AU2005223488A1 - Phenylethanolamine derivatives as Beta-2 agonists - Google Patents

Description

WO 2005/090287 PCT/IB2005/000640 1 COMPOUNDS USEFUL FOR THE TREATMENT OF DISEASES This invention relates to P2 agonists of general formula: OH H HN (CH 2 )n kQ1( HO

R

1 RR1(1) HO in which R', R 2, n and Q 1 have the meanings indicated below, 5 and to processes for the preparation of, intermediates used in 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 a and P subfamilies with the p sub-family being composed of at least 3 receptor sub 10 types: p1, P2 and p3. These receptors exhibit differential expression patterns in tissues of various systems and organs of mammals. p2 adrenergic (P2) receptors are mainly expressed in smooth muscle cells (e.g. vascular, bronchial, uterine or intestinal smooth muscles), whereas P3 adrenergic receptors are mainly expressed in fat tissues (therefore P3 agonists could 15 potentially be useful in the treatment of obesity and diabetes) and $1 adrenergic receptors are mainly expressed in cardiac tissues (therefore P1 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, 20 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.

WO 2005/090287 PCT/IB2005/000640 2 Glucocorticosteroids, anti-leukotrienes, theophylline, cromones, anti cholinergics and p2 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 5 include both short and long acting inhaled p2 agonists. Short acting, rapid onset p2 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 P2 adrenoceptor expressed on airway smooth muscle cells, which results in relaxation and 10 hence bronchodilation. Thus, as functional antagonists, P2 agonists can prevent and reverse the effects of all bronchoconstrictor substances, including leukotriene D4 (LTD4), acetylcholine, bradykinin, prostaglandins, histamine and endothelins. Because P2 receptors are so widely distributed in the airway, p2 agonists may also affect other types of cells that play a role in asthma. For 15 example, it has been reported that P2 agonists may stabilize mast cells. The inhibition of the release of bronchoconstrictor substances may be how p2 agonists block the bronchoconstriction induced by allergens, exercise and cold air. Furthermore, p2 agonists inhibit cholinergic neurotransmission in the human airway, which can result in reduced cholinergic-reflex bronchoconstriction. 20 In addition to the airways, it has also been established that P2 adrenoceptors are also expressed in other organs and tissues and thus P2 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, 25 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 p2 agonists are limited in their use due to their low selectivity or adverse side-effects driven by high systemic exposure and mainly 30 mediated through action at P2 adrenoreceptors expressed outside the airways WO 2005/090287 PCT/IB2005/000640 3 (muscle tremor, tachycardia, palpitations, restlessness). Therefore there is a need for improved agents in this class. Accordingly, there is still a need for novel P2 agonists that would have an appropriate pharmacological profile, for example in terms of potency, selectivity, 5 duration of action and/or pharmacodynamic properties. In this context, the present invention relates to novel P2 agonists. EP 0654534 B1 and EP0939134 B1 disclose a process for the preparation of compounds of formula (XI):

R

1 Oz R 6 R2 H R3j R5 R10 R8 R4 R 9 10 These compounds are disclosed as anti-obesity and anti-diabetic agents having specific P3 activity. US5,561,142 discloses selective P3 agonists of formula OH R4

CHCH

2 Nf(X)m \ / 2

(CH

2 )rR7

R

5 EP0236624 discloses compounds of formula OH R 1

R

2 I - 4 R

R

0 -X-CHCH-N (CH 2 ) -Y R 15 R 3 WO 2005/090287 PCT/IB2005/000640 4 having anti-obesity and/or anti-hyperglycaemic activity coupled with good selectivity from cardiac side-effects. The invention relates to compounds of general formula (1): OH H

HNR(CH

2 )n HO (1)R HO 5 wherein the (CH 2 )n-C(=O)Ql group is in meta or para position, - R 1 and R2 are independently selected from H and C 1

-C

4 alkyl, - n is 0, 1 or 2, and, - Q 1 is a group selected from: R3 R4 R 3 R3 R8 R4 R8 R4

(CH

2 ) * - R/ *- N- R R5H 2

R

5 R6 R6 R 10 *-NH-C1-C 4 alky, and a group *-N(Ra).

2 -A, wherein - Q 2 is a single bond or a C1-C 4 alkylene, - Ra is H or C 1

-C

4 alkyl, - pis 1 or2,and - A is a C 3

-C

1 O cycloalkyl, 2 carbon atoms or more of said cycloalkyl 15 being optionally bridged by one or more carbon atoms, preferably by 1, 2, 3 or 4 carbon atoms, 0-phenyl-pyrazolyl, 5 to 10 membered heterocyclic group, optionally aromatic, comprising one, two, three or WO 2005/090287 PCT/IB2005/000640 5 four heteroatoms selected from 0, S or N, optionally substituted with C1-C4 alkyl or O-CrC4 alkyl, or a group of formula R3 R4

R

3 cR4 R4

R

5 or R7 R 6 - R 3, R4, R', R' and R' are the same or different and are selected from H, C-C4 5 alkyl, OR 9 , SR', SOR 9 , SO 2

R

9 , halo, CN, CF 3 , OCF 3 , phenyl, O-phenyl, S phenyl, S0 2 -morpholinyl, O-(CH 2

)

3 -pyrrolidinyl, COOR 9 , S0 2

NR

9

R

0 ,

CONR

9

R

1 ", NR 9

R

1 0 and NHCOR 10 ; - R 9 and R 1 0 are the same or different and are selected from H or CrC4 alkyl and the * represents the attachment point to the carbonyl group; 10 or, if appropriate, their pharmaceutically acceptable salts and/or isomers, tautomers, solvates or isotopic variations thereof, with the proviso that when n is 0, then Q' is not -NHCH 3 , and, when n is 1 or 2, then: 1) Q 1 is *-NH-CiC 4 alkyl, or *-N(R8)_Q 2 -A where A is 15 - C3-C10 cycloalkyl, 2 carbon atoms or more of said cycloalkyl being optionally bridged by one or more carbon atoms, - 0-phenyl-pyrazolyl, - 5 to 10 membered heterocyclic group, optionally aromatic, comprinsing one, two, three or four heteroatoms selected from 0, S 20 or N optionally substituted with C1C4 alkyl or O-CrC4 alkyl, said heterocyclic group being other than pyridyl, - a group of formula WO 2005/090287 PCT/IB2005/000640 6 R3 R4 R3 R4

-.-

RR R5 or R7 R wherein one of R 3 to R 7 is CN, SOR 9 , SO 2

R

9 , phenyl, O-phenyl, S-phenyl, S0 2 -morpholinyl or O-(CH 2

)

3 pyrrolidinyl and/or, 2) when one of R 1 and R 2 is H, the other is not CH 3 . 5 It has now been found that the compounds of formula (1) are agonists of the P2 receptors, that are particularly useful for the treatment of p2-mediated diseases and/or conditions, and show good potency, in particular when administered via the inhalation route. In the present invention, the term "potent" means that the compounds of 10 formula (1) show an agonist potency for the P2 receptor, which is less than 10 nM as measured by the cell-based assay described herein. Preferably, the compounds of the invention are selective agonists of the P2 receptor. Preferably, the compounds of the invention show an agonist potency for the P2 receptor, which is at least about 100-fold higher as for the P3 receptor and 15 at least about 500-fold higher as for the P1 receptor. In the here above general formula (1), Cl-C 4 alkyl and C 1

-C

4 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-(C 1

-C

4 )alkyl radicals, S-(C1-C 4 )alkyl radicals etc... . 20 Examples of suitable (C1-C4)alkyl radicals are methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl.... Examples of suitable O-(C 1

-C

4 )alkyl radicals are methoxy, ethoxy, n-propyloxy, iso-propyloxy, n-butyloxy, iso-butyloxy, sec-butyloxy and tet-butyloxy....

WO 2005/090287 PCT/IB2005/000640 7 The C 3

-C

10 cycloalkyl wherein 2 carbon atoms or more are optionally bridged by one or more carbon atoms include 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 5 cyclohexyl and adamantyl. Examples of 5 to 10 membered heterocyclic group, optionally aromatic, comprinsing one, two, three or four heteroatoms independently selected from 0, S or N are morpholinyl, pyrrolidinyl, piperidyl, piperazinyl, thienyl, isothiazolyl, oxazolyl, pyridyl, pyrimidyl oxazolyl, isoxazolyl, thiazolyl, furanyl, imidazolyl, 10 pyrazolyl, pyrrolyl, pyridazinyl, pyrazinyl, triazolyl, tetrazolyl, oxadiazolyl, triazinyl, indolyl, quinolyl, isoquinolyl, benzofuranyl, quinazolyl, quinoxalyl, phthalazinyl, benzothiazolyl, benzoxazolyl, benzisothiazolyl, benzisoxazolyl, benzimidazolyl, indazolyl and benzotriazolyl. Preferred heterocyclic groups are pyrrolidinyl, pyridyl, pyrimidyl, quinolyl, 15 isoquinolyl, benzoimidazolyl and benzofuranyl. Preferably said heterocyclic group contains 1 or 2 heteroatoms selected from 0, S or N. More preferably said heterocyclic group contains one or two nitrogen atoms. Finally, halo denotes a halogen atom selected from the group consisting 20 of fluoro, chloro, bromo and iodo in particular fluoro or chloro. In the following, the free bond on the phenyl group such as in the structure below, means that the phenyl can be substituted in the meta or para position. 25 The compounds of the formula (1) WO 2005/090287 PCT/IB2005/000640 8 OH H HO N (CH 2 )n Q1( HO

R

1

R

2 (1 HO can be prepared using conventional procedures such as by the following illustrative methods in which Q1, Q2 , A and n are as previously defined for the compounds of the formula (1) unless otherwise stated. 5 The amide derivatives of the formula (1) may be prepared by coupling an acid of formula (2): OH H N (2) HO

R

1

R

2 OH HO with an amine of formula NH 2

-C-C

4 alkyl, -NH(R )-Q2 -A,

R

3 R4 R3 R3

R

8

R

4 R8R

(CH

2 )p

R

5 H H R5 2 R HN 10 R , or R, R 6 wherein R 8 , Q 2 , A, p and R 3 to R 6 are as previously defined for compounds of formula (1). 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 15 ethylcarbodiimide hydrochloride or N, N'-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.

WO 2005/090287 PCT/IB2005/000640 9 N-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 0 C and 40*C (room temperature) for a 5 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, protection, deprotection etc...) from commercially available material. 10 The acid of formula (2) may be prepared from the corresponding ester of formula (4): OH H N (4) (CH2)n ORa HO /

R

1

R

2 O HO wherein Ra is a suitable acid protecting group, preferably a (C 1

-C

4 )alkyl group, which includes, but is not limited to, methyl and ethyl, according to any method 15 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), 20 at a temperature comprised between 20 0 C and 100*C, for a period of 1 to 40 hours. The ester of formula (4) may be prepared by reaction of an amine of formula (5): WO 2005/090287 PCT/IB2005/000640 10 H2N (5) (CH2)n ORa R1lR2 0 wherein Ra and n are as previously defined, with a bromide of formula (6): OH Br HO (6) HO In a typical procedure, the amine of formula (5) is reacted with a bromide 5 of formula (6) optionally in the presence of a solvent or mixture of solvents (e.g. dimethyl sulphoxide, toluene, N,N-dimethylformamide, acetonitrile), optionally in the presence of a suitable base (e.g. triethylamine, diisopropylethylamine, potassium carbonate) at a temperature comprised between 80*C and 120 0 C, for 12 to 48 hours. 10 The bromide of formula (6) may be prepared from the ester of formula (7): OH Br HO (7) 0 0

CH

3 according to any method well-known to the one skilled in the art to prepare an alcohol from an ester, without modifying the rest of the molecule. 15 In a typical procedure, the ester of formula (7) is reduced with borane dimethylsulfide complex in tetrahydrofuran at a reflux for a period of 2 hours.

WO 2005/090287 PCT/IB2005/000640 11 The alcohol of formula (7) may be prepared as either the (R) or (S) enantiomer according to methods well described in the literature (Tetrahedron Letters 1994, 35(50), 9375). The amine of formula (5) may be prepared as either the (R) or (S) 5 enantiomer from the corresponding protected amine of formula (8): Rc RbN (CH 2 )n ORa (8)

R

1

R

2 -Y 0 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 a-methylbenzyl), provided that the bonds between N 10 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-Interscience Publication, 1981. The amine of formula (8) may be prepared as a single diastereomer by 15 reaction of an amine of formula HNRbRc with a ketone of formula (9): H C,. (9) H (CH 2 )n ORa wherein Ra, Rb, Rc and n are as previously defined. In a typical procedure, the reaction of the ketone of formula (9) with the amine of formula HNRbRc leads to a chiral intermediate which is in turn 20 reduced by a suitable reducing agent (e.g. sodium cyanoborohydride of formula NaCNBH 3 or sodium triacetoxyborohydride of formula Na(OAc) 3 BH) 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 WO 2005/090287 PCT/IB2005/000640 12 amine of formula (8) as a mixture of diastereomers. The reaction is generally done in a solvent such as tetrahydrofuran or dichloromethane at a temperature comprised between 20"C and 80 0 C for 3 to 72 hours. The resulting product is then converted to the hydrochloride salt and selectively crystallised from a 5 suitable solvent or mixture of solvents (e.g. isopropanol, ethanol, methanol, diisopropyl ether or diisopropyl ether/methanol) to give (8) as a single diastereomer. The ketone of formula (9) where n=1 may be prepared by palladium mediated coupling of an aryl halide of formula (10): Hal ' H ORa (10) 10 0 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 (10) is reacted with a tin 15 enolate generated in-situ by treatment of isopropenyl acetate with tri-n-butyltin methoxide of formula Bu 3 SnOMe in the presence of a suitable palladium catalyst (palladium acetate/ tri-ortho-tolylphosphine of formula Pd(OAc) 2 /P(o Tol) 3 ) in a non-polar solvent (e.g. toluene, benzene, hexane). Preferably, the reaction is carried out at a temperature comprised between 80*C and 110*C for 20 6 to 16 hours. The aryl halide of formula (10) may be obtained by esterification of the corresponding acid of formula (11): Hal O OH (11) 0 WO 2005/090287 PCT/IB2005/000640 13 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 (11) is reacted with an 5 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 10 0 C and 40 0 C (room temperature) for 8 to 16 hours. The acid of formula (11) is a commercial product. The amine of formula (5), where R 1 and R 2 are both the same C 1

-C

4 alkyl, may 10 be prepared according to the following scheme: Scheme 1 0 RaO 0 HO (CH2)n OH 1 1

(CH

2 )I OH RI R 2 (12) (13) H2N

(CH

2 )n ORa

RR

2 X15 (5) wherein R 1 , R 2 and Ra are as previously defined. In a typical procedure, the ester of formula (12) is reacted with an 15 "activated" alkyl (organometallic alkyl such as R 2 MgBr, R 2 MgCI or R 2 Li) to give the corresponding tertiary alcohol of formula (13) using the method described above. Said tertiary alcohol of formula (13) is then treated with an alkyl nitrile (e.g. acetonitrile, chloroacetonitrile) in the presence of an acid (e.g. sulphuric 20 acid, acetic acid) to give a protected intermediate which is in turn cleaved using standard methodology for cleaving nitrogen protecting group such as those WO 2005/090287 PCT/IB2005/000640 14 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 R are R 2 both the same C1-C 4 alkyl and n=0, may be prepared according to the following scheme: 5 Scheme 2 RaO Br HO Br 0 R 1 R (14) (15) H2N H2NR 0

R

1

R

2 BrR 1

R

2 ORa (16) (5) wherein R 1 , R 2 and Ra are as previously defined. In a typical procedure, the ester of formula (14) is reacted with an "activated" alkyl (organometallic alkyl such as R 2MgBr, R 2MgCI or R 2 Li) to give 10 the corresponding tertiary alcohol of formula (15) using the method described above. Said tertiary alcohol of formula (15) 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 15 standard methodology for cleaving nitrogen protecting group such as those mentioned in textbooks to give the bromo amine (16). The resulting bromo amine (16) is treated with a suitable palladium catalyst (e.g. [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(Il)) under an atmosphere of carbon monoxide using RaOH as solvent (e.g. MeOH, EtOH) 20 at elevated temperature (100 0 C) and pressure (100psi) to give the ester of formula (5).

WO 2005/090287 PCT/IB2005/000640 15 The ketone of formula (9) where n=2 may be prepared by reduction of an alkene of formula (17): H C 0 -~ (17) 0 ORa In a typical procedure, a solution of the olefin of formula (17) in a suitable 5 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 60 0 C for 8-24 hours. The alkene of formula (17) may be prepared by a palladium mediated 10 coupling of an activated olefin with an aryl halide of formula (18): H3C Hal (18) In a typical procedure, the aryl halide (18) 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(PPh 3

)

4 , palladium 15 acetate/tri-ortho-tolylphosphine of formula Pd(OAc) 2 /P(o-tol)3 or (diphenylphosphino)ferrocenyl palladium chloride of formula dppfPdC 2 ) in a sutiable solvent (e.g. acetonitrile, N, N-dimethylformamide, toluene), optionally in the presence of a base such as triethylamine at a temperature between 400C and 110*C for 8 to 24 hours. 20 The ketone of formula (18) is a commercial product. The amine of formula (5), where R1 and R2 are both H and n is 1, may be prepared according to the following scheme: Scheme 3 WO 2005/090287 PCT/IB2005/000640 16 HO HO HO(CH 2 ) ORa (CH ORa (19) (20) 0

H

2 N -~ H2N (CH 2 ) ORa wherein R 1 , R 2 and Ra are as previously defined. In a typical procedure, the acid of formula (19) is preferentially reduced to the corresponding alcohol (20) in the presence of the ester. This may be 5 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 (20) is then converted into a leaving group such as mesylate, tosylate, bromide or iodide and displaced with 10 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. 15 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 20 particular methods of protection and deprotection such as those described by T.W. GREENE (Protective Groups in Organic Synthesis, A. Wiley-Interscience WO 2005/090287 PCT/IB2005/000640 17 Publication, 1981) or by P. J. Kocienski (Protecting groups, Georg Thieme Verlag, 1994), can be used. Alternatively, compounds of general formula (1) can also be prepared according 5 to the following scheme: Where in R 1 , R 2 , Ra, Rb, Rc, n and Q 1 are as previously defined. Scheme 4 Rc Rc

R

1 2

(CH

2 )n ORa Rb'R2 if' R 1

R

2 I (CH) O 0 (8) (21) 0 Rc HR R(CH 2 )n Q Rb' Ri NR On 2 I (CH 2 ) Q (23) (22) 0 PG Br PG' , -0 (6) 9 HO H H "N

SR

1 2

(CH

2 )n Q HO -Y 10 HO O PG is a suitable bulky hydroxyl-protecting group and is preferably TBDMS PG' is a suitable hydroxyl-protecting group such as benzyl WO 2005/090287 PCT/IB2005/000640 18 In a typical procedure, the acid of formula (21) is obtained by hydrolysis of the ester of formula (8). This is achieved 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. 5 water, 1,4-dioxan, tetrahydrofuran/water), at a temperature comprised between 200C and 100*C, for a period of 1 to 40 hours. Amide of formula (22) is prepared by coupling of acid (21) with a suitable amine of formula (3), (3') or (3"). The coupling is generally carried out in an 10 excess of said amine as an acid receptor, with a conventional coupling agent (e.g. 2-chloro-1,3-dimethylimidazolidinum hexafluorophosphate, 1-(3 dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride or N, N' dicyclohexylcarbodiimide), optionally in the presence of a catalyst (e.g. 1 hydroxybenzotriazole hydrate or 1-hydroxy-7-azabenzotriazole), and optionally 15 in the presence of a tertiary amine base (e.g. N-methylmorpholine, triethylamine or N,N-diisopropylethylamine). The reaction may be undertaken in a suitable solvent such as pyridine, N,N-dimethylformamide, tetrahydrofuran, dimethylsulfoxide, dichloromethane or ethyl acetate, and at temperature comprised between 100C and 40'C (room temperature) for a period of 1-24 20 hours. Said amine (3), (3') or (3") 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, protection, deprotection etc) from commercially available 25 material. The amine of formula (23) can be prepared 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-Interscience 30 Publication, 1981.

WO 2005/090287 PCT/IB2005/000640 19 When Rb or Rc=a-methylbenzyl, a typical deprotection procedure involves treatment of a solution of the protected amine of formula (22), in a suitable solvent (e.g. methanol, ethanol, ethyl acetate), with a suitable hydrogen donor 5 such as ammonium formate or formic acid in the presence of a suitable palladium catalyst (e.g. 20% palladium hydroxide on charcoal), at a temperature between 25 0 C and elevated temperature, for 1-4 hours. Compounds of formula (1) can be obtained by reaction of said amine (23) with 10 a bromide of formula (6). In a typical procedure amine (23) and bromide (6) can be heated together, optionally in the presence of a suitable solvent (e.g. toluene or xylene) and a suitable tertiary amine base (e.g. N-methylmorpholine, triethylamine or N,N-diisopropylethylamine) at elevated temperature, for 18-48 hours. 15 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 hydroxyl functions that are not wished to react, and to cleave said protecting groups in consequence. In such a case, any compatible protecting radical can 20 be used. In particular methods of protection and deprotection such as those described by T.W. GREENE (Protective Groups in Organic Synthesis, A. Wiley Interscience Publication, 1981) or by P. J. Kocienski (Protecting groups, Georg Thieme Verlag, 1994), can be used. 25 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 30 hereto.

WO 2005/090287 PCT/IB2005/000640 20 Also, the compounds of formula (1) as well as intermediate for the preparation thereof can be purified according to various well-known methods, such as for example crystallization or chromatography. 5 Compounds of formula (I) wherein, - R1 and R2 are independently selected from H and C 1

-C

4 alkyl, - n is 0, 1 or 2 and, - Q 1 is a group selected from: R3 R4 RR 3 - I

(CH

2 )p R 5 * \ R5 NA# *R6 R6 10 *-NH-C1-C 4 alkyl, and a group *-N(R 8

)_Q

2 -A, wherein - Q 2 is a single bond or a C 1

-C

4 alkylene, - RB is H or C 1

-C

4 alkyl, - pis 1 or2, and - A is a C 3

-C

10 cycloalkyl, 2 carbon atoms or more of said cycloalkyl 15 being optionally bridged by one or more carbon atoms, pyridyl, or a group of formula R3 R4 R3 R4 -- R R5 or Ry R6 WO 2005/090287 PCT/IB2005/000640 21 - R 3, R4 R , R and R are the same or different and are selected from H, C1-C4 alkyl, OR 9 , SR9, SOR 9 , SO 2

R

9 , halo, CN, CF 3 , OCF 3 , COOR 9 , S0 2

NR

9

R

10 ,

CONR

9

R

1 , NR 9

R

0 , NHCOR 0 ; - R 9 and R 10 are the same or different and are selected from H or C1-C4 alkyl 5 and the * represent the attachment point to the carbonyl group; or, if appropriate, their pharmaceutically acceptable salts and/or isomers, tautomers, solvates or isotopic variations thereof, with the proviso that when n is 0, then Q 1 is not -NHCH 3 , and, when n is 1 or 2, then: 10 1) Q' is *-NH-C1-C 4 alkyl, or *-N(R8)_Q 2 -A where A is C3-C10 cycloalkyl, 2 carbon atoms or more of said cycloalkyl being optionally bridged by one or more carbon atoms, and/or, 2) when one of R 1 and R 2 is H, the other is not CH 3 15 are preferred A preferred *-NH-C1-C 4 alkyl is NH-isopropyl. Preferred compounds of formula 1 are those wherein Q 1 is *-N(R )_Q 2 -A where 20 A is C3-C10 cycloalkyl, 2 carbon atoms or more of said cycloalkyl being optionally bridged by one or more carbon atoms, preferably cyclohexyl, or adamantyl. More preferably, n is 1, Q2 is CH 2 or a bond and A is C3-C10 cycloalkyl, 2 carbon 25 atoms or more of said cycloalkyl being optionally bridged by one or more carbon atoms, preferably cyclohexyl, or adamantyl. Other preferred compounds of formula (1) are those wherein n is 0. Preferably n is 0 and Q 1 is a group of formula WO 2005/090287 PCT/IB2005/000640 22 R3 R4

R

3

R

8 R4 - I (CHO R5*-N|

(CH

2 )p \ / R 5

R

5

R

6 6 or *-N(RS).Q 2 -A, wherein Q 2 is a single bond or a Cl-C 4 alkylene, R 8 is H and A is naphthyl or R3 R4 R5 R7 R6 5 wherein R3, R 4, R , R and R are the same or different and are selected from H, Cr-C4 alkyl, OR 9 , SR', SOR 9 , S0 2

R

9 , halo, CF 3 , OCF 3 , COOR 9 , S0 2

NR

9 R'",

CONR

9 R 0 , NR 9

R

10 , NHCOR 10 , wherein at least 2 of R 3 to R 7 are equal to H; wherein R 9 and R 0 are the same or different and are selected from H or C-C 4 alkyl and the * represent the attachment point to the carbonyl group. 10 Preferably Q 1 is *-N *--N H or a group *-N(RS)_Q -A, wherein Q 2 is a single bond or a Cr-C4 alkylene, R8 is H or Cr-C4 alkyl, and A is a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 15 cycloheptyl, adamantyl, naphthyl or a group of formula WO 2005/090287 PCT/IB2005/000640 23 R3 R4 R5 R7 R 6 wherein R , R 4, R , R and R are as defined above. Preferably, A is a group of formula R3 R4 R5

R

7 R6 5 wherein R 3 , R 4 , R 5 , R 6 and R 7 are selected from H, C1-C4 alkyl, OR', SR', Cl, F,

CF

3 , OCF 3 , COOR 9 , SO 2

NR

9

R

10 , and at least 2 of R 3 to R 7 represent H, wherein R 9 and R 10 are the same or different and are selected from H or C1-C4 alkyl. Preferably, R 3, R 4, R5, R and R are the same or different and are selected 10 from H, CH 3 , OH, OCH 3 , SCH 3 , OCH 2

CH

3 , Cl, F, CF 3 , OCF 3 , COOH, SO 2

NH

2 , and at least 2 of R 3 to R 7 represent H. Preferably, R 3, R 4, R , R and R are the same or different and are selected from H, CH 3 , OH, OCH 3 , OCH 2

CH

3 , Cl, F, CF 3 , OCF 3 , COOH, SO 2

NH

2 , and at least 3 of R 3 to R 7 are represent H. 15 Preferably, R 8 is H, methyl or ethyl, more preferably H. Preferably, Q 2 is selected from a bond, -CH 2 -, -(CH 2

)

2 -, -(CH 2

)

3 -, -C(CH 3

)

2 CH 2 -, -CH 2

-C(CH

3

)

2 -, and -CH(CH 3 )-. 20 WO 2005/090287 PCT/IB2005/000640 24 Preferably n is 0 or 1. In the above groups of compounds,, the following substituents are preferred:

R

1 and R 2 are both CH 3 or, 5 R 1 is H and R 2 is CH 3 or CH 2

-CH

3 or,

R

1 and R 2 are both H. Particularly preferred are the compounds of the formula (1) as described in the Examples section hereafter, i.e. : 10 N-cycloheptyl-2-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3 (hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}acetamide; N-(cyclohexylmethyl)-2-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3 (hyd roxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N-methylacetamide; N-[(1 S)-1-cyclohexylethyl]-2-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3 15 (hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}acetamide; 2-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3 (hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N-isopropylacetamide; N-cyclopentyl-2-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3 (hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}acetamide; 20 N-(cyclobutylmethyl)-2-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3 (hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}acetamide; N-(cyclopentylmethyl)-2-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3 (hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl)acetamide; N-cyclohexyl-2-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3 25 (hydroxymethyl)phenyllethyl}amino)propyl]phenyl}acetamide; N-cyclobutyl-2-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3 (hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}acetamide; N-(cyclohexylmethyl)-2-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3 (hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}acetamide; 30 N-(cyclopropylmethyl)-2-{3-[(2R)-2-(((2R)-2-hyd roxy-2-[4-hydroxy-3 (hydroxymethyl)phenyllethyl}amino)propyl]phenyl}acetamide; WO 2005/090287 PCT/1B2005/0006tO 25 N-(cycloheptylmethyl )-2-{3-[(2R)-2-((2R)-2-hydroxy-2-14-hydroxy-3 (hyd roxymethyl )phenyllethyllami no)propyl] phenylacetamide; N-I -adamantyI-2-{3-[(2R)-2-({(2R)-2-hyd roxy-2-[4-hyd roxy-3 (hydroxymethyl )phenylethyllamino)propyllphenyllacetamide; 5 N-( 1 -adamantylmethyl )-2-{3-((2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3 (hydroxymethyl )phenyl]ethyl~a mino)propyl]phenyl~acetanhide; N-2-adama ntyI-2-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hyd roxy-3 (hydroxymethyl)phenyllethyllamilo)propyI]pheflIacetamide; N-(2-cyclohexylethy)-2-{3-[(2R)-2-((2R)-2-hydroxy-2-I4-hyd roxy-3 10 (hydroxymethyl)phenyllethyl}amino)propyllphel-N-methYlacetamide; N-cycloheptyl-2-{3-iI(2R)-2-({(2R)-2-hyd roxy-2-[4-hydroxy-3 (hydroxymethyl )phenyl]ethyl}amino)propyllphenyl}-N-mlethylaceta mide; N-cyclohexyl-N-ethyl-2-{3-[(2R)-2-((2R)-2-hyd roxy-2-14-hyd roxy-3 (hyd roxymethyl)p hen yl]ethyl)am io)propy] phelaceta mide; 15 N-(2-cycohexylethyl)-2-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3 (hyd roxymethyI)phenyl]ethyl)amilo)propyIphelIacetam ide; N-(4-chlorobenzyl )-2-{3-[2-({(2 R)-2-hyd roxy-2-[4-hydroxy-3 (hydroxymethyl)phenyl]ethyllamiflo)-2-methylpropylpheflyllacetamide; N-(2 ,6-dimethoxybenzyl)-2-{3-12-({(2R)-2-hydroxy-2-[4-hYdroxy-3 20 (hydroxymethy)phel]ethy}amilo)-2-methYlpropyllphefllacetamide; N-benzyl-2-{3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3 (hyd roxymethyl)phenylljethyl}amino)-2-methyl propyl]phenyl}acetamide; 4-[(l1 R)-2-[(2-(3-[2-(3 .4-dihyd roisoqu inolin-2( I H)-yI )-2-oxoethyl]phenyl}-l 11 dimethylethyl)amino]l1 -hyd roxyethyl}-2-(hydroxymethyl)pheflol; 25 N-[2-fluoro-5-(trifluoromethyl )benzylj-2-{3-[2-({(2R)-2-hyd roxy-2-[4-hydroxy-3 (hydroxymethyl)phenylethyllamino)-2-methypropyI]phel}acetamide; N-(2,6-dichlorobenzyl)-2-{3-[2-({(2R)-2-hydroxy-2-4-hydroxy-3 (hydroxymethyl )phenyllethyllamino)-2-methypropyIIIphenylaceta mide; 2-{3-12-({(2R)-2-hydroxy-2-[4-hyd roxy-3-(hyd roxymethyl)phenyl]ethyllamino)-2 30 methylpropyl]phenyl}-N-[2-(methylthio)benzylhlacetamide; N-(2,3-d imethyl benzyl)-2-{3-[2-({(2 R)-2-hyd roxy-2-[4-hydroxy-3 (hYdroxymethyl)phenyllethyl~am ino)-2-methylpropyI] phenylacetamide; WO 2005/090287 PCT/11B2005/000640 26 2-{3-[2-({(2R)-2-hyd roxy-2-[4-hyd roxy-3-(hydroxymethyl )phenyllethyl)amino)-2 methyl pro pyi]ph enyl)-N-[3-(trifluoromethyl) benzyflaceta mide; N-[4-chloro-3-(trifluoromethyl)benzyl]-2-{3-[2-({(2R)-2-hyd roxy-2-[4-hyd roxy-3 (hyd roxymethyl )phenyl]ethyl~amino)-2-methylpropyl] phenylacetamide; 5 N-[2-chloro-5-(trifluoromethyl)benzyl]-2-{3-[2-({(2R)-2-hyd roxy-2-[4-hyd roxy-3 (hydroxymethyl)pheny]ethyl}amino)-2-methylpropyl]phenyl}acetamide; N-[3 ,5-bis(trifl uoromethyl)benzyl]-2-{3-[2-({(2R)-2-hyd roxy-2-[4-hydroxy-3 (hyd roxymethyl )phenyl]ethyl}amino)-2-methylpropyl] phenylacetamide; N-[3-fluoro-5-(trifl uoromethyl )benzyl]-2-{3-[2-({(2R)-2-hyd roxy-2-[4-hyd roxy-3 10 (hydroxymethyl)phenyl]ethyl)amino)-2-methylpropyllphenyl~acetamide; N-[2-(4-chlorophenyl )ethyl]-3-{2-[(2R)-2-hydroxy-2-(4-hydroxy-3-hyd roxy methyiphenyl)ethylamino]-2-methylpropyl}benzamide; 3-{2-[(2R)-2-hyd roxy-2-(4-hyd roxy-3-hyd roxymethyiphenyl )-ethyla mino]-2 methyl pro pyl)-N-[2-(4-methyl phe nyl)ethyl] benzam ide; 15 3-{2-[(2R)-2-hyd roxy-2-(4-hyd roxy-3-hyd roxymethyiphenyl )-ethylamino]-2 methyI-propyI}-N-[2-(4-trifluoromethyI ph enyI)ethyIl benza mid e; N-[2-(3 ,4-d ichiorophenyl )ethyl]-3-{2-[(2R)-2-hyd roxy-2-(4-hyd roxy-3 hydroxymethylphenyl)ethylamino]-2-methyl-propyl}-benzamide; N-[2-(3,4-d imethyl phenyl )ethyl]-3-{2-[(2R)-2-hyd roxy-2-(4-hyd roxy-3 20 hydroxymethylpheny)-ethylamino]-2-methylpropyllbenzamide; 3-{2-[(2R)-2-hyd roxy-2-(4-hyd roxy-3-hyd roxymethyl-phenyl )ethyla mino]-2 methyl-propyl)-N-(2-naphthalen-2-yI-ethyl)benza mide; N-(l 1 -d imethyl-2-phenylethyl )-3-{2-[(2R)-2-hydroxy-2-(4-hyd roxy-3-hydroxy methylphenyl)-ethylamino]-2-methylpropyl~benzamide; 25 3-{2-[(2R)-2-hyd roxy-2-(4-hyd roxy-3-hyd roxymethyiphenyl )-ethylam ino]-2 methyl propyl}-N-(2-methyl-2-phe nyl pro pyl )benzam id e; N-(4-chlorobenzyl )-3-{2-[(2R)-2-hyd roxy-2-(4-hyd roxy-3-hyd roxy methylphenyl)ethylamino]-2-methylpropyllbenzamide; N-(2 ,6-d imethoxybenzyl )-2-{3-[2-({(2R)-2-hyd roxy-2-[4-hydroxy-3 30 (hydroxymethyl)phenyllethyl~amino)ethyl]phenyl~acetamide; N-(3 ,4-d ichlorobenzyl )-2-{3-12-({(2R)-2-hyd roxy-2-[4-hyd roxy-3 (hydroxymethyl )phenyllethyl~amino)ethyl]phenyl~acetamide; WO 2005/090287 PCT/11B2005/000640 27 N-benzyl-2-{3-[2.-({(2R)-2-hyd roxy-2-[4-hyd roxy-3 (hydroxymethyl)phenyljethyllamino)ethyflphenyl~acetamid e; N-(2 ,3-d ihydro-1 H-i nden-2-yI )-2-{3-[2-({(2R)-2-hyd roxy-2-[4-hyd roxy-3 (hydroxymethyl)phenyl]ethyllamino)ethyl]phenyl}acetamide; 5 2-(3-[2-({(2R)-2-hyd roxy-2-[4-hydroxy-3 (hydroxymethyI)pheny~ethy~amino)ethy]pheny}-N-(2-phenylethy)acetamide; 2-{3-[2-({(2R)-2-hyd roxy-2-[4-hyd roxy-3 (hydroxymethyl)phenyllethy~amino)ethyl]phenyl-N-(3-phenylpropyl )acetamide; N-benzyl-3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3 10 (hyd roxym ethyl) phenyl] ethyllam ino)propyl] be nzam id e; N-(3 ,4-dichlorobenzyl)-3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3 (hydroxymethyl)phenyl]ethyl}amino)propyl]benzamide; N-[2-fluoro-5-(trifluoromethyI)benzyI]-3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3 (hydroxymethyl)phenyl]ethyilamino)propyl]benzamide; 15 N-(2,6-dimethoxybenzyl)-3-[(2R)-2-({(2R)-2-hyd roxy-2-[4-hydroxy-3 (hydroxymethyl )phenyl]ethy!)amino)propyl]benzamide; N-[2-(4-chlorophenyl )ethylj-3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hyd roxy-3 (hydroxymethyl)phenyl]ethyl}amino)propyl]benzamide; N-(2 ,3-d ihydro- I H-nd en-2-yI)-3-[(2R)-2-({(2R)-2-hyd roxy-2-[4-hyd roxy-3 20 (hyd roxymethyl)phenyl]ethyl~amino)propyl]benzamide; 3-[(2R)-2-({(2R)-2-hyd roxy-2-[4-hyd roxy-3 (hydroxymethyl)phenyl]ethylamino)propyll-N-(2-phenylethyl )benzamide; 3-[(2R)-2-({(2R)-2-hyd roxy-2-[4-hyd roxy-3 (hydroxymethyl)phenyl]ethyl}amino)propyl]-N-[( I R)-1 -phenylethyl]benzamide; 25 3-[(2R)-2-({(2R)-2-hyd roxy-2-[4-hyd roxy-3 (hyd roxymethyl )phenyl]ethyllamino)propyl]-N-(3-phenylpropyl)benzamide; 4-[( 1 R)-2-({(1 R)-2-[3-(3,4-dihydroisoquinolin-2(1 H)-ylcarbonyl)phenyl]-l methylethyllamino)-1 -hydroxyethyl]-2-(hydroxymethyl)phenol; N-(2,3-d imethyl benzyl )-3-[(2R)-2-({(2R)-2-hyd roxy-2-[4-hydroxy-3 30 (h yd roxym ethyl )p henyl]ethyl}a mi no)propyll benza mid e; N-(5 ,6-d iethyl-2 ,3-d ihyd ro-1 H-inden-2-yI )-3-[(2R)-2-({(2R)-2-hyd roxy-2-[4 hyd roxy-3-(hydroxymethyl )phenyl]ethyllam ino)propyl] benzamide; WO 2005/090287 PCT/1B2005/000640 28 N-(4-ch Iorobenzyl )-3-I(2R)-2-({(2R)-2-hyd roxy-2-[4-hydroxy-3 (hyd roxymeth yl)p hen yl] ethyl~a m ino)propyll benza mid e; 3-[(2R)-2-({(2R)-2-hyd roxy-2-[4-hyd roxy-3 (hydroxymethyl)phenyl]ethyllamino)propyl]-N-phenylbenzamide; 5 N-[4-(a minosulfonyl )benzyl]-3-[(2R)-2-({(2R)-2-hyd roxy-2-[4-hyd roxy-3 (hydroxymethyl)phenyl]ethyl~amino)propyl]benzamide; N-[2-(3-Fluorophenyl )ethyl]-3-[2-({(2R)-2-hydroxy-2-[4-hyd roxy-3 (h yd roxymethyl)p henyl] ethylla mi no)-2-meth yl propylljbe nza mid e; 3-[2-({(2R)-2-hyd roxy-2-[4-hyd roxy-3-(hydroxymethyl )phenyl]ethyllamino)-2 10 methylpropyl]-N-(2-pyrrolidin- I -ylethyl)benzamide; N-[2-(2,6-d ich lorophenyl )ethyl]-3-[2-(((2R)-2-hyd roxy-2-[4-hyd roxy-3 (hyd roxymethyl)phenyl]ethyl~ami no)-2-methylpropyl] benzamide; N-(2 ,3-dihyd ro-1 H-inden-2-yI methyl )-3-[2-(((2 R)-2-hyd roxy-2-[4-hyd roxy-3 (hydroxymethyl)phenyl]ethyllamino)-2-methylpropyl]benza mide; 15 N-(2-{4-[(butylamino)carbonyl] phenyl~ethyl)-3-[2-({(2 R)-2-hyd roxy-2-[4-hyd roxy 3-(h yd roxymethyl )ph enyl]eth yl}a m ino)-2-methyl pro pyl] be nza mid e; 3-[2-({(2R)-2-hyd roxy-2-[4-hyd roxy-3-(hydroxymethyl)phenyl]ethyl~amino)-2 methylpropyl]-N-{2-[2-(phenylthio)phenyl]ethyl}benzamide; N-(2-cyclohexylethyl )-3-[2-({(2R)-2-hydroxy-2-[4-hyd roxy-3 20 (hydroxymethyl)phenyl]ethyl}a mino)-2-methyl propyl]benza mide; 3-[2-({(2R)-2-hydroxy-2-[4-hyd roxy-3-(hyd roxymethyl)phenyl]ethyl~a mi no)-2 methylpropyl]-N-(3-phenylpropyl)benzamide; 3-[2-({(2R)-2-hydroxy-2-[4-hyd roxy-3-(hyd roxymethyl)phenyl]ethyllami no)-2 methylpropyl]-N-(2-phenylethyl)benzamide; 25 N-[2-(3 ,6-d ichloro-2-methyl phenyl)ethyll-3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3 (hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]benzamide; N-[2-(5-chloro-2-methoxyphenyl )ethyl]-3-[2-({(2 R)-2-hydroxy-2-[4-hyd roxy-3 (hyd roxymethyl)phe nyl] ethyl}a m ino)-2-meth yl pro pyl] benzamrnide; 3-[2-({(2R)-2-hydroxy-2-[4-hyd roxy-3-(hyd roxymethyl)phenyljethyl}amino)-2 30 methylpropyl]-N-[2-(3-methoxyphenyl)ethyllbenzamide; N-[2-(3-ethoxyphenyl )ethyl]-3-[2-({(2R)-2-.hydroxy-2-[4-hyd roxy-3 (hydroxymethyl)phenyllethyllamino)-2-methylpropyl]benzamide; WO 2005/090287 PCT/11B2005/000640 29 3-[2-({(2 R)-2-hyd roxy-2-[4-hydroxy-3-(hyd roxymethyl)pheny]ethyl}a mino)-2 methylpropyl]-N-{2-[4-(3-pyrrolid in-I -ylpropoxy)phenyl]ethyl)benzamide; 3-[2-({(2 R)-2-hyd roxy-2-[4-hyd roxy-3-(hyd roxymethyl )phenyl]ethylla mino)-2 methylpropyl]-N-{2-[2-(3-pyrrolidin-1 -ylpropoxy)phenyi]ethyl~benzamide; 5 3-[2-({(2 R)-2-hyd roxy-2-[4-hyd roxy-3-(hyd roxymethyl )phenyl]ethyl}am ino)-2 methylpropyl]-N-{2-[3-(3-pyrrolidin- I -ylpropoxy)phenyl]ethyl)benzamide; N-12-(4-Ch loroph enyl)ethyl]-N-ethyl-3-[2-({(2 R)-2-hyd roxy-2-[4-hydroxy-3 (hydroxymethyl)phenyl]ethyllamino)-2-methylpropyl]benzamide; 2-{3-[2-({(2R)-2-hyd roxy-2-[4-hyd roxy-3-(hyd roxymethyl)phenyl] ethylla mi no)-2 10 methylipropyl] ph enyl}- N-(3-pyrrol id i n-I1 -yl pro pyl )aceta mid e; N-(Cycloheptylmethyl )-2-{3-[2-({(2 R)-2-hyd roxy-2-[4-hydroxy-3 (hyd roxymethyI)ph enyI~ethyIla m ino)-2-methyl propyI] phe nyllaceta mid e; N-i -Ada ma ntyl-2-{3-[2-({(2R)-2-hyd roxy-2-[4-hyd roxy-3 (hyd roxymethyI)phenyI]ethyIlamino)-2-methylpropyI]phenylacetamide; 15 N-Benzyl-2-{3-[2-({(2 R)-2-hyd roxy-2-[4-hyd roxy-3-(hyd roxymethyl) phenyl]ethylla mino)-2-methyl pro pyl] phenyl}- N-m ethyl aceta mide; N-[2-(4-Fluorophenyl)ethyl]-3-[2-({(2R)-2-hydroxy-2-[4-hyd roxy-3 (hydroxymethyl)phenyllethyl}amino)-2-methylpropyljbenzamide; 3-[2-({(2R)-2-hyd roxy-2-[4-hyd roxy-3-(hydroxymethyl)phenyljethyl~a mino)-2 20 methylpropyl]-N-[2-(4-phenoxypheny )ethyl]benzam ide; N-[2-(4-ethoxyphenyl)ethyl]-3-[2-({(2R)-2-hydroxy-2-[4-hyd roxy-3 (hydroxymethyl)phenyl]ethyllamino)-2-methylpropyl]benzamide; N-[2-(4-ethyl phenyl )ethyl]-3-[2-({(2 R)-2-hyd roxy-2-[4-hydroxy-3 (hydroxymethyl)phenyl]ethyllamino)-2-methylpropyl]benza mide; 25 3-[2-({(2 R)-2-hyd roxy-2-[4-hyd roxy-3-(hyd roxymethyl)p hen yl] eth yl}am in o)-2 methylpropyl]-N-[2-(6-methylpyridin-2-yl)ethyl]benzamide; 3-[2-({(2R)-2-hyd roxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyllam ino)-2 methylpropyll-N-[2-(2-methoxyphenyl)ethyl]benzamide; methyl 4-[({3-[2-({(2R)-2-hyd roxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl} 30 amino)-2-methylpropyllbenzoyllamino)methyllbenzoate; N-[4-(dimethylamino)benzyl]-3-[2-({(2R).2-hydroxy-2-[4-hyd roxy-3 (hyd roxymethyl)phe nyllethyllamni no)-2-methyl pro pyl] be nzam ide; WO 2005/090287 PCT/1B2005/000640 30 N-{2-[3-fluoro-4-(trifl uoromethyl )phenyl]ethyl}-3-[2-({(2R)-2-hyd roxy-2-[4 h yd roxy-3-(h yd roxymethyl )ph enyijethylja mi no)-2-m ethyl propyl] benza mid e; N-[2-(3-fluoro-4-methylphenyl )ethyl]-3-[2-({(2R)-2-hyd roxy-2-[4-hyd roxy-3 (hyd roxymethyl)ph enyl] ethyl~amni no)-2-methyl propyl] benza mid e; 5 N-[2-(2 ,3-d ifi uoro-4-methyl phenyl )ethyl]-3-[2-({(2R)-2-hyd roxy-2-[4-hydroxy-3 (hyd roxymethyl)phenyl] ethyi)amni no)-2-methyl propyl] benza mid e; 3-[2-({(2R)-2-hyd roxy-2-[4-hydroxy-3-(hyd roxymethyl )phenyl]ethyllamino)-2 methylpropyl]-N-(2-mesitylethyl)benzamide; N-[2-(2 ,6-d ifluoro-3-methylphenyl)ethyl]-3-[2-({(2R)-2-hydroxy-2-[4-hyd roxy-3 10 (hydroxymethyl)phenyl]ethyllamino)-2-methylpropyl]benzamide; N-[2-(6-chloro-2-fluoro-3-methylphenyl )ethyl]-3-[2-({(2 R)-2-hyd roxy-2-[4 hyd roxy-3-(hyd roxymethyl)p hen yl] ethyllamni no)-2-methyl propy[] benza mide; N-[2-(2-chloro-6-fluoro-3-methylphenyl )ethyl]-3-[2-({(2 R)-2-hyd roxy-2-[4 hyd roxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]benzamjde; 15 N-[2-(5-fluoro-2-methylphenyl)ethyl-3-12-({(2R)-2-hyd roxy-2-[4-hyd roxy-3 (hydroxymethyl)phenyl]ethyl~amino)-2-methylpropyI]benzamide; N-{2-[3-fluoro-5-(trifluoromethyl)phenyl]ethyl}-3-[2-({(2 R)-2-hyd roxy-2-[4 hydroxy-3-(hyd roxymethyl)phenyllethyl}amino)-2-methylpropyl]benzamide; 3-[2-({(2 R)-2-hyd roxy-2-[4-hyd roxy-3-(hyd roxymethyl)phenyljethyllamino)-2 20 methylpropyl]-N-{2-[2-(trifluoromethyl)phenyllethyl}benzamide; 3-[2-({(2R)-2-hyd roxy-2-[4-hyd roxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2 methylpropyl]-N-[2-(2,4,5-trimethylphenyl)ethyl]benzamide; 3-[2-({(2 R)-2-hyd roxy-2-[4-hyd roxy-3-(hydroxymethyl )phenylJethyllamino)-2 methyl propyi]-N-(2-pyrid in-2-ylethyl)benza mide; 25 N-[2-( 1 H-benzimid azol-2-yI )ethyl]-3-[2-({(2R)-2-hyd roxy-2-[4-hyd roxy-3 (hyd roxymethyl)ph enyl]eth yl}amni no)-2-m ethyl propyl] benzamid e; 3-[2-({(2 R)-2-hyd roxy-2-[4-hyd roxy-3-(hyd roxymethyl )phenyl]ethyl}a mino)-2 methylpropyl]-N-{2-[4-(morphol in-4-ylsulfonyl)phenyl]ethyl)benzamide; N-[2-(3-chloro-2-hydroxyphenyl )ethyl]-3-[2-({(2R)-2-hydroxy-2-[4-hyd roxy-3 30 (hydroxymethyl)phenyllethyllamino)-2-methylpropyl]benzamide; N-[4-fluoro-2-(trifluoromethyl )benzyl]-3-[2-({(2R)-2-hyd roxy-2-[4-hyd roxy-3 (hydroxymethyl)phenyllethyi}amino)-2-methylpropyl]benzamide; WO 2005/090287 PCT/11B2005/000640 31 N-(3-chlorobenzyl )-3-[2-({(2 R)-2-hyd roxy-2-[4-hyd roxy-3 (hydroxymethyl)phenyllethyl)amino)-2-methylpropyl]benzamide; N-(2-chlorobenzyl)-3-[2-({(2 R)-2-hyd roxy-2-[4-hyd roxy-3 (hydroxymethyl)phenyllethyl~amino)-2-methylpropyl]benzamide; 5 N-[2-(4,6-d imethyl pyrim id in-2-y )ethyi]-3-[2-({(2 R)-2-hyd roxy-2-[4-hyd roxy-3 (hydroxymethyl)phenyl]ethyl~amino)-2-methylpropyljbenzamide; 3-[2-({(2 R)-2-hyd roxy-2-[4-hyd roxy-3-(hyd roxymethyl)phenyl]ethyllam ino)-2 methyl propyl]-N-[2-(3-methyl pyridin-2-yl)ethyl] benzam ide; N-[2-(2-chlorophenyl )ethyl]-3-[2-({(2R)-2-hydroxy-2-[4-hyd roxy-3 10 (hydroxymethyl )phenyi]ethyllamino)-2-methylpropyl]benzamide; N-[2-( 1 -adama ntyl )ethyl]-3-[2-({(2 R)-2-hydroxy-2-[4-hyd roxy-3 (hydroxymethyl)phenyl]ethyl~amino)-2-methylpropyl]benzamide; 3-[2-({(2R)-2-hyd roxy-2-[4-hyd roxy-3-(hyd roxymethyl)phenyl]ethyl~amino)-2 methylpropyl]-N-[2-( I -naphthyl)ethyllbenzamide; 15 N-[2-(2,6-d imethylphenyl)ethyl]-3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3 (hydroxymethyl )phenyl]ethyl~amino )-2-methylpropyl] benzamide; 3-[2-({(2R)-2-hyd roxy-2-[4-hyd roxy-3-(hyd roxymethyl)phenyl]ethyl)amino)-2 methylpropyl]-N-{2-[4-(methylthio)phenyl]ethyllbenzamide; N-[2-(5-chloro-2-fl uorophenyl)ethyl]-3-[2-({(2 R)-2-hyd roxy-2-[4-hyd roxy-3 20 (hyd roxymethyl)phenyl]ethyl~amino)-2-methylpropyl]benzamide; N-[2-(2-ch loro-4-fluorophenyl)ethyl]-3-[2-({(2R)-2-hyd roxy-2-[4-hyd roxy-3 (hydroxymethyl )phenyl]ethyl~amino)-2-methylpropyl]benzamide; 3-[2-({(2R)-2-hyd roxy-2-[4-hyd roxy-3-(hyd roxymethyl )phenyl]ethyl~amino)-2 methylpropyll-N-[2-(4-methoxy-2,5-dimethylphenyl)ethyllbenzamide; 25 N-[2-(2 .3-dichlorophenyl)ethyl-3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3 (hydroxymethyl)phenyl]ethyl~amino)-2-methylpropyl]benzamide; 3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)pheny]ethy~amino)-2 methyl propyll-N -[2-(4-m ethoxy-2,3-d imeth yl phenyl)ethyl] benza mid e; N-(2-biphenyl-4-ylethyl)-3-[2-({(2R)-2-hyd roxy-2-[4-hydroxy-3 30 (hydroxymethyl)phenyl]ethyl~amino)-2-methylpropyllbenzamide; N-[2-(2 ,4-d imethyiphenyl )ethyl]-3-[2-({(2 R)-2-hydroxy-2-[4-hyd roxy-3 (hyd roxymethyl)phenyllethyl~amino)-2-methylpropyl]benzamide; WO 2005/090287 PCT/1B2005/0006tO 32 N-[2-(2,3-dimethylpheflyl)ethylj-3-[2-({(2R)-2-hyd roxy-2-[4-hyd roxy-3 (hyd roxymethyl )phenyllethyl~a mi no)-2-meth yl propyl]belzaflmid e; 3-[2-({(2R)-2-hyd roxy-2-[4-hydroxy-3-(hydroxymethyl)phelethylamilo)-2 methyl propyl]-N-{2-[3-(trifluoromethyl)pheflyl~ethyllbeflzamide; 5 N-[2-(4-chloro-2-fluorophenyl )ethyl]-3-I[2-({(2R)-2-hydroxy-2-[4-hydroxy-3 (hydroxymethyl)phenyl~ethyl~amino)-2-methylpropy~beflzamide; N-(2 ,5-d imethylbenzyl )-3-[2-({(2 R)-2-hyd roxy-2-[4-hyd roxy-3 (hydroxymethyl )phenyllethyl~amino)-2-methylpropylbelza mide; N-(3 ,4-Dichlorobenzyl )-3-{3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3 10 (hydroxymethyl )phenyl]ethyl)a mino)-2-methylpropylI~phenyllpropanamide; 3-[2-({(2 R)-2-Hyd roxy-2-14-hyd roxy-3-(hydroxymethyl)phenyl]ethyllamino)-2 methylpropylI-N-{2-[4-(trifluoromethoxy)phelyl]ethyl~beflzamide; 3-[2-({(2R)-2-hydroxy-2-[4-hyiroxy-3-(hydroxymethyl)phelylIethyl~amilo)-2 methylpropyl]-N-[2-(4-hydroxyphelyl)-2-methylpropyI]beflzamide; 15 3-[2-({(2R)-2-hydroxy-2-14-hydroxy-3-(hyd roxymethyl)phenyl]ethyl~amino)-2 methylpropyll-N-[2-(4-hyd roxy-3-methylphenyl)ethyl]benzamide; N-[2-(4-hydroxy-2 ,3-d imethyl phenyl)ethyl]-3-12-({(2R)-2-hydroxy-2-14-hyd roxy-3 (hydroxymethyl)phenyllethyllamilo)-2-methypropyll benzamide; N-[2--(4--hydroxy-2 ,5-d imethyl phenyl)ethyl]-3-[2-({(2R)-2-hydroxy-2-[4-hyd roxy-3 20 (hyd roxymethyl)phenyllethyl}amino)-2-methylpropylbelzamid e; N-(3 ,4-dichlorobenzyl )-2-{3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3 (hydroxymethyl)phenyllethyllamino)-2-methylpropyl~phelyl~acetamide; N-(3 ,5-dichlorobenzyt )-2-(3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3 (hyd roxymethyl )phenyl]ethyllamino )-2-methylpropyl]phenyl~acetamide; 25 2-{3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hyd roxymethyl)phenyl]ethyl}amino)-2 methyl propyfllph enyl}- N-(pyrid in-2-yl methyl)aceta mide; N-ethyl-3-[2-({(2R)-2-hyd roxy-2-(4-hydroxy-3-(hyd roxymethyl )phenyl]ethylI amino)-2-methylpropyl]-N-(3-phenylpropyl)beflzamide; 3-[2-({(2R)-2-hyd roxy-2-(4-hydroxy-3-(hyclroxymethyl )phenyl]ethyllamino)-2 30 methylpropyl]-N-[3-(4-hyd roxyphenyl )propyl]benzamide; 3-[2-({(2 R)-2-hyd roxy-2-[4-hydroxy-3-(hydroxymethyl )phenyl]ethyl}amino)-2 methyl propyl]-N- [2-(3-methyl phenyl)ethyll belza mide; WO 2005/090287 PCT/IB2005/000640 33 3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2 methylpropyl]-N-[2-(6-methoxypyridin-3-yl)ethyl]benzamide; 3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2 methylpropyl]-N-[3-(3-methoxyphenyl)propyl]benzamide; 5 N-[3-(4-Chlorophenyl)propyl]-3-{2-[(2R)-2-hydroxy-2-(4-hydroxy-3 hydroxymethylphenyl)ethylamino]-2-methylpropyl}benzamide; 3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2 methylpropyl]-N-{2-[4-(1 H-pyrazol-1 -yl)phenoxy]ethyl}benzamide; N-[2-(3,4-difluorophenyl)ethyl)-3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3 10 (hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]benzamide; 3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2 methylpropyl]-N-(2-quinolin-5-ylethyl)benzamide; and, N-[3-(2-ethyl-2,3-dihydro-1-benzofuran-5-yl)propyl]-3-[2-({(2R)-2-hydroxy-2-[4 hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]benzamide. 15 According to one aspect of the present invention, the compounds of formula (1) wherein the (CH 2 )n-C(=O)QI group is in position meta are generally preferred. The compounds of formula (1) may also be optionally transformed into pharmaceutically acceptable salts. In particular, these pharmaceutically acceptable salts of the compounds of the formula (1) include the acid addition 20 and the base salts (including disalts) 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, 25 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, 30 saccharate, stearate, succinate, tannate, D- and L-tartrate, 1-hydroxy-2 naphthoate tosylate and xinafoate salts.

