COMPOUNDS

The present invention relates to cyclic amine derivatives, a process for their preparation, pharmaceutical compositions containing them, a process for preparing such pharmaceutical compositions, their use in therapy, and intermediates for use in their preparation.

First-line treatment for a variety of pulmonary disorders including chronic obstructive pulmonary disease (COPD) and asthma is through the use of bronchodilators. Muscarinic- receptor antagonists (anti-cholinergics) are bronchodilators that exert their efficacy by reducing vagal cholinergic tone, the main reversible component of airway constriction in COPD. β-adrenoceptor agonists are also bronchodilators due to their ability to functionally antagonise the bronchoconstrictor responses to a range of mediators, including

acetylcholine.

In addition to improving lung function, these agents improve dyspnoea

(breathlessness), quality of life, exercise tolerance and they reduce exacerbations. A number of clinical studies have demonstrated that combined administration of an anticholinergic and a p ₂ -receptor agonist is more efficacious than either of the individual components (van Noord, J.A., Aumann, J-L., Janssens, E., Smeets, J.J., Verhaert, J., Disse, B., Mueller, A. & Cornelissen, P.J.G., 2005. "Comparison of tiotropium once daily, formoterol twice daily and both combined once daily in patients with COPD", Eur. Respir. J, vol 26, pp 214-222.). A single molecule possessing activities at muscarinic and β ₂ - receptors (MABAs) may provide additional benefits to COPD patients in terms of efficacy and side-effect profile over either single agent. Moreover, a molecule possessing dual activity may also offer benefits in terms of ease-of-use and patient compliance over coadministration of the single therapies. A single agent may also be beneficial from the perspective of formulation compared to two separate compounds, also offering the potential, if combined with another therapeutic, for triple action therapies.

According to a first aspect of the invention we now provide a compound of formula (I)

wherein

the group ArCH(OH)CH ₂ NH- represents a β-adrenoceptor binding group;

R ¹ is selected from a hydrogen atom or an optionally substituted Ci_ ₆ alkyl group wherein one or two of the carbon atoms can be replaced by O, S or N and wherein said alkyl group may be substituted by up to three Ci_ ₃ alkyl chains and two such chains may be joined to form a C ₃ _g cycloalkyl ring, or wherein said alkyl group is substituted by up to two cycloalkyl or cycloalkylalkyl groups comprising up to six carbon atoms;

m = 0, 1, 2 or 3;

n = 1 , 2, 3 or 4; provided that m + n is greater than or equal to 2;

R ² , R ² , R ³ and R ³ are each independently, hydrogen or Ci_ ₆ alkyl;

a = 1-6;

b = 1-6;

R ⁴ is selected from hydrogen, -OR ¹⁰ , halogen, -CF ₃ , -NR ⁸ R ⁹ , -NHS0 ₂ R ^u , -C(0)NR ⁸ R ⁹ or -CH ₂ OR ¹⁰ ;

G represents a group selected from:

(ι) -ΐ θ-;

(ii) -L ¹ -;

(iii) -L ¹ -C(0)-N(R ⁸ )-;

(iv) -L ¹ -S(=0) ₂ -N(R ⁸ )-;

(v) -0-;

(vi) a bond

wherein L ¹ is an aryl or heteroaryl group;

T is selected from a hydrogen atom or an aryl or heteroaryl group; R ⁸ and R ⁹ are independently hydrogen or Ci_ ₆ alkyl, or R ⁸ and R ⁹ may be joined together to form a heterocyclic ring comprising up to 9 ring atoms and optionally containing a further heteroatom selected from O, N or S;

R ¹⁰ and R ¹⁰ independently represent hydrogen, Ci_ ₆ alkyl or C3-6 cycloalkyl, wherein alkyl and cycloalkyl may be optionally substituted by up to three substituents independently selected from halogen, hydroxyl and Ci_ ₆ alkoxy;

R ¹¹ represents Ci_ ₆ alkyl or C3-6 cycloalkyl, wherein the Ci_ ₆ alkyl and C3-6 cycloalkyl may be optionally substituted by up to three substituents independently selected from halogen, hydroxyl or Ci_ ₆ alkoxy;

and pharmaceutically acceptable salts thereof.

By "β-adrenoceptor binding group" we mean a group capable of binding a β- adrenergic receptor; such as for example as outlined in the review article "β-adrenergic receptors in Comprehensive Medicinal Chemistry, 1990, B.E. Main, pi 87 (Pergamon Press). Such groups are also known from, for example in WO/2005092841 ,

US/20050215542, WO/2005070872, WO/2006023460, WO/2006051373,

WO/2006087315, WO/2006032627.

Example of the group Ar in such convenient β-adrenoceptor binding groups include

M ¹ is S, C(O), NA ⁵ , CA ⁶ A ⁷ , CH ₂ CH ₂ , CH=CH, CH ₂ 0 or OCH ₂ ;

M ² is S, C(O), NA ⁵ , CA ⁶ A ⁷ , CH ₂ CH ₂ , CH=CH, CH ₂ 0 or OCH ₂ ; A ¹ , A ² , A ³ and A ⁴ are, independently, hydrogen, halogen, trifluoromethyl, cyano, carboxy, hydroxy, nitro, S(0) ₂ A ⁸ , NA ⁹ S(0) ₂ A ¹⁰ , C(0)NA ⁿ A ¹² , NA ¹³ C(0)A ¹⁴ , Ci_ ₆ alkyl,

Ci_6 alkoxy, C(0)(Ci_ ₆ alkyl) or C(0)OCi_ ₆ alkyl;

A ³ can also be CH ₂ OH, NHCHO, NHC(0)OCi_ ₆ alkyl, NHC(0)Ci_ ₆ alkyl,

NHS(0) ₂ NA ¹⁵ A ¹⁶ or NHS0 ₂ A ¹⁷ ;

A ^1A and A ^2A are, independently, hydrogen, halogen, trifluoromethyl, cyano, carboxy, hydroxy, nitro, S(0) ₂ A ⁸ , NA ⁹ S(0) ₂ A ¹⁰ , C(0)NA ⁿ A ¹² , NA ¹³ C(0)A ¹⁴ , Ci_ ₆ alkyl,

Ci_6 alkoxy, C(0)(Ci_ ₆ alkyl) or C(0)OCi_ ₆ alkyl;

A ⁵ , A ⁶ , A ⁷ , A ⁹ , A ¹¹ , A ¹² , A ¹³ , A ¹⁴ , are independently, hydrogen, Ci_ ₆ alkyl;

A ¹⁵ or A ¹⁶ are independently, hydrogen, Ci_ ₆ alkyl or C ₃ _ ₆ cycloalkyl;

A ⁸ , A ¹⁰ and A ¹⁷ are, independently, Ci_ ₆ alkyl or C ₃ _ ₆ cycloalkyl;

and * defines the attachment point of Ar to the rest of the molecule

Convenientl the Ar group is selected from:

M ¹ is S, CH=CH, CH ₂ 0 or OCH ₂ ;

M ² is S, CH=CH, CH ₂ 0 or OCH ₂ ;

A ¹ , A ² , and A ⁴ are, independently, hydrogen, halogen, Ci_ ₆ alkyl, Ci_ ₆ alkoxy;

A ³ can be CH ₂ OH, NHCHO, NHS(0) ₂ NA ¹⁵ A ¹⁶ or NHS(0) ₂ A ¹⁷ ;

A ^1A and A ^2A are, independently, hydrogen, halogen, trifluoromethyl, cyano, carboxy, hydroxy, nitro, S(0) ₂ A ⁸ , NA ⁹ S(0) ₂ A ¹⁰ , C(0)NA ⁿ A ¹² , NA ¹³ C(0)A ¹⁴ , Ci_ ₆ alkyl,

Ci_6 alkoxy, C(0)(Ci_6 alkyl) or C(0)OCi_ ₆ alkyl;

A ¹⁵ or A ¹⁶ are independently selected from hydrogen, Ci_ ₆ alkyl or C ₃ _ ₆ cycloalkyl;

A ¹⁷ is Ci_6 alkyl or C ₃ _ ₆ cycloalkyl;

Examples of Ci_ ₆ alkyl include Ci_ ₄ alkyl and Ci_ ₂ alkyl.

Examples of C ₃ _ ₆ cycloalkyl include C ₃ _5 cycloalkyl and C ₃ _ ₄ cycloalkyl. Examples of Ci_ ₆ alkoxy include Ci_ ₄ alkoxy and Ci_ ₂ alkoxy.

Convenientl the Ar group is selected from:

wherein A ¹ , A ² , A ⁴ are all hydrogen, A ³ is CH ₂ OH or NHCHO, A ^1A and A ^2A are hydrogen, M ¹ is S, CH=CH, or OCH ₂ ; M ² is S, CH=CH, or OCH ₂ .

Conveniently the Ar group is selected from:

Most conveniently the Ar group is selected from:

The group R ¹

Conveniently R ¹ is a hydrogen atom or a Ci_ ₆ alkyl group; more conveniently R ¹ is a hydrogen atom, methyl, ethyl or isopropyl group;

The integers m and n

Conveniently m and n are both 1 ;

Conveniently m and n are both 2.

The group T

The group T may be an hydrogen atom, an aryl or a heteroaryl group.

Conveniently T is an aryl group; more conveniently T is phenyl. Conveniently T is a heteroaryl group; more conveniently T is a 5-memebered heteroaryl group such as a thienyl or thiazoloyl group.

Most conveniently T is phenyl.

The group -rC(R ² )(R ^2, )l _i ,-G-rC(R ² )(R ^2, )lh-

Conveniently G is a group (i) or (ii) as described above, L ¹ is a phenyl or monocyclic heteroaryl group such as thienyl, a is 1 or 2, b, is 1, 2 or 3;

Conveniently G is a group (iii) or (iv) as described above, L ¹ is a phenyl or monocyclic heteroaryl group such as thienyl, R8 is H or Ci_ ₃ alkyl, a is 1 or 2, b, is 1, 2 or 3

Conveniently G is -0-, a and b are each 2-6 and a + b is less than or equal to 10;

Conveniently G is a bond and a + b is less than or equal to 10.

The groups R ² , R ² ', R ³ and R ³ '

The groups R ² , R ² ', R ³ and R ³ ' are each hydrogen or Ci_6alkyl;

Conveniently the groups R ² , R ² ', R ³ and R ³ ' are each hydrogen or methyl; more conveniently the groups are each hydrogen.

The group R ⁴

Conveniently R ⁴ is a group -OR ¹⁰ ; more conveniently R ⁴ is -OH.

Each exemplified compound of the invention represents a particular and independent aspect of the invention.

It will be understood that certain compounds of the present invention may exist in solvated, for example hydrated, as well as unsolvated forms. It is to be understood that the present invention encompasses all such solvated forms. Certain compounds of formula (I) are capable of existing in stereoisomeric forms. It will be understood that the invention encompasses all geometric and optical isomers of the compounds of formula (I) and mixtures thereof including racemates. Tautomers and mixtures thereof also form an aspect of the present invention.

It is also to be understood that the present invention encompasses the replacement of any quaternary carbon by a silicon atom for example as disclosed in "Silicon switches of Marketed Drugs: Mini-reviews in Med. Chem.", 2006, 6, 1169-1177.

In the context of the present invention 'aryl' means an aromatic carbocyclic ring system containing one or more rings. Exemplary aryl rings are phenyl and naphthyl.

In the context of the present specification the term 'heteroaryl' denotes a group or part of a group comprising an optionally substituted aromatic monocyclic or multicyclic organic moiety of from 5 to 14 ring atoms, preferably from 5 to 10 ring atoms, in which up to four 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.

Unless otherwise stated, in the context of the present specification alkyl groups and moieties may be straight or branched chain and include, for example, methyl, ethyl, n- propyl, iso-propyl, n-butyl, iso-butyl or fert-butvl. 'C _1-8 alkyl' means a straight or branched chain alkyl group having from one to eight carbon atoms; similarly 'C _1-6 alkyl' means a straight or branched alkyl chain having from one to six carbon atoms. Cycloalkyl groups are monocyclic, for example cyclopentyl or cyclohexyl. 'C ₃ _8 cycloalkyl' means a cycloalkyl group having from three to eight carbon atoms'.

The cyclic groups referred to above, namely, aryl, heteroaryl and cycloalkyl, are unsubstituted or substituted by one or more of the same or different substituent groups. Examples of specific optional substituents include -CI, -F, -CH ₃ , -OCH ₃ , -OH, -CN, -COOCH ₃ , -CONH ₂ , -SO ₂ NH ₂ , -S0 ₂ N(CH ₃ ) ₂ . 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., -OCH ₃ ), alkoxycarbonyl (e.g. -COOCH ₃ ), alkylamino (e.g. -NHCH ₃ ), alkylsulfinyl (e.g. -SOCH ₃ ), alkylsulfonyl (e.g. -S0 ₂ CH ₃ ), alkylthio (e.g. -SCH ₃ ), -NH ₂ , aminoacyl (e.g. -CON(CH ₃ ) ₂ ), aminoalkyl (e.g. -CH ₂ NH ₂ ), cyano, dialkylamino (e.g. -N(CH ₃ ) ₂ ), halo, haloalkoxy (e.g.

-OCF ₃ or -OCHF ₂ ), haloalkyl (e.g. -CF ₃ ), alkyl (e.g. -CH ₃ or -CH ₂ CH ₃ ), -OH, -CHO,

-COOH, -NO ₂ , aminoacyl (e.g. -CONH ₂ , -CONHCH ₃ ), aminosulfonyl (e.g. -S0 ₂ NH ₂ , - S0 ₂ NHCH ₃ ), acylamino (e.g. -NHCOCH ₃ ) and sulfonylamino (e.g. -NHS0 ₂ CH ₃ ); and

(b) a second class of substituent includes arylalkyl (e.g. -CH ₂ Ph or -CH ₂ -CH ₂ -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).

Alkyl, alkoxy and alkenyl groups may be optionally substituted. Suitable optional substituent groups for alkyl and alkenyl include alkoxy (e.g., -OCH ₃ ), alkylamino (e.g. -

NHCH ₃ ), alkylsulfinyl (e.g. -SOCH ₃ ), alkylsulfonyl (e.g. -S0 ₂ CH ₃ ), alkylthio (e.g. -SCH ₃ ),

-NH ₂ , aminoalkyl (e.g. -CH ₂ NH ₂ ), arylalkyl (e.g. -CH ₂ Ph or -CH ₂ -CH ₂ -Ph), cyano, dialkylamino (e.g. -N(CH ₃ ) ₂ ), halo, haloalkoxy (e.g. -OCF ₃ or -OCHF ₂ ), haloalkyl (e.g.

-CF ), -OH, -CHO, and -N0 ₂ . Suitable optional substituent groups for alkoxy include alkylamino (e.g. -NHCH ₃ ), alkylsulfinyl (e.g. -SOCH ₃ ), alkylsulfonyl (e.g. -S0 ₂ CH ₃ ), alkylthio (e.g. -SCH ₃ ), -NH ₂ , aminoalkyl (e.g. -CH ₂ NH ₂ ), arylalkyl (e.g. -CH ₂ Ph or

-CH ₂ -CH ₂ -Ph), cyano, dialkylamino (e.g. -N(CH ₃ ) ₂ ), halo, haloalkoxy (e.g. -OCF ₃ or

-OCHF ₂ ), haloalkyl (e.g. -CF ₃ ), alkyl (e.g. -CH ₃ or -CH ₂ CH ₃ ), -OH, -CHO, and -N0 ₂ .

Alkylene or alkenylene groups may be optionally substituted. Suitable optional substituent groups include alkoxy (e.g., -OCH ₃ ), alkylamino (e.g. -NHCH ₃ ), alkylsulfinyl

(e.g. -SOCH ₃ ), alkylsulfonyl (e.g. -S0 ₂ CH ₃ ), alkylthio (e.g. -SCH ₃ ), -NH ₂ , aminoalkyl

(e.g. -CH ₂ NH ₂ ), arylalkyl (e.g. -CH ₂ Ph or -CH ₂ -CH ₂ -Ph), cyano, dialkylamino (e.g.

-N(CH ₃ ) ₂ ), halo, haloalkoxy (e.g. -OCF ₃ or -OCHF ₂ ), haloalkyl (e.g. -CF ₃ ), alkyl (e.g. -

CH ₃ or -CH ₂ CH ₃ ), -OH, -CHO, and -N0 ₂ .

In the context of the present specification, where it is stated that a group may be optionally substituted with up to three substituents, the group may be unsubstituted or substituted; when substituted the group will generally be substituted with one, two or three substituents. In general, a hydroxyl moiety will not be attached to a carbon atom which is adjacent to a nitrogen atom, another oxygen atom or a sulfur atom.

