WO2011048409A1 - Cyclic amine derivatives having beta2 adrenergic receptor agonist and muscarinic receptor antagonist activity - Google Patents

Abstract

Compounds of formula (I) having activities at muscarinic and β₂-receptors (MABAs) for use in therapy.

Description

CYCLIC AMINE DERIVATIVES HAVING BETA2 ADRENERGIC RECEPTOR AGONIST AND MUSCARINIC RECEPTOR ANTAGONIST ACTIVITY

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 p₂-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 β₂- 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

ArCH₂CH₂NH- represents a β-adrenoceptor binding group;

R¹ is selected from the following;

(i) 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 C₃_ 8 cycloalkyl ring; or wherein said alkyl group is substituted by up to two cycloalkyl or cycloalkylalkyl groups each comprising up to six carbon atoms;

or

(ii) a group

m = 0, 1, 2 or 3;

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

R², R² , R³, R³ , R⁴, R⁴ , R⁵, and R⁵ are each independently, hydrogen or Ci_₆ alkyl;

R⁶ is a Ci_8 alkyl group optionally substituted by up to 3 substituents selected from halogen, Ci_₆ alkyl, OR¹⁰, Ci_6 alkylS(O)₀-₂, NR⁸R⁹ , OC(0)(Ci_₆ alkyl), or C₃_₈ cycloalkyl

(wherein one or two of the carbon atoms can be replaced by O, S or N);

or R⁶ is a Ci_g alkyl group substituted by an optionally substituted aryl group or an optionally substituted 5- or 6-membered aromatic or non-aromatic heterocyclic ring containing up to three heteroatoms independently selected from N, O and S; or R⁶ is a C₃_₉ cycloalkyl group (wherein one or two of the ring carbon atoms can be replaced by O, S or N) and optionally substituted by up to 3 substituents independently selected from halogen, Ci_6 alkyl, OR¹⁰, Ci_₆ alkylS(O)₀-₂, NR⁸R⁹ , OC(0)(Ci_₆ alkyl), and an optionally substituted aryl group or an optionally substituted 5- or 6-membered aromatic or non- aromatic heterocyclic ring containing up to three heteroatoms independently selected from N, O and S; or R⁶ is a C7-9 bicycloalkyl group optionally substituted by up to 3 substituents independently selected from halogen, Ci_₆ alkyl, OR¹⁰ and Ci_₆ alkylS(0)o_₂; or R⁶ is a 5- or 6-membered aromatic or non-aromatic heterocyclic ring containing up to three heteroatoms independently selected from N, O and S;

R⁷ is selected from hydrogen, -OR¹⁰, halogen, -CF₃, -NR⁸R⁹, -NHS0₂R^u, -C(0)NR⁸R⁹ or -CH₂OR¹⁰;

G represents a group comprising a straight or branched hydrocarbyl chain of up to 9 carbon atoms;

wherein up to three of the carbon atoms in the chain are optionally substituted by up to four substituents independently selected from halogen, -OR¹⁰, Ci_₆ alkyl and

C₃_6 cycloalkyl;

wherein up to three carbon atoms of the chain may be replaced by groups independently selected from O, NR¹⁰, S, S(O), S(0)₂, C(0)0, OC(O), NR¹⁰C(O),

C(0)NR¹⁰, NR¹⁰S(O)₂, S(0)₂NR¹⁰, NR¹⁰C(O)NR^10', NR¹⁰S(O)₂NR^10', OC(0)NR¹⁰, NR¹⁰C(O)O, provided that any such groups in the chain are separated by at least two chain carbon atoms; and

wherein up to six carbon atoms of the chain may form part of an aryl, heteroaryl, fused bicyclic, alicyclic, or heteroaliphatic ring having up to four heteroatoms

independently selected from N, O or S, said ring comprising up to 10 ring atoms, and wherein the ring is optionally substituted by up to three substituents independently selected from halogen, S(O)₀_₂R¹⁰, NR⁸R⁹, S(0)₂NR⁸R⁹, C(0)NR⁸R⁹, C(0)OR¹⁰, NR¹⁰S(O)₂Rⁿ, NR¹⁰C(O)R^u, NR¹⁰C(O)ORⁿ, NR¹⁰C(O)NR⁸R⁹, OR¹⁰, Ci_₆ alkyl and C₃_₆ cycloalkyl, and wherein alkyl and cycloalkyl may be optionally substituted by up to three substituents independently selected from halogen, hydroxyl and Ci_₆ alkoxy;

and the chain may comprise up to two of such rings each selected independently; wherein the chain may additionally comprise up to three carbon-carbon double bonds; and wherein the chain may additionally comprise up to three carbon-carbon triple bonds;

and wherein the group G can be attached to the phenyl ring bearing R⁷ through any available position;

T is selected from an optionally substituted aryl group or an optionally substituted 5- or 6- membered aromatic or non-aromatic heterocyclic ring containing up to three heteroatoms independently selected from N, O and S, or Ci_₆alkyl or C3-8 cycloalkyl or a hydrogen atom;

R⁸ and R⁹ are independently hydrogen or Ci_₆ alkyl, or R⁸ and R⁹ 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;

R¹⁰ and R¹⁰ 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;

R¹¹ 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, hydroxy or Ci_₆ alkoxy;

R¹² and R¹³ are independently hydrogen, Ci_₆ alkyl, an optionally substituted aryl group or an optionally substituted 5- or 6-membered aromatic or non-aromatic heterocyclic ring containing up to three heteroatoms independently selected from N, O and S

t is 1-3;

u is 2-4;

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.

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

M¹ is S, C(O), NA⁵, CA⁶A⁷, CH₂CH₂, CH=CH, CH₂0 or OCH₂;

M² is S, C(O), NA⁵, CA⁶A⁷, CH₂CH₂, CH=CH, CH₂0 or OCH₂;

A¹, A², A³ and A⁴ are, independently, hydrogen, halogen, trifluoromethyl, cyano, carboxy, hydroxy, nitro, S(0)₂A⁸, NA⁹S(0)₂A¹⁰, C(0)NAⁿA¹², NA¹³C(0)A¹⁴, Ci_₆ alkyl,

Ci_6 alkoxy, C(0)(Ci_₆ alkyl) or C(0)OCi_₆ alkyl;

A³ can also be CH₂OH, NHCHO, NHC(0)OCi_₆ alkyl, NHC(0)Ci_6 alkyl,

NHS(0)₂NA¹⁵A¹⁶ or NHS0₂A¹⁷;

A and Α 2^ΆA are, independently, hydrogen, halogen, trifluoromethyl, cyano, carboxy, hydroxy, nitro, S(0)₂A⁸, NA⁹S(0)₂A¹⁰, C(0)NAⁿA¹², NA¹³C(0)A¹⁴, Ci_₆ alkyl,

Ci_6 alkoxy, C(0)(Ci_₆ alkyl) or C(0)OCi_₆ alkyl;

A⁵, A⁶, A⁷, A⁹, A¹¹, A¹², A¹³, A¹⁴, are independently, hydrogen, Ci_₆ alkyl;

A¹⁵ or A¹ 1⁰6 are independently, hydrogen, Ci_₆ alkyl or C₃_₆ cycloalkyl;

17

Α^δ, A and A¹ ' are, independently, Ci_₆ alkyl or C₃_₆ cycloalkyl;

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

Convenientl the Ar rou is selected from:

wherein M¹ is S, CH=CH, CH₂0 or OCH₂;

M² is S, CH=CH, CH₂0 or OCH₂;

A¹, A², and A⁴ are, independently, hydrogen, halogen, Ci_₆ alkyl, Ci_₆ alkoxy;

A³ can be CH₂OH, NHCHO, NHS(0)₂NA¹⁵A¹⁶ or NHS(0)₂A¹⁷;

A^1A and A^2A are, independently, hydrogen, halogen, trifluoromethyl, cyano, carboxy, hydroxy, nitro, S(0)₂A⁸, NA⁹S(0)₂A¹⁰, C(0)NAⁿA¹², NA¹³C(0)A¹⁴, Ci_₆ alkyl,

Ci_6 alkoxy, C(0)(Ci_₆ alkyl) or C(0)OCi_₆ alkyl;

A¹⁵ or A¹⁶ are independently selected from hydrogen, Ci_₆ alkyl or C₃_₆ cycloalkyl; A¹⁷ is Ci_6 alkyl or C₃_₆ cycloalkyl;

Examples of Ci_₆ alkyl include Ci_₄ alkyl and Ci_₂ alkyl.

Examples of C₃_₆ cycloalkyl include C₃_₅ cycloalkyl and C₃_₄ cycloalkyl.

Examples of Ci_₆ alkoxy include Ci_₄ alkoxy and Ci_₂ alkoxy.

Convenientl the Ar group is selected from:

wherein A¹, A², A⁴ are all hydrogen, A³ is CH₂OH or NHCHO, A^1A and A^2A are hydrogen, M¹ is S, CH=CH, or OCH₂; M² is S, CH=CH, or OCH₂.

Conveniently the Ar group is selected from:

Most conveniently the Ar group is

The group R¹

Conveniently R¹ is a hydrogen atom or a Ci_₆ alkyl group; more conveniently R¹ is methyl, ethyl or isopropyl;

Conveniently R¹ is a C^3"8 cycloalkyl group; more conveniently R¹ is cyclopropyl, cyclobutyl or cyclopentyl;

Conveniently R¹ is a group -C_1-6 alkyl - C3-8 cycloalkyl; more conveniently R¹ is -CH₂-^cPr or -CH₂-^cBu;

Conveniently R¹ is a Ci_₆ alkyl-0-Ci_6 alkyl group; more conveniently R¹ is a group - -CH₂CH₂-0-Ci_6 alkyl.

It will be understood that where the alkyl group (as defined) is substituted by up to three Ci_3 alkyl chains any given carbon atom in the group may be substituted by 1 , 2 or 3 Ci_₃ alkyl chains as appropriate.

The integers m and n

Conveniently m and n are both 1 ;

Conveniently m and n are both 2.

Most conveniently m and n are both 2.

The group T

Conveniently T is an aryl group; more conveniently T is phenyl.

Conveniently T is a heteroaryl group; more conveniently T is a 5-membered heteroaryl group such as a thienyl or thiazoloyl group.

Conveniently T is a Ci_₆alkyl group

Conveniently T is a hydrogen atom.

Most conveniently T is a phenyl group.

The group G

Conveniently the group G is a C₂_₄ alkylene group; more conveniently G is a group -(CH₂)₂- or a group -(CH₂)₃-;

Conveniently G is a group -C₂_₄ alkylene-N(R¹⁰)C(O)-;

Most conveniently G is a group -(CH₂)₂- or a group -(CH₂)₃-.

Conveniently the group G is attached to the phenyl ring in one of two regioisomeric positions:

More conve

niently the group G is attached para- to R ,

The groups R⁴, R⁴', R⁵ and R⁵'

The groups R⁴, R⁴', R⁵ and R⁵' are each hydrogen or Ci_6alkyl;

Conveniently the groups R⁴, R⁴', R⁵ and R⁵' are each hydrogen or methyl; more conveniently the groups are each hydrogen.

The group R⁶

Conveniently R⁶ is a Ci_g alkyl group;

Conveniently R⁶ is a Ci_g alkyl group optionally substituted by a C3-8 cycloalkyl group, such as cyclopentylmethyl or cyclopentyl-1 -ethyl, said cycloalkyl group optionally substituted by up to two Ci_₆ alkyl groups, more preferably by up to two Ci_₂ alkyl groups, or by up to two halogen atoms, such as fluoro;

Conveniently R⁶ is a Ci_g alkyl group optionally substituted by a Ci_g cycloalkyl group, wherein said cycloalkyl group has one of the carbon atoms replaced by -O- or -S-;

Conveniently R⁶ is a Ci_g alkyl group substituted by -0-Ci_₆ alkyl or -S-Ci_₆ alkyl or by up to three halogen atoms;

Conveniently R⁶ is a C₃_9 cycloalkyl group; more conveniently R⁶ is a cyclopentyl or cyclohexyl or cycloheptyl group, said cycloalkyl group optionally substituted by up to two Ci_6 alkyl groups, more preferably by up to two Ci_₂ alkyl groups, or by up to two halogen atoms, such as fluoro;

The group R⁷

Conveniently R⁷ is a group -OR¹⁰; more conveniently R⁷ is -OCH₃ or -OH; even more conveniently R⁷ 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-butyl. '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. 'C₃_g 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, -CH₃, -OCH₃, -OH, -CN, -COOCH₃, -CONH₂, -SO₂NH₂, -S0₂N(CH₃)₂. More generally the substituents can be divided into two classes:

(a) a first class of substituent includes acyl (e.g. -COCH₃), alkoxy (e.g., -OCH₃), alkoxycarbonyl (e.g. -COOCH₃), alkylamino (e.g. -NHCH₃), alkylsulfmyl (e.g. -SOCH₃), alkylsulfonyl (e.g. -S0₂CH₃), alkylthio (e.g. -SCH₃), -NH₂, aminoacyl (e.g. -CON(CH₃)₂), aminoalkyl (e.g. -CH₂NH₂), cyano, dialkylamino (e.g. -N(CH₃)₂), halo, haloalkoxy (e.g.