WO 2005/090287 PCT/IB2005/000640 34 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, 5 potassium, sodium, tromethamine and zinc salts. Hemisalts of acids and bases may also be formed, for example, hemisulphate and hemicalcium salts. 10 For a review on suitable salts, see Stahl and Wermuth, Handbook of Pharmaceutical Salts: Properties, Selection, and Use, Wiley-VCH, Weinheim, Germany (2002). Pharmaceutically acceptable salts of compounds of formula (1) may be 15 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 20 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. 25 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 30 forms. The term 'solvate' is used herein to describe a molecular complex comprising the compound of the invention and a stoichiometric amount of one WO 2005/090287 PCT/IB2005/000640 35 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, 5 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 10 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 15 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 20 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 25 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 30 Symposium Series (T. Higuchi and W. Stella) and 'Bioreversible Carriers in Drug Design', Pergamon Press, 1987 (ed. E. B Roche, American Pharmaceutical Association).

WO 2005/090287 PCT/IB2005/000640 36 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 5 described, for example, in "Design of Prodrugs" by H. Bundgaard (Elsevier, 1985). Some examples of prodrugs in accordance with the invention include: 10 (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 (C-Cs)alkyl; 15 (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 (C-Ce)alkanoyloxymethyl; and 20 (iii) where the compound of formula (1) contains a primary or secondary amino functionality (-NH 2 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 (C-C10)alkanoyl. 25 Further examples of replacement groups in accordance with the foregoing examples and examples of other prodrug types may be found in the aforementioned references. 30 Moreover, certain compounds of formula (1) may themselves act as prodrugs of other compounds of formula (1).

WO 2005/090287 PCT/IB2005/000640 37 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 5 (i) where the compound of formula (1) contains a methyl group, an hydroxymethyl derivative thereof (-CH 3 -+ -CH 2 OH): (ii) where the compound of formula (1) contains an alkoxy group, an hydroxy derivative thereof (-OR -- -OH); 10 (iii) where the compound of formula (1) contains a tertiary amino group, a secondary amino derivative thereof (-NR'R 2 -) -NHR' or -NHR 2 ); (iv) where the compound of formula (1) contains a secondary amino group, a 15 primary derivative thereof (-NHR -> -NH 2 ); (v) where the compound of formula (1) contains a phenyl moiety, a phenol derivative thereof (-Ph -- -PhOH); and 20 (1).(vi) where the compound of formula (1) contains an amide group, a carboxylic acid derivative thereof (-CONH 2 -4 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) 25 contains an alkenyl or alkenylene group, geometric cis/trans (or Z/E) isomers are possible. Where the compound contains, for example, a keto orstructural isomers are interconvertible via a low oxime group or an aromatic moiety,energy barrier, tautomeric isomerism ('tautomerism') can occur. This can take the form of proton tautomerism in compounds of formula (1) 30 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.

WO 2005/090287 PCT/IB2005/000640 38 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 5 of one or more thereof. Also included are acid addition or base salts wherein the counterion is optically active, for example, d-lactate or I-lysine, or racemic, for example, dl-tartrate or di-arginine.. Cisltrans isomers may be separated by conventional techniques well known to 10 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 15 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 20 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. 25 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 30 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.

WO 2005/090287 PCT/IB2005/000640 39 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). 5 According to one aspect of the present invention, the (R,R)-stereoisomer of the formula below wherein R' is hydrogen and R 2 is Cr1C4 alkyl, preferably methyl, and n and Q1 are as defined above, is generally preferred: is generally preferred: OH H HO

(CH

2 )n Q1 HO RI R2 -r HO 10 wherein n and Q1 are as defined above for compounds of formula (1). 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 15 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 2 H and 3 H, carbon, such as 11C, 13C and 14C, chlorine, such as 36 Cl, fluorine, such as 18F, iodine, such as 1231 and 1251, 20 nitrogen, such as 13N and 1N, oxygen, such as 150, 170 and 180, phosphorus, such as 32P, and sulphur, such as aS. Certain isotopically-labelled compounds of formula (1), for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue 25 distribution studies. The radioactive isotopes tritium, i.e. 3 H, and carbon-14, i.e.

WO 2005/090287 PCT/IB2005/000640 40 "C, 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 5 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 11 C, "IF, 150 and 13 N, can 10 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 15 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 20 those wherein the solvent of crystallization may be isotopically substituted, e.g. D20, d 6 -acetone, d 6 -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 25 p2 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 30 in conditions where there is an advantage in lowering gastric acidity, particularly in gastric and peptic ulceration.

WO 2005/090287 PCT/IB2005/000640 41 The compounds of formula (1) and their pharmaceutically acceptable salts and derived forms as mentioned above can be administered according to the invention to animals, preferably to mammals, and in particular to humans, as pharmaceuticals for therapy and/or prophylaxis. They can be administered 5 per se, in mixtures with one another or in the form of pharmaceutical preparations which as active constituent contain an efficacious dose of at least one compounds of formula (1), its pharmaceutically acceptable salts and/or derived forms, in addition to customary pharmaceutically innocuous excipients and/or additives. 10 The compounds of formula (1), their pharmaceutically acceptable salts and/or derived forms may be freeze-dried, spray-dried, or evaporatively dried to provide a solid plug, powder, or film of crystalline or amorphous material. Microwave or radio frequency drying may be used for this purpose. 15 The compounds of formula (1), their pharmaceutically acceptable salts and/or derived forms may be administered alone or in combination with other drugs and will generally be administered as a formulation in association with one or more pharmaceutically acceptable excipients. The term "excipient" is used 20 herein to describe any ingredient other than the compound of the invention. The choice of excipient will to a large extent depend on the particular mode of administration. The compounds of the invention may be administered orally. Oral 25 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 30 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.

WO 2005/090287 PCT/IB2005/000640 42 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 5 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 10 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 15 60 weight % of the dosage form. In addition to the drug, tablets generally contain a disintegrant. Examples of disintegrants include sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl -cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methyl cellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropyl cellulose, 20 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. 25 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, 30 microcrystalline cellulose, starch and dibasic calcium phosphate dihydrate.

WO 2005/090287 PCT/IB2005/000640 43 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 5 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 10 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. 15 Exemplary tablets contain up to about 80% drug, from about 10 weight % to about 90 weight % binder, from about 0 weight % to about 85 weight % diluent, from about 2 weight % to about 10 weight % disintegrant, and from about 0.25 weight % to about 10 weight % lubricant. 20 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 25 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). 30 Consumable oral films for human or veterinary use are typically pliable water soluble or water-swellable thin film dosage forms which may be rapidly WO 2005/090287 PCT/IB2005/000640 44 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. 5 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 10 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 15 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, 20 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, 25 or by freeze-drying or vacuuming. Solid formulations for oral administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release. 30 Suitable modified release formulations for the purposes of the invention are described in US Patent No. 6,106,864. Details of other suitable release WO 2005/090287 PCT/IB2005/000640 45 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 al (2001). The use of chewing gum to achieve controlled release is described in WO 00/35298. 5 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 10 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 15 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. 20 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 25 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-, 30 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 WO 2005/090287 PCT/IB2005/000640 46 release of the active compound. Examples of such formulations include drug coated stents and PGLApoly(dl-lactic-coglycolic)acid (PGLA) microspheres. The compounds of the invention may also be administered topically to the skin 5 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, 10 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, 15 iontophoresis, phonophoresis, sonophoresis and microneedle or needle-free (e.g. PowderjectTM, Bioject TM, etc.) injection. Formulations for topical administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, 20 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 25 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 30 use, the powder may comprise a bioadhesive agent, for example, chitosan or cyclodextrin.

WO 2005/090287 PCT/IB2005/000640 47 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 5 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 10 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 hydroxypropylmethylcellulose), 15 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 l-leucine, mannitol, or magnesium stearate. The lactose may be anhydrous or in the form of the monohydrate, preferably the latter. Other suitable excipients include 20 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 1pg to 20mg of the compound of the invention per actuation and the actuation volume may vary 25 from 1pl to 100pl. 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. 30 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.

WO 2005/090287 PCT/IB2005/000640 48 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-, 5 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" 10 containing from 0.001mg to 10mg of the compound of formula (1). The overall daily dose will typically be in the range 0.001mg to 40mg which may be administered in a single dose or, more usually, as divided doses throughout the day. 15 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 20 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 25 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 30 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 WO 2005/090287 PCT/IB2005/000640 49 polymer such as crossed-linked polyacrylic acid, polyvinylalcohol, hyaluronic acid, a cellulosic polymer, for example, hydroxypropylmethylcellulose, hydroxyethylcellulose, or methyl cellulose, or a heteropolysaccharide polymer, for example, gelan gum, may be incorporated together with a preservative, 5 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-, 10 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, 15 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 20 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. 25 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 30 the invention, may conveniently be combined in the form of a kit suitable for coadministration of the compositions.

WO 2005/090287 PCT/IB2005/000640 50 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 5 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 10 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 15 the invention is typically in the range 0.001mg 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 dosesand may, at the physician's discretion, fall outside of the typical range given herein. 20 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. 25 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 30 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) WO 2005/090287 PCT/IB2005/000640 51 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 formula (1), or a pharmaceutically acceptable salt, derived forms or compositions thereof, or one 5 or more P2 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 10 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 15 said patient, e 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 20 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 25 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 WO 2005/090287 PCT/IB2005/000640 52 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 5 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 10 acceptable salts, derived forms or compositions thereof, include, but are by no means limited to: (a) 5-Lipoxygenase (5-LO) inhibitors or 5-lipoxygenase activating protein (FLAP) antagonists, (b) Leukotriene antagonists (LTRAs) including antagonists of LTB 4 , LTC 4 , LTD 4 , 15 and LTE 4 , (c) Histamine receptor antagonists including HI and H3 antagonists, (d) a1- and a 2 -adrenoceptor agonist vasoconstrictor sympathomimetic agents for decongestant use, (e) muscarinic M3 receptor antagonists or anticholinergic agents, 20 (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), 25 (j) Oral and inhaled glucocorticosteroids, such as DAGR (dissociated agonists of the corticoid receptor) (k) Monoclonal antibodies active against endogenous inflammatory entities, (1) Anti-tumor necrosis factor (anti-TNF-c) agents, (m)Adhesion molecule inhibitors including VLA-4 antagonists, 30 (n) Kinin-B 1 - and B 2 -receptor antagonists, (o) Immunosuppressive agents, WO 2005/090287 PCT/IB2005/000640 53 (p) Inhibitors of matrix metalloproteases (MMPs), (q) Tachykinin NK 1 , NK 2 and NK 3 receptor antagonists, (r) Elastase inhibitors, (s) Adenosine A2a receptor agonists, 5 (t) Inhibitors of urokinase, (u) Compounds that act on dopamine receptors, e.g. D2 agonists, (v) Modulators of the NFrcp pathway, e.g. IKK inhibitors, (w)modulators of cytokine signalling pathways such as p38 MAP kinase, syk kinase or JAK kinase inhibitor, 10 (x) Agents that can be classed as mucolytics or anti-tussive, (y) Antibiotics, (z) HDAC inhibitors, and, (aa) P13 kinase inhibitors. According to the present invention, combination of the compounds of 15 formula (1) with : - H3 antagonists, - Muscarinic M3 receptor antagonists, - PDE4 inhibitors, - glucocorticosteroids, 20 - Adenosine A2a receptor agonists, - Modulators of cytokine signalling pathyways such as p38 MAP kinase or syk kinase, or, - Leukotriene antagonists (LTRAs) including antagonists of LTB 4 , LTC 4 , LTD 4 , and LTE 4 , 25 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, 30 flunisolide, triamcinolone acetonide, beclomethasone dipropionate, WO 2005/090287 PCT/IB2005/000640 54 budesonide, fluticasone propionate, ciclesonide, and mometasone furoate, or - muscarinic M3 receptor antagonists or anticholinergic agents including in particular ipratropium salts, namely bromide, tiotropium 5 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, 10 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 P2 receptor and thereby have a wide range of therapeutic applications, as described further below, because of the essential role which the p2 receptor 15 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 P2 receptor is involved. More specifically, the present 20 invention also concerns the compounds of formula (1), or pharmaceutically acceptable salts, derived forms or compositions thereof, for use in the treatment of diseases, disorders, and conditions selected from the group consisting of : . asthma of whatever type, etiology, or pathogenesis, in particular asthma 25 that is a member selected from the group consisting of atopic asthma, non-atopic asthma, allergic asthma, atopic bronchial IgE-mediated asthma, bronchial asthma, essential asthma, true asthma, intrinsic asthma caused by pathophysiologic disturbances, extrinsic asthma caused by environmental factors, essential asthma of unknown or WO 2005/090287 PCT/IB2005/000640 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 5 asthma, incipient asthma, wheezy infant syndrome and bronchiolytis, e chronic or acute bronchoconstriction, chronic bronchitis, small airways obstruction, and emphysema, e obstructive or inflammatory airways diseases of whatever type, etiology, or pathogenesis, in particular an obstructive or inflammatory airways 10 disease that is a member selected from the group consisting of chronic eosinophilic pneumonia, chronic obstructive pulmonary disease (COPD), COPD that includes chronic bronchitis, pulmonary emphysema or dyspnea associated or not associated with COPD, COPD that is characterized by irreversible, progressive airways obstruction, adult 15 respiratory distress syndrome (ARDS), exacerbation of airways hyper reactivity consequent to other drug therapy and airways disease that is associated with pulmonary hypertension, e bronchitis of whatever type, etiology, or pathogenesis, in particular bronchitis that is a member selected from the group consisting of acute 20 bronchitis, acute laryngotracheal bronchitis, arachidic bronchitis, catarrhal bronchitis, croupus bronchitis, dry bronchitis, infectious asthmatic bronchitis, productive bronchitis, staphylococcus or streptococcal bronchitis and vesicular bronchitis, * acute lung injury, 25 0 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.

WO 2005/090287 PCT/IB2005/000640 56 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 P2 5 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 p2 mediated diseases and/or conditions, in particular the diseases and/or conditions listed above. 10 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 15 a p2-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. 20 The following examples illustrate the preparation of the compounds of the formula (1): Example 1: N-cycloheptyl-2-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3 (hydroxymethyl)phenyl]ethyl)amino)propyl]phenyl)acetamide OH H H HON N3 HO CH 3 0 25

HO

WO 2005/090287 PCT/IB2005/000640 57 Ammonium fluoride (98mg, 2.64mmol) was added in one portion to a stirred solution of 2-{3-[(2R)-2-({(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3 (hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N-cycloheptylacetamide (Preparation 1) (150mg, 0.26mmol) in methanol (3ml) and water (1.5ml) at 5 room temperature. The reaction was heated at 40 0 C for 18 hours and then allowed to cool to room temperature. The solvent was removed in vacuo and the residue dissolved in ethyl acetate (30ml) and water (20ml), the organic layer was separated, washed with brine (10ml), dried (magnesium sulfate) and the solvent removed in vacuo to yield a clear oil. This was purified by flash column 10 chromatography on silica gel eluting with dichloromethane:methanol: ammonia (90:10:1 by volume) to furnish the title compound as a white foam (87mg). H NMR (400MHz, CD30D): 6 = 7.25-7.00 (6H, m), 6.85 (1H, d), 4.58 (3H, m), 3.80 (1H, m), 3.40 (2H, s), 2.95 (2H, m), 2.75 (2H, m), 2.58 (1H, m), 1.83 (2H, m), 1.70-1.40 (1OH, m), 1.05 (3H, d) ppm. 15 LRMS (electrospray) : m/z [M+Na]* 477, [M-H]~ 453. Example 2: N-(cyclohexylmethyl)-2-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4 hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N methylacetamide OH N N HO CH 3 0 20 HO Prepared from 2-{3-[(2R)-2-({(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-[4-hydroxy 3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N-(cyclohexylmethyl)-N methylacetamide (Preparation 2) using the method for example 1 to give the title compound as a white foam. 25 1 H NMR (400MHz, CD 3 0D): 8 = 7.21 (2H, m), 7.00 (4H, m), 6.68 (1H, d), 4.61 (3H, m), 3.71 (2H, s), 3.31 (2H, m), 3.20 (2H, m), 2.91 (5H, m), 2.71 (2H, m), 2.60 (1H, m), 1.70 (5H, m), 1.22 (4H, m), 1.04 (3H, d), 0.95 (2H, m) ppm.

WO 2005/090287 PCT/IB2005/000640 58 LRMS (electrospray): m/z [M+H]+ 469, [M+Na]* 491. Example 3: N-[(1S)-1-cyclohexylethyl]-2-{3-[(2R).2-({(2R)-2-hydroxy-2-[4 hydroxy-3-(hydroxymethyl)phenyl]ethyl)amino)propyl]phenyl}acetamide OH H H N N CH 3 HO J?

H

3 0 S HO Prepared from 2-{3-[(2R)-2-({(2R)-2-{[tert-butyl(dimethyl)silylloxy}-2-[4-hydroxy 3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N-[(1 S)-1 cyclohexylethyl]acetamide (Preparation 3) using the method for example 1 to give the title compound as a white foam. 10 1 H NMR (400MHz, CD 3 0D): 8 = 7.20 (4H, m), 7.01 (2H, dd), 6.71 (1H, d), 4.60 (3H, m), 3.62 (1H, m), 3.48 (1H, d), 3.41 (1H, d), 2.85 (2H, m), 2.63 (2H, m), 2.58 (1H, dd), 1.60 (5H, m), 1.40-1.02 (1OH, m), 0.93 (2H, m) ppm. LRMS (electrospray): m/z [M+H]* 469, [M+Na]* 491. 15 Example 4: 2-(3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3 (hydroxymethyl)phenyl]ethyl)amino)propyl]phenyl)-N-isopropylacetamide OH H H ON )N CH 3 HO OH 3 .- 0 OH 3 HO Prepared from 2-{3-[(2R)-2-({(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-[4-hydroxy 3 -(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N-isopropylacetamide 20 (Preparation 4) using the method for example 1 to give the title compound as a white foam. 'H NMR (400MHz, CD 3 OD): 8 = 7.22 (1H, d), 7.18-7.16 (1H, d), 7.12-7.10 (1H, d), 7.07 (1H, s), 7.04-6.99 (2H, t), 6.71-6.69 (1H, d), 4.63-4.60 (3H, m), 3.97- WO 2005/090287 PCT/IB2005/000640 59 3.90 (1H, m), 3.41 (2H, s), 2.98-2.93 (1H, q), 2.91-2.86 (1H, dd), 2.74-2.70 (2H, dd), 2.60-2.55 (1H, dd), 1.13-1.11 (6H, d), 1.08-1.07 (3H, d) ppm. LRMS (electrospray): m/z [M+H]* 401, [M-H]~ 399. 5 Example 5: N-cyclopentyl-2-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3 (hydroxymethyl)phenyijethyl}amino)propyl]phenyl}acetamide OH H H N N HO C 3 . 0 HO Prepared from 2-{3-[(2R)-2-({(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-[4-hydroxy 3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N-cyclopentylacetamide 10 (Preparation 5) using the method for example 3 to give the title compound as a white foam. H NMR (400MHz, CD 3 0D): S = 7.22 (1H, d), 7.18-7.16 (1H, d), 7.11-7.09 (1H, d), 7.06 (1H, s), 7.04-6.98 (2H, t), 6.71-6.69 (1H, d), 4.63-4.60 (3H, m), 4.10 4.04 (1 H, m), 3.42 (2H, s), 2.98-2.93 (1 H, q), 2.90-2.85 (1 H, dd), 2.74-2.69 (2H, 15 dd), 2.60-2.55 (1H, dd), 1.94-1.86 (2H, m), 1.73-1.65 (2H, m), 1.62-1.54 (2H, in), 1.47-1.39 (2H, m), 1.08-1.07 (3H, d), ppm. LRMS (electrospray): m/z [M+H]* 427, [M-H]~ 425. CHN analysis : found C 68.48%, H 8.20%, N 6.35%; C 25 H34N 2 0 4 +0.66H 2 0 requires C 68.49%, H 8.12%, N 6.39%. 20 Example 6: N-(cyclobutylmethyl)-2-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4 hydroxy-3-(hydroxymethyl)phenyl]ethyl)amino)propyl]phenyl}acetamide OH H H N NN HO 3

HO

WO 2005/090287 PCT/IB2005/000640 60 Prepared from 2-{3-[(2R)-2-({(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-[4-hydroxy 3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N (cyclobutylmethyl)acetamide (Preparation 6) using the method for example 1 to give the title compound as a white foam. 5 1H NMR (400MHz, CD 3 0D): 6 = 7.22 (1H, d), 7.18-7.16 (1H, d), 7.12-7.10 (1H, d), 7.07 (1H, s), 7.04-6.99 (2H, t), 6.71-6.69 (1H, d), 4.62-4.59 (3H, m), 3.44 (2H, s), 3.18-3.17 (2H, d), 2.97-2.92 (1H, q), 2.90-2.85 (1H, dd), 2.73-2.69 (2H, dd), 2.60-2.55 (1H, dd), 2.50-2.43 (1H, m), 2.04-1.97 (2H, m), 1.92-1.78 (2H, m), 1.72-1.63 (2H, m), 1.08-1.06 (3H, d), ppm. 10 LRMS (electrospray): m/z [M+H]* 427, [M-H]- 425. CHN analysis : found C 68.24%, H 8.09%, N 6.39%; C 25 H34N 2 0 4 +0.75H 2 0 requires C 68.23%, H 8.13%, N 6.37%. Example 7: N-(cyclopentylmethyl)-2-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4 15 hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}acetamide OH H H N N HO

OH

3 0 HO Prepared from 2-{3-[(2R)-2-({(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-[4-hydroxy 3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N (cyclopentylmethyl)acetamide (Preparation 7) using the method for example 1 20 to give the title compound as a white foam. 1 H NMR (400MHz, CD 3 0D): 5 = 7.22 (1H, d), 7.19-7.17 (1H, d), 7.12-7.11 (1H, d), 7.08 (1H, s), 7.04-7.00 (2H, t), 6.71-6.69 (1H, d), 4.63-4.60 (3H, m), 3.44 (2H, s), 3.10-3.08 (2H, d), 2.98-2.94 (1H, q), 2.90-2.85 (1H, dd), 2.74-2.70 (2H, dd), 2.60-2.55 (1H, dd), 2.07-2.00 (1H, m), 1.73-1.66 (2H, m), 1.62-1.46 (4H, 25 m), 1.22-1.12 (2H, m), 1.08-1.07 (3H, d), ppm. LRMS (electrospray) : m/z [M+H]+ 441, [M-H]- 439. CHN analysis : found C 69.12%, H 8.19%, N 6.26%; C 26

H

3 6

N

2 0 4 +0.62H 2 0 requires C 69.13%, H 8.31%, N 6.20%.

WO 2005/090287 PCT/IB2005/000640 61 Example 8: N-cyclohexyl-2-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3 (hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}acetamide OH H H N N HO

CH

3 0 HO 5 Prepared from 2-{3-[(2R)-2-({(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-[4-hydroxy 3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N-cyclohexylacetamide (Preparation 8) using the method for example 1 to give the title compound as a white foam. H NMR (400MHz, CD 3 0D): 8 = 7.22 (1H, d), 7.19-7.17 (1H, d), 7.12-7.10 (1H, 10 d), 7.07 (1H, s), 7.04-6.99 (2H, t), 6.71-6.69 (1H, d), 4.64-4.60 (3H, m), 3.64 3.56 (1H, m), 3.42 (2H, s), 3.00-2.94 (1H, q), 2.91-2.86 (1H, dd), 2.76-2.72 (2H, dd), 2.61-2.56 (1H, dd), 1.86-1.80 (2H, m), 1.75-1.70 (2H, m), 1.65-1.59 (1H, m), 1.38-1.28 (2H, m), 1.25-1.15 (3H, m), 1.09-1.07 (3H, d), ppm. LRMS (electrospray): m/z [M+H]* 441, [M-H]~ 439. 15 CHN analysis : found C 68.49%, H 8.27%, N 6.14%; C 26

H

3 6

N

2 0 4 +0.85H 2 0 requires C 68.50%, H 8.34%, N 6.14%. Example 9: N-cyclobutyl-2-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3 (hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}acetamide OH H H N N HO OH11 3 0 20 HO Prepared from 2-{3-[(2R)-2-({(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-[4-hydroxy 3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N-cyclobutylacetamide WO 2005/090287 PCT/IB2005/000640 62 (Preparation 9) using the method for example 1 to give the title compound as a white foam. 1H NMR (400MHz, CD 3 0D): 5 = 7.21 (1H, d), 7.18-7.16 (1H, d), 7.11-7.09 (1H, d), 7.06 (1H, s), 7.03-6.98 (2H, t), 6.70-6.68 (1H, d), 4.62-4.59 (3H, m), 4.29 5 4.21 (1H, m), 3.40 (2H, s), 2.88-2.43 (1H, q), 2.90-2.85 (1H, dd), 2.73-2.68 (2H, m), 2.61-2.56 (1H, dd), 2.29-2.21 (2H, m), 1.98-1.89 (2H, m), 1.76-1.66 (2H, m), 1.08-1.07 (3H, d), ppm. LRMS (electrospray) : m/z [M+H]* 413, [M-H] 411. CHN analysis : found C 67.18%, H 7.75%, N 6.51%; C 24

H

32

N

2 0 4 +0.93H 2 0 10 requires C 67.15%, H 7.95%, N 6.53%. Example 10: N-(cyclohexylmethyl)-2-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4 hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}acetamide OH H H HON N,,, HO

CH

3 0 HO 15 Prepared from 2-{3-[(2R)-2-({(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-[4-hydroxy 3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N (cyclohexylmethyl)acetamide (Preparation 10) using the method for example 1 to give the title compound as a yellow foam. 'H NMR (400MHz, CD 3 0D): 8 = 7.21-7.20 (1H, m), 7.18-7.16 (1H, d), 7.11-7.09 20 (1H, d), 7.06 (1H, s), 7.02-6.98 (2H, t), 6.70-6.68 (1H, d), 4.61-4.58 (3H, m), 3.44 (2H, s), 2.99-2.98 (2H, d), 2.94-2.83 (2H, m), 2.71-2.67 (2H, q), 2.58-2.53 (1H, dd), 1.70-1.60 (5H, m), 1.49-1.40 (1H, m), 1.26-1.12 (3H, m), 1.06-1.05 (3H, d), 0.93-0.83 (2H, m) ppm. LRMS (electrospray) : m/z [M+H]* 455, [M+Na]* 477, [M-H]- 453. 25 CHN analysis : found C 70.07%, H 8.50%, N 6.17%; C 27

H

38

N

2 0 4 +0.45H 2 0 requires C 70.09%, H 8.47%, N 6.05%.

WO 2005/090287 PCT/IB2005/000640 63 Example 11: N-(cyclopropylmethyl)-2-3-[(2R)-2-({(2R)-2-hydroxy-2-[4 hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl)acetamide OH HOH N H" N N HO CH 3 0 HO Prepared from 2-{3-[(2R)-2-({(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-[4-hydroxy 5 3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N (cyclopropylmethyl)acetamide (Preparation 11) using the method for example 1 to give the title compound as a white foam. H NMR (400MHz, CD 3 0D): 8 = 7.21-7.16 (2H, m), 7.12-7.10 (1H, d), 7.07 (1H, s), 7.02-6.98 (2H, m), 6.70-6.68 (1H, d), 4.61-4.58 (3H, m), 3.45 (2H, s), 3.03 10 3.01 (2H, d), 2.95-2.83 (2H, m), 2.71-2.67 (2H, m), 2.59-2.54 (1H, m), 1.07-1.06 (3H, d), 0.97-0.90 (1H, m), 0.48-0.43 (2H, q), 0.19-0.15 (2H, q) ppm. LRMS (electrospray) : m/z [M+H]* 413, [M+Na]* 435, [M-H]~ 411. CHN analysis : found C 67.85%, H 7.82%, N 6.48%; C 24

H

32

N

2 0 4 +0.70H 2 0 requires C 67.80%, H 7.92%, N 6.59%. 15 Example 12: N-(cycloheptylmethyl)-2-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4 hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}acetamide OH H H N N HO J ,CH 3 0 HO Prepared from 2-{3-[(2R)-2-({(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-[4-hydroxy 20 3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N (cycloheptylmethyl)acetamide (Preparation 12) using the method for example 1 to give the title compound as a white foam.

WO 2005/090287 PCT/IB2005/000640 64 'H NMR (400MHz, CD 3 0D): 6 = 7.24-6.95 (6H, m), 6.72-6.69 (1H, d), 4.62 (2H, s), 4.62-4.59 (1H, m), 3.26 (2H, s), 3.00-2.97 (2H, d), 2.98-2.54 (m, 5H), 1.70 1.02 (m, 13H), 1.05 (3H, d) ppm. LRMS (electrospray) : m/z [M+H]* 469. 5 Example 13: N-1 -adamantyl-2-(3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3 (hydroxymethyl)phenyl]ethyl)amino)propyl]phenyl}acetamide OH H H N N HO OH 3 o <J1 HO Prepared from N-I -adamantyl-2-{3-[(2R)-2-({(2R)-2-{[tert 10 butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3 (hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}acetamide (Preparation 13) using the method for example I to give the title compound as a white foam. 1 H NMR (400MHz, CD 3 0D): 6 = 7.22-6.96 (6H, m), 6.68-6.65 (1H, d), 4.63-4.59 (3H, m), 3.38 (2H, s), 2.98-2.92 (1H, q), 2.88-2.54 (4H, m), 2.02 (3H, s), 2.00 15 (6H, s), 1.68 (6H, s), 1.05-1.03 (3H, d) ppm. LRMS (electrospray) : m/z [M-H]~ 491. Example 14: N-(1 -adamantylmethyl)-2-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4 hydroxy-3-(hydroxymethyl)phenyl]ethyl)amino)propyl]phenyl}acetamide OH H H N N HO

OCH

3 14 0 20 HO Prepared from N-(1 -adamantylmethyl)-2-{3-[(2R)-2-({(2R)-2-{[tert butyl(dimethyl)si lyl]oxy}-2-[4-hydroxy-3- WO 2005/090287 PCT/IB2005/000640 65 (hydroxymethyl)phenyllethyl}amino)propyl]phenyl}acetamide (Preparation 14) using the method for example 1 to give the title compound as a white foam. H NMR (400MHz, CD 3 0D): 6 = 7.22-7.12 (5H, m), 7.06-7.00 (1H, t), 6.72-6.70 (1H, d), 4.62-4.59 (1H, m), 4.61 (2H, s), 3.46 (2H, s), 2.98-2.92 (1H, q), 2.91 5 2.54 (6H, m), 2.90 (3H, s), 1.68-1.56 (6H, m), 1.42 (6H, s), 1.06-1.04 (3H, d) ppm. LRMS (electrospray): m/z [M+H]* 507, [M+Na]* 529. Example 15: N-2-adamantyl-2-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3 10 (hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}acetamide OH H H HON N NN HO 0 3& HO Prepared from N-2-adamantyl-2-{3-[(2R)-2-({(2R)-2-{[tert-buty (dimethyl)silyl]oxy}-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino) propyl]phenyl}acetamide (Preparation 15) using the method for example I to 15 give the title compound as a white foam. 'H NMR (400MHz, CD 3 0D): 6 = 7.24-7.10 (5H, m), 7.05-6.98 (1H, t), 6.70-6.68 (2H, d), 4.61 (2H, s), 4.62-4.58 (1H, m), 3.94 (1H, s), 3.54 (2H, s), 2.96-2.52 (5H, m), 1.96-1.75 (12H, m), 1.62-1.56 (2H, d), 1.05-1.03 (3H, d) ppm. LRMS (electrospray) : m/z [M-H]~ 491. 20 Example 16: N-(2-cyclohexylethyl)-2-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4 hydroxy-3-(hydroxymethyl)phenyl]ethyl)amino)propyl]phenyl}-N methylacetamide WO 2005/090287 PCT/IB2005/000640 66 OH

CH

3 N N HO,

H

3 0 HO Prepared from 2-{3-[(2R)-2-({(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-[4-hydroxy 3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N-(2-cyclohexylethyl)-N methylacetamide (Preparation 16) using the method for example 1 to give the 5 title compound as a white foam. H NMR (400MHz, CD 3 0D): 6 = 7.23-7.00 (6H, m), 6.71-6.68 (1H, d), 4.61 (2H, s), 4.61-4.57 (1H, m), 3.71-3.68 (2H, m), 4.61-4.57 (1H, m), 3.71-3.68 (2H, m), 3.43-3.26 (2H, m), 2.97-2.52 (8H, m), 1.78-0.82 (13H, m), 1.08-1.06 (3H, d) ppm. 10 LRMS (electrospray): m/z [M+Na]* 505, [M-H]~ 491. Example 17: N-cycloheptyl-2-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3 (hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N-methylacetamide OH CH H 1 3 N N HO

CH

3 0 HO 15 Prepared from 2-{3-[(2R)-2-({(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-[4-hydroxy 3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N-cycloheptyl-N methylacetamide (Preparation 17) using the method for example 1 to give the title compound as a white foam. 'H NMR (400MHz, CD 3 0D): 6 = 7.23-6.96 (6H, m), 6.72-6.64 (1H, dd), 4.62 20 4.60 (2H, d), 4.61-4.58 (1H, m), 4.58-4.51 (0.5H, m), 3.70-3.63 (0.5H, m), 3.75 3.67 (2H, d), 2.95-2.50 (5H, m), 2.82-2.78 (3H, d), 1.72-1.20 (12H, m), 1.02 1.00 (3H, 2d) ppm. LRMS (electrospray) : m/z [M+Na]* 491.

WO 2005/090287 PCT/IB2005/000640 67 Example 18: N-cyclohexyl-N-ethyl-2-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4 hydroxy-3-(hydroxymethyl)phenyl]ethyl)amino)propyl]phenyl}acetamide OH CH3 N N HO

OCH

3 0 HO 5 Prepared from 2-{3-[(2R)-2-({(2R)-2-{[ted-butyl(dimethyl)silyl]oxy}-2-[4-hydroxy 3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N-cyclohexyl-N ethylacetamide (Preparation 18) using the method for example 1 to give the title compound as a white foam. H NMR (400MHz, CD 3 0D): 6 = 7.25-6.98 (6H, m), 6.70-6.67 (1H, d), 4.61 (2H, 10 s), 4.60-4.57 (1H, m), 3.72 (2H, s), 3.65-3.61 (1H, m), 3.30-3.24 (2H, q), 2.95 2.50 (5H, m), 1.84-1.08 (1OH, m), 1.12-1.08 (3H, t), 1.04-1.02 (3H, d) ppm. LRMS (electrospray) : m/z [M+Na] 4 491. Example 19: N-(2-cyclohexylethyl)-2-(3-[(2R)-2-({(2R)-2-hydroxy-2-[4 15 hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl)acetamide OH H H N N HO 0OH 3 0 HO Prepared from 2-{3-[(2R)-2-({(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-[4-hydroxy 3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N-(2 cyclohexylethyl)acetamide (Preparation 19) using the method for example 1 to 20 give the title compound as a white foam. H NMR (400MHz, CD 3 0D): J = 7.22-6.98 (6H, m), 6.68-6.66 (1H, d), 4.61 (2H, s), 4.60-4.58 (1H, m), 3.42 (2H, s), 3.20-3.16 (2H, t), 2.96-2.56 (5H, m), 1.73- WO 2005/090287 PCT/IB2005/000640 68 1.60 (5H, m), 1.40-1.35 (2H, q), 1.30-1.12 (4H, m), 1.07-1.05 (3H, d), 0.92-0.81 (2H, m) ppm. LRMS (electrospray) : m/z [M+Na]* 491. 5 Example 20: N-(4-chlorobenzyl)-2-{3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3 (hydroxymethyl)phenyl]ethyl)amino)-2-methylpropyl]phenyl}acetamide OH Cl H H HN H'N HOH 3 C N HO 3CCH 3 K0 HO Prepared according to the procedure used for preparation 1 using {3-[2-({(2R) 2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2 10 methylpropyl]phenyl}acetic acid (Preparation 50) and the appropriate amine to give the title compound as a white foam. H NMR (400MHz, CD 3 0D): 6 = 7.37-7.36 (1H, d), 7.32-7.17 (8H, m), 7.13-7.11 (1H, d), 6.82-6.80 (1H, d), 4.75-4.71 (1H, m), 4.70 (2H, s), 4.37 (2H, s), 3.58 (2H, s), 3.02-2.96 (1H, m), 2.93-2.89 (1H, m), 2.86-2.78 (2H, m), 1.16 (3H, s), 15 1.14 (3H, s) ppm. LRMS (electrospray) : m/z [M+H]* 497, [M+Na]* 519, [M-H]- 495. Example 21: N-(2,6-dimethoxybenzyl)-2-{3-[2-({(2R)-2-hydroxy-2-[4-hydroxy 3 -(hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]phenyl}acetamide

CH

3 OH O H H I 3 C CH 0 ON HO

OCH

3 20 HO WO 2005/090287 PCT/IB2005/000640 69 Prepared according to the procedure used for preparation 1 using {3-[2-({(2R) 2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl)amino)-2 methylpropyl]phenyl}acetic acid (Preparation 50) and the appropriate amine to give the title compound as a white foam. 5 1H NMR (400MHz, CD 3 0D): 6 = 7.39-7.38 (1H, d), 7.32-7.13 (6H, m), 6.83-6.81 (1H, d), 6.66 (1H, s), 6.64 (1H, s), 4.80-4.77 (1H, m), 4.70 (2H, s), 4.46 (2H, s), 3.80 (6H, s), 3.52 (2H, s), 3.15-3.00 (2H, m), 2.88 (2H, m), 1.21 (3H, s), 1.20 (3H, s) ppm. LRMS (electrospray): m/z [M+H]* 523, [M+Na]* 545, [M-H]~ 521. 10 Example 22: N-benzyl-2-{3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3 (hydroxymethyl)phenyl]ethyl)amino)-2-methylpropyl]phenyl)acetamide OH H H N N HO

H

3 C CH 3 t 0 HO Prepared according to the procedure used for preparation 1 using {3-[2-({(2R) 15 2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2 methylpropyl]phenyl}acetic acid (Preparation 50) and the appropriate amine to give the title compound as a white foam. 1H NMR (400MHz, CD 3 0D): 6 = 7.38-7.37 (1H, d), 7.33-7.17 (9H, m), 7.12-7.11 (1H, m), 6.82-6.80 (1H, d), 4.75-4.72 (1H, dd), 4.70 (2H, s), 4.40 (2H, s), 3.58 20 (2H, s), 3.02-2.96 (1H, m), 2.93-2.89 (1H, m), 2.86-2.78 (2H, m), 1.16 (3H, s), 1.15 (3H, s) ppm. LRMS (electrospray) : m/z [M+H]+ 463, [M+Na]* 485, [M-H]- 461. Example 23: 4-{(1 R)-2-[(2-(3-[2-(3,4-dihydroisoquinolin-2(1 H)-yI)-2 25 oxoethyl]phenyl}-1,1-dimethylethyl)amino]-1-hydroxyethyl}-2 (hydroxymethyl)phenol WO 2005/090287 PCT/IB2005/000640 70 OH H N N HO

H

3 C C HO Prepared according to the procedure used for preparation 1 using {3-[2-({(2R) 2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyljethyl}amino)-2 methylpropyl]phenyl}acetic acid (Preparation 50) and the appropriate amine to 5 give the title compound as a white foam. H NMR (400MHz, CD 3 0D): J = 7.36-7.35 (1H, d), 7.29-7.24 (1H, m), 7.22-7.13 (5H, m), 7.12-7.09 (2H, m), 7.04-7.02 (1H, d), 6.80-6.78 (1H, m), 4.74 (1H, s), 4.71-4.66 (4H, m), 3.90-3.89 (2H, m), 3.86-3.82 (1H, m), 3.78-3.75 (1H, m), 2.94-2.86 (2H, m), 2.81-2.66 (4H, m), 1.08-1.01 (6H, m) ppm. 10 LRMS (electrospray): m/z [M+H]* 489, [M+Na]* 511, [M-H]~ 487. Example 24: N-[2-fluoro-5-(trifluoromethyl)benzyl]-2-{3-[2-({(2R)-2-hydroxy 2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2 methylpropyl]phenyl}acetamide OH F N H N F ji HC Hx F 15 HO Prepared according to the procedure used for preparation 1 using {3-[2-({(2R) 2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2 methylpropyl]phenyl}acetic acid (Preparation 50) and the appropriate amine to give the title compound as a white foam. 20 1 H NMR (400MHz, CD 3 0D): 6 = 7.62-7.58 (1H, m), 7.56-7.54 (1H, m), 7.33 7.32 (1H, d), 7.28-7.12 (5H, m), 7.08-7.06 (1H, d), 6.78-6.76 (1H, d), 4.70-4.67 (1H, m), 4.65 (2H, s), 4.46 (2H, s), 3.55 (2H, s), 2.96-2.91 (1H, m), 2.86-2.81 (1H, m), 2.80-2.72 (2H, m), 1.10 (3H, s), 1.09 (3H, s) ppm.

WO 2005/090287 PCT/IB2005/000640 71 LRMS (electrospray): m/z [M+H]*+ 549, [M+Na]* 571, [M-H]~ 547. Example 25: N-(2,6-dichlorobenzyl)-2-{3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3 (hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]phenyl}acetamide OH CI H H N N HO

H

3 C N Cl 5 HO Prepared according to the procedure used for preparation 1 using {3-[2-({(2R) 2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2 methylpropyl]phenyl}acetic acid (Preparation 50) and the appropriate amine to give the title compound as a white foam. 10 1 H NMR (400MHz, CD 3 0D): 6 = 7.45-7.43 (2H, m), 7.39-7.38 (1H, d), 7.34-7.27 (2H, m), 7.23-7.19 (3H, m), 7.14-7.12 (1H, m), 6.83-6.81 (1H, d), 4.79-4.76 (1H, m), 4.71 (2H, s), 4.70 (2H, s), 3.55 (2H, s), 3.09-2.97 (2H, m), 2.88 (2H, s), 1.22 (3H, s), 1.21 (3H, s) ppm. LRMS (electrospray): m/z [M+H]+ 531, [M+Na]* 553, [M-H]~ 529. 15 Example 26: 2-{3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3 (hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]phenyl}-N-[2 (methylthio)benzyl]acetamide OH H H HO N CH 3 N H 3 CS HO 20 Prepared according to the procedure used for preparation 1 using {3-[2-({(2R) 2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyllamino)-2- WO 2005/090287 PCT/IB2005/000640 72 methylpropyllphenyl}acetic acid (Preparation 50) and the appropriate amine to give the title compound as a white foam. H NMR (400MHz, CD 3 0D): 6 = 7.36-7.10 (10H, in), 6.81-6.79 (1H, d), 4.73 4.69 (1H, m), 4.69 (2H, s), 4.47 (2H, s), 3.59 (2H, s), 2.99-2.94 (1H, m), 2.89 5 2.84 (1H, m), 2.81-2.76 (2H, in), 2.48 (3H,s), 1.15 (3H, s), 1.13 (3H, s) ppm. LRMS (electrospray): m/z [M+H]* 509, [M+Na]* 531, [M-H]~ 507. Example 27: N-(2,3-dimethylbenzyl)-2-{3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3 (hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]phenyl)acetamide OH H N N H I

CH

3 HO

H

3 C

CH

3 10 HO Prepared according to the procedure used for preparation 1 using {3-[2-({(2R) 2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2 methylpropyl]phenyl}acetic acid (Preparation 50) and the appropriate amine to give the title compound as a white foam. 15 'H NMR (400MHz, CD30D): 6 = 7.37-7.36 (1H, m), 7.30-7.16 (4H, m), 7.12 7.01 (4H, m), 6.82-6.80 (1H, d), 4.74-4.71 (1H, in), 4.69 (2H, s), 4.40 (2H, s), 3.56 (2H, s), 3.01-2.96 (1H, m), 2.92-2.88 (1H, m), 2.86-2.77 (2H, in), 2.29 (3H, s), 2.18 (3H, s), 1.16 (3H, s), 1.14 (3H, s) ppm. LRMS (electrospray): m/z [M+H]f 491, [M+Na]* 513, [M-H]~ 489. 20 Example 28: 2-{3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3 (hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]phenyl}-N.[3 (trifluoromethyl)benzyl]acetamide WO 2005/090287 PCT/IB2005/000640 73 OH H H HN N N. F

H

3 C' CH 3 1 FF HO O H F HO Prepared according to the procedure used for preparation 1 using {3-[2-({(2R) 2-hyd roxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl)amino)-2 methylpropyl]phenyl}acetic acid (Preparation 50) and the appropriate amine to 5 give the title compound as a white foam. H NMR (400MHz, CD 3 0D): 6 = 7.56-7.47 (4H, m), 7.36-7.35 (1H, m), 7.28 7.15 (4H, m), 7.11-7.09 (1H, d), 6.80-6.78 (1H, d), 4.73-4.69 (1H, m), 4.69 (2H, s), 4.47 (2H, s), 3.59 (2H, s), 2.99-2.94 (1H, m), 2.89-2.85 (1H, m), 2.84-2.75 (2H, m), 1.14 (3H, s), 1.13 (3H, s) ppm. 10 LRMS (electrospray) : m/z [M+H]* 531, [M+Na]* 553, [M-H]~ 529. Example 29: N-[4-ch loro-3-(trifluoromethyl)benzyl]-2 -{3-[2-({(2R)-2-hydroxy 2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl)amino)-2 methylpropyl]phenyl}acetam ide OH Cl H H I HO N N F 15 HO Prepared according to the procedure used for preparation 1 using {3-[2-({(2R) 2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2 methylpropyl]phenyl}acetic acid (Preparation 50) and the appropriate amine to give the title compound as a white foam. 20 'H NMR (400MHz, CD30D): 6 = 7.64-7.63 (1H, m), 7.54-7.52 (1H, m), 7.47 7.45 (1H, m), 7.34-7.33 (1H, m), 7.27-7.14 (4H, m), 7.09-7.08 (1H, d), 6.80-6.78 WO 2005/090287 PCT/IB2005/000640 74 (1H, d), 4.71-4.67 (1H, m), 4.69 (2H, s), 4.43 (2H, s), 3.58 (2H, s), 2.96-2.91 (1H, m), 2.84-2.80 (1H, m), 2.81-2.72 (2H, m), 1.12 (3H, s), 1.09 (3H, s) ppm. LRMS (electrospray): m/z [M+H]* 565, [M+Na]* 587, [M-H]~ 563. 5 Example 30: N-[2-chloro-5-(trifluoromethyl)benzyl]-2-{3-[2-({(2R)-2-hydroxy 2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl)amino)-2 methylpropyl]phenyl}acetamide OH CI H H N N F HO O H N X F

H

3 CH3 F H F HO Prepared according to the procedure used for preparation 1 using {3-[2-({(2R) 10 2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2 methylpropyl]phenyl}acetic acid (Preparation 50) and the appropriate amine to give the title compound as a white foam. 'H NMR (400MHz, CD30D): 6 = 7.63-7.56 (3H, m), 7.36-7.35 (1H, d), 7.30 7.21 (3H, m), 7.18-7.16 (1H, dd), 7.12-7.11 (1H, d), 6.81-6.79 (1H, d), 4.73-4.69 15 (1H, m), 4.69 (2H, s), 4.54 (2H, s), 3.62 (2H, s), 3.03-2.91 (1H, m), 2.89-2.84 (1H, m), 2.86-2.75 (2H, m), 1.14 (3H, s), 1.12 (3H, s) ppm. LRMS (electrospray) : m/z [M+H]* 565, [M+Na]* 587, [M-H]~ 563. Example 31: N-[3,5-bis(trifluoromethyl)benzyl]-2-(3-[2-({(2R)-2-hydroxy-2-[4 20 hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2 methylpropyl]phenyl}acetamide WO 2005/090287 PCT/IB2005/000640 75 F F F OH H H NN N.F HO

H

3

CH

3 F F HO Prepared according to the procedure used for preparation 1 using {3-[2-({(2R) 2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyljethyl}amino)-2 methylpropyl]phenyl}acetic acid (Preparation 50) and the appropriate amine to 5 give the title compound as a white foam. "H NMR (400MHz, CD 3 0D): 6 = 7.86-7.84 (3H, m), 7.35 (1H, s), 7.28-7.15 (4H, m), 7.11-7.09 (1H, d), 6.81-6.79 (1H, d), 4.71-4.68 (1H, m), 4.69 (2H, s), 4.54 (2H, s), 3.60 (2H, s), 2.96-2.91 (1H, m), 2.83-2.79 (1H, m), 2.80-2.71 (2H, m), 1.10 (3H, s), 1.08 (3H, s) ppm. 10 LRMS (electrospray): m/z [M+H]* 599, [M+Na]* 621, [M-H]~ 597. Example 32: N-[3-fluoro-5-(trifluoromethyl)benzyl]-2-{3-[2-({(2R)-2-hydroxy 2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2 methylpropyl]phenyl}acetamide F OH H H HO H N NF F HOHG CH 3 x 0 FEF 15 HO Prepared according to the procedure used for preparation 1 using {3-[2-({(2R) 2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2 methylpropyl]phenyl}acetic acid (Preparation 50) and the appropriate amine to give the title compound as a white foam.