The invention further provides a process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined above:

Compounds of the invention may be prepared according to the routes illustrated in

Schemes 1-6.

Compounds of formulae (7), (8) and (9) may be prepared from compounds of formula (10) by Friedel-Crafts reaction of a suitably substituted phenyl derivative in the presence of a suitable catalyst such as triflic acid or an aluminium trihalide in a compatible solvent such as nitrobenzene.

Compounds of formula (9) may be coupled with a suitable β-binding moiety by conversion of the functionality present to either (a) a leaving group such as halide (4) or (b) an aldehyde (3), using standard methods for functional group manipulation well known to those skilled in the art and further illustrated in the Examples herein.

Compounds of formula (4) may be coupled to compounds of formula (2) through reaction with a suitable amine, such amines being generally known in the art.

Compounds of formula (3) may also be converted to compounds of formula (2) through reductive amination with similar suitably protected amines and a suitable reducing agent, typically a borohydride.

Compounds of formulae (7) and (8) may be transformed to (3) and (4) by conversion to intermediates suitable for use in etherification reactions with a suitable alcohol partner. Such transformations (reduction, halogenation) may be performed using standard methods.

Compounds of formula (2) may be deprotected to give compounds of formula (1) using standard methods of deprotection well known to those skilled in the art, additionally described in, for example, "Greene's Protective groups in Organic Synthesis, 4 ^th Ed" by P.G.M. Wutts & T.W. Greene, Wiley-Interscience, and illustrated in the Examples below.

Using similar sequences of reactions, compounds of formula (6) may be converted to compounds of formula (11), Scheme 2.

Where, T = H, Ar, heteroAr; Y = H, Boc, alkyl, alkoxy; Rc m and n = 1-2; q and r = 0-2 Scheme 2

Where W = O, CH ₂ ; q and r = 0-5; T = H, Ar, heteroAr; Y = H, Boc, alkyl, alkoxy;

P = H, Bn; m and n = 1-2

Where Z = C=0, S0 ₂ ; U = Ar, heteroAr, q and r = 0-2; T = H, Ar, heteroAr; Y = H, Boc, alkyl, alkoxy;

P = H, Bn; m and n = 1-2; R = H, alkyl

Compounds of formula (13) which contain an amide or a sulfonamide may be prepared according to the method outlined in Scheme 3.

Compounds of formula (20) may be prepared from compounds of formula (6) by reaction with a metal azide, preferably sodium azide, followed by reduction to the amine and coupling with a suitable sulfonylating or acylating agent using standard conditions. Alternatively the amine functionality may be introduced by reaction of compounds of formula (6) with benzylamine followed by liberation of the primary amine by de- benzylation and coupling with the appropriate sulfonyl halide or acylating group as above. Subsequent functional group manipulation using standard methods gives aldehydes of formula (17) or halides of formula (15) which may then be coupled to a suitably protected β-binding group using standard methods as described above.

Scheme 4

Where, Y = H, Boc, alkyl, alkoxy; Rc = OH, F, OBn; m and n = 1 -2; q = 0-2.

Scheme 5

Where, Y = H, Boc, alkyl, alkoxy; Rc = OH, F, OBn; m and n = 1-2; q = 0-2.

Scheme 6

Where, Y = H, Boc, alkyl alkoxy; T = HeteroAr; m and n =1-2.

Compounds of Formula (I) wherein T is a hydrogen atom may be prepared according to methods outlined in Schemes 4 and 5. Boronate esters of formula (23) are known in the art, and may be coupled with suitably substituted aryl halides using a suitable palladium catalyst, for example Pd(PPh ₃ ) ₄ , to give compounds of formula (22). Functional group manipulation using standard methods and reduction of the double bond by hydrogenation lead to intermediates of formula (6), which can be converted to compounds of formula (1) using methods outlined in Scheme 1 above.

Alternatively, intermediates of formula (8) may be prepared from compounds of formula (24) by conversion of (24) to the organozinc reagen, followed by coupling with a suitably substituted aryl halide in the presence of a copper (I) salt such as copper (I) iodide, and a palladium catalyst, such as Pd(dppf) ₂ Cl ₂ . Compounds of formula (8) can be converted to compounds of formula (1) according to the methods described in Scheme 1 above.

Intermediates of formula (10) may generally be prepared from suitably protected ketones of formula (25) by reaction with a suitable nucleophile, such as a Grignard reagent or other organometallic species.

It will be appreciated by those skilled in the art that in the processes of the present invention certain functional groups such as hydroxyl or amino groups in the reagents may need to be protected by protecting groups. Thus, the preparation of the compounds of formula (I) may involve, at an appropriate stage, the addition or removal of one or more protecting groups.

The protection and deprotection of functional groups is described in 'Protective Groups in Organic Chemistry', edited by J.W.F. McOmie, Plenum Press (1973) and 'Protective Groups in Organic Synthesis', 3 ^rd edition, T.W. Greene and P.G.M. Wuts, Wiley-Interscience (1999).

Compounds of formula (I) can be converted into further compounds of formula (I) using standard procedures.

The compounds of formula I have activity as pharmaceuticals, in particular as dual adrenergic β receptor agonists and anticholinergic agents including muscarinic receptor (Ml, M2, and M3) antagonists, in particular M3 antagonists. Diseases and conditions which may be treated with the compounds of formula (I) and their pharmaceutically acceptable salts include:

1. respiratory tract: obstructive diseases of the airways including: asthma, including bronchial, allergic, intrinsic, extrinsic, exercise-induced, drug-induced (including aspirin and NSAID-induced) and dust-induced asthma, both intermittent and persistent and of all severities, and other causes of airway hyper-responsiveness; chronic obstructive pulmonary disease (COPD); bronchitis, including infectious and eosinophilic bronchitis; emphysema; bronchiectasis; cystic fibrosis; sarcoidosis; farmer's lung and related diseases;

hypersensitivity pneumonitis; lung fibrosis, including cryptogenic fibrosing alveolitis, idiopathic interstitial pneumonias, fibrosis complicating anti-neoplastic therapy and chronic infection, including tuberculosis and aspergillosis and other fungal infections; complications of lung transplantation; vasculitic and thrombotic disorders of the lung vasculature, and pulmonary hypertension; antitussive activity including treatment of chronic cough associated with inflammatory and secretory conditions of the airways, and iatrogenic cough; acute and chronic rhinitis including rhinitis medicamentosa, and vasomotor rhinitis; perennial and seasonal allergic rhinitis including rhinitis nervosa (hay fever); nasal polyposis; acute viral infection including the common cold, and infection due to respiratory syncytial virus, influenza, coronavirus (including SARS) or adenovirus; or eosinophilic esophagitis;

2. bone and joints: arthritides associated with or including

osteoarthritis/osteoarthrosis, both primary and secondary to, for example, congenital hip dysplasia; cervical and lumbar spondylitis, and low back and neck pain; osteoporosis; rheumatoid arthritis and Still's disease; seronegative spondyloarthropathies including ankylosing spondylitis, psoriatic arthritis, reactive arthritis and undifferentiated

spondarthropathy; septic arthritis and other infection-related arthopathies and bone disorders such as tuberculosis, including Potts' disease and Poncet's syndrome; acute and chronic crystal-induced synovitis including urate gout, calcium pyrophosphate deposition disease, and calcium apatite related tendon, bursal and synovial inflammation; Behcet's disease; primary and secondary Sjogren's syndrome; systemic sclerosis and limited scleroderma; systemic lupus erythematosus, mixed connective tissue disease, and undifferentiated connective tissue disease; inflammatory myopathies including

dermatomyositits and polymyositis; polymalgia rheumatica; juvenile arthritis including idiopathic inflammatory arthritides of whatever joint distribution and associated syndromes, and rheumatic fever and its systemic complications; vasculitides including giant cell arteritis, Takayasu's arteritis, Churg-Strauss syndrome, polyarteritis nodosa, microscopic polyarteritis, and vasculitides associated with viral infection, hypersensitivity reactions, cryoglobulins, and paraproteins; low back pain; Familial Mediterranean fever, Muckle-Wells syndrome, and Familial Hibernian Fever, Kikuchi disease; drug-induced arthalgias, tendonititides, and myopathies;

3. pain and connective tissue remodelling of musculoskeletal disorders due to injury [for example sports injury] or disease: arthitides (for example rheumatoid arthritis, osteoarthritis, gout or crystal arthropathy), other joint disease (such as intervertebral disc degeneration or temporomandibular joint degeneration), bone remodelling disease (such as osteoporosis, Paget's disease or osteonecrosis), polychondritits, scleroderma, mixed connective tissue disorder, spondyloarthropathies or periodontal disease (such as periodontitis);

4. skin: psoriasis, atopic dermatitis, contact dermatitis or other eczematous

dermatoses, and delayed-type hypersensitivity reactions; phyto- and photodermatitis;

seborrhoeic dermatitis, dermatitis herpetiformis, lichen planus, lichen sclerosus et atrophica, pyoderma gangrenosum, skin sarcoid, discoid lupus erythematosus, pemphigus, pemphigoid, epidermolysis bullosa, urticaria, angioedema, vasculitides, toxic erythemas, cutaneous eosinophilias, alopecia areata, male-pattern baldness, Sweet's syndrome, Weber- Christian syndrome, erythema multiforme; cellulitis, both infective and non-infective; panniculitis; cutaneous lymphomas, non-melanoma skin cancer and other dysplastic lesions; drug-induced disorders including fixed drug eruptions;

5. eyes: blepharitis; conjunctivitis, including perennial and vernal allergic

conjunctivitis; iritis; anterior and posterior uveitis; choroiditis; autoimmune; degenerative or inflammatory disorders affecting the retina; ophthalmitis including sympathetic ophthalmitis; sarcoidosis; infections including viral , fungal, and bacterial;

6. gastrointestinal tract: glossitis, gingivitis, periodontitis; oesophagitis, including reflux; eosinophilic gastro-enteritis, mastocytosis, Crohn's disease, colitis including ulcerative colitis, proctitis, pruritis ani; coeliac disease, irritable bowel syndrome, and food-related allergies which may have effects remote from the gut (for example migraine, rhinitis or eczema);

7. abdominal: hepatitis, including autoimmune, alcoholic and viral; fibrosis and cirrhosis of the liver; cholecystitis; pancreatitis, both acute and chronic;

8. genitourinary: nephritis including interstitial and glomerulonephritis; nephrotic syndrome; cystitis including acute and chronic (interstitial) cystitis and Hunner's ulcer; acute and chronic urethritis, prostatitis, epididymitis, oophoritis and salpingitis; vulvovaginitis; Peyronie's disease; erectile dysfunction (both male and female);

9. allograft rejection: acute and chronic following, for example, transplantation of kidney, heart, liver, lung, bone marrow, skin or cornea or following blood transfusion; or chronic graft versus host disease;

10. CNS: Alzheimer's disease and other dementing disorders including CJD and nvCJD; amyloidosis; multiple sclerosis and other demyelinating syndromes; cerebral atherosclerosis and vasculitis; temporal arteritis; myasthenia gravis; acute and chronic pain (acute, intermittent or persistent, whether of central or peripheral origin) including visceral pain, headache, migraine, trigeminal neuralgia, atypical facial pain, joint and bone pain, pain arising from cancer and tumor invasion, neuropathic pain syndromes including diabetic, post-herpetic, and HIV-associated neuropathies; neurosarcoidosis; central and peripheral nervous system complications of malignant, infectious or autoimmune processes;

11. other auto-immune and allergic disorders including Hashimoto's thyroiditis, Graves' disease, Addison's disease, diabetes mellitus, idiopathic thrombocytopaenic purpura, eosinophilic fasciitis, hyper-IgE syndrome, antiphospholipid syndrome;

12. other disorders with an inflammatory or immunological component; including acquired immune deficiency syndrome (AIDS), leprosy, Sezary syndrome, and

paraneoplastic syndromes;

13. cardiovascular: atherosclerosis, affecting the coronary and peripheral circulation; pericarditis; myocarditis , inflammatory and auto-immune cardiomyopathies including myocardial sarcoid; ischaemic reperfusion injuries; endocarditis, valvulitis, and aortitis including infective (for example syphilitic); vasculitides; disorders of the proximal and peripheral veins including phlebitis and thrombosis, including deep vein thrombosis and complications of varicose veins;

14. oncology: treatment of common cancers including prostate, breast, lung, ovarian, pancreatic, bowel and colon, stomach, skin and brain tumors and malignancies affecting the bone marrow (including the leukaemias) and lymphoproliferative systems, such as Hodgkin's and non-Hodgkin's lymphoma; including the prevention and treatment of metastatic disease and tumour recurrences, and paraneoplastic syndromes; and,

15. gastrointestinal tract: Coeliac disease, proctitis, eosinopilic gastro-enteritis, mastocytosis, Crohn's disease, ulcerative colitis, microscopic colitis, indeterminant colitis, irritable bowel disorder, irritable bowel syndrome, non-inflammatory diarrhea, food- related allergies which have effects remote from the gut, e.g., migraine, rhinitis and eczema.

Thus, the present invention provides a compound of formula (I) or a

pharmaceutically-acceptable salt thereof as hereinbefore defined for use in therapy. In a further aspect, the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined in the manufacture of a medicament for use in therapy.

In the context of the present specification, the term "therapy" also includes "prophylaxis" unless there are specific indications to the contrary. The terms "therapeutic" and "therapeutically" should be construed accordingly.

Prophylaxis is expected to be particularly relevant to the treatment of persons who have suffered a previous episode of, or are otherwise considered to be at increased risk of, the disease or condition in question. Persons at risk of developing a particular disease or condition generally include those having a family history of the disease or condition, or those who have been identified by genetic testing or screening to be particularly susceptible to developing the disease or condition.

The invention still further provides a method of treating, or reducing the risk of, an inflammatory disease or condition (including a reversible obstructive airways disease or condition) which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined.

In particular, the compounds of this invention may be used in the treatment of adult respiratory distress syndrome (ARDS), pulmonary emphysema, bronchitis, bronchiectasis, chronic obstructive pulmonary disease (COPD), asthma and rhinitis.

For the above-mentioned therapeutic uses the dosage administered will, of course, vary with the compound employed, the mode of administration, the treatment desired and the disorder indicated. For example, the daily dosage of the compound of the invention, if inhaled, may be in the range from 0.05 micrograms per kilogram body weight ^g/kg) to 100 micrograms per kilogram body weight ^g/kg). Alternatively, if the compound is administered orally, then the daily dosage of the compound of the invention may be in the range from 0.01 micrograms per kilogram body weight ^g/kg) to 100 milligrams per kilogram body weight (mg/kg).

The compounds of formula (I) and pharmaceutically acceptable salts thereof may be used on their own but will generally be administered in the form of a pharmaceutical composition in which the formula (I) compound/salt (active ingredient) is in association with a pharmaceutically acceptable adjuvant, diluent or carrier. Conventional procedures for the selection and preparation of suitable pharmaceutical formulations are described in, for example, "Pharmaceuticals - The Science of Dosage Form Designs", M. E. Aulton, Churchill Livingstone, 1988.

Depending on the mode of administration, the pharmaceutical composition will preferably comprise from 0.05 to 99 %w (per cent by weight), more preferably from 0.05 to 80 %w, still more preferably from 0.10 to 70 %w, and even more preferably from 0.10 to 50 %w, of active ingredient, all percentages by weight being based on total composition.

The present invention also provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined, in association with a pharmaceutically acceptable adjuvant, diluent or carrier.

The invention further provides a process for the preparation of a pharmaceutical composition of the invention which comprises mixing a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined with a pharmaceutically acceptable adjuvant, diluent or carrier.

The pharmaceutical compositions may be administered topically (e.g. to the skin or to the lung and/or airways) in the form, e.g., of creams, solutions, suspensions,

Hydro fluoroalkane (HFA) aerosols and dry powder formulations, for example,

formulations in the inhaler device known as the Turbuhaler ^® ; or systemically, e.g. by oral administration in the form of tablets, capsules, syrups, powders or granules; or by parenteral administration in the form of solutions or suspensions; or by subcutaneous administration; or by rectal administration in the form of suppositories; or transdermally.

Dry powder formulations and pressurized HFA aerosols of the compounds of the invention may be administered by oral or nasal inhalation. For inhalation, the compound is desirably finely divided. The finely divided compound preferably has a mass median diameter of less than 10 μιη, and may be suspended in a propellant mixture with the assistance of a dispersant, such as a C8-C20 fatty acid or salt thereof, (for example, oleic acid), a bile salt, a phospholipid, an alkyl saccharide, a perfluorinated or polyethoxylated surfactant, or other pharmaceutically acceptable dispersant.

