COMPOUNDS HAVING BETA-AGONIST ACTIVITY

This invention relates to β2 agonists of general formula:

y B— (CH2)n^ /-Q R R11 R R22 O (1 )

in which A, B, R1, R2, n 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 leukotriene 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 bronchoconstrictor 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.

EP0061907 discloses the following intermediate compound: N-Benzyl-4-

[2-(2-hydroxy-2-phenyl-ethylamino)-propyl]-benzamide.

The invention relates to compounds of formula (1)

OH H ,N A" B-(CH2Jn. Q1

^1 R2 O (1 ) wherein:

- A is selected from the following groups:

CF, Cl HO

H2N Br

Cl HO N-O

OH

Cl O

O H2N

1S^ Cl NH.

HO HO OMe HO SO2NH2 O. O O. O O=S^ ^O HN * HN HN HO SO2NH2 NH, HO HO H3COOC

HO HO HO NHCOCH,

HO HO H2N' W NHSO2CH3 O NHCOH

HO

N HO HO HO CH2OH OH NHCONH. and

wherein the dashed line represents an optional bond; - R1 and R2 are independently selected from H or C1-C4 alkyl; - B is selected from * * r^ ^

or wherein * represents the attachment points and wherein ** represents the attachment point to the (CH2)nC(=0)Qi group and R is selected from hydrogen, (C1-C4)alkyl and benzyl optionally substituted with 1 , 2 or 3 groups selected from hydroxy, hydroxy(C1-C-6)alkyl, (C1-C4)alkyl, 0-(Cr C4)alkyl, halo, 0-CF3, NR9SO2(C1-C4)alkyl, SO2NR9R10, trifluoromethyl and NR9R10; - n is an integer selected from 0, 1 or 2, - Q1 is a group selected from:

R12 <— N R13 */ R11

-N R12 * —N N-R12 »— N O

0 , *-NR8-Q2-Z or *-NR8-Q7, wherein - * represent the attachment point to the carbonyl group; - p is 1 or 2 and q is 1 or 2, - R8 is selected from hydrogen or (C-ι-C4)alkyl optionally substituted by a hydroxy; - Q2 is a bond or a CrC4 alkylene optionally substituted with OH; - Q7 is CrC6 alkyl optionally substituted with NR9R10, OR9 or phenoxy, - Z is selected from - C3-C10 cycloalkyl, said cycloalkyl being optionally bridged by one or more carbon atoms, preferably 1 2, 3 or 4 carbon atoms, and being optionally substituted with a group selected from hydroxy group and Cr C4 alkyl; - 5 to 10-membered heterocycle, optionally aromatic, containing from 1 to 3 heteroatoms, identical or different, selected from O, S or N, said heterocycle being optionally substituted with a group selected from (C1- C4)alkyl, cyclopropylmethyl and NR9R10 , or, - a group of formula R3 . R4 R3 // W -R5

■Dfi s , Q3-Q4-Q5-Q6 R5 R7 R6 κ , κ or ; - R3, R4, R5, R6 and R7 are the same or different and are selected from H, C1-C6 alkyl, benzyloxy, hydroxy(C1-C6)alkyl, OR9, SR9, SOR9, SO2R9, halo, CN, CF3, OCF3, (CH2)mCOOR9, NR9SO2(CrC4)aIkyl, SO2NR9R10, CONR9R10, NR9R10, NHCOR10; - m is an integer selected from O, 1 , and 2; - R9 and R10 are the same or different and are selected from H or CrCβ alkyl; - R11 is selected from H and OH; - R >1'2z and R ,1130 are the same or different and are selected from H, OR , C1-C4 alkyl optionally susbstituted with OR9, C(=O)NH2, C(=O)CH3, N(CH3)C(=O)CH3, C(=O)OR9, phenyl optionally substituted with halogen, pyridyl optionally substituted with CN, oxadiazolyl optionally substituted with C1-C4 alkyl, and - Q3 is (CH2)t wherein t is an integer selected from 0 and 1 ; - Q4 is a group selected from NH, -C(=O)NH-, -NHC(=O)-, NH-C(=O)-NH-, - NHSO2- and -SO2NH-; or - Q5 is a single bond, a CrC4 alkylene optionally substituted with OH or a group (CH2)q-O-(CH2)r wherein q and r are integers independently selected from 1 , 2 or 3; - Q6 is selected from R14 _ R15

and, wherein * represents the attachment point to Q5 and R14, R15, R16, R17 and R18 are independently selected from H, C1-C4 alkyl, OR19, SR19, SOR19, SO2R19, halo, CN, CF3, OCF3, COOR20, SO2NR19R20, CONR19R20, -NR19SO2R20, NHR19R20, NHCOR20, CH2-NHC(=O)NH-R20, - R19 is selected from H or C1-C4 alkyl and R20 is selected from H, C1-C4 alkyl, benzyl optionally substituted with 1 , 2, 3 or 4 C1-C4 alkoxy, and a group

— s CΛ /r°"(CH \ //

wherein s is an integer selected from 0, 1 , 2 and 3; or, if appropriate, their pharmaceutically acceptable salts and/or isomers, tautomers, solvates or isotopic variations thereof, with the proviso that when B is selected from

or then A is not

H2N' 'N' NHSO2CH3 NHCOH

CH2OH 2 or, and with the exception of N-Benzyl-4-[2-(2-hydroxy-2-phenyl-ethylamino)- propyl]-benzamide.

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 ), CrC4 alkyl and CrC4 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-(C1-C4)alkyl radicals, S-(C1-C-4)alkyl radicals etc... . C1-C6 alkyl denotes a straight-chain or branched group containing 1 , 2, 3, 4, 5 or 6 carbon atoms. Examples of suitable (C1-C4)alkyl radicals are methyl, ethyl, n-propyl, /so-propyl, π-butyl, /so-butyl, sec-butyl, fe/rf-butyl.... Examples of suitable O-(C1-C4)alkyl radicals are methoxy, ethoxy, n-propyloxy, /so-propyloxy, π-butyloxy, /so-butyloxy, sec-butyloxy and te/if-butyloxy....

The C3-C10 cycloalkyl wherein 2 carbon atoms or more are optionally bridged by one or more carbon atoms includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane. Preferred cycloalkyl groups are cyclohexyl and adamantyl.

Examples of preferred 5 to 10 membered heterocycle, optionally aromatic, containing from 1 to 3 heteroatoms are morpholinyl, pyrrolidinyl, piperidyl, piperazinyl, thienyl, isothiazolyl, oxazolyl, pyridyl, pyrimidyl oxazolyl, isoxazolyl, thiazolyl, furanyl, imidazolyl, pyrazolyl, pyrrolyl, pyridazinyl, pyrazinyl, triazolyl, tetrazolyl, oxadiazolyl, triazinyl, indolyl, quinolyl, isoquinolyl, benzofuranyl, quinazolyi, quinoxalyl, phthalazinyl, benzothiazolyl, benzoxazoiyl, benzisothiazolyl, benzisoxazolyl, benzimadazolyl, indazolyl and benzotriazolyl.

Preferred heterocyclic groups include 5 to 6 membered heterocyclic groups, optionally aromatic, containing one or two heteroatoms selected from O, N or S such as are morpholinyl, pyrrolidinyl, piperidyl, piperazinyl, pyrazolyl, thienyl, furanyl, imidazolyl, isothiazolyl, thiazolyl, isoxazolyl, oxazolyl, pyridyl and pyrimidyl. Preferably, said heterocyclic groups contain one nitrogen, two nitrogens or one nitrogen and one oxygen atom.

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

Preferred non aromatic 5 to 6 membered heterocyclic groups are morpholinyl, pyrrolidinyl, piperidyl and piperazinyl.

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

The compounds of the formula (1 ) OH

A UX^B-(CHΛ. Q1 R1 R2 O (1 ) can be prepared using conventional procedures such as by the following illustrative methods in which Q1, R1, R2, A, B and n are as previously defined for the compounds of the formula (1 ) unless otherwise stated. The amide derivatives of the formula (1 ) may be prepared by coupling an acid of formula (2): OH

A B (CH2) OH R2 Y (2) R1 O with an amine of formula R3 R3 R4

"(CH2),, .o- HN •R12 HN N— R12 HN N-R12 HN p HN V-J O

NHR8-Q2-Z or NHR8-Q7.

The coupling is generally carried out in an excess of said amine as an acid receptor, with a conventional coupling agent (e.g. 1-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride or N, A/'-dicyclohexylcarbodiimide), optionally in the presence of a catalyst (e.g. 1-hydroxybenzotriazole hydrate or 1-hydroxy-7- azabenzotriazole), and optionally in the presence of a tertiary amine base (e.g. /V-methylmorpholine, triethylamine or diisopropylethylamine). The reaction may be undertaken in a suitable solvent such as pyridine, dimethylformamide, tetrahydrofuran, dimethylsulfoxide, dichloromethane or ethyl acetate, and at temperature comprised between 100C and 400C (room temperature) for a period of 1-24 hours. Said amine is either commercially available or may be prepared by conventional methods well known to the one skilled in the art (e.g. reduction, oxidation, alkylation, transition metal-mediated coupling, protection, deprotection etc..) from commercially available material. The acid of formula (2) may be prepared from the corresponding ester of formula (4): OH H A^ V'NX^B —(CH2) ORa (4) W R2 ϊ O wherein Ra is a suitable acid protecting group, preferably a (C1-C4)alkyl group, which includes, but is not limited to, methyl and ethyl, according to any method well-known to the one skilled in the art to prepare an acid from an ester, without modifying the rest of the molecule. For example, the ester may be hydrolysed by treatment with aqueous acid or base (e.g. hydrogen chloride, potassium hydroxide, sodium hydroxide or lithium hydroxide), optionally in the presence of a solvent or mixture of solvents (e.g. water, 1 ,4-dioxan, tetrahydrofuran/water), at a temperature comprised between 200C and 1000C, for a period of 1 to 40 hours. The ester of formula (4) may be prepared by reaction of an amine of formula (5) : H2N B (CH2)n^0Ra (5) R1 R2 O wherein Ra and n are as previously defined, with a bromide of formula (6) : OH _ ^Br (6) A

In a typical procedure, the amine of formula (5) is reacted with a bromide of formula (6) optionally in the presence of a solvent or mixture of solvents (e.g. dimethylsulfoxide, toluene, N, Λ/-dimethylformamide, acetonitrile), optionally in the presence of a suitable base (e.g. triethylamine, diisopropylethylamine, potassium carbonate) at a temperature comprised between 8O0C and 12O0C, for 12 to 48 hours.

The bromide of formula (6) may be prepared according method well known to the man skilled in the art. The amine of formula (5), where R1 is Me and R2 is H, may be prepared as either the (R) or (S) enantiomer from the corresponding protected amine of formula (7) : Rc

Rb' '^^ B — (CH2) ORa (7) R1 R2 T

wherein Ra and n are as previously defined and Rb and Rc represent any suitable substituents so that HNRbRc is a chiral amine (for example, Rb may be hydrogen and Rc may be α-methylbenzyl), provided that the bonds between N and Rb and N and Rc can be easily cleaved to give the free amine of formula (5) using standard methodology for cleaving nitrogen protecting groups, such as those found in the text book T.W. GREENE, Protective Groups in Organic Synthesis , A. Wiley-lnterscience Publication, 1981.

The amine of formula (7) may be prepared as a single diastereomer by reaction of an amine of formula HNRbRc with a ketone of formula (8):

H3C B — (CH2)n ORa (8) Y

wherein Ra, Rb, Rc and n are as previously defined.

In a typical procedure, the reaction of the ketone of formula (8) with the amine of formula HNRbRc leads to a chiral intermediate which is in turn reduced by a suitable reducing agent (e.g. sodium cyanoborohydride of formula NaCNBH3 or sodium triacetoxyborohydride of formula Na(OAc)3BH) optionally in the presence of a drying agent (e.g. molecular sieves, magnesium sulfate) and optionally in the presence of an acid catalyst (e.g. acetic acid) to give the amine of formula (7) as a mixture of diastereomers. The reaction is generally done in a solvent such as tetrahydrofuran or dichloromethane at a temperature comprised between 2O0C and 800C for 3 to 72 hours. The resulting product is then 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 (7) as a single diastereomer.

The ketone of formula (8) where n=1 may be prepared by palladium mediated coupling of an aryl halide of formula (9):

Ha'^B v. /ORa 0)

O

wherein Ra is as previously defined and Hal represents an halogen atom, which includes, but is not limited to bromo and iodo, with an enolate or enolate equivalent. In a typical procedure, the aryl halide of formula (9) is reacted with a tin enolate generated in-situ by treatment of isopropenyl acetate with tri-n-butyltin methoxide of formula Bu3SnOMe in the presence of a suitable palladium catalyst (palladium acetate/ tri-o/t/jo-tolylphosphine of formula Pd(OAc)2/P(o- ToI)3) in a non-polar solvent (e.g. toluene, benzene, hexane). Preferably, the reaction is carried out at a temperature comprised between 800C and 11O0C for 6 to 16 hours. The aryl halide of formula (9) may be obtained by esterification of the corresponding acid of formula (10): HaK (10)

° wherein Hal is as previously defined, according to any method well-known to the one skilled in the art to prepare an ester from an acid, without modifying the rest of the molecule.

In a typical procedure, the acid of formula (10) is reacted with an alcoholic solvent of formula RaOH, wherein Ra is as previously defined, in the presence of an acid such as hydrogen chloride at a temperature between 100C and 4O0C (room temperature) for 8 to 16 hours.

The acid of formula (10) is a commercial product.

The amine of formula (5), where R1 and R2 are both CrC4 alkyl, may be prepared according to the following scheme:

Scheme 1

RaO HO Y^B (CH2)n OH X^B (CH^-^OH T W R2 O (11) (12) O H2N X"^ B (CH2)n^ORa R1 R2 (5) wherein R1, R2 and Ra are as previously defined.

In a typical procedure, the ester of formula (11 ) is reacted with an "activated" alkyl (organometallic alkyl such as R2MgBr, R2MgCI or R2Li) to give the corresponding tertiary alcohol of formula (12) using the method described above.

Said tertiary alcohol of formula (12) is then treated with an alkyl nitrile (e.g. acetonitrile, chloroacetonitrile) in the presence of an acid (e.g. sulphuric acid, acetic acid) to give a protected intermediate which is in turn cleaved using standard methodology for cleaving nitrogen protecting group such as those mentioned in textbooks. The resulting amino acid is then esterified using the method described herein to give the amine of formula (5).

Alternatively, the amine of formula (5), where R1 are R2 both C1-C4 alkyl and n=0, may be prepared according to the following scheme:

Scheme 2 /^ -Br ^Br H0> ΕT O R1 R2

(13) (14)

H2N H2 / \ R1 R2 R1 R2 i O°Ra (15) (5) wherein R1, R2 and Ra are as previously defined.

In a typical procedure, the ester of formula (13) is reacted with an "activated" alkyl (organometallic alkyl such as R2MgBr, R2MgCI or R2Li) to give the corresponding tertiary alcohol of formula (14) using the method described above. Said tertiary alcohol of formula (14) is then treated with an alkyl nitrile (e.g. acetonitrile, chloroacetonitrile) in the presence of an acid (e.g. sulphuric acid, acetic acid) to give a protected intermediate which is in turn cleaved using standard methodology for cleaving nitrogen protecting group such as those mentioned in textbooks to give the bromo amine (15).

The resulting bromo amine (15) is treated with a suitable palladium catalyst (e.g. [1 ,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(ll)) under an atmosphere of carbon monoxide using RaOH as solvent (e.g. MeOH, EtOH) at elevated temperature (1000C) and pressure (100psi) to give the ester of formula (5).

The ketone of formula (8) where n=2 may be prepared by reduction of an alkene of formula (16) : O H3C B ^A0Ra <16> O In a typical procedure, a solution of the olefin of formula (16) in a suitable solvent (e.g. methanol, ethanol, ethyl acetate) is treated with a palladium catalyst (e.g. 10% palladium on charcoal) and stirred under an atmosphere of hydrogen, optionally at elevated pressure (e.g. 60 psi), at temperature between room temperature and 6O0C for 8-24 hours.