WO 2005/090287 PCT/IB2005/000640 76 H NMR (400MHz, CD 3 0D): 6 = 7.40 (1H, s), 7.36-7.16 (7H, m), 7.13-7.11 (1H, d), 6.82-6.80 (1H, d), 4.74-4.69 (1H, m), 4.69 (2H, s), 4.47 (2H, s), 3.60 (2H, s), 3.01-2.94 (1H, m), 2.91-2.87 (1H, m), 2.85-2.77 (2H, m), 1.15 (3H, s), 1.13 (3H, s) ppm. 5 LRMS (electrospray) : m/z [M+H]+ 549, [M+Na]* 571, [M-H]~ 547. Example 33: N-[2-(4-chlorophenyl)ethyl]-3-{2-[(2R)-2-hydroxy-2-(4-hydroxy 3-hydroxy-methylphenyl)ethylamino]-2-methylpropyl}benzamide OH H CI H NN HO H3 H . H HO 10 3-{2-[(2R)-2-(tert-butyldimethylsilanyloxy)-2-(4-hydroxy-3-hydroxymethyl phenyl)ethylamino]-2-methylpropyl}-N-[2-(4-chlorophenyl)ethyl]benzamide (Preparation 38) (470mg, 0.77mmol) and ammonium fluoride (280mg, 7.70mmol) in methanol (3ml) and water (1.7ml) were heated to 43*C for 18 hours. The solvent was removed in vacuo and the product purified by flash 15 column chromatography on silica gel eluting with dichloromethane:methanol:ammonia (95:5:0.5 by volume). The resulting compound was taken up in methanol and evaporated (x3) to yield a white foam (320 mg). A small sample was recrystallised (hexane:ethyl acetate) to give a white solid (mp 139-140 0C). 20 'H NMR (400MHz, CD 3 0D) 8 = 7.64-7.60 (2H, m), 7.37-7.20 (7H, m), 7.11 (1H, dd), 6.74 (1H, d), 4.68-4.65 (3H, m), 3.57 (2H, m), 2.98-2.87 (4H, m), 2.77-2.70 (2H, m), 1.12 (3H, s), 1.05 (3H, s). LRMS (electrospray) m/z 497 [M+H]*, 519 [M+Na]* Analysis for C 28

H

33

CIN

2 0 4 .0.5 H 2 0 0.3 C 4 H1 0 0 Calc. (Found) C 66.63 (66.39), 25 H 6.95 (7.06), N 5.31 (5.30) %.

WO 2005/090287 PCT/IB2005/000640 77 Example 34: 3-{2-[(2R)-2-hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl) ethylamino]-2-methylpropyl}-N-[2-(4-methylphenyl)ethyl]benzamide OH H CH3 N N HO HO Prepared from 3-{2-[(2R)-2-(tert-butyldimethylsilanyloxy)-2-(4-hydroxy-3 5 hydroxymethyl-phenyl)ethylamino]-2-methylpropyl}-N-[2-(4 methylphenyl)ethyl]benzamide (Preparation 39) using the method for example 33 to give the title compound as a white foam. H NMR (400MHz, CD 3 0D) 8 = 7.69-7.65 (2H, m), 7.37-7.30 (3H, m), 7.14-7.06 (5H, m), 6.75 (1H, d), 4.67-4.64 (3H, m), 3.59-3.54 (2H, m), 2.96-2.84 (4H, m), 10 2.77-2.69.(2H, m), 2.28 (3H, s), 1.11 (3H, s), 1.04 (3H, s). LRMS (electrospray) m/z 477 [M+H]*, 499 [M+Na]* Analysis for C 29

H

3 6

N

2 0 4 .0.5 H 2 0 0.3 C 4

H,

0 0 Calc. (Found) C 71.42 (71.62), H 7.94 (7.88), N 5.52 (5.57) %. 15 Example 35: 3-{2-[(2R)-2-hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl) ethylamino]-2-methyl-propyl}-N-[2-(4 trifluoromethylphenyl)ethyl]benzamide OH H CF3 H N N HC/ CH 1 3O 3 - H HO Prepared from 3 -{2-[(2R)-2-(tert-butyldimethylsilanyloxy)-2-(4-hydroxy-3 20 hydroxymethyl-phenyl)ethylamino]-2-methyl-propyl}-N-[2-(4 trifluoromethylphenyl)ethyl]benzamide (Preparation 40) using the method for example 33 to give the title compound as a white foam.

WO 2005/090287 PCT/IB2005/000640 78 'H NMR (400MHz, CD 3 0D) 8 = 7.68-7.62 (1H, m), 7.61 (1H, bs), 7.66 (2H, d), 7.42 (2H, d), 7.38-7.30 (3H, m), 7.12 (1H, dd), 6.75 (1H, dd), 4.68-4.65 (1H), 4.65 (2H, s), 3.61 (2H, m), 3.00 (2H, t), 2.92 (1H, dd), 2.86 (1H, d), 2.73 (1H, dd), 2.69 (1H, d), 1.11 (3H, s), 1.04 (3H, s). 5 LRMS (electrospray) m/z 531 [M+H]+ HRMS for C 29 H34F 3

N

2 0 4 531.2447 [M+H]* found 531.2465. Example 36: N-[2-(3,4-dichlorophenyl)ethyl]-3-{2-[(2R)-2-hydroxy-2-(4 hydroxy-3-hydroxymethylphenyl)ethylamino]-2-methyl-propyl}-benzamide OH H0 H N N Cl HO 10 HO Prepared from 3-{2-[(2R)-2-(tert-butyldimethylsilanyloxy)-2-(4-hydroxy-3 hydroxymethyl-phenyl)ethylamino]-2-methyl-propyl}-N-[2-(3,4 dichlorophenyl)ethyl]benzamide (Preparation 41) using the method for example 33 to give the title compound as a white foam. 15 1 H NMR (400MHz, CD 3 0D) 8 = 7.62 (1H, d), 7.60 (1H, s), 7.42-7.40 (2H, m), 7.38-7.31 (3H, m), 7.18-7.11 (2H, in), 6.75 (1H, d), 4.68-4.66 (1H), 4.65 (2H, s), 3.56 (2H, m), 2.86-2.97 (4H, m), 2.69-2.77 (2H, m), 1.11 (3H, s), 1.04 (3H, s). LRMS (electrospray) m/z 531 [M+H]* HRMS for C 28

H

33 Cl 2

N

2 0 4 531.1801 [M+H]* found 531.1812. 20 Example 37: N-[2-(3,4-dimethylphenyl)ethyl]-3-{2.[(2R)-2-hydroxy-2-(4 hydroxy-3-hydroxymethylphenyl)-ethylamino]-2-methylpropyl}benzamide OH CH 3 H N N

CH

3 H CC H HO 33e

HO

WO 2005/090287 PCT/IB2005/000640 79 Prepared from 3-{2-[(2R)-2-(tert-butyldimethylsilanyloxy)-2-(4-hydroxy-3 hydroxymethyl-phenyl)ethylamino]-2-methyl-propyl}-N-[2-(3,4 dimethylphenyl)ethyl]benzamide (Preparation 42) using the method for example 33 to give the title compound as a white foam. 5 'H NMR (400MHz, CD 3 0D) 8 = 7.63 (1H, m), 7.61 (1H, bs), 7.38-7.31 (3H, m), 7.12 (1H, dd), 7.02-6.99 (2H, m), 6.92 (1H, dd), 6.75 (1H, d), 4.67-4.64 (1H, m), 4.65 (2H, s), 3.53 (2H, t), 2.92 (1H, dd), 2.86 (1H, d), 2.82 (2H, t), 2.72 (1H, dd),. 2.69 (1H, d), 2.20 (6H, s), 1.11 (3H, s), 1.04 (3H, s). LRMS (electrospray) m/z 491 [M+H]* 10 HRMS for C 30

H

39

N

2 0 4 491.2905 [M+H]* found 491.2892. Example 38: 3-(2-[(2R)-2-hydroxy-2-(4-hydroxy-3-hydroxymethyl phenyl)ethylamino]-2-methyl-propyl)-N-(2-naphthalen-2-yl-ethyl)benzamide O H O0 N H N N HO

H

3 C CH 3 I: H HO 15 Prepared from 3-{2-[(2R)-2-(tert-butydimethylsilanyloxy)-2-(4-hydroxy-3 hydroxymethyl-phenyl)ethylamino]-2-methyl-propyl}-N-(2-naphthalen-2-yl ethyl)benzamide (Preparation 43) using the method for example 33 to give the title compound as a white foam. 1 H NMR (400MHz, CD 3 0D) 6 7.80-7.75 (3H, m), 7.68 (1H, bs), 7.62 (1H, m), 20 7.57 (1H, bs), 7.44-7.29 (6H, m), 7.12 (1H, dd), 6.75 (1H, d), 4.67-4.63 (1H, m), 4.66 (2H, s), 3.67 (2H, m), 3.06 (2H, t), 2.90 (1H, dd), 2.82 (1h, d), 2.71 (1H, dd), 2.66 (1 H, d), 1.08 (3H, s), 1.01 (3H, s). LRMS (electrospray) m/z 513 [M+H]* HRMS for C 32

H

37

N

2 0 4 513.2748 [M+HJ found 513.2726. 25 Example 39: N-(1,1 -dimethyl-2-phenylethyl)-3-{2-[(2R)-2-hydroxy-2-(4 hydroxy-3-hydroxy-methylphenyl)-ethylamino]-2-methylpropyl}benzamide WO 2005/090287 PCT/IB2005/000640 80 OH 0 OHC N N

H

3 Cz OH CH 16- 3 HO 3 HO Prepared from 3-{2-[(2R)-2-(tert-butyldimethylsilanyloxy)-2-(4-hydroxy-3 hyd roxymethyl-phenyl)ethylamino]-2-methyl-propyl}-N-(1,1 -d imethyl-2-phenyl ethyl)benzamide (Preparation 44) using the method for example 33 to give the 5 title compound as a white foam. 1H NMR (400MHz, CD30D) 8 = 7.64 (1H, m), 7.60 (1H, bs), 7.35-7.27 (3H, m), 7.24-7.15 (5H, m), 7.06 (1H, dd), 6.72 (1H, d), 4.64 (2H, s), 4.644.61 (1H, m), 3.20 (1H, d), 3.12 (1H, d), 2.86 (1H, dd), 2.81 (1H, d), 2.73-2.69 (2H, m), 1.42 (3H, s), 1.39 (3H, s), 1.09 (3H, s), 1.05 (3H, s). 10 LRMS (electrospray) m/z 491 [M+H]* HRMS for C 32

H

37

N

2 0 4 491.2905 [M+H]* found 491.2885. Example 40: 3-(2-[(2R)-2-hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl) ethylamino]-2-methylpropyl}-N-(2-methyl-2-phenylpropyl)benzamide O H O H N 33 3X HO _ r H 15 HO Prepared from 3-{2-[(2R)-2-(tert-butyldimethylsilanyloxy)-2-(4-hydroxy-3 hydroxymethylpheny)ethylamino]-2-methylpropyl}-N-(2-methyl-2-phenylpropyl) benzamide (Preparation 45) using the method for example 33 to give the title compound as a white foam. 20 1H NMR (400MHz, CD 3 0D) 8 7.53 (1H, m), 7.60 (1H, bs), 7.43 (1H, dd), 7.34 7.28 (5H, in), 7.20-7.16 (1H, m), 7.10 (1H, dd), 6.74 (1H, d), 4.65 (2H, s), 4.65 4.61 (1H, dd), 3.57 (2H, s), 2.87 (1H, dd), 2.79 (1H, d), 2.75-2.69 (2H, m), 1.38 (6H, s), 1.07 (3H, s), 1.03 (3H, s).

WO 2005/090287 PCT/IB2005/000640 81 LRMS (electrospray) m/z 491 [M+H]* HRMS for C 30

H

39

N

2 0 4 491.2905 [M+H]* found 491.2897. Example 41: N-(4-chlorobenzyl)-3-{2.[(2R)-2-hydroxy-2-(4-hydroxy-3 5 hydroxy-methylphenyl)ethylamino]-2-methylpropyl}benzamide OH O HO Prepared from 3-{(2R)-2-[2-(tert-butyldimethylsilanyloxy)-2-(4-hydroxy-3 hydroxymethyl-phenyl)ethylamino]-2-methylpropyl}-N-(4 chlorobenzyl)benzamide (Preparation 46) using the method for example 33 to 10 give the title compound as a white foam. 1H NMR (400MHz, CD30D) 8 = 7.74-7.70 (3H, m), 7.40-7.29 (7H-, mn), 7.07 (1H-, dd), 6.71 (1 H, d), 4.67-4.63 (1 H, dd), 4.63 (2H, s), 4.60 (2H-, dd), 2.96-2.88 (2H-, m), 2.76-2.70 (2H-, m), 1.12 (3H-, s), 1.04 (3H-, s). LRMS (electrospray) m/z 481/483 [M+H]* 15 HRMS for C30H-32CIN204 483.2045 [M+H]* found 483.2038. Example 42: N-(2,6-dimethoxybenzyl)-2-{3-[2-({(2R)-2-hydroxy-2-[4-hydroxy 3-(hydroxymethyl)phenyl]ethyl~amino)ethyl]phenyl~acetamide CH3 OH O H H H O N N -3C ' O HO 20 Prepared according to the procedure used for Preparation 1 using {3-[2-({(2R) 2-hydroxy-2-[4-hydroxy-3- WO 2005/090287 PCT/IB2005/000640 82 (hydroxymethyl)phenyl]ethyl}amino)ethyl]phenyl)acetic acid (Preparation 51) and the appropriate amine to give the title compound as a white foam. 1H NMR (400MHz, CD 3 0D): 6 = 7.26-7.19 (3H, m), 7.11-7.07 (4H, m), 6.74 6.72 (1H, d), 6.61-6.59 (2H, d), 4.70-4.67 (1H, m), 4.63 (2H, s), 4.41 (2H, s), 5 3.75 (6H, s), 3.45 (2H, s), 2.91-2.75 (6H, m) ppm. LRMS (electrospray): m/z [M+H]* 495, [M+Na]* 517, [M-H]~ 493. CHN analysis : found C 66.15%, H 6.89%, N 5.53%; C 28

H

34

N

2 0 6 +0.75H 2 0 requires C 66.19%, H 7.04%, N 5.51%. 10 Example 43: N-(3,4-dichlorobenzyl)-2-{3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3 (hydroxymethyl)phenyl]ethyl}amino)ethyl]phenyl}acetamide OH CI HH NN HO CI HO Prepared according to the procedure used for Preparation 1 using {3-[2-({(2R) 2-hydroxy-2-[4-hydroxy-3 15 (hydroxymethyl)phenyl]ethyl)amino)ethyl]phenyl}acetic acid (Preparation 51) and the appropriate amine to give the title compound as a white foam. IH NMR (400MHz, CD 3 0D): 6 = 7.43-7.41 (1H, d), 7.36-7.35 (1H, d), 7.26-7.23 (2H, m), 7.15-7.06 (5H, m), 6.74-6.72 (1H, d), 4.70-4.66 (1H, m), 4.63 (2H, s), 4.32 (2H, s), 3.53 (2H, s), 2.94-2.75 (6H, m) ppm. 20 LRMS (electrospray): m/z [M+H]* 503, [M+Na]* 525, [M-H]- 501. CHN analysis : found C 59.26%, H 5.52%, N 5.20%; C 26

H

28

N

2 0 4 Cl 2 +1.35H 2 0 requires C 59.17%, H 5.86%, N 5.31%. Example 44: N-benzyl-2-{3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3 25 (hydroxymethyl)phenyl]ethyl}amino)ethyl]phenyl}acetamide WO 2005/090287 PCT/IB2005/000640 83 OH H H H O1 N HO Prepared according to the procedure used for Preparation 1 using {3-[2-({(2R) 2-hydroxy-2-[4-hydroxy-3 (hydroxymethyl)phenyl]ethyl}amino)ethyl]phenyl)acetic acid (Preparation 51) 5 and the appropriate amine to give the title compound as a white foam. 1H NMR (400MHz, CD 3 0D): 6 = 7.30-7.19 (7H, m), 7.15-7.14 (2H, m), 7.11 7.06 (2H, m), 6.74-6.72 (1H, d), 4.70-4.67 (IH, m), 4.63 (2H, s), 4.35 (2H, s), 3.52 (2H, s), 2.95-2.77 (6H, m) ppm. LRMS (electrospray) : m/z [M+H]+ 435, [M+Na]* 457, [M-H]~ 433. 10 CHN analysis : found C 67.21%, H 6.70%, N 5.99%; C 26

H

30

N

2 0 4 +0.45CH 2 Cl2 requires C 67.20%, H 6.59%, N 5.93%. Example 45: N-(2,3-dihydro-1 H-inden-2-yl)-2-{3-[2.({(2R)-2-hydroxy-2-[4 hydroxy-3-(hydroxymethyl)phenyl]ethyl)amino)ethyl]phenyl}acetamide OH H H N N HO0 15 HO Prepared according to the procedure used for Preparation 1 using {3-[2-({(2R) 2-hydroxy-2-[4-hydroxy-3 (hydroxymethyl)phenyl]ethyl}amino)ethyl]phenyl}acetic acid (Preparation 51) and the appropriate amine to give the title compound as a white foam. 20 1 H NMR (400MHz, CD 3 0D): 6 = 7.26 (1H, s), 7.24-7.17 (3H, m), 7.13-7.07 (6H, m), 6.74-6.72 (1H, d), 4.72-4.68 (1H, m), 4.63 (2H, s), 4.59-4.52 (1H, m), 3.45 (2H, s), 3.26-3.24 (1H, d), 3.22-3.20 (1H, d), 2.97-2.79 (8H, m) ppm.

WO 2005/090287 PCT/IB2005/000640 84 LRMS (electrospray) m/z [M+H]* 461, [M+Na]* 483, [M-H]~ 459. CHN analysis found C 65.30%, H 6.57%, N 5.57%;

C

28

H

32

N

2 0 4 +0.80CH 2 Cl 2 +0.10H 2 0 requires C 65.23%, H 6.42%, N 5.28%. 5 Example 46: 2-{3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3 (hydroxymethyl)phenyl]ethyl}amino)ethy]phenyl}-N-(2 phenylethyl)acetamide OH H H HO N N HO, 0 HO Prepared according to the procedure used for Preparation 1 using {3-[2-({(2R) 10 2-hydroxy-2-[4-hydroxy-3 (hydroxymethyl)phenyl]ethyllamino)ethyl]phenyl}acetic acid (Preparation 51) and the appropriate amine to give the title compound as a white foam. 'H NMR (400MHz, CD 3 0D): 6 = 7.27-7.26 (1H, d), 7.24-7.06 (10H, m), 6.74 6.72 (1H, d), 4.72-4.69 (1H, m), 4.64 (2H, s), 3.44-3.39 (4H, m), 3.00-2.92 (2H, 15 m), 2.89-2.82 (4H, m), 2.79-2.75 (2H, t) ppm. LRMS (electrospray): m/z [M+H]* 449, [M+Na]* 471, [M-H]- 447. CHN analysis : found C 64.80%, H 6.70%, N 5.52%; C 27

H

32

N

2 0 4 +0.75CH 2 Cl 2 requires C 65.07%, H 6.59%, N 5.47%. 20 Example 47: 2-{3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3 (hydroxymethyl)pheny]ethyl}amino)ethyl]phenyl}-N-(3 phenylpropyl)acetamide OH H NNN HO,

HO

WO 2005/090287 PCT/IB2005/000640 85 Prepared according to the procedure used for Preparation 1 using (3-[2-({(2R) 2-hydroxy-2-[4-hydroxy-3 (hydroxymethyl)phenyl]ethyl}amino)ethyl]phenyl}acetic acid (Preparation 51) and the appropriate amine to give the title compound as a white foam. 5 1H NMR (400MHz, CD 3 0D): 6 = 7.25-7.19 (4H, m), 7.15-7.05 (7H, m), 6.74 6.72 (1H, d), 4.69-4.64 (3H, m), 3.47 (2H, s), 3.21-3.17 (2H, t), 2.96-2.74 (6H, m), 2.60-2.56 (2H, t), 1.75-1.73 (2H, m) ppm. LRMS (electrospray) : m/z [M+H]+ 463, [M+Na]* 485, [M-H]~ 461. CHN analysis found C 68.54%, H 7.17%, N 5.80%; 10 C 28 H34N 2 0 4 +0.40CH 2 Cl 2 +0.10 H 2 0 requires C 68.45%, H 7.08%, N 5.62%. Example 48: N-benzyl-3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3 (hydroxymethyl)phenyljethyl}amino)propyl]benzamide OH O H N HO

OH

3 HO 15 To a solution of 3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3 (hyd roxymethyl)phenyl]ethyl}amino)propyl]benzoic acid (Preparation 59) (116mg, 0.22mmol) in DMF (2ml) was added triethylamine (62pl, 0.45mmol), benzylamine (29pl, 0.27mmol), HOBt (33mg, 0.25mmol) and WSCDI (47mg, 0.25mmol) and the resulting solution stirred at room temperature for 18 hours. 20 The solvent was removed in vacuo and the residue partitioned between saturated aqueous sodium hydrogen carbonate solution (5ml) and dichloromethane/methanol (95/5) (10ml). The aqueous layer was separated and extracted with further dichloromethane/methanol (95/5) (4xlOml). The combined organic layers were dried (sodium sulfate), filtered and evaporated in 25 vacuo. The resulting oil was purified by flash column chromatography on silica WO 2005/090287 PCT/IB2005/000640 86 gel eluting with dichloromethane:methanol:880 ammonia (90:10:1, by volume) to give the title compound as a white foam (70mg). H NMR (400MHz, CD 3 OD): 8 = 7.70-7.68 (1H, d), 7.66 (1H, s), 7.38-7.29 (6H, in), 7.26-7.21 (1H, m), 7.21 (1H, s), 7.03-7.01 (1H, d), 6.69-6.67 (1H, d), 4.64 5 4.61 (1H, m), 4.61 (2H, s), 4.58 (2H, s), 3.05-2.98 (1H, m), 2.92-2.86 (1H, dd), 2.84-2.79 (1H, dd), 2.75-2.71 (1H, dd), 2.68-2.63 (1H, dd), 1.10-1.08 (3H, d) ppm. LRMS (electrospray): m/z [M+H]+ 435, [M+Na]* 457, [M-H]~ 433. CHN analysis : found C 69.79, H 6.96, N 6.37; C 26

H

3 0

N

2 0 4 +0.7H 2 0 requires C 10 69.84, H 7.08, N 6.26. Example 49: N-(3,4-dichlorobenzyl)-3-[(2R)-2-({(2R)-2-hydroxy-2-[4 hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]benzamide OH O H HO C H HO

CH

3 s-Cl HO 15 Prepared according to the procedure used for example 49 using 3-[(2R)-2 ({(2R)-2-hydroxy-2-[4-hydroxy-3 (hydroxymethyl)phenyl]ethyl}amino)propyl]benzoic acid (Preparation 59) and the appropriate amine to give the title compound as a white foam. 1 H NMR (400MHz, CD 3 0D): 8 = 7.69-7.67 (1H, d), 7.65 (1H, s), 7.51 (1H, s), 20 7.48-7.46 (1H, d), 7.36-7.27 (3H, m), 7.21 (1H, s), 7.03-7.02 (1H, d), 6.69-6.66 (1H, d), 4.65-4.61 (1H, m), 4.61 (2H, s), 4.54 (2H, s), 3.02-2.97 (1H, m), 2.91 2.86 (1H, dd), 2.83-2.77 (1H, dd), 2.74-2.69 (1H, dd), 2.68-2.63 (1H, dd), 1.09 1.08 (3H, d) ppm. LRMS (electrospray): m/z [M+H]* 503, [M+Na]+ 525, [M-HJ~ 501. 25 WO 2005/090287 PCT/IB2005/000640 87 Example 50: N-[2-fluoro-5-(trifluoromethyl)benzyl]-3-[(2R)-2-({(2R)-2 hydroxy-2-[4-hydroxy-3 (hydroxymethyl)phenyl]ethyl}amino)propyl]benzamide OH 0 F N N F HI F1 HO CH 3 V F HO 5 Prepared according to the procedure used for example 49 using 3-[(2R)-2 ({(2R)-2-hydroxy-2-[4-hydroxy-3 (hydroxymethyl)phenyl]ethyl}amino)propyl]benzoic acid (Preparation 59) and the appropriate amine to give the title compound as a white foam. H NMR (400MHz, CD 3 0D): 8 = 7.74-7.60 (4H, m), 7.38-7.29 (3H, in), 7.22 (1H, 10 s), 7.04-7.02 (1H, d), 6.69-6.67 (1H, d), 4.67 (2H, s), 4.67-4.61 (1H, m) 4.61 (2H, s), 3.04-2.99 (1H, m), 2.93-2.80 (2H, m), 2.76-2.71 (1H, m), 2.68-2.63 (1H, m), 1.09-1.08 (3H, d) ppm. LRMS (electrospray): m/z [M+H]* 521, [M+Na]* 543, [M-H] 519. CHN analysis : found C 60.88, H 5.58, N 5.58; C 27

H

28

F

4

N

2 0 4 +0.7H 2 0 requires 15 C 60.83, H 5.56, N 5.25. Example 51: N-(2,6-dimethoxybenzyl)-3-[(2R)-2-({(2R)-2-hydroxy-2-[4 hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]benzamide OH O O-CH3 HOH HC HI HO

CH

3 0 HO C 3 WO 2005/090287 PCT/IB2005/000640 88 Prepared according to the procedure used for example 49 using 3-[(2R)-2 ({(2R)-2-hydroxy-2-[4-hydroxy-3 (hydroxymethyl)phenyl]ethyl}amino)propyl]benzoic acid (Preparation 59) and the appropriate amine to give the title compound as a white foam. 5 'H NMR (400MHz, CD 3 0D): 8 = 7.58-7.55 (2H, m), 7.31-7.24 (3H, m), 7.19 (1H, s), 7.00-6.98 (1H, dd), 6.68-6.64 (3H, m), 4.63 (2H, s), 4.63-4.58 (1H, m) 4.60 (2H, s), 3.84 (6H, s), 3.00-2.94 (1H, m), 2.90-2.85 (1H, in), 2.78-2.61 (3H, m), 1.08-1.06 (3H, d) ppm. LRMS (electrospray): m/z [M+H]* 495, [M+Na]* 517, [M-H]~ 493. 10 CHN analysis : found C 65.52, H 6.89, N 5.43; C 28 H34N 2 0 6 +1.OH 2 0 requires C 65.61, H 7.08, N 5.46. Example 52: N-[2-(4-chlorophenyl)ethyl]-3-[(2R)-2-({(2R)-2-hydroxy-2-[4 hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]benzamide OH N N H HO CH 15 HO Prepared according to the procedure used for example 49 using 3-[(2R)-2 ({(2R)-2-hydroxy-2-[4-hydroxy-3 (hydroxymethyl)phenyl]ethyl}amino)propyl]benzoic acid (Preparation 59) and the appropriate amine to give the title compound as a white foam. 20 'H NMR (400MHz, CD 3 0D): 6 = 7.60-7.58 (1H, d), 7.54 (1H, s), 7.35-7.23 (7H, m), 7.04-7.01 (1H, dd), 6.70-6.68 (1H, d), 4.64-4.61 (1H, m), 4.61 (2H, s), 3.60 3.57 (2H, t), 3.02-2.96 (1 H, m), 2.92-2.87 (3H, m), 2.83-2.78 (1 H, m), 2.75-2.71 (1H, dd), 2.66-2.61 (1H, dd), 1.09-1.08 (3H, d) ppm. LRMS (electrospray): m/z [M+H]* 483, [M+Na]+ 505, [M-H]- 481. 25 CHN analysis : found C 65.90, H 6.68, N 5.55; C 27

H

31

CIN

2 0 4 +0.5H 2 0 requires C 65.91, H 6.56, N 5.69.

WO 2005/090287 PCT/IB2005/000640 89 Example 53: N-(2,3-dihydro-1H-inden-2-yl)-3-[(2R)-2-(((2R)-2-hydroxy-2-[4 hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]benzamide O OH H N Z N H HO

CHV

3 HO0 Prepared according to the procedure used for example 49 using 3-[(2R)-2 5 ({(2R)-2-hydroxy-2-[4-hydroxy-3 (hydroxymethyl)phenyl]ethyl}amino)propyljbenzoic acid (Preparation 59) and the appropriate amine to give the title compound as a white foam. 'H NMR (400MHz, CD 3 0D): 5 = 7.66-7.63 (2H, m), 7.35-7.28 (2H, m), 7.22 7.21 (3H, m), 7.15-7.13 (2H, m), 7.03-7.02 (1H, dd), 6.70-6.68 (1H, d), 4.84 10 4.79 (1H, m), 4.64-4.60 (1H, m), 4.61 (2H, s), 3.37-3.30 (2H, dd), 3.03-2.97 (3H, m), 2.92-2.87 (1H, m), 2.84-2.78 (1H, m), 2.76-2.71 (1H, m), 2.68-2.63 (1H, dd), 1.09-1.08 (3H, d) ppm. LRMS (electrospray) : m/z [M+H]f 461, [M+Na]* 483, [M-H]~ 459. CHN analysis : found C 70.42, H 6.87, N 5.91; C 28

H

32

N

2 0 4 +0.9H 2 0 requires C 15 70.54, H 7.15, N 5.88. Example 54: 3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3 (hydroxymethyl)phenyl]ethyl}am ino)propyl]-N-(2-phenylethyl) benzam ide HO OH

HO

WO 2005/090287 PCT/IB2005/000640 90 Prepared according to the procedure used for example 49 using 3-[(2R)-2 ({(2R)-2-hydroxy-2-[4-hydroxy-3 (hydroxymethyl)phenyl]ethyl}amino)propyl]benzoic acid (Preparation 59) and the appropriate amine to give the title compound as a white foam. 5 'H NMR (400MHz, CD 3 0D): 5 = 7.60-7.58 (1H, d), 7.56 (1H, s), 7.35-7.17 (8H, m), 7.05-7.02 (1H, dd), 6.70-6.68 (1H, d), 4.64-4.60 (1H, m), 4.62 (2H, s), 3.61 3.57 (2H, t), 3.03-2.97 (1H, m), 2.93-2.87 (3H, m), 2.84-2.78 (1H, m), 2.77-2.71 (1H, n), 2.66-2.61 (1H, dd), 1.09-1.08 (3H, d) ppm. LRMS (electrospray) : m/z [M+H]+ 449, {M+Na]* 471, [M-H]~ 447. 10 CHN analysis: found C 70.10, H 7.16, N 6.09; C 27

H

32

N

2 0 4 +0.75H 2 0 requires C 70.18, H 7.31, N 6.06 Example 55: 3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3 (hydroxymethyl)phenylethyl}amino)propyl]-N-[(1 R)-1 15 phenylethyl]benzamide OH 0 CH H N N H HO CH 3 HO Prepared according to the procedure used for example 49 using 3-[(2R)-2 ({(2R)-2-hydroxy-2-[4-hydroxy-3 (hydroxymethyl)phenylethyl}amino)propyl]benzoic acid (Preparation 59) and 20 the appropriate amine to give the title compound as a white foam. 'H NMR (400MHz, CD 3 0D): 8 = 7.67-7.64 (2H, m), 7.41-7.39 (2H, d), 7.34-7.28 (4H, m), 7.24-7.21 (2H, m), 7.02-7.00 (1H, dd), 6.68-6.66 (IH, d), 5.26-5.21 (1H, q), 4.63-4.60 (1H, m), 4.60 (2H, s), 3.03-2.99 (1H, m), 2.91-2.86 (1H, dd), 2.83-2.78 (1H, dd), 2.74-2.70 (1H, dd), 2.69-2.63 (1H, dd), 1.57-1.55 (3H, d), 25 1.09-1.08 (3H, d) ppm. LRMS (electrospray): m/z [M+H]* 449, [M+Na]* 471, [M-Hj~ 447.

WO 2005/090287 PCT/IB2005/000640 91 CHN analysis : found C 68.96, H 7.07, N 5.91; C 27

H

32

N

2 0 4 +1.2H 2 0 requires C 68.97, H 7.37, N 5.96 5 Example 56: 3-[(2R)-2-((2R)-2-hydroxy-2-[4-hydroxy-3 (hydroxymethyl)phenyl]ethyl}amino)propyl]-N-(3-phenylpropyl)benzamide OH O HO HO

CH

3 HO Prepared according to the procedure used for example 49 using 3-[(2R)-2 ({(2R)-2-hydroxy-2-[4-hydroxy-3 10 (hydroxymethyl)phenyl]ethyl}amino)propyl]benzoic acid (Preparation 59) and the appropriate amine to give the title compound as a white foam. 'H NMR (400MHz, CD 3 0D): 8 = 7.63-7.61 (1H, d), 7.59 (1H, s), 7.35-7.21 (7H, m), 7.16-7.13 (1H, m), 7.03-7.01 (1H, dd), 6.69-6.67 (1H, d), 4.61 (3H, m), 3.42-3.39 (2H, t), 3.00-2.96 (1H, q), 2.91-2.86 (1H, dd), 2.81-2.76 (1H, dd), 15 2.74-2.61 (4H, m), 1.98-1.91 (2H, quin), 1.09-1.07 (3H, d) ppm. LRMS (electrospray) : m/z [M+H]* 463, [M+Na]* 485, [M-H]- 461. Example 57: 4-[(1 R)-2-({(1 R)-2-[3-(3,4-dihydroisoquinolin-2(1H) ylcarbonyl)phenyl]-1 -methylethyl}amino)-1 -hydroxyethyl]-2 20 (hydroxymethyl)phenol OH O H HO N

HO

WO 2005/090287 PCT/IB2005/000640 92 Prepared according to the procedure used for example 49 using 3-[(2R)-2 ({(2R)-2-hydroxy-2-[4-hydroxy-3 (hydroxymethyl)phenyl]ethyl}amino)propyl]benzoic acid (Preparation 59) and the appropriate amine to give the title compound as a white foam. 5 'H NMR (400MHz, CD 3 0D): 3 = 7.39-7.36 (1H, m), 7.29-7.17 (6H, m), 7.12 7.01 (3H, m), 6.71-6.69 (1H, d), 4.62 (2H, s), 4.62-4.55 (2H, m), 3.96 (2H, s), 3.60-3.56 (1H, m), 3.11-2.64 (7H, m), 1.10-1.08 (3H, d) ppm. LRMS (electrospray): m/z [M+H]+ 461, [M+Na]* 483, (M-H]~ 459. CHN analysis : found C 71.65, H 7.12, N 6.39; C 28

H

32

N

2 0 4 +0.41H 2 0 requires C 10 71.87, H 7.07, N 5.99. Example 58: N-(2,3-dimethylbenzyl)-3-[(2R)-2-({(2R)-2-hydroxy-2-[4 hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]benzamide OH 0

CH

3 H N CH3 SH Hj HO C 3 HO 15 Prepared according to the procedure used for example 49 using 3-[(2R)-2 ({(2R)-2-hydroxy-2-[4-hydroxy-3 (hydroxymethyl)phenyl]ethyl}amino)propyl]benzoic acid (Preparation 59) and the appropriate amine to give the title compound as a white foam. 'H NMR (400MHz, CD 3 0D): 8 = 7.68-7.66 (1H, d), 7.64 (1H, s), 7.36-7.28 (2H, 20 m), 7.21 (1H, d), 7.14-7.12 (1H, d), 7.08-6.99 (3H, m), 6.68-6.68 (1H, d), 4.63 4.59 (1H, m), 4.61 (2H, s), 4.59 (2H, s), 3.04-2.99 (1H, q), 2.92-2.89 (1H, dd), 2.83-2.79 (1H, dd), 2.75-2.71 (1H, dd), 2.69-2.64 (1H, dd), 2.30 (3H, s), 2.28 (3H, s), 1.11-1.09 (3H, d) ppm. LRMS (electrospray) : m/z [M+H]* 463, [M+Na]* 485, [M-H]- 461. 25 CHN analysis : found C 70.17, H 7.33, N 5.90; C 28 H34N 2

O

4 +0.90H 2 0 requires C 70.24, H 7.54, N 5.85.

WO 2005/090287 PCT/IB2005/000640 93 Example 59: N-(5,6-diethyl-2,3-dihydro-1H-inden-2-y)-3-[(2R)-2-({(2R)-2 hydroxy-2-[4-hydroxy-3 (hydroxymethyl)phenyl]ethyl}amino)propyl]benzamide

CH

3 OH O HO CH HO 5 Prepared according to the procedure used for example 49 using 3-[(2R)-2 ({(2R)-2-hydroxy-2-[4-hydroxy-3 (hydroxymethyl)phenyl]ethyllamino)propyljbenzoic acid (Preparation 59) and the appropriate amine to give the title compound as a white foam. 'H NMR (400MHz, CD 3 0D): 8 = 7.65-7.63 (1H, d), 7.61 (1H, s), 7.34-7.26 (2H, 10 in), 7.21 (1H, s), 7.03-7.01 (1H, m), 7.01 (2H, s), 6.69-6.67 (1H, d), 4.81-4.77 (1H, dd), 4.63-4.60 (1H, m), 4.61 (2H, s), 3.31-3.26 (2H, dd), 3.03-2.99 (1H, q), 2.97-2.92 (2H, dd), 2.92-2.87 (1H, dd), 2.83-2.78 (1H, dd), 2.75-2.71 (1H, dd), 2.68-2.61 (5H, m), 1.22-1.18 (6H, t), 1.10-1.09 (3H, d) ppm. LRMS (electrospray): m/z [M+H]* 517, [M+Na]* 539, [M-H]~ 515. 15 CHN analysis : found C 72.58, H 7.80, N 5.34; C 32

H

40

N

2 0 4 +0.7H 2 0 requires C 72.62, H 7.88, N 5.29. Example 60: N-(4-chlorobenzyl)-3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3 (hydroxymethyl)phenyl]ethyl}amino)propyl]benzamide OH O H0 N CHH HO Cl 20 HO WO 2005/090287 PCT/IB2005/000640 94 To a solution of 3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3 (hydroxymethyl)phenyl]ethyl}amino)propyl]benzoic acid (Preparation 59) (120mg, 0.27mmol) in DMF (3ml) was added triethylamine (111pi, 0.79mmol), 4-chlorobenzylamine ( 3 9 ptl, 0.32mmol), and HBTU (110mg, 0.29mmol) and the 5 resulting solution stirred at room temperature for 18 hours. The solvent was removed in vacuo and the residue purified by flash column chromatography on silica gel eluting with dichloromethane:methanol:880 ammonia (93:7:0.7 changing to 90:10:1, by volume) to give the title compound as a white foam (97mg). 10 1H NMR (400MHz, CD 3 0D): S = 7.70-7.68 (1H, d), 7.66 (1H, s), 7.38-7.30 (6H, m), 7.23 (1H, d), 7.05-7.03 (1H, dd), 6.70-6.68 (1H, d), 4.67-4.64 (1H, dd), 4.62 (2H, s), 4.55 (2H, s), 3.15-3.07 (1H, m), 3.00-2.86 (2H, m), 2.82-2.78 (1H, dd), 2.72-2.67 (1H, dd), 1.13-1.12 (3H, d) ppm. LRMS (electrospray) : m/z [M+H]* 469, [M+Na]* 491, [M-H]- 467. 15 Example 61: 3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3 (hydroxymethyl)phenyl]ethyl}amino)propyl]-N-phenylbenzamide OH H H HO

OH

3 V HO Prepared according to the procedure used for example 60 using 3-[(2R)-2 20 (((2R)-2-hydroxy-2-[4-hydroxy-3 (hydroxymethyl)phenyl]ethyl}amino)propyl]benzoic acid (Preparation 59) and the appropriate amine to give the title compound as a white foam. 'H NMR (400MHz, CD 3 0D): S = 7.77-7.74 (2H, m), 7.69-7.67 (2H, d), 7.41-7.33 (4H, m), 7.22 (1H, d), 7.16-7.12 (1H, t), 7.05-7.03 (1H, dd), 6.70-6.68 (1H, d), 25 4.66-4.61 (1H, m), 4.62 (2H, s), 3.09-3.04 (1H, m), 2.96-2.84 (2H, m), 2.79-2.69 (2H, m), 1.14-1.12 (3H, d) ppm. LRMS (electrospray): m/z [M+H]* 421, [M+Na]* 443, [M-H]~ 419 WO 2005/090287 PCT/IB2005/000640 95 CHN analysis : found C 67.98, H 6.64, N 6.48; C 25

H

28

N

2 0 4 +0.06CH 2 Cl 2 +0.95

H

2 0 requires C 67.99, H 6.83, N 6.33. Example 62: N-[4-(aminosulfonyl)benzyl]-3-[(2R)-2-({(2R)-2-hydroxy-2-[4 5 hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]benzamide OH O H NN HO

CH

3 H0NH HO

SO

2

NH

2 HO Prepared according to the procedure used for example 60 using 3-[(2R)-2 ({(2R)-2-hydroxy-2-[4-hydroxy-3 10 (hydroxymethyl)phenyl]ethyl}amino)propyl]benzoic acid (Preparation 59) and the appropriate amine, substituting with dichloromethane :methanol:880 ammonia (85:15:2, by volume) as eluent to give the title compound as a white foam. 1H NMR (400MHz, CD 3 0D): 5 = 7.87-7.85 (2H, d), 7.71-7.69 (1H, d), 7.67 (1H, 15 s), 7.53-7.50 (2H, d), 7.39-7.32 (2H, m), 7.23 (1H, d), 7.05-7.03 (1H, dd), 6.70 6.68 (1H, d), 4.67-4.65 (1H, m), 4.65 (2H, s), 4.62 (2H, s), 3.14-3.07 (1H, m), 2.97-2.92 (1H, dd), 2.91-2.86 (1H, dd), 2.82-2.78 (1H, dd), 2.72-2.67 (1H, dd), 1.13-1.12 (3H, d) ppm. LRMS (electrospray): m/z [M+H]* 514, [M+Na]* 536, [M-H]~ 512. 20 CHN analysis : found C 56.26, H 6.01, N 7.45; C 26

H

31

N

3 0S+2.1H 2 0 requires C 56.63, H 6.43, N 7.62. Example 63 N-[2-(3-Fluorophenyl)ethyl]-3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3 25 (hydroxymethyl)phenyl]ethyl)amino)-2-methylpropyl]benzamide WO 2005/090287 PCT/IB2005/000640 96 F OH 0 H NN

H

3 C CH 3 H HO HO 3-[2-({(2R)-2-{[tert-Butyl(dimethyl)silyl~oxy}-2-[4-hydroxy-3-(hydroxylmethyl) phenyllethyl}amino)-2-methylpropyl-N-[2-(3-fluorophenyl)ethyl]benzamid e (preparation 157), (343mg, 0.58mmol) and ammonium fluoride (213mg, 5 5.76mmol) in methanol (12mL) and water (2mL) were stirred at room temperature for 42 hours. The solvent was removed in vacuo and the residue was purified by column chromatography on silica gel, eluting with dichloromethane:methano:0.88 ammonia, 100:0:0 to 90:10:1. The appropriate fractions were concentrated in vacuo and the residue was azeotroped (x2) in 10 ethanol to give a white solid. This solid was then re-crystallised with ethanol/water and dried under vacuum to afford the title compound as very pale yellow crystals in 52% yield, 144mg. H NMR (400MHz, CD 3 0D) 5: 7.63 (2H, m) 7.38-7.23 (4H, m), 7.13 (1H, m), 7.05 (1H, m), 7.00 (1H, m), 6.91 (1H, m), 6.85 (1H, d), 4.65 (3H, m), 3.59 (2H, 15 m), 2.96-2.84 (2H, m), 2.78-2.68 (2H, m), 1.10 (3H, s), 1.04 (3H, s) ppm; LRMS ESI m/z 481 [M+H]* Examples 64 to 78 20 The following compounds, of the general formula shown below were prepared by a similar method to that described for example 63, using the appropriate starting material and ammonium fluoride. The reaction mixtures were warmed to 40 0 C until thin layer chromatography analysis indicated that all of the starting materials had been consumed. 25 WO 2005/090287 PCT/IB2005/000640 97 OH 0 N

H

3 C H 3 I Q HO HO No. Q 1 Data Yield 64 'H NMR (400MHz, CD 3 0D) 8: 7.78 N 7.71 (2H, m) 7.40-7.31 (3H, m), 7.15 (1H, m), 6.76 (1H, m), 4.70-4.64 (3H, m), 3.62-3.50 (2H, m), 3.01 2.94 (2H, m), 2.76-2.63 (4H, m), 2.59-2.46 (4H, m), 1.78-1.65 (4H, m), 1.13 (3H, s), 1.01 (3H, s) ppm; LRMS APCI m/z 456 [M+H]4 65 CI 'H NMR (400MHz, CD 3 0D) 8: 7.65 81% (2H, m) 7.37-7.29 (5H, m), 7.21-7.11 (2H, m), 6.77 (1H, m), 4.70-4.63 (3H, m), 3.66 (2H, m), 3.30 (2H, m), 2.96-2.69 (4H, m), 1.10 (3H, s), 1.05 (3H, s) ppm; LRMS APCI m/z 531 [M+H]+ 66 1H NMR (400MHz, CD 3 0D) 8: 7.64 35% (m, 2H), 7.40-7.30 (3H, m), 7.19 7.05 (5H, m), 6.75 (1H, m), 4.65 (3H, m), 3.42 (2H, m), 2.69-3.10 (9H, m), 1.14 (3H, s), 1.05 (3H, s) ppm LRMS APCI m/z 489 [M+H]* WO 2005/090287 PCT/IB2005/000640 98 67 0 H NMR (400MHz, CD 3 0D) 8: 7.74 31% NH (2H, m), 7.66-7.59 (2H, m), 7.37 N 7.25 (5H, m), 7.13 (1H, m), 6.75

CH

3 (1H, d), 4.65 (3H, m), 3.62 (2H, m), 3.32 (2H, m), 3.00-2.68 (6H, m), 1.59 (2H, m), 1.39 (2H, m), 1.12 (3H, s), 1.04 (3H, s), 0.97 (3H, t) ppm LRMS APCI m/z 562 [M+H]* 68 / H NMR (400MHz, CD 3 0D) 8: 7.68- 34% 7.56 (2H, m), 7.40-7.07 (13H, brm), s 6.74 (1H, m), 4.86-4.74 (3H, m), 3.70-3.58 (2H, m), 3.11 (2H, m), 2.68-2.95 (4H, m), 1.12 (3H, s), 1.06 (3H, s) ppm; LRMS APCI m/z 571 [M+H] + 69 1 H NMR (400MHz, CD 3 OD) 8: 7.66 69% (2H, m), 7.34 (3H, m), 7.13 (1H, m), 6.74 (1H, d), 4.67 (1H, d), 4.65 (2H, s), 3.42-3.34 (2H, m), 2.87-2.97 (2H, m), 2.70-2.77 (2H, m), 1.80-1.59 (5H, m), 1.47 (2H, q), 1.15-1.30 (4H, m), 1.12 (3H, s), 1.05 (3H, s), 1.00 0.90 (2H, m) ppm LRMS ESI m/z 469 [M+H]* 70 1 H NMR (400MHz, CD 3 0D) 5: 7.67 89% (2H, m), 7.39-7.32 (3H, m), 7.26 7.12 (6H, m), 6.75 (1H, d), 4.68-4.63 (3H, t), 3.43-3.38 (2H, m), 2.98-2.88 (2H, m), 2.76-2.64 (4H, m), 1.97 1.89 (2H, m), 1.12 (3H, s), 1.05 (3H, s) ppm; LRMS APCI m/z 477 [M+H]* WO 2005/090287 PCT/IB2005/000640 99 71 H NMR (400MHz, CD 3 0D) 5: 7.64 72% (2H, m), 7.38-7.13 (9H, m), 6.76 (1H, d), 4.65 (3H, m), 3.60 (2H, m), 2.97-2.86 (4H, m), 2.76-2.70 (2H, m), 1.11 (3H, s), 1.05 (3H, s) ppm; LRMS APCI m/z 463 [M+H]* 72 cl 1H NMR (400MHz, CD 3 0D) 8: 7.68- 16%

H

3 C 7.63 (2H, m), 7.39-7.31 (3H, m), 7.25 (2H, m), 7.26-7.19 (1H, m), 6.76 (1H, d), 4.69-4.64 (3H, m), C1 3.58-3.53 (2H, t), 3.23-3.18 (2H, m), 3.00-2.80 (2H, m), 2.71-2.69 (2H, t), 2.47 (3H, s), 1.12 (3H, s), 1.06 (3H, s) ppm; LRMS ESI m/z 545 [M+H]* 73 /CH 3 IH NMR (400MHz, CD 3 0D) 6: 7.61 48% 0 (2H, m), 7.40-7.30 (3H, m), 7.20 7.10 (3H, m), 6.90 (1H, d), 6.77 (1H; d), 4.75-4.60 (3H, m), 3.80 (3H, s), cI 3.60-3.50 (2H, m), 3.00-2.80 (4H, m), 2.80-2.70 (2H, m), 1.95-1.15 (3H, m), 1.10 (3H, s) ppm 74 N I'H NMR (400MHz, CD 3 0D) 6: 7.75- 10% 7.65 (2H, m), 7.40-7.10 (6H, m), 0 6.80-6.70 (3H, m), 4.70-4.60 (3H,

H

3 C m), 3.67 (3H, s), 3.60-3.50 (2H, m), 3.00-2.70 (6H, brm), 1.15 (3H, s), 1.05 (3H, s) ppm; LRMS APCI 493

[M+H]*

WO 2005/090287 PCT/IB2005/000640 100 75 H NMR (400MHz, CD 3 0D) 5: 7.67- 5% 7.60 (2H, m), 7.40-7.25 (3H, m), 7.20-7.10 (2H, m), 6.80-6.70 (4H, m), 4.70-4.60 (3H, m), 4.00-3.90 (2H, m), 3.63-3.53 (2H, m), 2.96 2.60 (6H, m), 1.40-1.30 (3H, m), 1.20-1.00 (6H, m) ppm; LRMS APCI 507 [MH]* 76 1N H NMR (400MHz, CD 3 0D) 8: 7.70 7.60 (2H, m) 7.40-7.35 (3H, m), 7.20-7.10 (3H, m), 6.90-6.70 (3H, m), 4.65-4.60 (3H, m), 4.10-4.00 (2H, m), 3.60-3.50 (2H, m), 3.00 2.80 (12H, m), 2.10 (2H, m), 1.95 (4H, m), 1.20 (3H, s), 1.17 (3H, s) ppm; LRMS APCI m/z 590 [M+H]* 77 fH NMR (400MHz, CD 3 0D) 5: 7.62 62% (2H, m), 7.36-7.29 (3H, m) 7.18-7.11 0 (3H, m), 6.90 (1H, m), 6.84 (1H, m), 6.74 (1H, m), 4.66-4.62 (3H, m), 4.05-3.97(2H, m), 3.61-3.57 (2H, m), 2.95-2.83 (4H, m), 2.65-2.76 (4H, m), 2.60 (4H, m), 2.04-1.92 (2H, m), 1.84-1.76 (4H, m), 1.09 (3H, s), 1.03 (3H, m) ppm; LRMS APCI m/z 590

[M+H]*

WO 2005/090287 PCT/IB2005/000640 101 78 ,H NMR (400MHz, CD 3 0D) 6: 7.65- 56% 7.61 (2H, m) 7.37-7.30 (3H, m), o 7.18-7.12 (2H, m), 6.81-6.72 (4H, m), 4.68-4.64 (3H, m), 3.96 (2H, m), 3.64-3.54 (2H, m), 2.96-2.85 (4H, N m), 2.75-2.56 (8H, m), 2.00-1.93 (2H, m), 1.84-1.79 (4H, m), 1.10 (3H, s), 1.03 (3H, s) ppm; LRMS ESI m/z 590 [M+H]* Example 65: Compound was further purified by trituration with diethyl ether. Example 72: Purified by column chromatography using an ISCO* silica cartridge, eluting with dichloromethane:methanol:0.88 ammonia, 100:0 to 90:10:1 5 Example 75: Purified by column chromatography using a 4g RediSepo silica cartridge, eluting with, dichloromethane:methanol:0.88 ammonia, 100:0:0 to 90:10:1, followed by ethyl acetate:methanol:0.88 ammonia, 100:0:0 to 80:20:2 Example 78: Crude compound was further purified by trituration with diethyl ether 10 Example 79 N-[2-(4-Chlorophenyl)ethyl]-N-ethyl-3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3 (hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]benzamide OH O H N ji I N HO

H

3 C CH3 H CI HO 15 The title compound was prepared from 3-[2-({(2R)-2-{[tert butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-(hydroxymethy)phenyl]ethyl}amino)-2 methylpropyl]-N-[2-(4-chlorophenyl)ethyl]-N-ethylbenzamide (preparation 110), using a similar method to example 33, as a colourless solid in 61% yield.

