MXPA06008311A - 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, 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

For two-letter cades nd other abhreviatians. It referred to the "Guidance Notes on Codes and Abbrevialions" appearing at the beginning of the regular issue of the PCT Gazette. i. i bronchoconstrictors, including leukotriene D4 (LTD4), acetylcholine, bradykinin, prostaglandins, histamine and endothelin. Because ß2 receptors are so widely distributed 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, β2 agonists show cholinergic neurotransmission in the airways of humans, which may result in a lower cholinergic reflex of bronchoconstriction. In addition to the respiratory tract, it has also been established that β2-adrenoceptors are also expressed in other organs and tissues and thus β2-agonists, such as those described in the present invention, may have application in the treatment of other diseases such as , but without limitation, those of the nervous system, premature birth, congestive heart failure, depression, inflammatory and allergic diseases of the skin, psoriasis, skin proliferative diseases, glaucoma and in conditions in which it is positive to reduce gastric acidity, particularly in gastric and peptic ulcers. However, many ß2 agonists are limited in their use, due to their low selectivity or adverse side effects produced by high systemic exposure and mediated mainly by action on ß2 adrenoreceptors expressed outside the respiratory tract (muscle tremor, tachycardia, palpitations , fatigue). Therefore, there is a need for better agents of this class. Accordingly, there is still a need for new β2 agonists having an appropriate pharmacological profile, for example in terms of potency, pharmacokinetics or duration of action. In this context, the present invention relates to new β2 agonists. Various sulfonamide derivatives have already been described. For example, WO02066250 describes active compounds as β3 agonists, selective on β2 of formula: wherein m can be 2, R can be H, OH or NR5SO2 /? 5 (with R5 H or C Cß alkyl), Z can be a bond, R2 can be H or Ci-Cß alkyl, R4 can be C-? -C6 alkyl, B can be phenyl, Y is Ci-C? alkyl, and A can be phenyl. WO02 / 000622 describes selective β3 agonists of 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 disclosed in U.S. Patent 5,776,983 as β3 agonists. More specifically, they are compounds of 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, where R6 and R6, can be H or lower alkyl. However, none of the above sulfonamide derivatives has shown a β2 agonist activity and a pharmacological profile that allows it to be used as an effective drug in the treatment of diseases and / or conditions mediated by β2, in particular allergic and non-allergic diseases of the respiratory tract or other diseases such as those cited above. The invention relates to compounds of general formula (1): in which the group (CH2) nC (= O) Q1 is in the meta or para position, R1 and R2 are independently selected from H and C? -C alkyl , n is 0, 1 or 2 and Q1 is a group selected from: and a group * -NR -Q -A, where p is 1 or 2, Q is an alkylene of C C4 optionally substituted with OH, R8 is H or C? -C alkyl, and A is pyridyl optionally substituted with OH, cycloalkyl of C3-C7 optionally substituted with OH or a group wherein R3, R4, R5, R6 and R7 are the same or different and are selected from H, C4 alkyl, OR9, SR9, halo, CN, CF3, OCF3, COOR9, SO2NR9R10, CONR9R10, NR9R1 °, NHCOR10 and phenyl optionally substituted with 1 to 3 groups selected from OR 9, halo and CrC 4 alkyl; where R9 and R10 are identical or different and are selected from H or C-? -C4 alkyl and the * represents the point of attachment to the carbonyl group; wherein the Q1 group is substituted with at least one hydroxy group; or, if appropriate, their pharmaceutically acceptable salts and / or isomers, tautomers, solvates or isotopic variations thereof. The compounds of formula (1) are agonists of the β2 receptors, which are particularly useful for the treatment of diseases and / or conditions mediated by β2, showing an excellent potency, in particular when administered by inhalation. In the general formula (1) given hereinabove, C? -C4 alkyl and C? -C4 alkylene denote a straight or branched chain group containing 1, 2, 3 or 4 carbon atoms. This also applies if they carry substituents or exist as substituents of other radicals, for example in O-alkyl radicals of (d-C4), S-alkyl radicals of (C- | -C4), etc ... They are examples of radicals suitable (d-C4) alkyl methyl, ethyl, n-propyl, / so-propyl, n-butyl, / so-butyl, sec-butyl, re-butyl ... Examples of alkoxy radicals of (C C4) are suitable are methoxy, ethoxy, n-propyloxy, so-propyloxy, n-butyloxy, / so-butyloxy, sec-butyloxy and tert-butyloxy. The C3-C7 cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. The preferred C3-C7 cycloalkyls are substituted with OH. Finally, halo denotes a halogen atom selected from the group consisting of fluorine, chlorine, bromine and iodine, in particular fluorine or chlorine.

Next, the free bond in the phenyl group such as in the structure indicated below, means that the phenyl can be substituted in the meta or para position. The compounds of formula (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 formula (1) unless otherwise indicated. The amide derivatives of formula (1) can be prepared by linking an acid of formula (2) or a salt thereof: with an amine of formula NHR -Q -A (3) The coupling is generally carried out in an excess of said amine as the acid receptor, with a conventional coupling agent (for example 1- (3-dimethylaminopropyl) -3- hydrochloride. ethylcarbodiimide or N, N'-dicyclohexylcarbodiimide), optionally in the presence of a catalyst (for example, 1-hydroxybenzotriazole hydrate or 1-hydroxy-7-azabenzotriazole hydrate), and optionally in the presence of a tertiary amine base (e.g. N-methylmorpholine, triethylamine or diisopropylethylamine). The reaction can 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 commercially available or can be prepared by conventional methods well known to those skilled in the art (eg, reduction, oxidation, alkylation, transition metal-mediated binding). , protection, deprotection etc.) from materials available in the market The acid of formula (2) can be prepared from the corresponding ester of formula (4): where Ra is a suitable acid protecting group, preferably an alkyl group of (C -? - C), which includes, but is not limited to, methyl and ethyl, according to any method known to the person skilled in the art to prepare an acid from an ester without modifying the remainder of the molecule. For example, the ester can be hydrolyzed by treatment with 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 formula (4) can be prepared by reaction of an amine of formula (5): wherein Ra and n are as defined above, with a bromide of formula (6): In a typical procedure, the amine of formula (5) is reacted with a bromide of formula (6) optionally in the presence of a solvent or mixture of solvents (for example, dimethylsulfoxide, toluene, N, N-dimethylformamide, propionitrile, acetonitrile ), optionally in the presence of a suitable base (for example triethylamine, diisopropylethylamine, potassium carbonate, potassium hydrogen carbonate) at a temperature between 80 ° C and 120 ° C, for a period of 12 to 48 hours. The bromide of formula (6) can be prepared according to the method of WO 02/06258 (p.36, example 14a). Alternatively, the ester of formula (4) wherein n = 1 can be prepared from the bromide of formula (7): In a typical procedure bromide (7) is treated with a suitable palladium catalyst (e.g. [1,1'-bis (diphenylphosphino) ferrocene] dichloro palladium (ll)) in an atmosphere of carbon monoxide using RaOH as solvent ( for example MeOH, EtOH) at high temperature (100 ° C) and pressure (up to 100 psi (690 kPa)) giving the ester of formula (4).

The amine of formula (5), wherein R-i is Me and R2 is H, can be prepared as the (R) or (S) -enantiomer from the corresponding protected amine of formula (8): wherein Ra and n are as defined above and Rb and Rc represent any suitable substituent such that HNRbRc is a quarry amine (for example, Rb may be hydrogen and Rc may be a-methylbenzyl), provided that the links between N and Rb and N and Rc can be easily cleaved to give the free amine of formula (5) using conventional methodology to cleave nitrogen protecting groups, such as that found in the textbook TW GREENE, Protective Groups in Organic Synthesis, A. Wiley-lnterscience Publication, 1981. The amine of formula (8) can be prepared as an individual diastereomer by reaction of an amine of formula HNRbRc with a ketone of formula (9): wherein Ra, Rb, Rc and n are as defined above.

In a typical procedure, the reaction of the ketone of formula (9) with the amine of formula HNRbRc leads to a chiral intermediate which in turn is reduced with a suitable reducing agent (for example sodium cyanoborohydride of formula NaCNBH3 or sodium triacetoxyborohydride of 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) giving the amine of formula (8) as a mixture of diastereomers . The reaction is generally carried out in a solvent such as tetrahydrofuran or dichloromethane at a temperature between 20 ° C and 80 ° C for a period of 3 to 72 hours. The resulting product is subsequently transformed into the hydrochloride salt and selectively crystallized from a solvent or a mixture of suitable solvents (for example isopropanol, ethanol, methanol, diisopropyl ether or diisopropyl ether / methanol) giving (8) as an individual diastereomer. The ketone of formula (9) in which n = 1 can be prepared by palladium-mediated coupling of an aryl halide of formula (10): (10) wherein Ra is as defined above and Hal represents a halogen atom, including, but not limited to, bromine and iodine, with an enolate or an enolate equivalent. In a typical procedure, the aryl halide of formula (10) is reacted with a tin enolate generated in-situ by treatment of isoprenyl acetate with tri-n-butyltin methoxide of formula Bu3SnOMe in the presence of a palladium catalyst suitable (palladium / tri-ortho-tolylphosphine acetate of 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 comprised between 80 ° C and 1 10 ° C for a period of 6 to 16 hours. The aryl halide of formula (10) can be obtained by esterification of the corresponding acid of formula (11): where Hal is as defined above, according to any method well 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 formula (11) is reacted with an alcohol solvent of the formula RaOH, where Ra is as defined above, in the presence of an acid such as hydrogen chloride at a temperature of between 10 °. C and 40 ° C (room temperature) for 8 to 16 hours. The acid of formula (11) is a commercial product. The amine of formula (5), wherein R-i = R2 = alkyl, can be prepared according to the following scheme: SCHEME 1 (5) where R1, R2 and Ra are as defined above. In a typical procedure, the ester of formula (12) is reacted with an "activated" alkyl (organometallic alkyl such as R2MgBr, R2MgCI or R2Li) to give the corresponding tertiary alcohol of formula (13) using the method described above. Said tertiary alcohol of formula (13) is then treated with an alkyl nitrile (e.g., acetonitrile, chloroacetonitrile) in the presence of an acid (e.g., sulfuric acid, acetic acid) to give a protected intermediate which in turn is cleaved using methodology conventional for cleaving nitrogen protecting groups such as that mentioned in textbooks. The resulting amino acid is then esterified using the method described herein to give the amine of formula (5). Alternatively, the amine of formula (5), wherein R1 = R2 = C? -C alkyl and n = 0, can be prepared according to the following scheme: SCHEME 2 (14) (15) (16) (5) where R1, R2 and Ra are as defined above. In a typical procedure, the ester of formula (14) is reacted with an "activated" alkyl (organometallic alkyl such as R2MgBr, R2MgCI or R2L) given the corresponding tertiary alcohol of formula (15) using the method described above. Said tertiary alcohol of formula (15) is then treated with an alkyl nitrile (for example, acetonitrile, chloroacetonitrile) in the presence of an acid (for example sulfuric acid, acetic acid) to give a protected intermediate which in turn is cleaved using conventional methodology to cleave nitrogen protecting groups such as the one mentioned in textbooks by giving bromine amine (16). The resulting amine bromine (16) is treated with a suitable palladium catalyst (eg, [1, 1'-bis (diphenylphosphino) ferronuchen] dichloropalladium (II)) in an atmosphere of carbon monoxide using RaOH as a solvent (e.g. , MeOH, EtOH) at high temperature (100 ° C) and pressure (100 psi (690 kPa)) to give the ester of formula (5). The ketone of formula (9) in which n = 2 can be prepared by reduction of an alkene of formula (17): In a typical procedure, a solution of the olefin of formula (17) in a suitable solvent (for example methanol, ethanol, ethyl acetate) is treated with a palladium catalyst (e.g. 10% palladium on carbon) and stirred in a hydrogen atmosphere, optionally at high pressure (eg 60 psi (414 kPa)), at a temperature between room temperature and 60 ° C for a period of 8-24 hours.

The alkene of formula (17) can be prepared by palladium mediated coupling of an activated olefin with an aryl halide of formula (18): In a typical procedure, the aryl halide (18) 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 formula Pd (PPh3) ) 4, palladium acetate / tri-ortho-tolylphosphine of formula Pd (OAc) 2 / P (o-tol) 3 or (diphenylphosphino) ferrocenyl palladium chloride of the formula dppfPdCI2) 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 1 10 ° C for a period of 8 to 24 hours. The ketone of formula (18) is a commercial product. The amine of formula (5), wherein R and R2 are both H, can be prepared according to the following scheme: SCHEME 3 (19) (20) where R1, R2 and Ra are as defined above. In a typical procedure, the acid of formula (19) is preferably reduced to the corresponding alcohol (20) in the presence of the ester. This can be done by forming the acyl imidazole or mixed anhydride and subsequent reduction with sodium borohydride or other suitable reducing agent. Said primary alcohol of formula (20) is then converted to a leaving group such as mesylate, tosylate, bromide or iodide and is displaced with an appropriate nucleophilic amine. The preferred nucleophile is the azide which can then be reduced to the primary amine by hydrogenation or triphenylphosphine. Other 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 formula (I) wherein R1 and R2 are methyl and n is 1, can be prepared by reacting a compound of formula (21) wherein X is H, K, Na, Li and potentially a base organic amine or other metal salt, with a suitable amine of formula NHR8-Q2-A (3) in the presence of a concen- trational coupling agent such as 1- (3-dimethylamidopropyl) -3-ethylcarbodiimide hydrochloride or dicyclohexylcarbodiimide in a suitable solvent such as pyridinedimethylformamide and dimethylacetamide optionally in the presence of an organic base ( such as Hunig base) and an additive (such as 1-hydroxybenzotriazole) to obtain a compound of formula (1): wherein R1 and R2 are methyl and n is 1.

Said compound of formula (21) can be obtained by hydrogenation of a compound of formula (22) wherein X is H, Na, Li or K and potentially an organic amine or other metal salts, in the presence of a suitable 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 formula (22) can be obtained by reacting a compound of formula (23) with M-OH where M is selected from Na, K or Li, optionally in the presence of a suitable solvent such as propionitrile, tetrahydrofuran or dioxane, preferably propionitrile. Said compound of formula (23) can be obtained by deprotecting a compound of formula (24) using a deprotecting agent such as tetrabutylammonium fluoride, HF, or triethylamine trifluorohydrate in the presence of a suitable solvent such as propionitrile. Said compound of formula (24) can be obtained by reacting a compound of formula with a compound of 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 hydrogen carbonate, potassium hydrogen carbonate, Hunig base. or triethylamine, at a temperature between 50 ° C and 150 ° C for 12 to 36 hours.