The alkene of formula (16) may be prepared by a palladium mediated coupling of an activated olefin with an aryl halide of formula (17): H3C B_ Ha| (1 7)

O

In a typical procedure, the aryl halide (1 7) is coupled with a vinyl ester (e.g. methyl acrylate) in the presence of a suitable palladium catalyst (e.g. tetrakis(triphenylphosphine)palladium(0) of formula Pd(PPh3)4, palladium acetate/tri-ort/70-tolylphosphine of formula Pd(OAc)2/P(o-tol)3 or (diphenylphosphino)ferrocenyl palladium chloride of formula dppfPdCb) in a suitable solvent (e.g. acetonitrile, N, /V-dimethylformamide, toluene), optionally in the presence of a base such as triethylamine at a temperature between 400C and 1100C for 8 to 24 hours.

The ketone of formula (17) is a commercial product.

Alternatively a compound of formula (1) may be prepared by reaction of a bromide of formula (6) and an amine of formula (18): H2N -(CH2) Q1 (18) R1 R2 O where R1, R2, Q1and n are as previously defined for the compounds of the formula (1 ) unless otherwise stated.

In a typical procedure, the amine of formula (18) is reacted with a bromide of formula (6) optionally in the presence of a solvent or mixture of solvents (e.g. dimethylsulfoxide, toluene, N, /V-dimethylformamide, acetonitrile), optionally in the presence of a suitable base (e.g. triethylamine, diisopropylethylamine, potassium carbonate) at a temperature comprised between 8O0C and 12O0C, for 12 to 48 hours. The amide of formula (18) may be prepared by coupling an acid of formula (19) incorporating a suitable amine protecting group P1 : H Pi /\ ^B (CH2) OH R1 R2 Y o (19) with an amine of formula R3 R3 R4

HN 4— R12 '(CH '22)I,q HN N—R12 HN N-R12 HN P HN X J v_v ( \__/ t v_y _ v_/ o^ t NHR8.Q2_

Z or NHR8-Q7.

The coupling is generally carried out in an excess of said amine as an acid receptor, with a conventional coupling agent (e.g. 1-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride or N, A/'-dicyclohexylcarbodiimide), optionally in the presence of a catalyst (e.g. 1-hydroxybenzotriazole hydrate or 1-hydroxy-7- azabenzotriazole), and optionally in the presence of a tertiary amine base (e.g. A/-methylmorpholine, triethylamine or diisopropylethylamine). The reaction may be undertaken in a suitable solvent such as pyridine, dimethylformamide, tetrahydrofuran, dimethylsulfoxide, dichloromethane or ethyl acetate, and at temperature comprised between 10°C and 400C (room temperature) for a period of 1-24 hours. Said amine is either commercially available or may be prepared by conventional methods well known to the one skilled in the art (e.g. reduction, oxidation, alkylation, transition metal-mediated coupling, protection, deprotection etc..) from commercially available material. The acid of formula (19) may be prepared from the corresponding ester of formula (5). The acid of formula (19), where R1 and R2 are both C1-C4 alkyϊ, may be prepared from the ester (5) incorporating a suitable amine protecting group P1 either before or after the acid formation:

HzN) B— (CH2) ORa

R1 R2 S (5) wherein Ra is a suitable acid protecting group, preferably a (CrC4)alkyl group, which includes, but is not limited to, methyl and ethyl, according to any method well-known to the one skilled in the art to prepare an acid from an ester, without modifying the rest of the molecule. For example, the ester may be hydrolysed by treatment with aqueous acid or base (e.g. hydrogen chloride, potassium hydroxide, sodium hydroxide or lithium hydroxide), optionally in the presence of a solvent or mixture of solvents (e.g. water, 1 ,4-dioxan, tetrahydrofuran/water), at a temperature comprised between 2O0C and 1000C, for a period of 1 to 40 hours.

The amine of formula (5), where R1 and R2 are both H, may be prepared according to the following scheme: Scheme 3

H°Y^B-(CH2)n'^ORa ^ B (CH2)n ORa O (21 ) (20)

X O ^- (CH2)n ORa (5) wherein R1, R2 and Ra are as previously defined.

In a typical procedure, the acid of formula (20) is preferentially reduced to the corresponding alcohol (21 ) in the presence of the ester. This ma/ be performed by formation of the acyl imidazole or mixed anhydride and subsequent reduction with sodium borohydride or another suitable reducing agent.

Said primary alcohol of formula (21 ) is then converted into a leaving group such as mesylate, tosylate, bromide or iodide and displaced with appropriate amine nucleophile. The preferred nucleophile is azide ion which can then be reduced to the primary amine via hydrogenation or triphenylphosphine. Alternative nucleophiles could include ammonia or alkylamines such as benzylamine or allylamine and subsequent cleavage of the alkyl group to furnish the amine.

In a typical procedure, the amine of formula (6) is reacted with a bromide of formula (7) (7) optionally in the presence of a solvent or mixture of solvents (e.g. dimethyl sulfoxide, toluene, N, N-dimethylformamide, acetonitrile, THF), optionally in the presence of a suitable base (e.g. triethylamine, N, ΛkJiisopropylethylamine, potassium carbonate) and optionally in the presence of a catalyst (e.g. potassium iodide) at a temperature comprised between 600C and 120°C, for 6 to 120 hours. The intermediate amino ketone can then be reduced using sodium borohydride or diisobutylaluminiumhydride to furnish the required aminoalcohol.

For some of the steps of the here above described process of preparation of the compounds of formula (1), it may be necessary to protect potential reactive functions that are not wished to react, and to cleave said protecting groups in consequence. In such a case, any compatible protecting radical can be used. In particular methods of protection and deprotection such as those described by T.W. GREENE (Protective Groups in Organic Synthesis, A. Wiley-lnterscience Publication, 1981) or by P. J. Kocienski (Protecting groups, Georg Thieme Verlag, 1994), can be used.

An alternative agent for deprotection would be one equivalent of triethylamine trihydrofluoride in tetrahydrofuran or suitable solvent at room temperature for 12 hours.

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 chromatograph y.

The sub-groups of compounds of formula (I) are preferred: OH

NHCONH

NHCOCH or,

O

(CH2)n ^Qi NHSO2CH3

In a preferred embodiment of the invention, Q is a s ingle bond.

In a preferred embodiment of the invention, Z is selected from morpholinyl, pyrrolidinyl, piperidyl, piperazinyl or pyrazolyl, optionally susbstituted by a methyl group.

In a preferred embodiment of the invention, Z is selected from pyrazolyl optionally substituted by one or two C1-C4alkyl group. In a preferred embodiment of the invention, Q1 is *-NR8-Q7.

In a preferred embodiment of the invention, Q1 is a group selected from, R12 *— N R13 -N. R12 *— N —R12 R11

-N N__R12 * — N P *— N

Subgroup of compounds of formula (1 ) containing the following substituents are preferred:

Preferably, Q1 is a group *-NH-Q2-Z, wherein Z is C3-C10 cycloalkyl, said cycloalkyl being optionally bridged by one or more carbon atoms, preferably 1 2, 3 or 4 carbon atoms.

Preferably Q1 is a group *-NH-Q2-Z, wherein Z is cyclohexyl or adamantyl.

Preferably, Q1 is

R3 R4

'— N R5 R6 wherein R3, R4, R5 and R6 are H.

Preferably, Q1 is a group *-NH-Q2-Z, wherein Z is a group

R7 R6 wherein R3, R4, R5, R6 and R7 are the same or different and are selected from H, C1-C4 alkyl, OR9, SR9, SOR9, SO2R9, CN, halo, CF3, OCF3, SO2NR9R10, CONR9R10, NR9R10, NHCOR10 and phenyl provided at least 2 of R3 to R7 are equal to H; wherein R9 and R10 are the same or different and are selected from H or CrC4 alkyl.

More preferably, Q1 is a group *-NH-Q2-Z, wherein Z is a group R3 . R4

R7 R6 wherein R3, R4, R5, R6 and R7 are the same or different and are selected from H, OH, CH3, OCH3, OCH2-CH3, SCH3, halo, CF3, provided at least 2 of R3 to R7 are equal to H.

Other preferred compounds of formula (1 ) are those wherein Q1 is a group *- NH-CH2-Z, wherein Z is a group

-Q3-Q4-Q5-Q6

Preferred compounds of formula (1 ) are those wherein Q3 is (CH2)t whe rein t is 0 and Q4 is -SO2NH- or C(=O)NH-.

Other preferred compounds of formula (1 ) are those wherein Q3 is (CH2: )t wherein t is 1 and Q4 is -NH-C(=O)- or -NH-C(=O)-NH-.

Preferably, Q5 is a bond, -CH2-, -(CH2)2-, -C(CHs)2-CH2-, -CH(CH3)-CH(OH)- or CH2-CH(CH3)-.

Preferably Q6 is R11

R15 R14 wherein R11, R12, R13, R14 and R15 are selected from H, d-C4 alkyl, phenyl, phenoxy OR16, SR16, halo, CF3, OCF3, COOR17, SO2NR16R17, CONR16R17, NHR16R17, NHCOR17, CH2-NHC(=O)NH-R17; and at least two of R11 to R15 represent H.

More preferably Q6 is

wherein R11, R12, R13, R14 and R15 are selected from H, C1-C4 alkyl, phenyl, phenoxy OR16, halo, CF3, OCF3; and at least two of R11 to R15 represent H.

In the above groups of compounds, the following substituents are particularly preferred: Q2 is a bond, -CH2-, -(CH2);.-, -(CH2)3-, or -C(CHs)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 Js CH3. n is O or 1. R1 is H and R2 is CH3 and n is O or 1. R1 is CH3, R2 is CH3 and n is O or 1.

