WO2006051373A1 - Compounds for the treatment of diseases - Google Patents

Abstract

The invention relates to compounds of formula (1) and to processes for the preparation of, intermediates used in the preparation of, compositions containing and the uses of, such derivatives. The compounds according to the present invention are useful in numerous diseases, disorders and conditions, in particular inflammatory, allergic and respiratory diseases, disorders and conditions.

Description

COMPOUNDS FOR THE TREATMENT OF DISEASES

This invention relates to β2 agonists of general formula:

in which R¹, R², R¹⁴, n, A and Q¹ have the meanings indicated below, and to processes for the preparation of, compositions containing and the uses of such derivatives.

Adrenoceptors are members of the large G-protein coupled receptor super-family. The adrenoceptor subfamily is itself divided into the α and β subfamilies with the β sub-family being composed of at least 3 receptor sub-types. β1 , β2 and β3. These receptors exhibit differential expression patterns in tissues of various systems and organs of mammals. β2 adrenergic (β2) receptors are mainly expressed in smooth muscle cells (e.g. vascular, bronchial, uterine or intestinal smooth muscles), whereas β3 adrenergic receptors are mainly expressed in fat tissues (therefore β3 agonists could potentially be useful in the treatment of obesity and diabetes) and β1 adrenergic receptors are mainly expressed in cardiac tissues (therefore β1 agonists are mainly used as cardiac stimulants).

The pathophysiology and treatments of airway diseases have been extensively reviewed in the literature (for reference see Barnes, P.J. Chest, 1997, 111 :2, pp 17S-26S and Bryan, S.A. et al, Expert Opinion on investigational drugs, 2000, 9:1 , pp25-42) and therefore only a brief summary will be included here to provide some background information.

Glucocorticosteroids, anti-leukotrienes, theophylline, cromones, anti-cholinergics and β2 agonists constitute drug classes that are currently used to treat allergic and non-allergic airways diseases such as asthma and chronic obstructive airways disease (COPD). Treatment guidelines for these diseases include both short and long acting inhaled β2 agonists. Short acting, rapid onset β2 agonists are used for "rescue" bronchodilation, whereas, long-acting forms provide sustained relief and are used as maintenance therapy.

Bronchodilation is mediated via agonism of the β2 adrenoceptor expressed on airway smooth muscle cells, which results in relaxation and hence bronchodilation. Thus, as functional antagonists, β2 agonists can prevent and reverse the effects of all bronchoconstrictor substances, including leukothene D4 (LTD4), acetylcholine, bradykinin, prostaglandins, histamine and endothelins. Because β2 receptors are so widely distributed in the airway, β2 agonists may also affect other types of cells that play a role in asthma. For example, it has been reported that β2 agonists may stabilize mast cells. The inhibition of the release of bronchoconsthctor substances may be how β2 agonists block the bronchoconstriction induced by allergens, exercise and cold air. Furthermore, β2 agonists inhibit cholinergic neurotransmission in the human airway, which can result in reduced cholinergic-reflex bronchoconstriction.

In addition to the airways, it has also been established that β2 adrenoceptors are also expressed in other organs and tissues and thus β2 agonists, such as those described in the present invention, may have application in the treatment of other diseases such as, but not limited to those of the nervous system, premature labor, congestive heart failure, depression, inflammatory and allergic skin diseases, psoriasis, proliferative skin diseases, glaucoma and in conditions where there is an advantage in lowering gastric acidity, particularly in gastric and peptic ulceration.

However, numerous β2 agonists are limited in their use due to their low selectivity or adverse side-effects driven by high systemic exposure and mainly mediated through action at β2 adrenoreceptors expressed outside the airways (muscle tremor, tachycardia, palpitations, restlessness). Therefore there is a need for improved agents in this class.

Accordingly, there is still a need for novel β₂ agonists that would have an appropriate pharmacological profile, for example in terms of potency, selectivity, pharmacokinetics or duration of action. In this context, the present invention relates to novel β2 agonists.

The invention relates to the compounds of general formula (1):

wherein the (CH₂)_n-NR¹⁴-Q¹ group is in the meta or para position, - A is selected from

wherein the clashed line represent an optional bond,

- R¹ and R² are independently selected from H and C₁-C₄ alkyl,

- n is 1 or 2 and

- Q¹ is a group selected from -C(=O)-R³, -C(=O)NH-R⁴, -SO₂-R⁵ or -R⁶ wherein R³, R⁴, R⁵ and R⁶ are selected from

or a group ^*-Q²-B , wherein

Q² is a single bond or a C₁-C₄ alkylene optionally substituted with OH, B is selected from: o C₃-C₁₀ cycloalkyl, said cycloalkyl being optionally bridged by one or more, preferably 1 , 2, 3 or 4, carbon atoms, and being optionally substituted with one hydroxy group, o a 5 to 6 membered heterocyclic group, optionally aromatic, containing one or two heteroatoms selected from O, N or S, or o a group

- R⁷, R⁸, R⁹, R¹⁰ and R¹¹ are the same or different and are selected from H, C₁-C₄ alkyl, OR¹², SR¹², halo, CN, CF₃, OCF₃, SO₂NR¹²R¹³, COOR¹², CONR¹²R¹³, NR¹²R¹³, NHCOR¹² and phenyl optionally substituted with OH,

- R¹² and R¹³ are the same or different and are selected from H or C₁-C₄ alkyl,

- R¹⁴ is H or C₁-C₄ alkyl; - ^* represents the attachment point to the NR¹⁴ group; or, if appropriate, their pharmaceutically acceptable salts and/or isomers, tautomers, solvates or isotopic variations thereof.

The compounds of formula (1) are agonists of the β2 receptors, that are particularly useful for the treatment of β2-mediated diseases and/or conditions, by showing excellent potency, in particular when administered via the inhalation route.

In the here above general formula (1), C₁-C₄ alkyl and C₁-C₄ alkylene denote a straight- chain or branched group containing 1 , 2, 3 or 4 carbon atoms. This also applies if they carry substituents or occur as substituents of other radicals, for example in O-(CrC₄)alkyl radicals, S- (C₁-C₄)aIkyI radicals etc... . Examples of suitable (C₁-C₄)aIkyI radicals are methyl, ethyl, n-propyl, iso-propyl, n-butyl, /so-butyl, sec-butyl, tert-butyl. .. Examples of suitable O-(C₁-C₄)aIkyI radicals are methoxy, ethoxy, n-propyloxy, iso-propyloxy, n-butyloxy, iso-butyloxy, sec-butyloxy and tert- butyloxy....

The C₃-C₁₀ cycloalKyl wherein 2 carbon atoms or more are optionally bridged by one or more carbon atoms include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, adamantyl, bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane. A preferred cycloalKyl group is cyclohexyl.

Non limitative examples of "5 to 6 membered heterocyclic group, optionally aromatic, containing one or two heteroatoms selected from O, N or S" are morpholinyl, pyrrolidinyl, piperidyl, piperazinyl, pyrazolyl, thienyl, furanyl, imidazolyl, isothiazolyl, thiazolyl, isoxazolyl, oxazolyl, pyridyl and pyrimidyl.

Preferably, said heterocyclic group contains one nitrogen, two nitrogens or one nitrogen and one oxygen atom.

Preferred aromatic 5 to 6 membered heterocyclic groups are pyrazolyl and pyridyl.

Finally, halo denotes a halogen atom selected from the group consisting of fluoro, chloro, bromo and iodo in particular fluoro or chloro.

In the following, the free bond on the phenyl group such as in the structure below,

means that the phenyl can be substituted in the meta or para position

The present invention provides compounds of formula (1)

Compounds of formula (1) may be prepared, in a known manner, in a variety of ways The following routes illustrate such ways of preparing these compounds, the skilled man will appreciate that other routes may be equally as practicable

Compounds of general formula (1), where A = 2-(hydroxymethyl)phenol, R = R = C₁-C₄ alkyl, R¹⁴=H, n=1 and where Q¹ is as described herein, may be prepared according to reaction scheme 1

Scheme 1 In scheme 1 , X represents a suitable leaving group such as OH or Cl, preferably OH

Compounds of general formula (2) may be prepared as described in scheme 2 Compounds of general formula (3) are commercially available or or may be prepared by conventional methods well known to the one skilled in the art

When Q¹-X is a functionalised carboxylic acid, compounds of general formula (4) may be prepared from compounds of general formula (2) and (3) by process step (i) - coupling of (2) and (3) in the presence of a suitable coupling agent (e g O-(1 H-benzotnazol-1-yl)-/V,Λ/,Λ/',Λ/'- tetramethyluromum hexafluorophosphate, 1 -(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride or Λ/, Λ/'-dicyclohexylcarbodnmide), optionally in the presence of a catalyst (e g 1- hydroxybenzotnazole hydrate or 1-hydroxy-7-azabenzotriazole), and optionally in the presence of a tertiary amine base (e g N-methylmorpholine, triethylamine or N.N-diisopropylethylamine) in a suitable solvent such as N,N-dimethylformamide, tetrahydrofuran, dimethylsulfoxide, N₁N- dimethylacetamide, at 10-40°C for 1-48 hours Typical conditions comprise of 1 0 equivalent of compound (2), 1 0 equivalent of compound (3) and 1 0 equivalent of O-(1 H-benzotriazol-1-yl)- Λ/,Λ/,Λ/',Λ/'-tetramethyluronium hexafluorophosphate, in N,N-dimethylacetamide, at room temperature for 18-72 hours

Compounds of general formula (1) may be prepared from compounds of general formula (4) by process step (iia) - De-protection of the hydroxyl group using standard methodology as described in "Protecting Groups in Organic Synthesis" by T W Greene and P Wutz Typical conditions comprise of 1 0 equivalent of compound (4), and 10-12 equivalents of ammonium fluoride, in a suitable solvent such as methanol or tetrahydrofuran, at 25-4O°C for 18-48 hours

Scheme 2

In scheme 2, PG represents a suitable amine protecting group, preferably trifluoroacetyl and PG' represents a suitable hydroxyl protecting group, preferably benzyl

Compounds of general formula (5) can be prepared as described in scheme 3 Compounds of general formula (6) can be prepared as described in scheme 4 Compounds of general formula (7) can be prepared from compounds of general formula (5) and (6) by process step (in) - In a typical procedure amine (5) and bromide (6) can be heated together, optionally in the presence of a suitable solvent (e g toluene or xylene) and a suitable tertiary amine base (e g N-methylmorpholine, triethylamine or N,N-diisopropylethylamine) at elevated temperature such as 90°C, for 18-48 hours Typical conditions comprise of 2 0 equivalents of amine (5) and 1.0 equivalent of bromide (6), heated as a melt at elevated temperature for 18-48 hours

Compounds of general formula (8) can be prepared from compound of general formula (7) by process step (iib)- De-protection of the phenol group using standard methodology as described in "Protecting Groups in Organic Synthesis" by T.W. Greene and P. Wutz. When PG'= Benzyl, typical conditions comprise of 1.0 equivalent of compound (7), in the presence of a suitable catalyst such as 10% Pd/C, in a suitable solvent such as methanol or tetrahydrofuran, under 60psi of hydrogen, at 25-40°C for 2-18 hours.

Compounds of general formula (2) can be prepared from compound of general formula (8) by process step (iva)- De-protection of the amine group using standard methodology as described in "Protecting Groups in Organic Synthesis" by T.W. Greene and P. Wutz. When PG represents trifluoroacetyl, the protecting group is typically removed by treatment of 1.0 equivalent of compound (8) with 10-12 equivalents of a suitable base such as potassium carbonate, in a mixture of methanol and water, at room temperature for 4-8 hours.

Scheme 3

In Scheme 3, Y represents halo, preferably iodo or bromo, more preferably bromo, R¹ and R² represent C₁-C₄ alkyl, preferably methyl, PG" is a suitable amine protecting group, preferably BOC and PG is a suitable amine protecting group, preferably trifluoroacetyl. Compounds of general formula (9) are commercially available

Compounds of general formula (10) can be prepared from compounds of general formula (9) by process step (v) - Reaction of ketone (9) with an "activated" alkyl (organometallic alkyl such as R²MgBr, R²MgCI or R²Li) to give the corresponding tertiary alcohol of formula (10). Typical conditions comprise of 1.0 equivalent of compound (9) and 2-2.5 equivalents of R²MgBr in a suitable solvent such as tetrahydrofuran or diethyl ether, at 0-25°C for 2-8 hours.

Compounds of general formula (11) can be prepared from compounds of general formula (10) by process step (vi)- treatment of alcohol (10) with an alkyl nitrile, R^aCN such as acetonitrile or chloroacetonitrile, in the presence of an acid (e.g. sulfuric acid, acetic acid), at low temperature for 1-8 hours. In a typical procedure 1.0 equivalent of compound (10) and 2.0 equivalents of R CN in acetic acid is treated with concentrated sulfuric acid at 0-10°C for 2-5 hours.

Compounds of general formula (12) can be prepared from compounds of general formula (11) by process step (vii)-cleavage of protected compound (11) using standard methodology as described in "Protecting Groups in Organic Synthesis" by T.W. Greene and P. Wutz. In a typical procedure compound (11) is treated with a suitable agent such as thiourea, in the presence of a suitable acid such as acetic acid, at elevated temperature for 18-24 hours.

Compounds of general formula (13) can be prepared from compounds of general formula (12) by process step (viii) - introduction of a suitable protecting group (PG") such as C(O)OR, where R is Me or 'Bu, and is preferably 'Bu.

When PG" is C(O)O¹Bu, typical conditions comprise of 1.0 equivalent of compound (12) and 1.1-1.2 equivalents of di-tert-butyl dicarbonate, optionally in the presence of base, in a suitable solvent such as dichloromethane or dioxan, at a temperature between 25-5O°C for 18 hours.

Compounds of general formula (14) can be prepared from compounds of general formula (13) by process step (ix) -halo aryl compound (13) is reacted with a suitable cyanide source such as zinc cyanide, in the presence of a suitable palladium catalyst such as tetrakis(triphenylphosphine)palladium(0), in a suitable solvent such as N,N-dimethylformamide or toluene, at elevated temperature for 2-10 hours. Typical conditions comprise of 1.0 equivalent of compound (13), 3.0 equivalents of zinc cyanide and tetrakis(triphenylphosphine)palladium(0) (cat) in N,N-dimethylformamide, heated under reflux for 5-7 hours.

Compounds of general formula (15) can be prepared from compounds of general formula (14) by process step (x)- reduction of compound (14) with a suitable metal hydride such as sodium borohydride or lithium aluminium hydride, optionally in the presence of a catalyst such as cobalt (II) chloride, in a suitable solvent such as methanol or tetrahydrofuran, at low to ambient temperature for 1-18 hours. Typical conditions comprise of 1.0 equivalent of compound (14), 9.0-10.0 equivalents of sodium borohydride and 1.5-2.0 equivalents of cobalt (II) chloride, in methanol, at 0-25°C for 3 hours. Compounds of general formula (16) can be prepared from compounds of general formula (15) by process step (viii) - introduction of a suitable protecting group (PG), where PG is not BOC and is preferably trifluoroacetyl, using standard methodology as described in "Protecting Groups in Organic Synthesis" by T.W Greene and P. Wutz.

When PG is trifluoroacetyl, typical conditions comprise of 1.0 equivalent of compound (16), 1.4- 10.0 equivalents of ethyl trifluoroacetate and 0.2-1.0 equivalent a suitable base such as pyridine of triethylamine in dichloromethane, at room temperature for 18-96 hours.

Compounds of general formula (5) can be prepared from compounds of general formula (16) by process step (ivb)- De-protection of the amine group using standard methodology as described in "Protecting Groups in Organic Synthesis" by T.W. Greene and P. Wutz. When PG"=BOC, compound (16) is typically treated with an excess of 4M hydrochloric acid or trifluoroacetic acid, in a suitable solvent such as dioxan dichloromethane or diethyl ether, at room temperature for 18 hours.

Scheme 4

Compounds of general formula 17 may be prepared as described in Tetrahedron Letters 1994, 35(50), 9375.

Compounds of general formula (18) can be prepared from compounds of general formula (17) by process step (xi) - treatment of compound (17) with terf-butyldimethylsilyl chloride in the presence of a suitable base such as imidazole and a suitable catalyst such as 4-(N₁N- dimethylamino)pyridine, in a suitable solvent such as N.N-dimethylformamide, at room temperature for 18-24 hours. Typical conditions comprise of 1.0 equivalent of compound (17), 1.1 equivalents tert-butyldimethylsilyl chloride, 1.4 equivalents of imidazole and 4-(N₁N- dimethylamino)pyridine (cat.) in N,N-dimethylformamide, at room temperature for 18 hours. Compounds of general formula (6) can be prepared from compounds of general formula (18) by process step (xii) - Reduction of ester (18) by a suitable reducing agent such as borane dimethylsulfide complex, in a suitable solvent such as tetrahydrofuran or dichloromethane, heated under reflux for 2-4 hours. Typical conditions comprise of 1.0 equivalent of ester (18) and 2 2 equivalents of borane dimethylsulfide complex in tetrahydrofuran, heated under reflux for 2 hours

Compounds of general formula (1), where A = 2-(hydroxymethyl)phenol, R¹ and R² are C₁-C₄ alkyl, R¹⁴ is H, n is 1 and where Q¹ is as described herein, may alternatively be prepared according to reaction scheme 5

Scheme 5

In scheme 5, X is a suitable functional group, preferably chloro, PG' is a suitable hydroxyl protecting group, preferably benzyl, and PG" is a suitable amine protecting group, preferably BOC

Compounds of general formula (14) may be prepared as described in scheme 3 Compounds of general formula (19) may be prepared from compounds of general formula (14) by process step (ivb), as described in scheme 3 Compounds of general formula (6) may be prepared as described in scheme 4. Compounds of general formula (20) may be prepared from compounds of general formula (19) and (6) by process step (iii), as described in scheme 2.

Compounds of general formula (21) may be prepared from compounds of general formula (20) by process step (x), as described in scheme 3.

Compounds of general formula (3) are commercially available.

When Q¹-X is a functionalised sulfonyl chloride, compounds of general formula (22) may be prepared from compounds of general formula (21) and (3) by process step (xiii)- Reaction of compounds (21 ) and (3), in the presence of a suitable base such as triethylamine or N, N- diisopropylamine in a suitable solvent such as dichloromethane or diethyl ether, under ambient conditions, for 18-72 hours. Typical conditions comprise of 1.0 equivalent of compound (21), 1.1-

1.3 equivalents of compound (3) and 1.5 equivalent s of N,N-diisopropylamine in dichloromethane at room temperature for 72 hours.

Compounds of general formula (4) may be prepared from compounds of general formula (22) by process step (iib), as described in scheme 2.

Compounds of general formula (1) may be prepared from compounds of general formula (4) by process step (iia), as described in scheme 1.

Compounds of general formula (1), where A = 2-(hydroxymethyl)phenol, and where R¹ and R² are H or C₁-C₄ alkyl, R¹⁴ is H or C₁-C₄ alkyl, n is 1 or 2 and Q¹, and n are as described herein, may alternatively be prepared according to reaction scheme 6.

Scheme 6

In scheme 6, p is 0 or 1 , PG' is a suitable hydroxyl protecting group, preferably benzyl. Compounds of general formula (23) may be prepared as described in schemes 7 and 8 and 9 or as disclosed in J. Med. Chem (1991) 34(8), 2570-9.

Compounds of general formula (6) may be prepared as described in scheme 4.

Compounds of general formula (24) may be prepared from compounds of general formulae

(23) and (6) by process step (iii) as described in scheme 2. Compounds of general formula (25) may be prepared from compounds of general formula (24) by process step (iib) as described in scheme 2.

Compounds of general formula (26) may be prepared from compounds of general formula (25) by process step (xvi)- compound (25) is hydrolysed by treatment with aqueous acid or base such as hydrogen chloride, potassium hydroxide, sodium hydroxide or lithium hydroxide, optionally in the presence of a solvent or mixture of solvents such as water, 1 ,4-dioxan, tetrahydrofuran/water, at 20-100°C, for 1-40 hours. Typical conditions comprise of 1 equivalent of compound (25) and 2 equivalents of lithium hydroxide in tetrahydrofuran/water, at room temperature for 18 hours.

Compounds of general formula (27) are commercially available. Compounds of general formula (28) may be prepared from compounds of general formulae (26) and (27) by process step (i) as described in scheme 1.

Compounds of general formula (1) may be prepared from compounds of general formula (28) by process step (xvii)- Reduction of compound (31) with a suitable reducing agent such as lithium aluminium hydride, aluminium hydride, or diborane, in a suitable solvent such as tetrahydrofuran or diethyl ether, at 0-80°C, for 3-8 hours. Removal of TBDMS group occurs concomitantly under these conditions Typical conditions comprise of 1.0 equivalent of compound (31) and 10-12 equivalents of lithium aluminium hydride in tetrahydrofuran, at 0-60°C for 3-6 hours.

When R¹ is C₁-C₄ alkyl, R² is H and p is1 , compounds of general formula (23), may be prepared according to reaction scheme 7.

