ES2343808T3 - FORMAT DERIVATIVES USEFUL AS ADRENOCEPTORS. - Google Patents

Abstract

A compound of general formula (1), ** (See formula) ** in which the group (CH2) nC (= O) Q1 is in the meta position or for, - R1 and R2 are independently selected from H and alkyl C1-C4; - n is 0, 1 or 2; - Q1 is a group selected from, ** (See formula) ** in which p is 1 or 2 and q is 1 or 2, said group being optionally linked by a carbon atom, ** (See formula) ** and a * -NR8-Q2-A group, wherein Q2 is a C1-C4 alkylene, R8 is H or C1-C4 alkyl and A is pyridyl, C3-C10 cycloalkyl, said alkyl being optionally linked by one or more atoms of Carbon, tetrahydropyranyl, piperidinyl, tetrahydrothiopyranyl or a group ** (See formula) ** - R3, R4, R5, R6 and R7 are the same or different and are selected from H, C1-C4 alkyl, OR9, SR9, SOR9, SO2R9 , halo, CN, CO2R9, CF3, OCF3, SO2NR9R10, CONR9R10, NR9R10, NHCOR10 and phenyl optionally substituted with 1 to 3 groups selected from OR9, halo and C1-C4-R9 and R10 alkyl are the same or different and are selected from H or C1-C4 alkyl and the * represents the point of attachment to the carbonyl group; or, when appropriate, its pharmaceutically acceptable salts and / or isomers, tautomers, solvates or isotopic variations.

Description

Formamide derivatives useful as adrenoceptors

The present invention relates to agonists of β2 of general formula:

one

in which R 1, R 2, n and Q1 have the meanings indicated below, a procedures for its preparation, to compositions that contain and to the uses of said derivatives.

Adrenoceptors are members of the great G protein-coupled receptor superfamily itself adrenoceptor superfamily is divided into the subfamily? and? making up the? subfamily of at least three receptor subtypes: β1, β2 and β3. These receptors show differential expression patterns in tissues of various mammalian systems and organs. Receivers β2 adrenergic agents (β2) are expressed primarily in the smooth muscle cells (for example, vascular smooth muscle, bronchial, uterine or intestinal) while the receptors β3 adrenergic agents are expressed primarily in tissues fatty (therefore, β3 agonists could be potentially useful in the treatment of obesity and diabetes) and β1 adrenergic receptors are expressed primarily in cardiac tissues (therefore, β1 agonists are mainly used as cardiac stimulants).

Pathophysiology and treatments of airway diseases have been extensively reviewed in the bibliography (for reference see Barnes, P.J. Chest, 1997, 11: 2, p. 17S-26S y Bryan, S.A. et al, Expert Opinion on investigational drugs, 2000, 9: 1, p. 25-42) and, therefore, only one Brief summary in this document to provide some information previous.

Glucocorticosteroids, anti-leukotrienes, theophylline, chromones, β2 anticholinergics and agonists constitute classes of drugs that are currently used to treat allergic diseases or non-allergic respiratory tract such as asthma and chronic obstructive pulmonary disease (COPD). The orientations for the treatment of these diseases include agonists of Inhaled β2 both short and long acting. The fast-acting, short acting β2 agonists will used to "rescue" bronchodilation, while Long acting forms provide prolonged relief and are used As maintenance therapy.

Bronchodilation is mediated by β2 adrenoceptor agonism expressed in the cells of the smooth musculature of the airways, resulting in relaxation and therefore bronchodilation. Therefore, as Functional antagonists, β2 agonists can prevent and reverse the effects of all bronchoconstrictor substances, including leukotriene D4 (LTD4), acetylcholine, bradykinin, prostaglandins, histamine and endothelin. Because the β2 receptors are so widely distributed in the pathways respiratory, β2 agonists can also affect other types of cells that play a role in asthma. By example, it has been described that β2 agonists can stabilize mast cells. The inhibition of the release of bronchoconstrictor substances can be how agonists of β2 block allergen-induced bronchoconstriction, Exercise and cold air. Additionally, β2 agonists inhibit cholinergic neurotransmission in the respiratory tract of human beings, which result in reduced bronchoconstriction Cholinergic reflex.

In addition to the airways, it has also established that β2 adrenoceptors are also expressed in other organs and tissues and therefore the 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 delivery, congestive heart failure, depression, diseases inflammatory and skin allergies, psoriasis, diseases proliferative dermal, glaucoma and in conditions in which there are an advantage decreasing gastric acidity, particularly in gastric and peptic ulcers.

However, numerous β2 agonists are limited to its use due to its low selectivity or effects Adverse side effects leading to high systemic exposure and mainly mediated through the action of β2 adrenoceptors expressed outside the respiratory tract (muscle tremor, tachycardia, palpitations, agitation). For the There is so much a need for improved agents of this class.

Therefore, there is still a need for new β2 agonists that would have a pharmacological profile appropriate, for example in terms of power, selectivity, Pharmacokinetics or duration of action. In this context, the The present invention relates to new β2 agonists.

Various derivatives of formamide For example, document US2004 / 0006102 describes active compounds as β2 agonists of formula:

2

US2003 / 0229058 describes agonists Selective β2 formula:

3

The document EP-A-1235787 describes agonists of β2 of formula (I):

(I) (L) p (X) q

Document CH 686 869 A describes agonists of β2 containing the following structural fragment:

4

The document ES-A-2 005 492 describes a procedure for the preparation of

5

However, none of the derivatives of Previous formamide has shown a pharmacological profile that allows  used as effective drugs in the treatment of β2 mediated diseases and / or conditions, such as allergic and non-allergic diseases of the respiratory tract; in particular by inhalation route.

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

6

in which the group (CH 2) n -C (= O) Q 1 is at the target position or for,

-

R1 and R2 are selected independently between H and alkyl C 1 -C 4;

-

n is 0, 1 or 2;

-

Q1 is a selected group between,

7

where p is 1 or 2 and q is 1 or 2, said group being optionally linked by a carbon atom,

8

and a group * -NR 8 -Q 2 -A, in which Q 2 is a C 1 -C 4 alkylene, R 8 is H or C 1 -C 4 alkyl and A is pyridyl, C 3 -C 10 cycloalkyl, said alkyl being optionally linked by one or more, preferably 1, 2, 3 or 4, carbon atoms, tetrahydropyranyl, piperidinyl, tetrahydrothiopyranyl or a group

9

-

R 3, R 4, R 5, R 6 and R 7 are the same or different and are selected from H, alkyl C 1 -C 4, OR 9, SR 9, SOR 9, SO 2 R 9, halo, CN, CO 2 R 9, CF 3, OCF 3, SO 2 NR 9 R 10, CONR 9 R 10, NR 9 R 10, NHCOR 10 and phenyl optionally substituted with 1 to 3 groups selected from OR9, halo and alkyl C_ {1} -C_ {4}

-

R 9 and R 10 are the same or different and are selected from H or alkyl C_ {1} -C_ {4} and * represents the junction point to the carbonyl group;

or, whenever appropriate, its pharmaceutically acceptable salts and / or isomers, tautomers, solvates or isotopic variations of same.

The compounds of formula (1) are agonists of β2 receptors, which are particularly useful for treatment of diseases and / or conditions mediated by β2, showing excellent power, particularly how much administered by inhalation route.

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

C3-C10 cycloalkyl in which 2 or more carbon atoms are optionally linked by one or more carbon atoms including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, bicyclo [3.1.1] heptane, bicyclo [2.2.1] heptane, bicycle [2.2.2] octane. They are cycloalkyl groups Preferred cyclohexyl and adamantyl.

Finally, the term halo represents an atom of halogen selected from the group consisting of fluorine, chlorine, bromine and iodine, in particular fluorine or chlorine.

In the following, the free link in the group phenyl as in the structure shown below,

10

it means that phenyl can be substituted in the target position or for.

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The compounds of formula (1)

eleven

can be prepared using conventional procedures, such as by the following illustrative procedures in which Q1, Q2, R1, R2, A and n are as defined above for the compounds of formula (1) unless another is indicated thing.

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The amide derivatives of formula (1) can be prepared by coupling an acid of formula (2):

12

with an amine of formula NHR 8 -Q 2 -A (3),

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13

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The coupling is generally carried out in an excess of said amine in the form of an acid receptor, with a conventional coupling agent (for example, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, N, N'- dicyclohexylcarbodiimide or O- (1 H -benzotriazol-1-yl) - N, N, N ', N ' -tetramethyluronium hexafluorophosphate), optionally in the presence of a catalyst (for example, 1-hydroxy-benzotriazole hydrate or 1-hydroxy-7- azabenzotriazole), and optionally in the presence of a tertiary amine base (for example, N- methylmorpholine, triethylamine or diisopropylethylamine). The reaction can be carried out in a suitable solvent such as pyridine, dimethylformamide, tetrahydrofuran, dimethylsulfoxide, 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 '), (3'') or (3''') is commercially available or can be prepared by conventional procedures well known to those skilled in the art (for example, reduction, oxidation, alkylation, transition metal-mediated coupling, protection, deprotection, etc ...) from materials available in the
market.

The acid of formula (2) can be prepared at from the corresponding ester of formula (4):

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14

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in which Ra is a protective group of suitable acid, preferably a benzyl group or a group (C 1 -C 4) alkyl, which includes, but is not limitation, methyl and ethyl, according to any procedure well known to those skilled in the art for preparing an acid to from an ester, without modifying the rest of the molecule. By For example, the ester can be hydrolyzed by treatment with an acid or aqueous base (e.g. hydrogen chloride, potassium hydroxide, sodium hydroxide or lithium hydroxide), optionally in the presence of a solvent or solvent mixture (for example, water, 1,4-dioxane, tetrahydrofuran / water), at a temperature between 20ºC and 100ºC, during a period of 1 at 40 hours Alternatively, if the ester is a benzyl group, the ester can be hydrogenated in the presence of a suitable catalyst (for example, palladium on carbon or palladium hydroxide on carbon) in a suitable solvent (such as methanol, ethanol, 2M ammonia in methanol) at a temperature between 20 ° C and 50 ° C for 1-48 h at 1-4 atmospheres from hydrogen.

The ester of formula (4) can be prepared by reaction of an amine of formula (5):

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fifteen

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in which Ra and n are as they have defined above, with a bromide of formula (6):

16

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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 solvent mixture (eg, dimethylsulfoxide, toluene, N , N- dimethylformamide, acetonitrile), optionally in the presence of a suitable base (for example, triethylamine, diisopropylethylamine, potassium carbonate) at a temperature between 80 ° C and 120 ° C, for 12 to 48 hours.

The bromide of formula (6) can be prepared from according to the procedure described in "Organic Process Research  and Development 1998, 2, 96-99 ".

The amine of formula (5), wherein R 1 is Me and R 2 is H, can be prepared as an enantiomer ( R ) or ( S ) from the corresponding protected amine of formula (7) :

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17

in which Ra and n are as they have defined above and Rb and Rc represent any substituent suitable so that HNRbRc is a chiral amine (for example, Rb it can be hydrogen and Rc can be α-methylbenzyl), with the proviso that links between N and Rb and N and Rc can be easily cleaved to give the free amine of formula (5) using the conventional methodology for the cleavage of nitrogen protecting groups, such as found in the Protective Groups in Organic textbook Synthesis Third Edition of T. W. Greene and P. G. M. Wuts, John Wiley and Sons Inc., 1999.

The amine of formula (7) can be prepared in form of an individual diastereomer by reaction of an amine of HNRbRc formula with a ketone of formula (8):

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18

in which Ra, Rb, Rc and n are like have been defined previously.

In a typical procedure, the reaction of the ketone of formula (8) with the amine of formula HNRbRc leads to a chiral intermediate that is reduced in turn with a reducing agent suitable (for example, sodium cyanoborohydride of formula NaCNBH 3 or sodium triacetoxyborohydride of formula Na (OAc) 3 BH) optionally in the presence of a drying agent (e.g. molecular sieves, sulfate magnesium) and optionally in the presence of an acid catalyst (for example, acetic acid) to give the amine of formula (7) in the form of  a mixture of diastereomers. The reaction is usually performed. in a solvent such as tetrahydrofuran or dichloromethane at a temperature between 20 ° C and 80 ° C for 3 to 72 hours. Then, the resulting product is converted into the hydrochloride or nitrate salt and selectively crystallized from a suitable solvent  or solvent mixture (for example, isopropanol, acetate ethyl, ethanol, methanol, diisopropyl ether or ether diisopropyl / methanol) to give (7) as a diastereomer individual.

The ketone of formula (8) in which n = 1 can be prepared by palladium-mediated coupling of a halide of aryl of formula (9):

19

in which Ra is as defined above and Hal represents a halogen atom, which includes, but without limitation, bromine and iodine, with an enolate or equivalent from enolato.

In a typical procedure, the aryl halide of formula (9) is reacted with a tin enolate generated in-situ by treatment of isopropenyl acetate with tri-n-butyltin methoxide of formula Bu 3 SnOMe in the presence of a suitable palladium catalyst (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 between 80 ° C and 110 ° C for a period of 6 to 16 hours.

The aryl halide of formula (9) can Obtained by esterification of the acid of formula (10) correspondent:

twenty

in which Hal is how it has been defined above, according to any procedure well known to the person skilled in the art for preparing an ester to from an acid, they are modifying the rest of the molecule.

In a typical procedure, the acid of formula (10) is reacted with an alcoholic solvent of formula RaOH, in which Ra is as defined above, in the presence of an acid such as hydrogen chloride at a temperature between 10 ° C and 40 ° C (room temperature) for 8 to 16 hours. Alternatively, the acid of formula (10) is reacted with a base (for example cesium or potassium carbonate) and treated with an alkyl halide (for example, methyl iodide, benzyl bromide) in an appropriate solvent such as N , N- dimethylformamide at a temperature between 10 ° C and 40 ° C (room temperature) for a period of 1 to 20 h.

The acid of formula (10) is a product available in the market.

The amine of formula (5), in which R1 and R 2 is the two C 1 -C 4 alkyl, it can Prepare according to the following scheme:

Scheme one

twenty-one

wherein R 1, R 2 and Ra are as defined previously.

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In a typical procedure, the ester of formula (11) is reacted with an "activated" alkyl (alkyl organometallic such as R2 MgBr, R2 MgCl or R2 Li) for give the corresponding tertiary alcohol of formula (12) using the procedure described above.

Then, said tertiary alcohol of formula (12) it is treated with an alkyl nitride (for example, acetonitrile, chloroacetonitrile) in the presence of an acid (for example, acid sulfuric acid, acetic acid) to give a protected intermediate that instead it is cleaved using the conventional methodology to split the nitrogen protecting group such as the one mentioned in the books of text. Then, the resulting amino acid is esterified using the procedure described herein to give the amine of formula (5).

Alternatively, the amine of formula (5), in the that R1 and R2 are both alkyl C_ {1} -C_ {4} and n = 0, can be prepared from according to the following scheme:

Scheme 2

22

wherein R 1, R 2 and Ra are as defined previously.

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In a typical procedure, the ester of formula (13) is reacted with an "activated" alkyl (alkyl organometallic such as R2 MgBr, R2 MgC or R2L) for give the corresponding tertiary alcohol of formula (14) using the procedure described above.

Then, said tertiary alcohol of formula (14) it is treated with a nitrile alkyl (for example, acetonitrile, chloroacetonitrile) in the presence of an acid (for example, acid sulfuric acid, acetic acid) to give a protected intermediate that Once it is cleaved using the conventional methodology to cleave the nitrogen protecting group as described in the books of text to give bromine amine (15).

The resulting bromine amine (15) is treated with a suitable palladium catalyst (for example, [1,1'-bis (diphenylphosphino) ferrocene] dichloropaladium  (II), palladium acetate (II) 1,1'-bis (diphenylphosphino) ferrocene], tris (dibenzylideneacetone) dipaladium (0), 2,2'-bis (diphenylphosphino) -1,1'-binaphthyldichloropaladium (II)) in an atmosphere of carbon monoxide using RaOH as solvent (for example, MeOH, EtOH, benzyl alcohol), or as alternative using a co-solvent such as DMF, to high temperature (100ºC) and high pressure (689.48 kPa (100 psi)) to give the ester of formula (5).

The ketone of formula (8) in which n = 2 can be prepared by reduction of an alkene of formula (16):

2. 3

In a typical procedure, a solution of the olefin of formula (16) in a suitable solvent (for example, methanol, ethanol, ethyl acetate) is treated with a catalyst of palladium (for example, 10% palladium on charcoal) and stir in a hydrogen atmosphere, optionally at elevated pressure (for example, 413.69 kPa (60 psi)), at a temperature between room temperature and 60 ° C for 8-24 hours.

The alkene of formula (16) can be prepared by a palladium-mediated coupling of an olefin activated with a aryl halide of formula (17):

24

In a typical procedure, the aryl halide (17) is coupled with a vinyl ester (for example, methyl acrylate) in the presence of a suitable palladium catalyst (for example, tetrakis (triphenylphosphine) palladium (0) of formula Pd ( PPh 3) 4, palladium / tri- ortho- tolylphosphine acetate of formula Pd (OAc) 2 / P (o-Tol) 3 or (diphenylphosphine) ferrocenyl palladium chloride of formula dppfPdCl2) in a suitable solvent (for example, acetonitrile, N , N- dimethylformamide, toluene), optionally in the presence of a base such as triethylamine at a temperature between 40 ° C and 110 ° C for a period of 8 to 24 hours.

The ketone of formula (17) is a product available in the market.

Alternatively, a compound of formula (1) it can be prepared by reacting a bromide of formula (6) and a formula amine (18):

25

in which R 1, R 2, Q 1 and n are as defined above for the compounds of formula (1) unless another is indicated thing.

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In a typical procedure, the amine of formula (18) is reacted with a bromide of formula (6) optionally in the presence of a solvent or solvent mixture (for example, dimethyl sulfoxide, toluene, N , N- dimethylformamide, acetonitrile), optionally in the presence of a suitable base (for example, triethylamine, diisopropylethylamine, potassium carbonate) at a temperature between 80 ° C and 120 ° C, for a period of 12 to 48 hours.

The amide of formula (18) can be prepared by coupling of an acid of formula (19) incorporating a group Suitable P1 amine protector:

26

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with an amine of formula NHR 8 -Q 2 -A (3),

27

Generally, the coupling is carried out in an excess of said amine in the form of an acid receptor, with a conventional coupling agent (for example, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride or N, N'- dicyclohexylcarbodiimide) , optionally in the presence of a catalyst (for example, 1-hydroxybenzotriazole hydrate or 1-hydroxy-7-azabenzotriazole) and optionally in the presence of a tertiary amine base (for example, N- methylmorpholine, triethylamine or diisopropylethylamine). The reaction can be carried out in a suitable solvent such as pyridine, N , N- 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 '), (3' ') and (3' '') is commercially available or can be prepared by procedures conventional well known by a person skilled in the art (for example, reduction, oxidation, alkylation, catalyzed coupling by transition metal, protection, unprotection, etc ...) from of a material available in the market.

The acid of formula (19) can be prepared at from the corresponding ester of formula (5).

The acid of formula (19), wherein R 1 and R 2 are both C 1 -C 4 alkyl, may be prepared from the ester (5) that incorporates a protective group of suitable P1 amine before or after acid formation:

28

in which Ra is a protective group of suitable acid, preferably an alkyl group (C_ {1} -C_ {4}), which includes, but without limitation, methyl and ethyl, according to any procedure well known to a person skilled in the art for preparing an acid from an ester, without modifying the rest of the molecule. By For example, the ester can be hydrolyzed by treatment with an acid or aqueous base (e.g. hydrogen chloride, potassium hydroxide, sodium hydroxide or lithium hydroxide), optionally in the presence of a solvent or solvent mixture (for example, water, 1,4-dioxane, tetrahydrofuran / water), at a temperature between 20ºC and 100ºC, during a period of 1 to 40 hours.

The amine of formula (5), in which R1 and R2 are the two Hs, can be prepared according to the following scheme:

Scheme 3

29

wherein R 1, R 2 and Ra are as defined previously.

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

Then, said primary alcohol of formula (21) it becomes a leaving group such as mesylate, tosylate, bromide or iodide and moves with a suitable nucleophilic amine. He Preferred nucleophile is an azide ion that can then be reduced to give the primary amine by hydrogenation or with triphenylphosphine. Alternative nucleophiles may include ammonia or alkylamines such as benzylamine or allylamine and subsequently the cleavage of the alkyl group to form the amine.

30

Alternatively, the amide of formula 22 may be prepared as described above using conventional amine bond formation reactions. Then, the compound of formula 22 can be reacted with a protected vinylamine (for example, N- vinylphthalimide) in the presence of a suitable catalyst (for example, palladium (II) acetate) and a phosphine (for example, triphenylphosphine, tri- ortho- tolylphosphine) in the presence of a base (for example, N, N-diisopropylethylamine) in a solvent (for example, N, N-dimethylformamide, acetonitrile) at a temperature between 20 ° C and 120 ° C and for a period of 1 to 48 hours. Then, the alkene of formula 23 can be reduced to give an alkane of formula 24 using conventional hydrogenation conditions and the phthalimide protecting group is removed using a conventional protecting group. The amine of formula 25 can be reacted with a bromide of formula 6 to give a compound of formula 1 using the conditions described above.

For some of the stages of the procedures of preparation of the compounds of formula (1) described earlier in this document, it may be necessary to protect potentially reactive functions that you don't want to react, and consequently split said protecting groups. In that case, any compatible protective radical can be used. In particular, you can use protection and deprotection procedures such as described by T. W. Greene and P. G. M. Wuts (Protective Groups in Organic Synthesis, John Wiley and Sons Inc., 1999) or by P. J. Kocienski (Protecting groups, Georg Thieme Verlag, 1994).