WO 2005/090287 PCT/IB2005/000640 102 1 H NMR (400MHz, CD 3 0D) 7.30-7.10 (8H, m), 6.87 (2H, m), 6.73 (1H, d), 4.63 (3H, m), 3.71 (1H, m), 3.61 (1H, m), 3.50 (1H, m), 3.16 (1H, m), 3.01-2.69 (6H, m), 1.29-1.26, 1.07-1.01 (9H, 2xm) ppm; LRMS APCI m/z 525 [M+H]* 5 Example 80 2-{3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl] ethyl}amino)-2-methylpropyl]phenyl}-N-(3-pyrrolidin-1 -ylpropyl)acetamide OH H N H H C CH 3 HO HO The title compound was prepared from 2-{3-[2-({(2R)-2-{[terIt 10 butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2 methylpropyl]phenyl}-N-(3-pyrrolidin-1-ylpropyl)acetamide (preparation 109), using a similar method to that of example 33. The crude residue was further purified by column chromatography on Biotageo amino silica gel, eluting with dichloromethane:methanol, 80:20, to afford the title compound as a colourless 15 gum in 54% yield. 'H NMR (400MHz, CD 3 0D) 7.70-7.64 (2H, m), 7.40-7.30 (3H, m), 7.13 (1H, m), 6.75 (m, 1H), 4.69-4.64 (3H, m), 3.42 (2H, m), 3.00-2.90 (2H, m), 2.77-2.64 (2H, m), 2.60-2.50 (6H, m), 1.88-1.75 (6H, m), 1.12 (3H, s), 1.03 (s, 3H) ppm; LRMS APCI m/z 470 [M+H]* 20 Example 81 N-(Cycloheptylmethyl)-2-{3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3 (hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]phenyl)acetamide WO 2005/090287 PCT/IB2005/000640 103 OH H H N N HO

H

3 C

CH

3 N HO The title compound was prepared from 2-{3-[2-({(2R)-2-{[tert butyl(dimethyl)silyl]oxy)-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2 methylpropyl]phenyl}-N-(cycloheptylmethyl)acetamide (preparation 151), using 5 a similar method to that of example 33 as a white foam in 69% yield. 1H NMR (400MHz, CD 3 0D) S: 7.65 (1H, m), 7.38 (1H, s), 7.18-7.07 (4H, m), 6.90 (1H, d), 4.93-4.78 (1H, m), 4.04 (2H, m), 3.51 (2H, d), 3.18-3.07 (2H, m), 3.02-2.93 (4H, m), 1.72-1.36 (10H, m), 1.28 (6H, m), 1.19-1.07 (3H, m) ppm; LRMS ESI m/z 483 [M+H]* 10 Example 82 N-1 -Adamantyl-2-{3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3 (hydroxymethyl)phenyl]ethyl)amino)-2-methylpropyl]phenyl}acetamide OH H H

H

3 C

H

3 _o HO 1H3C 0 HO 15 The title compound was prepared from N-1-adamantyl-2-{3-[2-({(2R)-2-{[tert butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2 methylpropyl]phenyl}acetamide (preparation 152), using a method similar to that of example 33, as a white foam in 41% yield. 1 H NMR (400MHz, CD 3 0D) 8: 7.19-7.12 (5H, m), 7.02 (1H, dd), 6.78 (1H, d), 20 4.65 (3H, m), 3.40 (2H, d), 2.97 (1H, m), 2.82 (1H, m), 2.78 (2H, dd), 2.03 (9H, m), 1.64 (6H, m), 1.05 (6H, dd) ppm; LRMS ESI m/z 507 [M+H]* WO 2005/090287 PCT/IB2005/000640 104 Example 83 N-Benzyl-2-{3-[2-({(2R)-2-hyd roxy-2-[4-hyd roxy-3-(hydroxymethyl) phenyl]ethyl}amino)-2-methylpropyl]phenyl}-N-methylacetamide OH CH 3 H I N N

H

3 C CHJ HOH HO 5 The title compound was prepared from N-benzyl-2-{3-[2-({(2R)-2-{[ter butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2 methylpropyl]phenyl}-N-methylacetamide (preparation 156), using a similar method to example 33, as a colourless solid in 75% yield. H NMR (400MHz, CD 3 0D) 8: 7.18 (11H, m), 6.75 (1H, m), 4.61 (5H, m), 3.80 10 (2H, m), 2.60-2.95 (7H, m), 1.01 (6H, m) ppm; LRMS APCI m/z 477 [M+H]* Example 84 N-[2-(4-Fluorophenyl)ethyl]-3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3 (hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]benzamide OH 0 H N H ' NCH N

H

3 C CH 3 F HO 15 HO Solutions of 3-{2-[(2R)-2-(tert-butyldimethylsilanyloxy)-2-(4-hydroxy-3-hydroxy methyl-phenyl)ethylamino]-2-methylpropyl}benzoic acid (preparation 37) (90mg, 0.19mmol) in NN-dimethylacetamide (1mL) and O-(1H-benzotriazol-1-yl) N,N,N',N'-tetramethyluronium hexafluorophosphate (61mg, 0.16mmol) in N,N 20 dimethylacetamide (0.5mL) were added to a solution of 4-fluorophenethylamine (33mg, 0.19mmol) in N,N-dimethylacetamide (0.5mL). The resulting mixture was stirred for 72 hours at room temperature. The solvent was removed in vacuo and the residue was partitioned between dichloromethane (4mL) and WO 2005/090287 PCT/IB2005/000640 105 saturated sodium hydrogen carbonate solution (1mL). The mixture was then filtered through a phase separation tube and the organic solution was concentrated in vacuo. Ammonium fluoride (70mg, 1.9mmol) was added to a suspension of the residue in methanol (2mL) and water (imL) and the mixture 5 was stirred at room temperature for 72 hours. The reaction mixture was then concentrated in vacuo and the residue was purified by column chromatography on silica gel, eluting with dichloromethane:methanol:0.88 ammonia, 100:0:0 to 91:9:1, followed by trituration with diethyl ether, to afford the title compound in 50% yield, 45mg. 10 1H NMR (400MHz, CD 3 0D) 8: 7.63 (2H, m), 7.40-7.30 (3H, m), 7.23 (2H, m), 7.14 (1H, m), 7.00 (2H, m), 6.75 (1H, d), 4.65 (3H, m), 3.58 (2H, m), 2.98-2.64 (6H, m), 1.11 (3H, s), 1.05 (3H, s) ppm; LRMS APCI m/z 481 [M+H]* Examples 85 to 91 15 The following compounds, of the general formula shown below were prepared by a similar method to that described for example 84, using 3-{2-[(2R)-2-(tert butyldimethylsilanyloxy)-2-(4-hydroxy-3-hydroxymethyl-phenyl) ethylamino]-2 methylpropyl}benzoic acid (preparation 37) and the appropriate amine starting 20 material. The amines were either commercially available or prepared as described in preparations 69-108 OH 0 N

H

3 C

CH

3 HO HO 25 No. Q Data Yield WO 2005/090287 PCT/IB2005/000640 106 85 1 H NMR (400MHz, CD 3 0D) 6: 58% 7.63 (2H, m), 7.39-7.27 (5H, m), 7.22 (2H, m), 7.13 (1H, m), 7.06 (1H, m), 6.98-6.85 (4H, m), 6.75 (1H, d), 4.65 (3H, m), 3.59 (2H, m), 2.96-2.66 (6H, m), 1.10 (3H, s), 1.03 (3H, s) ppm; LRMS APCI m/z 555 [M+H]+ 86 1H NMR (400MHz, CD 3 0D) 8: 45% H 3 l---7.63 (2H, m), 7.39-7.27 (3H, m), 7.16-7.09 (3H, m), 6.84-6.72 (3H, m), 4.65 (3H, m), 3.99 (2H, q), 3.56 (2H, m), 2.96-2.80 (4H, m), 2.78-2.66 (2H, m), 1.35 (3H, t), 1.10 (3H, s), 1.05 (3H, s) ppm; LRMS APCI m/z 507 [M+H]* 87 H 3 C 'H NMR (400MHz, CD 3 0D) 6: 45% 7.63 (2H, m), 7.39-7.27 (3H, m), N 7.16-7.07 (5H, m), 6.76 (1H, d), 4.65 (3H, m), 3.58 (2H, m), 2.96 2.83 (4H, m), 2.78-2.66 (2H, m), 2.59 (2H, q), 1.19 (3H, t), 1.11 (3H, s), 1.05 (3H, s) ppm; LRMS APCI m/z 491 [M+H]* 88 'H NMR (400MHz, CD 3 0D) 6: 22% 7.66-7.59 (3H, m), 7.39-7.29 (3H,

H

3 C N N m), 7.15-7.08 (3H, m), 6.75 (1H, d), 4.65 (3H, m), 3.70 (2H, t), 3.04 (2H, t), 2.99-2.83 (2H, m), 2.80 2.68 (2H, m), 2.49 (3H, s), 1.10 (3H, s), 1.03 (3H, s) ppm; LRMS APCI m/z 478 [M+H]* WO 2005/090287 PCT/IB2005/000640 107 89 'H NMR (400MHz, CD 3 0D) &: 25% 7.60 (2H, m), 7.42-7.10 (6H, m), 6.90-6.70 (3H, d), 4.65 (3H, m),

H

3 C- 3.75 (3H, s), 3.50-3.60 (2H, m), 2.95-2.60 (6H, m), 1.15 (3H, s), 1.05 (3H, s) ppm; LRMS APCI m/z 493 [M+H]* 90 0 1 H NMR (400MHz, CD 3 0D) 8: 32% 0 8.00-7.90 (2H, m), 7.80-7.70 (2H, C m), 7.50-7.10 (6H, m), 6.80-6.70 (1 H, m), 4.65 (3H, m), 3.90 (2H, s), 3.32 (3H, s), 2.80-3.00 (2H, m), 2.80-2.70 (2H, m), 1.17 (3H, s), 1.07 (3H, s) ppm; LRMS APCI m/z 507 [M+H]* 91 CH 3 H NMR (400MHz, CD 3 0D) 5:' 52% N CH3 7.80-7.60 (2H, m), 7.40-7.10 (6H, N m), 6.80-6.60 (3H, m), 5.00-4.80 (3H, m), 4.60-4.40 (2H, m), 2.80 3.00 (6H, m), 2.80-2.60 (4H, m), 1.15 (3H, s), 1.05 (3H, s) ppm; LRMS APCI m/z 492 [M+H]* Upon addition of ammonium fluoride, examples: 89, 90 and 91 were warmed at 500C for 18 hours. Example 92 5 N-[2-(4-Ethoxy-3-methoxyphenyl)ethyl]-3-[2-({(2R)-2-hydroxy-2-[4-hydroxy 3-(hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]benzamide WO 2005/090287 PCT/IB2005/000640 108 OH 0 H N H NN

H

3 C CH 3 HO O CH 3 HO H O H3 Solutions of 3-{2-[(2R)-2-(tert-butyldimethylsilanyloxy)-2-(4-hydroxy-3-hydroxy methyl-phenyl)ethylamino]-2-methylpropyl}benzoic acid (preparation 37) (90mg, 0.19mmol) in NN-dimethylacetamide (1mL) and 0-(1H-benzotriazol-1-yl) 5 N,N,N',N'-tetramethyluronium hexafluorophosphate (61mg, 0.16mmol) in N,N dimethylacetamide (0.5mL) were added to a solution of 4-ethoxy-3 methoxyphenethylamine (37mg, 0.19mmol) in NN-dimethylacetamide (0.5mL). The resulting mixture was stirred for 72 hours at room temperature. The solvent was removed in vacuo and the residue was partitioned between 10 dichloromethane (4mL) and saturated sodium hydrogen carbonate solution (1mL). The mixture was then filtered through a phase separation tube and the organic solution was concentrated in vacuo. The residue was dissolved in dimethylsulfoxide (700ptL), triethylamine trihydrofluoride (30jL, 0.19mmol) was added and the mixture was stirred at room temperature for 72 hours. The 15 reaction mixture was then purified directly by HPLC using a Phenomenex Luna C18 system, eluting with water/0.05% diethylamine:acetonitrile, 5:95 to 95:5, to afford the title compound in 30% yield (30.9mg). 1 H NMR (400MHz, CD 3 0D) 8: 7.60-7.68 (2H, m), 7.39-7.29 (3H, m), 7.13 (1H, m), 6.85-6.81 (2H, m), 6.78-6.72 (2H, m), 4.67-4.62 (3H, m), 4.00 (2H, q), 3.75 20 (3H, s), 3.58 (2H, m), 2.98-2.64 (6H, m), 1.37 (3H, t), 1.10 (3H, s), 1.03 (3H, s) ppm; LCMS m/z 537.28 [M+H]* Examples 93 to 112 25 The following compounds, of the general formula shown below were prepared by a similar method to that described for example 92, using 3-{2-[(2R)-2-(tert butyldimethylsilanyloxy)-2-(4-hydroxy-3-hydroxymethyl-phenyl) ethylamino]-2- WO 2005/090287 PCT/IB2005/000640 -- 109 methylpropyl}benzoic acid (preparation 37) and the appropriate amine as starting material. The amines were either commercially available or prepared as described in preparations 69-108 OH 0 H I H 3

COH

3 HO 5 HO No. Q Data Yield 93 F F F 1 H NMR (400MHz, CD 3 0D) 5: 11% F 7.60 (3H, m), 7.35 (3H, in), 7.22 (2H, m), 7.13 (1H, m), 6.76 (1H, m), 4.64 (3H, m), 3.62 (2H, m) 2.92 (4H, m), 2.75 (2H, m), 1.10 (3H, s), 1.03 (3H, s) ppm; LRMS ESI m/z 549 [M+H]* 94 F H NMR (400MHz, CD 3 0D) 6: 36%

H

3 C 7.62 (2H, m), 7.35 (3H, m), 7.10 (2H, m), 6.90 (2H, m), 6.75 (1H, N m), 4.65 (3H, m), 3.58 (2H, m), 2.90 (3H, m) 2.70 (3H, m), 2.20 (3H, s) 1.10 (3H, s), 1.03 (3H, s) ppm; LRMS APCI m/z 495 [M+H]* WO 2005/090287 PCT/IB2005/000640 110 95 F 1 H NMR (400MHz, CD 3 0D) 5: 63%

H

3 C F 7.62 (2H, m), 7.32 (3H, m), 7.13 (1H, m), 6.90 (2H, m), 6.75 (1H, m), 4.65 (3H, m), 3.60 (2H, m) 2.80 (6H, m), 2.22 (3H, s) 1.10 (3H, s), 1.05 (3H, s) ppm; LRMS APCI m/z 513 [M+H]* 96 H 3 C CH 3 IH NMR (400MHz, CD 3 0D) 5: 80% 7.69 (2H, m), 7.37 (3H, m), 7.15 (1H, m), 6.78 (3H, m), 4.63 (3H,

CH

3 m), 3.42 (2H, m), 2.95 (4H, m), 2.74 (2H, m), 2.32 (6H, s), 2.20 (3H, s) 1.12 (3H, s), 1.05 (3H, s) ppm; LRMS APCI m/z 505 [M+H]* 97 CH 3 'H NMR (400MHz, CD 3 0D) 5: 44% F 7.60 (2H, m), 7.32 (3H, m), 7.10 (2H, m), 6.78 (2H, m), 4.63 (3H, m), 3.60 (2H, m), 2.66 (6H, m), F 2.19 (3H, s) 1.10 (3H, s), 1.05 (3H, s) ppm; LRMS APCI mlz 513 [M+H]* 98 CH 3 'H NMR (400MHz, CD 3 0D) 5: 28% F 7.62 (2H, m), 7.35 (3H, m), 7.10 (3H, m), 6.76 (1H, m), 4.65 (3H, N m), 3.62 (2H, m) 3.14 (2H, m), Cl 2.81 (4H, m), 2.19 (3H, s) 1.10 (3H, s), 1.05 (3H, s) ppm; LRMS APCI m/z 529 [M+H]* WO 2005/090287 PCT/IB2005/000640 111 99 OH 3 'H NMR (400MHz, CD 3 0D) 8: 64% cI 7.61 (2H, m), 7.32 (3H, m), 7.17 (2H, m), 6.93 (1H, m), 6.76 (1H, m), 4.65 (3H, m), 3.62 (2H, m) F 3.17 (2H, m), 2.81 (4H, m), 2.32 (3H, s) 1.10 (3H, s), 1.05 (3H, s) ppm; LRMS APCI m/z 529 [M+H]* 100 F 'H NMR (400MHz, CD 3 0D) 5: 46% 7.67-7.61 (2H, m), 7.40-7.32 (3H, m), 7.17 (2H, m), 6.93 (1H, m), N 6.82 (1H, m), 6.76 (1H, m), 4.65

CH

3 (3H, m), 3.62 (2H, m) 3.17 (2H, m), 3.00-2.64 (4H, m), 2.32 (3H, s) 1.10 (3H, s), 1.05 (3H, s) ppm; LRMS APCI m/z 529 [M+H]* 101 F 1 H NMR (400MHz, CD 3 0D) 6: 35% 7.60 (4H, m), 7.34 (4H, m), 7.25 F (1H, m), 7.13 (1H, m), 6.75 (1H, F im), 4.65 (3H, m), 3.63 (2H, m), 3.04 (2H, m), 2.81 (4H, m), 1.10 (3H, s), 1.05 (3H, s) ppm; LRMS APCI m/z 549 [M+H]* 102 F F 1 H NMR (400MHz, CD 3 0D) 6: 50% F 7.66 (3H, m), 7.50 (2H, m), 7.37 (4H, m), 7.13 (1H, m), 6.75 (1H, m), 4.65 (3H, m), 3.63 (2H, m), 3.11 (2H, m), 2.90 (2H, m), 2.75 (2H, m), 1.10 (3H, s), 1.05 (3H, s) ppm; LRMS APCI m/z 531 [M+H]* WO 2005/090287 PCT/IB2005/000640 112 103 CH 3 'H NMR (400MHz, CD 3 OD) 6: 38%

H

3 C 7.66 (2H, i), 7.36 (3H, i), 7.15 I (1 H, in), 6.88 (2H, in), 6.76 (1 H, in), 4.65 (3H, in), 3.83 (6H, in),

OH

3 3.50 (2H, in), 2.25 (3H, s), 2.14 (6H, mn), 1.10 (3H, s), 1.05 (3H, s) ppm; LRMS APCI m/z 505 [M+H1 104 1H NMR (400MHz, CD 3 0D) 6: 52% 8.44 (in, 1IH), 7.75 (in, 1 H), 7.64 N 7.60 (2H, m), 7.38-7.23 (5H, in), 7.12 (1H, nm), 6.76 (1H, m), 4.69 4.60 (3H, i), 3.73 (2H, 6), 3.09 (2H, (), 2.98-2.65 (4H, s), 1.11 (3H, s), 1.04 (3H, s) ppm; LCMS m z 464.29 [M+H5 105 N N 'H NMR (400MHz, CD 3 0D) 6: 19% 7.67-7.61 (m, 2H), 7.50-7.43 (2H, H in), 7.38-7.27 (3H, 7), 7.20-7.10 (3H, im), 6.76 (1H, m), 4.69-4.64 (3H, m), 3.83 (2H, t), 3.20 (2H, t), 2.97-2.61 (4H, m), 1.08 (3H, s), 1.01 (3H, s) ppm; LCMS m/z 503.23 [M+H ]* 106 1 H NMR (400MHz, CD 3 0D) 8: 25% 7.68-7.46 (6H, 2), 7.28-7.38 (3H, m), 7.11 (H, ), 6.76 (H, i), ( m 4.67-4.62 (H, ), 3.60-3.70 (6H, (3 m), 3.03 (2H, t), 2.98-2.66 (8H, t), 1.10 (3H, s), 1.04 (3H, s) ppm; LCMS mz 612.23 [M+H WO 2005/090287 PCT/IB2005/000640 113 107 c1 LCMS m/z 513.17 [M+H]f 46% OH N 108 F F 1 H NMR (400MHz, CD 3 0D) 5: 33% F 7.81 (m, 2H), 7.60 (1H, m), 7.49 F (3H, m), 7.36 (2H, m), 7.20 (1H, m), 6.80 (1H, m), 4.84 (1H, m), 4.76 (2H, s), 4.65 (2H, m), 3.20 (2H, m), 3.08 (2H, s), 1.34 (6H, m) ppm; LRMS APCI m/z 535 [M+H]* 109 c1 1 H NMR (400MHz, CD 3 0D) 8: 45% 7.83-7.78 (m, 2H), 7.50-7.20 (8H, m), 6.90-6.80 (1H, d), 4.65 (2H, s), 4.58-4.50 (3H, m), 3.22-3.05 (4H, im), 1.40-1.25 (6H, m) ppm; LCMS m/z 483.2045 [M+H]* 110 c1 iH NMR (400MHz, CD 3 0D) 6: 21% 7.82-7.78 (2H, m), 7.45-7.20 (8H, m), 6.82-6.78 (1H, d), 4.90-4.80 (1H, s), 4.75-4.60 (4H, m), 3.25 3.05 (4H, m), 1.30-1.22 (6H, m) ppm; LCMS m/z 483.2045 [M+H]* WO 2005/090287 PCT/IB2005/000640 114 111 H NMR (400MHz, CD 3 0D) 5: 33%

CH

3 7.65-7.61 (2H, m), 7.38-7.27 (3H, N m), 7.13 (1H, m), 7.09 (1H, s),

H

3 C N N/ 6.76 (1H, m), 4.68-4.62 (3H, m), 3.82 (2H, t), 3.13 (2H, t), 2.98-2.64 (4H, m), 1.11 (3H, s), 1.04 (3H, s) ppm; LRMS APCI m/z 493.29 [M+H]* 112 N LRMS APCI m/z 478.28 [M+H]* 25% NI0

CH

3 Example 102: {2-[2-(trifluoromethyl)phenyl]ethyl}amine can be prepared as described in WO 2003093231 Example 106: 4-[[4-(2-aminoethyl)phenyl]sulfonyl]- morpholine is commercially available from Scientific Exchange Product List (K-046583) 5 Example 107: amine precursor (2-(2-aminoethyl)-6-chlorophenol) can be prepared as described in DE1959898 Example 108: crude compound was purified by HPLC using a Phenomenex Luna C18 system, eluting with water/acetonitrile/trifluoroacetic acid (5:95:0.1):acetonitrile, 95:5 to 5:95, to isolate the trifluoroacetic acid salt of the 10 desired product. Example 109 and 110: crude compound was purified by HPLC using a Phenomenex Luna C18 system, eluting with water/0.1 % formic acid:acetonitrile/0.1 % formic acid, 85:15 to 15:85 15 Example 113 N-[2-(2-Chlorophenyl)ethyl]-3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3 (hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]benzamide WO 2005/090287 PCT/IB2005/000640 115 OH O CI H N N HOH3 CX H3H HO A mixture of 3-[2-({(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3 (hyd roxymethyl)phenyl]ethyl}amino)-2-methylpropyl]-N-[2-(2-chlorophenyl) ethyl]benzamide (preparation 118), (147mg, 0.24mmol) and triethylamine 5 trihydrofluoride (39pL, 0.24mmol) was stirred at room temperature for 3 days. The mixture was then concentrated in vacuo and the residue was purified by column chromatography on silica gel, eluting with dichloromethane:methanol:0.88 ammonia, 100:0:0 to 95:5:0.5 . The appropriate fractions were evaporated under reduced pressure and the residue was 10 azeotroped with methanolic ammonia to afford the title compound as a colourless solid in 77% yield, 75mg. 1H NMR (400MHz, CD 3 0D) 5: 7.61 (2H, m), 7.37-7.29 (5H, m), 7.23-7.16 (2H, m), 7.12 (1H, dd), 6.74 (1H, d), 4.66 (1H, m), 4.64 (2H, s), 3.63 (2H, m), 3.05 (2H, t), 2.96-2.84 (2H, t), 2.76-2.69 (2H, m), 1.10 (3H, s), 1.04 (3H, s) ppm; 15 LRMS ESI m/z 497 [M+H]* Examples 114 to 128 The following compounds, of the general formula shown below were prepared 20 by a similar method to that described for example 113, using the appropriate starting material and triethylamine trihydrofluoride. The reactions were monitored by tic analysis and were stirred at room temperature for 18-72hours.

WO 2005/090287 PCT/IB2005/000640 116 OH 0 H

SH

3

CH

3 HO HO No. Q' Data Yield 114 1 H NMR (400MHz, CD 3 0D) 8: 7.66 67% N (2H, i), 7.38-7.31 (3H, m), 7.13 (1H, i), 6.75 (1H, d), 4.67 (1H, m), 4.65 (2H, d), 3.44-3.36 (2H, m), H,,, 2.99-2.88 (2H, m), 2.78-2.69 (2H, m), 1.94 (3H, s), 1.67-1.77 (6H, m), H 1.58 (6H, m), 1.37 (2H, m), 1.12 (3H, s), 1.05 (3H, s) ppm; LRMS APCI m/z 521 [M+H]+ 115 1 H NMR (400MHz, CD 3 0D) 8: 8.21 50% (1H, m), 7.85 (1H, m), 7.74 (1H, m), 7.65 (2H, m), 7.47 (2H, m), 7.39 - 7.31 (5H, m), 7.14 (1H, dd), 6.75 (1H, m), 4.68 (1H, m), 4.64 (2H, d), 3.71 (2H, m), 3.39 (2H, m), 2.99 2.87 (2H, m), 2.79-2.70 (2H, m), 1.12 (3H, s), 1.05 (3H, s) ppm; LRMS APCI m/z 513 [M+H]* WO 2005/090287 PCT/IB2005/000640 117 116 H 3 C H NMR (400MHz, CD 3 0D) 6: 7.68- 75% 7.61 (2H, m), 7.36 (2H, m), 7.33 (1H, m), 7.14 (1H, dd), 6.96 (3H, m),

H

3 C 6.75 (1H, m), 4.67 (1H, m), 4.63 (2H, m), 3.47 (2H, m), 3.00-2.89 (4H, m), 2.77-2.71 (2H, m), 2.35 (6H, s), 1.13 (3H, s), 1.05 (3H, s) ppm; LRMS APCI m/z 491 [M+H]* 117 'H NMR (400MHz, CD 3 0D) 6: 7.63 30% S CH 3 (2H, m), 7.37-7.31 (3H, m), 7.20 7.12 (5H, m), 6.74 (1H, m), 4.67 (1H, m), 4.65 (2H, d), 3.55-3.59 (2H, m), 2.97-2.85 (4H, m), 2.70-2.77 (2H, m), 2.42 (3H, s), 1.11 (3H, s), 1.05 (3H, s) ppm LRMS APCI m/z 509 [M+H]* 118 F 1H NMR (400MHz, CD30D) 8: 7.61 23% N (2H, m), 7.36-7.28 (4H, m), 7.21 --- o (1H, m), 7.11 (1H, m), 7.02 (1H, m), c1 6.74 (1H, d), 4.65 (3H, m), 3.60 (2H, m), 2.96-2.84 (4H, m), 2.77-2.69 (2H, m), 1.10 (3H, s), 1.04 (3H, s) ppm; LCMS m/z 515 [M]* 119 cl 1 H NMR (400MHz, CD 3 0D) 8: 7.62 45% N (2H, m), 7.30-7.37 (4H, m), 7.17 (1H, m), 7.11 (1H, dd), 6.96 (1H, m), 6.74 (1H, d), 4.67 (1H, m), 4.64 (2H, m), 3.61 (2H, m), 3.02 (2H, t), 2.96 2.85 (2H, m), 2.78-2.70 (2H, m), 1.11 (3H, s), 1.04 (3H, s) ppm; LRMS APCI m/z 515 [M+H]* WO 2005/090287 PCT/IB2005/000640 118 120 OH 3 1 H NMR (400MHz, CD 3 0D) 8: 7.65 52% (2H, m), 7.38-7.31 (3H, m), 7.12 (1H, dd), 6.88 (1H, s), 6.75 (1H, d), 6.66 (1H, s), 4.67 (1H, m), 4.65 (2H,

OH

3

H

3 n), 3.77 (3H, s), 3.49 (2H, m), 2.98 2.87 (2H, m), 2.84-2.70 (4H, m), 2.30 (3H, s), 2.08 (3H, s), 1.12 (3H, s), 1.05 (3H, s) ppm; LRMS ESI m/z 521 [M+H]* 121 CI 1 H NMR (400MHz, CD 3 0D) 5: 7.62 67% c I (2H, m), 7.38 (1H, dd), 7.32 (3H, m), 7.25 (1H, m), 7.19 (1H, m), 7.12 (1H, d), 6.74 (1H, d), 4.68 (1H, m), 4.65 (2H, m), 3.68 (2H, m), 3.10 (2H, m), 2.96 (2H, m), 2.73 (2H, m), 1.11 (3H, s), 1.05 (3H, s) ppm; LRMS APCI m/z 531 [M+H] 122 CH 3 1 H NMR (400MHz, CD 3 0D) 6: 7.65 83%

CH

3 (1H, m) 7.63 (1H, m), 7.38-7.31 (3H, m), 7.13 (1H, dd), 6.95 (1H, s), 6.75 (1H, d), 6.67 (1H, d), 4.67 (1H, m),

CH

3 4.65 (2H, m), 3.76 (3H, s), 3.49 (2H, m), 2.98-2.87 (4H, m), 2.79-2.70 (2H, m), 2.25 (3H, s), 2.12 (3H, s), 1.12 (3H, s), 1.05 (3H, s) ppm LRMS ESI m/z 521 [M+H]* Microanalysis: C 31

H

4 0

N

2 0 5 . 0.1 H 2 0 requires (%): C 71.27; H 7.76; N 5.36; found (%) C 70.87; H 7.36, N 5.36.

WO 2005/090287 PCT/IB2005/000640 119 123 N 1 H NMR (400MHz, CD 3 0D) 8: 7.63 74% (1H, m), 7.60 (1H, bs), 7.57-7.50 (4H, m), 7.41-7.26 (8H, m), 7.11 (1H, m), 6.73 (1H, dd), 4.66-4.62 (3H, m), 3.69 (2H, t), 2.96-2.83 (4H, m), 2.75-2.67 (2H, m), 1.09 (3H, s), 1.02 (3H, s) ppm LRMS ESI m/z 539 [M+Na]4 124 1 H NMR (400MHz, CD 3 0D) 8: 7.65 79% (2H, m) 7.63 (2H, m), 7.39-7.30 (1H, d), 7.12 (1H, dd), 7.01 (1H, d), 6.95 CH (1H, bs), 6.88 (1H, d), 6.74 (1H, d),

H

3 C 3 3 4.69-4.63 (3H, m), 3.60 (2H, m), 2.98-2.85 (4H, m), 2.78-2.68 (2H, m), 2.29 (3H, s), 2.24 (3H, s), 1.11 (3H, s), 1.04 (3H, s) ppm; LRMS ESI m/z 513 [M+Na]f 125 H NMR (400MHz, CD 3 0D) 8: 7.65 58% (2H, m), 7.39-7.31 (3H, m), 7.13 CH (IH, dd), 7.02-6.94 (3H, m), 6.75

H

3 C (1H, d), 4.65 (3H, m), 3.64-3.60 (2H, m), 2.99-2.93 (3H, m), 2.88 (1H, m), 2.74 (1H, dd), 2.71 (1H, m), 2.26 (3H, s), 2.25 (3H, s), 1.12 (3H, s), 1.06 (3H, s) ppm LRMS APCI m/z 491 [M+H]* WO 2005/090287 PCT/IB2005/000640 120 126 F F 1 H NMR (400MHz, CD 3 OD) 8: 7.66- 79% F 7.46 (6H, m), 7.33 (3H, m), 7.13 N (1H, d), 6.75 (1H, d), 4.67 (3H, m), 3.66-3.60 (2H, m), 3.04-2.85 (4H, m), 2.89-2.76 (2H, m), 1.11 (3H, s), 1.04 (3H, s) ppm LRMS APCI m/z 531 [M+H]* 127 N H NMR (400MHz, CDCl 3 ) 5: 7.60 85% cl (2H, m), 7.36-7.26 (4H, m), 7.16 F 7.09 (3H, m), 6.75 (1H, d), 4.66 (3H, m), 3.83-3.57 (2H, in), 2.98-2.69 (6H, m), 1.10 (3H, s), 1.04 (3H, s) ppm; LRMS APCI m/z 515 [M+H]* 128 H 3 C 1 H NMR (400MHz, CD 3 0D) 6: 7.72 44% (2H, m) 7.39-7.32 (2H, m), 7.26 (1H, d), 7.11 (1H, bs), 7.09-7.03 (2H, dd),

CH

3 6.95 (1H, d), 6.68 (1H, d), 4.63 (3H, m), 4.49 (2H, dd), 2.94-2.86 (2H, m), 2.73 (2H, dd), 2.29 (3H, s), 2.24 (3H, s), 1.11 (3H, s), 1.04 (3H, s) ppm; LRMS ESI m/z 499 [M+Na]* Example 129 N-(3,4-Dichlorobenzyl)-3-{3-[2-(((2R)-2-hydroxy-2-[4-hydroxy-3 (hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]phenyl}propanamide 5 WO 2005/090287 PCT/IB2005/000640 121 OH O H CH3 N N H HO CH3 Ci HO CI The title compound was prepared from 3-{3-[2-({(2R)-2-{[tert butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-(hydroxymethyl) phenyl]ethyl)amino)-2 methylpropyl]phenyl}-N-(3,4-dichlorobenzyl) propanamide (preparation 145), 5 using a method similar to that of example 113, as a white foam in 71% yield. H NMR (400MHz, CD 3 0D) 8: 7.38 (1H, d), 7.35 (2H, d), 7.08 (6H, m), 6.78 (1H, d), 5.61 (3H, m), 4.23 (2H, s), 2.95 (3H, m), 2.68 (3H, m), 2.58 (2H, t), 1.01 (6H, s) ppm; LRMS ESI m/z 545 [M+H]* 10 Example 130 3-[2-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino) 2-methylpropyl]-N-{2-[4-(trifluoromethoxy)phenyl]ethyl}benzamide OH 0 H N H X' N

H

3 C CH 3 O H3O HOF F F A mixture of 3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl] 15 ethyl}amino)-2-methylpropyl]benzoic acid (preparation 140) (100mg, 0.28mmol), 2-(4-trifluoromethoxyphenyl)ethylamine (US20020082454A1, p2), (46mg, 0.28mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (43mg, 0.28mmol), 1-hydroxybenzotriazloe hydrate (35mg, 0.28mmol) and triethylamine (60IL, 0.45mmol) in N,N-dimethylformamide 20 (5mL) was stirred at room temperature for 20 hours. The reaction mixture was then concentrated in vacuo and the residue was dissolved in dichloromethane. The solution was then washed with saturated sodium carbonate solution and WO 2005/090287 PCT/IB2005/000640 122 brine, dried over magnesium sulfate and concentrated in vacuo. Purification of the residue by column chromatography on silica gel, eluting with dichloromethane:methanol:0.88 ammonia, 100:0:0 to 95:5:1, afforded the title compound as a white powder in 51% yield, 79mg. 5 1H NMR (400MHz, CD 3 0D) 8: 7.63 (2H, m), 7.38-7.30 (5H, m), 7.17 (2H, m), 7.12 (1H, dd), 6.75 (1H, d), 4.66 (3H, m), 3.57 (2H, d), 2.99-2.85 (4H, m), 2.79 2.69 (2H, m), 1.12 (3H, s), 1.06 (3H, s) ppm; LRMS APCI m/z 547 [M+H]* Examples 131 to 137 10 The following compounds, of the general formula shown below were prepared by a similar method to that described for example 130, using the appropriate acid and amine starting materials. The amines were either commercially available or prepared as described in preparations 69-108 15 OH H K-/ CH no HO H C HO OH 0 H N HO H HO No. Q Data Yield WO 2005/090287 PCT/IB2005/000640 123 131 OH H NMR (400MHz, CD 3 0D) 8: 7.54 6% (1H, m), 7.50 (1H, m), 7.34-7.28 N I-x(3H, m), 7.25 (2H, m), 7.10 (1H, dd),

H

3 C CH 3 6.73 (3H, m), 4.62 (3H, m), 3.51 (2H, s), 2.92-2.87 (1H, m), 2.81 (1H, m), 2.76-2.70 (2H, m), 1.33 (6H, s), 1.08 (3H, s), 1.04 (3H, s) ppm; LRMS APCI m/z 507 [M+H]* 132 OH 1 H NMR (400MHz, CD 3 OD) 5: 7.88- 22% 7.80 (3H, m), 7.63 (2H, m), 7.12 N

CH

3 (1H, dd), 6.92 (1H, m), 6.84 (1H, dd), 6.75 (1H, d), 6.63 (1H, d), 4.67 (1H, m), 4.65 (2H, m), 3.51 (2H, m), 2.99-2.86 (2H, m), 2.78-2.70 (4H, m), 2.13 (3H, s), 1.12 (3H, s), 1.05 (3H, s) ppm; LRMS APCI m/z 493 [M+H]* 133 OH lH NMR (400MHz, CD 3 0D) 6: 7.98 6% (2H, m), 7.43-7.36 (3H, m), 7.16 N

CH

3 (1H, dd), 6.82-6.77 (2H, m), 6.52

CH

3 (1H, d), 4.75 (1H, m), 4.66 (2H, m), 3.47 (2H, m), 3.07 (1H, m), 2.98 (2H, m), 2.92 (1H, m), 2.85 (2H, m), 2.24 (3H, s), 2.11 (3H, s), 1.23 (3H, s), 1.19 (3H, s) ppm; LRMS APCI m/z 507 [M+H]* WO 2005/090287 PCT/IB2005/000640 124 134 CH 3 'H NMR (400MHz, CD 3 0D) 6: 7.66 16% OH (2H, m), 7.40-7.34 (3H, m), 7.14 (1H, dd), 6.83(1H, s), 6.76 (1H, m), N 6.50 (1H, d), 4.69 (1H, m), 4.66 (2H,

CH

3 s), 3.49 (2H, m), 3.04-2.98 (2H, m), 2.87 (1H, m), 2.82-2.77 (3H, m), 2.22 (3H, s), 2.08 (3H, s), 1.17 (3H, s), 1.12 (3H, s) ppm; LRMS APCI m/z 507 [M+H]* OH H N CHQ1

H

3 C H 3 I. HO H HO 135 cl 1H NMR (400MHz, CD 3 0D) 6: 41% 7.41-7.05 (9H, m), 6.78 (1H, d), Cl 4.65 (3H, m), 4.36 (2H, s), 3.55 (2H, s), 2.87 (2H, m), 2.81-2.69 (2H, m), 1.12 (3H, s), 1.05 (3H, s) ppm; LRMS ESI m/z 531 [M+H) 136 cl 1 H NMR (400MHz, CD 3 0D) 8: 24% 7.34-7.03 (9H, m), 6.79 (1H, d), 4.63 (3H, m), 4.37 (2H, s), 3.54 (2H, s), 2.90 (2H, m), 2.81-2.64 (2H, m), 1.12 (3H, s), 1.05 (3H, s) ppm; LRMS ESI m/z 531

[M+H]*

WO 2005/090287 PCT/IB2005/000640 125 137 1 H NMR (400MHz, CD 3 0D) 8: 66% 8.42 (1H, d), 7.77 (1H, t), 7.31 7.04 (8H, m), 6.76 (1H, d), 4.62 (3H, m), 4.44 (2H, s), 3.59 (2H, s), 2.92-2.65 (4H, m), 1.06 (3H, s), 1.04 (3H, s) ppm; LRMS ESI m/z 464 [M+H]+ Example 131: amine precursor (4-(2-amino-1,1-dimethylethyl)phenol) can be prepared as described in Acta Chem.Scand. 8, 1203, 1207; 1954 5 Examples 138 to 147 OH 0 H HO H 3 C H 3 HO 10 A mixture of 3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl) phenyl] ethyl)amino)-2-methylpropyl]benzoic acid (preparation 140), (0.2M in dimethylacetamide/3.75% triethylamine, 225pL, 45pmol), the appropriate amine (0.2M in dimethylacetamide/3.75% triethylamine, 150pL, 30pmol) and O-(1 H-benzotriazol-1 -yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate 15 (0.2M in dimethylacetamide, 225pL, 45pmol) was stirred at 600C for 3 days. The reaction mixture was then concentrated in vacuo, re-dissolved in dimethylsulfoxide (300pL) and stirred for 30 minutes at room temperature. The mixture was diluted with further dimethylsulfoxide (50pL) and water (100pL), stirred for one minute at room temperature and then purified by HPLC using a 20 Phenomenex Luna C18 system, eluting with water/acetonitrile/diethylamine (5:95:0.05):acetonitrile, 95:5 to 5:95, to afford the desired compound.

WO 2005/090287 PCT/IB2005/000640 126 No. Q' Data 138 CH 3 138LRMS ESI m/z 504.30 [M]* 139 OH 1O LRM S ESI m/z 492.26 [M ] * 140 140

CH

3 LRMS ESI m/z 476.26 [M]* 141 01

CH

3 LRMS ESI m/z 493.26 [M]* 142 N LRMS ESI m/z 506.28 [M]* 143 cO 1 4 CL R M S E S I m /z 5 1 0 .2 3 [M -H ] ~ 144 N N LRMS ESI m/z 544.27 [M]* WO 2005/090287 PCT/IB2005/000640 127 145 F F LRMS ESI m/z 498.23 [M]* 146 N N LRMS ESI m/z 513.26 [M]* 147 N- LRMS ESI m/z 546.31 [M]* Example 138: N-ethyl-3-phenylpropylamine can be prepared as described in J. Med. Chem. 34, 248; 1991 Example 141: 6-methoxy-3-pyridineethanamine can be prepared as described in Drug Design and Discovety, 10, 35; 1993 5 Example 143: 2-[4-(Pyrazol-1-yl)phenoxy]ethylamine can be prepared as described in W02002032897, p55 Example 146: 5-Quinolineethanamine can be prepared as described in J. Med. Chem., 28, 1803-10; 1985 Preparation 1: 2-{3-[(2R)-2-({(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-[4 10 hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N cycloheptylacetamide OTBDMS H H HON N ,,C HO H 3 0

HO

WO 2005/090287 PCT/IB2005/000640 128 A solution of (3-{(2R)-2-[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-hydroxy-3 hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-acetic acid (Preparation 20) (250mg, 0.45mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (94mg, 0.49mmol), hydroxybenzotriazole monohydrate (66mg, 5 0.49mmol) in N,N-dimethylformamide (4ml) was treated with triethylamine (0.12m, 0.89mmol) and cycloheptylamine (56mg, 0.49mmol) 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 (10ml) and saturated aqueous sodium bicarbonate (10ml). The 10 organic phase was separated, and the aqueous phase extracted with further ethyl acetate (2xlOml). The combined organic extracts were washed with water (5ml), brine (5ml), dried (sodium sulfate) and the solvent removed in vacuo. The residue was purified by flash column chromatography on silica gel eluting with dichloromethane:methanol: 880 ammonia (95:5:0.5 by volume) to give the 15 title compound as a pale yellow oil (150mg). H NMR (400MHz, CD 3 0D): 5 = 7.20-6.98 (6H, m), 6.68 (1H, d), 4.60 (3H, m), 3.80 (1H, m), 3.40 (2H, s), 2.85 (2H, m), 2.63 (2H, m), 2.58 (1H, m),-1.80 (2H, m), 1.75-1.40 (10H, m), 1.03 (3H, d), 0.83 (9H, s), 0.00 (3H, s), -0.20 (3H, s) ppm. 20 LRMS (electrospray): m/z [M+H]+ 569. Preparation 2: 2-{3-[(2R)-2-({(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-[4 hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N (cyclohexylmethyl)-N-methylacetamide OTBDMS CH H N N HO

CH

3 0 25 HO Prepared according to the procedure used for preparation 1 using (3-{(2R)-2 [(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-hydroxy-3-hydroxymethyl-phenyl)- WO 2005/090287 PCT/IB2005/000640 129 ethylamino]-propyl}-phenyl)-acetic acid (Preparation 20) and the appropriate amine to give the title compound as a colourless oil. H NMR (400MHz, CD 3 OD): S = 7.20-6.95 (6H, m), 6.63 (1H, d), 4.60 (3H, m), 3.68 (2H, s), 3.20 (2H, m), 2.85 (5H, m), 2.63 (2H, m), 2.57 (1H, m), 1.60 (5H, 5 m), 1.20 (4H, m), 1.03 (3H, d), 0.81 (11H, m), 0.00 (3H, s), -0.21 (3H, s) ppm. LRMS (electrospray): m/z [M+H]* 583. Preparation 3: 2-{3-[(2R)-2-({(2R)-2-{[tert-butyl(dimethyl)silyl]oxy)-2-[4 hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N-[(I S)-1 10 cyclohexylethyl]acetamide OTBDMS H CH HN N OH HO

CH

3 .x 0 HO Prepared according to the procedure used for preparation 1 using (3-{(2R)-2 [(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-hydroxy-3-hydroxymethyl-phenyl) ethylamino]-propyl}-phenyl)-acetic acid (Preparation 20) and the appropriate 15 amine to give the title compound as a colourless oil. 1 H NMR (400MHz, CD 3 0D): S = 7.20 (3H, m), 7.03 (1H, s), 6.98 (2H, dd), 6.68 (1H, d), 4.60 (3H, m), 3.68 (1H, m), 3.42 (1H, d), 3.38 (1H, d), 2.85 (2H, m), 2.63 (2H, m), 2.58 (1H, dd), 1.65 (4H, m), 1.40-0.83 (13H, m), ppm. LRMS (electrospray) : m/z [M+H]+ 583, [M+Na]* 605, [M-H]~ 582. 20 WO 2005/090287 PCT/IB2005/000640 130 Preparation 4: 2-{3-[(2R)-2-({(2R)-2-{[tert-butyl(dimethyl)silylloxy}-2-[4 hydroxy-3-(hydroxymethyl)phenyl]ethyl)amino)propyl]phenyl}-N isopropylacetamide OTBDMS H H N N

CH

3 HO CH 3 0 CH 3 HO 5 Prepared according to the procedure used for preparation 1 using (3-{(2R)-2 [(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-hydroxy-3-hydroxymethyl-phenyl) ethylamino]-propyl}-phenyl)-acetic acid (Preparation 20) and the appropriate amine to give the title compound as a colourless oil. 'H NMR (400MHz, CD 3 0D): 6 = 7.19-7.15 (2H, m), 7.11-7.10 (1H, d), 7.04 (1H, 10 s), 6.99-6.96 (2H, t), 6.69-6.67 (1H, d), 4.71-4.67 (1H, dd), 4.65-4.58 (2H, m), 3.96-3.90 (1 H, in), 3.39 (2H, s), 2.93-2.84 (2H, m), 2.70-2.62 (2H, m), 2.56-2.52 (1H, m), 1.12-1.11 (6H, d), 1.05-1.03 (3H, d), 0.83 (9H, s), -0.01 (3H, s), -0.20 (3H, s) ppm. LRMS (electrospray) : m/z [M+H]* 515, [M-H]~ 513. 15 Preparation 5: 2-{3-[(2R)-2-({(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-[4 hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N cyclopentylacetamide OTBDMS H H HO CH 3 0 HO 20 Prepared according to the procedure used for preparation 1 using (3-{(2R)-2 [(2R)-2-{[tert-butyl(dimethyl)silyl]oxy)-2-(4-hydroxy-3-hydroxymethyl-phenyl)- WO 2005/090287 PCT/IB2005/000640 131 ethylaminol-propyl}-phenyl)-acetic acid (Preparation 20) and the appropriate amine to give the title compound as a colourless oil. 'H NMR (400MHz, CD 3 0D): 6 = 7.19 (1H, d), 7.17-7.15 (1H, d), 7.11-7.09 (1H, d), 7.04 (1H, s), 6.99-6.95 (2H, t), 6.69-6.67 (1H, d), 4.71-4.67 (1H, dd), 4.65 5 4.58 (2H, m), 4.10-4.04 (1H, m), 3.40 (2H, s), 2.92-2.84 (2H, m), 2.69-2.62 (2H, m), 2.56-2.51 (1H, m), 1.94-1.86 (2H, m), 1.73-1.65 (2H, m), 1.62-1.53 (2H, m), 1.47-1.39 (2H, m), 1.05-1.03 (3H, d), 0.83 (9H, s), -0.01 (3H, s), -0.20 (3H, s) ppm. LRMS (electrospray) : m/z [M+H]* 541, [M-H]~ 539. 10 Preparation 6: 2

-{

3

-[(

2 R)-2-({(2R)-2-{[tert-butyl(dimethyl)silyloxy}-2-[4 hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N (cyclobutylmethyl)acetamide OTBDMS HOH N H HO 0OH 3 0 HO 15 Prepared according to the procedure used for preparation 1 using (3-{(2R)-2 [(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-hydroxy-3-hydroxymethyl-phenyl) ethylamino]-propyl}-phenyl)-acetic acid (Preparation 20) and the appropriate amine to give the title compound as a colourless oil. 'H NMR (400MHz, CD30D): S = 7.19-7.15 (2H, m), 7.12-7.10 (1H, m), 7.04 (1H, 20 s), 7.00-6.96 (2H, m), 6.69-6.67 (1H, d), 4.71-4.67 (1H, dd), 4.65-4.58 (2H, m), 3.43 (2H, s), 3.19-3.17 (2H, d), 2.93-2.85 (2H, m), 2.70-2.62 (2H, m), 2.56-2.51 (1H, m), 2.48-2.43 (1H, m), 2.04-1.96 (2H, m), 1.90-1.78 (2H, m), 1.72-1.65 (2H, m), 1.05-1.03 (3H, d), 0.83 (9H, s), 0.00 (3H, s), -0.20 (3H, s) ppm. LRMS (electrospray): m/z [M+H]* 541, [M-H]~ 539. 25 WO 2005/090287 PCT/IB2005/000640 132 Preparation 7: 2-{3-[(2R)-2-({(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-[4 hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N (cyclopentylmethyl)acetamide OTBDMS H N H, HO CH 0 HO 5 Prepared according to the procedure used for preparation 1 using (3-{(2R)-2 [(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-hydroxy-3-hydroxymethyl-phenyl) ethylamino]-propyl}-phenyl)-acetic acid (Preparation 20) and the appropriate amine to give the title compound as a colourless oil. H NMR (400MHz, CD 3 0D): 8 = 7.18 (1H, s), 7.16-7.14 (1H, d), 7.11-7.09 (1H, 10 d), 7.04 (1H, s), 6.99-6.95 (2H, m), 6.68-6.66 (1H, d), 4.70-4.67 (1H, dd), 4.65 4.57 (2H, in), 3.43 (2H, s), 3.10-3.08 (2H, d), 2.93-2.85 (2H, m), 2.70-2.63 (2H, m), 2.56-2.51 (1H, m), 2.08-2.00 (1H, m), 1.74-1.67 (2H, m), 1.64-1.50 (4H, m), 1.22-1.14 (2H, m), 1.06-1.04 (3H, d), 0.84 (9H, s), 0.01 (3H, s), -0.18 (3H, s) ppm. 15 LRMS (electrospray) : m/z [M+H]* 555, [M-H] 554. Preparation 8: 2-{3-[(2R)-2-({(2R)-2-{[tert-butyl(dimethyl)silyl]oxy)-2-[4 hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N cyclohexylacetamide OTBDMS H H N N HO CH 3 . 20 HO Prepared according to the procedure used for preparation 1 using (3-{(2R)-2 [(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-hydroxy-3-hydroxymethyl-phenyl)- WO 2005/090287 PCT/IB2005/000640 133 ethylamino]-propyl}-phenyl)-acetic acid (Preparation 20) and the appropriate amine to give the title compound as a colourless oil. H NMR (400MHz, CD 3 0D): 5 = 7.19 (1H, d), 7.17-7.15 (1H, d), 7.11-7.09 (1H, d), 7.04 (1H, s), 6.99-6.95 (2H, t), 6.69-6.67 (1H, d), 4.70-4.67 (1H, dd), 4.65 5 4.58 (2H, m), 3.65-3.57 (1H, m), 3.40 (2H, s), 2.92-2.84 (2H, m), 2.69-2.61 (2H, m), 2.56-2.51 (1H, m), 1.86-1.80 (2H, m), 1.75-1.70 (2H, m), 1.64-1.59 (1H, m), 1.39-1.28 (2H, m), 1.24-1.15 (3H, m), 1.05-1.03 (3H, d), 0.83 (9H, s), -0.01 (3H, s), -0.20 (3H, s) ppm. LRMS (electrospray): m/z [M+H]+ 555, [M-H]~ 554. 10 Preparation 9: 2-{3-[(2R)-2-({(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-[4 hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N cyclobutylacetamide OTBDMS H H qON N HO

CH

3 0 HO 15 Prepared according to the procedure used for preparation 1 using (3-{(2R)-2 [(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-hydroxy-3-hydroxymethyl-phenyl) ethylamino]-propyl}-phenyl)-acetic acid (Preparation 20) and the appropriate amine to give the title compound as a colourless oil. 'H NMR (400MHz, CD 3 0D): 6 = 7.19 (1H, d), 7.17-7.15 (1H, d), 7.11-7.09 (1H, 20 d), 7.03 (1H, s), 6.99-6.95 (2H, m), 6.68-6.66 (1H, d), 4.70-4.65 (1H, dd), 4.62 4.61 (2H, d), 4.29-4.21 (1H, m), 3.39 (2H, s), 2.92-2.84 (2H, m), 2.68-2.61 (2H, m), 2.57-2.52 (1H, m), 2.29- 2.21 (2H, m), 1.98-1.87 (2H, m), 1.74-1.66 (2H, m), 1.05-1.03 (3H, d), 0.82 (9H, s), -0.01 (3H, s), -0.20 (3H, s) ppm. LRMS (electrospray): m/z [M+H]* 527, [M-H]~ 525. 25 WO 2005/090287 PCT/IB2005/000640 134 Preparation 10: 2-{3-[(2R)-2-({(2R)-2-{[tert-butyl(dimethyl)silyljoxy}-2-[4 hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N (cyclohexylmethyl)acetamide OTBDMS H H N N HO

CH-

3 0 HO 5 Prepared according to the procedure used for preparation 1 using (3-{(2R)-2 [(2R)-2-{[tert-butyl(dimethyl)silyl]oxyl-2-(4-hydroxy-3-hydroxymethyl-phenyl) ethylamino]-propyl}-phenyl)-acetic acid (Preparation 20) and the appropriate amine to give the title compound as a white foam. H NMR (400MHz, CD 3 0D): 6 = 7.18-7.14 (2H, m), 7.11-7.09 (1H, m), 7.03 (1H, 10 s), 6.98-6.95 (2H, m), 6.68-6.66 (1H, d), 4.70-4.67 (1H, dd), 4.62-4.61 (2H, d), 3.43 (2H, s), 3.00-2.99 (2H, d), 2.91-2.84 (2H, m), 2.70-2.62 (2H, m), 2.55-2.50 (1H, m), 1.69-1.67 (5H, m), 1.49-1.43 (1H, m), 1.27-1.14 (3H, m), 1.05-1.03 (2H, m), 0.84 (9H, s), 0.01 (3H, s), -0.18 (3H, s) ppm. LRMS (electrospray): m/z [M+H]+ 569, [M+Na]* 591, [M-H]- 567. 15 Preparation 11: 2-(3-[(2R)-2-({(2R)-2-{[tert-butyl(dimethyl)silyl]oxy)-2-[4 hyd roxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl] phenyl}-N (cyclopropylmethyl)acetamide OTBDMS H N H

HOCH

3 0 HO 20 Prepared according to the procedure used for preparation 1 using (3-{(2R)-2 [(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-hydroxy-3-hydroxymethyl-phenyl)- WO 2005/090287 PCT/IB2005/000640 135 ethylamino]-propyl}-phenyl)-acetic acid (Preparation 20) and the appropriate amine to give the title compound as a white foam. 'H NMR (400MHz, CD 3 0D): 5 = 7.15-7.07 (3H, m), 7.01 (1H, s), 6.95-6.92 (2H, m), 6.65-6.63 (1H, d), 4.66-4.63 (1H, m), 4.58-4.57 (2H, d), 3.40 (2H, s), 3.00 5 2.98 (2H, d), 2.89-2.80 (2H, m), 2.65-2.57 (2H, m), 2.53-2.48 (1H, dd), 1.01 1.00 (3H, d), 0.93-0.87 (1H, m), 0.79 (9H, s), 0.44-0.40 (2H, q), 0.15-0.12 (2H, q), -0.04 (3H, s), -0.24 (3H, s) ppm. LRMS (electrospray) : m/z [M+H]* 527, [M+Na]* 549, [M-H]~ 525. 10 Preparation 12: 2-{3-[(2R)-2-({(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-[4 hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N (cycloheptylmethyl)acetamide OTBDMS H H N N H 0

CH

3 0 HO Prepared according to the procedure used for preparation 1 using (3-{(2R)-2 15 [(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-hydroxy-3-hydroxymethyl-phenyl) ethylamino]-propyl}-phenyl)-acetic acid (Preparation 20) and the appropriate amine to give the title compound as a white foam. 1H NMR (400MHz, CD 3 0D): 6 = 7.24-6.95 (6H, m), 6.70-6.67 (1H, d), 4.72-4.68 (1H, m), 4.67-4.58 (2H, m), 3.24 (2H, s), 3.02-2.99 (2H, d), 2.92-2.50 (5H, m), 20 1.72-1.08 (13H, m ), 1.06-1.04 (3H, d), 0.92 (9H, s), 0.00 (3H, s), -0.19 (3H, s) ppm. LRMS (electrospray) : m/z [M+H]* 583, [M+Na]* 605.