-OCF₃ or -OCHF₂), haloalkyl (e.g. -CF₃), alkyl (e.g. -CH₃ or -CH₂CH₃), -OH, -CHO,

-COOH, -NO₂, aminoacyl (e.g. -CONH₂, -CONHCH₃), aminosulfonyl (e.g. -S0₂NH₂, - S0₂NHCH₃), acylamino (e.g. -NHCOCH₃) and sulfonylamino (e.g. -NHS0₂CH₃); and

(b) a second class of substituent includes arylalkyl (e.g. -CH₂Ph or -CH₂-CH₂-Ph), aryl, heteroaryl, heterocycloalkyl, heteroarylalkyl, cyclic amine (e.g. morpholine), aryloxy, heteroaryloxy, arylalkyloxy (e.g. benzyloxy) and heteroarylalkyloxy, the cyclic part of any of which being optionally substituted by any of the first class of substituent referred to above (for example alkoxy, haloalkoxy, halogen, alkyl and haloalkyl).

Alkyl, alkoxy and alkenyl groups may be optionally substituted. Suitable optional substituent groups for alkyl and alkenyl include alkoxy (e.g., -OCH₃), alkylamino (e.g. -

NHCH₃), alkylsulfmyl (e.g. -SOCH₃), alkylsulfonyl (e.g. -S0₂CH₃), alkylthio (e.g. -SCH₃),

-NH₂, aminoalkyl (e.g. -CH₂NH₂), arylalkyl (e.g. -CH₂Ph or -CH₂-CH₂-Ph), cyano, dialkylamino (e.g. -N(CH₃)₂), halo, haloalkoxy (e.g. -OCF₃ or -OCHF₂), haloalkyl (e.g.

-CF ), -OH, -CHO, and -N0₂. Suitable optional substituent groups for alkoxy include alkylamino (e.g. -NHCH₃), alkylsulfmyl (e.g. -SOCH₃), alkylsulfonyl (e.g. -S0₂CH₃), alkylthio (e.g. -SCH₃), -NH₂, aminoalkyl (e.g. -CH₂NH₂), arylalkyl (e.g. -CH₂Ph or

-CH₂-CH₂-Ph), cyano, dialkylamino (e.g. -N(CH₃)₂), halo, haloalkoxy (e.g. -OCF₃ or

-OCHF₂), haloalkyl (e.g. -CF₃), alkyl (e.g. -CH₃ or -CH₂CH₃), -OH, -CHO, and -N0₂.

Alkylene or alkenylene groups may be optionally substituted. Suitable optional substituent groups include alkoxy (e.g., -OCH₃), alkylamino (e.g. -NHCH₃), alkylsulfmyl

(e.g. -SOCH₃), alkylsulfonyl (e.g. -S0₂CH₃), alkylthio (e.g. -SCH₃), -NH₂, aminoalkyl

(e.g. -CH₂NH₂), arylalkyl (e.g. -CH₂Ph or -CH₂-CH₂-Ph), cyano, dialkylamino (e.g. -N(CH₃)₂), halo, haloalkoxy (e.g. -OCF₃ or -OCHF₂), haloalkyl (e.g. -CF₃), alkyl (e.g. - CH₃ or -CH₂CH₃), -OH, -CHO, and -N0₂.

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 1-3. In the schemes below, q can be 0-8.

Scheme 1 Compounds of formula (1) represent compounds of formula (I) wherein R², R² , R³, R³ , R⁴, R⁴ , R⁵ and R⁵ are hydrogen, R⁷ is -OH and where G is an alkylene chain, and R¹, R⁶, Ar, T, n and m are as defined for formula (I).

Compounds of formula (1) may be prepared from compounds of formula (2) by initial acetal hydrolysis using a suitable acid in the presence of water, for example tosic acid monohydrate, in a solvent such as THF or an acetic acid/water mixture, followed by reaction with a compound of formula (9) or a salt thereof where Ar is defined as for formula (I):

,NH, (Q\

Ar ² 1»)

This reaction is carried out in the presence of a suitable reducing agent such as a metal borohyride, especially sodium triacetoxyborohydride in a variety solvents or solvent mixtures such as NMP/water or DMF/water mixtures. Compounds of formula (9) are known in the art, for example WO08/075025, Org. Proc. Res. Dev. 2004, 8(4), 628, EP0125052., WO08/075025, WO09/154557, J. Med. Chem. 1985, 28, 1803-10, J. Med. Chem. 1987, 30, 1 166-76.

Compounds of formula (2) may be prepared from compounds of formula (3) by reaction with a compound of formula (10) wherein R⁶ is defined as for formula (I):

This reaction is carried out in the presence of a suitable coupling reagent, examples of which include HATU and T3P in the presence or absence of a base such as DIPEA, in a solvent such as DMF.

Compounds of formula (10) are either commercially available (e.g. when R⁶ = Me), known in the literature (e.g. when R⁶ = Propyl, Liebigs Annalen der Chemie, 1979 (1 1), 1818-27) or may be prepared from an amine of formula (1 1) by reaction with 2,2- dimethoxyacetaldehyde in the presence of a suitable reducing agent such as a metal borohydride or hydrogen gas in the presence of a metal catalyst, in an apposite solvent such as methanol. Compounds of formula (11) are known or readily prepared by known methods.

R— NH₂ (11) Compounds of formula (3) may be prepared from compounds of formula (4) by a three step procedure: a) Simultaneous removal of the boc-group and deprotection of the tert-butyl ester by usual methods for example an acid such as TFA in a solvent such as DCM; b) Debenzylation using standard procedures such as hydrogen gas in the presence of a metal catalyst, especially palladium hydroxide on carbon, in a suitable solvent such as ethanol; c) Reductive amination with a suitable carbonyl compound (examples of which include formaldehyde or acetone) or alkylation with a suitable alkylating agent (e.g. ethyl bromide) under standard conditions known for these reactions. The requisite carbonyl compounds and alkylating agents are commercially available or are readily prepared by known methods.

Compounds of formula (4) may be prepared from compounds of formula (5) by reaction with fert-butylacrylate in the presence of a base for example

benzyltrimethylammonium hydroxide in a suitable solvent for example acetonitrile or toluene.

Compounds of formula (5), where q > 1, may be prepared from compounds of formula (6) by reaction with benzyl bromide in the presence of a suitable base such as caesium carbonate in a solvent such as DMF.

Compounds of formula (5) where q = 1 may be prepared from compounds of formula (7) by reaction with benzyl bromide, as above, followed by reaction with a reducing agent, especially a metal hydride such as lithium aluminium hydride.

Compounds of formulae (6) and (7) may be prepared from compounds of formula (8) by reacting with a strong acid such as triflic acid in the presence of compounds of formulae (12) and (13) in a suitable solvent such as nitrobenzene.

Compounds of formulae (8), (12) and (13) are commercially available, known in the literature (e.g. (12) where q = 3, c.f WO2008/13963) or are easily synthesised by methods known to those skilled in the art.

2 2' 3

Compounds of formula (14) represent compounds of formula (I) where R , R , R , R³ , R⁴, R⁴ , R⁵ and R⁵ are hydrogen, R⁷ is -OH and where G is a group -C_2-4 alkylene- NR¹⁰C(O)- wherein R¹⁰ , R¹, R⁶, Ar, T, n and m are as defined for formula (I). Compounds of formula (14) may be prepared from compounds of formula (15) using analogous methods to those described for the preparation of compounds of formula (1) from compounds of formula (3).

Compounds of formula (15) may be prepared from compounds of formula (16) using analogous methods to those described for the preparation of compounds of formula (3) from compounds of formula (4).

Compounds of formula (16) may be prepared from compounds of formula (17) by reaction with a compound of formula (19):

This reaction is carried out in the presence of a suitable coupling reagent, examples of which include HATU and T3P in the presence or absence of a base such as DIPEA, in a suitable solvent such as DMF.

Compounds of formula (19) may be prepared from compounds of formula (20), wherein PG¹ is a suitable protecting group (for example benzyloxycarbamate or phthalimide), and tert-butyl acrylate in the presence of a suitable base for example sodium hydride or benzyl trimethylammonium hydroxide in a suitable solvent such as THF or toluene. Followed by the appropriate deprotection protocol to remove PG¹.

Compounds of formula (20) are commercially available (e.g. when R⁴⁶ = H, q = 1, PG¹ = benzyloxycarbonyl), known in the literature (e.g. when R⁴⁶ = Me, q = 1, PG¹ = benzyloxycarbonyl, c.f. J. Org. Chem. 2004, 69 (2), 577-580) or are easily synthesised by methods known to those skilled in the art.

Compounds of formula (17) may be prepared from compounds of formula (18) by reaction with an aqueous base such as lithium hydroxide in the presence of a co-solvent such as dioxane at a temperature between ambient and the boiling point of the mixture. Compounds of formula (18) may be prepared from compounds of formula (8) by reaction with methyl 4-hydroxybenzoate in the presence of a strong acid such as triflic acid in a suitable solvent such as nitrobenzene.

Compounds of formulae (6) (R¹⁰⁰ is -C0₂Me) and (18) (R¹⁰⁰ is -(CH₂)_qCH₂OH) may also be synthesised using methods shown in scheme 3 :

Scheme 3

Compounds of formulae (6) and (18) may be prepared from compounds of formula (20) (wherein PG² is a suitable protecting group) by reaction with a fo^'s-alkylating agent of formula (25) (wherein LG² are suitable leaving groups e.g. chloride) in the presence of a base such as sodium hydride in a suitable solvent such as DMF; followed by the appropriate method for the removal of PG².

Compounds of formula (25) are commercially available (e.g. when n = 2, m = 2 and LG² = CI) or readily prepared using known methods.

Compounds of formula (20) may be prepared from compounds of formula (21) by use of various standard reduction protocols ( J. Med. Chem. 1989, 32, 2357-2362) or from compounds of formula (24) (wherein LG¹ is a suitable leaving group e.g. chloride) by reaction with a suitable nucleophilic form of T via standard procedures or via palladium mediated couplings (c.f. Eur. J. Org. Chem. 2008, 28, 4824-4827)

Compounds of formulae (21) and (24) may be prepared from the appropriate phenols (which are either commercially available or readily prepared using known procedures) using standard Friedel-Crafts or chloromethylation procedures.

Compounds of formulae (6) and (18) wherein T is a heterocyclic group may be prepared from compounds of formula (22) (wherein PG² is a suitable protecting group) by standard procedures for the conversion of a nitrile into various heterocycles e.g. To a thiazole via thioamide formation using hydrogen sulphide followed by cyclisation with 1 ,2-dichloroethyl ethyl ether (c.f. WO 98/43942); followed by the appropriate method for the removal of PG².

Compounds of formula (22) may be prepared from compounds of formula (23) using analogous methods to those mentioned above for the fo^'s-alkylation of compounds of formula (20).

Compounds of formula (23) may be prepared from compounds of formula (24) (wherein LG¹ is a suitable leaving group e.g. chloride) by reaction with a cyanide source e.g. sodium cyanide in a suitable solvent such as DMF.

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, raffmose, 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 CX₃CR1 for the C-X₃- 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, PvO-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 (TGF ); (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-amine (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 Examples wherein the following General Methods were used:

General Methods

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 or a Bruker Avance 600 (600 MHz), a Bruker DRX 500 (500 MHz) or a Varian Unitylnova 500 MHz, 400 MHz or 300 MHz instrument. Shifts are given in ppm relative to tetramethylsilane. NMR analysis of compounds purified by HPLC showed various amounts of formic acid equivalents.

Purification by chromatography refers to purification using the CombiFlash ® Companion purification system or the Biotage SPl 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, 254 or 265 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 was 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 split to MS with in-line UV detector). MS ionization method - Electrospray (positive and negative ion).

Method 2

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:

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

Gradient - Time flow ml -/mi 11 %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 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

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

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

0.00 1.0 85 15

1.00 1.0 85 15

13.00 1.0 5 95

20.00 1.0 5 95

22.00 1.0 85 15

25.00 1.0 85 15 Method 5

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/min %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 6

Waters Micromass ZQ2000 quadrupole mass spectrometer LC Column - Acquity BEH CI 8 column (100 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/min %A %B

0.00 0.4 95 5

0.40 0.4 95 5

6.00 0.4 5 95

6.80 0.4 5 95

7.00 0.4 95 5

8.00 0.4 95 5

Detection - MS, UV PDA

MS ionisation method - Electrospray (positive/negative ion)

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

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

Boc anhydride = di-fert-butyl dicarbonate CDI = Ι, -carbonyldiimidazole

dba = dibenzylideneacetone

DCE = 1 ,2-dichloroethane

DCM = dichloromethane

DIPEA = diisopropylethylamine

DMF = N,N-dimethylformamide

DMSO = dimethylsulphoxide

equiv. = equivalents

EtOAc = Ethyl acetate

HATU = O-(7-azabenzotriazol- 1 -yl)-N,N,N'N -tetramethyluroniumhexafluoro- phosphate

HPLC = high performance liquid chromatography

NMP = N-methyl-pyrrolidinone

pTS A = ara-toluenesulphonic acid

quant. = quantitative

RT = room temperature

Rt = retention time (LCMS or HPLC)

SCX-2 = strong cation exchange resin

TBDMS = tert-butyldimethylsilyl

TFA = trifluoroacetic acid

THF = tetrahydrofuran

TLC = thin layer chromatography

Intermediates

Intermediate 1

[4-Hydroxy-3-(4-phenyl-piperidin-4- l)-phenyl] -acetic acid methyl ester

To a stirred suspension of 4-phenylpiperidin-4-ol (5.32 g, 30 mmol) in nitrobenzene (25 mL) was added (4-hydroxy-phenyl)-acetic acid methyl ester (15 g, 90.3 mmol) and the reaction mixture slowly went into solution. The reaction mixture was cooled to 0 °C and then treated dropwise with triflic acid (7.9 mL, 90.3 mmol). The reaction contents were stirred at RT for 48 h then poured onto ice, basified to pH 8 by the addition of saturated aqueous NaHC0₃ and extracted with EtOAc. The combined organic layers were washed with water, brine, dried (Na₂S0₄), filtered and concentrated in vacuo The crude product was purified on SCX-2 cartridge (eluting with MeOH, then 2 M NH₃ in MeOH) to give the title compound as a cream solid (4.61 g, 47%).