All previous reactions and preparations of new starting materials used in previous procedures are conventional and the reagents and appropriate reaction conditions for its preparation or preparation  as well as the procedures to isolate the desired products will be well known to those skilled in the art with reference to bibliographic precedents and to the examples and preparations that are They find in them.

In addition, the compounds of formula (1), as well as the intermediates for the preparation thereof, may purified according to various well known procedures, such as, for example, crystallization or chromatography.

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

Preferably, Q1 is a group * -NH-Q2 -A, in which A is cyclohexyl or adamantyl.

Preferably, Q1 is

31

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or

310

in which R 3, R 4, R 5 and R 6 are H.

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Preferably, Q1 is

32

in which one from R 3 to R 6 it's OH and the rest are H.

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Preferably, Q1 is a group * -NH-Q2 -A, in which A is a group

33

in which R 3, R 4, R 5, R 6 and R 7 are the same or different and are selected between H, C 1 -C 4 alkyl, OR 9, SR 9, SOR 9, SO 2 R 9, halo, CN, CO 2 R 9, CF 3, OCF 3, SO 2 NR 9 R 10, CONR 9 R 10, NR 9 R 10, NHCOR 10 and optionally substituted phenyl with 1 to 3 groups selected from OR9, halo and alkyl C_ {1} -C_ {4} with the condition that at least 2 from R 3 to R 7 are equal to H; in which R 9 and R 10 they are the same or different and are selected from H or alkyl C_ {1} -C_ {4}.

More preferably, Q1 is a group * -NH-Q2 -A, in which A is a group

3. 4

in which R 3, R 4, R 5, R 6 and R 7 are the same or different and are selected between H, OH, CH 3, OCH 3, OCF 3, OCH_ {2} -CH_ {3}, SCH 3, N (CH 3) 2, N (C = O) CH 3, C (= O) NH 2, COOCH 3, SO 2 CH 3, SO 2 NH 2, halo, CN, CF 3 and phenyl optionally substituted with OH with the proviso that at least 2 from R 3 to R 7 are equal to H.

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In a preferred embodiment, A is a group

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35

in which one of R 3 to R 7 is OH or phenyl substituted with OH

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In a preferred embodiment, A is a group

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36

in which one of R 3 to R 7 is OH or substituted phenyl OH and the other is selected from H, Cl or CH 3 provided that at least 2 of R 3 to R 7 are H.

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Preferably, A is optionally naphthyl substituted with OH.

Preferably, A is naphthyl substituted with OH

In the groups of previous compounds, Particularly prefer the following substituents:

Q2 is -CH 2 -, - (CH 2) 2 -, - (CH 2) 3 -, -CH 2 -C (CH 3) 2 - or -C (CH 3) 2 -, preferably -CH_ {2} - or - (CH 2) 2.

R1 is H or C 1 -C 4 alkyl and R 2 is alkyl C_ {1} -C_ {4}. More preferably, R1 is H or CH 3 and R 2 is H or CH 3.

n is 0 or one.

R1 is H, R2 is CH3 and n is 0 or 1.

R1 is CH 3, R 2 is CH 3 and n is 0 or 1.

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Particularly preferred are the compounds of formula (1) described in the Examples section below in this document, that is:

N -Benzyl-2- (3- {2 - [(2 R ) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} phenyl) acetamide;

N - (3,4-Dimethylbenzyl) -2- (3- {2 - [(2 R ) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} phenyl) acetamide;

N - [2- (4-Chlorophenyl) ethyl] -3- {2 - [(2 R ) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} ben-
zamide;

N - [2- (2-Chlorophenyl) ethyl] -3- {2 - [(2 R ) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} ben-
zamide;

3- {2 - [(2 R ) -2- (3-Formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} - N - (2-naphthalen-1-ylethyl) benzamide;

3- {2 - [(2 R ) -2- (3-Formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} - N - [2- (4-methylphenyl) ethyl] benzamide;

N - [2- (2,6-Dimethylphenyl) ethyl] -3- {2 - [(2 R ) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methyl-propyl} benzamide ;

N - [2- (2,3-Dimethylphenyl) ethyl] -3- {2 - [(2 R ) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methyl-propylbenzamide;

3- {2 - [(2 R ) -2- (3-Formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} - N - [2- (4-hydroxy-2,3-dimethylphenyl) ethyl ]benzamide;

3- {2 - [(2 R ) -2- (3-Formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} - N - [2- (4-methoxyphenyl) ethyl] benzamide;

3- {2 - [(2 R ) -2- (3-Formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} - N -phenethyl-benzamide;

N- Cyclohexylmethyl-3- {2 - [(2 R ) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} benzamide;

N - [5 - ((1 R ) -2- {1,1-Dimethyl-2- [3- (piperidine-1-carbonyl) phenyl] ethylamino} -1-hydroxyethyl) -2-hydroxyphenyl] formamide;

3- {2 - [(2 R ) -2- (3-Formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} - N - [2- (3-trifluoromethylphenyl) ethyl] benzamide;

3- {2 - [(2 R ) -2- (3-Formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} - N - (3-phenylpropyl) benzamide;

3- {2 - [(2 R ) -2- (3-Formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} - N -indan-2-ylbenzamide;

3- {2 - [(2 R ) -2- (3-Formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} - N - (2-pyridin-2-ylethyl) benzamide;

3- {2 - [(2 R ) -2- (3-Formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} - N - [2- (4-sulfamoylphenyl) ethyl] benzamide;

N - (4-Dimethylaminobenzyl) -2- (3 - {(2 R ) -2 - [(2 R ) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] propyl} phenyl) acetamide;

N - [5- (2 - {(1 R ) -2- [3- (3,4-Dihydro-1H-isoquinoline-2-carbonyl) -phenyl] -1,1-dimethyl-ethylamino} -1-hydroxyethyl ) -2-hydroxyphenyl] formamide;

3- {2 - [(2 R ) -2- (3-Formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} - N - (4'-hydroxybiphenyl-3-yl-methyl) benzamide

3- {2 - [(2 R ) -2- (3-Formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} - N - [2- (4-hydroxy-2,5-dimethylphenyl) ethyl ]benzamide;

3- {2 - [(2 R ) -2- (3-Formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} - N - [2- (4-hydroxy-3-methyl-phenyl) ethyl ]benzamide;

N - (4-Acetylaminobenzyl) -2- (3 - {(2 R ) -2 - [(2 R ) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] propyl} phenyl) acetamide;

4 - {[2- (3 - {(2 R ) -2 - [(2 R ) -2- (3-Formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] propyl} phenyl) acetylamino] methyl} benzamide;

N -Adamantan-1-yl-3- {2 - [(2 R ) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} benzamide;

3- {2 - [(2 R ) -2- (3-Formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} - N - (2-hydroxy-naphthalen-1-ylmethyl) benzamide;

3- {2 - [(2 R ) -2- (3-Formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} - N - (4-hydroxy-3,5-dimethylbenzyl) benzamide;

3- {2 - [(2 R ) -2- (3-Formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} - N - (6-hydroxy-naphthalen- N -2-ylmethyl) benzamide;

N - (3,6-Dichloro-2-hydroxybenzyl) -3- {2 - [(2 R ) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methyl-propyl} benzamide;

N - (3,4-Dimethylbenzyl) -2- (3- {2 - [(2 R ) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] ethyl} phenyl) acetamide;

3- {2 - [(2 R ) -2- (3-Formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} - N - [2- (4-hydroxyphenyl) -2-methylpropyl] benzamide;

3- {2 - [(2 R ) -2- (3-Formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} - N - (4'-hydroxybiphenyl-4-yl-methyl) benzamide;

N -Adamantan-1-yl-2- (3 - {(2 R ) -2 - [(2 R ) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] propyl} phenyl) acetamide;

N - [5- (2- {2- [3- (10-Aza-tricycle [6.3.1.0 * 2.7 *] dodeca-2 (7), 3,5-triene-10-carbonyl) phenyl] - 1,1-dimethylethylamino} -1-hydroxyethyl) -2-hydroxyphenyl] -formamide;

2- (3 - {(2 R ) -2 - [(2 R ) -2- (3-Formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] propyl} phenyl) - N - (4'-hydroxybiphenyl-3- ilmethyl) acetamide;

4 - {[2- (3- {2 - [(2 R ) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} phenyl) -acetylamino] methyl} methyl ester benzoic;

2- (3 - {(2 R ) -2 - [(2 R ) -2- (3-Formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} phenyl) - N - (4-trifluoromethoxy- benzyl) acetamide;

N - (2-Chloro-4-hydroxybenzyl) - N -ethyl-2- (3 - {(2 R ) -2 - [(2 R ) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino ] -2-methylpropyl} phenyl) -cetamide;

N - (2-Chloro-4-hydroxybenzyl) -2- (3 - {(2 R ) -2 - [(2 R ) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2- methylpropyl} -phenyl) acetamide;

2- (3 - {(2 R ) -2 - [(2 R ) -2- (3-Formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] propyl} phenyl) - N - (4-hydroxy-3,5 -dimethylbenzyl) acetamide;

2- (3 - {(2 R ) -2 - [(2 R ) -2- (3-Formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] propyl} phenyl) - N - (2-hydroxynaphthalen-1-ylmethyl ) acetamide;

N - (5-Chloro-2-hydroxybenzyl) -2- (3 - {(2 R ) -2 - [(2 R ) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] propyl} phenyl ) acetamide;

N - (3,5-Dichloro-2-hydroxybenzyl) -2- (3 - {(2 R ) -2 - [(2 R ) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] propyl } phenyl) acetamide;

2- (3 - {(2 R ) -2 - [(2 R ) -2- (3-Formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] propyl} phenyl) - N - (6-hydroxynaphthalen-2-ylmethyl ) acetamide;

2- (3 - {(2 R ) -2 - [(2 R ) -2- (3-Formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] propyl} phenyl) - N - (4'-hydroxybiphenyl-4- ilmethyl) acetamide;

N - (4-Cyano-benzyl) -2- (3- {2 - [(2 R ) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} -phenyl) -acetamide ;

2- (3- {2 - [(2 R ) 2- (3-Formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} -phenyl) - N - (4-methanesulfonyl-benzyl) -acetamide;

2- (3- {2 - [(2 R ) -2- (3-Formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} -phenyl) - N - (4-methylsulfanyl-benzyl) -acetamide ;

2- (3- {2 - [(2 R ) -2- (3-Formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} -phenyl) - N - (4-trifluoromethyl-benzyl) -acetamide ;

2- (3- {2 - [(2 R ) -2- (3-Formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} phenyl) - N - (4'-hydroxybiphenyl-4-ylmethyl) acetamide;

N - [2- (5-Chloro-2-hydroxyphenyl) -ethyl] -3- {2 - [(2 R ) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} -benzamide;

2- (3- {2 - [(2 R ) -2- (3-Formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} phenyl) - N -0 (4'-hydroxy-biphenyl-3 -ylmethyl) -acetamide;

3- {2 - [(2 R ) -2- (3-Formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -propyl} - N- [2- (4-hydroxyphenyl) -2-methyl-propyl] -benzamide ;

N - (2-Chloro-4-hydroxybenzyl) -2- (3 - {(2 R ) -2 - [(2 R ) - (2 R ) -2- (3-formylamino-4-hydroxyphenyl) -2- hydroxyethylamino] propyl} phenyl) acetamide;

N - [2- (5-Chloro-2-hydroxyphenyl) -ethyl] -3- {2 - [(2 R ) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} benzamide;

3- {2 - [(2 R ) -2- (3-Formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -propyl} -N- [2- (4-hydroxyphenyl) -2-methyl-propyl] benzamide;

2- (3- {2 - [(2 R ) -2- (3-Formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} phenyl) - N - (tetrahydro-thiopyran-4-yl) acetamide ;

N - (5-Chloro-2-hydroxybenzyl) -2- (3- {2 - [(2 R ) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methyl-propyl} phenyl ) acetamide; Y,

N - {5 - [(1 R ) -2 - ((1 R ) -2- {3- [3- (3,4-Dihydro-1 H -isoquinolin-2-yl) -3-oxopropyl] phenyl} -1-methylethylamino) -1-hydroxyethyl] -2-hydroxyphenyl} formamide.

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In accordance with one aspect of the present invention, compounds of formula (1) are generally preferred in which the group (CH 2) n -C (= O) Q 1 is at the target position

The pharmaceutically acceptable salts of compounds of formula (1) include acid addition salts and of bases thereof.

Suitable acid addition salts are they form from acids that form non-toxic salts. The examples include acetate, adipate, aspartate, benzoate, besylate, bicarbonate / carbonate, bisulfate / sulfate, borate, camsilate, citrate, cyclamate, edisilate, silate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride / chloride, hydrobromide / bromide, iodide / iodide, phosphate acid, isothionate, D- and L-lactate, malate, maleate, malonate, mesylate, methylsulfate, 2-napsilate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogen, phosphate / phosphate diacid, pyroglutamate, sucrate, stearate, succinate, tannate, D- and L-tartrate, 1-hydroxy-2-naphthoate tosylate and xinafoate.

Suitable basic salts are formed from of bases that form non-toxic salts. Examples include salts aluminum, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine zinc.

They can also form hemispheres of acids and bases, for example, hemisulfate and hemicalcium salts.

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

The pharmaceutically acceptable salts of compounds of formula (1) can be prepared by one or more than three procedures:

(i)

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

(ii)

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

(iii)

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

The three reactions are typically performed in solution. The resulting salt can be removed by precipitation and collected by filtration or can be recovered by evaporation of solvent The degree of ionization in the resulting salt can vary from completely ionized to almost non-ionized.

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

They are included within the scope of the invention. complexes such as clathrates, inclusion complexes drug-host in which, unlike in the solvates mentioned above, the drug and the host are present in stoichiometric or non-stoichiometric quantities. Also included are drug complexes that contain two or more organic and / or inorganic components that may be in amounts stoichiometric or non-stoichiometric. The resulting complexes they can be ionized, partially ionized or not ionized. For one review of these complexes, see J Pharm Sci, 64 (8), 1269-1288 by Haleblian (August 1975).

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

The compounds of the invention include compounds of formula (1) as defined previously, including all polymorphs and habits crystals thereof, prodrugs and isomers thereof (including optical, geometric and tautomeric isomers) as defined hereinafter and compounds of formula (1) marked with isotopes

As indicated, the so-called "pro-drugs" of the compounds of formula (1) they are also within the scope of the invention. Thus, certain derivatives of compounds of formula (1) that may or may not have little pharmacological activity by themselves can, when administered in or on the body, become compounds of formula (1) that have the desired activity, for example, by hydrolytic cleavage. These derivatives are called "prodrugs." Additional information about the use of prodrugs in "Pro-drugs as Novel Delivery Systems ", Vol. 14, ACS Symposium Series (T. Higuchi and W. Stella) and "Bioreversible Carriers in Drug Design", Pergamon Press, 1987 (ed. E. B Roche, American Pharmaceutical Association).

Prodrugs in accordance with this invention can occur, for example, by replacing the appropriate functionalities present in the compounds of formula (1) with certain remains known to those skilled in the art such as "pro-remains" as described, by 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 (-COOH) functionality, an ester thereof, for example, a compound in which the hydrogen of the carboxylic acid functionality of the compound of formula (1) is replaces with (C 1 -C 8) alkyl;

(ii)

when the compound of formula (1) it contains an functionality of alcohol (-OH), an ether thereof, by example, a compound in which the hydrogen of the functionality of alcohol of the compound of formula (1) is replaced with (C 1 -C 6) alkanoyloxymethyl; Y

(iii)

when the compound of formula (1) contains a primary or secondary amino functionality (-NH2 or -NHR in which R \ Hq), an amide thereof, by example, a compound in which, as the case may be, one or both hydrogens of the amino functionality of the compound of formula (1) replaced with alkanoyl (C_ {1} -C_ {10}).

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Additional examples of replacement groups according to the previous examples and examples of other types of prodrugs can be found in the references that have been previously mentioned.

In addition, certain compounds of formula (1) may act for themselves as prodrugs of other compounds of Formula 1).

Also included within the scope of the invention are metabolites of compounds of formula (1), that is, compounds formed in vivo after drug administration. Some examples of metabolites according to the invention include

(i)

when the compound of formula (1) it contains a methyl group, a hydroxymethyl derivative thereof   (-CH_ {3} \ -igh -CH_ {2} OH):

(ii)

when the compound of formula (1) contains an alkoxy group, a hydroxy derivative thereof (-OR ? -OH);

(iii)

when the compound of formula (1) it contains a tertiary amino group, a secondary amino derivative of same (-NR 1 R 2? -NHR 1 or -NHR 2);

(iv)

when the compound of formula (1) it contains a secondary amino group, a primary derivative thereof (-NHR1 → -NH2);

(v)

when the compound of formula (1) it contains a phenyl moiety, a phenol derivative thereof (-Ph ? -PhOH); Y

(saw)

when the compound of formula (1) contains an amide group, a carboxylic acid derivative thereof (-CONH_ {2}? COOH).

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Compounds of formula (1) containing one or more asymmetric carbon atoms may exist in the form of two or more stereoisomers. When a compound of formula (1) contains an alkenyl or alkenylene group, cis / trans (or Z / E) geometric isomers are possible. When structural isomers are interchangeable with low energy protectors, tautomeric isomerism ("tautomerism") may appear. This can take the form of prototropic tautomerism in compounds of formula (1) that contain, for example, an imino, keto or oxime group, or the so-called valence tautomerism in compounds that contain an aromatic moiety. It follows that a single compound can show more than one type of isomerism.

All stereoisomers, geometric isomers and tautomeric forms of the compounds of formula (1), including compounds showing more than one type of isomerism and mixtures of one or more thereof, are included within the scope of the present invention. Acid addition salts or bases wherein the counterion is optically active, for example, d -lactate, l -lysine, or racemic, for example, dl -tartrate or dl -arginine also included.

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 preparation / isolation of individual enantiomers include chiral synthesis from suitable optically pure precursors 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 a precursor racemic) can be reacted with an optically compound suitable asset, for example, an alcohol, or, in the event that the compound of formula (1) contains an acidic or basic moiety, an acidic 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 become the corresponding enantiomer or pure enantiomers by means well known to an expert in the matter.

The chiral compounds of the invention (and chiral precursors thereof) can be obtained in the form enantiomerically enriched using chromatography, typically HPLC, on an asymmetric resin with a mobile phase constituted by a hydrocarbon, typically heptane or hexane, which contains 0 to 50% by volume of isopropanol, typically 2% to 20%, and 0 to 5% by volume of an alkylamine, typically diethylamine at 0.1%. The concentration of the eluate produces the mixture enriched

Stereoisomeric conglomerates can separated by conventional techniques known to experts in matter - see, for example, "Stereochemistry of Organic Compounds" by E. L. Eliel (Wiley, New York, 1994).

In accordance with one aspect of the present invention, the (R, R) -tereoisomer of formula shown at then, where R 1 is hydrogen and R 2 is alkyl C 1 -C 4, preferably methyl, and n and Q1 are as defined above:

37

The present invention includes all compounds labeled with acceptable isotopes of formula (1) in which  one or more atoms are replaced by atoms that have the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number that predominates in nature.

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

Certain compounds of formula (1) labeled with isotopes, for example, those that incorporate a radioactive isotope, they are useful in studies of drug distribution in substrates and / or tissues. The tritium radioactive isotopes, i.e. 3 H, and carbon-14, that is 14 C, are particularly useful for this purpose in view of its easy incorporation and the provision of detection means.

Substitution with heavier isotopes such as deuterium, i.e. 2 H, can produce certain therapeutic advantages that result in greater metabolic stability, for example, high in vivo half-life or reduced dosage requirements, and, therefore, , may be preferred in some circumstances.

The replacement with isotope emitting positrons, such as 11 C, 18 F, 15 O and 13 N, may be useful in studies of Positron Emission Topography (PET) to examine the recipient's occupation on the substratum.

Compounds labeled with isotopes of formula (1) can generally be prepared by conventional techniques known to those skilled in the art or by procedures analogous to those described in the accompanying Examples and Preparations using an isotopically labeled reagent in place of the unlabeled reagent previously used.

The pharmaceutically acceptable solvates of according to the invention include those in which the solvent crystallization may be isotopically substituted, for example D 2 O, d 6 -acetone or d_ {6} -DMSO.

The compounds of formula (1), their salts and / or pharmaceutically acceptable derivative forms are compounds valuable pharmaceutically active, which are suitable for the therapy and prophylaxis of numerous disorders in which it is involved the β2 receptor or in which the agonism of this receptor can induce benefits, particularly in the allergic and non-allergic diseases of the respiratory tract, but also in the treatment of other diseases such as, but without limitation, those of the nervous system, premature delivery, congestive heart failure, depression, diseases inflammatory and skin allergies, psoriasis, diseases proliferative dermal, glaucoma and in conditions in which there is a advantage decreasing gastric acidity, particularly in ulcers Gastric and peptic.

The compounds of the invention intended for Pharmaceutical use can be administered as crystalline products or amorphous They can be obtained, for example, as solid blocks, powders or films by procedures such as precipitation, crystallization, lyophilization, spray drying or drying by evaporation. Drying by can also be used for this purpose. Radio frequency or microwave.

They can be administered alone or in combination with one or more other compounds of the invention or in combination with one or more other drugs (or like any other combination thereof). Generally, they will be administered as a formulation in combination with one or more excipients pharmaceutically acceptable. The term "excipient" is used in this document to describe any ingredient other than compound or (compounds) of the invention. The choice of excipient will depend largely on factors such as mode of particular administration, the effect of the excipient on the solubility and stability, and the nature of the form Pharmaceutical

Pharmaceutical compositions suitable for the supply of the compounds of the present invention and the procedures for its preparation will be readily apparent to subject matter experts Such compositions and procedures for their preparation they can be found, for example, in "Remington Pharmaceutical Sciences ", 19th edition (Mack Publishing Company, nineteen ninety five).