For some of the steps of the methods of preparing the compounds of formula (1) described hereinabove, it may be necessary to protect potentially reactive functions that are not desired to react and cleave said protecting groups accordingly. In such a case, any compatible protective radical can be used. In particular, protection and deprotection methods such as those described in T.W. GREENE (Protective Groups in Organic Synthesis, A. Wiley-lnterscience Publication, 1981) or in P. J. Kocienski (Protecting groups, Georg Thieme Verlag, 1994). All the above reactions and preparations of new starting materials used in the foregoing methods are conventional and those skilled in the art will know the reaction conditions and reagents appropriate for their mode or preparation as well as methods for isolating the desired products, with reference to precedents in the bibliography and examples and adjunct preparations. In addition, the compounds of formula (1) as well as the intermediates for the preparation thereof can be purified according to various well-known methods, such as for example crystallization or chromatography. Preferably Q2 is -CH2-, - (CH2) 2-, - (CH2) 3-, - (C (CH3) 2) -, - (CH2) 4- or - (CH (CH2OH)) -. Preferably, Q1 is , where one of R3, R4, R5 and RT is OH and the others are H. Preferably Q1 is R3 , where one of R3, R4, R5 and R & is OH and the others are H. Preferably Q1 is a group * -NR8-Q2-A, where R8 is H, CH3 or CH2CH3, Q2 is an alkylene of C- | -C4 and A is naphthyl substituted with a hydroxy. Preferably, Q1 is a group * -NR8-Q2-A, where R8 is H, CH3 or CH2CH3, Q2 is an alkylene of C1-C and A is a group wherein one of R3, R4, R5, R6 and R7 is OH and the others are the same or different and are selected from H, CC alkyl, OR9, SR9, halo, CF3, OCF3, SO2NR9R10, CONR9R10, NR9R10, NHCOR 0, with the proviso that at least 2 of R3 to R7 are equal to H; where R9 and R10 are identical or different and are selected from H or C4 alkyl. More preferably, O1 is a group * -NH-Q2-A, where Q2 is -CH2-, - (CH2) 2-, - (CH2) 4-, -CH2-C (CH3) 2) - preferably -CH2- , and A is a group wherein one of R3, R4, R5, R6 and R7 is OH and the others are equal or different and are selected from H, OH, CH3, OCH2-CH3, SCH3, halo, CF3, OCF3, with the proviso that at least 2 of R3 to R7 be equal to H. Preferably, Q1 is a group * -NR8-Q2-A, where R8 is H, CH3 or CH2CH3, Q2 is an alkylene of C C4 and A is a group wherein one of R3, R4, R5, R6 and R7 is phenyl substituted with OH and the others are H. In the foregoing groups of compounds, the following substituents are particularly preferred: R1 is H or C-? -C4 alkyl and R2 is C? -C4 alkyl. More preferably, R1 is H or CH3 and R2 is CH3. n is 0 or 1. 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 formula (1) as described later in Examples section of this document, namely: 2- (3- { 2 - [((2r?) - 2-Hydroxy-2-. {4-hydroxy-3- [(methylsulfonyl) amino] phenyl} ethyl) amino] -2-methy1propyl] phenyl) -N- (4-hydroxy-3-methoxybenzyl) acetamide; N - [(4, -Hydroxy-phenyl-4-yl) methyl] -2- (3-. {2 - [((2f?) - 2-hydroxy-2-. {4-hydrox? - 3 - [(methylsulfonyl) amino] phenyl] ethyl) amino] -2-methylpropyl] phenol) acetamide; N- (4-Chloro-2-hydroxybenzyl) -2- (3- {2 - [((2R) -2-hydroxy-2-. {4-hydroxy-3- [(methylsulfonyl) ) amino] phenyl} ethyl) amino] -2-methylpropyl, phenyl, acetamide; N- (4-Hydroxy-3,5-dimethylbenzyl) -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) -N - [(2-hydroxy-1-naphthyl) methyl] acetamide; 2- (3- {2 - [((2R) -2-Hydroxy-2-. {4-hydroxy-3 - [(methylsulfonyl) amino] phenyl} ethyl) amino] -2-methylpropyl} phenyl) -N - [(6-hydroxy-2-naphthyl) methyl] acetamide; N - [(4, -Hydroxybiphenyl-3-yl) methyl] -2- (3- { 2 - [((2R) -2-hydroxy-2-. {4-hydroxy-3 - [( methylsulfonyl) amino] phenyl} ethyl) amino] -2-methylpropyl] phenyl) acetamide; N - [(3, -H -droxy-biphenyl-3-yl) methyl] -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) -N- [2- (4-hydroxyphenyl) -2-methylpropyllacetamide; N- (3,5-Dichloro-2-hydroxybenzyl) -N-ethyl-2- (3-. {2 - [((2R) -2-hydroxy-2-. {4-hydroxy-3- [ (methylsulphonyl) amino] phenyl} ethyl) amino] -2-methy1propyl; pheny1) acetamide; 2- (3- {2 - [((2R) -2-Hydroxy-2-. {4-hydroxy-3 - [(methylsulfonyl) amino] phenyl} ethyl) amino] -2-methylpropyl} phenyl) -N - [(6-hydroxy-1-naphthyl) methyl] -N-methylacetamide; N - [(2, -Hydroxybiphenyl-3-yl) methyl] -2- (3- {2 - [((2R) -2-hydroxy-2-. {4-hydroxyl-3- [ (methylsulfonyl) amino] phenyl} etl) amino] -2-methylpropyl. phenyl) acetamide; N- (2-Hydroxy-5- { (7?) - 1 -hydroxy-2 - [(2- {3- [2- (6-hydroxy-3,4-dihydroisoquinoline-2 (7H)} -yl) -2-oxoethyl] phenyl] -1-, 1-dimethylethyl) amino] ethyl, phenyl) methanesulfonamide; 2- (3- {2 - [((2r?) - 2-Hydroxy-2-. {4-hydroxy-3 - [(methylsulfonyl) amino] phenyl} ethyl) amino] -2-methylpropyl .}. phenyl) -N- [4- (4-hydroxyphenyl) butyl] acetamide; 2- (3- {2 - [((2R) -2-Hydroxy-2-. {4-hydroxy-3 - [(methylsulfonyl) amino] phenyl} ethyl) amino] -2- methy1propyl] phenyl) -N- [2- (4-hydroxyphenyl) ethyl] acetamide; N- (2-Chloro-4-hydroxybenzyl) -2- (3. {2 - [((2R) -2-hydroxy-2-. {4-hydroxy-3 - [(methylsulfonyl ) amino] phenyl} ethyl) amino] -2-methylpropyl.} phenol) acetamidate; N- (3,5-Dichloro-4-hydroxybenzyl) -2- (3- { 2 - [((2R) -2-hydroxy-2-. {4-hydroxy-3 - [(methylsulfonyl ) amino] phenol, ethyl) amino] -2-methylpropyl, phenyl) acetamide; N- (2,3-Dichloro-4-hydroxybenzyl) -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) -N - [(4-hydroxy-1-naphthyl) methyl] acetamide; 2- (3- {2 - [((2R) -2-Hydroxy-2-. {4-hydroxy-3 - [(methylsulfonyl) amino] phenyl} ethyl) amino] -2-methylpropyl} pheny1) -N- [3-hydroxy-5- (trifluoromethyl) benzyl] acetamide; N- (2-Chloro-4-hydroxybenzyl) -N-ethyl-2- (3. {2 - [((2) -2-hydroxy-2-. {4-hydroxy-3 - [(methylsulfonyl)] ) amino] phenyl} ethyl) amino] -2-methylpropyl. phenyl) acetamide; N- (2-Chloro-4-hydroxybenzyl) -2- (3- { 2 - [((2R) -2-hydroxy-2-. {4-hydroxy-3 - [(methylsulfonyl) amine ] phenyl} ethyl) amino] -2-methylpropyl.] phenol) -N-methylacetamide; N- (3-Fluoro-5-hydroxybenzyl) -2- (3- {2 - [((2R) -2-hydroxy] -2- {4-hydroxy-3 - [(methylsulfonyl)} amino] phenyl, ethyl) amino] -2-methylpropyl, phenyl) -N-methylacetamide; N - [(2, -H-droxy-benzyl-2-yl) methyl] -2- (3-. {2 - [((2R) -2-hydroxy-2-. {4- hydroxy-3 - [(methylsulfonyl) amino] phenol] ethyl) amino] -2-methylpropyl, phenyl) acetamide; N - [(3'-Hydroxy-phenyl-2-yl) methyl] -2- (3-. {2 - [((2) -2-hydroxy-2-. {4-hydroxy-3- [ (methylsulfonyl) amino] phenyl, ethyl) amino] -2-methylpropyl, phenyl) acetamide; N- (4-Hydroxy-2,6-dimethylbenzyl) -2- (3-. {2 - [((2R) -2-hydroxy-2-. {4-hydroxy-3 - [(methylsulfonyl) am No] phenyl.} Ethyl) amino] -2-methylpropyl. Phenyl) acetamide; ? / - (2-Hydroxy-5- { (1 R) -1-hydroxy-2 - [(2. {3 - [2- (7-hydroxy-3,4-dihydroisoquinoline-2 (7H ) -yl) -2-oxoethyl] phenyl] -1, 1-dimethylethyl) amino] ethyl, phenyl) methanesulfonamide; / V- (2-Hydroxy-5- { (TR) -1-hydroxy-2 - [(2- {3- [2- (5-hydroxy-3,4-dihydroisoquinoline-2 (7 / - /) - il) -2-oxoetyl] phenyl] -1, 1 -dimethylethyl) amino] ethyl} phenyl) methanesulfonamide; 2- (3- {2 - [((2R) -2-Hydroxy-2-. {4-hydroxy-3 - [(methylsulfonyl) amino] phenyl} ethyl) amino] -2- methylenepropyl) phenyl) -? / - [(1 R) -2-hydroxy-1-phenylethylketamide; 2- (3- {2 - [((2R) -2-Hydroxy-2- {4-hydroxy-3 - [(methylsulfonyl) amino] phenyl} ethyl) amino] -2 -methylpropyl.} phenyl) - / V - [(1S) -2-hydroxy-1-phenylethylketamide; ? / - [(3'-Hydroxybiphenyl-4-yl) methyl] -2- (3- {2 - [((2R) -2-hydroxy-2-. {4-hydroxy- 3- [ (methylsulfonyl) amino] phenyl} ethyl) amino] -2-methy1propyl] phenyl) acetamide; ? / - [(2'-Hydroxybiphenyl-4-yl) methyl] -2- (3- { 2 - [((2R) -2-hydroxy-2-. {4-hydroxy-3 - [( methylsulphonyl) amino] phenyl} etl) amino] -2-methylpropyl. phenyl) acetamide; A / - [(4-Hydroxybiphenyl-4-yl) methyl] -3-. { 2 - [((2R) -2-hydroxy-2-. {4-hydroxy-3 - [(methylsulfonyl) amino] phenyl} ethyl) amino] -2-methylpropyl} benzamide; 3-. { 2 - [((2R) -2-Hydroxy-2. {4-hydroxy-3 - [(methylsulfonyl) amino] phenyl} etl) amino] -2-methylpropyl} -? / - [2- (4-hydroxy-phenyl) -2-methylpropyl-benzamide; ? / - [(4'-Hydroxybiphenyl-3-yl) methyl] -3-. { 2 - [((2R) -2-hydroxy-2. {4-hydroxy-3 - [(methylsulfonyl) amino] phenol] et.l) amino] -2-methylpropyl} benzamide; ? / - [2- (4-Hydroxy-2,5-dimethylphenyl) ethyl] -3-. { 2 - [((2R) -2-hydroxy-2-. {4-hydroxy-3 - [(methylsulfonyl) amino] phenyl} ethyl) amino] -2-methylpropyl} benzamide; ? / - [2- (4-Hydroxy-2,3-dimethyphenyl) ethyl] -3-. { 2 - [((2R) -2-hydroxy-2-. {4-hydroxy-3- [(methylsulfonyl) amino] phenol] ethyl) amino] -2-methylpropyl} benzamide; and, 3-. { 2 - [((2R) -2-Hydroxy-2. {4-hydroxy-3 - [(methylsulfonyl) amino] phenyl} etl) amino] -2-methylpropyl} -? / - [2- (4-hydroxy-3-methylphenyl) ethyl] benzamide. According to one aspect of the present invention, compounds of formula (I) in which the (CH2) n-C (= O) Q1 group is in the meta position are generally preferred. The pharmaceutically acceptable salts of the compounds of formula (1) include the acid addition salts and base salts thereof. 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, hyd hydrate / bromide, iodide / iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylisulfate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / phosphate acid / diacid phosphate, saccharate, stearate, succinate, tartrate, tosylate and trifluoroacetate and xínafoate. Suitable base 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, hemisulfate and hemicálcic salts. As a review of the appropriate salts, see Stahl and Wermuth, "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" (Wíley-VCH, Weinheim, Germany, 2002). The pharmaceutically acceptable salts of compounds of formula (1) can be prepared by one or more of three methods: (i) by reacting the compound of formula (1) with the desired acid or base; (i) removing an acid or base labile protecting group from a suitable precursor of the compound of 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 formula (1) to another by reaction with an appropriate acid or base or by of a suitable ion exchange column. The three reactions are typically performed in solution. The resulting salt can be precipitated and collected by filtration or can be recovered by evaporation of 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 unsolvated form and in solvated form. 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-host inclusion complexes in which, unlike the solvates mentioned above, the drug and the host are present in stoichiometric or non-stoichiometric amounts. Also included are drug complexes containing two or more organic and / or inorganic components that may be in stoichiometric or non-stoichiometric amounts. The resulting complexes can be ionized, partially ionized or non-ionized. As a review of such complexes see J Pharm Scí, 64 (8), 1269-1288 of Haleblían (August, 1975). In the following, all references to compounds of formula (1) include references to salts, solvates and complexes thereof and to solvates and salt complexes thereof. The compounds of the invention include compounds of formula (1) as defined hereinabove, including all polymorphic and crystalline habits thereof, prodrugs and isomers thereof (including optical, geometric and tautomeric isomers) as defined then in this document and compounds labeled with isotopes of formula (1). As indicated, the so-called "pro-drugs" of the compounds of formula (1) are also within the scope of the invention. In this way, certain derivatives of compounds of formula (1) which may have little or no pharmacological activity per se may, when administered in or on the body, be converted to compounds of formula (1) with the desired activity, for example, by hydrolytic cleavage. Such derivatives are referred to as "pro-drugs". Additional information on the use of prodrugs can be found in 'Pro-drugs as Novel Delivery Systems', Vol. 14, ACS Symposium Series (T. Híguchi and W. Stella) and 'Bioreversible Carriers in Drug Design', Pergamon Press, 1987 (ed. EB Roche, American Pharmaceutical Association). Prodrugs according to the invention can, for example, be produced by replacing the appropriate functionalities present in the compounds of formula (1) with certain residues that those skilled in the art know 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 functionality (-COOH), an ester thereof, for example, a compound wherein the hydrogen of the carboxylic acid functionality of the compound of formula (1) is replaced by alkyl of (C- | -C8); (ii) when the compound of formula (1) contains an alcohol functionality (-OH), an ether thereof, for example, a compound in which the hydrogen of the alcohol functionality of the compound of formula (1) is replaced with alkanoyloxymethyl from (C C6); and (i) when the compound of formula (1) contains a primary or secondary amino functionality (-NH2 or -NHR where R? H), an amide thereof, for example, a compound in which, as the case may be, one or both hydrogens of the amino functionality of the compound of formula (1) are replaced by (C1-C-10) alkanoyl. Other examples of substitution groups according to the above examples and examples of other types of prodrugs can be found in the references mentioned above. In addition, certain compounds of formula (1) can act by themselves as prodrugs of other compounds of formula (1). Also included within the scope of the invention are metabolites of compounds of formula (1), ie, compounds formed in vivo after drug administration. Some examples of metabolites according to the invention include: (i) when the compound of formula (1) contains a methyl group, a hydroxymethyl derivative thereof (-CH3? -CH2OH); (ii) when the compound of formula (1) contains an alkoxy group, a hydroxy derivative thereof (-OR-> -OH); (iii) when the compound of formula (1) contains a tertiary amino group, a secondary amino derivative thereof (-NR1R2? -NHR1 or -NHR2); (V) when the compound of formula (1) contains a secondary amino group, a primary derivative thereof (-NHR1? -NH2); (v) when the compound of formula (1) contains a phenyl residue, a phenol derivative thereof (-Ph? -PhOH); and (vi) when the compound of formula (1) contains an amide group, a carboxylic acid derivative thereof (-CONH2 - »-COOH). The compounds of formula (1) containing one or more asymmetric carbon atoms can exist in the form of two or more stereoisomers. When a compound of formula (1) contains an alkenyl or alkenyllene group, the cis / trans (or Z / E) geometric isomers are possible. When the structural isomers are interconvertible through a low-energy barrier, they may occur tautomerically ("tautomerism"). This can take the form of proton tautomerism in compounds of formula (1) which contain, for example, a methyl group, keto or oxime, 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 present invention are all stereoisomers, geometric isomers and tautomeric forms of the compounds of formula (1), including compounds that display more than one type of isomerism and mixtures of one or more thereof. Also included are acid addition salts or bases in which the counterion is optically active, for example, d-lactate or / -lysine, or racemic, for example a7-tartrate or dl-arginine. The cis / trans isomers can be separated by conventional techniques well known to those skilled in the art, for example, chromatography and fractional crystallization. Conventional techniques for the preparation / isolation of individual enantiomers include the chemistry synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, high pressure chiral 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 formula (1) contains an acid or basic moiety, an acid or 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 of the diastereoisomers can be converted to the corresponding pure enantiomer (s) by means well known to those skilled in the art.

The chiral compounds of the invention (and chiral precursors thereof) can be obtained in enantiomerically enriched form using chromatography, typically HPLC, on an asymmetric resin with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing 0 at 50% by volume of isopropanol, typically from 2% to 20% and from 0 to 5% by volume of an alkylamine, typically 0.1% of diethylamine. The concentration of the eluate produces the enriched mixture. The stereoisomeric conglomerates can be separated by conventional techniques known to those skilled in the art - see, for example, "Stereochemistry of Organic Compounds" by E.L. Eliel (Wiley, New York, 1994). According to one aspect of the present invention, the stereoisomer (R, R) of the formula given below is generally preferred, wherein R 1 is hydrogen and R 2 is C 1 -C 4 alkyl, preferably methyl, yny Q1 are as defined above: The present invention includes all pharmaceutically acceptable isotope-labeled compounds of formula (1) in which one or more atoms are replaced by atoms having the same atomic number but an atomic mass or mass number other than the atomic mass or mass number that predominates in nature. Examples of suitable sotopes for inclusion in the compounds of the invention include hydrogen asotopes, such as 2H and 3H, carbon, such as 11C, 13C and 14C, chloro such as 36CI, fluorine, such as 18F, iodine, such as 123l and 125l, nitrogen, such as 13N and 15N, oxygen, such as 15O, 17O and 18O, phosphorus, such as 32P and sulfur, such as 35S. Certain compounds labeled with isotopes of formula (1), for example, those incorporating a radioactive isotope, are useful in studies of drug distribution and / or substrate in tissues. The radioactive isotopes tritium, i.e., 3H, and carbon 14, i.e., 14C, are particularly useful for this purpose in view of their ease of incorporation and detection. Substitution with heavier isotopes such as deuterium, ie, 2H, may produce certain therapeutic advantages as a result of increased metabolic stability, eg, increased in vivo half-life or lower dosage requirements and, therefore, may be preferred in some circumstances. Substitution with positron emitting isotopes, such as 1 1C, 18F, 1 O, and 13N may be useful in Positron Emission Tomography (PET) studies to examine the occupation of substrate receptors. The isotope-labeled compounds of formula (1) can be prepared generally by conventional techniques known to those skilled in the art or by procedures analogous to those described in the examples and adjunct preparations using appropriate isotope-labeled reagents instead of the unlabeled reagent previously employed. . The pharmaceutically acceptable solvates according to the invention include those in which the crystallization solvent can be substituted isotopically, for example, D2O, d6-acetone, d6-DMSO. The compounds of formula (1), their pharmaceutically acceptable salts and / or derivatized forms, are valuable pharmaceutically active compounds, which are suitable for the therapy and prophylaxis of various disorders in which the β2 receptor is involved or in which the agonism of this receptor can induce some benefit, in particular in 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, premature birth, congestive heart failure, depression, inflammatory diseases and allergic to the skin, psoriasis, skin proliferative diseases, glaucoma and in conditions in which it is positive to reduce gastric acidity, particularly in gastric and peptic ulcers. The compounds of the invention for pharmaceutical use can be administered in the form of crystalline or amorphous products. They can be obtained, for example, as short solid beds, powders or films by methods such as precipitation, crystallization, lyophilization, spray drying or evaporative drying. Microwave or radiofrequency drying can be used for this purpose. They may be administered alone or in combination with one or more compounds other than the invention or in combination with one or more other drugs (or as any combination thereof). Generally, they will be administered as a formulation together with one or more pharmaceutically acceptable excipients. The term "excipient" is used herein to describe any ingredient other than the compound or compounds 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 solubility and stability, and on the nature of the dosage form. Pharmaceutical compositions suitable for the administration of compounds of the present invention and methods for their preparation will be 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, 1995) The compounds of the invention can also be administered directly in the bloodstream, in the muscle or in an internal organ. Parenteral drugs include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intraessternal, intracranial, intramuscular, and subcutaneous devices suitable for parenteral administration include needle injectors (including microneedles), needleless injectors, and infusion techniques. they are typically aqueous solutions which may contain excipients such as salts, carbohydrates and pH regulating agents (preferably at a pH of 3 to 9) but, for some applications, may be formulated more adequately as a non-aqueous sterile solution or as a form dry to be used together with a suitable vehicle l as sterile water without pyrogens. The preparation of parenteral formulations under sterile conditions, for example, by lyophilization, can be easily achieved using conventional pharmaceutical techniques well known to those skilled in the art. The solubility of the compounds of formula (1) used in the preparation of parenteral solutions can be increased by the use of appropriate formulation techniques, such as the incorporation of agents that improve solubility. Formulations for parenteral administration can be formulated to be immediate and / or modified release. Modified release formulations include delayed, sustained, pulsed, controlled, directed and programmed release. In this way, the compounds of the invention can be formulated in the form of a solid, semi-solid or thixotropic liquid for administration as an implanted reservoir that provides a modified release of the active compound. Examples of such formulations include drug-coated stents and poI oV-lactic-coglycolic acid microspheres (PGLA). The compounds of the invention can also be administered topically to the skin or mucosa, ie, dermally or transdermally. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, powders, 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, white petrolatum, glycerin, polyethylene glycol, and propylene glycol. Penetration-enhancing agents 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 be immediate release and / or modified. 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 (alone or 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 in the form of an aerosol spray from a pressurized container, pump, nebulizer, atomizer (preferably an atomizer using electrohydrodynamics to produce a fine mist) or nebulizer, with or without the use of a suitable propellant, such as 1, 1, 1, 2-tetrafluoroethane or 1,1,1,3,3,3-heptafluoropropane. For intranasal use, the powder may comprise a bioadhesive agent, for example, chitosan or cyclodextrin. The pressurized container, pump, sprayer, atomizer or nebulizer contains a solution or suspension of the compound (s) of the invention comprising, for example, ethanol, aqueous ethanol or a suitable alternative agent to disperse, solubilize or extend the release of the active component, a propellant (s) as a solvent and an optional surfactant, such as sorbitan trioleate, oleic acid or an oligolactic acid. Before use in a dry powder or suspension formulation, the drug is micronized to a size suitable for administration by inhalation (typically less than 5 microns). This can be achieved by any suitable grinding method, such as by spiral jet grinding, fluid bed jet grinding, supercritical fluid processing to form nanoparticles, high pressure homogenization or spray drying. Capsules (made, for example, with gelatin or hydroxypropylmethylcellulose), blisters and cartridges for use in an inhaler or insufflator can be formulated 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 the monohydrate 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 electrohydrodynamics to produce a fine mist may contain from 1 μg to 20 mg of the compound of the invention per actuation and the volume of the actuation may vary from 1 μl to 100 μl. A typical formulation may comprise a compound of formula (1), propylene glycol, sterile water, ethanol and sodium chloride. Other alternative solvents that can be used in place of propylene glycol include glycerol and polyethylene glycol. Suitable flavors, such as menthol and levomenthol or sweeteners such as saccharin or sodium saccharin can be added to those formulations of the invention to be administered by inhalation or intranasally. Formulations for inhaled / intranasal administration can be formulated to be 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 dosage unit is determined by means of a valve that supplies a measured quantity. The units according to the invention are typically prepared to administer a measured quantity or "burst" containing from 0.001 mg to 10 mg of the compound of 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 usually, in divided doses throughout the day. The compounds of 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 suppositories, vaginal suppositories or enema. Cocoa butter is a conventional suppository base, but various alternatives may be used as appropriate. 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 of a suspension or micronized solution in sterile isotonic saline with adjusted pH. Other formulations suitable for ocular and aural administration include ointments, biodegradable implants (e.g., absorbable gel sponges, collagen) and non-biodegradable (for example silicone), wafers, lenses and particulate or vesicular systems, such as niosomes or liposomes. A polymer such as crosslinked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, a cellulose polymer, for example, hydroxypropylmethylcellulose, hydroxyethylcellulose or methylcellulose or a heteropolysaccharide polymer, for example, gellan gum, can be incorporated together with a preservative such as benzalkonium chloride. Such formulations can also be administered by iontophoresis. Formulations for ocular / aural administration can be formulated to be immediate and / or modified release. 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 polymers containing polyethylene glycol, to improve their solubility, dissolution rate, taste masking, bioavailability and / or stability for use in any of the modes of administration mentioned above. Drug-cyclodextrin complexes, for example, are generally useful for most dosage 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 vehicle, diluent or solubilizer. The most commonly used for these purposes are alpha-, beta- and gamma-cyclodextrins, examples of which can be found in the international patent applications No. WO 91/1,172, WO 94/02518 and WO 98/55148.

