MXPA06007786A - Sulfonamide derivatives for the treatment of diseases - Google Patents

Abstract

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

Description

DERIVATIVES OF SULFONAMIDE FOR THE TREATMENT OF DISEASES. FIELD OF THE INVENTION This invention relates to β2 agonists of the general formula: wherein R1, R2, n and Q1 have the meanings indicated below, and to processes for the preparation, compositions containing and uses of such derivatives. Adrenergic receptors are members of the large superfamily protein coupled receptors G. The family of adrenoceptors is in turn divided into subfamilies and ß, ß subfamily by at least 3 receptor subtypes being composed: SS1, SS2 and SS3 . These receptors show differentiated expression patterns in the tissues of various mammalian systems and organs. Β2 adrenergic receptors (β2) are expressed mainly in smooth muscle cells (eg, vascular, bronchial, uterine or intestinal muscles), whereas β3 adrenergic receptors are expressed mainly in fatty tissues (Therefore ß3 agonists could potentially be useful in the treatment of obesity and diabetes) and beta1 adrenergic receptors are mainly expressed in cardiac tissues (therefore ß1 agonists are mainly used as cardiac stimulants). BACKGROUND OF THE INVENTION The pathophysiology and treatments of diseases of the respiratory tract have been reviewed extensively in the literature (for reference see Barnes, PJ Chest, 1997, 111: 2, pp 17S-26S and Bryan, SA et al Expert Opinion on investigative drugs, 2000, 9: 1, pages 25-42) and therefore only a brief summary will be included in the present report to provide some background information. Glucocorticosteroids, antileukotrienes, theophylline, chromones, anticholinergics, and β2 agonists are classes of drugs that are currently used to treat allergic and non-allergic diseases of the respiratory tract, such as asthma and chronic obstructive airways disease (COPD). Treatment guidelines for these diseases include inhaled β2 agonists of both short and long-term action. Short-acting, fast-acting β2-agonists are used for "rescue" bronchodilation, while long-acting forms provide sustained relief and are used as maintenance therapy. Bronchodilation is mediated by β2 adrenergic receptor agonism expressed in smooth muscle cells of the pathways respiratory, which produces relaxation and, therefore, bronchodilation. Thus, as functional antagonists, ss2 agonists can prevent and reverse the effects of all bronchoconstrictor substances, including leukotriene D4 that (LTD4), acetylcholine, bradykinin, prostaglandins, hlstamina and endothelins. Because ß2 receptors are distributed so widely in the airways, ß2 agonists can also affect other cell types that play a role in asthma. For example, it has been reported that ß2 agonists can stabilize mast cells. The inhibition of the release of bronchoconstrictor substances may be the way in which ß2 agonists block the bronchoconstriction induced by allergens, exercise and cold air. In addition, ß2 agonists inhibit cholinergic neurotransmission in the human respiratory tract, which may cause less bronchoconstriction due to the cholinergic reflex. In addition to the respiratory tract, it has also been established that β2-adrenergic receptors are also expressed in other organs and tissues and thus β2-agonists, such as those described in the present invention, may have application in the treatment of other diseases such as, but not limited to, the nervous system, premature labor, congestive heart failure, depression, inflammatory and allergic skin diseases, psoriasis, proliferative skin diseases, glaucoma and in conditions where it is advantageous to reduce acidity gastric, in particular in gastric and peptic ulceration.

However, many ß2 agonists are of limited use due to their reduced selectivity or adverse side effects produced by elevated systemic exposure and mediated mainly by action on β2 adrenergic receptors expressed outside the airways (muscle tremors, tachycardia, palpitations , restlessness). Therefore, there is a need for improved agents in this class. Accordingly, there is still a need for novel β2 agonists that would have an adequate pharmacological profile, for example in terms of potency, pharmacokinetics or duration of action. In this context, the present invention relates to novel β2 agonists. Various sulfonamide derivatives have already been described. For example, WO02066250 discloses active compounds as β3 agonists, which are selective in relation to β2, of the formula: wherein m can be 2, R i can be H, OH or NR 5 SO 2 R 5 (where R 5 H or C C alkyl), Z can be a bond, R 2 can be H or C 1 -C 6 alkyl, R 4 can be C 6 alkyl, B it can be phenyl, and it is CrC6 alkyl and A can be phenyl. WO02 / 000622 describes selective β3 agonists of the formula: wherein R 1 can be phenyl substituted with hydroxy and alkylsulfonylamino, X-i can be a bond, R 2 can be hydrogen, R 3 is hydrogen or hydroxyalkyl, X 2 can be CH 2, X 3 is a bond, O or NH and R 4 is a cyclic group. Other sulfonamide derivatives are also described in US Pat. No. 5,776,983 as β3 agonists. More specifically they are of the formula: wherein R1 can be CH3, R2 can be OH, R6 can be H, R3 can be H or alkyl, R4 can be H, alkyl, R5 can be H, R5 'can be C (O) NR6R6 \ in which R6 and R6 can be H or lower alkyl. However, none of the above sulfonamide derivatives have demonstrated selective β2 agonist activity, allowing them to be used as efficient drugs in the treatment of diseases and / or conditions mediated by β2, in particular allergic and non-allergic diseases of the pathways. respiratory diseases or other diseases such as those mentioned above.

DETAILED DESCRIPTION OF THE INVENTION This invention relates to the compounds of the general formula wherein the group (CH2) nC (= O) Q1 is in relative position meta or para, R1 and R2 are independently selected from H and C1-C4 alkyl, n is 0, 1 or 2 and Q1 is a group that is select from, and a group * -NR11-Q2-A, wherein p is 1 or 2, Q2 is a C1-C4 alkylene, R11 is H or C1-C4 alkyl and A is pyridyl, C3-C10 cycloalkyl, said cycloalkyl being, which is optionally bridged by one or more, preferably 1, 2, 3 or 4, carbon atoms, tetrahydropyranyl, piperidinyl optionally substituted by benzyl, tetrahydrothiopyranyl or a group wherein R3, R4, R5, R6 and R7 are the same or different and are selected from H, C1-C4 alkyl, OR8, SR9, halo, CN, CF3, OCF3, COOR9, SO2NR9R10, CONR9R10, NR9R10, NHCOR10 and phenyl; wherein R8 is C1-C4 alkyl and R9 and R10 are the same or different and are selected from H or C1-C4 alkyl and the * represents the point of attachment to the carbonyl group; or, if appropriate, its pharmaceutically acceptable salts and / or isomers, tautomers, solvates or isotopic variations. The compounds of the formula (1) are agonists of the β2 receptors, which are particularly useful for the treatment of diseases and / or conditions mediated by β2, demonstrating an excellent potency, in particular when administered by the inhaled route. In general formula (1) above, C 1 -C 4 alkyl and C 1 -C 4 alkylene denote a straight or branched chain group containing 1, 2, 3 or 4 carbon atoms. This also applies if they carry substituents or appear as substituents of other radicals, for example on O-C 1 -C 4 alkyl radicals, S-C 1 -C 4 alkyl radicals, etc. Examples of suitable C 1 -C 4 alkyl radicals are methyl , ethyl, n-propyl, isopropyl, n-butyl, / so-butyl, sec-butyl, fer-butyl .... Examples of suitable O-C 1 -C 4 alkyl radicals are methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, / so-butyloxy, sec-butyloxy and tert-butyloxy .... C3-C10 cycloalkyl in which 2 carbon atoms or more are optionally linked by one or more carbon atoms includes cyclopropyl, Cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, adamantyl, bicyclo [3.1.1] heptane, bicyclo [2.2.1] heptane, bicyclo [2.2.2] octane. Preferred cycloalkyl groups are cyclohexyl and adamantyl. Finally, halo denotes a halogen atom which is selected from the group consisting of fluorine, chlorine, bromine and iodine, in particular fluorine or chlorine. Next, the free bond of the phenyl group as in the structure below, means that the phenyl may be substituted in the meta or para position. The compounds of the foa (1) they can be prepared using conventional procedures such as the following illustrative methods in which R1, R2, Q1 and n are as defined above for the compounds of the foa (1) unless otherwise specified. The amide derivatives of the foa (1) can be prepared by coupling an acid of the foa (2) or a salt thereof: with an amine of the foa NHR11-Q2-A (3), The coupling is generally carried out in an excess of said amine as an acid receptor, with a conventional coupling agent (for example 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride or? /,? / - dicyclohexylcarbodiimide), optionally in the presence of a catalyst (for example, 1-hydroxybenzotriazole hydrate or 1-hydroxy-7-azabenzotriazole) and optionally in the presence of a tertiary amine base (for example N-methylmorpholine, triethylamine or diisopropylethylamine). The reaction may be carried out in a suitable solvent such as pyridine, dimethylformamide, tetrahydrofuran, dimethyl sulfoxide, dichloromethane or ethyl acetate and at a temperature between 10 ° C and 40 ° C (room temperature) for a period of 1-24 hours. Said amine (3), (3 ') or (3") is either commercially available or can be prepared by well-known conventional methods for an expert in the art. the technique (for example, reduction, oxidation, alkylation, transition-mediated metal coupling, protection, deprotection, etc.) from materials available in the market. The acid of the foa (2) can be prepared from the corresponding ester of the foa (4): wherein Ra is a suitable acid protecting group, preferably a C1-C4 alkyl group, including, but not limited to, methyl and ethyl, according to any method known to one skilled in the art to prepare an acid from an ester, without modifying the rest of the molecule. For example, the ester can be hydrolysed by treatment with an aqueous acid or base (for example, hydrogen chloride, potassium hydroxide, sodium hydroxide or lithium hydroxide), optionally in the presence of a solvent or mixture of solvents (for example, water, propionitrile). , 1,4-dioxane, tetrahydrofuran / water) at a temperature between 20 ° C and 100 ° C for a period of 1 to 40 hours. The ester of the foa (4) can be prepared by reaction of the amine of the foa (5): wherein Ra and n are as defined above, with a bromide of the foa (6); In a typical procedure, the amine of the foa (5) is reacted with a bromide of the foa (6) optionally in the presence of a solvent or mixture of solvents (for example, dimethyl sulfoxide, toluene,? /,? dimethylformamide, propionitrile, acetonitrile), optionally in the presence of a suitable base (for example triethylamine, diisopropylethylamine, potassium carbonate, potassium hydrogencarbonate) at a temperature comprised between 80 ° C and 120 ° C, for 12 to 48 hours. The bromide of the foa (6) can be prepared according to the method of WO 02/06258 (page 36, example 14a). The amine of the foa (5), in which R-i is Me and R2 is H, can be prepared in the form of the (R) or (S) -enantiomer from the corresponding protected amine of the foa (7): wherein Ra and n are as defined above and Rb and Rc represent any suitable substituents such that HNRbRc is a chiral amine (e.g., Rb can be hydrogen and Rc can be a- methylbenzyl), with the proviso that the bonds between N and Rb and N and Rc can be easily cleaved by providing the free amine of the formula (5) using standard methodology to cleave nitrogen protecting groups, such as those found in the book Text TW GREENE, Protective Groups in Organic Synthesis, A. Wiley-lnterscience Publication, 1981. The amine of the formula (7) can be prepared in the form of a single diastereomer by reaction of an amine of the formula HNRbRc with a ketone of the formula (8). ): wherein Ra, Rb, Rc and n are as defined above. In a typical procedure, the reaction of the ketone of the formula (8) with the amine of the formula HNRbRc produces a chiral intermediate which in turn is reduced by a suitable reducing agent (for example sodium cyanoborohydride of the formula NaCNBH3 or sodium triacetoxyborohydride) of the formula Na (OAc) 3BH) optionally in the presence of a drying agent (for example, molecular sieves, magnesium sulfate) and optionally in the presence of an acid catalyst (for example acetic acid) providing the amine of the formula (7) in form of a mixture of diastereoisomers. The reaction is generally carried out in a solvent such as tetrahydrofuran or dichloromethane at a temperature between ° C and 80 ° C from 3 to 72 hours. The resulting product is then converted to the hydrochloride salt and selectively crystallized from a suitable solvent or mixture of solvents (eg isopropanol, ethanol, methanol, diisopropyl ether / methanol) to provide (7) as a single diastereomer. The ketone of the formula (8) in which n = 1 can be prepared by palladium mediated coupling of an aryl halide of the formula (9): wherein Ra is as defined above and Hal represents a halogen atom, including, but not limited to, bromine and iodine, with an enolate or enolate equivalent. In a typical procedure, the aryl halide of the formula (9) is reacted with a tin enolate generated in situ by treatment of isoprenyl acetate with tri-n-butyltin methoxide of the formula BusSnOMe in the presence of a suitable palladium (palladium acetate / tri-ortho-phosphine of the formula Pd (OAc) 2 / P (o-Tol) 3) in a non-polar solvent (for example toluene, benzene, hexane). Preferably, the reaction is carried out at a temperature between 80 ° C and 110 ° C for 6 to 16 hours. The aryl halide of the formula (9) can be obtained by esterification of the corresponding acid of the formula (10): wherein Hal is as defined above, according to any method known to one skilled in the art to prepare an ester from an acid without modifying the remainder of the molecule. In a typical procedure, the acid of the formula (10) is reacted with an alcohol solvent of the formula RaOH, wherein Ra is as defined above, in the presence of an acid such as hydrogen chloride at a temperature between 10 ° C and 40 ° C (room temperature) of 8 to 16 hours. The acid of the formula (10) is a commercial product. The amine of the formula (5), in which R1 = R2 = alkyl, can be prepared according to the following scheme: Scheme 1 O H2N XGT., ^. .CH? _... A ORa R1 R2 XA (5) wherein R1, R2 and Ra are as defined above. In a typical procedure, the ester of the formula (11) is reacted with an "activated" alkyl (organometallic alkyl such as R2MgBr, R2MgCl or R2Li) providing the corresponding tertiary alcohol of the formula (12) using the method described above. Said tertiary alcohol of formula (12) is then treated with an alkyl nitrile (for example acetonitrile, chloroacetonitrile) in the presence of an acid (for example sulfuric acid, acetic acid) providing a protected intermediate which in turn is cleaved using methodology standard for cleaving nitrogen-protecting groups such as those mentioned in textbooks. The resulting amino acid is then esterified using the method described herein providing the amine of formula (5). Alternatively, the amine of the formula (5), wherein R1 = R2 = C1-C4 alkyl and n = 0, can be prepared according to the following scheme Scheme 2 (13) (14) wherein R1, R2 and Ra are as defined above. In a typical procedure, the ester of the formula (13) is reacted with an "activated" alkyl (organometallic alkyl such as R2MgBr, R2MgCl or R2Li) providing the corresponding tertiary alcohol of the formula (14) using the method described above. Said tertiary alcohol of the formula (14) is then treated with an alkyl nitrile (for example acetonitrile, chloroacetonitrile) in the presence of an acid (for example sulfuric acid, acetic acid) providing a protected intermediate which in turn is cleaved using methodology standard for cleaving nitrogen protecting groups such as those mentioned in the textbooks providing bromoamine (15). The resulting bromoamine (15) is treated with a suitable palladium catalyst (eg, [1,1'- £ »/ s (diphenylphosphino) ferrocene] dichloropalladium (ll)) under carbon monoxide atmosphere using RaOH as solvent ( MeOH, EtOH) at elevated temperature (100 ° C) and pressure (7.03 kg / cm 2) to provide the ester of the formula (5). The ketone of the formula (8) wherein n = 2 can be prepared by reduction of an alkene of the formula (16): In a typical procedure, a solution of the olefin of the formula (16) in a suitable solvent (for example, methanol, ethanol, ethyl acetate) is treated with a palladium catalyst (for example 10% palladium on carbon) and it is stirred under a nitrogen atmosphere, optionally under pressure high (for example 4.22 kg / cm2), at a temperature between room temperature and 60 ° C for 8-24 hours. The alkene of the formula (16) can be prepared by palladium mediated coupling of an activated olefin with an aryl halide of the formula (17): In a typical procedure, the aryl halide (17) is coupled with a vinyl ester (for example methyl acrylate) in the presence of a suitable palladium catalyst (for example tetrakis (triphenylphosphine) palladium (0) of the formula Pd ( PPh3) 4, palladium acetate / tri-o / p-tolylphosphine of the formula Pd (OAc) 2 / P (o-tol) 3 or (diphenylphosphino) ferrocenylpalladium chloride of the formula dppfPdCk) in a suitable solvent (for example , acetonitrile, N, N-dimethylformamide, toluene), optionally in the presence of a base such as triethylamine at a temperature between 40 ° C and 110 ° C from 8 to 24 hours. The ketone of the formula (17) is a commercial product. The amine of the formula (5), in which R1 and R2 are both H, can be prepared according to the following scheme: Scheme 3 (18) (19) wherein R1, R2 and Ra are as defined above. In a typical procedure, the acid of the formula (18) is preferentially reduced to the corresponding alcohol (19) in the presence of the ester. This can be done by forming the acylimidazole or mixed anhydride and subsequent reduction with sodium borohydride or other suitable reducing agent. Said primary alcohol of the formula (19) is then converted to a leaving group such as mesylate, tosylate, bromide or iodide and is displaced with an appropriate amine nucleophile. The preferred nucleophile is the azide ion which can then be reduced to the primary amine by hydrogenation or triphenylphosphine. Alternative nucleophiles could include ammonia or alkylamines such as benzylamine or allylamine and subsequent cleavage of the alkyl group to provide the amine. In a typical procedure, the compounds of the formula (I) wherein R1 and R2 are both methyl and n is 1, can be prepared by reacting a compound of the formula (21) wherein X is H, Li, K or Na and an organic amine base or other metal salt, with a suitable amine of the formula NHR8-Q2-A (3) in the presence of a conventional coupling agent such as 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride or dicyclohexylcarbodiimide in a suitable solvent such as pyridine, dimethylformamide and dimethylacetamide, optionally in the presence of an organic base (such as Hünig's base) ) and an additive (such as 1-hydroxybenzotriazole) to obtain a compound of the formula (1): wherein R1 and R2 are methyl and n is 1.

Said compound of the formula (21) can be obtained by hydrogenating a compound of the formula (22) wherein X is H, Na, Li or K and potentially an organic amine or other metal salts in the presence of an appropriate solvent such as methanol, IPA, THF and water and in the presence of a suitable catalyst such as palladium hydroxide on carbon or palladium on carbon. Said compound of the formula (22) can be obtained by reacting a compound of the formula (23) C4 alkyl with M-OH wherein M is selected from Li, Na or K, optionally in the presence of a suitable solvent such as propionitrile, tetrahydrofuran or dioxane, preferably propionitrile. Said compound of the formula (23) can be obtained by deprotecting a compound of the formula (24) using a deprotection agent such as tetrabutylammonium fluoride, HF or triethylamine trifluorohydrate in the presence of a suitable solvent such as propionitrile. Said compound of the formula (24) can be obtained by reacting a compound of the formula C -C alkyl. with a compound of the formula in the presence of a suitable solvent such as propionitrile, THF, toluene, ethyl acetate, acetonitrile, propionitrile, dioxane, DMF, DMSO and optionally in the presence of a base such as hydrogen carbonate sodium, potassium hydrogencarbonate, Hünig base or triethylamine, at a temperature between 50 ° C and 150 ° C for 12 to 36 hours. For some of the steps of the process described above for the preparation of the compounds of the formula (1), it may be necessary to protect potential reactive functions that are not to be reacted and to cleave said protective groups accordingly. In such a case, any compatible protective radical can be used. In particular, protection and deprotection methods such as those described by T.W.

GREENE, (Protective Groups in Organic Synthesis, A. Wiley-lnterscience Publication, 1981) or by P. J. Kocienski (Protecting groups, Georg Thieme Verlag, 1994). All of the foregoing reactions and preparations of novel starting materials that are used in the above methods are conventional and the appropriate reagents and reaction conditions for their preparation or preparation as well as the methods for isolating the desired products will be well known to those skilled in the art. referring to the precedents published in the bibliography and to the examples and preparations of the present report. Also, the compounds of the formula (1) as well as the intermediates for their preparation can be purified according to several notorious methods such as, for example crystallization or chromatography.

Preferably Q1 is a group * -NH-Q2-A, wherein Q2 is CH2 and A is cyclohexyl, tetrahydrothiopyranyl, piperidinyl optionally substituted with benzyl or naphthyl. Preferably, Q1 is wherein R3, R4, R5 and R6 are H. Preferably, Q1 is a group * -NH-Q2-A, wherein Q2 is a C1-C4 alkylene and A is a group wherein R3, R4, R5, R6 and R7 are the same or different and are selected from H, C1-C4 alkyl, OR8, SR9, CN, halo, CF3, OCF3, SO2NR9R10, CONR9R10, NR9R10, NHCOR10 and phenyl with the condition that at least 2 of R3 to R7 are equal to H; wherein R8 is C1-C4 alkyl and R9 and R10 are the same or different and are selected from H or d-C alkyl. More preferably, Q1 is a group * -NH-Q2-A, wherein Q2 is a -CH2-, - (CH2) 2-, - (CH2) 3-, preferably -CH2- and A is a group wherein R3, R4, R5, R6 and R7 are the same or different and are selected from H, CH3, OCH2-CH3, SCH3, halo, CF3, OCF3, phenyl, dimethylamino, CN, fer-butyl, with the proviso that at least 2 of R3 to R7 be equal to H. More preferably, Q1 is a group * -NH-Q2-A, wherein Q2 is a -CH2-, - (CH2) 2-, - (CH2) 3-, preferably -CH2- and A is a group wherein R3, R4, R5, R6 and R7 are the same or different and are selected from H, CH3, Cl, F, CF3, with the proviso that at least 2 of R3 to R7 are equal to H. In the groups of the above compounds, the following substituents are particularly preferred: R1 is H or C1-C4 alkyl and R2 is C1-C4 alkyl. More preferably, R1 is H or CH3 and R2 is CH3. n is 1, 2 or 3. More preferably n is 1. R1 is H and R2 is CH3 and n is 1.