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

The right formulations for oral administration include solid formulations such as tablets, capsules containing particles, liquids or powders, lozenges (including liquid filling), chewing gum, multi and nano particles, gels, solid solutions, liposomes, films, ovules, sprayers and liquid formulations.

Liquid formulations include suspensions, solutions, syrups and elixirs. These formulations they can be used as fillers in soft or hard capsules and typically comprise a vehicle, for example, water, ethanol, polyethylene glycol, propylene glycol, methylcellulose or an oil suitable, and one or more emulsifying agents and / or suspension. Liquid formulations can also be prepared. by reconstituting a solid, for example, of a little envelope

The compounds of the invention can also be used in pharmaceutical forms of rapid dissolution and disintegration fast such as those described in Expert Opinion in Therapeutic Patents, 11 (6), 981-986, by Liang and Chen (2001).

For tablet dosage forms, depending on the dose, the drug may constitute 1% by weight 80% by weight of the pharmaceutical form, more typically 5% in weight at 60% by weight of the pharmaceutical form. In addition to the drug, The tablets usually contain a disintegrant. The examples of disintegrants include sodium starch glycolate, carboxymethyl sodium cellulose, carboxymethyl calcium cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methyl cellulose, microcrystalline cellulose, hydroxypropyl cellulose substituted with lower alkyl, starch, pregelatinized starch and alginate sodium. Generally, the disintegrant will comprise 1% by weight at 25% by weight, preferably 5% by weight to 20% by weight of the pharmaceutical form.

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

Optionally, the tablets can also comprise surfactants, such as lauryl sulfate sodium and polysorbate 80 and emollients such as silicon dioxide and talcum powder.

When present, surfactants they can comprise from 0.2% by weight to 5% by weight of the tablet and the emollients may comprise from 0.2% by weight to 1% by weight of the compressed.

The tablets usually also contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate and stearate mixtures of magnesium with sodium lauryl sulfate. Lubricants generally comprise from 0.25% by weight to 10% by weight, preferably from 0.5% by weight to 3% by weight of the tablet.

Other possible ingredients include antioxidants, dyes, flavoring agents, preservatives and taste masking agents.

Exemplary tablets contain up to about 80% of the drug, about 10% in weight to about 90% by weight of binder, of approximately 0% by weight to 85% in diluent walk, of about 2% by weight to about 10% by weight of disintegrant, and about 0.25% by weight at approximately 10% by weight of lubricant.

Tablet blends can compressed directly or by roller to form tablets.  The mixtures or parts of the tablet mixtures may, as alternatively, wet granulate, dry or molten, coagulate in a molten state or extrude before forming the compressed. The final formulation may comprise one or more layers and can be coated or uncoated; can even be encapsulated

The formulation of the tablets is described in Pharmaceutical Dosage Forms: Tablets, Vol. 1, by H. L. Lieberman and L. Lachman (Marcel Dekker, New York, 1980).

Oral films for consumption in beings human or for veterinary use are typically forms Water-soluble or inflatable flexible thin film pharmaceuticals in water that can dissolve rapidly or adhere to the mucosa and typically comprise a compound of formula (1), a polymer film former, a binder, a solvent, a humectant, a plasticizer, a stabilizer or emulsifier, a viscosity modifying agent and a solvent. Some formulation components can perform more than one function.

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

The film-forming polymer can be selected from natural polysaccharides, proteins or hydrocolloids synthetic and is typically present in the range of 0.01 to 99% by weight, more typically in the range of 30 to 80% in weight.

Other possible ingredients include antioxidants, dyes, flavorings and flavor enhancers, preservatives, salivation stimulating agents, agents refrigerants, co-solvents (including oils), emollients, dough forming agents, agents anti-foaming agents, surfactants and agents taste masks.

The films according to the invention are typically prepared by evaporative drying of the films aqueous thin coated on a support or reinforcing paper detachable This can be done in an oven or in a tunnel drying, typically a combined liner dryer or by lyophilization or vacuum.

Solid formulations for administration Oral can be formulated to be immediate release and / or modified Modified release formulations include delayed, prolonged, impulse, controlled release, Directed and scheduled.

In US Patent No. 6,106,864 it is describe modified release formulations suitable for Purposes of the invention Details of others can be found suitable release technologies such as high dispersions energy and osmotic and coating particles in Pharmaceutical On-line Technology, 25 (2), 1-14, by Verma et al (2001). The use of chewing gum to get the Controlled release is described in WO 00/35298.

The compounds of the invention can also administered directly in the bloodstream, in the muscle or in the internal organs. The appropriate means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular and subcutaneous. The Suitable devices for parenteral administration include needle injectors (including microneedles), needleless injectors and infusion techniques.

Parenteral formulations are typically aqueous solutions that may contain excipients such as salts, carbohydrates and buffering agents (preferably at pH 3 to 9) but, for some applications, more can be formulated suitably as a sterile non-aqueous solution or as a form dry to use together with a suitable vehicle such as water Sterile, without pyrogens.

The preparation of parenteral formulations under sterile conditions, for example, by lyophilization, they can easily performed 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 augmented using appropriate formulation techniques, such as incorporation of solubility enhancing agents.

Formulations for parenteral administration may be formulated to be immediate and / or modified release. Modified release formulations include delayed, prolonged, impulse, controlled, directed and programmed release. Therefore the compounds of the invention can be formulated as a solid, semi-solid or a thixotropic fluid for administration as an implanted reservoir that provides the modified release of the active compound. Examples of such formulations include vascular stents coated with drugs and microspheres of poly ( dl -lactic-coglycolic acid) (PGLA).

The compounds of the invention can also administered topically through the skin or mucosa, it is that is, dermally or transdermally. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, external use 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 enhancers may be incorporated, see, for example, J Pharm Spi, 88 (10), 955-958 by Finnin and Morgan (October 1999).

Other means of topical administration include electroporation, iontophoresis, phonophoresis, sonophoresis and microneedle or needleless injection (for example, PowderJect?, Bioject?, Etc).

Formulations for topical administration can be formulated to be immediate and / or modified release. Modified release formulations include release delayed, prolonged, impulse, controlled, directed and scheduled

The compounds of the invention can also administered intranasally or by inhalation, typically in form of a dry powder (alone or as a mixture, for example, in a dry mix with lactose or as a component particle mixed, for example, mixed with phospholipids such as phosphatidylcholine) from an inhaler for dry powder or as a aerosol sprayer from a container, pump, sprayer or pressurized atomizer (preferably an atomizer that uses electrodynamics to produce a fine mist) or a nebulizer, with or without the use of a suitable propellant, such as 1,1,1,2-tetrafluoroethane or 1, 1,1,2,3,3,3-heptafluoropropane. For use intranasally, the powder may comprise a bioadhesive agent, by example, chitosan or cyclodextrin.

The container, pump, sprayer, atomizer or pressurized nebulizer contains a solution or suspension of the compound (or compounds) of the invention comprising, for example, ethanol, aqueous ethanol or an alternative agent suitable for dispersion, solubilization or prolonged release of the principle active, a propellant (or propellants) as solvent and a optional surfactant, such as sorbitan trioleate, oleic acid or an oligolactic acid.

Before using in a suspension formulation or dry powder, the pharmaceutical product is micronized to a size suitable for inhalation delivery (typically less than 5 micrometers) This can be achieved through any proper crushing procedure, such as jet milling coiled, fluid bed jet grinding, processing supercritical fluids to form nanoparticles, homogenization to high pressure or spray drying.

Capsules (made, for example, of gelatin or hydroxypropylmethylcellulose), blisters and cartridges for use in an inhaler or insufflator may 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 l- leucine, mannitol or magnesium stearate. The lactose may be anhydrous or in the form of a monohydrate, preferably the latter. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose.

A solution formulation suitable for use in an atomizer using electrodynamics to produce a fine mist may contain 1 µg to 20 mg of the compound of the invention by drive and drive volume can vary from 1 µI to 100 µl. A typical formulation can comprise a compound of formula (1), propylene glycol, water sterile, ethanol and sodium chloride. The alternative solvents that  may be used instead of propylene glycol include glycerol and polyethylene glycol

Suitable saporifers, such as menthol and levomenthol, or sweeteners, such as saccharin or saccharin sodium, can be added to these formulations of the invention intended for inhaled / intranasal administration.

Formulations for administration Inhaled / intranasal may be formulated to be release immediate and / or modified, using, for example, PGLA. The modified release formulations include release delayed, prolonged, impulse, controlled, directed and scheduled

In the case of inhalers or dust sprays dry, the dosage unit is determined by means of a valve that supplies a measured quantity. The units of agreement with the invention they are typically arranged to administer a dose measure or "discharge" ("puff") containing from 0.001 mg to 10 mg of the compound of formula (1). The total daily dosage will typically be in the range of 0.001 mg to 40 mg that can administered in a single dose or, more commonly, as a dose divided throughout the day.

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

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

Formulations for administration via rectal / vaginal can be formulated to be immediate release and / or modified. Modified release formulations include delayed, prolonged, impulse, controlled, directed release and scheduled.

The compounds of the invention can also administered directly in the eye or ear, typically in drop form of a suspension or micronized solution in a Isotonic sterile saline solution, with adjusted pH. Other formulations suitable for ocular and otic administration include ointments, biodegradable implants (e.g. sponges absorbable gel, collagen) and non-biodegradable (for example silicone), wafers, lenses and particulate or vesicular systems, such as niosomes or liposomes.

A polymer such as acid may be incorporated. crosslinked polyacrylic, polyvinyl alcohol, hyaluronic acid, a cellulosic polymer, for example, hydroxypropyl methylcellulose, hydroxyethylcellulose or methyl cellulose or a polymer heteropolysaccharide, for example, gellan gum, together with a preservative, such as benzalkonium chloride. These formulations They can also be supplied by iontophoresis.

Formulations for administration Ocular / otic can be formulated to be immediate release and / or modified Modified release formulations include delayed, prolonged, impulse, controlled release, Directed or scheduled.

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 its solubility, speed of dissolution, taste masking, bioavailability and / or stability for use in any of the modes of Administration mentioned above.

It is observed that the complexes drug-cyclodextrin, for example, are generally useful for most pharmaceutical forms and routes of administration. Both inclusion and complexes can be used those of non-inclusion. As an alternative to lead the training of complexes with the drug, cyclodextrin can be used as a auxiliary additive, that is, as a vehicle, diluent or solubilizer The most commonly used cyclodextrins for these purposes are the alpha, beta and gamma, whose examples can be found in International Patent Applications No. WO 91/11172, WO 94/02518 and WO 98/55148.

To the extent that it may be desirable administer a combination of the active compounds, for example, For the purpose of treating a particular disease or condition, it It is within the scope of the present invention that two or more pharmaceutical compositions, of which at least one contains a compound according to the invention, can be combined conveniently in the form of a kit suitable for co-administration of the compositions.

Therefore, the kit of the invention comprises two or more different pharmaceutical compositions, of which at less one contains a compound of formula (1) according to the invention and means for containing said compositions separately, such as a container, a divided bottle, or a laminated container divided. An example of this type of kit is the known blister Used for the packaging of tablets, capsules and the like.

The kit of the invention is particularly suitable for administering different pharmaceutical forms, for parenteral example, to administer the various compositions to different dosing intervals or to adjust the different Compositions with each other. To help compliance, the kit typically comprises instructions for administration and may Provide yourself with a so-called reminder.

For administration in human patients, the Total daily dose of the compounds of the invention is found typically in the range of 0.001 mg to 5000 mg depending, by Of course, the mode of administration. For example, a daily dose Intravenous may only need 0.001 mg to 40 mg. The Total daily dose can be administered in single or divided doses and may, at the discretion of the doctor, be out of range typical provided in this document.

These dosages are based on a subject Average human having a weight of approximately 65 kg to 70 kg. The doctor can easily determine the doses for the subjects whose weight is outside this range, such as children and elderly.

For the avoidance of doubt, the references in this document to "treatment" include references to treatment curative, palliative and prophylactic.

In accordance with another embodiment of the present invention, the compounds of formula (1) or salts, derivative forms or pharmaceutically acceptable compositions thereof, also can be used as a combination with one or more agents additional therapies to co-administer to a patient to obtain some therapeutic final result particularly desired such as the process treatment of pathophysiologically relevant diseases that include, but without limitation, (i) bronchoconstriction, (ii) inflammation, (iii) allergy, (iv) tissue destruction, (v) signs and symptoms such as lack of breath, cough The second and more additional therapeutic agents it can also be a compound of formula (1) or a salt, forms derivatives or compositions thereof pharmaceutically acceptable, or one or more β2 agonists known in the technique. More typically, the second and more therapeutic agents are will select from classes of therapeutic agents different.

As used in this document, the expressions "co-administration", "co-administered" and "in combination with", referring to the compounds of formula (1) and one or more agents therapeutic, they mean, and they refer to and include what next:

?

simultaneous administration of said combination of compound (or compounds) of formula (1) and therapeutic agent (agents) to a patient who needs the treatment, when said components are formulated together in a single pharmaceutical form that releases these components to substantially the same time in said patient,

?

administration substantially simultaneous of said combination of compound (or compounds) of formula (1) and therapeutic agent (or agents) to a patient who you need the treatment, when these components are formulated separated from each other in different pharmaceutical forms than said patient takes substantially at the same time, whereby said components are released substantially at the same time in said patient,

?

sequential administration of said combination of compound (or compounds) of formula (1) and therapeutic agent (or agents) to a patient who needs the treatment, when said components are formulated separately between yes in different pharmaceutical forms that said patient takes consecutive times with a significant time interval between each administration, whereby said components are released substantially at different times in said patient; Y

?

sequential administration of said combination of compound (or compounds) of formula (1) and therapeutic agent (or agents) to a patient who needs the treatment, when said components are formulated together in a single pharmaceutical form that releases these components in a way controlled thereby administering to the patient simultaneous, consecutive and / or overlapping at the same time and / or at times different.

in which each party can be administered by the Same or different way.

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Suitable examples of other agents pharmaceuticals that can be used in combination with the compound (or compounds) of formula (1) or salts, derivative forms or compositions of the same pharmaceutically acceptable include but not limited to:

(to)

inhibitors of 5-lipoxygenase (5-LO) or antagonists of the 5-lipoxygenase activation protein (FLAP),

(b)

leukotriene antagonists (LTRA) including antagonists of LTB_4, LTC_ {4}, LTD_ {4} and LTE_ {4},

(C)

receptor antagonists histamine including H1 and H3 antagonists,

(d)

sympathomimetic agents agonist vasoconstrictors of the α1 adrenoceptors and α2 for decongestant use,

(and)

muscarinic receptor antagonists M3 or anticholinergic agents,

(F)

PDE inhibitors, for example, PDE3, PDE4 and PDE5 inhibitors,

(g)

theophylline,

(h)

sodium cromoglycate,

(i)

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

(j)

oral glucocorticosteroids e inhaled,

(k)

active monoclonal antibodies against endogenous inflammatory entities,

(l)

anti-factor agents tumor necrosis (anti-TNF-?),

(m)

adhesion molecule inhibitors including VLA-4 antagonists,

(n)

receptor antagonists quinine-B 1 and B 2,

(or)

immunosuppressive agents,

(p)

metalloprotease inhibitors of matrix (MPM),

(q)

receptor antagonists takinin NK 1, NK 2 and NK 3,

(r)

elastase inhibitors,

(s)

adenosine receptor antagonists A2a,

(t)

urokinase inhibitors

(or)

compounds that act on dopamine receptors, for example, D2 agonists,

(v)

route modulators NF??, For example, IKK inhibitors,

(w)

route modulators cytokine signaling such as MAP kinase p38 or syk kinase,

(x)

agents that can be classified as mucolytic or anti-tusives

(Y)

antibiotics,

(z)

HDAC inhibitors, e,

(aa)

P13 kinase inhibitors.

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In accordance with the present invention, prefers the combination of the compounds of formula (1) with:

-

H3 antagonists,

-

muscarinic receptor antagonists M3,

-

PDE4 inhibitors,

-

glucocorticosteroids,

-

adenosine receptor antagonists A2a,

-

signaling path modulators of cytokine such as MAP kinase p38 or syk kinase, or,

-

leukotriene antagonists (LTRA) including antagonists of LTB_4, LTC_ {4}, LTD_ {4} and LTE_ {4}.

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In accordance with the present invention, further prefers the combination of the compounds of formula (1) with:

-

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

-

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

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It should be noted that in this document all references regarding treatment include treatment curative, palliative and prophylactic. The following description is refers to therapeutic applications in which they can be incorporated the compounds of formula (1).

The compounds of formula (1) can interact with the β2 receptor and therefore have a wide range of therapeutic applications, as described additionally later, due to the essential role it plays the β2 receptor in the physiology of all mammals.

Therefore, another aspect of the present invention refers to the compounds of formula (1), or salts, derivative forms or compositions thereof pharmaceutically acceptable, for use in the treatment of diseases, disorders and conditions in which the recipient is involved β2. More specifically, the present invention is also refers to the compounds of formula (1), or salts, derivative forms or pharmaceutically acceptable compositions thereof, for use in the treatment of diseases, disorders and conditions selected from the group consisting of:

?

asthma of any kind, etiology or pathogenesis, in particular asthma that is a member selected from the group consisting of atopic asthma, asthma no atopic, allergic asthma, IgE-mediated atopic bronchial asthma, bronchial asthma, idiopathic asthma, true asthma, intrinsic asthma caused by pathophysiological discomfort, extrinsic asthma caused by environmental factors, idiopathic asthma of unknown cause or not apparent, 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 viral infection, non-allergic asthma, incipient asthma, wheezing infant syndrome and bronchiolitis,

?

chronic bronchoconstriction or acute, chronic bronchitis, airway obstruction inferior and emphysema,

?

obstructive diseases or inflammatory of the airways or of any kind, etiology or pathogenesis, in particular an obstructive disease or inflammatory of the airways that is a member selected from the group consisting of chronic eosinophilic pneumonia, chronic obstructive pulmonary disease (COPD), which includes COPD chronic bronchitis, pulmonary emphysema or associated or not associated dipnea associated with COPD, COPD characterized by obstruction of progressive, irreversible airways, distress syndrome Respiratory in adults (ARDS), worsening of hyperreactivity of the airways as a result of another therapy with drugs and respiratory disease associated with hypertension pulmonary,

?

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

?

acute lung injury,

?

bronchiectasis of any type, etiology or pathogenesis in particular bronchiectasis which is a  selected member of the group consisting of bronchiectasis cylindrical, saculated bronchiectasis, fusiform bronchiectasis, capillary bronchiectasis, cystic bronchiectasis, dry bronchiectasis and follicular bronchiectasis.

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Still another aspect of the present invention is also refers to the use of the compounds of formula (1) or salts, derivative forms or compositions thereof pharmaceutically acceptable for the manufacture of a drug that has a β2 agonist activity. In particular, the present invention refers to the use of the compounds of formula (1) or salts, forms derivatives or compositions thereof pharmaceutically acceptable, for the manufacture of a drug for treatment of diseases and / or conditions mediated by β2, in particular the diseases and / or conditions indicated above.

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

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

Preparation 1 Ethyl acid ester (3-ethoxycarbonylmethylphenyl) acetic

38

Acid dissolved 2,2 '- (1,3-phenylene) diacetic (10.0 g, 51 mmol) in ethanol (100 ml) and the solution was treated dropwise with acetyl chloride (2.5 ml). The reaction mixture was stirred at reflux temperature for 18 hours before it was left cool and concentrated in vacuo. The residue was taken up in acetate ethyl (100 ml) and extracted with a solution of sodium bicarbonate (3 x 50 ml) and brine (3 x 50 ml). The organic phase dried (MgSO 4), was concentrated in vacuo and the residue was triturated with pentane, producing the product (11.8 g).

1 H NMR (CDCl 3, 400 MHz) δ: 1.31 (6H, t), 3.65 (4H, s), 4.20 (4H, c), 7.24-7.36, (4H, m); LRMS ESI m / z 251 [M + H] +.

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Preparation 2 Acid (3-ethoxycarbonylmethylphenyl) acetic

39

A solution 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) was treated dropwise with hydrochloric acid (12 M, 4.9 ml, 58.8 mmol). The reaction mixture was stirred at reflux temperature for 18 hours before being allowed to cool and concentrated to a volume lower. 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 bicarbonate sodium to a neutral pH. The mixture was diluted with ethyl acetate. (200 ml) and the organic phase was separated and washed with a solution of sodium bicarbonate (5 x 30 ml) and brine (50 ml). Extracts Combined aqueous were acidified to pH 3 with 6 M hydrochloric acid and extracted with diethyl ether (3 x 30 ml). Extracts Organic were combined, dried (MgSO4) and concentrated under vacuum The residue was triturated with pentane, producing a solid. colorless (10.8 g).

1 H NMR (CD 3 OD, 400 MHz) δ: 1.25 (3H, t), 3.60 (2H, m), 3.63 (2H, m), 4.15 (2H, c), 7.18-7.32 (4H, m); EMBR IEN m / z 245 [M + Na] +.