Scheme 7 In scheme 7, Z is halo such as iodo or bromo, preferably bromo, R^bis a suitable alkyl group, preferably C₁-C₄ alkyl, PG" is a suitable amine protecting group, preferably (R)-α-methyl benzyl. When Z is bromo, compounds of general formula (29) may be prepared as described in Eur. J of Org. Chem., 2002, (23), 3966.

Compounds of general formula (30) can be prepared from compounds of general formula (29) by process step (xvi)- the aryl halide of formula (29) is treated with a tin enolate generated in-situ by treatment of suitable vinylacetate R¹C(CH₂)OAc such as isopropenyl acetate with a suitable organo tin reagent (e.g. Bu₃SnOMe) in the presence of a suitable palladium catalyst system such as palladium acetate/ tri-ortho -tolylphosphine, in a suitable solvent such as toluene, benzene or hexane at a 80-110°C for 6-16 hours. Typical conditions comprise of 1.0 equivalent of compound (29), 1.5 equivalents of Bu₃SnOMe, 1.5 equivalents of R¹C(CH₂)OAc, palladium acetate (cat) and 0.1 equivalents of tri-ortho -tolylphosphine in toluene, at 80-110°C for 6-16 hours.

Compounds of general formula (31 ) can be prepared from compounds of general formula (30) by process step (xvii)- Compound (30) is reacted with H₂NPG" (where PG" is a suitable protecting group such as (fi)-α-methyl benzyl) leading to a chiral intermediate which is in turn reduced by a suitable reducing agent such as sodium cyanoborohydride or sodium triacetoxyborohydride, optionally in the presence of a drying agent such as molecular sieves or magnesium sulfate, and optionally in the presence of an acid catalyst such as acetic acid, in a suitable solvent such as tetrahydrofuran or dichloromethane, at 20-80°C for 3-72 hours. A mixture of diastereomers is typically afforded that is converted to the hydrochloride salt and selectively crystallised from a suitable solvent or mixture of solvents (e.g. isopropanol, ethanol, methanol, diisopropyl ether or diisopropyl ether/methanol) to give (31) as a single diastereomer.

Compounds of general formula (23) can be prepared from compound of general formula (31) by process step (ivc)- De-protection of the amine group using standard methodology as described in "Protecting Groups in Organic Synthesis" by T.W. Greene and P. Wutz. When PG" is (R)-α-methyl benzyl, a typical de-protection procedure involves treatment of a solution compound (31), in a suitable solvent such as methanol, ethanol or ethyl acetate, with a suitable hydrogen donor such as ammonium formate or formic acid, in the presence of a suitable palladium catalyst such as 20% palladium hydroxide on charcoal, at a temperature between 25°C and elevated temperature, for 1-4 hours.

Alternatively, when R¹ and R² are C₁-C₄ alkyl and p is1 , compounds of general formula (23), may be prepared according to reaction scheme 8.

Scheme 8

R^c is a suitable C₁-C₄ alkyl group, typically ethyl

When R^c is ethyl, compounds of general formula (32) can be prepared as described in

International Journal of Peptide and Protein Research, 1987, 29, 331.

Compounds of general formula (33) can be prepared from compounds of general formula (32) by process step (v) as described in scheme 3.

Compounds of general formula (34) may be prepared from compounds of general formula (33) and R^dCN by process step (vi) as described in scheme 3. Compounds of general formula (35) can be prepared from compounds of general formula (34) by process step (vii) as described in scheme 3

Compounds of general formula (23) can be prepared from compounds of general formula (35) by process step (xvni) - esterification of (35), in the presence of a suitable acid catalyst such as acetic acid or hydrochloric acid, in a suitable alcohol, R⁶OH, (typically as methanol or ethanol), at 25°C to reflux, for 1-72 hours When R^b is Me, typical conditions comprise of 1 equivalent of compound (35) and 3 equivalents of acetic acid in methanol, heated under reflux for 18 hours

In a further embodiment where R¹ and R² are C₁-C₄ alkyl and p is 0, compounds of general formula (26), may be prepared according to reaction scheme 9

Scheme 9

In scheme 9, Y is halo, preferably bromo

Compounds of general formula (36) may be prepared from compounds of formula (13) by process step (xix)- Compound (13) is carbonylated in the presence of a suitable palladium catalyst such as [1 ,1 '-bis(diphenylphosphino)ferrocene]dichloro palladium(ll) or palladium (II) acetate, in the presence of a suitable tertiary amine such as triethylamine or pyridine, under an atmosphere of carbon monoxide, using R^bOH as solvent (typically methanol or ethanol) at elevated temperature and pressure Typical conditions comprise of 1 equivalent of compound

(12) and [1 ,1'-bis(diphenylphosphino) ferrocenejdichloro palladium(ll) (cat) in methanol, under

IOOpsi of carbon monoxide, at 100°C for 12-18 hours

Compounds of general formula (23) may be prepared from compounds of formula (36) by process step (ivb) as described in scheme 3

When A is N-(2-hydroxyphenyl)methanesulfonamide, R¹ and R² are C₁-C₄ alkyl, R¹⁴ is H, n is 1 and Q¹ is as described here in, compounds of formula (1) may be prepared as described in scheme 10

Scheme 10

X represents a suitable leaving group such as OH or Cl, preferably OH and PG" is a suitable amine protecting group, preferably BOC.

Compounds of general formula (15) may be prepared as described in scheme 3. Compounds of general formula (3) are commercially available.

Compounds of general formula (37) can be prepared from compounds of formulae (15) and (3) by process step (i) as described in scheme 1.

Compounds of general formula (38) can be prepared from compounds of formula (37) by process step (ivb) as described in scheme 3.

Compounds of general formula (39) can be prepared from as described in WO 02/06258, p36.

Compounds of general formula (40) can be prepared from compounds of formulae (38) and (39) by process step (iii) as described in scheme 2.

Compounds of general formula (41) can be prepared from compounds of formula (40) by process step (iib) as described in scheme 2. Compounds of general formula (1) can be prepared from compounds of formula (41) by process step (iia) as described in scheme 1.

When A is pyridin-2-amine, R¹ is C₁-C₄ alkyl, R² is H, n is 1 , R¹⁴ is H, and Q¹ is -C(=O)NH-R⁴, compounds of formula (1) may be prepared as described in scheme 1 1

Scheme 11

In scheme 11 , PG is a suitable amine protecting group, preferably BOC

Compounds of general formula (42) can be prepared as described in scheme 12.

Compounds of general formula (43) can be prepared from compounds of general formula (42) by process step (ivb) as described in scheme 3

Compounds of general formula (44) can be prepared by process step (xx)- conventional coupling of carbonyldiimidazole (CDI) with commercially available amines of formula NH₂R⁴, in a suitable solvent such as tetrahydrofuran or dichloromethane, under ambient conditions for 18-24 hours. Typical conditions comprise of 1 equivalent of NH₂R⁴ and 1.1 equivalents of CDI in tetrahydrofuran, under ambient conditions for 18 hours.

Compounds of general formula (45) can be prepared from compounds of general formulae (43) and (44) by process step (xxi)- The urea of formula (45) is prepared by reaction of compounds (43) and (44), in a suitable solvent such as toluene or xylene, at elevated temperature for 18-48 hours. Typical conditions comprise of 1.0 equivalent of compound (43) and 1-1.1 equivalents of compound (44) in toluene, at 6O°C for 48 hours.

Compounds of general formula (1) may be prepared from compounds of general formula (45) by process step (xxii)- De-protection of the amine group using standard methodology as described in "Protecting Groups in Organic Synthesis" by T.W. Greene and P. Wutz. Typical conditions comprise of 1 equivalent of compound (45) and 5 equivalents of hydroxylamine hydrochloride in ethanol, at elevated temperature and pressure, for 24-72 hours. Compounds of general formula (42) can be prepared as described in scheme 12.

Scheme 12

In scheme 12, PG" is a suitable amine protecting group, preferably (R)-α-methyl benzyl and PG is a suitable amine protecting group, preferably BOC. Compounds of general formula (46) may be prepared as described in Tett. Lett. 2003, 44, 8869

Compounds of general formula (47) may be prepared from compounds of general formula (46) by process step (xvii) as described in scheme 7.

Compounds of general formula (48) may be prepared from compounds of general formula (47) by process step (x) as described in scheme 3.

Compounds of general formula (49) may be prepared from compounds of general formula (48) by process step (viii) as described in scheme 3.

Compounds of general formula (50) may be prepared from compounds of general formula (49) by process step (ivc) as described in scheme 7. Compounds of general formula (51) may be prepared as described in JP 20011048864.

Compounds of general formula (42) may be prepared from compounds of general formula (50) and (51) by process step (xxiii)- compound (51) undergoes nucleophilic addition of compound

(50) via a ring opening step. Typical conditions comprise of 1 equivalent of compound (50) and 1 2 equivalents of compound (52) in a suitable solvent such as dimethylsulfoxide or N, N- dimethylformamide, at elevated temperature (85°C) for 18-24 hours

Compounds of formula (1) where A is

, or

may be prepared using the above processes using the appropriate starting material, such as those disclosed in WO 2003042164, WO200401 1416, and DE 3528700

All of the above reactions and the preparations of novel starting materials used in the preceding methods are conventional and appropriate reagents and reaction conditions for their performance or preparation as well as procedures for isolating the desired products will be well- known to those skilled in the art with reference to literature precedents and the examples and preparations hereto

Also, the compounds of formula (1) as well as intermediate for the preparation thereof can be purified according to various well-known methods, such as for example crystallization or chromatography

In a preferred embodiment, Q¹ is a group -C(=O)-R³, wherein R³ is a group *-Q²-B , wherein a Q² is a C₁-C₄ alkylene, preferably methylene, and B is selected from cyclohexyl, adamantyl, naphthyl or a group

. wherein R⁷, R⁸, R⁹, R¹⁰ and R¹¹ are as defined above

In a preferred embodiment, Q¹ is a group -C(=O)NH-R⁴, wherein R⁴ is selected from

, or a group ^*-Q²-B , wherein Q² is a C₁-C₄ alkylene, and B is selected from

R⁷, R⁸, R⁹, R¹⁰ and R¹¹ are as defined above.

In a preferred embodiment, Q¹ is a group -SO₂-R⁵, wherein R⁵ is selected from *-Q²-B wherein Q² is a single bond and B is selected from

wherein R⁷, R⁸, R⁹, R¹⁰ and R¹¹ are as defined above.

In a preferred embodiment Q¹ is a group R⁶, wherein R⁶ is selected from *-Q²-B wherein Q² is a C₁-C₄ alkylene, preferably methylene or ethylene, and B is selected from

wherein R⁷, R⁸, R⁹, R¹⁰ and R¹¹ are as defined above.

Preferably, Q¹ is a group *-Q²-B, wherein B is a group

wherein R⁷, R⁸, R⁹, R¹⁰ and R¹¹ are the same or different and are selected from H, C₁-C₄ alkyl, OR¹², SR¹², halo, CF₃, OCF₃, SO₂NR¹²R¹³, CONR¹²R¹³, NR¹²R¹³, NHCOR¹² and phenyl provided at least 2 of R⁷ to R¹¹ are equal to H;

wherein R¹² and R¹³ are the same or different and are selected from H or C₁-C₄ alkyl.

More preferably, Q¹ is a group -Q²-B, wherein B is a group

wherein R⁷, R⁸, R⁹, R¹⁰ and R¹¹ are the same or different and are selected from H, CH₃, OCH₃, OCH₂-CH₃, SCH₃, halo, CF₃, provided at least 2 of R⁷ to R¹¹ are equal to H.

In the above groups of compounds, the following substituents are particularly preferred: Q² is -CH₂-, -(CH₂)₂-, -(CHz)₃-, or (CH(CH₃)₂)-, preferably -CH₂-.

R¹ is H or C₁-C₄ alkyl and R² is C₁-C₄ alkyl. More preferably, R¹ is H or CH₃ and R² is CH₃. n is 1.

R¹ is H and R² is CH₃ and n is 1.

R¹ is CH₃, R² is CH₃ and n is 1.

The following compounds, which can be prepared according to the processes disclosed herein, are preferred: N-{3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2- methylpropyl]benzyl}-2-phenylacetamide; 2-cyclohexyl-N-{3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2- methylpropyl]benzyl}acetamide; N-{3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2- methylpropyl]benzyl}-2-(1-naphthyl)acetamide;

2-(2-chlorophenyl)-N-{3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)- 2-methylpropyl]benzyl}acetamide; N-{3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2- methylpropyl]benzyl}-2-(4-methylphenyl)acetamide;

2-(3,4-dichloroρhenyl)-N-{3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-

(hydroxymethyl)phenyl]ethyl}amino)-2-methy!propyl]benzyl}acetamide; N-{3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2- methylpropyl]benzyl}-3-phenylpropanamide; N-{3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2- methylpropyl]benzyl}-2,4,6-trimethylbenzenesulfonamide; N-{3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2- methylpropyl]benzyl}benzenesulfonamide; N-{3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxym ethyl) phenyl]ethyl}am ino)-2- methylpropyl]benzyl}-4-(trifluoromethyl)benzenesulfonamide; 4-((1 R)-2-{[(1 R)-2-(3-{2-[benzyl(methyl)amino]ethyl}phenyl)-1-methylethyl]amino}-1- hydroxyethyl)-2-(hydroxymethyl)phenol ,

2-(hydroxymethyl)-4-((1R)-1-hydroxy-2-{[(1R)-1-methyl-2-(3-{2-[methyl(2- phenylethyl)amino]ethyl}phenyl)ethyl]amino}ethyl)phenol , 4-((1R)-2-{[2-(3-{2-[benzyl(methyl)ammo]ethyl}phenyl)-1 ,1-dimethylethyl]amino}-1-hydroxyethyl)-

2-(hydroxymethyl)phenol ,

4-((1R)-2-{[1 ,1-dimethyl-2-(3-{2-[methyl(2-phenylethyl)amino]ethyl}phenyl)ethyl]amino}-1- hydroxyethyl)-2-(hydroxymethyl)phenol ,

4-((1R)-2-{[1 ,1-dimethyl-2-(3-{[methyl(2-phenylethyl)amino]methyl}phenyl)ethyl]amino}-1- hydroxyethyl)-2-(hydroxymethyl)phenol , N-[3-((2R)-2-{[(2R)-2-(6-aminopyridin-3-yl)-2-hydroxyethyl]amino}propyl)benzyl]-N'-(4- phenylbutyl)urea, N-[3-((2R)-2-{[(2R)-2-(6-aminopyridin-3-yl)-2-hydroxyethyl]amino}propyl)benzyl]-N'-[2-(4- ethylphenyl)ethyl]urea, N-[3-((2R)-2-{[(2R)-2-(6-aminopyridin-3-yl)-2-hydroxyethyl]amino}propyl)benzyl]-N'-(biphenyl-2- ylmethyl)urea, N-[3-((2R)-2-{[(2R)-2-(6-aminopyridin-3-yl)-2-hydroxyethyl]amino}propyl)benzyl]-N'-benzylurea, N-[3-((2R)-2-{[(2R)-2-(6-aminopyridin-3-yl)-2-hydroxyethyl]amino}propyl)benzyl]-N'-(2- phenylethyl)urea, N-[3-((2R)-2-{[(2R)-2-(6-aminopyridin-3-yl)-2-hydroxyethyl]amino}propyl)benzyl]-N'-(2,3-dihydro-

1/-/-inden-2-yl)urea,

4'-hydroxy-N-(3-{2-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-

2-methylpropyl}benzyl)biphenyl-4-carboxamide, N-(3-{2-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-2- methylpropyl}benzyl)-3-(4-hydroxyphenyl)propanamide,

4-hydroxy-N-(3-{2-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-

2-methylpropyl}benzyl)benzamide, N-(3-{2-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-2- methylpropyl}benzyl)-3-(2-hydroxyphenyl)propanamide, and, 1-hydroxy-N-(3-{2-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-

2-methylpropyl}benzyl)-2-naphthamide

According to one aspect of the present invention, the compounds of formula (1) wherein the (CH₂)_n-NR¹⁴ group is in the meta position are generally preferred

Pharmaceutically acceptable salts of the compounds of formula (1 ) include the acid addition and base salts thereof Suitable acid addition salts are formed from acids which form non-toxic salts Examples include the acetate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochlonde/chlonde, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, saccharate, stearate, succinate, tartrate, tosylate, tnfluoroacetate and xmafoate salts

Suitable base salts are formed from bases which form non-toxic salts Examples include the aluminium, argimne, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts Hemisalts of acids and bases may also be formed, for example, hemisulphate and hemicalcium salts

For a review on suitable salts, see "Handbook of Pharmaceutical Salts Properties, Selection, and Use" by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002)

Pharmaceutically acceptable salts of compounds of formula (1) may be prepared by one or more of three methods

(i) by reacting the compound of formula (1) with the desired acid or base,

(ii) by removing an acid- or base-labile protecting group from a suitable precursor of the compound of formula (1) or by ring-opening a suitable cyclic precursor, for example, a lactone or lactam, using the desired acid or base, or

(in) by converting one salt of the compound of formula (1) to another by reaction with an appropriate acid or base or by means of a suitable ion exchange column

All three reactions are typically carried out in solution The resulting salt may precipitate out and be collected by filtration or may be recovered by evaporation of the solvent The degree of ionisation in the resulting salt may vary from completely ionised to almost non-ionised

The compounds of the invention may exist in both unsolvated and solvated forms The term 'solvate' is used herein to describe a molecular complex comprising the compound of the invention and a stoichiometric amount of one or more pharmaceutically acceptable solvent molecules, for example, ethanol The term 'hydrate' is employed when said solvent is water

Included within the scope of the invention are complexes such as clathrates, drug-host inclusion complexes wherein, in contrast to the aforementioned solvates, the drug and host are present in stoichiometric or non-stoichiometnc amounts Also included are complexes of the drug containing two or more organic and/or inorganic components which may be in stoichiometric or non-stoichiometric amounts The resulting complexes may be ionised, partially ionised, or non- ionised For a review of such complexes, see J Pharm Sci, 64 (8), 1269-1288 by Halebhan (August 1975)

Hereinafter all references to compounds of formula (1 ) include references to salts, solvates and complexes thereof and to solvates and complexes of salts thereof

The compounds of the invention include compounds of formula (1) as hereinbefore defined, including all polymorphs and crystal habits thereof, prodrugs and isomers thereof (including optical, geometric and tautomeric isomers) as hereinafter defined and isotopically-labeled compounds of formula (1)

As indicated, so-called 'pro-drugs' of the compounds of formula (1) are also within the scope of the invention Thus certain derivatives of compounds of formula (1) which may have little or no pharmacological activity themselves can, when administered into or onto the body, be converted into compounds of formula (1) having the desired activity, for example, by hydrolytic cleavage Such derivatives are referred to as 'prodrugs' Further information on the use of prodrugs may be found in 'Pro-drugs as Novel Delivery Systems, VoI 14, ACS Symposium Series (T Higuchi and W Stella) and "Bioreversible Carriers in Drug Design', Pergamon Press, 1987 (ed E B Roche, American Pharmaceutical Association)

Prodrugs in accordance with the invention can, for example, be produced by replacing appropriate functionalities present in the compounds of formula (1) with certain moieties known to those skilled in the art as 'pro-moieties' as described, for example, in "Design of Prodrugs" by H Bundgaard (Elsevier, 1985)

Some examples of prodrugs in accordance with the invention include

(i) where the compound of formula (1) contains a carboxylic acid functionality (-COOH), an ester thereof, for example, a compound wherein the hydrogen of the carboxylic acid functionality of the compound of formula (1) is replaced by (C₁-C₈)BIkVl,

(ii) where the compound of formula (1) contains an alcohol functionality (-OH), an ether thereof, for example, a compound wherein the hydrogen of the alcohol functionality of the compound of formula (1) is replaced by (CrCgJalkanoyloxymethyl, and

(in) where the compound of formula (1) contains a primary or secondary amino functionality (-NH₂ or -NHR where R ≠ H), an amide thereof, for example, a compound wherein, as the case may be, one or both hydrogens of the ammo functionality of the compound of formula (1) is/are replaced by (Ci-Ci₀)alkanoyl

Further examples of replacement groups in accordance with the foregoing examples and examples of other prodrug types may be found in the aforementioned references

Moreover, certain compounds of formula (1) may themselves act as prodrugs of other compounds of formula (1)

Also included within the scope of the invention are metabolites of compounds of formula (1 ), that is, compounds formed in vivo upon administration of the drug Some examples of metabolites in accordance with the invention include

(i) where the compound of formula (1 ) contains a methyl group, an hydroxymethyl derivative thereof (-CH₃ → -CH₂OH)

(ii) where the compound of formula (1) contains an alkoxy group, an hydroxy derivative thereof (-OR → -OH)₁

(in) where the compound of formula (1) contains a tertiary ammo group, a secondary ammo derivative thereof (-NR¹R² → -NHR¹ or -NHR²),

(iv) where the compound of formula (1) contains a secondary ammo group, a primary derivative thereof (-NHR¹ → -NH₂),

(v) where the compound of formula (1) contains a phenyl moiety, a phenol derivative thereof (-Ph → -PhOH), and

(vi) where the compound of formula (1) contains an amide group, a carboxylic acid derivative thereof (-CONH₂ → COOH)

Compounds of formula (1) containing one or more asymmetric carbon atoms.can exist as two or more stereoisomers Where a compound of formula (1 ) contains an alkenyl or alkenylene group, geometric as/trans (or ZJE) isomers are possible Where structural isomers are interconvertible via a low energy barrier, tautomeric isomerism ('tautomerism') can occur This can take the form of proton tautomerism in compounds of formula (1) containing, for example, an imino, keto, or oxime group, or so-called valence tautomerism in compounds which contain an aromatic moiety It follows that a single compound may exhibit more than one type of isomerism Included within the scope of the present invention are all stereoisomers, geometric isomers and tautomeric forms of the compounds of formula (1), including compounds exhibiting more than one type of isomerism, and mixtures of one or more thereof Also included are acid addition or base salts wherein the counterion is optically active, for example, d-lactate or /-lysine, or racemic, for example, ^/-tartrate or d/-arginine

Cis/trans isomers may be separated by conventional techniques well known to those skilled in the art, for example, chromatography and fractional crystallisation

Conventional techniques for the preparation/isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC)

Alternatively, the racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where the compound of formula (1) contains an acidic or basic moiety, an acid or base such as tartaric acid or 1-phenylethylamine The resulting diastereomeric mixture may be separated by chromatography and/or fractional crystallization and one or both of the diastereoisomers converted to the corresponding pure enantiomer(s) by means well known to a skilled person

Chiral compounds of the invention (and chiral precursors thereof) may be obtained in enantiomerically-ennched form using chromatography, typically HPLC, on an asymmetric resin with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50% by volume of isopropanol, typically from 2% to 20%, and from 0 to 5% by volume of an alkylamine, typically 0 1 % diethylamine Concentration of the eluate affords the enriched mixture

Stereoisomers conglomerates may be separated by conventional techniques known to those skilled in the art - see, for example, "Stereochemistry of Organic Compounds" by E L Eliel (Wiley, New York, 1994)

According to one aspect of the present invention, the (R.R)-stereoisomer of the formula below, wherein R¹ is hydrogen and R² is C₁-C₄ alkyl, preferably methyl, and n and Q¹ are as defined above, is generally preferred

The present invention includes all pharmaceutically acceptable isotopically-labelled compounds of formula (1) wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number which predominates in nature.