WO 2005/090287 PCT/IB2005/000640 136 Preparation 13: N-1 -adamantyl-2-{3-[(2R)-2-({(2R)-2-{[tert butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3 (hydroxymethyl)phenyl]ethyllamino)propyl]phenyl}acetamide OTBDMS H H HO N H 3 0 HO 5 Prepared according to the procedure used for preparation 1 using (3-{(2R)-2 [(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-hydroxy-3-hydroxymethyl-phenyl) ethylamino]-propyl}-phenyl)-acetic acid (Preparation 20) and the appropriate amine to give the title compound as a white foam. 1H NMR (400MHz, CD 3 0D): 8 = 7.20-6.93 (6H, m), 6.68-6.65 (1H, d), 4.74-4.68 10 (1H, m), 4.65-4.58 (2H, m), 3.40 (s, 2H), 2.96-2.85 (m, 2H), 2.72-2.54 (3H, m), 2.04 (3H, s), 2.01 (6H, s), 1.70 (6H, s), 1.07-1.05 (3H, d), 0.85 (9H, s), 0.02 (3H, s), -0.19 (3H, s) ppm. LRMS (electrospray) : m/z [M-H]~ 605. 15 Alternative method The title compound was prepared from N-1-adamantyl-2-{3-[(2R)-2-({(2R)-2-[4 (benzyloxy)-3-(hydroxymethyl)phenyl]-2-hyd roxyethyl}amino)propyl]phenyl} acetamide (preparation 164) using a similar method to that of preparation 25, 20 as a colourless foam in 91% yield WO 2005/090287 PCT/IB2005/000640 137 Preparation 14: N-(1 -adamantylmethyl)-2-{3-[(2R)-2-({(2R)-2-{[tert butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3 (hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}acetamide OTBDMS H H HO CH 3 0 HO 5 Prepared according to the procedure used for preparation 1 using (3-{(2R)-2 [(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-hydroxy-3-hydroxymethyl-phenyl) ethylamino]-propyl}-phenyl)-acetic acid (Preparation 20) and the appropriate amine to give the title compound as a white foam. H NMR (400MHz, CD 3 0D): 8 = 7.22-6.96 (6H, rn), 6.71-6.68 (1H, d), 4.75-4.67 10 (1H, m), 4.66-4.58 (2H, m), 3.26 (2H, s), 2.88-2.50 (5H, m), 2.84 (2H, s), 1.90 (3H, s), 1.74-1.58 (6H, m), 1.44 (6H, s), 1.08-1.06 (3H, d), 0.84 (9H, s), 0.01 (3H, s), -0.19 (3H, s) ppm. LRMS (electrospray) : m/z [M-H] 619. 15 Preparation 15: N-2-adamantyl-2-{3-[(2R)-2-({(2R)-2-{[tert-buty (dimethyl)silyl]oxy}-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl)amino) propyl]phenyl}acetamide OTBDMS H H HO N CH3N HO Prepared according to the procedure used for preparation 1 using (3-{(2R)-2 20 [(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-hydroxy-3-hydroxymethyl-phenyl) ethylamino]-propyl}-phenyl)-acetic acid (Preparation 20) and the appropriate amine to give the title compound as a white foam.

WO 2005/090287 PCT/IB2005/000640 138 'H NMR (400MHz, CD 3 0D): 6 = 7.22-6.96 (6H, m), 6.70-6.68 (1H, d), 4.72-4.68 (1H, m), 4.67-4.58 (2H, m), 3.95 (1H, s), 3.52 (2H, s), 2.94-2.50 (5H, m), 1.96 1.78 (12H, m), 1.62-1.56 (2H, d), 1.05-1.03 (3H, d), 0.83 (9H, s), 0.00 (3H, s), 0.19 (3H, s) ppm. 5 LRMS (electrospray): m/z [M-H] 605. Preparation 16: 2

-{

3

-[(

2

R)-

2 -({(2R)-2-{([tert-butyl(dimethyl)silyl]oxy}-2.[4 hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N-(2 cyclohexylethyl)-N-methylacetamide OTBDMS CH H 1 3 N N HO0 CH 3 0 10 HO Prepared according to the procedure used for preparation 1 using (3-{(2R)-2 [(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-hydroxy-3-hydroxymethyl-phenyl) ethylamino]-propyl}-phenyl)-acetic acid (Preparation 20) and the appropriate amine to give the title compound as a white foam. 15 'H NMR (400MHz, CD 3 0D): 8 = 7.22-6.98 (6H, m), 6.70-6.68 (1H, d), 4.75-4.71 (1H, m), 4.70-4.58 (2H, m), 3.70-3.64 (2H, m), 3.45-3.37 (2H, m), 2.98-2.52 (8H, m), 1.80-0.80 (25H, m), 0.04 (3H, s), -0.19 (3H, s) ppm. LRMS (electrospray): m/z [M+H]* 619.

WO 2005/090287 PCT/IB2005/000640 139 Preparation 17: 2-{3-[(2R)-2-({(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-[4 hydroxy-3-(hyd roxymethyl)phenyl]ethyl}am i no)propyl] phenyl}-N cycloheptyl-N-methylacetamide OTBDMS CH H 1 3 N N HO CH 3 0 HO 5 Prepared according to the procedure used for preparation 1 using (3-{(2R)-2 [(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-hydroxy-3-hydroxymethyl-phenyl) ethylamino]-propyl)-phenyl)-acetic acid (Preparation 20) and the appropriate amine to give the title compound as a white foam. 1 H NMR (400MHz, CD 3 0D): 8 = 7.22-6.96 (6H, m), 6.72-6.64 (1H, dd), 4.72 10 4.65 (1H, m), 4.62-4.60 (2H, m), 4.58-4.51 (0.5H, m), 3.90-3.83 (0.5H, m), 3.77 (1H, s), 3.66 (1H, s), 2.96-2.50 (5H, m), 2.82-2.78 (3H, d), 1.76-1.20 (12H, m), 1.06-1.04 (3H, dd), 0.82-0.80 (9H, 2s), 0.01-0.00 (3H, 2s), -0.18- -- 0.19 (3H, 2s) ppm. LRMS (electrospray): m/z [M+H]+ 583, [M+Na]* 605. 15 Preparation 18: 2-{3-[(2R)-2-({(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-[4 hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N cyclohexyl-N-ethylacetamide OTBDMS CH3 H N N HO

OH

3 .- 0 HO 20 Prepared according to the procedure used for preparation 1 using (3-{(2R)-2 [(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-hydroxy-3-hydroxymethyl-phenyl)- WO 2005/090287 PCT/IB2005/000640 140 ethylamino]-propyl}-phenyl)-acetic acid (Preparation 20) and the appropriate amine to give the title compound as a white foam. 1H NMR (400MHz, CD 3 0D): 8 = 7.25-6.94 (6H, m), 6.70-6.66 (1H, d), 4.72-4.68 (1H, m), 4.64-4.58 (2H, m), 3.73 (2H, s), 3.70-3.60 (1H, m), 3.73 (2H, s), 3.70 5 3.60 (1H, m), 3.30-3.24 (2H, q), 2.95-2.48 (5H, m), 1.85-1.10 (10H, m), 1.12 1.08 (3H, t), 1.04-1.02 (3H, d), 0.92 (9H, s), 0.01 (3H, s), -0.20 (3H, s) ppm. LRMS (electrospray): m/z [M+H]. 605. Preparation 19: 2-{3-[(2R)-2-({(2R)-2-{[tert-butyl(dimethyl)silyl]oxy)-2-[4 10 hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N-(2 cyclohexylethyl)acetamide OTBDMS H H N H~, HO H 3 0 HO Prepared according to the procedure used for preparation 1 using (3-{(2R)-2 [(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-hydroxy-3-hydroxymethyl-phenyl) 15 ethylamino]-propyl}-phenyl)-acetic acid (Preparation 20) and the appropriate amine to give the title compound as a white foam. 'H NMR (400MHz, CD 3 0D): 8 = 7.22-6.96 (6H, m), 6.68-6.66 (1 H, d), 4.70-4.65 (IH, m), 4.64-4.58 (2H, m), 3.42 (2H, s), 3.21-3.17 (2H, t), 2.93-2.50 (5H, m), 1.74-1.60 (5H, m), 1.39-1.34 (2H, q), 1.30-1.12 (4H, m), 1.04-1.02 (3H, d), 20 0.96-0.91 (2H, m), 0.90 (9H, s), 0.00 (3H, s), -0.19 (3H, s)ppm. LRMS (electrospray) : m/z [M+Na]* 605. Preparation 20: ( 3 -{(2R)-2-[(2R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-2-(4 hydroxy-3-hydroxymethyl-phenyl) -ethylamino] -propyl}-phenyl) -acetic acid WO 2005/090287 PCT/IB2005/000640 141 OTBDMS H N OH HO CH 3 0 HO A solution of methyl (3-{(2RY-2-[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(4 hyd roxy-3-hyd roxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-acetate (Preparation 21) (7.04g, 14.43mmol) in tetrahydrofuran (40ml) was treated with 5 lithium hydroxide (28.9ml of a 1M aqueous solution, 28.9mmol) and the reaction left to stir at room temperature for 16 hours. Hydrochloric acid (28.9ml of a 1 M aqueous solution, 28.9mmol) was added and then the tetrahydrofuran was removed in vacuo. The remaining aqueous layer was decanted and the residue washed with further water (10ml). The residue was redisolved in 10 methanol (30ml) and the solvent removed in vacuo to give the title compound as a colorless foam (5.95g) which was used without further purification. H NMR (400MHz, CD 3 0D): 8 = 7.32 (1H, s), 7.25-7.18 (2H, m), 7.13 (1H, s), 7.12-7.10 (1H, d), 7.02-7.01 (1H, d), 6.79-6.77 (1H, d), 4.98-4.95 (1H, m), 4.65 4.64 (2H, d), 3.48 (2H, s), 3.48-3.43 (1H, m), 3.28-3.23 (1H, dd), 3.13-3.09 (1H, 15 dd), 2.98-2.93 (1H, dd), 2.77-2.72 (1H, dd), 1.23-1.21 (3H, d), 0.86 (9H, s), 0.06 (3H, s), -0.13 (3H, s) ppm. LRMS (electrospray) : m/z [M+H]* 474, [M+Na]* 496, [M-H]~ 472. CHN analysis : found C 64.15%, H 8.25%, N 2.84%; C 26

H

39

NO

5 Si+0.7H 2 0 requires C 64.22%, H 8.37%, N 2.88%. 20 Preparation 21: methyl ( 3

-((

2 R)-2-[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2 (4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-acetate WO 2005/090287 PCT/IB2005/000640 142 OTBDMS H 1 0, CH 3 HO NCH 3 O HO A suspension of methyl (3-{(2R)-2-[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(4 [benzyloxy]-3-hyd roxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-acetate (Preparation 22) (5.27g, 9.12mmol) and 10% palladium on carbon (1.00g) in 5 ethanol (50ml) was stirred under an atmosphere of hydrogen (60psi) at room temperature for 16 hours. The catalyst was filtered off through arbocel and the filtrate concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with dichloromethane:methanol:880 ammonia (96:4:0.4 changing to 95:5:0.5, by volume) to give the title compound 10 as a pale yellow oil (1.99g) which was used without further purification. 1H NMR (400MHz, CD 3 0D): 6 = 7.21-7.17 (2H, m), 7.11-7.09 (1H, d), 7.03-6.98 (3H, m), 6.69-6.67 (1H, d), 4.71-4.68 (1H, t), 4.62-4.61 (2H, d), 3.67 (3H, s), 3.59 (2H, s), 2.96-2.86 (2H, m), 2.69-2.55 (3H, m), 1.07-1.05 (3H, d), 0.82 (9H, s), -0.01 (3H, s), -0.20 (3H, s) ppm. 15 LRMS (electrospray) : m/z [M+H]+ 488, [M+Na]* 510, [M-H]- 486 Preparation 22: methyl (3-{(2R)-2-[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2 (4-[benzyloxy]-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl) acetate OTBDMS H O_ N O, CH3 0OH 3 0 20 HO A solution of [2-(benzyloxy)-5-((1 R)-2-bromo-1 -{[tert-butyl(dimethyl) silyl]oxy}ethyl) phenyl]methanol (Preparation 23) (12.5g, 27.7mmol) and methyl WO 2005/090287 PCT/IB2005/000640 143 {3-{(2R)-2-aminopropyl]phenyl}acetate (Preparation 25) (11.5g, 55.4mmol) in dichloromethane (130ml) was heated to 90 0 C, allowing the dichloromethane to evaporate. The resulting melt was left at 90 0 C for a further 16 hours. The reaction mixture was cooled to room temperature and purified by flash column 5 chromatography on silica gel eluting with dichloromethane:methanol:880 ammonia (98:2:0.2 changing to 97:3:0.3, by volume) to give the title compound (12.1g) as a white oil. 1 H NMR (400MHz, CD 3 0D): 8 = 7.47-7.45 (2H, m), 7.39-7.29 (4H, m), 7.19 7.15 (1H, t), 7.13-7.07 (2H, m), 7.03 (1H, s), 7.01-6.99 (1H, d), 6.93-6.91 (1H, 10 d), 5.12 (2H, s), 4.76-4.73 (1H, t), 4.67-4.66 (2H, d), 3.66 (3H, s), 3.58 (2H, s), 2.95-2.80 (2H, m), 2.68-2.55 (3H, m), 1.06-1.05 (3H, d), 0.83 (9H, s), 0.00 (3H, s), -0.19 (3H, s) ppm. LRMS (electrospray) : m/z [M+H]+ 578, [M+Na]* 600. Preparation 23: [2-(benzyloxy)-5-((1 R)-2-bromo-1 -{[tert-butyl(dimethyl) 15 silyl]oxy}ethyl) phenyl]methanol OTBDMS Br Cr 0 HO Borane dimethylsulfide complex (42.4ml of 10M solution in tetrahydrofuran, 424mmol) was added dropwise to a solution of methyl 2-(benzyloxy)-5-((1R)-2 bromo-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)benzoate (Preparation 24), (91.0g, 20 189mmol) in tetrahydrofuran (1600ml). The resulting mixture was then heated to reflux for 2 hours and then cooled to 0*C before quenching with methanol (270ml). The mixture was left to stir at room temperature for 16 hours and then the solvent removed in vacuo. The residue was partitioned between dichloromethane (500ml) and water (500ml). The aqueous phase was 25 separated and extracted with dichloromethane (500ml) and the combined organic extracts washed with saturated aqueous sodium chloride (500ml), dried WO 2005/090287 PCT/IB2005/000640 144 (magnesium sulfate) and the solvent removed in vacuo. The residue was purified by flash column chromatography on silica gel eluting with cyclohexane:ethyl acetate (100:0 changing to 80:20, by volume) to give the title compound (68.7g) as a colourless oil. 5 1H NMR (400MHz, CDCl 3 ): 8 = 7.42-7.36 (5H, m), 7.29-7.25 (3H, m), 6.94 (1H, d), 5.12 (2H, s), 4.84-4.81 (1H, m), 4.74 (2H, s), 3.48-3.40 (2H, m), 0.90 (9H, s), 0.11 (3H, s), -0.07 (3H, s) ppm. LRMS (electrospray): m/z [M+Na]* 473 / 475. Preparation 24: methyl 2-(benzyloxy)-5-((1 R)-2-bromo-1 -{[tert-butyl 10 (dimethyl)silyl]oxy}ethyl)benzoate OTBDMS Br O 0 0

CH

3 A solution of methyl 2-(benzyloxy)-5-[(1R)-2-bromo-1-hydroxyethyl]benzoate (71.05g, 195mmol), imidazole (18.52g, 272mmol), tert-butyldimethylsilyl chloride (32.23g, 214mmol) and 4-(N,N-dimethylamino)pyridine (0.44g, 15 3.6mmol) in N,N-dimethylformamide (270ml) was left to stir at room temperature under a nitrogen atmosphere for a period of 24 hours. The solvent was removed in vacuo and the residue partitioned between ethyl acetate (500ml) and water (500ml). The organic phase was separated and washed with 2N hydrochloric acid (2-fold 500ml), saturated aqueous sodium bicarbonate (2 20 fold 500ml) saturated sodium chloride (500ml), dried (magnesium sulfate) and the solvent removed in vacuo to give the title compound as a colourless oil (91.0g). 1 H NMR (400MHz, CDCl 3 ): 5 = 7.81 (1H, bs), 7.51-7.30 (6H, m), 7.01 (1H, d), 5.19 (2H, s), 4.85-4.82 (1H, m), 3.91 (3H, s), 3.48-3.39 (2H, m), 0.90 (9H, s), 25 0.11 (3H, s), -0.08 (3H, s) ppm.

WO 2005/090287 PCT/IB2005/000640 145 LRMS (electrospray): m/z [M+Na]* 501 / 503. Preparation 25: methyl {3-[(2R)-2-aminopropyl]phenyl}acetate

H

2 N O CH 3

OH

3 0 A solution of methyl [3-((2R)-2-{[(1R)-1-phenyl-ethyl]-amino}-propyl)-phenyl] 5 acetate hydrochloride (Preparation 26) (7.69g, 22mmol) and ammonium formate (6.94g, 110mmol) was heated to 750C in the presence of 20% palladium hydroxide-on-charcoal (Pd(OH) 2 /C, 2.00g). After 90 minutes the reaction mixture was cooled to room temperature, filtered through arbocel and the filtrate concentrated in vacuo. The residue was partitioned between 10 dichloromethane (100ml) and 880 ammonia (100ml) and the organic phase separated. The aqueous phase was extracted dichloromethane (100ml) and the combined organic extracts dried (magnesium sulfate) and reduced in vacuo to give the title compound as a colourless oil (4.78g). H NMR (400MHz, CD 3 0D): 5 = 7.27-7.23 (1H, t), 7.13-7.09 (3H, m),-3.67 (3H, 15 s), 3.63 (2H, s), 3.12-3.05 (1H, m), 2.67-2.57 (2H, m), 1.06 (3H, d) ppm. LRMS (electrospray) : m/z [M+H]* 208, [M+Na]* 230. Preparation 26: methyl [3-((2R)-2-{[(1 R)-1 -phenyl-ethyl]-amino}-propyl) phenyl]-acetate hydrochloride H N OCH 3 H O 20 A solution of methyl [3-(2-oxopropyl)phenyl]acetate (Preparation 27) (8.5g, 41.2mmol), (R)-a-methyl benzylamine (4.8ml, 37.2mmol), sodium triacetoxyborohydride (11.6g, 56mmol) and acetic acid (2.2ml, 38mmol) in dichloromethane (400ml) was stirred at room temperature for 48 hours. The 25 reaction mixture was quenched by addition of saturated aqueous sodium WO 2005/090287 PCT/IB2005/000640 146 bicarbonate (200ml) and allowed to stir until effervescence ceased. The organic phase was separated and the aqueous phase extracted with dichloromethane (100ml). The combined organic extracts were dried (magnesium sulfate) and reduced in vacuo. Purification by flash column chromatography eluting with 5 dichloromethane:methanol: ammonia (99:1:0.1 to 95:5:0.5 by volume) gave a 4:1 mixture of diastereomers (R,R major) as a pale yellow oil (8.71g). Treatment with hydrogen chloride (40ml of a 1 M solution in methanol, 40mmol) followed by three successive crystallisations (diisopropylether/ methanol) gave the title compound as a white crystalline solid (5.68g). 10 1H NMR (400MHz, CD 3 0D): 8 = 7.52-7.48 (5H, m), 7.28-7.25 (1H, m), 7.18 7.16 (1H, m), 7.02-6.99 (2H, m), 4.59 (1H, q), 3.62 (2H, s), 3.30 (3H, s), 3.30 3.25 (1H, m), 3.26-3.15 (1H, m), 2.66-2.60 (1H, m), 1.68 (3H, d), 1.18, (3H, d) ppm. LRMS (electrospray): m/z [M+H]+ 312, [M+Na]* 334. 15 Preparation 27: methyl [3-(2-oxopropyl)phenyl]acetate H3C

O'CH

3 0 0 Tributyltin methoxide (28.3 ml, 98mmol), preparation 28 (15.0g, 65mmol), isopropenyl acetate (10.8ml, 98mmol), pallad ium(l [)acetate (750mg, 3.30mmol) and tri-ortho-tolylphosphine (2.0g, 6.5mmol) were stirred together in toluene 20 (75ml) at 1000C under nitrogen for 5 hours. After cooling the reaction was diluted with ethyl acetate (150ml) and 4M aqueous potassium fluoride solution (90ml) and stirred for 15 minutes. The mixture was filtered through arbocel and the organic phase separated and reduced in vacuo. The residue was purified by flash column chromatography silica gel eluting with a solvent gradient of 25 diethyl ether:pentane (0:100 to 25:75, by volume) changing to dichloromethane to give the title compound as a pale yellow oil (12.6g). 1 H NMR (400MHz, CDCla): 8 = 7.30 (1H, t), 7.19 (1H, d), 7.13-7.10 (2H, m), 3.69 (5H, s), 3.61 (2H, s), 2.15 (3H, s) ppm. LRMS (electrospray) : m/z [M+NH4]* 224, [M+Na]* 229.

WO 2005/090287 PCT/IB2005/000640 147 Preparation 28: Methyl (3-bromophenyl)acetate Br O'CH3 Acetyl chloride (0.7ml, 9.3mmol) was slowly added to a solution of (3-bromo phenyl)-acetic acid (20.0g, 93mmol) in methanol (500ml) at O'C under nitrogen 5 and the reaction was allowed to warm gradually to room temperature over a period of 5 hours. The solvent was removed in vacuo and the residual oil was redissolved in dichloromethane, dried (sodium sulfate) and concentrated in vacuo to give the title compound as a colourless oil (20.6g). 'H NMR (400MHz, CDCl 3 ): 5 = 7.37-7.45 (2H, m), 7.24-7.17 (2H, m), 3.70 (3H, 10 s), 3.59 (2H, s) ppm. LRMS (electrospray): m/z [M+Na] 253. Preparation 29: 1-(3-bromophenyl)-2-methylpropan-2-ol) CH HO Br OH 3 1 15 Methylmagnesium bromide (3M solution in diethylether, 51.6ml, 155mmol) was slowly added to a solution of 1-(3-bromo-phenyl)propan-2-one (1 5.0g, 70mmol) in dry diethylether (200ml) at 0*C. The resulting mixture was left for 3 hours, then cooled to 0*C and slowly quenched with saturated aqueous ammonium chloride solution. The organic phase was washed with brine, dried (sodium 20 sulfate). The yellow oil was then purified by column chromatography on silica gel eluting with dichloromethane:pentane:methanol (90:5:5 by volume to afford a pale yellow oil (13.26 g). 1H NMR (400MHz, CDCl 3 ) 6 = 7.40 (2H, m), 7.15 (2H, m), 2.74 (2H, s), 1.42 (1H, bs), 1.22 (6H, s). 25 Preparation 30: N-[2-(3-bromophenyl)-1,1 -dimethylethyl]-2 chloroacetamide WO 2005/090287 PCT/IB2005/000640 148 H CH 3 Cl N Br 0

CH

3 Chloroacetonitrile (6.63ml, 105mmol) was added to a stirred solution of 1-(3 bromophenyl)-2-methylpropan-2-ol) (Preparation 29) (12.0g, 52.Ommol) in acetic acid (25ml) at room temperature. The resulting solution was cooled to 5 00C and concentrated sulfuric acid (25ml) was added keeping the temperature <100C. The resulting solution was left to stir for 1 hour and then poured onto ice and basified by the addition of, solid potassium carbonate. The product was extracted with ethyl acetate (2x500ml), the organics combined and washed with water (50ml), dried (sodium sulfate) and the solvent removed in vacuo to afford 10 the title compound as an orange solid (16.08 g). H NMR (400MHz, CDCl 3 ) 6 = 7.39-7.32 (1H, d), 7.26 (1H, s), 7.1-7.13 (1H, t), 7.08-7.03 (1H, d), 6.17 (1H, bs), 3.94 (2H, s), 3.02 (2H, s), 1.37 (6H, s). CHN for C 1 2

H

15 BrCINO calc. (found): C 47.32 (47.26), H 4.96 (4.87), N 4.60 (4.65). 15 LRMS (electrospray) m/z 306 [M+H] Preparation 31 : 2-(3-bromophenyl)-1,1 -dimethylethylamine

CH

3

H

2 N Br OH 3 I A solution of N-[2-(3-bromophenyl)-1,1-dimethylethyl]-2-chloroacetamide 20 (Preparation 30) (32.0g, 105mmol), thiourea (9.60g, 126mmol) and acetic acid (50ml) in ethanol (250ml) was heated to reflux overnight. The reaction mixture was cooled to room temperature and filtered, the filtrate was concentrated in vacuo and basified using aqueous sodium hydroxide solution (1M, 450ml). The product was extracted with dichloromethane (2x500ml) and the combined 25 organics washed with brine (50ml), dried (sodium sulfate) and the solvent removed in vacuo to afford the title compound as a black oil (23g).

WO 2005/090287 PCT/IB2005/000640 149 'H NMR (400MHz, CDC 3 ) 8 = 7.36-7.32 (2H, m), 7.16-7.08 (2H, m), 2.62 (2H, s), 1.84 (2H, bs), 1.12 (6H, s). LRMS (electrospray) m/z 228 [M+H]* 5 Preparation 32: [2-(3-bromophenyl)-1,1-dimethylethyl]carbamic acid tert butyl ester

H

3 C H CH 3 0 N Br CH3O CH3 2-(3-bromophenyl)-1,1-dimethylethylamine (Preparation 31) (5.0g, 22mmol) was treated with di-tedt-butyl dicarbonate (5.26g, 24mmol) in dichloromethane 10 (50ml) and stirred for 20 hours. The reaction mixture was washed with water (50ml) and the combined organics dried (sodium sulfate) and the solvent removed in vacuo. The crude material was purified using a cation exchange column (methanol followed by 2M ammonia in methanol), followed by purification by flash column chromatography on silica gel eluting with 15 dichloromethane to afford the title compound as a brown oil (7.23g). 'H NMR (400MHz, CDCl 3 ) 8 = 7.35 (1H, d), 7.30 (1H, s), 7.15-7.11 (1H, t), 7.05 (1H, d), 4.24 (1H, bs), 2.97 ( 2H, s), 1.50 (9H, s), 1.27 (6H, s). LRMS (electrospray) m/z 350 [M+NH4]* 20 Preparation 33: 3-(2-tert-butoxycarbonylamino-2-methylpropyl)benzoic acid methyl ester H3C H CH 3 0 0 N0

CH

3 O CH 3 OH 3 A solution of [2-(3-bromophenyl)-1,1-dimethylethyljcarbamic acid tert-butyl ester (Preparation 32) (7.0g, 21mmol), [1,1' 25 bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.74g, 2.1mmol) and triethylamine (5.94ml, 43mmol) in methanol (250ml) was heated to 1000C under 100psi carbon monoxide for 12 hours. The reaction mixture was filtered through WO 2005/090287 PCT/IB2005/000640 150 arbocel and the filtrate concentrated in vacuo and purified by flash column chromatography on silica gel eluting with dichloromethane:pentane (50:50 by volume) to afford the title compound as a yellow solid (3.76g). 'H NMR (400MHz, CDCl 3 ) 8 = 7.92-7.90 (1H, m), 7.82 (1H, s), 7.35-7.34 (2H, 5 m), 4.24 (1H, bs), 3.90 (3H, s), 3.05 (2H, s), 1.48 (9H, s), 1.26 (6H, s). LRMS (electrospray) m/z 208 [M+H-BOC]* Preparation 34: 3-(2-amino-2-methylpropyl)benzoic acid methyl ester

CH

3

H

2 N H

OH

3 OHM 3 10 A solution of 3-(2-tert-butoxycarbonylamino-2-methylpropyl)benzoic acid methyl ester (Preparation 33) (1.6g, 5.2mmol) in dichloromethane (160ml) at 0*C was treated with trifluoroacetic acid (13.6ml) and left to warm to room temperature over 2 hours. The solvent was removed in vacuo and the product purified by cation exchange chromatography (methanol followed by 2M ammonia in 15 methanol) to yield the title compound as an amber oil (1.06g). 1 H NMR (400MHz, CDCl 3 ) 8 = 7.90-7.88 (1H, m), 7.84 (1H, s), 7.36-7.35 (2H, m), 3.90 (3H, s), 2.71 (2H, s), 1.67 (2H, bs), 1.12 (6H, s). LRMS (electrospray) m/z 208 [M+H]* 20 Preparation 35: 3-{2-[(2R)-2-(4-benzyloxy-3-hydroxymethylphenyl)-2-(tert butyldimethyl-silanyloxy)ethylamino]-2-methylpropyllbenzoic acid methyl ester OTBDMS O H 0 OH C OHI 0 3 O H 3 ! HO 3-(2-amino-2-methylpropyl)benzoic acid methyl ester (Preparation 34) (1.36g, 25 6.60mmol), [2-(benzyloxy)-5-((1R)-2-bromo-1-{[tet-butyl(dimethyl) WO 2005/090287 PCT/IB2005/000640 151 silyl]oxylethyl) phenyl]methanol (Preparation 23) (2.96g, 6.60mmol), sodium iodide (980mg, 6.60mmol) and diisopropylethylamine (3.44ml, 19.7mmol) in acetonitrile (10ml) were heated to reflux for 48 hours under a nitrogen atmosphere. The solvent was then removed in vacuo and saturated aqueous 5 sodium hydrogen carbonate solution (20ml) added and the product extracted with ethyl acetate (3x30ml). The combined organics were washed with brine (3x20 ml), dried (sodium sulfate) and the solvent removed in vacuo. The residue was purified by flash column chromatography on silica gel eluting with dichloromethane:methano:ammonia (95:5:0.5 by volume) to furnish the title 10 compound, the purified product was dissolved in diethylether and evaporated (x3) to yield a white foam (1.70 g). 1 H NMR (400MHz, CDCl 3 ) 8 = 7.89-7.84 (2H, m), 7.44-7.21 (9H, m), 6.88 (1H, d), 5.10 (2H, s), 4.73-4.69 (3H, m), 3.91 (3H, s), 2.83-2.62 (4H, m), 2.86 (1H, t), 1.05 (3H, s), 1.02 (3H, s), 0.79 (9H, s), -0.04 (3H, s), -0.19 (3H, s). 15 LRMS (electrospray) m/z 578 [M+H]*, 600 [M+Na]* Preparation 36: 3-{2-[(2R)-2-(tert-butyldimethylsilanyloxy)-2-(4-hydroxy-3 hyd roxymethyl-phenyl)ethylam ino] -2-methyl propyl)benzoic acid methyl ester OTBDMS O H NO

H

3 C CH3 CH 3 HO J 1 H 20 HO 3-{2-[(2R)-2-(4-benzyloxy-3-hydroxymethylphenyl)-2-(tert-butyldimethyl silanyloxy)ethylamino]-2-methylpropyl}benzoic acid methyl ester (Preparation 35) (2.12g, 3.70mmol) and palladium-on-carbon (10%, 300mg) in methanol (50ml) were hydrogenated at room temperature and 60 psi for 18 hours. The 25 reaction mixture was filtered through arbocel and the filtrate concentrated in vacuo, the residue was purified by flash column chromatography on silica gel eluting with dichloromethane:methanol:ammonia (95:5:0.5 by volume) to furnish WO 2005/090287 PCT/IB2005/000640 152 the title compound, this material was taken up in diethylether and evaporated (x3) to yield a white foam (1.50 g). 'H NMR (400MHz, CDCl 3 ) 5 = 7.89-7.86 (1H, m), 7.82 (1H, bs), 7.33-7.31 (2H, m), 7.13 (1H, dd), 6.96 (1H, d), 6.79 (1H, d), 4.81 (2H, dd), 4.66 (1H, dd), 3.91 5 (3H, s), 2.81-2.76 (1H, m), 2.67 (2H, dd), 2.58 (1H, dd), 1.06 (3H, s), 1.03 (3H, s), 0.79 (9H, s), -0.03 (3H, s), -0.19 (3H, s). LRMS (electrospray) m/z 488 [M+H]*, 510 [M+Na]* Preparation 37: 3-{2-[(2R)-2-(tert-butyldimethylsilanyloxy)-2-(4-hydroxy-3 10 hydroxymethyl-phenyl)ethylamino]-2-methylpropyl)benzoic acid OTBDMS O H N OH O H3G CH 3 HO HO 3-{2-[(2R)-2-(tert-butyldimethylsilanyloxy)-2-(4-hydroxy-3-hydroxymethyl phenyl)ethylamino]-2-methylpropyl}benzoic acid methyl ester (Preparation 36) (1.50g, 3.08mmol), aqueous sodium hydroxide solution (5M, 3.07ml, 15 15.Ommol), water (2ml) and dioxane (20ml) were stirred at room temperature for 18 hours. The solvent was removed in vacuo and the residue dissolved in water (30ml) and acidified with aqueous hydrochloric acid (1N, 15.38ml). The resulting white precipitate was filtered off and dried in vacuo for 72 hours to furnish the title compound as a white solid (1.28g). 20 'H NMR (400MHz, CD 3 0D) 6 = 7.88 (1H, d), 7.81 (1H, bs), 7.38-7.28 (3H, m), 7.10 (1H, dd), 6.77 (1H, d), 4.92 (1H, m, partially under solvent peak), 4.61 (2H, dd), 3.23-3.12 (2H, m), 2.95 (2H, dd), 1.08 (6H, s), 0.81 (9H, s), -0.04 (3H, s), 0.15 (3H, s). LRMS (electrospray) m/z 474 [M+H]* 25 WO 2005/090287 PCT/IB2005/000640 153 Preparation 38: 3-{2-[(2R)-2-(tert-butyldimethylsilanyloxy)-2-(4-hydroxy-3 hydroxymethyl-phenyl)ethylamino-2-methylpropyl}-N-[2-(4 chlorophenyl)ethyl]benzamide OTBDMS O Cl H NN

H

3 C CH 3

I

HO3H HO 5 2-(4-Chlorophenyl)ethylamine (164mg, 1.06mmol) was added to a mixture of 1 (3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (203mg, 1.06mmol), 3-{2-[(2R)-2-(tert-butyld imethylsilanyloxy)-2-(4-hydroxy-3-hydroxymethyl phenyl)ethylamino]-2-methylpropyl}benzoic acid (Preparation 37) (500mg, 1.06mmol),1-hydroxybenzotriazole hydrate (160mg, 10 1.06mmol) and triethylamine (440WI, 3.20mmol) in dichloromethane (30ml). The resulting solution was stirred for 48 hours under nitrogen. The solvent was removed in vacuo and the residue taken up in ethyl acetate (30ml), washed with water (20ml), sodium hydrogen carbonate (0.5 M, 2x20 ml), brine (2x20 ml), dried (sodium sulfate) and the solvent removed in vacuo. The residue was 15 purified by flash column chromatography on silica gel eluting with dichloromethane:methanol:ammonia (95:5:0.5 by volume) to furnish the title compound, the resulting material was taken up in methanol and evaporated, then taken up in diethylether and evaporated to yield a white foam (480 mg). H NMR (400MHz, CD 3 0D) S = 7.64-7.60 (2H, m), 7.36-7.19 (7H, m), 7.05 (1H, 20 dd), 6.72 (1H, d), 4.71-4.67 (1H, m), 4.60 (2H, dd), 3.57 (2H, t), 2.93-2.61 (6H, m), 1.09 (3H, s), 1.06 (3H, s), 0.78 (9H, s), -0.04 (3H, s), -0.22 (3H, s). LRMS (electrospray) m/z 611 [M+H]*, 633 [M+Na]* Preparation 39: 3-{2-[(2R)-2-(tert-butyldimethylsilanyloxy)-2-(4-hydroxy-3 25 hydroxymethyl-phenyl)ethylam ino]-2-methyl propyl}-N-[2-(4 methylphenyl)ethyl]benzamide WO 2005/090287 PCT/IB2005/000640 154 OTBDMS CH 3 H HO H C HO Prepared according to the procedure used for preparation 38 using 3-{2-[(2R) 2-(tert-butyldimethylsilanyloxy)-2-(4-hydroxy-3-hydroxymethyl phenyl)ethylamino]-2-methylpropyllbenzoic acid (Preparation 37) and the 5 appropriate amine to give the title compound as a white foam. H NMR (400MHz, CD 3 0D) 6 = 7.65-7.61 (2H, m), 7.36-7.30 (2H, m), 7.27 (1H, d), 7.14-7.06 (5H, m), 6.72 (1H, d), 4.71-4.68 (1H, m), 4.60 (2H, dd), 3.54 (2H, t), 2.90-2.83 (3H, m), 2.70 (2H, dd), 2.61 (1H, dd), 2.28 (3H, s), 1.09 (3H, s), 1.05 (3H, s), 0.78 (9H, s), -0.04 (3H, s), -0.22 (1H, s). 10 LRMS (electrospray) m/z 591 [M+H]*, 613 [M+Na]* Preparation 40: 3-{2-[(2R)-2-(tert-butyldimethylsilanyloxy)-2-(4-hydroxy-3 hydroxymethyl-phenyl)ethylam ino]-2-methyl -propyl}-N-[2-(4 trifluoromethylphenyl)ethyl]benzamide OTBDMS CF 3 H N N HOC

CH

3 II HO H C 15 HO Prepared according to the procedure used for preparation 38 using 3-{2-[(2R) 2-(tert-butyldimethylsilanyloxy)-2-(4-hydroxy-3-hydroxymethyl phenyl)ethylamino]-2-methylpropyl}benzoic acid (Preparation 37) and the appropriate amine to give the title compound as a white foam. 20 'H NMR (400MHz, CDCl 3 ) 5 = 7.66 (2H, d), 7.45 (1H, m), 7.38 (1H, s), 7.33 (2H, d), 7.29-7.22 (2H, m), 7.07 (1H, dd), 6.88 (1H, dd), 6.75 (1H, dd), 6.15 (1H, t), 4.75 (1H, dd), 4.57 (1H, t), 3.73-3.68 (2H, m), 2.99 (2H, t), 2.76 (1H, WO 2005/090287 PCT/IB2005/000640 155 dd), 2.65 (2H, s), 2.58 (1H, dd), 1.03 (3H, s), 1.00 (3H, s), 0.79 (9H, s), -0.05 (3H, s), -0.20 (3H, s). LRMS (electrospray) m/z 646 [M+H]+ 5 Preparation 41: 3-{2-[(2R)-2-(tert-butyldimethylsilanyloxy)-2-(4-hydroxy-3 hydroxymethyl-phenyl)ethylamino]-2-methyl-propyl}-N-[2-(3, 4 dichlorophenyl)ethyl]benzamide OTBDMS O Cl H NJN Cl HC CH 3 I HOHC H HO Prepared according to the procedure used for preparation 38 using 3-{2-[(2R) 10 2-(tert-butyldimethylsilanyloxy)-2-(4-hydroxy-3-hydroxymethyl phenyl)ethylamino]-2-methylpropyl}benzoic acid (Preparation 37) and the appropriate amine to give the title compound as a white foam. 1 H NMR (400MHz, CDCl 3 ) 8 = 7.45 (1H, d), 7.40-7.36 (2H, m), 7.33 (1H, d), 7.30-7.22 (2H, m), 7.05 (2H, m), 6.88 (1H, dd), 6.75 (1H, d), 6.17 (1H, t), 4.75 15 (1H, dd), 4.69 (1H, t), 3.63 (2H, m), 2.89 (1H, t), 2.76 (1H, dd), 2.66 (2H, s), 2.59 (1H, dd), 1.04 (3H, s), 1.00 (3H, s), 0.79 (9H, s), -0.05 (3H, s), -0.20 (3H, s). LRMS (electrospray) m/z 646 [M+H]+ 20 Preparation 42: 3-{2-[(2R)-2-(tert-butyldimethylsilanyloxy)-2-(4-hydroxy-3 hydroxymethyl-phenyl)ethylamino]-2-methyl-propyl}-N-[2-(3, 4 dimethylphenyl)ethyl]benzamide OTBDMS 0 CH 3 H I HNJ" N

CH

3 HO

H

3 C H

HO

WO 2005/090287 PCT/IB2005/000640 156 Prepared according to the procedure used for preparation 38 using 3-{2-[(2R) 2-(tert-butyldimethylsilanyloxy)-2-(4-hydroxy-3-hydroxymethyl phenyl)ethylamino]-2-methylpropyl)benzoic acid (Preparation 37) and the appropriate amine to give the title compound as a white foam. 5 'H NMR (400MHz, CDCl 3 ) 8 = 7.43 (1H, d), 7.37 (1H, s), 7.20-7.27 (2H, m), 7.06-7.09 (2H, m), 7.01 (1H, s), 6.94 (1H, d), 6.88 (1H, dd), 6.74 (1H, dd), 6.13 (1H, t), 4.75 (1H, dd), 4.59 (1H, t), 3.64 (1H, dd), 2.85 (1H, t), 2.77 (1H, dd), 2.65 (2H, s), 2.59 (1H, dd), 2.24 (3H, s), 2.23 (3H, s), 1.03 (3H, s), 1.00 (3H, s), 0.79 (9H, s), -0.05 (3H, s), -0.20 (3H, s). 10 LRMS (APCI) m/z 606 [M+H]* Preparation 43: 3-(2-[(2R)-2-(tert-butyldimethylsilanyloxy)-2-(4-hydroxy-3 hydroxymethyl-phenyl)ethylamino]-2-methyl-propyl}-N-(2-naphthalen-2-yl ethyl)benzamide OTBDMS O H N IH HC HH HO H 15 HO Prepared according to the procedure used for preparation 38 using 3-{2-[(2R) 2-(tert-butyldimethylsilanyloxy)-2-(4-hydroxy-3-hydroxymethyl phenyl)ethylamino]-2-methylpropyl}benzoic acid (Preparation 37) and the appropriate amine to give the title compound as a white foam. 20 'H NMR (400MHz, CDCl 3 ) 8 7.77 (3H, m), 7.67 (1 H, s), 7.48-7.35 (5H, m), 7.23 7.19 (2H, m), 7.06 (1H, dd), 7.37 (1H, dd), 6.74 (1H, d), 6.17 (1H, t), 4.74 (2H, dd), 4.67 (1H, t), 3.76 (2H, dd), 3.09 (2H, t), 2.75 (1H, dd), 2.62 (2H, s), 2.57 (1H, dd), 1.00 (3H, s), 0.97 (3H, s), 0.78 (9H, s), -0.05 (3H, s), -0.21 (3H, s). LRMS (electrospray) m/z 628 [M+H]+ 25 WO 2005/090287 PCT/IB2005/000640 157 Preparation 44: 3-{2-[(2R)-2-(tert-butyldimethylsilanyloxy)-2-(4-hydroxy-3 hydroxymethyl-phenyl)ethylamino]-2-methyl-propyl}-N-(1,1 -dimethyl-2 phenyl-ethyl)benzamide TBDMS HC CH N N H HC CH II HO H H HO 5 Prepared according to the procedure used for preparation 38 using 3-{2-[(2R) 2-(tert-butydimethylsilanyloxy)-2-(4-hydroxy-3-hydroxymethyl phenyl)ethylamino]-2-methylpropyl}benzoic acid (Preparation 37) and the appropriate amine to give the title compound as a white foam. 1H NMR (400MHz, CDCl 3 ) 8 = 7.43 (1H, in), 7.36 (1H, s), 7.31-7.13 (7H, m), 10 7.08 (1H, dd), 6.84 (1H, dd), 6.75 (1H, d), 5.70 (1H, s), 4.73 (2H, dd), 4.68 (1H, t), 3.10 (2H, dd), 2.77 (1H, dd), 2.65 (2H, s), 2.68 (1H, dd), 1.45 (3H, s), 1.44 (3H, s), 1.06, (3H, s), 1.01 (3H, s), 0.79 (9H, s), -0.04 (3H, s), -0.21 (3H, s). LRMS (electrospray) m/z 605 [M+H]+ 15 Preparation 45: 3-{2-[(2R)-2-(tert-butyldimethylsilanyloxy)-2-(4-hydroxy-3 hydroxymethylphenyl)ethylamino]-2-methylpropyl}-N-(2-methyl-2 phenylpropyl)-benzamide OTBDMS O H NN

H

3 C CH 3 H H 3 C CH 3 HO HO Prepared according to the procedure used for preparation 38 using 3-{2-[(2R) 20 2-(tert-butyldimethylsilanyloxy)-2-(4-hydroxy-3-hydroxymethyl phenyl)ethylamino]-2-methylpropyl}benzoic acid (Preparation 37) and the appropriate amine to give the title compound as a white foam.

WO 2005/090287 PCT/IB2005/000640 158 1 H NMR (400MHz, CDCl 3 ) 8 = 7.42-7.34 (4H, m), 7.29-7.15 (5H, m), 7.05 (1H, dd), 6.87 (1H, dd), 6.74 (1H, d), 5.73 (1H, t), 4.74 (2H, dd), 4.64 (1H, dd), 3.62 (2H, dd), 2.75 (1H, dd), 2.61 (2H, dd), 2.66 (1H, dd), 1.40 (6H, s), 1.00 (3H, s), 0.97 (3H, s), 0.79 (9H, s), -.05 (3H, s), -0.20 (3H, s). 5 LRMS (electrospray) m/z 605 [M+H]* Preparation 46: 3-{(2R)-2-[2-(tert-butyldimethylsilanyloxy)-2-(4-hydroxy-3 hydroxymethyl-phenyl)ethylamino]-2-methylpropyl}-N-(4 chlorobenzyl)benzamide OTBDMS O H N HO H C C 10 HO Prepared according to the procedure used for preparation 38 using 3-{2-[(2R) 2-(tert-butyldimethylsilanyloxy)-2-(4-hydroxy-3-hydroxymethyl phenyl)ethylamino]-2-methylpropyl}benzoic acid (Preparation 37) and the appropriate amine to give the title compound as a white foam. 15 1 H NMR (400MHz, CDC13) 5 7.55 = (1H, m), 7.49 (1H, m), 7.33-7.24 (4H, m), 7.06 (1H, dd), 6.88 (1H, dd), 6.74 (1H, d), 6.49 (1H, t), 4.73 (1H, dd), 4.57 (2H, dd), 2.75 (1H, dd), 2.66 (2H, s), 2.66 (1H, dd), 1.04 (3H, s), 1.00 (3H, s), 0.78 (9H, s), -0.06 (3H, s), -0.21 (3H, s). LRMS (electrospray) m/z 597/599 [M+H]* 20 Preparation 47: [3-(2-amino-2-methyl-propyl)-phenyl]-acetic acid ethyl ester H3C O

NH

2 0~ H 3 67C O 3 A solution of {3-[ 2

-(

2 -chloro-acetylamino)-2-methyl-propyl]-phenyl}-acetic acid 25 (Preparation 48) (5.1g, 18mmol), thiourea (1.6g, 21mmol) and acetic acid (18ml) in ethanol (80ml) was heated to reflux under a nitrogen atmosphere for WO 2005/090287 PCT/IB2005/000640 159 16 hours. The reaction mixture was cooled and filtered. The filtrate was reduced in vacuo, the residue dissolved in ethanol (150ml), saturated with hydrogen chloride gas and the resulting solution heated to reflux for 16 hours. The solvent was reduced in vacuo and the residue partitioned between ethyl 5 acetate (200ml) and 5% aqueous sodium carbonate (200ml). The organic extract was washed with saturated sodium chloride (100ml), dried (sodium sulfate) and reduced in vacuo. The residue was purified by strong cation exchange resin, eluting with methanol and then 2N ammonia in methanol to elute the product. The eluent was concentrated in vacuo giving the title 10 compound as a yellow oil (2.68g, 63%). 1 H NMR (400MHz, CDCl 3 ): 8 = 7.29-7.04 (4H, m), 4.08 (2H, q), 3.64 (2H, s), 2.57 (2H, s), 1.18 (3H, t), 0.99 (6H, s) ppm. LRMS (electrospray) : m/z [M+H]* 236, [M+NH 4 ]* 258. 15 Preparation 48: {3-[2-(2-chloro-acetylamino)-2-methyl-propyl]-phenyl} acetic acid H HO N,,r C HO C CH Concentrated sulphuric acid (21ml) was added dropwise to a solution of [3-(2 hydroxy-2-methyl-propyl)-phenyl]-acetic acid (Preparation 49) (1 0.6g, 20 51.Ommol) and chloroacetonitrile (4.8ml, 76.Ommol) in glacial acetic acid (16ml) at 0*C. The reaction was allowed to warm to room temperature and after 2 hours was poured onto iced water (500ml). The aqueous was extracted with ethyl acetate (2x250ml) and the combined organics washed with brine (50ml), dried (sodium sulfate), and the solvent removed in vacuo to furnish the title 25 compound as a golden oil (14.0g). 1 H NMR (400MHz, CDCl 3 ): 8 = 7.31-7.06 (4H, m), 6.19 (1H, bs), 3.95 (2H, s), 3.62 (2H, s), 3.02 (2H, s), 1.36 (6H, s) ppm. LRMS (electrospray) : m/z [M-H]~ 282 / 284. 30 Preparation 49: [3-(2-hydroxy-2-methyl-propyl)-phenyl]-acetic acid WO 2005/090287 PCT/IB2005/000640 160 HO OH 0 - 3 C CH 3 Methyl magnesium chloride (51ml of a 3M solution in tetrahydrofuran, 153mmol) was added dropwise to a stirred solution of the ester (11.6g, 51mmol) (International Journal of Peptide and Protein Research, 1987, 29(3), 5 331) in tetrahydrofuran (300ml) at 0*C under nitrogen. The reaction was allowed to warm to room temperature overnight with the formation of a thick white precipitate and then water (50ml) and 2N hydrochloric acid (80ml) were cautiously added. The aqueous was extracted with ethyl acetate (2x300ml) and the combined organics washed with brine (50ml), dried (sodium sulfate), and 10 the solvent removed in vacuo to furnish the title compound as a golden oil (11.2g). 1H NMR (400MHz, CDC 3 ): 8 = 7.30-7.12 (4H, m), 3.63 (2H, s), 2.75 (2H, s), 1.22 (6H, s) ppm. LRMS (electrospray) : m/z [M+H]* 209. 15 Ester needs to be named? Preparation 50: {3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3 (hydroxymethyl)phenyl]ethyl)amino)-2-methylpropyl]phenyl}acetic acid OH H N OH HO

H

3 C 0 HO 20 Prepared according to the procedure used for preparation 20 using ethyl {3-[2 ({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2 methylpropyl]phenyl}acetate (Preparation 68) to give the title compound as a cream solid. 'H NMR (400MHz, CD 3 0D): 6 = 7.43-7.42 (1H, d), 7.37-7.22 (4H, m), 7.15-7.13 25 (1H, m), 6.85-6.83 (1H, d), 4.90-4.86 (1H, m), 4.71 (2H, s), 3.56-3.55 (2H, m), 3.25-3.13 (2H, m), 3.05-2.98 (2H, m), 1.40 (3H, s), 1.38 (3H, s) ppm.