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Preparation 3 Acid [3- (2-Hydroxy-2-methylpropyl) phenyl] acetic

40

Methyl magnesium chloride was added dropwise (51 ml of a 3 M solution in tetrahydrofuran, 153 mmol) at a stirred solution of Preparation 2 (11.6 g, 51 mmol) (International Journal of Peptide and Protein Research, 1987, 29 (3), 331) in tetrahydrofuran (300 ml) at 0 ° C in an atmosphere of nitrogen. The reaction was allowed to warm to room temperature. overnight with the formation of a thick precipitate of color  white and then water (50 ml) and acid were carefully added 2N hydrochloric (80 ml). The aqueous phase was extracted with acetate ethyl (2 x 300 ml) and the combined organic extracts were washed with brine (50 ml), dried (sodium sulfate), and the solvent was removed in vacuo, forming the title compound as a golden oil (11.2 g).

1 H NMR (CDCl 3, 400 MHz) δ: 1.22 (6H, s), 2.75 (2H, s), 3.63 (2H, s), 7.12-7.30 (4H, m); LRMS ESI m / z 209 [M + H] +.

Preparation 4 Acid (3- {2 - [(chloroacetyl) amino] -2-methylpropyl} phenyl) acetic acid

41

2-Chloroacetonitrile was added (8.8 ml, 140 mmol) to a solution of Preparation 3 (16.0 g, 70 mmol) in acetic acid (33 ml) and combined at 0 ° C. The solution resulting was treated with concentrated sulfuric acid (33 ml) and was Let it warm gradually to room temperature. After 4 hours the reaction mixture was poured on ice and made basic with solid sodium carbonate. The solution was extracted with ethyl acetate (2 x 500 ml) and the combined organic extracts were dried (MgSO 4) and concentrated in vacuo to give the product of title in the form of a colorless solid (19.0 g).

1 H NMR (CDCl 3, 400 MHz) δ: 1.36 (6H, s), 3.02 (2H, s), 3.62 (2H, s), 3.95 (2H, s), 6.19 (1H, m), 7.06-7.31 (4H, m); EMBR IEN m / z 282 [M-H] -.

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Preparation 5 Acid methyl ester [3- (2-amino-2-methylpropyl) phenyl] acetic

42

A solution of Preparation 4 (5.1 g, 18 mmol), thiourea (1.6 g, 21 mmol) and acetic acid (18 ml) in ethanol (80 ml) was heated to reflux under a nitrogen atmosphere during 16 hours. The reaction mixture was allowed to cool to temperature. ambient, filtered and the filtrate was concentrated in vacuo. The residue dissolved in ethanol (150 ml), saturated with gas chloride hydrogen and the resulting solution was heated at reflux for 16 hours. The mixture was concentrated in vacuo, ethyl acetate was added. (200 ml) and a 5% aqueous solution of sodium carbonate (200 ml). The organic phase was washed with brine (100 ml), dried (MgSO 4) and concentrated in vacuo. The residue was purified with resin strong cation exchange (methanol and then a 2M solution of ammonia in methanol), giving a yellow oil (2.68 g).

1 H NMR (CDCl 3, 400 MHz) δ: 1.14 (6H, s), 2.68 (2H, s), 3.62 (2H, s), 3.69 (3H, s), 7.08-7.16 (3H, m), 7.23-7.27 (1H, m); LRMS ESI m / z 222 [M + H] +.

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Preparation 6 [3- (2- tert -butoxycarbonylamino-2-methylpropyl) phenyl] acetic acid methyl ester

43

A solution of di- tert-butyl dicarboxylate (8.19 g, 38.0 mmol) in dichloromethane (40 ml) was added to a solution of Preparation 5 (8.4 g, 38.0 mmol) and triethylamine ( 5.2 ml, 38.0 mmol) in dichloromethane (60 ml) at 0-5 ° C. The mixture was allowed to warm to RT and stirred overnight. The solvent was removed and the residue was treated with a sodium carbonate solution and extracted with ethyl acetate (3 x 30 ml). The combined organic phases were washed with brine (3 x 20 ml) and dried (Na2SO4). The product was purified by chromatography (0 to 80% ethyl acetate in hexane), yielding a colorless oil that was dissolved in diethyl ether (x 3) and evaporated (10.1 g).

1 H NMR (CDCl 3, 400 MHz) δ: 1.26 (6H, s), 1.46 (9H, s), 2.97 (2H, s), 3.60 (2H, s), 3.68 (3H, s), 4.26 (1H, s a), 7.05-7.07 (2H, m), 7.13-7.17 (1H, m), 7.22-7.26 (1H, m); LRMS ESI m / z 344 [M + Na] +.

Preparation 7 [3- (2- tert -butoxycarbonylamino-2-methylpropyl) phenyl] acetic acid

44

Preparation 6 (7.45 g, 23.0 mmol), a sodium hydroxide solution (5 M, 4.6 ml, 115 mmol), dioxane (30 ml) and water (8 ml) were stirred at RT for 18 h. The solvent is removed and the material dissolved in water, cooled and acidified at pH 3 with hydrochloric acid (2 M). The product was extracted with ethyl acetate (3 x 30 ml), the organic extracts were washed with brine (3 x 30 ml) and dried (Na2SO4). Oil resulting was dissolved in diethyl ether and evaporated, yielding a colorless gum (7.0 g).

1 H NMR (CD 3 OD, 400 MHz) δ: 1.23 (6H, s), 1.48 (9H, s), 2.96 (2H, s), 3.57 (2H, s), 7.04-7.06 (2H, m), 7.11-7.13 (1H, m), 7.18-7.22 (1H, m); EMBR IQPA m / z 308 [M + H] +.

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Preparation 8 (2- {3 - [(3,4-Dichlorobenzylcarbamoyl) methyl] phenyl} -1,1-dimethyl-ethyl) carbamic acid tert -butyl ester

Four. Five

3,4-Dichlorobenzylamine was added (1.30 ml, 9.76 mmol) to a solution of Preparation 7 (3.00 g, 9.76 mmol), hydroxybenzotriazole hydrate (1.50 g, 9.76 mmol), hydrochloride 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide  (1.87 g, 9.76 mmol) and triethylamine (4.07 ml, 11: 2 mmol) and the resulting solution was stirred at RT for 18 h. The solvent is removed and the crude material was taken up in ethyl acetate (50 ml), washed with water (30 ml), a solution of sodium carbonate (2 x 30 ml), brine (30 ml), hydrochloric acid (0.5 M, 2 x 30 ml) and brine (30 ml) and then dried (Na2SO4). The solid of The resulting white color was triturated with diethyl ether (3.1 g).

1 H NMR (CDCl 3, 400 MHz) δ: 1.25 (6H, s), 1.45 (9H, s), 2.97 (2H, s), 3.62 (2H, s), 4.22 (1H, s a), 4.34 (2H, d), 5.78 (1H, s a), 6.99-7.01 (1H, dd), 7.04 (1H, s), 7.07-7.09 (1H, d), 7.12-7.14 (1H, d), 7.22 (1H, d), 7.27 (1H, d), 7.32 (1H, d); LRMS APCI m / z 465 [M + H] +.

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Preparation 9 (2- {3 - [(3,4-Dimethylbenzylcarbamoyl) methyl] phenyl} -1,1 dimethyl-ethyl) carbamic acid tert -butyl ester

46

It was prepared using the acid of Preparation 7, the procedure described for Preparation 8 and 3,4-dimethylbenzylamine.

1 H NMR (CDCl 3, 400 MHz) δ: 1.19 (6H, s), 1.46 (9H, s), 2.20 (6H, d), 2.95 (2H, s), 3.59 (2H, s), 4.15 (1H, s a), 4.32 (2H, d), 5.59 (1H, s a), 6.86-6.93 (2H, m), 7.02-7.06 (3H, m), 7.13-7.15 (1H, d), 7.23-7.27 (1 H, m); LRMS APCI m / z 425 [M + H] +.

Preparation 10 2- [3- (2-Amino-2-metlipropyl) phenyl] - N - (3,4-dichlorobenzyl) acetamide

47

Preparation 8 (3.0 g, 6.50 mmol) in dioxane (5 ml) was treated with hydrogen chloride (4 M in dioxane, 20 ml) and The resulting solution was allowed to stir at RT for 18 h. He solvent was removed and the compound was dissolved again in methanol (x 2) and evaporated, and then the resulting gum was suspended in diethyl ether (x 2) and evaporated, yielding a colored solid white (2.7 g). P.f. (ethyl acetate-methanol) 214-216 ° C (dec.).

1 H NMR (CD 3 OD, 400 MHz) δ: 1.33 (6H, s), 2.90 (2H, s), 3.59 (2H, s), 4.35 (2H, s), 7.13-7.19 (3H, m), 7.24-7.27 (1H, m), 7.31-7.38 (2H, m), 7.42 (1H, d); EMBR IEN m / z 365 [M + H] +.

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Preparation 11 2- [3- (2-Amino-2-methylpropyl) phenyl] - N - (3,4-dimethylbenzyl) acetamide

48

It was prepared using the amide of Preparation 9 and the procedure described for Preparation 10.

1 H NMR (CD 3 OD, 400 MHz) δ: 1.32 (6H, s), 2.21 (6H, s), 2.89 (2H, s), 3.56 (2H, s), 4.29 (2H, s), 6.95-7.05 (3H, m), 7, 14-7, 16 (2H, m), 7.24-7.26 (1H, m), 7.31-7.35 (1 H, m); LRMS m / z 325 [M + H] +.

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Preparation 12 N - {2-Benzyloxy-5 - [(1 R ) -2-bromo-1- ( tert -butyldimethyl-silanyloxy) ethyl] phenyl} formamide

49

To a solution of N - [2-benzyloxy-5- (2-bromo-1-hydroxyethyl) phenyl] formamide (Organic Process Research and Development 1998, 2, 96-99) (4.12 g, 11.8 mmol) in N , N- dimethylformamide (25 ml) at RT in a N 2 atmosphere, tert- butyldimethylsilyl chloride (3.50 g, 23.2 mmol), imidazole (1.90 g, 27.9 mmol) were added ) and 4- (dimethylamino) pyridine (40 mg, 330 µmol). The resulting solution was stirred at RT overnight, the solvent was removed and the product was taken up in ethyl acetate (70 ml). The organic extracts were washed with water (100 ml), and the aqueous phase was extracted with ethyl acetate (20 ml). The combined organic extracts were washed with hydrochloric acid (2 M, 50 ml) and brine (100 ml) and dried (MgSO 4). The crude material was purified by chromatography (5-25% ethyl acetate in pentane), yielding a colorless oil (5.7 g).

1 H NMR (CDCl 3, 400 MHz) δ: of -0.08 to -0.05 (3H, m), 0.09-0.11 (3H, s), 0.89-0.90 (9H, m), 3.38-3.55 (2H, m), 3.78-3.84 (1H, m), 5.06-5.11 (2H, m), 6.90-6.97 (1H, m), 7.03-7.12 (1H, m), 7.24 (m), 7.36-7.43 (5H, -m), -7.67-7.78 (m), 7.88 (d), 8.74 (d); EMBR APCI m / z 464/466 [M + H] +.

Preparation 13 2- (3- {2 - [(2 R ) -2- (4-Benzyloxy-3-formylaminophenyl) -2- ( tert -butyl-dimethylsilanyloxy) ethylamino] -2-methylpropyl} phenyl) - N - (3, 4-dichlorobenzyl) acetamide

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fifty

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Preparation 12 (500 mg, 1.08 mmol) and the Preparation 10 (780 mg, 216 mmol) was heated and stirred at 90 ° C for 24 h. After cooling, the material will dissolved in methanol and evaporated, the material was suspended in ether diethyl and the precipitate was filtered off. The filtrate is evaporated and the material was purified by chromatography (methanol at 0-5% in dichloromethane), then suspended in ether diethyl (x 3) and evaporated, producing a foam (425 mg).

1 H NMR (CD 3 OD, 400 MHz) δ: of -0.20 to -0.18 (3H, m), from -0.04 to 0.00 (3H, m), 0.78-0.81 (9H, m), 1.01-1.03 (3H, m), 1.05 (3H, s a), 2.62-2.74 (3H, m), 2.83-2.88 (1H, m), 3.52 (2H, d), 4.31 (2H, s), 4.68-4.71 (1H, m), 5.17-5.19 (2H, m), 7.00-7.23 (7H, m), 7.29-7.41 (5H, m), 7.44-7.49 (2H, m), 8.57 (s); LRMS ESI m / z 748 [M + H] +; EMAR C_ {41} H_ {51} Cl_ {N} {3} O4 {Yes} 748,3099 [M + H] + found 748,3066.

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Preparation 14 2- (3- {2 - [(2 R ) -2- (4-Benzyloxy-3-formylaminophenyl) -2- ( tert -butyl-dimethylsilanyloxy) ethylamino] -2-methylpropyl} phenyl) - N - (3, 4-dimethylbenzyl) acetamide

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It was prepared using the amide of Preparation 13, the bromide of Preparation 12 and the procedure described for Preparation 11.

1 H NMR (CDCl 3, 400 MHz) δ: -0.17, -0.16 (3H, 2 xs), from -0.05 to -0.01 (3H, m), 0.78-0.82 (9H, m), 0.97-1.01 (6H, m), 2.19 (3H, s), 2.20 (3H, s), 2.56-2, 90 (4H, m), 3.54-3.63 (2H, m), 4.28-4.35 (2H, m), 4.67-4.74 (1H, m), 5.06- 5.09 (2H, m), 5.58-5.62 and 5.99-6.03 (1H, m), 6.87-7.25 (9H, m), 7.35-7.44 (5H, m), 7.68-7.79 (1H, m), 8.30 (d), 8.43 (d), 8.71 (s), 8.74 (s); LRMS ESI m / z 748 [M + H] +; HRMS C 43 H 57 N 3 O 4 Si 708.4191 [M + H] + found
708.4156.

Preparation 15 N -Benzyl-2- (3- {2 - [(2 R ) -2- ( tert -butyldimethylsilyloxy) -2- (3-formylamino-4-hydroxyphenyl) ethylamino] -2-methylpropyl} phenyl) acetamide

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Preparation 13 (100 mg, 134 µmol) and Palladium on carbon (10%, 20 mg) in methanol (10 ml) is hydrogenated at 344.74 kPa (50 psi) / RT for 6 h. The mixture is filtered through a "filter aid" and solvent he retired. The material was suspended in a carbonate solution sodium acid and extracted with ethyl acetate (30 ml). The phase organic was washed with sodium carbonate solution and brine (2 x ml) and dried (Na2SO4). The material resulting was suspended in diethyl ether (x 3) and evaporated, producing a film (24 mg).

1 H NMR (CD 3 OD, 400 MHz) δ: -0.19 (3H, s), -0.02 (3H, s), 0.79 (9H, s), 1.04, (3H, s), 1.07 (3H, s), 2.62-2.89 (4H, m), 3.48-3.56 (2H, dd), 4.35 (2H, s), 4.61 (1H, s a), 4.69-4.72 (1H, m), 5.17-5.19 (2H, m), 6.79-6.85 (1H, m), 6.91-6.94 (1H, m), 7.04-7.06 (1H, m), 7.11-7.28 (7H, m), 8.12 (1H, d), 8.27, 8.59 (1H, 2 x s); LRMS ESI m / z 590 [M + H] +; EMAR C_ {34} H_ {47} N3 O4 {Yes} 590.3402 [M + H] + found 590.3409.

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Preparation 16 2- (3- {2 - [(2 R ) -2- ( tert- Butyl dimethylsilanyloxy) -2- (3-formylamino-4-hydroxyphenyl) ethylamino] -2-methylpropyl} phenyl) - N - (3,4- dimethylbenzyl) acetamide

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53

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It was prepared using the amide of Preparation 14 and the procedure described for Preparation 15. The product was purified by chromatography (methanol at 0-3.5% in dichloromethane + 0.3% ammonia), producing a foam (85 mg).

1 H NMR (CD 3 OD, 400 MHz) δ: of -0.20 to -18 (3H, m), -0.03-0.00 (3H, m), 0.79-0.81 (9H, m), 1.02-1.05 (6H, m), 2.19 (3H, s), 2.20 (3H, s), 2.61-2.73 (3H, m), 2.83-2.88 (1H, m), 3.46 (2H, dd), 4.27 (2H, s), 4.65 (1H, dd), 6.78-7.22 (8H, m), 8.12 (d), 8.27 (s), 8.59 (s); LRMS ESI m / z 618 [M + H] +; EMAR C 36 H 51 N 3 O 4 Si 618.3722 [M + H] + found 618.3701.

Preparation 17 (3-Bromophenyl) methyl acetate

54

Acetyl chloride (0.7 ml, slowly added 9.3 mmol) to an acid solution (3-bromophenyl) acetic acid (20.0 g, 93 mmol) in methanol (500 ml) at 0 ° C under a nitrogen atmosphere and the reaction it was allowed to warm gradually to room temperature during a 5 hour period. The solvent was removed in vacuo and the oil residual was dissolved again in dichloromethane, dried over sodium sulfate and concentrated in vacuo to give the compound of title in the form of a colorless oil (20.6 g).

1 H NMR (400 MHz, CDCl 3): δ: 3.59 (2H, s), 3.70 (3H, s), 7.17-7.24 (2H, m), 7.37-7.45 (2H, m); EMBR IEN m / z 253 [M + Na] +.

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Preparation 18 [3- (2-Oxopropyl) phenyl] acetate methyl

55

Tributyltin methoxide (28.3 ml, 98 mmol), the product of preparation 17 (15.0 g, 65 mmol), isopropenyl acetate (10.8 ml, 98 mmol), palladium acetate (II) were stirred together ) (750 mg, 3.30 mmol) and tri- ortho- tolylphosphine (2.0 g, 6.5 mmol) in toluene (75 ml) at 100 ° C for 5 hours. After cooling, the reaction was diluted with ethyl acetate (150 ml) and a 4M aqueous solution of potassium fluoride (90 ml) and stirred for 15 minutes. The mixture was filtered through Arbocel® and the organic phase was separated and concentrated in vacuo. Then, the residue was purified by column chromatography on silica gel eluting with diethyl ether: pentane, from 0: 100 to 25:75, followed by dichloromethane, to give the title compound as a pale yellow oil with a 94% yield (12.6 g).

1 H NMR (400 MHz, CDCl 3): δ: 2.15 (3H, s), 3.61 (2H, s), 3.69 (5H, s), 7.10-7.13 (2H, m), 7.19 (1H, d), 7.30 (1H, t); EMBR ESI: m / z 229 [M + Na] +.

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Preparation 19 [3 - ((2 R ) -2 - {[(1 R ) -1-phenylethyl] amino} propyl) -phenyl] methyl acetate hydrochloride

56

A solution of the product of Preparation 18 (8.5 g, 41.2 mmol), ( R ) -? -Methyl benzylamine (4.8 ml, 37.2 mmol), sodium triacetoxyborohydride (11.6 g, 56 mmol) and acetic acid (2.2 ml, 38 mmol) in dichloromethane (400 ml) was stirred at room temperature for 48 hours. The reaction mixture was quenched by the addition of a saturated solution of sodium acid carbonate (200 ml) and allowed to stir until the effervescence ceased. The aqueous phase was separated and extracted with dichloromethane (100 ml). Then, the combined organic solution was dried over magnesium sulfate and concentrated in vacuo. Purification by column chromatography on silica gel, eluting with dichloromethane: methanol: ammonia, from 99: 1: 0.1 to 95: 5: 0.5, gave a 4: 1 mixture of diastereomers ( R , main R ) in the form of a pale yellow oil (8.71 g). Treatment with hydrogen chloride (40 ml of a 1 M solution in methanol, 40 mmol) followed by three successive crystallizations (diisopropyl ether / methanol) gave the title compound as a white crystalline solid with a yield of 50 %, 5.68 g.

1 H NMR (400 MHz, CD 3 OD): δ: 1.18 (3H, d), 1.68 (3H, d), 2.60-2.66 (1H, m), 3.15-3.26 (1H, m), 3.25-3.30 (1H, m), 3.31 (3H, s), 3.62 (2H, s), 4.59 (1H, c), 6.99-7.02 (2H, m), 7.17 (1H, m), 7.25-7.28 (1H, m), 7.48-7.52 (5H, m) LRMS ESI m / z 312 [M + H] +.

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Preparation 20 {3 - [(2 R ) -2-Aminopropyl] phenyl} methyl acetate

57

A solution of the product of Preparation 19 (7.69 g, 22 mmol) and ammonium formate (6.94 g, 110 mmol) was heated at 75 ° C in the presence of 20% palladium hydroxide on carbon vegetable (2.00 g). After 90 minutes, the reaction mixture is cooled to room temperature, filtered through Arbocel® and the Filtrate was concentrated in vacuo. The residue was distributed between dichloromethane (100 ml) and 0.88 ammonia (100 ml) and the phases are separated. The aqueous phase was extracted with dichloromethane (100 ml) and the Combined organic solution was dried over magnesium sulfate and concentrated in vacuo to provide the title compound as of a colorless oil with a quantitative yield (4.78 g).

1 H NMR (400 MHz, CD 3 OD): δ: 1.06 (3H, d), 2.57-2.67 (2H, m), 3.05-3.12 (1H, m), 3.63 (2H, s), 3.67 (3H, s), 7.09-7.13 (3H, m), 7.23-7.27 (1H, t); LRMS ESI m / z 208 [M + H] +.

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Preparation 21 (3 - {(2 R ) -2 - [( tert -Butoxycarbonyl) amino] propyl} phenyl) methyl acetate

58

The title compound was prepared from the product of preparation 20 and di- tert-butyl dicarboxylate, using a procedure similar to that of preparation 6, in the form of a yellow oil with a yield of 97%.