Examples of isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as ²H and ³H, carbon, such as ¹¹C, ¹³C and ¹⁴C, chlorine, such as ³⁶CI, fluorine, such as ¹⁸F, iodine, such as ¹²³I and ¹²⁵I, nitrogen, such as ¹³N and ¹⁵N, oxygen, such as ¹⁵O, ¹⁷O and ¹⁸O, phosphorus, such as ³²P, and sulphur, such as ³⁵S.

Certain isotopically-labelled compounds of formula (1), for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies. The radioactive isotopes tritium, i.e. ³H, and carbon-14, i.e. ¹⁴C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.

Substitution with heavier isotopes such as deuterium, i.e. ²H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.

Substitution with positron emitting isotopes, such as ¹¹C, ¹⁸F, ¹⁵O and ¹³N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.

Isotopically-labeled compounds of formula (1) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopically-labeled reagents in place of the non-labeled reagent previously employed.

Pharmaceutically acceptable solvates in accordance with the invention include those wherein the solvent of crystallization may be isotopically substituted, e.g. D₂O, d₆-acetone, d₆-DMSO.

The compounds of formula (1), their pharmaceutically acceptable salts and/or derived forms, are valuable pharmaceutically active compounds, which are suitable for the therapy and prophylaxis of numerous disorders in which the β2 receptor is involved or in which agonism of this receptor may induce benefit, in particular the allergic and non-allergic airways diseases but also in the treatment of other diseases such as, but not limited to those of the nervous system, premature labor, congestive heart failure, depression, inflammatory and allergic skin diseases, psoriasis, proliferative skin diseases, glaucoma and in conditions where there is an advantage in lowering gastric acidity, particularly in gastric and peptic ulceration. Compounds of the invention intended for pharmaceutical use may be administered as crystalline or amorphous products They may be obtained, for example, as solid plugs, powders, or films by methods such as precipitation, crystallization, freeze drying, spray drying, or evaporative drying Microwave or radio frequency drying may be used for this purpose

They may be administered alone or in combination with one or more other compounds of the invention or in combination with one or more other drugs (or as any combination thereof) Generally, they will be administered as a formulation in association with one or more pharmaceutically acceptable excipients The term "excipient" is used herein to describe any ingredient other than the compound(s) of the invention The choice of excipient will to a large extent depend on factors such as the particular mode of administration, the_effect of the excipient on solubility and stability, and the nature of the dosage form

Pharmaceutical compositions suitable for the delivery of compounds of the present invention and methods for their preparation will be readily apparent to those skilled in the art Such compositions and methods for their preparation may be found, for example, in 'Remington's Pharmaceutical Sciences', 19th Edition (Mack Publishing Company, 1995)

The compounds of the invention may be administered orally Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be employed by which the compound enters the blood stream directly from the mouth

Formulations suitable for oral administration include solid formulations such as tablets, capsules containing particulates, liquids, or powders, lozenges (including liquid-filled), chews, multi- and nano-particulates, gels, solid solution, liposome, films, ovules, sprays and liquid formulations

Liquid formulations include suspensions, solutions, syrups and elixirs Such formulations may be employed as fillers in soft or hard capsules and typically comprise a carrier, for example, water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil, and one or more emulsifying agents and/or suspending agents Liquid formulations may also be prepared by the reconstitution of a solid, for example, from a sachet

The compounds of the invention may also be used in fast-dissolving, fast-disintegrating dosage forms such as those described in Expert Opinion in Therapeutic Patents, 11 (6), 981-986, by Liang and Chen (2001) For tablet dosage forms, depending on dose, the drug may make up from 1 weight % to 80 weight % of the dosage form, more typically from 5 weight % to 60 weight % of the dosage form In addition to the drug, tablets generally contain a disintegrant Examples of disintegrants include sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methyl cellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropyl cellulose, starch, pregelatinised starch and sodium alginate Generally, the disintegrant will comprise from 1 weight % to 25 weight %, preferably from 5 weight % to 20 weight % of the dosage form

Binders are generally used to impart cohesive qualities to a tablet formulation Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinised starch, hydroxypropyl cellulose and hydroxypropyl methylcellulose Tablets may also contain diluents, such as lactose (monohydrate, spray-dried monohydrate, anhydrous and the like), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dibasic calcium phosphate dihydrate

Tablets may also optionally comprise surface active agents, such as sodium lauryl sulfate and polysorbate 80, and glidants such as silicon dioxide and talc When present, surface active agents may comprise from 0 2 weight % to 5 weight % of the tablet, and glidants may comprise from 0 2 weight % to 1 weight % of the tablet

Tablets also generally contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulphate Lubricants generally comprise from 0 25 weight % to 10 weight %, preferably from 0 5 weight % to 3 weight % of the tablet

Other possible ingredients include anti-oxidants, colourants, flavouring agents, preservatives and taste-masking agents

Exemplary tablets contain up to about 80% drug, from about 10 weight % to about 90 weight % binder, from about 0 weight % to about 85 weight % diluent, from about 2 weight % to about 10 weight % disintegrant, and from about 0 25 weight % to about 10 weight % lubricant

Tablet blends may be compressed directly or by roller to form tablets Tablet blends or portions of blends may alternatively be wet-, dry-, or melt-granulated, melt congealed, or extruded before tabletting The final formulation may comprise one or more layers and may be coated or uncoated, it may even be encapsulated The formulation of tablets is discussed in Pharmaceutical Dosage Forms Tablets, VoI 1 , by H Lieberman and L Lachman (Marcel Dekker, New York, 1980)

Consumable oral films for human or veterinary use are typically pliable water-soluble or water- swellable thin film dosage forms which may be rapidly dissolving or mucoadhesive and typically comprise a compound of formula (1), a film-forming polymer, a binder, a solvent, a humectant, a plasticiser, a stabiliser or emulsifier, a viscosity-modifying agent and a solvent Some components of the formulation may perform more than one function

The compound of formula (1) may be water-soluble or insoluble A water-soluble compound typically comprises from 1 weight % to 80 weight %, more typically from 20 weight % to 50 weight %, of the solutes Less soluble compounds may comprise a greater proportion of the composition, typically up to 88 weight % of the solutes Alternatively, the compound of formula (1) may be in the form of multiparticulate beads

The film-forming polymer may be selected from natural polysaccharides, proteins, or synthetic hydrocolloids and is typically present in the range 0 01 to 99 weight %, more typically in the range 30 to 80 weight %

Other possible ingredients include anti-oxidants, colorants, flavourings and flavour enhancers, preservatives, salivary stimulating agents, cooling agents, co-solvents (including oils), emollients, bulking agents, anti-foaming agents, surfactants and taste-masking agents

Films in accordance with the invention are typically prepared by evaporative drying of thin aqueous films coated onto a peelable backing support or paper This may be done in a drying oven or tunnel, typically a combined coater dryer, or by freeze-drying or vacuuming

Solid formulations for oral administration may be formulated to be immediate and/or modified release Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release

Suitable modified release formulations for the purposes of the invention are described in US Patent No 6,106,864 Details of other suitable release technologies such as high energy dispersions and osmotic and coated particles are to be found in Pharmaceutical Technology On- line, 25(2), 1-14, by Verma et a/ (2001) The use of chewing gum to achieve controlled release is described in WO 00/35298

The compounds of the invention may also be administered directly into the blood stream, into muscle, or into an internal organ Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular and subcutaneous. Suitable devices for parenteral administration include needle (including microneedle) injectors, needle-free injectors and infusion techniques.

Parenteral formulations are typically aqueous solutions which may contain excipients such as salts, carbohydrates and buffering agents (preferably to a pH of from 3 to 9), but, for some applications, they may be more suitably formulated as a sterile non-aqueous solution or as a dried form to be used in conjunction with a suitable vehicle such as sterile, pyrogen-free water.

The preparation of parenteral formulations under sterile conditions, for example, by lyophilisation, may readily be accomplished using standard pharmaceutical techniques well known to those skilled in the art.

The solubility of compounds of formula (1) used in the preparation of parenteral solutions may be increased by the use of appropriate formulation techniques, such as the incorporation of solubility-enhancing agents.

Formulations for parenteral administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release. Thus compounds of the invention may be formulated as a solid, semi-solid, or thixotropic liquid for administration as an implanted depot providing modified release of the active compound. Examples of such formulations include drug-coated stents and poly(d/-lactic-coglycolic)acid (PGLA)jnicrospheres.

The compounds of the invention may also be administered topically to the skin or mucosa, that is, dermally or transdermally. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibres, bandages and microemulsions. Liposomes may also be used. Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol. Penetration enhancers may be incorporated - see, for example, J Pharm Sci, 88 (10), 955-958 by Finnin and Morgan (October 1999).

Other means of topical administration include delivery by electroporation, iontophoresis, phonophoresis, sonophoresis and microneedle or needle-free (e.g. Powderject™, Bioject™, etc.) injection.

Formulations for topical administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release. The compounds of the invention can also be administered intranasally or by inhalation, typically in the form of a dry powder (either alone, as a mixture, for example, in a dry blend with lactose, or as a mixed component particle, for example, mixed with phospholipids, such as phosphatidylcholine) from a dry powder inhaler or as an aerosol spray from a pressurised container, pump, spray, atomiser (preferably an atomiser using electrohydrodynamics to produce a fine mist), or nebuhser, with or without the use of a suitable propellant, such as 1 ,1 ,1 ,2-tetrafluoroethane or 1 ,1 ,1 ,2,3,3,3-heρtafluoropropane For intranasal use, the powder may comprise a bioadhesive agent, for example, chitosan or cyclodextrin

The pressurised container, pump, spray, atomizer, or nebuhser contains a solution or suspension of the compound(s) of the invention comprising, for example, ethanol, aqueous ethanol, or a suitable alternative agent for dispersing, solubilising, or extending release of the active, a propellant(s) as solvent and an optional surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid

Prior to use in a dry powder or suspension formulation, the drug product is micronised to a size suitable for delivery by inhalation (typically less than 5 microns) This may be achieved by any appropriate comminuting method, such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogemsation, or spray drying

Capsules (made, for example, from gelatin or hydroxypropylmethylcellulose), blisters and cartridges for use in an inhaler or insufflator may be formulated to contain a powder mix of the compound of the invention, a suitable powder base such as lactose or starch and a performance modifier such as /-leucine, manmtol, or magnesium stearate The lactose may be anhydrous or in the form of the monohydrate, preferably the latter Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose

A suitable solution formulation for use in an atomiser using electrohydrodynamics to produce a fine mist may contain from 1μg to 20mg of the compound of the invention per actuation and the actuation volume may vary from 1 μl to 100μl A typical formulation may comprise a compound of formula (1), propylene glycol, sterile water, ethanol and sodium chloride Alternative solvents which may be used instead of propylene glycol include glycerol and polyethylene glycol

Suitable flavours, such as menthol and levomenthol, or sweeteners, such as saccharin or saccharin sodium, may be added to those formulations of the invention intended for inhaled/intranasal administration Formulations for inhaled/intranasal administration may be formulated to be immediate and/or modified release using, for example, PGLA Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release

In the case of dry powder inhalers and aerosols, the dosage unit is determined by means of a valve which delivers a metered amount Units in accordance with the invention are typically arranged to administer a metered dose or "puff containing from 0 001 mg to 10mg of the compound of formula (1) The overall daily dose will typically be in the range 0 001 mg to 40mg which may be administered in a single dose or, more usually, as divided doses throughout the day

The compounds of formula (1) are particularly suitable for an administration by inhalation

The compounds of the invention may be administered rectally or vaginally, for example, in the form of a suppository, pessary, or enema Cocoa butter is a traditional suppository base, but various alternatives may be used as appropriate

Formulations for rectal/vaginal administration may be formulated to be immediate and/or modified release Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release

The compounds of the invention may also be administered directly to the eye or ear, typically in the form of drops of a micronised suspension or solution in isotonic, pH-adjusted, sterile saline Other formulations suitable for ocular and aural administration include ointments, biodegradable (e g absorbable gel sponges, collagen) and non-biodegradable (e g silicone) implants, wafers, lenses and particulate or vesicular systems, such as niosomes or liposomes A polymer such as crossed-hnked polyacrylic acid, polyvinylalcohol, hyaluronic acid, a cellulosic polymer, for example, hydroxypropylmethylcellulose, hydroxyethylcellulose, or methyl cellulose, or a heteropolysaccharide polymer, for example, gelan gum, may be incorporated together with a preservative, such as benzalkonium chloride Such formulations may also be delivered by iontophoresis

Formulations for ocular/aural administration may be formulated to be immediate and/or modified release Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted, or programmed release

The compounds of the invention may be combined with soluble macromolecular entities, such as cyclodextrin and suitable derivatives thereof or polyethylene glycol-containing polymers, in order to improve their solubility, dissolution rate, taste-masking, bioavailability and/or stability for use in any of the aforementioned modes of administration

Drug-cyclodextrin complexes, for example, are found to be generally useful for most dosage forms and administration routes Both inclusion and non-inclusion complexes may be used As an alternative to direct complexation with the drug, the cyclodextrin may be used as an auxiliary additive, / e as a carrier, diluent, or solubiliser Most commonly used for these purposes are alpha-, beta- and gamma-cyclodextrins, examples of which may be found in International Patent Applications Nos WO 91/11172, WO 94/02518 and WO 98/55148

Inasmuch as it may desirable to administer a combination of active compounds, for example, for the purpose of treating a particular disease or condition, it is within the scope of the present invention that two or more pharmaceutical compositions, at least one of which contains a compound in accordance with the invention, may conveniently be combined in the form of a kit suitable for coadministration of the compositions

Thus the kit of the invention comprises two or more separate pharmaceutical_compositions, at least one of which contains a compound of formula (1) in accordance with the invention, and means for separately retaining said compositions, such as a container, divided bottle, or divided foil packet An example of such a kit is the familiar blister pack used for the packaging of tablets, capsules and the like

The kit of the invention is particularly suitable for administering different dosage forms, for example parenteral, for administering the separate compositions at different dosage intervals, or for titrating the separate compositions against one another To assist compliance, the kit typically comprises directions for administration and may be provided with a so-called memory aid

For administration to human patients, the total daily dose of the compounds of the invention is typically in the range 0 001 mg to 5000mg depending, of course, on the mode of administration For example, an intravenous daily dose may only require from 0 001 mg to 40mg The total daily dose may be administered in single or divided doses_and may, at the physician's discretion, fall outside of the typical range given herein

These dosages are based on an average human subject having a weight of about 65kg to 70kg The physician will readily be able to determine doses for subjects whose weight falls outside this range, such as infants and the elderly For the avoidance of doubt, references herein to "treatment" include references to curative, palliative and prophylactic treatment

According to another embodiment of the present invention, the compounds of the formula (1), or pharmaceutically acceptable salts, derived forms or compositions thereof, can also be used as a combination with one or more additional therapeutic agents to be co¬ administered to a patient to obtain some particularly desired therapeutic end result such as the treatment of pathophysiologically-relevant disease processes including, but not limited to (i) bronchoconstnction, (ii) inflammation, (in) allergy, (iv) tissue destruction, (v) signs and symptoms such as breathlessness, cough The second and more additional therapeutic agents may also be a compound of the formula (1 ), or a pharmaceutically acceptable salt, derived forms or compositions thereof, or one or more β2 agonists known in the art More typically, the second and more therapeutic agents will be selected from a different class of therapeutic agents

As used herein, the terms "co-administration", "co-adm mistered" and "in combination with", referring to the compounds of formula (1) and one or more other therapeutic agents, is intended to mean, and does refer to and include the following

• simultaneous administration of such combination of compound(s) of formula (1) and therapeutic agent(s) to a patient in need of treatment, when such components are formulated together into a single dosage form which releases said components at substantially the same time to said patient,

• substantially simultaneous administration of such combination of compound(s) of formula (1 ) and therapeutic agent(s) to a patient in need of treatment, when such components are formulated apart from each other into separate dosage forms which are taken at substantially the same time by said patient, whereupon said components are released at substantially the same time to said patient,

• sequential administration of such combination compound(s) of formula (1 ) and therapeutic agent(s) to a patient in need of treatment, when such components are formulated apart from each other into separate dosage forms which are taken at consecutive times by said patient with a significant time interval between each administration, whereupon said components are released at substantially different times to said patient, and

• sequential administration of such combination of compound(s) of formula (1) and therapeutic agent(s) to a patient in need of treatment, when such components are formulated together into a single dosage form which releases said components in a controlled manner whereupon they are concurrently, consecutively, and/or overlapingly administered at the same and/or different times by said patient, where each part may be administered by either the same or different route

Suitable examples of other therapeutic agents which may be used in combination with the compound(s) of formula (1), or pharmaceutically acceptable salts, derived forms or compositions thereof, include, but are by no means limited to (a) 5-Lipoxygenase (5-LO) inhibitors or 5-lipoxygenase activating protein (FLAP) antagonists,

(b) Leukotriene antagonists (LTRAs) including antagonists of LTB₄, LTC₄, LTD₄, and LTE₄,

(c) Histamine receptor antagonists including H1 and H3 antagonists,

(d) α-i- and α₂-adrenoceptor agonist vasoconstrictor sympathomimetic agents for decongestant use, (e) muscarinic M3 receptor antagonists or anticholinergic agents,

(f) PDE inhibitors, e g PDE3, PDE4 and PDE5 inhibitors,

(g) Theophylline,

(h) Sodium cromoglycate,

(i) COX inhibitors both non-selective and selective COX-1 or COX-2 inhibitors (NSAIDs), (j) Oral and inhaled glucocorticosteroids, such as DAGR (dissociated agonists of the corticoid receptor),

(k) Monoclonal antibodies active against endogenous inflammatory entities,

(I) Anti-tumor necrosis factor (anti-TNF-α) agents,

(m) Adhesion molecule inhibitors including VLA-4 antagonists, (n) KmIn-B₁ - and B₂ -receptor antagonists,

(o) Immunosuppressive agents,

(p) Inhibitors of matrix metalloproteases (MMPs),

(q) Tachykinin NK₁, NK₂ and NK₃ receptor antagonists,

(r) Elastase inhibitors, (s) Adenosine A2a receptor agonists,

(t) Inhibitors of urokinase,

(u) Compounds that act on dopamine receptors, e g D2 agonists,

(v) Modulators of the NFiφ pathway, e g IKK inhibitors,

(w) modulators of cytokine signalling pathyways such as p38 MAP kinase, syk kinase or JAK kinase inhibitor,

(x) Agents that can be classed as mucolytics or anti-tussive, and

(y) Antibiotics

According to the present invention, combination of the compounds of formula (1) with

- H3 antagonists, - Muscarinic M3 receptor antagonists,

- PDE4 inhibitors,

- glucocorticosteroids, - Adenosine A2a receptor agonists,

- Modulators of cytokine signalling pathyways such as p38 MAP kinase or syk kinase, or,