LCMS (Method 1): Rt 2.72 min, m/z 326 [M+H]⁺

Intermediate 2

4-(2-Hydroxy-5-methoxycarbonylmethyl-phenyl)-4-phenyl-piperidine-l-carboxylic acid terf-butyl ester

To a stirred suspension of Intermediate 1 (4.6 g, 14.15 mmol) in DCM (100 mL) at 0 °C was added triethylamine (3.05 mL, 21.94 mmol) and tert-butoxycarbonyl anhydride (3.86 g, 17.69 mmol). The reaction mixture was warmed to RT and gradually went into solution. Stirring was continued for 3.5 h and the solution was concentrated in vacuo and the residue purified by chromatography, eluting with 0-30% EtOAc in cyclohexane to give the title compound as a white solid (5.2 g, 86%>).

LCMS (Method 1): Rt 4.61 min, m/z 448 [M+Na]⁺

Intermediate 3

4-(2-Benzyloxy-5-methoxycarbonylmethyl-phenyl)-4-phenyl-piperidine-l-carboxylic acid terf-butyl ester

A solution of Intermediate 2 (7.90 g, 18.59 mmol) in DMF (100 mL) was treated with cesium carbonate (9.06 g, 27.88 mmol) and benzyl bromide (2.67 mL, 22.31 mmol). The resulting mixture was warmed to 50 °C for 2 h, then cooled and concentrated in vacuo. The residue was partitioned between in EtOAc (x2) and water. The combined organic layers were dried (Na₂S0₄), concentrated in vacuo and purified by chromatography, eluting with 0-30% EtOAc in cyclohexane to give the title compound as a pale yellow oil (8.92 g, 93%).

LCMS (Method 1): Rt 5.13 min, m/z 538 [M+Na]⁺

Intermediate 4

4-[2-Benzyloxy-5-(2-hydroxy-ethyl)-phenyl]-4-phenyl-piperidine-l-carboxylic acid terf-butyl ester

To a cooled -5 °C (salt-ice bath) solution of Intermediate 3 (3.43 g, 6.66 mmol) in dry THF (100 mL) under nitrogen was cautiously added lithium aluminium hydride (303 mg, 7.99 mmol). After 15 min at -5 °C the solution was carefully quenched by the addition of a mixture of ice and 1 M aqueous NaOH [1 : 1]. The resulting salts were removed by filtration over a combined layer of anhydrous MgS0₄ and Celite^®. After washing the pad with

EtOAc the filtrate was concentrated in vacuo to afford the title compound as a white foam (3.16 g, 97%).

LCMS (Method 1): Rt 5.01 min, m/z 510 [M+Na]⁺

Intermediate 5

4-{2-Benzyloxy-5-[2-(2-tei"i-butoxycarbonyl-ethoxy)-ethyl]-phenyl}-4-phenyl- piperidine-l-carboxylic acid tert-buty\ ester

A solution of Intermediate 4 (2.30 g, 4.72 mmol) in toluene (20 mL) was treated with a solution of Triton B (40wt% in MeOH; 217 μί, 0.21 mmol). The reaction mixture was briefly stirred and the volume was then reduced to ~ 10 mL to remove most of the MeOH. The residue was cooled to 0 °C and treated with tert-butyl acrylate (0.76 mL, 5.26 mmol) and the reaction mixture was stirred at RT for 16 h. The reaction was then concentrated in vacuo and purified by chromatography eluting with 0-40% EtOAc in cyclohexane to afford the title compound as a colourless oil (2.25 g, 78 %).

LCMS (Method 1): Rt 5.58 min, m/z 638 [M+Na]⁺

Intermediate 6

3-{2-[4-Benzyloxy-3-(4-phenyl-piperidin-4-yl)-phenyl]-ethoxy}-propionic acid trifluoroacetic acid salt

A solution in DCM (30 mL) of Intermediate 5 (5.27 g, 8.57 mmol) was treated with TFA (10 mL) and stirred at RT for 2 h. Toluene (30 mL) was added and the reaction mixture was concentrated in vacuo to afford the title compound as a viscous oil (4.91 g, quant.) LCMS (Method 1): Rt 3.57 min, m/z 460 [M+H]⁺

Intermediate 7

3-{2-[4-Benzyloxy-3-(l-methyl-4-phenyl-piperidin-4-yl)-phenyl]-ethoxy}-propionic acid

A stirred solution of Intermediate 6 (4.91 g, 8.57 mmol) in DCE (100 mL) was treated with formaldehyde (37wt% in water; 2.36 mL, 85.70 mmol) and 10 mins later with sodium triacetoxyborohydride (7.23 g, 34.28 mmol). The resulting mixture was stirred for 16 h and the DCE was removed in vacuo. The crude product was partitoned between EtOAc and water and the organic extract was dried (Na₂S0₄), filtered and concentrated in vacuo to give the title compound as an oil (4.05 g, quant.)

LCMS (Method 1): Rt 3.51 min, m/z 474 [M+H]⁺

Intermediate 8

3-{2-[4-Hydroxy-3-(l-methyl-4- henyl-piperidin-4-yl)-phenyl]-ethoxy}-propionic acid

A stirred solution of Intermediate 7 (2.70 g, 5.71 mmol) in EtOH (100 mL) was degassed with Argon and 20% palladium hydroxide on charcoal (300 mg) was added. The resulting mixture was hydrogenated (hydrogen- filled balloon) for 16 h. The reaction mixture was filtered through Celite^® and concentrated in vacuo to afford the title compound as an off white foam (2.2 g, quant.).

LCMS (Method 1): Rt 2.51 min, m/z 384 [M+H]⁺

Intermediate 9

4-(3-Hydroxy-propyl)-2-(4-phen l-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 the addition of 25% aqueous sodium hydroxide then extracted with EtOAc (3 x 80 mL). The combined organic layers were washed with water, brine, dried (MgS0₄), filtered, evaporated and purified on SCX-2 cartridge (eluting with MeOH then 2 M NH₃ in MeOH) to give the title compound (5.5 g, 63 %).

LCMS (Method 1): Rt 2.59 min, m/z 312 [M+H] Intermediate 10

4-[2-Hydroxy-5-(3-hydroxy-propyl)-phenyl]-4-phenyl-piperidine-l-carboxylic acid tert-buty\ ester

The title compound was prepared from Intermediate 9 using a method similar to that described for Intermediate 2.

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

Intermediate 11

4-[2-Benzyloxy-5-(3-hydroxy-propyl)-phenyl]-4-phenyl-piperidine-l-carboxylic acid tert-buty\ ester

The title compound was prepared from Intermediate 10 using a method similar to that described for Intermediate 3.

LCMS (Method 1): Rt 5.10 min, m/z 524 [M+Na]⁺

Intermediate 12

4-{2-Benzyloxy-5-[3-(2-teri-butoxycarbonyl-ethoxy)-propyl]-phenyl}-4-phenyl- piperidine-l-carboxylic acid ieri-buty\ ester

The title compound was prepared from Intermediate 11 using a method similar to that described for Intermediate 5.

LCMS (Method 1): Rt 5.30 min, m/z 630 [M+H]⁺

Intermediate 13

3-{3- [4-Benzyloxy-3-(4-phenyl-piperidin-4-yl)-phenyl] -propoxy}-propionic acid hydrochloric acid salt

A cooled 0 °C solution of Intermediate 12 (3.4 g, 5.60 mmol) in 4 M HC1 in dioxane (50 mL) was allowed to warm to RT and stirred for 4 h. Toluene was added and the reaction mixture was concentrated in vacuo to afford the title compound as a viscous oil (3.2 g, quant.)

LCMS (Method 1): Rt 3.53 min, m/z 474 [M+H]⁺

Intermediate 14

3-{3-[4-Benzyloxy-3-(l-methyl-4-phenyl-piperidin-4-yl)-phenyl]-propoxy}-propionic acid

The title compound was prepared from Intermediate 13 using a method similar to that described for Intermediate 7.

LCMS (Method 1): Rt 3.60 min, m/z 488 [M+H]⁺ Intermediate 15

3-{3-[4-Hydroxy-3-(l-methyl-4-phenyl-piperidin-4-yl)-phenyl]-propoxy}-propionic acid

The title compound was prepared from Intermediate 14 using a method similar to that described for Intermediate 8.

LCMS (Method 1): Rt 2.87 min, m/z 398 [M+H]⁺

Intermediate 16

4-Hydroxy-3-(4-phenyl-piperidin-4- l)-benzoic acid methyl ester

The title compound was prepared from 4-hydroxy-benzoic acid methyl ester and 4- phenylpiperidin-4-ol using a method similar to that described for Intermediate 1.

LCMS (Method 2): Rt 2.55 min, m/z 312 [M+H]⁺

Intermediate 17

4-(2-Hydroxy-5-methoxycarbonyl-phenyl)-4-phenyl-piperidine-l-carboxylic acid tert- butyl ester

The title compound was prepared from Intermediate 16 using a method similar to that described for Intermediate 2.

LCMS (Method 2): Rt 4.67 min, m/z 412 [M+H]⁺ Intermediate 18

4-(5-Carboxy-2-hydroxy-phenyl)-4-phenyl-piperidine-l-carboxylic acid tert-butyl ester

A solution of Intermediate 17 (1 g, 2.43 mmol) was dissolved in dioxane by warming to 50 °C. An aqueous solution of 10 M LiOH (5 mL) was added followed by a further quantity of water (5 mL) to ensure homogeneity and the resulting solution was heated to 50 °C for 10 h. The reaction mixture was acidified to pH 6 by addition of aqueous 1 M HC1 then extracted with EtOAc and the organic layer was dried (MgSC^), filtered and evaporated to give the title compound as a white solid (0.95 g, 98%).

LCMS (Method 2): Rt 4.45 min, m/z 398 [M+H]⁺

Intermediate 19

3-(2-Benzyloxycarbonylamino-ethoxy)-propionic acid tert-butyl ester

A solution of (2-hydroxy-ethyl)-carbamic acid benzyl ester (5.25 g, 26.89 mmol) in dry THF (50 mL) was treated with sodium hydride (60wt%; 108 mg, 26.89 mmol). After stirring at RT for 2 min tert-butyl acrylate (4.3 mL, 29.58 mmol) was added and the turbid solution stirred was stirred at RT for 18 h. The reaction mixture was partitioned between water and EtOAc and the organic layer was washed with water, brine, dried (MgSC^), filtered and concentrated in vacuo. The title compound was obtained following

chromatography with 20-50% EtOAc/cyclohexane (3.5 g, 37%>).

LCMS (Method 2): Rt 4.25 min, m/z 346 [M+Na]⁺ Intermediate 20

3-(2-Amino-ethoxy)-propionic acid tert-buty\ ester

The title compound was prepared from Intermediate 19 using a method similar to that described for Intermediate 8.

LCMS (Method 2): Rt 0.28 min, m/z 190 [M+H]⁺

Intermediate 21

4-{5-[2-(2-tei"i-Butoxycarbonyl-ethoxy)-ethylcarbamoyl]-2-hydroxy-phenyl}-4-phen piperidine-l-carboxylic acid ieri-but \ ester

A solution of Intermediate 20 (115 mg, 0.29 mmol), Intermediate 18 (60 mg, 0.32 mmol) and DIPEA (111 μΐ_^, 0.64 mmol) in DMF (5 mL) was treated dropwise with a solution in DMF (1 mL) of HATU (122 mg, 0.32mmol). The reaction mixture was stirred at RT for 3 h then partitioned between water and EtOAc, and the organic extract was further washed with water, dried (Na₂S0₄), filtered and concentrated in vacuo. The crude product was purified by chromatography eluting with 0-50% EtOAc in cyclohexane (90 mg, 78 %).

LCMS (Method 2): Rt 4.69 min, m/z 569 [M+H]⁺

Intermediate 22

3-{2- [4-Hydroxy-3-(4-phenyl-piperidin-4-yl)-benzoylamino] -ethoxy}-propionic acid trifluoroacetic acid salt

The title compound was prepared from Intermediate 21 using a method similar to that described for Intermediate 6. LCMS (Method 2): Rt 2.39 min, m/z 413 [M+H]⁺

Intermediate 23

3-{2-[4-Hydroxy-3-(l-methyl-4-phenyl-piperidin-4-yl)-benzoylamino]-ethoxy}- propionic acid

The title compound was prepared from Intermediate 22 using a method similar to that described for Intermediate 7.

LCMS (Method 2): Rt 2.39 min, m/z 427 [M+H]⁺

Intermediate 24

3-[3-(l,3-Dioxo-l,3-dihydro-isoindol-2- l)-propoxy]-propionic acid tert-buty\ ester

The title compound was prepared from 2-(3-hydroxy-propyl)-isoindole-l,3- dione and tert-butyl acrylate using a method similar to that described for Intermediate 19.

