O.

In one aspect, the present invention provides a compound of formula (I) wherein Z is optionally substituted C₁-C₆ alkylene, optionally substituted C₂-C₆-alkenylene, or optionally substituted C₂-C₆-alkynylene group. In a further aspect, the present invention provides a compound of formula (I) wherein Z is optionally substituted C₁-C₆ alkylene.

In one aspect, the present invention provides a compound of formula (I) wherein X is optionally substituted C₁-C₆ alkylene. In another aspect of the invention X is C₁-C₂ alkylene.

In one aspect, the present invention provides a compound of formula (I) wherein R⁷ is an aryl (for example phenyl), aryl-fused-cycloalkyl (for example indanyl) or aryl(C_rC₈- alkyl)- (for example benzyl or 2-phenyleth-1 -yl) group.

In another aspect, the present invention provides a compound of formula (I) wherein R⁷ is a group selected from CrCs-alkenyl, aryl (for example phenyl), aryKCrCs-alkyl)- (for example benzyl or 2-phenyleth-1 -yl), aryl-fused-heterocycloalkyl (for example dihydrobenzofuranyl) and heteroaryl (for example isoxazolyl); wherein said groups may be optionally substituted with 1 or 2 substituents independently selected from C₁- C₆-alkyl, CrC₆-alkoxy and halo.

In one aspect, the present invention provides a compound of formula (I) wherein R¹¹ is hydrogen or C₁-C₃ alkyl.

In one aspect, the present invention provides a compound of formula (I) wherein Q is an oxygen atom.

In another aspect, the present invention provides a compound of formula (I) wherein Q is a bond.

In one aspect, the present invention provides a compound of formula (I) wherein R⁶ is a CrCe-alkyl.

In another aspect, the present invention provides a compound of formula (I) wherein R⁶ is -OH.

In one subset of the compounds of formula (I):

R¹ is d-Ce-alkyl; R² is -(Z)_p-R⁷ or a group -Z-Y-R⁷; and R³ is C_rC₆-alkyl;

p is 0 or 1 ;

represents the group , where R⁶ is -OH or a methyl group, and Q is an oxygen atom or a bond;

X is C₁-C₂-alkylene;

Z is CrCβ-alkylene; Y is oxygen atom or a group -S(O)_n;

n is an integer selected from 0, 1 or 2;

R⁷ is d-Cβ-alkenyl, aryl, heteroaryl, aryl(CrC₆-alkyl) or aryl-fused-heterocycloalkyl;

R⁸ is hydrogen;

or a pharmaceutically acceptable salt thereof;

wherein, each occurrence of each occurrence of alkyl may be optionally substituted with one or more two substituent groups independently chosen from CVCe-haloalkyl, CrCe-haloalkoxy, CN and halo; and each occurrence of aryl, heteroaryl, aryl(CrC₆- alkyl), aryl-fused-heterocycloalkyl or alkylene may be optionally substituted with one or more two substituent groups indepently chosen from Ci-C₆-alkyl, CrC₆-haloalkyl, C₁- C₆-haloalkoxy, CN and halo.

In the compounds of formula (I) as defined and further particularized above, R⁸ may be hydrogen.

Compounds of the invention may conveniently be represented by compounds of formula (Ia):

wherein A, Q, X, R¹⁴, R¹⁵, R⁶, R¹, R², R³, R⁸, a and b are as previously defined above.

A particular class of compounds of the invention consists of quaternary ammonium salts of formula (I) wherein the aliphatic nitrogen shown in formula (I) is a quaternary nitrogen carrying a positive charge. Such compounds may conveniently be represented by compounds of formula (Ib):

wherein A, Q, X, R¹⁴, R¹⁵, R⁶, R¹, R², R³, R⁸, a and b are as previously defined above and D^" is a pharmaceutically acceptable counter-ion.

Compounds of the invention may be useful in the treatment or prevention of diseases in which activation of muscarinic receptors are implicated, for example the present compounds are useful for treating a variety of indications, including but not limited to respiratory-tract disorders such as chronic obstructive lung disease (also known as chronic obstructive pulmonary disease or COPD), chronic bronchitis of all types (including dyspnoea associated therewith), asthma (allergic and non-allergic; 'wheezy- infant syndrome'), adult/acute respiratory distress syndrome (ARDS), chronic respiratory obstruction, bronchial hyperactivity, pulmonary fibrosis, pulmonary emphysema, and allergic rhinitis, exacerbation of airway hyperreactivity consequent to other drug therapy, particularly other inhaled drug therapy, pneumoconiosis (for example aluminosis, anthracosis, asbestosis, chalicosis, ptilosis, siderosis, silicosis, tabacosis and byssinosis); gastrointestinal-tract disorders such as irritable bowel syndrome, spasmodic colitis, gastroduodenal ulcers, gastrointestinal convulsions or hyperanakinesia, diverticulitis, pain accompanying spasms of gastrointestinal smooth musculature; urinary-tract disorders accompanying micturition disorders including neurogenic pollakisuria, neurogenic bladder, nocturnal enuresis, psychosomatic bladder, incontinence associated with bladder spasms or chronic cystitis, urinary urgency or pollakiuria; motion sickness; and cardiovascular disorders such as vagally induced sinus bradycardia.

In another aspect a compound of present invention is useful in the treatment or prevention of respiratory-tract disorders such as chronic obstructive lung disease (also known as chronic obstructive pulmonary disease, COPD), chronic bronchitis of all types (including dyspnoea associated therewith), asthma (allergic and non-allergic; 'wheezy-infant syndrome'), adult/acute respiratory distress syndrome (ARDS), chronic respiratory obstruction, bronchial hyperactivity, pulmonary fibrosis, pulmonary emphysema, and allergic rhinitis, exacerbation of airway hyperreactivity consequent to other drug therapy, particularly other inhaled drug therapy or pneumoconiosis (for example aluminosis, anthracosis, asbestosis, chalicosis, ptilosis, siderosis, silicosis, tabacosis and byssinosis).

For treatment of respiratory conditions, administration by inhalation will often be convenient, and in such cases administration of compounds (I) which are quaternary ammonium salts will often be convenient. In many cases, the duration of action of quaternary ammonium salts of the invention administered by inhalation is may be more than 12, or more than 24 hours for a typical dose. For treatment of gastrointestinal-tract disorders and cardiovascular disorders, administration by the parenteral route, usually the oral route, may be convenient.

Another aspect of the invention is a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient.

Another aspect of the invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in therapy.

Another aspect of the invention is the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment or prevention of a disease or condition in which muscarinic M3 receptor activity is implicated. Diseases or conditions in which muscarinic M3 receptor activity is implicated include respiratory-tract disorders, gastrointestinal-tract disorders and cardiovascular disorders. Specific examples of such diseases and conditions include those listed above.

Another aspect of the invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, for the treatment or prevention of a disease or condition in which muscarinic M3 receptor activity is implicated. Diseases or conditions in which muscarinic M3 receptor activity is implicated include respiratory- tract disorders, gastrointestinal-tract disorders and cardiovascular disorders. Specific examples of such diseases and conditions include those listed above.

Another aspect of the invention provides a method of treatment of a disease or condition in which M3 muscarinic receptor activity is implicated comprising administration to a subject in need thereof of an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof. Diseases or conditions in which muscarinic M3 receptor activity is implicated include respiratory-tract disorders, gastrointestinal-tract disorders and cardiovascular disorders. Specific examples of such diseases and conditions include those listed above.

Description of Definitions

Unless otherwise qualified in the context in which they are used, the following terms have the following meanings when used herein:

"Alkoxy" and "alkyloxy" means an -O-alkyl group in which alkyl is as described below. Exemplary alkoxy groups include methoxy (-OCH₃) and ethoxy (-OC₂H₅). "Alkyl" as a group or part of a group refers to a straight or branched chain saturated hydrocarbon group having from 1 to 12, for example 1 -8, such as 1 to 6, 1 -4 or 1-2 carbon atoms, in the chain. Exemplary alkyl groups include methyl, ethyl, 1 - propyl and 2-propyl.

"Alkenyl" as a group or part of a group refers to a straight or branched chain hydrocarbon group having from 2 to 12, conveniently 2 to 6, carbon atoms and one or more carbon-carbon double bonds in the chain. Exemplary alkenyl groups include ethenyl, 1 -propenyl, and 2-propenyl.

"Alkylene" means an -alkyl- group in which alkyl is as defined previously. Exemplary alkylene groups include -CH₂-, -(CH₂)₂- and -C(CH₃)HCH₂-.

"Alkenylene" means an -alkenyl- group in which alkenyl is as defined previously. Exemplary alkenylene groups include -CH=CH-, -CH=CHCH₂-, and - CH₂CH=CH-.

"Alkynylene" means an -alkynyl- group in which -alkynyl- refers to a straight or branched chain hydrocarbon group having from 2 to 12, conveniently 2 to 6, carbon atoms and one carbon-carbon triple bond in the chain. Exemplary alkynylene groups include ethynyl and propargyl. "Aryl" as a group or part of a group denotes an optionally substituted monocyclic or multicyclic aromatic carbocyclic moiety of from 6 to 14 carbon atoms, conveniently from 6 to 10 carbon atoms, such as phenyl or naphthyl. Phenyl is a specifically convenient aryl group. The aryl group, specifically a phenyl group, may be substituted by one or more substituent groups. "Arylalkyl" means an aryl-alkyl- group in which the aryl and alkyl moieties are as previously described. Convenient arylalkyl groups contain a C_{1 4} alkyl moiety. Exemplary arylalkyl groups include benzyl, phenethyl and naphthlenemethyl.

"Aryl-fused-cycloalkyl" means a monocyclic aryl ring, such as phenyl, fused to a cycloalkyl group, in which the aryl and cycloalkyl are as described herein. Exemplary aryl-fused-cycloalkyl groups include tetrahydronaphthyl and indanyl. The aryl and cycloalkyl rings may each be substituted by one or more substituent groups. The aryl- fused-cycloalkyl group may be attached to the remainder of the compound by any available carbon atom.

"Aryl-fused-heterocycloalkyl" means a monocyclic aryl ring, such as phenyl, fused to a heterocycloalkyl group, in which the aryl and heterocycloalkyl are as described herein. Exemplary aryl-fused-heterocycloalkyl groups include tetrahydroquinolinyl, indolinyl, benzodioxinyl, benxodioxolyl, dihydrobenzofuranyl and isoindolonyl. The aryl and heterocycloalkyl rings may each be substituted by one or more substituent groups. The aryl-fused-heterocycloalkyl group may be attached to the remainder of the compound by any available carbon or nitrogen atom. "Cyclic amine" means an optionally substituted 3 to 8 membered monocyclic cycloalkyl ring system where one of the ring carbon atoms is replaced by nitrogen, and which may optionally contain an additional heteroatom selected from O, S or NR (where R is as described herein). Exemplary cyclic amines include pyrrolidine, piperidine, morpholine, piperazine and Λ/-methylpiperazine. The cyclic amine group may be substituted by one or more substituent groups.

"Cycloalkyl" means an optionally substituted saturated monocyclic or bicyclic ring system of from 3 to 12 carbon atoms, conveniently from 3 to 8 carbon atoms, and more conveniently from 3 to 6 carbon atoms. Exemplary monocyclic cycloalkyl rings include cyclopropyl, cyclopentyl, cyclohexyl and cycloheptyl. The cycloalkyl group may be substituted by one or more substituent groups.

"Halo" or "halogen" means fluoro, chloro, bromo, or iodo. Convenient are fluoro or chloro.

"Haloalkoxy" means an -O-alkyl group in which the alkyl is substituted by one or more halogen atoms. Exemplary haloalkyl groups include trifluoromethoxy and difluoromethoxy.

"Haloalkyl" means an alkyl group which is substituted by one or more halo atoms. Exemplary haloalkyl groups include trifluoromethyl.