- Leukotnene antagonists (LTRAs) including antagonists of LTB₄, LTC₄, LTD₄, and LTE₄, are preferred

According to the present invention, combination of the compounds of formula (1) with

glucocorticosteroids, in particular inhaled glucocorticosteroids with reduced systemic side effects, including prednisone, prednisolone, flunisolide, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone propionate, ciclesonide, and mometasone furoate, or

muscarinic M3 receptor antagonists or anticholinergic agents including in particular ipratropium salts, namely bromide, tiotropium salts, namely bromide, oxitropium salts, namely bromide, perenzepine, and telenzepine,

are further preferred

It is to be appreciated that all references herein to treatment include curative, palliative and prophylactic treatment The description, which follows, concerns the therapeutic applications to which the compounds of formula (1) may be put

The compounds of formula (1) have the ability to interact with the β2 receptor and thereby have a wide range of therapeutic applications, as described further below, because of the essential role which the β2 receptor plays in the physiology of all mammals

Therefore, a further aspect of the present invention relates to the compounds of formula (1), or pharmaceutically acceptable salts, derived forms or compositions thereof, for use in the treatment of diseases, disorders, and conditions in which the β2 receptor is involved More specifically, the present invention also concerns the compounds of formula (1), or pharmaceutically acceptable salts, derived forms or compositions thereof, for use in the treatment of diseases, disorders, and conditions selected from the group consisting of

• asthma of whatever type, etiology, or pathogenesis, in particular asthma that is a member selected from the group consisting of atopic asthma, non-atopic asthma, allergic asthma, atopic bronchial IgE-mediated asthma, bronchial asthma, essential asthma, true asthma, intrinsic asthma caused by pathophysiologic disturbances, extrinsic asthma caused by environmental factors, essential asthma of unknown or inapparent cause, non-atopic asthma, bronchitic asthma, emphysematous asthma, exercise-induced asthma, allergen induced asthma, cold air induced asthma, occupational asthma, infective asthma caused by bacterial, fungal, protozoal, or viral infection, non-allergic asthma, incipient asthma, wheezy infant syndrome and bronchiolytis,

• chronic or acute bronchoconstriction, chronic bronchitis, small airways obstruction, and emphysema,

• obstructive or inflammatory airways diseases of whatever type, etiology, or pathogenesis, in particular an obstructive or inflammatory airways disease that is a member selected from the group consisting of chronic eosinophilic pneumonia, chronic obstructive pulmonary disease (COPD), COPD that includes chronic bronchitis, pulmonary emphysema or dyspnea associated or not associated with COPD, COPD that is characterized by irreversible, progressive airways obstruction, adult respiratory distress syndrome (ARDS), exacerbation of airways hyper-reactivity consequent to other drug therapy and airways disease that is associated with pulmonary hypertension,

• bronchitis of whatever type, etiology, or pathogenesis, in particular bronchitis that is a member selected from the group consisting of acute bronchitis, acute laryngotracheal bronchitis, arachidic bronchitis, catarrhal bronchitis, croupus bronchitis, dry bronchitis, infectious asthmatic bronchitis, productive bronchitis, staphylococcus or streptococcal bronchitis and vesicular bronchitis,

• acute lung injury,

• bronchiectasis of whatever type, etiology, or pathogenesis, in particular bronchiectasis that is a member selected from the group consisting of cylindnc bronchiectasis, sacculated bronchiectasis, fusiform bronchiectasis, capillary bronchiectasis, cystic bronchiectasis, dry bronchiectasis and follicular bronchiectasis

A still further aspect of the present invention also relates to the use of the compounds of formula (1), or pharmaceutically acceptable salts, derived forms or compositions thereof, for the manufacture of a drug having a β2 agonist activity In particular, the present inventions concerns the use of the compounds of formula (1), or pharmaceutically acceptable salts, derived forms or compositions thereof, for the manufacture of a drug for the treatment of β2-mediated diseases and/or conditions, in particular the diseases and/or conditions listed above

As a consequence, the present invention provides a particularly interesting method to treat a mammal, including a human being, with an effective amount of a compound of formula (1), or a pharmaceutically acceptable salt, derived form or composition thereof More precisely, the present invention provides a particularly interesting method for the treatment of a β2- mediated diseases and/or conditions in a mammal, including a human being, in particular the diseases and/or conditions listed above, comprising admidministering said mammal with an effective amount of a compound of formula (1), its pharmaceutically acceptable salts and/or derived forms

The following examples illustrate the preparation of the compounds of the formula (1)

Preparation 1 1-(3-Bromophenyl)-2-methylpropan-2-ol) Methylmagnesium bromide (3M solution in diethyl ether, 51 6mL, 155mmol) was slowly added to a solution of 1-(3-bromo-phenyl)propan-2-one (15 Og, 70mmol) in dry diethyl ether (20OmL) at 0°C and the mixture was stirred for 3 hours The reaction mixture was then re-cooled to 0°C and slowly quenched with saturated aqueous ammonium chloride solution The organic solution was washed with brine, dried over sodium sulfate and concentrated in vacuo The residual yellow oil was then purified by column chromatography on silica gel eluting with dichloromethane pentane methanol, 90 5 5, to afford a pale yellow oil in 83% yield, 13 26g ¹H NMR (400MHz, CDCI₃) δ 1 22 (s, 6H), 1 42 (bs, 1 H), 2 74 (s, 2H), 7 15 (m, 2H), 7 40 (m, 2H)

Preparation 2 W-[2-(3-Bromophenyl)-1,1-dimethylethyl]-2-chloroacetamide

Chloroacetonitrile (6 63mL, 105mmol) was added to a stirred solution of 1-(3-bromophenyl)-2- methylpropan-2-ol) (preparation 1) (12 Og, 52 Ommol) in acetic acid (25ml_) at room temperature The resulting solution was cooled to 0°C and concentrated sulfuric acid (25mL) was added whilst the temperature was maintained below 10°C The resulting solution was left to stir for 1 hour and was then poured onto ice and basified by the addition of solid potassium carbonate The product was extracted with ethyl acetate (2χ500mL) and the combined organic solution was washed with water (5OmL), dried over sodium sulfate and then concentrated in vacuo to afford the title compound as an orange solid in quantitative yield, 16 08g ¹H NMR (400MHz, CDCI₃) δ 1 37 (s, 6H), 3 02 (s, 2H), 3 94 (s, 2H), 6 17 (bs, 1 H), 7 08-7 03 (d, 1 H), 7 10-7 13 (t, 1 H), 7 26 (s, 1 H), 7 39-7 32 (d, 1 H), LRMS ESI m/z 306 [M+H]⁺, Microanalysis C₁₂H₁₅BrCINO requires C 47 32, H 4 96, N 4 60, found C 47 26, H 4 87, N 4 65

Preparation 3 2-(3-Bromophenyl)-1,1-dimethylethylamine A solution of N-[2-(3-bromophenyl)-1 ,1-dimethylethyl]-2-chloroacetamide (preparation 2) (32 Og, 105mmol), thiourea (9 6Og, 126mmol) and acetic acid (5OmL) in ethanol (25OmL) was heated to reflux overnight The reaction mixture was cooled to room temperature and filtered The filtrate was concentrated in vacuo, basified using aqueous sodium hydroxide solution (1 M, 45OmL) and extracted with dichloromethane (2χ500mL). The combined organic solution was washed with brine (5OmL), dried over sodium sulfate and then concentrated in vacuo to afford the title compound as a black oil in 96% yield, 23g.

¹H NMR (400MHz, CDCI₃) δ: 1.12 (s, 6H), 1.84 (bs, 2H), 2.62 (s, 2H), 7.16-7.08 (m, 2H), 7.36- 7.32 (m, 2H); LRMS ESI m/z 228 [M+Hf

Preparation 4

[2-(3-Bromophenyl)-1,1-dimethylethyl]carbamic acid tert-butyl ester

2-(3-Bromophenyl)-1 ,1-dimethylethylamine (preparation 3) (5.Og, 22mmol) was treated with di- tert-butyl dicarbonate (5.26g, 24mmol) in dichloromethane (5OmL) and stirred for 20 hours at room temperature. The reaction mixture was washed with water (5OmL) and the organic solution was dried over sodium sulfate and then concentrated in vacuo. The crude material was purified using a cation exchange column (methanol followed by 2M ammonia in methanol), followed by purification by flash column chromatography on silica gel eluting with dichloromethane to afford the title compound as a brown oil in quantitative yield, 7.23g.

¹H NMR (400MHz, CDCI₃) δ: 1.27 (s, 6H) 1.50 (s, 9H), 2.97 (s, 2H), 4.24 (bs, 1 H), 7.05 (d, 1 H), 7.15-7.11 (t, 1 H), 7.30 (s, 1 H), 7.35 (d, 1 H); LRMS ESI m/z 350 [M+NH₄]^*

Preparation 5 tert-Butyl [2-(3-cyanophenyl)-1,1-dimethylethyl]carbamate

Tetrakis(thphenylphosphine)palladium(0) (6.94g, 6mmol) and zinc cyanide (10.5g, 90mmol) were added to a solution of [2-(3-bromophenyl)-1 ,1-dimethylethyl]carbamic acid tert-butyl ester (preparation 4), (10g, 30.48mmol) in N,N-dimethylformamide (20OmL) and the mixture was heated at 11O°C for 3.5 hours. A further portion of [2-(3-bromophenyl)-1 ,1- dimethylethyljcarbamic acid tert-butyl ester (preparation 4), (2.5g, 7.6mmol) was then added and the mixture was heated at 100°C for 2 hours. The cooled reaction mixture was diluted with water (30OmL) and filtered through Arbocel^®, washing through with ethyl acetate (20OmL, 2x300mL). The filtrate layers were separated and the organic solution was washed with water (2x300mL) and brine (10OmL), dried over sodium sulfate and concentrated in vacuo. The crude compound was then re-dissolved in ethyl acetate (40OmL) re-washed with water (2x200mL), dried (sodium sulfate) and concentrated in vacuo to give an oily residue. Purification of the residue by column chromatography on silica gel, eluting with pentane:ethyl acetate, 100:0 to 50:50, then afforded the title compound as a white solid in 83% yield, 6.95g. ¹H NMR (400MHz, CDCI₃) δ: 1.26 (s, 6H) 1.40 (s, 9H), 3.08 (s, 2H), 4.21 (bs, 1 H), 7.37-7.40 (m, 2H), 7.46 (m, 1 H), 7.53 (m, 1 H); LRMS ESI m/z 275 [M+H]⁺

Preparation 6

(erf-Butyl {2-[3-(aminomethyl)phenyl]-1,1-dimethylethyl}carbamate Sodium borohydnde (8 36g, 220mmol) was added portionwise to a solution of tert-butyl [2-(3- cyanophenyl)-1 ,1-dimethylethyl]carbamate (preparation 5), (6 53g, 23 83mmol) and cobalt (II) chloride (5 72g, 44mmol) in methanol (250mL), at 0°C, and the mixture was stirred at room temperature for 3 hours The mixture was diluted with water/0 88 ammonia (250mL, 10 1), stirred for 20 minutes and was then concentrated in vacuo The residue was re-dissolved in methanol, filtered through a pad of silica, eluting with methanol 0 88 ammonia, 95 5, and concentrated in vacuo Purification of the residue by column chromatography on silica gel, eluting with dichloromethane methanol 0 88 ammonia, 100 0 0 to 90 10 1 to 85 15 1 , then afforded the title compound as a yellow glass in 66% yield, 4 4g ¹H NMR (400MHz, CD₃OD) δ 1 23 (s, 6H) 1 48 (s, 9H), 2 96 (s, 2H), 3 77 (s, 2H), 7 08 (m, 1 H), 7 11 (m, 1 H), 7 18-7 27 (m, 2H), LRMS ESI m/z 279 [M+H]⁺

Preparation 7 tert-Butyl [1,1-dimethyl-2-(3-{[(trifluoroacetyl)amino]methyl}phenyl)ethyl] carbamate Ethyl trifluoroacetate (1 85mL, 15 49mmol) and tnethylamine (308μL, 2 2mmol) were added to a solution of tert-butyl {2-[3-(aminomethyl)phenyl]-1 ,1-dimethylethyl}carbamate (preparation 6), (3 08g, 11 07mmol) in dichloromethane (150mL), at 0°C and the mixture was stirred at room temperature for 18 hours The mixture was then diluted with dichloromethane (30mL) and further ethyl trifluoroacetate (595μL, 5mmol) and triethylamine (153μL, 1 1mmol) were added at regular intervals until TLC analysis indicated that all of the starting material was consumed The reaction mixture was then concentrated in vacuo, the residue was dissolved in dichloromethane (30OmL) and washed with water (2OmL) and saturated sodium hydrogen carbonate solution (10mL) The organic solution was dried over sodium sulfate and concentrated in vacuo to afford the title compound as a white solid in 97% yield, 4g ¹H NMR (400MHz, CD₃OD) δ 1 22 (s, 6H) 1 45 (s, 9H), 2 96 (s, 2H), 4 42 (S, 2H), 5 90 (brs, 1 H), 7 08-7 12 (m, 2H), 7 15 (m, 1 H), 7 24 (m, 1 H), LRMS ESI m/z 373 [M-H]

Preparation 8

A/-[3-(2-Amiπo-2-methylpropyl)benzyl]-2,2,2-trifluoroacetamide Hydrochloric acid (4M in dioxane, 80mL) was added to a solution of tert-butyl [1 ,1-dimethyl-2-(3- {[(trifluoroacetyl)amino]methyl}phenyl)ethyl]carbamate (preparation 7), (4g, 10 70mmol) in dioxane (2OmL) and the mixture was stirred at room temperature for 18 hours The reaction mixture was then concentrated in vacuo, the residue was re-dissolved in dichloromethane (250mL) and washed with saturated sodium hydrogen carbonate solution (5mL) The aqueous solution was re-extracted with dichloromethane (5x100mL) and ethyl acetate (2x100mL) and the combined organic solution was dried over sodium sulfate and concentrated in vacuo to afford the title compound as a brown gum in quantitative yield, 3g

¹H NMR (400MHz, CD₃OD) δ 1 15 (s, 6H) 2 73 (s, 2H), 4 43 (s, 2H), 7 11-7 23 (m, 3H), 7 30 (m, 1 H), LRMS ESI m/z 275 [M+Hf Preparation 9

Methyl 2-(benzyloxy)-5-((1R )-2-bromo-1-{[tert-butyl (dimethyl)silyl]oxy} ethyl)benzoate

A solution of methyl 2-(benzyloxy)-5-[(1 R)-2-bromo-1-hydroxyethyl]benzoate (71 05g, 195mmol), imidazole (18 52g, 272mmol), tert-butyldimethylsilyl chloride (32 23g, 214mmol) and 4-(N,N- dimethylamino)pyridine (0 44g, 3 6mmol) in Λ/,N-dimethylformamide (27OmL) was stirred at room temperature for 24 hours The solvent was then removed in vacuo and the residue was partitioned between ethyl acetate (50OmL) and water (50OmL) The organic phase was separated and washed with 2M hydrochloric acid (2x500mL), saturated aqueous sodium bicarbonate (2x 50OmL) and brine (50OmL), dried over magnesium sulfate and concentrated in vacuo to afford the title compound as a colourless oil in 89% yield, 91 Og

¹H NMR (400MHz, CDCI₃) δ -0 08 (s, 3H), 0 11 (s, 3H) 0 90 (s, 9H), 3 39-3 48 (m, 2H), 3 91 (s, 3H), 4 85-4 82 (m, 1 H), 5 19 (s, 2H), 7 01 (d, 1 H), 7 51-7 30 (m, 6H), 7 81 (bs, 1 H), LRMS ESI m/z 501/503 [M+Na]⁺

Preparation 10

[2-(Benzyloxy)-5-((1R)-2-bromo-1-{[tert-butyl(dimethyl) silyl]oxy}ethyl) phenyl]methanol Borane dimethylsulfide complex (42 4mL of 10M solution in tetrahydrofuran, 424mmol) was added dropwise to a solution of methyl 2-(benzyloxy)-5-((1R)-2-bromo-1-{[tert- butyl(dimethyl)silyl]oxy}ethyl)benzoate (Preparation 9), (91 Og, 189mmol) in tetrahydrofuran (160OmL) The resulting mixture was heated under reflux for 2 hours and then cooled to 0°C before quenching with methanol (27OmL) The mixture was stirred at room temperature for 16 hours, concentrated in vacuo and the residue was partitioned between dichloromethane (50OmL) and water (50OmL) The aqueous phase was separated and extracted with dichloromethane (50OmL) and the combined organic solution was washed with brine (50OmL), dried over magnesium sulfate and the concentrated in vacuo The residue was purified by column chromatography on silica gel, eluting with cyclohexane ethyl acetate, 100 0 to 80 20, to afford the title compound as a colourless oil in 81% yield, 68 7g ¹H NMR (400MHz, CDCI₃) δ -0 07 (s, 3H)₁ 0 11 (s, 3H), 0 90 (s, 9H), 3 48-3 40 (m, 2H), 4 74 (s, 2H), 4 84-4 81 (m, 1 H), 5 12 (s, 2H), 6 94 (d, 1 H), 7 29-7 25 (m, 3H), 7 42-7 36 (m, 5H), LRMS ESI m/z 473 / 475 [M+Na]⁺

Preparation 11

Λ/-(3-{2-[((2R)-2-[4-(Benzyloxy)-3-(hydroxymethyl)phenyl]-2-{[tert- butyl(dimethyl)silyl]oxy}ethyl)amino]-2-methylpropyl}benzyl)-2,2,2-trifluoroacetamide

A solution of [2-(benzyloxy)-5-((1 R)-2-bromo-1-{[tert-butyl(dimethyl)silyl]oxy} ethyl)phenyl]methanol (preparation 10), (2 14g, 5 35mmol) in dichloromethane (50mL) was added to a suspension of N-[3-(2-amino-2-methylpropyl)benzyl]-2,2,2-tnfluoroacetamide (preparation 8), (2 93g, 10 70mmol) in dichloromethane (5OmL) The solvent was then removed in vacuo and the residue was heated to 9O°C for 42 hours The mixture was then cooled to room temperature and was purified by column chromatography on silica gel, eluting with dichloromethane methanol 0 88 ammonia, 100 0 0 to 85 15 1 , to afford the title compound as a pale brown solid in 49% yield, 1 7g

¹H NMR (400MHz, CD₃OD) δ -0 19 (s, 3H), -0 01 (s, 3H), 0 80 (S, 9H), 1 05 (s, 3H), 1 09 (s, 3H), 2 64-2 76 (m, 3H), 2 87 (m, 1 H), 4 43 (s, 2H), 4 67 (m, 2H), 4 72-4 77 (m, 1 H), 5 12 (s, 2H),

6 98 (d, 1 H), 7 06-7 47 (m, 11 H), LRMS ESI m/z 645 [M+H]⁺

Preparation 12

/V-{3-[2-({(2R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3- (hydroxymethyl)phenyl]ethyl}amiπo)-2-methylpropyl]benzyl}-2,2,2-trifluoroacetamide

A mixture of N-(3-{2-[((2R)-2-[4-(benzyloxy)-3-(hydroxymethyl)phenyl]-2-{[tert- butyl(dimethyl)silyl]oxy}ethyl)ammo]-2-methylpropyl}benzyl)-2,2,2-trifluoroacetamide (preparation 11), (200mg, 1 14mmol) and 10% Pd/C (50mg) in methanol (2OmL) was stirred under 60psi of hydrogen gas at room temperature for 2 hours The reaction mixture was then filtered through

Arbocel^® and the filtrate was concentrated in vacuo to afford the title product as a pale brown yellow in quantitative yield, 98mg

¹H NMR (400MHz, CD₃OD) δ -0 19 (s, 3H), -0 01 (s, 3H), 0 80 (s, 9H), 1 08 (s, 3H), 1 10 (s, 3H), 2 66-2 79 (m, 3H), 2 90 (m, 1 H), 4 43 (s, 2H), 4 62-4 75 (m, 3H), 6 74 (d, 1 H), 7 06-7 28

(m, 6H), LRMS ESI m/z 555 [M+ H]⁺

Preparation 13

4-((1/?)-2-({2-[3-(Aminomethyl)phenyl]-1,1-dimethylethyl}amino)-1-{[tert- butyl(dimethyl)silyl]oxy}ethyl)-2-(hydroxymethyl)phenol

Potassium carbonate (4 3g, 31mmol) was added to a solution of N-{3-[2-({(2R)-2-{[tert- butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-(hydroxymethyl)phenyl] ethyl}amino)-2- methylpropyl]benzyl}-2,2,2-tnfluoroacetamide (preparation 12), (1 6g, 2 89mmol) in methanol (58mL) and water (19mL) and the mixture was stirred for 4 hours at room temperature The reaction mixture was then concentrated in vacuo and the aqueous residue was partitioned between dichloromethane (20OmL) and water (15mL), and acidified to pH8 with dilute hydrochloric acid The organic layer was then separated and washed with brine (1OmL), dried over sodium sulfate and concentrated in vacuo Purification of the residue by column chromatography on silica gel, eluting with dichloromethane methanol 0 88 ammonia, 100 0 0 to 90 10 1 , afforded the title compound as a white solid in 86% yield, 1 14g