The following compounds are preferred: 2-(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphenyl}- 2- hydroxyethyl)amino]-2-methylpropyl}phenyl)-A/-benzylacetamid e; 2-(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphenyl}- 2- hydroxyethyl)amino]-2-methylpropyl}phenyl)-Λ/-cyclopropylac etamide; 2-(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphenyl}- 2- hydroxyethyl)amino]-2-methylpropyl}phenyl)-/\/-[(1 R,2S)-2- (hydroxymethyl)cyclohexyl]acetamide; 2-(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphenyl}- 2- hydroxyethyl)amino]-2-methylpropyl}phenyl)-Λ/-(3-morpholin- 4- ylpropyl)acetamide; 2-(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphenyl}- 2- hydroxyethyl)amino]-2-methylpropyI}phenyl)-Λ/-(pyridin-2-yl methyl)acetamide; 2-(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphenyl}- 2- hydroxyethyI)amino]-2-mθthylpropyl}phenyl)-Λ/-(2-morpholin -4- ylθthyl)acetamide; 2-(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphenyl}- 2- hydroxyethyl)amino]-2-methylpropyl}phenyl)-A/-isopropylaceta mide; 2-(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphenyl}- 2- hydroxyethyl)amino]-2-methylpropyl}phenyl)-A/-(4-chlorobenzy l)acetamide; 2-(3-{2-[((2R)-2-{3-[(aminocarbony!)annino]-4-hydroxyphenyl} -2- hydroxyethyl)amino]-2-methylpropyl}phenyl)-A/-[2- (dimethylamino)ethyl]acetamide; 2-(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphenyI}- 2- hydroxyethyl)amino]-2-methylpropyl}phenyl)-/\/-[2- (diethylamino)ethyl]acetamide; 2-(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphenyl}- 2- hydroxyethyl)amino]-2-methylpropyl}phenyl)-Λ/-[3- (dimethylamino)propyl]acetamide; 2-(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphenyl}- 2- hydroxyethyl)amino]-2-methylpropyl}phenyl)-Λ/-pentylacetami de; 2-(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphenyl}- 2- hydroxyethyl)amino]-2-methylpropyl}phenyl)-/V-(2-pyrrolidin- 1-ylethyl)acetamide; 2-(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphenyl}- 2- hydroxyethyl)amino]-2-methylpropyl}phenyl)-A/-(2,4-dichlorob enzyl)acetamide; 2-(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphenyl}- 2- hydroxyethyl)amino]-2-methylpropyl}phenyl)-/V-(3,4-dichlorob enzyI)acetannide; 2-(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphenyl}- 2- hydroxyethyl)amino]-2-methylpropyl}phenyl)-A/-(4-methoxybenz yI)acetamicle; 2-(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphenyl}- 2- hydroxyethyl)amino]-2-methylpropyl}phenyl)-Λ/-(2-hydroxyeth yl)acetamide; 2-(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphenyl}- 2- hydroxyethyl)amino]-2-methylpropyl}phenyl)-/\/-propylacetami de; 2-(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphenyl}- 2- hydroxyethyl)amino]-2-methylpropyl}phenyl)-A/-(3-methoxyprop yl)acetamide; 2-(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphenyl}- 2- hydroxyethyl)amino]-2-methylpropyl}phenyl)-Λ/-cyclobutylace tamide; 2-(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphenyl}- 2- hydroxyethyl)amino]-2-methylpropyl}phenyl)-/\/-[(1 R)-1-(1- naphthyl)ethyl]acetamide; 2-(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphenyl}- 2- hydroxyethyl)amino]-2-methylpropyl}phenyl)-/V-2,3-dihydro-1 H-inden-1 - ylacetamide; 2-(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphenyl}- 2- hydroxyethyi)amino]-2-methylpropyl}phenyl)-A/-[2-(1-methylpy rrolidin-2- yl)ethyl]acetamide 2-(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphenyl}- 2- hydroxyethyl)amino]-2-methylpropyl}phenyl)-Λ/-(4-fluorobenz yl)acetamide; 2-(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphenyl}- 2- hydroxyethyl)amino]-2-methylpropyl}phenyl)-A/-(4-phenylbutyl )acetamide; 2-(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphenyl}- 2- hydroxyethyl)amino]-2-methylpropyl}phenyl)-/\/-(3-methoxyben zyl)acetamide; 2-(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphenyl}- 2- hydroxyethyl)amino]-2-methylpropyl}phenyl)-/V-(3-ethoxypropy l)acθtamide; 2-(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphθnyl} -2- hydroxyethyl)amino]-2-methylpropyl}phenyl)-Λ/-(3,4,5- trimethoxybenzyl)acetamide; 2-(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphenyl}- 2- hydroxyethyl)amino]-2-methylpropyl}phenyl)-A/-[4- (trifluoromethyl)benzyl]acetamide; 2-(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphenyl}- 2- hydroxyethyl)amino]-2-methylpropyl}phenyl)-A/-[2- (trifluoromethyl)benzyl]acetamide; 2-(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphenyl}- 2- hydroxyethyl)amino]-2-methylpropyl}phenyl)-A/-(3,5- dimethoxybenzyl)acetamide; 2-(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphenyl}- 2- hydroxyethyl)amino]-2-methylpropyl}phenyl)-A/-(2-phenoxyethy l)acetamide; 2-(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphenyI}- 2- hydroxyethyl)amino]-2-methylpropyl}phenyl)-/V-[(1 S)-2-hydroxy-1- methylethyljacetamide; 2-(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphenyl}- 2- hydroxyethyl)amino]-2-methylpropyl}phenyl)-Λ/-[(1 S)-1-(hydroxymethyl)-2- methylpropyljacetamide; 2-(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphenyl}- 2- hydroxyethyl)amino]-2-methylpropyl}phenyl)-/\/-[(1 S,2S)-1-(hydroxymethyl)-2- methylbutyl]acetamide; 2-(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphenyl}- 2- hydroxyethyl)amino]-2-methylpropyl}phenyl)-/V-[(1R)-1-benzyl -2- hydroxyethyl]acetamide; 2-(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphenyl}- 2- hydroxyethyl)amino]-2-methylpropyl}phenyl)-Λ/-[(1 R)-1 - (hydroxymethyl)propyl]acetamide; 2-(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphenyl}- 2- hydroxyethyl)amino]-2-methylpropyl}phenyl)-A/-[(1 S)-1-(hydroxymethyl)-2,2- dimethylpropyl]acetamide; 2-(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphenyl}- 2- hydroxyethyl)amino]-2-ιnethylpropyl}phenyl)-Λ/-[(1S)-2-cyc lohexyl-1- (hydroxymethyl)ethyl]acetamide; 2-(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphenyl}- 2- hydroxyethyl)amino]-2-methylpropyl}phenyl)-Λ/-[(1 S,2R)-2-hydroxy-2,3-dihydro- 1 H-inden-1 -yl]acetamide; 2-(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphenyl}- 2- hydroxyethyl)amino]-2-methylpropyl}phenyl)-Λ/-(2-propoxyeth yl)acetamide; 2-(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphenyl}- 2- hydroxyethyl)amino]-2-methylpropyl}phenyl)-A/-(4-hydroxycycl ohexyl)acetamide; 2-(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphenyl}- 2- hydroxyethy!)amino]-2-methylpropyl}phenyl)-A/-(3-propoxyprop yl)acetamide; 2-(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphenyl}- 2- hydroxyethyl)amino]-2-methylpropyl}phenyl)-Λ/-ethyI-Λ/-(2- hydroxyethyl)acetamide; 1-[(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphenyl} -2- hydroxyethyl)amino]-2-methylpropyl}phenyl)acetyl]piperidine- 4-carboxamide; Λ/-(5-{(1 R)-2-[(2-{3-[2-(4-acetylpiperazin-1 -yl)-2-oxoethyl]phenyl}-1 ,1 - dimethylethyl)amino]-1-hydroxyethyl}-2-hydroxyphenyl)urea; A/-(5-{(1 R)-2-[(2-{3-[2-(3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl] phenyl}-1 ,1- dimethylethyl)amino]-1-hydroxyethyl}-2-hydroxyphenyl)urea; 2-(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphenyl}- 2- hydroxyethyl)amino]-2-methylpropyl}phenyl)-A/-benzyl-/\/-met hylacetamide; A/-[2-hydroxy-5-((1 R)-1 -hydroxy-2-{[2-(3-{2-[4-(2-hydroxyethyl)piperazin-1 -yl]-2- oxoethyl}phenyl)-1 ,1-dimethylethyl]amino}ethyl)phenyl]urea; Λ/-[5-((1 R)-2-{[2-(3-{2-[4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl]- 2- oxoethyl}phenyl)-1 ,1-dimethylethyl]amino}-1-hydroxyethyl)-2- hydroxyphenyljurea; /V-(5-{(1R)-2-[(1 ,1-dimethyl-2-{3-[2-(4-methylpiperazin-1-yl)-2- oxoethyI]phenyl}ethyl)amino]-1-hydroxyethyl}-2-hydroxyphenyl )urea; 2-(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphenyl}- 2- hydroxyethyI)amino]-2-methylpropyl}phenyl)-Λ/-methyl-Λ/-(2 - phenylethyl)acetamide; Λ/-(5-{(1 R)-2-[(1 ,1-dimethyl-2-{3-[2-oxo-2-(4-pyridin-2-ylpiperazin-1- yl)ethyl]phenyl}ethyl)amino]-1-hydroxyethyl}-2-hydroxyphenyl )urea; 2-(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphenyl}- 2- hydroxyethyl)amino]-2-methylpropyl}phenyl)-/V-[3-(dimethylam ino)propyl]-Λ/- methylacetamide; 2-(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphenyl}- 2- hydroxyethyl)amino]-2-methylpropyl}phenyl)-Λ/-(2-hydroxyeth yl)-Λ/- propylacetamide; 2-(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphenyl}- 2- hydroxyethyI)amino]-2-methylpropyl}phenyl)-A/-[2-(diethylami no)ethyl]-/\/- methylacetamide; Λ/-(5-{(1R)-2-[(1 ,1-dimethyl-2-{3-[2-(4-methyI-1 ,4-diazepan-1-yl)-2- oxoethyl]phenyl}ethyl)amino]-1-hydroxyethyl}-2-hydroxyphenyl )urea; /V-{5-[(1R)-2-({1 ,1-dimethyl-2-[3-(2-morpholin-4-yl-2- oxoethyl)phenyl]ethyl}amino)-1-hydroxyethyl]-2-hydroxyphenyl }urea; 2-(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphenyl}- 2- hydroxyethyl)amino]-2-methylpropyl}phenyl)-Λ/-methyl-Λ/-[( 1 S)-1 - phenylethyl]acetamide; Λ/-{5-[(1 R)-2-({1 ,1-dimethyl-2-[3-(2-oxo-2-piperidin-1- ylethyl)phenyl]ethyl}amino)-1-hydroxyethyl]-2-hydroxyphenyl} urea; Λ/-[2-hydroxy-5-((1R)-1-hydroxy-2-{[2-(3-{2-[(3R)-3-hydroxy pyrrolidin-1-yl]-2- oxoethyl}phenyl)-1 ,1-dimethylethyl]amino}ethyl)phenyl]urea; A/-[2-hydroxy-5-((1 R)-1-hydroxy-2-{[2-(3-{2-[(3R)-3-hydroxypiperidin-1-yl]-2- oxoethyl}phenyl)-1 ,1-dimethylethyl]amino}ethyl)phenyl]urea; Λ/-(5-{(1 R)-2-[(2-{3-[2-(4-acetyl-1 ,4-diazepan-1-yl)-2-oxoethyI]phenyl}-1 ,1- dimethyIethyl)amino]-1-hydroxyethyl}-2-hydroxyphenyl)urea; Λ/-[2-hydroxy-5-((1 R)-1 -hydroxy-2-{[2-(3-{2-[4-(hydroxymethyl)piperidin-1 -y!]-2- oxoethyl}phenyl)-1 ,1-dimethylethyl]amino}ethyl)phenyl]urea; A/-{1-[(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphe nyl}-2- hydroxyethyl)amino]-2-methylpropyl}phenyl)acetyl]pyrrolidin- 3-yl}-Λ/- methylacetamide; 2-(3-{2-[((2R)-2-{3-[(aminocarbonyI)amino]-4-hydroxyphenyI}- 2- hydroxyethyl)amino]-2-methylpropyl}phenyl)-Λ/-(2-methoxyeth yl)-Λ/- propylacetamide; 2-(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphenyl}- 2- hydroxyethyl)amino]-2-methylpropyl}phenyl)-Λ/-ethyl-Λ/-(2- methoxyethyl)acetamide; 2-(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphenyl}- 2- hydroxyethyl)amino]-2-methylpropyl}phenyl)-/V-[3-(dimethylam ino)-2,2- dimethylpropyl]acetamide; 2-(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphenyl}- 2- hydroxyethyI)amino]-2-methylpropyl}phenyl)-Λ/-[3-fluoro-5- (trifluoromethyl)benzyl]acetamide; 2-(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphenyl}- 2- hydroxyethyl)amino]-2-methylpropyl}phenyl)-/V-f(1 S)-1-(hydroxymethyl)-3- methylbutyl]acetamide; 2-(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphenyl}- 2- hydroxyethyl)amino]-2-methylpropyl}phenyl)-Λ/-[(1 S)-2-hydroxy-1 - phenylethyl]acetamide; 2-(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphenyl}- 2- hydroxyethyl)amino]-2-methyIpropyl}phenyl)-A/,A/-diethylacet amide; 2-(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphenyl}- 2- hydroxyethyl)amino]-2-methylpropyl}phenyl)-A/-1H-pyrazol-5-y lacetamide; 2-(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphenyl}- 2- hydroxyethyl)amino]-2-methylpropyl}phenyl)-/V-(5-methyl-1H-p yrazol-3- yl)acetamide; 2-(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphenyl}- 2- hydroxyethyl)amino]-2-methylpropyl}phenyl)-/\/-(cyclohexylme thyl)acetamide; ethyl 4-[(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphenyl} -2- hydroxyethyOaminol^-methylpropylJphenyOacetyOpiperazine-i-ca rboxylate; 2-(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphenyl}- 2- hydroxyethyl)amino]-2-methylpropyl}phenyl)-A/-(5-chloropyrid in-2-yl)acetamide; 2-(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphenyl}- 2- hydroxyethyl)amino]-2-methylpropyl}phenyl)-/\/-(6-methylpyri din-2-yl)acetamide; 2-(3-{2-[((2/:?)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphenyl }-2- hydroxyethyl)amino]-2-methylpropyl}phenyl)-A/-(3-methylpyrid in-2-yl)acetamide; 2-(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydr0xyphenyl}- 2- hydroxyethyl)amino]-2-methylpropyl}phenyl)-Λ/-isoquinolin-1 -ylacetamide; 2-(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphenyl}- 2- hydroxyethyl)amino]-2-methylpropyl}phenyl)-Λ/-(4,6-dimethyl pyridin-2- yl)acetamide; 2-(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphenyl}- 2- hydroxyethyl)amino]-2-methylpropyl}phenyl)-Λ/-(2-methoxyben zyl)acetamide; 2-(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphenyl}- 2- hydroxyethyl)amino]-2-methylpropyl}phenyl)-A/-[(1 S)-1-benzyi-2- hydroxyethyl]acetamide; 2-(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphenyI}- 2- hydroxyθthyl)amino]-2-methylpropyl}phenyl)-Λ/-(1-ethyl-1/- /-pyrazol-5- yl)acetamide; 2-(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphenyl}- 2- hydroxyethyl)amino]-2-methylpropyl}phenyl)-/V-(1 ,3-dimethyl-1 H-pyrazol-5- yl)acetamide; 2-(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphenyl}- 2- hydroxyethyl)amino]-2-methylpropyl}phenyl)-A/-(3-fluorobenzy l)acetamide; 1-[(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphenyl} -2- hydroxyethyl)amino]-2-methylpropyl}phenyl)acetyl]-L-prolinam ide; Λ/-(5-{(1 R)-2-[(2-{3-[2-(5-amino-3-fe/if-butyl-1 H-pyrazol-1 -yl)-2-oxoethyl]phenyl}- 1 ,1-dimethylethyl)amino]-1-hydroxyethyl}-2-hydroxyphenyl)urea ; 2-(3-{2-[((2R)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphenyl}- 2- hydroxyethyl)amino]-2-methylpropyl}phenyl)-/V-[(1 S)-1-phenylethyl]acetamide, Λ/-(5-{(1 R)-2-[(2-{3-[2-(1 ,4-dioxa-8-azaspiro[4. 5]dec-8-yi)-2-oxoethyl]phenyl}- 1 ,1-dimethyIethyl)amino]-1-hydroxyethyl}-2-hydroxyphenyl)urea , Λ/-benzyl-2-[3-(2-{[2-hydroxy-2-(4-hydroxyphenyl)ethyl]amin o}-2- methylpropyl)phenyl]acetamide; Λ/-cyclopropyl-2-[3-(2-{[2-hydroxy-2-(4-hydroxyphenyl)ethyl ]amino}-2- methylpropyl)phenyl]acetamide; 2-[3-(2-{[2-hydroxy-2-(4-hydroxyphenyl)θthyl]amino}-2-methy lpropyl)phenyl]-Λ/- [(1R,2S)-2-(hydroxymethyl)cyclohexyl]acetamide; 2-[3-(2-{[2-hydroxy-2-(4-hydroxyphenyl)ethyl]amino}-2-methyl propyl)phenyl]-/\/- (3-morpholin-4-ylpropyl)acetamide; 2-[3-(2-{[2-hydroxy-2-(4-hydroxyphenyl)ethyl]amino}-2-methyl propyl)phenyl]-/V- (pyridin-2-ylmethyl)acetamide; 2-[3-(2-{[2-hydroxy-2-(4-hydroxyphenyl)ethyl]amino}-2-methyl propyl)phenyl]-A/- (2-morpholin-4-ylethyl)acetamide; 2-[3-(2-{[2-hydroxy-2-(4-hydroxyphenyl)ethyl]amino}-2-methyl propyl)phenyl]-Λ/- isopropylacetamide; A/-(4-chlorobenzyI)-2-[3-(2-{[2-hydroxy-2-(4-hydroxyphenyl)e thyl]amino}-2- methylpropyl)phenyl]acetamide; /V-[2-(dimethylamino)ethyl]-2-[3-(2-{[2-hydroxy-2-(4- hydroxyphenyl)ethyl]amino}-2-methylpropyl)phenyl]acetamide; /V-[2-(diethylamino)ethyl]-2-[3-(2-{[2-hydroxy-2-(4-hydroxyp henyl)ethyl]amino}- 2-methylpropyl)phenyl]acetamide; Λ/-[3-(dimethylamino)propyl]-2-[3-(2-{[2-hydroxy-2-(4- hydroxyphenyl)ethyl]amino}-2-methylpropyl)phenyl]acetamide; 2-[3-(2-{[2-hydroxy-2-(4-hydroxyphenyl)ethyl]amino}-2-methyl propyl)phenyI]-A/- pentylacetamide; 2-[3-(2-{[2-hydroxy-2-(4-hydroxyphenyI)ethyl]amino}-2-methyl propyl)phenyl]-/V- (2-pyrrolidin-1 -ylethyl)acetamide; /V-(2,4-dichlorobenzyl)-2-[3-(2-{[2-hydroxy-2-(4-hydroxyphen yl)ethyl]amino}-2- methylpropyl)phenyl]acetamide; A/-(3,4-dichlorobenzyl)-2-[3-(2-{[2-hydroxy-2-(4-hydroxyphen yl)ethyl]amino}-2- methylpropyl)phenyl]acetamide; 2-[3-(2-{[2-hydroxy-2-(4-hydroxyphenyl)ethyl]amino}-2-methyi propyl)phenyl]-/\/- (4-methoxybenzyl)acetamide; Λ/-(2-hydroxyethyl)-2-[3-(2-{[2-hydroxy-2-(4-hydroxyphenyl) ethyi]amino}-2- methylpropyl)phenyl]acetamide; 2-[3-(2-{[2-hydroxy-2-(4-hydroxyphenyl)ethyl]amino}-2-methyl propyl)phenyl]-Λ/- propylacetamide; 2-[3-(2-{[2-hydroxy-2-(4-hydroxyphenyl)ethyl]amino}-2-methyl propyl)phenyl]-Λ/- (3-mθthoxypropyl)acetamide; Λ/-cyclobutyl-2-[3-(2-{[2-hydroxy-2-(4-hydroxyphenyl)ethyl] amino}-2- methylpropyl)phenyl]acetamide; 2-[3-(2-{[2-hydroxy-2-(4-hydroxyphenyl)ethyl]amino}-2-methyl propyl)phenyl]-Λ/- [(1R)-1-(1-naphthyl)ethyl]acetamide; Λ/-2,3-dihydro-1 H-inden-1 -yl-2-[3-(2-{[2-hydroxy-2-(4- hydroxyphenyl)ethyl]amino}-2-methylpropyl)phenyl]acetamide; 2-[3-(2-{[2-hydroxy-2-(4-hydroxyphenyl)ethyl]amino}-2-mθthy lpropyl)phenyl]-Λ/- [2-(1-methylpyrrolidin-2-yl)ethyl]acetamide; Λ/-(4-fluorobenzyl)-2-[3-(2-{[2-hydroxy-2-(4-hydroxyphθnyl )ethyl]amino}-2- methylpropyl)phenyl]acetamide; 2-[3-(2-{[2-hydroxy-2-(4-hydroxyphenyl)ethyl]amino}-2-methyl propyl)phenyl]-A/- (4-phenylbutyl)acetamide; 2-[3-(2-{[2-hydroxy-2-(4-hydroxyphenyl)ethyl]amino}-2-methyl propyl)phenyl]-Λ/- (3-methoxybenzyl)acetamide; Λ/-(3-θthoxypropyl)-2-[3-(2-{[2-hydroxy-2-(4-hydroxyphenyl )ethyl]amino}-2- methylpropyl)phenyl3acetamide; 2-[3-(2-{[2-hydroxy-2-(4-hydroxyphenyl)ethyl]amino}-2-methyl propyl)phenyl]-A/- (3,4,5-trimethoxybenzyl)acetamide; 2-[3-(2-{[2-hydroxy-2-(4-hydroxyphenyl)ethyl]amino}-2-methyl propyl)phenyl]-Λ/- [4-(trifluoromethyl)benzyl]acetamide; 2-[3-(2-{[2-hydroxy-2-(4-hydroxyphenyl)ethyl]amino}-2-methyl propyl)phenyl]-Λ/- [2-(trifluoromethyl)benzyl]acetamide; Λ/-(3,5-dimethoxybenzyl)-2-[3-(2-{[2-hydroxy-2-(4-hydroxyph enyl)θthyl]amino}- 2-methylpropyl)phenyl]acetamide; 2-[3-(2-{[2-hydroxy-2-(4-hydroxyphenyl)ethyl]amino}-2-methyi propyl)phenyl]-Λ/- (2-phenoxyethyl)acetamide; 2-[3-(2-{[2-hydroxy-2-(4-hydroxyphenyl)ethyl]amino}-2-methyl propyl)phenyl]-Λ/- [(1 S)-2-hydroxy-1 -methylethyl]acetamide; 2-[3-(2-{[2-hydroxy-2-(4-hydroxyphenyl)ethyl]amino}-2-methyl propyl)phenyl]-Λ/- [(1 S)-1 -(hydroxymethyl)-2-methylpropyl]acetamide; 2-[3-(2-{[2-hydroxy-2-(4-hydroxyphenyl)ethyl]amino}-2-methyl propyl)phenyl]-/\/- [(1 S,2S)-1 -(hydroxymethyl)-2-methylbutyl]acetamide; Λ/-[(1 R)- 1 -benzyl-2-hydroxyethyl]-2-[3-(2-{[2-hydroxy-2-(4- hydroxyphenyl)ethyI]amino}-2-methylpropyl)phenyl]acetamicle; 2-[3-(2-{[2-hydroxy-2-(4-hydroxyphenyl)ethyl]amino}-2-methyl propyl)phenyl]-A/- [(1 R)- 1 -(hydroxymethyl)propyl]acetamide; 2-[3-(2-{[2-hydroxy-2-(4-hydroxyphenyl)ethyl]amino}-2-methyl propyI)phenyl]-Λ/- [(1S)-1-(hydroxymethyl)-2,2-dimethylpropyl]acetamide; Λ/-[(1 S)-2-cyclohexyI-1-(hydroxymethyl)θthyl]-2-[3-(2-{[2-hydroxy -2-(4- hydroxyphenyl)ethyl]amino}-2-methylpropyl)phenyl]acetamide; Λ/-[(1 S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-y[]-2-[3-(2-{[2-hydro xy-2-(4- hydroxyphenyl)ethyl]amino}-2-methylpropyl)phenyl]acetamide; 2-[3-(2-{[2-hydroxy-2-(4-hydroxyphenyl)ethyl]amino}-2-methyl propyl)phenyl]-Λ/- (2-propoxyethyl)acetamide; Λ/-(4-hydroxycyclohexyl)-2-[3-(2-{[2-hydroxy-2-(4-hydroxyph enyl)ethyl]amino}-2- methylpropyl)phenyl]acetamide; 2-[3-(2-{[2-hydroxy-2-(4-hydroxyphenyl)ethyl]amino}-2-methyl propyl)phenyl]-A/- (3-propoxypropyl)acetamide; Λ/-ethyi-Λ/-(2-hydroxyethyl)-2-[3-(2-{[2-hydroxy-2-(4- hydroxyphenyl)ethyl]amino}-2-methylpropyl)phenyl]acetamide; 1-{[3-(2-{[2-hydroxy-2-(4-hydroxyphenyl)ethyl]arnino}-2- methylpropyl)phenyl]acetyl}piperidine-4-carboxamide; 4-{2-[(2-{3-[2-(4-acetylpiperazin-1-yl)-2-oxoethyl]phenyl}-1 ,1- dimethylethyl)amino]-1-hydroxyethyl}phenol; 4-{2-[(2-{3-[2-(3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl] phenyl}-1 ,1- dimethylethy1)amino]-1-hydroxyethyl}phenol; A/-benzyl-2-[3-(2-{t2-hydroxy-2-(4-hydroxyphenyI)ethyI]amino }-2- methylpropyl)phenyl]-A/-methylacetamide; 4-(1-hydroxy-2-{[2-(3-{2-[4-(2-hydroxyethyl)piperazin-1-yl]- 2-oxoethyl}phenyi)- 1 ,1-dimethylethyl]amino}ethyl)phenol; 4-(4-chlorophenyl)-1-{[3-(2-{[2-hydroxy-2-(4-hydroxyphenyl)e thyl]amino}-2- methylpropyl)phenyl]acetyl}piperidin-4-ol; 4-{2-[(1 ,1-dimethyl-2-{3-[2-(4-methylpiperazin-1-yl)-2- oxoethyl]phenyl}ethyl)amino]-1-hydroxyethyl}phenol; 2-[3-(2-{[2-hydroxy-2-(4-hydroxyphenyl)ethyl]amino}-2-methyl propyl)phenyl]-/\/- methyl-A/-(2-phenylethyl)acetamide; 4-{2-[(1 ,1-dim6thyl-2-{3-[2-oxo-2-(4-pyridin-2-ylpiperazin-1- yl)ethyl]phenyl}ethyl)amino]-1-hydroxyethyl}phenol; Λ/-[3-(dimethylamino)propyl]-2-[3-(2-{[2-hydroxy-2-(4- hydroxyphenyl)ethyl]amino}-2-methylpropyl)phenyl]-/V-methyla cetamide; Λ/-(2-hydroxyethyl)-2-[3-(2-{[2-hydroxy-2-(4-hydroxyphenyl) ethyl]amino}-2- methylpropyl)phenyl]-/V-propylacetamide; N-[2-(diethylamino)ethyl]-2-[3-(2-{[2-hydroxy-2-(4-hydroxyph enyl)ethyl]amino}- 2-methylpropyl)phenyl]-Λ/-methylacetamide; 4-{2-[(1 ,1-dimethyl-2-{3-[2-(4-methyl-1 ,4-diazepan-1-yl)-2- oxoethyl]phenyl}ethyl)amino]-1-hydroxyethyl}phenol; 4-[2-({1 , 1 -dimethyl-2-[3-(2-morpholin-4-yl-2-oxoethyl)phenyl]ethyl}ami no)-1 - hydroxyethyljphenol; 2-[3-(2-{[2-hydroxy-2-(4-hydroxyphenyl)ethyl]amino}-2-methyl propyl)phenyl]-/V- methyl-Λ/-[(1 S)-I -phenylethyl]acetamide; 4-[2-({1 ,1-dimethyl-2-[3-(2-oxo-2-piperidin-1-ylethyl)phenyI]ethyI}a mino)-1- hydroxyethyOphenol; (3f?)-1-{[3-(2-{[2-hydroxy-2-(4-hydroxyphenyl)ethyl]amino}-2 - methylpropyOphenyOacetylJpyrrolidin-S-ol; (3R)-1-{[3-(2-{[2-hydroxy-2-(4-hydroxyphenyl)ethyl]amino}-2- methyIpropyl)phenyl]acetyl}piperidin-3-ol; 4-{2-[(2-{3-[2-(4-acetyl-1 ,4-diazepan-1-yl)-2-oxoethyl]phenyl}-1 ,1- dimethylethyl)amino]-1 -hydroxyethyljphenol; 4-(1-hydroxy-2-{[2-(3-{2-[4-(hydroxymethyl)piperidin-1-yl]-2 -oxoethyi}phenyl)- 1 , 1 -dimethylethyl]amino}ethyl)phenol; Λ/-(1-{[3-(2-{[2-hydroxy-2-(4-hydroxyphenyl)ethyl]amino}-2- methylpropyl)phenyl]acetyl}pyrrolidin-3-yl)-Λ/-methylacetam ide; 2-[3-(2-{[2-hydroxy-2-(4-hydroxyphenyl)ethyl]amino}-2-methyl propyl)phenyl]-A/- (2-methoxyethyl)-Λ/-propylacetamide; Λ/-ethyl-2-[3-(2-{[2-hydroxy-2-(4-hydroxyphenyl)ethyl]amino }-2- methylpropyl)phenyl]-A/-(2-methoxyethyl)acetamide; A/-[3-(dimethylamino)-2,2-dimethylpropyl]-2-[3-(2-{[2-hydrox y-2-(4- hydroxyphenyl)ethiyl]amino}-2-methylpropyl)phenyl]acetamide; /V-[3-fluoro-5-(trifluoromethyl)benzyl]-2-[3-(2-{[2-hydroxy- 2-(4- hydroxyphenyl)ethyl]amino}-2-methylpropyl)phenyl]acetamide; 2-[3-(2-{[2-hydroxy-2-(4-hydroxyphenyl)ethyl]amino}-2-methyl propyl)phenyl]-/V- [(1 S)- 1 -(hydroxymethyl)-3-methylbutyl]acetamide; 2-[3-(2-{[2-hydroxy-2-(4-hydroxyphenyl)ethyl]amino}-2-methyl propyl)phenyl]-Λ/- [(1 S)-2-hydroxy-1 -phenylethyl]acetamide; A/,/'\/-di6thyl-2-[3-(2-{[2-hydroxy-2-(4-hydroxyphenyl)ethyl ]amino}-2- methylpropyl)phenyl]acetamide; 2-[3-(2-{[2-hydroxy-2-(4-hydroxyphenyl)ethyl]amino}-2-methyl propyl)phenyl]-Λ/- 1 /-/-pyrazol-5-ylacetamide; 2-[3-(2-{[2-hydroxy-2-(4-hydroxyphenyI)ethyl]amino}-2-methyl propyl)phenyl]-A/- (5-methyl-1H-pyrazol-3-yl)acetamide; A/-(cyclohexylmethyl)-2-[3-(2-{[2-hydroxy-2-(4-hydroxyphenyl )ethyl]amino}-2- methylpropyl)phenyl]acetamide; ethyl 4-{[3-(2-{[2-hydroxy-2-(4-hydroxyphenyl)ethyl]amino}-2- methylpropyl)phenyl]acetyl}piperazine-1-carboxylate; Λ/-(5-chloropyridin-2-y!)-2-[3-(2-{[2-hydroxy-2-(4-hydroxyp henyl)ethyl]amino}-2- methylpropyl)phenyl]acetamide; 2-[3-(2-{[2-hydroxy-2-(4-hydroxyphenyl)ethyl]amino}-2-methyl propyl)phenyl]-A/- (6-methylpyridin-2-yl)acetamide; 2-[3-(2-{[2-hydroxy-2-(4-hydroxyphenyl)ethyl]amino}-2-methyl propyl)phenyl]-/V- (3-methylpyridin-2-yl)acetamide; 2-[3-(2-{[2-hydroxy-2-(4-hydroxyphenyl)ethyl]amino}-2-methyl propyl)phenyl]-/V- isoquinolin-1 -ylacetamide; Λ/-(4,6-dimethylpyridin-2-yl)-2-[3-(2-{[2-hydroxy-2-(4- hydroxyphenyl)ethyl]amino}-2-methylpropyl)phenyl]acetamide; 2-[3-(2-{[2-hydroxy-2-(4-hydroxyphenyl)ethyl]amino}-2-methyl propyl)phenyI]-Λ/- (2-methoxybenzyl)acetamide; Λ/-[(1 S)-1 -benzyl-2-hydroxyethyl]-2-[3-(2-{[2-hydroxy-2-(4- hydroxyphenyl)ethyl]amino}-2-methylpropyl)phenyl]acetamide; Λ/-(1 -ethyl-1 H-pyrazol-5-yl)-2-[3-(2-{[2-h>/droxy-2-(4- hydroxyphenyl)ethyl]amino}-2-methylpro pyl)phenyl]acetamide; Λ/-(1 ,3-dimethyl-1 H-pyrazol-5-yl)-2-[3-(2-{[2-hydroxy-2-(4- hydroxyphθnyl)ethyl]amino}-2-mθthylpro pyl)phenyl]acθtamide; Λ/-(3-fluorobenzyl)-2-[3-(2-{[2-hydroxy-2-(4-hydroxyphenyl) ethyl]amino}-2- methylpropyl)phenyl]acetamide; 1 -{[3-(2-{[2-hydroxy-2-(4-hydroxyphenyI )ethyl]amino}-2- methylpropyl)phenyl]acetyl}-L-prolinamide; Λ/-(3-terf-butyl-1H-pyrazol-5-yl)-2-[3-(2-{[2-hydroxy-2-(4- hydroxyphenyl)ethyl]amino}-2-methylprα> pyl)phenyl]acetamide; 2-[3-(2-{[2-hydroxy-2-(4-hydroxyphenyl)ethyl]amino}-2-methyl propyl)phenyl]-N- [(1 S)- 1 -phenylethyl]acetamide; and, 4-{2-[(2-{3-[2-(1 ,4-dioxa-8-azaspiro[4. 5]dec-8-yl)-2-oxoethyl]phenyl}-1 ,1 - dimethylethyl)amino]-1-hydroxyethyl}phenol.