Whenever it is desirable to administer a combination of active compounds, for example, for the purpose of treating a particular disease or condition, it is within the scope of the present invention that two or more pharmaceutical compositions can conveniently be combined, at least one of the which contains a compound according to the invention, in the form of suitable equipment for the co-administration of the compositions. In this way, the equipment of the invention comprises two or more different pharmaceutical compositions, at least one of which contains a compound of formula (1) according to the invention and means for keeping said compositions separate, such as a container, a divided pot or a container with divided aluminum foil. An example of such equipment is the family blister pack used for the packaging of tablets, capsules and the like. The equipment of the invention is particularly suitable for administering different dosage forms, for example parenteral, for administering the different compositions in different dosage ranges or for assessing the different compositions among themselves. To improve acceptance, the equipment typically comprises instructions for administration and can be provided with the so-called reminder. 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 route 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 divided doses and may, at the discretion of the physician, be outside the typical range provided herein. These dosages are based on an average human subject with a weight of approximately 65 kg to 70 kg. The doctor will be able to easily determine doses for subjects whose weights are outside this range, such as children and the elderly. For the avoidance of doubt, the references in this document to "treatment" include references to curative, palliative and prophylactic treatment. According to another embodiment of the present invention, the compounds of formula (1), or pharmaceutically acceptable salts, derivative forms or compositions thereof, can also be used as a combination with one or more additional therapeutic agents to be co-administered to a patient to obtain some desired therapeutic result such as the treatment of pathophysiologically significant disease processes including, but not limited to (i) bronchoconstriction, (i) inflammation, (iii) allergy, (v) tissue destruction, (v) signs and symptoms such as shortness of breath, cough. The second and the other additional therapeutic agents may also be a compound of formula (1), or a pharmaceutically acceptable salt, derivative forms or compositions thereof, or one or more β2 agonists known in the art. More typically, the second and the other therapeutic agents will be selected from a different class of therapeutic agents. As used herein, the terms "co-administration", "co-administered" and "in combination with", in reference to the compounds of formula (1) and one or more other therapeutic agents, means, refers to and includes following: • simultaneous administration of such combination of compound (s) of formula (1) and therapeutic agent (s) to a patient in need of treatment, when such components are formulated together in a single dosage form that releases said components substantially at the same time in said patient, • substantially simultaneous administration of such combination of compound (s) of formula (1) and therapeutic agent (s) to a patient in need of treatment, when such components are formulated separately in different dosage forms that the patient takes substantially at the same time, after which said cnents are substantially released at the same time in the patient, • sequential administration of the combination of cunds of formula (1) and therapeutic agent (s) to a patient in need of treatment, when such cnents are formulated separately in different dosage forms that the patient takes at consecutive times with a significant time interval between each administration, after which said cnents are released at substantially different times in the patient, • concurrent administration of such combination of cund (s) ) of formula (1) and therapeutic agent (s) to a patient in need of treatment, when such cnents are formulated together in a single dosage form that releases said cnents in a controlled manner after which they are released in a controlled manner. concurrent, consecutive and / or overlapping on the patient at the same time or at different times, where each party can administer be by the same or different route. Some suitable examples of other therapeutic agents that can be used in combination with the cund (s) of formula (1), or pharmaceutically acceptable salts, derivative forms or csitions thereof include, but are not limited to: (a) Inhibitors of -lipoxygenase (5-LO) or antagonists of the 5-lipoxygenase activation protein (FLAP), (b) Leukotriene antagonists (LTRA) including LTB4, LTC4, LTD4 and LTE4 antagonists, (c) Receptor antagonists. histamine, including H1 and H3 antagonists, (d) vasoconstrictor and sympathomimetic agonist agents of the ai and 2 adrenoreceptor 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, (!) COX inhibitors, both selective and non-selective inhibitors of COX-1 or COX-2 (NSAIDs), (j) Oral and inhaled glucocorticosteroids, such as DAGR (dissociated agonists of the corticoid receptor) (k) Monoclonal antibodies active against endogenous inflammatory entities, (I) Anti-tumor necrosis factor agents a (anti-TNF-a) (m) Adhesion molecule inhibitors including VLA antagonists -4 (n) Quinine-B and B2 receptor antagonists (o) Immunosuppressive agents, (p) Matrix metalloprotease (MMP) inhibitors, (q) Tachykinin receptor antagonists NK-i, NK2 and NK3, (r) ) Elastase inhibitors, (s) Adenosine A2a receptor agonists, (t) Urokinase inhibitors, (u) Cunds that act on dopamine receptors, for example D2 agonists, (v) Modulators of the NFkß pathway, by Example IKK inhibitors (w) Modulators of cytokine signaling pathways such as p38 MAP kinase inhibitors, 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 cunds of formula (1) with: - H3 antagonists, - M3 muscarinic receptor antagonists, - PDE4 inhibitors - Glucocorticosteroids, - Adenosine A2a receptor agonists, - Modulators of cytokine signaling pathways such as p38 MAP kinase or syk kinase, - Leukotriene antagonists (LTRA) including LTB4, LTC4, LTD4 and LTE4 antagonists. According to the present invention, the combination of the cunds of formula (1) with: - Glucocorticosteroids, in particular inhaled glucocorticosteroids with few systemic side effects, including prednisone, prednisolone, flunisolide, triamcinolone, acetonide, beclomethasone dipropionate, budesonide is preferred , fluticasone propionate, ciclesonide and mometasone furoate, or - M3 muscarinic receptor antagonists or anticholinergic agents including in particular ipratropium salts, particularly bromide, tiotropium salts, particularly bromide, oxitropium salts, particularly bromide, perenzepine and telenzepine. It should be appreciated that all references in this document to treatment include curative, palliative and prophylactic treatment. The description given below, relates to the therapeutic applications in which the compounds of formula (1) can be used. The compounds of formula (1) have the ability to interact with the β2 receptor and therefore have a wide range of therapeutic applications, as described further below, given the essential role that the β2 receptor plays in the physiology of all patients. mammals Therefore, a further aspect of the invention relates to the compounds of formula (1), or pharmaceutically acceptable salts, derivative forms or compositions thereof, 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 formula (1), or pharmaceutically acceptable salts, derivative forms or compositions thereof, for use in the treatment of diseases, disorders and conditions 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 atopic asthma, non-atopic asthma, allergic asthma, bronchial atopic asthma mediated by IgE, bronchial asthma, essential asthma, true asthma, intrinsic asthma caused by pathophysiological alterations, extrinsic asthma caused by environmental factors, essential asthma of unknown or non-obvious origin, non-atopic asthma, bronchitic asthma, emphysematous asthma, exercise-induced asthma, allergen-induced asthma, cold-air-induced asthma, occupational asthma , infectious asthma caused by infection by bacteria, fungi, protozoa or viruses, asthma not Rgica, incipient asthma, infantile wheezing syndrome and bronchiolitis, • chronic or acute bronchoconstriction, chronic bronchitis, obstruction of the small airways and emphysema, • obstructive or inflammatory diseases of the respiratory tract of any type, etiology or pathogenesis, in particular a disease obstructive or inflammatory airway 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 obstruction progressive irreversible airways, respiratory distress syndrome in adults (ARD), exacerbation of airway hyperreactivity after therapy with other drugs and respiratory 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 laryngotracheal bronchitis, arachidic bronchitis, catarrhal bronchitis, crupal bronchitis, dry bronchitis, infectious asthmatic bronchitis, productive bronchitis, bronchitis by staphylococcus or streptococcus and vesicular bronchitis, • acute damage to the lung, • 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, capillary bronchiectasis, Cystic bronchiectasis, dry bronchiectasis and follicular bronchiectasis. Another aspect of the present invention also relates to the use of the compounds of formula (1), or pharmaceutically acceptable salts, derivative forms or compositions thereof, for the manufacture of a drug having a β2 agonist activity. In particular, the present invention relates to the use of compounds of formula (1), or pharmaceutically acceptable salts, derivative forms or compositions thereof, 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 human, with an effective amount of a compound of formula (1), or a pharmaceutically acceptable salt, derivative form or composition thereof. More precisely, the present invention provides a particularly interesting method for the treatment of diseases and / or conditions mediated by β2 in a mammal, including a human being, in particular the diseases and / or conditions listed above, which comprises administering to said mammal a effective amount of a compound of formula (1), its pharmaceutically acceptable salts and / or derivatized forms. The following examples illustrate the preparation of compounds of formula (1): Preparation 1: 2,2 '- (1,3-phenylene) diethyl diacetate Acetyl chloride (12.5 ml, 175 mmol) was added to a suspension of 2,2 '- (1,3-phenylene) diacetic acid (50.0 g, 260 mmol) in ethanol (500 ml) and the solution The resulting mixture was heated to reflux for 16 hours. The reaction was cooled to room temperature and the solvent removed in vacuo. The residue was partitioned between saturated aqueous sodium hydrogen carbonate (300 ml) and ethyl acetate (500 ml). The organic phase was washed with water (200 ml), saturated aqueous sodium chloride (300 ml), dried (sodium sulfate) and the solvent removed in vacuo to give the title compound as a pale yellow oil (63.5 g) . 1 H NMR (CDCl 3, 400 MHz) d 1.31 (t, 6 H), 3.65 (s, 4 H), 4.20 (c, 4 H), 7.24-7.36 (m, 4 H) ppm. MS (electrospray): m / z 251 [M + H] + Preparation 2: [3- (2-Oxo-propyl) -phene-acetic acid ethyl ester A solution of the diester of preparation 1 (44.3 g, 177 mmol) and 2,2 '- (1,3-phenylene) diacetic acid (59.2 g, 308 mmol) in ethanol (24 ml) and dioxane (290 ml) were added. treated dropwise with 12 M hydrochloric acid (4.9 ml, 58.8 mmol). The reaction mixture was stirred at reflux for 18 hours before being allowed to cool and concentrated to low volume. The reaction mixture was diluted with toluene (125 ml) and the resulting suspension was filtered. The filtrate was concentrated in vacuo and the residue was taken up in water and basified with sodium bicarbonate to neutral pH. The mixture was diluted with ethyl acetate (200 ml) and the organic layer was separated and washed with a solution of sodium bicarbonate (5x30 ml) and saturated aqueous sodium chloride (50 ml). The combined aqueous extracts were acidified to pH 3 with 6 M hydrochloric acid and extracted with ether (3x30 ml). The organic extracts 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. 1H NMR (CD3OD, 400 MHz) d: 1.25 (t, 3H), 3.60 (m, 2H), 3.63 (m, 2H), 4.15 (c, 2H), 7.18-7.32 (m, 4H) ppm. EM (electrospray): m / z 245 [MNa] + Preparation 3: [3- (2-Hydroxy-2-methyl-propyl) -pheny] -acetic acid Methyl magnesium chloride (51 ml of a 3 M solution in tetrahydrofuran, 153 mmol) was added dropwise to a stirred solution of preparation 2 (1 1.6 g, 51 mmol) (International Journal of Peptide and Protein Research, 1987. 29 (3), 331) in tetrahydrofuran (300 ml) at 0 ° C in a nitrogen atmosphere. The reaction was allowed to warm to room temperature overnight with formation of a thick white precipitate and then water (50 ml) and 2N hydrochloric acid (80 ml) were added cautiously. The aqueous phase was extracted with ethyl acetate (2x300 ml) and the combined organic extracts were washed with brine (50 ml), dried (sodium sulfate) and the solvent removed in vacuo to give the title compound as a golden oil (1.2 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 (ESI): m / z 209 [M + H] + Preparation 4: Acid. { 3-f2- (2-Chloroacetylamino) -2-methyl-propyn-phenyl-acetic 2-Chloroacetonitrile (8.8 ml, 140 mmol) was added to a solution of the alcohol of preparation 3 (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 onto ice and basified with solid sodium carbonate. The solution was extracted with ethyl acetate (2x500 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 HNMR (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, 1 H), 7.06-7.31 (m , 4H) ppm. MS (electrospray): m / z 282 [M-H] "Preparation 5: R3- (2-amino-2-methyl-propiD-phenyl-acetic acid methyl ester A solution of the amide from Preparation 4 (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 a nitrogen atmosphere 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 methanol (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 was partitioned 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 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. 1H NMR (CDCl 3, 400 MHz) d: 1.14 (s, 6H), 2.68 (s, 2H), 3.62 (s, 2H), 3.69 (s, 3H), 7.08-7.16 (m, 3H), 7.23-7.27 ( m, 1 H) ppm. MS (electrospray): m / z 222 [M + H] + Preparation 6:? / -. { 2- (benzyloxy) -5 - [(1 R) -2-bromo-1-hydroxyethylphenyl, methanesulfonamide A solution of (1 R) -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 2N hydrochloric acid (110 ml) and the organic phase was separated, dried (magnesium sulfate) and the solvent 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 HNMR (DMSO-d6, 400 MHz) d: 2.93 (s, 3 H), 3.52-3.66 (m, 2 H), 4.74 (m, 1 H), 5.19 (s, 2 H), 7.11 (d, 1 H), 7.19-7.22 (m, 1 H), 7.33-7.36 (m, 2H), 7.40-7.43 (m, 2H), 7.56 (d, 2H), 8.95 (s, 1 H) ppm. MS (electrospray): m / z 398/400 [MH] "Preparation 7:? / - [2- (benzyloxy) -5: - ((1 R) -2-bromo-1-, tert-butyl (dimethyl) Siliconium) ethyl) phenanmethane sulfonamide A solution of the bromide from Preparation 6 (21.5 g, 53.7 mmol) in N, / V-dimethylformamide (125 mL) was treated with midazole (4.16 g, 75.2 mmol) and tert-butyl chloride (dimethyl) s. Lilo (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 2 N 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), 0.1 1 (s, 3 H), 0.89 (s, 9 H), 2.91 (s, 3 H), 4.80-4.83 (m, 1 H), 6.80 (sa, 1 H), 6.98 (d, 1 H), 7.12 (d, 1 H), 7.36-7.44 (m, 5H), 7.52-7.54 (m, 1 H) ppm.

Alternative procedure for the preparation of preparation Jl A solution of the bromide from preparation 6 (10 g, 24.98 mmol) was dissolved in DCM (20 ml, 2 ml / g) and then imidazole (4.58 g, 37.47 mmol, 1.5 ml) was added. eq) followed by TBDMSiCI (5.27 g, 34.97 mmol, 1.4 eq). 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 2M HCl (50 ml, 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 organic phase was subsequently reduced in volume at reduced pressure at 45 ° C to 25-30 ml. 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 subsequently 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 give the title compound as a white solid (1.05 g, 86% yield). 1 H NMR (CDCl 3, 400 MHz) d: -0.07 (s, 3 H), 0.1 1 (s, 3 H), 0.89 (s, 9 H), 2.91 (s, 3 H), 4.80-4.83 (m, 1 H), 6.80 (sa, 1 H), 6.98 (d, 1 H), 7.12 (d, 1 H), 7.36-7.44 (m, 5H), 7.52-7.54 (m, 1 H) ppm.

Preparation 8: (3- (2-r ((2R) -2- (4- (Benzyloxy) -3-r (methylsulfonyl) amino] pheny] -2-hydroxyethyl) amino] -2-methylpropyl Phenyl) methyl acetate The bromide of preparation 7 (36.0 g, 70.8 mmol) and the amine of preparation 5 (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 on silica gel eluting with pentane: ethyl acetate (50:50 by volume) yielding the title product as a pale yellow oil (37.2 g) . 1 HNMR (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, 1 H), 5.09 (s, 2H), 6.79 (sa, 1 H), 6.95 (d, 1 H) , 7.04-7.21 (m, 7H), 7.37-7.44 (m, 5H), 7.56 (d, 1 H) ppm. MS (APCI): m / z 655 [M + H] + Preparation 9: (3- (2-f ((2R) -2- (f-Tert-butyl (dimethyl) sil.noxy) -2- (4-hydroxy-3-f (methylsulfonyl) amino-phenyl) ethyl) amino ] -2-methylpropyl) phenyl) methyl acetate A solution of the protected benzyl alcohol from preparation 8 (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 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) yielding the title product as a pale yellow oil (20.6 g). 1H 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, 1 H), 6.58 (d, 1 H), 6.88 (dd, 1 H), 7.05-7.14 (m , 3H), 7.21-7.25 (m, 1 H), 7.30 (s, 1 H) ppm. MS (electrospray): m / z 565 [M + H] + Preparation 10: Acid (3- {2-f (2r?) -2- (tert-Butyl-dimethyl-silanyloxy) -2- (4-hydroxy-3-methanesulfonylamino-phenyl) -ethylamino-1-2- methyl-propyl) -phenol) -acetic The ester of preparation 9 (20.6 g, 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 the addition of 1 M hydrochloric acid (72 ml, 72 mmol) and concentrated at low volume. The aqueous phase was decanted and the residue was washed with water (2 × 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), 1.32 (m, 6H), 2.93 (m, 5H), 3.23 (m, 2H) , 3.54 (m, 2H), 4.94 (m, 1 H), 6.91 (d, 1 H), 7.03-7.16 (, 3H), 7.26 (m, 2H), 7.60 (m, 1 H) ppm. MS (electrospray): m / z 236 [M + H] + Preparation 5a: [3- (2-amino-2-methyl-propiD-phenyl-acetic acid, ethyl ester A mixture of the amide from Preparation 4 (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 a nitrogen atmosphere 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) and then treated with ethanol (1.5 L) and stirred for 1 hour. The solid precipitate was removed by filtration and the filtrate was cooled 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) and then with ethyl acetate (1.0 I). The combined biphasic filtrate layers and washings were separated and the aqueous layer was re-extracted with ethyl acetate (1.0 L + 500 mL). The combined extracts of ethyl acetate 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 (de-DMSO, 400 MHz) d: 0.99 (s, 6H), 1.16 (t, 3H), 2.59 (s, 2H), 3.61 (s, 2H), 4.06 (c, 2H), 7.06 (m , 3H), 7.21 (m, 1 H).

Preparation 5b: [3- (2-amino-2-methyl-propyl-phenyl-acetic acid, ethyl ester, di-p-tolyl-L-tartrate] A solution of the. Amine from Preparation 5a (124.9 g, 531 mmol) in acetonitrile (1.0 L) was treated with a solution of di-p-tolyl-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 (d 6 -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 (c , 2H), 5.61 (s, 2H), 7.02 (d, 2H), 7.15 (d, 1 H), 7.25 (m, 5H), 7.80 (d, 4H).

Preparation 5c: [3- (2-Amino-2-methyl-propip-phenyl-acetic acid) ethyl ester A solution of potassium carbonate (37.90 g, 274.22 mmol) in water (213 ml) was added to a suspension of preparation 5b (42.62 g, 68.56 mmol) in propionitrile (213 ml) and stirred until all the solid dissolved. . The phases were separated and the propionitrile phase was washed with water (107 ml). The solution was reduced in volume at reduced pressure to about 30 ml giving the title compound as a solution in propionitrile. A sample was removed and concentrated to dryness to obtain a weight-weight test and an 81% yield was demonstrated. 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 (c, 2H), 7.06 (m , 3H), 7.21 (m, 1 H).

Preparation 8a: (3- (2-r ((2R) -2- (r-Tert-butyl (dimethyl) ylkyloxy} -2- (4-benzyloxy-3-f (methylsulfonyl) amino] phenyl) ethyl ) amino] -2-methylpropyl) phenylacetate ethyl Added? / - [2- (benzyloxy) -5 - ((R) -2-bromo-1-. {[[Tert-butyl (dimethyl) silyl] oxy} ethyl) phenyl] methanesulfonamide (14.34 g, 27.88 mmol) was added to the solution of Preparation 5c (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 (aq) (70 ml) and then with water (35 ml) and the solution was used directly in the next step assuming a 100% yield.