"Heteroaryl" as a group or part of a group denotes an optionally substituted aromatic monocyclic or multicyclic organic moiety of from 5 to 14 ring atoms, conveniently from 5 to 10 ring atoms, in which one or more of the ring atoms is/are element(s) other than carbon, for example nitrogen, oxygen or sulfur. Examples of such groups include benzimidazolyl, benzoxazolyl, benzothiazolyl, benzofuranyl, benzothienyl, furyl, imidazolyl, indolyl, indolizinyl, isoxazolyl, isoquinolinyl, isothiazolyl, oxazolyl, oxadiazolyl, pyrazinyl, pyridazinyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, tetrazolyl, 1 ,3,4-thiadiazolyl, thiazolyl, thienyl and triazolyl groups. The heteroaryl group may be substituted by one or more substituent groups. The heteroaryl group may be attached to the remainder of the compound of the invention by any available carbon or nitrogen atom.

"Heteroarylalkyl" means a heteroaryl-alkyl- group in which the heteroaryl and alkyl moieties are as previously described. Convenient heteroarylalkyl groups contain a lower alkyl moiety. Exemplary heteroarylalkyl groups include pyridylmethyl.

"Heterocycloalkyl" means: (i) an optionally substituted cycloalkyl group of from 4 to 8 ring members which contains one or more heteroatoms selected from O, S or NR; (ii) a cycloalkyl group of from 4 to 8 ring members which contains CONR or CONRCO (examples of such groups include succinimidyl and 2-oxopyrrolidinyl). The heterocycloalkyl group may be substituted by one or more substituent groups. The heterocycloalkyl group may be attached to the remainder of the compound by any available carbon or nitrogen atom.

"Pharmaceutically acceptable salt" means a physiologically or toxicologically tolerable salt and includes, when appropriate, pharmaceutically acceptable base addition salts, pharmaceutically acceptable acid addition salts, and pharmaceutically acceptable quaternary ammonium salts. For example (i) where a compound of the invention contains one or more acidic groups, for example carboxy groups, pharmaceutically acceptable base addition salts that may be formed include sodium, potassium, calcium, magnesium and ammonium salts, or salts with organic amines, such as, diethylamine, Λ/-methyl- glucamine, diethanolamine or amino acids (e.g. lysine) and the like; (ii) where a compound of the invention contains a basic group, such as an amino group, pharmaceutically acceptable acid addition salts that may be formed include hydrochlorides, hydrobromides, sulfates, phosphates, acetates, citrates, lactates, tartrates, mesylates, napadisylate (naphthalene-1 ,5-disulfonate or naphthalene-1 - (sulfonic acid)-5-sulfonate), edisylate (ethane-1 ,2-disulfonate or ethane-1 -(sulfonic acid)- 2-sulfonate), maleates, fumarates, succinates and the like; (iii) when R³ is not a lone pair the compound of formula (I) has a quaternary ammonium group for which the pharmaceutically acceptable counter-ion may be, for example, chloride, bromide, sulfate, methanesulfonate, benzenesulfonate, toluenesulfonate (tosylate), napadisylate (naphthalene-1 , 5-disulfonate or naphthalene-1 -(sulfonic acid)-5-sulfonate), edisylate (ethane-1 ,2-disulfonate or ethane-1 -(sulfonic acid)-2-sulfonate), isethionate (2- hydroxyethylsulfonate), phosphate, acetate, citrate, lactate, tartrate, mesylate, maleate, malate, fumarate, xinafoate, p-acetamidobenzoate and succinate; wherein the number of quaternary ammonium species balances the counter-ion such that compound of formula (I) has no net charge. The present invention covers all permissible ratios of cationic ammonium species to counter-ion, for example hemi-napadisylate and napadisylate.

In another aspect of the invention D^' is bromide or napadisylate (for example naphthalene- 1 ,5-disulfonate).

It will be understood that, as used herein, references to the compounds of the invention are meant to also include the pharmaceutically acceptable salts.

"Prodrug" refers to a compound which is convertible in vivo by metabolic means (e.g. by hydrolysis, reduction or oxidation) to a compound of the invention. Suitable groups for forming pro-drugs are described in 'The Practice of Medicinal Chemistry, 2^nd Ed. pp561 -585 (2003) and in F. J. Leinweber, Drug Metab. Res., 18, 379. (1987)

It will be understood that, as used in herein, references to the compounds of the invention are meant to also include the prodrug forms.

"Saturated" pertains to compounds and/or groups which do not have any carbon-carbon double bonds or carbon-carbon triple bonds. The cyclic groups referred to above, namely, aryl, heteroaryl, cycloalkyl, and cyclic amine are unsubstituted or substituted by one or more of the same or different substituent groups. Examples of specific optional substituents include -Cl, -F, -CH₃, -OCH₃, -CN, More generally the substituents can be divided into two classes:

(a) a first class of substituent includes acyl (e.g. -COCH, 3), alkoxy (e.g., -OCHJ 3 , alkoxycarbonyl (e.g. -COOCH 3J, alkylamino (e.g. -NHCHJ o , alkylsulfinyl (e.g. -SOCH 3J, alkylsulfonyl (e.g. -SO₂CH₃), alkylthio (e.g. -SCH₃), -NH₂, aminoacyl (e.g. -CON(CH₃)₂), aminoalkyl (e.g. -CH₂NH₂), cyano, dialkylamino (e.g. -N(CH₃)₂), halo, haloalkoxy (e.g. -OCF₃ or -OCHF₂), haloalkyl (e.g. -CF₃), alkyl (e.g. -CH₃ Or -CH₂CH₃), -OH, , -COOH, , aminoacyl (e.g. -CONH₂, -CONHCH₃), aminosulfonyl (e.g. -SO₂NH₂, -SO₂NHCH₃), acylamino (e.g. -NHCOCH₃) and sulfonylamino (e.g. -NHSO₂CH₃); and

(b) a second class of substituent includes arylalkyl (e.g. -CH₂Ph or

-CH₂-CH₂-Ph), aryl, heteroaryl, heterocycloalkyl, heteroarylalkyl, cyclic amine (e.g. morpholine), aryloxy, heteroaryloxy, arylalkyloxy (e.g. benzyloxy) and heteroarylalkyloxy, the cyclic part of any of which being optionally substituted by any of the first class of substituent referred to above (for example alkoxy, haloalkoxy, halogen, alkyl and haloalkyl).

"Alkylene" or "alkenylene" groups may be optionally substituted. Suitable optional substituent groups include alkoxy (e.g., -OCH₃), alkylamino (e.g. -NHCH₃), alkylsulfinyl (e.g. -SOCHJ, alkylsulfonyl (e.g. -SO CHJ, alkylthio (e.g. -SCHJ, -NH₂, aminoalkyl (e.g. -CH₂NHJ, arylalkyl (e.g. -CH₂Ph or -CH₂-CH₂-Ph), cyano, dialkylamino (e.g. -N(CHJ 3 J 2 , halo, haloalkoxy (e.g. -OCF 0, or -OCHF 2J, haloalkyl (e.g.

-CF 0J, alkyl (e.g. -CH 3₀ or -CH 2 CH 3J, -OH, -CHO, and -NO₂.

Compounds of the invention may exist in one or more geometrical, optical, enantiomeric, diastereomeric and tautomeric forms, including but not limited to cis- and transforms, E- and Z-forms, R-, S- and mesoforms, keto-, and enol-forms. Unless otherwise stated a reference to a particular compound includes all such isomeric forms, including racemic and other mixtures thereof. Where appropriate such isomers can be separated from their mixtures by the application or adaptation of known methods (e.g. chromatographic techniques and recrystallisation techniques). Where appropriate such isomers may be prepared by the application of adaptation of known methods (e.g. asymmetric synthesis).

The present invention also encompasses the following alternative embodiments and combinations thereof:

The groups R¹, Ff and R³

In one aspect, the present invention provides compounds of formula (I) wherein R¹ is d-Cβ-alkyl; R² is -(Z)_p-R⁷ or a group -Z-Y-R⁷; and R³ is C_rC₆-alkyl;

In another aspect, the present invention provides compounds of formula (I) wherein the groups R¹, R² and R³ are combined so that:

R¹ is d-Ce-alkyl; and R² is a group (Z)_p-R⁷, -Z-Y-R⁷, -Z-CO-NR⁹R¹⁰, or -Z-C(O)-R⁷; and R³ is Ci-C₆-alkyl; p is O or 1.

In a further aspect, where a group (Z)_p-R⁷, or -Y-R⁷, -Z-Y-R⁷, or a group -Z-CO- NR⁹R¹⁰, or a group -Z-C(O)-R⁷, is present in R²: Z may be, for example -(CH₂)_V16- optionally substituted on up to three carbons in the chain by methyl;

Y is -O- or a group -S(O)_n (where n is 0,1 or 2), C(O)O, OC(O), N(R¹²JS(O)₂ or S(O)₂N(R¹²);

R⁷ may be

Ci-C₆-alkyl, such as methyl, ethyl, n- or isopropyl, n-, sec- or tertbutyl;

Optionally substituted aryl such as phenyl or naphthyl, or aryl-fused- heterocycloalkyl such as 3,4-methylenedioxyphenyl, 3,4- ethylenedioxyphenyl, or dihydrobenzofuranyl;

Optionally substituted heteroaryl such as pyridyl, pyrrolyl, pyrimidinyl, oxazolyl, isoxazolyl, benzisoxazolyl, benzoxazolyl, thiazolyl, benzothiazolyl, quinolyl, thienyl, benzothienyl, furyl, benzofuryl, imidazolyl, benzimidazolyl, isothiazolyl, benzisothiazolyl, pyrazolyl, isothiazolyl, triazolyl, benzotriazolyl, thiadiazolyl, oxadiazolyl, pyridazinyl, pyridazinyl, triazinyl, indolyl and indazolyl;

Optionally substituted aryl(CrC₆-alkyl)- such as those wherein the aryl part is any of the foregoing specifically mentioned aryl groups and the -(CrC₆-alkyl)- part is -CH₂- or -CH₂CH₂-;

Optionally substituted heteroaryl(CrC₈-alkyl)- such as those wherein the heteroaryl part is any of the foregoing specifically mentioned heteroaryl groups and the -(Ci-C₆-alkyl)- part is -CH₂- or -CH₂CH₂-;

Optionally substituted cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, or move conveniently, such as cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl;

More conveniently, R⁷ may be

Optionally substituted aryl such as phenyl or naphthyl, or aryl-fused- heterocycloalkyl such as 3,4-methylenedioxyphenyl, 3,4- ethylenedioxyphenyl, or dihydrobenzofuranyl; or Optionally substituted aryl(CrC₆-alkyl)- such as those wherein the aryl part is any of the foregoing specifically mentioned aryl groups and the -(C_rC₆-alkyl)- part is -CH₂- Or -CH₂CH₂-.

R⁹ and R¹⁰ may be independently selected from hydrogen; CrC_θ-alkyl such as methyl, ethyl or n- or isopropyl; or any of those optionally substituted aryl, aryl- fused-heterocycloalkyl, heteroaryl or aryl(CrC₈-alkyl)- groups specifically mentioned in the discussion of R⁷ above; or

R⁹ and R¹⁰ together with the nitrogen atom to which they are attached may form a heterocyclic ring of 4-8 ring atoms, more conveniently 4-6 ring atoms, optionally containing a further nitrogen or oxygen atom, such as azetidinyl, piperidinyl, piperazinyl, N-substituted piperazinyl such as methylpiperazinyl, pyrrolidinyl, morpholinyl, and thiomorpholinyl.

In a yet further aspect, the present invention provides compounds of formula (I) wherein R² may represent an optionally substituted aryl(CrC₆-alkyl)- moiety such as, for example, a moiety wherein the aryl part is optionally substituted phenyl (for example, 3-chlorophenyl) and the -(CrCβ-alkyl)- part is, for example, -CH₂CH₂-.