WO 2005/090287 PCT/IB2005/000640 161 LRMS (electrospray): m/z [M+H]* 374, [M-H]~ 372. Preparation 51: {3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3 (hydroxymethyl)phenyl]ethyl}amino)ethyl]phenyl}acetic acid OH H N OH HO 0 5 HO Prepared according to the procedure used for preparation 20 using ethyl {3-[2 ({(2R)-2-hydroxy-2-[4-hydroxy-3 (hydroxymethyl)phenyl]ethyl}amino)ethyl]phenyl}acetate (Preparation 52) to give the title compound as a white solid. 10 'H NMR (400MHz, CD 3 0D): 6 7.26 (1H, d), 7.20-7.16 (1H, t), 7.09-6.97 (5H, m), 6.74-6.72 (1H, d), 4.68-4.65 (1H, in), 4.44 (2H, s), 3.42 (2H, s), 2.95-2.71 (6H, m) ppm. LRMS (electrospray) : m/z [M-H]~ 344. 15 Preparation 52: ethyl {3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3 (hydroxymethyl)phenyl]ethyl}amino)ethyl]phenyl}acetate OH H N 0 -CH3 HO HO Prepared according to the procedure used for preparation 21 using ethyl {3-[2 ({(2R)-2-[4-(benzyloxy)-3-(hydroxymethyl)phenyl]-2 20 hydroxyethyl}amino)ethyl]phenyl}acetate (Preparation 53) to give the title compound as an orange oil.

WO 2005/090287 PCT/IB2005/000640 162 1 H NMR (400MHz, CD 3 0D): 6 7.25-7.20 (2H, m), 7.11-7.05 (4H, m), 6.73-6.71 (1H, d), 4.68-4.63 (3H, m), 4.15-4.09 (2H, m), 3.59 (2H, s), 2.89-2.71 (6H, m), 1.24-1.21 (3H, t) ppm. LRMS (electrospray) : m/z [M+H]* 374, [M-H] 372. 5 Preparation 53: ethyl {3-[2-({(2R)-2-[4-(benzyloxy)-3 (hydroxymethyl)phenyl]-2-hydroxyethyl}amino)ethyl]phenyl}acetate OH H N Oy

CH

3 HO A solution of ethyl (3-{2-[((2R)-2-[4-(benzyloxy)-3-(hydroxymethyl)phenyl]-2 10 {[tert-butyl(dimethyl)silyl]oxy}ethyl)amino]ethyl}phenyl)acetate (Preparation 54) (2.39g, 4.14mmol) in methanol (15ml) and water (10ml) was treated with ammonium fluoride (1.53g, 41.4mmol) and the reaction heated to 40 0 C for 16 hours. The methanol was removed in vacuo and the aqueous residue extracted with dichloromethane (3x50ml). The combined organics were dried (sodium 15 sulfate) and the sovent removed in vacuo and the residue purified by flash column chromatography on silica gel eluting with dichloromethane:methanol:880 ammonia (97:3:0.3 changing to 95:5:0.5, by volume) to give the title compound as an orange gum (1.90g). 1 H NMR (400MHz, CD 3 0D): 6 = 7.45-7.34 (5H, m), 7.31-7.27 (1H, m), 7.24-716 20 (2H, m), 7.11-7.09 (3H, m), 2.96-2.94 (1H, d), 5.12 (2H, s), 4.72-4.68 (3h, M), 4.15-4.09 (2H, m), 3.59 (2H, s), 2.91-2.74 (6H, m), 1.24-1.20 (3H, t) ppm. LRMS (electrospray) : m/z [M+H]+ 464, [M-H]~ 462. Preparation 54: ethyl(3-{2-[((2 R)-2-[4-(benzyloxy)-3 25 (hydroxymethyl)phenyl]-2-{[tert butyl(dimethyl)silyl]oxy}ethyl)amino]ethyl}phenyl)acetate WO 2005/090287 PCT/IB2005/000640 163 OTBDMS H N 0 -. CH 3 0 0 HO Prepared according to the procedure used for preparation 22 using [2 (benzyloxy)-5-((1 R)-2-bromo-1 -{[tert-butyl(dimethyl) silyl]oxy}ethyl) phenyl]methanol (Preparation 23) and ethyl [3-(2-aminoethyl)phenyl]acetate 5 (Preparation 58) to give the title compound as a yellow oil. 1H NMR (400MHz, CD 3 0D): 6 = 7.44-7.43 (2H, d), 7.37-7.33 (3H, m), 7.30-7.27 (1H, t), 7.24-7.20 (1H, t), 7.15-7.08 (4H, m), 6.94-6.92 (1H, d), 5.10 (2H, s), 4.77-4.74 (1H, m), 4.67-4.66 (2H, d), 4.14-4.09 (2H, m), 3.58 (2H, s), 2.90-2.75 (5H, m), 2.66-2.62 (1H, m), 1.24-1.21 (3H, t), 0.78 (9H, s), -0.05 (3H, s), -0.22 10 (3H, s) ppm. LRMS (electrospray): m/z [M+H]I 578, [M-H]- 576. Preparation 55: ethyl [3-(2-hydroxyethyl)phenyl]acetate HO 0 ,CH 3 0 15 Carbonyl diimidazole (5.11g, 31.5mmol) was added in one portion to a stirred solution of the ester (International Journal of Peptide and Protein Research, 1987, 29(3), 331) (7.00g, 31.5mmol) in tetrahydrofuran (100ml) at room temperature under nitrogen. The reaction was stirred for 2 hours and water (26ml) was added and the reaction cooled to OC. Sodium borohydride (6.00g, 20 0.15mmol) was then added portionwise and the reaction allowed to warm to room temperature with continued stirring over 2 hours. Ethyl acetate (300ml) was added followed by dropwise addition of 2N aqueous hydrochloric acid (20ml). The organic layer was separated and the aqueous extracted with ethyl acetate (2x75ml), the combined organics were dried (sodium sulfate) and the 25 solvent removed in vacuo to furnish a white solid which was purified by flash WO 2005/090287 PCT/IB2005/000640 164 column chromatography on silica gel eluting with ethyl acetate:penatane (50:50, by volume) to give the title compound as a colourless oil (4.60g). 'H NMR (400MHz, CDCl 3 ): 8 = 7.28-7.24 (1H, m), 7.15-7.11 (3H, m), 4.17-4.08 (2H, m), 3.84-3.81 (2H, t), 3.59 (2H, s), 2.86-2.82 (2H, t), 1.29-1.23 (3H, t) ppm. 5 LRMS (electrospray) : m/z [M+Na]* 231, [M-H]~ 207. Preparation 56: ethyl (3-{2-[(methylsulfonyl)oxy]ethyl}phenyl)acetate 0 -s-0 0 CH3 I I 0 0 Methane sulfonyl chloride (2.78g, 24.3mmol) was added dropwise to a solution 10 of ethyl [3-(2-hydroxyethyl)phenyl]acetate (Preparation 55) (4.60g, 22.1mmol) and triethylamine (3.40mi, 24.3mmol) in dichloromethane (250ml) at 0*C under nitrogen. The reaction was allowed to warm to room temperature over 1 hour and washed with saturated aqueous sodium hydrogen carbonate (75mi). The aqueous was washed with dichloromethane (2xlOOml) and the .combined 15 organics washed with water (25ml), dried (sodium sulfate) and the solvent removed in vacuo to furnish the title compound as a colourless oil (6.2g). 1 H NMR (400MHz, CDCl 3 ): 8 = 7.29-7.25 (1H, t), 7.17-7.12 (3H, t), 4.41-4.38 (2H, t), 4.164.10 (2H, m), 3.58 (2H, s), 3.04-3.00 (2H, t), 2.81 (3H, s), 1.26 1.22 (3H, t) ppm. 20 LRMS (electrospray): m/z [M+H]+ 578, [M-H]~ 576. Preparation 57: ethyl [3-(2-azidoethyl)phenyl]acetate Na O CH 3 Sodium azide (2.82g, 43.3mmol) was added in one portion to a stirred solution 25 of ethyl(3-{2-[(methylsulfonyl)oxylethyl}phenyl)acetate (Preparation 56) (6.20g, 21.7mmol) in NN-dimethylformamide (400ml) at room temperature. The reaction was heated at 600C for 1 hour and then allowed to cool to room WO 2005/090287 PCT/IB2005/000640 165 temperature and the solvent removed in vacuo. Ethyl acetate (200ml) and water (75ml) was added and the organics separated, the aqueous was washed with ethyl acetate (2xlOOml) and the combined organics evaporated in vacuo to yield an oil that was purified by flash column chromatography on silica gel 5 eluting with ethyl acetate:penatane (5:95, by volume) to give the title compound as a colourless oil (4.65g). 1H NMR (400MHz, CDCl 3 ): 6 = 7.27-7.23 (1H, t), 7.17-7.12 (3H, m), 4.15-4.06 (2H, m), 3.60 (2H, s), 3.51-3.47 (2H, t), 2.87-2.84 (2H, t), 1.24-1.20 (3H, t) ppm. LRMS (electrospray) : m/z [M+Na] 256, [M-H]~ 232. 10 Preparation 58: ethyl [3-(2-aminoethyl)phenyl]acetate

H

2 N 0-,O-.

CH

3 1 0 Triphenylphosphine (3.88g, 23.3mmol) was added in one portion to a stirred solution of ethyl [3-(2-azidoethyl)phenyl]acetate (Preparation 57) (3.88g, 16.6mmol) in tetrahydrofuran (100ml) at room temperature under nitrogen. The 15 reaction was stirred for 18 hours and water (5ml) added and the reaction heated at 50'C for 4 hours, the reaction was cooled to room temperature and the solvent removed in vacuo. The residue was dissolved in saturated aqueous sodium hydrogen carbonate (40ml) and the aqueous extracted with dichloromethane (3x50ml). The combined organics were dried (sodium sulfate), 20 the solvent removed in vacuo and the residue purified by flash column chromatography on silica gel eluting with dichlromethane:methanol (95:5, by volume) to give the title compound as a colourless oil (3.1 1g). 1 H NMR (400MHz, CDCla): 8 = 7.26-7.22 (1H, t), 7.13-7.08 (3H, t), 4.16-4.11 (2H, m), 3.58 (2H, s), 2.96-2.93 (2H, t), 2.74-2.71 (2H, t), 1.25-1.22 (3H, t) ppm. 25 LRMS (electrospray) : m/z [M+H]* 208, [M+Na]+ 230, [M-H]~ 206. Preparation 59: 3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3 (hydroxymethyl)phenyl]ethyl)amino)propyl]benzoic acid WO 2005/090287 PCT/IB2005/000640 166 OH HO OH HO

CH

3 V HO To a solution of methyl 3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3 (hydroxymethyl)phenyl]ethyl}amino)propyllbenzoate (Preparation 60) (5.12g, 14.24mmol) in tetrahydrofuran (35ml), was added aqueous lithium hydroxide 5 solution (1M, 29ml, 29mmol) and the solution left to stir at room temperature for 18 hours. Aqueous hydrochloric acid (1M, 29ml, 29mmol) was added and the tetrahydrofuran/water removed in vacuo to give the title compound as an off white solid (5.87g) that was used without further purification. "H NMR (400MHz, CD 3 0D): 8 = 7.86-7.84 (1H, d), 7.82 (1H, s), 7.37-7.30 (3H, 10 m), 7.17-7.15 (1H, dd), 6.79-6.77 (1H, d), 4.89-4.85 (1H, m), 4.65 (2H, s), 3.60 3.50 (1H, m), 3.21-3.15 (3H, m), 2.84-2.78 (1H, dd), 1.25-1.23 (3H, d) ppm. LRMS (electrospray) : m/z [M+H]* 346, [M+Na]* 368, [M-H] 344. CHN analysis : found C 50.29, H 6.07, N 3.07; C 19

H

23

NO

5 +2.0LiCI+1.3H 2 0 requires C 50.31, H 5.69, N 3.09. 15 Preparation 60: methyl 3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3 (hydroxymethyl)phenyl]ethyl}amino)propyl]benzoate OH O JH N O H 3 HO

OH

3 ' HO A suspension of methyl 3

-[(

2 R)-2-({(2R)-2-[4-(benzyloxy)-3 20 (hydroxymethyl)phenyl]-2-hydroxyethyl}amino)propyl]benzoate (Preparation 61) (6.83g, 15.2mmol) and 10% palladium on carbon (683mg) in ethanol (100ml) was stirred under an atmosphere of hydrogen (60psi) at room temperature for WO 2005/090287 PCT/IB2005/000640 167 18 hours. The catalyst was filtered off through arbocel and the filtrate concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with dichloromethane:methanol:880 ammonia (95:5:0.5 changing to 90:10:1, by volume) to give the title compound 5 as a pale yellow gum (5.12g). H NMR (400MHz, CD 3 0D): 8 = 7.85-7.83 (1H, m), 7.79 (1H, s), 7.36-7.35 (2H, m), 7.20 (1H, s), 7.02-6.99 (1H, dd), 6.68-6.65 (1H, d), 4.61-4.58 (1H, m), 4.60 (2H, s), 3.90 (3H, s), 2.97-2.87 (2H, m), 2.80-2.62 (3H, m), 1.08-1.07 (3H, d) ppm. 10 LRMS (electrospray): m/z [M+H]* 360, [M+Na]* 382, [M-H]~ 358 Preparation 61: methyl 3-[(2R)-2-({(2R)-2-[4-(benzyloxy)-3 (hydroxymethyl)phenyl]-2-hydroxyethyl)amino)propyl]benzoate O H 0 0H 3 HO 15 A solution of methyl 3-{(2R)-2-[((2R)-2-[4-(benzyloxy)-3-(hydroxymethyl)phenyl] 2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)amino]propyl}benzoate (Preparation 62) (10g, 17.74mmol) and ammonium fluoride (6.57g, 177mmol) in methanol (180ml) and water (60ml) was heated at 40 0 C for 18hrs. The methanol was removed in vacuo and the remaining aqueous layer extracted with 20 dichloromethane (2x1Oml). The combined organic layers were dried (sodium sulfate), filtered and evaporated in vacuo. The resulting oil was purified by flash column chromatography on silica gel eluting with dichloromethane:methanol:880 ammonia (95:5:0.5, by volume) to give the title compound (6.83g) as a pale yellow gum. 25 'H NMR (400MHz, CD 3 0D): 3 = 7.83-7.82 (1H, d), 7.78 (1H, s), 7.47-7.45 (2H, m), 7.39-7.28 (6H, m), 7.11-7.10 (1H, d), 6.89-6.87 (1H, d), 5.11 (2H, s), 4.65 WO 2005/090287 PCT/IB2005/000640 168 (2H, s), 4.65-4.62 (1H, m), 3.88 (3H, s), 2.98-2.89 (2H, m), 2.79-2.64 (3H, m), 1.09-1.08 (3H, d) ppm. LRMS (electrospray) : m/z [M+H]* 450, [M+Na]* 472, [M-H]~ 448. 5 Preparation 62: methyl 3-{(2R)-2-[((2R)-2-[4-(benzyloxy)-3 (hydroxymethyl)phenyl]-2-{[tert butyl(dimethyl)silyl]oxy}ethyl)amino]propyl}benzoate OTBDMS O H N CH3 O

CH

3 HO A solution of [2-(benzyloxy)-5-((1 R)-2-bromo-1 -{[tert-butyl(dimethyl) 10 silyl]oxy}ethyl) phenyl]methanol (Preparation 23) (9.23g, 20.5mmol) and methyl {3-[(2R)-2-aminopropyl]phenyl}acetate (Preparation 63) (8.48g, 40.9mmol) in dichloromethane (70ml) was heated to 90 0 C, allowing the dichloromethane to evaporate. The resulting melt was left at 90 0 C for a further 18 hours. The reaction mixture was cooled to room temperature and purified by flash column 15 chromatography on silica gel eluting with dichloromethane:methanol:880 ammonia (98:2:0.2 changing to 97.5:2.5:0.25, by volume) to give the title compound (10g) as an orange oil. 1H NMR (400MHz, CD 3 0D): 6 = 7.84-7.82 (1H, m), 7.79 (1H, s), 7.47-7.43 (2H, m), 7.39-7.30 (6H, m), 7.08-7.06 (1H, d), 6.89-6.86 (1H, d), 5.10 (2H, s), 4.74 20 4.71 (1H, t), 4.65-4.64 (2H, d), 3.88 (3H, s), 2.97-2.87 (2H, m), 2.69-2.68 (2H, d), 2.65-2.61 (1H, dd), 1.08-1.07 (3H, d), 0.80 (9H, s), -0.03 (3H, s), -0.21 (3H, s) ppm. LRMS (electrospray): m/z [M+H]* 564, [M+Na]* 586. 25 Preparation 63: methyl {3-[(2R)-2-aminopropyl]phenyl}acetate WO 2005/090287 PCT/IB2005/000640 169 0

H

2 N O.CH3

CH

3 A solution of methyl [3-((2R)-2-{[(1R)-1-phenyl-ethyl]-amino}-propyl)-phenyl] acetate (Preparation 64) (13.65g, 40.9mmol) and ammonium formate (12.9g, 204mmol) in ethanol (200ml) was heated at reflux in the presence of 20% of 5 palladium hydroxide on charcoal (Pd(OH) 2 /C, 1.36g). After 3 hours the reaction mixture was cooled to room temperature, filtered through arbocel and the filtrate concentrated in vacuo. The residue was partitioned between dichloromethane (200ml) and 880 ammonia (100ml) and the organic phase separated. The aqueous phase was extracted with further dichlorormethane 10 (3xlOOml) and the combined organic extracts washed with brine (100ml), dried (sodium sulfate) and reduced in vacuo to give the title compound (8.48g) as a pale yellow oil. 1H NMR (400MHz, CDCI 3 ): 8 = 7.90-7.87 (2H, m), 7.38-7.34 (2H, m), 3.90 (3H, s), 3.26-3.17 (1H, m), 2.78-2.73 (1H, dd), 2.64-2.59 (1H, dd), 1.14-1.12 (3H, d) 15 ppm. LRMS (electrospray) : m/z [M+H]* 194. Preparation 64: methyl [3-((2R)-2-{([(1 R)-1 -phenyl-ethyl]-amino}-propyl) phenyl]-acetate hyrdrochloride H 0 OOH-OH CH3 CH3CH 20 A solution of methyl [3-(2-oxopropyl)phenyl]acetate (Preparation 65) (45.3g, 236mmol), (R)-a-methyl benzylamine (27.6ml, 214mmol), sodium triacetoxyborohydride (68.1g, 321mmol) and acetic acid (14.7ml, 257mmol) in dichloromethane (1500ml) was stirred at room temperature for 18 hours. The 25 reaction mixture was quenched by addition of saturated aqueous sodium bicarbonate (600ml) and allowed to stir until effervescence ceased. The organic WO 2005/090287 PCT/IB2005/000640 170 phase was separated and the aqueous phase extracted with further dichloromethane (2x100ml). The combined organic extracts were washed with brine (100ml), dried (sodium sulfate), filtered through celite and reduced in vacuo. The oil was dissolved in methanol (200ml), treated with 1M hydrogen 5 chloride in methanol (300ml) and reduced in vacuo to give a 4:1 mixture of diastereomers (R,R major) as an off-white, hydrochloride salt. Two successive crystallisations (diisopropylether/methanol) gave the title compound (27.3g) as a colourless crystalline solid. H NMR (400MHz, CD 3 0D): 8 = 7.92-7.90 (1H, d), 7.75 (1H, s), 7.55-7.49 (5H, 10 m), 7.45-7.42 (1H, dd), 7.35-7.33 (1H, d), 4.68-4.63 (1H, q), 3.90 (3H, s), 3.43 3.38 (1H, dd), 3.25-3.19 (1H, m), 2.71-2.65 (1H, dd), 1.71-1.69 (3H, d), 1.17 1.16, (3H, d) ppm. Preparation 65: methyl [3-(2-oxopropyl)phenyl]acetate 0

H

3 C CH3 0 15 Tributyltin methoxide (80.3ml, 279mmol), methyl 3-bromobenzoate (53.5g, 249mmol), isopropenyl acetate (39.4ml, 358mmol), palladium(II)acetate (2.6g, 11.6mmol) and tri-o-tolylphosphine (7.1g, 23.2mmol) were stirred together in toluene (350ml) at 100*C under nitrogen for 18 hours. After cooling, the 20 reaction was treated with 4M aqueous potassium fluoride solution (560ml) and stirred for 2 hours. The resulting mixture was diluted with further toluene (200ml) and filtered through celite, washing the filter pad with ethyl acetate. The organic phase was separated, dried (sodium sulfate) and reduced in vacuo. The residue was purified by flash column chromatography on silica gel eluting 25 with ethylacetate:pentane (10:90, changing to 20:80, by volume) to give the title compound (45.3g) as an orange oil. 1 H NMR (400MHz, CDCl 3 ): 8 = 7.95-7.93 (1H, d), 7.87 (1H, s), 7.43-7.37 (2H, m), 3.91 (3H, s), 3.75 (2H, s), 2.18 (3H, s) ppm. LRMS (electrospray) : m/z [M+Na]* 215, [M-H]~ 191.

WO 2005/090287 PCT/IB2005/000640 171 Preparation 66: ethyl (3-(2-[((2R)-2-[4-(benzyloxy)-3 (hydroxymethyl)phenyl]-2-([tert-butyl(dimethyl)silyloxy}ethyl)amino].2 methylpropyl}phenyl)acetate OTBDMS H N 0 CIOH 3

H

3 N CHOH 5 HO Prepared according to the procedure used for preparation 22 using [2 (benzyloxy)-5-((1 R)-2-bromo-1 -{[terd-butyl(dimethyl) silyl]oxy}ethyl) phenyl]methanol (Preparation 23) and [3-(2-amino-2-methyl-propyl)-phenyl] acetic acid ethyl ester (Preparation 47) to give the title compound as a yellow 10 oil. 1H NMR (400MHz, CD 3 0D): 8 = 7.48-7.05 (11H, m), 7.04-6.96 (1H, d), 5.10 (2H, s), 4.80-4.74 (1H, m), 4.78-4.63 (2H, q), 4.16-4.05 (2H, q), 3.60 (2H, s), 2.89-2.63 (2H, m), 2.70-2.62 (2H, m), 1.24-1.20 (3H, t), 1.07-1.04 (6H, d), 0.81 (9H, s), 0.00 (3H, s), -0.18 (3H, s) ppm. 15 LRMS (electrospray): m/z [M+HJ 606, [M-H]~ 604. Preparation 67: ethyl {3-[2-({(2R)-2-[4-(benzyloxy).3 (hydroxymethyl)phenyl]-2-hydroxyethyl}amino)-2 methyl propyl] phenylacetate OH H N 0 CH 3 0 1- 3 C CH) 0 20 HO Prepared according to the procedure used for preparation 53 using ethyl (3-{2 [((2R)-2-[4-(benzyloxy)-3-(hydroxymethyl)phenyl]-2-{[tert- WO 2005/090287 PCT/IB2005/000640 172 butyl(dimethyl)silyl]oxy}ethyl)amino]-2-methylpropyl}phenyl)acetate (Preparation 66) to give the title compound as an oil. 'H NMR (400MHz, CD 3 0D): 8 = 7.47-7.03 (11H, m), 6.98-6.95 (1H, d), 5.14 (2H, s), 4.68 (2H, s), 4.68-4.66 (1H, m), 4.15-4.10 (2H, q), 3.60 (2H, s), 2.90 5 2.64 (4H, m), 1.26-1.22 (3H, t), 1.08-1.05 (6H, d) ppm. LRMS (electrospray) : m/z [M+H]+ 492, [M-H]- 490. Preparation 68: ethyl (3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3 (hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]phenyl)acetate OH H J1 -- HN O-,_CH3

H

3 C CH3 O HO 10 HO Prepared according to the procedure used for preparation 21 using ethyl {3-[2 ({(2R)-2-[4-(benzyloxy)-3-(hydroxymethyl)phenyl]-2-hydroxyethyllamino)-2 methylpropyl]phenyl}acetate (Preparation 67) to give the title compound as a colourless oil. 15 'H NMR (400MHz, CD 3 0D): 8 = 7.30-7.02 (6H, m), 6.77-6.75 (1H, d), 4.62 (2H, s), 4.62-4.60 (1H, m), 4.17-4.09 (2H, q), 3.65-3.50 (2H, m), 2.90-2.63 (4H, m), 1.14-1.10 (3H, t), 1.08-1.05 (6H, d) ppm. LRMS (electrospray): m/z [M+H]+ 402, [M-H]~ 400. 20 Preparation 69 2-(3-Fluoro-4-trifluoromethyl-phenyl)-ethylamine

NH

2 F F F Chlorotrimethylsilane (2mL, 16mmol) was added dropwise to lithium borohydride (2M in tetrahydrofuran, 4mL, 8mmol). A solution of 3-fluoro-4 25 (trifluoromethyl)phenylacetonitrile (312mg, 4mmol) in tetrahydrofuran (2mlL) WO 2005/090287 PCT/IB2005/000640 173 was then added at 00C and the mixture was allowed to stir for 24 hours, whilst warming to room temperature. The mixture was then diluted with methanol (20mL) and concentrated in vacuo. The residue was taken up in 20% potassium hydroxide solution (20mL), extracted with dichloromethane (3x2OmL) 5 and the combined organic solution was dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography using an Isolute* SCX-2 cartridge, eluting with methanol followed by 1M ammonia in methanol, to give an oily residue. The oil was triturated with diethyl ether to afford the title compound in 59% yield, 485mg. 10 1H NMR (400MHz, CDCl 3 ) 8: 7.53 (1H, m), 7.08 (2H, m), 3.02 (2H, t) 2.82 (2H, t) ppm; LRMS APCI m/z 208 [M+H]* Preparation 70 2-(5-Chloro-2-methoxy-phenyl) -ethylamine O CH 3

H

2 N 15 C1 The title compound was prepared from (5-chloro-2-methoxy-phenyl)acetonitrile (W02004039377, p40), using a similar method to that of preparation 69, in 52% yield. 1 H NMR (400MHz, CDC 3 ) S: 7.11-7.00 (2H, m), 6.75-6.65 (1H, m) 3.72 (3H, s), 20 2.90-2.80 (2H, m), 2.70-2.60 (2H, m) ppm Preparations 71 to 79 The following compounds, of the general formula shown below were prepared by a similar method to that described for preparation 69 using the appropriate 25 phenylacetonitrile starting material. Unless otherwise stated R 3 to R 7 are hydrogen.

WO 2005/090287 PCT/IB2005/000640 174

R

3 R 4

NH

2 R 6 No. Data Yield 71 R"=H; R 4 = F; R5=CH 3 95% H NMR (400MHz, CDCl 3 ) 6: 7.12 (1H, m), 6.90 (2H, m), 2.95 (2H, t) 2.70 (2H, t) 2.25 (3H, s) ppm; LRMS APCI m/z 154 [M+H]* 72 R3=F; R 4 = F; R=CH 3 61% H NMR (400MHz, CDCl 3 ) 8: 6.83 (2H, m), 2.94 (2H, t) 2.78 (2H, t) 2.25 (3H, s) ppm; LRMS APCI m/z 172 [M+H]* 73 R*=CH 3 ; R=CH 3 ; R'=CH 3

CH

3 80% 'H NMR (400MHz, CDC13) 8: 6.84 (2H, m), 2.88-2.69 (4H, m) 2.30 (6H, s) 2.24 (3H, s) ppm; LRMS APCI m/z 163 [M+H]* 74 R3=F; R 4 = CH 3 ; R'=F 66% 'H NMR (400MHz, CDC13) 6: 6.97 (1H, m), 6.75 (1H, m), 2.92 (2H, t) 2.82 (2H, t) 2.24 (3H, s) ppm; LRMS APCI m/z 172 [M+H]* 75 R"=F; R 4 = CH 3 ; R'=Cl 58% 'H NMR (400MHz, CDCl 3 ) 6: 7.05 (1H, m), 6.97 (1H, m), 2.96 (4H, m) 2.23 (3H, s) ppm; LRMS APCI m/z 228

[M+CH

3 CN]+ 76 R=Cl; R 4

=CH

3 ; R'=F 63% H NMR (400MHz, CDC13) 6: 7.14-6.99 (1H, m), 6.97-6.73 (1H, m), 3.07-2.83 (4H, m) 2.35 (3H, s) ppm; LRMS APCI m/z 228 [M+CH 3 CN]f WO 2005/090287 PCT/IB2005/000640 175 77 R"=H; R 4 =F; R'=CH 3 62% 'H NMR (400MHz, CDCI 3 ) 6: 7.07 (1H, m), 6.83 (2H, m), 2.97 (2H, t), 2.78 (2H, m) 2.27 (3H, s) ppm; LRMS APCI m/z 154 [M+H]* 78 R 4 =F; Rb=H; Rb=CF 3 53% 1H NMR (400MHz, CDC13) 8: 7.44-7.26 (1H, m), 7.09-6.86 (2H, m), 2.98-2.84 (2H, t) 2.72-2.84 (2H, t) ppm; LRMS APCI m/z 208 [M+H]* 79 R3=CH 3 ; R 4 = CH 3 ; R'= CH 3 62% 1 H NMR (400MHz, CDC13) 8: 6.98 (2H, m), 2.95 (2H, m), 2.77 (2H, m), 2.25 (3H, s), 2.19 (6H, s) ppm; LRMS APCI m/z 164 [M+H]* Preparation 79: compound was purified by use of sulfonic acid functionalised lanterns. Preparation 80 5 2-(4-Chloro-phenyl)-N-ethyl-acetamide H N CH3 C1 A mixture of 4-chlorophenyl acetic acid (1g, 5.88mmol), ethylamine (2M in tetrahydrofuran, 5.88mL, 11.76mmol), 1-hydroxybenzotriazole hydrate (90mg, 5.88mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride 10 (1.13g, 5.88mmol), and triethylamine (1.78g, 17.64mmol) in dichloromethane (30mL) was stirred at room temperature for 18 hours. The mixture was then diluted with 1M sodium hydroxide solution (30mL) and the aqueous layer was extracted with dichloromethane (30mL). The combined organic solution was washed with 1 M hydrochloric acid and brine, dried over magnesium sulfate and 15 concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with dichloromethane:methanol, 100:0 to 90:10, to afford the title compound as a colourless solid in 37% yield, 443mg.

WO 2005/090287 PCT/IB2005/000640 176 'H NMR (400MHz, CDCl 3 ) 8: 7.31-7.28 (2H, m), 7.27-7.24 (2H, m), 3.45 (2H, s), 3.18 (2H, m), 1.08 (3H, t) ppm; LRMS APCI m/z 198 [M+H]* Preparation 81 5 [2-(4-Chloro-phenyl)-ethyl]-ethyl-amine hydrochloride H N CH CIC A mixture of 2-(4-chloro-phenyl)-N-ethyl-acetamide (preparation 80), (437mg, 2.22mmol) and borane tetrahydrofuran complex (1M, 8.88mL, 8.88mmol) in 10 tetrahydrofuran was heated under reflux for 18 hours. The cooled reaction mixture was then diluted with methanol (5mL) and 12M hydrochloric acid (2mL) and the re-heated to reflux for a further hour. The mixture was cooled to room temperature and concentrated in vacuo. Trituration of the residue with ethyl acetate afforded the title compound as a colourless solid in 99% yield, 403mg. 15 1H NMR (400MHz, CDCI 3 ) 5: 7.35 (2H, m), 7.27 (2H, n), 3.22 (2H, m), 3.05 (2H, q), 2.97 (2H, m), 1.29 (3H, t) ppm; LRMS APCI m/z 184 [M+H]* Preparation 82 2-(4-Methylsulfanyl-phenyl)-ethylamine

NH

2 20 H 3 C A solution of 4 -(methylthio)phenylacetonitrile (828mg, 5.08mmol) in tetrahydrofuran (1OmL) was added dropwise to lithium aluminium hydride (1M in tetrahydrofuran, 5.6mL, 5.6mmol) and the mixture was stirred for 1 hour at 0*C. Further lithium aluminium hydride (1M in tetrahydrofuran, 5.6mL, 5.6mmol) WO 2005/090287 PCT/IB2005/000640 177 was added and the mixture was stirred at room temperature for 18 hours then heated under reflux for 1 hour. The reaction mixture was cooled to O*C, 1M sodium hydroxide solution (3mL) was added dropwise, and stirring continued for a further hour. The mixture was then filtered through Celite*, washing 5 through with ethyl acetate, and the filtrate was washed with 1M sodium hydroxide solution. The organic solution was then loaded onto an Isolute* SCX cartridge, washed with methanol and eluted with 1M ammonia in methanol. The relevant fractions were concentrated in vacuo and the residue was purified by column chromatography on silica gel, eluting with 10 dichloromethane:methanol:0.88 ammonia, 100:0:0 to 95:5:0.5, to afford the title compound as a yellow oil in 18% yield, 154mg. 'H NMR (400MHz, CDCl 3 ) 8: 7.20 (2H, m), 7.14 (2H, m), 2.84 (2H, m), 2.71 (2H, m), 2.43 (3H, s) ppm; LRMS APCI m/z 168 [M+H]* 15 Preparation 83 (4-Hydroxy-3-methyl-phenyl)-acetonitrile

CH

3 OH Boron tribromide (1M in dichloromethane, 6.2mL, 6.2mmol) was added to a solution of 4-methoxy-3-methylphenylacetonitrile (0.2g, 1.24mmol) in 20 dichloromethane (10mL), cooled to -78 0 C. The reaction mixture was stirred at this temperature for 1 hour and then at room temperature for 2 hours. The mixture was then re-cooled to -78 0 C, diluted with sodium hydrogen carbonate solution and allowed to warm to room temperature. The organic layer was separated, washed with brine, dried over sodium sulfate and concentrated in 25 vacuo to afford the title compound as a white solid in 87% yield, 0.16g. 'H NMR (400MHz, CDC13) 8: 7.07 (1H, s), 7.00 (1H, d), 6.76 (1H, d), 3.65 (2H, s), 2.25 (3H, s) ppm; LRMS APCI m/z 146 [M-H]~ Preparation 84 30 (4-Hydroxy-2,5-dimethyl-phenyl)-acetonitrile WO 2005/090287 PCT/IB2005/000640 178

CH

3 OH

CH

3 The title compound was prepared from (4-methoxy-2,5-dimethylphenyl) acetonitrile using a similar method to that of preparation 83, as a colourless 5 solid in 60% yield. H NMR (400MHz, CDCl 3 ) : 6.98 (1H, s), 6.60 (1H, s), 3.66 (2H, s), 2.25 (3H, s), 2.13 (3H, s) ppm; LRMS APCI m/z 160 [M-H]~ Preparation 85 10 (4-Hydroxy-2,3-dimethyl-phenyl)-acetonitrile

CH

3 CH OH The title compound was prepared from (4-methoxy-2,3-dimethyl-phenyl) acetonitrile using a similar method to that of preparation 83, as a colourless solid in 94% yield. 15 1 H NMR (400MHz, CDCl 3 ) 6: 7.03 (1H, d), 6.64 (1H, d), 3.62 (2H, s), 2.24 (3H, s), 2.20 (3H, s) ppm; LRMS APCI m/z 160 [M-H]~ Preparation 86 2-(4-Methoxy-2,5-dimethyl-phenyl)-ethylamine 20

CH

3

H

2 N 0,CH 3

CH

3 WO 2005/090287 PCT/IB2005/000640 179 A mixture of (4-methoxy-2,5-dimethyl-phenyl)-acetonitrile (200mg, 1.14mmol) and Raney* nickel (50mg) in 2M methanolic ammonia (10mL) was stirred under 60psi of hydrogen gas at room temperature for 18 hours. Tic analysis showed that not all of the starting material had been consumed and so further Raney* 5 nickel (50mg) in 2M methanolic ammonia (10mL) was added. The reaction mixture was stirred under 60psi of hydrogen gas for an additional 18 hours at room temperature and was then filtered through Arbocel*. The filtrate was concentrated in vacuo and the residue was purified by column chromatography on silica gel, eluting with dichloromethane:methanol:0.88 ammonia, 100:0:0 to 10 90:10:1 to afford the title product as a pale brown solid in 38% yield, 98mg. 'H NMR (400MHz, CDCl 3 ) 8: 6.87 (1H, s), 6.68 (1H, s), 3.77 (3H, s), 2.80 (2H, m), 2.69 (2H, m), 2.28 (3H, s), 2.10 (3H, s) ppm; LRMS APCI m/z 180 [M+H]* Preparation 87 15 2-(4-Methoxy-2,3-dimethyl-phenyl)-ethylam ne

H

2 N .CH3

H

3 C O

CH

3 The title compound was prepared from (4-methoxy-2,3-dimethyl-phenyl) acetonitrile, using a similar method to that of preparation 86, as a clear oil in 93% yield. 20 1 H NMR (400MHz, CDCl 3 ) 8: 6.96 (1H, d), 6.66 (1H, d), 3.80 (3H, s), 2.96-2.84 (2H, m), 2.81-2.73 (2H, m), 2.22 (3H, s), 2.17 (3H, s), 1.63 (2H, s) ppm; LRMS APCI m/z 180 [M+H]* Preparation 88 25 4-(2-Amino-ethyl)-2-methyl-phenoI

H

2 N OH

CH

3 WO 2005/090287 PCT/IB2005/000640 180 The title compound was prepared from (4-hydroxy-3-methylphenyl)acetonitrile (preparation 83), using a similar method to that of preparation 86, as a clear oil in 85% yield. H NMR (400MHz, CDCl 3 ) 5: 6.90 (1H, s), 6.82 (1H, d), 6.65 (1H, d), 2.83-2.79 5 (2H, m), 2.61 (2H, m), 2.15 (3H, s) ppm; LRMS APCI m/z 152 [M+H]* Preparation 89 4-(2-Amino-ethyl)-2,5-dimethyl-phenol

CH

3

H

2 N OH

CH

3 10 The title compound was prepared from (4-hydroxy-2,5-dimethyl-phenyl) acetonitrile (preparation 84), using a similar method to that of preparation 86, as a solid in 73% yield. 1 H NMR (400MHz, CDCl 3 ) 8: 6.81 (1H, s), 6.54 (1H, s), 2.79-2.64 (4H, m), 2.19 (3H, s), 2.11 (3H, s) ppm; LRMS APCI m/z 166 [M+H]* 15 Preparation 90 4-(2-Amino-ethyl)-2,3-dimethyl-phenol

CH

3

H

2 N

CH

3 OH The title compound was prepared from (4-hydroxy-2,3-dimethyl-phenyl) 20 acetonitrile (preparation 85) using a similar method to that of preparation 86, as a colourless solid in 95% yield. 'H NMR (400MHz, CDCl 3 ) 5: 6.78 (1H, d), 6.55 (1H, d), 2.75-2.68 (4H, m), 2.19 (3H, s), 2.12 (3H, s) ppm; LRMS APCI m/z 166 [M+H]* WO 2005/090287 PCT/IB2005/000640 181 Preparation 91 2-(2,3-Dimethyl-phenyl)-ethylamine H2N

CH

3

H

3 C A mixture of 2,3-dimethylphenylacetonitrile (J. Org Chem, 51(26), 5157-60; 5 1986), (190mg, 1.31mmol) and Raney* nickel (100mg) in 2M methanolic ammonia (5mL) was stirred under 50psi of hydrogen gas for 4 days. The mixture was then filtered through Arbocel* and concentrated in vacuo to afford the title compound as a solid in 66% yield, 130mg. H NMR (400MHz, CDCl 3 ) 5: 7.02-6.94 (3H, m), 2.26-2.13 (10H, m) ppm; LRMS 10 ESI m/z 150 [M+H]* Preparation 92 2-(2,3-Dichloro-phenyl)-ethylamine

H

2 N CI CI 15 A solution of 2,3-dichlorophenylacetonitrile (0.5g, 2.7mmol) in diethyl ether (5mL) was added to an ice-cold solution of lithium aluminium hydride (1M in diethyl ether, 2.7mL, 2.7mmol) and aluminium trichloride (359mg, 2.7mmol). The mixture was stirred at room temperature 2.5 hours and was then quenched with 1M sodium hydroxide solution (5mL). The mixture was stirred for a further 20 30 minutes and filtered through Celite*. The layers of the filtrate were separated and the organic solution was concentrated in vacuo. Purification of the residue by column chromatography on silica gel, eluting with dichloromethane:methanol:0.88 ammonia, 100:0:0 to 95:5:0.5 afforded the title compound as a clear oil in 26% yield, 135mg. 25 'H NMR (400MHz, CDCl) 8: 7.38 (1H, dd), 7.27-7.19 (2H, m), 2.95 (2H, m), 2.87 (2H, m) ppm; LRMS APCI m/z 190 [M+HJ* WO 2005/090287 PCT/IB2005/000640 182 Preparation 93 2-(5-Chloro-2-fluoro-phenyl)-ethylamine

H

2 N CI F 5 Sodium borohydride (1.73g, 45.51 mmol) was added portionwise to a solution of 5-chloro-2-fluorophenylacetonitrile (1.04g, 6.15mmol) and cobalt (II) chloride hexahydrate (2.18g, 9.22mmol) in methanol (30mL) and the mixture was stirred at room temperature for 3 hours. The suspension was then filtered though Celite, concentrated in vacuo and the residue was partitioned between 1M 10 hydrochloric acid (40mL) and dichloromethane (40mL). The aqueous phase was separated, basified to pH 11 with 1 M ammonia solution and extracted with dichloromethane (2x4OmL). The combined organic solution was washed with brine (30mL), dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with 15 dichloromethane:methanol:0.88 ammonia, 100:0:0 to 98:2:0.2, to afford the title compound as a yellow oil in 33% yield, 350mg. H NMR (400MHz, CDCl 3 ) 8: 7.28 (1H, m), 7.22 (1H, in), 7.05 (1H, m), 2.85 (2H, m), 2.77 (2H, m) ppm; LRMS APCI m/z 174 [M+H]* 20 Preparation 94 2-(2-Chloro-4-fluoro-phenyl)-ethylamine

H

2 N CI F The title compound was prepared from 2-chloro-4-fluorophenylacetonitrile, using a similar method to that of preparation 93, as a light brown oil in 46% 25 yield. 1 H NMR (400MHz, CDCl 3 ) 6: 7.30 (1H, dd), 7.17 (1H, dd), 6.99 (1H, m), 2.86 (4H, m) ppm; LRMS APCI m/z 174 [M+H]* WO 2005/090287 PCT/IB2005/000640 183 Preparation 95 2-(4-Chloro-2-fluoro-phenyl)-ethylamine

H

2 NC F C1 5 The title compound was prepared from 4-chloro-2-fluorophenylacetonitrile, using a similar method to that of preparation 93. The crude compound was purified using an Isco SCX* cartridge, eluting with methanol followed by 1 M methanolic ammonia. The appropriate fractions were concentrated in vacuo and the residue was further purified by column chromatography on silica gel, 10 eluting with dichloromethane:methanol:0.88 ammonia, 95:5:0.3 to afford the title compound as a pale yellow oil in 29% yield. 'H NMR (400MHz, CDC 3 ) 8: 7.30 (1H, dd), 7.17 (1H, dd), 6.99 (1H, dt), 2.86 (4H, m) ppm; LRMS APCI m/z 174 [M+H]+ 15 Preparation 96 (2,3-Dihydro-benzofuran-2-yl)-methanol 0 OH A solution of meta-chloroperbenzoic acid (96.4g, 335mmol) in dichloromethane (500mL) was added to an ice-cold solution of 2-allylphenol (30g, 224mmol) in 20 dichloromethane (1 L) and the mixture was stirred at 0"C for 30 minutes and at room temperature for 18 hours. The reaction mixture was then re-cooled to 0"C, quenched with 2M sodium hydroxide solution (700mL) and stirred for 30 minutes. The organic layer was then separated, dried over magnesium sulfate and concentrated in vacuo to give a yellow oil. The oil was 25 purified by HPLC using a Chiralpak AD 2 50*4.6mm column and hexane:isopropanol (90:10) as the eluant, to afford the title compound. 'H NMR (400MHz, CDC1 3 ) 6: 7.20-7.10 (2H, m), 6.85 (IH, m), 6.78 (IH, n), 4.90 (1H, m), 3.86 (1H, m), 3.70 (1H, m), 3.30-3.20 (1H, n) 3.10 (1H, in) ppm WO 2005/090287 PCT/IB2005/000640 184 Preparation 97 2,3-Dihydro-1-benzofuran-2-ylmethyl 4-methyl benzenes u Ifonate 0 0 O-S CH 3 IF& 5 p-Toluenesulphonyl chloride (26.7g, 140mmol) was added to a solution of (2,3 dihydro-benzofuran-2-yl)-methanol (preparation 96) (21g, 140mmol) in pyridine (400mL) and the mixture was stirred at room temperature for 4 days. The reaction mixture was then concentrated in vacuo and the residue was 10 azeotroped with toluene, diluted with ethyl acetate (500mL) and washed with 2M hydrochloric acid (2x300mL). The organic solution was dried over magnesium sulfate and concentrated in vacuo to give a brown oil. Trituration of the oil in cyclohexane then afforded the title compound as a white solid in 79% yield, 33.5g. 15 LRMS APCI m/z 305 [M+H]* Preparation 98 2-Ethyl-2,3-dihyd ro-benzofu ran

CH

3 20 Methyl lithium (1.6M in diethyl ether, 313mL, 500mmol) was added to a solution of copper (1) iodide (47.6g, 250mmol) in diethyl ether (750mL) at -70 0 C. The solution was then allowed to warm to -10C and was stirred for 30 minutes. The mixture was then added to a solution of 2,3-dihydro-1 benzofuran-2-ylmethyl 4-methylbenzenesulfonate (preparation 97) (15.2g, 25 50mmol) in diethyl ether (500mL) and the reaction mixture was stirred at -40 0 C for 1 hour and at room temperature for 2 hours. The mixture was then cooled to -700C and quenched with 10% ammonium chloride solution (750mL) and 2M hydrochloric acid (50mL), diluted with 0.88 ammonia (1OOmL) and then stirred WO 2005/090287 PCT/IB2005/000640 185 for 18 hours. The reaction mixture was extracted with diethyl ether (3x500mL) and the organic solution was dried over magnesium sulfate and concentrated in vacuo to afford the title compound as a brown oil in 98% yield, 7.25g. 5 Preparation 99 (+) and (-) 5-Bromo-2-ethyl-2,3-dihydro-benzofuran Br 0

CH

3 N-Bromosuccinimide (8.66g, 48.6mmol) was added to a solution of 2-ethyl-2,3 10 dihydro-benzofuran (preparation 98) in dichloromethane (70mL) and the mixture was stirred at room temperature for 18 hours. The mixture was then diluted with dichloromethane (200mL) and washed with water (200mL) and sodium meta-bisulphite (200mL). The organic solution was dried over magnesium sulfate and concentrated in vacuo to give a yellow oil that was 15 purified by HPLC using a Chiralcel OJ 250*20mm column and hexane:isopropanol (95:5) as the eluant to afford the first enantiomer of the title compound. Further elution provided the second isomer of the title compound, 2.95g. 'H NMR (400MHz, CDC1 3 ) 8: 7.24 (1H, m), 7.18 (LH, m), 6.62 (1H, d), 4.75 (1H, m), 20 3.30-3.20 (IH, m), 2.92-2.80 (IH, m), 1.77-1.88 (1H, m), 1.75-1.65 (1H, m) 1.00 (3H, m) ppm Preparation 100 di-tert-Butyl [3-(2-ethyl-2,3-dihydro-1 -benzofuran-5 25 yl)propyl]imidodicarbonate WO 2005/090287 PCT/IB2005/000640 186 CH 0

H

3 C 0 N H3C O

OCH

3

H

3 C

CH

3

CH

3 N,N-Bis-Boc-N-allylamine (2.99g, 11.6mmol) was azeotroped with toluene (2x5OmL) then dissolved in tetrahydrofuran (12mL). The solution was cooled to 5 Q 0 C, 9-borabicyclo[3.3.1]nonane dimer (0.5M in tetrahydrofuran, 46.5mL, 23.2mmol) was added and the mixture was stirred at 00C for 3 hours. A mixture of 5-bromo-2-ethyl-2,3-dihyd ro-benzofuran (preparation 98, enantiomer 2), (2.9g, 12.8mmol), tripotassium phosphate (7.7mL, 23.2mmol) and [1,1' bis(diphenylphosphino)ferrocene]palladium(ll) chloride (4.74mg, 0.58mmol) in 10 N,N-dimethylformamide (12mL) was added and the reaction mixture was stirred at room temperature for 18 hours. The reaction was then quenched with 2M sodium hydroxide solution (30mL) and water (1OmL) and stirred for 1 hour at room temperature. The mixture was then extracted with diethyl ether, dried over magnesium sulfate and concentrated in vacuo. The residue was suspended in 15 ethyl acetate:petroleum ether, 25:75, filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with ethyl acetate:petroleum ether, 7:93, to afford the title compound as a clear oil in 46% yield, 2.15g. LRMS ESI m/z 428 [M+Na]* 20 Preparation 101 3-(2-Ethyl -2,3-d i hydro-benzofu ran-5-yl)-propylam ine hydrochloride

H

2 N CH . HCICH WO 2005/090287 PCT/IB2005/000640 187 A solution of di-tert-butyl [3-(2-ethyl-2,3-dihydro-1 -benzofuran-5 I)propyl]imidodicarbonate (preparation 100), (2.19g, 5.4mmol) in hydrochloric acid (4M in dioxane, 20mL) was stirred at room temperature for 18 hours. The reaction mixture was then concentrated in vacuo to afford the title compound in 5 quantitative yield. 'H NMR (400MHz, CDC1 3 ) 8: 7.00-6.85 (2H, m), 6.60 (lH, d), 4.75 (1H, m), 3.20 (LH, m), 2.97 (2H, m), 2.80 (1H, m), 2.60 (2H, m), 2.10-1.95 (2H, m), 1.90-1.60 (2H, m) 1.00 (3H, m) ppm 10 Preparation 102 tert-Butyl (2-{4-[(butylam ino)carbonyl] phenyl}ethyl)carbamate H

H

3 C 0 N H c~ C H CH3 O N , CH3 0 A mixture of 4-{2-[(ter-butoxycarbonyl)amino]ethyl}benzoic acid (22.2g, 15 83.6mmol) (EP0836839, p60) carbonydiimidazole (21.36g, 131.7mmol), and N,N-diisopropylethylamine (20mL, 115.1mmol) in dichloromethane (600mL) was stirred at room temperature for 2 hours. "Butylamine (10mL, 101.18mmol) was then added and the mixture was stirred for a further 18 hours at room temperature. The reaction mixture was concentrated in vacuo and the residue 20 was dissolved in ethyl acetate and washed with 10% citric acid (2x5OmL), saturated sodium hydrogen carbonate solution (200mL), water (200mL) and brine (200mL). The organic solution was dried over sodium sulfate and concentrated in vacuo to give a cream powder. The powder was purified by column chromatography on silica gel, eluting with dichloromethane:methanol, 25 99:1, to afford the title compound in 65% yield, 17.5g. LRMS Cl m/z 338.3 [M+NH 4 ]*, m.p.= 118'C Preparation 103 4-(2-Aminoethyl)-N-butylbenzamide hydrochloride WO 2005/090287 PCT/IB2005/000640 188

H

2 N H .HCI N CH 3 0 The title compound was prepared from tert-butyl(2-{4 [(butylamino)carbonyl]phenyl}ethyl)carbamate (preparation 102), using a similar method to preparation 101, as white powder in 84% yield. 5 1H NMR (400MHz, DMSO-d 6 ) 5: 8.38 (1H, m), 8.04 (3H, m), 7.78 (2H, d), 7.34 (2H, d), 3.24 (2H, m), 3.06 (2H, m), 2.82 (2H, m), 1.46 (2H, m), 1.28 (2H, m), 0.86 (3H, t) ppm LRMS Cl m/z 221.2 [M+H]* 10 Preparation 104 [4-(3-Pyrrolidin-1 -yI-propoxy)-phenyl]-acetonitrile N N A mixture of 1-(3-chloropropyl)pyrrolidine (J. Am. Chem. Soc., 77, 2270; 1955) (133g, 0.9mol), 4-hydroxybenzonitrile (100g, 0.75mol) and caesium carbonate 15 (256g, 0.78mol) in acetonitrile (1L) was stirred at 45 0 C for 18 hours. The reaction mixture was then concentrated in vacuo and the residue was partitioned between ethyl acetate (800mL) and water (800mL). The aqueous layer was separated and extracted with ethyl acetate (800mL) and the combined organic solution was washed with water (500mL) and extracted with 20 2M hydrochloric acid (2x600mL). The acidic solution was basified to pH8-9 with 40% potassium hydroxide solution and extracted with ethyl acetate (800mL). The aqueous solution was then further basified to pH10-11 using 40% potassium hydroxide solution and extracted with ethyl acetate (800mL). The combined organic solution was dried over sodium sulfate, filtered through a pad 25 of silica and concentrated in vacuo to afford the title compound as a red oil in 79% yield, 150g.