R1 is CH3, R2 is CH3 and n is 1. Particularly preferred are the compounds of the formula (1) as described in the Examples section below, ie:? / - Benzyl-2- (3- { 2 - [((2R) -2-hydroxy-2-. {4-hydroxy-3 - [(methylsulfonyl) amino] phenyl] ethyl) amino] -2-methylpropyl. Phenyl) acetamide, 2- (3- {2 - [((2R) -2-Hydroxy-2-. {4-hydroxy-3 - [(methylsulfonyl) amino] phenyl} ethyl) amino] -2-methylpropyl. phenol) -? / - (4-methoxybenzyl) acetamide, 2- (3. {2 - [((2R) -2-Hydroxy-2-. {4-hydroxy-3 - [( methylsulfonyl) amino] phenyl.} ethyl) amino] -2-methylpropyl. phenyl) -? / - (2-methoxybenzyl) acetamide,? / - (2-Ethoxybenzyl) -2- (3- {.2 - [((2R) -2-hydroxy-2- {4-hydroxy-3 - [(methylsulfonyl) amino] phenyl} ethyl) amino] -2-methylpropyl} phenyl) acetamide 2- (3- {2 - [((2R) -2-Hydroxy-2-. {4-hydroxy-3 - [(methylsulfonyl) amino] phenyl} ethyl) amino] -2-methylpropyl .}. phenyl) -? / - (3-methoxybenzyl) acetamide, 2- (3- { 2 - [((2R) -2-Hydroxy-2-. {4-hydroxy-3 - [(met Lysulfonyl) amino] phenyl.} Ethyl) amino ] -2-methylpropyl} phenyl) -? / - (4-methylbenzyl) acetamide, 2- (3- { 2 - [((2R) -2-Hydroxy-2-. {4-hydroxy-3- [(methylsulfonyl) amino]] phenyl.} ethyl) amino] -2-methylpropyl] phenyl) - # V- (2-methylbenzyl) acetamide, 2- (3- {2 - [((2R) -2-Hydroxy-2-. {4-hydroxy-3 - [(methylsulfonyl) amino] phenyl} ethyl) amino] -2- methy1propyl. phenyl) -? / - (3-methylbenzyl) acetamide, / V- (3,4-dimethoxybenzyl) -2- (3- { 2 - [((2R) -2-hydroxy- 2- {4-hydroxy-3 - [(methylsulphonyl) amino] phenyl} etl) amino] -2-methylpropyl} phenyl) acetamide,? / - (2, 4-Dimethoxybenzyl) -2- (3- {2 - [((2R) -2-hydroxy-2-. {4-hydroxy-3 - [(methylsulfonyl) amino] phenyl} ethyl) amino ] -2-methylpropyl.} Phenyl) acetamide,? / - (3,5-D-methoxybenzyl) -2- (3- { 2 - [((2R) -2-hydroxy-2- { 4-Hydroxy-3 - [(methylsulfonyl) amino] phenyl] ethyl) amino] -2-methy1propyl} phenyl) acetamide,? / - (4-chlorobenzyl) -2- (3-. {2 - [((2R) -2-hydroxy-2-. {4-hydroxy-3- [(methylsulfonyl) amino] phenyl} ethyl) amino] -2-methylpropyl} phenyl) acetamide ,? / - (2-Chlorobenzyl) -2- (3- { 2 - [((2R) -2-hydroxy-2-. {4-hydroxy-3 - [(methylsulfonyl) amino] phenyl}. ethyl) amino] -2-methylpropyl.} phenyl) acetamide,? / - (3-Chlorobenzyl) -2- (3-. {2 - [((2R) -2-hydroxy-2- { 4-hydroxy-3 - [(methylsulfonyl) amino] f enyl) ethyl) amino] -2-methylpropyl} phenyl) acetamide,? / - (4-Fluorobenzyl) -2- (3- { 2 - [((2R) -2-hydroxy-2-. {4-hydroxy-3 - [(methylsulfonyl) amino] phenyl.} ethyl) amino] -2-methylpropyl. phenyl) acetamide, / V- (2,4-dichlorobenzyl) -2- (3-. {2 - [((2R) -2-hydroxy) 2- {4-hydroxy-3 - [(methylsulfonyl) amino] phenyl} ethyl) amino] -2-methylpropyl.} Phenyl) acetamide,? / - (3,4-dichlorobenzyl) - 2- (3- {2 - [((2R) -2-hydroxy-2-. {4-hydroxy-3- [(methylsulfonyl) amino] phenyl} ethyl) amino] -2-methylpropyl} phenyl) acetamide,? / - (4-ferc-Butylbenzyl) -2- (3- { 2 - [((2R) -2-hydroxy-2-. {4-hydroxy-3 - [( methylsulfonyl) amino] phenyl.} ethyl) amino] -2-methylpropyl. phenyl) acetamide, ? / - (2-Chloro-6-fluorobenzyl) -2- (3- { 2 - [((2R) -2-hydroxy-2-. {4-hydroxy-3 - [(methylsulfonyl) amino] ] phenyl.} ethyl) amino] -2-methylpropyl. phenyl) acetamide,? / - (2,3-Dimethylbenzyl) -2- (3-. {2 - [((2R) -2-hydroxy] -2- {4-hydroxy-3 - [(methylsulfonyl) amino] phenyl} ethyl) amino] -2-methylpropyl.} Phenyl) acetamide,? / - (3,5-Dichlorobenzyl) -2- (3- {2 - [((2R) -2-hydroxy-2-. {4-hydroxy-3- [(methylsulfonyl) amino] phenyl} ethyl) amino] -2-methylpropyl. phenyl) acetamide,? / - [3,5-) / 's (trifluoromethyl) benzyl] -2- (3- {2 - [((2R) -2-hydroxy-2-. {4 -hydroxy-3 - [(methylsulfonyl) amino] phenyl.} ethyl) amino] -2-methylpropyl. phenyl) acetamide, ? - (3,4-Dimethylbenzyl) -2- (3- { 2 - [((2R) -2-hydroxy-2. {4-hydroxy-3 - [(methylsulfonyl) amino] phenyl} ethyl) amino] -2-methylpropyl. phenyl) acetamide,? / - (2,5-dichlorobenzyl) -2- (3- {(2R) -2 - [((2R) -2- hydroxy-2- {4-hydroxy-3 - [(methylsulfonyl) amino] phenyl} ethyl) amino] propyl} phenyl) acetamide, 2- (3-. {2 - [((2R) -2-Hydroxy-2- {4-hydroxy-3 - [(methylsulfonyl) amino] phenyl} ethyl) amino] -2-methylpropyl} phenyl) - / V- (2-phenylethyl) Acetamida, 2- (3- {2 - [((2R) -2-Hydroxy-2-. {4-hydroxy-3 - [(methylsulfonyl) amino] phenyl} ethyl) amino] - 2-methylpropyl.}. Phenyl) -? / - (3-phenylpropyl) acetamide,? / - (2,3-Dichlorobenzyl) -2- (3 { (2R) -2 - [((2R) - 2-hydroxy-2- {4-hydroxy-3 - [(methylsulfonyl) amine] phenyl} ethyl) amino] propyl} phenyl) acetamide,? / - (2,4-Dichloro-6-methylbenzyl) ) -2- (3- {2 - [((2R) -2-hydroxy-2-. {4-hydroxy-3 - [(methylsulfonyl) amino] phenyl} ethyl) amino] -2- methylpropyl.}. phenyl) acetamide,? / - (Cyclohexylmethyl) -2- (3. {2 - [((2R) -2-hydroxy-2-. {4-hydroxy-3 - [(methylsulfonyl)] amino] feni l.}. ethyl) amino] -2-methylpropyl} phenyl) acetamide, ? / - (2-Chloro-6-methylbenzyl) -2- (3- { 2 - [((2R) -2-hydroxy-2-. {4-hydroxy-3 - [(methylsulfonyl) amino] phenyl.} ethyl) amino] -2-methylpropyl. phenyl) acetamide,? / - (2-Ethoxybenzyl) -2- (3 { (2R) -2 - [((2R) -2- hydroxy-2- {4-hydroxy-3 - [(methylsulfonyl) amino] phenyl} ethyl) amino] propyl} phenyl) acetamide,? / - (3,4-Dimethylbenzyl) -2- ( 3- {(2R) -2 - [((2R) -2-hydroxy-2- {4-hydroxy-3- [(methylsulfonyl) amino] phenyl} ethyl) amino] propyl}. phenyl) acetamide,? / - (3,4-Dichlorobenzyl) -2- (3 { (2R) -2 - [((2R) -2-hydroxy-2-. {4-hydroxy-3- [(methylsulfonyl) amino] phenyl.} ethyl) amino] propyl. phenyl) acetamide, 2- (3 { (2R) -2 - [((2R) -2-Hydroxy-2-. { 4-hydroxy-3 - [(methylsulfonyl) amino] phenyl} ethyl) amino] propyl. Phenyl) -? / - (3-phenylpropyl) acetamide,? / - (Cyclohexylmethyl) -2- ( 3- {(2R) -2 - [((2R) -2-hydroxy-2- {4-hydroxy-3 - [(methylsulfonyl) amino] phenyl} ethyl) amino] propyl}. phenol) acetamide,? / - (2-Chloro-6-fluorobenzyl) -2- (3 { (2R) -2 - [((2R) -2-hydroxy-2-. {4- hydroxy-3 - [(methylsulfonyl) amino] phenyl .}. ethyl) amino] propii} phenyl) acetamide,? / - (2-Chloro-4-fluorobenzyl) -2- (3 { (2R) -2 - [((2R) -2-hydroxy-2-. {4-hydroxy} 3 - [(methylsulfonyl) amind] phenyl.} Ethyl) amino] propyl. Phenyl) acetamide,? / - (3,5-D-chlorobenzyl) -2- (3- { (2R) -2 - [((2R) -2-hydroxy-2-. {4-hydroxyl-3 - [(methylsulfonyl) amino] phenyl} ethyl) amino] propyl, phenyl) acetamide, - (3- {(2R) -2 - [((2R) -2-Hydroxy-2- {4-hydroxy-3 - [(methylsulfonyl) amino] phenyl} ethyl) amino] propyl} phenyl) -? / - [4- (trifluoromethyl) benzyl] acetamide,? / - (2,5-Dichlorobenzyl) -2- (3- { (2R) -2 - [((2R) -2 -hydroxy-2- {4-hydroxy-3 - [(methylsulfonyl) amino] phenyl} ethyl) amino] propyl} phenyl) acetamide, ? / - [4-Fluoro-2- (trifluoromethyl) benzyl] -2- (3 { (2R) -2 - [((2R) -2-hydroxy-2-. {4-hydroxy-3 - [(methylsulfonyl) amino] phenyl.} ethyl) amino] propyl. phenyl) acetamide,? / - [4-Fluoro-3- (trifluoromethyl) benzyl] -2- (3- {(2R)} -2 - [((2R) -2-hydroxy-2- {4-hydroxy-3 - [(methylsulfonyl) amino] phenyl} ethyl) amino] propyl} phenyl) acetamide,? / - [ 2-Fluoro-4- (trifluoromethyl) benzyl] -2- (3 { (2R) -2 - [((2R) -2-hydroxy-2-. {4-hydroxy-3 - [(methylsulfonyl ) amino] phenyl} ethyl) amino] propyl, phenyl) acetamidane,? / - (2,4-Dichloro-6-methylbenzyl) -2- (3 { (2R) - 2 - [((2R) -2-hydroxy-2. {4-hydroxy-3 - [(methylsulfonyl) amino] phenyl} ethyl) amino] propyl} phenyl) acetamide,? / - [ 4-Chloro-3- (trifluoromethyl) benzyl] -2- (3 { (2R) -2 - [((2R) -2-hydroxy-2-. {4-hydroxy-3- [(methylsulfonyl) amino] phenyl} ethyl) amino] propyl.] phenol) acetamide,? / - [2-Chloro-5- (trifluoromethyl) benzyl] -2- (3 { (2R ) -2 - [((2R) -2-hydroxy-2- {4-hydroxy-3 - [(methylsulfonyl) amino] phenyl} ethyl) amino] propyl} phenyl) acetamide,? / - [3,5- / 3 / s (Trif luoromethyl) benzyl] -2- (3-. { (2R) -2 - [((2R) -2-hydroxy-2-. {4-hydroxy-3 - [(methylsulfonyl) amino] phenyl] ethyl) amino] propyl} phenyl) acetamide,? / - [3-Fluoro-5- (trifluoromethyl) benzyl] -2- (3 { (2R) -2 - [((2R) -2-hydroxy- 2-. {4 -hydroxy-3 - [(methylsulfonyl) amino] phenyl.} ethyl) amino] propyl. phenyl) acetamide, / V- (3,4-dichlorobenzyl) -2- (4-. {2 - [( (2R) -2-hydroxy-2- {4-hydroxy-3 - [(methylsulfonyl) amino] phenyl} ethyl) amino] -2-methylpropyl} phenyl) acetamide,? / - [2- Chloro-5- (trifluoromethyl) benzyl] -2- (4-. {2 - [((2R) -2-hydroxy-2-. {4-hydroxy-3 - [(methylsulfonyl) amino] phenyl] .) ethyl) amino] -2-methylpropyl. phenyl) acetamide,? / - [4-chloro-3- (trifluoromethyl) benzyl] -2- (4-. {2 - [((2R) - 2-hydroxy-2- {4-hydroxy-3 - [(methylsulfonyl) amino] phenyl} ethyl) amino] -2-methylpropyl} phenyl) acetamide, ? / - [3,5-) / s (Trifluoromethyl) benzyl] -2- (4- { 2 - [((2R) -2-hydroxy-2-. {4-hydroxy-3 - [( methylsulfonyl) amino] phenyl} ethyl) amino] -2-methylpropyl. phenyl) acetamide, ? / - [3-Fluoro-5- (trifluoromethyl) benzyl] -2- (4-. {2 - [((2R) -2-hydroxy-2-. {4-hydroxy-3 - [(methylsulfonyl ) amino] phenyl} ethyl) amino] -2-methylpropyl.} phenyl) acetamide, V- [2-Fluoro-5- (trifluoromethyl) benzyl] -2- (4-. {2 - [(( 2R) -2-hydroxy-2- {4-hydroxy-3 - [(methylsulfonyl) amino] phenyl} ethyl) amino] -2-methylpropyl} phenyl) acetamide, ? / - [4-Fluoro-2- (trifluoromethyl) benzyl] -2- (4-. {2 - [((2R) -2-hydroxy-2-. {4-hydroxy-3- [ (methylsulfonyl) amino] phenyl.} ethyl) amino] -2-methylpropyl. phenyl) acetamide, ? / - [4-Fluoro-3- (trifluoromethyl) benzyl] -2- (4-. {2 - [((2R) -2-hydroxy-2-. {4-hydroxy-3 - [(methylsulfonyl amino) phenyl, ethyl) amino] -2-methylpropyl, phenyl, acetamide, 2- (4- { (2R) -2 - [((2R) -2-Hydroxy-2-. {4-hydroxy-3 - [(methylsulfonyl) amino] phenyl} ethyl) amino] propyl .}. phenyl) -? / - (2-methoxybenzyl) acetamide,? / - (2-Ethoxybenzyl) -2- (4- { (2R) -2 - [((2R) -2-hydroxy -2- { 4-hydroxy-3 - [(methylsulfonyl) amino] phenyl}. Ethyl.}. Amino] propyl. Phenyl) acetamide,? / - Benzyl-2- (4- { (2R) -2 - [((2R) -2-hydroxy-2-. {4-hydroxy-3- [(methylsulfonyl) amino] phenyl}. ethyl) amino] propyl.} phenyl) acetamide, 2- (4- { (2R) -2 - [((2R) -2-Hydroxy-2- {4-hydroxy) 3 - [(methylsulfonyl) amino] phenyl.} Ethyl) amino] propyl. Phenyl) -? / - (3-phenylpropyl) acetamide,? / - (2,3-Dihydro-1H-inden-2 -yl) -2- (3- { (2R) -2 - [((2R) -2-hydroxy-2. {4-hydroxy-3 - [(methylsulfonyl) amino] phenyl}. ethyl) amino] propyl.} phenyl) acetamide, 2- (3 { (2R) -2 - [((2R) -2-Hydroxy-2-. {4-hydroxy-3 - [( methylsulfonyl) amino] phenol.} ethyl) amino] propyl. phenyl) -? / - (2-methoxybenzyl) acetamide, ? / - Benzyl-2- (3- { (2R) -2 - [((2R) -2-hydroxy-2-. {4-hydroxy-3 - [(methylsulfonyl) amino] phenyl}. ethyl) amino] propyl] phenyl) -acetamide, 2- (3 { (2R) -2 - [((2R) -2-Hydroxy-2-. {4-hydroxy-3- [(methylsulfonyl) amino] phenyl.} ethyl) amino] propyl. phenyl) -? / - (2-phenylethyl) acetamide, 2- (3- { (2R) -2 - [((2R) -2-Hydroxy-2- {4-hydroxy-3 - [(methylsulfonyl) amino] phenyl.} Ethyl) amino] propyl. Phenyl) -? / - (mesitylmethyl) acetamide, 2- ( 3- {(2R) -2 - [((2R) -2-Hydroxy-2- {4-hydroxy-3 - [(methylsulfonyl) amino] phenyl} ethyl) amino] propyl. phenyl) -? / - (2,3,6-trichlorobenzyl) acetamide, 2- (3. {2 - [((2R) -2-Hydroxy-2-. {4-hydroxy) 3 - [(methylsulfonyl) amino] phenyl] ethyl) amino] -2-methylpropyl. Phenyl) -? / - [3- (trifluoromethyl) benzyl] acetamide,? / - (2,3-Dichlorobenzyl) ) -2- (3- { (2R) -2 - [((2R) -2-hydroxy-2-. {4-hydroxy-3 - [(methylsulfonyl) amino] phenyl} ethyl) amino ] propyl.} phenyl) acetamide, / V- (3-chloro-4-methylbenzyl) -2- (3 { (2R) -2 - [((2R) -2-hydroxy-2-. { 4-hydroxy-3 - [(methylsulfonyl) amino] phenyl} ethyl) amino] propyl} phenyl) acetamide, 2- (3. {2 - [((2R) -2-Hydroxy-2. {4-hydroxy-3 - [(methylsulfonyl) amino] phenyl} ethyl) amino] - 2-methylpropyl.) Phenyl) -? / - [2- (methylthio) benzyl] acetamide, 2- (3. {2 - [((2R) -2-Hydroxy-2-. {4 -hydroxy-3 - [(methylsulfonyl) amino] phenyl.} ethyl) amino] -2-methylpropyl. phenyl) -? / - [4- (methylthio) benzyl] acetamide, 2- (3-. 2 - [((2R) -2-Hydroxy-2- {4-hydroxy-3 - [(methylsulfonyl) amino] phenyl} ethyl) amino] -2-methylpropyl} phenyl) -? / - (tetrahydro-2H-thiopyr-4-yl) acetamide,? / - (Biphenyl-2-ylmethyl) -2- (3- { 2 - [((2R) -2-hydroxy-2-. {4 -hydroxy-3 - [(methylsulfonyl) amino] phenyl] ethyl) amino] -2-methylpropyl. phenyl) acetamide, 2- (3- { (2R) -2 - [((2R) -2-Hydroxy-2-. {4-hydroxy-3 - [(methylsulfonyl) amino] phenyl} ethyl) amino] propyl phenyl) -? / - (1-naphthylmethyl) acetamide, 2- (3 { (2R) -2 - [((2R) -2-Hydroxy-2-. {4-hydroxy-3 - [(methylsulfonyl) amino] phenyl.} ethyl) amino] propyl. phenyl) -? / - (pyridin-2-ylmethyl) acetamide, 2- (3 { (2R) -2 - [( (2R) -2-Hydroxy-2- {4-hydroxy-3 - [(methylsulfonyl) amino] phenyl} ethyl) amino] propyl} phenyl) -? / - [4- (trifluoromethoxy) benzyl ] acetamide,? / - (4-Cyanobenzyl) -2- (3 { (2R) -2 - [((2R) -2-hydroxy-2. {4-hydroxy-3 - [( methylsulfonyl) amino] phenyl.} ethyl) amino] propyl. phenyl) acetamide, / / - [4- (D-methylammon) benzyl] -2- (3 { (2R) - 2 - [((2R) -2-hydroxy-2- {4-hydroxy-3 - [(methylsulfonyl) amino} phenyl} etl) amino] propyl} phenyl) acetam , 2- (3- { (2R) -2 - [((2R) -2-Hydroxy-2-. {4-hydroxy-3 - [(methylsulfonyl) amino] phenyl} ethyl) amino] propyl.}. phenyl) -? / - phenylacetamide,? / - (1-Benzylpiperidin-4-yl) -2- (3 { (2R) -2 - [((2R) -2-h Drox¡-2- { 4-hydroxy-3 - [(methylsulfonyl) amino] phenyl.} ethyl) amino] propyl} phenyl) acetamide and, 2- (3. {2 - [((2R) -2-Hydroxy-2. {4-hydroxy-3 - [(methylsulfonyl) amino] phenyl} ethyl) amino] -2-methylpropyl.}. Phenyl) -? V- (mesitylmethyl) acetamide. According to one aspect of the present invention, compounds of the formula (I) in which (CH2) n-C (= O) Q1 is in the meta relative position are generally preferred. Pharmaceutically acceptable salts of the compounds of the formula (1) include their acid and base addition salts.

Suitable acid addition salts are formed from acids that form non-toxic salts. Examples include the salts acetate, aspartate, benzoate, besylate, bicarbonate / carbonate, bisulfate / sulfate, borate, camsylate, citrate, edisilate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hybienate, hydrochloride / chloride, hydrobromide / bromide, iodide / iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylisulfate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, saccharate, stearate, succinate , tartrate, tosylate, trifluoroacetate and xinafoate. Suitable basic salts are formed from bases that form non-toxic salts. Examples include aluminum salts, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc. Hemisal acids and bases can also be formed, for example hemisulphate and hemicalcium salts. For a review of suitable salts, see "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002). Pharmaceutically acceptable salts of compounds of the formula (1) can be prepared by one or more of three methods: (i) by reacting the compound of the formula (1) with the desired acid or base; (ii) removing an acid or base-labile protecting group from a suitable precursor of the compound of the formula (1) or opening the ring of a suitable cyclic precursor, for example a lactone or lactam, using the desired acid or base; or (iii) converting one salt of the compound of the formula (1) to another by reaction with an appropriate acid or base or by a suitable ion exchange column. The three reactions are typically carried out in solution. The resulting salt can be precipitated and collected by filtration or can be recovered by evaporating the solvent. The degree of ionization of the resulting salt can vary from completely ionized to almost non-ionized. The compounds of the invention can exist in both unsolvated and solvated forms. The term "solvate" is used herein to describe a molecular complex comprising the compound of the invention and a stoichiometric amount of one or more pharmaceutically acceptable solvent molecules, for example ethanol. The term "hydrate" is used when said solvent is water. Included within the scope of the invention are complexes such as clathrates, drug and host inclusion complexes in which, in place of the solvates mentioned above, the drug and the host are present in stoichiometric or non-stoichiometric amounts. Also included are drug complexes that contain two or more organic and / or inorganic components that may be in amounts stoichiometric or non-stoichiometric. The resulting complexes can be ionized, partially ionized or non-ionized. For a review of such complexes, see J Pharm Sci, 64 (8), 1269-1288 of Haleblian (August 1975). Hereinafter, all references to compounds of the formula (1) include references to their salts, solvates and complexes and to solvates and complexes of their salts. The compounds of the invention include compounds of the formula (1) as defined herein above, including all their polymorph and crystalline habits, their prodrugs and isomers (including optical, geometric and tautomeric isomers) as defined below and compounds of the formula (1) isotopically labeled. As indicated, the so-called "prodrugs" of the compounds of the formula (1) are also within the scope of the invention. Thus, certain derivatives of the compounds of the formula (1) which may have little or no pharmacological activity per se, when administered to the organism, may be converted to compounds of the formula (1) having the desired activity, example by hydrolytic cleavage. Such derivatives are referred to as "prodrugs". Additional information on the use of prodrugs can be found in "Pro-drugs as Novel Delivery Systems, Vol. 14, ACS Symposium Series (T. Higuchi and W. Stella) and "Bioreversible Carriers in Drug Design", Pergamon Press, 1987 (E. B. Roche editors, American Pharmaceutical Association). The prodrugs according to the invention can, for example, be produced by substituting appropriate functions present in the compounds of the formula (1) with certain residues known to those skilled in the art as "pro-residues" as described, for example in " Design of Prodrugs "by H. Bundgaard (Elsevier, 1985) Some examples of prodrugs according to the invention include: (i) when the compound of formula (1) contains a carboxylic acid function (-COOH), an ester thereof , for example a compound in which the hydrogen of the carboxylic acid function of the compound of the formula (1) is replaced by a Ci-Ca alkyl, (ii) when the compound of the formula (1) contains an alcohol function (- OH), an ether thereof, for example a compound in which the hydrogen of the alcohol function of the compound of the formula (1) is replaced by a (Ci-Cβmethyl) alkanoyloxy, (iii) when the compound of the formula (1) ) contains a primary or secondary amino function (-NH2 or -NHR in which R? H), an amide thereof, for example a compound in which, as the case may be, one or both hydrogens of the amino function of the compound of the formula (1) is replaced (n) by C1-C10 alkanoyl.