One aspect of the present invention provides compounds of formula (I) wherein, R¹ is methyl or ethyl, R² is -Z-Y-R⁷ as defined and discussed above, Y is -O- and -Z- is a straight or branched alkylene radical linking the nitrogen and -YR⁷ by a chain of up to 16, for example up to 10, and more conveniently from 2 to 4, carbon atoms, and R³ is methyl. In these cases, R⁷ is conveniently a cyclic lipophilic group such as phenyl, benzyl, dihydrobenzofuranyl or phenylethyl (wherein the phenyl rings are optionally substituted as described above).

Another aspect of the present invention provides compounds of formula (I) wherein, R¹ is methyl or ethyl, R² is -(Z)_p-R⁷ as defined and discussed above, p is 1 , and -Z- is a straight or branched alkylene radical linking the nitrogen and -R⁷ by a chain of up to 16, for example up to 10, and more conveniently from 2 to 5, carbon atoms, and R³ is methyl. In these cases, R⁷ is conveniently a cyclic lipophilic group such as phenyl or dihydrobenzofuranyl (wherein the phenyl rings are optionally substituted as described above). The groups R⁴, R⁵ and R⁶

In one aspect, the present invention provides compounds of formula (I) wherein R⁴ and R⁵ are joined together to form a tricyclic ring so that the group R⁴R⁵R⁶C-

represents the group , wherein R⁶ is -OH, C₁-C₆-SIkVl, CrCβ-alkoxy or a hydrogen atom, and Q is an oxygen atom, -CH₂-, -CH₂CH₂- or a bond. A convenient case is where R⁶ is -OH or C₁-C₆-SIkVl.

The Radical X

Although X may be an alkylene, alkenylene or alkynylene radical, it is convenient that it be alkylene, for example ethylene or methylene.

A subclass of compounds with which the invention is concerned consists of those of formula (Ic)

m is 1 or 2; ring A is an optionally substituted phenyl ring, or phenyl-fused- heterocycloalkyl ring system wherein the heterocycloalkyl ring is a monocyclic heterocyclic ring of 5 or 6 ring atoms; Q is -O- or a bond; R⁶ is -OH or -CH₃; Y is -O-, or a group -S(O)_n; n is 0,1 or 2, and D^" is a pharmaceutically acceptable counter- ion.

In one aspect the present invention provides a compound of formula (Ic) wherein A is optionally substituted phenyl (wherein optional substituents are selected from alkoxy, halo (such as fluoro or chloro), C₁-C₃-SIkVl, cyano, -CF₃, amino C₁-C₃-SCyI or amino Ci-C₃-alkyl; or more conveniently optional substituents are selected from alkoxy, halo (such as fluoro or chloro), Ci-C₃-alkyl, cyano, or -CF₃ or a phenyl-fused- heterocycloalkyl ring system (wherein the heterocycloalkyl ring is a monocyclic heterocyclic ring of 5 or 6 ring atoms, such as dihydrobenzofuranyl).

In subclass (Ic), s+t is, for example, 2, 3, 4, 5, 6, or 7 and may arise from suitable combinations of t and s such as where t is 0, 1 , 2, 3, 4, 5 or 6 and s is 2, 3, 4, 5, 6 or 7.

In compounds (Ic) a combination of t, Y and s is where t is 0, s is 3, and Y is -O. A further combination of t, Y and s is where t is 1 , s is 2 and Y is -O-. A further combination of t, Y and s is where t is 2, s is 2 and Y is -O-.

A yet further combination of t, Y and s is where t is 0, s is 3, and Y is -S-.

In one aspect m is 1 for compounds of (Ic).

Examples of compounds of the invention include those of the non-limiting Examples provided herein.

In one embodiment, the present invention provides a compound of formula (I) selected from:

Dimethyl-[2-(9-methyl-9H-xanthen-9-yl)-oxazol-5-ylmethyl]-(3-phenoxy-propyl)- ammonium;

[2-(9-Hydroxy-9H-fluoren-9-yl)-oxazol-5-ylmethyl]-dimethyl-(2-m-tolyloxy-ethyl)- ammonium;

[2-(9-Hydroxy-9H-fluoren-9-yl)-oxazol-5-ylmethyl]-{2-[2-(4-methoxy-phenyl)- ethoxy]-ethyl}-dimethyl-ammonium; [2-(4-Cyano-benzyloxy)-ethyl]-[2-(9-hydroxy-9H-fluoren-9-yl)-oxazol-5- ylmethylj-dimethyl-ammonium;

[3-(4-Chloro-phenylsulfanyl)-propyl]-[2-(9-hydroxy-9H-fluoren-9-yl)-oxazol-5- ylmethyl]-dimethyl-ammonium;

[2-(2,3-Dihydro-benzofuran-5-yl)-ethyl]-[2-(9-hydroxy-9H-fluoren-9-yl)-oxazol-5- ylmethylj-dimethyl-ammonium;

[2-(9-Hydroxy-9H-fluoren-9-yl)-oxazol-5-ylmethyl]-dimethyl-(4-methyl-pent-3- enyl)-ammonium;

[2-(9-Hydroxy-9H-fluoren-9-yl)-oxazol-5-ylmethyl]-dimethyl-(3-phenoxy-propyl)- ammonium;

[2-(4-Chloro-benzyloxy)-ethyl]-dimethyl-[2-(9-methyl-9H-xanthen-9-yl)-oxazol- 5-ylmethyl]-ammonium; and

[2-(4-Chloro-benzyloxy)-ethyl]-[2-(9-hydroxy-9H-fluoren-9-yl)-oxazol-5- ylmethylj-dimethyl-ammonium; wherein each ammonium salt comprises a pharmaceutically acceptable counter-ion.

Examples of pharmaceutically acceptable anions that may be present in the ammonium salts according to this embodiment include chlorides, bromides, sulfates, methanesulfonates, benzenesulfonates, toluenesulfonates (tosylates), napadisylates (naphthalene-1 ,5-disulfonates or naphthalene-1 -(sulfonic acid)-5-sulfonates), edisylates (ethane-1 ,2-disulfonates or ethane-1 -(sulfonic acid)-2-sulfonates), isethionates (2-hydroxyethylsulfonates), phosphates, acetates, citrates, lactates, tartrates, mesylates, maleates, malates, fumarates, succinates, xinafoates, p- acetamidobenzoates. More specific examples include chloride, bromide, iodide, mesylate, tosylate, benzenesulfonate and napadisylate.

Each of the compounds identified above, taken alone or with any combination of the other compounds identified herein, represents an independent aspect of the invention.

The present invention is also concerned with pharmaceutical formulations comprising, as an active ingredient, a compound of the invention. Other compounds may be combined with compounds of this invention for the prevention and treatment of inflammatory diseases of the lung. Thus the present invention is also concerned with pharmaceutical compositions for preventing and treating respiratory-tract disorders such as chronic obstructive lung disease, chronic bronchitis, asthma, chronic respiratory obstruction, pulmonary fibrosis, pulmonary emphysema, and allergic rhinitis comprising a therapeutically effective amount of a compound of the invention and one or more other therapeutic agents.

Other compounds may be combined with compounds of this invention for the prevention and treatment of inflammatory diseases of the lung. Accordingly the invention includes a combination of an agent of the invention as hereinbefore described with one or more anti-inflammatory, bronchodilator, antihistamine, decongestant or anti-tussive agents, said agents of the invention hereinbefore described and said combination agents existing in the same or different pharmaceutical compositions, administered separately or simultaneously. Convenient combinations would have two or three different pharmaceutical compositions. Suitable therapeutic agents for a combination therapy with compounds of the invention include:

One or more other bronchodilators such as PDE3 inhibitors; Methyl xanthines such as theophylline; Other muscarinic receptor antagonists;

A corticosteroid, for example fluticasone propionate, ciclesonide, mometasone furoate or budesonide, or steroids described in WO02/88167, WO02/12266, WO02/100879, WO02/00679, WO03/35668, WO03/48181 , WO03/62259, WO03/64445, WO03/72592, WO04/39827 and WO04/66920; A non-steroidal glucocorticoid receptor agonist;

A β2-adrenoreceptor agonist, for example albuterol (salbutamol), salmeterol, metaproterenol, terbutaline, fenoterol, procaterol, carmoterol, indacaterol, formoterol, arformoterol, picumeterol, GSK-159797, GSK-597901 , GSK-159802, GSK-64244, GSK-678007, TA-2005 and also compounds of EP1440966, JP05025045, WO93/18007, WO99/64035, US2002/0055651 , US2005/0133417, US2005/5159448, WO00/075114, WO01/42193, WO01/83462, WO02/66422, WO02/70490, WO02/76933, WO03/24439, WO03/42160, WO03/42164, WO03/72539, WO03/91204, WO03/99764, WO04/16578, WO04/016601 , WO04/22547, WO04/32921 , WO04/33412, WO04/37768, WO04/37773, WO04/37807, WO0439762, WO04/39766, WO04/45618, WO04/46083, WO04/71388, WO04/80964, EP1460064, WO04/087142, WO04/89892, EP01477167, US2004/0242622, US2004/0229904, WO04/108675, WO04/108676, WO05/033121 , WO05/040103, WO05/044787, WO04/071388, WO05/058299, WO05/058867, WO05/065650, WO05/066140, WO05/070908, WO05/092840, WO05/092841 , WO05/092860, WO05/092887, WO05/092861 , WO05/090288, WO05/092087,

WO05/080324, WO05/080313, US20050182091 , US20050171 147, WO05/092870, WO05/077361 , DE10258695, WO05/11 1002, WO05/1 11005, WO05/110990, US2005/0272769 WO05/1 10359, WO05/121065, US2006/0019991 , WO06/016245, WO06/014704, WO06/031556, WO06/032627, US2006/0106075, US2006/0106213, WO06/051373, WO06/056471 ;

A leukotriene modulator, for example montelukast, zafirlukast or pranlukast; protease inhibitors, such as inhibitors of matrix metalloprotease for example MMP12 and TACE inhibitors such as marimastat, DPC-333, GW-3333;

Human neutrophil elastase inhibitors, such as sivelestat and those described in

WO04/043942, WO05/021509, WO05/021512, WO05/026123, WO05/026124, WO04/024700, WO04/024701 , WO04/020410, WO04/020412, WO05/080372,

WO05/082863, WO05/082864, WO03/053930;

Phosphodiesterase-4 (PDE4) inhibitors, for example roflumilast, arofylline, cilomilast,

ONO-6126 or lC-485;

Phosphodiesterase-7 inhibitors; An antitussive agent, such as codeine or dextramorphan;

Kinase inhibitors, particularly P38 MAPKinase inhibitors;

P2X7 anatgonists; iNOS inhibitors;

A non-steroidal anti-inflammatory agent (NSAID), for example ibuprofen or ketoprofen;

A dopamine receptor antagonist;

TNF-α inhibitors, for example anti-TNF monoclonal antibodies, such as Remicade and CDP-870 and TNF receptor immunoglobulin molecules, such as Enbrel;

A2a agonists such as those described in EP1052264 and EP1241 176; A2b antagonists such as those described in WO2002/42298;

Modulators of chemokine receptor function, for example antagonists of CCR1 , CCR2,

CCR3, CXCR2, CXCR3, CX3CR1 and CCR8, such as SB-332235, SB-656933, SB-

265610, SB-225002, MC P- 1 (9-76), RS-504393, MLN-1202, INCB-3284;

Compounds which modulate the action of prostanoid receptors, for example a PGD₂ (DP1 or CRTH2), or a thromboxane A₂ antagonist eg ramatrobant;

Compounds which modulate Th1 or Th2 function, for example, PPAR agonists; lnterleukin 1 receptor antagonists, such as Kineret; lnterleukin 10 agonists, such as llodecakin;

HMG-CoA reductase inhibitors (statins); for example rosuvastatin, mevastatin, lovastatin, simvastatin, pravastatin and fluvastatin;

Mucus regulators such as INS-37217, diquafosol, sibenadet, CS-003, talnetant, DNK-

333, MSI-1956, gefitinib;

Antiinfective agents (antibiotic or antiviral), and antiallergic drugs including, but not limited to, anti-histamines.