LCMS (Method 2): Rt 4.27 min, m/z 334 [M+H]⁺

Intermediate 25

3-(3-Amino-propoxy)-propionic acid ieri-buty\ ester

To a stirred solution of Intermediate 24 (1.87 g, 5.62 mmol) in EtOH (20 mL) was added hydrazine hydrate (874 mg, 28.10 mmol) and the mixture was heated to reflux for 18 h. The resulting solid precipitate was removed by filtration and the mother liquor was concentrated in vacuo to afford the title compound as yellow oil (1.09 g, 96%). Ή NMR (300 MHz, CDC1₃): 3.65 (t, 2H, J = 6.4 Hz), 3.53 (t, 2H, J = 6.1 Hz), 3.15 (br s, 2H), 2.81 (t, 2H, J = 6.7 Hz), 2.48 (t, 2H, J = 6.3 Hz), 1.78-1.64 (m, 2H), 1.45 (s, 9H).

Intermediate 26

4-{5-[3-(2-tei"i-Butoxycarbonyl-ethoxy)-propylcarbamoyl]-2-hydroxy-phenyl}-4- phenyl-piperidine-l-carboxylic acid terf-butyl ester

The title compound was prepared from Intermediate 25 using a method similar to that described for Intermediate 21.

LCMS (Method 2): Rt 4.73 min, m/z 583 [M+H]⁺

Intermediate 27

3-{3- [4-Hydroxy-3-(4-phenyl-piperidin-4-yl)-benzoylamino] -propoxy}-propionic acid trifluoroacetic acid salt

The title compound was prepared from Intermediate 26 using a method similar to that described for Intermediate 6.

LCMS (Method 2): Rt 2.46 min, m/z 427 [M+H]⁺

Intermediate 28

3-{3-[4-Hydroxy-3-(l-methyl-4-phenyl-piperidin-4-yl)-benzoylamino]-propoxy}- propionic acid

The title compound was prepared from Intermediate 27 using a method similar to that described for Intermediate 7. LCMS (Method 2): Rt 2.63 min, m/z 441 [M+H]⁺ Intermediate 29

4-{5-[2-(2-teri-Butoxycarbonyl-ethoxy)-ethyl]-2-hydroxy-phenyl}-4-phenyl- piperidine-l-carboxylic a

The title compound was prepared from Intermediate 5 using a method similar to that described for Intermediate 8.

LCMS (Method 1): Rt 4.57 min, m/z 548 [M+Na]⁺

Intermediate 30

3-{2-[4-Hydroxy-3-(l-isopropyl-4-phenyl-piperidin-4-yl)-phenyl]-ethoxy}-propionic acid

The title compound was prepared from Intermediate 29 using similar methods to those used for Intermediates 6 and 7, replacing aqueous formaldehyde with acetone.

LCMS (Method 1): Rt 2.75 min, m/z 412 [M+H]⁺

Intermediate 31

3-(2-{4-Hydroxy-3-[l-(2-methoxy-ethyl)-4-phenyl-piperidin-4-yl]-phenyl}-ethoxy)- propionic acid

The title compound was prepared from Intermediate 29 using similar methods to those used for Intermediates 6 and 7, replacing aqueous formaldehyde with aqueous methoxy- acetaldehyde.

LCMS (Method 1): Rt 2.78 min, m/z 428 [M+H] Intermediate 32

4-{5-[3-(2-teri-Butoxycarbonyl-ethoxy)-propyl]-2-hydroxy-phenyl}-4-phenyl- piperidine-l-carboxylic acid ieri-but \ ester

The title compound was prepared from Intermediate 12 using a method similar to that described for Intermediate 8.

LCMS (Method 1): Rt 5.03 min, m/z 540 [M+H]⁺

Intermediate 33

3-(3-{4-Hydroxy-3-[l-(2-methoxy-ethyl)-4-phenyl-piperidin-4-yl]-phenyl}-propoxy)- propionic acid

The title compound was prepared from Intermediate 32 using similar methods to those used for Intermediates 6 and 7, replacing aqueous formaldehyde with aqueous methoxy- acetaldehyde.

LCMS (Method 1): Rt 2.74 min, m/z 442 [M+H]⁺

Intermediate 34

3-{2-[3-(l-Ethyl-4-phenyl-piperidin-4-yl)-4-hydroxy-phenyl]-ethoxy}-propionic acid

The title compound can be prepared from Intermediate 6 using similar methods to those used for Intermediates 7 and 8, respectively.

LCMS (Method 2): Rt 2.56 min, m/z 398 [M+H]⁺ Intermediate 35

(2,2-Dimethoxy-ethyl)-((R)-l-meth l-pentyl)-amine

A steel reaction vessel was charged with as solution of (R)-l-methyl-pentylamine (10 g, 98.8 mmol) and dimethoxy-acetaldehyde (60wt% aqueous; 19.5 g, 187.8 mmol) in MeOH (20 mL) and the contents stirred at RT for 18 h. The reaction mixture was purged with Argon and 10% palladium on carbon (1 g) was added and the mixture hydrogenated at 60 psi for 24 h at RT. The reaction mixture was filtered through Celite^® and concentrated in vacuo then purified on an SCX-2 cartridge (eluting with MeOH, then 2 M NH₃ in MeOH) to give the title compound as a colourless oil (18.6 g, 98%>).

Ή NMR (300 MHz, CDC1₃): 4.47 (t, 1H, J = 5.6 Hz), 3.39 (s, 6H), 2.80-2.64 (m, 2H), 2.64-2.55 (m, 1H), 1.66 (br s, 1H), 1.54-1.39 (m, 1H), 1.37-1.21 (m, 5H), 1.04 (d, 3H, J = 6.3 Hz), 0.90 (t, 3H, J = 6.8 Hz).

The following amino acetals (Table 1) were prepared in a similar manner to Intermediate 35 using commercial amines (unless otherwise noted) and dimethoxy-acetaldehyde:

Intermediate Amine Structure Reference / NMR CDC1₃ (MHz) δ

(300 MHz): 4.48 (t, IH, J = 5.6 Hz), 3.39 (s, 6H), 2.73 (d, 2H, J = 5.5 Hz),

4-Methyl- 2.63-2.56 (m, 2H), 1.62- 1.42 (m, 3H),

46 pentylamine

1.25- 1.12 (m, 2H), 0.88 (d, 6H, J = 6.6 (Note 1)

Hz). One exchangeable proton not observed.

(400 MHz): 4.48 (t, IH, J = 5.6 Hz), 3.39 (s, 6H), 2.73 (d, 2H, J = 5.6 Hz),

3-Cyclopropyl- 2.67-2.61 (m, 2H), 1.65- 1.55 (m, 2H),

47 propylamine

1.47 (br s, IH), 1.28- 1.16 (m, 2H), 0.72- (Note 1)

0.59 (m, IH), 0.45-0.36 (m, 2H), 0.04- 0.03 (m, 2H).

(400 MHz): 4.47 (t, IH, J = 5.5 Hz),

2-Cyclobutyl- 3.39 (s, 6H), 2.72 (d, 2H, J = 5.6 Hz),

48 ethylamine 2.53 (t, 2H, J = 7.4 Hz) 2.35-2.20 (m,

(Note 1) ^'J IH), 2.10- 1.97 (m, 2H), 1.90- 1.75 (m,

2H), 1.68- 1.51 (m, 4H), 1.49 (br s, IH).

(400 MHz): 4.46 (t, IH, J = 5.6 Hz), 3.37 (s, 6H), 2.69 (d, 2H, J = 5.5 Hz),

Cyclohexyl-

49 2.43 (d, 2H, J = 6.7 Hz), 1.76- 1.59 (m, methylamine

4H), 1.53 (br s, IH), 1.49- 1.37 (m, 2H), 1.28- 1.06 (m, 3H), 0.94-0.80 (m, 2H).

(300 MHz): 4.49 (t, IH, J = 5.6 Hz), 3.39 (s, 6H), 2.72 (d, 2H, J = 5.6 Hz),

50 2-Ethyl-butylamine 2.51 (d, 2H, J = 5.7 Hz), 1.49- 1.24 (m,

5H), 0.90 (t, 6H, J = 7.1 Hz), one exchangeable proton not observed.

51 Hexylamine x/ US 5561 142

Intermediate Amine Structure Reference / NMR CDC1₃ (MHz) δ

(CD₃OD, 400 MHz): 4.47 (t, 1H, J = 5.5

(R)- l -Cyclopentyl- Hz), 3.39 (s, 6H), 2.82 (m, 1H), 2.64

67 ethylamine

(m, 1H), 2.42 (m, 1H), 1.87- 1.45 (m, (Note 3)

7H), 1.18 (m, 2H), 1.04 (d, 3H).

(400 MHz): 4.51 -4.45 (m, 1H), 4.03- 3.94 (m, 1H), 3.88-3.81 (m, 1H), 3.78-

[(S)- l -(Tetrahydro- 3.70 (m, 1H), 3.38 (s, 6H), 2.77-2.75

68 furan-2-yl)]-m

(m, 2H), 2.69-2.66 (m, 2H), 2.01 - 1.82 ethylamine

(m, 3H), 1.70 (br s, 1H), 1.59- 1.47 (m, 1H).

(300 MHz): 4.47 (t, 1H, J = 5.5 Hz), 3.38 (s, 6H), 2.72 (d , 2H, J = 5.6 Hz),

Cyclobutyl- 2.65 (d, 2H, J = 7.3 Hz), 2.53-2.43 (m,

69

methylamine 1H), 2.1 1 -2.02 (m, 2H), 1.95- 1.79 (m,

2H), 1.70- 1.60 (m, 2H), one exchangeable proton not observed.

(300 MHz): 4.48 (t, 1H, J = 5.7 Hz), 3.38 (s, 3H), 3.37 (s, 3H), 2.90-2.84 (m,

(R)- 1,2,2-Trimethyl-

-o ^

70 1H), 2.61 -2.55 (m, 1H), 2.27-2.21 (m, propylamine

1H), 0.98 (d, 3H, J = 6.5 Hz), 0.89 (s, 9H).

(300 MHz): 4.49 (t, 1H, J = 5.5 Hz), 3.40 (s, 6H), 2.76-2.70 (m, 4H), 1.40 (q,

2-Cyclopropyl-

71 2H, J = 7.1 Hz), 0.72-0.61 (m, 1H), ethylamine -^J 0.46-0.38 (m, 2H), 0.08-0.01 (m, 2H), one exchangeable proton not observed. Intermediate Amine Structure Reference / NMR CDC1₃ (MHz) δ

(400 MHz): 4.48 (t, 1H, J = 5.6 Hz), 3.40 (s, 3H), 3.39 (s, 3H), 2.86 - 2.82 (m, 1H), 2.77 - 2.72 (m, 1H), 1.88 -

((R)- 1 -Cyclopropyl- 1.81 (m, 1H), 1.15 (d, 3H, J = 6.3 Hz),

72 ethyl)-(2,2-dime

0.75 - 0.67 (m, 1H), 0.56 - 0.50 (m, thoxy-ethyl)-amine

1H), 0.47 - 0.40 (m, 1H), 0.23 - 0.18 (m, 1H), 0.09 - 0.04 (m, 1H), one exchangeable proton not observed.

(400 MHz): 4.49 (t, 1H, J = 5.6 Hz),

2,2-Dimethyl- 3.38 (s, 6H), 2.73 (d, 2H, J = 5.6 Hz),

73

propylamine 2.36 (s, 2H), 1.45 (br s, 1H), 0.91 (s,

9H).

(300 MHz): 4.46 (t, 1H, J = 5.5 Hz),

(Tetrahydro- 3.39 (s, 6H), 2.73-2.56 (m, 4H), 2.70 (d,

74 thiopyran-4-yl)- 2H, J = 5.6 Hz), 2.48 (d, 2H, J = 6.5 methylamine Hz), 2.09-2.00 (m, 2H), 1.47 (br s, 1H),

1.42- 1.29 (m, 3H).

(300 MHz): 4.50 (t, 1H, J = 5.6 Hz),

3.39 (s, 6H), 2.74 (d, 2H, J = 5.6 Hz),

(1 -Methyl- 2.47 (s, 2H), 1.67- 1.53 (m, 4H), 1.51 -

75 cyclopentyl)-

1.40 (m, 2H), 1.36- 1.27 (m, 2H), 0.99 methylamine

(s, 3H), one exchangeable proton not observed.

(300 MHz): 4.48 (t, 1H, J = 5.6 Hz),

(R)-2- Λ 3.39 (s, 6H), 2.95-2.51 (m, 6H), 1.27 (d,

76 Isopropylsulfanyl- 1 - 6H, J = 6.8 Hz), 1.13 (d, 3H, J = 6.1 methyl-ethylamine Hz), one exchangeable proton not

observed.

(400 MHz): 4.47 (t, 1H, J = 5.6 Hz), 3.39 (s, 6H), 2.71 (d, 2H, J = 5.6 Hz),

77 1 -Ethyl-propylamine

2.36 (m, 2H), 1.42 (m, 4H), 0.88 (t, 6H, J = 7.3 Hz). Intermediate Amine Structure Reference / NMR CDC1₃ (MHz) δ

(300 MHz, CDC1₃) δ 4.46 (t, 1H, J = 2.4 Hz), 3.38 (s, 6H), 2.78 (dd, 1H, J = 5.5, 1 1.9 Hz), 2.67 (dd, 1H, J = 5.5, 1 1.6

(R)- 1 ,2-Dimethyl- Hz), 2.49 - 2.39 (m, 1H), 1.76 - 1.62

78

propylamine (m, 1H), 0.96 (d, 3H, J = 6.7 Hz), 0.90

(d, 3H, J = 6.7 Hz), 0.85 (d, 3H, J = 6.7 Hz). One exchangeable proton not observed.

(300MHz): 4.45 (t, 1H, J = 5.5 Hz), 3.39 (s, 6H), 2.75 (d, 2H, J = 5.5 Hz),

Tetrahydro-

79 2.71 -2.63 (m, 4H), 2.50-2.40 (m, 1H), thiopyran-4-ylamine

2.1 1 -2.21 (m, 2H), 1.66- 1.45 (m, 2H), one exchangeable proton not observed.