The following compounds are particularly preferred: 5-{(2R)-2-[((2f?)-2-Hydroxy-2-{4-hydroxy-3-[(methylsuIfonyl) amino]phenyl}ethyl)amino]propyl}-Λ/-[3-riydroxy-5-(trifluor omethyl) benzyl]-1H- indoIe-2-carboxamide; N-(3,4-Dichloro-benzyl)-2-(3-{2-[2-hydroxy-2-(4-hydroxy-3-ur eido-phenyl)- ethylamino]-2-methyl-propyl}-phenyl)-acetamide; 2-(3-{2-[2-Hydroxy-2-(4-hydroxy-3-ureido-phenyl)-ethylamino] -2-methyl-propyl}- phenyl)-N-(4-phenyl-butyl)-acetamide; N-(4-Chloro-benzyl)-2-(3-{2-[2-hydroxy-2-(4-hydroxy-3-ureido -phenyl)- ethy!arnino]-2-methyl-propyl}-phenyl)-acetamide; N-(2,4-Dichloro-benzyl)-2-(3-{2-[2-hydroxy-2-(4-hydroxy-3-ur eido-phenyl)- ethyIamino]-2-methyl-propyl}-phenyl)-acetamide; 2-(3-{2-[2-Hydroxy-2-(4-hydroxy-3-ureido-phenyl)-ethylamino] -2-methyl-propyl}- phenyl)-N-(1 -naphthalen-1-yl-ethyl)-acetamide; 2-(3-{2-[2-Hydroxy-2-(4-hydroxy-3-ureido-phenyl)-ethylamino] -2-methyl-propyl}- phenyl)-N-(4-methoxy-benzyl)-acetamide; 2-(3-{2-[2-Hydroxy-2-(4-hydroxy-3-ureido-phenyl)-ethylamino] -2-methyl-propyl}- phenyl)-N-(3,4,5-trimethoxy-benzyl)-acetamide; 2-(3-{2-[2-Hydroxy-2-(4-hydroxy-3-ureido-phenyl)-ethylamino] -2-methyl-propyl}- phenyl)-N-(3,4,5-trimethoxy-benzyl)-acetamide; 2-(3-{2-[2-Hydroxy-2-(4-hydroxy-3-ureido-phenyl)-ethylamino] -2-methyl-propyi}- phenyl)-N-(3-methoxy-benzyl)-acetamide; N-(4-Fluoro-benzyl)-2-(3-{2-[2-hydroxy-2-(4-hydroxy-3-ureido -phenyl)- ethylamino]-2-methyl-propyl}-phenyl)-acetamide; 2-(3-{2-[2-Hydroxy-2-(4-hydroxy-3-ureido-phenyl)-ethylamino] -2-methyl-propyl}- phenyl)-N-(4-trifluoromethyl-benzyl)-acetamide; N-(3,5-Dimethoxy-benzyl)-2-(3-{2-[2-hydroxy-2-(4-hydroxy-3-u reido-pheny!)" ethylamino]-2-methyl-propyl}-phenyl)-acetamide; 2-(3-{2-[2-Hydroxy-2-(4-hydroxy-3-ureido-phenyl)-ethylamino] -2-methyl-propyl}- pheny!)-N-(2-trifluoromethyl-benzyl)-acetamide; 2-(3-{2-[2-Hydroxy-2-(4-hydroxy-3-ureido-phenyl)-ethylamino] -2-methyl-propyl}- phenyl)-N-(2-hydroxy-indan-1-yl)-acetamide; (5-{2-[2-(3-{2-[4-(4-Chloro-phenyl)-4-hydroxy-piperidin-1 -yl]-2-oxo-ethyl}- phenyl)-1 ,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-2-hydroxy-phenyl)-u rea; 2-(3-{2-[2-Hydroxy-2-(4-hydroxy-3-ureido-phenyl)-ethylamino] -2-methyl-propyl}- phenyl)-N-methyl-N-phenethyl-acetamide; {5-[2-(2-{3-[2-(3,4-Dihydro-1 H-isoquinolin-2-yl)-2-oxo-ethyl]-phenyl}-1 ,1- dimethyI-ethylamino)-1-hydroxy-ethyl]-2-hydroxy-phenyl}-urea ; N-Benzyl-2-(3-{2-[2-hydroxy-2-(4-hydroxy-3-ureido-phenyl)-et hylamino]-2- methyl-propyl}-phenyl)-N-methyl-acetamide; {5-[2-(1 ,1-Dimethyl-2-{3-[2-oxo-2-(4-pyridin-2-yl-piperazin-1-yl)-et hyi]-phenyl}- ethylamino)-1-hydroxy-ethyl]-2-hydroxy-phenyl}-urea; {2-Hydroxy-5-[1-hydroxy-2-(2-{3-[2-(4-hydroxymethyl-piperidi n-1-yl)-2-oxo- ethyl]-phenyl}-1 ,1-dimethyl-ethylamino)-ethyl]-phenyl}-urea; 2-(3-{2-[2-Hydroxy-2-(4-hydroxy-3-ureido-phenyl)-ethyIamino] -2-methyl-propyl}- phenyl)-N-methyl-N-(1-phenyl-ethyl)-acetamide; 2-(3-{2-[2-Hydroxy-2-(4-hydroxy-3-ureido-phenyl)-ethylamino] -2-methyl-propyl}- phenyl)-N-(2-hydroxy-1 -phenyl-ethyl)-acθtamide; N-(3-FIuoro-5-trifluoromethyl-benzyl)-2-(3-{2-[2-hydroxy-2-( 4-hydroxy-3-ureido- phenyl)-ethylamino]-2-methyl-propyl}-phenyl)-acetamide; N-(4,6-Dimethy!-pyriciin-2-yI)-2-(3-{2-[2-hyclroxy-2-(4-hydr ox^-3-ureiclo-phenyl)- ethylamino]-2-methyl-propyl}-phenyl)-acetamide; 2-(3-{2-[2-Hydroxy-2-(4-hydroxy-3-ureido-phenyl)-ethylamino] -2-methyl-propyl}- phenyl)-N-(5-propyl-1 H-pyrazol-3-yl)-acetamide; N-(3-Fluoro-benzyI)-2-(3-{2-[2-hydroxy-2-(4-hydroxy-3-ureido -phenyl)- θthylamino]-2-methyl-propyl}-phenyl)-acetamide; 2-(3-{2-[2-Hydroxy-2-(4-hydroxy-3-ureido-phenyl)-ethylamino] -2-methyl-propyl}- phenyl)-N-(2-methoxy-benzyl)-acetamide; N-(5-tert-Butyl-2H-pyrazol-3-yl)-2-(3-{2-[2-hydroxy-2-(4-hyd roxy-3-ureido- phenyl)-ethylamino]-2-methyl-propyl}-phenyl)-acetamide; N-Benzyl-2-(3-{2-[2-hydroxy-2-(4-hydroxy-phenyl)-ethylamiÏ€o ]-2-methyl-propyl}- phenyl)acetamide; 2-(3-{2-[2-Hydroxy-2-(4-hydroxy-phenyl)-ethylamino]-2-metl-Î ¹yl-propyl}-phenyl)- 1 -(4-pyridin-2-yl-piperazin-1 -yl)-ethanone; 2-(3-{2-[2-Hydroxy-2-(4-hydroxy-phenyl)-ethylamino]-2-methiy l-propyl}-phenyl)- N-(1-naphthalen-1 -yl-ethyl)-acetamide; 2-(3-{2-[2-Hydroxy-2-(4-hydroxy-phenyl)-ethylamino]-2-methι yl-propyl}-phenyl)- N-pyridin-2-ylmethyl-acetamide; 2-(3-{2-[2-Hydroxy-2-(4-hydroxy-phenyl)-ethylamino]-2-methyl -propyl}-phenyl)- N-pyridin-2-ylmethyl-acetamide; N-(4-Fluoro-benzyl)-2-(3-{2-[2-hydroxy-2-(4-hydroxy-phenyl&g t;-ethylamino]-2- methyl-propyl}-phenyl)-acetamide; 2-(3-{2-[2-Hydroxy-2-(4-hydroxy-phenyl)-ethylamino]-2-methyl -propyl}-phenyl)- N-methyl-N-(1-phenyl-ethyl)-acetamide; 2-(3-{2-[2-Hydroxy-2-(4-hydroxy-phenyl)-ethylamino]-2-methyl -propyi}-phenyi)- N-(2-methoxy-benzyl)-acetamide; 2-(3-{2-[2-Hydroxy-2-(4-hydroxy-phenyl)-ethylamino]-2-methyl -propyl}-phenyl)- N-(3-methoxy-benzyl)-acetamide; N-(4-Chloro-benzyl)-2-(3-{2-[2-hydroxy-2-(4-hydroxy-phenyl >ethylamino]-2- methyl-propyl}-phenyl)-acetamide; 1-(3,4-Dihydro-1 H-isoquinolin-2-yl)-2-(3-{2-[2-hydroxy-2-(4-hydroxy-phenyl)- ethylamino]-2-methyl-propyl}-phenyl)-ethanone; N-(3-Fluoro-benzyl)-2-(3-{2-[2-hydroxy-2-(4-hydroxy-phenyl)- ethylamino]-2- methyl-propyl}-phenyl)-acetamide; 2-(3-{2-[2-Hydroxy-2-(4-hydroxy-phenyl)-ethylamino]-2-methyl -propyl}-phenyl)- N-methyl-N-phenethyl-acetamide; N-(5-tert-Butyl-2H-pyrazol-3-yl)-2-(3-{2-[2-hydroxy-2-(4-hyd roxy-phenyl)- ethylamino]-2-methyl-propyl}-phenyl)-acetamide, and, 3-{2-[(2R)-2-(3-AcetyIamino-4-hydroxyphenyl)-2-hydroxyethyla mino]-2- methylpropyl}-Λ/-[2-(2-chlorophenyl)ethyl]-benzamide.