The weight ratio of the first and second active ingredients may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used.

A further aspect of the present invention provides a combination comprising a compound of formula (Ia), as defined herein above, and a β2-adrenoreceptor agonist.

Any suitable route of administration may be employed for providing a mammal, especially a human, with an effective dosage of a compound of the present invention. In therapeutic use, the active compound may be administered by any convenient, suitable or effective route. Suitable routes of administration are known to those skilled in the art, and include oral, intravenous, rectal, parenteral, topical, ocular, nasal, buccal and pulmonary.

The magnitude of prophylactic or therapeutic dose of a compound of the invention will, of course, vary depending upon a range of factors, including the activity of the specific compound that is used, the age, body weight, diet, general health and sex of the patient, time of administration, the route of administration, the rate of excretion, the use of any other drugs, and the severity of the disease undergoing treatment. In general, the daily dose range for inhalation will lie within the range of from about 0.1 μg to about 10 mg per kg body weight of a human, preferably 0.1 μg to about 0.5 mg per kg, and more preferably 0.1 μg to 50μg per kg, in single or divided doses. On the other hand, it may be necessary to use dosages outside these limits in some cases. Compositions suitable for administration by inhalation are known, and may include carriers and/or diluents that are known for use in such compositions. The composition may contain 0.01 -99% by weight of active compound. Preferably, a unit dose comprises the active compound in an amount of 1 μg to 10 mg. For oral administration suitable doses are 10μg per kg to 100mg per kg, preferably 40μg per kg to 4 mg per kg.

Another aspect of the present invention provides pharmaceutical compositions which comprise a compound of the invention and a pharmaceutically acceptable carrier. The term "composition", as in pharmaceutical composition, is intended to encompass a product comprising the active ingredient(s), and the inert ingredient(s) (pharmaceutically acceptable excipients) that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more !

24 of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of the invention, additional active ingredient(s), and pharmaceutically acceptable excipients.

The pharmaceutical compositions of the present invention comprise a compound of the invention as an active ingredient or a pharmaceutically acceptable salt thereof, and may also contain a pharmaceutically acceptable carrier and optionally other therapeutic ingredients. The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic bases or acids and organic bases or acids, and salts of quaternary ammonium compounds with pharmaceutically acceptable counter-ions.

For delivery by inhalation, the active compound is preferably in the form of microparticles. They may be prepared by a variety of techniques, including spray- drying, freeze-drying and micronisation.

By way of example, a composition of the invention may be prepared as a suspension for delivery from a nebuliser or as an aerosol in a liquid propellant, for example for use in a pressurised metered dose inhaler (PMDI). Propellents suitable for use in a PMDI are known to the skilled person, and include CFC-12, HFA-134a, HFA-227, HCFC-22 (CCI₂F₂) and HFA-152 (C₂H₄F₂) and isobutane.

In a convenient embodiment of the invention, a composition of the invention is in dry powder form, for delivery using a dry powder inhaler (DPI). Many types of DPI are known.

Microparticles for delivery by administration may be formulated with excipients that aid delivery and release. For example, in a dry powder formulation, microparticles may be formulated with large carrier particles that aid flow from the DPI into the lung. Suitable carrier particles are known, and include lactose particles; they may have a mass median aerodynamic diameter of greater than 90 μm.

In the case of an aerosol-based formulation, an example is: Compound of the invention 24 mg / canister

Lecithin, NF Liq. Cone. 1 .2 mg / canister Trichlorofluoromethane, NF 4.025 g / canister Dichlorodifluoromethane, NF 12.15 g / canister.

The active compounds may be dosed as described depending on the inhaler system used. In addition to the active compounds, the administration forms may additionally contain excipients, such as, for example, propellants (e.g. Frigen in the case of metered aerosols), surface-active substances, emulsifiers, stabilizers, preservatives, flavorings, fillers (e.g. lactose in the case of powder inhalers) or, if appropriate, further active compounds.

For the purposes of inhalation, a large number of systems are available with which aerosols of optimum particle size can be generated and administered, using an inhalation technique which is appropriate for the patient. In addition to the use of adaptors (spacers, expanders) and pear-shaped containers (e.g. Nebulator®, Volumatic®), and automatic devices emitting a puffer spray (Autohaler®), for metered aerosols, in particular in the case of powder inhalers, a number of technical solutions are available (e.g. Diskhaler®, Rotadisk®, Turbohaler® or the inhalers for example as described EP-A-0505321). Additionally, compounds of the invention may be delivered in multi-chamber devices thus allowing for delivery of combination agents.

Methods of Synthesis

The compounds of the invention of the present invention can be prepared according to the procedures of the following schemes and examples, using appropriate materials, and are further exemplified by the following specific examples. Moreover, by utilising the procedures described with the disclosure contained herein, one of ordinary skill in the art can readily prepare additional compounds of the present invention claimed herein. The compounds illustrated in the examples are not, however, to be construed as forming the only genus that is considered as the invention. The examples further illustrate details for the preparation of the compounds of the present invention. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds.

The compounds of the invention may be isolated in the form of their pharmaceutically acceptable salts, such as those described previously herein above. It may be necessary to protect reactive functional groups (e.g. hydroxy, amino, thio or carboxy) in intermediates used in the preparation of compounds of the invention to avoid their unwanted participation in a reaction leading to the formation of the compounds. Conventional protecting groups, for example those described by T. W. Greene and P. G. M. Wuts in "Protective groups in organic chemistry" John Wiley and Sons, 1999, may be used.

In the schemes below the group R⁴R⁵R⁶C represents the group

wherein R⁶, Q, R¹⁴, R¹⁵, a and b are as defined above for compounds of formula (I).

Compounds of the invention may be prepared according to the routes illustrated in Schemes 1 -9.

Scheme 1

Scheme 2

Scheme 3

(V) (IX) Scheme 4

Scheme 5

Scheme 6

It will be apparent that some compounds can contain a chiral centre and thus exist in enantiomeric forms which can be separated by chiral preparative HPLC techniques using conditions known to those skilled in the art.

Compounds of general formula (l-a), may be prepared from compounds of general formula (l-z):

by reaction with an alkylating agent of formula (XVII):

R^e-D (XVII)

wherein D is a leaving group such as halogen, tosylate, mesylate. The reaction can be performed in a range of solvents, preferably DMF, chloroform or acetonitrile at a temperature from 0⁰C to the reflux temperature of the solvent.

Compounds of general formula (l-z), may be prepared from compounds of general formula (II):

wherein LG represents a leaving group such as bromide, chloride, iodide, by reaction with an amine of formula (XVIII):

R^cR^dNH (XVIII)

wherein R^c and R^dare as defined for R¹ and R² in general formula (I). The reaction is performed in a range of solvents, preferably THF/DCM at a range of temperatures, preferably between 0 and 100⁰C.

Compounds of general formula (XVIII) are well known in the art and can be prepared by known methods, or are commercially available.

Compounds of formula (II) wherein LG is bromide can be prepared from compounds of general formula (III):

by reaction with a brominating agent such as N-bromosuccinimide in the presence of a radical initiator such as AIBN or benzoyl peroxide. The reaction can be carried out in suitable solvents, such as CCI₄, at a range of temperatures, typically between ambient temperature and the reflux temperature of the solvent.

Compounds of formula (III) can be prepared from compounds of general formula (IV):

by reaction with an acid such as hydrochloric acid, sulphuric acid, or more typically methanesulfonic or trifluoromethansulfonic acid in a range of solvents such as THF, DCM, water, and typically 1 ,4-dioxan at a range of temperatures, typically between ambient temperature and the reflux temperature of the solvent.

Alternatively compounds of formula (III) can be prepared from compounds of general formula (IV) by palladium-catalysed cyclisation using a palladium catalyst such as bis(dibenzylideneacetone)palladium in the presence of a ligand such as triphenylphosphine and a base such as sodium tert-butoxide in a solvent such as THF from ambient temperature to the reflux temperature of the solvent.

Alternatively compounds of general formula (III) maybe prepared according to the route shown in Scheme 3 from compounds of general formula (Vl):

by reaction with a reducing agent such as Raney Nickel in a solvent such as ethanol at a temperature from ambient temperature to the reflux temperature of the solvent according to the method described in J. Org. Chem. 2006, 71(8), 3026.

Compounds of general formula (Vl) may be prepared from compounds of general formula (VII):

by reaction with 1 -(methylthio)acetone in the presence of trifluoromethanesulfonic anhydride in a solvent such as DCM at a temperature from O⁰C to the reflux temperature of the solvent according to the method described in J. Org. Chem. 2006, 71(8), 3026.

Compounds of formula (VII) are commercially available or are known in the art (for example Tetrahedron 1994, 50(33), 1001 1 ; Org. Syn. 1981 , 60,14; Can. J. Chem. 1964, 42(6), 1409) or can be prepared by known methods such as conversion of the carboxylic acid (V) to the carboxamide followed by dehydration with a suitable dehydrating agent such as trifluoroacetic anhydride.

Alternatively compounds of formula (III) can be prepared according to the routes shown in Scheme 4 from compounds of formula (VIII):

according to the method described in J. Chem. Soc. 1948, 1960.

Compounds of general formula (VIII) can be prepared from compounds of formula (VII):

RV _^CN

R^5> R£° (VIi)

Alternatively compounds of formula (III) can be prepared from compounds of formula (IX):

according to the method described in J. Org. Chem., 1938, 2, 319.

Compounds of general formula (IX) can be prepared from compounds of general formula (V):

by known methods such as those described in GB2214180.

Compounds of general formula (IV) can be prepared from compounds of general formula (V) by reaction with propargylamine in the presence of a suitable coupling agent, such as HATU or EDCI/HOBT or DCC/HOBt or many other known coupling methodologies. Alternatively compounds of formula (V) may be converted to, for example, the acid chloride and amide formation effected optionally in the presence of a suitable non- nucleophilic base and compatible solvent under well-known conditions.

Compounds of general formula (V) are readily available or can be prepared according to the routes in Scheme 6.

Compounds of general formula (V-a) can be prepared from compounds of formula (XIII):

in which R is a suitable alkyl group (such as ethyl or methyl) by reaction with an aqueous solution of an inorganic base such as lithium or potassium hydroxide in a suitable solvent such as methanol or ethanol or 1 ,4-dioxane at a temperature from 0⁰C to the reflux temperature of the solvent, typically at 5O⁰C.

Compounds of general formula (XIII) can be prepared from compounds of formula (XIV):

by reaction with air or oxygen gas in the presence of a suitable base such as potassium tert-butoxide in a solvent such as THF typically at a temperature between 0⁰C and ambient temperature.

Compounds of general formula (V-b) can be prepared from compounds of formula (XV):

by methods similar to those described above for the preparation of compounds (V-a) from (XIII).

Compounds of general formula (XV) can be prepared from compounds of formula (XIII) by reaction with an alkylating agent of formula (XIX):

R^aLG (XIX)

wherein R^a is CrCβ-alkyl and LG is a leaving group such as halogen, tosylate, mesylate. The reaction is performed in the presence of a base such as sodium hydride in a solvent such as THF from O⁰C to the reflux temperature of the solvent.

Compounds of general formula (V-c) can be prepared from compounds of formula (XVI):

Compounds of general formula (XVI) can be prepared from compounds of formula (XIV):

by reaction with an alkylating agent of formula (XIX):

R³LG (XIX)

wherein R^a is CrCValkyl and LG is a leaving group such as halogen, tosylate, mesylate. The reaction is performed in the presence of a base such as potassium tert-butoxide in a solvent such as THF from O⁰C to the reflux temperature of the solvent.

Alternatively, compounds of formula (l-a) may be prepared directly from compounds of formula (II) by quaternisation with a suitably substituted tertiary amine as described above.