The compounds of the invention may also be administered by means of a dry powder inhaler. The inhaler may be a single or a multi dose inhaler, and may be a breath actuated dry powder inhaler. One possibility is to mix the finely divided compound of the invention with a carrier substance, for example, a mono-, di- or polysaccharide, a sugar alcohol, or another polyol. Suitable carriers are sugars, for example, lactose, glucose, raffinose, melezitose, lactitol, maltitol, trehalose, sucrose, mannitol; and starch. Alternatively the finely divided compound may be coated by another substance. The powder mixture may also be dispensed into hard gelatine capsules, each containing the desired dose of the active compound.

Another possibility is to process the finely divided powder into spheres which break up during the inhalation procedure. This spheronized powder may be filled into the drug reservoir of a multidose inhaler, for example, that known as the Turbuhaler ^® in which a dosing unit meters the desired dose which is then inhaled by the patient. With this system the active ingredient, with or without a carrier substance, is delivered to the patient.

For oral administration the compound of the invention may be admixed with an adjuvant or a carrier, for example, lactose, saccharose, sorbitol, mannitol; a starch, for example, potato starch, corn starch or amylopectin; a cellulose derivative; a binder, for example, gelatine or polyvinylpyrrolidone; and/or a lubricant, for example, magnesium stearate, calcium stearate, polyethylene glycol, a wax, paraffin, and the like, and then compressed into tablets. If coated tablets are required, the cores, prepared as described above, may be coated with a concentrated sugar solution which may contain, for example, gum arabic, gelatine, talcum and titanium dioxide. Alternatively, the tablet may be coated with a suitable polymer dissolved in a readily volatile organic solvent.

For the preparation of soft gelatine capsules, the compound of the invention may be admixed with, for example, a vegetable oil or polyethylene glycol. Hard gelatine capsules may contain granules of the compound using either the above-mentioned excipients for tablets. Also liquid or semisolid formulations of the compound of the invention may be filled into hard gelatine capsules.

Liquid preparations for oral application may be in the form of syrups or suspensions, for example, solutions containing the compound of the invention, the balance being sugar and a mixture of ethanol, water, glycerol and propylene glycol. Optionally such liquid preparations may contain colouring agents, flavouring agents, saccharine and/or carboxymethylcellulose as a thickening agent or other excipients known to those skilled in art. In particular, the compounds of the present invention and salts thereof may be used in the treatment of the inflammatory diseases such as (but not restricted to) rheumatoid arthritis, osteoarthritis, asthma, allergic rhinitis, chronic obstructive pulmonary disease (COPD), psoriasis, and inflammatory bowel disease, the compounds of the invention may be combined with the following agents: non-steroidal anti-inflammatory agents

(hereinafter NSAIDs) including non-selective cyclo-oxygenase COX-1 / COX-2 inhibitors whether applied topically or systemically (such as piroxicam, diclofenac, propionic acids such as naproxen, flurbiprofen, fenoprofen, ketoprofen and ibuprofen, fenamates such as mefenamic acid, indomethacin, sulindac, azapropazone, pyrazolones such as

phenylbutazone, salicylates such as aspirin); selective COX-2 inhibitors (such as meloxicam, celecoxib, rofecoxib, valdecoxib, lumarocoxib, parecoxib and etoricoxib); cyclo-oxygenase inhibiting nitric oxide donors (CINODs); glucocorticosteroids (whether administered by topical, oral, intramuscular, intravenous, or intra-articular routes);

methotrexate; leflunomide; hydroxychloroquine; d-penicillamine; auranofm or other parenteral or oral gold preparations; analgesics; diacerein; intra-articular therapies such as hyaluronic acid derivatives; and nutritional supplements such as glucosamine.

The compounds of the invention may also be administered in conjunction with other compounds used for the treatment of the above conditions.

The invention therefore further relates to combination therapies wherein a compound of the invention, or a pharmaceutically acceptable salt thereof, or a

pharmaceutical composition or formulation comprising a compound of the invention, is administered concurrently or sequentially or as a combined preparation with another therapeutic agent or agents, for the treatment of one or more of the conditions listed above.

The present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, together with a cytokine or agonist or antagonist of cytokine function, (including agents which act on cytokine signalling pathways such as modulators of the SOCS system) including alpha-, beta-, and gamma- interferons; insulin- like growth factor type I (IGF-1); interleukins (IL) including ILl to 17, and interleukin antagonists or inhibitors such as anakinra; tumour necrosis factor alpha (TNF-a) inhibitors such as anti-TNF monoclonal antibodies (for example infliximab; adalimumab, and CDP-870) and TNF receptor antagonists including immunoglobulin molecules (such as etanercept) and low-molecular-weight agents such as pentoxyfylline. In addition the invention relates to a combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, with a monoclonal antibody targeting B- Lymphocytes (such as CD20 (rituximab), MRA-aIL16R) or T-Lymphocytes (CTLA4-Ig, HuMax 11-15).

The present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, with a modulator of chemokine receptor function such as an antagonist of CCR1, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10 and CCR11 (for the C-C family); CXCR1, CXCR2, CXCR3, CXCR4 and CXCR5 (for the C-X-C family) and CX ₃ CR1 for the C-X ₃ - C family.

The present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, with an inhibitor of matrix metalloprotease (MMPs), i.e., the stromelysins, the collagenases, and the gelatinases, as well as aggrecanase; especially collagenase-1 (MMP-1), collagenase-2 (MMP-8), collagenase-3 (MMP-13), stromelysin-1 (MMP-3), stromelysin-2 (MMP-10), and stromelysin-3 (MMP-11) and MMP-9 and MMP-12, including agents such as doxycycline.

The present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a leukotriene biosynthesis inhibitor, 5 -lipoxygenase (5-LO) inhibitor or 5 -lipoxygenase activating protein (FLAP) antagonist such as; zileuton; ABT-761; fenleuton; tepoxalin; Abbott-79175; Abbott-85761; a N-(5-substituted)-thiophene-2-alkylsulfonamide; 2,6-di-tert-butylphenolhydrazones; a methoxytetrahydropyrans such as Zeneca ZD-2138; the compound SB-210661 ; a pyridinyl-substituted 2-cyanonaphthalene compound such as L-739,010; a 2- cyanoquinoline compound such as L-746,530; or an indole or quinoline compound such as MK-591, MK-886, and BAY x 1005.

The present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a receptor antagonist for leukotrienes (LT) B4, LTC4, LTD4, and LTE4 selected from the group consisting of the phenothiazin-3-ls such as L-651,392; amidino compounds such as CGS-25019c;

benzoxalamines such as ontazolast; benzenecarboximidamides such as BIIL 284/260; and compounds such as zafirlukast, ablukast, montelukast, pranlukast, verlukast (MK-679), RG-12525, Ro-245913, iralukast (CGP 45715A), and BAY x 7195. The present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a phosphodiesterase (PDE) inhibitor such as a methylxanthanine including theophylline and aminophylline; a selective PDE isoenzyme inhibitor including a PDE4 inhibitor an inhibitor of the isoform PDE4D, or an inhibitor of PDE5.

The present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a histamine type 1 receptor antagonist such as cetirizine, loratadine, desloratadine, fexofenadine, acrivastine, terfenadine, astemizole, azelastine, levocabastine, chlorpheniramine, promethazine, cyclizine, or mizolastine; applied orally, topically or parenterally.

The present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a proton pump inhibitor (such as omeprazole) or a gastroprotective histamine type 2 receptor antagonist.

The present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and an antagonist of the histamine type 4 receptor.

The present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and an alpha- l/alpha-2

adrenoceptor agonist vasoconstrictor sympathomimetic agent, such as propylhexedrine, phenylephrine, phenylpropanolamine, ephedrine, pseudoephedrine, naphazoline hydrochloride, oxymetazoline hydrochloride, tetrahydrozoline hydrochloride,

xylometazoline hydrochloride, tramazoline hydrochloride or ethylnorepinephrine hydrochloride.

The present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a chromone, such as sodium cromoglycate or nedocromil sodium.

The present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, with a glucocorticoid, such as flunisolide, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone propionate, ciclesonide or mometasone furoate. The present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, with an agent that modulates a nuclear hormone receptor such as PPARs.

The present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, together with an immunoglobulin (Ig) or Ig preparation or an antagonist or antibody modulating Ig function such as anti-IgE (for example omalizumab).

The present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and another systemic or topically- applied anti-inflammatory agent, such as thalidomide or a derivative thereof, a retinoid, dithranol or calcipotriol.

The present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and combinations of

aminosalicylates and sulfapyridine such as sulfasalazine, mesalazine, balsalazide, and olsalazine; and immunomodulatory agents such as the thiopurines, and corticosteroids such as budesonide.

The present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, together with an antibacterial agent such as a penicillin derivative, a tetracycline, a macrolide, a beta-lactam, a fluoroquinolone, metronidazole, an inhaled aminoglycoside; an antiviral agent including acyclovir, famciclovir, valaciclovir, ganciclovir, cidofovir, amantadine, rimantadine, ribavirin, zanamavir and oseltamavir; a protease inhibitor such as indinavir, nelfmavir, ritonavir, and saquinavir; a nucleoside reverse transcriptase inhibitor such as didanosine, lamivudine, stavudine, zalcitabine or zidovudine; or a non-nucleoside reverse transcriptase inhibitor such as nevirapine or efavirenz.

The present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a cardiovascular agent such as a calcium channel blocker, a beta-adrenoceptor blocker, an angiotensin-converting enzyme (ACE) inhibitor, an angiotensin-2 receptor antagonist; a lipid lowering agent such as a statin or a fibrate; a modulator of blood cell morphology such as pentoxyfylline;

thrombolytic, or an anticoagulant such as a platelet aggregation inhibitor. The present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a CNS agent such as an antidepressant (such as sertraline), an anti-Parkinsonian drug (such as deprenyl, L-dopa, ropinirole, pramipexole, a MAOB inhibitor such as selegine and rasagiline, a comP inhibitor such as tasmar, an A-2 inhibitor, a dopamine reuptake inhibitor, an NMDA antagonist, a nicotine agonist, a dopamine agonist or an inhibitor of neuronal nitric oxide synthase), or an anti-Alzheimer's drug such as donepezil, rivastigmine, tacrine, a COX-2 inhibitor, propentofylline or metrifonate.

The present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, and an agent for the treatment of acute or chronic pain, such as a centrally or peripherally-acting analgesic (for example an opioid or derivative thereof), carbamazepine, phenytoin, sodium valproate, amitryptiline or other anti-depressant agent-s, paracetamol, or a non-steroidal anti-inflammatory agent.

The present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, together with a parenterally or topically-applied (including inhaled) local anaesthetic agent such as lignocaine or a derivative thereof.

A compound of the present invention, or a pharmaceutically acceptable salt thereof, can also be used in combination with an anti-osteoporosis agent including a hormonal agent such as raloxifene, or a biphosphonate such as alendronate.

The present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, together with a: (i) tryptase inhibitor; (ii) platelet activating factor (PAF) antagonist; (iii) interleukin converting enzyme (ICE) inhibitor; (iv) IMPDH inhibitor; (v) adhesion molecule inhibitors including VLA-4 antagonist; (vi) cathepsin; (vii) kinase inhibitor such as an inhibitor of tyrosine kinase (such as Btk, Itk, Jak3 or MAP, for example Gefitinib or Imatinib mesylate), a serine / threonine kinase (such as an inhibitor of a MAP kinase such as p38, JNK, protein kinase A, B or C, or IKK), or a kinase involved in cell cycle regulation (such as a cylin dependent kinase); (viii) glucose-6 phosphate dehydrogenase inhibitor; (ix) kinin-B.subl . - or B.sub2. -receptor antagonist; (x) anti-gout agent, for example colchicine; (xi) xanthine oxidase inhibitor, for example allopurinol; (xii) uricosuric agent, for example probenecid, sulfinpyrazone or benzbromarone; (xiii) growth hormone secretagogue; (xiv) transforming growth factor (TGFP); (xv) platelet-derived growth factor (PDGF); (xvi) fibroblast growth factor for example basic fibroblast growth factor (bFGF); (xvii) granulocyte macrophage colony stimulating factor (GM-CSF); (xviii) capsaicin cream; (xix) tachykinin NK.subl . or NK.sub3. receptor antagonist such as NKP-608C, SB-233412 (talnetant) or D-4418; (xx) elastase inhibitor such as UT-77 or ZD-0892; (xxi) TNF-alpha converting enzyme inhibitor (TACE); (xxii) induced nitric oxide synthase (iNOS) inhibitor; (xxiii) chemoattractant receptor-homologous molecule expressed on TH2 cells, (such as a CRTH2 antagonist); (xxiv) inhibitor of P38; (xxv) agent modulating the function of Toll-like receptors (TLR), (xxvi) agent modulating the activity of purinergic receptors such as P2X7; (xxvii) inhibitor of transcription factor activation such as NFkB, API or STATS; or (xxviii) a glucocorticoid receptor (GR-receptor) agonist.

In a further aspect the present invention provides a combination (for example for the treatment of COPD, asthma or allergic rhinitis) of a compound of formula (I) and one or more agents selected from the list comprising:

• a non-steroidal glucocorticoid receptor (GR-receptor) agonist;

• a PDE4 inhibitor including an inhibitor of the isoform PDE4D;

• a modulator of chemokine receptor function (such as a CCR1 receptor

antagonist);

• a steroid (such as budesonide); and

• an inhibitor of p38 kinase function.

A compound of the invention, or a pharmaceutically acceptable salt thereof, can also be used in combination with an existing therapeutic agent for the treatment of cancer, for example suitable agents include:

(i) an antiproliferative/antineoplastic drug or a combination thereof, as used in medical oncology, such as an alkylating agent (for example cis-platin, carboplatin,

cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan or a

nitrosourea); an antimetabolite (for example an antifolate such as a fluoropyrimidine like 5-fluorouracil or tegafur, raltitrexed, methotrexate, cytosine arabinoside, hydroxyurea, gemcitabine or paclitaxel); an antitumour antibiotic (for example an anthracycline such as adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin or mithramycin); an antimitotic agent (for example a vinca alkaloid such as vincristine, vinblastine, vindesine or vinorelbine, or a taxoid such as taxol or taxotere); or a topoisomerase inhibitor (for example an epipodophyllotoxin such as etoposide, teniposide, amsacrine, topotecan or a camptothecin);

(ii) a cytostatic agent such as an antioestrogen (for example tamoxifen, toremifene, raloxifene, droloxifene or iodoxyfene), an oestrogen receptor down regulator (for example fulvestrant), an antiandrogen (for example bicalutamide, flutamide, nilutamide or cyproterone acetate), a LHRH antagonist or LHRH agonist (for example goserelin, leuprorelin or buserelin), a progestogen (for example megestrol acetate), an aromatase inhibitor (for example as anastrozole, letrozole, vorazole or exemestane) or an inhibitor of 5a-reductase such as finasteride;

(iii) an agent which inhibits cancer cell invasion (for example a metalloproteinase inhibitor like marimastat or an inhibitor of urokinase plasminogen activator receptor function);

(iv) an inhibitor of growth factor function, for example: a growth factor antibody (for example the anti-erbb2 antibody trastuzumab, or the anti-erbbl antibody cetuximab

[C225]), a farnesyl transferase inhibitor, a tyrosine kinase inhibitor or a serine/threonine kinase inhibitor, an inhibitor of the epidermal growth factor family (for example an EGFR family tyrosine kinase inhibitor such as N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3- morpholinopropoxy)quinazolin-4-amine (gefitinib, AZD1839), N-(3-ethynylphenyl)-6,7- bis(2-methoxyethoxy)quinazolin-4-amine (erlotinib, OSI-774) or 6-acrylamido-N-(3- chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)quinazolin-4-a mine (CI 1033)), an inhibitor of the platelet-derived growth factor family, or an inhibitor of the hepatocyte growth factor family;

(v) an antiangiogenic agent such as one which inhibits the effects of vascular endothelial growth factor (for example the anti-vascular endothelial cell growth factor antibody bevacizumab, a compound disclosed in WO 97/22596, WO 97/30035, WO 97/32856 or WO 98/13354), or a compound that works by another mechanism (for example linomide, an inhibitor of integrin ανβ3 function or an angiostatin);

(vi) a vascular damaging agent such as combretastatin A4, or a compound disclosed in WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 or WO 02/08213;

(vii) an agent used in antisense therapy, for example one directed to one of the targets listed above, such as ISIS 2503, an anti-ras antisense;

(viii) an agent used in a gene therapy approach, for example approaches to replace aberrant genes such as aberrant p53 or aberrant BRCAl or BRCA2, GDEPT (gene-directed enzyme pro-drug therapy) approaches such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme and approaches to increase patient tolerance to chemotherapy or radiotherapy such as multi-drug resistance gene therapy; or

(ix) an agent used in an immunotherapeutic approach, for example ex-vivo and in-vivo approaches to increase the immunogenicity of patient tumour cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor, approaches to decrease T-cell anergy, approaches using transfected immune cells such as cytokine-transfected dendritic cells, approaches using

cytokine-transfected tumour cell lines and approaches using anti-idiotypic antibodies.