According to one aspect of the present invention, the compounds of formula (1) wherein the (CH2)n-C(=O)Q1 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, adipate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, hydrogen phosphate, isethionate, D- and L-lactate, malate, maleate, malonate, mesylate, methylsulphate, 2- napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen, phosphate/phosphate dihydrogen, pyroglutamate, saccharate, stearate, succinate, tannate, D- and L-tartrate, 1-hydroxy-2- naphthoate tosylate and xinafoate salts. Suitable base salts are formed from bases which form non-toxic salts. Examples include the aluminium, arginine, 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 (iii) 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-stoichiometric 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 Haleblian (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, Vol. 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-Cβ)alkyl; (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 (C1-C6)alkanoyloxymethyl; and (iii) 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 amino functionality of the compound of formula (1 ) is/are replaced by (C1-C1o)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 hydroxymethyi derivative thereof (-CH3 -» -CH2OH): -(ii) where the compound of formula (1) contains an alkoxy group, an hydroxy derivative thereof (-OR -» -OH); (iii) where the compound of formula (1) contains a tertiary amino group, a secondary amino derivative thereof (-NR1R2 -» -NHR1 or -NHR2); _(iv) where the compound of formula (1) contains a secondary amino 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 cisftrans (or Z/E) 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, c//-tartrate or c//-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-enriched 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.

Stereoisomeric 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 A, B, n and Q1 are as defined above, is generally preferred: OH

R1 R2

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, de-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, croscarrnellose sodium, crospovidone, polyvinylpyrrolidone, methyi 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 % iubricant.

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, Vol. 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-d rying 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(cf/-lactic-coglycolic)acid (PGLA)_microspheres.

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. Powderjectâ„¢, Biojectâ„¢, 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 nebuliser, with or without the use of a suitable propellant, such as 1 ,1 ,1 ,2-tetrafluoroethane or 1 ,1 ,1 ,2,3,3,3-heptafluoropropane. For intranasal use, the powder may comprise a bioadhesive agent, for example, chitosan or cyclodextrin.

The pressurised container, pump, spray, atomizer, or nebuliser 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 homogenisation, or spray drying.

Capsules (made, for example, from gelatin or hydroxypropyimethylcellulose), 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, mannitol, 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 1μl 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-linked polyacrylic acid, polyvinylalcohol, hyalu ronic 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, i.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 0.001mg 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) bronchoconstriction, (ii) inflammation, (iii) 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-administered" 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-Lipdxygenase (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 HI and H3 antagonists, (d) αr 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) KJnJn-B1 - and B2-receptor antagonists, (o) Immunosuppressive agents, (p) Inhibitors of matrix metalloproteases (MMPs), (q) Tachykinin NK-i, 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, (y) Antibiotics, (z) HDAC inhibitors, and, (aa) PI3 kinase inhibitors.

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, - Leukotriene 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 furcate, 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 tine 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 Ig E- 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 diseases (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 disea se 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, staphyloco ccus 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.

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 example illustrate the preparation of the indole derivatives of the formula (1) :

Preparation 1 : 5-{(2R)-2-[((2R)-2-{[fert-Butyl(dimethyl)silyl]oxy}-2-{4- hydroxy-3-[(methylsulfonyI)amino]phenyl}ethyl)amino]propyl}- Λf-[3- hydroxy-5«(trifluoromethyl)benzyl]-1H-indole-2-carboxamide A solution of 5-{(2R)-2-[((2R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-2-{4-hyd roxy-3- [(methylsulfonyl)amino]phenyl}ethyl)amino]propyl}-1 /-/-indole-2-carboxylic acid (Preparation 2, 0.27g, 0.48mmol), 1-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (109mg, 0.57mmol), hydroxybenzotriazole (71 mg, 0.53mmol) in N, Λ/-dimethylformamide (5ml) was treated with N,N diethylisopropylamine (0.42ml, 0.24mmol) and 3-(aminomethyl)-5- (trifluoromethyl)phenol (Preparation 11 , 79mg, 0.58 mmol) and the resulting suspension left to stir at room temperature under a nitrogen atmosphere for 18 hours. The solvent was removed in vacuo and the residue partitioned between ethyl acetate (20 ml) and saturated aqueous sodium chloride (20 ml). The organic phase was separated, dried (sodium sulphate) and the solvent removed in vacuo. Partial purification by flash column chromatography on silica gel eluting with dichloromethane:methanol: 0.88 ammonia (98:2:0 changing to 93:7:1 , by volume) gave the title compound contaminated with inseparable material (360mg). The material was used without further purification.

Preparation 2 : 5-{(2/?)-2-[((2R)-2-{[fert-Butyl(dimethyl)silyl]oxy}-2-{4- hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]propyl}- 1 H-indole-2- carboxylic acid A solution of methyl 5-{(2R)-2-[((2R)-2-{[te/t-butyl(dimethyl)silyl]oxy}-2-{4- hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]propyl}- 1 H-indole-2- carboxylate (Preparation 3, 0.74g, 1.28mmol) in tetrahydrofuran (15ml) was treated with 1M aqueous lithium hydroxide (2.6ml 2.6mmol) and the reaction mixture stirred at room temperature fro 48 hours. The reaction was neutralsied by addition of hydrochloric acid (2.6ml of 1 M solution) and the solvent removed in vacuo. The residue was purified by flash column chromatography on silica gel eluting with dichloromethane : methanol : 0.88 ammonia (90:10:1 changing to 80:20:3, by volume) to give the title compound as a yellow foam (0.27g). 1H NMR (400MHz, CD3OD): δ = 7.42-7.37 (3H, m), 7.05-7.02 (1 H, rn), 6.98- 6.94 (2H, m), 6.84 (1 H, d), 4.95-4.90 (1 H, m), 3.54-2.89 (8H, m), 1.30 (3H, d), 0.79 (9H, s), 0.01 (3H, s), -0.16 (s, 3H) ppm. LRMS (electrospray) : m/z [M+H]+ 562 Preparation 3 : Methyl 5-{(2/?)-2-[((2R)-2-{[fert-butyl(dimethyl)silyl]oxy}-2- {4-hydroxy-3-[(methylsulfonyI)amino]phenyl}ethyl)amino]propy l}-1H- indole-2-carboxylate A solution of methyl 5-{(2R)-2-[((2R)-2-{4-(benzyloxy)-3- [(methylsulfonyl)amino]phenyl}-2-{[te/t-butyI(dimethyl)silyl ]oxy}ethyl) amino]propyl}-1H-indole-2-carboxylate (Preparation 4, 0.9Og, 1.35mmol) in ethanol (10 ml) was treated with ammonium formate (0.42g, 6.7 mmoi) and palladium hydroxide on carbon (0.2g, 20% b/w palladium). The resulting suspension was purged with nitrogen and then heated to reflux for an hour. The reaction mixture was cooled to room temperature and filtered through arbocel to remove catalyst residues. The filtrate was reduced in vacuo and the residue was partitioned between sat. aq. sodium chloride (20 ml) and dichloromethane (20 ml). The organic phase was separated and the aqueous extracted with more dichloromethane (20 ml). The combined organic extracts were dried (sodium sulphate) and the solvent removed in vacuo to give the title compound as a colourless oil (0.74 g). 1H NMR (400MHz, CD3OD): δ = 7.39-7.35 (2H, m), 7.29 (1 H, m), 7.11 (1 H, s), 7.09-7.06 (1 H1 m), 6.92-6.90 (1 H, m), 6.74 (1 H, d), 4.71-4.68 (1 H1 m), 3.93 (3H, s), 3.01-2.85 (5H, m), 2.74-2.64 (3H, m), 1.12 (3H, d), 0.72 (9H, s), -0.07 (s, 3H), -0.23 (s, 3H) ppm. LRMS (electrospray) : m/z [M+H]+ 576

Preparation 4 : Methyl 5-{(2/?)-2-[((2/?)-2-{4-(benzyloxy)-3- [(methylsulfonyl)amino]phenyl}-2-{[fert-butyl(dimethyl)silyl ]oxy}ethyl) amino]propyi}-1 H-indole-2-carboxylate A solution of methyl 5-[(2R)-2-aminopropyl]-1H-indole-2-carboxylate (Preparation 5, 1.12g, 4.8mmol) and N-[2-(benzyloxy)-5-((1 S)-2-bromo-{[ferf- butyl(dimethyl)silyl]oxy}ethyl)~phenyl]methanesulphonamide (WO 02/06258, pg. 36, example 14a) (0.8Og, 1.6mmol) in dimethylsufoxide (2ml) was heated at 105°C for 3h. The reaction mixture was cooled to room temperature and partitioned between sat. aq. sodium chloride (50ml) and ethyl acetate (50ml). The organic phase was separated and the solvent removed in vacuo. The residue was purified by flash column chromatography on silica gel eluting with dichloromethane : methanol : 0.88 ammonia (98:2:0 changing to 95:5:0.5, by volume) to give the title compound as a yellow foam (0.9Og). 1H NMR (400MHz, CD3OD): δ = 7.48-7.32 (8H1 m), 7.12 (1H1 s), 7.07 (1H, d), 6.92 (1 H1 d), 5.07 (2H1 s), 4.71-4.68 (1 H1 m), 3.85 (3H1 s), 2.96-2.90 (2H, m), 2.80-2.74 (4H1 m), 2.67-2.58 (2H, m), 1.12 (3H1 d), 0.74 (9H, s), -0.06 (3H1 s), - 0.22 (3H1 s) ppm. LRMS (electrospray) : m/z [M+H]+ 666, [M-H] ' 664.