Alternatively compounds of formula (l-z) wherein -NR^cR^d is a secondary amine (i.e. one of R^c or R^d is a hydrogen atom) may be prepared from compounds of formula (l-z) wherein -NR^cR^d is a -NH₂ group by reductive alkylation with a suitably substituted aldehyde. The reaction is carried out in the presence of a reducing agent such as sodium cyanoborohydride or sodium borohydride, preferably sodium triacetoxyborohydride in a range of organic solvents, preferably dichloroethane.

Compounds of formula (l-c) can be prepared from compounds of formula (l-b) by reaction with an alkylating agent of formula (XX): R^fLG (XX)

wherein R^f is CrC₆-alkyl and LG is a leaving group such as halogen, tosylate, mesylate. The reaction is performed in the presence of a base such as sodium hydride in a solvent such as THF from O⁰C to the reflux temperature of the solvent.

Alternatively compounds of formula (l-c) can be prepared from compounds of formula (I- y) using methods analogous to those described above for the preparation of compounds (l-a) from (l-z).

Compounds of formula (l-y) can be prepared from compounds of formula (l-x) using the methods described for the preparation of compounds (l-c) from (l-b).

Compounds of formula (l-d) can be prepared from compounds of formula (l-b) by reaction with a reducing agent such as triethylsilane in the presence of an acid such as trifluoroacetic acid in a solvent such as DCM from ambient temperature to the reflux temperature of the solvent.

Alternatively compounds of formula (l-d) can be prepared from compounds of formula (I- w) by methods analogous to those described above for the preparation of (l-a) from (l-z).

Compounds of formula (l-w) can be prepared from compounds of formula (l-x) using methods analogous to thosed described above for the preparation of (l-d) from (l-b).

Alternatively, compounds of formula (I l-a) may be prepared using the route shown in Scheme 5 from compounds of formula (X):

by reaction with bromine in a compatible solvent such as carbon tetrachloride, at a temperature of 0° C to the reflux temperature of the solvent, typically at a temperature between 0 and 25⁰C. Compounds of formula (X) may be prepared from compounds of formula (Xl);

by treatment with a non-nucleophilic base such as 1 ,5-diazabicyclo[4.3.0]non-5-ene (DBN) or 1 ,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in a compatible solvent, for example toluene, at a temperature from 0-60 ⁰C, typically 0-10 ⁰C.

Compounds of formula (III) may be prepared from compounds of formula (X) or from compounds of formula (Xl) by treatment with a non-nucleophilic base such as 1 ,5- diazabicyclo[4.3.0]non-5-ene (DBN) or 1 ,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in a compatible solvent, for example toluene, at a temperature from ambient temperature to the reflux temperature of the solvent, typically 80⁰C.

Compounds of formula (Xl) may be prepared from compounds of formula (XII);

by cyclisation in the presence of iodine and a base such as potassium t-butoxide or potassium carbonate in a compatible solvent such as toluene. The reaction is typically conducted at a temperature of 10-30 ⁰C.

Compounds of formula (XII) may be prepared from compounds of formula (V) using methods analogous to those used in the preparation of compounds of formula (IV) from compounds of formula (V) as described above using allylamine in place of propargylamine.

(l-e)

Scheme 7

Compounds of formula (l-e) can be prepared from compounds of general formula (l-v) by methods analogous to those described above for the preparation of compounds (I- a) from (l-z).

Compounds of formula (l-v) can be prepared from compounds of general formula (XXI):

by reaction with a reducing agent such as lithium aluminium hydride, diisobutyl aluminium hydride, or borane in a range of aprotic solvents such as diethyl ether, or THF or preferably by hydrogenation in the presence of a catalyst such as Raney Nickel in a suitable solvent such as EtOAc or EtOH at a range of temperatures from ambient temperature to the reflux temperature of the solvent to give the primary amine (FT = R^d =H). The primary amine is then reacted with a suitable aldehyde in the presence of a reducing agent such as sodium triacetoxyborohydride in a suitable solvent such as dichloroethane at ambient temperature or alternatively the primary amine can be sequentially reacted with alkylating agents of formula (XXII) and (XXIII):

R^CLG (XXII)

R^dLG (XXIII) wherein LG is a leaving group such as halogen, tosylate, mesylate. The reaction is performed in the presence of a suitable base such as triethylamine in a suitable solvent such as DCM or DMSO.

Compounds of general formula (XXI) can be prepared from compounds of general formula (II) by reaction with a source of cyanide ion such as acetone cyanohydrin or an inorganic cyanide, preferably sodium cyanide, in the presence of a non- nucleophilic base such as tetramethyl guanidine, in a range of solvents, preferably ethanol, at a range of temperatures, preferably between ambient temperature and the reflux temperature of the solvent.

D

(l-f) ^R

Scheme 8

Compounds of Formula (l-f) may be prepared from compounds of Formula (XXV) by employing a similar sequence of reactions as used to prepare compounds of Formula (l-a) from compounds of Formula (III) in Scheme 1 above.

Compounds of formula (XXV) are known in the literature (for example WO9827979) of may be prepared by standard methods such as those shown in Scheme 9:

Scheme 9

Compounds of general formula (XXV-a) may be prepared from compounds of formula (XXVI):

by reaction with 5-methyl-thiazole in the presence of a strong base such as n- butyllithium in a suitable solvent such as THF or diethylether at a temperature of between ambient temperature and -78⁰C, preferably at -78⁰C (for example as described in WO9827979).

The following non-limiting Examples illustrate the invention.

General Experimental Details:

All reactions were carried out under an atmosphere of nitrogen unless specified otherwise.

NMR spectra were obtained on a Varian Unity Inova 400 spectrometer with a 5mm inverse detection triple resonance probe operating at 400MHz or on a Bruker Avance DRX 400 spectrometer with a 5mm inverse detection triple resonance TXI probe operating at 400MHz or on a Bruker Avance DPX 300 spectrometer with a standard 5mm dual frequency probe operating at 300MHz. Shifts are given in ppm relative to tetramethylsilane.

Where products were purified by column chromatography, 'flash silica' refers to silica gel for chromatography, 0.035 to 0.070 mm (220 to 440 mesh) (e.g. Fluka silica gel 60), and an applied pressure of nitrogen up to 10 p.s.i accelerated column elution or use of the CombiFlash ® Companion purification system. Where thin layer chromatography (TLC) has been used, it refers to silica gel TLC using plates, typically 3 x 6 cm silica gel on aluminium foil plates with a fluorescent indicator (254 nm), (e.g. Fluka 60778). All solvents and commercial reagents were used as received. The Liquid Chromatography Mass Spectroscopy (LC/MS) and chiral preparative HPLC systems used:

Method 1

Waters Micromass ZQ with a C18-reverse-phase column (30 x 4.6 mm Phenomenex Luna 3 μm particle size), elution with A: water + 0.1 % formic acid; B: acetonitrile + 0.1 % formic acid. Gradient:

Gradient - Time flow ml_/min %A %B

0.00 2.0 95 5

0.50 2.0 95 5

4.50 2.0 5 95

5.50 2.0 5 95

6.00 2.0 95 5

Detection - MS, ELS, UV (100 μl split to MS with in-line UV detector) MS ionisation method - Electrospray (positive and negative ion)

Method 2 Waters Micromass ZQ2000 with a C18-reverse-phase column (100 x 3.0 mm Higgins Clipeus with 5 μm particle size), elution with A: water + 0.1 % formic acid; B: acetonitrile + 0.1 % formic acid. Gradient:

Gradient - Time flow mL/min %A %B

0.00 1.0 95 5

1.00 1.0 95 5

15.00 1.0 5 95

20.00 1.0 5 95

22.00 1.0 95 5

25.00 1.0 95 5

Detection - MS, ELS, UV (100 μl split to MS with in-line UV detector) MS ionisation method - Electrospray (positive ion)

Method 3 Waters Platform LC Quadrupole mass spectrometer with a C18-reverse-phase column (30 x 4.6 mm Phenomenex Luna 3 μm particle size), elution with A: water + 0.1 % formic acid; B: acetonitrile + 0.1 % formic acid. Gradient:

Gradient - Time flow mLΛnin %A %B

0.00 2.0 95 5

0.50 2.0 95 5

4.50 2.0 5 95

5.50 2.0 5 95

6.00 2.0 95 5

Detection - MS, ELS, UV (200 μl split to MS with in-line UV detector) MS ionisation method - Electrospray (positive and negative ion).

Abbreviations used in the experimental section: AIBN = 2,2'-azobis(2-methylpropionitrile); DCE = 1 ,2-dichloroethane; DCM = dichloromethane; DEA = diethylamine; DIPEA = diisopropylethylamine; DMAP = 4-dimethylaminopyridine; DMF = dimethylformamide; DMSO = dimethyl sulfoxide; EDCI = 1-[3-(Dimethylamino)propyl]-3-ethylcarbodiimide methiodide; EtOAc = ethyl acetate; EtOH = ethanol; IMS = industrial methylated spirit; IPA = 2-propanol; MeOH - methanol; RT = ambient temperature; Rt = retention time; TFA = trifluoroacetic acid; THF = tetrahydrofuran; Sat = saturated; MeCN = acetonitrile; SCX = strong cation exchange chromatography.

Intermediate 1

9-Methyl-9H-xanthene-9-carboxylic acid ethyl ester

Potassium tert-butoxide (3.88 g, 34.60mmol) was added to a degassed solution of ethyl xanthene-9-carboxylate (8.0 g, 31.46mmol) in dry THF (150 ml.) at 0⁰C under a stream of N₂. lodomethane (2.35 ml_, 37.75mmol) was then added to the mixture and the reaction was allowed to warm up to ambient temperature under stirring. After 6 hours the mixture was quenched with sat. NH₄CI solution (20 ml.) and extracted with EtOAc (2x40 ml_). The organic phase was dried (MgSO₄), and concentrated in vacuo. Purification by column chromatography using 0-5% EtOAc/Cyclohexane as eluent gave the title compound as a colourless oil (7.88 g, 93%) LCMS (Method 3): Rt 4.19 min, m/z no [MH]⁺.

Intermediate 2

θ-Methyl-ΘH-xanthene-θ-carboxylic acid

An aqueous solution of LiOH (5N, 65 mL, 325mmol) was added to a solution of 9-Methyl- 9H-xanthene-9-carboxylic acid ethyl ester (3.95 g, 14.7mmol) in IMS (35 mL) and MeOH (35 mL). The mixture was heated at 60°C for 3 hours and then allowed to cool down to ambient temperature. The solvent was evaporated in vacuo and the residue was suspended in H₂O (80 mL). The mixture was acidified to pH1 by addition of 4N HCI (80 mL) and extracted with EtOAc (2x80 mL). The combined organic phase was washed with brine, dried (MgSO₄) and evaporated in vacuo to give the title compound as a white solid (3.52 g, 100%) LCMS (Method 3): Rt 3.52 min, m/z no [MH]⁺.

Intermediate 3

9-Methyl-9H-xanthene-9-carboxylic acid prop-2-ynylamide

HATU (6.13 g, 16.1 mmol) was added to a solution of 9-Methyl-9H-xanthene-9-carboxylic acid (3.52 g, 14.7mmol) in DMF (35 mL) followed by DIPEA (3.82 mL, 22.0mmol) and propargylamine (1.11 mL, 16.1 mmol). The mixture was allowed to stir at ambient temperature for 24 hours then the solvent was evaporated in vacuo and the residue partitioned between H₂O (40 mL) and EtOAc (60 mL). The phases were separated and the aqueous layer was extracted with EtOAc (2x60 mL).The combined organic phase was washed with 10% citric acid, sat. NaHCO₃, brine and dried (MgSO₄). The solvent was evaporated in vacuo and the residue was suspended in H₂O and stirred vigorously for 2 hours. The solid was filtered off, washed with H₂O and dried under reduced pressure at 45⁰C to give the title compound as a white solid (3.54 g, 87%) LCMS (Method 3): Rt 3.64 min, m/z 278 [MH]⁺.