(300MHz): 4.47 (t, 1H, J = 5.5 Hz), 3.92 (dd, 2H, J = 1 1 , 3.9 Hz), 3.43-3.31

2-(Tetrahydro- (m, 2H), 3.40 (t, 6H), 2.74 (d, 2H, J =

80 pyran-4-yl)- 5.5 Hz), 2.65 (t, 2H, J = 7.4 Hz), 1.66- ethylamine

1.53 (m, 2H), 1.50- 1.40 (m, 4H), 1.38- 1.21 (m, 2H).

(300MHz): 4.47 (t, 1H, J = 5.5 Hz), 3.57 (q, 1H, 6.0 Hz), 3.52 (t, 2H, J =

2-Isopropoxy-

81 5.5 Hz), 3.38 (s, 6H), 2.81 -2.74 (m, ethylamine

4H), 1.15 (d, 6H, J = 6.0 Hz), one exchangeable proton not observed.

(300MHz): 4.80 (t, 1H, J = 5.6 Hz),

(R)- l -Methyl-2- 3.40 (s, 6H), 2.87-2.76 (m, 2H), 2.74-

82 methylsulfanyl-ethyl 2.67 (m, 1H), 2.59-2.48 (m, 2H), 2.01 amine (s, 3H), 1.80 (br s, 1H), 1.14 (d, 3H, J =

6.3 Hz). Intermediate Amine Structure Reference / NMR CDC1₃ (MHz) δ

(300 MHz): 4.48 (t, 1H, J = 5.5 Hz),

(R)-2-Ethylsulfanyl- 3.40 (s, 6H), 2.84-2.49 (m, 6H), 1.26 (t,

83 1 -methyl- ethyla 3H, J = 6.8 Hz), 1.15 (d, 3H, J = 5.0 mine

Hz), one exchangeable proton not observed.

[(R)-l-(4,4- (300 MHz): 4.61 (1 H, t, J = 5.38 Hz), Difluorocyclohexyl) 3.43 (3 H, s, 3.42 (3 H, s), 2.90 (1 H, ethyl] -(2,2- dd, J = 12.24, 5.37 Hz), 2.76 (2 H, dd, J

83a

dimethoxyethyl)ami F = 1 1.92, 5.59 Hz), 2.25-2.02 (3 H, m), ne 1.77- 1.66 (6 H, m), 1.12 (3 H, d, J = (Note 4) 6.54 Hz).

Table 1 Note l:\VO2005011657, Note 2: Prepared according to JOC 1970, 35(6), 2050., Note 3: US5225591, Note 4: Aldehyde prepared according to WO2006/134341 and chiral amine was prepared via JOC 1997, 119(41), 9913..

Intermediate 84

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 dropwise n-butyllithium (2.5 M in hexanes; 10.23 mL, 25.60 mmol) and the solution was stirred for 30 min under Argon. A solution of 4-oxo-piperidine-l- carboxylic acid tert-butyl ester (5 g, 25.10 mmol) in THF (9 mL) was added dropwise 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 (Na₂S0₄), and concentrated in vacuo. The crude product was crystallised from hot heptane/EtOAc to afford the title compound (6 g, 74%).

LCMS (Method 2) Rt 4.54 min, m/z 340 [M+Na⁺]. Intermediate 85

4-(5-Chloro-thiophen-2-yl)-4-[2-hydroxy-5-(3-hydroxy-propyl)-phenyl]-piperidine-l- carboxylic acid tert-butyl ester

The title compound was prepared using similar methods to those used for Intermediates 9 and 10, replacing 4-phenylpiperidin-4-ol with Intermediate 84.

LCMS (Method 1): Rt 4.70 min, m/z 474 [M+Na]⁺

Intermediate 86

4-[2-Hydroxy-5-(3-hydroxy-propyl)-phenyl]-4-thiophen-2-yl-piperidine-l-carboxylic acid tert-butyl ester

A solution of Intermediate 85 (1.23 g, 2.72 mmol) in a mixture of THF/EtOAc [5:2] (42 mL) was treated with Et₃N (1.13 mL, 8.16 mmol) and 10% palladium on charcoal (1 g) was added. The resulting mixture was hydrogenated (hydrogen-filled balloon) for 2.5 h. The reaction mixture was filtered through Celite^® and concentrated in vacuo to afford the title compound as a white foam (1.14 g, quant.).

LCMS (Method 1): Rt 4.45 min, m/z 440 [M+Na]⁺

Intermediate 87

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

A 3 M solution in ether of phenyl magnesium bromide (10.2 mL, 30.67 mmol) was added dropwise over 15 minutes to a cooled (0 °C) stirred solution in THF (50 mL) of 3-oxo- azetidine-l-carboxylic acid tert-butyl ester (5g, 29.21 mmol). During addition the reaction temperature was maintained <10 °C. After stirring at ice bath temperature for 30 minutes the reaction mixture was allowed to warm to RT overnight. The reaction was quenched by addition of saturated aqueous ammonium chloride and the resulting mixture was partitioned between water (100 mL) and EtOAc (2 x lOOmL). The combined organic extracts were washed with water, dried (MgS0₄), filtered and concentrated in vacuo.

Purification by column chromatography, eluting with 0-100% EtOAc in cyclohexane gave the title compound, 6.56g (90%).

Ή NMR (400 MHz, CDC1₃): 7.52-7.47 (m, 2H), 7.43-7.37 (m, 2H), 7.35-7.29 (m, 1H), 4.27 (d, 2H, J = 9.6 Hz), 4.17 (dd, 2H, J = 9.3, 0.9 Hz), 2.71 (br s, 1H), 1.46 (s, 9H).

Intermediate 88

4-Hydroxy-3-(3-phenyl-azetidin-3- l)-phenyl] -acetic acid methyl ester

The title compound was prepared using a similar method to that used for Intermediate 1 , replacing 4-phenylpiperidin-4-ol with Intermediate 87.

LCMS (Method 1): Rt 2.58 min, m/z 298 [M+H]⁺

Intermediate 89

3-[2-Benzyloxy-5-(2-hydroxy-ethyl)-phenyl]-3-phenyl-azetidine-l-carboxylic acid tert- butyl ester

The title compound was prepared from Intermediate 88 using similar methods to those used for Intermediates 2, 3 and 4.

LCMS (Method 2): Rt 4.82 min, m/z 460 [M+H] Intermediate 90

3-{2-Benzyloxy-5-[2-(2-tei"i-butoxycarbonyl-ethoxy)-ethyl]-phenyl}-3-phenyl- azetidine-l-carboxylic acid tert-but l ester

To a solution of Intermediate 89 (1.40g, 3.05 mmol) in acetonitrile (20 mL) was added tert-butyl acrylate (0.98 mL, 6.71 mmol) followed by addition of

benzyltrimethylammonium hydroxide (40wt% solution in water; 0.38 mL, 0.92 mmol). The resulting mixture was stirred at RT for 4 h. The reaction mixture was concentrated in vacuo and purified by chromatography, eluting with 0-50% EtOAc in cyclohexane.

LCMS (Method 1): Rt 5.35 min, m/z 588 [M+H]⁺

Intermediate 91

3-{2-[4-Benzyloxy-3-(3-phenyl-azetidin-3-yl)-phenyl]-ethoxy}-propionic

acid trifluoroacetic acid salt

The title compound was prepared from Intermediate 90 using a similar method to that used for Intermediate 6.

LCMS (Method 2): Rt 3.44 min, m/z 432 [M+H]⁺

Intermediate 92

3-{2-[4-Hydroxy-3-(l-methyl-3- henyl-azetidin-3-yl)-phenyl]-ethoxy}-propionic acid

The title compound was prepared from Intermediate 91 using similar methods to those used for Intermediates 7 and 8. LCMS (Method 1): Rt 2.67 min, m/z 356 [M+H]⁺

Intermediate 93

3-{2-[4-Hydroxy-3-(3-phenyl-azetidin-3-yl)-phenyl]-ethoxy}-propionic acid trifluroacetic acid salt

The title compound was prepared from Intermediate 90 using similar methods to those used for Intermediate 8 and 6.

LCMS (Method 1): Rt 2.51 min, m/z 342 [M+H]⁺

Intermediate 94

3-{2-[4-Hydroxy-3-(l-isopropyl-3-phenyl-azetidin-3-yl)-phenyl]-ethoxy} propionic acid

The title compound was prepared from Intermediate 93 using a similar method to that used for Intermediate 7, replacing aqueous formaldehyde with acetone.

LCMS (Method 1): Rt 2.54 min, m/z 384 [M+H]⁺

Intermediate 95

4-(2-Benzyloxy-5-bromo-phenyl)-4-c ano-piperidine-l-carboxylic acid tert-butyl ester

To a stirred solution of (2-benzyloxy-5-bromo-phenyl)-acetonitrile (prepared according to EP752421) (4.82 g, 15.95 mmol) in DMF (60 mL) was added to-(2-chloro-ethyl)- carbamic acid tert-butyl ester (4.24 g, 17.54 mmol) (prepared from ¾z^'s-(2-chloro-ethyl)- amine-HCl (WO2008152149)). Sodium hydride (60wt%; 2.55 g, 63.80 mmol) was added portionwise and the reaction mixture was warmed to 60 °C and stirred for 18 h then allowed to cool to RT, quenched by careful addition of water under stirring. After 5 min the reaction mixture was extracted with EtOAc, and the organic layer was further washed with water, brine, dried (Na₂S0₄), filtered and concentrated in vacuo. The crude product was purified by chromatography, eluting with 0-50% EtOAc in cyclohexane to give the title compound as a yellow solid (4.56 g, 60%).

LCMS (Method 2): Rt 4.89 min, m/z 471/473 [M+H]⁺

Intermediate 96

4-(2-Benzyloxy-5-bromo-phenyl)-4-thiocarbamoyl-piperidine-l-carboxylic acid tert- butyl ester

To a stirred solution of Intermediate 95 (1.8 g, 3.81 mmol) in dry pyridine (3.2 mL) was added triethylamine (0.74 mL, 5.34 mmol). Hydrogen sulphide gas was bubbled into the solution at 0 °C for ~15 min and the reaction vessel was sealed, warmed to 60 °C. After stirring for 42 h the reaction mixture was cooled to RT and nitrogen was bubbled into the solution for 10 min to evacuate the remaining H₂S. The solution was concentrated in vacuo and purified by chromatography, eluting with 0-50% EtOAc in cyclohexane to give the title compound as a yellowish foam (1.65 g, 86%>).

LCMS (Method 1): Rt 4.80 min, m/z 527/529 [M+Na]⁺

Intermediate 97

4-(2-Benzyloxy-5-bromo-phenyl)-4-thiazol-2-yl-piperidine-l-carboxylic acid terf-butyl ester

To a stirred solution of Intermediate 96 (1.21 g, 2.40 mmol) in DMF (20 mL) was added 1,2-dichloro-l-ethoxy-ethane (0.51 g, 3.60 mmol). The reaction vessel was sealed and the reaction mixture was warmed to 75 °C. After stirring for 16 h, the reaction mixture was cooled to RT and quenched by addition of saturated NaHC0₃ solution and diluted with EtOAc. The organic phase was separated then washed with saturated NaHC0₃, water, brine, dried (Na₂S0₄), filtered and concentrated in vacuo. To a stirred solution of the crude reaction mixture in DCM (8 mL) was added triethylamine (0.37 mL, 2.64 mmol) followed by tert-butoxycarbonyl anhydride (0.55 g, 2.52 mmol). After 30 min the solution was diluted with EtOAc and washed with water and the organic was separated and washed successively with water, brine, dried (Na₂S0₄), filtered and concentrated in vacuo.

Purification by chromatography, eluting with 0-20% EtOAc in cyclohexane to give the title compound as a yellow foam (0.59 g, 46%>).

LCMS (Method 1): Rt 5.08 min, m/z 551/553 [M+Na]⁺

Intermediate 98

4-(2-Benzyloxy-5-tei"i-butoxycarbonylmethyl-phenyl)-4-thiazol-2-yl-piperidine-l- carboxylic acid terf-butyl ester

Pd(dba)₂ (70 mg, 0.12 mmol) and 2-dicyclohexylphosphino-2'-(N,N-dimethylamino) biphenyl (44 mg, 0.11 mmol) were placed into a round bottom flask and submitted to vacuum/Ar cycle prior to addition of a solution of Intermediate 97 (588 mg, 1.11 mmol) in dry THF (8 mL). A 0.5 M solution in Et₂0 of 2-tert-butoxy-2-oxoethylzinc chloride (4.44 mL, 2.22 mmol) was added and the reaction mixture was stirred at 80 °C under Argon for 16 h. The reaction mixture was cooled to RT, filtered through a small pad of hyflo, washed with THF and concentrated in vacuo. Purification by chromatography, eluting with 0-40% EtOAc in cyclohexane to give the title compound as a colourless oil (0.48 g, 78%).

LCMS (Method 2): Rt 4.94 min, m/z 565 [M+H]⁺ Intermediate 99

4- [2-Benzyloxy-5-(2-hydroxy-ethyl)-phenyl] -4-thiazol-2-yl-piperidine- 1 carboxylic acid tert-buty\ ester

To a stirred solution of Intermediate 98 (0.48 g, 0.84 mmol) in dry THF (14 mL) under Ar was added dropwise a 2 M solution of lithium borohydride in THF (2.73 mL, 5.47 mmol). The reaction mixture was warmed to 40 °C and stirred for 16 h then cooled and quenched by careful addition of water (effervescence observed) at 0 °C with stirring. The reaction mixture was treated with EtOAc and stirred for 20 min and the organic phase was separated washed successivley with water, brine, dried (Na₂S0₄), filtered and concentrated in vacuo. Purification by chromatography, eluting with 30-50% EtOAc in cyclohexane to give the title compound as a sticky white foam (366 mg, 88%).