Preparation 5 : Methyl 5-[(2R)-2-aminopropyl]-1H-indole-2-carboxylate A solution of methyl 5-((2R)-2-{[(1R)-1-phenylethyl]amino}propyl)-1H-indole-2- carboxylate (Preparation 6, 9.34 g, 25.0 mmol) in ethanol (125 ml) was treated with ammonium formate (7.90 g, 125 mmol) and palladium hydroxide on carbon (2.81 g, 20% b/w palladium). The resulting suspension was purged with nitrogen and then heated to reflux for an hour. The reaction mixture was cooled to room temperature and filtered through arbocel to remove catalyst residues. The filtrate was reduced in vacuo and the residue was partitioned between 0.88 ammonia (100 ml) and dichloromethane (100 ml). The organic phase was separated and the aqueous extracted with more dichloromethane (100 ml). The combined organic extracts were dried (sodium sulphate) and the solvent removed in vacuo to give the title compound as a colourless oil (6.25 g, trace solvent remaining by 1H NMR). 1H NMR (400MHz, CD3OD): δ = 7.44 (1 H1 bs), 7.36 (1 H, d), 7.13 (1 H, d), 7.11 (1H1 s), 3.90 (3H1 s), 3.17-3.07 (1H1 m), 2.77-2.61 (2H1 m), 1.10 (3H, d) ppm. LRMS (electrospray) : m/z [M+H]+ 233, [M+Na]+ 255. Optical Rotation [α]D25 = -22.58° 6.76mg/ml MeOH 589nm

Preparation 6 : Methyl 5-((2f?)-2-{[(1R)-1-phenylethyl]amino}propyI)-1H- indole-2-carboxylate A solution of 1-ferf-butyl 2-methyl 5-((2R)-2-{[(1 R)-1-phenylethyl]amino}propyl)- 1H-indole-1 ,2-dicarboxylate (Preparation 7, 20.48 g, 46.9 mmol) was treated with 4M hydrogen chloride in methanol and the resulting solution left to stir at room temperature for 16 hours and then heated at 500C for a further 2 hours. The solvent was removed in vacuo to give a solid which was crystallised from a mixture of methanol (125 ml) and diisopropylether (50 ml) to give the title compound as a colourless crystalline solid (9.34 g, d.e.>98% as determined by 1H NMR). 1H NMR (400MHz, CD3OD): δ = 7.53-7.49 (5H1 m), 7.40-7.38 (2H, m), 7.10, 1 H1 bs), 6.97 (1 H, bd), 4.61 (1 H, q), 3.91 (3H, s), 3.42-3.37 (1 H, m), 3.26-3.19 (1 H1 m), 2.72-2.66 (1 H, m), 1.69 (3H, d), 1.19 (3H, d) ppm. LRMS (electrospray) : m/z [M+H]+ 337.

Preparation 7 : 1-terf-butyl 2-methyl 5-((2R)-2-{[(1 R)-1-phenylethyl] amino}propyl)-1 H-indole-1 ,2-dicarboxyIate A solution of 1 -terf-butyl 2-methyl 5-(2-oxopropyl)-1H-indole-1 ,2-dicarboxylate (18.0 g, 54.32 mmol), (R)-α-methyl benzylamine (Preparation 8, 6.4 ml, 49.65 mmol), sodium triacetoxyborohydride (15.80 g, 74.55 mmol) and acetic acid (3.0 ml, 52.38 mmol) in dichloromethane (500 ml) was stirred at room temperature for 16 hours. The reaction mixture was quenched by addition of saturated aqueous sodium bicarbonate (200 ml) and allowed to stir until effervescence ceased. The organic phase was separated and the aqueous phase extracted with further dichloromethane (100 ml). The combined organic extracts were dried (magnesium sulphate) and the solvent removed in vacuo. The residue was purified by flash column chromatography on silica gel eluting with dichloromethane : methanol : 0.88 ammonia (99:1 :0.1 changing to 98:2:0.2, by volume) to give a 4:1 mixture of diastereomers (R,R major) as a pale yellow oil (20.48 g). 1H NMR (400MHz, CD3OD): δ = 7.97-7.92 (1 H, m), 7.41-7.02 (8H, m), 4.04- 3.99 (1 H, m), 3.96-3.94 (3H, m), 3.15-3.10 (1H, m), 2.80-2.70 (1H, m), 2.53- 2.48 (1 H, m), 1.66 (9H, s), 1.39-1.31 (3H, 2d), 1.10-0.95 (3H, 2d) ppm. LRMS (electrospray) : m/z [M+H]+ 437.

Preparation 8 : 1-terf-butyl 2-methyl 5-(2«oxopropyl)-1H-indole-1,2- dicarboxylate A solution of 1-terf-butyl 2-methyl 5-bromo-1H-indole-1 ,2-dicarboxylate (Preparation 9, 12.5 g, max 32.04 mmol), tributyltin methoxide (11.0 ml, 38.2 mmol), isoprenylacetate (5.3 ml, 48.1 mmol), palladium acetate (0.36 g, 5 mol%), tri-o-tolylphosphine (0.97 g, 10 mol%) in toluene (40 ml) was degassed and then heated at 100°C for 8 hours. The reaction mixture was diluted with ethyl acetate (50 ml), 4M potassium fluoride (aqueous, 100 ml) and left to stir at room temperature overnight. The resulting mixture was filtered through arbocel washing the precipitate thoroughly with ethyl acetate (100 ml) and the organic phase of the filtrate separated, dried (magnesium sulphate) and the solvent removed in vacuo. The residue was purified by flash column chromatography on silica gel eluting with pentane:ethyl acetate (95:5 changing to 90:10, by volume) to give the title compound (8.2 g) as a yellow oil. 1H NMR (400MHz, CDCI3): δ = 8.05 (1 H, d), 7.44 (1 H, s), 7.25 (1 H, d), 7.05 (1H, s), 3.92 (3H, s), 3.78 (2H, s), 2.16 (3H, s), 1.61 (9H, s) ppm. LRMS (electrospray) : m/z [M-H]" 330, [M+Na]+ 354.

Preparation 9 : 1 -ferf-butyl 2-methyl 5-bromo-1f/-indole-1 , 2-dicarboxylate A solution of methyl 5-bromo-1H-indole-2-carboxylate (Preparation 10, 8.14 g, 32.04 mmol) in tetrahydrofuran (300 ml) was added to sodium hydride (1.35 g of a 40% dispersion in mineral oil, 33.7 mmol) at O0C under nitrogen. The resulting mixture was left to stir until effervescence ceased (50 minutes). A solution of di-te/Y-butyldicarbonate in further tetrahydrofuran (30 ml) was added to the reaction and the resulting mixture stirred vigorously, warming gradually to room temperature overnight. The solvent was removed in vacuo and the residue partitioned between ethyl acetate (200 ml) and water (200 ml). The organic phase was separated and the aqueous extracted with more ethyl acetate (2-fold 200 ml). The combined organics were dried (magnesium sulphate) and the solvent removed in vacuo to give the title compound as a pale yellow oil (12.5 g - trace solvent remaining). 1H NMR (400MHz, CDCI3): δ = 7.98 (1 H, d), 7.74 (1 H, s), 7.50 (1 H, dd), 7.00 (1 H, s), 3.92 (3H, s), 1.61 (9H, s) ppm. LRMS (electrospray) : m/z [M+H]+ 352 / 354, [M+Na]+ 376 / 378. Preparation 10 : Methyl δ-bromo-IH-indole^-carboxylate A solution of δ-Bromq-IH-indole-^-carboxylic acid (commercial, 10.0 g, 41.6 mmol) in methanol (200 ml) was cooled to O0C and saturated with HCI(g). The resulting solution was allowed to warm gradually to room temperature overnight. The solvent was removed in vacuo and the residue treated with 0.88 ammonia (500 ml). The resulting solution was extracted with dichloromethane (3-fold 150 ml) and the combined organics dried (magnesium sulphate) and the solvent removed in vacuo to give the required product as a colourless oil (8.35 g). 1H NMR (400MHz, CDCI3): δ = 8.96 (1 H, bs), 7.83 (1 H, s), 7.40 (1 H, d), 7.30 (1 H, d), 7.14 (1 H, s), 3.95 (3H, s) ppm. LRMS (electrospray) : m/z [M-H]" 252 / 254.

Preparation 11 : 3-(aminomethyl)-5-(trifluoromethyl)phenol A solution of 3-hydroxy-5-(trifluoromethyl)benzamide (Preparation 12, 0.67g, 3.29mmol) in tetrahydrofuran (10ml) was cooled to 0°C and treated with borane.tetrahydrofuran complex (9.9ml of a 1 M solution in tetrahydrofuran, 9.9mmoi). The resulting solution was allowed to warm to room temperature aover 20 minutes and then heated to relux for 16 hours. The reaction mixture was cooled to 00C and quenched by addition of methanol (until effervescence ceased). The resulting solution was allowed to warm to room temperature over 2 hours and then the solvent was removed in vacuo. The residue was dissolved in dichloromethane (40ml) and washed with water (10ml x 2), sat aq. sodium chloride (10ml), dried (sodium sulfate) and reduced in vacuo to give a colourless oil. Purification by column chromatography on silica gel eluting with dichloromethane:methanol (98:2 changing to 95:5) gave the title compound as a pale yellow oil. 1HNMR (400MHz, CD3OD) δ : 3.81 (s, 2H), 6.91 (s, 1 H), 6.98 (s, 1H), 7.09 (s, 1 H) ppm. MS (electrospray) m/z 192 [M+H]+ Preparation 12 : 3-Hydroxy-5-(trifluoromethyl)benzamide A solution of 3-hydroxy-5-(trifluoromethyl)benzoic acid (JyACS, 1954, 76, 1051 , 2.26g, 9.99mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.11g, 10.98mmol), 1-hydroxybenzotriazole (1.48g, 10.98mmol) and ammonium carbonate (4.8Og, 49.95mmol) in Λ/,Λ/-dimethylformamide (70ml) was left to stir at room temperature under a nitrogen atmosphere for 3 days. The solvent was removed in vacuo and the residue partitioned between saturated aqueous sodium hydrogen carbonate (50ml) and ethyl acetate (6 x 50ml). The combined organic extracts were washed with water (25ml), saturated aqueous sodium chloride (25ml), dried (sodium sulfate) and the solvent removed in vacuo. The solid was absorbed onto silica gel and purified by column chromatography on silica gel eluting with dichloromethane:methanol:0.880 ammonia (95:5:0.5 changing to 90:10:1) to give the title compound as a pale yellow solid (1.1g). 1HNMR (400MHz, CD3OD) δ : 7.18 (t, 1 H), 7.50 (t, 1 H), 7.60-7.61 (m, 1 H) ppm. MS (electrospray) m/z 204 [M-H]"

Preparation 13 Diethyl 2,2'-(1 ,3-phenylene)diacetate 2,2'-(1 ,3-Phenylene)diacetic acid (10.0g, 51 mmol) was dissolved in ethanol (10OmL) and the solution treated dropwise with catalytic acetyl chloride (2.5mL). The reaction mixture was stirred at reflux for 18 hours before being allowed to cool and concentrated under reduced pressure. The residue was taken up in ethyl acetate (10OmL) and washed with sodium bicarbonate solution (3x50mL) and brine (3x50mL). The organic phase was dried over magnesium sulphate and concentrated under reduced pressure. The residue was triturated with pentane to yield the title product, 1 1.8g. 1HNMR (CDCI3, 400MHz) δ: 1.31 (t, 6H), 3.65 (s, 4H), 4.20 (q, 4H), 7.24-7.36 (m, 4H). LRMS : m/z ES+ 251 [MH]+

Preparation 14 [3-(2-Ethoxy-2-oxoethyl)phenyI]acetic acid A solution of the diester from preparation 13 (44.3g, 177mmol) and 2,2'-(1 ,3- phenylene)diacetic acid (59.2g, 308mmol) in ethanol (24mL) and dioxan (29OmL) was treated dropwise with 12M hydrochloric acid (4.9ml_, 58.8mmol). The reaction mixture was stirred at reflux for 18 hours before being allowed to cool and concentrated to low volume. The reaction mixture was diluted with toluene (125mL) and the resulting slurry filtered. The filtrate was concentrated under reduced pressure and the residue taken up in water and neutralised with sodium bicarbonate. The mixture was diluted with ethyl acetate (20OmL) and the organic layer was separated and washed with sodium bicarbonate solution (5x30mL) and brine (5OmL). The combined aqueous extracts were acidified to pH 3 with 6M hydrochloric acid and extracted with ether (3x30mL). The organics were combined, dried over magnesium sulphate and concentrated under reduced pressure. The residue was triturated with pentane giving the title compound as a colourless solid 10.8g. 1Hnmr (CD3OD, 400MHz) δ: 1.25 (t, 3H), 3.60 (m, 2H), 3.63 (m, 2H), 4.15 (q, 2H), 7.18-7.32 (m, 4H) LRMS : m/z ES+ 245 [MNa]+

Preparation 15 [3-(2-Hydroxy-2-methyl-propyI)-phenyl]-acetic acid A solution of the acid of preparation 14 (6.85g, 32mmol) in diethyl-ether (10OmL) under an atmosphere of N2, was cooled to 0°C and treated with a 3M solution of methylmagnesium bromide in ether (23.5mL, 70.0mmol). The reaction mixture was allowed to warm gradually to room temperature. After 2 hours the reaction was quenched by addition of saturated aqueous ammonium chloride solution (20OmL). The organic phase was separated and washed with brine (10OmL), dried (MgSO4) and concentrated under reduced pressure. Purification by column chromatography on silica gel eluting with pentane:dichloromethane (60:40 to 0:100) gave the title compound as a colourless oil, 6.23g. 1H nmr (CDCI3, 400MHz) δ: 1.22 (s, 6H), 2.75 (s, 2H)1 3.63 (s, 2H), 7.12-7.30 (m, 4H). LRMS : m/z ES+ 209 [MH]+

Preparation 16 {3-[2-(2-Chloro-acetylamino)-2-methyl-propyl]-phenyI}-acetic acid 2-Chloroacetonitrile (8.8ml_, 140mmol) was added to a solution of the alcohol from preparation 15 (16.Og, 70mmol), in acetic acid (33mL). The resulting solution was cooled to 0°C, treated with concentrated sulphuric acid (33ml_), and the reaction mixture allowed to warm gradually to room temperature. After 4 hours the reaction mixture was poured onto ice and basified with solid sodium carbonate. The solution was extracted with ethyl acetate (2x500mL) and the combined organic extracts dried over magnesium sulphate and concentrated under reduced pressure to give the title product as a colourless solid, 19.Og. 1H nmr (CDCI3, 400MHz) δ : 1.36 (s, 6H), 3.02 (s, 2H), 3.62 (s, 2H), 3.95 (s, 2H), 6.19 (br s, 1 H), 7.06-7.31 (m, 4H) LRMS : m/z ES" 282, 284 [M-KT

Preparation 17 Methyl [3-(2-amino-2-methylpropyl)phenyl]acetate A solution of the amide from preparation 16 (5.1g, 18mmol), thiourea (1.6g, 21mmol) and acetic acid (18mL) in methanol (8OmL) was heated to reflux under a nitrogen atmosphere for 16 hours. The reaction mixture was cooled and filtered. The filtrate was concentrated under reduced pressure and the residue dissolved in methanol (15OmL). The solution was saturated with hydrogen chloride gas and then heated to reflux for 16 hours. The solvent was reduced in vacuo and the residue partitioned between ethyl acetate (20OmL) and 5% aqueous sodium carbonate (20OmL). The organic extract was washed with saturated sodium chloride (10OmL), dried over sodium sulphate and reduced in vacuo. The residue was purified on strong cation exchange resin, eluting with methanol and then 2N ammonia in methanol to elute the product. The eluant was concentrated in vacuo to give the title compound as a yellow oil, 2.68g. 1H nmr (CDCI3, 400MHz) δ :1.14 (s, 6H)1 2.68 (s, 2H), 3.62 (s, 2H)1 3.69 (s, 3H), 7.08-7.16 (m, 3H), 7.23-7.27 (m, 1 H). LRMS : m/z ES+ 236 [MH]+

Preparation 18 (1/?)-1-[3-Amino-4-(benzyIoxy)phenyI]-2-bromoethan ol Platinum oxide (1g) was added to a solution of (fi)-2-bromo-1-[4-(benzyloxy)-3- nitrophenol]ethanol (Org. Proc. Res. And Dev. 1998; 2; 96-99) (5Og, 142mmol) in toluene (10OmL) and tetrahydrofuran (10OmL) and the mixture was hydrogenated at 30 psi and room temperature for 18 hours. The reaction mixture was filtered through Arbocel®, washing through with dichloromethane (4x200mL). The combined filtrate was evaporated under reduced pressure and the residual yellow solid was purified using a Biotage® silica gel column and dichloromethane:ethyl acetate (100:0 to 50:50 to 0:1 00) as the eluant. The impure fractions were combined and purified again using a Biotage® silica gel column using toluene:dichloromethane (100:0 to 50:50 to 0:100) as the eluant, to provide the title compound as a solid. 1Hnmr (CDCI3, 400MHz) δ : 2.97-3.38 (br s, 2H), 3.55 (dd, 2H), 4.78 (m, 1 H), 5.03 (s, 2H), 6.63 (d, 1 H), 6.75 (s, 1 H), 6.80 (d, 1 H), 7.26-7.42 (m, 5H).