In the above references, additional examples of substitution groups can be found according to the above examples and examples of other types of prodrugs. In addition, certain compounds of the formula (1) can themselves act as prodrugs of other compounds of the formula (1). Also included within the scope of the invention are metabolites of compounds of the formula (1), ie, compounds formed in vivo upon administration of the drug. Some examples of metabolites according to the invention include (i) when the compound of the formula (1) contains a methyl group, a hydroxymethyl derivative thereof (-CH3 -> -CH2OH); (ii) when the compound of the formula (1) contains an alkoxy group, a hydroxy derivative thereof (-OR - > -OH); when the compound of the formula (1) contains a tertiary amino group, a secondary amino derivative thereof (-NR1R2 - -NHR1 or -NHR2); (iv) when the compound of the formula (1) contains a secondary amino group, a primary amino derivative thereof (-NHR1? -NH2); (v) when the compound of the formula (1) contains a phenyl residue, a phenol derivative thereof (-Ph? -PhOH); and (vi) when the compound of the formula (1) contains an amide group, a carboxylic acid derivative thereof (-CONH2 - -COOH).

The compounds of the formula (1) containing one or more asymmetric carbon atoms can exist in the form of two or more stereoisomers. When a compound of the formula (1) contains an alkenyl or alkenylene group, cis / trans (or Z / E) geometric isomers are possible. When structural isomers are interconvertible via a low energy barrier, tautomeric isomerism ("tautomerism") can occur. This can take the form of proton tautomerism in the compounds of formula (1) which contain, for example, an imino, keto or oxime group, or the so-called valence tautomerism in compounds containing an aromatic moiety. It follows that a single compound can show more than one type of isomerism. Included within the scope of the invention of the present invention are all stereoisomers, geometric isomers and tautomeric forms of the compounds of formula (1), including compounds that exhibit more than one type of isomerism, and mixtures of one or more of the same. Also included are acid addition salts or bases in which the conjugated ion is optically active, for example d-lactate or / -lysine or racemic, for example - / - tartrate or .//-arginine. The cis / trans isomers can be separated by conventional techniques well known to those skilled in the art, for example by chromatography and fractional crystallization. Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from a precursor optically pure or by resolution of the racemate (or the racemate of a salt or derivative) using, for example, high pressure liquid chromatography (HPLC). Alternatively, the racemate (or racemic precursor) can be reacted with an optically active compound, for example an alcohol or, in the case where the compound of the formula (1) contains an acid or basic moiety, an acid or a base such as tartaric acid or 1-phenylethylamine. The resulting diastereomeric mixture can be separated by chromatography and / or fractional crystallization and one or both diastereoisomers converted to the corresponding pure enantiomer (s) by means known to a person skilled in the art. The chiral compounds of the invention (and their chiral precursors) can be obtained in enantiomerically enriched form using chromatography, typically HPLC, with an asymmetric resin with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing 0 to 50% in volume of isopropanol, typically from 2% to 20% and from 0% to 5% by volume of an alkylamine, typically 0.1% diethylamine. The concentration of the eluate provides the enriched mixture. Stereoisomeric conglomerates can be separated by conventional techniques well known to those skilled in the art - see, for example, "Stereochemistry of Organic Compounds" by E.L. Eliel (Wiley, New York, 1994).

According to one aspect of the invention, the (R, R) stereoisomer is generally preferred. following formula, wherein R 1 is hydrogen and R 2 is C 1 -C 4 alkyl, preferably methyl and n and Q 1 are as defined above: The present invention includes all compounds of formula (1) isotopically labeled in which one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number that predominates In nature. Examples of suitable sotopes to include in the compounds of the invention include hydrogen asotopes, such as 2H and 3H, of carbon, such as 11C, 13C and 14C, of chlorine, such as 36CI, of fluorine, such as 18F, of iodine, such as 123l and 125l, of nitrogen, such as 13N and 15N, of oxygen, such as 150, 17O and 18O, of phosphorus, such as 32P and of sulfur such as 35S. Certain compounds of the formula (1) labeled isotopically, for example those that incorporate a radioactive isotope, are useful in studies of drug distribution and / or substrate tissue. The radioactive isotopes tritium, that is, 3H, and carbon-14, that is 14C are particularly useful for this end, due to the ease of its incorporation and availability of the means for its detection. Substitution with heavier isotopes such as deuterium, ie 2H, may provide certain therapeutic advantages as a result of increased metabolic stability, for example an increased half-life in vivo or need for lower doses and, therefore, may be preferred in some circumstances . Substitution with positron emitting isotopes, such as C, F, O, and N, may be useful in positron emission topography (PET) studies to determine substrate receptor occupancy. The isotopically-labeled compounds of the formula (1) can be prepared generally by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using isotopically-appropriate labeled reagents instead of the non-reactive reagent. Marking previously used. The pharmaceutically acceptable solvates according to the invention include those in which the crystallization solvent can be substituted isotopically, for example D2O, d-acetone, dd-DMSO. The compounds of the formula (1), their salts and / or pharmaceutically acceptable derivative forms, are pharmaceutically valuable active compounds, which are suitable for the therapy and prophylaxis of numerous disorders in which the β2 receptor is involved or in which the agonist activity of this receptor can induce benefits, in particular allergic and non-allergic diseases of the respiratory tract but also in the treatment of other diseases, such as, but not limited to, those of the nervous system, preterm birth, congestive heart failure, depression, inflammatory and allergic diseases of the skin, psoriasis, skin proliferative diseases, glaucoma and in conditions in which it is advantageous to reduce gastric acidity, in particular in gastric and peptic ulceration. The compounds of the invention intended for pharmaceutical use can be administered in the form of crystalline or amorphous products. They can be obtained, for example in the form of solid tablets, powders or films by methods such as precipitation, crystallization, lyophilization, spray drying or evaporative desiccation. For this purpose, microwave or radiofrequency drying can be used. They can be administered alone or in combination with another or other compounds of the invention or combined with another or other drugs (or in the form of any combinations thereof). In general, they will be administered in the form of a formulation associated with one or more pharmaceutically acceptable excipients. The term "excipient" is used herein to describe any ingredient other than the compound (s) of the invention. The choice of excipient will depend to a large extent on factors such as the particular mode of administration, the effect of the excipient on the solubility and stability and the nature of the pharmaceutical form. Pharmaceutical compositions suitable for the administration of compounds of the present invention and methods for their preparation will be readily apparent to those skilled in the art. Such compositions and methods for their preparation can be found, for example in "Remington's Pharmaceutical Sciences", 19th Edition (Mack Publishing Company, 1985). The compounds of the invention can also be administered directly to the bloodstream, to the muscle or to an internal organ. Suitable routes for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, and subcutaneous. Suitable devices for parenteral administration include needle injectors (including microneedles), needleless injectors and infusion techniques. Parenteral formulations are typically aqueous solutions which may contain excipients such as salts, carbohydrates and buffering agents (preferably at a pH of 3 to 9) but, for some applications, may be more adequately formulated in a sterile non-aqueous solution or in a dried form for use in conjunction with a suitable vehicle such as pyrogen-free sterile water.

The preparation of parenteral formulations under sterile conditions, for example by lyophilization, can be easily achieved using standard pharmaceutical techniques well known to those skilled in the art. The solubility of the compounds of the formula (1) which are used in the preparation of parenteral solutions can be increased by using appropriate formulation techniques, such as the incorporation of solubility enhancing agents. Formulations for parenteral administration can be formulated for immediate and / or modified release. Modified release formulations include delayed, sustained, pulsed, controlled, directed and programmed release. Thus, the compounds of the invention can be formulated in a solid, semi-solid or thixotropic liquid form for administration in implanted depot form which provides a modified release of the active compound. Examples of formulations of that type include drug-coated implants and poly (d / -lactico-co-glycolic acid) (PGLA) microspheres. The compounds of the invention can also be administered topically on the skin or mucosa, that is, dermally or transdermally. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusts, dressings, foams, films, skin patches, wafers, implants, sponges, fibers, bandages and microemulsions. Liposomes can also be used. Typical vehicles include alcohol, water, mineral oil, liquid petrolatum, petroleum jelly, glycerin, polyethylene glycol and propylene glycol. Penetration enhancers can be incorporated - see, for example, J Pharm Sci, 88 (10), 955-958 by Finnin and Morgan (October 1999). Other means of topical administration include administration by electroporation, iontophoresis, phonophoresis, sonophoresis, and microneedle or needle-free injection (e.g. Powderject ™, Bioject ™, etc.). Formulations for topical administration can be formulated to provide immediate and / or modified release. Modified release formulations include delayed, sustained, pulsed, controlled, directed 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, in the form of a mixture, for example in a dry mixture with lactose, or in the form of a particle of mixed components). , for example mixed with phospholipids, such as phosphatidylcholine) with a dry powder inhaler or an aerosol spray in a pressurized container, pump, spray, atomizer (preferably an atomizer that uses electrodynamics to produce a fine vapor) or nebulizer using or not a suitable propellant, such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane. For intranasal use, the powder may comprise a bioadhesive agent, for example chitosan or cyclodextrin. The pressurized container, pump, spray, atomizer or nebulizer contains a solution or suspension of the compound (s) of the invention comprising, for example ethanol, aqueous ethanol or an alternative agent suitable for dispersing, solubilizing or extending the release of the active compound, a propellant (s) as a solvent and an optional surfactant, such as sorbitan trioleate, oleic acid or an oligolactic acid. Prior to use in a formulation in the form of a dry powder or suspension, the medicament is micronized to a size suitable for administration by inhalation (typically less than 5 microns). This can be achieved by a suitable spraying method, such as grinding in a spiral injector, grinding in a fluid bed injector, supercritical fluid processing to form nanoparticles, high pressure homogenization or spray drying. Capsules (formed, for example by gelatin or hydroxypropylmethylcellulose), blisters and cartridges for use in an insufflator inhaler can be formulated so as to contain a powder mixture of the compound of the invention, a suitable powder base such as lactose or starch and a performance modifier such as / -leucine, mannitol or magnesium stearate. The lactose may be anhydrous or in monohydrated form, preferably the latter. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose. A solution formulation suitable for use in an atomizer using electrodynamics to produce fine vapor can containing from 1 μg to 20 mg of the compound of the invention per pulse and the volume per pulse can vary from 1 μl to 100 μl. A typical formulation may comprise a compound of the formula (1), propylene glycol, sterile water, ethanol and sodium chloride. Alternative solvents that can be used in place of propylene glycol include glycerol and polyethylene glycol. To the formulations of the invention to be used for inhaled / intranasal administration, suitable flavors may be added, such as menthol or levomenthol, or sweeteners such as saccharin or sodium saccharin. Formulations for inhaled / intranasal administration can be formulated so that they are immediate release and / or modified using, for example, PGLA. Modified release formulations include delayed, sustained, pulsed, controlled, directed and programmed release. In the case of dry powder inhalers and aerosols, the single dose is determined by a valve that delivers a dosed amount. The units according to the invention are typically arranged to deliver a metered amount or "puff" containing from 0.001 mg to 10 mg of the compound of the formula (1). The total daily dose will typically be in the range of 0.001 mg to 40 mg that can be administered in a single dose or, more commonly, divided into intakes during the day. The compounds of the formula (1) are particularly suitable for administration by inhalation.

The compounds of the invention can be administered rectally or vaginally, for example in the form of a suppository, pessary or enema. Cocoa butter is a traditional suppository base, but several alternatives can be used appropriately. Formulations for rectal / vaginal administration can be formulated to be immediate and / or modified release. Modified release formulations include delayed, sustained, pulsed, controlled, directed and programmed release. The compounds of the invention can also be administered directly to the eye or ear, typically in the form of drops or a suspension or micronized solution in isotonic, pH-adjusted and sterile saline. Other formulations suitable for ocular and otic administration include ointments, biodegradable (e.g. absorbable gel sponge, collagen) and non-biodegradable (e.g. silicone) implants, wafers, lenses and particulate or vesicle systems, such as niosomes or liposomes. A polymer such as a cross-linked polyacrylic acid can be incorporated, polyvinyl alcohol, hyaluronic acid, a cellulosic polymer, for example hydroxypropylmethylcellulose, hydroxyethylcellulose or methylcellulose or a heteropolysaccharide polymer, for example gellan gum, together with a preservative, such as benzalkonium chloride. Formulations of that type can also be administered by iontophoresis. Formulations for ocular / otic administration can be formulated to be immediate and / or modified release. The Modified release formulations include delayed, sustained, pulsed, controlled, directed or programmed release. The compounds of the invention can be combined with soluble macromolecular entities, such as cyclodextrin and suitable derivatives thereof or polyethylene glycol-containing polymers, to improve their solubility, dissolution rate, taste concealment, bioavailability and / or stability for use in any of the modes of administration mentioned above. It is noted that the drug and cyclodextrin complexes, for example, are generally useful for most pharmaceutical forms and routes of administration. Inclusion and non-inclusion complexes can be used. As an alternative to direct complex formation with the drug, the cyclodextrin can be used as an auxiliary additive, that is, as a carrier, diluent or solubilizer. The most commonly used for these purposes are alpha, beta and gamma cyclodextrins, examples of which can be found in International Patent Applications No. WO 91/11172, WO 94/02518 and WO 98/55148. Since it may be desirable to administer a combination of active compounds, for example for the purpose of treating a particular disease or condition, within the scope of the present invention two or more pharmaceutical compositions may be conveniently combined, at least one of which contains a compound according to the invention, in the form of a kit suitable for the concomitant administration of the compositions. Thus, the kit of the invention comprises two or more different pharmaceutical compositions, at least one of which contains a compound of the formula (1) according to the invention and means for maintaining said separate compositions, such as a container, divided jar or package of divided aluminum foil. An example of such a kit is the familiar blister pack used to pack tablets, capsules and the like. The kit of the invention is particularly suitable for administering different pharmaceutical forms, for example parenteral, for administering the separated compositions with different intervals between the intakes, or for evaluating the separate compositions one in relation to the other. For greater compliance, the kit typically comprises instructions for administration and may be provided with a so-called memory aid. For administration to human patients, the total daily dose of the compounds of the invention is typically in the range of 0.001 mg to 5000 mg depending, of course, on the mode of administration. For example, an intravenous daily dose may only require 0.001 mg to 40 mg. The total daily dose may be administered in a single dose or in several doses and may, at the discretion of the physician, be outside the typical range provided herein.

These doses are based on an average human subject weighing between 65 kg and 70 kg. The doctor can easily determine doses for subjects whose weight falls outside this range, such as children and the elderly. To avoid doubts, in the present report the references to "treatment" includes references to curative, palliative and prophylactic treatment. According to another embodiment of the present invention, the compounds of the formula (1) or their pharmaceutically acceptable salts, derivative forms or compositions can also be used in combination with one or more therapeutic agents additions that will be administered concomitantly to a patient to obtain some particularly desired therapeutic end result such as the treatment of pathophysiologically relevant morbid processes including, but not limited to (i) bronchoconstriction, (ii) inflammation, (iii) allergy, (iv) tissue destruction, (v) signs and symptoms such as dyspnea, cough. The second and more additional therapeutic agents can also be a compound of the formula (1) or a salt, pharmaceutically acceptable derivative forms or compositions thereof, or one or more β2 agonists known in the art. More typically, the second and more therapeutic agents will be selected from a different class of therapeutic agents. As used herein, the terms "concomitant administration", "concomitantly administered" and "combined with", in reference to the compounds of the formula (1) and one or more other therapeutic agents, are meant to mean and refer to and include the following: - simultaneous administration of a combination of that type of compound (s) of the formula (1) and therapeutic agent (s) to a patient in need of treatment, when such components are formulated together in a single dosage form that releases said components and substantially at the same time to said patient. - substantially simultaneous administration of a combination of that type of compound (s) of the formula (1) and therapeutic agent (s) to a patient in need of treatment, when such components are formulated separated from one another in separate pharmaceuticals that are taken substantially at the same time by said patient, after which said components are substantially released at the same time to said patient. - sequential administration of a combination of that type of compound (s) of the formula (1) and therapeutic agent (s) to a patient in need of treatment, when such components are formulated separately from one another in pharmaceutical forms different ones that are taken at consecutive moments by said patient with a significant time interval between each administration, after which said components are released substantially at the same time to said patient. - sequential administration of a combination of that type of compound (s) of the formula (1) and therapeutic agent (s) to a patient in need of treatment, when such components are formulated together in a single dosage form that releases said components in a controlled manner, after which they are administered concurrently, consecutively and / or superimposed at the same time or at different times to said patient, where each part can be administered by the same route or by different routes. Suitable examples of other therapeutic agents that can be used in combination with the compound (s) of the formula (1) or salts, pharmaceutically acceptable derivative forms or compositions of the same, include, but are not limited to, are limited to: (a) 5-lipoxygenase (5-LO) inhibitors or 5-lipoxygenase activation protein (FLAP) antagonists, (b) leukotriene antagonists (LTRA) including LTB4, LTC4, LTD4 antagonists and LTE4, (c) histamine receptor antagonists including H1 and H3 antagonists, (d) sympathomimetic vasoconstrictor agents agonists of a1 and a2 adrenergic receptors for decongestant use, (e) M3 muscarinic receptor antagonists or anticholinergic agents, (f) PDE inhibitors, for example inhibitors of PDE3, PDE4 and PDE5, (g) theophylline, (h) sodium cromoglycate, (i) COX inhibitors, both non-selective and selective inhibitors of COX-1 or COX-2 (NSAID), (j) oral and inhaled glucocorticosteroids, such as DAGR (agonists dissociated from the corticoid receptor), (k) monoclonal antibodies active against endogenous inflammatory entities, (I) agents against tumor necrosis factor (anti-TNF-a), (m) inhibitors of adhesion molecules including antagonists of VLA-4, (n) quinine receptor antagonists Bi and B2, (o) immunosuppressive agents, (p) inhibitors of matrix metalloproteases (MMP), (q) tachykinin receptor antagonists NKi, NK2 and (r) elastase inhibitors, adenosine A2a receptor agonists, (t) urokinase inhibitors, (u) compounds that act on dopamine receptors, for example D2 agonists, (v) modulators of the pathway NFicß, for example inhibitors of IKK, (w) modulators of cytokine signaling pathways, such as inhibitors of p38 MAP kinase, syk kinase or JAK kinase, (x) agents that can be classified as mucolytic or antitussive, and (and) antibiotics. According to the present invention, the combination of the compounds of the formula (1) with: - H3 antagonists is more preferred., - M3 muscarinic receptor antagonists, - PDE4 inhibitors, - Glucocorticosteroids, - Adenosine A2a receptor agonists, - Modulators of cytokine signaling pathways such as p38 MAK kinase or syk kinase, or - Leukotriene antagonists (LTRA) which include LTB4, LTC4, LTD4 and LTE4 antagonists. According to the present invention, the combination of the compounds of formula (1) with: - glucocorticosteroids, in particular glucocorticosteroids with reduced systemic side effects, including prednisone, prednisolone, flunisolide, triamcinolone acetonide, beclomethasone dipropionate, budesonide is more preferred. , fluticasone propionate, ciclesonide and mometasone fuorate, or M3 muscarinic receptor antagonists or anticholinergic agents, in particular ipratropium salts, namely bromide, tiotropium salts, namely bromide, oxitropium salts, namely bromide, perenzepine and telenzepine. It should be appreciated that all references herein to treatment include curative, palliative and prophylactic treatment. The description, next, refers to the therapeutic applications for which the compounds of the formula (1) can be used. The compounds of the formula (1) have the ability to interact with the β2 receptor and therefore have a wide range of therapeutic applications, as further described below, due to the essential role that the β2 receptor plays in the physiology of all mammals. Therefore, a further aspect of the present invention relates to the compounds of the formula (1), or their salts, derivatized forms or pharmaceutically acceptable compositions, for use in the treatment of diseases, disorders and conditions in which it is involved the ß2 receptor. More specifically, the present invention also relates to the compounds of the formula (1), or their salts, derivatized forms or pharmaceutically acceptable compositions, for use in the treatment of diseases, disorders and conditions which are selected from the group consisting of: - asthma of any type, etiology or pathogenesis, in particular asthma which is a member selected from the group consisting of asthma atopic, non-atopic asthma, allergic asthma, atopic bronchial asthma mediated by IgE, bronchial asthma, essential asthma, true asthma, intrinsic asthma caused by pathophysiological alterations, extrinsic asthma caused by environmental factors, essential asthma due to unknown or not apparent causes, asthma no atopic, bronchitic asthma, emphysematous asthma, exercise-induced asthma, allergen-induced asthma, cold-air-induced asthma, occupational asthma, infectious asthma caused by bacterial, fungal, protozoal or viral infection, nonallergic asthma, incipient asthma, syndrome of wheezing in the child and bronchiolitis, - chronic or acute bronchoconstriction, chronic bronchitis, obstruction of the minor airways and emphysema, obstructive or inflammatory diseases of the respiratory tract of any type, etiology or pathogenesis, in particular an obstructive or inflammatory disease of the airway that is a member that is selected a of 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 characterized by irreversible, progressive airway obstruction, syndrome dysfunction in the adult (ARDS), exacerbation of airway overactivity resulting from treatment with other drugs and respiratory tract disease associated with pulmonary hypertension, - bronchitis of any kind, etiology or pathogenesis, in particular bronchitis which is a member selected from the group consisting of acute bronchitis, acute lantrarotracheal bronchitis, arachidic bronchitis, catarrhal bronchitis, pseudomembranous bronchitis, dry bronchitis, infectious asthmatic bronchitis, productive bronchitis , bronchitis due to staphylococcus or streptococcus and gallbladder bronchitis, - acute lung injury, - bronchiectasis of any kind, etiology or pathogenesis, in particular bronchiectasis which is a member selected from the group consisting of cylindrical bronchiectasis, bronchiectasis sacculate, fusiform bronchiectasis, bronchiectasis capillary, cystic bronchiectasis, dry bronchiectasis and follicular bronchiectasis. Yet a further aspect of the present invention also relates to the use of the compounds of the formula (1), or their salts, derivatized forms or pharmaceutically acceptable compositions, for the manufacture of a drug having β2 agonist activity. In particular, the present invention relates to the use of the compounds of the formula (1), or their salts, derivatized forms or pharmaceutically acceptable compositions, for the manufacture of a drug for the treatment of diseases and / or conditions mediated by β2, in particular the diseases and / or conditions listed above. As a consequence, the present invention provides a particularly interesting method for treating a mammal, including a mammal human, with an effective amount of a compound of the formula (1), or a pharmaceutically acceptable salt, derivative form or composition thereof. More specifically, the present invention provides a particularly interesting method for treating diseases and / or conditions mediated by β 2 in a mammal, including a human being, in particular the diseases and / or conditions listed above, which comprises administration said mammal of an effective amount of a compound of the formula (1), its salts and / or pharmaceutically acceptable derivative forms. The following examples illustrate the preparation of the compounds of the formula (1): PREPARATION 1: [3- (2-OXOPROPIL) PHENYL] METHYL ACETATE Tributyltin methoxide (28.3 ml, 98 mmol), (3-bromophenyl) methyl acetate (WO 95/27692, page 16, for example 5a) (15.0 g, 65.0 mmol), isopropenyl acetate ( 10.8 ml, 98.0 mmol), palladium acetate (11) (750 mg, 3.30 mmol) and tri-ortho-tolylphosphine (2.0 g, 6.5 mmol) were stirred together in toluene (75 ml) at 100 ° C under nitrogen atmosphere for 5 hours. After cooling the reaction was diluted with ethyl acetate (150 ml) and aqueous 4 M potassium fluoride solution (90 ml) and stirred for 15 minutes. The mixture was filtered with Arbocel® and the organic phase was separated and concentrated in vacuum. The residue was purified by column chromatography on silica gel eluting with diethyl ether: pentane (0: 100 to 25:75, then changing to dichloromethane), affording the title compound as a pale yellow oil, 12.6 g . 1 H NMR (CDCl 3, 400 MHz) d: 2.15 (s, 3 H), 3.61 (s, 2 H), 3.69 (s, 5 H), 7.10-7.13 (m, 2 H) , 7.19 (d, 1H), 7.30 (t, 1H) ppm. MS (electrospray): m / z 229 [M + Na] +. PREPARATION 2: HYDROCHLORIDE OF [3 - ((2R) -2- { [(1fi) -1- FENILETIL] AMINO.}. PROPYL) PHENYL] METHYL ACETATE A solution of the ketone from Preparation 1 (8.59, 41.2 mmol), (f?) - a-methylbenzylamine (4.8 mL, 37.2 mmol), sodium triacetoxyborohydride (11.6 g, 56 mmol) ) and acetic acid (2.2 ml, 38 mmol) in dichloromethane (400 ml) was stirred at room temperature for 48 hours. The reaction mixture was quenched by adding saturated aqueous sodium bicarbonate (200 ml) and allowed to stir until the effervescence ended. The organic phase was separated and the aqueous phase was extracted with dichloromethane (100 ml). The combined organic extracts were dried (magnesium sulfate) and concentrated in vacuo. Purification by column chromatography on silica gel eluting with dichloromethane: methanol: 0.880 ammonia (99: 1: 0.1 changing to 95: 5: 0.5) provided a 4: 1 mixture of diastereoisomers (R, R the major) in the form of a pale yellow oil (8.71 g). Treatment with a 1M solution of hydrogen chloride in methanol (40 ml, 40 mmol), followed by three crystallizations of a mixture of diisopropyltene-methanol gave the title compound as a colorless crystalline solid, 5.68 g. PREPARATION 3:. { 3 - [(2R) -2-AMINOPROPIL] PHENYL} METHYL ACETATE A solution of the amine from Preparation 2 (7.69 g, 22 mmol) and ammonium formate (6.94 g, 110 mmol) in methanol (50 mL) was heated to 75 ° C in the presence of 20% palladium hydroxide. % on carbon (2.00 g). After 90 minutes the reaction mixture was cooled to room temperature, filtered with Arbocel® and the filtrate was concentrated in vacuo. The residue was partitioned between dichloromethane (100 ml) and 0.880 ammonia (100 ml) and the organic phase was separated. The aqueous phase was extracted with dichloromethane (100 ml) and the combined organic extracts were dried (magnesium sulfate) and concentrated in vacuo to give the title compound as a colorless oil, 4.78 g. 1 H NMR (CD 3 OD, 400 MHz) d: 1.06 (d, 3 H), 2.57-2.67 (m, 2H), 3.05-3.12 (m, 1H), 3.63 (s, 2H), 3.67 (s, 3H), 7.09-7.13 (m, 3H), 7.23 -7.27 (t, 1H) ppm. MS (electrospray): m / z 208 [M + H] +.