LCMS (Method 1): Rt 4.70 min, m/z 495 [M+H]⁺

Intermediate 100

4-{5-[2-(2-tei"i-Butoxycarbonyl-ethoxy)-ethyl]-2-hydroxy-phenyl}-4-thiazol-2-yl- piperidine-l-carboxylic acid ieri-buty\ ester

The title compound was prepared from Intermediate 99 using similar methods to those described for Intermediates 90 and 8.

LCMS (Method 1): Rt 4.73 min, m/z 533 [M+H]⁺ Intermediate 101

3-{2-[4-Hydroxy-3-(4-thiazol-2-yl-piperidin-4-yl)-phenyl]-ethoxy}-propionic acid trifluroacetic acid salt

The title compound was prepared from Intermediate 100 using a method similar to that described for Intermediate 6.

LCMS (Method 2): Rt 2.31 min, m/z 377 [M+H]⁺

Intermediate 102

3-{2-[4-Hydroxy-3-(l-methyl-4-thiazol-2-yl-piperidin-4-yl)-phenyl]-ethoxy}-propionic acid

The title compound was prepared from Intermediate 101 using a method similar to that described for Intermediate 7.

LCMS (Method 2): Rt 2.29 min, m/z 391 [M+H]⁺

Intermediate 103

V-(2,2-Dimethoxy-ethyl)-3-{2-[4-hydroxy-3-(l-methyl-4-phenyl-piperidin-4-yl)- phenyl]-ethoxy}- V-((R)-l-meth l-pentyl)-propionamide

A solution of Intermediate 8 (350 mg, 0.91 mmol) and DIPEA (0.80 mL, 4.60 mmol) in DMF (10 mL) was treated dropwise with a solution in DMF (1 mL) of HATU (520 mg, 0.91 mmol). After 10 min a solution in DMF (ImL) of Intermediate 35 (170 mg, 0.32 mmol) was added. The reaction mixture was stirred at RT for 18 h then partitioned between water and EtOAc. The organic extract was further washed with water, dried (Na₂S0₄), filtered and concentrated in vacuo. The crude product was used directly.

LCMS (Method 2): Rt 3.53 min, m/z 555 [M+H]⁺

The following intermediate compounds (Table 2) were prepared similarly to Intermediate 54:

Table 2

Intermediate 176

3-{2-[3-(l-Cyclobutyl-3-phenyl-azetidin-3-yl)-4-hydroxy-phenyl]-ethoxy}-propionic acid

The title compound was prepared from Intermediate 93 using a similar method to that used for Intermediate 7, replacing aqueous formaldehyde with cyclobutanone.

LCMS (Method 1): Rt 2.83 min, m/z 396 [M+H⁺]

Intermediate 177

3-{2-[3-(l-Ethyl-3-phenyl-azetidin-3-yl)-4-hydroxy-phenyl]-ethoxy}-propionic acid

The title compound was prepared from Intermediate 93 using a similar method to that used for Intermediate 7, replacing aqueous formaldehyde with acetaldehyde.

LCMS (Method 1): Rt 2.76 min, m/z 370 [M+H⁺]

Intermediate 178

3-{2-[3-(l-Cyclopropylmethyl-3-phenyl-azetidin-3-yl)-4-hydroxy-phenyl]-ethoxy}- propionic acid

The title compound was prepared from Intermediate 93 using a similar method to that used for Intermediate 7, replacing aqueous formaldehyde with cyclopropane carboxaldehyde.

LCMS (Method 1): Rt 2.06 min, m/z 396 [M+H⁺]

Intermediate 179

3-{2-[3-(l-Cyclopentyl-3-phenyl-azetidin-3-yl)-4-hydroxy-phenyl]-ethoxy}-propionic acid

The title compound was prepared from Intermediate 93 using a similar method to that used for Intermediate 7, replacing aqueous formaldehyde with cyclopentanone.

LCMS (Method 4): Rt 2.74 min, m/z 410 [M+H⁺]

Intermediate 180

3-{2- [4-Methoxy-3-(l-methyl-4-phenyl-piperidin-4-yl)-phenyl] -ethoxy}-propionic acid

The title compound was prepared using similar methods to those used for Intermediate 7, replacing benzyl bromide with methyl iodide.

LCMS (Method 4): Rt 2.95 min, m/z 398 [M+H⁺]

Intermediate 181

3-{3-[4-Hydroxy-3-(l-methyl-3-phenyl-azetidin-3-yl)-phenyl]-propoxy}-propionic acid

The title compound was prepared using similar methods to those used for Intermediate 14, replacing 4-phenylpiperidin-4-ol with 3-phenylazetidin-3-ol.

LCMS (Method 1): Rt 2.62 min, m/z 370 [M+H⁺]

Intermediate 182

4-{2-Benzyloxy-5-[2-(2-tert-butoxycarbonyl-ethoxy)-ethyl]-phenyl}-piperidine-l- carboxylic acid tert-butyl ester

A mixture of 3-[2-(4-benzyloxy-3-bromo-phenyl)-ethoxy]-propionic acid tert-butyl ester (418 mg, 0.96 mmol), 4-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H- pyridine-l-carboxylic acid tert-butyl ester (300 mg, 0.96 mmol), potassium phosphate tribasic (600 mg, 2.9 mmol) and Pd(PPh₃)₄ (22 mg, 0.02 mmol) in DMF (10 mL) was degassed then heated at 95 °C for 16 h. The reaction mixture was concentrated in vacuo and the resulting residue loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH₃/MeOH affording the title compound (440 mg, 85%).

LCMS (Method 1): Rt 3.67 min, m/z 436 [M-Boc+H⁺] Intermediate 183

3-{2-[4-Benzyloxy-3-(l-ethyl-piperidin-4-yl)-phenyl]-ethoxy}-propionic acid

The title compound was prepared using similar methods to those used for Intermediates 6 and 7, replacing Intermediate 6 with Intermediate 182 and formaldehyde with

acetaldehyde.

LCMS (Method 1): Rt 3.26 min, m/z 410 [M+H⁺]

Intermediate 184

3-{2-[3-(l-Ethyl-piperidin-4-yl)-4-hydroxy-phenyl]-ethoxy}-propionic acid

The title compound was prepared using similar methods to those used for Intermediate 8, replacing Intermediate 7 with Intermediate 183.

LCMS (Method 1): Rt 2.06 min, m/z 322 [M+H⁺]

Intermediate 185

3-{2-Benzyloxy-5-[3-(2-tert-butoxycarbonyl-ethoxy)-propyl]-phenyl}-azetidine-l- carboxylic acid tert-butyl e

To a suspension of zinc (660 mg, 10.0 mmol) and Cellpure® (200 mg) in DMA (2 mL) was added a solution of trimethylsilyl chloride :dibromoethane (7:5, 0.2 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 (2.3 g, 8.2 mmol) in DMA (4 mL) was added dropwise to the mixture and allowed to stir for 1 hour. In a separate flask, copper(I) iodide (67 mg, 0.35 mmol), Pd(dppf)₂Cl₂.DCM (140 mg, 0.18 mmol) and 3-[3-(4-benzyloxy-3-bromo-phenyl)- propoxy] -propionic acid tert-butyl ester (2.63 g, 5.9 mmol) were combined in DMA (8 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 (MgS0₄) and concentrated in vacuo. The resulting residue was purified by chromatography eluting from 0-20% EtOAc yclohexane affording the title compound as an oil (1.3 g, 42%).

1H NMR (300 MHz, CDC1₃): 7.39 (d, 4H, J = 4.4 Hz), 7.33-7.32 (m, 1H), 7.04- 7.03 (m, 2H), 6.83 (d, 1H, J = 8.3 Hz), 5.03 (s, 2H), 4.29-4.17 (m, 2H), 4.07-4.00 (m, 3H), 3.66 (t, 2H, J = 6.4 Hz), 3.45 (t, 2H, J = 6.3 Hz), 2.67-2.59 (m, 2H), 2.50 (t, 2H, J = 6.4 Hz), 1.88-1.81 (m, 2H), 1.46 (s, 9H), 1.44 (s, 8H).

Intermediate 186

3-{3-[3-(l-Cyclopentyl-azetidin-3- l)-4-hydroxy-phenyl]-propoxy}-propionic acid

The title compound was prepared using similar methods to those used for Intermediate 184, using Intermediate 185 and replacing acetaldehyde with cyclopentanone.

LCMS (Method 1): Rt 1.97 min, m/z 348 [M+H⁺]

Intermediate 187

4-{5-[2-(2-Carboxy-ethoxy)-ethyl]-2-hydroxy-phenyl}-4-phenyl-piperidine-l- carboxylic acid tert-butyl ester

A solution of Intermediate 5 (2.0 g, 3.25 mmol) in DCM (18 mL) was treated with TFA (9 mL) and stirred at RT for 1 h. The reaction mixture was concentrated in vacuo then azeotroped with toluene. The resulting residue was re-dissolved in DCM (30 mL) before triethylamine (1.2 mL, 8.1 mmol) and tert-butoxycarbonyl anhydride (780 mg, 3.6 mmol) were added. The resulting mixture was allowed to stir at RT for 1 h then concentrated in vacuo. The resulting residue was purified by chromatography eluting with 0-100% EtOAc in cyclohexane to afford the title compound (1.5 g, 98%).

LCMS (Method 4): Rt 4.50 min, m/z 560 [M+H⁺]

This intermediate was then treated like Intermediate 8 for benzyl deprotection.

Intermediate 188

4-(2-Hydroxy-5-methoxycarbonylmethyl-phenyl)-4-methyl-piperidine-l-carboxylic acid tert-butyl ester

To a solution of (4-hydroxy-phenyl)-acetic acid methyl ester (200 mg, 0.93 mmol) and 4- hydroxy-4-methyl-piperidine-l-carboxylic acid tert-butyl ester (772 mg, 4.64 mmol) in nitrobenzene (0.8 mL) was added triflic acid (2.05 mL, 23.22 mmol). The resulting mixture was stirred for 18 h then neutralised with saturated aqueous NaHC0₃ and extracted with CHC1₃. The combined organic phases were washed with water, brine, dried (Na₂S0₄) and concentrated in vacuo. The resulting residue was purified on SCX-2 cartridge (eluting with 2M NH₃ in MeOH) then dissolved in DCM (30 mL) before the addition of triethylamine (762 μί, 5.47 mmol) and tert-butoxycarbonyl anhydride (1.1 g, 5.02 mmol). The resulting mixture was stirred for 30 min then diluted with DCM and washed with saturated aqueous NaHC0₃. The organic phase was dried (Na₂S0₄) and cocnetrated in vacuo and the resulting residue purified by chromatography wluting with 30% EtOAc in cyclohexane to afford the title compound as a yellow foam (1.0 g, 45%).

LCMS (Method 4): Rt 3.70 min, m/z 364 [M+H⁺]

Intermediate 189

3-{2-[3-(l-Ethyl-4-methyl-piperidin-4-yl)-4-hydroxy-phenyl]-ethoxy}-propionic acid

The title compound was prepared from Intermediate 188 using similar methods to those used for Intermediate 7 replacing formaldehyde with aceetaldehyde.

LCMS (Method 4): Rt 1.83 min, m/z 336 [M+H⁺]

Examples

The following non-limiting examples of the invention are provided below.

Example 1

3-{2-[4-Hydroxy-3-(l-methyl-4-phenyl-piperidin-4-yl)-phenyl]-ethoxy}-N-{2-[2-(5- hydroxy-3-oxo-3,4-dihydro-2H-benzo[l,4]oxazin-8-yl)-ethylamino]-ethyl}-N-((R)-l- methyl-pentyl)-propionamide diformic acid salt

To a solution of Intermediate 103 (504 mg, 0.91 mmol) in THF (10 mL) was added para- TSA.H₂0 (430 mg, 2.26 mmol) and the reaction was stirred at RT for 45 min. This solution was added to a suspension of 8-(2-amino-ethyl)-5-hydroxy-4H-benzo[l,4]oxazin-3- one.HCl (220 mg, 0.91 mmol) (WO 2008075025) and NaHC0₃ (270 mg, 3.21 mmol) in [10: 1] NMP/water (11 mL), and the mixture was stirred for 10 minutes prior to the addition of glacial AcOH (50 μί) and NaBH(OAc)₃ (480 mg, 2.26 mmol). The resulting solution was stirred at RT for 18 hours, then partitioned between 2-methyl-THF (x2) and saturated aqueous NaHC0₃. The combined organic extracts were washed with water and brine, then dried (MgS0₄), filtered and concentrated in vacuo. The crude material was purified by chromatography eluting with 0-15% (0.7 M NH₃ in MeOH), followed by purification by HPLC, eluting with 5-95% MeOH/water (0.1 % formic acid) over 30 minutes to give the title compound as a diformic acid salt (35 mg, 5%)

LCMS (Method 4): Rt 6.82 min, m/z 701 [M+H⁺]

Ή NMR (400 MHz, CD₃OD): 7.32-7.19 (m, 4H), 7.12 (t, 1H, J = 7.0 Hz), 7.04 (br s, 1H), 6.92 (d, 1H, J = 8.2 Hz), 6.68 (d, 1H, J = 8.3 Hz), 6.60 (d, 1H, J = 8.2 Hz), 6.46 (d, 1H, J = 8.3 Hz), 4.59 (s, 2H), 4.10-3.90 (m, 1H), 3.68 (t, 2H, J = 6.1 Hz), 3.63-3.56 (t, 2H, J = 7 Hz), 3.55-2.97 (m, obscured, 14H), 2.87 (t, 2H, J = 7.1 Hz), 2.78-2.71 (m, 2H), 2.70 (s, 3H), 2.67-2.51 (m, 2H), 1.53-1.43 (m, 2H), 1.37-1.17

(m, 4H), 1.15 (d, 3H, J = 6.6 Hz), 0.88 (t, 3H, J = 7.0 Hz).