Preparation 19 Λ/-{2-(Benzyloxy)-5-[(1 R)-2-bromo-1-hydroxyethyl]phenyl}urea Potassium cyanate (2.01g, 24mmol) was added to a solution of the amine from preparation 18 (4g, 12mmol) in a solution of acetic acid:water (40OmL, 1 :2 by volume), and the reaction stirred at room temperature for 1.5 hours. The solution was carefully basified by the addition of sodium hydroxide, and the resulting precipitate filtered off. The solid was washed with water (160OmL), then ether (50OmL) and dried in vacuo for 18 hours, to afford the title compound, 2.44g. 1Hnmr (CD3OD, 400MHz) δ : 3.58 (m, 2H), 4.71 (m, 1 H), 5.21 (s, 2H), 6.98 (m, 2H), 7.40 (m, 5H), 8.00 (s, 1 H). LRMS : m/z APCI+ 285 [MH]+ Preparation 20 W-[2-(BenzyIoxy)-5-((1R)-2-bromo-1-{[fert-butyl(dimethyl)sil yl]oxy}ethyl) phenyl]urea Imidazole (1.24g, 18.2mmol) and fe/f-butyldimethylsilyl chloride (2.36g, 15.6mmol) were added to a solution of the alcohol from preparation 19 (4.75g, 13.0mmol) in N,N-dimethylformamide (3OmL). 4-(Dimethylamino)pyridine (48mg, 0.39mmol) was then added and the reaction stirred at room temperature for 3 days. The reaction mixture was diluted with ethyl acetate (5OmL), washed with water (2x25mL), dried over magnesium sulphate and evaporated under reduced pressure. The residual orange oil was purified on a Biotage® silica gel cartridge using dichloromethane as eluant to provide the title compound, 4.3g. 1Hnmr (CD3OD, 400MHz) δ: -0.10(s, 3H), 0.09(s, 3H), 0.91(s, 9H)1 3.50(m, 2H), 4.81 (m, 1 H), 5.20(s, 2H), 6.98(m, 2H), 7.40(m, 3H), 7.48(d, 2H), 8.05(s, 1 H). LRMS : m/z APCI+ 479, 481 [MH]+

Preparation 21 Methyl (3-{2-[((2R)-2-[3-[(aminocarbonyI)amino]-4-(benzyloxy)phenyl ]-2- {[terf-butyl(dimethyl)silyl]oxy}ethyl)amino]-2-methyIpropyI} phenyl)acetate A mixture of the bromide from preparation 20 (3.52g, 7.3mmol), the amine from preparation 17 (1.63g, 7.3mmol), potassium carbonate (2.03g, 15mmol) and potassium iodide (1.22g, 7.3mmol) in acetonitrile (5OmL) was stirred at 800C for 5 days. The cooled mixture was concentrated under reduced pressure and the residue suspended in water and extracted with ethyl acetate (3x10OmL). The combined organic extracts were washed with brine (3x50mL), dried over sodium sulphate and evaporated under reduced pressure. The residual oil was purified by column chromatography on silica gel using an elution gradient of dichloromethane:methanol:0.88 ammonia (99.7:0:0.3 to 96.7:3:0.3). The impure fractions were further purified using a RediSEP™ flash silica gel column and an elution gradient of dichloromethane:methanol:0.88 ammonia (99.7:0:0.3 to 96.7:3:0.3). The resulting oils were combined and triturated with ether, to afford the title compound as a pale yellow solid, 2.1g. 1Hnmr (CDCI3, 400MHz) δ: -0.45 (s, 3H),-0.01 (s, 3H), 0.82 (s, 9H), 1.00 (s, 3 H), 1.03 (s, 3H), 2.60-2.68 (m, 3H), 2.78-2.84 (m, 1 H), 3.58 (s, 2H), 3.67 (s, 3H), 4.54 (s, 2H), 4.72 (m, 1 H), 5.06 (s, 2H)1 6.78 (s, 1 H), 6.89 (d, 1 H), 6.96-7.18 <m, 6H), 7.38-7.41 (m, 5H). LRMS : m/z APCI+ 620 [MH]+

Preparation 22 Methyl (3-{2-[((2/?)-2-{3-[(aminocarbonyl)amino]-4-hydroxyphenyl}-2 -{[fe/-f- butyl(dimethyl)silyl]oxy}ethyl)amino]-2-methylpropyl}phenyl) acetate A mixture of the compound from preparation 21 (2.27g, 3.7mmol) and 1 0% palladium on charcoal (300mg) in methanol (4OmL) was hydrogenated at 50 psi and room temperature for 18 hours. The reaction mixture was filtered through Arbocel®, and the filtrate evaporated under reduced pressure. The residual foam was purified by column chromatography on silica gel using an elution gradient of dichloromethane:methanol:0.88 ammonia (99.7:0:0.3 to 95.7:4:0.3) to provide the title compound as a colourless foam, 1.45g. 1Hnmr (CDCI3, 400MHz) δ: -0.19 (s, 3H)1 -0.06 (s, 3H), 0.78 (s, 9H), 1.02 (s, 3H)1 1.05 (s, 3H), 2.59-2.68 (m, 3H), 2.77-2.81 (m, 1 H), 3.61-3.66 (dd, 2H), 4.57-4.60 (m, 1 H), 5.03 (s, 2H), 6.79 (d, 1H), 6.86 (d, 1 H), 6.94-7.04 (m, 2H), 7.08-7.12 (m, 2H), 7.18-7.22 (m, 1 H), 7.39 (s, 1 H). HRMS [C28H43N3O5Si] 530.3045 found 530.3042 [MH]+

Preparation 23

(3-{2-[((2/?)-2-{3-[(Aminocarbonyl)amino]-4-hydroxyphenyl }-2-{[terf- butyI(dimethyl)silyl]oxy}ethyl)amino]-2-methylpropyl}phenyl) acetic acid Sodium hydroxide solution (5M, 2.74mL, 13.7mmol) was added to a solution of the ester from preparation 22 (1.45g, 2.74mmol) in dioxan (2OmL) and water (2mL) and the reaction stirred at room temperature for 18 hours. The mixture was concentrated under reduced pressure and the residual solution diluted with water. This solution was cooled in ice, acidified to pH 6 using 1M hydrochloric acid and the resulting precipitate filtered off, and dried in vacuo at 50°C for 4 days to afford the title compound as a white solid, 1.27g. 1Hnmr (CD3OD, 400MHz) δ: -0.11 (s, 3H), 0.05 (s, 3H), 0.83 (s, 9H), 1.32 (d, 6H), 2.91-2.99 (dd, 2H), 3.22-3.28 (m, 2H), 3.51 (s, 2H), 4.58-4.62 (m, 1 H), 6.82 (d, 1 H), 6.87-6.92 (m, 1 H), 7.05-7.09 (m, 1 H), 7.13 (s, 1 H), 7.25-7.29 (m, 2H), 7.76 (d, 1 H). LRMS : m/z APCI+ 516 [MH]+

Preparation 24 1-[4-(Benzyloxy)phenyl]-2-bromoethanone A solution of tetrabutylammonium tribromide (53g, 110mmol) in tetrahydrofuran (7OmL) was added dropwise to a suspension of 4-benzyloxyacetophenone (27.38g, 121mmol) in tetrahydrofuran (10OmL) and methanol (25mL) over 1 hour. The reaction mixture was then left to stir for 48 hours and the solvent removed in vacuo. The residue was dissolved in ethyl acetate (25OmL) and washed with water (25OmL). The phases were separated and the aqueous layer was extracted with ethyl acetate (2 x 10OmL). The organic layers were combined, dried over magnesium sulfate and concentrated in vacuo to give a solid. The crude residue was recrystallised using cyclohexane to afford the desired product, 22g (65%). 1H NMR (400 MHz, CDCI3) δ 4.38 (2H, s), 5.10 (2H, s), 7.00 (2H, m), 7.21-7.40 (5H, m), 7.9 (2H, m). LRMS: m/z APCI+ 305 [MH+].

Preparation 25 Methyl {3-[2-({2-[4-(benzyloxy)phenyl]-2-hydroxyethyl}amino)-2- methylpropyl]phenyl}acetate A solution of the compound of preparation 24 (6.7g, 21.9mmol), the compound of preparation 17 (4.86g, 21.9mmol) and Λ/-ethyldiisopropylamine (3.8mL, 21.9mmol) in tetrahydrofuran (20OmL) was heated under reflux for 24 hours. The reaction mixture was cooled to room temperatre and sodium borohydride (1.24g, 32.8mmol) was added and the solution stirred for 4 hours. The solution was quenched by the addition of methanol (3OmL) and evaporated to a yellow gum. The yellow gum was partitioned between saturated sodium hydrogen carbonate solution (3OmL) and dichloromethane (3OmL). The phases were separated and the aqueous phase was extracted with dichloromethane (3 x 5OmL). The organic extracts were combined and concentrated in vacuo to give the crude residue. Purification by column chromatography on silica gel using dichloromethane and then dichloromethane:methanol:0.88 ammonia (95:5:0.5) afforded the desired product, 2.72g (28%). 1H NMR (400 MHz, CDCI3) δ 1.05 (3H, s), 1.07 (3H1 s), 2.66-2.78 (3H, m), 2.84- 2.89 (1 H, m), 3.60 (2H, s), 3.65 (3H, s), 4.65-4.68 (1 H, q), 5.06 (2H, s), 6.95- 6.97 (2H, d), 7.03-7.05 (1 H, d), 7.10-7.12 (2H, d), 7.17-7.21 (1 H, t), 7.27-7.31 (3H, m), 7.33-7.37 (2H, t), 7.41-7.43 (2H, d). LRMS: m/z APCI+ 448 [MH+].

Preparation 26 Methyl [3-(2-{[2-hydroxy-2-(4-hydroxyphenyl)ethyl]amino}-2- methylpropyl)phenyl]acetate A solution of the compound of preparation 25 (3.15g, 7.04mmol), ammonium formate (3.11g, 49.3mmol) and palladium hydroxide on carbon (320mg) in ethanol (7OmL) was heated under reflux for 2 hours. The reaction mixture was cooled to room temperature, filtered over Arbocel® and evaporated to give the crude residue. Purification by column chromatography on silica gel using dichloromethane and then dichloromethane:methanol:0.88 ammonia (90:10:1 ) afforded the desired product, 2.28g (91 %). 1H NMR (400 MHz, CDCI3) δ 1.06 (3H, s), 1.08 (3H1 s), 2.68-2.78 (3H, m), 2.86- 2.91 (1 H, dd), 3.61 (2H, s), 3.66 (3H, s), 4.62-4.66 (1 H1 dd), 6.75-6.77 (2H, d), 7.03-7.05 (1 H, d), 7.11-7.13 (2H, d), 7.18-7.20 (3H1 d). LRMS: m/z APCI+ 358 [MH+].

Preparation 27 3-(2-{[2-Hydroxy-2-(4-hydroxyphenyl)ethyl]amino}-2-methylpro pyI)phenyl] acetic acid A 1 M lithium hydroxide (12.8mL) solution was added dropwise to a solution of the compound of preparation 26 (2.28g, 6.38mmol) in tetrahydrofuran (2OmL) at room temperature and stirred for 24 hours. The reaction was acidified with 1 M solution of hydrochloric acid and the solvent was evaporated in vacuo to give the crude residue as a gum. The crude residue was azeotrop ed with methanol and used without further purification. 1H NMR (400 MHz, DMSO-d6) δ 1.05 (6H, s), 2.76-2.88 (4H, m), 3.39 (2H1 s), 4.69-4.71 (1 H, dd), 6.73-6.75 (2H, d), 6.95-6.97 (1 H, d), 7.07-7.09 (2H1 d), 7.14-7.16 (3H1 m). LRMS: m/z APCI+ 344 [MH+].

Preparation 28: Λ/-{2-Benzyloxy-5-[(7R)-2-bromo-1 -(.erf-butyldimethyl silanyloxy)ethyl]phenyl}formamide To a solution of A/-[2-benzyloxy-5-(2-bromo-1-hydroxyethyl)phenyl]formamide (Organic Process Research and Development 1998, 2, 96-9S) (16.58 g, 47.4 mmol, containing about 20 % of the corresponding acetamide) in N, N- dimethylformamide (100 mL) at RT under N2 was added te/f-butyldimethylsilyl chloride (14.3 g, 94.7 mmol), imidazole (7.73 g, 113.7" mmol) and 4- (dimethylamino)pyridine (100 mg, 825 μmol). The resulting solution was stirred at RT overnight, the solvent was removed and the product "taken up in ethyl acetate (200 mL). The organics were washed with 10% hyd rochloric acid (2x 250 mL) brine (500 mL) and dried (MgSO4). The crude material was purified by chromatography (0-30 % ethyl acetate in heptane) to yield a colourless oil (18.65 g). Major product : 1HNMR (CDCI3, 400 MHz) δ: -0.08 to -0.05 (SH, m), 0.09-0.11 (3H, s), 0.89-0.90 (9H, m), 3.38-3.55 (2H, m), 3.78-3.84 (1 H, rn), 5.06-5.11 (2H, m), 6.90-6.97 (1H, m), 7.03-7.12 (1 H, m), 7.24 (m), 7.36-7.-43 (5H, m), 7.67- 7.78 (m), 7.88 (d), 8.74 (d); LRMS ES m/z 486 [M+Na]+ Minor product : 1HNMR (CDCI3, 400 MHz) δ: distinguishing peak at 2.14 (3H1 s); LRMS ES m/z 500 [M+Na]+

Preparation 29: 1-(3-Bromophenyl)-2-methylpropan-2-ol) Methylmagnesium bromide (3M solution in diethyl ether, 51.6 ml_, 155 mmol) was slowly added to a solution of 1-(3-bromo-phenyl)propan-2-one (15.0 g, 70 mmol) in dry diethyl ether (200 ml_) at 0 0C and the mixture was stirred for 3 hours. The reaction mixture was then re-cooled to 0 0C 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, 13.26 g. 1H NMR (400MHz, CDCI3) δ: 1.22 (6H, s), 1.42 (1 H, bs), 2.74 (2H, s), 7.15 (2H, m), 7.40 (2H, m)

Preparation 30: Λ/-[2-(3-Bromophenyl)-1,1-dimethylethyl]-2- chloroacetamide Chloroacetonitrile (6.63 mL, 105 mmol) was added to a stirred solution of the product of preparation 29 (12.0 g, 52.0 mmol) in acetic acid (25 mL) at room temperature. The resulting solution was cooled to 0 0C and concentrated sulfuric acid (25 mL) was added whilst the temperature was maintained below 10 0C. 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 (2χ 500 mL) and the combined organic solution was washed with water (5OmL), dried over sodium sulfate and the concentrated in vacuo to afford the title compound as an orange solid in quantitative yield, 16.08 g. 1H NMR (400MHz, CDCI3) δ: 1.37 (6H, s), 3.02 (2H, s), 3.94 (2H, s), 6.17 (1H, bs), 7.08-7.03 (1 H, d), 7.10-7.13 (1 H, t), 7.26 (1 H, s), 7.39-7.32 (1 H d ,); 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 31 : 2-(3-Bromophenyl)-1,1-dimethylethylamine A solution of the product of preparation 30 (32.0 g, 105 mmol), thiourea (9.60 g, 126 mmol) and acetic acid (50 mL) in ethanol (250 mL) was heated to reflux overnight. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated in vacuo, basified using aqueous sod ium hydroxide solution (1M, 450 ml_) and extracted with dichloromethane (2χ 500 ml_). The combined organic solution was washed with brine (50 ml_), dried over sodium sulfate and concentrated in vacuo to afford the title compound as a black oil in 96% yield, 23 g. 1H NMR (400MHz, CDCI3) δ: 1.12 (6H, s), 1.84 (2H, bs), 2.62 (2H1 s), 7.16-7.08 (2H, m), 7.36-7.32 (2H, m); LRMS ESI m/z 228 [M+H]+