PREPARATION 4:? / -. { 2- (BENCILOXI) -5 - [(1R) -2-BROMO-1- HYDROXYETHYL] PHENYL} METANOSULPHONAMIDE A solution of (1f?) - 1- [3-amino-4- (benzyloxy) phenyl] -2-bromoethanol (Org. Process Research and Development, 1998, 2, 96) (30.8 g, 95.6 mmol ) in dichloromethane (300 ml) was treated with pyridine (9.3 ml, 115 mmol). The resulting solution was cooled to 5 ° C and a solution of methanesulfonyl chloride (7.8 mL, 100.7 mmol) in dichloromethane (10 mL) was added dropwise. The mixture was stirred at 5 ° C for a further 30 minutes and then allowed to warm gradually to room temperature over a period of 16 hours. The reaction mixture was washed with 2 N hydrochloric acid (110 ml) and the organic phase was separated, dried (magnesium sulfate) and the solvent was removed in vacuo to give an orange oil. The residue was crystallized from hot toluene (100 ml) to give the title compound as a pale pink solid (33.7 g). 1 H NMR (DMSO-d 6, 400 MHz) d: 2.93 (s, 3 H), 3.52-3.66 (m, 2H), 4.74 (m, 1H), 5.19 (s, 2H), 7.11 (d, 1H), 7.19-7.22 (m, 1H), 7.33-7.36 (m, 2H), 7.40-7.43 (m, 2H), 7.56 (d, 2H), 8.95 (s, 1H) ppm. MS (electrospray): m / z 398/400 [M-H] ".

PREPARATION 5:? / - [2- (BENCILOXI) -5 - ((1f?) - 2-BROMO-1- { [7 £ /? C- BUTIL (DIMETHYL) SILYL] OXY.}. ETHYL) FENIL ] METANOSULPHONAMIDE A solution of the bromide of preparation 4 (21.5 g, 53.7 mmol) in? /, / V-dimethylformamide (125 ml) was treated with imidazole (4.16 g, 75.2 mmol) and tert. -butyl (dimethyl) silyl (9.73 g, 64.5 mmol) and the resulting solution was allowed to stir at room temperature for 16 hours. The reaction mixture was diluted with ethyl acetate (200 ml) and washed with water (2 x 100 ml). The aqueous phases were combined and extracted with ethyl acetate (100 ml). The combined organic extracts were washed with 2N hydrochloric acid (100 ml), dried (magnesium sulfate) and reduced in vacuo. The residue was suspended in pentane: ethyl acetate (200 ml, 1: 1 by volume) and the solvent was evaporated. The residue was triturated with more pentane: ethyl acetate (200 ml, 1: 1 by volume) and the resulting solid was removed by filtration and dried in vacuo to give the title compound as a colorless solid (23.7 g ). 1 H-NMR (CDCl 3, 400 MHz) d: -0.07 (s, 3 H), 0.11 (s, 3 H), 0.89 (s, 9 H), 2.91 (s, 3 H), 4, 80-4.83 (m, 1H), 6.80 (bs, 1H), 6.98 (d, 1H), 7.12 (d, 1H), 7.36-7.44 (m, 5H) , 7.52-7.54 (m, 1H) ppm.

ALTERNATIVE PROCESS FOR THE PREPARATION OF PREPARATION 5: A solution of the bromide from preparation 4 (10 g, 24.98 mmol) was dissolved in DCM (20 ml, 2 ml / g) and then imidazole (4.58 g) was added. , 37.47 mmol, 1.5 equiv.) Followed by TBDMSiCl (5.27 g, 34.97 mmol, 1.4 equiv.). The reaction mixture was heated to reflux for 1 hour and then allowed to cool to 30 ° C. The mixture was diluted with isopropyl acetate (80 ml, 8 ml / g) and then quenched with 2 M HCl (50.5 ml / g) and stirred vigorously for 10 minutes. The phases were separated and the organic phase was washed with water (50 ml, 5 ml / g). The volume of the organic phase was then reduced to 25-30 ml under reduced pressure and 45 ° C. The solution was then cooled to room temperature and a suspension rapidly formed and stirred at room temperature for 30 minutes. Then heptane (20 ml, 2 ml / g) was added for 10 minutes and the suspension was cooled to 5-10 ° C and stirred for 1 hour. The suspension was then filtered and washed on the filter paper with heptane (2 X 10 ml). The resulting filter cake was dried in a vacuum oven at 50 ° C for 12 hours to provide the title compound as a white solid (11.05 g, 86% yield). 1 H-NMR (CDCl 3, 400 MHz) d: -0.07 (s, 3 H), 0.11 (s, 3 H), 0.89 (s, 9 H), 2.91 (s, 3 H), 4, 80-4.83 (m, 1H), 6.80 (bs, 1H), 6.98 (d, 1H), 7.12 (d, 1H), 7.36-7.44 (m, 5H) , 7.52-7.54 (m, 1H) ppm.

PREPARATION 6: (3- { (2R) -2 - [((2R) -2- { 4- (BENCILOXI) -3- [(METILSULFONIL) AMINO] PHENYL.}. -2- { [T £ flC-BUTIL (DIMETHYL) SILYL] OXY.} ETHYL) AMINO] PROPYL.} PHENYL) METHYL ACETATE The amine from preparation 3 (4.2 g, 20.2 mmol) was dissolved in dichloromethane (20 ml), it was treated with the bromide of preparation 5 (8.0 g, 15.6 mmol) and the reaction mixture was heated at 90 ° C for 16 hours (the solvent was allowed to evaporate). The reaction mixture was diluted with ethyl acetate (200 ml), washed with 1 M aqueous sodium hydroxide (30 ml), dried (magnesium sulfate) and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with ethyl acetate: pentane (1: 1 changing to 3: 2) to give the title product (5.8 g). 1 H NMR (CD 3 OD, 400 MHz) d: -0.18 (s, 3H), -0.01 (s, 3H), 0.82 (s, 9H), 1.05 (d, 3H), 2 , 54-2.66 (m, 3H), 2.83 (s, 3H), 2.85-2.93 (m, 2H), 3.59 (s, 2H), 3.66 (s, 3H) ), 7.69-4.72 (m, 1H), 5.18 (s, 2H), 6.97-7.07 (m, 5H), 7.14-7.18 (m, 1H), 7.30-7.40 (m, 4H), 7.48 (d, 2H) ppm. MS (electrospray): m / z 641 [M + Hf.

PREPARATION 7: HYDROCHLORIDE OF [4 - ((2R) -2- { [(1f?) - 1-PHENYLETHYL] AMINO.}. PROPYL) PHENYL] METHYL ACETATE The title compound was prepared by a method similar to that described for preparation 2 using methyl 4- (oxopropyl) phenylacetate (WO 97/24331, page 68, example 24D). 1 H NMR (CD 3 OD, 400 MHz) d: 1, 18 (d, 3 H), 1.70 (d, 3 H), 2.62 (dd, 1H), 3.18 (m, 1H), 3.30 (m, 1H), 3.62 (s, 2H), 3.66 (s, 3H), 4.61 (q, 1H) , 7.06 (d, 2H), 7.21 (d, 2H), 7.53 (m, 5H) ppm. MS (electrospray): m / z 312 [M + H] +. PREPARATION 8:. { 4 - [(2R) -2-AMINOPROPIL] PHENYL} METHYL ACETATE The title compound was prepared by a method similar to that described for Preparation 3 using the amine of Preparation 7. 1 H NMR (CDCl 3, 400 MHz) d: 1.14 (d, 3 H), 2.79 (m, 2H), 3.39 (q, 1H), 3.60 (s, 2H), 3.68 (s, 3H), 7.17 (d, 2H), 7.22 (d, 2H) ppm. MS (electrospray): m / z 208 [M + H] +.

PREPARATION 9: (4 { (2R) -2 - [((2R) -2- { 4- (BENCILOXI) -3- [(METILSULFONIL) AMINO] FENIL.}. -2- { [ T-RC- BUTIL (DIMETHYL) SILYL] OXY.} ETHYL) AMINO] PROPYL.} PHENYL) METHYL ACETATE The bromide from Preparation 5 (2.0 g, 4.11 mmol), the amine from Preparation 6 (852 mg, 4.11 mmol) and N-ethyldissopropylamine (531 mg, 4.11 mmol) were dissolved in sulfoxide. of dimethyl (6 ml) and the reaction mixture was heated at 90 ° C for 16 hours. The reaction mixture was diluted with ethyl acetate (100 ml) and washed with aqueous sodium chloride solution (4 x 50 ml), dried (magnesium sulfate) and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with dichloromethane: methanol (100: 0 changing to 95: 5) to give the title product, 520 mg. 1 H NMR (CDCl 3, 400 MHz) d: -0.16 (s, 3H), -0.04 (s, 3H), 0.83 (s, 9H), 1.07 (s, 3H), 2.51 (m, 1H), 2.75 (m, 2H), 2.88 (s, 3H), 2.96 (m, 2H) , 3.18 (s, 2H), 3.67 (s, 3H), 4.73 (m, 1H), 5.09 (s, 2H), 6.77 (m, 1H), 6.93 ( d, 1H), 7.04 (dd, 2H), 7.10 (m, 2H), 7.16 (m, 2H), 7.35-7.43 (m, 5H), 7.50 (d, 1 H) ppm. MS (electrospray): m / z 641 [M + H] A PREPARATION 10: 2,2 '- (1,4-PHENYLENE) DIETHYLENE DIACETATE 2,2 '- (1,4-phenylene) diacetic acid (10.0 g, 51 mmol) was dissolved in ethanol (100 ml) and the solution was treated dropwise with catalytic acetyl chloride (2.5 ml) . The reaction mixture was stirred at reflux for 18 hours before being allowed to cool and concentrated in vacuo. The residue was dissolved in ethyl acetate (100 ml) and extracted with sodium bicarbonate solution (3 x 50 ml) and brine (3 x 50 ml). Then the organic phase was dried (magnesium sulfate) and concentrated in vacuo. The residue was triturated with pentane to give the title product, 11.8 g. 1 H NMR (CDCl 3, 400 MHz) d: 1.26 (t, 6H), 3.57 (s, 4H), 4.12 (q, 4H), 7.21 (m, 4H). MS (electrospray): m / z 273 [M + H] + .. PREPARATION 11: ACID [4- (2-ETOXY-2-OXOETHYL) PHENYL] ACETIC A solution of the diester of preparation 9 (11.8 g, 47.0 mmol) and 2,2 '- (1,4-phenylene) diacetic acid (15.73 g, 81.0 mmol) in ethanol (6, 14 ml) and dioxane (75 ml) was treated dropwise with 12 M hydrochloric acid (1.57 ml, 18.8 mmol).

The reaction mixture was stirred at reflux for 18 hours before allowing to cool and concentrated at reduced volume. The reaction mixture was diluted with toluene (125 ml) and the resulting suspension was filtered. The filtrate was concentrated in vacuo and the residue dissolved in water and basified with sodium bicarbonate at neutral pH. The mixture was diluted with ethyl acetate (200 ml) and the organic phase was separated and washed with sodium bicarbonate solution (5 x 30 ml) and aqueous sodium chloride solution (50 ml). The combined aqueous extracts were acidified to pH 3 with 6 M hydrochloric acid and extracted with ether (3 x 30 ml). The organic phases were combined, dried (magnesium sulfate) and concentrated in vacuo. The residue was triturated with pentane to give the title compound as a colorless solid 10.8 g. 1 H NMR (CD 3 OD, 400 MHz) d: 1.23 (t, 3 H), 3.56 (m, 2 H), 3.60 (m, 2 H), 4.10 (q, 2 H), 7.22 (m, 4H) ppm. MS (electrospray): m / z 245 [M + Na] +. PREPARATION 12: ACID [4- (2-H? DROXY-2-METHYLPROPIL) PHENYL] ACETIC The carboxylic acid from preparation 11 (18.26 g, 82.0 mmol) was dissolved in tetrahydrofuran (450 ml) and the solution was cooled to 0 ° C and treated dropwise with a solution of methylmagnesium chloride in tetrahydrofuran. (82 mL, 246 mmol). The reaction mixture was allowed to warm to room temperature and was allowed to stand for 18 hours. The reaction mixture was slowly diluted with water (80 ml) followed by 2 M hydrochloric acid (120 ml, 240 mmol). The mixture was extracted with ethyl acetate (3 x 100 ml) and the organic extracts were combined and washed with brine (3 x 50 ml). The ethyl acetate phase was dried (magnesium sulfate) and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with dichloromethane: methanol: acetic acid (99.6: 0: 0.4 changing to 94.6: 5: 0.4) to give the title product as a a colorless solid. 1 H NMR (CDCl 3, 400 MHz) d: 1.15 (s, 6H), 2.70 (s, 2H), 3.55 (s, 2H), 7.18 (s, 4H) MS (electrospray): m / z 207 [M - H] "PREPARATION 13: ACID (4- { 2 - [(CHLOROACEHYL) AMINO] -2 - METILPROPIL.} FENIL) ACETIC The title product was prepared by a method similar to that described for Preparation 19 using the alcohol in Preparation 12. 1 H NMR (CD3OD, 400 MHz) d: 1.30 (s, 6H), 3.02 (s, 2H), 3.55 (s, 2H), 3.90 (s, 2H), 7.10 (d, 2H), 7.20 (d, 2H), 7.55 (m, 1H) ppm. MS (electrospray): m / z 282 [M-H] ".

PREPARATION 14: METHYL ESTER OF ACID [4- (2-AMINO-2-METHYLPROPIL) PHENYL] ACETIC The amide of preparation 13 (500 mg, 1.77 mmol) was dissolved in acetic acid (10 ml) and the solution treated with thiourea (160 mg, 2.10 mmol) and stirred at 95 ° C for 2 hours. . The reaction mixture was allowed to cool to room temperature and concentrated in vacuo. The residue was dissolved in methanol (40 ml), treated with methanolic hydrochloric acid (10 ml) and heated to reflux for 18 hours. The reaction mixture was allowed to cool to room temperature and then concentrated in vacuo. The residue was dissolved in water and extracted with ether (3 x 20 ml). The aqueous phase was basified to pH 11 with sodium carbonate solution and extracted with ethyl acetate (3 x 30 ml). The ethyl acetate extracts were combined, dried (magnesium sulfate) and concentrated in vacuo. Then the resulting oil was evaporated from ether (x5) to give the title product, 280 mg. 1 H NMR (CDCl 3, 400 MHz) d: 1.10 (s, 6H), 2.60 (s, 2H), 3.60 (s, 2H), 3.70 (s, 3H), 7.12 (d, 2H), 7.20 (d, 2H) ppm. MS (electrospray): m / z 222 [M + H] +.

PREPARATION 15: (4- {2 - [((2R) -2- { 4- (BENCILOXI) -3- [(METILSULFONIL) AMINO] FENIL.}. -2- { [7 £ RC -BUTIL (DIMETHYL) SILLL] - OXY.}. ETHYL) AMINO] -2-METHYLPROPYL.}. PHENYL) METHYL ACETATE The bromide from Preparation 5 (2.00 g, 3.90 mmol) and the amine from Preparation 12 were heated together in molten form at 95 ° C under nitrogen for 44 hours and then allowed to cool to room temperature. The reaction mixture was suspended in dichloromethane: 0.880 99.8: 0.2 ammonia and purified by silica gel column chromatography eluting with dichloromethane: methanol: 0.880 99.8: 0: 0.2 to 97.8 ammonia. : 2: 0.2 to 80: 20: 5. The crude product was evaporated from ether (x3) to give the title product, 1.76 g. 1 H NMR (CDCl 3, 400 MHz) d: -0.09 (s, 3H), 0.00 (s, 3H), 0.90 (s, 9H), 1.00 (s, 3H), 1, 05 (s, 3H), 2.55-2.70 (m, 3H), 2.80-2.85 (m, 1H), 2.85 (s, 3H), 3.60 (s, 2H) , 3.70 (s, 3H), 4.71 (m, 1H), 5.10 (s, 2H), 6.70-6.90 (m, 1H), 6.90-7.15 (m , 6H), 7.35-7.45 (m, 5H), 7.55 (d, 1H) ppm. MS (APCI): m / z 655 [M + H] +.

PREPARATION 16: 2,2 '- (1,3-PHENYLENE) DI DIETATE ACETATE 2,2 '- (1,3-phenylene) diacetic acid (10.0 g, 51 mmol) was dissolved in ethanol (100 ml) and the solution was treated dropwise with catalytic acetyl chloride (2.5 ml) . The reaction mixture was stirred at reflux for 18 hours before allowing to cool and concentrated in vacuo. The residue was dissolved in ethyl acetate (100 ml) and extracted with sodium bicarbonate solution (3 x 50 ml) and brine (3 x 50 ml). Then the organic phase was dried (magnesium sulfate) and concentrated in vacuo. The residue was triturated with pentane to give the title product, 11.8 g. 1 H NMR (CDCl 3, 400 MHz) d: 1.31 (t, 6H), 3.65 (s, 4H), 4.20 (q, 4H), 7.24-7.36 (m, 4H) ppm. MS (electrospray): m / z 251 [M + H] +. PREPARATION 17: ACID [3- (2-ETOXY-2-OXOETHYL) PHENYL] ACETIC A solution of the diester from Preparation 16 (44.3 g, 177 mmol) and 2,2 '- (1,3-phenylene) diacetic acid (59.2, 308 mmol) in ethanol (24 mL) and dioxane (290 ml) was treated dropwise with 12 M hydrochloric acid (4.9 ml, 58.8 mmol). The reaction mixture was stirred at reflux for 18 hours before Allow to cool and concentrate at reduced volume. The reaction mixture was diluted with toluene (125 ml) and the resulting suspension was filtered. The filtrate was concentrated in vacuo and the residue dissolved in water and basified with sodium bicarbonate at neutral pH. The mixture was diluted with ethyl acetate (200 ml) and the organic phase was separated and washed with sodium bicarbonate solution (5 x 30 ml) and brine (50 ml). The combined aqueous extracts were added to pH 3 with 6 M hydrochloric acid and extracted with ether (3 x 30 ml). The organic phases were combined, dried (magnesium sulfate) and concentrated in vacuo. The residue was triturated with pentane to give the title compound as a colorless solid 10.8 g. 1 H NMR (CD 3 OD, 400 MHz) d: 1.25 (t, 3 H), 3.60 (m, 2 H), 3.63 (m, 2 H), 4.15 (q, 2 H), 7.18 -7.32 (m, 4H) ppm. MS (electrospray): m / z 245 [M + Na] +. PREPARATION 18: ACID [3- (2-HYDROXY-2-METHYLPROPYL) PHENYL] ACETIC Methylmagnesium chloride (51 ml of a 3M solution in tetrahydrofuran, 153 mmol) was added dropwise to a stirred solution of preparation 17 (11.6 g, 51 mmol) (International Journal of Peptide and Protein Research, 1987 , 29 (3), 331) in tetrahydrofuran (300 ml) at 0 ° C under nitrogen. The reaction was allowed to warm to room temperature until the next morning, forming a thick white precipitate and then water (50 ml) and 2 N hydrochloric acid (80 ml) were added with caution. The aqueous phase was extracted with ethyl acetate (2 x 300 ml) and the combined organic phases were washed with brine (50 ml), dried (sodium sulfate) and the solvent was removed in vacuo to give the title compound as a a golden oil (11.2 g). 1 H NMR (CDCl 3, 400 MHz) d: 1.22 (6H, s), 2.75 (2H, s), 3.63 (2H, s), 7.12-7.30 (4H, m) . MS (ES /): A? 7 / Z 209 [M + H] +. PREPARATION 19: ACID (3- {2 - [(CHLOROACETILE) AMINO] -2- METHYLPROPIL.}. PHENYL) ACETIC 2-Chloroacetonitrile (8.8 ml, 140 mmol) was added to a solution of the alcohol of preparation 18 (16.0 g, 70 mmol), in acetic acid (33 ml). The resulting solution was cooled to 0 ° C, treated with concentrated sulfuric acid (33 ml) and the reaction mixture allowed to warm gradually to room temperature. After 4 hours, the reaction mixture was poured on ice and basified with solid sodium carbonate. The solution was extracted with ethyl acetate (2 x 500 ml) and the combined organic extracts were dried (magnesium sulfate) and concentrated in vacuo to give the title product as a colorless solid, 19.0 g. 1 H NMR (CDCl 3, 400 MHz) d: 1.36 (s, 6 H), 3.02 (s, 2 H), 3.62 (s, 2 H), 3.95 (s, 2 H), 6.19 (m, 1H), 7.06-7.31 (m, 4H) ppm.