Preparation 9a: () -2- (3- (2-22-Hydroxy-2- (4-benzyloxy-3-methanesulfonamidophenyl) ethylamino-2-methylpropyl) phenol) ethyl acetate Triethylamine trifluorohydrate (9.1 ml, 8.99 g, 55.76 mmol) was added to the solution of preparation 8a (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 5 M NH 3 (aq) (72 ml) and stirred for 10 minutes and the phases were separated. The propionitrile solution was subsequently washed with water (72 ml) and the solution was used directly in the next step assuming a 100% yield.

Preparation 10a: Acid (R) -2- (3- (2- [2-hydroxy-2- (4-benzyloxy-3-methanesulfonamidophenyl) ethylamino-2-methylpropyl) phenyl) acetic acid A solution of sodium hydroxide (6.69 g, 167.28 mmol) in water (72 ml) was added to the solution of preparation 9a (15.47 g, 27.88 mmol) in propionylyl (72 ml). Then, the biphasic mixture was stirred vigorously for 3 hours. The phases were separated 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 (aq) and the resulting suspension was stirred for one hour. Then, the suspension was filtered and washed on the filter paper with water and then dried to give the title compound as an off-white solid (13.55 g, 92% in 3 steps). 1H NMR (400 MHz, CD3OD) d: 1.33 (s, 3H), 1.35 (s, 3H), 2.89 (s, 3H), 2.96 (s, 2H), 3.06-3.19 (m, 2H), 3.50 ( s, 2H), 4.50 (m, 1 H), 5.22 (s, 2H), 7.08 (d, 1 H), 7.13 (d, 1H), 7.19 (s, 1 H), 7.24 (t, 2H), 7.27 (d, 1 H), 7.31 (d, 1 H), 7.38 (t, 2 H), 7.48 (d, 2 H), 7.49 (s, 1 H) ppm.

Preparation 10b: Sodium salt of (R) -2- (3 ~, 2-r2-hydroxy-2- (4-hydroxy-3-methanesulfonamidophenyl) ethylamino1-2-methylpropyl) phenyl) acetic acid A solution of sodium hydroxide (1.40 g, 35.05 mmol) in water (100 ml) was added to a suspension of preparation 10a (18.46 g, 35.05 mmol) in methanol (600 ml). The mixture was hydrogenated on 20% by weight palladium hydroxide on carbon at 150 psi (1034 kPa) and at 60 ° C for 5 hours. The mixture was filtered to remove catalyst residues and then reduced in volume at reduced pressure to 100 ml. The mixture was distilled and replaced under reduced pressure with acetonitrile at 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%). 1H 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, 1 H), 6.84 (d, 1 H), 6.92 (d, 1 H), 7.04 (d, 1 H), 7.11 (s, 1 H), 7.14 (d, 1 H), 7.15 (t, 1 H), 7.34 (s, 1 H) ppm. Said compounds of formula 10b can then be reacted with a suitable amine of 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 formula (1): wherein R1 and R2 are methyl and n is 1.

Preparation 1 1: 1 - (3-Bromophenyl) -2-methylpropan-2-ol Methylmagnesium bromide (3 M solution in diethyl ether, 51.6 ml, 155 mmol) was added slowly to a solution of 1- (3-bromo-phenyl) propan-2-one (15.0 g, 70 mmol) in dry diethyl ether (200 ml) at 0 ° C. The resulting mixture was allowed to stand for 3 hours, then cooled to 0 ° C and quenched slowly with a saturated aqueous solution of ammonium chloride. The organic phase was washed with brine, dried (sodium sulfate). The yellow oil was purified by column chromatography on silica gel eluting with dichloromethane: pentane: methanol (90: 5: 5 by volume to yield a pale yellow oil (13.26 g). 1 H NMR (400 MHz, CDCl 3): d 1.22 (s, 6H), 1.42 (sa, 1 H), 2.74 (s, 2H), 7.15 (m, 2H), 7.40 (m, 2H) ppm.

Preparation 12:? / - r2- (3-Bromophenyl) -1,1-dimethylethyl-2-chloroacetamide Chloroacetonitrile (6.63 ml, 105 mmol) was added to a stirred solution of the alcohol of preparation 11 (12.0 g, 52.0 mmol) in acetic acid (25 ml) at room temperature. The resulting solution was cooled to 0 ° C and concentrated sulfuric acid (25 ml) was added maintaining the temperature < 10 ° C. The resulting solution was allowed to stir for 1 hour and then poured onto ice and basified by the addition of solid potassium carbonate. The product was extracted with ethyl acetate (2x500 ml), the organic extracts were combined and washed with water (50 ml), dried (sodium sulfate) and the solvent removed in vacuo yielding the title compound as a solid orange (16.08 g). 1 H NMR (400 MHz, CDCl 3): d 1.37 (s, 6H), 3.02 (s, 2H), 3.94 (s, 2H), 6.17 (sa, 1 H), 7.03-7.08 (d, 1 H), 7.1 1-7.13 (t, 1 H), 7.26 (s, 1 H), 7.32-7.39 (d, 1 H) ppm. LRMS (electrospray) m / z 306 [M + Hf Preparation 13: f2- (3-Bromophenyl) -1,1-dimethylethylamine A solution of the amide of preparation 12 (32.0 g, 105 mmol), thiourea (9.60 g, 126 mmol) and acetic acid (50 ml) in ethanol (250 ml) was heated to reflux overnight. The reaction mixture was cooled to room temperature and filtered, the filtrate was concentrated in vacuo and basified using an aqueous solution of sodium hydroxide (1 M, 450 mL). The product was extracted with dichloromethane (2x500 ml) and the combined organic extracts were washed with brine (50 ml), dried (sodium sulfate) and the solvent removed in vacuo to yield the title compound as a black oil (23). g). 1 H NMR (400 MHz, CDCl 3): d 1.12 (s, 6H), 1.84 (br s, 2H), 2.62 (s, 2H), 7.08-7.16 (m, 2H), 7.32-7.36 (m, 2H) ppm. LRMS (electrospray) m / z 228 [M + H] + Preparation 14:? / - f2- (Benzyloxy) -5 - ((1R) -2- (r2- (3-bromophenin-1,1-dimethylethyl-amino) ) -1-hydroxyethyl) phen-p-methanesulfonamide The amine from Preparation 13 (5.04 g, 22.3 mmol) was dissolved in dichloromethane (20 mL) and treated with? / - [2- (Benzyloxy) -5 - ((1 S) -2-bromo-. [tert-butyl (dimethyl) silyl] oxy] ethyl) -phenyl] methanesulfonamide (WO 02/06258, p.36, example 14a) (1.90 g, 45.0 mmol). The resulting solution was heated to 90 ° C until the solvent was evaporated and then stirred at 90 ° C for a further 16 hours. The reaction mixture was cooled to room temperature and the residue was purified by column chromatography on silica gel eluting with pentane: ethyl acetate (90:10) yielding the title product as a brown oil (8.36 g). 1H NMR (CD3OD, 400 MHz) d: -0.14 (s, 3H), 0.04 (s, 3H), 0.84 (s, 9H), 1.10 (s, 3H), 1.13 (s, 3H), 2.87 (s, 3H) ), 2.67-2.90 (m, 4H), 4.73-4.77 (m, 1 H), 5.25 (s, 2H), 7.12-7.23 (m, 4H), 7.36-7.48 (m, 6H), 7.53-7.55 ( m, 2H) ppm. MS (electrospray): m / z 661/663 [M + Hf, 683/685 [M + Hf Preparation 15: 3- (2-r ((2R) -2- (4- (benzyloxy) -3- [( Methylsulfonyl) amino} phenyl) -2 - (methyl [methyl] -2,5-methylpropylbenzoate (methyl tert-butyl (dimethyl) silyloxy) ethyl) amino] -2-methylpropylbenzoate A solution of the bromide from Preparation 14 (8.36 g, 12.6 mmol), (1,1'-bis (diphenylphosphino) ferrocene) dichloropalladium (II) (1.03 g, 1.26 mmol) and triethylamine (3.5 mL, 25.1 mmol) in methanol was heated at 100 ° C with a pressure of 100 psi (690 kPa) of carbon monoxide for 16 hours. The reaction mixture was cooled to room temperature, filtered and the solvent removed in vacuo. Purification by column chromatography on silica gel eluting with dichloromethane: methanol: 0.880 ammonia (90: 10: 1) gave the title compound as an orange oil, 7.79 g (traces of contamination with catalyst residues). 1H NMR (400 MHz, CD3OD) d: -0.17 (s, 3H), 0.00 (s, 3H), 0.80 (s, 9H), 1.12 (s, 3H), 1.15 (s, 3H), 2.67-2.92 (m , 3H), 3.96 (s, 3H), 4.73-4.77 (m, 1 H), 5.24 (s, 2H), 7.1 1 (d, 1 H), 7.19 (dd, 1 H), 7.36-7.48 (m , 6H), 7.54 (d, 2H), 7.91-7.93 (m, 2H) ppm. MS (electrospray) m / z 641 [M + H] +, 663 [M + Na] + Preparation 16: 3-, 2-f ((2R) -2- (rterc-butyl (dimethyl) silyloxy) -2- (Methyl 4-hydroxy-3-f (methylsulfonyl) amino1phenyl) etl) amino] -2-methylpropyl) benzoate Prepared from the ester of preparation 15 using the method of preparation 7 to give the title compound as a colorless oil. 1H NMR (400 MHz, CD3OD) d: -0.21 (s, 3H), -0.05 (s, 3H), 0.75 (s, 9H), 1.08 (s, 3H), 1.12 (s, 3H), 2.62-2.88 ( m, 7H), 3.92 (s, 3H), 4.64-4.69 (m, 1 H), 6.84 (d, 1 H), 7.03 (dd, 1 H), 7.35-7.36 (m, 1 H), 7.39- 7.42 (m, 2H), 7.87-7.89 (m, 2H) ppm. MS (electrospray) m / z 551 [M + H] +, 573 [M + Na] + Preparation 17: Acid 3-. { 2-r ((2R) -2- (fterc-Butyl (dimethyl) sililloxy) -2-. {4-hydroxy-3 - [(methylsulfonyl) amino] phenyl) etl) amino] - 2-methylpropyl | benzoic acid Prepared from the ester of preparation 16 using the method of preparation 8 to give the title compound as a colorless solid. 1H NMR (400 MHz, CD3OD) d: -0.14 (s, 3H), 0.04 (s, 3H), 0.82 (s, 9H), 1.23 (s, 3H), 1.24 (s, 3H), 2.88-2.96 (m , 5H), 3.00-3.14 (m, 2H), 4.83-4.87 (m, 1 H), 6.89 (d, 1 H), 7.07 (dd, 1 H), 7.24-7.26 (m, 1 H), 7.32 (t, 1 H), 7.37 (s, 1 H), 7.82 (s, 1 H), 7.86 (d, 1 H) ppm. MS (electrospray) m / z 537 [M + Hf, 559 [M + Naf] Preparation 18-53 A solution of the appropriate carboxylic acid (preparation 10 or 17) (0.15 mmol), 1-hydroxybenzotriazole hydrate (22 mg, 0.16 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (34 mg , 0.18 mmol) and ? / -ethyldiisopropylamine (130 μl, 0.73 mmol) in N,? / - dimethylformamide (2 ml) 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 was partitioned between dichloromethane (3 ml) and water (1 ml). The phases were separated and the organic phase was washed with brine (1 ml), dried (sodium sulfate) and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with dichloromethane: methanol: 0.88 ammonia (98: 2: 0 changing to 94: 6: 0.5 by volume) yielding the desired product. Alternatively, the following procedure can be used for the synthesis of preparations 18 to 53: A solution of the appropriate carboxylic acid from preparation 10 or 17 (5.08 mmol) in N,? / - dimethylformamide (60 ml) is treated with 1-hydroxybenzotriazole hydrate (0.755 g, 5.59 mmol), the appropriate amine (5.08 mmol) , 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1.07 g, 5.59 mmol) and triethylamine (1.49 mL, 10.67 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 (100 ml) and saturated aqueous sodium bicarbonate (50 ml). The organic phase is separated and the aqueous phase is extracted with dichloromethane: methanol (95: 5 by volume, 2 x 20 ml). The combined organic extracts are separated, washed with saturated aqueous sodium chloride (100 ml), dried (sodium sulfate) and the solvent removed in vacuo. The residue is purified by column chromatography on silica gel eluting with dichloromethane: methanol: 0.88 ammonia (95: 5: 0.5 by volume) to yield the desired compound.

Preparations 18 to 47 N ° Data 1H NMR (CDCl 3, 400 MHz) d: -0.19 (s, 3H), -0.11 (s, 3H), 0.75 (s, 9H), 1.03 (s, 3H), 1.05 (s, 3H), 2.57-2.85 ( m, 7H), 3.57 (m, 2H), 3.74 18 (s, 3H), 4.31 (m, 2H), 4.65 (m, 1 H), 6.22 (m, 1 H), 6.63 (d, 1 H), 6.67 (m, 1 H), 6.76 (m, 1 H), 6.82 (d, 1 H), 7.03 (m, 2 H), 7.12 (m, 1 H), 7.22 (m, 1 H), 7.34 (m, 1 H) EM (electrospray) m / z 686 [M + Hf HRMN (400 MHz, CD3OD) S: -0.19 (s, 3H), -0.02 (s, 3H), 0.79 (s, 9H), 1.02 (s, 3H), 1.04 (s, 3H), 2.60-2.71 (m, 3H), 2.82-2.87 (4H, m), 3.52 (s, 2H), 4.36 (s, 2H), 4.65-4.68 (m, 1 H), 19 6.81-6.85 (m, 3H), 6.99-7.03 (m, 2H), 7.10 (s, 1 H), 7.16-7.22 (m, 2H), 7.24-7.26 (d, 2H), 7.35 (d, 1 H), 7.40 (d, 2H), 7.45 (d, 2H). MS (electrospray) m / z 730 [MH] ", 732 [M + Hf 1 H NMR (400 MHz, CD3OD): -0.17 (s, 3H), 0.00 (s, 3H), 0.17 (s, 6H), 0.80 ( s, 9H), 0.98 (s, 9H), 1.09 (s, 3H), 1.12 (s, 3H), 1.21 (s, 6H), 2.67-2.78 (m, 3H), 2.87 (s, 3H), 2.91 - 2.96 (m, 1 H), 3.36 (s, 2H), 3.43 (s, 2H), 4.71-4.75 (m, 1 H), 6.73 (d, 2H), 6.86 (d, 1 H), 7.03- 7.06 (m, 4H), 7.15-7.22 (m, 3H), 7.37 (d, 1 H) MS (APCI) m / z 812 [M + Hf 1 H NMR (400 MHz, CD3OD): -0.18 (s, 3H ), - 0.01 (s, 3H), 0.80 (s, 9H), 1.03 and 1.08 (2s, 3H), 1.01 and 1.07 (2s, 3H), 1.25-1.29 (2t, 3H), 2.65-2.69 (m, 2H), 2.87 and 2.88 (2s, 3H), 2.92 (c, 2H), 3.75 and 3.82 (2s, 2H), 4.04 (s, 2H), 4.55 and 4.57 (2s, 2H), 4.68-4.71 (m, 1 H), 6.86 (dd, 1 H), 6.98 (d, 2H), 7.03 (dd, 1 H), 7.10 (d, 1 H), 7.13-7.15 (m, 1H), 7.20 (d, 1 H) ), 7.24 (dd, 1 H), 7.36 (dd, 1 H) EM (electrospray) m / z 750/752 [MH] "1HRMN (400 MHz, CD3OD) d: -0.21 and -0.19 (2s, 3H) ), -0.05 and -0.03 (2s, 3H), 0.76 and 0.78 (2s, 9H), 0.96 and 0.98 (2s, 3H), 0.93 and 0.97 (2s, 3H), 2.52-2.56 (m, 2H), 2.60-2.64 (m, 2H), 2.86 (s, 3H), 2.85 and 3.02 (2s, 2H), 3.34 (s, 3H), 3.84 (s, 2H), 6.84 ( d, 2H), 6.97-7.01 (m, 1 H), 7.02-7.03 (m, 1 H), 7.05 (d, 1 H), 7.1 1 (d, 1 H), 7.13-7.15 (m, 1 H ), 7.17-7.20 (m, 1 H), 7.27-7.31 (m, 1 H), 7.35-7.36 (m, 1 H), 7.56-7.60 (m, 2H), 7.65-7.68 (m, 1 H) 7.97 (d, 1 H). MS (electrospray) m / z 750/752 [M-H] " 15 twenty Preparations 48-53 Preparation 54:? / - (4-bromobenzy) -2- (3- (2 - [((2) -2- (fterc-butyl (dimethyl) silyl] oxy) -2-. {4-hydroxy -3 - [(methylsulfonyl) amino] pheny1) et1) amino] -2-methyl-propyl) phenyl) acetamide Prepared using the procedure for preparation 18 using the acid of preparation 10 and (4-bromobenzyl) amine to give the title compound as a yellow gum. 1 HNMR (400 MHz, CDCl 3): d -0.18 (s, 3 H), 0.00 (s, 3 H), 0.81 (s, 9 H), 1.02 (s, 3 H), 1.04 (s, 3 H), 2.61-2.72 (m , 4H), 2.83 (s, 3H), 3.53 (s, 2H), 4.33 (s, 2H), 4.65-4.70 (m, 1 H), 6.83-6.86 (d, 1 H), 7.00-7.44 (m , 10H) ppm. MS (electrospray) m / z 720 [M + Hf, 742 [M + Hf] Preparation 55: 2- (3-. {2-r ((2R) -2- (rterc-butyl (dimethyl] silyl] oxy) -2- (4-hydroxy-3 - [(methylsulfonyl) amino-1-phenyl) ethyl) amino] -2-methylpropyl) phenyl) -? / - [(3'-Hydroxybiphenyl-4-yl) methyl] acetamide A bromide solution of preparation 56 (0.50 g, 0.70 mmol), (3-hydroxyphenyl) boronic acid (0.19 g, 1.4 mmol), (1,1'-bis (diphenylphosphino) ferrocene) dichloropalladium (II) (36 mg, 0.04 mmol) in N,? / - dimethylformamide (8 ml) was treated with 2 M aqueous sodium carbonate (2 ml) and the resulting suspension was heated at 80 ° C for 16 hours. The reaction mixture was cooled to room temperature and the solvent was removed in vacuo. The residue was distilled to form an azeotrope with toluene (50 ml), redissolved in ethyl acetate (50 ml) and neutralized with 1 N aqueous hydrochloric acid (to pH 7). The organic phase was separated and the aqueous phase was extracted with more ethyl acetate (2 x 50 ml). The combined organic extracts were washed with water (100 ml), saturated aqueous sodium chloride (100 ml), dried (sodium sulfate) and the solvent removed in vacuo to give an orange gum (515 mg) which was used without further purification. 1 H NMR (400 MHz, CD3OD): d -0.13 (s, 3H), 0.04 (s, 3H), 0.84 (s, 9H), 1.11 (s, 3H), 1.13 (s, 3H), 2.74-2.97 (m , 7H), 3.55-3.63 (m, 2H), 4.42-4.45 (m, 2H), 4.73-4.76 (m, 1 H), 6.89-6.94 (m, 3H), 7.15-7.30 (m, 9H), 7.41 (d, 1 H), 7.51 (s, 1 H), 7.53 (s, 1 H) ppm. MS (electrospray) m / z 732 [M + Hf, 754 [M + Hf] Preparation 56: 2- (3- (2-f ((2R) -2- (rterc-butyl (dimethyl) sililloxy) -2- (4-hydroxy-3-f (methylsulfonyl) amino1phenyl) ethyl) amino ] -2-methylpropyl) phenyl) - / V - [(2'-hydroxy-biphenyl-4-yl) methyl-1-acetamide I Prepared from (2-hydroxy-phenyl) boronic acid using the method of preparation 55 to give the title compound as a brown oil. 1 HNMR (400 MHz, CD3OD): d -0.13 (s, 3H), 0.04 (s, 3H), 0.84 (s, 9H), 1.12 (s, 3H), 1.14 (s, 3H), 2.72-2.99 (s) , 7H), 3.58-3.61 (m, 2H), 4.43-4.45 (m, 2H), 4.74-4.78 (m, 1 H), 6.78-6.81 (m, 1 H), 6.90-6.92 (m, 1 H) ), 7.02-7.10 (m, 2H), 7.15-7.39 (m, 8H), 7.41 (d, 1 H), 7.53 (s, 1 H), 7.55 (s, 1 H) ppm. MS (electrospray) m / z 755 [M + Hf Preparation 57: 2-Hydroxy-1-naphthamide] A solution of 2-hydroxy-1-naphthoic acid (5.0 g, 26.6 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (5.6 g, 29.2 mmol), and 1-hydroxybenzotriazole (3.95 g, 29.2 g) mmol) in tetrahydrofuran (70 ml) was stirred at room temperature for 30 minutes before the addition of 0.880 NH 3 (6 ml). The resulting suspension was stirred at room temperature for 2 hours. The reaction mixture was filtered and the filtrate was diluted with water (80 ml) and extracted with ethyl acetate (4 x 80 ml). The combined organic extracts were washed with water (50 ml x 2), saturated aqueous sodium chloride (50 ml), dried (sodium sulfate) and the solvent removed in vacuo to give an orange oil. Purification by column chromatography on silica gel eluting with dichloromethane: methanol: 0.880 ammonia 95: 5: 0.5 gave the title compound as a pink solid (1.83 g). 1HRMN (400 MHz, CDC! 3): d 6.1 1-6.35 (sa, 2H), 7.17 (d, 1 H), 7.36 (dd, 1 H), 7.54 (dd, 1 H), 7.79 (d, 1 H), 7.84 (d, 1 H), 8.22 (d, 1 H), 1 1.70-1 1.88 (s, 1 H) ppm. MS (electrospray) m / z 186 [M-H] "Preparation 58: 6-Hydroxy-2-naphthamide A solution of 6-hydroxy-2-naphthoic acid (1.88 g, 9.99 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (2.1 1 g, 10.98 mmol), 1-hydroxybenzotriazole (1.48 g, 10.98 mmol ) and ammonium carbonate (4.80 g, 49.95 mmol) in N,? / - dimethylformamide (70 ml) was allowed to stir at room temperature under a nitrogen atmosphere for 3 days. The solvent was removed in vacuo and the residue was partitioned between saturated aqueous sodium hydrogen carbonate (50 ml) and ethyl acetate (6 x 50 ml). The combined organic extracts were washed with water (25 ml), saturated aqueous sodium chloride (25 ml), dried (sodium sulfate) and the solvent removed in vacuo. The solid was absorbed on silica gel and purified by column chromatography on silica gel eluting with dichloromethane: methanol: 0.880 ammonia (95: 5: 0.5 changing to 90: 10: 1) to give the title compound as a pale yellow solid (1.1 g). 1 H NMR (400 MHz, CD3OD): 7.14 (d, 1 H), 7.15 (s, 1 H), 7.79 (d, 1 H), 7.83 (d, 2 H), 8.32 (s, 1 H) ppm. MS (electrospray) m / z 186 [M-H] "Preparation 59: 1- (Aminometi!) - 2-naphthol A solution of borane in tetrahydrofuran (19.23 ml of a 1 M solution, 19.23 mmol) was added dropwise to a solution of the amide of preparation 57 (0.90 g, 4.81 mmol) in tetrahydrofuran (10 ml) under an atmosphere of nitrogen. The reaction was then heated to reflux for 2 hours. The solution was cooled, treated with 6 M hydrochloric acid (10 ml) and heated to reflux for a further 2 hours. The resulting suspension was cooled and the pH was adjusted to pH 9 by addition of NH30,880 and extracted with ethyl acetate (50 ml x 3). The combined organic extracts were washed with saturated aqueous sodium chloride (20 ml), dried (sodium sulfate) and the solvent was removed under reduced pressure. Purification by column chromatography on silica gel eluting with dichloromethane: methanol: 0.880 ammonia (95: 5: 0.5 changing to 90: 10: 1) gave the title compound as a pink solid (0.19 g). 1 H NMR (400 MHz, CD3OD): 4.41 (s, 2 H), 7.07 (d, 1 H), 7.23 (1 H, dd), 7.43 (dd, 1 H), 7.66 (d, 1 H), 7.72 (d, 1H), 7.87 (d, 1 H) ppm. MS (electrospray) m / z 174 [M + Hf, 172 [M-H] ".