Preparation 32: [2-(3-Bromophenyl)-1,1-dimethylethyl]carbamic acid tert- butyl ester The product of preparation 31 (5.Og, 22mmol) was treated with di-ferf-butyl dicarbonate (5.26g, 24mmol) in dichloromethane (5OmL) and stirred for 20 hours. The reaction mixture was washed with water (5OmL) and the combined organic solution was dried over sodium sulfate and concentrated in vacuo. The crude material was purified using a cation exchange column (methanol follcrwed 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 (6H, s) 1.50 (9H1 s), 2.97 (2H, s), 4.24 <1 H, bs), 7.05 (1H, d), 7.15-7.11 (1H, t), 7.30 (1H, s), 7.35 (1 H1 d); LRMS ESI m/z 350 [M+NH4]+

Preparation 33: Benzyl 3-{2-[(terf-butoxycarbonyl)amino]-2- methylpropyl}benzoate A solution of the product of preparation 32 (3.9 g, 12 mmol), [ 1 ,1'- b/s(diphenylphosphino)ferrocene]dichloropalladium(ll) (1.00 g, 1.3 mmol) and triethylamine (3.3 mL, 24 mmol) in benzyl alcohol (60 mL) was heated to 10O 0C under IOOpsi carbon monoxide for 5 hours. The cooled reaction mixture was then filtered through Arbocel® and the filtrate concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with sodium hydrogen carbonate solution (50 mL) and brine (2x 50 mL). The organic solution was then dried over sodium sulfate and concentrated in vacuo to give a dark oil. This oil was purified by column chromatography on silica gel, eluting with hexane:ethyl acetate 100:0 to 84:16, to afford the title compound as a pale yellow oil in 61% yield, 2.81 g. 1H NMR (400MHz, CDCI3) δ: 1.25 (6H1 s), 1.45 (9H1 s), 3.05 (2H, s), 4.22 (1 H, bs), 5.35 (2H, s), 7.32-7.48 (7H, m), 7.86 (1 H, s), 7.93-7.97 (1 H, m)

Preparation 34: Benzyl 3-(2-amino-2-methylpropyl)benzoate hydrochloride Hydrogen chloride (4M in dioxane, 25 ml_, 10 mmol) was added to a solution of the product of preparation 33 (2.80 g, 7.30 mmol) in dioxane (10 ml_) and the resulting solution stirred at room temperature for 18 hours. The solvent was removed in vacuo and the residue was evaporated from diethylether (x3), then suspended in diethylether and filtered to yield a white precipitate in 91 % yield. 1H NMR (400MHz, CD3OD) δ: 1.33 (6H, s), 2.98 (2H, s), 5.37 (2H, s), 7.31-7.53 (7H, m), 7.93 (1 H, s), 8.00-8.04 (1 H, m); LRMS APCI m/z 284 [M+H]+

Preparation 35 : 3-{2-[(2R)-2-(3-Acetylamino-4-benzyloxyphenyl)-2-(ferf- butyldimethylsilanyloxy)ethylamino]-2-methylpropyl}benzoic acid benzyl ester A mixture of preparation 28 (2.21 g, 4.79 mmol, containing some of the acetyl analogue) and the free-base of preparation 34 (2,69 g, 9.49 mmol) were heated to 95 0C for 24 h. The mixture was allowed to cool and then triturated with diethyl ether and the solid filtered off. The filtrate was evaporated and purified by chromatography, eluting with dichloromethane:methanol:ammonia 100:0 to 96:4. A second chromatography eluting with ethyl acetate:hexane:triethylamine 30:70:1 furnished preparation 41 (1.70 g, 53 %) and an oil which was evaporated from diethylether (x3) to yield a colourless gum (283 mg, 10 %). 1H NMR (400MHz, CDCI3) δ: -0.17 (3H, s), -0.04 (3H, s), 0.80 (9H, s), 1.00 (3H, s), 1.04 (3H, s), 2.13 (3H, s), 2.64-2.84 (4H, m), 4.69-4.72 (1 H, m), 5.09 (2H, s), 5.35 (2H1 s), 6.85 (1 H, d), 6.99 (1 H, d), 7.24-7.45 (12H, m), 7.72 (1 H, s), 7.87- 7.93 (2H, m), 8.37 (s); LCMS APCI m/z 681 [M+H]+. Preparation 36 : 3-{2-[(2R)-2-(3-Acetylamino-4-hydroxyphenyl)-2-(fe/t- butyldimethylsilanyloxy)ethylamino]-2-methylpropyl}benzoic acid The product of preparation 35 (283 mg, 420 μmol) and 10% Pd/C (300 mg) were suspended in methanol and the mixture was stirred under 50psi of hydrogen gas, at room temperature for 18 hours. The reaction mixture was then filtered through Filter aid® and the filtrate was concentrated in vacuo and evaporated from diethylether (x3) to yield an off-white foam (220 mg, 100 %). 1H NMR (400MHz, CD3OD) δ: -0.13 (3H, s), -0.03 (3H, s), 0.81 (9H1 s), 1.126 (3H: s), 1.27 (3H, s), 2.19 (3H, s), 2.94-3.24 (4H, m), 4.89-4.94 (1 H1 m), 6.87 (1 H, d), 7.02 (1 H, d), 7.30-7.40 (2H, m), 7.78-7.95 (3H, m); LCMS APCI m/z 501 [M+H]+.

Preparation 37 : 3-{2-[(2/?)-2-(3-Acetylamino-4-hydroxyphenyl)-2-(tert- butyldimethylsilanyloxy)ethylamino]-2-methylpropyl}-N-[2-(2- chlorophenyl)ethyl]benzamide A mixture of the product of preparation 36 (220 mg, 440 μmol), hydroxybenzotriazole hydrate (67 mg, 440 μmol), 1-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (85 mg, 440 μmol) and triethylamine (120 μl_, 880 μmol) in dichloromethane (20 ml_ was stirred at room temperature for 10 minutes. 2-chlorophenethylamine (69 mg, 440 μmol) was then added and the mixture was stirred at room temperature for 20 hours. The solvent was then removed in vacuo and the residue was diluted with ethyl acetate, washed with sodium hydrogen carbonate solution (20 ml_) and brine (20 ml_), dried over sodium sulfate. The crude material was purified by chromatography eluting with dichloromethane:methanol:ammonia 99.7:0:0.3 to 95.7:4:0.3. The fractions were concentrated in vacuo and evaporated from diethylether (x3) to yield an off-white foam (55 mg, 20 %). 1H NMR (400MHz, CDCI3) δ: -0.25 (3H, s), -0.11 (3H, s), 0.67 (9H, s), 1 .06 (3H, s), 1.07 (3H, s), 2.35 (3H, s), 2.60-2.82 (4H1 m), 3.08-3.12 (2H, t), 3.72-3.82 (2H, m), 4.58-4.62 (1 H1 m), 6.40 (1 H, bs), 6.89-7.00 (2H1 m), 7.05 (1 H1 s), 7.19- 7.32 (5H1 m), 7.39-7.41 (2H, m), 7.81 (1 H1 s), 9.45 (1 H, bs); LCMS APCI m/z 638 [M+H]+. Example 1 : 5-{(2/?)-2-[((2R)-2-Hydroxy-2-{4-hydroxy-3-[(methylsulfonyl) amino]phenyl}ethyl)amlno]propyl}-/V-[3-hydroxy-5-(trifluorom ethyl) benzyl]-1H-indole-2-carboxamide OH

NHSO2Me A solution of 5-{(2R)-2-[((2R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-2-{4-hyd roxy-3- [(methylsulfonyl)amino]phenyl}ethyl)amino]propyl}-Λ/-t3-hyc iroxy-5- (trifluoromethyl)benzyl]-1H-indole-2-carboxamide (Preparation 1 , crude, 0.48mmol assumed) in a mixture of methanol (10ml) and water (5ml) was treated with ammonium fluoride (100 mg, 2.7mmol) and the resulting suspension heated at 400C for a period of 16 hours. The solvent was removed in vacuo and the residue purified by flash column chromatography on silica gel eluting with dichloromethane : methanol : 0.88 ammonia (95:5:0.5 changing to 85:15:1.5, by volume) to give the title compound. Crystallisation from aqueous methanol gave the title compound as a colourless solid (20mg). 1H NMR (400 MHz, CD3OD) : δ = 7.37-7.29 (3H, m), 7.11 (1 H, m), 7.05-7.00 (3H, m), 6.94-6.91 (2H, m), 6.71 (1 H, d), 4.65-4.61 (1 H, m), 3.05-2.68 (8H1 m), 1.12 (3H, d) ppm. LRMS (electrospray) : m/z [M+H]+ 621.

Examples 2 to 29

o

A solution of the acid from preparation 23 (12.5mg, 24μmol) in N, N- dimethylformamide (200μL) was added to the appropriate amine (HNRARB) (30μmol) in N,N-dimethylformamide (150μL) and the reaction sealed and shaken. A solution of O-benzotriazol-1-yl-Λ/,Λ/,A/',Λ/-tetramθthyluronium hexafluorophosphate (9.19mg, 24μmol) in N,N-dimethylformamide (200μl_) was added, the reaction mixture sealed and shaken and allowed to stand at room temperature for 48 hours. The solvent was removed in vacuo, and the residue re-dissolved in dichloromethane (200μL). Sodium bicarbonate solution (0.5M, 200μl_) was added and the mixture sealed and shaken vigorously. The phases were separated using a phase separation tube, washing through with additional dichloromethane (200μL). The combined organic solutions were allowed to evaporate over 2 days. A solution of triethylamine trihydrofluoride (4μL, 0.024mmol) in dimethylsulphoxide (500μl_) was added, the mixture sealed and shaken and allowed to stand for 48 hours. The reaction mixture was purified directly by HPLC using a Phenomenex Luna C18 column (150x1 Omm, 10μm), at a flow rate of 8mL/min and detection at 225nm, using the following gradient system. A-0.05% aqueous diethylamine B-acetonitrile Time (min) %B 0-0.2 5 0.2-8 5-95 8-9.6 95

Each product was analysed using a Phenomenex Luna C18 (30 x 4.6mm, 5μm) column at a flow rate of 2.5mL/min using the gradient described in the table belnw. A-5% 6.5mM ammonium acetate in wateπacetonitrile (95:5) B-acetonitrile Time (min) %B 0 0 3 95 3.5 95 Example -NFTR M- Retention time

(min)

N. 491.25 1.62 >NMH

CI ^NMH 558.18 2.3

Cl

532.3 2.42

524.22 2.37 ""NsIH

Cl

6 Cl 558.18 2.51

*N\IH

Cl

554.29 2.34

^-NH

CH

8 "NMH 520.27 1.92 .CHQ O

Us 580.29 1.65 ^SvIH' -CH3 ,CH, O' ,0 H3C

10 520.27 1.88 "*NMH ^CH, 508.25 1.87 *NsiH

558.25 2.32 ^NsIH

CF,

CX 'NslH ^CH, 550.28 2.02

.0 H3C

558.25 2.35 ^^NH

532.27 1.66

HO

594.26 2.18

CH 518.29 2.12

516.27 2,13

504.27 2.28 CH ^N 546.3 2.04

N' ^N

498.28 1.32 OH

H 3,C \ CH, 518.29 2.22

/

520.27 1.67

^N

OH

576.24 2.55

J^ CF,

y NH- ,CH, 505.27 2.18

CH.

A H 508.29 N-N

NH Λ //J^ CH; /

508.25 1.95

^H

.0 520.27 1.94 H3C

^NH 29 H 522.3 2.22 N-N

CH3

A= 3-amino-5-ethyl-1 H-pyrazole (WO 03/048133, method 6)

Example 30 /V-BenzyI-2-[3-(2-{[2-hydroxy-2-(4-hydroxyphenyl)ethyl]amino }-2- methylpropyl)phenyl]acetamide

A solution of the acid of preparation 27 (50mg, 0.12mmol), benzylamine (16mg, 0.15mmol) and O-(1 H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (58mg, 0.15mmol) in N, Λ/-dimethylformamide (3ml_) was stirred for 48 hours at room temperature. The solvent was removed iη vacuo to give the crude residue. Purification by column chromatography on silica gel using dichloromethane and then dichloromethane:methanol:0.88 ammonia (92.5:7.5:0.75) as eluent to give the desired product as a white foam, 17mg (34%). 1H NMR (400 MHz, CD3OD) δ 1.01 (3H, s), 1.04 (3H, s), 2.63-2.72 (3H1 m), 2.82-2.87 (1 H, t), 3.51 (2H, s), 4.34 (2H, s), 4.59-4.62 (1 H, bq). LRMvS: m/z APCS+ 433 [MH+].

Examples 31-42

O A solution of the acid from preparation 9 (30μmol) in N,N-dimethylformamide (200μL) was added to the appropriate amine (HNRARB) (30μmol) in N1N- dimethylformamide (100μL) and the reaction sealed and shaken. A solution of O-benzotriazoI-1-yl-A/,Λ/,/\/',/\/-tetramethyluronium hexafluorophosphate (11.38mg, 30μmol) in N,N-dimethylformamide (100μL) was added, the reaction mixture sealed and shaken and allowed to stand at room temperature for 4 days. The reaction mixture was purified directly by HPLC using a Phenomenex Luna C18 column (150x10mm, 10μm), at a flow rate of 8mL/min and detection at 225nm, using the following gradient system.

A-0.05% aqueous diethylamine B-acetonitrile Time (min) %B 0-0.2 5 0.2-8 5-95 8-9.6 95

Each product was analysed using a Phenomenex Luna C18 (30 x 4.6mm, 5μm) column at a flow rate of 2.5mL/min using the gradient described in the table below.

A-5% 6.5mM ammonium acetate in water.acetonitrile (95:5) B-acetonitrile Time (min) %B 0 0 3 95 3.5 95

Example -NRARB M+ Retention time (min) 31 488.28 1.44 32 496.27 1.66 HsC < > 33 433.24 1.19 34 450.23 1.61 35 460.27 1.74 H3C ^^ 36 ^ OCH3 462.25 1.6 37 X^ 0-CH3 462.25 1.57 38 466.2 1.7 39 458.26 1.72 40 450.23 1.62 F 41 H3C 460.27 1.7 N- Λ f- =\ / \ J

42 464.28 1.44 / N-. Λ ΛJ

H3C >

Example 43 3-{2-[(2R)-2-(3-Acetylamino-4-hydroxyphenyl)-2-hydroxyethyla mino]-2- methylpropyl}-Λ/-[2-(2-chlorophenyl)ethyl]-benzamide OH

Cl

The amide of preparation 37 and triethylamine trihydrofluoride (1 equivalent) in tetrahydrofuran (5 ml_) were stirred at room temperature for 2 days. The mixture was then concentrated in vacuo and the residue treated with methanolic ammonia and evaporated (x3) to leave a foam which was taken up in dichloromethane:methanol:0.88 ammonia, 90:10:1 filtered, then purified by column chromatography on silica gel, eluting with dichloromethane:methanol:0.88 ammonia, 90:10:1 to afford the title compound as a film which was dissolved in methanol and evaporated (x3), then suspended in diethylether and evaporated (x3) to yield colourless foam (40 mg, 95 %) 1H NMR (400MHz, CD3OD) δ: 1.05 (3H, s), 1.11 (3H, s), 2.16 93H, s), 2.70-2.97 (4H, m), 3.05 (2H, t), 3.61-3.66 (2H, m), 4.62-4.66 (1 H, m), 6.83 (1 H, d), 7.03 (1 H, d), 7.18-7.20 (2H, m), 7.30-7.38 (4H, m), 7.61-7.65 (2H, m), 7.70 (1 H, d); LRMS APCI m/z 524 [M+H]+. 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 370C 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 15627) 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 1e"9 to 1e/3e"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 (EC5O 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. lsoprenaline (Sigma, I-5627) was used as a standard in every experiment and for control wells on each plate. Data was expressed as % lsoprenaline response.

Cell Culture CHO (Chinese Hamster Ovary) cells recombinantly expressing the human β2 adrenergic receptor (from Kobilka et al., PNAS 8<4: 46-50, 1987 and Bouvier et al., MoI Pharmacol 33: 133-139 1988 CHOhβ2) were grown in Dulbeccos MEM/ NUT MIX F12 (Gibco, 21331-020) supplemented ΛΛ/ith 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/rnl 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 lsoprenaline as max controls. This was diluted 1 :2 by the add ition 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 '25I-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 been found that the compounds of formula (1 ) according to the present invention that are illustrated in examples 1 to 43 above show a β2 cAMP EC50 below 10 nM.