MS (electrospray): m / z 282 [M - H]. "PREPARATION 20: METHYL ESTER OF ACID [3- (2-AMINO-2-METHYLPROPYL) PHENYL] ACETIC A solution of the amide of preparation 19 (5.1 g, 18 mmol), thiourea (1.6 g, 21 mmol) and acetic acid (18 ml) in ethanol (80 ml) was heated under reflux under nitrogen for 16 hours. The reaction mixture was allowed to cool to room temperature and filtered. The filtrate was concentrated in vacuo, the residue was dissolved in ethanol (150 ml), saturated with hydrogen chloride gas and the resulting solution was heated to reflux for 16 hours. The mixture was concentrated in vacuo and the residue fractionated between ethyl acetate (200 ml) and 5% aqueous sodium carbonate solution (200 ml). The organic phase was washed with brine (100 ml), dried (magnesium sulfate) and concentrated in vacuo. The residue was purified by a strong cation exchange resin, eluting with methanol and then with a 2M solution of ammonia in methanol, to elute the product. The eluent was concentrated in vacuo to give the title compound as a yellow oil, 2.68 g. 1 H NMR (CDCl 3, 400 MHz) d: 1.14 (s, 6 H), 2.68 (s, 2 H), 3.62 (s, 2 H), 3.69 (s, 2 H), 7.08 -7.16 (m, 3H), 7.23-7.27 (m, 1H) ppm. MS (electrospray): m / z 222 [M + H] +.

PREPARATION 21: METHYL ESTER OF ACID (3- {2 - [((2R) -2- (4-BENZYLOXY-3-METHANOSULFONYLAMINOFENYL) -2- (T-RC- BUTILDIMETILSILANYLOXY) ETHYLAMINE] -2-METHYLPROPYLE.} FENIL) ACETIC The bromide of preparation 5 (36.0 g, 70.8 mmol) and the amine of preparation 20 (36.0 g, 153 mmol) were heated at 85 ° C for 72 hours. The reaction mixture was cooled to room temperature and purified by column chromatography with silica gel eluting with pentane: ethyl acetate (50:50 by volume) to afford the title product as a pale yellow oil (37.2 g). 1 H NMR (CDCl 3, 400 MHz) d: -0.15 (s, 3H), 0.00 (s, 3H), 0.83 (s, 9H), 1.01 (s, 3H), 1.04 (s, 3H), 2.57-2.97 (m, 7H), 3.59 (s, 2H), 3.68 ( s, 3H), 4.68-4.72 (m, 1H), 5.09 (s, 2H), 6.79 (bs, 1H), 6.95 (d, 1H), 7.04-7 , 21 (m, 7H), 7.37-7.44 (m, 5H), 7.56 (d, 1H) ppm. MS (APCI): m / z 655 [M + Hf.

PREPARATION 22: (4- { (2R) -2 - [((2R) -2- { [7 £ RC-BUTIL (DIMETHYL) SILYL] OXI.}. -2- {4-HYDROXY -3 - [(METILSULFONIL) AMINO] PHENYL.} ETHYL) AMINO] PROPYL.} PHENYL) METHYL ACETATE The benzyl protected product of preparation 9 (520 mg, 0.813 mmol) was added to a solution of 10% Pd / C (100 mg) in methanol (25 ml) and the reaction mixture was stirred at room temperature at 4.22 kg / cm 2 of hydrogen for 8 hours. The reaction mixture was filtered with Arbocel® and the filtrate was concentrated in vacuo to provide the title product. 1 H NMR (CDCl 3, 400 MHz) d: -0.16 (s, 3H), -0.01 (s, 3H), 0.80 (s, 9H), 1.25 (d, 3H), 2 , 77-2.87 (m, 3H), 2.91 (s, 3H), 3.08-3.19 (m, 2H), 3.61 (s, 2H), 3.74 (s, 3H) ), 4.84 (m, 1H), 6.65 (d, 1H), 6.80 (d, 1H), 7.08 (d, 2H), 7.16 (d, 2H), 7.18 (m, 1 H) MS (electrospray) m / z 551 [M + H] +. PREPARATION 23: ACID (4 { (2R) -2 - [((2R) -2- { [T £ fC-BUTIL (DIMETHYL) SILYL] OXI.}. -2- {4-HYDROXY -3 - [(METILSULFONIL) AMINO] FENIL.} ETHYL) AMINO] PROPIL.} FENIL) ACETIC The ester of preparation 22 (844 mg, 1.53 mmol) was added to a solution of lithium hydroxide (71 mg, 1.69 mmol) in tetrahydrofuran: water 10: 1 (11 mL) and the reaction mixture was stirred. stirred at room temperature for 4 hours. Additional lithium hydroxide (142 mg, 3.38 mmol) was added and the reaction mixture was stirred at room temperature for a further 18 hours. The reaction mixture was diluted with a solution of 4 M hydrochloric acid in dioxane (1.27 ml, 5.0 mmol) and concentrated in vacuo. The residue was dissolved in water (20 ml) and ethyl acetate (20 ml), the organic phase was separated, dried (magnesium sulfate) and concentrated in vacuo to give the title product, 748 mg. NMR of H (CD3OD, 400 MHz) d: -0.19 (s, 3H), -0.01 (s, 3H), 0.79 (s, 9H), 1.13 (d, 3H), 2 , 66 (m, 1H), 2.82 (m, 1H), 2.84 (s, 3H), 3.00 (m, 1H), 3.17 (m, 1H), 3.32 (m, 1H), 3.42 (s, 2H), 4.86 (m, 1H), 6.80 (d, 1H), 6.95 (d, 1H), 7.00 (d, 2H), 7, 17 (d, 2H), 7.31 (d, 1H) ppm. MS (electrospray): m / z 537 [M + H] +. PREPARATION 24: (4- { 2 - [((2R) -2- { [7 £? C-BUTIL (DIMETHYL) SILYL] OXY.}. -2- { 4- HIDROXI 3- [ (METILSULFONIL) AMINO] PHENYL.}. ETHYL) AMINO] -2-METHYL-PROPYL.} PHENYL) METHYL ACETATE The benzyl-protected alcohol of preparation 15 (1.72 g, 2.60 mmol) was dissolved in methanol (40 ml) and the solution treated with 10% Pd / C (200 mg) and subjected to 4, 22 kg / cm2 of hydrogen at room temperature for 18 hours. The reaction mixture was filtered with Arbocel® and the filtrate was concentrated at reduced volume in vacuo. The solution was treated with 10% Pd / C (250 mg) and subjected to 4.22 kg / cm 2 of hydrogen at room temperature for 72 hours. The reaction mixture was filtered with Arbocel® and the filtrate was concentrated in vacuo. The oil produced was evaporated from ether (x3) yielding the title product, 1.43 g. 1 H NMR (CD 3 OD, 400 MHz) d: -0.08 (s, 3H), 0.00 (s, 3H), 0.80 (s, 9H), 1.12 (d, 6H), 2.65-3.00 (m, 7H), 3.60 (s, 2H), 3.70 (s, 3H), 4 , 70 (m, 1 H), 6.85 (d, 1 H), 7.00-7.20 (m, 5H), 7.35 (d, 1 H) ppm. MS (APCI): m / z 565 [M + H] +. PREPARATION 25: ACID (4- {2 - [((2R) -2- { [T £ f? C-BUTIL (DIMETHYL) SILYL] OXY.}. -2- {4-HYDROXY- 3 - [(METILSULFONIL) AMINO] PHENYL.}. ETHYL) AMINO] -2- METHYLPROPIL.] PHENYL) ACETIC The ester of preparation 24 (1.41 g, 2.50 mmol) was dissolved in dioxane (16 ml) and water (2 ml) and the solution was treated dropwise with sodium hydroxide 5 M (3.49 ml, 17.5 mmol). The reaction mixture was stirred at room temperature for 18 hours and then concentrated in vacuo. The residue was dissolved in water and cooled before being treated with 2M hydrochloric acid (8.78 ml, 17.6 mmol). The solution was diluted with ethyl acetate and concentrated in vacuo due to lack of separation. The residue was evaporated from ethyl acetate (x3) to give the title product, 1.67 g. 1 H-NMR (DMSO-de, 400 MHz) d: -0.08 (s, 3H), 0.00 (s, 3H), 0.85 (s, 9H), 0.90 (s, 3H), 0.95 (s, 3H), 2.50-2.80 (m, 4H), 2.85 (s, 3H), 2.90 (s, 2H), 4.60 (m, 1H), 6 , 75-7.30 (m, 10H) ppm. MS (APCI): m / z 551 [M + H] +. PREPARATION 26: ACID (3- { (2R) -2 - [((2R) -2- { 4- (BENCILOXY) -3 - [(METHYL-SULFONYL) AMINO] PHENYL.} -2- { [T £ fC-BUTIL (DIMETHYL) SILYL] OXY.}. ETHYL) AMINO] PROPIL.}. PHENYL) ACETIC The ester of preparation 6 (2.90 g, 4.5 mmol) was dissolved in a solution of lithium hydroxide (216 mg, 9.0 mmol) in water (30 mL) and tetrahydrofuran (60 mL) and the mixture of reaction was stirred at room temperature for 48 hours. The reaction mixture was acidified to pH 6 with 2M hydrochloric acid and concentrated at reduced volume in vacuo. Mix it was extracted with ethyl acetate (x2) and the organic phases were combined and washed with brine, dried (magnesium sulfate) and concentrated in vacuo to give the title product. 1 H-NMR (CDCl 3, 400 MHz) d: -0.21 (s, 3 H), 0.01 (s, 3 H), 0.80 (s, 9 H), 1, 09 (d, 3 H), 2, 54-2.61 (m, 1H), 2.84-2.98 (m, 2H), 3.15-3.20 (m, 1H), 3.52 (s, 2H), 4.91- 4.94 (m, 1H), 5.08 (s, 2H), 6.59 (bs, 3H), 6.90-6.93 (m, 2H), 7.04-7.17 (m, 4H), 7.35-7.42 (m, 5H), 7.49 (s, 1H) ppm. MS (electrospray): m / z 627 [M + H] +. PREPARATION 27: ACID (3- { (2R) -2 - [((2R) -2- { [7 £ f? C-BUTIL (DIMETHYL) SILYL] OXY.}. -2- { 4-HYDROXY-3 - [(METILSULFONIL) AMINO] PHENYL.} ETHYL) AMINO] PROPYL.} PHENYL) ACETIC The benzyl protected product of Preparation 26 (250 mg, 0.40 mmol) was added to a mixture of 20% Pd / C (30 mg) and ammonium formate (126 mg, 2.0 mmol) in ethanol (15 mg). ml) and the reaction mixture was heated to reflux for 3 hours. The reaction mixture was allowed to stand at room temperature for 18 hours and then concentrated in vacuo. The residue, which contained catalyst was purified by column chromatography of silica gel eluting with dichloromethane: methanol: ammonia 0.880 95: 5: 0.5 a 90: 10: 1 to 80: 20: 5 providing the title product. 1 H NMR (CD 3 OD, 400 MHz) d: -0.07 (s, 3H), 0.12 (s, 3H), 0.90 (s, 9H), 1.25 (d, 3H), 2.73-2.79 (m, 1H), 2.95-3.05 (m, 4H), 3.14-3, 49 (m, 3H), 3.53 (s, 2H), 5.00-5.03 (m, 1H), 6.96 (d, 1H), 7.06-7.17 (m, 3H) , 7.23-7.30 (m, 2H), 7.45 (m, 1H) ppm. MS (electrospray): m / z 537 [M + H] +, 559 [M + Na] +. PREPARATION 28: (3- { 2 - [((2R) -2- { 4- (BENCILOXI) -3 - [(METILSULFONIL) AMINO] FENIL} -2-. { [T £ f? C-BUTIL (DIMETHYL) SILYL] -OXI} ETHYL) AMINO] -2- METILPROPIL} FENIL) METHYL ACETATE A solution of the benzyl-protected alcohol from preparation 21 (36.8 g, 56 mmol) in ethanol (550 ml) was treated with ammonium formate (16.0 g, 254 mmol) and 20% palladium hydroxide on carbon ( 1.5 g). The resulting suspension was heated at 85 ° C for 2 hours. After 2 hours, more 20% palladium hydroxide on carbon (1.0 g) was added and heating continued for 1 hour. The reaction mixture was cooled to room temperature, filtered and the solvent removed in vacuo. The residue was partitioned between ethyl acetate (500 ml) and 2 N aqueous ammonia (100 ml). The The organic phase was separated, dried (magnesium sulfate) and the solvent was removed in vacuo. The residue was purified by column chromatography on silica gel eluting with dichloromethane: methanol: 0.88 ammonia (95: 5: 0.5 by volume) to give the title product as a pale yellow oil (20.6 g. ). 1 H NMR (400 MHz, CDCl 3) d: -0.17 (s, 3H), -0.05 (s, 3H), 0.80 (s, 9H), 1.07 (s, 3H), 1 , 09 (s, 3H), 2.66-2.91 (m, 7H), 3.62 (d, 2H), 3.69 (s, 3H), 4.71-4.74 (m, 1H) ), 6.58 (d, 1H), 6.88 (dd, 1H), 7.05-7.14 (m, 3H), 7.21-7.25 (m, 1H), 7.30 ( s, 1H) ppm. MS (electrospray): m / z 565 [M + H] +. PREPARATION 29: ACID (3- { 2 - [((2R) -2- { [7 £ fC-BUTIL (DIMETHYL) SILYL] OXY.}. -2- {4-HYDROXY-3- [(METILSULFONIL) AMINO] PHENYL.}. ETHYL) AMINO] -2-METHYLPROPIL.}. PHENYL) ACETIC The ester of preparation 28 (20.6, 36 mmol) was dissolved in tetrahydrofuran (150 ml) and the solution treated dropwise with 1 M aqueous lithium hydroxide (72 ml, 72 mmol). The reaction mixture was stirred at room temperature for 72 hours. The reaction mixture was neutralized by adding 1 M hydrochloric acid (72 ml, 72 mmol) and concentrated to volume reduced. The aqueous phase was decanted and the residue was washed with water (2 x 50 ml). The residue was redissolved in tetrahydrofuran (50 ml) and toluene (50 ml) and the solvent was removed in vacuo to give the title compound as a pale brown foam (20.17 g). 1 H NMR (400 MHz, CD3OD): -0.14 (s, 3H), 0.07 (s, 3H), 0.83 (s, 9H), 0.91 (m, 1H), 1.32 (m, 6H), 2.93 (m, 5H), 3.23 (m, 2H), 3.54 (m, 2H) , 4.94 (m, 1H), 6.91 (d, 1 H), 7.03-7.16 (m, 3H), 7.26 (m, 2H), 7.60 (m, 1H) . MS (APCI): m / z 551 [M + H] +. PREPARATION 20A: ETHYL ESTER OF ACID [3- (2-AMINO-2-METHYLPROPIL) PHENYL] ACETIC A mixture of the amide of Preparation 19 (151.4 g, 534 mmol), thiourea (48.7 g, 640 mmol) and acetic acid (303 mL) in ethanol (1.5 L) was heated to reflux in an atmosphere. of nitrogen for 5 hours. The reaction mixture was allowed to cool to room temperature and the suspension was concentrated in vacuo. The residues were azeotropically distilled with toluene (2 x 900 ml), then treated with ethanol (1.5 L) and stirred for 1 hour. The solid precipitate was removed by filtration, and the filtrate was refrigerated in an ice bath, treated with 98% sulfuric acid (227 ml) and stirred for 1 hour at room temperature. The solution was concentrated in vacuo to remove most of the ethanol and adjusted to pH 9 using aqueous sodium bicarbonate. The solid precipitate was removed by filtration and washed with water (300 ml) then with ethyl acetate (1.0 L). The combined biphasic filtrate and wash phases were separated and the aqueous phase was back extracted with ethyl acetate (1.0 L + 500 mL). The combined ethyl acetate extracts were dried over magnesium sulfate, filtered and concentrated in vacuo to give the title compound as a brown oil (89.5 g). 1 H NMR (d6-DMSO, 400 MHz) d: 0.99 (s, 6H), 1.16 (t, 3H), 2.59 (s, 2H), 3.61 (s, 2H), 4 , 06 (q, 2H), 7.06 (m, 3H), 7.21 (m, 1H). PREPARATION 20B: DI-P-TOLUIL-L-TARTRATE OF THE ETHYL ESTER OF THE ACID [3- (2-AMINO-2-METHYLPROPIL) PHENYL] ACETIC A solution of the amine from preparation 20a (124.9 g, 531 mmol) in acetonitrile (1.0 L) was treated with a solution of di-p-toluyl-L-tartaric acid (194.8 g, 504 mmol ) in acetonitrile (750 ml). The resulting suspension was stirred for 3 hours and the solid precipitate was isolated by filtration and washed with acetonitrile (2 x 250 ml) to give the title compound as an off-white solid (210 g). 1 H NMR (d6-DMSO, 400 MHz) d: 1.13 (s, 6H), 1.17 (t, 3H), 2.34 (s, 6H), 2.78 (s, 2H), 3 , 63 (s, 2H), 4.06 (q, 2H), 5.61 (s, 2H), 7.02 (d, 2H), 7.15 (d, 1H), 7.25 (m, 5H), 7.80 (d, 4H).

PREPARATION 20C: ETHYL ESTER OF ACID [3- (2-AMINO-2-METHYLPROPIL) PHENYL] ACETIC A solution of potassium carbonate (37.90 g, 274.22 mmol) in water (213 ml) was added to a suspension of preparation 20b (42.62 g, 68.56 mmol) in propionitrile (213 ml) and stirred until all the solid dissolved. The phases were then separated and the propionitrile phase was washed with water (107 ml). The volume of the solution was reduced to about 30 ml under reduced pressure to provide the title compound in the form of a propionitrile solution. A sample was extracted and concentrated to dryness obtaining a weight test by weight and the yield was shown to be 81%. 1 H NMR (d6-DMSO, 400 MHz) d: 0.99 (s, 6H), 1.16 (t, 3H), 2.59 (s, 2H), 3.61 (s, 2H), 4 , 06 (q, 2H), 7.06 (m, 3H), 7.21 (m, 1 H). PREPARATION 21A: (3- { 2 - [((2R) -2- { [7 £ f? C-BUTIL (DIMETHYL) SILYL] OXY.}. -2- { 4- BENCILOXI-3 - [(METILSULFONIL) AMINO] PHENYL.}. ETHYL) AMINO] -2-METHYL-PROPYL.} PHENYL) ETHYL ACETATE ? / - [2- (benzyloxy) -5 - ((1R) -2-bromo-1- { [Ferc-butyl (dimethyl) silyl] oxy]. Ethyl) phenyl] methanesulfonamide (14.34 g) , 27.88 mmol) was added to the solution of preparation 20c (13.12 g, 55.75 mmol) in propionitrile (15 ml). The mixture was then heated to reflux for 3 days. The solution was diluted with propionitrile (55 ml) and cooled to 20-25 ° C. The solution was washed with 1 M HCl (aqueous) (70 ml) and then with water (35 ml) and the solution was taken directly to the next step assuming a 100% yield. PREPARATION 28A: (fl) -2- (3- { 2- [2-HYDROXY-2- (4-BENZYLOXY-3-METHAN-SULFONAMIDOPHENYL) ETHYLAMINE] -2-METHYLPROPYL.}. PHENYL) ACETATE OF Triethylamine trifluorohydrate (9.1 ml, 8.99 g, 55.76 mmol) was added to the solution of preparation 21a (18.64 g, 27.88 mmol) in propionitrile (72 ml). The solution was stirred at 20-25 ° C for 3 hours. The solution was then quenched with 3 M NH 3 (aqueous) (72 ml), stirred for 10 minutes and the phases were separated. Then the propionitrile solution was washed with water (72 ml) and the solution was taken directly to the next step assuming a 100% yield.

PREPARATION 29A: ACID (R) -2- (3- { 2- [2-HYDROXY-2- (4-BENCILOXY-3-METANOSULFONAMIDOFENIL) ETILAMINO] -2-METHYLPROPIL.}. PHENYL) ACETIC A solution of sodium hydroxide (6.69 g, 167.28 mmol) in water (72 ml) was added to the solution of preparation 28a (15.47 g, 27.88 mmol) in propionitrile (72 ml). The two phase mixture was then vigorously stirred for 3 hours. The phases were allowed to separate and the aqueous phase was washed with fresh propionitrile (72 ml), then diluted with 1,4-dioxane (72 ml). Then the pH of the solution was adjusted to pH 6-7 by the addition of 37% w / w HCl (aqueous) and the resulting suspension was stirred for one hour. Then the suspension was filtered and washed on the filter paper with water. It was then dried to provide the title compound as an off-white solid (13.55 g, 92% in 3 steps). 1 H NMR (400 MHz, CD3OD) d: 1.33 (s, 3 H), 1.35 (s, 3 H), 2.89 (s, 3 H), 2.96 (s, 2 H), 3.06 -3.19 (m, 2H), 3.50 (s, 2H), 4.50 (m, 1H), 5.22 (s, 2H), 7.08 (d, 1H), 7.13 ( d, 1H), 7.19 (s, 1H), 7.24 (t, 2H), 7.27 (d, 1H), 7.31 (d, 1H), 7.38 (t, 2H) , 7.48 (d, 2H), 7.49 (s, 1 H) ppm.

PREPARATION 29B: SODIUM SALT OF ACID (f?) - 2- (3- { 2- [2-HYDROXY-2- (4-HYDROXY-3-METHANOSULPHONAMIDEPHENYL) ETHYLAMINE] -2-METHYLPROPYL.} PHENYL) ACETYL A solution of sodium hydroxide (1.40 g, 35.05 mmol) in water (100 ml) was added to a suspension of preparation 29a (18.46 g, 35.05 mmol) in methanol (600 ml). The mixture was hydrogenated on 20% by weight palladium hydroxide on carbon at 10.55 kg / cm2 and 60 ° C for 5 hours. The mixture was filtered to remove the catalyst residues and then the volume was reduced to 100 ml under reduced pressure. The mixture was distilled and re-introduced into acetonitrile under reduced pressure and constant volume. The resulting suspension was filtered and washed on the paper with acetonitrile, then dried to provide the title compound as an off-white solid (15.34 g, 95%). 1 H NMR (400 MHz, CD3OD) d: 1, 07 (s, 3H), 1, 09 (s, 3H), 2.70 (s, 2H), 2.73-2.81 (m, 2H) , 2.87 (s, 3H), 3.44 (s, 2H), 4.60-4.63 (m, 1H), 6.84 (d, 1 H), 6.92 (d, 1H) , 7.04 (d, 1H), 7.11 (s, 1H), 7.14 (d, 1H), 7.15 (t, 1H), 7.34 (s, 1H) ppm. Said compounds of the formula 29b can then be reacted with a suitable amine of the formula NHR8-Q2-A (3) in the presence of a conventional coupling agent such as 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride or dicyclohexylcarbodiimide in a suitable solvent such as pyridine, dimethylformamide or dimethylacetamide. To obtain a compound of the formula (1): wherein R1 and R2 are methyl and n is 1. Preparations 30-106 The appropriate carboxylic acid from preparation 23, 25, 27 or 29 (0.15 mmol) was dissolved in a solution of hydrated 1-hydroxybenzotriazole (22 mg, 0.16 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (34 mg, 0.18 mmol) and N-ethyldiisopropylamine (130 μl, 0.73 mmol) in N, N-dimethylformamide ( 2 ml). The solution was treated with the appropriate amine (0.23 mmol) and the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo and the residue fractionated between dichloromethane (3 ml) and water (1 ml). The phases were separated and the organic phase was washed with brine (1 ml), dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with dichloromethane: methanol: ammonia 0.88 to 98: 2: 0 to 96: 4: 0.5 to 94: 6: 0.5 to provide the desired product. Alternatively, the following method can be used for the synthesis of preparations 30 to 106: A solution of the appropriate acid from preparation 23, 25, 27 or 29 (36 mmol) in N,? / - dimethylformamide (200 ml) is treated with 1-hydroxybenzotriazole hydrate (5.26 g, 39 mmol), the appropriate amine (43 mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (7.5 g, 39 mmol). The resulting suspension is allowed to stir at room temperature for 18 hours. The solvent is removed in vacuo and the residue is partitioned between dichloromethane (400 ml) and water (100 ml). The organic phase is separated, washed with saturated aqueous sodium chloride (100 ml), dried (magnesium sulfate) and the solvent is removed in vacuo. The residue is purified by column chromatography on silica gel eluting with dichloromethane: methanol: ethyl acetate: 0.88 ammonia (95: 5: 0.5 changing to 0.5: 95: 0) by volume to provide the desired product . 15 20 15 20 15 20 15 20 20 15 20 15 20 15 20 15 20 fifteen twenty 15 20 20 15 20 -HO- 15 20 -in- Preparation 95-102: were not purified by column chromatography.