The compounds of formula (I) above may be converted to a pharmaceutically acceptable salt thereof, for example an acid addition salt such as a hydrochloride (for example a dihydrochloride), hydrobromide (for example a dihydrobromide),

trifluoroacetate (for example a di-trifluoroacetate), sulphate, phosphate, acetate, fumarate, maleate, tartrate, lactate, citrate, pyruvate, succinate, oxalate, methanesulphonate or p- toluenesulphonate.

The invention will now be illustrated but not limited by reference to the following specific description and Examples wherein the followingwere used

General Experimental Details

The nomenclature of structures was assigned using Autonom 2000 Name software from MDL Inc.

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. NMR analysis of compounds purified by HPLC showed various amounts of formic acid equivalents (not described).

Purification by chromatography refers to purification using the CombiFlash ® Companion purification system or the Biotage SP1 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. Compounds purified by preparative HPLC were purified using a C18-reverse-phase column (100 x 22.5 mm i.d Genesis column with 7 μιη particle size or 250 x 21.2 mm i.d. Gemini column with 5 μιη particle size), or a Phenyl-Hexyl column (250 x 21.2 mm i.d. Gemini column with 5 μιη particle size), UV detection at 220, 230 or 254 nm, flow 10-20 mL/min, eluting with gradients from 95-5 to 5-95 % water/acetonitrile or water/MeOH containing 0.1 % TFA or 0.1 % formic acid.

Fractions containing the required product (identified by TLC and/or LCMS analysis) were pooled, the organic fraction removed by evaporation, and the remaining aqueous fraction lyophilised, to give the final product.

The Liquid Chromatography Mass Spectroscopy (LCMS) systems used:

Method 1

Waters ZMD quadrupole mass spectrometer with a C18-reverse-phase column (30 x 4.6 mm Phenomenex Luna 3 μιη particle size), elution with A: water + 0.1% formic acid; B: methanol + 0.1 % formic acid. Gradient:

Detection - MS, ELS, UV (200 μΐ, split to MS with in-line UV detector). MS ionization 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 μιη particle size), elution with A: water + 0.1% formic acid; B: acetonitrile + 0.1 % formic acid. Gradient: Gradient - Time flow ml -/miii %A %B

0.00 1.0 95 5

1.00 1.0 5 95

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 split to MS with in-line UV detector). MS ionisation method - Electrospray (positive ion)

Method 3

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

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

Method 4

Waters Platform LC Quadrupole mass spectrometer with a C18-reverse-phase column (30 x 4.6 mm Phenomenex Luna 3 μιη particle size), elution with A: water + 0.1% formic acid; B: methanol + 0.1 % formic acid. Gradient: Gradient - Time flow ml -/miii %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 split to MS with in-line UV detector). MS ionization method - Electrospray (positive and negative ion).

Method 5

Micromass Quattro Micro Quadrupole mass spectrometer with a C18-reverse-phase column (100 x 3.0 mm Higgins Clipeus with 5 μιη particle size), elution with A: water + 0.1% formic acid; B: methanol + 0.1 % formic acid. Gradient:

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

Method 6

Waters Micromass ZQ2000 quadrupole mass spectrometer LC Column - Acquity BEH CI 8 column (50 x 2.1 mm with 1.7μιη particle size, maintained at 40°C), elution with water + 0.1% formic acid; B: methanol + 0.1 % formic acid. Gradient:

Time flow ml/min %A %B Gradient - Time flow ml -/mi 11 %A %B

0.00 0.4 85 15

0.40 0.4 85 15

6.00 0.4 5 95

8.00 0.4 5 95

8.80 0.4 85 15

10.00 0.4 85 15

Detection - MS, UV PDA

MS ionisation method - Electrospray (positive/negative ion)

Method 7

Finnigan AQA single quadrupole mass spectrometer with a C 18-reverse-phase column (30 x 4.6 mm Phenomenex Luna 3 μιη particle size), elution with A: water + 0.1% formic acid; B: methanol + 0.1 % formic acid. Gradient:

Detection - MS, ELS, UV (200 split to ESI Source). MS ionization method - Electrospray (positive ion).

Abbreviations

AIBN = (2,2'-azobis(2-methylproprionitrile)

(R)-(+)-CBS = (R)-(+)-methyl-CBS-oxazaborolidine

Boc anhydride = di-tert-butyl dicarbonate

CDI = Ι, Γ-carbonyldiimidazole

DCE = 1,2-dichloroethane

DCM = dichloromethane

DIPEA = diisopropylethylamine DMF = NN-dimethylformamide

DMSO = dimethylsulfoxide

e.e. = enantiomeric excess

EtOAc = ethyl acetate

EtOH = ethanol

equiv. = equivalents

h = hour(s)

HC1 = hydrochloric acid

HATU = 0-(7-azabenzotriazol- 1 -yl)-N,N,N'N -tetramethyluroniumhexafluorophosphate HPLC = high performance liquid chromatography

MeCN = acetonitrile

MeOH = methanol

min = minutes

NaHC0 ₃ = sodium hydrogen carbonate

NaOH = sodium hydroxide

Na ₂ S0 ₄ = sodium sulphate

NH ₄ C1 = ammonium chloride

NMP = N-methyl-pyrrolidinone

pTSA =/?ara-toluenesulphonic acid

quant. = quantitative

RT = room temperature

Rf = retention factor (TLC)

Rt = retention time (LCMS or HPLC)

SCX-2 = strong cation exchange resin

TBDMS = tert-butyldimethylsilyl

TFA = trifluoroacetic acid

THF = tetrahydrofuran

TLC = thin layer chromatography Example 1

8-Hydroxy-5-{(i?)-l-hydroxy-2-[2-(4-{3-[4-hydroxy-3-(l-methy l-4-phenyl-piperidin-4-yl)- phenyl]-propoxy}-phenyl)- rmic acid salt

a. 4-(3-Hydroxy-propyl)-2-(4-phen -piperidin-4-yl)-phenol

To a solution of 4-phenylpiperidin-4-ol (5 g, 28.2 mmol) and 3-(4-hydroxyphenyl)- l -propanol (12.9 g, 84.6 mmol) in nitrobenzene (25 mL) at 0 °C was added dropwise triflic acid (7.5 mL, 84.6 mmol). The reaction mixture was stirred at RT for 48 h, poured onto ice, basified to pH 9 by addition of 25% aq. sodium hydroxide then extracted with EtOAc (3 x 80 mL). The combined organic layers were washed with water, brine, dried (MgSO/t), filtered, evaporated and purified on SCX cartridge (gradient MeOH to 2N NH ₃ in MeOH) to give the title compound (5.5 g, 63%).

LCMS (Method 1): Rt 2.59 min, m/z 312 [M+H] ⁺

b. 4-[2-Hydroxy-5-(3-hydroxy-propyl)-phenyl]-4-phenyl-piperidin e-l-carboxylic acid tert- butyl ester

To a solution of Example 1(a) (5.5 g, 17.7 mmol) in DCM (120 mL) was added triethylamine (3.7 mL, 26.6 mmol) and tert-butoxycarbonyl anhydride (4.6 g, 21.2 mmol). The reaction mixture was stirred at RT for 16 h and filtered. The filtrate was washed with sat. sodium bicarbonate, dried (MgSO/t), filtered, evaporated and purified by chromatography (cyclohexane to cyclohexane/EtOAc 9/1 to DCM/MeOH 9/1) to give the title compound (1.84 g, 25%).

LCMS (Method 1): Rt 4.06 min, m/z 412 [M+H] ⁺

c. 4-[5-(3-Bromo-propyl)-2-hydroxy-phenyl]-4-phenyl-piperidine- l-carboxylic acid tert-butyl ester

To a solution of Example 1(b) (1.84 g, 4.5 mmol) and carbon tetrabromide (3.1 g, 9.5 mmol) in DCM (80 mL) at 0 °C was added triphenylphosphine (1.9 g, 7.2 mmol). The reaction mixture was stirred at 0 °C for 1 h then at RT for 1.5 h, diluted with DCM, washed with water, dried (MgS0 ₄ ), filtered, evaporated and purified by chromatography (cyclohexane to cyclohexane/EtOAc 8/2) to give the title compound as a white solid (1.77 g, 83%).

¾ NMR (300 MHz, DMSO-d ₆ ): 7.28-7.14 (5 H, m), 7.13-7.06 (1 H, m), 6.86 (1 H, dd, J = 8.1, 2.0 Hz), 6.59 (1 H, d, J = 8.1 Hz), 5.76 (1 H, s), 3.49 (4 H, t, J = 6.6 Hz), 3.18 (2 H, m), 2.63 (4 H, t, J = 7.2 Hz), 2.21-1.97 (4 H, m), 1.42- 1.36 (9 H, s). d. 4-(2-Hydroxy-5-{3-[4-(2-hydroxy-ethyl)-phenoxy]-propyl}-phen yl)-4-phenyl-piperidine-l- carboxylic acid teri-butyl este

A solution of 2-(4-hydroxyphenyl)-ethanol (0.61 g, 4.4 mmol) and potassium carbonate (0.61 g, 4.4 mmol) in DMF (40 mL) was stirred at RT for 0.5 h then treated with Example 1(c) (1.05 g, 2.2 mmol) and stirred at 60 °C for 16 h. The reaction mixture was diluted with EtOAc, washed with water, brine, dried (MgS0 ₄ ), filtered, evaporated and purified by chromatography (DCM to DCM/MeOH 95/5) to give the title compound as a yellow oil (1.25 g, quant.).

LCMS (Method 1): Rt 4.36 min, m/z 532 [M+H] ⁺

e. 4-(5-{3-[4-(2-Bromo-ethyl)-phenoxy]-propyl}-2-hydroxy-phenyl )-4-phenyl-piperidine-l- carboxylic acid teri-butyl este

The title compound was prepared from Example 1(d) using a method similar to that described for Example 1 , step c.

LCMS (Method 1): Rt 4.83 min, m/z 594/596 [M+H] f. 4-{3-[4-(2-Bromo-ethyl)-phenoxy]-propyl}-2-(4-phenyl-piperid in-4-yl)-phenol

trifluoroacetic acid salt

A solution of Example 1(e) (0.207g, 0.35 mmol) in DCM (4 mL) at 0 °C was treated with TFA (4 mL). The reaction mixture was stirred for 1 h, then co-evaporated with toluene and dried in vacuo. The resulting residue was used directly in the next step.

LCMS (Method 4): Rt 3.90 min, m/z 494/496 [M+H] ⁺

g. 4-{3-[4-(2-Bromo-ethyl)-ph -piperidin-4-yl)-phenol

A solution of Example 1(f) (0.35 mmol) in DCE (5 mL) was treated with 37% aq. formaldehyde (0.13 mL, 1.75 mmol) and after 10 min of vigorous stirring, was treated portion- wise with sodium triacetoxyborohydride (0.15 g, 0.7 mmol). The reaction mixture was stirred at RT for 2 h, diluted with DCM, washed with sat. sodium bicarbonate, dried (MgSO/ _t ), filtered, evaporated and purified by chromatography (DCM to DCM/MeOH 9/1) to give the title compound as a colourless oil (95 mg, 54%).

Ή NMR (300 MHz, CDC1 ₃ ): 7.25-7.20 (4 H, m), 7.22-7.04 (4 H, m), 6.94 (1 H, dd, J = 8.1, 2.0 Hz), 6.88-6.81 (2 H, m), 6.63 (1 H, d, J = 8.1 Hz), 5.30 (1 H, s), 3.92 (2 H, t, J = 6.2 Hz), 3.51 (2 H, t, J = 7.6 Hz), 3.09 (2 H, t, J = 7.6 Hz), 2.75 (4 H, t, J = 7.4 Hz), 2.74- 2.40 (6 H, m), 2.25 (3 H, s), 2.12-2.00 (2 H, m).

h. 5-{(J?)-l-(½ri-Butyl-dimethyl-silanyloxy)-2-[2-(4-{3-[4-hyd roxy-3-(l-methyl-4-phenyl- piperidin-4-yl)-phenyl]-p xy-lH-quinolin-2-one

A solution of Example 1(g) (95 mg, 0.19 mmol) in DMF (6 mL) under a nitrogen atmosphere was treated with 5-[(R)-2-amino- 1 -(tert-butyl-dimethyl-silanyloxy)-ethyl]-8-hydroxy- lH-quinolin-2- one (WO2006/023454) (93 mg, 0.28 mmol) and DIPEA (50 jiL, 0.28 mmol). The reaction mixture was stirred at 50 °C for 16 h, diluted with EtOAc, washed with water, brine, dried (MgS0 ₄ ), filtered, evaporated and purified by chromatography (DCM to DCM/MeOH/2M NH ₃ in MeOH 87.5/10/2.5) to give the title compound (40 mg, 28%).

LCMS (Method 1): Rt 3.03 min, m/z 762 [M+H] ⁺

i. 8-Hydroxy-5-{(i?)-l-hydroxy-2-[2-(4-{3-[4-hydroxy-3-(l-methy l-4-phenyl-piperidin-4-yl)- phenyl]-propoxy}-phenyl)- rmic acid salt

A solution of Example 1(h) (40 mg, 0.05 mmol) in THF (3 mL) was treated with triethylamine trihydrofluoride (85 μΐ _^ , 0.52 mmol). The reaction mixture was stirred at RT for 16 h, neutralised with sodium bicarbonate (10 eq), diluted with water and concentrated in vacuo. The reaction mixture was dissolved in HPLC starting eluent, a few drops of formic acid were added (up to 20vol% DMF can be added to aid dissolution) and the solution and purified by preparative HPLC to afford the title compound as a white solid (9 mg, 33%).

LCMS (Method 2) Rt 5.82 min, m/z 648 [M+H] ⁺ .

Ή NMR (400 MHz, CD ₃ OD): 8.48 (s, 1H), 8.40 (d, 1H, J = 9.9 Hz), 7.29 (d, 1H, J = 8.2 Hz), 7.20-7.07 (m, 7H), 7.02 (d, 1H, J = 8.2 Hz), 6.95 (d, 2H, J = 7.1 Hz), 6.89 (d, 2H, J = 8.4 Hz), 6.69 (d, 1H, J = 9.8 Hz), 6.65 (d, 1H, J = 8.2 Hz), 5.43 (dd, 1H, J = 7.9, 5.5 Hz), 3.90 (t, 2H, J = 6.0 Hz), 3.21-3.16 (m, 8H), 2.96 (m, 6H), 2.74 (m, 2H), 2.71 (s, 3H), 2.04- 1.97 (m, 2H).

The following compounds (Table 1) were prepared as formic acid salts using similar methods to those described for Example 1 (N.B. in Example 2, 8-[(R)-2-amino-l(tert-butyl-dimethyl- silanyloxy)-ethyl]-5-hydroxy-4H-benzo[l,4]oxazin-3-one (WO2008/1491 10) was used in place of 5-[(R)-2-amino- l-(tert-butyl-dimethyl-silanyloxy)-ethyl]-8-hydroxy- lH-quinolin-2-one)).

Table 1

Example 6

5-Hydroxy-8-{(i?)-l-hydroxy-2-[2-(4-{2-[4-hydroxy-3-(l-methy l-4-phenyl-piperidin-4-yl)- phenyl]-ethoxy}-phenyl)-eth lamino -ethyl}-4H-benzo[l,4]oxazin-3-one formic acid salt

a. {4-[2-(4-Benzyloxy-pheny ester

A solution of 2-(4-benzyloxyphenyl)ethanol (43.63 g, 191.1 mmol), (4-hydroxy-phenyl)-acetic acid methyl ester (40 g, 238.8 mmol) and triphenylphosphine (72.6 g, 277 mmol) in THF (1.2 L) under an atmosphere of argon, was treated dropwise with diisopropylazodicarboxylate (57.4 mL, 277 mmol). The reaction mixture was stirred at RT for 48 h, concentrated in vacuo and purified by chromatography (cyclohexane to cyclohexane/EtOAc 8/2). Impure fractions were concentrated in vacuo and re-crystallised from hot cyclohexane containing a few drops of EtOAc. The resulting solid was combined with the pure fractions from chromatography to give the title compound as a white solid (33 g, 45%).