¹H NMR (400MHz, CD₃OD) δ -0 20 (s, 3H), -0 01 (s, 3H), 0 80 (s, 9H), 1 05 (s, 3H), 1 09 (s, 3H), 2 60-2 76 (m, 3H), 2 83-2 87 (m, 1 H), 3 76 (s, 2H), 4 63-4 71 (m, 3H), 6 71 (d, 1 H), 7 03-

7 23 (m, 6H), LRMS ESI m/z 459 [M+H]⁺ Preparation 14

N-{3-[2-({(2R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-

(hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]benzyl}-2-phenylacetamide Phenylacetic acid (41 mg, 0 30mmol) and O-(1 H-benzotnazol-1-yl)-Λ/,Λ/,Λ/',Λ/'-tetramethyluronium hexafluorophosphate (111 mg, 0 30mmol) were added to a solution of 4-((1R)-2-({2-[3- (aminomethyl)phenyl]-1 ,1-dimethylethyl}amino)-1 -{[tert-butyl (dimethyl)silyl] oxy}ethyl)-2- (hydroxymethyl)phenol (preparation 13), (135mg, 0 30mmol) in N,N-dimethylacetamide (3mL) and the mixture was stirred at room temperature for 18 hours The reaction mixture was then concentrated in vacuo and the residue was partitioned between dichloromethane (5OmL) and saturated sodium hydrogen carbonate solution (1OmL) The organic solution was separated, dried over sodium sulfate and concentrated in vacuo The residue was purified by column chromatography on silica gel, eluting with dichloromethane methanol 0 88 ammonia, 100 0 0 to 95 5 1 The appropriate fractions were then evaporated under reduced pressure and the residue was partitioned between ethyl acetate (5OmL) and saturated sodium hydrogen carbonate solution (5mL) The organic layer was washed with further sodium hydrogen carbonate solution (2mL), dried over sodium sulfate and concentrated in vacuo to afford the title compound as a glass in 61 % yield, 105mg ¹H NMR (400MHz, CD₃OD) δ -0 19 (s, 3H), -0 01 (s, 3H), 0 80 (s, 9H), 1 01 (s, 3H), 1 04 (s, 3H), 2 58-2 68 (m, 3H), 2 80-2 87 (m, 1 H), 3 53 (s, 2H), 4 35 (s, 2H), 4 64 (m, 2H), 4 66-4 72 (m, 1 H), 6 74 (d, 1 H), 6 98-7 10 (m, 4H), 7 15-7 32 (m, 7H), LRMS ESI m/z 577 [M+H]⁺

Preparations 15 to 20

The following compounds, of the general formula shown below, were prepared by a similar method to that described for preparation 14, using 4-((1R)-2-({2-[3-(aminomethyl)phenyl]-1 ,1- dimethylethyl}amino)-1-{[tert-butyl(dimethyl)silyl]oxy} ethyl) -2-(hydroxymethyl)phenol

(preparation 13) and the appropriate acid starting material The reactions were monitored by TLC (Thin Layer Chromatography) analysis and were stirred at room temperature for 18- 72hours

Preparation 21

Methyl (3-bromophenyl)acetate

Acetyl chloride (0 7ml, 9 3mmol) was added dropwise to a solution of (3-bromo-phenyl)-acetic acid (20 Og, 93mmol) in methanol (500ml) at 0°C The reaction was stirred for 5 hours, allowing the temperature to warm gradually to 25°C The solvent was removed in vacuo and the residual oil was re-dissolved in dichloromethane, dried over sodium sulfate and concentrated in vacuo to afford the title compound as a colourless oil in 96% yield, 20 6g

¹H NMR (400MHz, CDCI₃) δ 3 59 (s, 2H) 3 70 (s, 3H), 7 24-7 17 (m, 2H), 7 37-7 45 (m, 2H), LRMS ESI m/z 253 [M+Na]⁺

Preparation 22

Methyl [3-(2-oxopropyl)phenyl]acetate

A mixture of tributyltin methoxide (28 3mL, 98mmol), methyl (3-bromophenyl)acetate (preparation 21), (15 Og, 65mmol), isopropenyl acetate (10 8ml, 98mmol), palladium(ll)acetate

(750mg, 3 30mmol) and tn-ortho-tolylphosphine (2.0g, 6 5mmol) in toluene (75mL) was stirred at

100°C for 5 hours The cooled reaction mixture was then diluted with ethyl acetate (15OmL) and

4M aqueous potassium fluoride solution (90mL) and stirred for 15 minutes The mixture was filtered through Arbocel^® and the organic phase was separated and concentrated in vacuo The residue was purified by column chromatography on silica gel eluting with, diethyl ether pentane,

0 100 to 25 75, followed by dichloromethane to afford the title compound as a pale yellow oil in

95% yield, 12 6g

¹H NMR (400MHz, CDCI₃) δ 2 15 (s, 3H), 3 61 (s, 2H), 3 69 (s, 5H), 7 13-7 10 (m, 2H), 7 19 (d, 1 H), 7 30 (t, 1 H), LRMS ESI m/z 229 [M+Na]⁺

Preparation 23

Methyl [3-((2R)-2-{[(1R )-1-phenyl-ethyl]-amino}-propyl)-phenyl]-acetate hydrochloride

A solution of methyl [3-(2-oxopropyl)phenyl]acetate (preparation 22) (8 5g, 41 2mmol), (R)-α- methyl benzylamme (4 8ml, 37 2mmol), sodium tnacetoxyborohydnde (11 6g, 56mmol) and acetic acid (2 2ml, 38mmol) in dichloromethane (40OmL) was stirred at room temperature for 48 hours The reaction mixture was quenched by addition of saturated aqueous sodium bicarbonate (20OmL) and allowed to stir until effervescence ceased The aqueous layer was separated extracted with dichloromethane (10OmL) and the organic solution was dried over magnesium sulfate and concentrated in vacuo Purification by column chromatography on silica gel, eluting with dichloromethane methanol ammonia, 99 1 0 1 to 95 5 0 5, gave a 4 1 mixture of diastereomers (R₁R major) as a pale yellow oil (8 71 g) Treatment with hydrogen chloride (1M solution in methanol, 4OmL, 40mmol) followed by three successive crystallisations (dnsopropylether/ methanol) afforded the title compound as a white crystalline solid in 49% yield, 5 68g

¹H NMR (400MHz, CD₃OD) δ 1 18, (d, 3H) 1 68 (d, 3H), 2 66-2 60 (m, 1 H), 3 26-3 15 (m, 1 H), 3 30-3 25 (m, 1H), 3 30 (s, 3H), 3 62 (s, 2H), 4 59 (q, 1 H), 7 02-6 99 (m, 2H), 7 18-7 16 (m, 1 H), 7 28-7 25 (m, 1 H), 7 52-7 48 (m, 5H), LRMS ESI m/z 312 [M+H]⁺

Preparation 24

Methyl {3-[(2R)-2-aminopropyl]phenyl}acetate

A solution of methyl [3-((2R)-2-{[(1R)-1-phenyl-ethyl]-amino}-propyl)-phenyl]-acetate hydrochloride (preparation 23) (7 69g, 22mmol) and ammonium formate (6 94g, 110mmol) in ethanol (10OmL) was heated to 75°C in the presence of 20% palladium hydroxide-on-charcoal (Pd(OH)₂/C, 2 0Og) After 90 minutes the reaction mixture was cooled to room temperature, filtered through Arbocel^® and the filtrate was concentrated in vacuo The residue was partitioned between dichloromethane (10OmL) and 0 88 ammonia (10OmL) and the organic layer was separated The aqueous solution was extracted with dichloromethane (10OmL) and the organic solution was dried over magnesium sulfate and concentrated in vacuo to afford the title compound as a colourless oil in quantitative yield, 4 78g

¹H NMR (400MHz, CD₃OD) δ 1 06 (d, 3H) 2 67-2 57 (m, 2H), 3 12-3 05 (m, 1 H), 3 63 (s, 2H), 3 67 (s, 3H), 7 13-7 09 (m, 3H), 7 27-7 23 (t, 1H), LRMS ESI m/z [M+Hf 208

Preparation 25

Methyl (3-{(2R)-2-[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-[benzyloxy]-3-hydroxymethyl- phenyl)-ethylamino]-propyl}-phenyl)-acetate

A solution of [2-(benzyloxy)-5-((1R)-2-bromo-1-{[tert-butyl(dimethyl) silyl]oxy}ethyl) phenyljmethanol (preparation 10), (12 5g, 27 7mmol) and methyl {3-[(2R)-2- aminopropyl]phenyl}acetate (preparation 24), (11 5g, 55 4mmol) in dichloromethane (13OmL) was heated to 90°C, allowing the dichloromethane to evaporate The resulting melt was heated at 90°C for a further 16 hours The reaction mixture was then cooled to room temperature and purified by column chromatography on silica gel, eluting with dichloromethane methanol 0 880 ammonia, 98 2 0 2 to 97 3 0 3, to afford the title compound as a white oil in 76% yield, 12 1 g

¹H NMR (400MHz, CD₃OD) δ -0 19 (s, 3H), 0 00 (s, 3H), 0 83 (s, 9H), 1 06-1 05 (d, 3H), 2 68- 2 55 (m, 3H), 2 95-2 80 (m, 2H), 3 58 (s, 2H), 3 66 (s, 3H), 4 67-4 66 (d, 2H), 4 76-4 73 (t, 1 H), 5 12 (S, 2H), 6 93-6 91 (d, 1 H), 7 01-6 99 (d, 1 H), 7 03 (s, 1 H), 7 13-7 07 (m, 2H), 7 19-7 15 (t, 1 H), 7 39-7 29 (m, 4H), 7 47-7 45 (m, 2H),

LRMS ESI m/z [M+H]⁺ 578

Preparation 26

Methyl (3-{(2R)-2-[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-hydroxy-3-hydroxymethyl- phenyl)-ethylamino]-propyl}-pheπyl)-acetate

A suspension of methyl (3-{(2R)-2-[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-[benzyloxy]-3- hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-acetate (preparation 25), (5 27g, 9 12mmol) and 10% palladium on carbon (1 0Og) in ethanol (5OmL) was stirred under an atmosphere of hydrogen (60psi) at room temperature for 16 hours The catalyst was filtered off through Arbocel^® and the filtrate concentrated in vacuo The residue was purified by column chromatography on silica gel, eluting with dichloromethane methanol 0 880 ammonia, 96 4 0 4 to 95 5 0 5 to afford the title compound as a pale yellow oil in 45% yield, 1 99g ¹H NMR (400MHz, CD₃OD) δ -0 20 (s, 3H), -0 01 (s, 3H), 0 82 (s, 9H), 1 07-1 05 (d, 3H), 2 69- 2 55 (m, 3H), 2 96-2 86 (m, 2H), 3 59 (s, 2H), 3 67 (s, 3H), 4 62-4 61 (d, 2H), 4 71-4 68 (t, 1 H),

6 69-6 67 (d, 1 H), 7 03-6 98 (m, 3H), 7 11-7 09 (d, 1 H), 7 21-7 17 (m, 2H), LRMS ESI m/z 488 [M+H]⁺

Preparation 27

(3-{(2R)-2-[(2R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-2-(4-hydroxy-3-hydroxymethyl-phenyl)- ethylamino]-propyl}-phenyl)-acetic acid

A solution of methyl (3-{(2R)-2-[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-hydroxy-3- hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-acetate (preparation 26) (7 04g, 14 43mmol) in tetrahydrofuran (4OmL) was treated with lithium hydroxide (28 9mL of a 1 M aqueous solution, 28 9mmol) and the reaction was stirred at room temperature for 16 hours Hydrochloric acid (28 9mL of a 1 M aqueous solution, 28 9mmol) was then added and the tetrahydrofuran was removed in vacuo The aqueous solution was decanted off and the residue was washed with further water (1OmL) The residue was then azeotroped with methanol (3OmL) to afford the title compound as a colourless foam in 87% yield, 5 95g

¹H NMR (400MHz, CD₃OD) δ -0 13 (s, 3H), 0 06 (s, 3H), 0 86 (S, 9H), 1 23-1 21 (d, 3H), 2 72-

2 77 (dd, 1 H), 2 93-2 98 (dd, 1 H), 3 09-3 13 (dd, 1 H), 3 23-3 28 (dd, 1 H), 3 43-3 48 (m, 1 H),

3 48 (s, 2H), 4 64-4 65 (d, 2H), 4 95-4 98 (m, 1 H), 6 78 (d, 1 H), 7 01 (d, 1 H), 7 11 (d, 1 H), 7 13 (s, 1 H), 7 18-7 32 (m, 2H), 7 32 (s, 1 H), LRMS ESI m/z 474 [M+H]⁺, micro analysis found C 64 15%, H 8 25%, N 2 84%, C₂₆H₃₉NO₅Si+0.7H₂O requires C 64 22%, H 8 37%, N 2 88% Preparation 28

N-Benzyl-2-{3-[(2R)-2-({(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3- (hydroxymethyl)phenyl]ethyl}amiπo)propyl]phenyl}-A/-methylacetamide

N-Methylbenzylamine (145μL, 1mmol) was added to a mixture of 1-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (250mg, 1 3mmol), (3-{(2R)-2-[(2R)-2-{[tert- butyl(dimethyl)silyl]oxy}-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-acetic acid (preparation 27) (473mg, 1 mmol), 1-hydroxybenzotnazole hydrate (135mg, 1mmol) and N,N-diisopropylethylamine (181 μL, 1 3mmol) in N,N-dimethylacetamide (6mL) The resulting solution was stirred for 72 hours at room temperature The solvent was removed in vacuo and the residue was partitioned between dichloromethane (4OmL) and saturated sodium hydrogen carbonate solution (1 OmL) The organic solution was dried over sodium sulfate and concentrated in vacuo The residue was purified by column chromatography on silica gel, eluting with dichloromethane isopropylalcohol 0 88 ammonia, 100 0 0 to 80 20 2, The appropriate fractions were then evaporated under reduced pressure and the residue was azeotroped with toluene (3OmL) to afford the title compound as a glass in 36% yield, 206mg LRMS ESI m/z 577 [M+H]⁺

Preparation 29

2-{3-[(2R)-2-({(2R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3- (hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N-methyl-A/-(2-phenylethyl)acetamide

The title compound was prepared from (3-{(2R)-2-[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(4- hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-acetic acid (preparation 27) and N-methyl-2-phenylethanamine, using a method similar to that described for preparation 28, as a glass in 27% yield LRMS ESI m/z 591 [M+H]⁺

Preparation 30 [3-(2-Hydroxy-2-methyl-propyl)-phenyl]-acetic acid

Methyl magnesium chloride (51 mL of a 3M solution in tetrahydrofuran, 153mmol) was added dropwise to a stirred solution of 1 ,3-benzenediacetic acid, monoethyl ester (11 6g, 51mmol), (International Journal of Peptide and Protein Research, 1987, 29(3), 331) in tetrahydrofuran (30OmL) at 0°C The reaction mixture was stirred for 18 hours, with the formation of a thick white precipitate, and was then quenched with water (5OmL) and 2N hydrochloric acid (8OmL) The aqueous layer was separated and extracted with ethyl acetate (2x300mL) and the combined organic solution was washed with brine (5OmL), dried over sodium sulfate and concentrated in vacuo to afford the title compound as a golden oil in quantitative yield, 11 2g ¹H NMR (400MHz, CDCI₃) δ 1 22 (s, 6H), 2 75 (s, 2H), 3 63 (s, 2H), 7 12-7 30 (m, 4H), LRMS ESI m/z 209 [M+H]⁺ Preparation 31 {3-[2-(2-Chloro-acetylamino)-2-methyl-propyl]-phenyl}-acetic acid

Concentrated sulphuric acid (21 mL) was added dropwise to a solution of [3-(2-hydroxy-2- methyl-propyl)-phenyl]-acetic acid (preparation 30), (10 6g, 51 Ommol) and chloroacetonitrile

(4 8ml, 76 Ommol) in glacial acetic acid (16m L) at 0°C The reaction was stirred for 2 hours, allowing the mixture to warm to room temperature, and was then poured onto iced water

(50OmL) The aqueous layer was separated and was extracted with ethyl acetate (2x250mL) and the combined organic solution was washed with brine (5OmL), dried over sodium sulfate and concentrated in vacuo to afford the title compound as a golden oil in 97% yield, 14 Og

¹H NMR (400MHz, CDCI₃) δ 1 36 (s, 6H), 3 02 (s, 2H), 3 62 (s, 2H), 3 95 (s, 2H), 6 19 (bs, 1 H), 7 06-7 31 (m, 4H), LRMS ESI m/z 282 / 284 [M-H]^"

Preparation 32 [3-(2-Amino-2-methyl-propyl)-phenyl]-acetic acid methyl ester

Acetyl chloride (154 5g, 1 97mol) was added to a solution of {3-[2-(2-chloro-acetylamino)-2- methyl-propyl]-phenyl}-acetic acid (preparation 31), (2Og, 0 66mol) in methanol (35OmL) and the mixture was heated under reflux for 18 hours The reaction mixture was then concentrated in vacuo to afford the title compound as a brown oil in 87% yield, 154 5g ¹H NMR (300MHz, CDCI₃) δ 1 12 (s, 6H), 2 62 (s, 2H), 3 58 (s, 2H)₁ 3 71 (s, 3H), 7 05-7 18 (m, 3H), 7 22 (m, 1 H), GCMS m/z 206 [M-H]

Preparation 33

Methyl (3-{2-[((2R)-2-[4-(benzyloxy)-3-(hydroxymethyl)phenyl]-2-{[(ert- butyl(dimethyl)silyl]oxy}ethyl)amino]-2-methylpropyl}pheπyl)acetate

A mixture of [2-(benzyloxy)-5-((1R)-2-bromo-1-{[terf-butyl(dimethyl)silyl] oxyjethyl) phenyl]methanol (preparation 10), (3 4g, 7 5mmol), [3-(2-amino-2-methylpropyl) phenyljacetic acid methyl ester (preparation 32), (1 7g, 7 5mmol) and N,N-diisopropylethylamine (1 4mL, 8mmol) in dimethylsulfoxide (7 5mL) was stirred at 9O°C for 28 hours The reaction mixture was then cooled, diluted with ethyl acetate and washed with water The organic solution was dried over magnesium sulfate, concentrated in vacuo and the residue was purified by column chromatography on silica gel, eluting with ethyl acetate pentane, 66 33, to afford the title compound as a colourless oil in 50% yield, 2 2g ¹H NMR (400MHz, CDCI₃) δ -0 28 (s, 3H), -0 06 (s, 3H), 0 70 (s, 9H), 1 09-1 22 (m, 6H), 2 72- 2 90 (m, 4H), 3 59 (s, 2H), 3 68 (s, 3H), 4 66-4 75 (m, 3H), 6 80 (d, 1 H), 7 05-7 13 (m, 2H), 7 19- 7 30 (m, 3H), 7 31-7 44 (m, 6H)

Preparation 34 Methyl {3-[2-({(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-

(hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]phenyl}acetate

The title compound was prepared from methyl (3-{2-[((2R)-2-[4-(benzyloxy)-3-

(hydroxymethyl)phenyl]-2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)amino]-2-methyl propyl}phenyl)acetate (preparation 33), using a similar method to preparation 26 as a brown oil in 80% yield

¹H NMR (400MHz, CDCI₃) δ -0 20 (s, 3H), -0 02 (s, 3H), 0 80 (s, 9H), 1 01-1 10 (m, 6H), 2 62-

2 85 (m, 4H), 3 59 (s, 2H), 3 68 (s, 3H), 4 66-4 75 (m, 3H), 6 80 (d, 1 H), 7 00-7 19 (m, 4H), 7 20-

7 30 (m, 2H)

Preparation 35

{3-[2-({(2R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-(hydroxy methyl)phenyl]ethyl}amino)-2-methylpropyl]phenyl}acetic acid

A mixture of methyl {3-[2-({(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3- (hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]phenyl}acetate (preparation 34), (5g, l Ommol) and lithium hydroxide (1 M in water, 3OmL, 30mmol) in tetrahydrofuran (5OmL) was stirred for 48 hours at room temperature The reaction mixture was then acidified with 1 M hydrochloric acid (3OmL), concentrated in vacuo, and the residue was triturated with water and azeotroped (x3) with methanol to afford the title compound as a white solid in 84% yield, 4 1g ¹H NMR (400MHz, CD₃OD) δ -0 12 (s, 3H), 0 06 (s, 3H), 0 82 (s, 9H), 1 33 (s, 6H), 3 00 (m,

2H), 3 34-3 24 (m, 2H), 3 61 (s, 2H), 4 .65 (m, 2H), 4 92-4 83 (m, 1 H), 6 81 (d, 1 H), 7 20-7 10

(m, 3H), 7 28 (m, 1 H), 7 39-7 31 (m, 2H)

Preparation 36 Λ/-Benzyl-2-{3-[2-({(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}^-[4-hydroxy-3-

(hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]phenyl}-N-methylacetamide