PREPARATION 107: 2- (3- { (2R) -2 - [((2R) -2- { 4- (BENCILOXI) -3 - [(METILSUL-FONIL) AMINO] PHENYL.} -2 - { [7 £ fC-BUTIL (DIMETHYL) SILYL] OXY.}. ETIL) AMINO] PROPIL} PHENYL) -? / - (2,3-DIHYDRO-1H-INDEN-2-IL) ACETAMIDE The carboxylic acid from preparation 26 (200 mg, 0.32 mmol) was added to a solution of hydrated 1-hydroxybenzotriazole (48 mg, 0.36 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride ( 74 mg, 0.42 mmol), ? / - ethyldiisopropylamine (226 μl, 1.26 mmol) and indan-2-ylamine (51 mg, 0.42 mmol) in? /,? / - dimethylformamide (3 ml). The reaction mixture was stirred at room temperature for 18 hours and then concentrated in vacuo. The residue was partitioned between ethyl acetate and water and the organic phases were separated, dried (magnesium sulfate) and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with dichloromethane: methanol 99: 1 to 98: 2 to give the title product, 157 mg. 1 H NMR (CDCl 3, 400 MHz) d: -0.15 (s, 3H), 0.00 (s, 3H), 0.85 (s, 9H), 0.99 (m, 3H), 2.73 (m, 8H), 3.31 (m, 2H), 3.28 (m, 3H), 4.73 (m, 2H) , .07 (m, 2H), 5.75 (m, 1H), 6.91-7.11 (m, 10H), 7.40 (m, 6H) ppm. MS (APCI) m / z 742 [M + H] +.

PREPARATION 108: 2- (3- { (2R) -2 - [((2R) -2- { 4- (BENCILOXI) -3 - [(METILSUL-FONIL) AMINO] PHENYL.} -2 - { [7ERC-BUTIL (DIMETHYL) SILYL] OXY.} ETHYL) AMINO] PROPYL.}. PHENYL) -? / - (2-METOXYBENCIL) ACETAMIDE The title compound was prepared by a method similar to that described for Preparation 107 using the carboxylic acid of Preparation 26 and 2-methoxybenzylamine. 1 H-NMR (CDCl 3, 400 MHz) d: -0.15 (s, 3 H), 0.00 (s, 3 H), 0.85 (s, 9 H), 0.99 (m, 3 H), 2, 73 (m, 8H), 3.65 (s, 3H), 4.38 (m, 2H), 5.08 (m, 2H), 6.02 (m, 1H), 6.7-7.08 (m, 7H), 7.12 (m, 4H), 7.40 (m, 5H) ppm. MS (APCI) m / z 746 [M + H] +. PREPARATION 109:? / - BENCIL-2- (3- { (2R) -2 - [((2R) -2- { 4- (BENCILOXI) -3- [(METILSULFONIL) AMINO] PHENYL.} -2- { [7EKC-BUTIL (DIMETHYL) SILYL] OXY.} ETHYL) AMINO] PROPIL.}. PHENYL) ACETAMID -lis¬ The title compound was prepared by a method similar to that described for Preparation 107 using the carboxylic acid of preparation 26 and benzylamine. 1 H-NMR (CDCl 3, 400 MHz) d: -0.17 (s, 3 H), 0.01 (s, 3 H), 0.86 (s, 9 H), 0.96 (m, 3 H), 2, 66-2.91 (m, 8H), 4.40 (m, 2H), 4.69 (m, 1H), 5.07 (m, 2H), 5.81 (m, 1H), 6.91 (d, 1H), 7.04 (m, 3H), 7.24 (m, 6H), 7.40 (m, 6H), 7.52 (m, 1H) ppm. MS (APCI): m / z 716 [M + H] +. PREPARATION 110: 2- (3- { (2R.}. -2 - [((2R) -2- { 4- (BENCILOXI.}. -3 - [(METILSUL-FONIL) AMINO] PHENYL} -2- { [GE /? C-BUTIL (DIMETHYL.} SILYL] OXY.}. ETHYL) AMINO] PROPIL.}. PHENYL.}. -N- (2-PHENYLETHYL.}. ACETAMIDE The title compound was prepared by a method similar to that described for preparation 107 using the carboxylic acid of preparation 26 and phenethylamine. 1 H NMR (CDCl 3, 400 MHz) d: -0.17 (s, 3H), 0.00 (s, 3H), 0.84 (s, 9H), 0.98 (t, 3H), 2, 63-2.88 (m, 8H), 3.43 (m, 5H), 4.69 (m, 1H), 5.07 (m, 2H), 5.47 (m, 1H), 6.93 (m, 2H), 7.06 (m, 5H), 7.16 (m, 4H), 7.40 (m, 5H), 7.49 (m, 1H) ppm. MS (APCI) m / z 730 [M + H] +.

Examples 1-77 The suitable protected alcohol (0.075 mmol) was dissolved in ethanol (4 ml) and the solution treated with a solution of ammonium fluoride (16 mg, 0.43 mmol) in water (300 μl). The reaction mixture was then stirred at 50 ° C for 18 hours before allowing to cool to room temperature. If a solid product precipitated, the reaction mixture was filtered and washed with methanol (2 ml, 1: 1 by volume) to give the title compound. If no product precipitated, the reaction mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography eluting with dichloromethane: methanol: ammonia 0.88 (98: 2: 0 changing to 90: 10: 1) providing the title product. Alternatively, the following process can be used for the preparation of Examples 1 to 77. A solution of the appropriate protected alcohol from Preparation 30 to 106 (25.4 mmol) in methanol (450 mL) was treated with a fluoride solution. of ammonium (6.6 g, 178 mmol) in water (200 ml) and the resulting solution was heated at 40 ° C for 24 hours. The reaction mixture was cooled to room temperature and the precipitate was filtered and washed with methanol: water (50:50 by volume, 100 ml). The solid was suspended in ethanol (150 ml) and heated at 65 ° C for 30 minutes, cooled to room temperature and filtered, washing the solid with diethyl ether (50 ml). Recrystallization from aqueous pyridine (1: 1, 150 ml) provided the desired compound.

EXAMPLE 1:? / - Benzyl-2- (3- { 2 - [((2R) -2-hydroxy-2-. {4-hydroxy-3 - [(methylsulfonyl) amino] phenyl}. L) amino] -2-methylpropyl. Phenyl) acetylamide Preparation 30 (0.075 mmol) was dissolved in ethanol (4 ml) and the solution treated with a solution of ammonium fluoride (16 mg, 0.43 mmol) in water (300 μl). Then, the reaction mixture was stirred at 50 ° C for 18 hours before allowing to cool to room temperature. The reaction mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography eluting with dichloromethane: methanol: 0.88 ammonia (98: 2: 0 changing to 90: 10: 1) to provide the title product in the form of a colorless solid. 1 H NMR (CD 3 OD, 400 MHz) d: 1.04 (s, 3 H), 1.07 (s, 3 H), 2.68-2.93 (m, 7 H), 3.53 (s, 3 H) , 4.37 (m, 2H), 4.60 (m, 1H), 6.84 (m, 1H), 7.02-7.28 (m, 10H), 7.37 (m, 1H). MS (electrospray) m / z 526 [M + Hf. Example 2: 2- (3- {2 - [((2R) -2-Hydroxy-2- {4-hydroxy-3- [(methylsulfonyl) amino] phenyl} ethyl) amino] -2 -methylpropyl.}. phenyl) -? / - (4-methoxybenzyl) acetamide Preparation 31 (0.075 mmol) was dissolved in ethanol (4 ml) and the solution treated with a solution of ammonium fluoride (16 mg, 0.43 mmol) in water (300 μl). Then, the reaction mixture was stirred at 50 ° C for 18 hours before allowing to cool to room temperature. The reaction mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography eluting with dichloromethane: methanol: 0.88 ammonia (98: 2: 0 changing to 90: 10: 1) to provide the title product in the form of a colorless solid. 1 H NMR (CD 3 OD, 400 MHz) d: 1.04 (s, 3 H), 1.07 (s, 3 H), 2.65-2.89 (m, 7 H), 3.52 (s, 2 H) , 3.76 (s, 3H), 4.29 (s, 3H), 4.60 (m, 1H), 6.92 (m, 3H), 6.98-7.20 (m, 7H), 7.35 (m, 1H) ppm. MS (electrospray) m / z 556 [M + H] +. Example 3: 2- (3- {2 - [((2R) -2-Hydroxy-2-. {4-hydroxy-3- [(methylsulfonyl) amino] phenyl} ethyl) amino] - 2-methylpropyl.}. Phenyl) -? / - (2-methoxybenzyl) acetamide Preparation 32 (0.075 mmol) was dissolved in ethanol (4 ml) and the solution treated with a solution of ammonium fluoride (16 mg, 0.43 mmol) in water (300 μl). After, the reaction mixture was stirred at 50 ° C for 18 hours before allowing to cool to room temperature. The reaction mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography eluting with dichloromethane: methanol: 0.88 ammonia (98: 2: 0 changing to 90: 10: 1) to provide the title product in the form of a colorless solid. 1 H NMR (CD 3 OD, 400 MHz) d: 1.04 (s, 3 H), 1.07 (s, 3 H), 2.65-2.91 (m, 7 H), 3.56 (m, 2 H) , 3.71 (m, 3H), 4.35 (m, 2H), 4.42 (m, 1 H), 6.81-7.23 (m, 10H), 7.37 (m, 1 H) ) MS (electrospray) m / z 556 [M + H] +. Example 4:? / - (2-Ethoxybenzyl) -2- (3- { 2 - [((2R) -2-hydroxy-2-. {4-hydroxy-3 - [(methylsulfonyl) amino] phenyl .}. ethyl) amino] -2-methylpropyl. phenyl) acetamide Preparation 33 (0.075 mmol) was dissolved in ethanol (4 ml) and the solution treated with a solution of ammonium fluoride (16 mg, 0.43 mmol) in water (300 μl). Then, the reaction mixture was stirred at 50 ° C for 18 hours before allowing to cool to room temperature. The reaction mixture was concentrated in vacuo and the residue was purified by column chromatography. silica gel eluting with dichloromethane: methanol: 0.88 ammonia (98: 2: 0 changing to 90: 10: 1) to give the title product as a colorless solid. 1 H NMR (CD 3 OD, 400 MHz) d: 1.04 (s, 3 H), 1.07 (s, 3 H), 1.33 (t, 3 H), 1.66-1.68 (m, 7 H) , 3.53 (m, 2H), 4.01 (q, 2H), 4.36 (s, 2H), 4.61 (m, 1H), 6.79-6.91 (m, 3H), 7.01-7.22 (m, 7H), 7.35 (m, 1H) ppm. MS (electrospray) m / z 570 [M + H] +. Example 5: 2- (3- {2 - [((2R) -2-Hydroxy-2-. {4-hydroxy-3- [(methylsulfonyl) amino] phenyl} ethyl) amino] -2 -methylpropyl.}. phenyl) -? / - (3-methoxybenzyl) acetamide Preparation 34 (0.075 mmol) was dissolved in ethanol (4 ml) and the solution treated with a solution of ammonium fluoride (16 mg, 0.43 mmol) in water (300 μl). Then, the reaction mixture was stirred at 50 ° C for 18 hours before allowing to cool to room temperature. The reaction mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography eluting with dichloromethane: methanol: 0.88 ammonia (98: 2: 0 changing to 90: 10: 1) to provide the title product in the form of a colorless solid. 1 H NMR (CD 3 OD, 400 MHz) d: 1.04 (s, 3 H), 1.07 (s, 3 H), 2.65-2.91 (m, 7 H), 3.56 (m, 2 H) , 3.71 (m, 3H), 4.35 (m, 2H), 4.42 (m, 1H), 6.78 (m, 2H), 6.85 (m, 1H), 7.00- 7.22 (m, 7H), 7.38 (m, 1H) ppm. MS (electrospray) m / z 556 [M + Hf. Example 6: 2- (3- {2 - [((2R) -2-Hydroxy-2-. {4-hydroxy-3- [(methylsulfonyl) amino] phenyl} ethyl) amino] -2 -methylpropyl.}. phenyl) -? / - (4-methylbenzyl) acetamide Preparation 35 (0.075 mmol) was dissolved in ethanol (4 ml) and the solution treated with a solution of ammonium fluoride (16 mg, 0.43 mmol) in water (300 μl). Then, the reaction mixture was stirred at 50 ° C for 18 hours before allowing to cool to room temperature. The reaction mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography eluting with dichloromethane: methanol: 0.88 ammonia (98: 2: 0 changing to 90: 10: 1) to provide the title product in the form of a colorless solid. 1 H NMR (CD 3 OD, 400 MHz) d: 1.04 (s, 3 H), 1.07 (s, 3 H), 2.26 (s, 3 H), 2.65-2.86 (m, 7 H) , 3.56 (m, 2H), 4.29 (m, 2H), 4.62 (m, 1H), 6.84 (d, 1H), 6.98-7.22 (m, 9H), 7.36 (m, 1H) ppm.

MS (electrospray) m / z 540 [M + H] +. Example 7: 2- (3- {2 - [((2R) -2-Hydroxy-2- {4-hydroxy-3- [(methylsulfonyl) amino] phenyl} ethyl) amino] -2 -methylpropyl.}. phenyl) -? / - (2-methylbenzyl) acetamide Preparation 36 (0.075 mmol) was dissolved in ethanol (4 ml) and the solution treated with a solution of ammonium fluoride (16 mg, 0.43 mmol) in water (300 μl). Then, the reaction mixture was stirred at 50 ° C for 18 hours before allowing to cool to room temperature. The reaction mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography eluting with dichloromethane: methanol: 0.88 ammonia (98: 2: 0 changing to 90: 10: 1) to provide the title product in the form of a colorless solid. 1 H NMR (CD 3 OD, 400 MHz) d: 1.04 (s, 3 H), 1.07 (s, 3 H), 2.26 (s, 3 H), 2.65-2.86 (m, 7 H) , 3.56 (m, 2H), 4.29 (m, 2H), 4.62 (m, 1 H), 6.84 (d, 1H), 6.98-7.22 (m, 9H) 7.36 (m, 1H) ppm. MS (electrospray) m / z 540 [M + H] +.

Example 8: 2- (3- {2 - [((2R) -2-Hydroxy-2-. {4-hydroxy-3- [(methylsulfonyl) amino] phenyl} ethyl) amino] -2 -methylpropyl.}. phenyl) -? / - (3-methylbenzyl) acetamide Preparation 37 (0.075 mmol) was dissolved in ethanol (4 ml) and the solution treated with a solution of ammonium fluoride (16 mg, 0.43 mmol) in water (300 μl). Then, the reaction mixture was stirred at 50 ° C for 18 hours before allowing to cool to room temperature. The reaction mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography eluting with dichloromethane: methanol: 0.88 ammonia (98: 2: 0 changing to 90: 10: 1) to provide the title product in the form of a colorless solid. 1 H NMR (CD 3 OD, 400 MHz) d: 1.04 (s, 3 H), 1.07 (s, 3 H), 2.26 (s, 3 H), 2.65-2.86 (m, 7 H) , 3.56 (m, 2H), 4.29 (m, 2H), 4.62 (m, 1H), 6.84 (d, 1H), 6.98-7.22 (m, 9H), 7.36 (m, 1H) ppm. MS (electrospray) m / z 540 [M + Hf.

Example 9:? / - (3,4-Dimethoxybenzyl) -2- (3- { 2 - [((2R) -2-hydroxy-2-. {4-hydroxy-3 - [(methylsulfonyl) amino] ] phenyl} ethyl) amino] -2-methylpropyl. phenyl) acetamida Preparation 38 (0.075 mmol) was dissolved in ethanol (4 ml) and the solution treated with a solution of ammonium fluoride (16 mg, 0.43 mmol) in water (300 μl). Then, the reaction mixture was stirred at 50 ° C for 18 hours before allowing to cool to room temperature. The reaction mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography eluting with dichloromethane: methanol: 0.88 ammonia (98: 2: 0 changing to 90: 10: 1) to provide the title product in the form of a colorless solid. 1 H NMR (CD 3 OD, 400 MHz) d: 1.04 (s, 3 H), 1.07 (s, 3 H), 2.66-2.90 (m, 7 H), 3.64 (m, 2 H) , 3.68 (s, 6H), 4.28 (s, 2H), 4.62 (m, 1H), 6.76-6.88 (m, 4H), 7.00-7.21 (m , 6H), 7.38 (m, 1H) ppm. MS (electrospray) m / z 586 [M + Hf. Example 10:? / - (2,4-Dimethoxybenzyl) -2- (3- { 2 - [((2R) -2-hydroxy-2-. {4-hydroxy-3 - [(methylsulfonyl) amino] ] phenyl} ethyl) amino] -2-methylpropyl. phenyl) acetamide Preparation 39 (0.075 mmol) was dissolved in ethanol (4 ml) and the solution treated with a solution of ammonium fluoride (16 mg, 0.43 mmol) in water (300 μl). Then, the reaction mixture was stirred at 50CC for 18 hours before allowing to cool to room temperature. The reaction mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography eluting with dichloromethane: methanol: 0.88 ammonia (98: 2: 0 changing to 90: 10: 1) to provide the title product in the form of a colorless solid. 1 H NMR (CD 3 OD, 400 MHz) d: 1.04 (s, 3 H), 1.07 (s, 3 H), 2.66-2.90 (m, 7H), 3.64 (m, 2H), 3.68 (s, 6H), 4.28 (s, 2H), 4.62 (m, 1H), 6 , 40 (d, 1 H), 6.47 (s, 1 H), 6.85 (d, 1 H), 7.00-7.21 (m, 6H), 7.35 (m, 1 H) ). MS (electrospray) m / z 586 [M + Hf. Example 11:? / - (3,5-Dimethoxybenzyl) -2- (3- { 2 - [((2R) -2-hydroxy-2-. {4-hydroxy-3 - [(methylsulfonyl) amino] ] phenyl} ethyl) amino] -2-methylpropyl. phenyl) acetamide Preparation 40 (0.075 mmol) was dissolved in ethanol (4 ml) and the solution treated with a solution of ammonium fluoride (16 mg, 0.43 mmol) in water (300 μl). Then, the reaction mixture was stirred at 50 ° C for 18 hours before allowing to cool to room temperature. The reaction mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography eluting with dichloromethane: methanol: 0.88 ammonia (98: 2: 0 changing to 90: 10: 1) to provide the title product in the form of a colorless solid. 1 H NMR (CD 3 OD, 400 MHz) d: 1.04 (s, 3 H), 1.07 (s, 3 H), 2.66-2.90 (m, 7 H), 3.64 (m, 2 H) , 3.68 (s, 6H), 4.28 (s, 2H), 4.62 (m, 1H), 6.32 (m, 1H), 6.37 (m, 2H), 6.83 ( m, 1H), 7.01-7.20 (m, 5H), 7.37 (m, 1H). MS (electrospray) m / z 586 [M + Hf. Example 12:? / - (4-Chlorobenzyl) -2- (3- { 2 - [((2R) -2-hydroxy-2-. {4-hydroxy-3 - [(methylsulfonyl) amino] phenyl .}. ethyl) amino] -2-methylpropyl. phenyl) acetamide Preparation 41 (0.075 mmol) was dissolved in ethanol (4 ml) and the solution treated with a solution of ammonium fluoride (16 mg, 0.43 mmol) in water (300 μl). Then, the reaction mixture was stirred at 50 ° C for 18 hours before allowing to cool to room temperature. The reaction mixture was concentrated in vacuo and the residue was purified by column chromatography. silica gel eluting with dichloromethane: methanol: 0.88 ammonia (98: 2: 0 changing to 90: 10: 1) to give the title product as a colorless solid. 1 H NMR (CD 3 OD, 400 MHz) d: 1.04 (s, 3 H), 1.07 (s, 3 H), 2.66-2.91 (m, 7 H), 3.54 (m, 2 H) , 4.37 (m, 2H), 4.62 (m, 1H), 6.84 (d, 1H), 7.00-7.26 (m, 9H), 7.36 (m, 1H). MS (electrospray) m / z 560 [M + Hf. Example 13:? / - (2-Chlorobenzyl) -2- (3- {2 - [((2R) -2-hydroxy-2-. {4-hydroxy-3 - [(methylsulfonyl) amino] phenyl .}. ethyl) amino] -2-methylpropyl.} phenyl) acetamida Preparation 42 (0.075 mmol) was dissolved in ethanol (4 ml) and the solution treated with a solution of ammonium fluoride (16 mg, 0.43 mmol) in water (300 μl). Then, the reaction mixture was stirred at 50 ° C for 18 hours before allowing to cool to room temperature. The reaction mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography eluting with dichloromethane: methanol: 0.88 ammonia (98: 2: 0 changing to 90: 10: 1) to provide the title product in the form of a colorless solid. 1 H NMR (CD 3 OD, 400 MHz) d: 1.04 (s, 3 H), 1.07 (s, 3 H), 2.66-2.91 (m, 7 H), 3.54 (m, 2 H) , 4.37 (m, 2H), 4.62 (m, 1H), 6.84 (m, 1H), 7.00-7.26 (m, 8H), 7.38 (m, 2H). MS (electrospray) m / z 560 [M + Hf. Example 14:? / - (3-Chlorobenzyl) -2- (3- { 2 - [((2R) -2-hydroxy-2-. {4-hydroxy-3 - [(methylsulfonyl) amino] phenyl .}. etl) amino] -2-methylpropyl. phenyl) acetamide Preparation 43 (0.075 mmol) was dissolved in ethanol (4 ml) and the solution treated with a solution of ammonium fluoride (16 mg, 0.43 mmol) in water (300 μl). Then, the reaction mixture was stirred at 50 ° C for 18 hours before allowing to cool to room temperature. The reaction mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography eluting with dichloromethane: methanol: 0.88 ammonia (98: 2: 0 changing to 90: 10: 1) to provide the title product in the form of a colorless solid. 1 H NMR (CD 3 OD, 400 MHz) d: 1.04 (s, 3 H), 1.07 (s, 3 H), 2.66-2.91 (m, 7 H), 3.54 (m, 2 H) , 4.37 (m, 2H), 4.62 (m, 1H), 6.84 (m, 1H), 7.01-7.29 (m, 9H), 7.36 (m, 1H). MS (electrospray) m / z 560 [M + H] +.