The following compounds (Table 3) were prepared similarly to Example 1, as formic acid salts, utilising the appropriate acetals (see Table 1) and amines (see Table 2):

Acetal NMR (CD₃OD, 400 LCMS (Rt,

Amine Structure

Example Int. MHz) δ m/z)

7.32-7.18 (m, 4H), 7.12

(t, 1H, J = 7.1 Hz), 6.97

(br s, 1H), 6.87 (d, 1H, J

= 8.1 Hz), 6.69 (d, 1H, J

= 8.4 Hz), 6.60 (d, 1H, J

= 8.3 Hz), 6.46 (d, 1H, J

= 8.3 Hz), 4.56 (s, 2H),

8-(2- 4.05-3.94 (m, 1H), 3.65

Amino- (t, 2H, J = 6.0 Hz), 3.54- ethyl)-5- 3.49 (m, 1H), 3.41 (t, (Method 6) hydroxy- 2H, J = 6.3 Hz), 3.40- 3.08 min,

2 104

4H-benz <A-° ^H ° A 3.35 (m, obscured, 1H), m/z 715 o[l,4]oxaz 3.24-2.97 (m, obscured [M+H⁺] in-3-one 8H), 3.12 (t, 2H, J = 6.4

(Note 1) Hz), 3.07 (t, 2H, J = 5.7

Hz), 2.86 (t, 2H, J = 7.2

Hz), 2.71 (s, 3H), 2.69- 2.47 (m, 6H), 1.81-1.70

(m, 2H), 1.55-1.45 (m,

2H), 1.38-1.23 (m, 2H),

1.17 (d, 3H, J = 6.6 Hz),

0.89 (t, 3H, J = 6.9 Hz).

Acetal NMR (CD₃OD, 400 LCMS (Rt,

Amine Structure

Example Int. MHz) δ m/z)

7.34-7.17 (m, 5H), 7.12

(t, 1H, J = 7.0 Hz), 7.05

(br s, 1H), 6.98-6.87 (m,

2H), 6.84 (d, 1H, J = 8.2

Hz), 6.62 (d, 1H, J = 8.2

N-[5-(2- Hz), 3.75-3.65 (m, 3H),

Amino- 3.61 (t, 2H, J = 6.9 Hz),

ethyl)-2- 3.52 (t, 2H, J = 6.1 Hz),

(Method 4) hydroxy- ^HOri Q 3.42-2.94 (m, obscured,

6.29 min,

5 106 phen 8H), 3.14 (t, 2H, J = 7.3

m/z 721 yi]- Hz), 3.04 (t, 2H, J = 5.8

[M+H⁺] methanesul Hz), 2.90 (s, 3H), 2.85

fonamide (t, 2H, J = 8.0 Hz), 2.78- (Note 2) 2.74 (m, 2H), 2.73 (s,

3H), 2.64 (t, 2H, J = 6.1

Hz), 1.85-1.66 (m, 4H),

1.66-1.58 (m, 1H), 1.54- 1.20 (m, 4H), 1.20-1.05

(m, 1H).

Acetal NMR (CD₃OD, 400 LCMS (Rt,

Amine Structure

Example Int. MHz) δ m/z)

7.34-7.22 (m, 4H), 7.14

(t, 1H, J = 7.1 Hz), 7.05

(br s, 1H), 6.95 (d, 1H, J

= 7.7 Hz), 6.89 (d, 1H, J

= 8.3 Hz), 6.75 (d, 1H, J

7-(2- = 8.3 Hz), 6.64 (d, 1H, J

Amino- = 8.3 Hz), 3.73 (t, 2H, J

ethyl)-4- (Method 4)

= 6.2 Hz), 3.65-3.47 (m,

hydroxy- 6.23 min,

10 1 10 4H), 3.36-3.26 (m,

3H-benz m/z 675 obscured, 8H), 3.20-3.09

othiazol- [M+H⁺]

(m, 6H), 2.89 (t, 2H, J =

2-one

7.7 Hz), 2.80-2.73 (m,

(Note 3)

2H), 2.75 (s, 3H), 2.62

(t, 2H, J = 6.2 Hz), 1.61- 1.52 (m, 2H), 1.39-1.26

(m, 2H), 0.96 (t, 3H, J =

7.1 Hz).

Acetal NMR (CD₃OD, 400 LCMS (Rt,

Amine Structure

Example Int. MHz) δ m/z)

7.27-7.18 (m, 4H), 7.10

(t, 1H, J = 7.2 Hz), 7.05

(br s, 1H), 6.88-6.86 (m,

1H), 6.67 (d, 1H, J = 8.2

Hz), 6.58 (d, 1H, J = 8.2

8-(2- Hz), 6.44 (t, 1H, J = 8.2

Amino- Hz), 4.58 (s, 2H), 3.66

ethyl)-5- (t, 2H, J = 6.2 Hz), 3.62- (Method 4) hydroxy- 3.54 (m, 4H), 3.42-3.38 6.83 min,

11 I l l

4H-benz (m, 2H), 3.35-3.33 (m, m/z 731 o[l,4]oxaz 2H), 3.33 (s, 3H), 3.06- [M+H⁺] in-3-one 3.02 (m, obscured, 1 1H),

(Note 1) 3.04 (2H, t, J = 6.7 Hz),

2.63-2.53 (m, 6H), 1.79-

1.75 (2H, m), 1.59-1.55

(2H, m), 1.36-1.25 (3H,

m), 0.94 (t, 3H, J = 7.2

Hz).

7.28-7.19 (m, 4H), 7.1 1

(t, 1H, J = 7.3 Hz), 7.03

(br s, 1H), 6.92-6.83 (m,

7-(2- 2H), 6.71 (d, 1H, J = 8.3

Amino- Hz), 6.60 (d, 1H, J = 8.3 (Method 4) ethyl)-4- Hz), 3.69 (t, 2H, J = 6.2 6.16 min, hydroxy-

12 1 12 Hz), 3.60 - 3.55 (m, 4H), m/z 675

3H-benz

3.15-3.04 (m, obscured, [M+H⁺] othiazol- 13H), 2.96-2.82 (m, 3H),

2-one

2.78-2.73 (m, 2H), 2.73

(Note 3)

(s, 3H), 2.60-2.56 (m,

2H), 1.96-1.87 (m, 1H),

0.89 (d, 6H, J = 6.6 Hz).

Acetal NMR (CD₃OD, 400 LCMS (Rt,

Amine Structure

Example Int. MHz) δ m/z)

7.34-7.18 (m, 4H), 7.12

(t, 1H, J = 6.9 Hz), 7.04

(br s, 1H), 6.92 (d, 1H, J

= 8.1 Hz), 6.69 (d, 1H, J

8-(2- = 8.4 Hz), 6.61 (d, 1H, J

Amino- = 8.0 Hz), 6.46 (d, 1H, J

ethyl)-5- = 8.3 Hz), 4.58 (s, 2H), (Method 4) hydroxy- 3.70 (t, 2H, J = 6.0 Hz), 5.73 min,

14 1 14

4H-benz 3.67-3.46 (m, 6H), 3.30- m/z 713 o[l,4]oxaz 3.25 (m, 2H), 3.24-3.05 [M+H⁺] in-3-one (m, 8H), 2.98-2.93 (m,

(Note 1) 2H), 2.86 (t, 2H, J = 7.2

Hz), 2.78-2.70 (m,

obscured, 2H), 2.74 (s,

3H), 2.61 (t, 2H, J = 5.8

Hz), 2.58-2.46 (m, 2H).

Acetal NMR (CD₃OD, 400 LCMS (Rt,

Amine Structure

Example Int. MHz) δ m/z)

16

7.32-7.22 (m, 4H), 7.14

(t, 2H, J = 7.6 Hz), 6.96

(d, 1H, J = 8.1 Hz), 6.88

(d, 1H, J = 8.3 Hz), 6.74

7-(2- (d, 1H, J = 8.3 Hz), 6.64

Amino- (d, 1H, J = 8.0 Hz), 3.74

ethyl)-4- (Method 3)

(t, 2H, J = 5.9 Hz), 3.63

hydroxy- 5.46 min,

1 17 (t, 2H, J = 7.0 Hz), 3.57

3H-benz m/z 675

(t, 2H, J = 5.9 Hz), 3.48- othiazol- [M+H⁺]

3.00 (m, obscured, 15H),

2-one

2.87 (t, 2H, J = 7.6 Hz),

(Note 3)

2.79 (t, 2H, J = 7.1 Hz),

2.62 (t, 2H, J = 6.1 Hz),

1.28 (d, 6H, J = 6.6 Hz),

1.24 (t, 3H, J = 7.0 Hz).

Acetal NMR (CD₃OD, 400 LCMS (Rt,

Amine Structure

Example Int. MHz) δ m/z)

7.28-7.20 (m, 4H), 7.1 1

(t, 1H, J = 8.3 Hz), 7.03

(br s, 1H), 6.92-6.83 (m,

2H), 6.71 (d, 1H, J = 8.3

Hz), 6.60 (d, 1H, J = 8.3

7-(2- Hz), 3.89 (q, 1H, J = 7.2

Amino- Hz), 3.69 (t, 2H, J = 6.2

ethyl)-4- (Method 4)

Hz), 3.60 (t, 2H, J = 6.7

hydroxy- R5.96 min,

18 1 18 Hz), 3.54-3.47 (m, 1H),

3H-benz m/z 675

3.39-3.31 (m, 2H), 3.16- othiazol- [M+H⁺]

3.02 (m, obscured, 9H),

2-one

2.87 (t, 2H, J = 6.7 Hz),

(Note 3)

2.76-2.72 (m, 3H), 2.72

(s, 3H), 2.68-2.54 (m,

3H), 1.54-1.47 (m, 2H),

1.14 (d, 3H, J = 6.6 Hz),

0.85 (t, 3H, J = 7.2 Hz).

Acetal NMR (CD₃OD, 400 LCMS (Rt,

Amine Structure

Example Int. MHz) δ m/z)

7.34-7.20 (m, 4H), 7.14

(t, 1H, J = 7.0 Hz), 7.06

(br s, 1H), 6.95 (d, 1H, J

= 8.3 Hz), 6.90 (d, 1H, J

= 8.2 Hz), 6.75 (d, 1H, J

= 7.9 Hz), 6.64 (d, 1H, J

7-(2- = 8.1 Hz), 4.30-4.19 (m,

Amino- 1H), 3.72 (t, 2H, J = 6.0

ethyl)-4- Hz), 3.64 (t, 2H, J = 7.3 (Method 4) hydroxy- Hz), 3.48 (t, 2H, J = 6.0 6.18 min,

20 1 19

3H-benz Hz), 3.41-3.12 (m, m/z 687 othiazol- obscured, 8H), 3.06 (t, [M+H⁺]

2-one 2H, J = 6.0 Hz), 2.89 (t,

(Note 3) 2H, J = 7.9 Hz), 2.81- 2.73 (m, 2H), 2.72 (s,

3H), 2.68 (t, 2H, J = 6.1

Hz), 2.63-2.42 (m, 2H),

1.92-1.82 (m, 2H), 1.80- 1.69 (m, 2H), 1.66-1.43

(m, 4H).

Acetal NMR (CD,OD, 400 LCMS (Rt,

Amine Structure

Example Int. MHz) δ m/z)

7.35-7.19 (m, 4H), 7.12

(t, 1H, J = 7.9 Hz), 7.04

(br s, 1H), 6.92 (d, 1H, J

= 7.9 Hz), 6.68 (t, 1H, J

8-(2- = 7.9 Hz), 6.61 (d, 1H, J

Amino- = 7.9 Hz), 6.46 (d, 1H, J

ethyl)-5- = 7.9 Hz), 4.58 (s, 2H), (Method 6) hydroxy- O 3.69 (t, 2H, J = 6.9 Hz), 2.89 min,

40 140

4H-benz ₀ ^» T 3..63-3.50 (m, 4H), 3.25- m/z 749 o[l ,4]oxaz 2.98 (m, obscured, 14H), [M+H⁺] in-3-one 2.93 (t, 2H, J = 8.8 Hz),

(Note 1) 2.85 (t, 2H, J = 8.0 Hz),

2.71 (s, 3H), 2.57 (t, 2H,

J = 7.2 Hz), 2.00 (m,

2H), 1.80- 1.55 (m, 5H),

1.31-1.17 (m, 2H).