LCMS (Method 4): Rt 4.1 1 min, m/z 399 [M+Na] ⁺

b. {4-[2-(4-Hydroxy-phenyl)-ethoxy]-phenyl}-acetic acid methyl ester

A solution of Example 6(a) (17.9 g, 47.6 mmol) in MeOH (750 mL) was treated with 20 % palladium hydroxide on charcoal (2.86 g) and ammonium formate (44.6 g, 714 mmol). The reaction mixture was stirred at 70 °C for 1 h, allowed to cool to RT, filtered through Hyflo®, washed with MeOH and concentrated in vacuo. The residue was dissolved in DCM, washed several times with water, dried (Na ₂ SOzt), filtered and concentrated in vacuo to afford the title compound as a white solid (14 g, quant.).

LCMS (Method 1): Rt 4.22 min, m/z 309 [M+Na] ⁺ c. 4-{2-Hydroxy-5-[2-(4-methoxycarbonylmethyl-phenoxy)-ethyl]-p henyl}-4-phenyl- piperidine-l-carboxylic acid teri-but l ester

The title compound was prepared from Example 6(b) using methods similar to those described for Example 1 , steps a-b.

LCMS (Method 1): Rt 5.06 min, m/z 546 [M+H] ⁺

d. 4-(2-Hydroxy-5-{2-[4-(2-hydroxy-ethyl)-phenoxy]-ethyl}-pheny l)-4-phenyl-piperidine-l- carboxylic acid teri-butyl ester

A solution of Example 6(c) (51 1 mg, 0.94 mmol) in THF (25 mL) at 0 °C under an atmosphere of nitrogen was treated dropwise with lithium aluminium hydride (1M in THF, 0.94 mL, 0.94 mmol). The reaction mixture was stirred at 0 °C for 2 h then quenched with water (39 iL), stirred for 5 min, treated with IN sodium hydroxide (78 μί), stirred for 5 min then treated with water (1 10 μΐ.) and stirred for 10 min. The reaction mixture was dried (MgSO/ _t ) and filtered over a phase separator. The organic layer was concentrated in vacuo and purified by chromatography (cyclohexane to cyclohexane/EtOAc 3/7) to afford the title compound as a white foam (470 mg, 88%).

LCMS (Method 1): Rt 4.37 min, m/z 540 [M+Na] ⁺

e. 4-(5-{2-[4-(2-Bromo-ethyl)-phenoxy]-ethyl}-2-hydroxy-phenyl) -4-phenyl-piperidine-l- carboxylic acid teri-butyl ester

A solution of Example 6(d) (317 mg, 0.61 mmol), carbon tetrabromide (426 mg, 1.28 mmol) and imidazole (62 mg, 0.91 mmol) in DCM (8 mL) at 0 °C was treated with a solution of triphenylphosphine (255 mg, 0.97 mmol) in DCM. The reaction mixture was stirred at 0 °C for 10 min then at RT for 2.5 h, diluted with DCM (50 mL), washed with water, dried (Na ₂ S0 ₄ ), filtered, concentrated and purified by chromatography (cyclohexane to cyclohexane/acetone 85/15) to afford the title compound as a white foam (303 mg, 86%).

LCMS (Method 4): Rt 4.33 min, m/z 580/582 [M+H] ⁺

f. 5-Hydroxy-8-{(i?)-l-hydroxy-2-[2-(4-{2-[4-hydroxy-3-(l-methy l-4-phenyl-piperidin-4-yl)- phenyl]-ethoxy}-phenyl)-eth lamino]-ethyl}-4H-benzo[l,4]oxazin-3-one diformic acid salt

The title compound was prepared from Example 6(e) using methods similar to those described for Example 1 steps f-i, using 8-[(R)-2-amino-l-(tert-butyl-dimethyl-silanyloxy)-ethyl]-5-h ydroxy-4H- benzo[l,4]oxazin-3-one (WO2008/1491 10) in place of 5-[(R)-2-amino-l-(tert-butyl-dimethyl- silanyloxy)-ethyl]-8-hydroxy- lH-quinolin-2-one.

LCMS (Method 2) Rt 5.67 min, m/z 638 [M+H] ⁺ .

Ή NMR (400 MHz, CD ₃ OD): 8.50 (s, 2H), 7.31 (d, 2H, J = 7.9 Hz), 7.25 (t, 2H, J = 7.6 Hz), 7.20-7.1 1 (m, 4H), 7.06-7.00 (m, 2H), 6.88 (d, 2H, J = 8.5 Hz), 6.67 (d, 1H, J = 8.1 Hz), 6.56 (d, 1H, J = 8.5 Hz), 5.16 (dd, 1H, J = 9.6, 3.2 Hz), 4.57 (A-B syst, 2H), 4.13 (t, 2H, J = 6.6 Hz), 3.23-3.10 (m, 10H), 3.06 (dd, 2H, J = 12.6, 9.5 Hz), 3.00-2.89 (m, 4H), 2.71 (s, 3H).

The following compounds (

Table 2) were prepared as formic acid salts using similar methods to that described for

Example 6:

Table 2 Example 12

8-Hydroxy-5-((i?)-l-hydroxy-2-{2-[4-hydroxy-3-(l-isopropyl-4 -phenyl-piperidin-4-yl)- phenyl]-ethylamino}-ethyl)-lH-qu salt

a. 4-[2-Hydroxy-5-(2-hydroxy-ethyl)-phenyl]-4-phenyl-piperidine -l-carboxylic acid tert-buty\ ester

The title compound was prepared using methods similar to those described for Example 6, steps c-d using (4-hydroxy-phenyl)-acetic acid methyl ester in place of Example 6(b).

LCMS (Method 1) Rt 4.53 min, m/z 420 [M+Na] ⁺ . b. 4-(2-Hydroxy-ethyl)-2-(l-isoprop -4-phenyl-piperidin-4-yl)-phenol

The title compound was prepared from Example 12(a) using methods similar to that described for Example 1 steps f-g using acetone in place of formaldehyde in step g.

LCMS (Method 4) Rt 2.70 min, m/z 340 [M+H] ⁺ . c. 8-Hydroxy-5-((i?)-l-hydroxy-2-{2-[4-hydroxy-3-(l-isopropyl-4 -phenyl-piperidin-4-yl)- phenyl]-ethylamino}-ethyl)-lH-qu alt

The title compound was prepared from Example 12(b) using methods similar to that described for Example 1 , steps c, h-i.

LCMS (Method 2) Rt 4.32 min, m/z 542 [M+H] ⁺ .

Ή NMR (400 MHz, CD ₃ OD): 8.48 (br s, 1H), 8.40 (d, 1H, J = 9.8 Hz), 7.28 (m, 4H), 7.22 (m, 2H), 7.1 1 (t, 1H, J = 7.3 Hz), 7.01 (d, 2H, J = 8.0 Hz), 6.66 (d, 2H, J = 9.5 Hz), 5.48 (d, 1H, J = 9.4 Hz), 3.42-3.32 (m, 2H), 3.25-3.15 (m, 10H), 3.02 (m, 3H), 1.27 (d, 6H, J = 8 Hz).

Example 13

8-Hydroxy-5-((i?)-l-hydroxy-2-{3-[4-hydroxy-3-(l-isopropyl-4 -phenyl-piperidin-4-yl)- phenyl]-propylamino}-ethyl)-lH- uinolin-2-one diformic acid salt

The title compound was prepared from Example 1(a) using methods similar to those described for Example 1, steps g, c, h-i using acetone in place of formaldehyde.

LCMS (Method 2) Rt 4.53 min, m/z 556 [M+H] ⁺ .

Ή NMR (400 MHz, DMSO-d ₆ ): 8.90 (br s, 1H), 8.30 (s, 2H), 8.18 (d, 1H, J = 9.9 Hz), 7.25-7.14 (m, 5H), 7.10 (d, 1H, J = 8.2 Hz), 7.07-7.02 (m, 1H), 6.95 (d, 1H, J = 8.1 Hz), 6.82 (dd, 1H, J = 8.1, 1.9 Hz), 6.55 (d, 1H, J = 8.1 Hz), 6.52 (d, 1H, J = 9.9 Hz), 5.19 (t, 1H, J = 6.0 Hz), 2.89-2.83 (m, 2H), 2.78-2.63 (m, 7H), 2.54 (t, 4H, J = 7.6 Hz), 2.34 (m, 2H), 1.80 (m, 2H), 0.93 (d, 6H, J = 10 Hz).

Example 14

8-Hydroxy-5-((i?)-l-hydroxy-2-{2-[4-hydroxy-3-(4-phenyl-pipe ridin-4-yl)-phenyl]- ethylamino}-ethyl)-lH-quinolin-2

a. 4-[5-(2-Bromo-ethyl)-2-hydroxy-phenyl]-4-phenyl-piperidine-l -carboxylic acid tert-butyl ester

The title compound was prepared from Example 12(a) using a method similar to that described for Example 6, step e.

LCMS (Method 1): Rt 5.05 min, m/z 482/484 [M+Na] ⁺

b. 8-Hydroxy-5-((i?)-l-hydroxy-2-{2-[4-hydroxy-3-(4-phenyl-pipe ridin-4-yl)-phenyl]- ethylamino}-ethyl)-lH-quinolin-2

The title compound was prepared from Example 14(a) using methods similar to those described for Example 1 , steps h, f, i.

LCMS (Method 2) Rt 4.01 min, m/z 500 [M+H] ⁺ .

Ή NMR (400 MHz, CD ₃ OD): 8.38 (br s, 2H), 8.31 (d, 1H, J = 9.5 Hz), 7.34-7.20 (m, 5H), 7.17-7.10 (m, 2H), 7.06-7.00 (m, 2H), 6.72 (d, 1H, J = 8.2 Hz), 6.66 (d, 1H, J = 9.8 Hz), 5.39 (t, 1H, J = 6.6 Hz), 3.30-3.19 (m, 8H), 3.22-2.88 (m, 2H), 3.02-2.92 (m, 2H), 2.62- 2.53 (m, 2H).

The following compounds (Table 3) were prepared using similar methods to those described in Example 14, step b, starting from Example 6(e) and Example 1(e) respectively.

Example No. Structure NMR (400 MHz) δ LCMS

(CD ₃ OD): 8.40 (br s, 2H), 8.33

(d, 1H, J = 9.9 Hz), 7.33-7.22

(m, 5H), 7.21-7.12 (m, 4H),

(Method 2) 7.05-7.00 (m, 2H), 6.90-6.84 (m,

15 Rt 5.57 min,

2H), 6.69 (d, 1H, J = 4.5 Hz),

m/z 620

O 6.66 (d, 1H, J = 2.8 Hz), 5.39 (t,

OH ^H [M+H] ⁺

1H, J = 6.7 Hz), 4.12 (t, 2H, J =

6.7 Hz), 3.30-3.17 (m, 8H),

3.15-3.05 (m, 2H), 3.00-2.93 (m, 4H), 2.55-2.46 (m, 2H).

(CD ₃ OD): 8.50 (br s, 1H), 8.37

(d, 1H, J = 9.9 Hz), 7.28 (d, 1H,

J = 8.21 Hz), 7.24-7.16 (m, 6H),

7.14-7.07 (m, 1H), 7.04-7.00 (m,

2H), 6.95 (dd, 1H, J = 8.2, 2.0

(Method 2) Hz), 6.88 (d, 2H, J = 8.5 Hz),

Rt 5.75 min,

16 6.68 (d, 1H, J = 9.8 Hz), 6.64 (d,

m/z 634 1H, J = 8.1 Hz), 5.41 (t, 1H, J =

[M+H] ⁺ 6.7 Hz), 3.91 (t, 2H, J = 6.1 Hz),

3.26-3.14 (m, 6H), 3.14-3.05 (m,

2H), 2.96 (m, 4H), 2.74 (t, 2H, J

= 7.2 Hz), 2.50-2.40 (m, 2H),

2.06-1.96 (m, 2H).

Table 3

Example 17

8-Hydroxy-5-{(i?)-l-hydroxy-2-[2-(4-{2-[4-hydroxy-3-(l-methy l-4-phenyl-piperidin-4-yl)- phenyl]-ethoxy}-phenyl)-ethylamino]-ethyl}-lH-quinolin-2-one formic acid salt

The title compound was prepared starting from Example 6(b) using a method similar to that described for Example 1, step a, using l-methyl-4-phenyl-piperidin-4-ol in place of 4-phenyl- piperidin-4-ol, followed by methods similar to Example 6, step d and Example 1 , steps c, h-i.

LCMS (Method 2) Rt 5.49 min, m/z 634 [M+H ⁺ ].

Ή NMR (400 MHz, CD ₃ OD): 8.50 (br s, 1H), 8.35 (d, 1H, J = 9.9 Hz), 7.33-7.21 (m, 5H), 7.20-7.09 (m, 4H), 7.05-6.99 (m, 2H), 6.86 (d, 2H, J = 8.4 Hz), 6.67 (d, 1H, J = 9.8 Hz), 6.66 (d, 1H, J = 7.9 Hz), 5.38 (t, 1H, J = 6.7 Hz), 4.13 (t, 2H, J = 6.5 Hz), 3.25-3.10 (m, 12H), 3.02-2.92 (m, 4H), 2.71 (s, 3H).

Example 18

8-Hydroxy-5-[(i?)-l-hydroxy-2-(6-{2-[4-hydroxy-3-(l-methyl-4 -phenyl-piperidin-4-yl)- phenyl]-ethoxy}-hexylamino)-ethyl]-lH-quinolin-2-one diformic acid salt

a. 4-[2-Benzyloxy-5-(2-hydroxy-ethyl)-phenyl]-4-phenyl-piperidi ne-l-carboxylic acid tert- butyl ester

A solution of Example 12(a) (1.525 g, 3.84 mmol) in DMF (50 mL) was treated with potassium carbonate (954 mg, 6.91 mmol) and benzyl bromide (0.6 mL, 4.99 mmol). The reaction mixture was stirred at RT for 2 days, treated with further benzyl bromide (0.2 eq), stirred at 50 °C for 4 h and at RT for 18 h. The solvent was removed in vacuo. The resulting residue was dissolved in EtOAc, washed with water, dried (Na ₂ S0 ₄ ), concentrated in vacuo and purified by chromatography (cyclohexane to cyclohexane/EtOAc 4/6) to afford the title compound as a clear foam (963 mg,

51%).

LCMS (Method 1): Rt 4.68 min, m/z 488 [M+H] b. 4-{2-Benzyloxy-5-[2-(6-bromo-hexyloxy)-ethyl]-phenyl}-4-phen yl-piperidine-l-carboxylic acid teri-butyl ester

A solution of Example 18(a) (300 mg, 0.62 mmol) in THF (10 mL) was treated with sodium hydride (60 %, 27 mg, 0.68 mmol). The reaction mixture was stirred at RT for 30 mins, then treated with 1,6-dibromohexane (0.5 mL, 3.1 mmol) and stirred at 80 °C for 48 h. The reaction mixture was diluted with EtOAc, washed with aq. ammonium chloride solution, and purified by chromatography (cyclohexane/diethyl ether 1/0 to 1/1) to give the title compound (280 mg, 69%).

LCMS (Method 1) Rt 5.21 min, m/z 673 [M+Na] ⁺ . c. 4-{5-[2-(6-Bromo-hexyloxy)-ethyl]-2-methyl-phenyl}-4-phenyl- piperidine-l-carboxylic acid tert-butyl ester

A suspension of Example 18(b) (280 mg, 0.43 mmol) and 10% palladium on charcoal (28 mg) in EtOH (10 mL) was stirred under an atmosphere of hydrogen for 16 h. The reaction mixture was filtered over Celite®, concentrated in vacuo and the resulting residue purified by chromatography eluting from 0-20% EtOAc/cyclohexane to afford the title compound (180 mg, 75%).

LCMS (Method 1) Rt 5.37 min, m/z 562 and 560 (1 : 1) [M+H] ⁺ . d. 8-Hydroxy-5-[(i?)-l-hydroxy-2-(6-{2-[4-hydroxy-3-(l-methyl-4 -phenyl-piperidin-4-yl)- phenyl]-ethoxy}-hexylamino -ethyl]-lH-quinolin-2-one diformic acid salt

The title compound was prepared from Example 18(c) using methods similar to those described for Example 1 , steps f-i.

LCMS (Method 2) Rt 5.29 min, m/z 614 [M+H] ⁺ .