Example 15:? / - (4-Fluorobenzyl) -2- (3- { 2 - [((2R) -2-hydroxy-2-. {4-hydroxy-3 - [(methylsulfonyl) amino] phenyl .}. ethyl) amino] -2-methylpropyl. phenyl) acetamide Preparation 44 (0.075 mmol) was dissolved in ethanol (4 ml) and the solution treated with a solution of ammonium fluoride (16 mg, 0.43 mmol) in water (300 μl). Then, the reaction mixture was stirred at 50 ° C for 18 hours before allowing to cool to room temperature. The reaction mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography eluting with dichloromethane: methanol: 0.88 ammonia (98: 2: 0 changing to 90: 10: 1) to provide the title product in the form of a colorless solid. 1 H NMR (CD 3 OD, 400 MHz) d: 1.04 (s, 3 H), 1.07 (s, 3 H), 2.67-2.90 (m, 7H), 3.53 (m, 2H), 4.32 (m, 2H), 4.61 (m, 1H), 6.83 (d, 1H), 6 , 96-7.23 (m, 9H), 7.35 (m, 1H). MS (electrospray) m / z 544 [M + Hf. Example 16:? / - (2,4-Dichlorobenzyl) -2- (3- { 2 - [((2R) -2-hydroxy-2-. {4-hydroxy-3 - [(methylsulfonyl amino) phenyl} ethyl) amino] -2-methylpropyl] phenyl) acetamide Preparation 45 (0.075 mmol) was dissolved in ethanol (4 ml) and the solution treated with a solution of ammonium fluoride (16 mg, 0.43 mmol) in water (300 μl). Then, the reaction mixture was stirred at 50 ° C for 18 hours before allowing to cool to room temperature. The reaction mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography eluting with dichloromethane: methanol: 0.88 ammonia (98: 2: 0 changing to 90: 10: 1) to provide the title product in the form of a colorless solid. 1 H NMR (CD 3 OD, 400 MHz) d: 1.04 (s, 3 H), 1.07 (s, 3 H), 2.71-2.89 (m, 7 H), 3.54 (s, 2 H) , 4.32 (m, 2H), 4.64 (m, 1H), 6.85 (d, 1H), 7.02-7.23 (m, 6H), 7.38 (m, 2H). MS (electrospray) m / z 594 [M + H] +. Example 17:? / - (3,4-Dichlorobenzyl) -2- (3- { 2 - [((2R) -2-hydroxy-2. {4-hydroxy-3 - [(methylsulfonyl) amino] phenyl} ethyl) amino] -2-methylpropyl] phenyl) acetamide Preparation 46 (0.075 mmol) was dissolved in ethanol (4 ml) and the solution treated with a solution of ammonium fluoride (16 mg, 0.43 mmol) in water (300 μl). Then, the reaction mixture was stirred at 50 ° C for 18 hours before allowing to cool to room temperature. The reaction mixture was filtered and washed with methanol (2 ml, 1: 1 by volume) to give the title product as a colorless solid. 1 H NMR (CD 3 OD, 400 MHz) d: 1.04 (s, 3 H), 1.07 (s, 3 H), 2.71-2.89 (m, 7 H), 3.54 (s, 2 H) , 4.32 (m, 2H), 4.64 (, 1H), 6.85 (d, 1H), 7.02-7.23 (m, 6H), 7.38 (m, 2H). MS (electrospray) m / z 594 [M + Hf. Example 18:? / - (4-tert-Butylbenzyl) -2- (3-. {2 - [((2R) -2-hydroxy-2-. {4-hydroxy-3 - [(methylsulfonyl) amino] ] phenyl} ethyl) amino] -2-methylpropyl. phenyl) acetamide Preparation 47 (0.075 mmol) was dissolved in ethanol (4 ml) and the solution treated with a solution of ammonium fluoride (16 mg, 0.43 mmol) in water (300 μl). Then, the reaction mixture was stirred at 50 ° C for 18 hours before allowing to cool to room temperature. The reaction mixture was concentrated in vacuo and the residue was purified by column chromatography on silica gel eluting with dichloromethane: methanol: 0.88 ammonia (98: 2: 0) changing to 90: 10: 1) providing the title product as a colorless solid. 1 H NMR (CD 3 OD, 400 MHz) d: 1.04 (s, 3 H), 1.07 (s, 3 H), 1.30 (s, 9 H), 2.67-2.88 (m, 7 H) , 3.54 (s, 2H), 4.32 (m, 2H), 4.62 (m, 1H), 6.84 (m, 1H), 7.00-7.21 (m, 7H), 7.34 (d, 2H), 7.37 (m, 1H) ppm. MS (electrospray) m / z 582 [M + Hf. Example 19:? / - (2-Chloro-6-fluorobenzyl) -2- (3- { 2 - [((2R) -2-hydroxy-2-nyl) acetamide Preparation 48 (0.075 mmol) was dissolved in ethanol (4 ml) and the solution treated with a solution of ammonium fluoride (16 mg, 0.43 mmol) in water (300 μl). Then, the reaction mixture was stirred at 50 ° C for 18 hours before allowing to cool to room temperature. The reaction mixture was filtered and washed with methanol (2 ml, 1: 1 by volume) to give the title product as a colorless solid. 1 H NMR (DMSO-de, 400 MHz) d: 0.89 (s, 3H), 0.90 (s, 3H), 2.54 (s, 2H), 2.63 (m, 2H), 2 , 89 (s 3H), 3.36 (s, 2H), 4.36-4.43 (m, 3H), 6.81 (d, 1H), 6.93-7.04 (m, 4H) , 7.11-7.23 (m, 3H), 7.29-7.39 (m, 2H), 8.31 (m, 1H) ppm. MS (electrospray) m / z 576 [M-H] '.

Example 20:? / - (2,3-Dimethylbenzyl) -2- (3-. {2 - [((2R) -2-hydroxy-2-. {4-hydroxy-3 - [(methylsulfonyl) amino] ] phenyl} ethyl) amino] -2-methylpropyl. phenyl) acetamide Preparation 49 (0.075 mmol) was dissolved in ethanol (4 ml) and the solution treated with a solution of ammonium fluoride (16 mg, 0.43 mmol) in water (300 μl). Then, the reaction mixture was stirred at 50 ° C for 18 hours before allowing to cool to room temperature. The reaction mixture was filtered and washed with methanol (2 ml, 1: 1 by volume) to give the title product as a colorless solid. 1 H NMR (CD 3 OD, 400 MHz) d: 0.95 (s, 3 H), 0.96 (s, 3 H), 2.12 (s, 3H), 2.24 (s, 3H), 2.60 (s, 2H), 2.66-2.70 (m, 2H), 2.93 (s, 3H), 3.45 ( s, 2H), 4.25 (m, 2H), 4.46 (m, 1H), 6.84 (m, 1H), 6.98-7.21 (m, 8H), 8.32 (m , 1H) ppm. MS (electrospray) m / z 552 [M-H] ". 0.99 (m, 3.45 6.84 (d, 8.59) H] ". D: 0.90 2.62- (s, 2H), (m, (m, H] ". -1.08 (s, (s, 3.55 (m, 1H), (m, 1H) Hf. 1.09 (s, 3.61 1H), Hf. 1.10 (s, 4.65- (d, 1H), ppm. Hf. 1.09 (s, 2.60- (m, 7.11 (m, Hf. 15 20 15 20 15 20 15 20 1.08 (d, 2.90 (s, (s, (d, (d, 1H), Hf. 1.08 (d, 2.89 (s, (s, 2H), 1H), 7.08 7.27 (s, Hf. 1.08 (d, 2.90 (s, (s, 7.28) Hf. d: 1.06 2.53- 4.62-2H), , 576 [M 15 20 15 20 15 20 Example 78:? / - (2,3-Dihydro-1 H-inden-2-yl) -2- (3 { (2R) -2 - [((2R) -2-hydroxy-2- {4-hydroxy-3- (methylsulfonyl) amino] phenyl} ethyl) amino] propyl} phenyl) acetamide The preparation product 107 (157 mg, 0.21 mmol), ammonium formate (66 mg, 1.0 mmol) and 20% Pd / C (5 mg) were dissolved in ethanol (10 mL) and the mixture of reaction was heated to reflux for 3 hours. The reaction mixture was cooled to 50 ° C, treated with a solution of ammonium fluoride (40 mg, 1.0 mmol) in water (1 ml) and then stirred at 50 ° C for 18 hours. The reaction mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate and 0.880 ammonia solution. The organic phase was dried (magnesium sulfate) and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with dichloromethane: methanohamonia 0.880 98: 2: 0 to 95: 5: 0.5 to 90: 10.1 affording the title compound, 90 mg. 1 H NMR (CD3OD, 400 MHz) d: 1.06 (t, 3H), 2.53-2.97 (m, 12H), 3.23 (m, 2H), 3.45 (m, 2H), 4.56 (m, 2H), 6.81 (m, 1H), 6.96-7.31 (m, 11H) ) ppm. MS (APCI) m / z 538 [M + Hf. Examples 79-81 The following compounds, of the general formula shown below, were prepared by a method similar to that described for Example 78 using the appropriate amide starting material.

Unless otherwise indicated, all reactions were performed under a nitrogen atmosphere. Abbreviations TBDMS = .e / -c-butyl (dimethyl) silyl IPA = isopropyl alcohol THF = tetrahydrofuran s = singlet d = doublet dd = double doublet t = triplet q = quartet m = multiplet bs = wide singlet, for example NH or OH. IN VITRO ACTIVITY OF THE COMPOUNDS OF THE FORMULA (1) The ability of the compounds of formula (1) to act as potent agonists of β2 and therefore to mediate smooth muscle relaxation can be determined by measuring the effect of the stimulation of beta-2 adrenergic receptors on contraction stimulated by electric field in guinea pig trachea strips. Guinea Pig Trachea Dunkin-Hartley male guinea pigs (475-525 g) are killed by asphyxia and bleeding through the femoral artery and the trachea is isolated. Four preparations of each animal are obtained, initiating the dissection immediately below the larynx and removing 2.5 cm of length from the trachea. The piece of trachea is opened by cutting the cartilage opposite the tracheal muscle, then cross sections of 3-4 rings of cartilage are cut. The resultant strip preparations are suspended in 5 ml organ baths using cotton yarns attached to the upper and lower cartilage bands. The strips are equilibrated, without tension, for 20 minutes in a Krebs Ringer buffer (Sigma K0507) containing indomethacin 3 μM (Sigma 17378), 10 μM guanethidine (Sigma G8520) and 10 μM Atenolol (Sigma A7655), are heated to 37 ° C and gassed with 95% O2 / 5% CO2, before applying an initial tension of 1 g. The preparations are allowed to equilibrate for another 30-45 minutes, during which time they are subjected to tension (1 g) twice at intervals of 15 minutes. Changes in voltage are recorded and controlled by standard isometric transducers coupled to a data collection system (custom designed in Pfizer). After equilibration with tension, the tissues are subjected to electric field stimulation (EFS) using the following parameters: series of 10 s every 2 minutes, pulse amplitude of 0.1 ms, 10 Hz and maximum voltage (25 volts) continuously throughout the experiment. The SAI of the postganglionic cholinergic nerves of the trachea produces monophasic smooth muscle contractions and the height of the contraction is recorded. The organ baths are perfused constantly with the Krebs Ringer buffer described above by a peristaltic pump system (pump flow rate of 7.5 ml / minute) throughout the experiment, except when an agonist is added. beta-2 according to the present invention, then the pump is stopped during the cumulative administration time to the bath and turned on again when a maximum response for the wash period is reached. Experimental protocol for the evaluation of power and efficiency After balancing the SAI, the peristaltic pump is stopped and the preparations are "primed" with a single dose of 300 nM isoprenaline (Sigma 15627) to establish a maximum response in terms of inhibition of the contractile response to the SAI. The isoprenaline is then washed for a period of 40 minutes. After priming and recovery by washing, a standard curve of isoprenaline is made in all tissues (Curve 1 of isoprenaline) by a cumulative addition, bolted to the bath using semilogarithmic increments of the concentration. The concentration range used is from 1e ~ 9 to 1e / 3e "6 M. At the end of the isoprenaline curve, the preparations are washed again for 40 minutes before beginning a second curve, or with isoprenaline (as control). internal) or with a beta-2 agonist according to the present invention.The responses to beta-2 agonists are expressed in the form of percentage inhibition of the response to the EFS.The data for the beta-2 agonist is normalize by expressing the inhibition in terms of percentage of the maximal inhibition induced by isoprenaline in Curve 1. The EC50 value for the beta-2 agonist according to the present invention is to the concentration of compound needed to produce half the maximum effect. The data for the beta-2 agonists according to the present invention are then expressed in terms of relative potency as a function of isoprenaline defined by the ratio between (EC50 of the beta-2 agonist) / (isoprenaline-ECD). Confirmation of functional activity mediated by beta-2 Beta-2 agonist activity of experimental compounds is confirmed using the previous protocol, however, before constructing the beta-2 agonist curve according to the present invention, the preparations are pre-incubated (for a minimum of 45 minutes) with ICI 300 nM 118551 (a selective β2 antagonist) which produces, in the case of a beta-2 mediated effect, a shift to the right of the curve of response of the test compound. According to another alternative, the agonist potency for the β2 receptor of the compounds of the formula (1) can also be determined by measuring the concentration of a compound according to the present invention necessary to produce half the maximum effect (EC50) for the ß2 receptor. Preparation of compounds A 10 mM stock solution of 100% DMSO (dimethyl sulfoxide) is diluted to the maximum required dose in 4% DMSO. This maximum dose is used to construct a semilogarithmic dilution curve of 10 points, all in 4% DMSO. Isoprenaline (Sigma, I-5627) was used as a standard in all the experiments and for the control wells in each plate. The data were expressed as a percentage response to isoprenaline. Cell culture CHO cells (Chinese hamster ovary) expressing the human β2 adrenergic receptor were cultured recombinantly (de Kobilka et al., PNAS 84: 46-50, 1987 and Bouvier et al., Mol Pharmacol 33: 133 -139 1988 CHOhß2) in Dulbecco MEM / NUT MIX F12 medium (Gibco, 21331-020) supplemented with 10% fetal bovine serum (Sigma, F4135, Lot 90K8404, expiration date 09/04), 2 mM glutamine (Sigma , G7513), 500 μg / ml of geneticin (Sigma, G7034) and 10 μg / ml of puromycin (Sigma, P8833). Cells were seeded providing approximately 90% confluence for the experiments. Assay method Doses of 25 μl / well of each compound were transferred to one CAMP-Flashplate® (NEN, SMP004B) with 1% DMSO as minimum controls and 100 nM isoprenaline as maximum controls. This was diluted 1: 2 by adding 25 μl / well of PBS. The cells were trypsinized (0.25% Sigma, T4049), washed with PBS (Gibco, 14040-174) and resuspended in stimulation buffer (NEN, SMP004B) to provide 1 x 10 6 CHOhB2 cells / ml. The compounds were incubated with 50 μl / well of cells for 1 hour. The cells were then lysed by the addition of 100 μl / well of detection buffer (NEN, SMP004B) containing 0.18 μCi / ml 125l-cAMP (NEN, NEX-130) and the plates were incubated at room temperature for 2 more hours The amount of 12dl-cAMP bound to the Flashplate® was quantified using a Topcount NXT (Packard), with normal count efficiency for 1 minute. The dose-response data were expressed in terms of percent isoprenaline activity and adjusted using a four-parameter sigmoid fit. Thus, it was observed that the compounds of the formula (1) according to the present invention illustrated in examples 1 to 81 above show an EC50 of β2 cAMP between 0.02 nM and 1 nM.

The following table illustrates the activity of the compounds of the invention:

Claims (35)