Preparation 60: 6- (Aminomethyl) -2-naphthol Prepared according to the method for preparation 59 using the amide of preparation 58. 1H NMR (400 MHz, CD3OD) d: 3.91 (s, 2H), 7.03-7.08 (m, 2H), 7.36 (dd, 1 H) , 7.61 (d, 1 H), 7.66 (d, 1 H), 7.69 (s, 1 H) ppm. EM (electrospray) m / z 172 [M-H] " Preparation 61: tere-butyl (3-iodobenzyl) carbamate A suspension of 3-iodobenzylamine hydrochloride (4.95 g, 18.4 mmol) in dichloromethane (100 ml) was treated with triethylamine (3.1 ml, 22 mmol) and di-t-butyl dicarbonate (4.40 g, 20 mmol) and the solution The resulting mixture was allowed to stir at room temperature under a nitrogen atmosphere for 1.5 hours. The reaction mixture was washed with 2M hydrochloric acid (30 ml), water (30 ml), dried (sodium sulfate) and the solvent removed in vacuo to give the title compound as a colorless solid (6.43 g) . 1H NMR (400 MHz, CDCl 3) d: 1.46 (s, 9H), 4.21-4.30 (m, 2H), 4.79-4.89 (sa, 1 H), 7.06 (dd, 1 H), 7.25 (d, 1 H) , 7.60 (d, 1 H), 7.63 (s, 1 H) ppm.

MS (electrospray) m / z 332 [M-H] ", 356 [M + Naph Preparation 62: tere-butyl (2-Bromobenzyl) carbamate Prepared from 2-bromobenzylamine using the method of preparation 61 to give the title compound as a colorless solid. 1H NMR (400 MHz, CD3OD) d: 1.50 (s, 9H), 4.33 (s, 2H), 7.18-7.22 (m, 1 H), 7.35-7.38 (m, 2H), 7.59 (d, 1 H) ppm . MS (electrospray) m / z 308/310 [M + Naf Preparation 63: tert-butyl [(4'-hydroxybiphenl-3-yl) methyl] carbamate A solution of the iodide from Preparation 61 (0.75 g, 2.25 mmol), 4-hydroxyphenylboronic acid (0.62 g, 4.50 mmol), 1,1 '-bis (diphenylphosphino) ferrocenylpalladium chloride (ll) (0.11 g, 0.14 mmol) , in N,? / - dimethylformamide (14 ml) was treated with 2 M aqueous sodium carbonate (4 ml) and the resulting mixture was heated at 80 ° C under a nitrogen atmosphere for 16 hours. The solvent was removed in vacuo and the residue was purified by column chromatography on silica gel eluting with ethyl acetate: pentane (1: 3) to give the title compound as a pale pink palladium (0.73 g) crystalline solid. . NMR (400 MHz, CDCl 3) d: 1.47 (s, 9H), 4.33-4.41 (m, 2H), 4.87-4.94 (sa, 1 H), 6.89 (d, 2H), 7.21 (d, 1 H), 7.37 (dd, 1 H), 7.43-7.45 (m, 4H) ppm. (electrospray) m / z 298 [M-H] ", 322 [M + Naf Preparation 64: f (2'-hydroxy-benzyl-3-yl) tert-butyl methylcarbamate Prepared from the iodide of preparation 61 and 2-hydroxyboronic acid using the procedure of preparation 63 to give the title compound as a colorless solid. 1H NMR (400 MHz, CDCl 3) d: 1.46 (s, 9H), 4.38 (d, 2H), 4.90 (sa, 1 H), 5.24 (sa, 1 H), 6.97-7.01 (m, 2H), 7.22- 7.47 (m, 6H) ppm. MS (electrospray) m / z 322 [M + Naf Preparation 65: tert-butyl [(2'-hydroxy-biphenyl-2-yl) methyl-carbamate Prepared from the bromide of preparation 62 and 2-hydroxyboronic acid using the procedure of preparation 63 to give the title compound as a colorless solid. 1 HNMR (400 MHz, CD3OD): 1.46 (s, 9H), 4.15 (d, 2H), 6.91-6.96 (m, 2H), 7.10 (dd, 1 H), 7.17-7.41 (m, 5H) ppm. MS (electrospray) m / z 298 [M-H] " Preparation 66: tert-butyl [(3'-hydroxybiphenyl-2-yl) methylcarbamate Prepared from the bromide of preparation 62 and 3-hydroxyboronic acid using the procedure of preparation 63 to give the title compound as a colorless solid. 1 H NMR (400 MHz, CD3OD) d: 1.48 (s, 9H), 4.21 (s, 2H), 6.76-6.83 (m, 3H), 7.21-7.43 (m, 5H) ppm. MS (electrospray) m / z 298 [M-H] " Preparation 67: tert-butyl [(3'-hydroxybiphenyl-3-yl) methyl] carbamate Prepared from the iodide of preparation 61 and 3-hydroxyphenylboronic acid using the method of preparation 63 to give the title compound as a brown gum. 1H NMR (400 MHz, CDCl 3) d: 1.48 (s, 9H), 4.37 (d, 2H), 4.86-4.91 (sa, 1H), 6.82 (dd, 1H), 7.04 (t, 1 H), 7.11 (d , 1H), 7.24-7.30 (m, 2H), 7.36 (t, 1 H), 7.43 (d, 1 H), 7.45 (d, 1 H) ppm. MS (electrospray) m / z 298 [M-H] \ 597 [2 M-H] " Preparation 68: 3 '- (Amomethyl) biphenyl-4-ol The phenol from preparation 63 (0.73 g, 2.43 mmol) was treated with 4 M HCl in dioxane (6 mL, 24.3 mmol) and the resulting solution was allowed to stir at room temperature for 3 hours. The solvent was removed in vacuo to give the title compound as a colorless solid. 1H NMR (400 MHz, CD3OD) d: 4.17 (s, 2H), 6.87 (d, 2H), 7.34 (d, 1 H), 7.45-7.50 (m, 3H), 7.61 (d, 1 H), 7.65 ( s, 1 H) ppm. MS (electrospray) m / z 198 [M-H] ", 200 [M + Hf Preparation 69: 3 '- (Aminomethyl) biphenyl-3-ol Prepared from the phenol of preparation 67 using the method of preparation 68 to give the title compound as a brown gum. 1 H NMR (400 MHz, CD3OD): 4.17 (s, 2 H), 6.80 (dd, 1 H), 7.04 (t, 1 H), 7.08-7.11 (m, 1 H), 7.26 (t, 1 H), 7.41 (d, 1 H), 7.50 (t, 1 H), 7.63 (d, 1 H), 7.69 (s, 1 H) ppm. MS (electrospray) m / z 198 [M-H] ", 200 [M + Hf Preparation 70: 3 '- (Aminomethyl) biphenyl-2-ol Prepared from the phenol of preparation 63 using the method of preparation 68 to give the title compound as a colorless solid. 1 H NMR (400 MHz, CD3OD): 4.19 (s, 2 H), 6.93-6.97 (m, 2 H), 7.19-7.23 (m, 1 H), 7.31 (d, 1 H), 7.41 (dd, 1 H), 7.50-7.53 (m, 1 H), 7.65-7.69 (m, 2H) ppm. EM (electrospray) m / z 200 [M + Hf Preparation 71: 2 '- (Aminomethyl) biphenyl-2-ol Prepared from Preparation 65 using the method of preparation 68 to give the title compound as a colorless solid. 1 H NMR (400 MHz, CD3OD) d: 4.03 (s, 2H), 6.99-7.04 (m, 2H), 7. 19 (dd, 1 H), 7.30-7.34 (m, 2H), 7.50-7.58 (m, 3H) ppm. MS (electronebuliation) m / z 200 [M + Hf Preparation 72: 2 '- (Aminomethyl) bifeni! -3-ol Prepared from Preparation 66 using the method of preparation 68 to give the title compound as a colorless solid. 1 HNMR (400 MHz, CD3OD): 4.15 (s, 2H), 6.79-6.84 (m, 2H), 6.88-6.91 (m, 1 H), 7.31-7.35 (m, 1 H), 7.37-7.40 (m, 1 H), 7.48-7.54 (m, 2H), 7.56-7.60 (m, 1 H) ppm. EM (electrospray) m / z 200 [M + Hf Preparation 73: (4 - ([tert-Butyl (dimethyl) silyl] oxy) phenyl) acetonitrile A solution of (4-hydroxyphenyl) acetonitrile (6.01 g, 45.1 mmol) in? /,? / - dimethylformamide (60 ml) was treated with imidazole (3.81 g, 58.6 mmol), ferd-butyldimethylsilyl chloride (7.49 g, 49.6 g) mmol) and N,? / - dimethylaminopyridine (20 mg) and the resulting solution was allowed to stir at room temperature under a nitrogen atmosphere for 16 hours. The reaction mixture was diluted with water (200 ml) and extracted with ethyl acetate (200 ml x 2). The combined organic extracts were washed with saturated aqueous sodium chloride (200 ml), dried (sodium sulfate) and the solvent removed in vacuo. Purification by column chromatography on silica gel eluting with ethyl acetate: pentane (0: 100 changing to 10:90) gave the title compound as a pale yellow oil (9.44 g). 1H NMR (400 MHz, CDCl 3) d: 0.19 (s, 6H), 0.97 (s, 9H), 3.66 (s, 2H), 6.82 (d, 2H), 7.17 (d, 2H) ppm. MS (APCI) m / z 265 [M + NH4f] Preparation 74 2- (4-. {Fterc-Butyl (dimethyl) silyl] oxy) phenol) -2-methylpropanonitrile A solution of the nitrile from Preparation 73 (5.62 g, 22.7 mmol), methyl iodide (3.11 mL, 50 mmol), and 18-crown-6 (1.5 g, 5.6 mmol) in dry tetrahydrofuran (300 mL) was cooled to -78 ° C in a nitrogen atmosphere. Potassium fer-butoxide (50 ml of a 1M solution in tetrahydrofuran, 50 mmol) was added dropwise over 20 minutes and the reaction mixture was allowed to warm gradually to room temperature. After 2 hours the reaction was re-cooled to -78 ° C and quenched by the addition of saturated aqueous ammonium chloride (200 ml) and allowed to warm to room temperature. The resulting solution was extracted with ethyl acetate (300 ml x 2), the combined organic extracts were dried (sodium sulfate) and the solvent was removed in vacuo. Purification by column chromatography on silica gel eluting with ethyl acetate: pentane (0: 100 changing to 10:90) gave the title compound as a colorless oil (4.75 g). 1H NMR (400 MHz, CDCl 3) d: 0.19 (s, 6H), 0.97 (s, 9H), 1.68 (s, 6H), 6.82 (d, 2H), 7.30 (d, 2H) ppm. MS (APCI) m / z 293 [M + NH4f] Preparation 75: [2- (4- { Fterc-Butyl (dimethyl) sil.poxy) phenyl) -2-methyl propylamine A solution of the nitrile from preparation 74 (0.75 g, 2.7 mmol) in diethyl ether (5 ml) was added dropwise to a cold (0 ° C) solution of lithium aluminum hydride in diethyl ether (2.98 ml of a 1 M solution). The resulting solution was stirred at 0 ° C for 3 hours and then quenched by the addition of water (0.1 ml), 2N aqueous sodium chloride (0.1 ml) and more water (0.3 ml). The resulting suspension was filtered and the filtrate was concentrated in vacuo. Purification by column chromatography on silica gel eluting with dichloromethane: methanol: 0.880 ammonia (97: 3: 0.5 changing to 93: 7: 0.5) gave the title compound as a colorless oil (0.52 g). 1H NMR (400 MHz, CDCl 3) d: 0.18 (s, 6H), 0.97 (s, 9H), 1.00 (s, 2H), 1.25 (s, 6H), 2.73 (s, 2H), 6.78 (d, 2H) , 7.16 (d, 2H) ppm. MS (APCI) m / z 280 [M + Hf Preparation 76: 4- (Aminomethyl) -2,6-dimethylphenol Hydrochloride A solution of borane in tetrahydrofuran (27.1 ml of a 1M solution, 27.1 mmol) was added dropwise to a solution of 3,5-dimethyl-4-hydroxybenzonitrile (1.0 g, 6.79 mmol) in tetrahydrofuran (70 ml) and The resulting solution was heated to reflux in a nitrogen atmosphere for 16 hours. The reaction was cooled to room temperature and treated with 6N hydrochloric acid (20 ml) and heated to reflux for a further 30 minutes. The reaction mixture was cooled to room temperature and the solvent was removed in vacuo. Purification using strong cation exchange resin, eluting by-products with methanol followed by 2M ammonia in methanol to elute the product gave the title compound as an orange oil. The oil was treated with 1 M hydrogen chloride in methanol (20 ml) and the solvent was removed in vacuo to give the title compound as a pale yellow solid (1.12 g). 1 H NMR (400 MHz, CDCl 3): 2.22 (s, 6 H), 3.75 (s, 2 H), 6.90 (s, 2 H).

Preparation 77: 2- (Aminomethyl!) - 4-chlorophenol hydrochloride Prepared from 5-chloro-2-hydroxybenzonitrile using the procedure described in Preparation 76. 1 HNMR (400 MHz, CDCl 3) d: 4.08 (s, 2H), 6.87 (d, 1 H), 7.27 ( d, 1 H), 7.35 (s, 1H). MS (APCI) m / z 156 [M-H] ", 158 [M + Hf] Preparation 77: 4 '- (aminomethyl) biphenyl-4-ol hydrochloride Prepared from 4'-hydroxybiphenyl-4-carbonitrile using the procedure described in preparation 76. 1H NMR (400 MHz, CD3OD) d: 4.10 (s, 2H), 6.83 (d, 2H), 7.44-7.46 (m, 4H ), 7.60 (d, 2H) ppm.

Preparation 79: 3,5-Dichloro -? / - ethyl-2-hydroxybenzamida Prepared from 3,5-dichloro-2-hydroxybenzoic acid and ethylamine using the method of preparation 57 to give the title compound as a pale yellow solid. 1H NMR (400 MHz, CDCl 3) d: 1.28 (t, 3H), 3.47-3.54 (m, 2H), 6.29-6.36 (sa, 1 H), 7.27 (d, 1 H), 7.48 (d, 1 H) ppm. MS (electrospray) m / z 232 [M-H] " Preparation 80: 2,4-Dichloro-6 - [(ethylamino) methyl-1-phenol A solution of the amide from preparation 79 (0.77 g, 3.29 mmol) in tetrahydrofuran (10 ml) was cooled to 0 ° C and treated with a borane-tetrahydrofuran complex (9.9 ml of a 1 M solution in tetrahydrofuran, 9.9 mmol). The resulting solution was allowed to warm to room temperature for 20 minutes and then heated to reflux for 16 hours. The reaction mixture was cooled to 0 ° C and quenched by the addition of methanol (until the effervescence ceased). The resulting solution was allowed to warm to room temperature for 2 hours and then the solvent was removed in vacuo. The residue was dissolved in dichloromethane (40 ml) and washed with water (10 ml x 2), saturated aqueous sodium chloride (10 ml), dried (sodium sulfate) and reduced in vacuo to give a colorless oil. Purification by column chromatography on silica gel eluting with dichloromethane: methanol (98: 2 changing to 95: 5) gave the title compound as a colorless solid (0.53 g). 1 H NMR (400 MHz, CDCl 3) d: 1.17 (t, 3 H), 2.72 (c, 2 H), 3.98 (s, 2 H), 6.86 (d, 1 H), 7.23 (d, 1 H) ppm.