The title compound was prepared from {3-[2-({(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-[4-hydroxy- 3-(hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]phenyl}acetic acid (preparation 35) and N- benzylmethylamine, using a similar method to that of preparation 28, in 55% yield ¹H NMR (400MHz, CD₃OD) δ -0 19 (s, 3H), -0 00 (s, 3H), 0 80 (s, 9H), 1 03 (m, 6H), 1 87 (m, 1 H), 2 68 (m, 3H), 2 72 (m, 1 H), 2 80 (m, 2H), 2 85 (m, 2H), 4 63 (m, 5H), 6 73 (m, 1 H), 7 01- 7 55 (m, 11 H), LRMS APCI m/z 591 [M+H]⁺

Preparation 37 2-{3-[2-({(2R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-

(hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]phenyl}-N-methyl-N-(2- phenylethyl)acetamide The title compound was prepared from {3-[2-({(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-[4-hydroxy- 3-(hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]phenyl}acetic acid (preparation 35) and N- methyl-2-phenylethanamine, using a similar method to that of preparation 28, in 32% yield ¹H NMR (400MHz, CD₃OD) δ -0 20 (s, 3H), -0 01 (s, 3H), 0 80 (s, 9H), 1 05 (m, 6H), 2 59-2 96 (m, 8H), 3 35 (s, 3H), 3 59 (m, 2H), 4 65 (m, 3H), 6 75 (m, 1 H), 6 88-7 32 (m, 1 1 H)₁ LRMS APCI m/z 605 [M+H]⁺

Preparation 38

3-(2-tert-Butoxycarbonylamino-2-methylpropyl)benzoic acid methyl ester A solution of [2-(3-bromophenyl)-1 ,1-dimethylethyl]carbamic acid tert-butyl ester (preparation 4) (7 Og, 21 mmol), [1 ,1'-bis(diphenylphosphino)ferrocene]dichloro palladium(ll) (1 74g, 2 1 mmol) and tnethylamine (5 94mL, 43mmol) in methanol (25OmL) was heated to 100°C under I OOpsi carbon monoxide for 12 hours The reaction mixture was filtered through Arbocel^® and the filtrate was concentrated in vacuo The residue was purified by column chromatography on silica gel, eluting with dichloromethane pentane, 50 50, to afford the title compound as a yellow solid in 58% yield, 3 76g

¹H NMR (400MHz, CDCI₃) δ 1 26 (s, 6H) 1 48 (s, 9H), 3 05 (S, 2H), 3 90 (s, 3H), 4 24 (bs, 1 H), 7 34-7 35 (m, 2H), 7 82 (s, 1 H), 7 90-7 92 (m, 1 H)

Preparation 39

3-(2-Amino-2-methylpropyl)benzoic acid methyl ester

A solution of 3-(2-tert-butoxycarbonylamino-2-methylpropyl)benzoic acid methyl ester

(preparation 38), (1 6g, 5 2mmol) in dichloromethane (16OmL) at 0°C was treated with trifluoroacetic acid (13 6mL) and stirred for 2 hours, allowing the mixture to warm to room temperature The mixture was then concentrated in vacuo and the product was purified by cation exchange chromatography (methanol followed by 2M ammonia in methanol) to yield the title compound as an amber oil in 98% yield, 1 06g

¹H NMR (400MHz, CDCI₃) δ 1 12 (s, 6H), 1 67 (bs, 2H), 2 71 (s, 2H), 3 90 (s, 3H), 7 35-7 36

(2H, m), 7 84 (1 H, s), 7 88-7 90 (1 H, m), LRMS ESI m/z 208 [M+H]⁺

Preparation 40

3-{2-[(2R)-2-(4-Benzyloxy-3-hydroxymethylphenyl)-2-(tert-butyldimethyl- silanyloxy)ethylamino]-2-methylpropyl}benzoic acid methyl ester

3-(2-Amino-2-methylpropyl)benzoic acid methyl ester (preparation 39), (1 36g, 6.60mmol), [2- (benzyloxy)-5-((1 R)-2-bromo-1-{[tert-butyl(dimethyl) silyl]oxy}ethyl) phenyl]methanol (preparation

10), (2 96g, 6 60mmol), sodium iodide (980mg, 6 60mmol) and N,N-diisopropylethylamine

(3 44mL, 19 7mmol) in acetonitrile (1OmL) were heated under reflux for 48 hours The solvent was then removed in vacuo and the residue was suspended in saturated aqueous sodium hydrogen carbonate solution (2OmL) and extracted with ethyl acetate (3x30ml_) The combined organic solution was washed with brine (3x20mL), dried over sodium sulfate and concentrated in vacuo The residue was then purified by column chromatography on silica gel eluting with dichloromethane methanol ammonia, 95 5 0 5 The appropriate fractions were evaporated under reduced pressure and the residue was azeotroped with diethyl ether (x3) to afford the title compound as a white foam in 45% yield, 1 7Og

¹H NMR (400MHz, CDCI₃) δ -0 19 (s, 3H), -0 04 (s, 3H), 0 79 (s, 9H), 1 02 (s, 3H), 1 05 (S, 3H), 2 86 (t, 1 H), 2 62-2 83 (m, 4H), 3 91 (s, 3H), 4 69-4 73 (m, 3H), 5 10 (s, 2H), 6 88 (d, 1 H), 7 21- 7 44 (m, 9H), 7 84-7 89 (m, 2H), LRMS ESI m/z 578 [M+H]⁺

Preparation 41

3-{2-[(2R)-2-(tert-Butyldimethylsilanyloxy)-2-(4-hydroxy-3-hydroxymethyl- phenyl)ethylamino]-2-methylpropyl}benzoic acid methyl ester 3-{2-[(2R)-2-(4-Benzyloxy-3-hydroxymethylphenyl)-2-(tert-butyldimethyl-silanyloxy) ethylamino]- 2-methylpropyl}benzoic acid methyl ester (preparation 40) (2 12g, 3 70mmol) and palladium-on- carbon (10%, 300mg) in methanol (5OmL) were stirred at room temperature under 60 psi of hydrogen for 18 hours The reaction mixture was then filtered through Arbocel^® and the filtrate was concentrated in vacuo The residue was purified by column chromatography on silica gel, eluting with dichloromethane methanol ammonia, 95 5 0 5 The appropriate fractions were evaporated under reduced pressure and the residue was azeotroped with diethyl ether (x3) to afford the title compound as a white foam in 83% yield, 1 5O g

¹H NMR (400MHz, CDCI₃) δ -0 19 (s, 3H) -0 03 (s, 3H), 0 79 (s, 9H), 1 03 (s, 3H), 1 06 (s, 3H), 2 58 (dd, 1 H), 2 67 (dd, 2H), 2 76-2 81 (m, 1 H), 3 91 (s, 3H), 4 66 (dd, 1 H), 4 81 (dd, 2H), 6 79 (d, 1 H), 6 96 (d, 1 H), 7 13 (dd, 1 H), 7 31-7 33 (m, 2H), 7 82 (bs, 1 H), 7 86-7 89 (m, 1 H), LRMS ESI m/z 488 [M+H]^*

Preparation 42

3-{2-[(2R)-2-(tert-Butyldimethylsilanyloxy)-2-(4-hydroxy-3-hydroxymethyl- phenyl)ethylamino]-2-methylpropyl}benzoic acid A mixture of 3-{2-[(2R)-2-(tert-butyldimethylsilanyloxy)-2-(4-hydroxy-3-hydroxymethyl-phenyl) ethylamino]-2-methylpropyl}benzoic acid methyl ester (preparation 41), (1 5Og, 3 08mmol), aqueous sodium hydroxide solution (5M, 3 07mL, 15 35mmol), water (2mL) and dioxane (2OmL) was stirred at room temperature for 18 hours The mixture was concentrated in vacuo and the residue was dissolved in water (3OmL) and acidified with 1 M aqueous hydrochloric acid (15 38ml) The resulting white precipitate was filtered off and dried in vacuo for 72 hours to afford the title compound as a white solid in 88% yield, 1 28g ¹H NMR (400MHz, CD₃OD) δ -0 15 (s, 3H), -0 04 (s, 3H), 0 81 (s, 9H), 1 08 (s, 6H), 2 95 (dd, 2H), 3 23-3 12 (m, 2H), 4 61 (dd, 2H), 4 92 (m, 1 H), 6 77 (d, 1 H), 7 10 (dd, 1 H), 7 38-7 28 (m, 3H), 7 81 (bs, 1 H), 7 88 (d, 1 H), LRMS ESI m/z 474 [M+H]⁺

Preparation 43

3-[2-({(2R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-

(hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]-N-methyl-N-(2- phenylethyl)benzamide

The title compound was prepared from 3-{2-[(2R)-2-(tert-butyldimethylsilanyloxy)-2-(4-hydroxy-3- hydroxymethyl-phenyl)ethylamino]-2-methylpropyl}benzoic acid (preparation 42) and N-methyl-

2-phenylethanamine, using a similar method to that of preparation 28, in 60% yield

¹H NMR (400MHz, CD₃OD) δ -0 18 (s, 3H), 0 01 (s, 3H), 0 83 (s, 9H), 1 03 (m, 6H), 2 58-3 04

(m, 7H), 3 12 (s, 2H), 3 50 (m, 1 H), 3 78 (m, 1 H), 4 65 (m, 3H), 6 75 (m, 1 H), 6 80-7 36 (m,

11 H), LRMS APCI m/z 591 [M+H]⁺

Preparation 44

3-(2-Amino-2-methylpropyl)benzonitrile

The title compound was prepared from tert-butyl [2-(3-cyanophenyl)-1 ,1- dimethylethyl]carbamate (preparation 5), using a method similar to that described for preparation 39, as a colourless oil in 84% yield

¹H NMR (400MHz, CD₃CI₃) δ 1 11 (s, 6H), 1 27 (bs, 2H), 2 67 (s, 2H), 7 37 (m, 2H), 7 48 (s,

1 H), 7 51-7 54 (m, 1 H), LRMS APCI m/z 175 [M+H]⁺

Preparation 45 3-{2-[((2R)-2-[4-(Benzyloxy)-3-(hydroxymethyl)phenyl]-2-{[tert- butyl(dimethyl)silyl]oxy}ethyl)amino]-2-methylpropyl}benzonitrile

The title compound was prepared from [2-(benzyloxy)-5-((1 R)-2-bromo-1-{[tert- butyl(dimethyl)silyl]oxy}ethyl)phenyl] methanol (preparation 10) and 3-(2-amino-2- methylpropyl)benzonitrile (preparation 44), using a similar method to that of preparation 25, as a colourless oil in 64% yield,

¹H NMR (400MHz, CD₃OD) δ -0 19 (s, 3H), -0 01 (s, 3H), 0 79 (s, 9H), 1 06-1 09 (m, 6H), 2 62- 2 68 (m, 1 H), 2 71-2 76 (m, 1 H), 2 78-2 79 (m, 2H), 4 65-4 70 (m, 2H), 4 70-4 78 (m, 1 H), 5 10 (S, 2H), 7 17-7 23 (m, 1 H), 7 26-7 58 (m, 11 H), LRMS APCI m/z 546 [M+H]⁺

Preparation 46

[5-((1 R)-2-({2-[3-(Aminomethyl)phenyl]-1 ,1 -dimethylethyl}amino)-1 -{[tert- butyl(dimethyl)silyl]oxy}ethyl)-2-(benzyloxy)phenyl]methanol The title compound was prepared from 3-{2-[((2R)-2-[4-(benzyloxy)-3-(hydroxymethyl)phenyl]-2- {[tert-butyl(dimethyl)silyl]oxy}ethyl)amino]-2-methylpropyl} benzonitnle (preparation 45), using a similar method to that described for preparation 6, as a colourless oil in 53% yield ¹H NMR (400MHz, CD₃OD) δ -0 24 (s, 3H), -0 06 (s, 3H), 1 00 (s, 9H), 1 25 (s, 3H), 1 29 (s, 3H), 2 82-2 86 (m, 2H), 2 86-2 96 (m, 1 H), 3 04-3 09 (m, 1 H), 3 96 (s, 2H), 4 89 (d, 2H), 4 93- 4 98 (m, 1 H), 5 32 (s, 2H), 7 18-7 16 (d, 1 H), 7 25 (d, 1 H), 7 33 (s, 1 H), 7 38-7 42 (m, 3H), 7 50 (m, 1 H), 7 55-7 58 (m, 2H), 7 62-7 66 (m, 3H), LRMS APCI m/z 550 [M+H]⁺

Preparation 47 N-(3-{2-[((2R)-2-[4-(Benzyloxy)-3-(hydroxymethyl)phenyl]-2-{[tert- butyl(dimethyl)silyl]oxy}ethyl)amiπo]-2-methylpropyi}benzyl)-2,4,6- trimethylbeπzenesulfonamide

2,4,6-Trimethylbenzene sulfonyl chloride (95mg, 0 43mmol) was added to a solution of [5-((1 R)- 2-({2-[3-(aminomethyl)phenyl]-1 ,1-dimethylethyl}amino)-1-{[tert-butyl (dimethyl)silyl]oxy}ethyl)-2- (benzyloxy)phenyl]methanol (preparation 46), (200mg, 0 36mmol) and N,N-diisopropylamine (95μL, 0 54mmol) in dichloromethane (5mL) at 0°C and the mixture was stirred for 72 hours at room temperature The reaction mixture was then washed with water and the organic solution was dried over sodium sulfate, and concentrated in vacuo Purification of the residue by column chromatography on silica gel, eluting with dichloromethane methanol 0 88 ammonia, 100 0 0 to 94 6 0 6, afforded the title compound as a colourless oil in 71 % yield, 180mg

¹H NMR (400MHz, CD₃OD) δ -0 21 (s, 3H), -0 03 (s, 3H), 0 79 (s, 9H), 0 97 (s, 3H), 1 00 (s, 3H), 2 23 (S, 3H), 2 25 (s, 6H), 2 48-2 62 (m, 3H), 2 79-2 84 (m, 1 H), 4 03 (s, 2H), 4 68 (d, 2H), 4 70-4 74 (m, 1 H), 5 09 (s, 2H), 6 84-7 10 (bm, 6H), 7 17-7 19 (m, 2H), 7 28-7 44 (bm, 6H), LRMS APCI m/z 732 [M+H]⁺

Preparation 48

/V-(3-{2-[((2R)-2-[4-(Beπzyloxy)-3-(hydroxymethyl)phenyl]-2-{[tert- butyl(dimethyl)silyl]oxy}ethyl)amino]-2-methylpropyl}benzyl)-4- (trifluoromethyl)benzenesulfonamide The title compound was prepared from [5-((1R )-2-({2-[3-(aminomethyl)phenyl]-1 ,1- dimethylethyl}amino)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-2-(benzyloxy)phenyl] methanol

(preparation 46) and 4-trifluoromethanebenzene sulfonyl chloride using a similar method to that of preparation 47, as a colourless oil in 69% yield ¹H NMR (400MHz, CD₃OD) δ -0 21 (s, 3H), -0 03 (s, 3H), 0 79 (s, 9H), 0 98 (s, 3H), 1 01 (s, 3H), 2 49-2 68 (m, 3H), 2 80-2 85 (m, 1 H), 4 10 (s, 2H), 4 68 (d, 2H), 4 71-4 74 (m, 1 H), 5 10 (s, 2H), 6 93-7 13 (bm, 5H), 7 17-7 20 (m, 1H), 7 28-7 45 (bm, 6H), 7 75 (d, 2H), 7 93 (d, 2H), LRMS APCI m/z 758 [M+H]⁺ Preparation 49

/V-(3-{2-[((2R)-2-[4-(Benzyloxy)-3-(hydroxymethyl)phenyl]-2-{[tert-butyl (dimethyl)silyl]oxy}ethyl)amino]-2-methylpropyl}benzyl)benzene sulfonamide

The title compound was prepared from [5-((1 R)-2-({2-[3-(aminomethyl)phenyl]-1 ,1- dimethylethyl}amino)-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-2-(benzyloxy)phenyl] methanol

(preparation 46) and benzene sulfonyl chloride, using a similar method to that of preparation 47, as a colourless oil in 78% yield

¹H NMR (400MHz, CD₃OD) δ -0 21 (s, 3H), -0 03 (S₁ 3H), 1 00 (s, 9H), 1 21 (s, 3H), 1 24 (s, 3H), 2 77-2 87 (m, 3H), 3 02-3 07 (m, 1 H), 4 24 (s, 2H), 4 88 (d, 2H), 4 92-4 95 (m, 1 H), 5 32 (s, 2H), 7 13-7 41 (bm, 6H), 7 80-7 48 (bm, 9H), 8 03 (d, 2H), LRMS APCI m/z 690 [M+H]⁺

Preparations 50 to 52

The following compounds, of the general formula shown below, were prepared by a similar method to that described for preparation 12, using the appropriate benzyl-protected starting material (preparations 47-49)

Preparation 53 fert-Butyl {2-[3-({[(4"-hydroxybiphenyl-4-yl)carbonyl]amino}methyl)phenyl]-1,1- dimethylethyl}carbamate

1-Hydroxybenzotriazole hydrate (123 5mg, 0 91 mmol), tnethylamine (0 3mL, 2 1 mmol) and 1-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (197 4mg, 1 03mmol) were added to a mixture of tert-butyl {2-[3-(aminomethyl)phenyl]-1 ,1-dimethylethyl}carbamate (preparation 6), (252 5mg, 0 91 mmol) and 4'-hydroxy-4-biphenylcarboxylic acid (149 6mg, 0 70mmol) in N₁N- dimethylformamide (11 5mL) and the mixture was stirred at room temperature for 18 hours The reaction mixture was then concentrated in vacuo and the residue was azeotroped with toluene and purified by column chromatography on silica gel, eluting with dichloromethane methanol 0 88 ammonia, 100 0 0 to 90 10 1 , to afford the title compound as a cream foam in quantitative yield, 345mg ¹H NMR (400MHz, CD₃OD) δ 1 26 (s, 6H), 1 49 (s, 9H), 3 01 (s, 2H), 4 61 (s, 2H), 6 90 (m, 1 H),

6 93 (m, 1 H), 7 10-7 13 (m, 1 H), 7 22 (s, 1 H), 7 25-7 30 (m, 2H), 7 55 (m, 1 H), 7 58 (m, 1 H),

7 69 (m, 1 H), 7 71 (m, 1 H), 7 92 (m, 1 H), 7 94 (m, 1 H) LRMS APCI m/z 474 [M-H]

Preparations 54 to 57 The following compounds, of the general formula shown below, were prepared by a similar method to that described for preparation 53, using fert-butyl {2-[3-(aminomethyl)phenyl]-1 ,1- dimethylethyl}carbamate (preparation 6) and the appropriate acid starting material The reactions were monitored by TLC analysis and were stirred at room temperature for 18-72hours

Preparation 58 Λ/-[3-(2-Amino-2-methylpropyl)benzyl]-4'-hydroxybiphenyl-4-carboxamide hydrochloride

Hydrochloric acid (4M in dioxane, 3 6mL, 14 4mmol) and acetic acid (3mL) were added to tert- butyl {2-[3-({[(4'-hydroxybiphenyl-4-yl)carbonyl]amino} methyl)phenyl]-1 ,1- dimethylethyl}carbamate (preparation 53), (341 mg, 0 72mmol) and the mixture was stirred for 3 hours at room temperature The reaction mixture was then concentrated in vacuo to afford the title compound as a beige foam in quantitative yield, 305mg

¹H NMR (400MHz, CD₃OD) δ 1 37 (s, 6H), 2 95 (S, 2H), 4 64 (s, 2H), 6 90-6 92 (m, 1 H), 6 93 (m, 1 H)₁ 7 13-7 29 (m, 2H), 7 38-7 43 (m, 2H), 7 55 (m, 1 H), 7 58 (m, 1 H), 7 70 (m, 1 H), 7 73 (m, 1 H), 7 93 (m, 1 H), 7 95 (m, 1 H), LRMS ESI m/z 375 [M+H]⁺

Preparation 59 /V-[3-(2-Amino-2-methylpropyl)benzyl]-3-(4-hydroxyphenyl)propanamide

Hydrochloric acid (4M in dioxane, 3 6mL, 14 4mmol) was added to a solution of tert-butyl {2-[3- ({[3-(4-hydroxyphenyl)propanoyl]amino}methyl)phenyl]-1 ,1-dimethylethyl} carbamate (preparation 54), (310mg, 0 73mmol) in acetic acid (1 mL) and the mixture was stirred for 2 hours at room temperature The reaction mixture was then concentrated in vacuo and the residue was purified using a 5g 1ST bond elute SCX-2^® silica cartridge, eluting with methanol followed by 1 M ammonia in methanol to afford the title compound as a white solid in 89% yield, 212mg

¹H NMR (400MHz, CD₃OD) δ 1 13 (S, 6H), 2 52 (t, 2H), 2 70 (s, 2H), 2 88 (t, 2H), 4 35 (s, 2H), 6 70-6 74 (m, 2H), 7 02-7 07 (m, 4H), 7 10-7 12 (m, 1 H), 7 24-7 28 (m, 1 H), LRMS ESI m/z 327 [M+H]⁺

Preparation 60

Λ/-[3-(2-Amino-2-methylpropyl)benzyl]-4-hydroxybenzamide

Hydrochloric acid (4M in dioxane, 3 8mL, 15 6mmol) was added to a solution of tert-butyl tert- butyl [2-(3-{[(4-hydroxybenzoyl)amino]methyl}phenyl)-1 ,1 -dimethyl ethyl]carbamate (preparation 55), (299mg, 0 75mmol) in acetic acid (3mL) and the mixture was stirred for 2 hours at room temperature The reaction mixture was then concentrated in vacuo and the residue was purified by column chromatography on silica gel, eluting with dichloromethane methanol 0 88 ammonia to afford the title compound 76% yield, 171 mg

¹H NMR (400MHz, CD₃OD) δ 1 17 (s, 6H), 2 75 (s, 2H), 4 58 (s, 2H), 6 83 (m, 1 H), 6 85 (m, 1 H), 7 14 (m, 1 H), 7 23 (s, 1 H), 7 27-7 34 (m, 2H), 7 75 (m, 1 H), 7 77 (m, 1 H)

Preparation 61

N-[3-(2-Amino-2-methylpropyl)benzyl]-3-(2-hydroxyphenyl)propanamide

The title compound was prepared from tert-butyl {2-[3-({[3-(2- hydroxyphenyl)propanoyl]amino}methyl)phenyl]-1 ,1-dimethylethyl}carbamate (preparation 56), using a similar method to that of preparation 59, as a white foam in 87% yield

¹H NMR (400MHz, CD₃OD) δ 1 13 (s, 6H), 2 58 (t, 2H), 2 70 (s, 2H), 2 95 (t, 2H), 4 37 (s, 2H), 6 73-6 79 (m, 2H), 7 03-7 13 (m, 5H), 7 24-7 28 (m, 1 H), LRMS ESI m/z 327 [M+Hf

Preparation 62 Λ/-[3-(2-amino-2-methylpropyl)benzyl]-1-hydroxy-2-naphthamide

The title compound was prepared from [2-(3-{[(1-Hydroxy-naphthalene-2-carbonyl)-amino]- methyl}-phenyl)-1 ,1-dimethyl-ethyl]-carbamic acid tert-butyl ester (preparation 57), using a similar method to that of preparation 59, as a brown oil in 82% yield.