1 H NMR (400 MHz, CD 3 Cl 3): δ: 1.07 (3H, d), 1.43 (9H, s), 2.61 (1H, dd), 2.81 (1H, dd), 3.60 (2H, s), 3.69 (3H, s), 3.89 (1H, s a), 4.36 (1H, s a), 7.06-7.19 (3H, m), 7.22-7.27 (1H, m); LRMS APCI m / z 306 [M-H] -

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Preparation 22 (3 - {(2r) -2 - [( tert -butoxycarbonyl) amino] propyl} phenyl) acetic acid

59

A mixture of preparation 21 (8.31 g, 27.1 mmol) and a solution of lithium hydroxide (1 M in water, 54 ml, 54 mmol) in tetrahydrofuran (100 ml) was stirred at room temperature for 20 hours Then, the reaction mixture was concentrated at vacuum and the acid residue was acidified to pH 2 with hydrochloric acid 2 M. The mixture was then extracted with ethyl acetate (3 x 75 ml) and The combined organic solution was washed with brine (100 ml), dried over magnesium sulfate and concentrated in vacuo, providing the title compound in the form of an oil of yellow color with a yield of 82% (6.50 g).

1 H NMR (400 MHz), CD 3 Cl 3): δ: 1.07 (3H, d), 1.40 (9H, s), 2.61 (1H, dd), 2.77-2.88 (1H, s a), 3.62 (2H, s), 3.89 (1H, s a), 4.39 (1H, s a), 7.07-7.16 (3H, m), 7.22-7.27 (1 H, m); EMBR IQPA m / z 292 [M-H]

Preparation 23 (3 - {(2 R ) -2 - [( tert -Butoxycarbonyl) amino] propyl} phenyl) benzyl acetate

60

The product of preparation 22 (6.30 g, 21.5 mmol), hydrochloride 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide  (4.14 g, 21.5 mmol), 1-hydroxybenzotriazole hydrate (3.30 g, 21.5 mmol) and triethylamine (4.85 ml, 43 mmol) were stirred together in dichloromethane (100 ml) for 10 minutes at temperature ambient. Then, benzyl alcohol (2.2 ml, 21.5 mmol) was added and the mixture was stirred at room temperature for 18 hours. Then, the reaction mixture was diluted with dichloromethane (50 ml), washed with sodium carbonate solution (100 ml) and brine (100 ml), dried over magnesium sulfate and concentrated under vacuum, providing the title compound as a transparent oil with a yield of 50%, 4.16 g.

1 H NMR (400 MHz, CD 3 Cl 3): δ: 1.04 (3H, d), 1.44 (9H, s), 2.59 (1H, dd), 2.81 (1H, dd), 3.64 (2H, s), 3.87 (1H, s a), 4.34 (1H, s a), 5.13 (2H, s), 7.07-7.11 (2H, m), 7.13 (1H, d a), 7.22-7.27 (1H, m), 7.29-7.38 (5H, m); LRMS APCI m / z 382 [M-H] -.

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Preparation 24 {3 - [(2 R ) -2-Aminopropyl] phenyl} benzyl acetate

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Hydrogen chloride (4 M in dioxane, was added, 5.43 ml, 21.72 mmol) to a solution of the product of the preparation 23 (4.16 g, 10.86 mmol) in dioxane (50 ml) and the resulting solution It was stirred at room temperature for 72 hours. The solvent is removed in vacuo and the residue was dissolved in dichloromethane and washed with a solution of sodium acid carbonate (50 ml) and brine (50 ml) Then, the organic solution was dried over sulfate. magnesium was concentrated in vacuo to provide the compound of title in the form of a yellow oil with a yield 93% (2.85 g).

1 H NMR (400 MHz, CD 3 Cl 3): δ: 1.09 (3H, d), 1.55 (2H, s a), 2.48 (1H, dd), 2.66 (1H, dd), 3.10-3.18 (1H, m), 3.65 (2H, s), 5.17 (2H, s), 7.09-7.13 (2H, m), 7.14-7.18 (1H, d a), 7.24-7.38 (6H, m); EMBR IQPA m / z 284 [M-H] -.

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Preparation 25 (3 - {(2 R ) -2 - [((2 R ) -2- [4- (Bencyloxy) -3- (formylamino) phenyl] -2 - {[ tert -butyl (dimethyl) silyl] oxy} ethyl ) amino] -propyl} phenyl) benzyl acetate

62

The title compound was prepared from the products of preparation 12 and preparation 24, using a procedure similar to that of preparation 13, in the form of an oil brown with a yield of 25%.

LRMS APCI m / z 667 [M + H] +.

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Preparation 26 {3 - [(2 R ) -2 - ({(2 R ) -2 - {[ tert -Butyl (dimethyl) silyl) oxy} -2- [3- (formylamino) -4-hydroxyphenyl] ethyl} amino ) propyl] phenyl} acetic

63

The product of preparation 25 (851 mg, 1.27 mmol) and 10% Pd / C (50 mg) were suspended in methanol and the mixture stirred under an atmosphere of 413.69 kPa (60 psi) of hydrogen gas, at room temperature for 72 hours. Then the mixture of reaction was filtered through a Filter aid® and the filtrate was concentrated in vacuo, providing the title product as of a brown foam with a yield of 94%, 580 mg

1 H NMR (400 MHz, CDCl 3): δ: -0.09 (3H, s), 0.08 (3H, s), 0.88 (9H, s), 1.12.1.24 (3H, 2 x d), 2.07-2.82 (2H, m), 2.99 (1H, dd), 3.18 (1H, dd), 3.60 (2H, s), 4.16-4.22 (1H, m), 4.97-5.07 (1H, m), 6.87 (1H, d), 6.99-7.32 (6H, m), 7.93 (s), 8.17, (d), 8.33 (s); LRMS APCI m / z 487 [M + H] -.

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Preparation 27 2- {3 - [(2 R ) -2 - ({(2 R ) -2 - {[ tert -Butyl (dimethyl) silyl) oxy} -2- [3- (formylamino) -4-hydroxyphenyl] ethyl} amino) propyl] phenyl} - N - [4- (dimethyl-amino) benzyl] acetamide

64

A mixture of the product of preparation 26 (100 mg, 206 µmol), hydroxybenzotriazole hydrate (32 mg, 206 um), hydrochloride 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (40 mg, 206 µmol) and triethylamine (58 µL, 412 µmol) in N, N-dimethylformamide (2 ml) was stirred at temperature ambient for 10 minutes. Then, it was added 4- (dimethylamino) benzylamine (31 mg, 206 µmol) and the mixture It was stirred at room temperature for 20 hours. After the solvent was removed in vacuo and the residue was diluted with dichloromethane, washed with sodium carbonate solution (20 ml) and brine (20 ml), dried over magnesium sulfate and concentrated in vacuo to provide the title compound as of a brown gum with a yield of 10%, 131 mg.

1 H NMR (400 MHz, CD 3 Cl 3): 0.17 (3H, s), 0.00 (3H, s), 0.83 (9H, s), 1.08 (3H, m), 2.80-3.00 (10H, m), 3.47 (1H, m), 3.66 (2H, m), 4.23 (2H, m), 5.48 (1H, m), 6.66 (1H, d), 6.70-7.23 (10H, m), 7.97 (m), 8.27 (s); EMBR IQPA m / z 504 [M + H] -.

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Preparations 28 a 29

The following compounds, of general formula shown below, were prepared from the product of preparation 26 and the appropriate amine, using a procedure similar to that described for preparation 27. The reactions are monitored by TLC analysis and stirred at temperature Ambient for 18-72 hours.

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Preparation 28: Can be prepared N- [4- (aminomethyl) phenyl] acetamide as described in J. Med. Chem, 46.3116; 2003

Preparation 29: Can be prepared 4- (aminomethyl) benzamide as described in WO 02085860 p. 239

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Preparation 30 [3 - ((2 R ) -2 - {[(1 R ) -1-Phenylethyl] amino} propyl) phenyl] acetic acid

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A solution of lithium hydroxide (1 M in water, 90 ml, 90 mmol) to a solution of the product of the Preparation 19 (13.50 g, 43.5 mmol) in methanol (200 ml) and the mixture It was stirred at room temperature for 18 hours. Then at reaction mixture was added 1M hydrochloric acid (90 ml) and the methanol was removed in vacuo. The resulting precipitate was removed by filtration and washed with water (20 ml) and a mixture of ethanol / ether diethyl, 20:80, providing the title compound as a solid with a yield of 91%, 11.8 g.

1 H NMR (400 MHz, CD 3 OD) δ: 1.16 (3H, d), 1.62 (3H, d), 2.66-2.62 (1H, m), 3.13-3.26 (2H, m), 3.46 (2H, s), 4.48-4.56 (1H, c), 6.92 (1H, d), 7.19 (1H, s), 7.18-7.22 (2H, m), 7.45-7.52 (5H, m); LRMS ESI m / z 298 [M + H] +.

Preparation 31 N -1-adamantyl-2- [3 - ((2 R ) -2 - {[(1 R ) -1-phenylethyl] amino} propyl) phenyl] acetamide

67

1-Adamantylamine was added (5.44 g, 36.0 mmol) and triethylamine (15 ml, 108 mmol) at a solution of the product of preparation 30 (10.7 g, 36.0 mmol) in dichloromethane (200 ml). Then, hexafluorophosphate was added 2-Chloro-1,3-dimethylimidazolidinium (10.0 g, 36.0 mmol) and the mixture was stirred at room temperature for 2 hours The reaction mixture was washed with water and the organic solution was dried over magnesium sulfate and concentrated under vacuum Purification of the residue by column chromatography on silica gel, eluting with dichloromethane: methanol: ammonia 0.88, 95: 5: 0.5, provided the product as a foam with a quantitative yield, 17.6 g.

1 H NMR (400 MHz, CD 3 OD) δ: 0.89 (3H, d), 1.35 (3H, d), 1.65-1.75 (6H, m), 1.98 (6H, m), 2.04 (3H, m), 2.37-2.42 (1H, dd), 2.65-2.74 (1H, m), 2.95-3.00 (1H, dd), 3.36 (2H, s), 3.98 (1H, c), 6.89 (1H, d), 6.98 (1H, s), 7.09 (1H, d), 7.17 (1H, t), 7.22-7.27 (1H, m), 7.30-7.38 (4H, m); EMBR IEN m / z 431 [M + H] +.

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Preparation 32 N -1-adamantyl-2- {3 - [(2 R ) -2-aminopropyl] phenyl} -acetamide

68

The title compound was prepared from Preparation 31, using a procedure similar to that of the Preparation 20, in the form of a solid with a yield of 92%

1 H NMR (400 MHz, CD 3 OD) δ: 1.09 (3H, d), 1.66-1.72 (6H; m); 2.00 (6H, m), 2.03 (3H, m), 2.58-2.70 (2H, m), 3.10-3.16 (1H, c), 3.40 (2H, s), 7.05-7.28 (4H, m); EMBR IEN m / z 327 [M + H] +.

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Preparation 33 2- (3 - {(2 R ) -2 - [((2 R ) -2- [3- (Acetylamino) -4- (benzyloxy) phenyl] -2 - {[ tert -butyl (dimethyl) silyl] oxy } ethyl) amino] propyl} -phenyl) - N -1-adamantylacetamide

69

A mixture of the products of preparation 12 (696 mg, 1.5 mmol) and of preparation 32 (978 mg, 3.0 mmol) in dichloromethane (0.5 ml) was heated at 90 ° C for 5 minutes allowing dichloromethane to evaporate. Then the mixture The reaction was heated as a melt at 90 ° C for 18 hours before cooling to room temperature. The product crude was then purified by column chromatography on gel of silica, eluting with dichloromethane: methanol: 0.88 ammonia, 98: 2: 0.2, providing the title compound as a Pale color foam with a yield of 59%, 630 mg.

1 H NMR (400 MHz, CD 3 OD) δ: -0.18 (3H, s), 0.00 (3H, s), 0.83 (9H, s), 1.05-1.08 (d, 3H), 1.66-1.72 (6H, m), 2.00 (6H, m), 2.02 (3H, m), 2.52-2.71 (3H, m), 2.84-2.96 (2H, m), 3.36-3.41 (2H, m), 4.68-4.72 (1H, m), 5.20 (2H, s), 6.92-7.18 (6H, m), 7.30-7.50 (5H, m), 8.22 (m), 8.36 (s), 8.54 (s); EMBR IEN m / z 710 [M + H] +.

Preparation 34 N -Adamantan-1-yl-2- (3- {2 - [(2 R ) -2 - ({(2 R ) -2- ( tert -butyldimethylsilyloxy) -2- (3-formylamino-4-hydroxyphenyl) ethylamino] propyl} phenyl) acetamide

70

The title compound was prepared from product of preparation 33, using a procedure similar to of preparation 20, in the form of a transparent foam with a quantitative yield

1 H NMR (400 MHz, CD 3 O) δ -0.17 (3H, s), 0.00 (3H, s), 0.83 (9H, s), 1.04-1.06 (d, 3H), 1.69-1.70 (6H, m), 2.00 (6H, m), 2.03 (3H, m), 2.52-2.70 (3H, m), 2.88-2.94 (2H, m), 3.37-3.38 (2H, m), 4.64-4.69 (1H, m), 6.92-7.18 (6H, m), 8.00 (1H, d), 8.30 (s), 8.56 (s); EMBR IEN m / z 620 [M + H] +.

Preparation 35 1- (3-Bromophenyl) -2-methylpropan-2-ol)

71

Methylmagnesium bromide was added slowly (a 3M solution in diethyl ether, 51.6 ml, 155 mmol) at a solution of 1- (3-Bromo-phenyl) propan-2-one (15.0 g, 70 mmol) in dry diethyl ether (200 ml) at 0 ° C and the mixture It was stirred for 3 hours. Then, the reaction mixture was cooled. again at 0 ° C and slowly quenched with an aqueous solution saturated ammonium chloride. The organic solution was washed with brine, dried over sodium sulfate and concentrated in vacuo. Then, the yellow residual oil was purified by column chromatography on silica gel eluting with dichloromethane: pentane: methanol, 90: 5: 5, providing an oil of pale yellow color with a yield of 83%, 13.26 g.

1 NMR (400 MHz, CDCl 3) δ 1.22 (6H, s), 1.42 (1H, s a), 2.74 (2H, s), 7.15 (2H, m), 7.40 (2H, m).

Preparation 36 N - [2- (3-bromophenyl) -1,1-dimethylethyl] -2-chloroacetamide

72

Chloroacetonitrile (6.63 ml, 105 mmol) was added to a stirred solution of the product of preparation 35 (12.0 g, 52.0 mmol) in acetic acid (25 ml) at room temperature. The resulting solution was cooled to 0 ° C and concentrated. Acid was added sulfuric (25 ml) while the temperature remained below of 10 ° C. The resulting solution was allowed to stir for 1 hour, then poured on ice and made basic by adding of solid potassium carbonate. The product was extracted with acetate ethyl (23,500 ml) and the combined organic solution was washed with water (50 ml), dried over sodium sulfate and concentrated in vacuo, providing the title compound as a solid of Orange color with a quantitative yield, 16.08 g.

1 H NMR (400 MHz, CDCl 3) δ: 1.37 (6H, s), 3.02 (2H, s), 3.94 (2H, s), 6.17 (1H, s a), 7.08-7.03 (1H, d), 7.10-7.13 (1H, t), 7.26 (1H, s), 7.39-7.32 (1H d,); EMBR IEN m / z 306 [M + H] +; Microanalysis: C 12 H 15 BrClNO requires: C 47.32; H, 4.96; N, 4.60; found C 47.26; H 4.87; N 4.65.

Preparation 37 2- (3-Bromophenyl) -1,1-dimethylethylamine

73

A solution of the product of preparation 36 (32.0 g, 105 mmol), thiourea (9.60 g, 126 mmol) and acetic acid (50 ml) in ethanol (250 ml) was refluxed overnight. The reaction mixture was cooled to room temperature and filtered. He filtrate was concentrated in vacuo, basified using a solution aqueous sodium hydroxide (1 M, 450 ml) and extracted with dichloromethane (2 x 500 ml). The combined organic solution was washed with brine (50 ml), dried over sodium sulfate and concentrated under vacuum, providing the title compound as a black oil with a yield of 96%, 23 g.

1 H NMR (400 MHz, CDCl 3) δ: 1.12 (6H, s), 1.84 (2H, s a), 2.62 (2H, s), 7.16-7.08 (2H, m), 7.36-7.32 (2H, m); EMBR IEN m / z 228 [M + H] +.

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Preparation 38 [2- (3-Bromophenyl) -1,1-dimethylethyl] carbamic acid tert -butyl ester

74

The product of preparation 37 (5.0 g, 22 mmol) was treated with di- tert-butyl dicarbonate (5.26 g, 24 mmol) in dichloromethane (50 ml) and stirred for 20 hours. The reaction mixture was washed with water (50 ml) and the combined organic solution was dried over sodium sulfate and concentrated in vacuo. The crude material was purified using a cation exchange column (methanol followed by 2M ammonia in methanol), followed by purification by flash column chromatography on silica gel eluting with dichloromethane, to give the title compound as an oil of Brown color with a quantitative yield, 7.23 g.

1 H NMR (400 MHz, CDCl 3) δ: 1.27 (6H, s) 1.50 (9H, s), 2.97 (2H, s), 4.24 (1H, s a), 7.05 (1H, d), 7.15-7.11 (1H, t), 7.30 (1H, s), 7.35 (1H, d); EMBR ESI m / z 350 [M + NH4] +.

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Preparation 39 3- {2 - [( tert -Butoxycarbonyl) amino] -2-methylpropyl} benzyl benzoate

75

A solution of the product of preparation 38 (3.9 g, 12 mmol), [1,1'-bis (diphenylphosphino) ferrocene] dichloropaladium  (II) (1.00 g, 1.3 mmol) and triethylamine (3.3 ml, 24 mmol) in alcohol benzyl (60 ml) was heated at 100 ° C in an atmosphere of 649.48 kPa (100 psi) of carbon monoxide for 5 hours. Then the mixture cooled reaction was filtered through Arbocel® and the filtrate concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with sodium carbonate solution (50 ml) and brine (2 x 50 ml). The organic solution was then dried over sodium sulfate and concentrated in vacuo, giving a colored oil black. This oil was purified by column chromatography on silica gel, eluting with hexane: ethyl acetate, from 100: 0 to 84:16, providing the title compound in the form of an oil pale yellow with a yield of 61%, 2.81 g.

1 H NMR (400 MHz, CDCl 3) δ: 1.25 (6H, s), 1.45 (9H, s), 3.05, (2H, s), 4.22 (1H, s a), 5.35 (2H, s), 7.32-7.48 (7H, m), 7.86 (1H, s), 7.93-7.97 (1H, m).

Preparation 40 Hydrochloride 3- (2-amino-2-methylpropyl) benzoate of benzyl

76

The title compound was prepared from product of preparation 39, using a procedure similar to of preparation 24, in the form of a white solid with a 91% yield.

1 H NMR (400 MHz, CD 3 OD) δ: 1.33 (6H, s), 2.98 (2H, s), 5.37 (2H, s), 7.31-7.53 (7H, m), 7.93 (1H, s), 8.00-8.04 (1H, m); EMBR IQPA m / z 284 [M + H] +.

Preparation 41 3- {2 - [((2 R ) -2- [4- (Benzyloxy) -3- (formylamino) phenyl] -2 - {[ tert -butyl (dimethyl) silyl] oxy} ethyl) amino] -2- methylpropyl} benzyl benzoate

77

A mixture of the product of preparation 40 (1.81 g, 6.38 mmol), preparation 12 (2.96 g, 6.38 mmol) and potassium carbonate (1.76 g, 12.8 mmol) in dimethylsulfoxide (10 ml) It was heated at 95 ° C for 40 hours. Then the reaction mixture cooled was diluted with water (250 ml) and extracted with acetate ethyl (3 x 50 ml.). The combined organic solution was washed with a sodium carbonate solution (50 ml) and brine (2 x 50 ml), dried over sodium sulfate and concentrated in vacuo, giving a orange oil This oil was purified by chromatography. in column on silica gel, eluting with dichloromethane: hexane, 50:50, followed by dichloromethane: methanol, from 100: 0 to 98: 2. The appropriate fractions were evaporated under reduced pressure and the residue it was further purified by column chromatography on gel of silica, eluting with dichloromethane: methanol, from 100: 0 to 98: 2, Giving a yellow gum. Then the colored rubber yellow was azeotropically distilled with diethyl ether (x 3), providing the title compound in the form of a yellow gum with a yield of 20%, 0.83 g.

1 H NMR (400 MHz, CDCl 3): δ: of -0.15 to -0.17 (3H, m), -0.03 (3H, s), 0.79-0.82 (9H, s), 1.01 (3H, s), 1.04 (3H, s), 2.62-2.86 (4H, m), 4.66-4.74 (1H, m), 5.06-5.07 (2H, m), 5.36 (2H, s), 6.88 (1H, d), 7.01-7.05 (1H, m), 7.27-7.50 (12H, m), 7.74 (1H, m), 7.87-7.96 (2H, m), 8.39 (s), 8.40 (s), 8.76 (s), 8.78 (s); LRMS APCI m / z 667 [M + H] -.

Preparation 42 3- [2 - ({(2 R ) -2 - {[ tert -butyl (dimethyl) silyl] oxy} -2- [3- (formylamino) -4-hydroxyphenyl] ethyl} amino) -2-methylpropyl acid] benzoic

78

The title compound was prepared from product of preparation 41, using a procedure similar to of preparation 26. The crude product was distilled off azeotropically with diethyl ether (x 3), providing the title compound in the form of a pale yellow solid with a yield of 97%.

1 H NMR (400 MHz, CD 3 OD) δ: -0.12 (3H, s), 0.05 (3H, s), 0.81 (9H, s), 1.24 (6H, s), 2.98 (2H, dd), 3.26-3.30 (2H, m), 4.91 (1H, t), 6.89 (1H, d), 7.02 (1H, m), 7.37-7.49 (2H, m), 7.85 (1H, s a), 7.93-7.96 (1H, d), 8.11 (s, 1H), 8.32 (s), 8.61 (s); LRMS ESI m / z 4.87 [M + H] -.