1. CLAIMS 1. - A compound of the general formula (1): wherein the group (CH2) nC (= O) Q1 is in relative position meta or para, R1 and R2 are independently selected from H and C1-C4 alkyl, n is 0, 1 or 2 and Q1 is a group that is select from, "it's an alkylene
2. C1-C4, R11 is H or C1-C4 alkyl and A is pyridyl, C3-C10 cycloalkyl, said cycloalkyl, which is optionally bridged by one or more carbon atoms, tetrahydropyranyl, piperidinyl optionally substituted by benzyl, tetrahydrothioDiranyl or an OGUDO wherein R3, R4, R5, R6 and R7 are the same or different and are selected from H, C1-C4 alkyl, OR8, SR9, halo, CN, CF3, OCF3, COOR9, SO2NR9R10, CONR9R10, NR9R10, NHCOR10 and phenyl; wherein R8 is C1-C4 alkyl and R9 and R10 are the same or different and are selected from H or C1-C4 alkyl and the * represents the point of attachment to the carbonyl group; or, if appropriate, its pharmaceutically acceptable salts and / or isomers, tautomers, solvates or isotopic variations. 2. A compound according to claim 1, wherein Q1 is NH-Q2-A, wherein Q2 is CH2 and A is cycloh, tetrahydropyranyl, piperidinyl optionally substituted with benzyl or naphthyl.
3. 3. A compound according to claim 1, wherein Q- is < * 3 ~ * < A R6 wherein R3, R4, R5 and R6 are H.
4. 4. A compound according to claim 1, wherein Q1 is a group * -NH-Q2-A, in which Q2 is a C1-C4 alkylene and A is a group wherein R3, R4, R5, R6 and R7 are identical or different and are selected from H, C1-C4 alkyl, OR8, SR9, CN, halo, CF3, OCF3, SO2NR9R10, CONR9R10, NR9R10, NHCOR10 and phenyl with the proviso that at least 2 of R3 to R7 are equal to H; wherein R8 is C1-C4 alkyl and R9 and R10 are the same or different and are selected from H or C1-C4 alkyl.
5. 5. A compound according to claim 4 wherein Q2 is -CH2-, - (CH2) 2- or - (CH2) 3.
6. 6. A compound according to claim 5 wherein Q2 is -CH2-.
7. 7. A compound according to any one of claims 4 to 6 wherein A is a group wherein R3, R4, R5, R6 and R7 are the same or different and are selected from H, CH3, OCH2-CH3, SCH3, halo, CF3, OCF3, phenyl, dimethylamino, CN, fer-butyl, with the proviso that that at least 2 of R3 to R7 be equal to H.
8. 8. A compound according to claim 7 wherein R3, R4, R5, R6 and R7 are the same or different and are selected from H, CH3, Cl, F, CF3, with the proviso that at least 2 of R3 to R7 are equal to H.
9. 9. - A compound according to any one of claims 1 to 8, wherein R 1 is H or C 1 -C 4 alkyl and R 2 is C 1 -C 4 alkyl.
10. 10. A compound according to claim 9, wherein R1 is H or CH3 and R2 is CH3.
11. 11. A compound according to claim 10, wherein n is 1.
12. 12. The stereoisomer (R, R) of a compound according to any one of claims 1 to 11.
13. 13.- A compound of according to any one of claims 1 to 11, wherein the group (CH2) nC (= O) Q1 is in the meta relative position.
14. 14. A compound according to claim 1, which is selected from the group consisting of? / - Benzyl-2- (3-. {2 - [((2R) -2-hydroxy-2- { 4-hydroxy-3 - [(methylsulfonyl) amino] phenyl] -ethyl) amino] -2-methylpropyl. Phenyl) acetamide, 2- (3-. {2 - [((2R) -2- Hydroxy-2- {4-hydroxy-3 - [(methylsulfonyl) amino] phenyl} ethyl) amino] -2-methylpropyl} phenyl) -? / - (4-methoxybenzyl) acetamide, 2- ( 3- {2 - [((2R) -2-Hydroxy-2- {4-hydroxy-3 - [(methylsulfonyl) amino] phenyl} ethyl} amino] -2-methylpropyl} phenyl ) -? / - (2-methoxybenzyl) acetamide,? / - (2-Ethoxybenzyl) -2- (3- { 2 - [((2R) -2-hydroxy-2- {4-hydroxy -3- [(methylsulfonyl) amino] -phenyl.} Ethyl) amino] -2-methylpropyl. Phenyl) acetamide, 2- (3. {2 - [((2R) -2-Hydroxy-2) - { 4-hydroxy-3 - [(methylsulfonyl) amino] phenyl.} Ethyl) amino] -2-methylpropyl. Phenyl) -? / - (3-methoxybenzyl) acetamide, 2- (3- {2 - [((2R) -2-Hydroxy-2-. {4-hydroxy-3 - [(methylsulfonyl) amino] phenyl} ethyl) amino] -2- methylpropyl.}. phenyl) -? / - (4-methylbenzyl) acetamide2- (3- {2 - [((2R) -2-Hydroxy-2-. {4-hydroxy-3 - [(methylsulfonyl) amino] phenyl} ethyl) amino] -2-methylpropyl phenyl) -? / - (2-methylbenzyl) acetamide, 2- (3- { 2 - [((2R) -2-Hydroxy-2-. {4-hydroxy-3 - [(methylsulfonyl ) amino] phenol, ethyl) amino] -2-methylpropyl, phenyl) -? / - (3-methylbenzyl) acetamido,? y- (3,4-dimethoxybenzyl) -2- (3 - {2 - [((2R) -2-hydroxy-2- {4-hydroxy-3 - [(methylsulfonyl) amino] phenyl} ethyl) amino] -2-methylpropyl} phenyl) Acetamidate,? / - (2,4-Dimethoxybenzyl) -2- (3- {2 - [((2R) -2-hydroxy} -2- {4-hydroxy-3 - [(methylsulfonyl ) amino] phenyl} ethyl) amino] -2-methylpropyl.} phenyl) acetamide,? / - (3,5-dimethoxybenzyl) -2- (3- { 2 - [((2R) -2 -hydroxy-2- {4-hydroxy-3 - [(methylsulfonyl) amino] phenyl} ethyl) amino] -2-methylpropyl.} phenyl) acetamide,? / - (4-chlorobenzyl) -2- (3- {2 - [((2R) -2-hydroxy-2-. {4-hydroxy-3 - [(methylsulfonyl) amino] phenyl} ethyl) amino] -2-methylpropyl. phenyl) acetamide,? / - (2-Chlorobenzyl) -2- (3-. {2 - [((2R) -2-hydroxy-2-. {4-hydroxy-3- [(methylsulfonyl) amino]] fen il.}. ethyl) amino] '- 2-methylpropyl} phenyl) acetamide,? / - (3-Chlorobenzyl) -2- (3- { 2 - [((2R) -2-hydroxy-2-. {4-hydroxy-3 - [(methylsulfonyl) amino] phenyl.} ethyl) amino] -2-methylpropyl. phenyl) acetamide,? / - (4-Fluorobenzyl) -2- (3-. {2 - [((2R) -2-hydroxy-2- {.4-hydroxy-3 - [(methylsulfonyl) amino] phenyl} ethyl) amino] -2-methylpropyl.] Phenol) acetamide, / V- (2,4-dichlorobenzyl) -2- (3- {2 - [((2R) -2-hydroxy-2-. {4-hydroxy-3 - [(methylsulfonyl) amino] phenyl} ethyl) amino] -2-methylpropyl .}. phenyl) acetamide, ? / - (3,4-Dichlorobenzyl) -2- (3- { 2 - [((2R) -2-hydroxy-2-. {4-hydroxy-3 - [(methylsulfonyl) amino] phenyl} ethyl) amino] -2-methylpropyl.] phenol) acetamide,? / - (4-tert-Butylbenzyl) -2- (3-. {2 - [((2R) -2-hydroxy) 2- {4-hydroxy-3 - [(methylsulfonyl) amino] phenyl} ethyl) amino] -2-methylpropyl} phenyl) acetamide, / V- (2-chloro-6-fluorobenzyl) -2 - (3- {2 - [((2R) -2-hydroxy-2-. {4-hydroxy-3- [(methylsulfonyl) amino] phenyl} ethyl) amino] -2-methylpropyl. phenyl) acetamide, / V- (2,3-Dimethylbenzyl) -2- (3-. {2 - [((2R) -2-hydroxy-2-. {4-hydroxy-3 - [(methylsulfonyl ) amino] phenyl} etl) amino] -2-methylpropyl.} phenyl) acetamidate,? / - (3,5-Dichlorobenzyl) -2- (3-. {2- 2- [ ((2R) -2-hydroxy-2-. {4-hydroxy-3 - [(methylsulfonyl) amino] phenyl} ethyl) amino] -2-methylpropyl.} Phenyl) acetamide,? / - [3,5-jb / s (trifluoromethyl) benzyl] -2- (3-. {2 - [((2R) -2-hydroxy-2-. {4-hydroxy-3 - [(methylsulfonyl) amino] ] phenol] ethyl) amino] -2-methylpropyl. phenyl) acetamide, ? / - (3,4-Dimethylbenzyl) -2- (3- { 2 - [((2R) -2-hydroxy-2-. {4-hydroxy-3 - [(methylsulfonyl) amino] phenyl} ethyl) amino] -2-methylpropyl.} phenyl) acetamide, / V- (2,5-dichlorobenzyl) -2- (3 { (2R) -2 - [((2R) -2- hydroxy-2- {4-hydroxy-3- [(methylsulfonyl) amino] phenyl} ethyl) amino] propyl} phenyl) acetamide, 2- (3-. {2 - [((2R)} -2-Hydroxy-2- {4-hydroxy-3 - [(methylsulfonyl) amino] phenyl.} Ethyl) amino] -2-methylpropyl. Phenyl) -? / - (2-phenylethyl) acetamide, 2- (3- {2 - [((2R) -2-Hydroxy-2-. {4-hydroxy-3 - [(methylsulfonyl) amino] phenyl} ethyl) amino] -2- methylpropyl.}. phenyl) -? / - (3-phenylpropyl) acetamide,? / - (2,3-Dichlorobenzyl) -2- (3- { (2R) -2 - [((2R) -2- hydroxy-2- {4-hydroxy-3 - [(methylsulfonyl) amino] phenyl} ethyl) amino] propyl} phenyl) acetamide, ? / - (2,4-Dichloro-6-methylbenzyl) -2- (3- { 2 - [((2R) -2-hydroxy-2-. {4-hydroxy-3 - [(methylsulfonyl) amino3-phenyl.}. ethyl) amino] -2-methylpropyl.} phenyl) acetamide,? / - (Cyclohexylmethyl) -2- (3- { 2 - [((2R) -2-hydroxy-2-. { 4-hydroxy-3 - [(methylsulfonyl) amino] phenyl] ethyl) amino] -2-methylpropyl. Phenyl) acetamide,? / - (2-chloro-6-methylbenzyl) -2- (3- {.2 - [((2R) -2-hydroxy-2-. {4-hydroxy-3- [(methylsulfonyl) amino] phenyl} ethyl) amino] -2-methylpropyl phenyl) acetamide,? / - (2-Ethoxybenzyl) -2- (3 { (2R) -2 - [((2R) -2-hydroxy-2-. {4-hydroxy-3 - [(methylsulfonyl) amino] phenyl.} ethyl) amino] propyl. phenyl) acetamide,? / - (3,4-dimethylbenzyl) -2- (3- { (2R) -2 - [( (2R) -2-hydroxy-2- {4-hydroxy-3 - [(methylsulfonyl) amino] phenyl} ethyl) amino] propyl} phenyl) acetamide,? / - (3,4-Dichlorobenzyl) ) -2- (3- { (2R) -2 - [((2R) -2-hydroxy-2-. {4-hydroxy-3 - [(methylsulfonyl) amino] phenyl} ethyl) amino ] propyl.} phenyl) acetamide, 2- (3 { (2R) -2 - [((2R) -2-Hydroxy-2-. {4-hydroxy-3 - [(methylsulfonyl) amino]] phenyl.} ethyl) a mino] propyl} fenll) -? / - (3-phenylpropyl) acetamide,? / - (Cyclohexylmethyl) -2- (3 { (2R) -2 - [((2R) -2-hydroxy-2- { 4 -hydroxy-3- [(methylsulfonyl) amino] phenyl] ethyl) amino] propyl, phenyl) acetamide,? / - (2-Chloro-6-fluorobenzyl) -2- (3-. (2R) -2 - [((2R) -2-hydroxy-2-. {4-hydroxy-3 - [(methylsulfonyl) amino] phenol] et.l) amino] propyl. phenyl) acetamide,? / - (2-Chloro-4-fluorobenzyl) -2- (3 { (2R) -2 - [((2R) -2-hydroxy-2-. {4- hydroxy-3 - [(methylsulfonyl) amino] phenyl.} ethyl) amino] propyl. phenyl) acetamide,? / - (3,5-dichlorobenzyl) -2- (3- { (2R) -2 - [((2R) -2-hydroxy-2-. {4-hydroxy-3 - [(methylsulfonyl) amino] phenyl] ethyl) amino] propyl, phenyl) acetamide, 2- (3- { (2R) -2 - [((2R) -2-Hydroxy-2-. {4-hydroxy-3 - [(methylsulfonyl) amino] phenyl} ethyl) amino] propyl phenyl) -? / - [4- (trifluoromethyl) benzyl] acetamide, / V- (2,5-dichlorobenzyl) -2- (3- {(2R) -2 - [((2R) - 2-hydroxy-2- {4-hydroxy-3 - [(methylsulfonyl) amino] phenyl} ethyl) amino] propyl} phenyl) acetamide,? / - [4-Fluoro-2- (trifluoromethyl) benzyl] -2- (3- { (2R) -2 - [((2R) -2-hydroxy] -2 { 4-hydroxy-3 - [(methylsulfonyl) amino] phenyl .) ethyl) amino] propyl] phenyl) acetamide,? / - [4-Fluoro-3- (trifluoromethyl) benzyl] -2- (3 { (2R) -2 - [(( 2R) -2-hydroxy-2- {4-hydroxy-3 - [(methylsulfonyl) amino] phenyl} etl) amino] propyl] phenyl) acetamide,? / - [ 2-Fluoro-4- (trifluoromethyl) benzyl] -2- (3 { (2R) -2 - [((2R) -2-hydroxy-2-. {4-hydroxy-3 - [(methylsulfonyl) amino] phenyl.} ethyl) amino] propyl. phenyl) acetamide,? / - (2,4-Dichloro-6-methylbenzyl) -2- (3-. {(2R) - 2 - [((2R) -2-hydroxy-2- {4-hydroxy-3 - [(methylsulfonyl) amino] phenyl} ethyl) amino] propyl} phenyl) acetamide,? / - [4 -Cloro-3- (trifluoromethyl) benzyl] - 2- (3- { (2R) -2 - [((2R) -2-idroxy-2-. {4-hydroxy-3 - [(methylsulfonyl) amino] phenyl} ethyl) amino] propyl} phenol) acetamide,? / - [2-Chloro-5- (trifluoromethyl) benzyl] -2- (3 { (2R) -2 - [((2R) -2-hydroxy-2-. { 4-hydroxy-3 - [(methylsulfonyl) amino] phenyl.} Ethyl) amino] propyl.] Phenol) acetamide,? / - [3,5-¿) / s (Trifluoromethyl) benzyl] -2- (3 { (2R) -2 - [((2R) -2-hydroxy-2-. {4- hydroxy-3 - [(methylsulfonyl) amino] phenyl.} ethyl) amino] propyl. phenyl) acetamide,? / - [3-Fluoro-5- (trifluoromethyl) benzyl] -2- (3-. (2R) -2 - [((2R) -2-hydroxy-2- {4-hydroxy-3 - [(methylsulfonyl) amino] phenyl} ethyl) amino] propyl} phenyl) acetamide,? / - (3,4-Dichlorobenzyl) -2- (4- { 2 - [((2R) -2-hydroxy-2-. {4-hydroxy-3 - [(methylsulfonyl) amino] phenyl .}. ethyl) amino] -2-methylpropyl.] phenol) acetamide, ? / - [2-Chloro-5- (trifluoromethyl) benzyl] -2- (4-. {2 - [((2R) -2-hydroxy-2-. {4-hydroxy-3 - [(methylsulfonyl ) amino] phenol, etl) amino] -2-methylpropyl, phenyl) acetamidate, ? / - [4-Chloro-3- (trifluoromethyl) benzyl] -2- (4-. {2 - [((2R) -2-hydroxy-2-. {4-hydroxy-3 - [(methylsulfonyl ) amino] phenyl} ethyl) amino] -2-methylpropyl.} phenyl) acetamida,? / - [3,5-D / s (Trifluoromethyl) benzyl] -2- (4-. {2 - [((2R) -2-hydroxy-2- {4-hydroxy-3 - [(methylsulfonyl) amino] phenyl} ethyl) amino] -2-methylpropyl} phenyl) acetamide, ? / - [3-Fluoro-5- (trifluoromethyl) benzyl] -2- (4-. {2 - [((2R) -2-hydroxyl-2-. {4-hydroxy-3- [(methylsulfonyl) amino] phenyl.} ethyl) amino] -2-methylpropyl] phenyl) acetamida, ? - [2-Fluoro-5- (trifluoromethyl) benzyl] -2- (4-. {2 - [((2R) -2-hydroxy-2-. {4-hydroxy-3 - [( methylsulfonyl) amino] phenyl.} ethyl) amino] -2-methylpropyl. phenyl) acetamide, ? / - [4-Fluoro-2- (trifluoromethyl) benzyl] -2- (4-. {2 - [((2R) -2-hydroxy-2-. {4-hydroxy-3 - [(methylsulfonyl ) amino] phenyl} ethyl) amino] -2-methylpropyl. phenyl) acetamide, ? / - [4-Fluoro-3- (trifluoromethyl) benzyl] -2- (4-. {2 - [((2R) -2-hydroxy-2-. {4-hydroxy-3 - [(methylsulfonyl ) amino] phenyl} ethyl) amino] -2-methylpropyl.} phenyl) acetamida, 2- (4- { (2R) -2 - [((2R) -2-Hydroxy-2- {.4-hydroxy-3- [(methylsulfonyl) amino] phenyl} et.l) amino] propyl} phenyl) -? / - (2-methoxybenzyl) acetamide, ? / - (2-Ethoxybenzyl) -2- (4- { (2R) -2 - [((2R) -2-hydroxy-2-. {4-hydroxy-3 - [(methylsulfonyl)] amino] phenyl} ethyl} amino) propyl, phenyl) acetamide,? / - Benzyl-2- (4- { (2R) -2 - [((2R) -2-hydroxy-2) - { 4-hydroxy-3 - [(methylsulfonyl) amino] phenyl.} Ethyl) amino] propyl. Phenyl) acetamide, 2- (4- { (2R) -2 - [((2R ) -2-Hydroxy-2- {4-hydroxy-3 - [(methylsulfonyl) amino] phenyl} ethyl) amino] propyl} phenyl) - / V- (3-phenylpropyl) acetamide, ? / - (2,3-Dihydro-1H-inden-2-yl) -2- (3 { (2R) -2 - [((2R) -2-hydroxy-2-. {4- hydroxy-3 - [(methylsulfonyl) amino] phenyl.} ethyl) amino] propyl. phenyl) acetamide, 2- (3 { (2R) -2 - [((2R) -2-Hydroxy) 2- {4-hydroxy-3 - [(methylsulfonyl) amino] phenyl} ethyl) amino] propyl} phenyl) -? / - (2-methoxybenzyl) acetamide,? / - Benzyl-2- ( 3- {(2R) -2 - [((2R) -2-hydroxy-2- {4-hydroxy-3- [(methylsulfonyl) amino] phenyl} ethyl) amino] propyl}. phenyl) -acetamide, 2- (3 { (2R) -2 - [((2R) -2-Hydroxy-2. {4-hydroxy-3 - [(methylsulfonyl) amino] phenyl}. ethyl) amino] propyl] phenyl) - / V- (2-phenylethyl) acetamide, 2- (3 { (2R) -2 - [((2R) -2-Hydroxy-2-. {4-hydroxy-3 - [(methylsulfonyl) amino] phenyl} ethyl) amino] propyl} phenyl) -? / - (mesitylmethyl) acetamide, 2- (3-. {(2R) -2 - [((2R) -2-Hydroxy-2-. {4-hydroxy-3 - [(methylsulfonyl) amino] phenyl} ethyl) amino] propyl, phenyl) -? / - (2 , 3,6-trichlorobenzyl} acetamide, 2- (3. {2 - [((2R) -2-Hydroxy-2. {4-hydroxy-3 - [(methylsulfonyl) amino] phenyl]} ethyl) amino] -2-methylpropyl. l) -? / - [3- (Trifluoromethyl) benzyl] acetamide,? / - (2,3-Dichlorobenzyl) -2- (3-. { (2R) -2 - [((2R) -2-hydroxy-2-. {4-hydroxy-3- [(methylsulfonyl) amino] phenyl} ethyl) amino] propyl} phenyl) acetamide,? / - (3-Chloro-4-methylbenzyl) -2- (3 { (2R) -2 - [((2R) -2-hydroxy-2-. {4-hydroxy- 3 - [(methylsulfonyl) amino] phenyl.} Ethyl) amino] propyl. Phenyl) acetamide, 2- (3. {2 - [((2R) -2-Hydroxy-2-. {4 -hydroxy-3 - [(methylsulfonyl) amino] phenyl.} ethyl) amino] -2-methylpropyl. phenyl) -? / - [2- (methylthio) benzyl] acetamide, 2- (3-. 2 - [((2R) -2-Hydroxy-2- {4-hydroxy-3 - [(methylsulfonyl) amino] phenyl} ethyl) amino] -2-methylpropyl} phenyl) -? / - [4- (methylthio) benzyl] acetamide, 2- (3- {2 - [((2R) -2-Hydroxy-2-. {4-hydroxy-3 - [(methylsulfonyl) amino] phenyl} ethyl) amino] -2-methylpropyl} phenyl) - / V- (tetrahydro-2H-thiopyran-4-yl) acetamida, ? / - (Biphenyl-2-ylmethyl) -2- (3- { 2 - [((2R) -2-hydroxy-2-. {4-hydroxy-3 - [(methylsulfonyl) amino] phenyl .) ethyl) amino] -2-methylpropyl. phenyl) acetamide, 2- (3 { (2R) -2 - [((2R) -2-Hydroxy-2-. {4-hydroxy -3 - [(methylsulfonyl) amino] phenyl.} Ethyl) amino] propyl. Phenyl) -? / - (1-naphthylmethyl) acetamide, 2- (3 { (2R) -2- [((2R) -2-Hydroxy-2- { 4-hydroxy-3 - [(methylsulfonyl) amino] phenyl]. Et.l) amino] propyl, phenyl) - # V- (pyridine- 2-ylmethyl) acetamide, 2- (3 { (2R) -2 - [((2R) -2-Hydroxy-2-. {4-hydroxy-3 - [(methylsulfonyl) amino] phenyl}. ethyl) amino] propyl.] phen.l) -? / - [4- (trifluoromethoxy) benzyl] acetamide,? / - (4-Cyanobenzyl) -2- (3 { (2R) - 2 - [((2R) -2-hydroxy-2- {4-hydroxy-3 - [(methylsulfonyl) amino] phenyl} ethyl) amino] propyl} phenyl) acetamide,? / - [4 - (Dimethylamino) benzyl] -2- (3 { (2R) -2 - [((2R) -2-hydroxy-2-. {4-hydroxy-3 - [(methylsulfonyl) amino] phenyl} ethyl) amino] propyl.] phenyI) acetamide, 2- (3 { (2R) -2 - [((2R) -2-Hydroxy-2-. {4-hydroxy-3- [ (methylsulfonyl) amino] phenyl.} ethyl) amino ] propyl} phenyl) -? / - phenylacetamide,? / - (1-Benzylpiperidn-4-yl) -2- (3 { (2R) -2 - [((2R) -2-hydroxy- 2- {4-hydroxy-3 - [(methylsulfonyl) amino] phenyl} ethyl) amino] propyl} phenyl) acetamide and > 2- (3- {2 - [((2R) -2-Hydroxy-2-. {4-hydroxy-3 - [(methylsulfonyl) amino] phenyl} ethyl) amino] - 2-methylpropyl, phenyl) -? / - (mesyltin) acetamide.
15. 15. -? / - Benzyl-2- (3- { 2 - [((2R) -2-hydroxy-2-. {4-hydroxy-3 - [(methylsulfonyl) amino] phenyl} ethyl) amino ] -2-methylpropyl.} Phenyl) acetamide.
16. 16. 2- (3- {2 - [((2R) -2-Hydroxy-2-. {4-hydroxy-3 - [(methylsulfonyl) amino] phenyl} ethyl) amino] -2 -methylpropyl.}. phenol) -? / - (4-methoxybenzyl) acetamide.
17. 17. 2- (3- {2 - [((2R) -2-Hydroxy-2-. {4-hydroxy-3 - [(methylsulfonyl) amino] phenyl} ethyl) amino] -2-methylpropyl.}. phenyl) -? / - (4-methylbenzyl) acetamide.
18. 18.-? / - (4-Chlorobenzyl) -2- (3- {2 - [((2R) -2-hydroxy-2-. {4-hydroxy-3 - [(methylsulfonyl) amino] phenyl .) ethyl) amino] -2-methylpropyl. phenyl) acetamide.
19. 19.-? / - (3,4-Dichlorobenzyl) -2- (3- { 2 - [((2R) -2-hydroxy-2-. {4-hydroxy-3 - [(methylsulfonyl) amino] ] phenyl} ethyl) amino] -2-methylpropyl. phenyl) acetamide.
20. 20. A pharmaceutical composition that includes a compound of the formula (1) as described in any one of claims 1 to 19 or a pharmaceutically acceptable salt or pharmaceutically acceptable derivative thereof, together with customary pharmaceutically acceptable excipients and / or additives. .
21. 21. A compound of the formula (1) as described in any one of claims 1 to 19 or a pharmaceutically acceptable salt, pharmaceutically acceptable derivative or composition thereof, for use as a medicament.
22. 22. A compound of the formula (1) as described in any one of claims 1 to 19 or a pharmaceutically acceptable salt or derivative form thereof, for use in the treatment of diseases, disorders and conditions in which the ß2 receptor is involved.
23. 23. A compound of the formula (1) as described in any one of claims 1 to 19 or a pharmaceutically acceptable salt or derivative form thereof, for use in the treatment of diseases, disorders and conditions that are they select from the group consisting of: • asthma of any type, etiology or pathogenesis, in particular asthma which is a member selected from the group consisting of atopic asthma, non-atopic asthma, allergic asthma, IgE-mediated atopic bronchial asthma, asthma bronchial, essential asthma, true asthma, intrinsic asthma caused by pathophysiological alterations, extrinsic asthma caused by environmental factors, essential asthma due to unknown or not apparent causes, non-atopic asthma, bronchitic asthma, emphysematous asthma, exercise-induced asthma, asthma induced by allergens, asthma induced by cold air, professional asthma, infectious asthma caused by bacterial, fungal, protozoal or viral infection , non-allergic asthma, incipient asthma, wheezing syndrome in the child and bronchiolitis, • chronic or acute bronchoconstriction, chronic bronchitis, obstruction of the minor airways and emphysema, • obstructive or inflammatory diseases of the respiratory tract of any type, etiology or pathogenesis, in particular an obstructive or inflammatory disease of the respiratory tract 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 characterized by irreversible, progressive obstruction of the respiratory tract, adult respiratory distress syndrome (ARDS), exacerbation of airway hyperactivity following treatment with other drugs and respiratory tract disease associated with pulmonary hypertension, • bronchitis of any type, etiology or pathogenesis, in particular bronchitis which is a member selected from the group consisting of acute bronchitis, acute lantrarotracheal bronchitis, arachidic bronchitis, catarrhal bronchitis, pseudomembranous bronchitis, dry bronchitis, infectious asthmatic bronchitis, productive bronchitis, staphylococcal bronchitis or streptococcus and vesicular bronchitis, • injury acute pulmonary 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.
24. 24. The use of a compound of the formula (1) as described in any one of claims 1 to 19 or of a salt, a pharmaceutically acceptable derivative or composition thereof, for the manufacture of a drug having a β2 agonist activity.
25. 25. The use of a compound of the formula (1) as described in claim 1 or of a pharmaceutically acceptable salt, solvate or composition thereof, for the manufacture of a drug for the treatment of diseases, disorders and conditions. which are selected from the group as described in claim 23.
26. 26.- A method of treatment of a mammal, including a human, with a β2-agonist that includes treating said mammal with an effective amount of a compound of the formula (1) as described in any one of claims 1 to 19 or with a salt, derivative form or pharmaceutically acceptable composition thereof.
27. 27. A method according to claim 26, wherein the disease, disorder or condition is selected from the group as described in claim 19.
28. 28.- A process for the preparation of a compound of the formula (1) ) according to any one of claims 1 to 19, said process comprising the following steps: (a) coupling an acid of the formula (2): wherein R1, R2 and n are as defined in claim 1, with an amine of the formula NH2-Q2-A (3), wherein R3 to R6, Q2 and A are as defined in claim 1, (b) isolating said compound of the formula (1).
29. 29. A process for the preparation of a compound of the formula (1) according to claim 1, wherein R1 and R2 are methyl and n is 1, said process comprising the following steps (a) reacting a compound of the formula (21) wherein X is H, Li, K or Na and potentially an organic amine base or other metal salt, with a suitable amine of the formula NHR8-Q2-A (3) in the presence of a conventional coupling agent such as 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride or dicyclohexylcarbodiimide in a suitable solvent such as pyridine, dimethylformamide and dimethylacetamide, optionally in the presence of an organic base and an additive to obtain said composed of the formula (1). (b) isolating said compound of the formula (1).
30. 30. A process according to claim 29 wherein said compound of the formula (21) is obtained by hydrogenating a compound of the formula (22) wherein X is H, Na, Li or K and potentially an organic amine or other metal salts in the presence of an appropriate solvent such as methanol, IPA, THF and water and in the presence of a suitable catalyst such as palladium hydroxide on carbon or palladium on carbon.
31. 31. A process according to claim 30 wherein said compound of the formula (22) is obtained by reacting a compound of the formula (23) with M-OH wherein M is selected from Na, K or Li, optionally in the presence of a suitable solvent such as propionitrile, tetrahydrofuran or dioxane.
32. 32. A process according to claim 31, wherein said compound of the formula (23) is obtained by deprotecting a compound of the formula (24) using a deprotection agent such as tetrabutylammonium fluoride, HF or triethylamine trifluorohydrate in the presence of a suitable solvent such as propionitrile.
33. 33. A method according to claim 32 wherein said compound of the formula (24) is obtained by reacting a compound of the formula C1-C4 alkyl with a compound of the formula in the presence of a suitable solvent such as propionitrile, THF, toluene, ethyl acetate, acetonitrile, propionitrile, dioxane, DMF, DMSO and optionally in the presence of a base such as sodium hydrogencarbonate, potassium hydrogencarbonate, Hünig base or triethylamine, at a temperature between 50 ° C and 150 ° C during 12 to 36 hours.
34. 34.- Combination of a compound according to any one of claims 1 to 19 with another therapeutic agent (s) selected from: (a) 5-lipoxygenase inhibitors (5-) LO) or antagonists of the 5-lipoxygenase activation protein (FLAP), (b) leukotriene antagonists (LTRA) including LTB4, LTC4, LTD4 and LTE4 antagonists, (c) histamine receptor antagonists that include H1 and H3 antagonists, (d) sympathomimetic vasoconstrictor agents, adrenergic receptor agonists a1 and a2 for decongestant use, (e) M3 muscarinic receptor antagonists or anticholinergic agents, (f) PDE inhibitors, for example PDE3, PDE4 and PDE5 inhibitors, (g) theophylline, (h) sodium cromoglycate, (i) COX inhibitors, both non-selective and selective inhibitors of COX-1 or COX-2 (NSAID), G) oral and inhaled glucocorticosteroids, such as DAGR (dissociated agonists of the corticoid receptor), (k) active monoclonal antibodies against endogenous inflammatory entities, (I) agents against tumor necrosis factor (anti-TNF-a), (m) inhibitors of adhesion molecules including VLA-4 antagonists, (n) quinine receptor antagonists Bi and B2, (o) immunosuppressive agents, (p) matrix metalloprotease inhibitors (MMPs), (q) tachykinin receptor antagonists NK1, NK2, and NK3, (r) elastase inhibitors, (s) receptor agonists adenosine A2a, (t) urokinase inhibitors, (u) compounds that act on dopamine receptors, for example D2 agonists, (v) modulators of the NF? ß > for example inhibitors IKK, (w) modulators of cytokine signaling pathways, such as inhibitors of p38 MAP kinase, syk kinase or JAK kinase, (x) agents that can be classified as mucolytic or antitussive, and (and) antibiotics.
35. 35. A compound of the formula (2) or a salt thereof wherein R > 1, D R2 and n are defined in claim 1.