Acetal NMR (CD₃OD, 400 LCMS (Rt,

Amine Structure

Example Int. MHz) δ m/z)

7.38-7.21 (m, 4H), 7.15

(t, IH, J = 8.1 Hz), 7.06

(br s, IH), 6.94 (d, IH, J

= 6.9 Hz), 6.72 (d, IH, J

= 6.7 Hz), 6.62 (d, IH, J

8-(2- = 7.6 Hz), 6.48 (d, IH, J

Amino- = 8.1 Hz), 4.62 (s, 2H),

ethyl)-5- 3.70 (m, 3H), 3.61 (m, (Method 6)

.

hydroxy- 3H), 3.41 (m, 2H), 3.32- 2.99 min,

43 143

4H-benz _a ^H I I 3.04 (br m - obscured, m/z 713 o[l,4]oxaz 10H), 2.89 (t, 2H, J = 6.6 [M+H⁺] in-3-one Hz), 2.76 (t, 2H, J = 7.0

(Note 1) Hz), 2.72 (s, 3H), 2.7- 2.56 (m, 3H), 1.98 (m,

IH), 1.80 (m, IH), 1.69

(lH, m), 1.58 (m, 4H),

1.25-1.20 (m, 2H), 1.18

(d, 3H, J = 6.8 Hz) .

Acetal NMR (CD₃OD, 400 LCMS (Rt,

Amine Structure

Example Int. MHz) δ m/z)

7.32-7.16 (m, 4H), 7.1 1

(t, 1H, J = 7.1 Hz), 7.07

(br s, 1H), 6.92 (d, 1H, J

= 8.5 Hz), 6.70 (d, 1H, J

= 8.5 Hz), 6.60 (d, 1H, J

8-(2- = 6.6 Hz), 6.46 (d, 1H, J

Amino- = 8.5 Hz), 4.57 (s, 2H),

ethyl)-5- 3.68 (t, 2H, J = 5.8 Hz), (Method 6) hydroxy- ^ΗΟΤ -V i 3.63-3.50 (m, 4H), 3.33- 2.85 min,

53 154

4H-benz ₀ ^H I 2.90 (m, obscured, 13H), m/z 701 o[l,4]oxaz 2.84 (t, 2H, J = 7.4 Hz), [M+H⁺] in-3-one 2.75 (t, 2H, J = 6.8 Hz),

(Note 1) 2.70-2.46 (m, 4H), 1.71

(m, 1H), 1.23 (t, 3H, J =

7.4 Hz), 1.17 (d, 3H, J =

6.8 Hz), 0.95 (d, 3H, J =

6.8 Hz), 0.82 ( t, 3H, J =

6.2 Hz).

Table 3: Note 1 WO 2008075025; Note 2 US 19651 1 15; Note 3 Org. Proc. Res. Dev. 2004, 8(4).

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 cm² flasks incubator at 37 °C, 5% C0₂ in RPMI medium containing 10% (v/v) FBS (foetal bovine serum) and 2 mM L-glutamine.

Experimental Method

Adherent H292 cells re 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% C0₂. Detached cells are re-suspended in RPMI media (containing 10% (v/v) FBS and 2 mM L-glutamine) at 0.1 x 10⁶ cells per mL. 10000 cells in 100 μΙ_, 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% C0₂. The culture media is removed and cells are washed twice with 100 μΐ, 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 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 μΐ_^ assay buffer and replacing with 50 μΐ_^ 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 pEC₅o 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 (pIC₅o) of compounds binding to the M₃ receptor is determined by competition binding of [³H]N-methyl scopolamine (NMS) to CHO-K1 (Chinese Hamster Ovary) cell membranes expressing the human muscarinic acetylcholine M₃ receptor (M₃- 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, [³H]NMS at 0.1 nM, quarter Ka (experimentally determined dissociation constant) and assay buffer (20 mM HEPES pH 7.4 containing 5 mM MgCl₂ and 0.1% (w/v) bovine serum albumin). The assay is conducted in a final volume of 200 uL, in the presence of 1% (v/v) dimethyl sulphoxide (DMSO). Total binding of [³H]NMS is determined in the absence of competing compound and nonspecific binding of [³H]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 ³H protocol. The pIC₅o, defined as the negative logarithm of the molar concentration of compound required for 50%> reduction in specific [³H]-NMS binding, is determined.

Compounds of the invention were tested in the above assays and the following results obtained: β2 β2 M₃ Binding

Example No.

pECso Intrinsic Activity pICso

1 +++ 0.9 ++

2 ++ 1.0 +++

3 + 1.0 ++

4 ++ 0.9 ++

5 + 0.8 +++

6 + 0.9 +++

7 + 0.7 +++

8 ++ 0.8 +

9 ++ 0.9 ++

10 ++ 0.9 ++

11 + 0.7 +++

12 ++ 0.8 ++

13 ++ 0.7 ++

14 + 0.7 ++

15 ++ 0.9 +

16 ++ 0.9 ++

17 + 0.9 ++

18 ++ 0.9 ++ β2 β2 M₃ Binding

Example No.

pECso Intrinsic Activity pICso

19 ++ 0.9 ++

20 ++ 1.0 ++

21 ++ 0.9 ++

22 ++ 1.0 ++

23 ++ 1.0 ++

24 ++ 1.0 ++

25 +++ 1.1 ++

26 ++ 0.9 ++

27 ++ 1.1 ++

28 ++ 1.0 ++

29 +++ 1.0 ++

30 ++ 1.0 ++

31 ++ 1.0 ++

32 ++ 0.8 +++

33 ++ 1.0 +++

34 ++ 0.9 ++

35 ++ 0.6 ++

36 ++ 0.6 ++

37 ++ 0.9 ++

38 ++ 0.8 ++

39 ++ 0.8 ++

40 ++ 0.9 ++

41 ++ 0.8 ++

42 ++ 0.8 ++

43 ++ 0.9 +++

44 ++ 0.6 ++

45 ++ 0.9 ++

46 ++ 0.7 ++ β2 β2 M₃ Binding

Example No.

pECso Intrinsic Activity pICso

47 ++ 0.7 ++

48 ++ 0.9 ++

49 ++ 0.8 ++

50 ++ 0.8 ++

51 ++ 0.8 ++

52 ++ 0.9 +++

53 ++ 1 +++

54 + 0.8 ++

55 + 0.9 ++

56 ++ 0.8 ++

57 +++ 0.8 +++

58 ++ 0.9 ++

59 ++ 1 ++

60 ++ 1 +++

61 ++ 0.9 ++

62 ++ 0.8 +++

63 +++ 0.9 ++

64 ++ 0.9 ++

65 ++ 0.8 +++

66 ++ 1.0 ++

67 +++ 0.8 +

68 + 1.0 ++

69 ++ 0.8 +++

70 ++ 1.0 +++

71 +++ 1.1 ++

72 +++ 1.0 ++

73 ++ 1.1 ++

74 +++ 0.9 + β₂ pEC₅₀ >8 +++, >7 ++, >6 +; M₃ pIC₅₀ >9 +++; >8 ++, >7 +

As a further illustration of the invention, Example 1 exhibited a β₂ pEC50 of 8.3 (intrinsic activity 0.9) and an M₃ pIC₅o of 8.8; Example 32 exhibited a β₂ pEC₅o of 8.0 (intrinsic activity 0.8) and an M₃ pIC₅o of 9.4; Example 43 exhibited a β₂ pEC₅o of 7.9 (intrinsic activity 0.9) and an M₃ pIC₅o of 9.3 and Example 57 exhibited a β₂ pEC₅o of 8.1 (intrinsic activity 0.8) and an M₃ p!C₅o of 9.3.

Claims

1. A compound of formula (I)

wherein

ArCH₂CH₂NH- represents a β-adrenoceptor binding group;

R¹ is selected from the following;

(i) 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 C₃_ 8 cycloalkyl ring; or wherein said alkyl group is substituted by up to two cycloalkyl or cycloalkylalkyl groups each comprising up to six carbon atoms;

or

(ii) a group

m = 0, 1, 2 or 3;

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

R², R² , R³, R³ , R⁴, R⁴ , R⁵, and R⁵ are each independently, hydrogen or Ci_₆ alkyl;

R⁶ is a Ci_8 alkyl group optionally substituted by up to 3 substituents selected from halogen, Ci_₆ alkyl, OR¹⁰, Ci_₆ alkylS(O)₀-₂, NR⁸R⁹ , OC(0)(Ci_₆ alkyl), or C₃_₈ cycloalkyl

(wherein one or two of the carbon atoms can be replaced by O, S or N);

or R⁶ is a Ci_g alkyl group substituted by an optionally substituted aryl group or an optionally substituted 5- or 6-membered aromatic or non-aromatic heterocyclic ring containing up to three heteroatoms independently selected from N, O and S; or R⁶ is a C₃_g cycloalkyl group (wherein one or two of the ring carbon atoms can be replaced by O, S or N) and optionally substituted by up to 3 substituents independently selected from halogen, Ci_6 alkyl, OR¹⁰, Ci_₆ alkylS(O)₀-₂, NR⁸R⁹ , OC(0)(Ci_₆ alkyl), and an optionally substituted aryl group or an optionally substituted 5- or 6-membered aromatic or non- aromatic heterocyclic ring containing up to three heteroatoms independently selected from N, O and S; or R⁶ is a C7-9 bicycloalkyl group optionally substituted by up to 3 substituents independently selected from halogen, Ci_₆ alkyl, OR¹⁰ and Ci_₆ alkylS(0)o_₂; or R⁶ is a 5- or 6-membered aromatic or non-aromatic heterocyclic ring containing up to three heteroatoms independently selected from N, O and S;

R⁷ is selected from hydrogen, -OR¹⁰, halogen, -CF₃, -NR⁸R⁹, -NHS0₂R^u, -C(0)NR⁸R⁹ or -CH₂OR¹⁰;

G represents a group comprising a straight or branched hydrocarbyl chain of up to 9 carbon atoms;

wherein up to three of the carbon atoms in the chain are optionally substituted by up to four substituents independently selected from halogen, -OR¹⁰, Ci_₆ alkyl and

C₃_6 cycloalkyl;

wherein up to three carbon atoms of the chain may be replaced by groups independently selected from O, NR¹⁰, S, S(O), S(0)₂, C(0)0, OC(O), NR¹⁰C(O),

C(0)NR¹⁰, NR¹⁰S(O)₂, S(0)₂NR¹⁰, NR¹⁰C(O)NR^10', NR¹⁰S(O)₂NR^10', OC(0)NR¹⁰, NR¹⁰C(O)O, provided that any such groups in the chain are separated by at least two chain carbon atoms; and

wherein up to six carbon atoms of the chain may form part of an aryl, heteroaryl, fused bicyclic, alicyclic, or heteroaliphatic ring having up to four heteroatoms

independently selected from N, O or S, said ring comprising up to 10 ring atoms, and wherein the ring is optionally substituted by up to three substituents independently selected from halogen, S(O)₀_₂R¹⁰, NR⁸R⁹, S(0)₂NR⁸R⁹, C(0)NR⁸R⁹, C(0)OR¹⁰, NR¹⁰S(O)₂Rⁿ, NR¹⁰C(O)R^u, NR¹⁰C(O)ORⁿ, NR¹⁰C(O)NR⁸R⁹, OR¹⁰, Ci_₆ alkyl and C₃_₆ cycloalkyl, and wherein alkyl and cycloalkyl may be optionally substituted by up to three substituents independently selected from halogen, hydroxyl and Ci_₆ alkoxy;

and the chain may comprise up to two of such rings each selected independently; wherein the chain may additionally comprise up to three carbon-carbon double bonds; and

wherein the chain may additionally comprise up to three carbon-carbon triple bonds;

and wherein the group G can be attached to the phenyl ring bearing R⁷ through any available position;

T is selected from an optionally substituted aryl group or an optionally substituted 5- or 6- membered aromatic or non-aromatic heterocyclic ring containing up to three heteroatoms independently selected from N, O and S, or Ci_₆alkyl or C₃_₈ cycloalkyl or a hydrogen atom;

R⁸ and R⁹ are independently hydrogen or Ci_₆ alkyl, or R⁸ and R⁹ 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;

R¹⁰ and R¹⁰ 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;

R¹¹ 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, hydroxy or Ci_₆ alkoxy;

R¹² and R¹³ are independently hydrogen, Ci_₆ alkyl, an optionally substituted aryl group or an optionally substituted 5- or 6-membered aromatic or non-aromatic heterocyclic ring containing up to three heteroatoms independently selected from N, O and S

t is 1-3;

u is 2-4;

and pharmaceutically acceptable salts thereof.

2. A compound as claimed in claim 1 and pharmaceutically acceptable salts thereof wherein the group R¹ is a hydrogen atom, a Ci_₆ alkyl group or a Ci_₆ alkyl-0-Ci_6 alkyl group.

3. A compound as claimed in claim 1 and pharmaceutically acceptable salts thereof wherein T is an optionally substituted aryl group or an optionally substituted heteroaryl ring.

4. A compound as claimed in claim 1 and pharmaceutically acceptable salts thereof wherein the group G is a C₂_₄ alkylene group.

5. A compound as claimed in claim 1 and pharmaceutically acceptable salts thereof wherein the group R⁶ is a Ci_₈ alkyl group optionally substituted by a C₃_₈ cycloalkyl group, wherein said cycloalkyl group has one of the carbon atoms replaced by -O- or -S.

6. A compound according to any one of Examples 1-74 and pharmaceutically acceptable salts thereof.

7. A compound as claimed in claim 1 and pharmaceutically acceptable salts thereof for use in therapy.

8. Use of a compound as claimed in any one of claims 1-6 in the manufacture of a medicament for use in the treatment of respiratory diseases or disorders.

9. 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.

10. A process for the preparation of a compound as claimed in claim 1 or a

pharmaceutically acceptable salt thereof as set out in Scheme 1 or Scheme 2 herein.

11. 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.

12. 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.

13. A combination therapy wherein a compound as claimed in claim 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition or formulation comprising a compound as claimed in claim 1 , is administered concurrently or sequentially or as a combined preparation with another therapeutic agent or agents.