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Preparation 43 (4-Hydroxy-2,5-dimethylphenyl) acetonitrile

79

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 boron tribromide (1 M in dichloromethane, 14.3 ml, 14.3 mmol). The reaction mixture was stirred. at -80 ° C for another 30 minutes and then left heat at room temperature for a period of 2 hours. The reaction mixture was quenched with a saturated solution of sodium carbonate (20 ml) and the organic phase was separated. The Organic solution was washed with brine (20 ml), dried over sodium sulfate and concentrated in vacuo to provide a solid of light brown color Purification by column chromatography on silica gel, eluting with 20:80 to 33:67 acetate ethyl: pentane, provided the title compound as a colorless solid with a yield of 60% in a dispersion of mineral oil, 0.28 g.

1 H NMR (400 MHz, CD 3 OD) δ: 2.13 (3H, s), 2.23 (3H, s), 3.66 (2H, s), 6.60 (1H, s), 6.98 (1H, s); LRMS ESI m / z 160 [M-H] -.

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Preparation 44 (4-Hydroxy-2,3-dimethyl-phenyl) acetonitrile

80

The title compound was prepared from (4-methoxy-2,3-dimethylphenyl) acetonitrile using a procedure similar to that of preparation 43, in form of a colorless solid with a yield of 94%.

1 H NMR (400 MHz, CDCl 3) δ: 2.20 (3H, s), 2.24 (3H, s), 3.62 (2H, s), 6.64 (1H, d), 7.03 (1H, d); LRMS APCI m / z 160 [M-H] -.

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Preparation 45 (4-Hydroxy-3-methylphenyl) acetonitrile

81

The title compound was prepared from (4-methoxy-3-methylphenyl) acetonitrile using a procedure similar to that of preparation 43, in form of a pale yellow solid.

1 H NMR (400 MHz, CDCl 3) δ: 2.25 (3H, s), 3.65 (2H, s), 4.98 (1H, s a), 6.76 (1H, d), 7.01 (1H, d), 7.07 (1H, s); EMBR IEN m / z 146 [M-H] -.

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Preparation 46 4- (2-aminoethyl) -2,5-dimethylphenol

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82

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A solution of the product of preparation 43 (0.28 g, 1.74 mmol) in ethanol (15 ml) was hydrogenated at 413.69 kPa (60 psi) on Raney Nickel® (0.1 g, 50% p / p) for 16 hours. Then, the reaction mixture was filtered and the solvent removed in vacuo. The residue was purified using a cation exchange resin, eluting with methanol and then 1M ammonia in methanol, to provide the title compound as an oil.
colorless.

1 H NMR (400 MHz, CD 3 OD) δ: 2.11 (3H, s), 2.19 (3H, s), 2.63-2.67 (2H, m), 2.72-2.76 (2H, m), 6.54 (1H, s), 6.81 (1H, s); EMBR ESI m / z 166 [M + H] +.

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Preparation 47 4- (2-Amino-ethyl) -2,3-dimethyl-phenol

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83

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The title compound was prepared from product of preparation 44 using a procedure similar to that of Preparation 46, in the form of a colorless solid with a yield 95%

1 H NMR (400 MHz, CDCl 3) δ: 6.78 (1H, d), 6.55 (1H, d), 2.75-2.68 (4H, m), 2.19 (3H, s), 2.12 (3H, s); LRMS APCI m / z 166 [M + H] +.

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Preparation 48 4- (2-aminoethyl) -2-methylphenol

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84

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The title compound was prepared from product of preparation 45, using a procedure similar to of preparation 46, in the form of a colorless oil.

1 H NMR (400 MHz, CD 3 OD) δ: 2.15 (3H, s), 2.60-2.64 (2H, m), 2.79-2.83 (2H, m), 6.66 (d, 1H), 6.82 (1H, d), 6.90 (1H, s); LRMS ESI m / z 152 [M + H] +.

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Preparation 49 (3-Yodobenzyl) carbonate tert-butyl

85

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- tert-butyl dicarbonate (4.40 g, 20 mmol) and the resulting solution was stirred at room temperature for 1.5 hours. The reaction mixture was then washed with 2M hydrochloric acid (30 ml) and water (30 ml), dried over sodium sulfate and concentrated in vacuo to give the title compound as a colorless solid with a quantitative yield, 6.43 g

1 H NMR (400 MHz, CDCl 3) δ: 1.46 (9H, s), 4.21-4.30 (2H, m), 4.79-4.89 (1H, s a), 7.06 (1H, dd), 7.25 (1H, d), 7.60 (1H, d), 7.63 (1H, s); EMBR IEN m / z 332 [M-H] -.

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Preparation 50 [(4'-Hydroxybiphenyl-3-yl) methyl] tert -butyl carbamate

86

A solution of the product of preparation 49 (0.75 g, 2.25 mmol), 4-hydroxy phenylboronic acid (0.62 g, 4.50 mmol) and 1,1'-bis (diphenylphosphino) ferrocenyl palladium chloride ( II) (0.11 g, 0.14 mmol) in N , N- dimethylformamide (14 ml) was treated with a 2M sodium carbonate solution (4 ml) and the resulting mixture was heated at 80 ° C 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, 25:75, to give the title compound as a pale pink crystalline solid with a yield. quantitative, 0.73 g.

1 H NMR (400 MHz, CDCl 3) δ: 1.47 (9H, s), 4.33-4.41 (2H, m), 4.87-4.94 (1H, s a), 6.89 (2H, d), 7.21 (1H, d), 7.37 (1H, dd), 7.43-7.45 (4H, m); EMBR IEN m / z 298 [M-H] -.

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Preparation 51 Hydrochloride 3 '- (aminomethyl) biphenyl-4-ol

87

The product of preparation 50 (0.73 g, 2.43 mmol) was treated with 4M dioxane hydrochloric acid (6.1 ml, 24.3 mmol) and the resulting solution was allowed to stir at temperature atmosphere for 3 hours. Then, the reaction mixture is concentrated in vacuo to provide the title compound as of a colorless solid.

1 H NMR (400 MHz, CD 3 OD δ: 4.17 (2H, s), 6.87 (2H, d), 7.34 (1H, d), 7.45-7.50 (3H, m), 7.61 (1H, d), 7.65 (1H, s); EMBR IEN m / z 198 [M-H] -.

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Preparation 52 2-Hydroxy-1-naphthamide

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88

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An acid solution 2-hydroxy-1-naptoic (5.0 g, 26.6 mmol), hydrochloride 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide  (5.6 g, 29.2 mmol), and 1-hydroxybenzotriazole (3.95 g, 29.2 mmol) in tetrahydrofuran (70 ml) was stirred at temperature ambient for 30 minutes before the addition of 0.88 ammonia (6 ml) The resulting suspension was stirred at room temperature for 2 hours Then, the reaction mixture was filtered, and the The filtrate was diluted with water (80 ml) and extracted with acetate ethyl (4 x 80 ml). The combined organic extracts were washed with water (2 x 50 ml) and brine (50 ml), dried over sulfate sodium and concentrated in vacuo, giving a colored oil orange. Oil purification by column chromatography on silica gel, eluting with dichloromethane: methanol: 0.880 ammonia, 95: 5: 0.5, provided the title compound as a pink solid with a yield of 37%, 1.83 g.

1 H NMR (400 MHz, CDCl 3) δ: 6.11-6.35 (2H, s a), 7.17 (1H, d), 7.36 (1H, dd), 7.54 (1H, dd), 7.79 (1H, d), 7.84 (1H, d), 8.22 (1H, d), 11.70-11.88 (1H, s a); EMBR IEN m / z 186 [M-H] -

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Preparation 53 3,5-Dichloro- N -ethyl-2-hydroxybenzamide.

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89

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The title compound was prepared from acid 3,5-dichloro-2-hydroxybenzoic and ethylamine, using a procedure similar to that of the preparation 52, producing the title compound as a solid of pale yellow color.

1 H NMR (400 MHz, CDCl 3) δ: 1.28 (3H, t), 3.47-3.54 (2H, m), 6.29-6.36 (1H, s a), 7.27 (1H, d), 7.48 (1H, d); LRMS ESI m / z 232 [M-H] -.

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Preparation 54 Hydrochloride 4- (Aminomethyl) -2,6-dimethylphenol

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90

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A solution of borane was added dropwise in tetrahydrofuran (1 M in tetrahydrofuran, 27.1 ml, 27.1 mmol) at a solution of 3,5-dimethyl-4-hydroxybenzonitrile (1.0 g, 6.79 mmol) in tetrahydrofuran (70 ml) and the solution resulting heated at reflux for 16 hours. The mixture of reaction was cooled to room temperature, treated with acid 6M hydrochloric (20 ml) and heated at reflux for 30 minutes plus. Then, the reaction mixture was cooled to temperature ambient and the solvent removed in vacuo. The residue was purified using a strong cation exchange resin, eluting with methanol followed by 2M ammonia in methanol, giving an oil of Orange. Then, this oil was treated with 1 M hydrogen in methanol (20 ml) and the reaction mixture is concentrated in vacuo to provide the title compound as of a pale yellow solid with a yield quantitative, 1.12 g.

1 H NMR (400 MHz, CDCl 3) δ: 2.22 (6H, s), 3.75 (2H, s), 6.90 (2H, s).

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Preparation 55 Hydrochloride 2- (aminomethyl) -4-chlorophenol

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91

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The title compound was prepared from 5-Chloro-2-hydroxybenzonitrile, using a procedure similar to that described for the preparation 54.

\hbox{156 [M-H] ^{-} .}

1 H NMR (400 MHz, CDCl 3) δ: 4.08 (2H, s), 6.87 (1H, d), 7.27 (1H, d), 7.35 (1H , s); EMBR IQPA m / z

 ? {156 [MH] -.} 

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Preparation 56 Hydrochloride 4 '- (Aminomethyl) biphenyl-4-ol

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92

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The title compound was prepared from 4'-hydroxybiphenyl-4-carbonitrile, using a procedure similar to that of preparation 54.

1 H NMR (400 MHz, CD 3 OD) δ: 4.10 (s, 2H), 6.83 (d, 2H), 7.44-7.46 (m, 4H), 7.60 (d, 2H).

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Preparation 57 1- (Aminomethyl) -2-naphthol

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93

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A solution of borane was added dropwise in tetrahydrofuran (19.23 ml of a 1 M solution, 19.23 mmol) at a solution of the amide of preparation 52 (0.90 g, 4.81 mmol) in tetrahydrofuran (10 ml) and then the reaction was heated to reflux for 2 hours The solution was cooled, treated with acid 6M hydrochloric (10 ml) and heated at reflux for a further 2 hours. The resulting suspension was cooled to room temperature and the pH it was adjusted to pH 9 by the addition of 0.88 ammonia and extracted with ethyl acetate (3 x 50 ml). The combined organic solution is washed with brine (20 ml), dried over sodium sulfate and concentrated in vacuo. Purification of the residue by column chromatography on silica gel, eluting with dichloromethane: methanol: 0.88 ammonia, 95: 5: 0.5 to 90: 10: 1, provided the title compound in the form of a pink solid with a 23% yield, 0.19 g.

1 H NMR (400 MHz, CD 3 OD) δ: 4.41 (2H, s), 7.07 (1H, d), 7.23 (dd, 1H), 7.43 (1H, dd), 7.66 (1H, d), 7.72 (1H, d), 7.87 (1H, d); LRMS ESI m / z 174 [M + H] +.

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Preparation 58 2,4-Dichloro-6 - [(ethylamino) methyl] phenol

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94

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A solution of the product of preparation 53 (0.77 g, 3.29 mmol) in tetrahydrofuran (10 ml) was cooled to 0 ° C and treated with borane-tetrahydrofuran complex (1 M in tetrahydrofuran, 9.9 ml, 9.9 mmol). The resulting solution is let it warm to room temperature for 20 minutes and then heated to reflux for 16 hours. The reaction mixture was cooled. at 0 ° C and was interrupted by the addition of methanol. The solution resulting was allowed to warm to room temperature for 2 hours and then it was concentrated in vacuo. The residue was dissolved in dichloromethane (40 ml) and washed with water (2 x 10 ml) and brine (10 ml), dried over sodium sulfate and reduced in vacuo, giving a colorless oil Oil purification by chromatography on column on silica gel, eluting with methanol: dichloromethane, from 2:98 to 5:95, provided the title compound in the form of a Colorless solid with a yield of 74%, 0.53 g.

1 H NMR (400 MHz, CDCl 3) δ: 1.17 (3H, t), 2.72 (2H, c), 3.98 (2H, s), 6.86 (1H, d), 7.23 (1H, d).

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Preparations 59 a 68

The following compounds, of the general formula shown below, were prepared from the product of preparation 42 and the appropriate amine, using a similar procedure to that described for preparation 27. The reactions were monitored by TLC analysis and stirred at room temperature for 18-72 hours.

95

96

Preparation. 60: purified by chromatography in column using a 12g Redisep® cartridge, eluting with dichloromethane: methanol: 0.88 ammonia, 96: 4: 0.3.

Preparation 62: azeotropically distilled with diethyl ether (x 3), producing the desired product

Preparation 68: Can be prepared 6- (aminomethyl) -2-naphthaleneol as described in document US20040204455, p. 19.

Preparation 69 3- [2 - ({(2 R ) -2 - {[ tert -Butyl (dimethyl) silyl] oxy} -2- [3- (formylamino) -4-hydroxyphenyl] ethyl} amino) -2-methylpropyl] - N - [2- (4-hydroxyphenyl) -2-methylpropyl] benzamide

97

4- (2-Amino-1,1-dimethylethyl) phenol hydrochloride (Acta Chem. Scand. 8, 1203, 1207; 1954), (41 mg, 0.21 mmol) was added to a mixture of the product of the preparation 42 (100 mg, 0.21 mmol), O - (1 H -benzotriazol-1-yl) - N , N , N , N'- tetramethyluronium hexafluorophosphate (78 mg, 0.21 mmol) and triethylamine (35 µl , 0.4 mmol) in N, N-dimethylformamide (3 ml) and the mixture was stirred for 18 hours at room temperature. Then, the solvent was removed in vacuo and the residue was taken up in ethyl acetate and washed with a saturated sodium carbonate solution (3 x 20 ml) and brine (3 x 20 ml). Then, the organic solution was dried over sodium sulfate and concentrated in vacuo to give the title compound as a brown foam in 54% yield.

LRMS APCI m / z 634 [M + H] +

Preparations 70 a 76

The following compounds, of general formula shown below, were prepared from the product of preparation 42 and the appropriate amine, using a similar procedure to that described for preparation 69. The reactions were monitored by TLC analysis and stirred at room temperature for 18-72 hours.

98

99

Preparation 77 2,2 '- (1,3-Phenylene) diacetate diethyl

100

Acetyl chloride (12.5 ml, 175 mmol) was added to an acid suspension 2,2 '- (1,3-phenylene) diacetic (50.0 g, 260 mmol) in ethanol (500 ml) and the resulting solution was heated to reflux for 16 hours. Then, the reaction was cooled to room temperature and the solvent was removed in vacuo. The residue it was partitioned between a saturated sodium carbonate solution (300 ml) and ethyl acetate (500 ml). The organic phase separated, washed with water (200 ml) and brine (300 ml), dried over sulfate sodium and concentrated in vacuo to provide the compound of title in the form of a pale yellow oil with a quantitative yield, 63.5 g.

1 H NMR (CDCl 3, 400 MHz) δ: 1.31 (6H, t), 3.65 (4H, s), 4.20 (4H, c), 7.24-7.36 (4H, m); LRMS ESI m / z 251 [M + H] +.

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Preparation 78 Ethyl acid ester [3- (2-oxo-propyl) -phenyl] -acetic acid

101

A solution of the diester of preparation 77 (44.3 g, 177 mmol) and acid 2,2 '- (1,3-phenylene) diacetic (59.2 g, 308 mmol) in ethanol (24 ml) and dioxane (290 ml) was treated dropwise with 12M hydrochloric acid (4.9 ml, 58.8 mmol). Reaction mixture stirred at reflux temperature for 18 hours, cooled to room temperature and concentrated in vacuo. Then the mixture of reaction was diluted with toluene (125 ml) and the resulting suspension leaked The filtrate was concentrated in vacuo and the residue was collected. in water and basified with sodium bicarbonate to a neutral pH. The mixture was diluted with ethyl acetate (200 ml) and the organic phase separated and washed with sodium carbonate solution (5 x 30 ml) and brine (50 ml). The combined aqueous extracts are acidified to pH 3 with 6 M hydrochloric acid and extracted with diethyl ether (3 x 30 ml). The combined organic solution was dried over magnesium sulfate and concentrated in vacuo. Crushing of the residue with pentane provided the title compound as of a colorless solid with a yield of 27%, 10.8 g.

1 H NMR (CD 3 OD, 400 MHz) δ: 1.25 (3H, t), 3.60 (2H, m), 3.63 (2H, m), 4.15 (2H, c), 7.18-7.32 (4H, m); EMBR ESI: m / z 245 [M + Na] +.

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Preparation 79 Acid [3- (2-Hydroxy-2-methyl-propyl) -phenyl] -acetic acid

102

Methyl magnesium chloride was added dropwise (51 ml of a 3 M solution in tetrahydrofuran, 153 mmol) at a stirring solution of the product of preparation 78 (11.6 g, 51 mmol) (International Journal of Peptide and Protein Research, 1987, 29 (3), 331) in tetrahydrofuran (300 ml) at 0 ° C. Then the reaction was allowed to warm to room temperature overnight with the formation of a thick white precipitate and then Water (50 ml) and 2 N hydrochloric acid (80 were carefully added ml) The aqueous phase was separated and extracted with ethyl acetate (2 x 300 ml). The combined organic solution was washed with brine (50 ml), dried over sodium sulfate, concentrated in vacuo, providing the title compound in the form of an oil of golden color with a quantitative yield, 11.2 g.

1 H NMR (CDCl 3, 400 MHz) δ: 1.22 (6H, s), 2.75 (2H, s), 3.63 (2H, s), 7.12-7.30 (4H, m); LRMS ESI m / z 209 [M + H] +.

Preparation 80 Acid {3- [2- (2-Chloro-acetylamino) -2-methyl-propyl] -phenyl} -acetic acid

103

2-Chloroacetonitrile (8.8 ml, 140 mmol) was added to a solution of the products of preparation 79 (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 was allowed to gradually warm to room temperature. After 4 hours, the reaction mixture was poured on ice and made basic with solid sodium carbonate. The solution was extracted with ethyl acetate
(2 x 500 ml) and the combined organic extract solution was dried over magnesium sulfate and concentrated in vacuo to give the title product as a colorless solid in 96% yield 19.0 g.

1 H NMR (CDCl 3, 400 MHz) δ: 1.36 (6H, s), 3.02 (2H, s), 3.62 (2H, s), 3.95 (2H, s), 6.19 (1H, m), 7.06-7.31 (4H, m); EMBR IEN m / z 282 [M-H] -.

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Preparation 81 Acid methyl ester [3- (2-amino-2-methyl-propyl) -phenyl) -acetic acid

104

A solution of the product of preparation 80 (5.1 g, 18 mmol), thiourea (1.6 g, 21 mmol) and acetic acid (18 ml) in ethanol (80 ml) it was heated at reflux for 16 hours. Then the reaction mixture was allowed to cool to room temperature and was filter. The filtrate was concentrated in vacuo and the residue dissolved. in methanol (150 ml) and saturated with hydrogen chloride gas. The resulting solution was heated at reflux for 16 hours. The mixture was concentrated in vacuo and the residue was partitioned between acetate of ethyl (200 ml) and a 5% aqueous solution of sodium carbonate (200 ml). The organic phase was washed with brine (100 ml), dried over magnesium sulfate and concentrated in vacuo. The residue is purified with strong cation exchange resin, eluting with methanol followed by a 2M solution of ammonia in methanol, providing the title compound in the form of an oil of yellow color with a yield of 67%, 2.68 g.

1 H NMR (CDCl 3, 400 MHz) δ: 1.14 (6H, s), 2.68 (2H, s), 3.62 (2H, s), 3.69 (3H, s), 7.08-7.16 (3H, m), 7.23-7.27 (1H, m); LRMS ESI m / z 222 [M + H] +.

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Preparation 82 (3- {2 - [( tert -Butoxycarbonyl) amino] -2-methyl propyl} phenyl) methyl acetate

105

The title compound was prepared from product of preparation 81, using a procedure similar to of preparation 49, producing the title compound in form of a colorless oil with a yield of 81%.

1 H NMR (CDCl 3, 400 MHz) δ: 1.25 (6H, s), 1.45 (9H, s), 2.95 (2H, s), 3.60 (2H, s), 3.70 (3H, s), 4.25 (1H, s a), 7.02-7.06 (2H, m), 7.15 (1H, d), 7.25 (1 H, m); LRMS ESI m / z 344 [M + Na] +.

Preparation 83 (3- {2 - [( tert -butoxycarbonyl) amino] -2-methylpropyl} phenyl) acetic acid

106

A 5M sodium hydroxide solution was added (4.6 ml 23 mmol) to a solution of the product of preparation 82 (7.45 g, 23 mmol) in dioxane (30 ml) and water (8 ml) and the mixture is stirred at room temperature for 18 hours. Then the mixture The reaction was concentrated in vacuo and the residue was dissolved in water and it was acidified to pH 3 with 2M hydrochloric acid. Then, the mixture it was extracted with ethyl acetate (3 x 30 ml) and the organic solution combined, washed with brine (3 x 30 ml), dried over sulfate sodium and concentrated in vacuo, giving an oil. Later this oil was azeotropically distilled with diethyl ether, producing the title compound in the form of a colorless gum with a 99% yield, 7.0 g.