Preparation 81: 6-Hydroxy -? / -? T? Etl-1-naphtamide Prepared from 6-hydroxy-1-naphthoic acid and methylamine using the method of preparation 57 giving the title compound as a pale orange solid. 1H NMR (400 MHz, CD3OD) d: 2.97 (s, 3H), 7.10-7.14 (m, 2H), 7.34-7.40 (m, 2H), 7.73 (dd, 1 H), 8.04 (d, 1 H) ppm .

Preparation 82: 5-r (Methalamino) methyl] -2-naphthol Prepared from the amide of preparation 81 using the method of preparation 80 to give the title compound as a pale pink solid. 1 H NMR (400 MHz, CD3OD) d: 2.48 (s, 3 H), 4.14 (s, 2 H), 7.11-7.14 (m, 2 H), 7.25 (d, 1 H), 7.33 (t, 1 H), 7.59 ( d, 1 H), 7.94 (d, 1 H) ppm. MS (electrospray) m / z 186 [M-H] ", 188 [M + H] Preparation 83: 3-Hydroxy-5- (trifluoromethyl) benzamide Prepared from 3-hydroxy-5- (trifluoromethyl) benzoic acid using the method of Preparation 58 to give the title compound as a pale yellow solid. 1 H NMR (400 MHz, CD3OD) d: 7.18 (t, 1 H), 7.50 (t, 1 H), 7.60-7.61 (m, 1 H) ppm. MS (electrospray) m / z 204 [M-H] "Preparation 84: 3- (Aminomethyl) -5- (trifluoromethyl) phenol Prepared from the amide of preparation 83 using the method of preparation 80 to give the title compound as a pale yellow oil. 1 H NMR (400 MHz, CD3OD) d: 3.81 (s, 2 H), 6.91 (s, 1 H), 6.98 (s, 1 H), 7.09 (s, 1 H) ppm. EM (electrospray) m / z 192 [M + Hf Preparation 85: 3- (Aminomethyl) -5-chlorophenol Prepared from 3-chloro-5-hydroxybenzonitrile using the method of preparation 76 to give the title compound as a pale yellow solid. 'HRMN (400 MHz, CD3OD) d: 3.69 (s, 2H), 6.65 (d, 2H), 6.79 (t, 1 H) ppm. MS (electrospray) m / z 158 [M + Hf Preparation 86: Acetate of 3-f (Acetylamino) methyl] -5-chlorophenol A solution of the amine of preparation 85 (700 mg, 4.46 mmol) in tetrahydrofuran (20 ml) was treated with triethylamine (1.3 ml, 8.9 mmol) and acetyl chloride (0.64 ml, 8.9 mmol). The resulting mixture was allowed to stir at room temperature for 1 hour. The reaction mixture was filtered and the filtrate was reduced in vacuo to give the title compound as a colorless solid (1.07 g). 1 H NMR (400 MHz, CDCl 3) d: 2.15 (s, 3 H), 2.27 (s, 3 H), 3.71-3.75 (m, 1 H), 4.38-4.41 (m, 2 H), 6.92 (s, 1 H), 7.02 (s, 1 H), 7.13 (s, 1 H) ppm. MS (electrospray) m / z 264 [M + Naf Preparation 87:? / - (3-Chloro-5-hydroxybenzyl) acetamide A solution of the diacetate from Preparation 86 (1.07 g, 4.44 mmol) in methanol (10 mL) was treated with sodium methoxide (30 mg, 0.55 mmol) and the resulting mixture was allowed to stir at room temperature for 6 hours. The solvent was removed in vacuo and the residue was purified by column chromatography on silica gel eluting with ethyl acetate: pentane (1: 1 changing to 1: 0) and gave the title compound as a yellow solid (0.78 g). g). 1 H NMR (400 MHz, CDCl 3) d: 2.05 (s, 3 H), 4.33 (d, 2 H), 6.08-6.14 (m, 1 H), 6.73 (d, 2 H), 6.79 (t, 1 H) ppm. EM (electrospray) m / z 200 [M + Hf Preparation 88: 3-Chloro-5 - [(ethylamino) methyphenol Prepared from the amide of preparation 87 (0.75 g, 3.76 mmol) using the method of preparation 59 to give the title compound as a colorless solid (0.48 g). 1H NMR (400 MHz, CD3OD) d: 1.14 (t, 3H), 2.71 (c, 2H), 3.25-3.27 (m, 1 H), 3.72 (s, 2H), 6.66-6.68 (m, 2H), 6.79 (s, 1H) ppm. EM (electrospray) m / z [M-H] " Preparation 89: 4 - ([tert-Butyl (dimethyl) silyl] oxy) -2-chlorobenzaldehyde A solution of 2-chloro-4-hydroxybenzaldehyde (5.0 g, 32 mmol), re-tert-butyl (dimethyl) silyl chloride (5.3 g, 35 mmol), imidazole (2.9 g, 45 mmol) and ? /,? / - dimethylaminopyridine (10 mg) in N,? / - dimethylformamide (40 ml) was stirred at room temperature under a nitrogen atmosphere for 16 hours. The solvent was removed in vacuo and the residue was partitioned between ethyl acetate (100 ml) and water (100 ml). The organic phase was separated, washed with saturated aqueous sodium chloride (50 ml), dried (sodium sulfate) and reduced in vacuo. Subsequent purification by column chromatography on silica gel eluting with pentane: ethyl acetate (3: 1 changing to 2: 1) gave the title compound as a colorless oil (6.50 g). 1H NMR (400 MHz, CDCl 3) d: 0.25 (s, 6H), 0.97 (s, 9H), 6.80 (dd, 1 H), 6.87 (d, 1 H), 7.84 (d, 1 H), 10.32 (s, 1 H) ppm.

Preparation 90: / V- (4-. {Fterc-Butyl (di? T? Etl) silyl] oxy-2-chlorobenzyl) prop-2-en-1-amine A solution of the aldehyde from Preparation 89 (6.50 g, 24.0 mmol) and allylamine (1.51 g, 26.4 mmol) in dichloromethane (60 mL) was treated with sodium triacetoxyborohydride (7.6 g, 35.6 mmol) and the resulting suspension allowed to stir room temperature for 16 hours. Saturated aqueous sodium bicarbonate (50 ml) was added and the organic phase was separated. The organic phase was washed with saturated aqueous sodium chloride (50 ml), dried (sodium sulfate) and the solvent removed in vacuo to give a yellow oil. Purification by column chromatography on silica gel eluting with pentane: ethyl acetate (3: 1 changing to 2: 1) gave the title compound as a colorless oil (2.80 g). HRMN (400 MHz, CDCl 3) d: 0.19 (s, 6H), 0.97 (s, 9H), 1.84 (s, 1 H), 3.26 (d, 2H), 3.81 (s, 2H), 5.12 (dd, 1 H), 5.20 (dd, 1 H), 5.88-5.98 (m, 1 H), 6.71 (dd, 1 H), 6.85-6.86 (d, 1 H), 7.24 (d, 1 H) ppm. EM (electronebulization) m / z 312 [M + Hf Preparation 91: 4 - [(Allylamino) methylene-2,6-dichlorophenol Prepared from 3,5-dichloro-4-hydroxybenzaldehyde and allylamine using the method of preparation 90 to give the title compound as a colorless oil. 1 H NMR (400 MHz, DMSO-d6) d: 3.1 1 (d, 2 H), 3.50 (s, 2 H), 5.06 (d, 1 H), 5.16 (d, 1 H), 5.77-5.90 (m, 1 H ), 7.10 (s, 2H) ppm. EM (electrospray) m / z 232/234 [M + Hf Preparation 92: (4- (fterc-Butyl (dimethyl) silyloxy) -2-chlorobenzamine A solution of the amine of preparation 91 (2.8 g, 9.0 mmol), dimethylbarbituric acid (7.0 g, 45 mmol) and tetrakis (trphenylphosphine) palladium (0) (0.10 g, 0.08 mmol) in dichloromethane (80 ml) was heated to reflux for 4 hours. The cooled solution was reduced in vacuo and the residue was partitioned between ethyl acetate (50 ml) and 1 N aqueous sodium hydroxide (50 ml). The organic phase was separated, washed with saturated aqueous sodium chloride (50 ml), dried (sodium sulfate) and reduced in vacuo. Further purification by column chromatography on silica gel eluting with dichloromethane: methanol: 0.880 ammonia (98: 2: 0 changing to 95: 5: 0.5) gave the title compound as a colorless oil (1.70 g). 1H NMR (400 MHz, CDCl 3) d 0.19 (s, 6H), 0.97 (s, 9H), 1.89 (s, 2H), 3.85 (s, 2H), 6.70 (dd, 1 H), 6.85-6.86 (dd, 1 H), 7.21 (d, 1 H) ppm.

Preparation 93: (4-. {Fterc-Butyl (dimethyl) silyl] oxy, benzyl) methylamine Prepared from the aldehyde of preparation 89 and methylamine using the method of preparation 90 to give the title compound as a yellow oil. 1H NMR (400 MHz, CDCl 3) d: 0.23 (s, 6H), 1.00 (s, 9H), 2.50 (s, 3H), 3.93 (s, 2H), 6.70-6.73 (m, 1 H), 6.76 (d , 1 H), 7.20 (d, 1 H) ppm. EM (electronebuliation) m / z 286/288 [M + Hf Preparation 94: 4- (aminomethyl) -2,6-dichlorophenol barbiturate Prepared from the amine of preparation 91 using the method of preparation 92 to give the title compound in the form of the salt of barbituric acid. 1HRMN (400 MHz, DMSO-d6) d: 2.60-4.40 (broad multiplet, 2H), 3.03 (s, 6H), 3.93 (s, 2H), 7.49 (s, 2H) ppm. EM (electronebuliation) m / z 192/194 [M + Hf Preparation 95: 4-L-butyl (dimethyl) silyl] oxy) -2.3-dichlorobenzaldehyde Prepared from 2,3-dichloro-4-hydroxybenzaldehyde according to the method for preparation 89 to give the title compound as a yellow oil. HRMN (400 MHz, CDCl 3): 0.29 (s, 6H), 1.04 (s, 9H), 6.88 (d, 1 H), 7.76 (d, 1 H), 10.32 (s, 1 H) ppm.

Preparation 96:? - (4-merc-Butyl (dimethyl) silyloxi> 2, 3-dichlorobenzyl) prop-2-en-1 -amine Prepared according to preparation 90 using allylamine and the aldehyde of preparation 95 to give the title compound as a colorless oil. 1H NMR (400 MHz, CDCl 3) d: 0.20 (s, 6H), 1.01 (s, 9H), 3.25 (d, 2H), 3.82 (s, 2H), 5.10 (dd, 1 H), 5.18 (dd, 1 H), 5.85-5.93 (m, 1 H), 6.76 (d, 1 H), 7.13 (d, 1 H) ppm. EM (electrospray) m / z 346/348 [M + Hf Preparation 97: (4-fflerc-Butyl (dimethyl) silinox) -2,3-dichlorobenzamine Prepared according to preparation 92 using the amine of preparation 96 to give the title compound as a colorless oil. 1 H NMR (400 MHz, CD3OD) d: 0.23 (s, 6 H), 1.03 (s, 9 H), 3.92 (s, 2 H), 6.77 (d, 1 H), 7.12 (d, 1 H) ppm.

Preparation 98: 4-. { [tert-Butyl (dimethyl) silyl] oxy) -1-naphthaldehyde OTBDMS Prepared from 2,3-dichloro-4-hydroxybenzaldehyde according to the method for preparation 89 to give the title compound as a brown solid. 1H NMR (400 MHz, CDCl 3) d: 0.36 (s, 6H), 1.10 (s, 9H), 6.94 (d, 1 H), 7.56 (dd, 1 H), 7.68 (dd, 1 H), 7.86 (d , 1 H), 8.27 (dd, 1 H), 9.30 (dd, 1 H), 10.21 (s, 1 H) ppm.

Preparation 99:? / - r (4-ffterc-Butyl (dimethyl) silyl-oxy) -1-naphthyl) methyl] prop-2-en-1 -amine Prepared according to preparation 90 using allylamine and the aldehyde of preparation 98 to give the title compound as a yellow oil. 1H NMR (400 MHz, CDCl 3) d: 0.30 (s, 6H), 1.11 (s, 9H), 1.97 (s, 1 H), 3.39 (d, 2H), 4.17 (s, 2H), 5.16 (dd, 1 H), 5.25 (dd, 1 H), 5.95-6.05 (m, 1 H), 6.82 (d, 1H), 7.32 (d, 1H), 7.47-7.57 (m, 2H), 8.07 (d, 1H) , 8.25 (d, 1H) ppm. MS (electrospray) m / z 328 [M + Hf, 655 [2 M + Hf Preparation 100: [(4- (fterc-butyl (dimethyl) silyl-oxy]. -1-naphthyldimethyl amine Prepared according to preparation 92 using the amine of preparation 99 to give the title compound as a colorless oil. 1 H NMR (400 MHz, CDCl 3) d: 0.28 (s, 6 H), 1.09 (s, 9 H), 2.31 (s, 2 H), 4.24 (s, 2 H), 6.80 (d, 1 H), 7.27 (t, 1 H), 7.46-7.55 (m, 4H), 8.00 (d, 1 H), 8.25 (d, 1H).

Preparation 101: 3-Hydroxy -? / - methyl-5- (trifluoromethyl) benzamide Prepared from 3-hydroxy-5- (trifluoromethyl) benzoic acid and methylamine using the method of preparation 58 to give the title compound as a pale orange solid. HRMN (400 MHz, CD3OD) d: 2.99 (s, 3H), 7.14 (s, 1 H), 7.43 (s, 1 H), 7.52 (s, 1 H) ppm. MS (electrospray) m / z 218 [M-H] " Preparation 102: 3-f (Methalamino) methyl-1-5- (trifluoromethyl) phenol Prepared from the amide of preparation 101 using the method of preparation 59 to give the title compound as a colorless solid. 1 H NMR (400 MHz, CD3OD) d: 2.41 (s, 3 H), 3.75 (s, 2 H), 6.93 (s, 1 H), 6.98 (s, 1 H), 7.09 (s, 1 H) ppm. MS (electrospray) m / z 206 [M + Hf Preparation 103: 4- (Aminomethyl) -3,5-dimethylphenol Prepared from 4-hydroxy-2,6-dimethylbenzonitrile using the method of preparation 76 to give the title compound as a colorless solid. 1 H NMR (400 MHz, D2O): 2.09 (s, 6H), 3.90 (s, 2H), 6.95 (s, 2H) ppm.

Preparation 104: (4-Hydroxy-2,5-dimethylphenyl) acetonitrile A solution of (4-methoxy-2,5-dimethylphenyl) acetonitrile (0.5 g, 2.9 mmol) in dichloromethane (10 ml) was cooled to -80 ° C and treated with a solution of boron tribromide in dichloromethane (14.3 ml. of a 1 M solution, 14.3 mmol). The reaction mixture was stirred at -80 ° C for a further 30 minutes and then allowed to warm gradually to room temperature over a period of 2 hours. The reaction mixture was quenched with saturated aqueous sodium bicarbonate (20 ml) and the organic phase was separated. The organic phase was washed with saturated aqueous sodium chloride (20 ml), dried (sodium sulfate) and the solvent removed in vacuo to give a pale brown solid. Purification by column chromatography on silica gel eluting with ethyl acetate: pentane (1: 4 changing to 1: 2) gave the title compound as a colorless solid (0.28 g). 1 H NMR (400 MHz, CD3OD) d: 2.13 (s, 3 H), 2.23 (s, 3 H), 3.66 (s, 2 H), 6.60 (s, 1 H), 6.98 (s, 1 H) ppm. MS (electrospray) m / z 160 [M-H] " Preparation 105: (4-Hydroxy-213-dimethyphenyl) acetonitrile Prepared from (4-methoxy-2,3-dimethylphenyl) acetonitrile using the method of preparation 104 to give the title compound as a pale yellow solid. 1 H NMR (400 MHz, CDCl 3) d: 2.20 (s, 3 H), 2.24 (s, 3 H), 3.62 (s, 2 H), 4.91 (s, 1 H), 6.64 (d, 1 H), 7.03 (d, 1 H) ) ppm. MS (electrospray) m / z 160 [M-H] " Preparation 106: (4-Hydroxy-3-methylphenyl) acetonitrile Prepared from (4-methoxy-3-methylphenyl) acetonitrile using the method of preparation 104 to give the title compound as a pale yellow solid. 1 H NMR (400 MHz, CDCl 3) d: 2.25 (s, 3 H), 3.65 (s, 2 H), 4.98 (s, 1 H), 6.76 (d, 1 H), 7.01 (d, 1 H), 7.07 (s) , 1 H) ppm. MS (electrospray) m / z 146 [M-H] " Preparation 107: 4- (2-Aminoetyl) -2,5-dimethylphenol A solution of the nitrile from preparation 104 (0.28 g, 1.74 mmol) in ethanol (15 ml) was hydrogenated at 60 psi (414 kPa) over Raney nickel (0.1 g, 50% w / w) for 16 hours. The reaction mixture was filtered and the solvent removed in vacuo. The residue was purified by strong cation exchange resin by eluting non-basic impurities with methanol and then 1M ammonia in methanol to give the title compound as a colorless oil. 1 H NMR (400 MHz, CD3OD) d: 2.1 1 (s, 3 H), 2.19 (s, 3 H), 2.63-2.67 (m, 2 H), 2.72-2.76 (m, 2 H), 6.54 (s, 1 H), 6.81 (s, 1 H) ppm. EM (electrospray) m / z 166 [M + Hf Preparation 108: 4- (2-Aminoethyl) -2,3-dimethylphenol Prepared from the nitrile of preparation 105 using the method of preparation 107 to give the title compound as a colorless oil. 1 H NMR (400 MHz, CD3OD): 2.12 (s, 3 H), 2.19 (s, 3 H), 2.68-2.75 (m, 4 H), 6.55 (d, 1 H), 6.78 (d, 1 H) ppm. EM (electrospray) m / z 166 [M + Hf Preparation 109: 4- (2-Aminoethyl) -2-methylphenol Prepared from the nitrile of preparation 106 using the method of preparation 107 to give the title compound as a colorless oil. 1 H NMR (400 MHz, CD3OD) d: 2.15 (s, 3 H), 2.60-2.64 (m, 2 H), 2.79-2.83 (m, 2 H), 6.66 (d, 1 H), 6.82 (d, 1 H), 6.90 (s, 1 H) ppm. MS (electrospray) m / z 152 [M + Hf EXAMPLES 1 - 38 The appropriate 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 being allowed to cool to room temperature. If a solid product is precipitated, the reaction mixture is filtered and washed with methanol (2 ml, 1: 1 by volume) to give the title compound. If no product precipitates, the reaction mixture is concentrated in vacuo and the residue is purified by column chromatography on silica gel eluting with dichloromethane: methanol: ammonia 0.88 98: 2: 0 to 95: 5: 0.5 to 90:10: 1 producing the title product. Alternatively, the following procedure can be used for the synthesis of examples 1 to 38: A solution of the appropriate protected alcohol (2.87 mmol) in methanol (80 ml) is treated with a solution of ammonium fluoride (1.06 g, 28.7 mmol) in water (53 ml) and the resulting mixture was heated at 40 ° C for 16 hours. The reaction was cooled to room temperature and filtered, washing with a mixture of water and methanol (1: 1 by volume, 3 x 10 ml), methanol (2 x 10 ml). The solid is dried in vacuo to give the desired compound.