¹H NMR (400MHz, CD₃OD) δ: 1.28 (s, 6H), 2.85 (s, 2H), 4.72 (s, 2H), 7.01 (d, 1 H), 7.15 (m, 1 H), 7.31 (s, 1 H), 7.34-7.40 (m, 3H), 7.45-7.49 (m, 1 H), 7.69 (d, 1 H), 7.91 (d, 1 H), 8.43 (d, 1 H)

Preparation 63

Λ/-(3-{2-[((2R)-2-{4-(Benzyloxy)-3-[(methylsulfonyl)amino]phenyl}-2-{[tert- butyl(dimethyl)silyl]oxy}ethyl)amino]-2-methylpropyl}benzyl)-4'-hydroxybiphenyl-4- carboxamide

A mixture of N-[3-(2-amino-2-methylpropyl)benzyl]-4'-hydroxybiphenyl-4-carboxamide hydrochloride (preparation 58), (251 mg, 0.67mmol) and N-[5-[(1S)-2-bromo-1-[[(1 ,1- dimethylethyl)dimethylsilyl]oxy]ethyl]-2-(phenylmethoxy) phenyl]-methane sulfonamide (WO 02/06258, p36), (165.9, 0.32mmol) in dichloromethane (1OmL) and N,N-dimethylformamide (0.5mL) was heated to 90°C for 24 hours. The crude product was then purified by column chromatography on silica gel, eluting with dichloromethane:methanol:0.88 ammonia, 100:0:0 to 90:10:1 , to afford the title compound as a pale yellow powder in 22% yield, 57mg. ¹H NMR (400MHz, CD₃OD) δ: -0.15 (s, 3H), 0.03 (s, 3H), 0.84 (s, 9H), 1.10 (s, 3H), 1.13 (s, 3H), 2.68-2.92 (m, 7H), 4.61 (s, 2H), 4.73-4.76 (dd, 1 H), 5.22 (s, 2H), 6.90-6.93 (m, 2H), 7.07-7.16 (m, 3H), 7.23-7.28 (m, 3H), 7.36-7.44 (m, 3H), 7.47 (d, 1 H), 7.51-7.58 (m, 4H), 7.69 (m, 1 H), 7.71 (m, 1 H), 7.92 (m, 1 H), 7.94 (m, 1 H) LCMS m/z 808.5 [M+H]⁺. Preparations 64 to 65

The following compounds, of the general formula shown below, were prepared by a similar method to that described for preparation 63, using N-[5-[(1S)-2-bromo-1-[[(1 ,1- dimethylethyl)dimethylsilyl]oxy]ethyl]-2-(phenylmethoxy) phenyl]-methane sulfonamide (WO 02/06258, p36) and the appropriate amine starting material.

Preparation 66

N-(3-{2-[2-(4-Benzyloxy-3-methanesulfonylamiπo-phenyl)-2-(tert-butyl-dimethyl- silanyloxy)-ethylamino]-2-methyl-propyl}-benzyl)-3-(2-hydroxy-phenyl)-propionamide

A mixture of N-[3-(2-amino-2-methylpropyl)benzyl]-3-(2-hydroxyphenyl) propanamide (preparation 61), (121 mg, 0 37mmol), N-[5-[(1 S)-2-bromo-1-[[(1 ,1-dimethylethyl) dimethylsilyl]oxy]ethyl]-2-(phenylmethoxy)phenyl]-methane sulfonamide (WO 02/06258, p36), (192mg, 0 37mmol) and N N-dnsopropylethylamine (85μL, 0 5mmol) in dimethylsulfoxide (0 36mL) was heated to 9O°C for 48 hours The reaction mixture was then concentrated in vacuo and the residue was purified by column chromatography on silica gel, eluting with dichloromethane methanol 0 88 ammonia, 100 0 0 to 98 2 0 2, to afford the title compound in 33% yield, 93mg

¹H NMR (400MHz, CD₃OD) δ -0 14 (s, 3H), 0 04 (s, 3H), 0 85 (s, 9H), 1 08 (s, 3H), 1 1 1 (s, 3H), 2 56-2 60 (m, 2H), 2 65-2 97 (m, 9H), 4 35 (s, 2H), 4 74-4 77 (m, 1 H), 5 25 (s, 2H), 6 73-6 79 (m, 2H), 7 02-7 14 (m, 6H), 7 17-7 22 (m, 2H), 7 35-7 48 (m, 4H), 7 53-7 55 (m, 2H), LRMS ESI m/z 760 [M+H]⁺

Preparation 67

1 -Hydroxy-naphthalene-2-carboxylic acid 3-{2-[2-(4-benzyloxy-3-methanesulfonylamino- phenyl)-2-(tert-butyl-dimethyl-silanyloxy)-ethylamino]-2-methyl-propyl}-benzylamide

A mixture of N-[3-(2-amino-2-methylpropyl)benzyl]-3-(2-hydroxyphenyl) propanamide (preparation 62), (233mg, 0 67mmol), N-[5-[(1S)-2-bromo-1-[[(1 ,1- dimethylethyl)dimethylsilyl]oxy]ethyl]-2-(phenylmethoxy) phenyl]-methane sulfonamide (WO 02/06258, p36), (352mg, 0 68mmol) and N,N-diisopropylethylamine (224μL, 1 32mmol) in dimethylsulfoxide (0 7OmL) was heated to 90°C for 108 hours The reaction mixture was then concentrated in vacuo and the residue was purified by column chromatography on silica gel, eluting with dichloromethane methanol 0 88 ammonia, 100 0 0 to 98 2 0 2 The appropriate fractions were then evaporated under reduced pressure and the residue was further purified using an lsco SCX^® silica cartridge, eluting with methanol followed by 2M ammonia in methanol, to afford the title compound as a brown oil in 13% yield, 66mg

¹H NMR (400MHz, CD₃OD) δ -0 17 (s, 3H), 0 01(s, 3H), 0 81 (s, 9H), 1 10 (s, 3H), 1 13 (s, 3H), 2 69-2 93 (m, 7H), 4 65 (s, 2H), 4 72-4 75 (m, 1 H), 5 19 (s, 2H), 7 06-7 54 (m, 14H), 7 57-7 61 (m, 1 H), 7 77-7 81 (m, 2H), 8 39 (d, 1 H)

Preparation 68

Λ/-(3-{2-[((2R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-2-{4-hydroxy-3-

[(methylsulfonyl)amino]phenyl}ethyl)amino]-2-methylpropyl}benzyl)-4'-hydroxybiphenyl-

4-carboxamide

The title compound was prepared from N-(3-{2-[((2R)-2-{4-(benzyloxy)-3- [(methylsulfonyl)amino]phenyl}-2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)amino]-2- methylpropyl}benzyl)-4'-hydroxybiphenyl-4-carboxamide (preparation 63), using a similar method to that of preparation 24, as a white powder in quantitative yield

¹H NMR (400MHz, CD₃OD) δ -0 08 (s, 3H), 0 09 (s, 3H), 0 86 (s, 9H), 1 32 (s, 6H), 2 95 -3 00 (m, 7H), 464 (s, 2H), 4 93-4 98 (m, 1H), 6 90-6 98 (m, 3H), 7 14-7 19 (m, 2H), 7 30 (s, 1H), 7 37-7 40 (m, 2H), 7 45 (d, 1 H), 7 55-7 57 (m, 2H), 7 70-7 72 (m, 2H), 7 91-7 95 (m, 2H), LRMS ESI m/z 718 [M+H]⁺

Preparations 69 to 72

The following compounds, of the general formula shown below, were prepared by a similar method to that described for preparation 24, using the appropriate benzyl protected starting material

Preparation 73 3-((2R)-2-{[(1R)-1-Phenylethyl]amino}propyl)benzonitrile hydrochloride

The title compound was prepared from 3-(2-oxopropyl)benzonitrile (Tett Lett , 2003, 44, 8869) and (R)-α-methyl benzylamine, using a similar method as that described for preparation 23, as a white solid in 56% yield LRMS ESI m/z 265 [M+H]⁺ Preparation 74 {(1R)-2-[3-(Aminomethyl)phenyl]-1-methylethyl}[(1R)-1-phenylethyl]amine

The title compound was prepared from 3-((2R)-2-{[(1 R)-1-phenylethyl] amino}propyl)benzonitrile hydrochloride (preparation 73), using a similar method to that described for preparation 6 as an orange oil in 78% yield. LRMS ESI m/z 269 [M+H]⁺

Preparation 75 tert-Butyl [3-((2R)-2-{[(1R)-1-phenylethyl]amino}propyl)benzyl]carbamate The title compound was prepared from {(1R)-2-[3-(aminomethyl)phenyl]-1-methylethyl}[(1 R)-1- phenylethyl]amine (preparation 74) and di-tert-butyl dicarbonate, using a similar method to that of preparation 4 as a yellow oil in 84% yield. LRMS ESI m/z 369 [M+H]⁺

Preparation 76 tert-Butyl {3-[(2R)-2-aminopropyl]benzyl}carbamate

The title compound was prepared from tert-butyl [3-((2R)-2-{[(1R)-1- phenylethyl]amino}propyl)benzyl]carbamate (preparation 75), using a similar method to that of preparation 24, in 46% yield. LRMS APCI m/z 265 [M+H]⁺

Preparation 77 tert-Butyl {3-[(2R)-2-({(2R)-2-[6-(2,5-dimethyl-1H-pyrrol-1-yl)pyridin-3-yl]-2- hydroxyethyl}amino)propyl]benzyl}carbamate A mixture of tert-butyl {3-[(2R)-2-aminopropyl]benzyl}carbamate (preparation 76), (1.65g, 6.24mmol) and 2-(2,5-dimethyl-1H-pyrrol-1-yl)-5-[(2R)-oxiran-2-yl]pyridine [(1.61g, 7.49mmol), JP 20011048864] in dimethylsulfoxide (20mL) was heated at 85°C for 20 hours. The reaction mixture was then cooled to room temperature and purified using an lsco SCX^® cartridge, eluting with methanol followed by 2M ammonia in methanol. The appropriate fractions were evaporated under reduced pressure and the residue was further purified by column chromatography on silica gel, eluting with dichloromethane:methanol:0.88 ammonia to afford the title compound as a yellow oil in 49% yield, 1.45g LRMS APCI m/z 479 [M+H]⁺

Preparation 78 (1R)-2-({(1R)-2-[3-(Aminomethyl)phenyl]-1-methylethyl}amino)-1-[6-(2,5-dimethyl-1H- pyrrol-1-yl)pyridin-3-yl]ethanol

Trifluoroacetic acid (6mL, 35mmol) was added to a solution of tert-butyl {3-[(2R)-2-({(2R)-2-[6- (2,5-dimethyl-1/-/-pyrrol-1-yl)pyridin-3-yl]-2-hydroxyethyl}amino)propyl] benzyl} carbamate (preparation 77), (1 12g, 2 33mmol) in dichloromethane (15mL) and the mixture was stirred at room temperature for 2 hours The reaction mixture was then concentrated in vacuo and the residue was purified using an lsco SCX^® cartridge, eluting with methanol followed by 2M ammonia in methanol, to afford the title compound as an orange oil in 78% yield, 693 8mg LRMS APCI m/z 379 [M+H]⁺

Preparation 79 Λ/-(2,3-Dihydro-1H-inden-2-yl)-1H-imidazole-1-carboxamide A solution of 2-aminoindane hydrochloride (1g, 7 δOmmol) in N,N-dimethylformamide (15mL) was added to a solution of N,N'-carbonyldiimidazole (1 34g, 8 25mmol) in N₁N- dimethylformamide (15mL) and the mixture was stirred for 2 hours at room temperature The reaction mixture was then concentrated in vacuo and the residue was purified by column chromatography on silica gel, eluting with dichloromethane methanol 0 88 ammonia, 100 0 0 to 96 4 0 5, to afford the title compound as a white solid in 70% yield, 1 20g

¹H NMR (400MHz, CDCI₃) δ 2 97-3 02 (m, 2H), 3 30-3 40 (m, 2H), 4 70-4 82 (m, 1 H), 6 89 (s, 1 H), 7 12-7 20 (m, 4H), 7 46 (s, 1 H), 8 09 (s, 1 H)

Preparations 80 to 84 The following compounds, of the general formula shown below, were prepared by a similar method to that described for preparation 79, using the appropriate amine and N₁N¹- carbonyldnmidazole

Preparation 85

N-(2,3-Dihydro-1H-inden-2-yl)-N-'{3-[(2R)-2-({(2R)-2-[6-(2,5-dimethyl-1H-pyrrol-1-yl)pyridiπ-

3-yl]-2-hydroxyethyl}amino)propyl]benzyl}urea

A solution of (1 R)-2-({(1 R)-2-[3-(aminomethyl)phenyl]-1-methylethyl}ammo)-1-[6-(2,5-dimethyl- 1 H-pyrrol-1-yl)pyndin-3-yl]ethanol (preparation 78), (150mg, 0 40mmol) in dichloromethane (1mL) was added to a solution of N-(2,3-dihydro-1H-inden-2-yl)-1/-/-imidazole-1-carboxamide (preparation 79), (126mg, 0 54mmol) and the mixture was stirred at 60°C for 24 hours The reaction mixture was then cooled to room temperature and concentrated in vacuo The residue was partitioned between ethyl acetate and water, and the organic layer was separated, washed with brine, dried over sodium sulfate and concentrated in vacuo Purification of the residue by column chromatography on silica gel, eluting with pentane dichloromethane methanol 0 88 ammonia, 20 80 0 0 to 0 98 2 0 5, to afforded the title compound as a yellow oil in 35% yield ¹H NMR (400MHz, CD₃OD) δ 1 09 (d, 3H), 2 03 (s, 6H), 2 56-2 65 (m, 1 H), 2 72-2 83 (m, 3H), 2 87-2 91 (m, 2H), 2 96-3 03 (m, 1 H), 3 17-3 23 (m, 2H), 4 29 (s, 2H), 4 40-4 49 (m, 1 H), 4 84- 4 88 (m, 1H), 5 81 (s, 2H), 7 04-7 30 (m, 9H), 7 94-7 96 (m, 1 H), 8 57 (s, 1H), LRMS APCI m/z 538 [M+H]⁺ Preparations 86 to 90

The following compounds, of the general formula shown below, were prepared by a similar method to that described for preparation 85, using (1 /?)-2-({(1R)-2-[3-(aminomethyl)phenyl]-1- methylethyl}amino)-1-[6-(2,5-dimethyl-1 H-pyrrol-1-yl)pyridin-3-yl]ethanol (preparation 78) and the appropriate urea. The reactions were monitored by TLC analysis and were stirred at room temperature for 1-4 days.

Example 1

W-{3-[2-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl} amino)-2- methylpropyl]benzyl}-2-phenylacetamide

A mixture of N-{3-[2-({(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-

(hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]benzyl}-2-phenylacetamide (preparation 14), (103mg, 0 18mmol) and ammonium fluoride (66mg, 1 8mmol) in methanol (3mL) and water (1 5mL) was stirred at room temperature for 36 hours The reaction mixture was then concentrated in vacuo and the residue was purified by column chromatography on silica gel, eluting with dichloromethane methanol 0 88 ammonia, 100 0 0 to 90 10 0 1 The appropriate fractions were evaporated under reduced pressure and the residue was recrystallised from hot ethyl acetate/hexane to afford the title compound as a white solid in 29% yield, 24mg

¹H NMR (400MHz, CD₃OD) δ 1 01 (S₁ 3H), 1 03 (s, 3H), 2 60-2 75 (m, 3H), 2 82-2 87 (m, 1 H), 3 54 (S, 2H), 4 34 (s, 2H), 4 61-4 67 (m, 3H), 6 75 (d, 1 H), 7 02 (m, 2H), 7 06-7 24 (m, 4H), 7 25- 7 33 (m, 5H), LRMS APCI m/z 463 [M+H]⁺

Examples 2 to 7

The following compounds, of the general formula shown below, were prepared by treatment of the appropriate starting material (1eq) with ammonium fluoride (12eq), in methanol and water, at 4O°C for 18 hours Purification of the crude reaction mixtures was by analogy to the method described for example 1

Examples 8 to 10

The following compounds, of the general formula shown below, were prepared by a similar method to that described for examples 2-7, using the appropriate starting material

Example 11

4-((1 R)-2-{[(1R )-2-(3-{2-[benzyl(methyl)amino]ethyl}phenyl)-1-methylethyl]amino}-1- hydroxyethyl)-2-(hydroxymethyl)phenol

Lithium aluminium hydride (1M in tetrahydrofuran, 4 27mL, 4 27mmol) was added to a solution of N-benzyl-2-{3-[(2R)-2-({(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}2-[4-hydroxy-3-

(hydroxymethyl)phenyl]ethyl}amino) propyl]phenyl}-N-methylacetamide (preparation 28), (205mg, 0 36mmol) in tetrahydrofuran (8mL) at O°C and the solution was stirred for 40 minutes The reaction mixture was then warmed to 6O°C for 2 hours, diluted with tetrahydrofuran (3mL) and heated at 6O°C for a further 3 hours The mixture was then cooled to O°C and was quenched slowly with water (180μL), 1 M sodium hydroxide solution (340μL) and water (180μL) The reaction mixture was then stirred for 20 minutes, filtered and the filtrate was evaporated under reduced pressure The residue was suspended in methanol (5mL) and dilute acetic acid (2mL) and loaded onto a 10g IST bond elute SCX-2^® silica cartridge The cartridge was then eluted with dilute acetic acid (3 column equivalents), water (2 column equivalents), methanol (3 column equivalents) and 2M ammonia in methanol (3 column equivalents) The appropriate fractions were evaporated under reduced pressure and the residue was further purified by column chromatography on silica gel, eluting with cyclohexane diethyl ether methanol 0 88 ammonia, 50 50 18 1 to give a foam This foam was triturated with diethyl ether to afford the title compound as a solid in 38% yield, 60mg ¹H NMR (400MHz, CD₃OD) 1 05 (d, 3H), 2 28 (s, 3H), 2 52-2 92 (m, 9H), 3 59 (s, 2H), 4 57- 4 62 (m, 3H), 6 67 (d, 1H), 6 92-7 03 (m, 4H), 7 14 (m, 1 H), 7 21 (m, 1H), 7 22-7 32 (m, 5H), LRMS ESI m/z 449 [M+H]⁺

Examples 12 to 15

The following compounds, of the general formula shown below, were prepared by treatment of the appropriate starting material (preparation 29, 36, 37 and 43) with lithium aluminium hydride, using a similar method to that described for the preparation of example 11 The reactions were monitored by TLC analysis and were heated at 6O°C until all starting material had been consumed

Examples 16 to 19

The following compounds, of the general formula shown below, were prepared using a similar method to that described for examples 2-7 using the appropriate starting materials (preparations 68, 69, 70 and 72)

Example 20

/V-[3-((2R)-2-{[(2R)-2-(6-Aminopyridin-3-yl)-2-hydroxyethyl]amino} propyl)benzyl]-N'- (2,3- dihydro-1H-inden-2-yl)urea

A mixture of N-(2,3-dihydro-1 H-inden-2-yl)-N-'{3-[(2R)-2-({(2R)-2-[6-(2,5-dimethyl-1H-pyrrol-1- yl)pyridin-3-yl]-2-hydroxyethyl}amino)propyl]benzyl}urea (preparation 85), (76mg, 0.14mmol) and hydroxylamine hydrochloride (49mg, 0.71 mmol) in ethanol (3mL) was heated in a Reactivial^® for 2 days. The reaction mixture was then cooled to room temperature and directly purified using an lsco SCX^® cartridge, eluting with methanol followed by 2M ammonia in methanol, to afford the title compound as a brown oil in 74% yield.