Intermediate 4

5-Methyl-2-(9-methyl-9H-xanthen-9-yl)-oxazole

Trifluoromethanesulfonic acid (1.15 ml_, 10.8mmol) was added dropwise to a solution of 9-Methyl-9H-xanthene-9-carboxylic acid prop-2-ynylamide (3.0 g, 10.8mmol) in 1 ,4- dioxane (30 ml_). The resulting solution was heated at 90 °C for 16 hours. The reaction mixture was cooled and the solvent was removed. The residue was partitioned between DCM (30 ml.) and cone, ammonia solution (20 mL). The phases were separated and the aqueous phase was extracted with DCM (2x40 mL). The combined organic phases were washed with 10% citric acid, sat. NaHCO₃, brine and dried (MgSO₄). Purification by column chromatography using 0-50% diethyl ether/ petroleum ether as eluent gave the title compound as a golden oil that crystallised on standing (2.79 g, 79%) LCMS (Method 3): Rt 4.01 min, m/z 278 [MH]⁺.

Intermediate 5

5-Bromomethyl-2-(9-methyl-9H-xanthen-9-yl)-oxazole

A solution of 5-methyl-2-(9-methyl-9H-xanthen-9-yl)-oxazole (2.79 g, 10.1 mmol) in 1 ,2- dichloroethane (28 ml.) was treated with N-bromo-succinimide (2.53 g, 1 1.4 mmol) followed by 2,2'-azobis(2-methylpropionitrile) (0.45 g, 2.67 mmol). The mixture was heated to 80 ⁰C for 18 h, then allowed to cool to ambient temperature and filtered to remove the white precipitate from the reaction mixture. Sat. NaHCO₃ solution was added and the phases were separated. The organic layer was washed with brine and the combined aqueous layers were extracted with DCM. The combined organic phases were dried (MgSO₄) and concentrated in vacuo to give the crude product as a brown oil. Purification by column chromatography using 0-30% EtOAc/Cyclohexane as eluent gave the title compound (1.5Og, 42%). LCMS (Method 3): Rt 4.16 min, m/z 356, 358 [MH]⁺.

Intermediate 6

Dimethyl-[2-(9-methyl-9H-xanthen-9-yl)-oxazol-5-ylmethyl]-amine

A solution of 5-bromomethyl-2-(9-methyl-9H-xanthen-9-yl)-oxazole (0.45 g, 1.3mmol) in THF (4.5 ml_) was treated with a 2M solution of dimethylamine in THF (1.9 ml_, 3.8mmol). The reaction mixture was stirred at ambient temperature for 16 hours and concentrated under reduced pressure. The residue was partitioned between EtOAc (20 ml_) and 1 N HCI (10 ml_). The organic layer was extracted with 1 N HCI (2x10 ml.) and the combined acqueous layesr were back-extracted with EtOAc. The aqueous layer was made basic with a sat. NaHCO₃ solution and extracted with EtOAc (3x20 ml_). The combined organic layers were separated and washed with brine, dried (MgSO₄) and evaporated in vacuo to give the crude product as a colourless foam. Purification using column chromatography using 0-10% MeOH/DCM as eluent gave the title compound (0.41 g, 10%). LCMS (Method 3): Rt 2.40, 2.45 min, m/z 321 [MH]⁺

Intermediate 7

9-Hydroxy-9H-fluorene-9-carboxylic acid allylamide

Allylamine (1.1 1 mL, 16.1 mmol), DIPEA (3.5 mL, 20.1 mmol) and HOBt (6.77 g, 44.2mmol), were added to a solution of θ-Hydroxy-ΘH-fluorene-θ-carboxylic acid (10.0 g, 44.2mmol) in DMF (100 mL) followed by EDCI (10.2 g, 53.1 mmol). The mixture was allowed to stir at 0⁰C for 10 minutes then allowed to stir at ambient temperature overnight. The solvent was evaporated in vacuo and the residue partitioned between EtOAc (100 mL) and water (80 mL). The phases were separated and the aqueous was extracted with EtOAc (2x100 mL). The combined organic layer was washed with 10% citric acid solution, sat. NaHCO₃ solution, brine, dried (MgSO₄) and evaporated to dryness under reduced pressure. The product was purified by trituration with diethyl ether, filtered off, washed with diethyl ether and dried under vacuum to afford the title compound as a white solid (7.06 g, 60%). LCMS (Method 3): Rt 3.02 min, m/z266 [MH]⁺.

Intermediate 8

9-(5-lodomethyl-4,5-dihydro-oxazol-2-yl)-9H-fluoren-9-ol Potassium tert-butoxide (4.48 g, 40.0mmol) was added to a suspension of 9-Hydroxy- 9H-fluorene-9-carboxylic acid allylamide (7.06 g, 26.6mmol) in toluene (140 mL) under N₂, followed by portionwise addition of I₂. The reaction mixture was stirred at O⁰C for ten minutes, then allowed to warm up to ambient temperature and stirred for 3 hours. The reaction mixture was treated with 20% w/w aqueous solution of Na₂S₂O₃ (140 mL) and stirred vigorously for 15 minutes before filtration. The solid was washed with water, toluene, diethyl ether then dried (MgSO₄) to afford the title compound as a yellow solid (7.32 g, 70%) LCMS (Method 3): Rt 3.19 min, m/z 392 [MH]⁺.

Intermediate 9

9-(5-Methylene-4,5-dihydro-oxazol-2-yl)-9H-fluoren-9-ol

1 ,5-Diazabicyclo[4.3.0]non-5-ene (29.0 ml_, 230mmol) was added to a suspension of 9- (5-lodomethyl-4,5-dihydro-oxazol-2-yl)-9H-fluoren-9-ol (6.12 g, 15.7mmol) in toluene (61 ml_) at 0⁰C under N₂. The reaction mixture was allowed to stir at 0⁰C for 6 hours then was treated with sat. NH₄CI solution (50 mL). The resulting solid was filtered off, washed with water and toluene and dried at 45°C under vacuum to give the title compound contaminated with NH₄CI. The solid was stirred in water (1 OmL) for 5 mins then filtered off, washed with water (~10mL) and dried at 50⁰C under vacuum to give the title compound as a white solid (0.67g, 16%). The two phases of the filtrate were separated and the organic phase was dried (MgSO₄) and evaporated in vacuo to give a second batch of the title compound as a white solid (2.14 g, 52%) LCMS (Method 3): Rt 3.15 min, m/z 264 [MH]⁺.

Intermediate 10

9-(5-Methyl-oxazol-2-yl)-9H-fluoren-9-ol

A suspension of 9-(5-methylene-4,5-dihydro-oxazol-2-yl)-9H-fluoren-9-ol (500mg, 1.9mmol) in toluene (19mL) was treated with 1 ,5-diazabicyclo[4.3.0]non-5-ene (3.52 mL, 28.5mmol) and the resulting pale yellow solution was heated at 80⁰C overnight. After cooling to ambient temperature sat. NH₄CI solution was added and the phases were separated. The organic layer was washed with sat. NH₄CI solution, dried (MgSO₄) and evaporated in vacuo to afford the title compound as a peach coloured solid (399 mg, 80%). LCMS (Method 3): Rt 3.15 min, m/z 264 [MH]⁺. Intermediate 1 1

9-(5-Bromomethyl-oxazol-2-yl)-9H-fluoren-9-ol

A suspension of 9-(5-Methylene-4,5-dihydro-oxazol-2-yl)-9H-fluoren-9-ol (0.38 g, 1.4mmol) in CCI₄ (1.9 ml.) was treated at O⁰C with a solution of Br₂ (89 μl_, 1.7mmol) in CCI₄ (1.9 ml_) dropwise over five minutes. The reaction mixture was allowed to warm up to ambient temperature. After 1.5h 1 mL CHCI₃ was added to aid dissolution and stirring was continued for another 1 h. The solvent was removed under reduced pressure and the residue was partitioned between water (10 mL) and DCM (20 mL). The phases were separated and the aqueous layer was extracted with DCM (2x20 mL). The combined organic phase was washed with sat. NaHCO₃ solution, brine and dried (MgSO₄). Evaporation of the solvent under reduced pressure gave the crude product which was purified by column chromatography using 20-70% EtOAc/Cyclohexane as eluent to give the title compound as a white solid (0.190 g, 38%). LCMS (Method 3): Rt 3.38 min, m/z 342, 344 [MH]⁺.

Alternatively the title compound can be prepared as follows:

A solution of 9-(5-Methyl-oxazol-2-yl)-9H-fluoren-9-ol (396mg, 1.51 mmol) in DCE (15mL) was treated with N-Bromosuccinimide (325mg, 1.81 mmol) followed by AIBN (25mg, 0.15mmol). The mixture was heated to 80⁰C for 1 hour and was then allowed to cool to ambient temperature. The mixture was washed with sat. sodium bicarbonate solution and brine, dried (MgSO₄) and evaporated in vacuo to afford the crude product. The resulting solid was triturated with diethyl ether, filtered off, washed with diethyl ether (x2) and dried at ambient temperature in vacuo overnight to give the title compound (300mg, 58%).

Intermediate 12

9-(5-Dimethylaminomethyl-oxazol-2-yl)-9H-fluoren-9-ol

A solution of dimethylamine in THF (2M, 2.17ml_, 4.34mmol) was treated dropwise over about 5 mins with a cloudy solution of 9-(5-bromomethyl-oxazol-2-yl)-9H-fluoren-9-ol (297mg, 0.87mmol) in THF (3ml_) generating a deep red solution. The reaction mixture was stirred at ambient temperature for 24h. The volatiles were evaporated in vacuo and the residue partitioned between EtOAc/1 N HCI. The organic layer was extracted with 1 N HCI (x2) and the combined aqueous phase was washed with EtOAc, made basic to pH 9 with sat. sodium bicarbonate solution generating a milky suspension that was extracted with EtOAc (x3). The combined organic layer was washed with brine, dried (MgSO₄) and evaporated in vacuoto afford the title compound as an off-white crystalline solid (167mg, 63%). LCMS (Method 3): Rt 1.84, 1.97mins, m/z 307 [MH]⁺.

Intermediate 13

1-(3-Bromo-propylsulfanyl)-4-chloro-benzene A mixture of 4-chloro thiophenol (4 g, 25.2 mmol), 1 ,3-dibromopropane (14.0 ml_, 138.3 mmol) and potassium carbonate (5.73 g, 41.5 mmol) in acetonitrile (40 mL) was heated to 70 ^°C for 16h. The solvent was removed in vacuo and the residue was partitioned between ethyl acetate (50 mL) and water (50 mL). The organic layer was separated, dried (MgSO₄) and evaporated to dryness. Purification by column chromatography using 0-15% DCM/diethyl ether as eluent provided the title compound as colourless oil (2.91 g, 40%). ¹H NMR (300 MHz, CDCI₃): δ 7.32-7.24 (m, 4 H), 3.52 (t, 2 H), 3.05 (t, 2 H), 2.18-2.07 (m, 2 H).

Intermediate 14

1-[2-(2-Bromo-ethoxy)-ethyl]-4-methoxy-benzene

A solution of 2-[2-(4-methoxy-phenyl)-ethoxy]-ethanol (4.4Og, 22.4mmol) in DCM (44ml_) at O⁰C was treated with carbon tetrabromide (1 1.2g, 33.7mmol) followed by a solution of triphenylphosphine (8.82g, 33.7mmol) in DCM (15ml_) dropwise. The reaction mixture was stirred at ambient temperature overnight and then diluted with water. The aqueous phase was extracted with DCM (x2) and the combined organic phase was washed with 10% citric acid solution, sat. sodium bicarbonate solution and brine, dried (Na₂SO₄) and evaporated in vacuo to afford a pale brown oil containing solid material. The solid was triturated with cyclohexane (5OmL) and filtered. The filtrate was concentrated in vacuo and the residue purified by silica gel chromatography eluting with 7.5% EtOAc/cyclohexane to give the title compound as a colourless liquid (4.84g, 83%). LC- MS (Method 1 ): Rt 3.67 mins, no [MH]⁺.