EXAMPLE 1 2- (3- {2-r ((2ff) -2-Hydroxy-2- {4-hydroxy-3- [(methylsulfonyl) amino-1-phenyl) -ethyl) -amino] -2-metpyl > fenii) -? / - (4-hydroxy-3-methoxybenz-acetamide) Preparation 18 (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 subsequently stirred at 50 ° C for 18 hours before being allowed 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: ammonia 0.88 98: 2: 0 to 95: 5: 0.5 to 90: 10: 1 yielding the product of title in the form of a colorless solid. 1H NMR (CD3OD, 400 MHz) d: 1.04 (s, 3H), 1.06 (s, 3H), 2.68-2.90 (m, 7H), 3.53 (s, 2H), 3.74 (s, 3H), 4.23 (m, 2H), 4.62 (m, 1 H), 6.67 (m, 2H), 6.77 (m, 1 H), 6.85 (d, 1 H), 7.01-7.22 (m, 6H), 7.37 (m, 1 H) ppm. EM (electronebulization) m / z 572 [M + Hf EXAMPLE 2? -r (4'-Hydroxy-phenyl-4-yl) metin-2- (3- 2-r ((2R) -2-hydroxy-2- 4-hydroxy-3- [(methylsulfonyl) amino1-phenyl) -ethyl) -amino-1-2-methylpropyl) phenyl) acetamide Preparation 19 (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 subsequently stirred at 50 ° C for 18 hours before being allowed to cool to room temperature. The reaction mixture was filtered and the solid was washed with methanol: water (2 ml, 1: 1 by volume) to give the title compound as a colorless solid. 1 H NMR (400 MHz, DMSOd6): 0.90 (s, 3 H), 0.92 (s, 3 H), 2.56 (s, 2 H), 2.62-2.65 (m, 2 H), 2.88 (s, 3 H), 3.43 (s, 2 H) ), 4.25 (2H, d), 4.40-4.43 (m, 1 H), 6.80-6.82 (m, 3H), 6.96-7.01 (m, 2H), 7.07-7.10 (m, 2H), 7.14-7.18 ( m, 2H), 7.23 (d, 2H), 7.42-7.48 (m, 4H), 8.47 (t, 1 H). EM (electrospray) m / z 618 [M + Hf EXAMPLE 3 A - (4-Chloro-2-hydroxybenzyl) -2- (3 2-r ((2ff) -2-hydroxy-2- (4-hydroxy-3-f (methylsulfonyl) amino-1-phenyl) -ethyl) amino] - 2-methylpropyl) phenyl) acetamide Preparation 20 (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 subsequently stirred at 50 ° C for 18 hours before being allowed to cool to room temperature. The reaction mixture was filtered and washed with methanol (2 ml, 1: 1 by volume) to give the title compound as a colorless solid. 1H NMR (400 MHz, DMSO-d6) d: 0.90 (s, 3H), 0.91 (s, 3H), 2.56 (s, 2H), 2.59-2.67 (m, 2H), 2.88 (s, 3H), 3.44 ( s, 2H), 4.16 (s, 2H), 4.40-4.43 (m, 1 H), 6.76-6.81 (m, 2H), 6.96-7.18 (m, 8H), 8.42 (s, 1 H). MS (electrospray) m / z 574 [MH] ", 576 [M + Hf EXAMPLE 4? / - (4-Hydroxy-3,5-dimethylbenzyl) -2- (3-f2-rí (2?) - 2-hydroxy-2- 4-hydroxy-3-r (methylsulfonyl) amino] phenyl) ethyl) amino-2-methylpropyl} phenyl) acetamide Preparation 21 (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 subsequently stirred at 50 ° C for 18 hours before being allowed to cool to room temperature. The reaction mixture was filtered and washed with methanol (2 ml, 1: 1 by volume) to give the title compound as a colorless solid. 1 HNRM (400 MHz, DMSOd6) d: 0.90 (s, 3H), 0.91 (s, 3H), 2.08 (s, 6H), 2.55 (s, 2H), 2.62-2.65 (m, 2H), 2.88 (s, 3H), 3.38 (s, 2H partially darkened by H2O), 4.05 (d, 2H), 4.40-4.43 (m, 1 H), 6.71 (s, 2H), 6.81 (d, 1 H), 6.95-7.01 ( m, 2H), 7.05-7.09 (m, 2H), 7.13-7.18 (m, 2H), 8.28-8.31 (t, 1 H).

EXAMPLE 5 2- (3- 2-rf (2R) -2-Hydroxy-2-. {4-hydroxy-3- [(methylsulfonyl) amino1pheny1) ethyl) amino1-2-methylpropyl) phenyl ) - / Vf (2-hydroxy-1r naftiDmetipacetamide Preparation 22 (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 subsequently stirred at 50 ° C for 18 hours before being allowed 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: ammonia 0.88 98: 2: 0 to 95: 5: 0.5 to 90: 10: 1 yielding the product of title in the form of a colorless solid. 1H NMR (400 MHz, DMSOd6) d: 0.86 (s, 3H), 0.87 (s, 3H), 2.46-2.68 (m, 4H), 2.90 (s, 3H), 3.40 (s, 2H), 4.41-4.47 ( m, 1 H), 4.63 (d, 2H), 6.83 (d, 1 H), 6.94-7.05 (m, 4H), 7.1 1-7.16 (m, 2H), 7.19 (s, 1 H), 7.27 ( t, 1 H), 7.40 (t, 1 H), 7.72 (d, 1 H), 7.79 (d, 1 H), 7.88 (d, 1 H), 8.48-8.52 (sa, 1 H). MS (electrospray) m / z 590 [M- H] "EXAMPLE 6 2- (3- { 2-r ((2R) -2-Hydroxy-2- 4-hydroxy-3-r (methylsulfonyl) amino1phenyl) ethyl) amino1-2-methylpropyl) phenyl) -? -r (6-hydroxy-2-naphthyl) methinacetamide Preparation 23 (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 subsequently stirred at 50 ° C for 18 hours before being allowed to cool to room temperature. The reaction mixture was filtered and washed with methanohagua (2 ml, 1: 1 by volume) to give the title compound as a colorless solid. 1 HNRM (400 MHz, DMSO 6): 0.90 (s, 3 H), 0.92 (s, 3 H), 2.49-2.68 (m, 4 H), 2.89 (s, 3 H), 3.44 (s, 2 H), 4.34 (d, 2 H) ), 4.40-4.43 (m, 1H), 6.80 (d, 1 H), 6.96-7.17 (m, 7H), 7.23 (d, 1 H), 7.51 (s, 1 H), 7.58 (d, 1 H) ), 7.61 (d, 1 H), 8.50 (dd, 1 H). MS (electronebulization) m / z 590 [MH] ", 592 [M + Hf, 614 [M + Naf EXAMPLE 7? -r (4-H -droxybiphenyl-3-yl) metin-2- (3-. 2-r ((2 /?) - 2-hydroxy-2- (4-hydroxy-3-r (methylsulfonyl) amino-1-phenyl >ethyl) amino1-2-methylpropyl) phenyl) acetamide Preparation 24 (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 subsequently stirred at 50 ° C for 18 hours before being allowed to cool to room temperature. The reaction mixture was filtered and washed with methanol (2 ml, 1: 1 by volume) to give the title compound as a colorless solid. 1 HNMR (400 MHz, DMSO 6): 0.88 (s, 3 H), 0.90 (s, 3 H), 2.66-2.54 (m, 4 H), 2.88 (s, 3 H), 3.43 (s, 2 H), 4.29 (d, 2 H) ), 4.39-4.43 (m, 1 H), 6.79-6.82 (m, 3H), 6.96-7.01 (dd, 2H), 7.07-7.17 (m, 5H), 7.27-7.31 (dd, 1 H), 7.36 -7.41 (m, 4H), 8.52 (dd, 1H) ppm. MS (electrospray) m / z 618 [M + Hf EXAMPLE 8? / - r (3'-HydroxybifenH-3-ii) metin-2- (3- { 2-r ((2 /?) - 2- hydroxy-2- (4-hydroxy-3-r (methylsulfonyl) amino] phenyl) ethyl) amino 1-2-methylpropyl) phenyl) acetamide Preparation 25 (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 subsequently stirred at 50 ° C for 18 hours before being allowed to cool to room temperature. The reaction mixture was filtered and washed with methanol (2 ml, 1: 1 by volume) to give the title compound as a colorless solid. 1HRMN (400 MHz, DMSOd6): 1.16 (s, 6H), 2.85 (s, 2H), 2.92 (s, 3H), 2.96-3.03 (m, 2H), 3.57 (s, 2H), 4.42 (s, 2H), 4.77-4.79 (m, 1 H), 6.74 (d, 1 H), 6.90 (d, 1 H) ), 6.95-6.97 (m, 2H), 7.09-7.27 (m, 7H), 7.32 (t, 1 H), 7.41-7.42 (m, 3H) ppm. MS (electrospray) m / z 618 [M + Hf, 640 [M + Naf, 616 [M-HV EXAMPLE 9 2- (3- (2-r ((2?) - 2-Hydroxy-2- (4 -hydroxy-3-f (methylsulfonyl) aminogolfylene] ethyl) amino1-2-methylpropyl> phenyl) -? -f2- (4-hydroxyphenyl) -2-methylpropyl-1-acetamide Preparation 26 (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 subsequently stirred at 50 ° C for 18 hours before being allowed 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: ammonia 0.88 98: 2: 0 to 95: 5: 0.5 to 90: 10: 1 yielding the product of title in the form of a colorless solid. 1H NMR (400 MHz, DMSOd6) d: 0.91 (s, 3H), 0.92 (s, 3H), 1.11 (s, 6H), 2.56 (s, 2H), 2.64-2.66 (m, 2H), 2.89 (s, 3H), 3.15 (s, 2H), 3.35 (s, 2H), 4.42-4.45 (m, 1 H), 6.65 (d, 2H), 6.81 (d, 1 H), 6.94-7.03 (m, 4H) , 7.07-7.14 (m, 3H), 7.18 (s, 1 H), 7.60 (t, 1 H). MS (APCI) m / z 582 [MH] ", 584 [M + Hf EXAMPLE 10 / V- (3,5-D-chloro-2-hydroxybenz [] - A / -eti-2- (3- (2-r ((2 /?) -2-hydroxy-2- (4-hydroxy-3 - [(methylsulfonyl) amino] phenyl) ethyl) aminol-2-methylpropyl. Phenyl) acetamide Preparation 27 (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 subsequently stirred at 50 ° C for 18 hours before being allowed to cool to room temperature. The reaction mixture was filtered and washed with methanol (2 ml, 1: 1 by volume) to give the title compound as a colorless solid. 1HRMN (400 MHz, CD3OD) d: 1.05-1.16 (m, 9H), 2.70-2.96 (m, 7H), 3.32 and 3.34 (2t, 2H), 3.74 and 3.83 (2s, 2H), 4.56 and 4.58 (2s) , 2H), 4.64-4.66 (m, 1 H), 6.85 (dd, 1 H), 7.01-7.26 (m, 7H), 7.36 (dd, 1 H). MS (electrospray) m / z 637 [M-H] " EXAMPLES 11 TO 32 EXAMPLES 34-38 1 H NMR (400 MHz, DMSO 6): 0.95 (s, 3 H), 0.98 (s, 3 H), 2.65-2.71 (m, 4 H), 2.93 (s, 3 H), 4.46-4.52 (m, 3 H), 6.83- 6.86 (m, 3H), 7.03-33 7.06 (m, 1 H), 7.22-7.23 (m, 1 H), 7.30-7.38 (m, 4H), 7.47 (d, 2H), 7.54 (d, 2H) , 7.73-7.76 (m, 2H), 8.96-8.99 (m, 1 H) ppm. MS (electronebulization) m / z 604 [M + Hf 1 H NMR (400 MHz, DMSOd 6) d: 0.95 (s, 3 H), 0.97 (s, 3 H), 1.26 (s, 6 H), 2.63-2.70 (m, 4 H) ), 2.93 (s, 3H), 3.39-3.40 (m, 2H), 4.44-4.48 (m, 34 1 H), 6.71 (d, 2H), 6.84 (d, 1 H), 7.05 (d, 1 H), 7.20-7.34 (m, 4H), 7.58-7.60 (m, 2H), 8.02- 8.06 ( m, 1 H) ppm. MS (electrospray) m / z 570 [M + Hf 1 H NMR (400 MHz, DMSOd 6) d: 0.95 (s, 3 H), 0.98 (s, 3 H), 2.64-2.71 (m, 4 H), 2.93 (s, 3 H) ), 4.45-4.48 (m, 1 H), 4.54-4.56 (m, 2H), 6.82-35 6.86 (m, 3H), 7.04 (d, 1 H), 7.22-7.40 (m, 5H), 7.45- 7.48 (m, 3H), 7.54 (s, 1 H), 7.73-7.75 (m, 2H), 8.98-9.01 (m, 1 H) ppm. EM (electronebulization) m / z 604 [M + Hf Unless otherwise indicated, all reactions are carried out in a nitrogen atmosphere.

Abbreviations TBDMS = tert-butyl (dimethyl) silyl IPA: isopropyl alcohol THF: tetrahydrofuran s = singlet d = doublet dd = double doublet t = triplet c = quadruple m = multiplet sa = broad singlet, for example NH or OH Capacity of the compounds of formula (1) to act as potent β2-agonists thereby mediating relaxation of smooth muscle can be determined by measuring the effect of stimulation of the beta-2-adrenergic receptor on stimulation contraction with electric field strips of guinea pig trachea.

Guinea Pig Trachea Male Dunkin-Hartley guinea pigs (475-525 g) are slaughtered by CO2 asphyxiation and bleeding through the femoral artery and the trachea is isolated. Four preparations of each animal are obtained, beginning the dissection immediately below the larynx and taking 2.5 cm of trachea. The piece of trachea is opened by cutting the cartilage in front of the tracheal muscle and then cross sections of 3-4 rings of cartilage are cut. The resultant strip preparations are suspended in 5 ml organ baths using cotton threads attached to the lower and upper cartilage strips. The strips are equilibrated and de-stressed for 20 minutes in a Krebs Ringer modified pH regulatory solution (Sigma K0507) containing 3 μM Indometacin (Sigma 17378), 10 μM Guanetidin (Sigma G8520) and 10 μM Atenolol (Sigma A7655), heat at 37 ° C and apply a gas with 02 to 95% / CO2 at 5% before applying an initial tension of 1 g. The preparations are allowed to equilibrate for an additional 30-45 minutes, during which time they are re-tensed (at 1 g) twice at 15 minute intervals. Changes in tension are recorded and controlled by conventional isometric transducers coupled to a data collection system (custom designed in Pfizer). After equilibrium of the tension, the tissues are subjected to electric field stimulation (EFS) using the following parameters: trains of 10 s every 2 minutes, pulse width 0.1 ms, 10 Hz and maximum voltage (25 volts) continuously throughout the experiment. The SAI of post-ganglionic cholinergic nerves in the trachea results in monophasic smooth muscle contractions and the height of muscle spasm is recorded. The organ baths are constantly perfused with the Krebs Ringer buffer solution described above by means of a peristaltic pump system (pump flow rate 7.5 ml / minute) throughout the experiment, with the exception of when a β2 agonist is added. according to the invention, the pump is then stopped during the cumulative dosing to the bath and starts again after reaching the maximum response during the washing period.

Experimental protocol for evaluation of potency and efficacy After equilibration of EFS, the peristaltic pump is stopped and the preparations are "primed" with a single dose of 300 nM soprenaline (Sigma 15627) to establish a maximum response in terms of inhibition of the contractile response to EFS. Then, the isoprenaline is removed by washing for a period of 40 minutes. After priming and wash recovery, a standard curve for isoprenaline is made in all tissues (isoprenaline curve 1) by cumulative addition of a bolus in the bath using semilogarithmic increases in concentration. The concentration range used is 1e "9 a 1e / 3e" 6 M. At the end of the isoprenaline curve, the preparations are again washed for 40 minutes before starting a second curve for either isoprenaline (as internal control) or beta 2 agonist according to the present invention. Responses to the beta 2 agonist are expressed as percent inhibition of the response to EFS. Data for agonists beta 2 are normalized by expressing the inhibition as a percentage of the maximal inhibition induced by isoprenaline in curve 1. The value of EC50 for the beta2 agonist according to the present invention refers to the concentration of compound that is required to produce half of the maximum effect. The data for beta 2 agonists according to the present invention are expressed as relative potency to isoprenaline defined by the ratio (EC50 beta 2 agonist) / (EC50 isoprenaline).

Confirmation of functional activity mediated by beta-2 The beta 2 agonist activity of the test compounds is confirmed using the above protocol, however, prior to constructing the β2 agonist curve according to the present invention, the preparations are pre-prepared. incubate (for a minimum of 45 minutes) with ICI 118551 (a selective beta 2 antagonist) 300 nM, which results in the case of a beta-2 mediated effect a shift to the right of the dose response curve of the test compound. According to another alternative, the agonist potency for the β2 receptor of the compounds of formula (1) can also be determined by measuring the concentration of compound according to the present invention which is required to produce half the maximum effect (EC50) for the ß2 receptor.

Preparation of the Compound A 10 mM stock solution is diluted in 100% DMSO (dimethylsulfoxide) compound at the maximum dose required in 4% DMSO. This maximum dose is used to construct a semi-log dilution curve of 10 points, in 4% DMSO. Isoprenaline (Sigma, 1-5627) was used as a standard in each experiment and for control wells in each plate. The data were expressed as% response to soprenaline.

Cell culture CHO (Chinese Hamster Ovary) cells recombinantly expressing the human β2 adrenergic receptor (from Kobilka et al., PNAS 84: 46-50, 1987 and Bouvier et al., Mol Pharmacol 33: 133-139 were cultured. 1988 CHOhß2) in Dulbecco's MEM / NUT MIX F12 medium (Gibco, 21331-020) supplemented with 10% fetal bovine serum (Sigma, F4135, Lot 90K8404 Exp 09/04), 2 mM glutamine (Sigma, G7513), 500 μg / ml geneticin (Sigma G7034) and 10 μg / ml puromycin (Sigma, P8833). The cells were seeded giving approximately 90% confluency for the assay.

Method of analysis 25 μl / well of each dose of compound were transferred to a cAMP-Flashplate® (NEN, SMP004B) with 1% DMSO as baseline controls and 100 nM Isoprenaline as max control. This was diluted 1: 2 by the addition of 25 μl / well of PBS. The cells were treated with trypsin (0.25%, Sigma T4049), washed with PBS (Gibco, 14040-174) and resuspended in stimulation pH regulator (NEN, SMP004B) giving 1x106 cells / ml of CHOhB2. 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 of 25l-cAMP (NEN, NEX-130) and the plates were incubated at room temperature for 2 more hours The amount of 125l-cAMP bound to the Flashplate® was quantified using a Topcount NXT (Packard), normal count efficiency for 1 minute. The dose response data were expressed as% isoprenaline activity and adjusted using a four-parameter sigmoid fit. In this way, it has been found that the compounds of formula (1) according to the present invention illustrated in examples 1 to 38 above show an EC50 value of cAMP-AM2 comprised between 0.02 nM and 3.03 nM. The following table illustrates the activity of the compounds of the invention.

Claims (33)

NOVELTY OF THE INVENTION CLAIMS

1. - A compound of general formula (1): wherein the group (CH2) n-C (= O) Q1 is in the meta or para position, R1 and R2 are independently selected from H and C? -C alkyl? n is 0, 1 or 2 and Q1 is a group selected from: and a group * -NR8-Q2-A, where p is 1 or

2, Q is an alkylene of C? -C optionally substituted with a hydroxy group, R8 is H or C4 alkyl, and A is pyridyl optionally substituted with OH , C3-C7 cycloalkyl optionally substituted with OH or a group wherein R3, R4, R5, R6 and R7 are the same or different and are selected from H, d-C4 alkyl, OR9, SR9, halo, CN, CF3, OCF3, COOR9, SO2NR9R10, CONR9R1 °, NR9R1 °, NHCOR 0 and phenyl optionally substituted with 1 to 3 groups selected from OR 9, halo and C 1 -C 4 alkyl, where R 9 and R 10 are the same or different and are selected from H or C 4 alkyl and the * represents the point of attachment to the carbonyl group; wherein the Q1 group is substituted with at least one hydroxy group; or, if appropriate, their pharmaceutically acceptable salts and / or isomers, tautomers, solvates or isotopic variations thereof. 2 - The compound according to claim 1, further characterized in that Q1 is a group * -NR8-Q2-A, where R8 is H, CH3 or CH2CH3 and A is naphthyl substituted with a hydroxy.

3. The compound according to claim 1, further characterized in that Q1 is a group * -NR8-Q -A, where R8 is H, CH3 or CH2CH3 and A is a group wherein one of R3, R4, R5, R6 and R7 is OH and the others are the same or different and are selected from H, CrC4 alkyl? OR9, SR9, halo, CF3, OCF3, SO2NR9R10, CONR9R10, NR9R10, NHCOR10, with the proviso that at least 2 of R3 to R7 are equal to H; where R9 and R10 are the same or different and are selected from H or C-? -C4 alkyl.