WO 2005/090287 PCT/IB2005/000640 189 'H NMR (400MHz, CDC13) 8: 7.24 (2H, d), 6.85 (2H, d), 4.09-3.89 (2H, m), 3.75 (2H, s), 2.71-2.36 (6H, in), 2.14-1.93 (2H, m), 1.89-1.65 (4H, m) ppm; LRMS APCI m/z 245 [M+H]+ 5 Preparation 105 2-[4-(3-Pyrrolidin-I -yl-propoxy)-phenyl] -ethylami ne

NH

2 A mixture of [4-(3-pyrrolidin-1-yl-propoxy)-phenyl]-acetonitrile (preparation 104), (1g, 4.1mmol) and Raney* nickel (100mg) in 2M methanolic ammonia (35mL) 10 was stirred under 60psi of hydrogen gas at 50'C for 6 hours. Tic analysis showed that not all of the starting material had been consumed and so further Raney* nickel (200mg) was added to the reaction mixture and heating continued for 5 hours. Tic analysis again showed that starting material was still present and so additional Raney* nickel (200mg) was added and the mixture 15 was stirred at 500C for 3 hours. The reaction mixture was then filtered through Arbocel* and was concentrated in vacuo to give a yellow oil. The oil was purified by column chromatography using a 4g RediSep* silica cartridge, eluting with dichloromethane:methanol:0.88 ammonia, 85:15:1.5 to 80:20:2, to afford the title compound in 16% yield, 160mg. 20 1 H NMR (400MHz, CDCl 3 ) 6: 7.10 (2H, d), 6.81 (2H, d), 4.10-4.00 (2H, m), 3.05 2.65 (10H, m), 2.25-2.14 (2H, m), 2.05-1.95 (4H, m) ppm; LRMS APCI m/z 249 [M+H]+ Preparation 106 25 [2-(3-Pyrrolidin-1-yl-propoxy)-phenyl]-acetonitrile WO 2005/090287 PCT/IB2005/000640 190 N The title compound was prepared from 2-hydroxy-benzeneacetonitrile (J. Org. Chem.; 66, 3435; 2001) and 1-(3-chloropropyl)pyrrolidine, using a method similar to that of preparation 104, as a pale brown gum in 58% yield. 5 1H NMR (400MHz, CD 3 0D) 5: 7.33-7.25 (2H, m), 7.02-6.90 (2H, m), 4.12-4.09 (2H, m), 3.75 (2H, s), 2.76-2.72 (2H, m), 2.62-2.57 (4H, m), 2.09-2.02 (2H, m), 1.87-1.78 (4H, m); LRMS APCI m/z 245 [M+H]* Preparation 107 10 2-[2-(3-Pyrrolidin-1-yl-propoxy)-phenyl]-ethylamine

NH

2 The title compound was prepared from the product of preparation 106, using a method similar to that of preparation 69, in 48% yield. 1 H NMR (400MHz, CD 3 0D) 5: 7.19-7.16 (2H, m), 6.92 (1H, m), 6.86 (1H, m), 15 4.06-4.02 (2H, m), 2.87-2.83 (2H, m), 2.80-2.75 (2H, m), 2.71-2.67 (2H, m), 2.62-2.55 (4H, m), 2.07-2.00 (2H, m), 1.86-1.81 (4H, m); LRMS APCI m/z 249 [M+H]* Preparation 108 20 {2-[3-(3-Pyrrolidin-1-ylpropoxy)phenyl]ethyl}amine

NH

2 WO 2005/090287 PCT/IB2005/000640 191 The title compound was prepared from [3-(3-pyrrolidin-1 ylpropoxy)phenyl]acetonitrile (170mg, 0.70mmol), using a method similar to that of preparation 69. The crude compound was then further purified by column chromatography using a 4g RediSep* silica cartridge, eluting with 5 dichloromethane:methanol:0.88 ammonia, 100:0:0 to 80:20:2, to afford the desired product in 30% yield. H NMR (400MHz, CD 3 0D) 5: 7.23-7.19 (1H, m), 6.81-6.78 (3H, m), 4.04-3.98 (2H, m), 2.99-2.95 (2H, m), 2.81-2.77 (2H, m), 2.74-2.70 (2H, m), 2.66-2.62 (4H, m), 2.05-1.98 (2H, m), 1.87-1.82 (4H, m); LRMS APCI m/z 249 [M+H]+ 10 Preparation 109 3-{2-[(2R)-(tert-Butyl-d imethyl -si lanyloxy)-2-(4-hydroxy-3-hyd roxymethyl phenyl)-ethylamino]-2-methyl-propyl}-N-(3-pyrrolidin-1 -yl-propyl) -benzamide OTBDMS O H N H N 11111:H 3 C CH 3 HO 15 HO 1-(3-Aminopropyl)pyrrolidine (38pL, 0.30mmol) was added to a mixture of 1-(3 dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (79mg, 0.41mmol), 3 {2-[(2R)-2-(tert-butyldimethylsilanyloxy)-2-(4-hydroxy-3-hydroxy methyl phenyl)ethylamino]-2-methylpropyl}benzoic acid (preparation 37) (130mg, 20 0.28mmol), 1-hydroxybenzotriazole hydrate (40mg, 0.29mmol) and N,N diisopropylethylamine (210pL, 1.49mmol) in N,N-dimethylformamide (4mL). The resulting solution was stirred for 9 days at room temperature, after which time, tic analysis showed that starting material still remained. Further 1-(3 dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (79mg, 0.41mmol), 1 25 hydroxybenzotriazole hydrate (40mg, 0.29mmol) and N,N-diisopropylethylamine (210pl, 1.49mmol) were then added and stirring continued for 2 days at room temperature. The solvent was removed in vacuo and the residue was partitioned between ethyl acetate (25mL) and saturated sodium hydrogen WO 2005/090287 PCT/IB2005/000640 192 carbonate solution (20mL). The organic solution was separated, dried (sodium sulfate) and concentrated in vacuo to give an orange oil. The oil was purified by flash column chromatography on silica gel eluting with dichloromethane:methanol:0.88 ammonia, 100:0:0 to 75:25:2 to afford the title 5 compound as a glass in 43% yield, 70mg H NMR (400MHz, CD 3 0D) 8: 7.48 (2H, m) 7.40- 7.31 (2H, m), 7.27 (1H, m), 7.07 (1H, dd), 6.74 (1H, d), 4.69 (1H, m), 4.64 (2H, m), 3.43 (2H, m), 2.90- 2.50 (1OH, m), 1.90-1.70 (6H, m), 1.11 (3H, s), 1.07 (3H, s), 0.79 (9H, s), -0.02 (3H, s), -0.21 (3H, s) ppm; LRMS APCI m/z 584 [M+H] 10 Preparation 110 3-[2-({(2R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3 (hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]-N-[2-(4 chlorophenyl)ethyl]-N-ethylbenzamide OTBDMS O H N H O H 3 C 3C HC cH 3 c 15 HO The title compound was prepared from 3-{2-[(2R)-2-(tert butyldimethylsilanyloxy)-2-(4-hydroxy-3-hydroxy methyl-phenyl)ethylamino]-2 methylpropyl}benzoic acid (preparation 37) and [2-(4-chloro-phenyl)-ethyl] ethyl-amine hydrochloride (preparation 81), using a similar method to that of 20 preparation 109, as a white solid in 43% yield. 1 H NMR (400MHz, CD 3 0D) 7.90-6.90 (1OH, m), 6.72 (1H, d), 4.69 (1H, m), 4.63 (2H, m), 3.70 (1H, m), 3.61 (1H, m), 3.49 (1H, m), 3.10 (1H, m), 3.03-2.58 (6H, m), 1.29-1.26, 1.07-1.01 (9H, 2xm), 0.82 (9H, s), 0.01 (3H, s), -0.18 (3H, s) ppm; LRMS APCI m/z 639 [M+H]* 25 Preparation 111 WO 2005/090287 PCT/IB2005/000640 193 3-[2-({(2R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-(hydroxyl methyl)phenyl]ethyljamino)-2-methylpropyl]-N-(2-pyrrolidin-1 -ylethyl) benzamide OTBDMS O H NH H3C CH 3 N HO HO 5 1-(2-Aminoethyl)pyrrolidine (83pL, 0.63mmol) was added to a mixture of 1-(3 dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (122mg, 0.63mmol), 3 {2-[(2R)-2-(tert-butyldimethylsilanyloxy)-2-(4-hydroxy-3-hydroxy methyl phenyl)ethylamino]-2-methylpropyl}benzoic acid (preparation 37) (200mg, 0.42mmol), 1-hydroxybenzotriazole hydrate (63mg, 0.47mmol) and N,N 10 diisopropylethylamine (88piL, 0.63mmol) in N,N-dimethylformamide (5mL). The resulting solution was stirred for 18 hours at room temperature. The solvent was removed in vacuo and the residue was partitioned between ethyl acetate (50mL) and saturated sodium hydrogen carbonate solution (10mL). The aqueous layer was separated and re-extracted with dichloromethane (30mL), 15 and the combined organic solution was dried (sodium sulfate) and concentrated in vacuo to give a yellow oil. The oil was purified by flash column chromatography on silica gel eluting with dichloromethane:methanol:0.88 ammonia, 100:0:0 to 75:25:2 to afford the title compound as a pale yellow solid. "H NMR (400MHz, CD 3 0D) 6: 7.69 (2H, m) 7.40-7.31 (2H, m), 7.26 (1H, m), 20 7.14-7.03 (1H, dd), 6.85 (1H, d), 4.69 (1H, m), 4.62 (2H, m), 3.58 (2H, m), 2.89 2.59 (10H, m), 1.82-1.79 (4H, m), 1.12 (3H, s), 1.07 (3H, s), 0.79 (9H, s), -0.01 (3H, s), -0.21 (3H, s) ppm; LRMS APCI m/z 570 [M+H]H Preparations 112 to 138 25 The following compounds, of the general formula shown below were prepared by a similar method to that described for preparation 38, using 3-{2-[(2R)-2 (tert-butyldimethylsilanyloxy)-2-(4-hydroxy-3-hydroxymethyl-phenyl) WO 2005/090287 PCT/IB2005/000640 194 ethylamino]-2-methylpropyl}benzoic acid (preparation 37) and the appropriate amine starting material. The reactions were monitored by tic analysis and were stirred at room temperature for 18-72hours. OTBDMS O H HO 3 C CH 3 I ~ Q HO HC 5 HO No. Q1 Data Yield 112 CI 1-H NMR (400MHz, CD 3 0D) 5: 7.64 44% (2H, m) 7.37-7.28 (5H, m), 7.20 (1H, im), 7.08 (1H, m), 6.75 (1H, d), 4.72 Cl (1H, m), 4.65 (2H, m), 3.68 (2H, m), 3.30 (2H, m), 2.95-2.60 (4H, m), 1.12 (3H, s), 1.08 (3H, s), 0.80 (9H, s), -0.02 (3H, s), -0.19 (3H, s) ppm; LRMS APCI m/z 645 [M+H]* 113 1 H NMR (400MHz, CD 3 0D) 5: 7.65 16% (2H, m), 7.40-7.05 (8H, m), 6.75 (1H, m), 4.78-4.63 (3H, m), 3.46 (2H, m), 3.15- 2.70 (9H, m), 1.15 (3H, s), 1.11 (3H, s), 0.79 (9H, s), 0.01 (3H, s), -0.20 (3H, s) ppm; LRMS APCI m/z 603 [M+H]* WO 2005/090287 PCT/IB2005/000640 195 114 0 7H NMR (400MHz, CD 3 0D) 5: 7.75 22% NH (2H, m), 7.65 (2H, m), 7.40-7.25 N"- (5H, m), 7.09 (1H, m), 6.73 (1H, m), 4.75-4.62 (3H, m), 3.62 (2H, m),

CH

3 3.37 (2H, m), 3.02-2.62 (6H, m), 1.59 (2H, m), 1.41 (2H, m), 1.14 1.07 (6H, m), 0.97 (3H, t), 0.79 (9H, s), -0.01 to -0.21 (6H, m) ppm; LRMS APCI m/z 676 [M+H]+ 115 1 H NMR (400MHz, CD 3 0D) 6: 7.63 34% (2H, m), 7.25 (12H, m), 7.05 (1H, S m), 6.73 (1H, m), 4.68 (3H, m), 3.62 (2H, m), 3.13 (2H, m), 2.80 (4H, brm), 1.08 (6H, m), 0.80 (9H, s), -0.05 (3H, s). -0.21 (3H, s) ppm LRMS ESI m/z 685 [M+H]* 116 cl 'H NMR (400MHz, CD 3 0D) 5: 7.63 30%

H

3 C (2H, m), 7.40-7.20 (5H, m), 7.10 (1H, m), 6.75 (1H, m), 4.62 (3H, m), 3.59 (2H, m), 3.22 (2H, m), 2.92 C1 2.64 (4H, brm), 2.51 (3H, s), 1.10 (6H, m), 0.80 (9H, s), -0.02 (3H, s), 0.21 (3H, s) ppm; LRMS ESI m/z 659 [M+H]* WO 2005/090287 PCT/IB2005/000640 196 117 H NMR (400MHz, CD 3 0D) 8: 7.66 34% (2H, m), 7.34 (2H, m), 7.26 (1H, d), 7.07 (1H, m), 6.72 (1H, m), 4.69 (1H, m), 4.63 (2H, d), 3.39 (2H, t), 2.75 (3H, brm), 2.63 (1H, m), 1.81 (2H, m), 1.75-1.63 (3H, m), 1.52 (2H, m), 1.36 (1H, m), 1.28 (1H, m), 1.17-1.24 (2H, m), 1.11 (3H, s), 1.08 (3H, s), 1.03-0.92 (2H, m), 0.77 (9H, S), -0.05 (3H, s) -0.27 (3H, s) ppm LRMS ESI m/z 583 [M+H] * 118 1 H NMR (400MHz, CD 3 0D) 8: 7.65 38% (2H, m), 7.38-7.31 (4H, m), 7.27 (1H, d), 7.20 (2H, m), 7.06 (1H, dd), ct 6.72 (1H, d), 4.69 (1H, m), 4.63 (2H, d), 3.62 (2H, m), 3.07 (2H, t), 2.89 2.82 (2H, t), 2.79-2.71 (1H, m), 2.65 (1H, m), 1.10 (3H, s), 1.07 (3H, s), 0.78 (9H, s), -0.04 (3H, s) -0.21 (3H, s) ppm; LRMS ESI m/z 611 [M+H]* 119 1 H NMR (400MHz, CD 3 0D) 8: 7.66 37% (2H, m), 7.37-7.30 (2H, m), 7.26 (1H, m), 7.09-7.00 (1H, m), 6.72 (1H, d), 4.69 (1H, m), 4.63 (2H, d), 3.43-3.38 (2H, m), 2.83-2.89 (2H, m), 2.80-2.71 (1H, m), 2.61-2.65 (1H, m), 1.96 (3H, s), 1.68 (6H, m), 1.61 (6H, d), 1.42 (2H, m), 1.10 (3H, s), 1.07 (3H, s) 0.78 (9H, s), -0.04 (3H, s) -0.22 (3H, s) ppm; LRMS ESI m/z 635 [M+H]* WO 2005/090287 PCT/IB2005/000640 197 120 /H NMR (400MHz, CD 3 0D) 8: 8.26 24% (1H, m), 7.86 (1H, m), 7.74 (1H, m), 7.64 (2H, m), 7.53 (1H, m), 7.46 (IH, m), 7.41-7.31 (4H, m), 7.27 (1H, m), 7.06 (1H, dd), 6.73 (1H, m), 4.70 (1H, m), 4.63 (2H, d), 3.72 (2H, m), 3.40 (2H, t), 2.90-2.70 (3H, m), 2.64 (1H, m), 1.09 (3H, s), 1.07 (3H, s), 0.78 (9H, s), -0.03 (3H, s), -0.21 (3H, s) ppm; LRMS ESI mlz 627 [M+H]* 121 H C 1 H NMR (400MHz, CD 3 0D) 8: 7.67 40% (2H, m), 7.39-7.32 (2H, m), 7.27 N_. 1H, m), 7.07 (1H, dd), 6.98 (3H, m),

H

3 C 6.72 (1H, m), 4.70 (1H, m), 4.63 (2H, d), 3.46 (2H, t), 2.99 (2H, m), 2.87 (2H, m), 2.73 (1H, m), 2.66 (1H, m), 2.39 (6H, s), 1.11 (3H, s), 1.09 (3H, s), 0.79 (9H, s), -0.03 (3H, s), -0.21 (3H, s) ppm; LRMS ESI m/z 605 [M+H]* 122 N H NMR (400MHz, CD 3 0D) 8: 7.63 46% NS S CH (2H, m), 7.35 (2H, m), 7.27 (1H, m), 7.17 (4H, m), 7.06 (1H, dd) 6.72 (1H, m), 4.70 (1H, m), 4.63 (2H, d), 3.56 (2H, t), 2.87 (3H, m), 2.71 (2H, m), 2.64 (1H, m), 2.43 (3H, s), 1.09 (3H, s), 1.07 (3H, s), 0.78 (9H, s), 0.04 (3H, s), -0.22 (3H, s) ppm; LRMS ESI m/z 623 [M+H]* WO 2005/090287 PCT/IB2005/000640 198 123 F 'H NMR (400MHz, CD 3 OD) S: 7.62 61% N (2H, m), 7.34-7.27 (3H, m), 7.22 (2H, m), 7.03-7.09 (2H, m), 6.72 cl (1H, d), 4.69 (1H, m), 4.63 (2H, m), 3.59 (2H, m), 2.96 (2H, m), 2.71 (2H, m), 2.63 (2H, m), 1.09 (3H, s), 1.06 (3H, s), 0.78 (9H, s), -0.04 (3H, s), -0.21 (3H, s) ppm; LRMS APCI m/z 629 [M+H]* 124 C1 1 H NMR (400MHz, CD 3 0D) &: 7.62 60% N/F (2H, m), 7.34 (3H, m), 7.27 (1H, d), 7.18 (1H, m), 7.06 (1H, dd), 6.97 (1H, m), 6.72 (1H, d), 4.69 (1H, m), 4.63 (2H, m), 3.62 (2H, m), 3.04 (2H, t), 2.89-2.70 (3H, m), 2.61 (1H, m), 1.09 (3H, s), 1.07 (3H, s), 0.78 (9H, s), -0.04 (3H, s), -0.21 (3H, s) ppm; LRMS APCI m/z 629 [M+H]* 125 CH 3 1 H NMR (400MHz, CD 3 0D) 8: 7.54- 19% 7.75 (2H, m), 7.42-7.24 (3H, m), 7.17-7.04 (1H, m), 6.98-6.83 (1H, 0 dd), 6.79-6.64 (2H, m), 4.70 (1H, m),

CH

3

CH

3 4.63 (2H, d), 3.77 (3H, s), 3.51 (2H, t), 2.89-2.82 (4H, m), 2.79-2.71 (1H, m), 2.64 (1H, m), 2.33 (3H, s), 2.09 (3H, s), 1.07 (6H, s), 0.78 (9H, s), 0.03 (3H, s), -0.21 (3H, s) ppm; LRMS ESI m/z 635 [M+H]* WO 2005/090287 PCT/IB2005/000640 199 126 cl 1 H NMR (400MHz, CD 3 0D) 6: 7.62 67% C' (2H, m) 7.44-7.14 (6H, m), 7.08 (1H, d), 6.73 (1H, d), 4.71 (1H, m), 4.60 (2H, m), 3.68 (2H, m), 3.14 (2H, m), 2.93-2.58 (4H, m), 1.10 (3H, s), 1.07 (3H, s), 0.78 (9H, s), -0.04 (3H, s), 0.21 (3H, s) ppm; LRMS APCI m/z 645 [M+H]+ 127 CH 3 1 H NMR (400MHz, CD 3 0D) 6: 7.65 39% N CH 3 (2H, m) 7.37-7.31 (2H, m), 7.27 (1H, d), 7.06 (1H, dd), 6.97 (1H, d), 6.73 0 (1H, d), 6.68 (1H, d), 4.73-4.68 (1H,

CH

3 m), 4.60 (2H, m), 3.76 (3H, s), 3.49 (2H, m), 2.93-2.60 (6H, m), 2.28 (3H, s), 2.13 (3H, s), 1.10 (3H, s), 1.07 (3H, s), 0.78 (9H, s), -0.04 (3H, s), -0.21 (3H, s) ppm LRMS APCI m/z 635 [M+H]* 128 N H NMR (400MHz, CD 3 0D) 6: 7.67- 43% 7.62 (2H, m), 7.59-7.52 (4H, dd), 7.42-7.36 (2H, dd), 7.35-7.26 (6H, m), 7.05 (1H, dd), 6.71 (1H, dd), 4.67 (1H, dd), 4.60 (2H, dd), 3.61 (2H, t), 2.95 (2H, t), 2.83 (1H, dd), 2.70 (2H, dd), 2.60-2.65 (1H, m), 1.08 (3H, s), 1.06 (3H, s), 0.77 (9H, s), -0.05 (3H, s), -0.23 (3H, s) ppm; LRMS APCI m/z 653 [M+HJ+ WO 2005/090287 PCT/IB2005/000640 200 129 CH3 'H NMR (400MHz, CD 3 0D) 8: 7.65 46% (2H, m) 7.37-7.31 (2H, m), 7.27 (1H, d), 7.06 (1H, dd), 7.03 (1H, d), 6.96

H

3 C (1H, bs), 6.90 (1H, d), 6.72 (1H, d), 4.72-4.68 (1H, m), 4.60 (2H, m), 3.51 (2H, m), 2.91-2.84 (3H, m), 2.71 (2H, dd), 2.64 (1H, m), 2.33 (3H, s), 2.24 (3H, s), 1.10 (3H, s), 1.07 (3H, s), 0.78 (9H, s), -0.04 (3H, s), -0.22 (3H, s) ppm; LRMS APCI m/z 605 [M+H]+ 130 H NMR (400MHz, CD 3 0D) 8: 7.87- 35% N 7.80 (2H, m), 7.38-7.30 (2H, m), cl 7.27 (1H, d), 7.06 (1H, dd), 7.02

H

3 C 6.94 (3H, m), 6.72 (1H, d), 4.68 (1H, m), 4.60 (2H, m), 3.51 (2H, m), 2.94 (2H, m), 2.84 (1H, m), 2.71 (2H, dd), 2.61 (1H, m), 2.29 (3H, s), 2.27 (3H, s), 1.10 (3H, s), 1.07 (3H, s), 0.78 (9H, s), -0.04 (3H, s), -0.21 (3H, s) ppm; LRMS APCI m/z 605 [M+H]* 131 1 H NMR (400MHz, CDCI 3 ) S: 7.44- 45% 7.38 (2H, m), 7.33-7.20 (7H, m), 7.06 (1H, d), 6.88 (1H, s), 6.75 (1H, d), 6.13-6.09 (1H, m), 4.82-4.60 (2H, m), 4.58 (1H, t), 3.51-3.44 (2H, m), 2.84-2.55 (6H, m), 2.00-1.90 (2H, m), 1.04 (3H, s), 1.00 (3H, s), 0.79 (9H, s), -0.05 (3H, s), -0.21 (3H, s) ppm; LRMS APCI m/z 592 [M+H]+ WO 2005/090287 PCT/IB2005/000640 201 132 | 'H NMR (400MHz, CDCl 3 ) &: 7.44 45% (1H, d), 7.38 (1H, m), 7.32-7.22 (7H, m), 7.08 (1H, d), 6.88 (1H, s), 6.75 (1H, d), 6.14 (1H, m), 4.83-4.75 (2H, m), 4.59 (1H, t), 3.72-3.68 (2H, q), 2.92 (2H, t), 2.82-2.75 (1 H, m), 2.65 2.56 (3H, m), 1.03 (3H, s), 1.00 (3H, s), 0.79 (9H, s), -0.05 (3H, s), -0.20 (3H, s) ppm; LRMS APCI m/z 592 [M+H]+ 133 F F 'H NMR (400MHz, CDCI 3 ) 8: 7.51- 53% F 7.39 (6H, m), 7.27-7.23 (2H, m), N- 7.10 (1H, d), 6.89 (1H, s), 6.77-6.65 (1H, d), 6.16 (1H, m), 4.84-4.76 (2H, m), 4.62-4.58 (1H, t), 3.72-3.68 (2H, m), 2.99 (2H, t), 2.83-2.76 (1H, m), 2.66-2.58 (3H, m), 1.03 (3H, s), 1.00 (3H, s), 0.79 (9H, s), -0.04 (3H, s), 0.20 (3H, s) ppm; LRMS APCI m/z 645 [M+H]* 134 N 'H NMR (400MHz, CDCl 3 ) 8: 7.45 46% cl (1H, d), 7.39 (1H, m), 7.29-7.23 (2H, F m), 7.20-7.06 (4H, m), 6.90 (1H, s), 6.76 (1H, d), 6.19 (1H, m), 4.83-4.76 (2H, m), 4.59 (1H, t), 3.69-3.63 (2H, m), 2.99 (2H, m), 2.84-2.76 (1H, m), 2.66-2.60 (3H, m), 1.04 (3H, s), 1.01 (3H, s), 0.80 (9H, s), -0.04 (3H, s), 0.19 (3H, s) ppm; LRMS APCI m/z 629 [M+H]+ WO 2005/090287 PCT/IB2005/000640 202 135 H 3 C 1 H NMR (400MHz, CD 3 0D) 8: 7.73 44% (2H, m) 7.40-7.33 (2H, m), 7.26 (1H, N d), 7.11 (1H, bs), 7.07-7.04 (2H, dd),

CH

3 6.96 (1H, d), 6.71 (1H, d), 4.66 (2H, dd), 4.63 (2H, dd), 4.54 (2H, s), 2.83 (1H, t), 2.72 (2H, dd), 2.61 (1H, dd), 2.32 (3H, s), 2.26 (3H, s), 1.11 (3H, s), 1.08 (3H, s), 0.78 (9H, s), -0.06 (3H, s), -0.23 (3H, s) ppm; LRMS APCI m/z 591 [M+H]* 136 N 1H NMR (400MHz, CD 3 0D) 6: 7.69- 2% 7.58 (2H, m) 7.39-7.03 (5H, m), 6.90-6.68 (4H, m), 4.75-4.57 (3H, N m), 3.62-3.49 (2H, m), 3.18-3.07 (2H, m), 2.91-2.53 (10H, m), 2.05 1.90 (4H, m), 1.87-1.73 (2H, m), 1.11-1.06 (6H, m), 0.78 (9H, s), 0.05 (3H, s), -0.22 (3H, s) ppm; LRMS APCI m/z 691 [M+H]* 137 N 1 H NMR (400MHz, CD 3 0D) 8: 7.65- 78% 7.61 (2H, m), 7.34-7.30 (2H, m), o 7.26 (2H, m), 7.17-7.15 (2H, m) 7.06 NC] (1H, m), 6.93 (1H, m), 6.85 (1H, m), 6.73 (1H, m), 4.71-4.63 (3H, m), 4.06-4.02 (2H, m), 3.61-3.57 (2H, m), 2.96-2.58 (15H, m), 2.07-2.02 (2H, m), 1.84-1.79 (4H, m), 1.09 1.06 (6H, m), 0.79 (9H, s), -0.03 (3H, s), -0.21 (3H, s) ppm; LRMS APCI m/z 705 [M+H]* WO 2005/090287 PCT/IB2005/000640 203 138 H NMR (400MHz, CD 3 0D) 5: 7.63 56% (2H, m) 7.34-7.21 (3H, m), 7.17 (1H, m), 7.07 (1H, m), 6.79-6.65 (4H, m), 4.67-4.57 (3H, m), 3.95-3.92 (2H, N im), 3.57-3.53 (2H, m), 2.86-2.53 (12H, m), 1.98-1.85 (2H, m), 1.82 1.70 (4H, m), 1.04-1.01 (6H, m), 0.78 (9H, s), -0.02 (3H, s), -0.20 (3H, s) ppm Preparation 115: 2-(2-phenylsulfanyl-phenyl)-ethylamine can be prepared as described in Collection of Czechoslovak Chemical Communications, 54(7), 1995-2008; 1989 Preparation 116: appropriate fractions were concentrated in vacuo and the 5 residue was further purified by column chromatography on amino silica gel, eluting with ethyl acetate:pentane, 100:0 to 80:20, followed by dichloromethane:imethanol, 100:0 to 80:20. Preparation 139 10 Methyl 3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl) amino)-2-methyl propyl] benzoate OH O H N HO HC 3

CH

3 HO A mixture of 3-{2-[(2R)-2-(tert-butyldimethylsilanyloxy)-2-(4-hydroxy-3 hydroxymethyl-phenyl)ethylamino]-2-methylpropyl}benzoic acid methyl ester 15 (preparation 36), (4.Og, 8.21 mmol) and ammonium fluoride (3.04g, 82.Ommol) in methanol (20mL) and water (5mL) was heated at 40 0 C for 18 hours. The reaction mixture was then concentrated in vacuo and the residue was purified by column chromatography on silica gel, eluting with WO 2005/090287 PCT/IB2005/000640 204 dichloromethane:methanol: 0.88 ammonia, 100:0:0 to 90:10:0.1, to afford the title compound as a white foam in 81% yield, 2.42g. 'H NMR (400MHz, CD 3 0D) 6: 7.87 (2H, m), 7.40 (2H, m), 7.29 (1H, m), 7.09 (1H, dd), 6.72 (1H, d), 4.69-4.61 (3H, m), 3.90 (3H, s), 2.90-2.73 (4H, m), 1.08 5 (3H, s), 1.06 (3H, s) ppm; LRMS ESI m/z 374 [M+H]* Preparation 140 3-[2-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino) 2-methylpropyl]benzoic acid 10 OH H N N OH

H

3 C CH 3 HO 2LiCI HO A mixture of 3-{2-[2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino] 2-methyl-propyl}-benzoic acid methyl ester (preparation 139) (2.35g, 6.32mmol) and lithium hydroxide (303mg, 12.64mmol) in tetrahydrofuran (20mL) and water 15 (20mL) was stirred at room temperature for 3 days. The reaction mixture was then concentrated in vacuo and the residue was diluted with water and acidified with IM hydrochloric acid (12mL). The mixture was stirred for 2 hours at room temperature and was then concentrated in vacuo. The crude residue was used in subsequent reactions without further purification. 20 IH NMR (400MHz, CD 3 OD) 6: 7.87 (1H, m), 7.84 (1H, bs), 7.39-7.31 (3H, m), 7.19 (1H, dd), 6.79 (IH, d), 4.86 (1H, m), 4.66 (2H, s), 3.22-3.11 (2H, m), 3.02 (2H, m), 1.32 (6H, s) ppm; LRMS ESI m/z 360 [M+H]+ Preparation 141 25 3-[3-(2-tert-Butoxycarbonylamino-2-methyl-propyl)-phenyl]-acrylic acid benzyl ester WO 2005/090287 PCT/IB2005/000640 205 0 H CH 3

H

3 C O N H3C~I O

CH

3 0 CH 3 A mixture of [2-(3-bromophenyl)-1,1-dimethylethyl]carbamic acid tert-butyl ester (preparation 32), (2g, 6.09mmol), benzyl acrylate (2g, 12.19), palladium (II) acetate (204mg, 0.91mmol), tri-p-tolyl phosphite (556mg, 1.83mmol) and 5 triethylamine (2.12mL, 15.22mmol) in acetonitrile (100mL) was heated under reflux for 48 hours. The reaction mixture was then concentrated in vacuo and the residue was purified by column chromatography on silica gel, eluting with ethyl acetate:pentane to afford the title compound as a pale yellow oil in 90% yield, 2.23g 10 1 H NMR (400MHz, CD 3 0D) 6: 7.75 (1H, d), 7.35 (7H, m), 7.20 (1H, d), 6.58 (IH, d), 6.00 (1H, brs), 5.20 (2H, s), 3.00 (2H, s), 1.43 (9H, s), 1.22 (6H, s) ppm; LRMS ESI m/z 310 [M+H]* Preparation 142 15 3-[3-(2-Amino-2-methyl-propyl)-phenyl]-acrylic acid benzyl ester 0

H

2 N CH 3

CH

3 A mixture of 3

-[

3 -(2-tert-butoxycarbonylamino-2-methy-propyl)-phenyl]-acrylic acid benzyl ester (preparation 141), (2.23g, 5.45mmol), and trifluoroacetic acid (5mL) in dichloromethane (10mL) was stirred for 1 hour at room temperature. 20 The mixture was then concentrated in vacuo and the residue was diluted with sodium hydrogen carbonate solution (10mL) and extracted with ethyl acetate (3x2OmL). The combined organic solution was dried over magnesium sulfate and concentrated in vacuo to afford the title compound as a yellow oil in quantitative yield.

WO 2005/090287 PCT/IB2005/000640 206 'H NMR (400MHz, CD 3 0D) 8: 7.78 (1H, d), 7.60 (1H, d), 7.48 (1H, s), 7.38 (7H, m), 6.60 (1H, brs), 5.23 (2H, s), 2.91 (2H, s), 1.30 (6H, s) ppm; LRMS ESI m/z 408 [M-H]~ 5 Preparation 143 Benzyl -3-(3-{2 -[((2R)-2-[4-(benzyloxy)-3-(hydroxymethyl)phenyl]-2-{[tert butyl(dimethyl)silyl]oxy)ethyl)amino]-2-methylpropyl}phenyl)acrylate OTBDMS 0 H CH 3 N O

OCH

3 .. HO 10 A mixture of [2-(benzyloxy)-5-((1 R)-2-bromo-1 -{[tet butyl(dimethyl)silyl]oxy}ethyl) phenylimethanol (Preparation 23) (800mg, 1.77mmol) and 3-[3-(2-amino-2-methyl-propyl)-phenyl]-acrylic acid benzyl ester (preparation 142), (1.10g, 3.55mmol) was stirred at 90'C for 18 hours. The reaction mixture was then cooled to room temperature, diluted with diethyl ether 15 (40mL) and stirred for 4 hours. The resulting precipitate was filtered off, washing though with diethyl ether, and the filtrate was concentrated in vacuo to give a brown oil. Purification of the oil by column chromatography on silica gel, eluting with dichloromethane:methanol:0.88 ammonia afforded the title compound in 25% yield, 300mg. 20 1 H NMR (400MHz, CD 3 0D) 6: 7.78 (1H, d), 7.38 (16H, m), 6.95 (1H, m), 6.58 (1H, d), 5.25 (2H, s), 5.04 (2H, s), 4.78 (1H, m), 4.64 (2H, m), 2.80 (2H, m), 2.68 (2H, m), 1.14 (3H, s), 1.10 (3H, s), 0.78 (9H, s), -0.03 (3H, s), -0.21 (3H, s) ppm; LRMS ESI m/z 680 [M+H]* 25 Preparation 144 3-{3-[2-({(2R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3 (hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]phenyl)propanoic acid WO 2005/090287 PCT/IB2005/000640 207 OTBDMS O H CH 3 OH HO CHa HO Ammonium formate (139mg, 2.20mmol) and palladium (II) hydroxide (50mg) was added to a solution of 3-(3-{2-[2-(4-benzyloxy-3-hydroxymethyl-phenyl)-2 5 (tert-butyl-dimethyl-silanyloxy)-ethylamino]-2-methyl-propyl}-phenyl)-acrylic acid benzyl ester (preparation 143), (300mg, 0.44mmol) in ethanol (1OmL) and the mixture was heated under reflux for 30 minutes. The reaction mixture was then cooled, filtered through Arbocel* and concentrated in vacuo to afford the title compound in 90% yield, 200mg. 10 1H NMR (400MHz, CD 3 0D) 5: 7.30 (1H, s), 7.20 (1H, m), 7.18 (1H, d), 7.09 (2H, m), 7.00 (1H, d), 6.78 (1H, d), 4.88 (1H, m), 4.63 (2H, m), 3.11 (2H, m), 2.83 (4H, m), 2.48 (2H, m), 1.23 (6H, s), 0.81 (9H, s), -0.03 (3H, s), -0.18 (3H, s) ppm; LRMS ESI m/z 502 [M+H]* 15 Preparation 145 3-{3-[2-({(2R)-2-([tert-Butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3 (hydroxymethyl) phenyl]ethyl}amino)-2-methylpropyl]phenyl}-N-(3,4 dichlorobenzyl) propanamide OTBDMS O H N ) C1

H

3 C CH 3 H HO C1 20 HO The title compound was prepared from 3-{3-[2-({(2R)-2-{[tert butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2 methylpropyl]phenyl}propanoic acid (preparation 144) and 3,4- WO 2005/090287 PCT/IB2005/000640 208 dichlorobenzylamine, using a method similar to that of preparation 38, as a clear oil in 64% yield. 'H NMR (400MHz, CD 3 0D) 8: 7.40 (3H, m), 7.18 (1H, m), 7.08 (5H, m), 6.78 (1H, d), 4.61 (3H, m), 4.23 (2H, s), 2.90 (3H, m), 2.60 (5H, m), 1.08 (3H, s), 5 1.04 (3H, s), 0.81 (9H, s), 0.00 (3H, s), -0.18 (3H, s) ppm; LRMS ESI m/z 659 [M+H]* Preparation 146 [3-(2-Amino-2-methyl-propyl)-phenyl]-acetic acid methyl ester

H

3 C OC 10 2 Acetyl chloride (154.5g, 1.97mol) was added to a solution of {3-[2-(2-chloro acetylamino)-2-methyl-propyl]-phenyl}-acetic acid (preparation 48), (20g, 0.66mol) in methanol (350mL) and the mixture was heated under reflux for 18 hours. The reaction mixture was then concentrated in vacuo to afford the title 15 compound as a brown oil in 87% yield, 154.5g. 'H NMR (300MHz, CDCl 3 ) 6: 7.22 (1H, m), 7.18-7.05 (3H, m), 3.71 (3H, s), 3.58 (2H, s), 2.62 (2H, s), 1.12 (6H, s) ppm; GCMS m/z 206 [M-H] Preparation 147 20 Methyl (3-{2-[((2R)-2 -[4-(benzyloxy)-3-(hydroxym ethyl)phenyl]-2-{[tert butyl(dimethyl)silyl]oxy}ethyl)amino]-2-methylpropyl}phenyl)acetate OTBDMS H N 0 OHC OHJ CH 3 HO A mixture of [2-(benzyloxy)-5-((1R)-2-bromo-1-{[tert-butyl(dimethyl)silyl] oxy}ethyl) phenyl]methanol (preparation 23), (3.4g, 7.5mmol), [3-(2-amino-2 25 methylpropyl)phenyl]acetic acid (preparation 146), (1.7g, 7.5mmol) and N,N diisopropylethylamine (1.4mL, 8mmol) in dimethylsulfoxide (7.5mL) was stirred WO 2005/090287 PCT/IB2005/000640 209 at 90'C for 28 hours. The reaction mixture was then cooled, diluted with ethyl acetate and washed with water. The organic solution was then dried over magnesium sulfate, concentrated in vacuo and the residue was purified by column chromatography on silica gel, eluting with ethyl acetate:pentane, 66:33, 5 to afford the title compound as a colourless oil in 50% yield, 2.2g. 'H NMR (400MHz, CDCl 3 ) 8: 7.44-7.31 (6H, m), 7.30-7.19 (3H, m), 7.13-7.05 (2H, m), 6.80 (1H, d), 4.75-4.66 (3H, m), 3.68 (3H, s), 3.59 (2H, s), 2.90-2.72 (4H, m), 1.22-1.09 (6H, m), 0.70 (9H, s), -0.06 (3H, s), -0.28 (3H, s) ppm 10 Preparation 148 (3-{2-[((2R)-2-[4-(Benzyloxy)-3-(hydroxymethyl)phenyl]-2-{[tert butyl(dimethyl)silyl]oxy}ethyl)amino]-2-methylpropyl}phenyl)acetic acid OTBDMS H N OH

H

3 C CH 3 I 0 HO Lithium hydroxide solution (1M in water, 16.2mL, 16.2mmol) was added to a 15 solution of methyl (3-{2-[((2R)-2-[4-(benzyloxy)-3-(hydroxymethyl)phenyl]-2 {[tert-butyl(dimethyl)silyl]oxy}ethyl)amino]-2-methylpropyl}phenyl)acetate (preparation 147), (4.80g, 8.1mmol) in tetrahydrofuran (49mL) and methanol (17mL) and the mixture was stirred at room temperature for 18 hours. The reaction mixture was then concentrated in vacuo and the residue was diluted 20 with water and acidified to pH 7 with 1M hydrochloric acid. The resulting precipitate was filtered off and washed with water to afford the title compound as a pale yellow solid in 94% yield, 4.37g 'H NMR (400MHz, DMSO-d 6 ) 8: 7.45-7.38 (6H, m), 7.31 (2H, m), 7.13 (1H, m) 7.02 (3H, m), 5.04 (3H, m), 4.52 (2H, d), 3.52 (2H, d), 2.43 (2H, d), 3.37 (2H, 25 d), 1.24 (6H, m), 0.78 (9H, s), 0.02 (3H, s), -0.92 (3H, s) ppm; LRMS ESI m/z 659 [M+H]* WO 2005/090287 PCT/IB2005/000640 210 Preparation 149 2-(3-{2-[((2R)-2-[4-(Benzyloxy)-3-(hydroxymethyl)phenyl]-2-{[tert butyl(dimethyl)silyl]oxy)ethyl)amino]-2-methylpropyl}phenyl)-N (cycloheptylmethyl)acetamide OTBDMS H H N N H9'C CH 3 I 0 5 HO The title compound was prepared from (3-{2-[((2R)-2-[4-(benzyloxy)-3 (hydroxymethyl)phenyl]-2-{[tert-butyl (d imethyl)silyl]oxy}ethyl)amino]-2-methyl propyl}phenyl)acetic acid (preparation 148) and cycloheptane methylamine, using a similar method to that of preparation 38, as a white solid in 97% yield. 10 1H NMR (400MHz, CD 3 0D) 8: 7.72 (1H, dd), 7.44 (1H, d), 7.42 (2H, m), 7.38 7.21 (5H, m), 7.19 (1H, d), 7.07 (1H, d), 7.02 (1H, m), 5.08 (2H, d), 5.03 (1H, m), 4.71 (2H, d), 3.51 (2H, d), 3.03-2.96 (4H, m), 1.77-1.34 (13H, m), 1.28 (6H, m), 1.07 (2H, m), 0.93 (9H, s), 0.07 (3H, s), -0.92 (3H, s) ppm; LRMS ESI m/z 688 [M+H]* 15 Preparation 150 N-1 -Adamantyl-2-(3-{2-[((2R)-2-[4-(benzyloxy)-3-(hydroxymethyl)phenyl]-2 {[tert-butyl(dimethyl)silyl]oxy}ethyl)amino]-2 methylpropyl)phenyl)acetamide OTBDMS H H N _ CF< ,y H 3 C CH 3 I 0 rK 20 HO The title compound was prepared from (3-{2-[((2R)-2-[4-(benzyloxy)-3 (hydroxymethyl)phenyl]-2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)amino]-2-methy WO 2005/090287 PCT/IB2005/000640 211 propyl}phenyl)acetic acid (preparation 148) and 1-adamantylamine, using a similar method to that of preparation 38, as a yellow oil in 71 % yield. 'H NMR (400MHz, DMSO-d 6 ) 5: 7.52 (3H, m), 7.52-7.24 (4H, m), 7.18-7.08 (2H, m), 7.07-6.98 (2H, m), 6.94 (1H, m), 5.09 (2H, d), 5.01 (1H, t), 4.66-4.61 (1H, 5 m), 4.54 (2H, d), 3.25 (2H, d), 3.15 (1H, d), 2.59-2.43 (2H, m), 1.98-1.92 (3H, m), 1.87 (6H, n), 1.57 (6H, m), 0.96 (6H, dd), 0.79 (9H, d), -0.98 (3H, s), -0.93 (3H, s) ppm; LRMS ESI m/z 712 [M+H]* Preparation 151 10 2-{3-[2-({(2R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3 (hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl] phenyl}-N (cycloheptylmethyl)acetamide OTBDMS H H N N H H 3 C CH 3 N H09 0 HO 15 The title compound was prepared from 2-(3-{2-[((2R)-2-[4-(benzyloxy)-3 (hydroxymethyl)phenyl]-2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)amino]-2-methy propyl}phenyl)-N-(cycloheptylmethyl)acetamide (preparation 149), using a similar method to that of preparation 144, as a yellow oil in 96% yield. 1 H NMR (400MHz, CD 3 0D) 8: 7.67 (1H, m), 7.18-7.04 (5H, m), 6.79 (1H, d), 20 4.92-4.84 (1H, in), 4.67 (2H, m), 3.51 (2H, d), 3.21-3.03 (2H, m), 3.02 (2H, n), 2.96 (2H, m), 1.86-1.38 (11H, in), 1.24 (6H, m), 1.21-1.11 (2H, m), 0.82 (9H, s), 0.06 (3H, s), -0.93 (3H, s) ppm; LRMS ESI m/z 597 [M+H]* Preparation 152 25 N-1 -Adamantyl -2-{3-[2-({(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-[4-hydroxy 3-(hydroxymethyl)phenyl]ethyl)am i no)-2-methylpropyl]phenyl}acetam ide WO 2005/090287 PCT/IB2005/000640 212 OTBDMS H H HO H 3 C CH 3 I HO The title compound was prepared from N-1-adamantyl-2-(3-{2-[((2R)-2-[4 (benzyloxy)-3-(hydroxymethyl)phenyl]-2-{[tert-butyl(dimethyl)silyl] oxy}ethyl) amino]-2-methylpropyl}phenyl)acetamide (preparation 150), using a similar 5 method to that of preparation 144, as a white solid in 73% yield. 1H NMR (400MHz, DMSO-d 6 ) 5: 7.42 (1H, m), 7.12 (1H, d), 7.09-7.05 (1H, m), 7.03-6.95 (4H, m), 6.64 (1H, d), 4.95 (1H, brs), 4.60 (1H, m), 4.42 (2H, d), 3.24 (2H, d), 2.75 (1H, d), 2.57 (2H, d), 1.97 (3H, m), 1.93 (6H, m), 1.57 (6H, m), 0.92 (6H, dd), 0.78 (9H, d), -0.03 (3H, s), -0.18 (3H, s) ppm; LRMS ESI m/z 621 10 [M+H]* Preparation 153 Methyl {3-[2-({(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3 (hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]phenyl}acetate OTBDMS H HO

H

3 C

H

3

H

3 15 HO The title compound was prepared from methyl (3-{2-[((2R)-2-[4-(benzyloxy)-3 (hyd roxymethyl)phenyl]-2-{[tert-butyl(d imethyl)silyl]oxylethyl)amino]-2 methylpropyl}phenyl)acetate (preparation 147), using a similar method to preparation 21 as a brown oil in 80% yield. 20 'H NMR (400MHz, CDCl 3 ) 8: 7.30-7.20 (2H, m), 7.19-7.00 (4H, m), 6.80 (1H, d), 4.75-4.66 (3H, m), 5.10 (2H, s), 3.68 (3H, s), 3.59 (2H, s), 2.85-2.62 (4H, m), 1.10-1.01 (6H, in), 0.80 (9H, s), -0.02 (3H, s), -0.20 (3H, s) ppm WO 2005/090287 PCT/IB2005/000640 213 Preparation 154 {3-[2-({(2R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3 (hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]phenyl}acetic acid OTBDMS H N OH HO

H

3 C COH 0 HO 5 A mixture of methyl {3-[2-({(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3 (hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]phenyl}acetate (preparation 153), (5g, 10mmol) and lithium hydroxide (1M in water, 30mL, 30mmol) in tetrahydrofuran (50mL) was stirred for 48 hours at room temperature. The 10 reaction mixture was then acidified with 1M hydrochloric acid (30mL), concentrated in vacuo, and the residue was triturated with water and azeotroped (x3) with methanol to afford the title compound as a white solid in 84% yield, 4.1g 1H NMR (400MHz, CD 3 0D) 5: 7.39-7.31 (2H, m), 7.28 (1H, m), 7.20-7.10 (3H, 15 m), 6.81 (1H, d), 4.92-4.83 (1H, m), 4.65 (2H, m), 3.61 (2H, s), 3.34-3.24 (2H, m), 3.00 (2H, m), 1.33 (6H, s), 0.82 (9H, s), 0.06 (3H, s), -0.12 (3H, s) ppm Preparation 155 2-{3-[2-({(2R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3 20 (hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]phenyl}-N (3-pyrrolidin-1 -ylpropyl)acetamide OTBDMS H H N Nr H C CH3 O HO

HO

WO 2005/090287 PCT/IB2005/000640 214 The title compound was prepared from {3-[2-({(2R)-2-{[tert butyl(dimethyl)silyl]oxy}-2-[4-hyd roxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2 methylpropyl]phenyl}acetic acid (preparation 154) and 1 pyrrolidinepropanamine, using a similar method to that of preparation 38, in 5 16% yield. H NMR (400MHz, CDCl 3 ) 6: 7.20 (1H, m), 7.08-6.96 (3H, m), 6.85 (1H, m), 6.70 (1H, m), 6.58 (1H, m), 4.75 (2H, s), 4.64 (1H, m), 3.42 (2H, m), 3.24 (2H, m), 2.80 (1H, m), 2.62 (3H, m), 2.43 (6H, m), 1.68 (4H, m), 1.60 (2H, m), 1.00 (6H, s), 0.81 (9H, s), -0.05 (3H, s), -0.19 (3H, s) ppm 10 Preparation 156 N-Benzyl-2-{3-[2-({(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3 (hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]phenyl}-N methylacetamide 15 OTBDMS CH3 H I N N

H

3 C CH 3 I 0 HO HO The title compound was prepared from {3-[2-({(2R)-2-{[tert 20 butyl(dimethyl)silyljoxy}-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2 methylpropyl]phenyl}acetic acid (preparation 154) and N-benzylmethylamine, using a similar method to that of preparation 38 in 55% yield. 'H NMR (400MHz, CD 3 0D) 6: 7.55-7.01 (11H, m), 6.73 (1H, m), 4.63 (5H, m), 2.85 (2H, m), 2.80 (2H, m), 2.72 (1H, m), 2.68 (3H, m), 1.87 (1H, m), 1.03 (6H, 25 m), 0.80 (9H, s), -0.00 (3H, s), -0.19 (3H, s) ppm Preparation 157 WO 2005/090287 PCT/IB2005/000640 215 3-[2-({(2R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-(hydroxy methyl)phenyl]ethyl}amino)-2-methylpropyl]-N-[2-(3-fluorophenyl)ethyl] benzamide OTBDMS 0 H N N N F I H

H

3 C CH V 3 HO HO 5 A mixture of 3-{2-[(2R)-2-(tert-butyldimethylsilanyloxy)-2-(4-hydroxy-3-hydroxy methyl-phenyl)ethylamino]-2-methylpropyl}benzoic acid (preparation 37) (473mg, 1mmol) and O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (379mg, 1mmol) was added to a solution of 3 fluorophenethylamine (139mg, 1mmol) in N,N-dimethylacetamide (6mL) and 10 the mixture was stirred for 18 hours at room temperature. The solvent was removed in vacuo and the residue was re-dissolved in dichloromethane (1OOmL) and washed with saturated sodium hydrogen carbonate solution (3x20mL) and brine (10mL). The organic solution was then dried over sodium sulfate, concentrated in vacuo and the residue was purified by column 15 chromatography on silica gel, eluting with dichloromethane:methanol:0.88 ammonia, 100:0:0 to 90:10:1. The appropriate fractions were then concentrated in vacuo and the residue was re-dissolved in ethyl acetate, washed with saturated sodium hydrogen carbonate solution, dried over sodium sulfate and concentrated in vacuo to afford the title compound in 52% yield, 343mg. 20 1 H NMR (400MHz, CD 3 0D) 5: 7.65-7.62 (2H, m), 7.38-7.23 (4H, m), 7.09-6.99 (3H, m), 6.92 (1H, d), 6.74 (1H, d), 4.70 (1H, m), 4.65 (2H, m), 3.61 (2H, m), 2.96-2.60 (6H, m), 1.10 (3H, s), 1.07 (3H, s), 0.79 (9H, s), -0.03 (3H, s), -0.21 (3H, s) ppm; LRMS ESI m/z 595 [M+H]* 25 Preparation 158 WO 2005/090287 PCT/IB2005/000640 216 3-[2-({(2R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3 (hydroxymethyl)phenyl]ethyl)amino)-2-methylpropyl]-N-[2-(5-chloro-2 methoxyphenyl)ethyl]benzamide C1 OTBDMS 0 H NN