1 H NMR (CDCl 3, 400 MHz) δ: 1.25 (6H, s), 1.50 (9H, s), 2.95 (2H, s), 3.55 (2H, s), 3.65 (s, 1H), 7.05 (2H, m), 7.10 (1H, d), 7.20 (1H, m), 7.25 (1H, m).

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Preparation 84 (3- {2 - [( tert -Butoxycarbonyl) amino] -2-methylpropyl} phenyl) benzyl acetate

107

Cesium carbonate (6.03 g, 18.6 mmol) was added to a solution of the product of preparation 83 (5.7 g, 18.6 mmol) in N, N-dimethylformamide (40 ml) and the mixture was stirred for 1 hour at room temperature. Then the mixture of reaction was concentrated in vacuo and the residue was dissolved in N, N-dimethylformamide (80 ml), was treated with bromide of benzyl (3.18 g, 18.6 mmol) and stirred for 3 hours at room temperature. Then, the mixture was filtered and concentrated. in vacuo and the residue was dissolved in ethyl acetate (60 ml), washed with brine (60 ml), dried over magnesium sulfate and concentrated in vacuo to produce the title compound as of a pale yellow oil with a yield of 76%, 5.6 g

1 H NMR (CDCl 3, 400 MHz) δ: 1.25 (6H, s), 1.49 (9H, s), 2.98 (2H, s), 3.65 (2H, s), 4.30 (s, 1H), 5.14 (2H, s), 7.06-7.10 (2H, d), 7.15-7.20 (1H, m), 7.22-7.39 (6H, m); LRMS ESI m / z 396 [M-H] -.

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Preparation 85 [3- (2-Amino-2-methylpropyl) phenyl] acetate of benzyl

108

Trifluoroacetic acid (30 ml) was added to the product of preparation 84 (5.6 g, 14.1 mmol) and the mixture is stirred at room temperature for 18 hours. Then the mixture of reaction was concentrated in vacuo and the residue was diluted with dichloromethane (100 ml) and was basified with a saturated solution of sodium carbonate (300 ml). The organic phase was separated, it was washed with brine, dried over magnesium sulfate and concentrated under vacuum, providing the title compound as a Yellow oil with a yield of 76%.

1 H NMR (CDCl 3, 400 MHz) δ: 1.10 (6H, s), 1.50 (9H, s), 2.64 (2H, s), 3.66 (2H, s), 5.13 (2H, s), 7.07-7.12 (2H, d), 7.14-7.18 (1H, m), 7.22-7.38 (6H, m); EMBR IEN m / z 298 [M + H] +.

Preparation 86 (3- {2 - [((2 R ) -2- [4- (Benzyloxy) -3- (formylamino) phenyl] -2 - {[ tert -butyl (dimethyl) silyl] oxy} ethyl) amino] -2 -methylpropyl} phenyl) benzyl acetate

109

The title compound was prepared from the products of preparation 12 and preparation 85, using a procedure similar to that of preparation 13, with a yield 55%

1 H NMR (400 MHz, CDCl 3) δ: -0.20 (3H, m), -0.06 (3H, s), 0.78 (9H, s), 0.92 (3H, s), 0.95 (3H, s), 2.53-2.77 (4H, m), 3.57 (2H, s), 4.61-4.68 (1H, m), 5.01-5.02 (2H, m), 5.06 (2H, s), 6.84-6.87 (1H, m), 6.97-7.36 (14H, m), 7.62-7.70 (1H, m), 8.33-8.35 (1H, m), 8.34 (s), 8.67 (s), 8.70 (s); LRMS ESI m / z 681 [M + H] -.

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Preparation 87 {3- [2 - ({(2 R ) -2 - {[ tert -butyl (dimethyl) silyl] oxy} -2- [3- (formylamino) -4-hydroxyphenyl] ethyl} amino) -2-methylpropyl acid ] phenyl} acetic

110

The title compound was prepared from the products of preparation 86, using a similar procedure to that of preparation 26, with a yield of 93%.

1 H NMR (400 MHz, CDCl 3) δ: -0.06 (3H, s), 0.05 (3H, s), 0.88 (9H, s), 1.00 (3H, s), 1.04 (3H, s), 2.58-2.88 (4H, m), 3.58 (2H, s), 4.64-4.67 (1H, m), 6.88-6.90 (1H, m), 6.95-6.98 (1H, m), 7.07-7.27 (5H, m), 8.04-8.05 (d), 8.25 (s), 9.55 (s a); EMBR ESI m / z 501 [M + H] -.

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Preparation 88 2-Chloro- N -ethyl-5-hydroxybenzamide

111

The title compound was prepared from acid 2-chloro-5-hydroxybenzoic and ethylamine, using a procedure similar to that used for Preparation 52, in the form of a colorless solid.

1 H NMR (400 MHz, CDCl 3) δ: 1.22 (3H, t), 3.42-3.49 (2H, m), 6.48-6.52 (1H, m), 6.80 (1H, dd), 7.13 (1H, d), 7.38 (1H, d); LRMS ESI m / z 200 [M + H] +.

Preparation 89 4-Chloro-3 - [(ethylamino) methyl] phenol

112

The title compound was prepared from product of preparation 88 using the procedure of the Preparation 57, in the form of a colorless solid.

1 H NMR (400 MHz, CD 3 OD) δ: 1.15 (3H, t), 2.68 (2H, c), 3.79 (2H, s), 6.67-6.70 (1H, m), 6.84 (1H, d), 7.16 (1H, d).

Preparation 90 4 - {[ tert -Butyl (dimethyl) silyl] oxy} -2-chlorobenzaldehyde

113

A solution of 2-chloro-4-hydroxybenzaldehyde (5.0 g, 32 mmol), tert- butyl (dimethyl) silyl chloride (5.3 g, 35 mmol), imidazole (2.9 g, 45 mmol) and N , N- dimethylaminopyridine (10 mg) in N , N- dimethylformamide (40 ml) was stirred at room temperature 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 brine (50 ml), dried over sodium sulfate and concentrated in vacuo. Purification by column chromatography on silica gel, eluting with pentane: ethyl acetate, from 75:25 to 67:33, provided the title compound as a colorless oil with a yield of 75%, 6.50 g .

1 H NMR (400 MHz, CDCl 3) δ: 0.25 (6H, s), 0.97 (9H, s), 6.80 (1H, dd), 6.87 (1H, d), 7.84 (1H, d), 10.32 (1H, s).

Preparation 91 N - (4 - {[ tert -butyl (dimethyl) silyl] oxy} -2-chlorobenzyl) prop-2-en-1-amine

114

An aldehyde solution of preparation 90 (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 was stirred at room temperature for 16 hours A saturated solution of bicarbonate was added sodium (50 ml) and the organic phase separated. Organic solution washed with brine (50 ml), dried (sodium sulfate) and dried concentrated in vacuo, giving a yellow oil. The oil purification by column chromatography on gel silica, eluting with 75:25 to 67:33 of pentane: ethyl acetate, provided the title compound as a colorless oil with a yield of 38%, 2.80 g.

1 H NMR (400 MHz, CDCl 3) δ: 0.19 (6H, s), 0.97 (9H, s), 1.84 (1H, s a), 3.26 (2H, d), 3.81 (2H, s), 15.12 (1H, dd), 5.20 (1H, dd), 5.88-5.98 (1H, m), 6.71 (1H, dd), 6.85-6.86 (1H, d), 7.24 (1H, d); LRMS ESI m / z 312 [M + H] +.

Preparation 92 (4 - {[ tert -Butyl (dimethyl) silyl] oxy} -2-chlorobenzyl) amine

115

A solution of the product of preparation 91 (2.8 g, 9.0 mmol), dimethylbarbituric acid (7.0 g, 45 mmol) and tetrakis (triphenylphosphine) palladium (0) (0.10 g, 0.08 mmol ) in dichloromethane (80 ml) was heated at reflux for 4 hours. Then, the cooled solution was concentrated in vacuo and the residue was partitioned between ethyl acetate (50 ml) and a 1 N aqueous solution of sodium hydroxide (50 ml). The organic phase was separated, washed with brine (50 ml), dried over sodium sulfate and concentrated in vacuo. Purification of the residue by column chromatography on silica gel, eluting with dichloromethane: methanol: 0.880 ammonia, from 98: 2: 0 to 95: 5: 0.5, provided the title compound as a colorless oil with a 70% yield, 1.70 g.

1 H NMR (400 MHz, CDCl 3) δ: 0.19 (6H, s), 0.97 (9H, s), 1.89 (2H, s), 3.85 (2H, s), 6.70 (1H, dd), 6.85-6.86 (1H, dd), 7.21 (1H, d).

Preparations 93 a 95

The following compounds, of general formula shown below, were prepared from the product of preparation 87 and the appropriate amine, using a procedure similar to that described for preparation 27. The reactions are monitored by TLC analysis and stirred at temperature Ambient for 18-72 hours.

116

Preparation 96 2- {3- [2 - ({(2 R ) -2 - {[tert-Butyl (dimethyl) silyl] oxy} -2- [3- (formylamino) -4-hydroxyphenyl] ethyl} amino) -2- methylpropyl] phenyl} - N - (2-chloro-4-hydroxybenzyl) acetamide

117

The title compound was prepared from the products of preparations 87 and 92 using a procedure similar to that of preparation 27, in the form of a colored foam brown with a yield of 62%.

1 H NMR (400 MHz, CD 3 OD δ: -0.19 (3H, s), -0.03 (3H, s), 0.79 (9H, s), 1.01-1.10 (6H, m), 2.62-2.76 (3H, m), 2.85 (1H, m), 3.37-3.92 (2H, m), 4.34 (2H, s), 4.66 (1H, m), 6.62 (1H, m), 6.78-6.82 (2H, m), 6.91 (1 H, m); 7.02-7.23 (5H, m), 8.09-8.11 (1H, m), 8.27 (s), 8.59 (s); EMBR IQPA m / z 640 [M + H] +

Preparation 97 2- (3-Bromophenyl) - N - (3,4-dimethylbenzyl) acetamide

118

The title compound was prepared from 3,4-dimethylbenzylamine and acid 3-bromophenylacetic, using a procedure similar to that of preparation 27, in the form of a colored solid white with a yield of 93%.

1 H NMR (400 MHz, CDCl 3) δ: 2.20 (6H, s), 3.50 (2H, s), 4.30 (2H, d), 5.80 (1H, s a), 7.60-7.80 (7H, m); EMBR IEN 332 [M] +.

Preparation 98 N - (3,4-dimethylbenzyl) -2- {3 - [( E ) -2- (1,3-dioxo-1,3-dihydro-2 H -isoindol-2-yl) vinyl] phenyl} acetamide

119

The product of preparation 97 (5.0 g, 15 mmol), N-vinylphthalimide (2.62 g, 15.1 mmol), tri- ortho- tolylphosphine (473 mg, 1.55 mmol), palladium acetate ( II) (98 mg, 0.4 mmol) and N, N-diisopropylethylamine (30 ml, 172 mmol) in acetonitrile (35 ml) were heated at reflux for 16 hours. Then, the reaction mixture was cooled to room temperature and the precipitate was filtered off. Then, the solid was dissolved dichloromethane, activated charcoal was added and the solution was filtered through Celite®. The filtrate was concentrated in vacuo and the residue was recrystallized from hot dichloromethane / methanol to give the title compound as a yellow solid in 55% yield, 3.5 g.

1 H NMR (400 MHz, CDCl 3) δ: 2.20 (6H, s), 3.80 (2H, s), 4.30 (2H, d), 6.0 (1H, s a), 6.90 (2H, m), 7.01 (1H, m), 7.18 (1H, m), 7.26-7.40 (4H, m), 7.56-7.61 (1H, m), 7.75 (2H, m), 7.88 (2H, m).

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Preparation 99 N - (3,4-Dimethylbenzyl) -2- {3- [2- (1,3-dioxo-1,3-dihydro-2 H -isoindol-2-yl) ethyl] phenyl} acetamide

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120

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The product of preparation 98 (3.3 g, 7.7 mmol) and 10% palladium on carbon (1 g) were suspended in ethanol and the mixture was stirred under an atmosphere of 344.74 kPa (50 psi) of hydrogen gas, at room temperature for 16 hours. The reaction mixture was then filtered through Arbocel®, washed with ethanol and the filtrate was concentrated in vacuo to give the title product as a yellow solid in 52% yield,
1.7 g

1 H NMR (400 MHz, CDCl 3) δ: 2.20 (6H, s), 2.95 (2H, t), 3.60 (2H, s), 3.90 (2H, t), 4.39 (2H, d), 5.95 (1H, s a), 6.90-7.20 (8H, m), 7.60-7.70 (3H, m).

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Preparation 100 2- [3- (2-aminoethyl) phenyl] - N - (3,4-dimethylbenzyl) -acetamide

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121

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Hydrazine monohydrate (6 ml, 123.6 was added mmol) to a suspension of the product of preparation 99 (3.5 g, 8.2 mmol) in ethanol (125 ml) and the mixture was heated to reflux During 4 hours. Then, the reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated in vacuo. and the residue was purified by column chromatography on gel silica, eluting with dichloromethane: methanol: 0.88 ammonia, 95: 5: 1, providing the title compound with a yield of 57%, 1.4 g

1 H NMR (400 MHz, CD 3 OD) δ: 2.18 (6H, s), 2.73 (2H, m), 2.86 (2H, m), 3.50 (2H, s), 4.25 (2H, s), 6.87-7.25 (7H, m); EMBR IEN 297 [M + H] +.

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Preparation 101 2- (3- {2 - [((2 R ) -2- [4- (Benzyloxy) -3- (formylamino) phenyl] -2 - {[ tert -butyl (dimethyl) silyl) oxy} ethyl) amino] ethyl} phenyl) - N - (3,4-dimethylbenzyl) acetamide

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122

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The title compound was prepared from products of preparation 12 and preparation 100, using a procedure similar to that of preparation 33, in the form of an oil yellow with a yield of 37%.

1 H NMR (400 MHz, CD 3 OD) δ: -0.18 (3H, s), -0.03 (3H, s), 0.80 (9H, s), 2.20 (6H, m), 2.80 (4H, m), 3.40 (2H, m), 3.50 (2H, s), 4.25 (2H, s), 4.76 (1H, m), 5.18 (2H, s), 6.85-7.45 (15H, m), 8.23 (s), 8.30 (s); LRMS 680 [M + H] +.

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Preparation 102 2- {3- [2 - ({(2 R ) -2 - {[ tert -butyl (dimethyl) silyl] oxy} -2- [3- (formylamino) -4-hydroxyphenyl] ethyl} amino) ethyl] phenyl } - N - (3,4-dimethylbenzyl) acetamide

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123

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The title compound was prepared from product of preparation 101, using a procedure similar to of preparation 20, in the form of a white foam with a 83% yield.

1 H NMR (400 MHz, CD 3 OD) δ: -0.18 (3H, s), -0.05 (3H, s), 0.81 (9H, s), 2, 18 (6H, m), 2.80 (4H, m), 3.29 (2H, m), 3.51 (2H, s), 4.25 (2H, s), 4.70 (1H, m ), 6.80 (1H, d), 6.91-7.20 (9H, m), 8.03 (s), 8.25 (s); EMBR IEN 590
[M + H] +.

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Preparations 103 a 110

The following compounds, of general formula shown below, were prepared from the product of preparation 87 and the appropriate amine, using a similar procedure to that described for preparation 27. The reactions were monitored by TLC analysis and stirred at room temperature for 18-72 hours.

124

125

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Preparations 111 a 119

Hydrochloride was added 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (40 mg, 205 µmol) to a solution of preparation 42 (100 mg, 206 µmol), hydroxybenzotriazole hydrate (32 mg, 205 µmol) and triethylamine (0.55 µm, 412 µmol) in dichloromethane (2 ml) followed by the amine (205 µmol) and the mixture was stirred at room temperature for 18 hours. Then the solvent is removed in vacuo and the residue was diluted with ethyl acetate, washed with sodium carbonate solution (20 ml) and brine (20 ml), dried (Na2SO4) and concentrated in vacuo, leaving a film that was suspended in diethyl ether (x 3), producing a foam

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126

127

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Preparation 122 N - {5 - [(2 R ) -2- {2- [3- (10-Aza-tricycle [6.3.1.0 * 2.7 *] dodeca-2 (7), 3,5-triene-10- carbonyl) phenyl] -1,1-dimethylethylamino} -1- ( tert -butyldimethylsilyloxy) ethyl] -2-hydroxyphenyl} formamide

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128

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The title compound was prepared with 10-aza-tricycle [6.3.1.0 * 2.7 *] dodeca-2 (7), 3,5-triene, using a procedure similar to that of preparation 69.

LRMS APCI m / z 628 [M + H] +.

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Preparation 123 3- {2 - [(2 R ) -2- ( tert- Butyldimethylsilyloxy) -2- (3-formylamino-4-hydroxyphenyl) ethylamino] -2-methylpropyl} - N - [2- (5-chloro-2- hydroxyphenyl) ethyl] benzamide

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129

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The title compound was prepared with 2- (2-aminoethyl) -4-chlorophenol, using a procedure similar to that of preparation 69.

LRMS APCI m / z 640 [M + H] +.

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Preparations 124 a 128

The amine (412 µmol) was added to a mixture of preparation 42 (200 mg, 412 µmol), hydroxybenzotriazole hydrate (63 mg, 412 µmol), hydrochloride 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (79 mg, 412 µmol) and triethylamine (0.11 ml, 824 µmol) in dichloromethane (2 ml) and the mixture was stirred at room temperature for 18 hours Then, the solvent was removed in vacuo and the residue was diluted with ethyl acetate, washed with solution of sodium carbonate (3 x 20 ml) and brine (3 x 20 ml) and dried (MgSO 4). The crude material was purified by chromatography. on silica gel, eluting with dichloromethane: 0.88 ammonia, 99.7: 0.3, The appropriate fractions and the residue were evaporated to reduced pressure and concentrated in vacuo and colored foam resulting white was suspended in diethyl ether (x 3) and was evaporated.

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130

131

Preparation 129 Acid methyl ester 3- (2-oxo-propyl) benzoic

132

Tributyltin methoxide (80.3 ml, 279 mmol), methyl 3-bromobenzoate (53.5 g, 249 mmol), isopropenyl acetate (39.4 ml, 358 mmol), palladium (II) acetate were stirred together (2.6 g, 11.6 mmol) and tri- ortho- tolylphosphine (7.1 g, 23.2 mmol) in toluene (350 ml) at 100 ° C under a nitrogen atmosphere for 18 hours. After a period of cooling, the reaction was treated with a solution of potassium fluoride (4M, 560 ml) and stirred for 2 hours. The resulting mixture was diluted with more toluene (200 ml) and filtered through Celite ®, washing the filter layer with ethyl acetate. The organic phase was separated, dried (sodium sulfate) and reduced in vacuo. The residue was purified by chromatography eluting with 10:90 to 20:80 ethyl acetate: pentane, to give the title compound (45.3 g) as an orange oil.

1 H NMR (400 MHz, CDCl 3) δ: 2.18 (3H, s), 3.75 (2H, s), 3.91 (3H, s), 7.43-7.37 (2H, m), 7.87 (1H, s), 7.95-7.93 (1H, d); EMBR IEN m / z 215 [M + Na] +, 191 [M-H] -.

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Preparation 130 3 - [(2 R ) -2 - ((1R) -1-enylethylamino) propyl] benzoic acid methyl ester hydrochloride

133

The title compound was prepared with the Preparation 129, using a procedure similar to that of the Preparation 19, giving the title compound (27.3 g) as a colorless crystalline solid.

1 H NMR (400 MHz, CD 3 OD) δ: 1.17-1.16, (3H, d), 1.71-1.69 (3H, d), 2.71-2.65 (1H, dd), 3.25-3.19 (1H, m), 3.43-3.38 (1H, dd), 3.90 (3H, s), 4.68-4.63 (1H, c), 7.35-7.33 (1H, d), 7.45-7.42 (1H, dd), 7.55-7.49 (5H, m), 7.75 (1H, s), 7.92-7.90 (1H, d).

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Preparation 131 {3 - [(2 R ) -2-Aminopropyl] phenyl} methyl acetate

134

The title compound was prepared with the preparation 130, using a procedure similar to that of the Preparation 20, giving the title compound (8.48 g) as a pale yellow oil.

1 H NMR (400 MHz, CDCl 3) δ: 1.14-1.12 (3H, d), 2.64-2.59 (1H, dd), 2.78-2.73 (1H, dd), 3.26-3.17 (1H, m), 3.90 (3H, s), 7.38-7.34 (2H, m), 7.90-7.87 (2H, m); EMBR IEN m / z 194 [M + H] +.

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Preparation 132 3 - ((2 R ) -2- tert -butoxycarbonylaminopropyl) benzoic acid methyl ester

135

A mixture of preparation 131 (5.00 g, 26.0 mmol), di- tert-butyl dicarboxylate (6.22 g, 28.5 mmol) and sodium acid carbonate (4.35 g, 52 mmol) are stirred in a mixture of 1,4-dioxane (100 ml) and water (10 ml) for 20 h. The solvent was removed, the material was partitioned between ethyl acetate (200 ml) and hydrochloric acid (2 M, 100 ml) and the organic phases were washed with brine (100 ml) and dried (MgSO 4). Solvent removal left a white solid (7.12 g, 93%).