Ή NMR (400 MHz, CD ₃ OD): 8.52 (br s, 2H), (8.36 (d, 1H, J = 9.9 Hz), 7.28 (m, 3H), 7.22 (t, 2H, J = 7.2 Hz), 7.12 (t, 2H, J = 7.9 Hz), 7.03 (d, 1H, J = 8.2 Hz), 6.95 (d, 1H, J = 8.2 Hz), 6.68 (d, 1H, J = 9.8 Hz), 6.64 (d, 1H, J = 8.1 Hz), 5.37 (dd, 1H, J = 7.9, 5.5 Hz), 3.60 (t, 2H, J = 6.8 Hz), 3.45 (t, 2H, J = 6.4 Hz), 3.30-3.10 (m, 10H), 2.96 (t, 2H, J = 8.0 Hz), 2.78 (m, 2H), 2.74 (s, 3H), 1.67 (m, 2H), 1.57 (m, 2H), 1.39-1.34 (m, 4H).

Example 19

8-Hydroxy-5-[(i?)-l-hydroxy-2-(4-{3-[4-hydroxy-3-(l-methyl-4 -phenyl-piperidin-4-yl)- phenyl]-propoxy}-benzylamino)-ethyl]-lH-quinolin-2-one diformic acid salt

a. 4-{3-[4-Hydroxy-3-(l-methyl-4- henyl-piperidin-4-yl)-phenyl]-propoxy}-benzaldehyde

The title compound was prepared from Example 1(c) using methods similar to those described for Example 1, steps f-g-d using 4-hydroxybenzaldehyde in place of 2-(4-hydroxyphenyl)-ethanol.

LCMS (Method 1) Rt 3.48 min, m/z 430 [M+H] ⁺ . b. 5-[(i?)-l-(tert-Butyl-dimethyl-silanyloxy)-2-(4-{3-[4-hydrox y-3-(l-methyl-4-phenyl- piperidin-4-yl)-phenyl]-pro oxy}-benzylamino)-ethyl]-8-hydroxy-lH-quinolin-2-one

A solution of Example 19(a) (57 mg, 0.133 mmol) and 5-[(R)-2-amino- l-(tert-butyl-dimethyl- silanyloxy)-ethyl]-8-hydroxy- lH-quinolin-2-one in dry MeOH (3 mL) was allowed to stir with 3A mol sieves for 18 h at RT. Sodium triacetoxyborohydride was added and the reaction stirred at RT for 30 min. The reaction mixture was quenched with sat. NaHC0 ₃ (20 mL) and the DCE layer was separated. The aqueous was further extracted with DCM and combined organic extracts washed with sat. brine (20 mL), dried (Na ₂ S0 ₄ ), filtered and concentrated in vacuo, then purified by chromatography, loading in 2.5% MeOH/DCM (NB: a few drops of 2M NH3 in MeOH was needed to solubilise crude RXN mixture for column loading) and eluting from 2.5-20% MeOH/DCM, then 2.5-20% (2M NH ₃ /MeOH)/DCM to give the title compound as a straw-coloured stiff oil (55 mg, 55%).

LCMS (Method 1) Rt 3.70 min, m/z 748 [M+H] ⁺ . c. 8-Hydroxy-5-[(i?)-l-hydroxy-2-(4-{3-[4-hydroxy-3-(l-methyl-4 -phenyl-piperidin-4-yl)- phenyl]-propoxy}-benzylamino -ethyl]-lH-quinolin-2-one diformic acid salt

The title compound was prepared from Example 19(b) using a method similar to that described for Example 1 , step i.

LCMS (Method 3) Rt 5.91 min, m/z 634 [M+H] ⁺ .

Ή NMR (400 MHz, CD ₃ OD): 8.50 (br s, 2H), 8.22 (d, 1H, J = 9.9 Hz), 7.40 (d, 2H, J = 8.4 Hz), 7.26-7.15 (m, 5H), 7.08 (t, 1H, J = 7.1 Hz), 7.03 (br s, 1H), 7.00 (d, 2H, J = 8.2 Hz), 7.00-6.92 (m, 2H), 6.64 (d, 1H, J = 8.1 Hz), 6.61 (d, 1H, J = 9.8 Hz), 5.36 (dd, 1H, J = 8.0, 5.3 Hz), 4.17 (s, 2H), 3.94 (t, 2H, J = 6.1 Hz), 3.30-3.03 (m, 10H), 2.82-2.67 (m, 2H), 2.73 (s, 3H), 2.07- 1.98 (m, 2H).

The following compounds (Table 4) were prepared as formic acid salts using similar methods to those described for Example 19. In Examples 21-23 5-[(R)-2-amino- l-(tert-butyl-dimethyl- silanyloxy)-ethyl]-8-hydroxy- lH-quinolin-2-one is replaced with N- {5-[(R)-2-amino- l -(tert-butyl- dimethyl-silanyloxy)-ethyl]-2-hydroxy-phenyl} -formamide (US2007249675) and N- {5-[(R)-2- amino- 1 -(tert-butyl-dimethyl-silanyloxy)-ethyl]-2-hydroxy-phenyl} -formamide (US2007249675).

Table 4

Example 23

8-Hydroxy-5-((i?)-l-hydroxy-2-{2-[4-(3-{4-hydroxy-3-[l-(2-me thoxy-ethyl)-4-phenyl- piperidin-4-yl]-phenyl}-propoxy)-phenyl]-ethylamino}-ethyl)- lH-quinolin-2-one formic acid salt

The title compound was prepared from Example 1(f) using methods similar to those described for Example 1, steps g-i, using methoxy-acetaldehyde (prepared in situ from 1 , 1 ,2-trimethoxy-ethane by action of 1M HC1) in place of aqueous formaldehyde.

LCMS (Method 3) Rt 6.58 min, m/z 692 [M+H] ⁺ . Ή NMR (400 MHz, CD ₃ OD): 8.46 (d, 1H, J = 10 Hz), 8.34 (br s, 1H), 7.29 (d, 1H, J = 8.2 Hz), 7.18-7.07 (m, 6H), 7.07-7.01 (m, 1H), 6.99 (d, 1H, J = 8 Hz), 6.92 (d, 1H, J = 8.2 Hz), 6.87-6.81 (m, 3H), 6.69 (d, 1H, J = 9.8 Hz), 6.61 (d, 1H, J = 8.1 Hz), 5.48 (dd, 1H, J = 9.6, 2.6 Hz), 3.87 (m, 2H), 3.66 (t, 2H, J = 4.5 Hz), 3.45 (m, 1H), 3.31 (s, 3H) 3.21-3.06 (m, 8H), 2.94 (t, 2H, J = 8.3 Hz), 2.73 (t, 2H, J = 6.1 Hz), 2.69-2.52 (br s, 1H), 2.50-2.10 (br s, 2H), 2.04-1.90 (m, 2H), 1.28 (t, 2H, J = 7.3 Hz).

Example 24

4-{[(i?)-2-Hydroxy-2-(8-hydroxy-2-oxo-l,2-dihydro-quinolin-5 -yl)-ethylamino]-methyl}-N-{3- [4-hydroxy-3-(l-methyl-4-phenyl-piperidin-4-yl)-phenyl]-prop yl}-benzamide diformic acid salt

a. 4-[5-(3-Azido-propyl)-2-hydroxy-phenyl]-4-phenyl-piperidine- l-carboxylic acid tert-butyl ester

A solution of Example 1(c) (2 g, 4.22 mmol) in DMF (25 mL) was treated with sodium azide and the reaction was warmed to 80°C for 1 h. The reaction mixture was cooled then quenched with sat. NaHCC>3 and then extracted with EtOAc (3 x 50 mL). The combined organic extract was washed with water, dried (Na ₂ S0 ₄ ), concentrated in vacuo and purified by chromatography (10- 15% EtO Ac/Petrol (40-60 °C)) to afford the title compound as a colourless stiff oil (1.48 g, 80%).

LCMS (Method 4) Rt 4.90 min, m/z 459 [M+Na] ⁺ . b. 4-(3-Amino-propyl)-2-(l-methyl-4-phenyl-piperidin-4-yl)-phen ol

The title compound was prepared from Example 24(a) using methods similar to those described for Example 1, steps f-g and Example 18, step c. LCMS (Method 4) Rt 1.90 min, m/z 325 [M+H] ⁺ . c. 4-Formyl-N-{3-[4-hydroxy-3-(l-methyl-4-phenyl-piperidin-4-yl )-phenyl]- propylj-benzamide

A solution of 4-formyl-benzoic acid (148 mg, 0.99 mmol) in DMF (2 mL) was treated with dizsopropylethylamine (310 pL, 1.79 mmol) and HATU (374 mg, 0.99 mmol) and allowed to stir for 5 min before the dropwise addition of a solution of Example 24(b) (290 mg, 0.90 mmol) in DMF (1 mL). The resulting mixture was stirred for 30 min then partitioned between sat. NaHC0 ₃ and EtOAc (2 x 25 mL). The combined organic extracts were washed with water then brine, dried (Na ₂ S0 ₄ ) and concentrated in vacuo. The resulting residue was purified by chromatography eluting from 2.5-5% MeOH/DCM affording the title compound as a foam (1 15 mg, 28%).

LCMS (Method 1 10149145) Rt 3.09 min, m/z 457 [M+H] ⁺ d. 4-{[(R)-2-Hydroxy-2-(8-hydroxy-2-oxo-l,2-dihydro-quinolin-5- yl)-ethylamino]-methyl}-N- {3-[4-hydroxy-3-(l-methyl-4-phenyl-piperidin-4-yl)-phenyl]-p ropyl}-benzamide diformic acid salt

The title compound was prepared from Example 24(c) using methods similar to those described Example 19, steps b-c.

LCMS (Method 3) Rt 4.73 min, m/z 661 [M+H] ⁺ .

Ή NMR (400 MHz, CD ₃ OD): 8.42 (br s, 2H), 8.25 (d, 1H, J = 9.8 Hz), 7.78 (d, 2H, J = 8.2 Hz), 7.52 (d, 2H, J = 8.2 Hz), 7.34-7.17 (m, 5H), 7.10 (t, 2H, J = 7.2 Hz), 6.97 (d, 1H, J = 8.4 Hz), 6.94 (d, 1H, J = 8.4 Hz), 6.62 (d, 1H, J = 7.3 Hz), 6.60 (d, 1H, 9.8 Hz), 5.34 (dd, 1H, J = 8.4, 4.8 Hz), 4.17 (s, 2H), 3.36 (d, 2H, J = 7 Hz), 3.32-3.08 (m, 8H), 3.08-3.04 (m, 2H), 2.76 (s, 3H), 2.61 (t, 2H, J = 6.7 Hz), 1.89 (m, 2H).

The following compound (Table 5) was prepared as formic acid salts using similar methods to those described for Example 24: Example No. Structure NMR (400 MHz) δ LCMS

(CD ₃ OD): 8.44 (br s, 2H), 7.81 (d,

2H, J = 8.2 Hz), 7.51 (d, 2H, J = 8.2

Hz), 7.34-7.17 (m, 4H), 7.10 (t, 2H,

J = 7.2 Hz), 6.96 (d, 1H, J = 7.4

Hz), 6.94 (d, 1H, J = 7.4 Hz), 6.62 (Method 3)

25 (d, 1H, J = 8.1 Hz), 6.51 (d, 1H, 8.5 Rt 4.77 min,

Hz), 5.12 (dd, 1H, J = 9.5, 3.1 Hz), m/z 665 4.47 (AB-syst, 2H), 4.19 (s, 2H), [M+H] ⁺ 3.36 (d, 2H, J = 7 Hz), 3.33-3.09

(m, 8H), 3.06 (m, 1H), 2.94 (m,

1H), 2.76 (s, 3H), 2.61 (t, 2H, J =

6.8 Hz), 1.89 (m, 2H).

Table 5

Example 26

4- {2- [(i?)-2-Hydroxy-2-(8-hydroxy-2-oxo-l ,2-dihydro-quinolin-5-yl)-ethylamino] -ethyl}-N- {3- [4-hydroxy-3-(l-methyl-4- henyl-piperidin-4-yl)-phenyl]-propyl}-benzamide formic acid salt

a. 4-[5-(3-Amino-propyl)-2-hydroxy-phenyl]-4-phenyl-piperidine- l-carboxylic acid tert-butyl ester

The title compound was prepared from Example 24(a) using a method similar to that described for Example 18, step c.

LCMS (Method 1) Rt 3.64 min, m/z 41 1 [M+H] ⁺ . b. 4-{2-[(R)-2-Hydroxy-2-(8-hydroxy-2-oxo-l,2-dihydro-quinolin- 5-yl)-ethylamino]-ethyl}-N- {3-[4-hydroxy-3-(l-methyl-4-phenyl-piperidin-4-yl)-phenyl]-p ropyl}-benzamide formic acid salt

The title compound was prepared from Example 26(a) using methods similar to those described for Example 24, step c using 4-(2-hydroxy-ethyl)-benzoic acid (prepared according to US2006135770) in place of 4-formyl-benzoic acid, and Example 1, steps e-i.

LCMS (Method 3) Rt 5.09 min, m/z 675 [M+H] ⁺ .

Ή NMR (400 MHz, CD ₃ OD): 8.41 (br s, 1H), 8.35 (d, 1H, J = 9.9 Hz), 7.72 (d, 2H, J = 8.2 Hz), 7.35 (d, 2H, J = 8.2 Hz), 7.32-7.16 (m, 5H), 7.15-7.01 (m, 2H), 6.98 (d, 1H, J = 8.2 Hz), 6.93 (d, 1H, J = 7.5 Hz), 6.64 (d, 1H, J = 9.8 Hz), 6.61 (d, 1H, J = 8.1 Hz), 5.39 (m, 1H), 3.35 (t, 2H, J = 7 Hz), 3.31-3.03 (m, 14H), 2.76 (s, 3H), 2.60 (m, 2H), 1.88 (m, 2H).

The following compound (Table 6) was prepared as a formic acid salt using similar methods to those described for Example 26:

Table 6 Example 28

8-Hydroxy-5-[(i?)-l-hydroxy-2-(4-{3-[4-hydroxy-3-(l-methyl-4 -thiophen-2-yl-piperidin-4-yl)- phenyl]-propoxy}-benzylamino -ethyl]-lH-quinolin-2-one diformic acid salt.

a. 4-(5-Chloro-thiophen-2-yl)-4-hydroxy-piperidine-l-carboxylic acid tert-butyl ester

To a cooled (-78 °C) solution of 2-bromo-5-chlorothiophene (5.05 g, 25.60 mmol) in THF (35 mL) was added drop-wise n-butyllithium (2.5 M in hexanes; 10.23 mL) and the solution was stirred for 30 min under argon. A solution of 4-oxo-piperidine- 1 -carboxylic acid tert-butyl ester (5 g, 25.10 mmol) in THF (9 mL) was added drop-wise over 25 min while the temperature was maintained <- 40 °C and the solution was then allowed to warm to -20 °C for 1.5 h, then 0 °C for 1 h. The reaction mixture was quenched by addition of brine (7 mL) and then partitioned between water and EtOAc and the organic extract was washed with water, dried (Na ₂ S0 ₄ ), and concentrated in vacuo. The crude product was crystallised from hot heptane/EtOAc to afford the title compound (6 g, 74%).

LCMS (Method 4) Rt 4.54 min, m/z 340 [M+Na] ⁺ . b. 4-(3-Bromo-propyl)-2-(l-methyl-4-thio hen-2-yl-piperidin-4-yl)-phenol

The title compound was prepared from Example 28(a) and 4-(3 -hydroxy -propyl)-phenol using methods similar to those described for Example 1, steps a-b, Example 18, step c and Example 1, steps e-g.

LCMS (Method 1) Rt 3.23 min, m/z 394, 396 [M+H] ⁺ .

c. 8-Hydroxy-5-[(R)-l-hydroxy-2-(4-{3-[4-hydroxy-3-(l-methyl-4- thiophen-2-yl-piperidin-4- yl)-phenyl]-propoxy}-benzylamino)-ethyl]-lH-quinolin-2-one diformic acid salt.

The title compound was prepared from Example 28(b) using methods similar to those described for Example 19, steps a-c.

LCMS (Method 5) Rt 5.98 min, m/z 640 [M+H] ⁺ .

Ή NMR (400 MHz, CD ₃ OD): 8.42 (br s, 2H), 8.22 (d, 1H, J = 9.8 Hz), 7.37 (d, 2H, J = 8.7 Hz), 7.22 (d, 1H, J = 8.2 Hz), 7.16 (br m, 1H), 6.97 (d, 1H, J = 8.2 Hz), 6.95-6.70 (m, 6H), 6.66 (d, 1H, J = 8.1 Hz), 6.58 (d, 1H, J = 9.8 Hz), 5.37 (m, 1H), 4.17 (m, 2H), 3.88 (t, 2H, J = 6.1 Hz), 3.30-3.14 (m, 8H), 2.73 (s, 3H), 2.64 (m, 2H), 2.53-2.25 (br m. 2H), 1.94 (m, 2H).