¹H NMR (400MHz, CD₃OD) δ: 1.10 (d, 3H), 2.62-2.69 (m, 3H), 2.75-2.80 (m, 2H), 2.87-2.95 (m, 2H), 3.20-3.23 (m, 2H), 4.26 (s, 2H), 4.47 (m, 1 H), 4.55 (m, 1 H), 6.50 (d, 1 H), 6.99 (d, 1 H), 7.04 (s, 1 H), 7.09-7.11 (m, 3H), 7.16-7.20 (m, 3H), 7.38 (d, 1 H), 7.78 (s, 1 H); LRMS ESI m/z 460 [M+H]⁺

Examples 21 to 25

The following compounds, of the general formula shown below, were prepared by a similar method to that described for example 20, using the appropriate protected starting material (preparations 86 to 90) and hydroxylamine hydrochloride.

The ability of the compounds of the formula (1) to act as potent β2 agonists therefore mediating smooth muscle relaxation may be determined by the measure of the effect of beta-2 adrenergic receptor stimulation on electrical field stimulated-contraction of guinea pig trachea strips

Guinea-pig trachea

Male, Dunkin-Hartley guinea pigs (475-525g) are killed by CO₂ asphyxiation and exsanguination from the femoral artery and the trachea is isolated Four preparations are obtained from each animal, starting the dissection immediately below the larynx and taking 2 5 cm length of trachea The piece of trachea is opened by cutting the cartilage opposite the trachealis muscle, then transverse sections, 3-4 cartilage rings wide, are cut The resulting strip preparations are suspended in 5 ml organ baths using cotton threads tied through the upper and lower cartilage bands The strips are equilibrated, un-tensioned, for 20 minutes in a modified Krebs Ringer buffer (Sigma K0507) containing 3 μM lndomethacin (Sigma I7378), 10 μM Guanethidine (Sigma G8520) and 10 μM Atenolol (Sigma A7655), heated at 37°C and gassed with 95% O₂/5% CO₂, before applying an initial tension of 1 g The preparations are allowed to equilibrate for a further 30-45 minutes, during which time they are re-tensioned (to 1 g) twice at 15-minute intervals Changes in tension are recorded and monitored via standard isometric transducers coupled to a data-collection system (custom-designed at Pfizer) Following the tensioning equilibration, the tissues are subjected to electrical field stimulation (EFS) using the following parameters 10 s trains every 2 minutes, 0 1 ms pulse width, 10 Hz and just-maximal voltage (25 Volts) continuously throughout the length of the experiment EFS of post-ganglionic cholinergic nerves in the trachea results in monophasic contractions of the smooth muscle and twitch height is recorded The organ baths are constantly perfused with the above-described Krebs Ringer buffer by means of a peristaltic pump system (pump flow rate 7 5 ml / minute) throughout the experiment, with the exception of when a beta-2 agonist according to the present invention is added, the pump is then stopped for the time of the cumulative dosing to the bath and started again after maximal response is reached for the wash-out period

Experimental protocol for assessment of potency and efficacy

Following equilibration to EFS, the peristaltic pump is stopped and the preparations 'primed' with a single dose of 300 nM isoprenaline (Sigma I5627) to establish a maximal response in terms of inhibition of the contractile EFS response The isoprenaline is then washed out over a period of 40 minutes Following the priming and wash-out recovery, a standard curve to isoprenaline is carried out on all tissues (Isoprenaline Curve 1) by means of cumulative, bolus addition to the bath using half log increments in concentration The concentration range used is 1^6"9 to 1^e/3^e'6 M At the end of the isoprenaline curve the preparations are washed again for 40 minutes before commencing a second curve, either to isoprenaline (as internal control) or a beta-2 agonist according to the present invention Beta-2 agonist responses are expressed as percentage inhibition of the EFS response Data for beta-2 agonist are normalised by expressing inhibition as a percentage of the maximal inhibition induced by isoprenaline in Curve 1 The EC₅₀ value for beta-2 agonist according to the present invention refers to the concentration of compound required to produce half maximal effect. Data for beta-2 agonists according to the present invention are then expressed as relative potency to isoprenaline defined by the ratio (EC₅₀ beta- 2 agonist)/(EC50 Isoprenaline).

Confirmation of beta-2 mediated functional activity

Beta-2 agonist activity of test compounds is confirmed using the protocol above, however, prior to constructing the curve to beta-2 agonist according to the present invention, the preparations are pre-incubated (for a minimum of 45 minutes) with 300 nM ICI 118551 (a selective β2 antagonist) which results in the case of a beta-2 mediated effect in a rightward-shift of the test compound dose response curve.

According to another alternative, the agonist potency for the β2 receptor of the compounds of the formula (1) may also be determined by the measure of the concentration of compound according to the present invention required to produce half maximal effect (EC₅₀) for the β2 receptor.

Compound Preparation

10 mM/100% DMSO (dimethylsulfoxide) stock of compound is diluted to required top dose in 4 % DMSO. This top dose is used to construct a 10-point semi-log dilution curve, all in 4 % DMSO. Isoprenaline (Sigma, I-5627) was used as a standard in every experiment and for control wells on each plate. Data was expressed as % Isoprenaline response.

Cell Culture

CHO (Chinese Hamster Ovary) cells recombinantly expressing the human β2 adrenergic receptor (from Kobilka et al., PNAS 84: 46-50, 1987 and Bouvier et al., MoI Pharmacol 33: 133- 139 1988 CH0hβ2) were grown in Dulbeccos MEM/ NUT MIX F12 (Gibco, 21331-020) supplemented with 10 % foetal bovine serum (Sigma, F4135, Lot 90K8404 Exp 09/04), 2 mM glutamine (Sigma, G7513), 500 μg/ml geneticin (Sigma, G7034) and 10 μg/ml puromycin (Sigma, P8833). Cells were seeded to give about 90 % confluency for testing.

Assay Method

25 μl / well each dose of compound was transferred into a cAMP- Flashplate® (NEN, SMP004B), with 1% DMSO as basal controls and 100 nM Isoprenaline as max controls. This was diluted 1 :2 by the addition of 25 μl / well PBS. Cells were trypsinised (0.25% Sigma, T4049), washed with PBS (Gibco, 14040-174) and resuspended in stimulation buffer (NEN, SMP004B) to give 1x10⁶ cells / ml CHOhB2. Compounds were incubated with 50 μl / well cells for 1 hour. Cells were then lysed by the addition of 100 μl / well detection buffer (NEN, SMP004B) containing 0.18 μCi / ml ¹²⁵I-CAMP (NEN, NEX-130) and plates were incubated at room temperature for a further 2 hours. The amount of ¹²⁵I-CAMP bound to the Flashplate® was quantified using a Topcount NXT (Packard), normal counting efficiency for 1 minute. Dose- response data was expressed as % lsoprenaline activity and fitted using a four parameter sigmoid fit.

It has thus been found that the compounds of formula (1) according to the present invention that have been tested show a β2 cAMP EC₅₀ below 1 OnM.

Claims

1. A compound of formula (1)

wherein the (CH_z)_n-NR¹⁴ -Q¹ group is in the meta or para position, - A is selected from

wherein the dashed line represent an optional bond,

- R¹ and R² are independently selected from H and C₁-C₄ alkyl, - n is 1 or 2, and,

- Q¹ is a group selected from -C(=O)-R³, -C(=O)NH-R⁴, -SO₂-R⁵ or -R⁶ wherein R³, R⁴, R⁵ and R⁶ are selected from

R¹⁰ , or a group *-Q²-B , wherein

Q² is a single bond or a C₁-C₄ alkylene optionally substituted with OH, B is selected from: o C₃-C₁₀ cycloalkyl, said cycloalkyl being optionally bridged by one or more, preferably 1 , 2, 3 or 4, carbon atoms, and being optionally substituted with one hydroxy group, o a 5 to 6 membered heterocyclic group, optionally aromatic, containing one or two heteroatoms selected from O, N or S, or o a group

- R⁷, R⁸, R⁹, R¹⁰ and R¹¹ are the same or different and are selected from H, C₁-C₄ alkyl, OR¹², SR¹², halo, CN, CF₃, OCF₃, SO₂NR¹²R¹³, COOR¹², CONR¹²R¹³, NR¹²R¹³, NHCOR¹² and phenyl optionally substituted with OH, - R¹² and R¹³ are the same or different and are selected from H or C₁-C₄ alkyl,

- R¹⁴ is H or C₁-C₄ alkyl,

- ^* represents the attachment point to the NR¹⁴ group, or, if appropriate, their pharmaceutically acceptable salts and/or isomers, tautomers, solvates or isotopic variations thereof.

2. A compound according to claim 1 wherein Q¹ is a group *-Q²-B, wherein B is cyclohexyl or adamantyl.

3. A compound according to claim 1 wherein Q¹ is a group *-Q²-B, wherein B is a group

wherein R⁷, R⁸, R⁹, R¹⁰ and R¹¹ are the same or different and are selected from H, C₁-C₄ alkyl, OR¹², SR¹², halo, CF₃, OCF₃, SO₂NR¹²R¹³, CONR¹²R¹³, NR¹²R¹³, NHCOR¹² and phenyl provided at least 2 of R⁷ to R⁹ are equal to H;

wherein R¹² and R¹³ are the same or different and are selected from H or C₁-C₄ alkyl.

4. A compound according to claim 3 wherein Q¹ is a group *-Q²-B, wherein B is a group

wherein R⁷, R⁸, R⁹, R¹⁰ and R¹¹ are the same or different and are selected from H, OH, CH₃, OCH₃, OCH₂-CH₃, SCH₃, halo, CF₃, provided at least 2 of R⁷ to R¹¹ are equal to H. 5 A compound according to any one of claims 1 to 4 wherein Q is -CH₂-, -(CH₂)₂-, -(CH₂)₃-, or C(CH₃)₂-

6 A compound according to claim 5 wherein Q² is -CH₂-

7 A compound according to claim 1 wherein Q¹ is a group -C(=O)-R³, wherein R³ is a group *- Q²-B, wherein Q² is a C₁-C₄ alkylene, preferably methylene, and B is selected from cyclohexyl, adamantyl, naphthyl or a group

, wherein R⁷, R⁸, R⁹, R¹⁰ and R¹¹ are as defined in claim 1

8 A compound according to claim 1 wherein Q¹ is a group -C(=O)NH-R⁴, wherein R⁴ is selected from

, , or a group *-Q²-B , wherein Q² is a C₁-C₄ alkylene, and B is selected from

R⁷, R⁸, R⁹, R¹⁰ and R¹¹ are as defined above

9 A compound according to claim 1 wherein Q¹ is a group -SO₂-R⁵, wherein R⁵ is selected from *-Q²-B wherein Q² is a single bond and B is selected from

wherein R⁷, R⁸, R⁹, R¹⁰ and R¹¹ are as defined above

10 A compound according to claim 1 wherein Q¹ is a group -R⁶, wherein R⁶ is selected from ^*- Q²-B wherein Q² is a C₁-C₄ alkylene and B is selected from

wherein R⁷, R⁸, R⁹, R¹⁰ and R¹¹ are as defined above

11 A compound according to any one of claims 1 to 10 wherein R¹ is H or C₁-C₄ alkyl and R² is C₁-C₄ alkyl

12 A compound according to claim 11 wherein R¹ is H or CH₃ and R² is CH₃

13 A compound according to any one of claim 1 to 12 wherein n is 1 or 2

14 A compound according to any one of claim 1 to 13 wherein the (CH₂)_n-NR⁸-Q¹ group is in the meta position

15 The (R.R)-stereoisomer of a compound according to any one of claims 1 to 14

16 A compound according to claim 1 selected from the group consisting of N-{3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2- methylpropyl]benzyl}-2-phenylacetamide,

2-cyclohexyl-N-{3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2- methylpropyl]benzyl}acetamide, N-{3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2- methylpropyl]benzyl}-2-(1-naphthyl)acetamide,

2-(2-chlorophenyl)-N-{3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-

2-methylpropyl]benzyl}acetamide, N-{3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2- methylpropyl]benzyl}-2-(4-methylphenyl)acetamide, 2-(3,4-dichlorophenyl)-N-{3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-

(hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]benzyl}acetamide, N-{3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2- methylpropyl]benzyl}-3-phenylpropanamide, N-{3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2- methylpropyl]benzyl}-2,4,6-trimethylbenzenesulfonamide, N-{3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2- methylpropyl]benzyl}benzenesulfonamide, N-{3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2- methylpropyl]benzyl}-4-(trifluoromethyl)benzenesulfonamide, 4-((1 R)-2-{[(1R)-2-(3-{2-[benzyl(methyl)amino]ethyl}phenyl)-1-methylethyl]amino}-1- hydroxyethyl)-2-(hydroxymethyl)phenol , 2-(hydroxymethyl)-4-((1R)-1-hydroxy-2-{[(1 R)-1-methyl-2-(3-{2-[methyl(2- phenylethyl)amino]ethyl}phenyl)ethyl]amino}ethyl)phenol ,

4-((1R)-2-{[2-(3-{2-[benzy!(methyl)amino]ethyl}phenyl)-1 ,1-dimethylethyl]amino}-1-hydroxyethyl)-

2-(hydroxymethyl)phenol , 4-((1R)-2-{[1 ,1-dimethyl-2-(3-{2-[methyl(2-phenylethyl)amino]ethyl} phenyl)ethyl]amino}-1 - hydroxyethyl)-2-(hydroxymethyl)phenol ,

4-((1R)-2-{[1 ,1-dimethyl-2-(3-{[methyl(2-phenylethyl)amino] methyl}phenyl)ethyl]amino}-1 - hydroxyethyl)-2-(hydroxymethyl)phenol , N-[3-((2R)-2-{[(2R)-2-(6-aminopyndin-3-yl)-2-hydroxyethyl]amino}propyl)benzyl]-N-'(4- phenylbutyl)urea, N-[3-((2R)-2-{[(2R)-2-(6-aminopyridin-3-yl)-2-hydroxyethyl]amino}propyl)benzyl]-N-'[2-(4- ethylphenyl)ethyl]urea, N-[3-((2R)-2-{[(2R)-2-(6-aminopyridin-3-yl)-2-hydroxyethyl]amino}propyl)benzyl]-N-'(biphenyl-2- ylmethyl)urea, N-[3-((2R)-2-{[(2R)-2-(6-ammopyridin-3-yl)-2-hydroxyethyl]amino}propyl)benzyl]-N-'benzylurea, N-[3-((2R)-2-{[(2R)-2-(6-aminopyridin-3-yl)-2-hydroxyethyl]amino}propyl)benzyl]-N-'(2- phenylethyl)urea, N-[3-((2R)-2-{[(2R)-2-(6-aminopyridin-3-yl)-2-hydroxyethyl]amino}propyl)benzyl]-N-'(2,3-dihydro-

1 H-inden-2-yl)urea, 4'-hydroxy-N-(3-{2-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-

2-methylpropyl}benzyl)biphenyl-4-carboxamide, N-(3-{2-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl) amino]-2- methylpropyl}benzyl)-3-(4-hydroxyphenyl)propanamide,

4-hydroxy-N-(3-{2-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino] phenyl}ethyl)amino]- 2-methylpropyl}benzyl)benzamide, N-(3-{2-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-2- methylpropyl}benzyl)-3-(2-hydroxyphenyl)propanamide, and,

1-hydroxy-N-(3-{2-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino] phenyl}ethyl)amino]-

2-methylpropyl}benzyl)-2-naphthamide

17 A pharmaceutical composition comprising at least an effective amount of a compound of the formula (1) as described in any one of claims 1 to 16 or a pharmaceutically acceptable salt or derived form thereof

18 A compound of the formula (1) as described in any one of claims 1 to 16 or a pharmaceutically acceptable salt, derived form or composition thereof, for use as a medicament 19 The use of a compound of the formula (1) as described in any one of claims 1 to 16 or of a pharmaceutically acceptable salt, derived form or composition thereof, for the manufacture of a drug having a β2 agonist activity

20 The use of a compound of the formula (1 ) as described in any one of claims 1 to 16 or of a pharmaceutically acceptable salt, solvate or composition thereof, for the manufacture of a drug for the treatment of diseases, disorders, and conditions selected from

• asthma of whatever type, etiology, or pathogenesis, in particular asthma that is a member selected from the group consisting of atopic asthma, non-atopic asthma, allergic asthma, atopic bronchial IgE-mediated asthma, bronchial asthma, essential asthma, true asthma, intrinsic asthma caused by pathophysiologic disturbances, extrinsic asthma caused by environmental factors, essential asthma of unknown or inapparent cause, non-atopic asthma, bronchitic asthma, emphysematous asthma, exercise-induced asthma, allergen induced asthma, cold air induced asthma, occupational asthma, infective asthma caused by bacterial, fungal, protozoal, or viral infection, non-allergic asthma, incipient asthma, wheezy infant syndrome and bronchiolytis,

• chronic or acute bronchoconstnction, chronic bronchitis, small airways obstruction, and emphysema,

• obstructive or inflammatory airways diseases of whatever type, etiology, or pathogenesis, in particular an obstructive or inflammatory airways disease that is a member selected from the group consisting of chronic eosinophilic pneumonia, chronic obstructive pulmonary disease (COPD), COPD that includes chronic bronchitis, pulmonary emphysema or dyspnea associated or not associated with COPD, COPD that is characterized by irreversible, progressive airways obstruction, adult respiratory distress syndrome (ARDS), exacerbation of airways hyper-reactivity consequent to other drug therapy and airways disease that is associated with pulmonary hypertension,

• bronchitis of whatever type, etiology, or pathogenesis, in particular bronchitis that is a member selected from the group consisting of acute bronchitis, acute laryngotracheal bronchitis, arachidic bronchitis, catarrhal bronchitis, croupus bronchitis, dry bronchitis, infectious asthmatic bronchitis, productive bronchitis, staphylococcus or streptococcal bronchitis and vesicular bronchitis,

• acute lung injury,

bronchiectasis of whatever type, etiology, or pathogenesis, in particular bronchiectasis that is a member selected from the group consisting of cylindric bronchiectasis, sacculated bronchiectasis, fusiform bronchiectasis, capillary bronchiectasis, cystic bronchiectasis, dry bronchiectasis and follicular bronchiectasis

21 A method of treatment of a mammal, including a human being, with a β2 agonist including treating said mammal with an effective amount of a compound of the formula (1 ) as described in any one of claims 1 to 16 or with a pharmaceutically acceptable salt, derived form or composition thereof

22 A method according to claim 21 where the disease, disorder or condition is selected from the group as described in claim 20

23 Combination of a compound according to any one of claims 1 to 16 with other therapeutic agent(s) selected from

(a) 5-Lipoxygenase (5-LO) inhibitors or 5-lipoxygenase activating protein (FLAP) antagonists,

(b) Leukotriene antagonists (LTRAs) including antagonists of LTB₄, LTC₄, LTD₄, and LTE₄,

(c) Histamine receptor antagonists including H1 and H3 antagonists, (d) Ct₁- and α₂-adrenoceptor agonist vasoconstrictor sympathomimetic agents for decongestant use,

(e) muscarinic M3 receptor antagonists or anticholinergic agents,

(f) PDE inhibitors, e g PDE3, PDE4 and PDE5 inhibitors,

(g) Theophylline, (h) Sodium cromoglycate,

(i) COX inhibitors both non-selective and selective COX-1 or COX-2 inhibitors (NSAIDs),

(j) Oral and inhaled glucocorticosteroids, such as DAGR (dissociated agonists of the corticoid receptor),

(k) Monoclonal antibodies active against endogenous inflammatory entities, (I) Anti-tumor necrosis factor (anti-TNF-α) agents,

(m) Adhesion molecule inhibitors including VLA-4 antagonists,

(n) KmIn-B₁ - and B₂ -receptor antagonists,

(o) Immunosuppressive agents,

(p) Inhibitors of matrix metalloproteases (MMPs), (q) Tachykinin NK₁, NK₂ and NK₃ receptor antagonists,

(r) Elastase inhibitors,

(s) Adenosine A2a receptor agonists,

(t) Inhibitors of urokinase,

(u) Compounds that act on dopamine receptors, e g D2 agonists, (v) Modulators of the NFicβ pathway, e g IKK inhibitors,

(w) modulators of cytokine signalling pathyways such as p38 MAP kinase, syk kinase or JAK kinase inhibitor, (x) Agents that can be classed as mucolytics or anti-tussive, and (y) Antibiotics.