General Procedure A - Formation of quaternary ammonium salts from tertiary amine and alkyl halides

A solution of tertiary amine (0.1 mmol) and alkylating agent (0.2 mmol) was heated at 50⁰C in chloroform (0.3 mL) and acetonitrile (0.2 mL) overnight. The resulting mixture was evaporated to dryness under reduced pressure and the product isolated by silica gel chromatography and/or HPLC.

Example 1

Dimethyl-[2-(9-methyl-9H-xanthen-9-yl)-oxazol-5-ylmethyl]-(3-phenoxy-propyl)- ammonium bromide

A solution of Dimethyl-[2-(9-methyl-9H-xanthen-9-yl)-oxazol-5-ylmethyl]-amine (41 mg, 0.13mmol) and (3-Bromo-propoxy)-benzene (40 μL, 0.26mmol) in chloroform (0.3 mL) and acetonitrile (0.2 mL) was heated at 50 ⁰C for 19h. The RM was concentrated to dryness and purified by column chromatography eluting 0-10% MeOH/DCM to give the title compound as a foam (0.41 g, 10%). LCMS (Method 2): R, 8.33 min, m/z 455 [MH]⁺.

¹H NMR (400 MHz, CDCI₃): δ 7.68 (s, 1 H), 7.30 (dd, 2 H), 7.22 (ddd, 2 H), 7.10 (dd, 2

H), 7.03-6.95 (m, 5 H), 6.80-6.77 (m, 2 H), 5.11 (s, 2 H), 3.77 (t, 2 H), 3.43-3.36 (m, 2 H), 3.25 (s, 6 H), 2.20-2.10 (m, 2 H), 2.08 (s, 3 H).

Example 2

[2-(9-Hydroxy-9H-fluoren-9-yl)-oxazol-5-ylmethyl]-dimethyl-(2-m-tolyloxy-ethyI)- ammonium bromide

The title compound was prepared from 1 -(2-Bromo-ethoxy)-3-methyl-benzene and Intermediate 12 by application of General Procedure A. LCMS (Method 2): Rt 7.35 min, m/z 441 [MH]⁺. ¹H NMR (400 MHz, CD₃OD): δ 7.76 (dt, 2 H), 7.63 (dt, 2 H), 7.49 (s, 1 H), 7.45 (td, 2 H), 7.34 (td, 2 H), 7.20 (t, 1 H), 6.85 (dd, 1 H), 6.79 (s, 1 H), 6.74 (dd, 1 H), 4.81 (s, 2 H), 4.40-4.35 (m, 2 H), 3.73-3.68 (m, 2 H), 3.16 (s, 6 H), 2.33 (s, 3 H).

Example 3

[2-(9-Hydroxy-9H-fluoren-9-yl)-oxazol-5-ylmethyl]-{2-[2-(4-methoxy-phenyl)- ethoxy]-ethyl}-dimethyl-ammonium bromide

The title compound was prepared from Intermediate 14 and Intermediate 12 by application of General Procedure A. LCMS (Method 2): Rt 7.24 min, m/z 485 [MH]⁺. ¹H NMR (400 MHz, CD₃OD): δ 7.78 (dt, 2 H), 7.63 (dt, 2 H), 7.46 (td, 2 H), 7.39-7.31 (m, 3

H), 7.10-7.06 (m, 2 H), 6.77-6.72 (m, 2 H), 4.48 (s, 2 H), 3.79 (m, 2 H), 3.70 (t, 2 H), 3.67 (s, 3 H), 3.43-3.38 (m, 2 H), 2.93 (s, 6 H), 2.80 (t, 2 H).

Example 4

[2-(4-Cyano-benzyloxy)-ethyl]-[2-(9-hydroxy-9H-fluoren-9-yl)-oxazol-5-ylmethyl]- dimethyl-ammonium bromide

The title compound was prepared from 4-(2-Bromo-ethoxymethyl)-benzonitrile (prepared according to WO/2005/104745) and 2 by application of General Procedure A. LCMS (Method 2): Rt 6.85 min, m/z 466 [MH]⁺. ¹H NMR (400 MHz, CD₃OD): δ 7.76-7.69 (m, 4 H), 7.61 (dt, 2 H), 7.52 (d, 2 H), 7.45-7.40 (m, 3 H), 7.32 (td, 2 H), 4.76 (s, 2 H), 4.64 (s, 2 H), 3.95-3.87 (m, 2 H), 3.57-3.52 (m, 2 H), 3.10 (s, 6 H).

Example 5

[3-(4-Chloro-phenylsulfanyl)-propyl]-[2-(9-hydroxy-9H-fluoren-9-yl)-oxazol-5- ylmethyl]-dimethyl-ammonium bromide

The title compound was prepared from Intermediate 12 and Intermediate 13 by application of General Procedure A. LCMS (Method 2): Rt 7.87 min, m/z 491 [MH]⁺. ¹H NMR (400 MHz, CD₃OD): δ 7.76 (d, 2 H), 7.61 (d, 2 H), 7.46-7.41 (m, 3 H), 7.37-7.31 (m, 6 H), 4.65 (s, 2 H), 3.29-3.24 (m, 2 H), 3.01 (s, 6 H), 2.83 (t, 2 H), 2.08-1.98 (m, 2 H).

Example 6

[2-(2,3-Dihydro-benzofuran-5-yl)-ethyl]-[2-(9-hydroxy-9H-fluoren-9-yl)-oxazol-5- ylmethylj-dimethyl-ammonium bromide

The title compound was prepared from 5-(2-Bromo-ethyl)-2,3-dihydro-benzofuran and Intermediate 12 by application of General Procedure A. LCMS (Method 2) Rt 6.69 min, m/z453 [MH]⁺. ¹H NMR (400 MHz, CD₃OD): δ 7.72 (d, 2 H), 7.57-7.52 (m, 2 H), 7.45 (s, 1 H), 7.40 (td, 2 H), 7.24 (td, 2 H), 7.13 (s, 1 H), 6.95-6.90 (m, 1 H), 6.66 (d, 1 H), 4.73 (s, 2 H), 4.51 (t, 2 H), 3.40-3.29 (m, 2 H), 3.15 (t, 2 H), 3.09 (s, 6 H), 3.06-2.99 (m, 2 H).

Example 7

[2-(9-Hydroxy-9H-fluoren-9-yl)-oxazol-5-ylmethyl]-dimethyl-(4-methyI-pent-3-enyl)- ammonium bromide

The title compound was prepared from 5-Bromo-2-methyl-pent-2-ene and Intermediate 12 by application of General Procedure A. LCMS (Method 2): Rt 6.71 min, m/z 389 [MH]⁺. ¹H NMR (400 MHz, CD₃OD): δ 7.76 (d, 2 H), 7.64-7.58 (m, 2 H), 7.47-7.42 (m, 3 H), 7.33 (td, 2 H), 4.93-4.88 (m, 1 H), 4.67 (s, 2 H), 3.16-3.08 (m, 2 H), 3.04 (s, 6 H), 2.51-2.42 (m, 2 H), 1.74 (s, 3 H), 1.66 (s, 3 H).

[2-(9-Hydroxy-9H-fluoren-9-yl)-oxazol-5-ylmethyl]-dimethyl-(3-phenoxy-propyl)- ammonium; bromide

The title compound was prepared from (3-bromo-propoxy)-benzene and Intermediate 12 by application of General Procedure A. LCMS (Method 2): Rt 7.28 min, m/z 441 [M]⁺. ¹H

NMR δ (PPiD)(CH₃ 0H-d4 ): 7.74-7.68 (2 H, m), 7.59 (2 H, dd, J = 7.54, 0.91 Hz), 7.48 (1

H, s), 7.41 -7.36 (2 H, m), 7.31 -7.23 (4 H, m), 6.97-6.87 (3 H, m), 4.72 (2 H, s), 3.98-3.92 (2 H, m), 3.42-3.35 (2 H, m), 3.08 (6 H, s), 2.28-2.18 (2 H, m).

Example 9

P^-Chloro-benzyloxyJ-ethyπ-dimethyl-p^-methyl-ΘH-xanthen-θ-yO-oxazol-δ- ylmethyl]-ammonium; bromide

The title compound was prepared from 1 -(2-bromo-ethoxymethyl)-4-chloro-benzene and Intermediate 6 by application of General Procedure A. LCMS (Method 2): Rt 8.98 min, m/z 489 [M]⁺. ¹H NMR δ (ppm)(CH₃ OH-d₄ ): 7.52 (1 H, s), 7.35-7.25 (6 H, m), 7.14-7.11

(2 H, m), 7.09-7.01 (4 H, m), 4.66 (2 H, s), 4.46 (2 H, s), 3.78-3.73 (2 H, m), 3.40-3.35 (2 H, m), 2.97 (6 H, s), 2.04 (3 H, s).

[2-(4-Chloro-benzyloxy)-ethyl]-[2-(9-hydroxy-9H-fluoren-9-yl)-oxazol-5-ylmethyl]- dimethyl-ammonium; bromide

The title compound was prepared from 1 -(2-bromo-ethoxymethyl)-4-chloro-benzene and Intermediate 12 by application of General Procedure A. LCMS (Method 2): Rt 7.78 min, m/z 475 [M]⁺. ¹H NMR δ (ppm)(CH₃ 0H-d₄ ): 7.76-7.73 (2 H, m), 7.62-7.59 (2 H, m),

7.47-7.41 (3 H, m), 7.38-7.30 (6 H, m), 4.74 (2 H, s), 4.54 (2 H, s), 3.89-3.84 (2 H, m), 3.53-3.49 (2 H, m), 3.09 (6 H, s). BIOLOGICAL EXAMPLES

The inhibitory effects of compounds of the present invention at the M3 muscarinic receptor were determined by the following binding assays:

Muscarinic Receptor Radioligand Binding Assays

Recombinant human M3 receptor was expressed in CHO-K1 cells. Cell membranes were prepared and binding of [3H]-N-methyl scopolamine ([3H]-NMS) and compounds was assessed by a scintillation proximity assay (SPA). The incubation time was 16 hours at ambient temperature in the presence of 1 % (v/v) DMSO. The assay was performed in white 96 well clear-bottomed NBS plates (Corning). Prior to the assay, the CHO cell membranes containing M3 receptor were coated onto SPA WGA (Wheat germ agglutinin) beads (GE Healthcare). Non specific binding was determined in the presence of 1 μM Atropine.

Radioactivity was measured on a Microbeta scintillation counter (PerkinElmer) using a 3H protocol with a 2 minutes per well read time. Compound inhibition of [3H]-NMS binding was determined typically using concentrations in the range 0.03 nM to 1 μM and expressed as percent inhibition relative to the plate specific radioligand binding for the plate. Concentration dependent inhibition of [3H]-NMS binding by compounds was expressed as plC50.

Binding data for Examples of the invention, where tested, are shown in the table below.

M3 plC50 >8.3 "+++"; 8.3 - 7.7 "++", <7.7 For further illustration of the invention, Example 4 had a plC50 of 8.7 and Example 5 had a plC50 of 8.8.

The compounds of the invention may also be tested for appropriate pharmaceutical activity using assays know in the art, such as for example:

Evaluation of potency and duration of action in Isolated Guinea Pig Tracheae

Experiments are carried out at 37⁰C in modified Krebs-Henseleit solution, (114mM NaCI, 15mM NaHCO₃, 1 mM MgSO₄, 1.3mM CaCI₂, 4.7mM KCI, 1 1.5mM glucose and 1.2mM KH₂PO₄ , pH 7.4) gassed with 95% O₂/5% CO₂. lndomethacin is added to a final concentration of 3μM.