The following compound (Table 7) was prepared as a formic acid salt using similar methods to those described for Example 28:

Table 7 Example 30

5-[(i?)-2-(3-Fluoro-4-{3-[4-hydroxy-3-(l-methyl-4-phenyl-pip eridin-4-yl)-phenyl]-propoxy}- benzylamino)-l-hydroxy-eth l]-8-hydroxy-lH-quinolin-2-one formic acid salt.

a. 3-Fluoro-4-{3-[4-hydroxy-3-(l-methyl-4-phenyl-piperidin-4-yl )-phenyl]-propoxy}- benzaldehyde

The title compound was prepared from Example 1(c) using methods similar to those described for Example 1, steps f-g-d starting from and using 3-fluoro-4-hydroxy-benzaldehyde in place of 2-(4- hydroxyphenyl)-ethanol.

LCMS (Method 1) Rt 3.37 min, m/z 448 [M+H] ⁺ . b. 5-[(R)-2-(3-Fluoro-4-{3-[4-hydroxy-3-(l-methyl-4-phenyl-pipe ridin-4-yl)-phenyl]- propoxy}-benzylamino)-l-h droxy-ethyl]-8-hydroxy-lH-quinolin-2-one formic acid salt.

The title compound was prepared from Example 30(a) using methods similar to those described for Example 19, steps b-c.

LCMS (Method 5) Rt 5.95 min, m/z 652 [M+H] ⁺ .

Ή NMR (400 MHz, CD ₃ OD): 8.46 (br s, 1H), 8.25 (d, 1H, J = 9.8 Hz), 7.28 (m, 1H), 7.21 (d, 1H, J = 8.3 Hz), 7.19-7.09 (m, 5H), 7.08-6.99 (m, 3H), 6.97 (d, 1H, J = 8.2 Hz), 6.93 (d, 1H, J = 7.2 Hz), 6.61 (d, 1H, J = 7.8 Hz), 6.59 (d, 1H, J = 9.8 Hz), 5.35 (m, 1H), 4.10 (s, 2H), 3.97 (m, 2H), 3.20-2.78 (m, 10H), 2.74 (m, 2H), 2.71 (s, 3H), 2.03 (m, 2H). The following compounds (Table 8) were prepared as formic acid salts using similar methods to those described for Example 30, except that in Example 34, 7-((R)-2-amino- l -hydroxy-ethyl)-4- hydroxy-3H-benzothiazol-2-one (prepared according to WOO2007027133) was used, removing the need for the final deprotection step (Example 19, step c):

(CD ₃ OD): 8.47 (br s, 2H), 8.25 (d,

1H, J = 9.9 Hz), 7.39 (t, 1H, J = 8.5

Hz), 7.24-7.11 (m, 5H), 7.05 (t, 1H,

J = 6.9 Hz), 6.99 (br m, 1H), 6.97

(d, 1H, J = 8.2 Hz), 6.91 (d, 1H, J (Method 5)

33 = 8 Hz), 6.78-6.70 (m, 2H), 6.62 Rt 6.14 min,

0 (d, 1H, J = 8.2 Hz), 6.59 (d, 1H, J = m/z 652

OH ^H

9.9 Hz), 5.35 (dd, 1H, J = 7.9, 5.3 [M+H] ⁺ Hz), 4.17 (m, 2H), 3.90 (t, 2H, J =

6.1 Hz), 3.26-2.83 (m, 8H), 2.74- 2.64 (m, 5H), 2.64-2.20 (br m, 2H),

2.02 (m, 2H).

(CD ₃ OD): 8.45 (br s, 2H), 7.36 (d,

2H, J = 8.6 Hz), 7.26-7.14 (m, 4H),

7.07 (t, 1H, J = 6.9 Hz), 7 (bs, 1H),

6.94 (d, 2H, J = 8.6 Hz), 6.91 (d, (Method 5)

34 2H, J = 8.3 Hz), 6.71 (d, 1H, J = 8.2 Rt 6.19 min,

Hz), 6.61 (d, 1H, J = 8.1 Hz), 4.91 m/z 640

OH

(dd, 1H, J = 9.6, 4.1 Hz), 4.12 (s, [M+H] ⁺ 2H), 3.91 (t, 2H, J = 6.1 Hz), 3.24- 2.88 (m, 8H), 2.76-2.64 (m, 5H),

2.63-2.14 (br m, 2H), 2.01 (m, 2H).

Table 8

Example 35

5-{[(i?)-2-Hydroxy-2-(8-hydroxy-2-oxo-l,2-dihydro-quinolin-5 -yl)-ethylamino]-methyl}- thiophene-2-carboxylic acid {3-[4-hydroxy-3-(l-methyl-4-phenyl-piperidin-4-yl)-phenyl]- propyl}-amide formic acid salt.

The title compound was prepared from Example 24(b) using methods similar to those described for Example 24, step c and Example 19, steps b-c, using 5-formyl-thiophene-2-carboxylic acid in place of cyclohexyl-(2,2-dimethoxy-ethyl)-amine.

LCMS (Method 5) Rt 4.80 min, m/z 667 [M+H ⁺ ]. Ή NMR (400 MHz, CD ₃ OD): 8.40 (br s, IH), 8.25 (d, IH, J = 9.9 Hz), 7.49 (d, IH, J = 3.8 Hz), 7.36-7.15 (m, 5H), 7.14-7.02 (m, 3H), 6.97 (d, IH, J = 8.2 Hz), 6.92 (d, IH, J = 8 Hz), 6.61 (d, IH, J = 8.2 Hz), 6.59 (d, IH, J = 9.8 Hz), 5.26 (dd, IH, J = 8.2, 4.7 Hz), 4.20 (m, 2H), 3.31 (t, 2H, J = 7 Hz), 3.22-3 (br m, 8H), 3-2.90 (m, 2H), 2.78 (m, 3H), 2.60 (m, 2H), 1.87 (m, 2H).

The following compounds (Table 9) were prepared as formic acid salts using similar methods to those described for Example 35:

Example No. Structure NMR (400 MHz) δ LCMS

(CD ₃ OD): 8.40 (br s, IH), 7.53 (d,

IH, J = 3.8 Hz), 7.37-7.16 (m, 4H),

7.15-6.99 (m, 3H), 6.94 (d, IH, J =

8.5 Hz), 6.92 (m, IH), 6.61 (d, IH,

(Method 5) J = 8.1 Hz), 6.51 (d, IH, J = 8.4

36 Rt 4.89 min,

Hz), 5.09 (dd, IH, J = 9.2, 3.3 Hz),

m/z 671

IH ^H 4.48 (s, 2H), 4.27 (m, 2H), 3.46- [M+H] ⁺

3.06 (br m, 6H), 3.31 (t, 2H, J = 7

Hz), 3.03 (m, IH), 2.91 (m, IH),

2.78 (s, 3H), 2.60 (m, 2H), 2.50-2

(br m, 2H), 1.86 (m, 2H).

(CD ₃ OD): 8.36 (br s, IH), 8.26 (d,

IH, J = 9.8 Hz), 7.95 (s, IH), 7.47

(br s, IH), 7.35-7.15 (m, 5H), 7.1

(m, 2H), 6.97 (d, IH, J = 8.2 Hz), (Method 5)

37 6.92 (m, IH), 6.60 (d, 2H, J = 9.8 Rt 4.73 min,

Hz), 5.31 (m, IH), 4.25 (m, 2H), m/z 667 3.54-2.93 (br m, 6H), 3.31 (m, 2H), [M+H] ⁺ 3.03 (d, 2H, J = 6.3 Hz), 2.78 (s,

3H), 2.60 (m, 2H), 2.50-1.97 (br m,

2H), 1.87 (m, 2H). (CD ₃ OD): 8.42 (br s, 2H), 8.27 (d,

1H, J = 9.9 Hz), 7.78 (d, 2H, J = 8.3

Hz), 7.60 (d, 2H, J = 8.3 Hz), 7.36-

7.16 (m, 4H), 7.21 (d, 1H, J = 8.2

r Hz), 7.16-7 (m, 2H), 6.97 (d, 1H, J (Method 5)

41 JL = 8.2 Hz), 6.81 (m, 1H), 6.59 (d, Rt 4.78 min,

1H, J = 9.8 Hz), 6.58 (d, 1H, J = 7.8 m/z 697

Hz), 5.32 (dd, 1H, J = 8.2, 5 Hz), [M+H] ⁺ 4.14 (m, 2H), 3.54-3.05 (m, 6H),

3.04-2.96 (m, 2H), 2.8 (m, 2H),

2.76 (s, 3H), 2.54 (m, 2H), 2.44- 1.91 (br m, 2H), 1.70 (m, 2H).

Table 9

Example 42

4- { [(i?)-2-Hydroxy-2-(5-hydroxy-3-oxo-3,4-dihydro-2H-benzo [1 ,4] oxazin-8-yl)-ethylamino] - methyl}-N-{3-[4-hydroxy-3-(l-methyl-4-phenyl-piperidin-4-yl) -phenyl]-propyl}-N-methyl- benzamide formic acid salt

a. 4-[3-(Benzyl-methyl-amino)-p iperidin-4-yl)-phenol

The title compound was prepared from Example 1(c) using methods similar to those described for Example 1, steps f,g,d using benzyl-methyl-amine in place of the 4- hydroxybenzaldehyde/potassium carbonate mixture.

LCMS (Method 1) Rt 4.08 min, m/z 429 [M+H] ⁺ . b. 4-(3-Methylamino-propyl)-2-(l-methyl-4-phenyl-piperidin-4-yl )-phenol

The title compound was prepared from Example 42(a) using a method similar to that described for Example 18, step c.

¾ NMR (400 MHz, CDC1 ₃ ): 7.35-7.20 (m, 5H), 7.09 (d, 1H, J = 2.6 Hz), 6.87 (dd, 1H, J = 10.8, 2.9 Hz), 6.61 (d, 1H, J = 10.8 Hz), 2.80-2.49 (m, 7H), 2.47 (s, 3H), 2.44 (s, 3H), 2.42- 2.20 (br m, 7H), 1.98-1.80 (m, 2H).

c. 4-{[(i?)-2-Hydroxy-2-(5-hydroxy-3-oxo-3,4-dihydro-2H-benzo[l ,4]oxazin-8-yl)-ethylamino]- methyl}-N-{3-[4-hydroxy-3-(l-methyl-4-phenyl-piperidin-4-yl) -phenyl]-propyl}-N-methyl- benzamide formic acid salt

The title compound was prepared from Example 42(b) using methods similar to those described for Example 24, step c, using 4-formyl-benzoic acid in place of cyclohexyl-(2,2-dimethoxy-ethyl)- amine, and Example 19, steps b-c.

LCMS (Method 5) Rt 5.08 min, m/z 679 [M+H] ⁺ .

Ή NMR (400 MHz, CD ₃ OD): 8.40 (br s, 1H), 7.59-7.22 (m, 8H), 7.14 (t, 2H, J = 7.3 Hz), 6.97 (d, 1H, J = 8.5 Hz), 6.95 (br s, 1H), 6.63 (br s, 1H), 6.55 (d, 1H, J = 8.5 Hz), 5.14 (dd, 1H, J = 8.2, 4.7 Hz), 4.09 (s, 2H), 3.63-2.82 (m, 15H), 2.74 (s, 3H), 2.71-2.22 (br s, 3H), 2.52-2.24 (br m, 1H), 2.10- 1.71 (br m, 2H).

Example 43

4-{[(i?)-2-Hydroxy-2-(8-hydroxy-2-oxo-l,2-dihydro-quinolin-5 -yl)-ethylamino]-methyl}-N-{2- [4-hydroxy-3-(l-methyl-4-phenyl-piperidin-4-yl)-phenyl]-ethy l}-benzamide formic acid salt

a. 4-(2-Amino-ethyl)-2-(l-methyl-4- henyl-piperidin-4-yl)-phenol

The title compound was prepared using methods similar to those described for Example 1 , step a, using (4-hydroxy-phenyl)-acetonitrile in place of 4-(3-hydroxy-propyl)-phenol, followed by Example 18, step c.

LCMS (Method 4) Rt 1.57 min, m/z 31 1 [M+H] ⁺ . b. 4-[l,3]Dioxolan-2-yl-N-{2-[4-hydroxy-3-(l-methyl-4-phenyl-pi peridin-4-yl)-phenyl]-ethyl}- benzamide

The title compound was prepared from Example 43(a) using methods similar to those described for Example 25, step c, using 4-[l,3]dioxolan-2-yl-benzoic acid in place of cyclohexyl-(2,2- dimethoxy-ethyl)-amine.

LCMS (Method 4) Rt 2.92 min, m/z 487 [M+H] ⁺ . c. 4-Formyl-N-{2-[4-hydroxy-3- l-methyl-4-phenyl-piperidin-4-yl)-phenyl]-ethyl}-benzamide

A solution of Example 43(b) (200 mg, 0.41 mmol) in THF (5 mL) was treated with 1 N HC1 and allowed to stir for 17 h at RT. The reaction mixture was extracted with EtOAc and washed with sodium bicarbonate (x 2), dried (MgS0 ₄ ), filtered and concentrated in vacuo to afford the title compound as white solid (1 15 mg, 63%).

LCMS (Method 4): Rt 2.84 min, m/z 443 [M+H] ⁺ d. 4-{[(R)-2-Hydroxy-2-(8-hydroxy-2-oxo-l,2-dihydro-quinolin-5- yl)-ethylamino]-methyl}-N- {2-[4-hydroxy-3-(l-methyl-4-phenyl-piperidin-4-yl)-phenyl]-e thyl}-benzamide formic acid salt

The title compound was prepared from Example 43(c) using methods similar to those described for Example 19, steps b-c.

LCMS (Method 5) Rt 4.28 min, m/z 647 [M+H ⁺ ].

Ή NMR (400 MHz, CD30D): 8.46 (br s, 1H), 8.23 (d, 1H, J = 9.9 Hz), 7.75 (d, 2H, J = 8.2 Hz), 7.49 (d, 2H, J = 8.2 Hz), 7.25-7.07 (m, 6H), 7.03 (t, 1H, J = 7.2 Hz), 6.96 (t, 1H, J = 8.2 Hz), 6.95 (dd, 1H, J = 8.1, 1.7 Hz), 6.60 (d, 1H, J = 8.2 Hz), 6.56 (d, 1H, J = 9.8 Hz), 5.31 (dd, 1H, J = 8.8, 4.4 Hz), 4.12 (s, 2H), 3.60 (t, 2H, J = 6.8 Hz), 3.31-3.02 (br m, 6H), 3.03-2.92 (m, 2H), 2.84 (t, 2H, J = 7 Hz), 2.73 (s, 3H), 2.66-2.05 (br m, 2H).

Example 44

8-Hydroxy-5-{(R)-l-hydroxy-2-[4-(3-{4-hydroxy-3-[l-(2-methox y-ethyl)-4

phenyl-piperidin-4-yl]-phenyl}-propoxy)-benzylamino]-ethy l}-lH-quinolin-2-one formic acid

a. 4-(3-Bromo-propyl)-2-[l-(2-methoxy-ethyl)-4-phenyl-piperidin -4-yl]-phenol

The title compound was prepared from Example 1(c) using methods similar to those in Example 1, steps f-g, using methoxy-acetaldehyde (prepared in situ from 1, 1,2-trimethoxy-ethane by action of IN HC1) in place of aqueous formaldehyde.

LCMS (Method 1) Rt 3.18 min, m/z 432, 434 [M+H] ⁺ . b. 8-Hydroxy-5-{(R)-l-hydroxy-2-[4-(3-{4-hydroxy-3-[l-(2-methox y-ethyl)-4 phenyl-piperidin-4-yl]-phenyl}-propoxy)-benzylamino]-ethyl}- lH-quinolin-2-one formic acid salt

The title compound was prepared from Example 44(a) and using methods similar to those described for Example 19, steps a-c.

LCMS (Method 5) Rt 6.23 min, m/z 678 [M+H] ⁺ .

Ή NMR (400 MHz, CD ₃ OD): 8.50 (s, 1H), 8.24 (d, 1H), 7.42 (d, 2H), 7.12-7.31 (m, 6H), 7.10 (m, 2H), 6.92-7.01 (m, 4H), 6.68-6.58 (m, 2H), 5.40 (t, 1H), 4.20 (m, 2H), 4.93 (t, 2H), 3.66 (t, 2H), 3.38 (s, 3H), 3.25-2.90 (m, 9H), 2.75 (t, 2H), 2.52 (br s, 2H), 2.05 (m, 2H).