H

3 C CH 3 O H HO H3 HO 5 A mixture of 3-{2-[(2R)-2-(tert-butyld imethylsilanyloxy)-2-(4-hyd roxy-3-hyd roxy methyl-phenyl)ethylamino]-2-methylpropyl}benzoic acid (preparation 37) (400mg, 0.85mmol), 0-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (320mg, 0.85mmol), triethylamine (225puL, 1.6mmol) and 2-(5-chloro-2-methoxy-phenyl)-ethylamine (preparation 70), (64mg, 0.85mmol) 10 in N,N-dimethylacetamide (8mL) was stirred for 18 hours at room temperature. The solvent was removed in vacuo and the residue was partitioned between dichloromethane (4mL) and saturated sodium hydrogen carbonate solution (1mL). The organic solution was then dried over magnesium sulfate, concentrated in vacuo and the residue was purified using an ISCO Companion* 15 silica cartridge, eluting with dichloromethane:methanol:0.88 ammonia, 90:10:1 to 80:20:2, to afford the title compound in 22% yield. H NMR (400MHz, CD 3 0D) 5: 7.70-7.60 (2H, m), 7.50-7.38 (3H, m), 7.20-7.10 (3H, m), 6.95 (1H, d), 6.85 (1H, d), 4.95 (1H, s), 4.75-4.60 (2H, m), 3.81 (3H, s), 3.57 (2H, m), 3.10-2.90 (6H, m), 1.25 (6H, s), 0.82 (9H, s), -0.03 (3H, s), -0.16 20 (3H, s) ppm Preparation 159 3-[2-(((2R)-2-{[tert-Butyl(dimethyl)silyl]oxy)-2-[4-hydroxy-3 (hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]-N-[2-(3 25 ethoxyphenyl)ethyl]benzamide WO 2005/090287 PCT/IB2005/000640 217

CH

3 CH

H

3 C CH 3 3

H

3 C Si .CH 3 0 O 0 H N N HO

H

3 C

H

3 H HO The title compound was prepared from 3-{2-[(2R)-2-(tert-butyldimethyl silanyloxy)-2-(4-hydroxy-3-hydroxymethyl-phenyl)ethylamino]-2-methylpropyl} benzoic acid (preparation 37) and 3-ethoxyphenethylamine, using a similar 5 method to that of preparation 158, in 67% yield. LRMS APCI m/z 621 [M+H]* Preparation 160 3-[2-({(2R)-2-{[tert-Butyl(dimethyl)silyl]oxy)-2-[4-hydroxy-3 10 (hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]-N-[2-(3 methoxyphenyl)ethyl]benzamide 0O H 3 OTBDMS 0 H NN HO HC

H

3 H HO The title compound was prepared from 3-{2-[(2R)-2-(tert butyldimethylsilanyloxy)-2-(4-hydroxy-3-hydroxy methyl-phenyl)ethylamino]-2 15 methylpropyl}benzoic acid (preparation 37) and 3-methoxyphenethylamine, using a similar method to that of preparation 158, in 98% yield. LRMS ESI m/z 607 [M+H]* WO 2005/090287 PCT/IB2005/000640 218 Preparation 161 [3-((2R)-2-{[(1 R)-1 -Phenylethyl]amino}propyl)phenyl]acetic acid H N OH

CH

3 CH 3 0 5 Lithium hydroxide solution (1M in water, 90mL, 90mmol) was added to a solution of methyl [3-((2R)-2-{[(1R)-1-phenyl-ethyll-amino}-propyl)-phenyl] acetate hydrochloride (preparation 26), (13.5g, 43.5mmol) in methanol (200mL) and the mixture was stirred at room temperature for 18 hours. 1M Hydrochloric acid (90mL) was then added to the reaction mixture and the methanol removed 10 in vacuo. The resulting precipitate was filtered off and washed with water (20mL) and a mixture of ethanol/diethyl ether, 20:80, to afford the title compound as a solid in 91% yield, 11.8g H NMR (400MHz, CD 3 0D) &: 7.52-7.45 (5H, m), 7.22-7.18 (2H, m), 7.19 (1H, s), 6.92 (1H, d), 4.56-4.48 (1H, q), 3.46 (2H, s), 3.26-3.13 (2H, m), 2.66-2.62 15 (1 H, m), 1.62 (3H, d), 1.16 (3H, d) ppm; LRMS ESI m/z 298 [M+H]* Preparation 162 N-1-Adamantyl-2-[3-((2R)-2-{[(1R)-1 phenylethyl]amino}propyl)phenyl]acetamide H H N N 203 1-Adamantylamine (5.44g, 36mmol) and triethylamine (15mL, 108mmol) were added to a solution of [3-((2R)-2-{[(1R)-1-phenylethyl]amino}propyl)phenyl] acetic acid (preparation 161), (10.7g, 36mmol) in dichloromethane (200mL). 2 Chloro-1,3-dimethylimidazolidinum hexafluorophosphate (10g, 36mmol) was 25 then added and the mixture was stirred at room temperature for 2 hours. The reaction mixture was washed with water and the organic solution was dried over WO 2005/090287 PCT/IB2005/000640 219 magnesium sulfate and concentrated in vacuo. Purification of the residue by column chromatography on silica gel, eluting with dichloromethane:methanol:0.88 ammonia, 95:5:0.5, afforded the product as a foam in quantitative yield, 17.6g. 5 'H NMR (400MHz, CD 3 0D) 5: 7.38-7.30 (4H, m), 7.27-7.22 (1H, m), 7.17 (1H, t), 7.09 (1H, d), 6.98 (1H, s), 6.89 (1H, d), 3.98 (1H, q), 3.36 (2H, s), 3.00-2.95 (1H, dd), 2.74-2.65 (1H, m), 2.42-2.37 (1H, dd), 2.04 (3H, m), 1.98 (6H, m), 1.75-1.65 (6H, m), 1.35 (d, 3H), 0.89 (d, 3H) ppm; LRMS ESI m/z 431 [M+H]* 10 Preparation 163 N-1 -Adamantyl-2-{3-[(2R)-2-aminopropylphenyl}acetamide H

H

2 N N

CH

3 0 K$i The title compound was prepared from N-1-adamantyl-2-[3-((2R)-2-{[(1R)-1 phenylethyl]amino}propyl)phenyl]acetamide (preparation 162), using a similar 15 method to that of preparation 25, as a solid in 92% yield. 1 H NMR (400MHz, CD 3 0D) 5: 7.28-7.05 (4H, m), 3.40 (2H, s), 3.16-3.10 (1H, q), 2.70-2.58 (2H, m), 2.03 (3H, m), 2.00 (6H, in), 1.72-1.66 (6H, m), 1.09 (d, 3H) ppm; LRMS ESI m/z 327 [M+H]+ 20 Preparation 164 N-1 -Adamantyl-2-{3-[(2R)-2-({(2R)-2-[4-(benzyloxy)-3 (hydroxymethyl)phenyl]-2-hydroxyethyl}amino)propyl]phenyl}acetamide OTBDMS H H O N N 0 ocH 3 ' HO A mixture of [2-(benzyloxy)-5-((1 R)-2-bromo-1 -{[tert-butyl(dimethyl) 25 silylloxy}ethyl) phenyl]methanol (preparation 23), (900mg, 2mmol) and N-1- WO 2005/090287 PCT/IB2005/000640 220 adamantyl-2-{3-[(2R)-2-aminopropyl]phenyl}acetamide (preparation 163), (1.3g, 4mmol) were heated at 90'C for 24 hours. The reaction mixture was then cooled to room temperature and the crude product was purified by column chromatography on silica gel, eluting with dichloromethane:methanol:0.88 5 ammonia, 95:5:0.5, to afford the title compound as a pale foam in 83% yield, 1.16g. H NMR (400MHz, CD 3 0D) 8: 7.48-7.28 (6H, m), 7.17-6.72 (6H, m), 5.14 (2H, s), 4.78-4.74 (1H, m), 4.73-4.64 (m, 2H), 3.36 (2H, s), 2.95-2.84 (2H, m), 2.70 2.63 (2H, m), 2.59-2.50 (1H, m), 2.03 (3H, m), 2.00 (6H, m), 1.70-1.64 (6H, m), 10 1.05 (3H, d), 0.84 (9H, s), 0.00 (3H, s), -0.18 (3H, s) ppm Abbreviations TBDMS = tert-butyl(dimethyl)silyl 15 In vitro activity of the compounds of formula (1) The ability of the compounds of the formula (1) to act as potent P2 agonists therefore mediating smooth muscle relaxation may be determined by the measure of the effect of beta-2 adrenergic receptor stimulation on electrical 20 field stimulated-contraction of guinea pig trachea strips. Guinea-pig trachea Male, Dunkin-Hartley guinea pigs (475-525g) are killed by CO 2 asphyxiation and exsanguination from the femoral artery and the trachea is isolated. Four preparations are obtained from each animal, starting the dissection immediately 25 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 30 in a modified Krebs Ringer buffer (Sigma K0507) containing 3 pM Indomethacin (Sigma 17378), 10 pM Guanethidine (Sigma G8520) and 10 pM Atenolol (Sigma WO 2005/090287 PCT/IB2005/000640 221 A7655), heated at 37'C and gassed with 95% 02/5% C02, 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 5 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 10 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 15 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 20 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, 25 bolus addition to the bath using half log increments in concentration. The concentration range used is 1 e9 to 19-/3.6 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 30 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 EC 5 0 value for beta-2 agonist WO 2005/090287 PCT/IB2005/000640 222 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 (EC 5 o beta-2 agonist)/(EC50 Isoprenaline). 5 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 P 2 antagonist) which results in 10 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 02 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 15 produce half maximal effect (EC 5 o) for the 02 receptor. Compound Preparation 10 mM/100% DMSO (dimethylsulfoxide) stock of compound is diluted to required top dose in 4 % DMSO. This top dose is used to construct a 10-point semi-log dilution curve, all in 4 % DMSO. Isoprenaline (Sigma, 1-5627) was 20 used as a standard in every experiment and for control wells on each plate. Data was expressed as % Isoprenaline response. Cell Culture CHO (Chinese Hamster Ovary) cells recombinantly expressing the human P2 adrenergic receptor (from Kobilka et al., PNAS 84: 46-50, 1987 and Bouvier et 25 al., Mol Pharmacol 33: 133-139 1988 CHOhP2) were grown in Dulbeccos MEM/ NUT MIX F12 (Gibco, 21331-020) supplemented with 10 % foetal bovine serum (Sigma, F4135, Lot 90K8404 Exp 09/04), 2 mM glutamine (Sigma, G7513), 500 pg/ml geneticin (Sigma, G7034) and 10 pg/mI puromycin (Sigma, P8833). Cells were seeded to give about 90 % confluency for testing.

WO 2005/090287 PCT/IB2005/000640 223 Assay Method 25 pl / well each dose of compound was transferred into a cAMP- Flashplate@ (NEN, SMP004B), with 1% DMSO as basal controls and 100 nM Isoprenaline as max controls. This was diluted 1:2 by the addition of 25 pl / well PBS. Cells 5 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 pl / well cells for 1 hour. Cells were then lysed by the addition of 100 pl / well detection buffer (NEN, SMP004B) containing 0.18 pCi / ml 1 25 1-cAMP (NEN, NEX-130) and plates were 10 incubated at room temperature for a further 2 hours. The amount of 125l-cAMP bound to the Flashplate@ was quantified using a Topcount NXT (Packard), normal counting efficiency for 1 minute. Dose-response data was expressed as % Isoprenaline activity and fitted using a four parameter sigmoid fit. It has thus been found that the compounds of formula (1) according to the 15 present invention that have been tested show a P2 cAMP EC 50 below 1OnM. The following table illustrate the activity of the compounds of the invention: Example EC 50 (nM) 1 0.143 14 0.0640 16 0.874 23 0.0800 24 0.150 46 0.838 62 0.444 WO 2005/090287 PCT/IB2005/000640 224 63 0.0750 66 1.16 88 0.434 102 0.100 114 0.134

Claims (26)

1. A compound of formula (1) O H 0 N (CH 2 )n Q1k Q HO R 1 R 2 () HO wherein the (CH 2 )n-C(=O)Ql group is in meta or para position, 5 - R and R2 are independently selected from H and C 1 -C 4 alkyl, - n is 0, 1 or 2, and, - Q is a group selected from: R3 R4 R 3 R 3 R 8 R4 R8 R4 (CH 2 )p \ / R 5 *-N *-N-C R5 H2

2 R 5 NR 6 R 6 6 R *-NH-C1-C 4 alkyl, and a group *-N(R )-Q2 -A, wherein 10 - Q 2 is a single bond or a C 1 -C 4 alkylene, - R 8 is H or C 1 -C 4 alkyl, - pis 1 or2,and - A is a C 3 -C 10 cycloalkyl, 2 carbon atoms or more of said cycloalkyl being optionally bridged by one or more carbon atoms, preferably by 15 1, 2, 3 or 4 carbon atoms, 0-phenyl-pyrazolyl, 5 to 10 membered heterocyclic group, optionally aromatic, comprising one, two, three or WO 2005/090287 PCT/IB2005/000640 226 four heteroatoms selected from 0, S or N, optionally substituted with C1-C4 alkyl or 0-C1-C4 alkyl, or a group of formula R3 R4 R3 R4 R5 R5 or R 7 R 6 - R 3 , R 4 , R', R 6 and R 7 are the same or different and are selected from H, C1-C4 5 alkyl, OR 9 , SR 9 , SOR 9 , S0 2 R 9 , halo, CN, CF 3 , OCF 3 , phenyl, O-phenyl, S phenyl, S0 2 -morpholinyl, 0-(CH 2 ) 3 -pyrrolidinyl, COOR 9 , S0 2 NR'R 10 , CONR 9 R 10 , NR 9 R 10 and NHCOR 1 0 ; - R 9 and R 10 are the same or different and are selected from H or C1-C 4 alkyl and the * represents the attachment point to the carbonyl group; 10 or, if appropriate, their pharmaceutically acceptable salts and/or isomers, tautomers, solvates or isotopic variations thereof, with the proviso that when n is 0, then Q1 is not -NHCH 3 , and, when n is I or 2, then: 1) Q 1 is *-NH-C1-C 4 alkyl, or *-N(R )-Q2 -A where A is 15 - C3-C10 cycloalkyl, 2 carbon atoms or more of said cycloalkyl being optionally bridged by one or more carbon atoms, - O-phenyl-pyrazolyl, - 5 to 10 membered heterocyclic group, optionally aromatic, comprinsing one, two, three or four heteroatoms selected from 0, S 20 or N optionally substituted with C1-C4 alkyl or 0-C1-C4 alkyl, said heterocyclic group being other than pyridyl, - a group of formula WO 2005/090287 PCT/IB2005/000640 227 R3 R4 R3 R4 R R5 or R7 R 6 wherein one of R 3 to R 7 is CN, SOR 9 , S0 2 R 9 , phenyl, 0-phenyl, S-phenyl, S02-morpholinyl or O-(CH 2 ) 3 pyrrolidinyl, and/or, 2) when one of R1 and R2 is H, the other is not CH 3 . 5 2. A compound according to claim 1 wherein Q' is a group of formula R 3 R4 R3 RN R 5 -- 2 \6 R6 or *-N(R )-Q2 -A, wherein Q 2 is a single bond or a C1-C4 alkylene, R 8 is H and A is R 3 R4 R5 R 7 R6 10 wherein R 3 , R4 R , R6 and R are as defined in claim 1.

3. A compound according to claims 1 or 2 wherein Q 1 is a group*-N(R )_ 2-A wherein A is a group of formula WO 2005/090287 PCT/IB2005/000640 228 R3 R4 R5 R7 R 6 wherein R 3 , R 4 R , R 6 and R 7 are selected from H, C1-C4 alkyl, OR', SR', CI, F, CF 3 , OCF 3 , COOR 9 , S0 2 NR 9 R 10 , and at least 2 of R 3 to R 7 represent H, wherein R 9 and R 10 are the same or different and are selected from H or C1-C4 5 alkyl.

4. A compound according to claim 3 wherein R3, R4 R', R' and R 7 are the same or different and are selected from H, CH 3 , OH, OCH 3 , SCH 3 , OCH 2 CH 3 , Cl, F, CF 3 , OCF 3 , COOH, SO 2 NH 2 , and at least 2 of R 3 to R 7 represent H.

5. A compound according to claim 4 wherein R 3 , R 4 R 5 , R 6 and R 7 are the same 10 or different and are selected from H, CH 3 , OH, OCH 3 , SCH 3 , OCH 2 CH 3 , Cl, F, CF 3 , OCF 3 , COOH, SO 2 NH 2 , and at least 3 of R 3 to R 7 represent H.

6. A compound according to claim 1 wherein Q1 is *-N(R 8 )-Q 2 -A where A is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or adamantyl.

7. A compound according to any one of claims 1 to 6 wherein R is H, methyl or 15 ethyl.

8. A compound according to any one of claims 1 to 7 wherein Q2 is selected from a bond, -CH 2 -, -(CH 2 ) 2 -, -(CH 2 ) 3 -, -C(CH 3 ) 2 -CH 2 -, -CH 2 -C(CH 3 ) 2 -, and CH(CH 3 )-. 20

9. A compound according to claim 1 or 2 wherein Q1 is WO 2005/090287 PCT/IB2005/000640 229 *-N o N or

10. A compound according to any one of claims 1 to 9 wherein n is 0 or 1.

11. A compound according to any one of claims 1 to 10 wherein R1 is H and R2 is H or CH 2 CH 3 . 5

12. A compound according to any one of claims 1 to 10 wherein R, is CH 3 and R2 is CH 3 .

13. The (R,R)-stereoisomer of a compound according to any one of claims 1 to 12.

14. A compound according to any one of claims 1 to 13 wherein the (CH 2 )n 10 C(=O)Ql group is in position meta.

15. A compound according to claim 1 selected from the group consisting of N-cycloheptyl-2-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3 (hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}acetamide; N-(cyclohexylmethyl)-2-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3 15 (hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N-methylacetamide; N-[(1S)-1-cyclohexylethyl]-2-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3 (hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}acetamide; 2-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3 (hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}-N-isopropylacetamide; 20 N-cyclopentyl-2-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3 (hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}acetamide; N-(cyclobutylmethyl)-2-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3 (hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}acetamide; N-(cyclopentylmethyl)-2-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3 25 (hydroxymethyl)phenyl]ethyl}amino)propyl]phenyl}acetamide; WO 2005/090287 PCT/11B2005/000640 230 N-cyclohexyl-2-{3-[(2R)-2-(((2R)-2-hyd roxy-2-[4-hyd roxy-3 (hyd roxymethyl)phenyl]ethyllam ino)propyl] phenyllaceta mide; N-cyclobutyI-2-{3-[(2R)-2-({(2R)-2-hyd roxy-2-[4-hyd roxy-3 (hydroxymethyl)phenyl]ethyl~amino)propyl]phenyllacetamide; 5 N-(cyclohexyl methyl )-2-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4- hyd roxy-3 (hyd roxymeth yl)p hen yl]ethylla m ino)propyl] ph enyl~aceta mid e; N-(cyclopropyl methyl )-2-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3 (hyd roxymethyl)phenyl]ethyl)amino)propyl] phenyl)aceta mide; N-(cycloheptyl methyl )-2-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3 10 (hyd roxymethyl)p henyl] ethy~a m in o)propyl] phe nyl)aceta mid e; N-I -adamantyl-2-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hyd roxy-3 (hyd roxymethyl )phe nyi] ethylla min o)propyl] phe nyl)aceta mid e; N-(1 -adamantylmethyl )-2-{3-[(2R)-2-({(2R)-2-hyd roxy-2-[4-hyd roxy-3 (hydroxymethyl)phenyl]ethyl~amino)propyljphenyl)acetamide; 15 N-2-adamantyl-2-{3-[(2R)-2-({(2R)-2-hyd roxy-2-[4-hydroxy-3 (hyd roxymethyl )p henyl] ethylla m ino)p ropy[] phe nyI~aceta mide N-(2-cyclohexylethyl )-2-{3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3 (hyd roxymethyl)p he nyl]ethyl~a m ino)propyl] phenyl)-N-methyl aceta mid e; N-cycloheptyi-2-{3-[(2R)-2-({(2R)-2-hyd roxy-2-[4-hydroxy-3 20 (hyd roxymethyl)p he nyl]ethyl~a m ino)pro pyl] phenyl}-N-methyl aceta mid e; N-cyclohexyl-N-ethyl-2-{3-[(2R)-2-({(2R)-2-hyd roxy-2-[4-hyd roxy-3 (hydroxymethyl )phenyljethyllamino)propyllphenyl}acetamide; N-(2-cyclohexylethyl)-2-{3-[(2R)-2-({(2R)-2-hyd roxy-2-[4-hyd roxy-3 (hydroxymethyl)phenyi]ethyllamino)propyl]phenyl~acetamide; 25 N-(4-chlo robe nzyl)-2-{3-[2-({(2 R)-2-hyd roxy-2-[4-hyd roxy-3 (hydroxymethyl) phenyl]ethylla mino)-2-methylpropyl] phenyl~acetam ide; N-(2 ,6-dimethoxybenzyl )-2-{3-[2-({(2R)-2-hyd roxy-2-[4-hyd roxy-3 (hyd roxymethyl) phe nyl]ethylla min o)-2-methyl propyl] ph enylla ceta mid e; N-benzyl-2-{3-[2-({(2R)-2-hyd roxy-2-[4-hyd roxy-3 30 (hydroxymethyl )phenyl]ethyllamino)-2-methylpropyl]phenyllacetamide; 4-{(l R)-2-[(2-{3-[2-(3,4-d ihydroisoqu inol in-2( 1 H)-yI)-2-oxoethyl]phenyl}-1 , 1 dimethylethyl)amino]-1 -hydroxyethyl}-2-(hydroxymethyl)phenol; WO 2005/090287 PCT/11B2005/000640 231 N-[2-fluoro-5-(trifluoromethyl )benzyl]-2-{3-[2-({(2R)-2-hyd roxy-2-[4-hydroxy-3 (hyd roxymethyl)p hen yl] ethylla mino)-2-methyl pro pyll phe nyl~aceta mide; N-(2,6-d ichlorobenzyl )-2-{3-[2-({(2R)-2-hyd roxy-2-[4-hyd roxy-3 (h yd roxymethyl)p hen yl] ethylla m ino)-2-meth yl propyl] ph enyl~a ceta mide; 5 2-{3-[2-({(2R)-2-hyd roxy-2-[4-hyd roxy-3-(hyd roxymethyl )phenyl]ethyllamino)-2 m ethyl propyl] ph enyl}-N-[2-(methylth io)benzyl]aceta mide; N-(2 ,3-d imethylbenzyl )-2-{3-[2-({(2R)-2-hyd roxy-2-[4-hydroxy-3 (hydroxymethyl)phenyl]ethyllamino)-2-methylpropyl]phenyl~acetamide; 2-{3-[2-({(2R)-2-hyd roxy-2-[4-hyd roxy-3-(hyd roxymethyl )phenyllethyl~amino)-2 10 m ethyl pro pyl] phenyl}-N-[3-(trifl u oromethyl )be nzyl] acetam ide; N-[4-chloro-3-(trifluoromethyl)benzyl]-2-3-[2-({(2R)-2-hyd roxy-2-[4-hyd roxy-3 (hydroxymethyl )phenyllethyllamino)-2-methylpropyl]phenyllacetamide; N-[2-chloro-5-(trifluoromethyl)benzy]-2-3-[2-({(2R)-2-hyd roxy-2-[4-hydroxy-3 (hydroxymethyl)phenyl]ethyi}amino)-2-methylpropyl]phenyllacetamide; 15 N-[3 ,5-bis(trifl uoromethyl)benzyl-2-{3-[2-({(2R)-2-hyd roxy-2-[4-hyd roxy-3 (hydroxymethyl)phenyllethyl~amino)-2-methylpropyl]phenyl~acetamide; N-[3-fluoro-5-(trifluoromethyl )benzyl]-2-{3-[2-({(2R)-2-hyd roxy-2-[4-hydroxy-3 (hyd roxymethyl)phenyl]ethyllamino)-2-methylpropyl]phenyllacetamide; N-[2-(4-chlorophenyl )ethyl]-3-{2-[(2R)-2-hydroxy-2-(4-hyd roxy-3-hyd roxy 20 methylphenyl)ethylamino]-2-methylpropyl~benzamide' 3-{2-[(2 R)-2-h yd roxy-2-(4-hyd roxy-3-h yd roxymethy p hen yl )-ethyl am ino] -2 methylpropyl)-N-[2-(4-methylphenyl )ethyl] benzamide; 3-{2-[(2R)-2-hyd roxy-2-(4-hyd roxy-3-hyd roxymethyiphenyl )-ethylamino]-2 methyl-propyl}-N-[2-(4-trifluoromethyl phenyl)ethyljbenzamide; 25 N-[2-(3,4-d ichlorophenyl)ethyl]-3-{2-[(2R)-2-hyd roxy-2-(4-hyd roxy-3 hydroxymethyl phenyl)ethylamino]-2-methyl-propyl}-benzamide; N-[2-(3,4-d imethyiphenyl )ethyl]-3-{2-I(2R)-2-hyd roxy-2-(4-hyd roxy-3 hydroxymethylphenyl)-ethylaminoj-2-methylpropyllbenzamide; 3-{2-[(2R)-2-hyd roxy-2-(4-hyd roxy-3-hyd roxymethyl-phenyl)ethylam ino]-2 30 methyl-propyl}-N-(2-n ap hth ale n-2-yi-ethyl)benza mide; N-( 1, 1 -d imethyl-2-phenylethyl )-3-{2-[(2R)-2-hyd roxy-2-(4- hyd roxy-3-hyd roxy methyi ph enyl )-eth yla mi no]-2-methyl pro pyll benza mid e; WO 2005/090287 PCT/11B2005/000640 232 3-{2-[(2R)-2-hyd roxy-2-(4-hyd roxy-3-hyciroxymethyiphenyl )-ethyla mino]-2 methylpropyl}-N-(2-methyl-2-phenylpropyl)benzamide; N-(4-chlorobenzyl )-3-{2-[(2R)-2-hydroxy-2-(4-hyd roxy-3-hyd roxy methyl phe nyl)ethyl am ino]-2-methyl pro pyl)be nza mid e; 5 N-(2 ,6-d imethoxybenzyl )-2-{3-[2-({(2R)-2-hyd roxy-2-[4-hydroxy-3 (hyd roxymethyl )phenyl]ethyl~am ino)ethyl]phenyl~acetamide; N-(3 ,4-d ichlorobenzyl )-2-{3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3 (hydroxymethyl)phenyl~ethyl~amino)ethyl]phenyllacetamide; N-benzyl-2-{3-[2-({(2R)-2-hydroxy-2-[4-hyd roxy-3 10 (hydroxymethyi)phenyllethyl}amino)ethyl]phenyl~acetamide; N-(2 ,3-d ihyd ro- 1 H-inden-2-yi )-2-{3-[2-({(2R)-2-hyd roxy-2-[4-hydroxy-3 (hyd roxymethyl)ph enyljethylla m ino)ethyl] ph enyl~aceta mid e; 2-{3-[2-({(2R)-2-hyd roxy-2-[4-hyd roxy-3 (hydroxymethyl)phenyl]ethyl~amino)ethyl]phenyl}-N-(2-phenylethyl)acetamide; 15 2-{3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3 (hyd roxymethyl)p hen yl] ethyllam ino)ethyl] phe nyl}-N-(3-p henyl pro pyl)a ceta mide; N-benzyl-3-[(2R)-2-({(2R)-2-hyd roxy-2-14-hyd roxy-3 (hydroxymethyl)phenyllethyllamino)propyl]benzamide; N-(3,4-d ichlorobenzyl)-3-[(2R)-2-({(2R)-2-hyd roxy-2-[4-hyd roxy-3 20 (hyd roxymethyl)p hen yl]ethyllam ino)propyl] benza mid e; N-[2-fiuoro-5-(trifluoromethyl)benzyl]-3-[(2R)-2-({(2R)-2-hyd roxy-2-[4-hyd roxy-3 (hydroxymethyl)phenyl]ethyl~amino)propyl]benzamide; N-(2 ,6-dimethoxybenzyl)-3-[(2R)-2-({(2R)-2-hyd roxy-2-[4-hyd roxy-3 (hyd roxymethyl)phe nyl]ethyllam ino)propylj benza mid e; 25 N-[2-(4-ch lorophenyl )ethyl]-3-[(2R)-2-({(2R)-2-hyd roxy-2-[4-hydroxy-3 (hyd roxymethyl)p he nyl] ethylla mino)p ropyl] be nza mid e; N-(2 ,3-d ihyd ro- I H-inden-2-yi )-3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hyd roxy-3 (hydroxymethyl)phenyl]ethyi)amino)propyl]benzamide; 3-[(2R)-2-({(2R)-2-hyd roxy-2-[4-hydroxy-3 30 (hydroxymethyl)phenyl]ethyllamino)propyl]-N-(2-phenylethyl)benzamide; 3-[(2R)-2-({(2R)-2-hyd roxy-2-[4-hyd roxy-3 (hydroxymethyl)phenyl]ethyl~amino)propyl-N-[( I RP- -phenylethyl]benzamide; WO 2005/090287 PCT/IB2005/000640 233 3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3 (hydroxymethyl)phenyl]ethyl}amino)propyl]-N-(3-phenylpropyl)benzamide; 4-[(1 R)-2-({(1 R)-2-[3-(3,4-dihydroisoquinolin-2(1 H)-ylcarbonyl)phenyl]-1 methylethyl}amino)-1 -hydroxyethyl]-2-(hydroxymethyl)phenol; 5 N-(2,3-dimethylbenzyl)-3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3 (hydroxymethyl)phenyl]ethyl}amino)propyl]benzamide; N-(5,6-diethyl-2,3-dihydro-1 H-inden-2-yl)-3-[(2R)-2-({(2R)-2-hydroxy-2-[4 hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)propyl]benzamide; N-(4-chlorobenzyl)-3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3 10 (hydroxymethyl)phenyl]ethyl}amino)propyl]benzamide; 3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3 (hydroxymethyl)phenyl]ethyl}amino)propyl]-N-phenylbenzamide; N-[4-(aminosulfonyl)benzyl]-3-[(2R)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3 (hydroxymethyl)phenyl]ethyl}amino)propyljbenzamide; 15 N-[2-(3-Fluorophenyl)ethyl]-3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3 (hydroxymethyl)phenyl]ethyllamino)-2-methylpropyl]benzamide; 3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2 methylpropyl]-N-(2-pyrrolidin-1 -ylethyl)benzamide; N-[2-(2,6-dichlorophenyl)ethyl]-3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3 20 (hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]benzamide; N-(2,3-dihydro-1 H-inden-2-ylmethyl)-3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3 (hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]benzamide; N-(2-{4-[(butylamino)carbonyl]phenyl}ethyl)-3-[2-({(2R)-2-hydroxy-2-[4-hydroxy 3-(hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]benzamide; 25 3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2 methylpropyl]-N-{2-[2-(phenylthio)phenyl]ethylybenzamide; N-(2-cyclohexylethyl)-3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3 (hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]benzamide; 3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2 30 methylpropyl]-N-(3-phenylpropyl)benzamide; 3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2 methylpropyl]-N-(2-phenylethyl)benzamide; WO 2005/090287 PCT/11B2005/000640 234 N-[2-(3,6-d ichloro-2-methylphenyl)ethyl]-3-[2-({(2R)-2-hyd roxy-2-[4-hyd roxy-3 (hyd roxymeth yl)p henyljethyl~a m ino)-2-methyl pro pyl] be nza mid e; N-[2-(5-ch Ioro-2-methoxyphenyl )ethyl]-3-[2-({(2 R)-2-hydroxy-2-[4-hyd roxy-3 (hyd roxymethyI) phenyI]eth yI~am in o)-2-methyl pro pyi]be nza mid e; 5 3-[2-(((2 R)-2-hyd roxy-2-[4-hyd roxy-3-(hyd roxymethyl )pheny]ethyl~a mino)-2 meth yipropyi]-N-[2-(3-methoxyp hen yl)ethyl]benza mid e; N-[2-(3-ethoxyphenyl)ethyl]-3-[2-({ (2R)-2-hydroxy-2-[4-hydroxy-3 (hydroxymethyl)phenyllethyllamino)-2-methylpropyl]benzamide; 3-[2-({(2R)-2-hyd roxy-2-[4-hyd roxy-3-(hyd roxymethyl )phenyllethyl}a mino)-2 10 methyl pro pyl]-N-{2-[4-(3-pyrrol id in- 1 -ylpropoxy)phenyl]ethyl~benzamide; 3-[2-({(2R)-2-hyd roxy-2-[4-hydroxy-3-(hyd roxymethyl )phenyljethyl~amino)-2 methyl pro pyl]-N-{2-[2-(3-pyrro id in- 1 -yIpropoxy)phenyI]ethyI~benzamide; 3-[2-({(2R)-2-hyd roxy-2-[4-hydroxy-3-(hyd roxymethyl )phe nyljethyliam ino)-2 methylpropyl]-N-{2-[3-(3-pyrrolid in-i -ylpropoxy)phenyl]ethyl~benzamide; 15 N-[2-(4-Chlorophenyl )ethyl]-N-ethyl-3-[2-({(2 R)-2-hyd roxy-2-[4-hydroxy-3 (hyd roxymethyl)phenyl]ethyllam ino)-2-methyl pro pyl] be nzam ide; 2-{3-[2-({(2 R)-2-hydroxy-2-[4-hyd roxy-3-(hydroxymethyl)phenyl] ethyllam ino)-2 methyl pro pyl] phe nyl}-N-(3-pyrrol id in- 1 -ylpropyl)acetamide; N-(Cycloheptyl methyl)-2-{3-[2-({(2 R)-2-hyd roxy-2-[4-hyd roxy-3 20 (hyd roxymethyl)p henyl] ethylla min o)-2- methylp ropyl] phen yl}aceta mid e; N-i -Ada ma ntyl-2-{3-[2-({(2 R)-2-hyd roxy-2-[4-h yd roxy-3 (hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl] phenyl)acetamide; N-Benzyl-2-{3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hyd roxymethyl) phenyl]ethyl~amino)-2-methylpropyl]phenyl}-N-methylacetamide; 25 N-[2-(4-Fluorophenyl)ethyll-3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3 (hyd roxymeth yl)p henyl]ethyl~a mi no)-2-meth yl propyl] benza mid e; 3-[2-({(2R)-2-hydroxy-2-[4-hyd roxy-3-(hyd roxymethyl )phenyljethyl}amino)-2 methylpropyl]-N-[2-(4-phenoxyphenyl)ethyl]benzamide; N-[2-(4-ethoxyphenyl )ethyl]-3-[2-({(2 R)-2-hyd roxy-2-[4-hyd roxy-3 30 (hydroxymethyI)phenyI]ethyIlamino)-2-methylpropyI]benzamde; N-[2-(4-ethylphenyl)ethyl]-3-[2-({(2 R)-2-hydroxy-2-[4-hydroxy-3 (hydroxymethyl)phenyllethyllamino)-2-methylpropyl] benzamide; WO 2005/090287 PCT/1B2005/000640 235 3-[2-({(2 R)-2-hyd roxy-2-[4-hyd roxy-3-(hyd roxymethyl)phenyl]ethyllamino)-2 methylpropyl]-N-[2-(6-methylpyridin-2-yl)ethyl]benzamide; 3-[2-(f{(2 R)-2-hyd roxy-2-[4-hyd roxy-3-(hyd roxymethyl )phenyl]ethyllam ino)-2 methyl pro pyl]- N-[2-(2-methoxyp henyl)ethyl] be nza mid e; 5 methyl 4-[({3-[2-({(2 R)-2-hyd roxy-2-[4-hyd roxy-3-(hydroxymethyl)phenyllethyl} am ino)-2-methylpro pyl] benzoyl}amni no)m ethyl] benzoate; N-[4-(dimethyla mino)benzyl]-3-[2-({(2 R)-2-hyd roxy-2-[4-hydroxy-3 (hydroxymethyl)phenyl]ethyl~amino)-2-methylpropyl]benzamide; N-{2-[3-fluoro-4-(trifl uoromethyl )pheny]ethyl}-3-[2-({(2 R)-2-hydroxy-2-[4 10 hyd roxy-3-(hyd roxymnethyl)phe nyl] ethyl~amnin o)-2-meth yl pro pyl] be nzam id e; N-[2-(3-fluoro-4-methyl phenyl )ethyl]-3-[2-({(2R)-2-hydroxy-2-[4-hyd roxy-3 (hydroxymethyl )phenyl]ethyllamino)-2-methylpropyllbenzamde; N-[2-(2 ,3-difluoro-4-methylphenyl )ethyl]-3-[2-({(2 R)-2-hydroxy-2-[4-hyd roxy-3 (h yd roxymethyl) ph enyl]ethylla m ino)-2-methyl propyl] benza mid e; 15 3-[2-({(2R)-2-hyd roxy-2-[4-hyd roxy-3-(hydroxymethyl)phenyl]ethyl~amino)-2 m ethyl propyl]-N-(2-mes ityl ethyl )benza mid e; N-[2-(2,6-d iflu oro-3-methyl phen yl )ethyl]-3-[2-({(2 R)-2-hyd roxy-2-[4-hyd roxy-3 (hydroxymethyl)phenyl]ethyllamino)-2-methylpropyljbenzamide; N-[2-(6-chloro-2-fluoro-3-methyl phenyl )ethyl]-3-[2-({(2 R)-2-hyd roxy-2-[4 20 hyd roxy-3-(hyd roxymnethyl)phe nyl]ethyllamrnino)-2-methyl pro pyl] be nza m ide; N-[2-(2-chloro-6-fl uoro-3-.methylphenyl )ethyl]-3-[2-({(2 R)-2-hyd roxy-2-[4 hyd roxy-3-(hyd roxymnethyl)phe nyl] eth yjam ino )-2-methyl pro pyl] benza mid e; N-[2-(5-fluoro-2-methylphenyl )ethyl]-3-[2-({(2R)-2-hyd roxy-2-[4-hydroxy-3 (hydroxymethyl)phenyl]ethyl~amino)-2-methylpropyl]benzamide; 25 N-{2-[3-fluoro-5-(trifl uoromethyl)phenyl]ethyl}-3-[2-({(2 R)-2-hydroxy-2-[4 hyd roxy-3-(hyd roxymethyl)phe nyl] ethyllamni no)-2-methyl propyl] benza mid e; 3-[2-(((2 R)-2-hyd roxy-2-[4-hyd roxy-3-(hydroxymethyl )phenyl]ethyllamino)-2 methylpropyl]-N-{2-[2-(trifluoromethyl)phenyl]ethyl}benzamide; 3-[2-({(2 R)-2-hyd roxy-2-[4-hyd roxy-3-(hydroxymethyl )phenyl]ethylla mino)-2 30 methylpropyl]-N-[2-(2,4,5-trimethylphenyl)ethyl]benzamide; 3-[2-({(2 R)-2-hyd roxy-2-[4-hyd roxy-3-(hyd roxymethyl)phenyljethy~amino)-2 methyl pro pyl]- N-(2-pyrid in-2-yleth yl )be nza mide; WO 2005/090287 PCT/1B2005/000640 236 N-[2-(1 H-benzimidazo-2-y)ethy]-3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3 (hyd roxymethyl)p hen yljethyilam ino)-2-methyl pro pyl] benza mid e; 3- [2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hyd roxymethyl )phenyl]ethyllam ino)-2 m ethyl pro pyll- N-{2-[4-(morp holi n-4-yl sulIfonyl)phe nyl] ethyllbenza mid e; 5 N-[2-(3-chloro-2-hyd roxyphenyl )ethyl]-3-[2-({(2 R)-2-hyd roxy-2-t4-hyd roxy-3 (hyd roxymeth yl)phenyl] ethyl}am in o)-2-methyl pro pyl] benza mide; N-[4-fluoro-2-(trifluoromethyl )benzyl]-3-[2-({(2R)-2-hyd roxy-2-[4-hydroxy-3 (hyd roxym ethyl)phe nyl]ethyl}a m ino)-2-methyl pro pyl] benza mide; N-(3-chlorobenzyl)-3-[2-({(2 R)-2-hyd roxy-2-[4-hyd roxy-3 10 (hydroxymethyl)phenyl]ethyllamino)-2-methylpropyllbenzamide; N-(2-chlorobenzyl )-3-[2-({(2 R)-2-hyd roxy-2-[4-hyd roxy-3 (hydroxymethyI)pheny]ethyI~amino)-2-methylpropyl~benzamide; N-[2-(4 ,6-dimethyl pyrim id in-2-yI )ethyi]-3-[2-({(2R)-2-hyd roxy-2-[4-hyd roxy-3 (hyd roxymethyl)phenyl]ethyl}amino)-2-methylpropyl]benzamide; 15 3-[2-({(2 R)-2-hyd roxy-2-[4-hyd roxy-3-(hyd roxymethyl)phenyl]ethyl~am ino)-2 m ethyl propy]- N -[2-(3-meth ylpyrid in-2-yI)ethy] benza mide; N-[2-(2-ch lo ro phen yl )eth yl]-3-[2-({(2 R)-2-hyd roxy-2-[4-hyd roxy-3 (hydroxymethyI)pheny]ethyI}amino)-2-methylpropyI]benzamide; N-[2-( I -adama ntyl )ethyl]-3-[2-({(2 R)-2-hyd roxy-2-[4-hydroxy-3 20 (hyd roxym ethyl) ph enyl] eth yl~a m ino)-2-methyl propyl] be nza mid e; 3-[2-({(2 R)-2-hyd roxy-2-[4-hyd roxy-3-(hyd roxymethyl)phe nyl]ethyl}ami no)-2 methylpropyl]-N-[2-( I -naphthyl)ethyl]benzamide; N-[2-(2, 6-dimethyiphenyl )ethyl]-3-[2-({(2 R)-2-hydroxy-2-[4-hyd roxy-3 (hydroxymethyI)pheny]ethyI~amino)-2-methylpropyI]benzamide; 25 3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyI~ethyI}amino)-2 methyl pro pyI]-N-{2-[4-(m ethylth io)pheny] ethyllbe nza mid e; N-[2-(5-chloro-2-fI uorophenyl)ethyl]-3-[2-({(2 R)-2-hyd roxy-2-[4-hydroxy-3 (hyd roxymethyl)p henyll eth yl~a m ino)-2-m ethyl pro pyl] be nza mid e; N-[2-(2-chloro-4-fl uorophenyl)ethyl]-3-[2-({(2 R)-2-hyd roxy-2-[4-hyd roxy-3 30 (hydroxymethyI)phenyl~ethyIlamino)-2-methylpropyI]benzamide; 3-[2-({(2R)-2-hyd roxy-2-[4-hyd roxy-3-(hyd roxymethyl )phenyl]ethyllamino)-2 methylpropyll-N-[2-(4-methoxy-2,5-dimethyl phenyl)ethyllbenzamide; WO 2005/090287 PCT/11B2005/000640 237 N-[2-(2,3-d ichlorophenyl)ethyl]-3-[2-({(2 R)-2-hyd roxy-2-[4-hyd roxy-3 (hyd roxymnethyl)p hen yl] ethylla min o)-2-methyl pro pyl] benza mide; 3-[2-({(2R)-2-hyd roxy-2-[4-hyd roxy-3-(hyd roxymethyl )phenyl]ethyl}am ino)-2 methylpropyl]-N-[2-(4-methoxy-2,3-dimethylphenyl )ethyl]benzamide; 5 N-(2-biphenyl-4-ylethyl)-3-[2-({(2R)-2-hydroxy-2-[4-hyiroxy-3. (hydroxymethyl)phenyl]ethyllamino)-2-methylpropyl]benzamide; N-[2-(2 ,4-d imethyl phenyl )ethyl]-3-[2-({(2 R)-2-hyd roxy-2-[4-hydroxy-3 (hydroxymethyl )phenyl]ethyl~amino)-2-methylpropyllbenzamide; N-[2-(2 ,3-d imethyl phenyl)ethyl]-3-[2-({(2R)-2-hyd roxy-2-[4-hyd roxy-3 10 (hydroxymethyl)phenyllethyllamino)-2-methylpropyllbenzamide; 3-[2-({(2R)-2-hyd roxy-2-[4-hyd roxy-3-(hyd roxymethyl )phenyI]ethyI~amino)-2 methylpropyl]-N-{2-[3-(trifl uoromethyl)phenyl]ethyllbenza m ide; N-[2-(4-ch Ioro-2-fluorophenyl )ethyl]-3-[2-({(2R)-2-hyd roxy-2-[4-hyd roxy-3 (hydroxymethyl)phenyl]ethyllamino)-2-methylpropyljbenzamide; 15 N-(2 ,5-di methylbenzyl )-3-[2-({(2 R)-2-hyd roxy-2-[4-hyd roxy-3 (hydroxymethyl )phenyl]ethyl}amino)-2-methylpropyljbenzamide; N-(3 ,4-Dichlorobenzyl)-3-{3-[2-({(2 R)-2-hydroxy-2-[4-hydroxy-3 (h yd roxymethyl) phe nyllethylla mino)-2-methyl propyl] ph enyllp ro pan am ide; 3-[2-({(2R)-2-Hydroxy-2-[4-hyd roxy-3-(hyd roxymethyl)phenyl]ethyllamino)-2 20 methylpropyl]-N-{2-[4-(trifluoromethoxy)phenyllethyllbenzamide; 3-[2-({(2 R)-2-hyd roxy-2-[4-hydroxy-3-(hydroxymethyl )phenyl]ethyl~amino)-2 methylpropyI]-N-[2-(4-hydroxypheny)-2-methylpropy]benzamide; 3-[2-({(2 R)-2-hyd roxy-2-[4-hyd roxy-3-(hyd roxymethyl)phenyl]ethyl~amino)-2 methylpropy]-N-[2-(4-hyd roxy-3-methylphenyl )ethyl]benzamide; 25 N-[2-(4-hyd roxy-2 ,3-d i methylp he nyl )ethyl]-3-[2-({(2 R)-2-hyd roxy-2-[4-hyd roxy-3 (hyd roxymethyl )phenyl]ethyl~a mi no)-2-methyl propyt] benzamide; N-[2-(4-hyd roxy-2 ,5-d imethyl phenyl )ethyl]-3-[2-({(2 R)-2-hyd roxy-2-[4-hyd roxy-3 (hyd roxymethyl)phenyl]ethyl~a mi no)-2-meth yipro pyl] be nzamid e; N-(3 ,4-d ichlorobenzyl )-2-{3-[2-(((2R)-2-hydroxy-2-[4-hydroxy-3 30 (hyd roxymethyi)phenyllethylla mi no)-2-methyl propyllphenyllaceta m de; N-(3 ,5-d ichlorobenzyl )-2-{3-[2-({(2 R)-2-hydroxy-2-[4-hydroxy-3 (hydroxymethyl)pheny~ethy~amino)-2-methylpropyl~phenyl~acetamide; WO 2005/090287 PCT/IB2005/000640 238 2-{3-[2-({(2 R)-2-hyd roxy-2-[4-hyd roxy-3-(hyd roxymethyl)phenyl]ethyl}am i no)-2 methylpropyl]phenyl}-N-(pyridin-2-ylmethyl)acetamide; N-ethyl-3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl} amino)-2-methylpropyl]-N-(3-phenylpropyl)benzamide; 5 3-[2-({(2 R)-2-hyd roxy-2-[4-hyd roxy-3-(hyd roxymethyl)phe nyl]ethyl}amino)-2 methylpropyl]-N-[3-(4-hydroxyphenyl)propyl]benzamide; 3-[2-({(2 R)-2-hyd roxy-2-[4-hyd roxy-3-(hyd roxymethyl)phe nyljethyl}ami no)-2 methylpropyl]-N-[2-(3-methylphenyl)ethyl]benzamide; 3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2 10 methylpropyl]-N-[2-(6-methoxypyridin-3-yl)ethyl]benzamide; 3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2 methyl propyl]-N-[3-(3-methoxyphenyl)propyl] benzam ide; N-[3-(4-Chlorophenyl)propyl]-3-{2-[(2R)-2-hyd roxy-2-(4-hyd roxy-3 hydroxymethylphenyl)ethylamino]-2-methylpropyl}benzamide; 15 3-[2-({(2R)-2-hyd roxy-2-[4-hyd roxy-3-(hyd roxymethyl)phenyl]ethyl}am i no)-2 methylpropyl]-N-{2-[4-(1 H-pyrazol-1 -yl)phenoxy]ethyl}benzamide; N-[2-(3,4-difluorophenyl)ethyl]-3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3 (hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyljbenzamide; 3-[2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2 20 methylpropyl]-N-(2-quinolin-5-ylethyl)benzamide; and, N-[3-(2-ethyl-2,3-dihydro-1-benzofuran-5-yl)propyl]-3-[2-({(2R)-2-hydroxy-2-[4 hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]benzamide.

16. A process for the preparation of a compound of formula (1) as described in any one of claims 1 to 15 or a pharmaceutically acceptable salt or derived form 25 thereof comprising the step of coupling an acid of formula (2): OH H N (2) (CH 2 )n OH HO R 1 R 2 0 HO with an amine of formula N(R 8 )_Q 2 -A (3), WO 2005/090287 PCT/IB2005/000640 239 R 3 R4 R 3 R 8 R4 (CH 2 )p R 5 -N R 5 (3'), or (3"), wherein R 8 , Q 2 , A, p and R 3 to R 6 are as previously defined for compounds of formula (1). 5

17. A pharmaceutical composition comprising at least an effective amount of a compound of the formula (1) as described in any one of claims 1 to 15 or a pharmaceutically acceptable salt or derived form thereof.

18. A pharmaceutical composition according to any one of claims I to 15, further comprising one or more pharmaceutically acceptable excipients and/or 10 additives.

19. A compound of formula (1) as described in any one of claims 1 to 15 or a pharmaceutically acceptable salt, derived form or composition thereof, for use as a medicament.

20. A compound of formula (1) as described in any one of claims 1 to 15 or a 15 pharmaceutically acceptable salt, derived form or composition thereof, for use in the treatment of diseases, disorders, and conditions in which the P2 receptor is involved.

21. A compound of formula (1) as described in any one of claims 1 to 15 or a pharmaceutically acceptable salt, derived form or composition thereof, for use 20 in the treatment of diseases, disorders, and conditions selected from the group consisting of: e asthma of whatever type, etiology, or pathogenesis, in particular asthma that is a member selected from the group consisting of atopic asthma, WO 2005/090287 PCT/IB2005/000640 240 non-atopic asthma, allergic asthma, atopic bronchial IgE-mediated asthma, bronchial asthma, essential asthma, true asthma, intrinsic asthma caused by pathophysiologic disturbances, extrinsic asthma caused by environmental factors, essential asthma of unknown or 5 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, 10 e 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 15 eosinophilic pneumonia, chronic obstructive pulmonary disease (COPD), COPD that includes chronic bronchitis, pulmonary emphysema or dyspnea associated or not associated with COPD, COPD that is characterized by irreversible, progressive airways obstruction, adult respiratory distress syndrome (ARDS), exacerbation of airways hyper 20 reactivity consequent to other drug therapy and airways disease that is associated with pulmonary hypertension, * bronchitis of whatever type, etiology, or pathogenesis, in particular bronchitis that is a member selected from the group consisting of acute bronchitis, acute laryngotracheal bronchitis, arachidic bronchitis, 25 catarrhal bronchitis, croupus bronchitis, dry bronchitis, infectious asthmatic bronchitis, productive bronchitis, staphylococcus or streptococcal bronchitis and vesicular bronchitis, e acute lung injury, WO 2005/090287 PCT/IB2005/000640 241 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 5 bronchiectasis and follicular bronchiectasis.

22. The use of a compound of formula (1) as described in any one of claims 1 to 15 or of a pharmaceutically acceptable salt, derived form or composition thereof, for the manufacture of a drug having a P2 agonist activity.

23. The use of a compound of formula (1) as described in any one of claims 1 10 to 15 or of a pharmaceutically acceptable salt, solvate or composition thereof, for the manufacture of a drug for the treatment of diseases, disorders, and conditions selected from the group as described in claim 21.

24. A method of treatment of a mammal, including a human being, with a P2 agonist including treating said mammal with an effective amount of a compound 15 of formula (1) as described in any one of claims 1 to 15 or with a pharmaceutically acceptable salt, derived form or composition thereof.

25. A method according to claim 24 where the disease, disorder or condition is selected from the group as described in claim 21.

26. A combination of a compound according to any one of claims 1 to 15 with a 20 therapeutic agent selected from: (a) 5-Lipoxygenase (5-LO) inhibitors or 5-lipoxygenase activating protein (FLAP) antagonists, (b) Leukotriene antagonists (LTRAs) including antagonists of LTB 4 , LTC 4 , LTD 4 , and LTE 4 , 25 (c) Histamine receptor antagonists including HI and H3 antagonists, (d) a- and a 2 -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, WO 2005/090287 PCT/IB2005/000640 242 (g) Theophylline, (h) Sodium cromoglycate, (i) COX inhibitors both non-selective and selective COX-1 or COX-2 inhibitors (NSAIDs), 5 (j) Oral and inhaled glucocorticosteroids, such as DAGR (dissociated agonists of the corticoid receptor) (k) Monoclonal antibodies active against endogenous inflammatory entities, (1) Anti-tumor necrosis factor (anti-TNF-a) agents, (m)Adhesion molecule inhibitors including VLA-4 antagonists, 10 (n) Kinin-B 1 - and B 2 -receptor antagonists, (o) Immunosuppressive agents, (p) Inhibitors of matrix metalloproteases (MMPs), (q) Tachykinin NK 1 , NK 2 and NK 3 receptor antagonists, (r) Elastase inhibitors, 15 (s) Adenosine A2a receptor agonists, (t) Inhibitors of urokinase, (u) Compounds that act on dopamine receptors, e.g. D2 agonists, (v) Modulators of the NFKp pathway, e.g. IKK inhibitors, (w)modulators of cytokine signalling pathways such as p38 MAP kinase, 20 syk kinase or JAK kinase inhibitor, (x) Agents that can be classed as mucolytics or anti-tussive, (y) Antibiotics, (z) HDAC inhibitors, and, (aa) P13 kinase inhibitors. 25