Tracheae are removed from adult male Dunkin Hartley Guinea pigs and dissected free of adherent tissue before being cut open longitudinally in a line opposite the muscle. Individual strips of 2-3 cartilage rings in width are cut and suspended using cotton thread in 10mL water-jacketed organ baths and attached to a force transducer ensuring that the tissue is located between two platinum electrodes. Responses are recorded via a MPI OOW/Ackowledge data acquisition system connected to a PC. Tissues are equilibrated for one hour under a resting tone of 1 g and were then subjected to electrical field stimulation at a frequency of 80Hz with a pulse width of 0.1 ms, a unipolar pulse, triggered every 2 minutes. A "voltage-response" curve is generated for each tissue and a submaximal voltage then applied to every piece of tissue according to its own response to voltage. Tissues are washed with Krebs solution and allowed to stabilize under stimulation prior to addition of test compound. Concentration response curves are obtained by a cumulative addition of test compound in half-log increments. Once the response to each addition had reached a plateau the next addition is made. Percentage inhibition of EFS-stimulated contraction is calculated for each concentration of each compound added and dose response curves constructed using Graphpad Prism software and the EC₅₀ calculated for each compound.

Onset time and duration of action studies are performed by adding the previously determined EC₅₀ concentration of compound to EFS contracted tissues and the response allowed to plateau. The time taken to reach 50% of this response is determined to be the onset time. Tissues are then washed free of compound by flushing the tissue bath with fresh Krebs solution and the time taken for the contraction in response to EFS to return to 50% of the response in the presence of compound is measured. This is termed the duration of action. Methacholine Induced Bronchoconstriction in vivo

Male Guinea pigs (Dunkin Hartley), weighing 500-60Og housed in groups of 5 are individually identified. Animals are allowed to acclimatize to their local surroundings for at least 5 days. Throughout this time and study time animals are allowed access to water and food ad libitum.

Guinea pigs are anaesthetized with the inhaled anaesthetic Halothane (5%). Test compound or vehicle (0.25 - 0.50 ml_/kg) is administered intranasally. Animals are placed on a heated pad and allowed to recover before being returned to their home cages.

Up to 72hrs post dosing guinea pigs are terminally anaesthetized with Urethane (250μg/ml_, 2ml_/kg). At the point of surgical anaesthesia, the jugular vein is cannulated with a portex i.v. cannula filled with heparinised phosphate buffered saline (hPBS) (10U/mL) for i.v. administration of methacholine. The trachea is exposed and cannulated with a rigid portex cannula and the oesophagus cannulated transorally with a flexible portex infant feeding tube.

The spontaneously breathing animal is then connected to a pulmonary measurement system (EMMS, Hants, UK) consisting of a flow pneumotach and a pressure transducer. The tracheal cannula is attached to a pneumotach and the oesophageal cannula attached to a pressure transducer.

The oesophageal cannula is positioned to give a baseline resistance of between 0.1 and 0.2cmH20/ml_/s. A 2 minute baseline reading is recorded before i.v. administration of methacholine (up to 30μg/kg, 0.5mL/kg). A 2 minute recording of the induced constriction is taken from the point of i.v. administration. The software calculates a peak resistance and a resistance area under the curve (AUC) during each 2 minute recording period which are used to analyse the bronchoprotective effects of test compounds.

Inhibition of pilocarpine induced salivation by Ln. administered compounds Guinea pigs (450-55Og) supplied by Harlan UK or David Hall, Staffs UK are acclimatised to the in-house facilities for a minimum of three days before use. Guinea pigs are randomly assigned into treatment groups and weighed. Each animal is lightly anaesthetised (4% Halothane) and administered compound or vehicle intranasally (0.5ml_/kg) at up to 24 hours before challenge with pilocarpine. At the test time point, guinea pigs are terminally anaesthetised with urethane (25% solution in H₂O, 1.5g/kg). Once sufficient anaesthesia has developed (absence of toe pinch reflex) each animal has an absorbent pad placed in the mouth for 5 minutes to dry residual saliva, this pad is removed and replaced with a new pre-weighed pad for 5 minutes to establish a reading of baseline saliva production. At the end of this 5 minute period the pad is removed and weighed. A new pre-weighed pad is inserted into the mouth before each animal receives s. c. pilocarpine administered under the skin at the back of the neck (0.6mg/kg @ 2ml_/kg). The pad is removed, weighed and replaced with a new pre-weighed pad every 5 minutes up to 15 minutes.

Saliva production is calculated by subtracting the pre-weighed weight of the pad from each 5 minute period post weighed pad and these numbers added together to produce an accumulation of saliva over 15 minutes. Each 5 minute period could be analysed in addition to the whole 15 minute recording period. Baseline production of saliva is assumed to be constant and multiplied by three to produce a reading for baseline saliva production over 15 minutes.

Inhibition of saliva produced by the compound could be calculated by using the following equation:

(1 -(Test-baseline)/(Veh-baseline))*100.

Claims

A compound of formula (I):

wherein

(i) R¹ is d-Ce-alkyl; and R² is a group -(Z)_p-R⁷, -Z-Y-R⁷, -Z-CO-NR⁹R¹⁰, or -Z- C(O)-R⁷; and R³ is a lone pair or R³ is Ci-C₆-alkyl, in which case the nitrogen to which they are attached is quaternary and carries a positive charge; or

(ii) R¹ and R³ together with the nitrogen to which they are attached form a heterocycloalkyl ring, and R² is a group -(Z)_p-R⁷, -Z-Y-R⁷, -Z-CO-NR⁹R¹⁰, or -Z-C(O)-R⁷, in which case the nitrogen to which they are attached is quaternary and carries a positive charge; or

(iii) R¹ and R² together with the nitrogen to which they are attached form a heterocycloalkyl ring, said ring being substituted by a group -R⁷, -Y-R⁷, -Z-Y- R⁷, -Z-CO-NR⁹R¹⁰ or -Z-C(O)-R⁷; and R³ is a lone pair or R³ is C_rC₆-alkyl, in which case the nitrogen to which they are attached is quaternary and carries a positive charge;

p is 0 or 1 ;

R⁴ and R⁵ are joined together to form a tricyclic ring so that the group

R⁴R⁵R⁶C- represents the group , where R⁶ is - OH, C_rC₆-alkyl, C_rC₆-alkoxy or a hydrogen atom, Q is an oxygen atom, -CH

, -CH₂CH₂- or a bond, R¹⁴ and R¹⁵ are independently selected from halo, C₁- C₆-alkyl and d-Ce-alkoxy, and a and b are, independently, O or 1 ;

A is oxygen or sulfur; X is a CrC₁₂-alkylene, C₂-C₁₂-alkenylene or C₂-C₁₂-alkynylene group;

R⁷ is an Ci-C₆-alkyl, d-C₆-alkenyl, aryl, aryl-fused-cycloalkyl, aryl-fused- heterocycloalkyl, heteroaryl, aryl(d-C₈-alkyl)-, heteroaryl(CrC₈-alkyl)-, cycloalkyl or heterocycloalkyl group;

Z is a CrC^-alkylene, C₂-C₁₆-alkenylene or C₂-C₁₆-alkynylene group;

Y is an oxygen atom, a group -S(O)_n, C(O)O, OC(O), N(R¹²)S(O)₂ or

S(O)₂N(R¹²);

n is O, 1 or 2;

R⁹ and R¹⁰ are independently a hydrogen atom, d-C₆-alkyl, aryl, aryl-fused- heterocycloalkyl, aryl-fused-cycloalkyl, heteroaryl, aryl(d-C₆-alkyl)-, or heteroaryl(d-C6-alkyl)- group; or R⁹ and R¹⁰ together with the nitrogen atom to which they are attached form a heterocyclic ring of 4-8 atoms, optionally containing a further nitrogen or oxygen atom;

R⁸, R¹¹, R¹² and R¹³ are, independently, hydrogen atom or d-C₆-alkyl group;

or a pharmaceutically acceptable salt thereof;

wherein, unless otherwise specified, each occurrence of alkyl, alkenyl, heterocycloalkyl, aryl, aryl-fused-heterocycloalkyl, heteroaryl, cycloalkyl, alkoxy, alkylene, alkenylene, alkynylene or aryl-fused-cycloalkyl may be optionally substituted; and wherein each alkenylene chain may contain, where possible, up to 2 carbon- carbon double bonds and each alkynylene chain may contain, where possible, up to 2 carbon-carbon triple bonds.

2. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R¹ is Ci-C₆-alkyl; R² is -(Z)_p-R⁷ or a group -Z-Y-R⁷; and R³ is d-Ce-alkyl.

3. A compound as claimed in claim 1 or claim 2, or a pharmaceutically acceptable salt thereof, wherein R⁶ is -OH or a methyl group.

4. A compound as claimed in any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein X is C₁-C₂ alkylene.

5. A compound as claimed in any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R⁷ is a group selected from CrC_a-alkenyl, aryl, aryl(CrC₈-alkyl)-, aryl-fused-heterocycloalkyl and heteroaryl; wherein said groups may be optionally substituted with 1 or 2 substituents independently selected from

CrCβ-alkyl, CrC₆-alkoxy and halo.

6. A compound according to claim 1 , selected from:

Dimethyl-[2-(9-methyl-9H-xanthen-9-yl)-oxazol-5-ylmethyl]-(3-phenoxy- propyl)-ammonium;

[2-(9-Hydroxy-9H-fluoren-9-yl)-oxazol-5-ylmethyl]-dimethyl-(2-m- tolyloxy-ethyl)-ammonium;

[2-(9-Hydroxy-9H-fluoren-9-yl)-oxazol-5-ylmethyl]-{2-[2-(4-methoxy- phenyl)-ethoxy]-ethyl}-dimethyl-ammonium; [2-(4-Cyano-benzyloxy)-ethyl]-[2-(9-hydroxy-9H-fluoren-9-yl)-oxazol-5- ylmethyl]-dimethyl-ammonium;

[3-(4-Chloro-phenylsulfanyl)-propyl]-[2-(9-hydroxy-9H-fluoren-9-yl)- oxazol-5-ylmethyl]-dimethyl-ammonium;

[2-(2,3-Dihydro-benzofuran-5-yl)-ethyl]-[2-(9-hydroxy-9H-fluoren-9-yl)- oxazol-5-ylmethyl]-dimethyl-ammonium;

[2-(9-Hydroxy-9H-fluoren-9-yl)-oxazol-5-ylmethyl]-dimethyl-(4-methyl- pent-3-enyl)-ammonium;

[2-(9-Hydroxy-9H-fluoren-9-yl)-oxazol-5-ylmethyl]-dimethyl-(3-phenoxy- propyl)-ammonium; [2-(4-Chloro-benzyloxy)-ethyl]-dimethyl-[2-(9-methyl-9H-xanthen-9-yl)- oxazol-5-ylmethyl]-ammonium; and

[2-(4-Chloro-benzyloxy)-ethyl]-[2-(9-hydroxy-9H-fluoren-9-yl)-oxazol-5- ylmethyl]-dimethyl-ammonium; wherein each ammonium salt comprises a pharmaceutically acceptable counter- ion.

7. A compound as claimed in any of the preceding claims, or a pharmaceutically acceptable salt thereof, for use in therapy.

8. A pharmaceutical composition comprising a compound as claimed in any of claims 1 to 6, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

9. A pharmaceutical composition as claimed in claim 8 in a form suitable for inhalation.

10. Use of a compound as claimed in any of claims 1 to 6, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for use in the treatment of prevention of a disease or condition in which M3 muscarinic receptor activity is implicated.

11. A method of treatment of a disease or condition in which M3 muscarinic receptor activity is implicated comprising administration to a subject in need thereof of a therapeutically effective amount of a compound as claimed in any of claims 1 to 6, or a pharmaceutically acceptable salt thereof.

12. Use as claimed in claim 10 or a method of treatment as claimed in claim 1 1 , wherein the disease or condition is a respiratory-tract disorder.

13. Use as claimed in claim 10 or a method of treatment as claimed in claim 1 1 , wherein the disease or condition is chronic obstructive lung disease, chronic bronchitis, asthma, adult/acute respiratory distress syndrome, chronic respiratory obstruction, bronchial hyperactivity, pulmonary fibrosis, pulmonary emphysema, or allergic rhinitis.