Example 45

8-Hydroxy-5-{(i?)-l-hydroxy-2-[2-(4-{2-[4-hydroxy-3-(l-isopr opyl-3-phenyl-azetidin-3-yl)- phenyl]-ethoxy}-phenyl)-eth lamino]-ethyl}-lH-quinolin-2-one ditrifluoroacetic acid salt

a. 3-Hydroxy-3-phenyl-azetidine-l-carbox lic acid tert-butyl ester

A solution of 3-oxo-azetidine-l-carboxylic acid tert-butyl ester (200 g, 1.17 mol) in THF (1.2 L) was cooled to 0 °C before the addition of phenylmagnesium bromide (410 mL, 1.23 mol) slowly over 2 h. The resulting mixture was warmed to r.t. over 1 h then quenched with sat. NH ₄ C1 and extracted with EtOAc (3 x 1 L). The combined organic phases were dried (MgSO/t), concentrated in vacuo and the resulting residue was purified by chromatography eluting from 0-50% EtOAc/cyclohexane. The resulting residue was triturated with cyclohexane affording the title compound (192 g, 66%).

Ή NMR (300 MHz, CD ₃ OD): 7.43-7.42 (m, 5H), 4.27 (d, 2H, J = 9.3 Hz), 4.17 (d, 2H, J = 9.3 Hz), 1.46 (s, 9H).

b. 8-Hydroxy-5-{(i?)-l-hydroxy-2-[2-(4-{2-[4-hydroxy-3-(l-isopr opyl-3-phenyl-azetidin-3-yl)- phenyl]-ethoxy}-phenyl)-eth lamino]-ethyl}-lH-quinolin-2-one ditrifluoroacetic acid salt

The title compound was prepared from Example 45(a) using methods similar to those described for Example 1, steps a-b, Example 6, steps b, c and e, Example 1, steps d and c, Example 18, step c and Example 1 , steps f-i.

LCMS (Method 6) Rt 2.00 min m/z 634 [M+H] ⁺

lH NMR (400 MHz, CD ₃ OD): 8.43 (s, 1H), 8.35 (d, 1H, J = 9.9 Hz), 7.60 (s, 2H), 7.25-7.24 (m, 2H), 7.19-7.17 (m, 3H), 7.02-7.01 (m, 2H), 6.86 (d, 2H, J = 8.41 Hz), 6.72-

6.65 (m, 2H), 5.40 (s, 1H), 4.90-4.70 (m obs., 4H), 4.1 1 (t, 2H, J = 6.74 Hz), 3.39-3.38 (m, 1H), 3.34-3.29 (m obs., 2H), 3.23-3.22 (m, 4H), 3.01-2.94 (m, 4H), 1.21 (d, 6H, J = 6.5 Hz).

The following compounds (Table 10) were prepared as trifluoroacetic acid salts using similar methods to those described for Example 46.

Example No. Structure NMR (400 MHz) δ LCMS

(CD ₃ OD): 8.18 (d, 1H, J = 9.9 Hz),

7.69 (d, 1H, J = 7.8 Hz), 7.42-7.32

(m, 4H), 7.26-7.23 (m, 3H), 7.10 (s,

1H), 7.05-6.93 (m, 4H), 6.68 (d,

(Method 6) 1H, J = 8.2 Hz), 6.60 (d, 1H, J = 9.8

46 Rt 2.51 min,

Hz), 5.35 (t, 1H, J = 6.7 Hz), 4.98- m/z 620 4.96 (m, 2H), 4.72-4.60 (m, 2H),

[M+H] ⁺ 4.22 (s, 2H), 4.15-4.13 (m, 2H),

3.48-3.41 (m, 1H), 3.16 (d, 2H, J =

6.7 Hz), 3.03-3.02 (m, 2H), 1.23 (d,

6H, J = 6.4 Hz).

Table 10

Example 48

8-Hydroxy-5-{(i?)-l-hydroxy-2-[2-(4-{3-[4-hydroxy-3-(l-isopr opyl-azetidin-3-yl)-phenyl]- propoxy}-phenyl)-ethylamino] oroacetic acid salt

a. 3-(4-Benzyloxy-3-bromo-ph

The title compound was prepared using methods similar to those described for Example 18, step a (using 3-(3-bromo-4-hydroxy-phenyl)-propionic acid ethyl ester).

lH NMR (300 MHz, CDC1 ₃ ): 7.39-7.38 (m, 6H), 7.05 (dd, 1H, J = 8.4, 2.2 Hz), 6.84

(d, 1H, J = 8.4 Hz), 5.13 (s, 2H), 4.12 (q, 2H, J = 7.1 Hz), 2.86 (t, 2H, J = 7.7 Hz), 2.57 (t,

2H, J = 7.7 Hz), 1.24-1.23 (m, 3H). b. 3-[2-Benzyloxy-5-(2-ethoxycarbonyl-ethyl)-phenyl]-azetidine- l-carboxylic acid tert-butyl ester

To a suspension of zinc (1.6 g, 25.2 mmol) and Cellpure® (500 mg) in DMA (5 mL) was added a solution of trimethylsilyl chloride:dibromoethane (7:5, 0.5 mL, 0.034 mL/mmol) and the resulting mixture stirred for 45 min. A solution of 3-iodo-azetidine-l-carboxylic acid tert-butyl ester (5.9 g, 20.7 mmol) in DMA (10 mL) was added dropwise to the mixture and allowed to stir for 1 hour. In a separate flask, copper(I) iodide (170 mg, 0.89 mmol), Pd(dppf) ₂ Cl ₂ .DCM (360 mg, 0.44 mmol) and Example 48(a) (5.35 g, 14.8 mmol) were combined in DMA (20 mL) before the addition of the zincate solution via filtration. The resulting mixture was allowed to stir at 85 °C for 16h then partitioned between water and EtOAc. The organic phase was washed with brine, dried (MgSO/t) and concentrated in vacuo. The resulting residue was purified by chromatography eluting from 0- 20% EtOAc :cyclohexane affording the title compound as a yellow oil (3.23 g, 50%).

LCMS (Method 6) Rt 4.51 min, m/z 440 [M+H] ⁺ c. 8-Hydroxy-5-{(i?)-l-hydroxy-2-[2-(4-{3-[4-hydroxy-3-(l-isopr opyl-azetidin-3-yl)-phenyl]- propoxy}-phenyl)-ethylamino]- oroacetic acid salt

The title compound was prepared from Example 48(b) using methods similar to those described for Example 6, step d, Example 1, steps d, c and f-h, Example 18, step c and Example 1, step i.

LCMS (Method 6) Rt 2.41 min, m/z 572 [M+H] ⁺

lH NMR (400 MHz, CD ₃ OD): 8.33 (d, 1H, J = 9.9 Hz), 7.28 (d, 1H, J = 8.2 Hz), 7.19 (d, 2H, J = 8.4 Hz), 6.98-6.97 (m, 3H), 6.91-6.84 (m, 2H), 6.70- 6.69 (m, 2H), 5.38 (dd, 1H, J = 8.0, 5.5 Hz), 4.44-4.42 (m, 3H), 4.31-4.29 (m, 2H), 4.09-4.08 (m, 1H), 3.93-3.91 (m, 2H), 3.47-3.39 (m, 1H), 3.31-3.28 (m obs., 3H), 2.98-2.97 (m, 2H), 2.72-2.70 (m, 2H), 2.02-2.01 (m, 2H), 1.24 (d, 6H, J = 6.5 Hz).

The following compound (Table 11) was prepared as a trifluoroacetic acid salt using similar methods to those described for Example 48.

Table 11

Example 50

8-Hydroxy-5-{(i?)-l-hydroxy-2-[2-(4-{3-[4-hydroxy-3-(l-methy l-piperidin-4-yl)-phenyl]- propoxy}-phenyl)-ethylamino]- oroacetic acid salt

a. 2- {4- [2-(4-Benzyloxy-3-bromo- henyl)-ethoxy] -phenylj-ethanol

The title compound was prepared from Example 48(a) using methods similar to those described for Example 6, step d and Example 1 , steps c and d.

Ti NMR (400 MHz, CDC1 ₃ ): 7.49-7.28 (m, 6H), 7.16-7.09 (m, 2H), 7.05 (dd, 1H, J = 8.3, 2.2 Hz), 6.84-6.83 (m, 3H), 5.13 (s, 2H), 3.93 (t, 2H, J = 6.2 Hz), 3.83 (q, 2H, J = 6.3 Hz), 2.81 (t, 2H, J = 6.5 Hz), 2.73-2.71 (m, 2H), 2.06-2.04 (m, 2H). b. 4-(2-Benzyloxy-5-{2-[4-(2-hydroxy-ethyl)-phenoxy]-ethyl}-phe nyl)-3,6-dihydro-2H- pyridine-l-carboxylic acid tert-butyl ester

A mixture of Example 50(a) (794 mg, 1.8 mmol), 4-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2- yl)-3,6-dihydro-2H-pyridine-l-carboxylic acid teil-butyl ester (500 mg, 1.6 mmol), potassium phosphate tribasic (1.0 g, 4.8 mmol) and Pd(PPh ₃ ) ₄ (35 mg, 0.03 mmol) in DMF (10 mL) was degassed then heated at 95 °C for 6 h. The reaction mixture was concentrated in vacuo and the resulting residue suspended in EtOAc and filtered through Celite®. The filtrated was concentrated in vacuo the purified by chromatography eluting from 0-20% EtOAc/DCM affording the title compound (730 mg, 86%).

LCMS (method 6) Rt 4.68 min, m/z 544 [M+H] ⁺ c. 8-Hydroxy-5-{(i?)-l-hydroxy-2-[2-(4-{3-[4-hydroxy-3-(l-methy l-piperidin-4-yl)-phenyl]- propoxy}-phenyl)-ethylamino]- oroacetic acid salt

The title compound was prepared from Example 50(b) using methods similar to those described for Example 18, step c and Example 1, steps c and f-i.

LCMS (Method 6) Rt 2.33 min, m/z 572 [M+H ⁺ ]

lH NMR (400 MHz, CD ₃ OD): 8.33 (d, 1H, J = 9.9 Hz), 7.27 (d, 1H, J = 8.2 Hz), 7.18 (d, 2H, J = 8.4 Hz), 7.02 (d, 1H, J = 8.2 Hz), 6.90-6.89 (m, 4H), 6.68-6.67 (m, 2H), 5.38-5.37 (m, 1H), 3.92 (t, 2H, J = 6.2 Hz), 3.59-3.55 (m, 2H), 3.30-3.30 (m, 4H), 3.12-3.1 1 (m, 3H), 2.97- 2.96 (m, 2H), 2.89 (s, 3H), 2.69-2.67 (m, 2H), 2.08-1.97 (m, 6H).

The following compounds (Table 12) were prepared as trifluoroacetic acid salts using similar methods to those described for Example 50. 6) min,

Table 12

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

Assay for adrenergic 32 mediated cAMP production

Cell preparation

H292 cells are grown in 225 cm ² flasks incubator at 37 °C, 5% C0 ₂ in RPMI medium containing 10% (v/v) FBS (foetal bovine serum) and 2 mM L-glutamine.

Experimental Method

Adherent H292 cells were removed from tissue culture flasks by treatment with Accutase™ cell detachment solution for 15 minutes. Flasks are incubated for 15 minutes in a humidified incubator at 37 °C, 5% C0 ₂ . Detached cells are re-suspended in RPMI media (containing 10% (v/v) FBS and 2 mM L-glutamine) at 0.1 x 10 ⁶ cells per mL. 10000 cells in 100 are added to each well of a tissue-culture-treated 96-well plate and the cells incubated overnight in a humidified incubator at 37 °C, 5% C0 ₂ . The culture media is removed and cells are washed twice with 100 assay buffer and replaced with 50 μΐ. assay buffer (HBSS solution containing lOmM HEPES pH7.4 and 5 mM glucose). Cells are rested at room temperature for 20 minutes after which time 25 μΐ _^ of rolipram (1.2 mM made up in assay buffer containing 2.4%> (v/v) dimethylsulphoxide) is added. Cells are incubated with rolipram for 10 minutes after which time test compounds are added and the cells are incubated for 60 minutes at room temperature. The final rolipram concentration in the assay is 300 μΜ and final vehicle concentration is 1% (v/v) dimethylsulphoxide. The reaction is stopped by removing supematants, washing once with 100 assay buffer and replacing with 50 lysis buffer. The cell monolayer is frozen at -80 °C for 30 minutes (or overnight).

AlphaScreen™ cAMP detection

The concentration of cAMP (cyclic adenosine monophosphate) in the cell lysate is determined using AlphaScreen™ methodology. The frozen cell plate is thawed for 20 minutes on a plate shaker then 10 μί of the cell lysate is transferred to a 96-well white plate. 40 [iL of mixed AlphaScreen™ detection beads pre-incubated with biotinylated cAMP, is added to each well and the plate incubated at room temperature for 3 hours in the dark. The AlphaScreen™ signal is measured using an En Vision spectrophotometer (Perkin-Elmer Inc.) with the recommended manufacturer's settings. cAMP concentrations are determined by reference to a calibration curve determined in the same experiment using standard cAMP concentrations. Concentration response curves for agonists are constructed and data is fitted to a four parameter logistic equation to determine both the pEC ₅ o and Intrinsic Activity. Intrinsic Activity is expressed as a fraction relative to the maximum activity determined for formoterol in each experiment.

Muscarinic 3 receptor binding assay

The affinity (pIC ₅ o) of compounds binding to the M ₃ receptor is determined by competition binding of [ ³ H]N-methyl scopolamine (NMS) to CHO-K1 (Chinese Hamster Ovary) cell membranes expressing the human muscarinic acetylcholine M ₃ receptor (M ₃ - ACh) in a scintillation proximity assay (SPA) format.

SPA beads are precoated with membranes and then incubated at 2mg of beads per well with serial dilutions of compounds of the invention, [ ³ H]NMS at 0.1 nM, quarter Ka (experimentally determined dissociation constant) and assay buffer (20 mM HEPES pH 7.4 containing 5 mM MgCl ₂ and 0.1% (w/v) bovine serum albumin). The assay is conducted in a final volume of 200 μί, in the presence of 1% (v/v) dimethyl sulphoxide (DMSO). Total binding of [ ³ H]NMS is determined in the absence of competing compound and nonspecific binding of [ ³ H]NMS is determined in the presence of 1 μΜ atropine. The plates are incubated for 16 hours at room temperature and then read on Wallac Microbeta ^™ using a normalised ³ H protocol. The pICso, defined as the negative logarithm of the molar concentration of compound required for 50% reduction in specific [ ³ H]-NMS binding, is determined. Compounds of the invention were tested in the above assays. All compounds tested showed PEC ₅₀ IC ₅₀ >5 against both receptors. Additionally, the following data are provided; β ₂

M ₃ Binding

Example No. β ₂ Intrinsic

pICso

pEC ₅₀ Activity

1 ++ 1.0 +++

2 ++++ 1.1 ++++

3 ++ 0.9

4 +++ 1.0 +++

5 ++ 1.1 +++

6 +++ 0.9 ++++

7 ++ 1.1 ++++

8 +++ 1.2 ++++

9 +++ 1.0 +++

10 +++ 1.0 +++

11 +++ 0.9 +++

12 NT ++

13 >0.4 ++

14 NT ++

15 +++ 0.5 +++

16 +++ 0.8 +++

17 ++ 1.1 +++

18 +++ 1.0 +++

19 ++ 1.0 ++++

20 + 0.9 +++

21 +++ 0.9 ++++

22 + 0.6 +++

23 ++ 1.1 +++ β ₂

M ₃ Binding

Example No. β ₂ Intrinsic

pICso pEC ₅₀ Activity

24 ++ 1.0 ++++

25 +++ 1.0 ++++

26 +++ 1.0 +++

27 +++ 0.8 +++

28 ++ 0.8 ++++

29 +++ 0.7 ++++

30 ++ 0.9 ++++

31 ++ 1.0 ++++

32 ++ 0.9 ++++

33 + 0.9 ++++

34 ++ 1.0 +++

35 + >0.8 ++++

36 +++ 0.9 ++++

37 + >0.7 +++

38 ++ 0.8 +++

39 +++ 1.0 ++++

40 +++ 1.1 +++

41 + 1.0 +++

42 ++ 1.1 +++

43 ++ 1.0 ++

44 + 0.9 +++

45 +++ 1.0 +++

46 + 0.8 ++++

47 ++ 1.0 ++++

48 +++ 1.1 ++

49 +++ 0.9 +

50 +++ 0.9 ++

51 ++++ 1.1 + β ₂

M ₃ Binding

Example No. β ₂ Intrinsic

pICso

pEC ₅₀ Activity

52 ++ 0.9 ++

53 ++ 0.9 ++

54 ++ 0.9 ++ pEC ₅₀ >9 ++++, >8 +++, >7 ++, >6 +; M ₃ p!C ₅₀ >9 ++++; >8 +++, >7 ++, >6 +