4. The compound according to claim 3, further characterized in that Q1 is a group * -NH-Q2-A and A is a group wherein one of R3, R4, R5, R6 and R7 is OH and the others are the same or different and are selected from H, OH, CH3, OCH2-CH3, SCH3, halo, CF3, OCF3, with the proviso that at least 2 of R3 to R7 are equal to H.

5. The compound according to claim 1, further characterized in that Q1 is a group * -NR8-Q2-A, where R8 is H , CH3 or CH2CH3 and A is a group wherein one of R3, R4, R5, R6 and R7 is phenyl substituted with OH and the others are H.

6. The compound according to any one of claims 1 to 5, further characterized in that Q2 is -CH2 -, - (CH2) 2-, - (CH2) 3-, - (C (CH3) 2) -, - (CH2) 4- or - (CH (CH2OH)) -.

7. - The compound according to claim 6, further characterized in that Q2 is -CH2-.

8. The compound according to claim 1, further characterized in that Q1 is in which one of R3? R4, R5 and R6 is OH and the others are H.

9. The compound according to claim 1, further characterized in that Q1 is in which one of R3, R4? R5 and R6 is OH and the others are H.

10. The compound according to any one of claims 1 to 10, further characterized in that R1 is H or CC alkyl and R2 is CC alkyl

11. The compound of according to claim 11, further characterized in that R1 is H or CH3 and R2 is CH3.

12. The compound according to claim 12, further characterized in that n is 1.

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

14. The compound according to any one of claims 1 to 13, further characterized in that the group (CH2) nC ( = O) Q1 is in the meta position.

15. The compound according to claim 1, further characterized in that it is selected from the group consisting of 2- (3- { 2 - [((2R) -2-Hydroxy-2- {4-hydroxy -3 - [(methylsulfonyl) amino] phenyl.} Ethyl) amino] -2-methylpropyl. Phenyl) -N- (4-hydroxy-3-methoxybenzyl) acetamide; N - [(4'-Hydroxybiphenyl-4-yl) methyl] -2- (3- { 2 - [((2R) -2-hydroxy-2-. {4-hydroxy-3- [ (methylsulfonyl) amino] phenol.} ethyl) amino] -2-methylpropyl] phenyl) acetamide; N- (4-Chloro-2-hydroxybenzyl) -2- (3- {2 - [((2R) -2-hydroxy-2-. {4-hydroxy-3- [(methylsulfonyl) amino] phenyl) .}. ethyl) amino] -2-methylpropyl. phenyl) acetamide; N- (4-Hydroxy-3,5-dimethylbenzyl) -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) -N - [(2-hydroxy-1-naphthyl) methyl] acetamide; 2- (3- {2 - [((2R) -2-Hydroxy-2-. {4-hydroxy-3 - [(methylsulfonyl) amino] phenyl} ethyl) amino] -2-methylpropyl} phenyl) -N - [(6-hydroxy-2-naphthyl) methyl] acetamide; N - [(4'-Hydroxybiphenyl-3-yl) methyl] -2- (3- { 2 - [((2R) -2-hydroxy-2-. {4-hydroxy-3 - [(methylsulfon L) amino] phenyl, ethyl) amino] -2-methylpropyl, phenyl) acetamide; N - [(3'-Hydroxybiphenyl-3-yl) methyl] -2- (3- { 2 - [((2R) -2-hydroxy-2 { 4-hydroxy-3 - [( methylsulphonyl) amino] phenyl} etl) amino] -2-methylpropyl. phenyl) acetamide; 2- (3- {2 - [((2R) -2-Hydroxy-2-. {4-hydroxy-3- [(methylsulfonyl) amino] phenyl} ethyl) amino] -2-methylpropyl} phenyl] -N- [2- (4-hydroxy-phenyl) -2-methylpropylactatamide; N- (3,5-Dichloro-2-hydroxybenzyl) -N-ethyl-2- (3-. {2 - [((2?) - 2-hydroxy-2-. {4-hydroxy-3 - [(methylsulfonyl) amino] phenyl] ethyl) amino] -2-methy1propyl. phenyl) acetamide; 2- (3- {2 - [((2R) -2-Hydroxy-2-. {4-hydroxy-3 - [(methylsulfonyl) amino] phenyl] ethyl) amino] -2-methylpropyl} phenyl) -N - [(6-hydroxy-1-naphthyl) methyl] -N-methylacetamide; N - [(2'-Hydroxybiphenyl-3-yl) methyl] -2- (3. {2 - [((2R) -2-hydroxy-2-. {4-hydroxy-3 - [(methylsulfonyl ) amino] phenyl} ethyl) amino] -2-methylpropyl} phenyl) acetamide; N- (2-Hydroxy-5- { (1R) - -hydroxy-2 - [(2- {3- [2- (6-hydroxy-3,4-dihydroisoquinolyl-2 (1H)} -yl) -2-oxoethyl] phenyl] -1-, 1-dimethylethyl) amino] etl.} phenyl) methanesulfonamide; 2- (3- {2 - [((2) -2-Hydroxy-2-. {4-hydroxy-3 - [(methylsulfonyl) amino] phenyl} ethyl) amino] -2-methylpropyl} phenyl) -N- [4- (4-hydroxyphenyl) butyl] acetamide; 2- (3- {2 - [((2R) -2-Hydroxy-2-. {4-hydroxy-3- [(methylsulfonyl) amino] phenyl}. Et.l) amino] -2- methylpropyl, phenyl) -N- [2- (4-hydroxyphenyl) ethyl] acetamide; N- (2-Chloro-4-hydroxybenzyl) -2- (3- { 2 - [((2R) -2-hydroxy-2. {4-hydroxy-3 - [(methylsulfonyl) amino] phenyl.}, ethyl) amino] -2-methylpropyl, phenyl) acetamide; N- (3,5-Dichloro-4-hydroxybenzyl) -2- (3- { 2 - [((2R) -2-hydroxy-2-. {4-hydroxy-3 - [(methylsulfonyl) amino] ] phenyl] ethyl) amino] -2-methylpropyl, phenyl) acetamide; N- (2,3-Dichloro-4-hydroxybenzyl) -2- (3- { 2 - [((2) -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} etl) amino] - 2-methylpropyl] phenol) -N - [(4-hydroxy-1-naphthyl) methyl] acetamide; 2- (3- {2 - [((2R) -2-Hydroxy-2-. {4-hydroxy-3- [(methylsulfonyl) amino] phenyl} ethyl) amino] -2-methylpropyl} phenol) -N- [3-hydroxy-5- (trifluoromethyl) benzyl] acetamide; N- (2-Chloro-4-hydroxybenzyl) -N-ethyl-2- (3-. {2- 2- [((2) -2-hydroxy-2-. {4-hydroxy-3 - [(methylsulfonyl)] ) amino] phenyl} etl) amino] -2-methylpropyl.} phenyl) acetamide; N- (2-Chloro-4-hydroxybenzyl) -2- (3- {2 - [((2R) -2-hydroxy-2-. {4-hydroxy-3 - [(methylsulfonyl) amino] phenyl) .) ethyl) amino] -2-methylpropyl. phenyl) -N-methylacetamide; N- (3-Fluoro-5-hydroxybenzyl) -2- (3- { 2 - [((2R) -2-hydroxy-2-. {4-hydroxy-3 - [(methylsulfonyl) amino] phenyl) .) ethyl) amino] -2-methylpropyl. phenyl) -N-methylacetamide; N - [(2, -Hydroxybiphenyl-2-yl) methyl] -2- (3- { 2 - [((2R) -2-hydroxy-2-. {4-hydroxy-3 - [(methylsulfonyl ) amino] phenyl} ethyl) amino] -2-methylpropyl. phenyl) acetamide; N - [(3'-Hydroxybiphenyl-2-yl) methyl] -2- (3. {2 - [((2R) -2-hydroxy-2-. {4-hydroxy-3 - [(methylsulfonyl ) amino] phenyl} ethyl) amino] -2-methylpropyl.] phenol) acetamide; N- (4-Hydroxy-2,6-dimethylbenzyl) -2- (3. {2 - [((2R) -2-hydroxy-2-. {4-hydroxy-3 - [( methylsulfonyl) amino] phenyl, ethyl) amino] -2-methylpropyl, phenyl, acetamide; ? / - (2- Hydroxy-5- { (1 R) -1-hydroxy-2 - [(2- {3- [2- (7-hydroxy-3,4-d-hydroxisoquinoline-2) (1 H) -? \) - 2-oxoethyl] phenyl] -1, 1-d-methylethyl) amino] ethyl} phenyl) methanesulfonamide; ? / - (2-Hydroxy-5 { (7R) -1-hydroxy-2 - [(2- {3- [2- (5-hydroxy-3,4-dihydroxyquinoline- 2 (1H) -yl) -2-oxoethyl] phenyl] -1, 1-dimethylethyl) amino] ethyl} phenyl) methanesulfonamide; 2- (3- {2 - [((2R) -2-Hydroxy-2- { 4-hydroxy-3 - [(methylsulfonyl amino] phenyl] et.l) amino] -2 -methylpropyl] phenyl) -? / - [(1 R) -2-hydroxy-1-phenyletyl] acetamide; 2- (3-. {2 - [((2R ) -2- Hydroxy-2-. {4-hydroxy-3 - [(methylsulfonyl) amino] phenol.] Etl) amino] -2-methylpropyl} phenyl) -? / - [(1 S) -2-hydroxy-1-phenyletyl] acetamide; ? / - [(3'-Hydroxybiphenyl-4-yl) methyl] -2- (3- { 2 - [((2R) -2-hydroxy-2- { 4-hydroxy-3 - [( methylsulfonyl) amino] phenol, ethyl) amino] -2-methylpropyl, phenyl) acetamide; ? / - [(2'-Hydroxybiphenyl-4-yl) methyl] -2- (3- { 2 - [((2R) -2-hydroxy-2-. {4-hydroxy-3 - [( methylsulfonyl) amino] phenyl, ethyl) amino] -2-methylpropyl, phenyl) acetamide; ? / - [(4'-Hydroxy-phenyl-4-yl) methyl] -3-. { 2 - [((2R) -2-hydroxy-2- {4-hydroxy-3 - [(methylsulfonyl) amino] phenyl} ethyl) amino] -2-methy1propyl} benzamide; 3- . { 2 - [((2R) -2-Hydroxy-2-. {4-hydroxy-3 - [(methylsulfonyl) amino] phenyl} ethyl) amino] -2-methylpropyl} -? / - [2- (4-hydroxyphenyl) -2-methylpropyl] benzamide; ? / - [(4'-Hydroxybiphenyl-3-yl) methyl] -3-. { 2 - [((2R) -2-hydroxy-2-. {4-hydroxy-3- [(methylsulfonyl) amino] phenyl} ethyl) amino] -2-methy1propyl} benzamide; ? / - [2- (4-Hydroxy-2,5-dimethylphenyl) ethyl] -3-. { 2 - [((2R) -2-hydroxy-2-. {4-hydroxy-3- [(methylsulfonyl) amino] phenyl] ethyl) amino] -2-methy1propyl} benzamida; ? / - [2- (4-Hydroxy-2,3-dimethylphenyl) ethyl] -3-. { 2 - [((2R) -2-Hydroxy-2-. {4-hydroxy-3 - [(methylsulfonyl) amino] phenyl} ethyl) amino] -2-methy1propyl} benzamida; and, 3-. { 2 - [((2R) -2- Hydroxy-2. {4-hydroxy-3 - [(methylsulfonyl) amino] phenyl} ethyl) amino] -2-methylpropyl} -? / - [2- (4-hydroxy-3-methylphenyl) ethyl] benzamide.

16.-? / - [(4, -Hydroxybiphenyl-4-yl) methyl] -2- (3- {2 - [((2R) -2-hydroxy-2-. {4-hydroxy) -3 - [(methylsulfonyl) amino] phenyl.} Ethyl) amino] -2-methylpropyl. Phenyl) acetamide.

17.-? / - [(4, -Hydroxybiphenyl-3-yl) methyl] -2- (3- { 2 - [((2R) -2-hydroxy-2-. {4-hydroxy-3 - [(methylsulfonyl) amino] phenyl.} ethyl) amino] -2-methylpropyl. phenyl) acetamide.

18. 2- (3- {2 - [((2R) -2-Hydroxy-2- {4-hydroxy-3- [(methylsulfonyl) amino] phenyl} ethyl) amino] -2 -methylpropyl.} phen.l) -? / - [2- (4-hydroxyphenyl) -2-methylpropyl] acetamide.

19.-? / - [(3'-Hydroxybiphenyl-3-yl) methyl] -2- (3- { 2 - [((2R) -2-hydroxy-2-. {4-hydroxy-3 - [(methylsulfonyl) amino] phenyl.} ethyl) amino] -2-methylpropyl] phenyl) acetamide.

20.-? / - (3,5-D-chloro-2-hydroxybenzyl) -? / - ethyl-2- (3- { 2 - [((2R) -2-hydrox¡- 2-. { 4-hydroxy-3 - [(methylsulfonyl) amino] phenyl] ethyl) amino] -2-methylpropyl, phenyl) acetamide.

21. A pharmaceutical composition comprising a compound of formula (1) as described in any one of claims 1 to 20 or a pharmaceutically acceptable salt or derivative thereof, together with customary pharmaceutically acceptable excipients and / or additives.

22. A compound of formula (1) as described in any one of claims 1 to 20 or a pharmaceutically acceptable salt thereof, derivative form or composition thereof, for use as a medicament.

23. A compound of formula (1) as described in any one of claims 1 to 20 or a pharmaceutically acceptable salt thereof, derivative form or composition thereof, for use in the treatment of diseases, disorders and conditions in which is involved in the ß2 receptor.

24. A compound of formula (1) as described in any one of claims 1 to 20 or a pharmaceutically acceptable salt thereof, derivative form or composition thereof, for use in the treatment of selected diseases, disorders and conditions. among the group consisting of: • asthma of any type, etiology or pathogenesis, in particular asthma that is a member selected from the group consisting of atopic asthma, non-atopic asthma, allergic asthma, bronchial atopic asthma mediated by IgE, bronchial asthma, asthma essential, true asthma, intrinsic asthma caused by pathophysiological alterations, extrinsic asthma caused by environmental factors, essential asthma of unknown or non-obvious origin, non-atopic asthma, bronchitic asthma, emphysematous asthma, exercise-induced asthma, allergen-induced asthma, asthma induced by cold air, occupational asthma, infectious asthma caused by infection by bacteria, fungi, protozoa or viruses, asthma non-allergic, incipient asthma, infantile wheezing syndrome and bronchiolitis, • chronic or acute bronchoconstriction, chronic bronchitis, obstruction of the small airways and emphysema, • obstructive or inflammatory diseases of the respiratory tract of any type, etiology or pathogenesis, in particular an obstructive or inflammatory respiratory disease which is a member selected from the group consisting of chronic eosinophilic pneumonia, chronic obstructive pulmonary disease (COPD), COPD including chronic bronchitis, pulmonary emphysema or dyspnea associated or not associated with COPD , COPD characterized by progressive irreversible obstruction of the respiratory tract, respiratory distress syndrome in adults (ARD), exacerbation of airway hyperreactivity after therapy 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 laryngotracheal bronchitis, arachidic bronchitis, catarrhal bronchitis, crupal bronchitis, dry bronchitis, infectious asthmatic bronchitis, productive bronchitis, bronchitis staphylococcal or streptococcal and vesicular bronchitis, • acute damage to the lung, • bronchiectasis of any type, etiology or pathogenesis, in particular bronchiectasis that is a member selected from the group consisting of cylindrical bronchiectasis, bronchiectasis sacculate, fusiform bronchiectasis, capillary bronchiectasis, cystic bronchiectasis, dry bronchiectasis and follicular bronchiectasis.

25. The use of a compound of formula (1) as described in any one of claims 1 to 20 or of a pharmaceutically acceptable salt, derivative form or composition thereof, for the manufacture of a drug having agonist activity ß2.

26. The use of a compound of formula (1) as described in any one of claims 1 to 20 or a pharmaceutically acceptable salt, solvate or composition thereof, for the manufacture of a drug for the treatment of diseases , disorders and conditions selected from the group described in claim 24.

27.- A process for the preparation of a compound of formula (1) according to any one of claims 1 to 20, said method comprising the following steps: a) coupling an acid of formula (2): , Wherein R R and n are as defined in claim 1, with an amine of formula NR8-Q2-A (3), wherein R3 to R6, R8, Q2 and A are as defined in claim 1, (b) isolating said compound of formula (1).

28. The process for the preparation of a compound of formula (1) according to claim 1, further characterized in that R1 and R2 are methyl and n is 1, said process comprising the following steps (a) reacting a compound of formula (twenty-one) wherein X is H, K, Na, Li 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-ethylcarbodimide hydrochloride or dicyclohexylcarbodiimide in a suitable solvent such as pyridinedimethylformamide and dimethylacetamide optionally in the presence of an organic base and an additive to obtain said compound of formula (1), (b) isolating said compound of formula (1).

29. The process according to claim 28, further characterized in that said compound of formula (21) is obtained by hydrogenation of a compound of formula (22) wherein X is H, Na, Li or K and potentially an organic amine or other metal salts, in the presence of a suitable solvent such as methanol, IPA, THF and water and in the presence of a suitable catalyst such as hydride of palladium on carbon or palladium on carbon.

30. The process according to claim 29, further characterized in that said compound of formula (22) is obtained by reacting a compound of formula (23) C 1-4 alkyl (23) with M-OH where M is selected from Na, K or Li, optionally in the presence of a suitable solvent such as propionitrile, tetrahydrofuran or dioxane.

31. The process according to claim 30, further characterized in that said compound of formula (23) is obtained by deprotecting a compound of formula (24) using a deprotecting agent such as tetrabutylammonium fluoride, HF, or triethylamine trifluorohydrate in the presence of a suitable solvent such as propionitrile.

32. The method according to claim 31, further characterized in that said compound of formula (24) is obtained by reacting a compound of formula with a compound of 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 hydrogen carbonate, potassium hydrogen carbonate, Hunig base. or triethylamine, at a temperature between 50 ° C and 150 ° C for 12 to 36 hours.

33. The combination of a compound according to any one of claims 1 to 20 with another therapeutic agent (s) selected from: (a) 5-lipoxygenase (5-LO) inhibitors or antagonists of the activation protein of 5-lipoxygenase (FLAP), (b) leukotriene antagonists (LTRA) including LTB, LTC, LTD4 and LTE antagonists? (c) histamine receptor antagonists, including H1 and H3 antagonists. (d) vasoconstrictive and sympathomimetic agonist agents of the adrenoreceptor ai and a2 for decongestant use, (e) antagonists of the muscarinic M3 receptor or anticholinergic agents, (f) PDE inhibitors, eg inhibitors of PDE3, PDE4 and PDE5, (g) theophylline (h) sodium cromoglycate, (i) COX inhibitors, both selective and non-selective inhibitors of COX-1 or COX-2 (NSAIDs), (j) oral and inhaled glucocorticosteroids, such as DAGR (dissociated agonists of the corticoid receptor) (k) ) monoclonal antibodies active against endogenous inflammatory entities, (I) anti-tumor necrosis factor agents (anti-TNF-a), (m) inhibitors of adhesion molecules including VLA-4 antagonists, (n) receptor antagonists Quinine-Br and B2 (o) immunosuppressive agents, (p) matrix metalloprotease inhibitors (MMPs), (q) tachykinin receptor antagonists NK ^ NK2 and NK3 (r) elastase inhibitors, (s) adenosine A2a receptor agonists, (t) urokinase inhibitors , (u) compounds acting on dopamine receptors, for example D2 agonists, (v) modulators of the NFkβ pathway, for example IKK inhibitors, (w) modulators of cytokine signaling pathways such as p38 kinase inhibitors MAP, kinase syk or JAK kinase, (x) agents that can be classified as mucolytic or anti-tusive, and (and) antibiotics.