1 H NMR (400 MHz, CD 3 OD) δ: 1.09 (3H, d), 1.35 (9H, s), 2.73-2.79 (2H, m), 3.76-3.83 (1H, m), 3.89 (3H, s), 6.54 (1H, d), 7.26-7.46 (2H, m), 7.84-7.87 (2H, m); LCMS Tr 4.53 min m / z 294 [M + H] +.

Preparation 133 3 - ((2 R ) -2- tert -butoxycarbonylaminopropyl) benzoic acid

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136

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A mixture of preparation 132 (7.10 g, 24.3 mmol) and lithium hydroxide (1.00 M, 50.0 ml, 50.0 mmol) in Tetrahydrofuran (100 ml) was stirred for 20 h. The mixture of reaction was diluted with ethyl acetate (250 ml) and acidified to pH 2 with hydrochloric acid (2 M). The aqueous phase was extracted again. with ethyl acetate (150 ml) and the combined organic extracts they were washed with brine (300 ml) and dried (MgSO4). The filtration and solvent removal gave 5.53 g (82%) of title compound.

1 H NMR (400 MHz, CD 3 OD) δ: 1.10 (3H, d), 1.36 (9H, s), 2.82-2.81 (2H, m), 3.77-3.84 (1H, m), 7.35-7.45 (2H, m), 7.84-7.89 (2H, m); EMBR IQPA m / z 278 [M-H] -.

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Preparation 134 3 - ((2 R ) -2- tert -butoxycarbonylaminopropyl) benzoic acid benzyl ester

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137

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Cesium carbonate (6.50 g, 19.8 mmol) was added in water (10 ml) to a solution of preparation 133 (5.50 g, 19.8 mmol) in N, N-dimethylformamide (50 ml) and the mixture The resulting was stirred at room temperature for 1 h. Later benzyl bromide (3.42 g, 19.8 mmol) was added and the mixture was stirred for 20 h. Ethyl acetate (50 ml) was added, the suspension was filtered and the filtrate was washed saturated brine (100 ml) and dried (MgSO 4). Filtration and solvent removal gave 7.20 g of the title compound.

1 H NMR (400 MHz, CD 3 OD) δ: 1.09 (3H, d), 1.32 (9H, s), 2.74 (2H, d), 2.75-2.83 (1H, m), 5.34 (2H, s), 7.29-7.40 (4H, m), 7.43-7.47 (3H, m), 7.85-7.90 (2H, m); LRMS APCI m / z 270 [M-BOC] +.

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Preparation 135 3 - ((2 R ) -2-Aminopropyl) benzoic acid benzyl ester

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138

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Preparation 134 (7.20 g, 19.0 mmol) was treated with trifluoroacetic acid (35 ml) and the mixture was allowed to stir for 20 h. The trifluoroacetic acid was removed in vacuo and dichloromethane (175 ml) was added. The mixture was basified with carbonate saturated sodium acid (150 ml) and washed with sodium hydroxide (1 M, 50 ml) The combined organic extracts were washed with brine (150 ml) and dried (MgSO4), leaving a colored oil brown (3.70 g, 72%).

1 H NMR (400 MHz, CD 3 OD) δ: 1.04 (3H, d), 2.66 (2H, d), 3.05 (1H, dt), 5.33 (2H, s), 7.28-7.44 (7H, m), 7.86-7.90 (2H, m); LRMS APCI m / z 270 [M + H] +.

Preparation 136 3 - {(2 R ) -2 - [(2 R ) -2- (4-benzyloxy-3-formylaminophenyl) -2- ( tert- butyldimethylsilyloxy) ethyl-amino] propyl} benzoic acid benzyl ester

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139

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Preparation 135 (3.70 g, 13.8 mmol) and the Preparation 12 (3.20 g, 6.9 mmol) was heated at 90 ° C for 26 h. The mixture was allowed to cool and diluted with dichloromethane (100 ml). The organic extracts were washed with sodium acid carbonate saturated (200 ml) and concentrated in vacuo. Raw material it was purified by chromatography (x 2), eluting with from 0: 100 to 40:60 of ethyl acetate: heptane, yielding 2.0 g (52%) of the compound of the title. LRMS APCI m / z 270 [M + H] +.

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Preparation 137 3 - {(2 R ) -2 - [(2 R ) -2- ( tert -butyldimethylsilyloxy) -2- (3-formylamino-4-hydroxyphenyl) ethyl-amino] propyl} benzoic acid

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140

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Preparation 136 (2.0 g, 3.1 mmol) and palladium on carbon (10%, 205 mg) in methanol (100 ml) was hydrogenated at 413.69 kPa (60 psi) / RT for 20 h. A solution of ammonia in methanol (2 M, 50 ml) was added and the mixture was allowed to stir for 2 min. Then, the mixture was filtered through a filter aid, which was washed with ammonia in methanol solution (2M, 250 ml) and the resulting organic phases were concentrated, yielding a dark green solid. The crude material was purified by chromatography, eluting with 100: 0: 0 to 75: 20: 5 dichloromethane: methanol: 0.88 ammonia, yielding the title compound as a dark green solid.
(131 mg).

1 H NMR (400 MHz, DMSO-d_ {6}) δ: -0.18 (3H, s), -0.06 (3H, s), 0.77 (9H, s), 0.89 (3H, d), 2.61-2.68  (2H, m), 2.65-2.73 (2H, m), 2.80-2.86 (1H, m), 4.56-4.60 (1H, m), 6.75 (1H, d), 6.81 (1H, dd), 7.83 (2H, d), 7.70-7.75 (2H, m), 8.00 (d), 8.25 (s), 9.53 (s); LRMS APCI m / z 473 [M + H] +

Preparation 138 3 - {(2 R ) -2 - [(2 R ) -2- ( tert -butyldimethylsilyloxy) -2- (3-formylamino-4-hydroxyphenyl) ethyl-amino] propyl} - N - [2- (4- hydroxyphenyl) -2-methylpropyl] benzamide

141

The title compound was prepared with hydrochloride 4- (2-amino-1,1-dimethylethyl) phenol (Acta Chem. Scand. 8, 1203, 1207; 1954), using a procedure similar to preparation 27.

1 H NMR (400 MHz, CD 3 OD) δ: -0.24 (3H, s), -0.08 (3H, s); 0.76 (9H, s), 0.99 (3H, d), 1.28 (6H, s), 2.54-2.92 (5H, m), 3.46 (2H, s), 4.60-4.63 (1H. M), 6.66-6.70 (3H, m), 6.77-6.80 (1H, dd), 7.20-7.34 (4H, m), 7.45 (1H, s), 7.50 (1H, d), 7.92-7.93 (1H, d), 8.21 (s), 8.55 (s); LRMS APCI m / z 620 [M + H] +.

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Preparation 139 (2 E ) -3- [3- (2-Oxopropyl) phenyl] methyl acrylate

142

A solution of 3-bromophenylacetone (50.0 g, 235 mmol), acrylate methyl (40.4 g, 469 mmol), palladium (II) acetate (7.9 g, 35.2 mmol), tri-ortho-tolylphosphine (21.4 g, 70.4 mmol) and triethylamine (82 ml) in acetonitrile (900 ml) is heated to reflux in a nitrogen atmosphere for 16 hours. The reaction mixture was cooled to room temperature and the solvent He retired in a vacuum. Purification by column chromatography ultrafast eluting with 90:10 to 70:30 pentane: ethyl acetate gave the title compound as an orange oil (54.3 g).

1 H NMR (400 MHz, CD 3 OD) δ: 2.15 (3H, s), 3.70 (2H, s), 3.77 (3H, s), 6.43-6.39 (1H. d), 7.20-7.18 (1H, d), 7.34-7.31 (2H, t), 7.41-7.39 (1H, d), 7.66-7.62 (1H. D); EMBR IEN: m / z 241 [M + Na] +, 217 [M-H] -.

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Preparation 140 3- [3- (2-Oxopropyl) phenyl] propanoate of methyl

143

It was prepared according to the procedure used for preparation 26 using preparation 139, giving the title compound in the form of an orange oil.

1 H NMR (400 MHz, CD 3 OD) δ: 2.14 (3H, s), 2.64-2.60 (2H, t), 2.96-2.92 (2H, t), 3.66 (5H, s), 7.05-7.04 (2H, d), 7.11-7.09 (1H, d), 7.27-7.23 (1H, c); EMBR IEN m / z 243 [M + Na] +, 219 [M-H] -.

Preparation 141 Methyl [3 - ((2 R ) -2 - {[(1 R ) -1-phenyl-ethyl] amino} propyl) phenyl] propanoate hydrochloride

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144

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It was prepared according to the procedure used for preparation 19, using preparation 140, giving the title compound in the form of a colored crystalline solid White.

1 H NMR (400 MHz, CD 3 OD) δ: 1.18-1.16 (3H, d), 1.71-1.69 (3H, d), 2.62-2.56 (3H, m), 2.89-2.85 (2H, t), 3.20-3.12 (1H. M), 3.34-3.29 (1H, m), 3.61 (3H, s), 4.64-4.59 (1H. Q), 6.92-6.91 (2H, d), 7.12-7.10 (1H, d), 7.23-7.19 (1H, t), 7.54-7.47 (5H, m); EMBR IEN m / z 326 [M + H] +.

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Preparation 142 3- {3 - [(2 R ) -2 - ((1 R ) -1-phenylethylamino) propyl] phenyl} -propionic acid

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145

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Preparation 141 (3.25 g, 8.98 mmol) and sodium hydroxide (5 M, 9.0 ml, 45.0 mmol) was stirred in 1,4-dioxane (40 ml) and water (40 ml) for 18 h. He solvent was removed in vacuo and the material was dissolved in water and it was acidified to pH 6 with hydrochloric acid (2 M), which solidified for 18 h. The solid was filtered off and dried in vacuo (1.0 g, 36%). The filtrate was concentrated, tetrahydrofuran was added and The mixture was filtered. The filtrate was evaporated to leave a foam which was suspended in diethyl ether (x 3), producing a foam colorless (1.96 g, 70%).

1 H NMR (400 MHz, CD 3 OD) δ: 1.13 (3H, d), 1.62 (3H, d), 2.42 (2H, t), 2.55-2.64 (1H, m), 2.84 (2H, t), 3.08-3.42 (2H, m), 4.46-4.52 (1H. M), 6.86 (1H, d), 6.98 (1H, s), 7.11-7.22 (2H, m), 7.45-7.52 (5H, m); LCMS APCI m / z 312 [M + H] +.

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Preparation 143 1- (3,4-Dihydro-1 H -isoquinolin-2-yl) -3- {3 - [(2 R ) -2 - ((1 R ) -1-phenylethylamino) propyl] phenyl} propan-1- ona

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146

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Preparation 142 (1.95 g, 6.27 mmol) and triethylamine (2.62 ml, 19.0 mmol) in dichloromethane (80 ml) is treated with hexafluorophosphate 2-Chloro-1,3-dimethylimidazoline (1.75 g, 6.27 mmol) and the resulting solution was allowed to stir for 3 h. The solvent was removed and the residue was taken up in ethyl acetate, washed with saturated sodium carbonate (3 x 20 ml) and brine (3 x 20 ml) and dried (Na2SO4). After from filtration and solvent removal, the material is purified by chromatography, eluting with 99.7: 0: 0.3 to 96.7: 3: 0.3 of dichloromethane: methanol: 0.88 ammonia. The product was evaporated in ether diethyl (x 3), producing a semi-solid (2.3 g, 86%).

1 H NMR (400 MHz, CDCl 3) δ: 0.88 (3H, d), 1.30 (3H, d), 2.42-2.50 (1H. M), 2.64-2.98 (8H, m), 3.55-3.62 (1H. m), 3.78-3.96 (2H, m), 4.51 (1H, s), 4.72 (1H, s), 6.88-7.38 (13H, m); CLEM IQPA m / z 427 [M + H] +.

Preparation 144 3- [3 - ((2 R ) -2-Aminopropyl) phenyl] -1- (3,4-dihydro-1 H -isoquinolin-2-yl) propan-1-one

147

Preparation 143 (2.20 g, 5.16 mmol), formate ammonium (1.63 g, 26.0 mmol) and palladium hydroxide (500 mg) in Ethanol (40 ml) was heated and stirred at 70 ° C for 4 h. The mixture was filtered through a filter aid and solvent he retired. The material was purified by chromatography, eluting with 99.7: 0: 0.3 to 94.7: 5: 0.3 dichloromethane: methanol: ammonia 0.88, producing a colorless oil that evaporated in diethyl ether (x 3) (1.26 g, 76%).

1 H NMR (400 MHz, CDCl 3) δ: rotamers 1.10 / 1.11 (3H, 2 x d), 2.43-2.48 (1H, m), 2.62-2.76 (3H, m), 2.78-2.86 (2H, m), 2.96-3.02 (2H, m), 3.08-3.18 (1H, m), 3.58 (1H, t), 3.81 (1H, t), 4.53 / 4.73 (2H, 2 x s), 6.98-7.24 (8H, m); CLEM IQPA m / z 323 [M + H] +.

Preparation 145 N - {2-Benzyloxy-5 - [(1 R ) -1- ( tert -butyldimethylsilyloxy) -2 - ((1 R ) -2- {3- [3- (3,4-dihydro-1 H -isoquinolin -2-yl) -3-oxo-propyl] phenyl} -1-methylethylamino) ethyl] phenyl} formamide

148

The title compound was prepared with the Preparation 144 and Preparation 12, using a similar procedure  of preparation 136 (216 mg, 67%).

1 H NMR (400 MHz, CD 3 OD) δ: rotamers -0.19 (3H, s), -0.01 (3H, s), 0.82 (9H, s), 0.98-1.04 (3H, s), 2.48-2.96 (11H, m), 3.57-3.62 / 3.72-3.76 (2H, m), 4.53-4.70 (3H, m), 5.18 (2H, m), 6.87-6.97 (3H, m), 6.99-7.18 (7H, m), 7.28-7.39 (3H, m), 7.45-7.60 (2H, m), 8.20 (d), 8.31 (d); CLEM IQPA m / z 707 [M + H] +.

Preparation 146 N - {5 - [(1 R ) -1- ( tert- Butyl dimethylsilyloxy) -2 - ((1 R ) -2- (3- [3- (3,4-dihydro-1 H -isoquinolin-2-yl ) -3-oxo-propyl] phenyl} -1-methylethylamino) ethyl] -2-hydroxyphenyl} formamide

149

It was prepared using the amide of preparation 145 and the procedure described for preparation 15, producing a brown foam (280 mg, 100%).

1 H NMR (400 MHz, CD 3 OD) δ: rotamers -0.14 (3H, s), -0.03 (3H, s), 0.84 (9H, s), 1.08-1.12 (3H, m), 2.54-3.20 (11H. m), 3.60-3.65 / 3.74-3.77 (2H, 2 x t), 4.56-4.66 (2H, 2 x s), 4.78-4.84 (1H, m), 6.80-7.24 (1H, m), 8.10 (s), 8.31 (s); LCMS APCI m / z 617 [M + H] +.

Example 1 N -Benzyl-2- (3- {2 - [(2 R ) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} phenyl) acetamide

150

Preparation 15 (24 mg, 40 mmol), acid formic (0.5 ml), tetrahydrofuran (5 ml) and water (0.5 ml) are heated at 90 ° C for 18 h. One more aliquot of formic acid (0.5 ml) and tetrahydrofuran (5 ml) and heating It was continued for 18 h. The solvent was removed and the product was purified by chromatography (0-10% methanol in dichloromethane + 0.3% ammonia). The product dissolved in methanol (x 3) and evaporated (10 mg).

1 H NMR (CD 3 OD, 400 MHz) δ: 1.05-1.09 (6H, m), 2.69-2.78 (2H, m), 2.78-2.83 (1H, m), 2.87-2.93 (1H, m), 3.53 (2H, s), 4.35 (2H, s), 4.65 (1H, dd), 6.82-6.86 (1H, m), 6.99 (1H, dd), 7.03-7.06 (1H, m), 7.13-7.28 (7H, m), 8.08 (d), 8.28 (s), 8.55 (s), 8.61 (s); MS (IQPA) m / z 476 [M + H] +; EMAR C 28 H 33 N 3 O 4 476.2544 [M + H] + found 476.2533.

Example 2 N - (3,4-Dimethylbenzyl) -2- (3- {2 - [(2 R ) -2- (3-formylamino-4-hydroxy-phenyl) -2-hydroxyethylaminol-2-methylpropyl} phenyl) acetamide

151

It was prepared using the amine of preparation 16 and the procedure described in Example 1.

1 H NMR (CD 3 OD, 400 MHz) δ: 1.05-1.08 (6H, m), 2.18 (3H, s), 2.19 (3H, s), 2.67-2.94 (4H, m), 3.52 (2H, s), 4.27 (2H, s), 4.62 (1H, dd), 4.65 (1H, dd), 6.81-7.06 (6H, m), 7.12-7.24 (3H, m), 8.07 (d), 8.27 (s), 8.55 (s), 8.61 (s).

MS (APCI) M / Z 504 [M + H] +; EMAR C 30 H 37 N 3 O 4 504.2857 [M + H] + found 504.2842.

Example 3 N - [4- (dimethylamino) benzyl] -2- {3 - [(2 R ) -2 - ({(2 R ) -2- [3- (formylamino) -4-hydroxyphenyl] -2-hydroxyethyl} amino ) propyl] phenyl} acetamide

152

A mixture of the product of preparation 27, (131 mg, 0.21 mmol) and triethylamine trifluorhydrate (16 µl, 0.10 mmol) in tetrahydrofuran (2 ml) was stirred at temperature atmosphere for 3 days. Then, the mixture was concentrated in vacuo and The residue was purified by column chromatography on gel. silica, eluting with dichloromethane: methanol: 0.88 ammonia, 100: 0: 0 a 90: 10: 1, providing the title compound in the form of a brown foam with a yield of 36%, 18 mg.

1 H NMR (400 MHz, CD 3 Cl 3) δ: 1.07 (3H, m), 2.57 (1H, dd), 2.67-2.76 (2H, m), 2.85-2.99 (2H, m), 2.87 (6H, s), 3.47 (1H, m), 4.23 (2H, s), 4.68 (1H, dd), 6.67-6.71 (2H, m), 6.77-6.79 (2H, d), 6.90 (1H, m), 6.97-7.70 (m, 6H), 7.97 (d), 8.27 (s), 8.35 (s); LRMS APCI m / z 619 [M + H] -.

Examples 4 to 12

The following compounds, of general formula shown below, were prepared using a procedure  similar to that described for example 3. The starting material adequate was treated with 1-1.1 equiv. from Triethylamine Trifluorhydrate at room temperature for 18-72 hours.

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153

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154

155

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Examples 13 a 2. 3

The following compounds, of general formula shown below, were prepared using a procedure  similar to that described for example 3. The starting material adequate was treated with 1-1.1 equiv. from Triethylamine Trifluorhydrate at room temperature for 18-72 hours.

156

157

158

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Example 14: azeotropically distilled with 2M methanolic ammonia before purification. * The compounds raw were azeotropically distilled with 2M methanolic ammonia before purification by column chromatography on gel silica, eluting with 90: 10: 1 dichloromethane: methanol: 0.88 ammonia. This was followed by more azeotropes in methanol (x 3) and diethyl ether (x 3), providing the desired products in White solid form.

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Examples 24 a 27

The following compounds, of general formula shown below, were prepared using a procedure  similar to that described for example 3. The starting material adequate was treated with 1-1.1 equiv. from Triethylamine Trifluorhydrate at room temperature for 18-72 hours.

159

160

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Example 28 N -1-Adamantil-2- {3 - [(2 R ) -2 - ({(2 R ) -2- [3- (formylamino) phenyl] -2-hydroxyethyl} amino) propyl] phenyl} acetamide

161

A mixture of the product of preparation 34 (500 mg, 0.81 mmol) and ammonium fluoride (200 mg, 5.4 mmol) in methanol (5 ml) and water (1.5 ml) was heated at 40 ° C for 18 hours. Then, the reaction mixture was concentrated in vacuo and the residue purified by column chromatography on silica gel, eluting with dichloromethane: methanol: 0.88 ammonia, 90: 10: 0.1, providing the title compound as a foam with a yield of 84%, 347 mg.

1 H NMR (400 MHz, CD 3 OD) δ: 1.05-1.10 (m, 3H), 1.64-1.74 (6H, m), 1.98-2.03 (9H, m), 2.36-2.98 (5H, m), 3.36 (2H, s), 4.46-4.60 (1H, m), 6.46-7.20 (6H, m), 7.96 (1H, s), 8.28 (s), 8.56 (s); LRMS ESI m / z 506 [M + H] +.

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Example 29 N - (3,4-Dimethylbenzyl) -2- {3- [2 - ({(2 R ) -2- [3- (formylamino) -4-hydroxyphenyl] -2-hydroxyethyl} amino) ethyl] phenyl} acetamide

162

The title compound was prepared from product of preparation 102, using a procedure similar to of examples 4-12, in the form of a solid.

1 H NMR (400 MHz, CD 3 OD) 2.20 (6H, m), 3.00 (2H, m), 3.18 (2H, m), 3.28 (2H, m), 3.56 (2H, s), 4.28 (2H, s), 4.81 (1H, m), 6.81 (1H, d), 6.98 (2H, m), 7.05 (2H, m), 7.20 (4H, m), 7.30 (1H, t), 8.10 (s), 8.30 (s); EMBR IEN 476 [M + H] +.

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Examples 30 to 37

The following compounds, of general formula shown below, were prepared using a procedure  similar to that described by example 3. The starting material adequate was treated with 1-1.1 equiv. from Triethyleneamine trifluorhydrate at room temperature for 18-72 hours.

163

164

165

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Examples 38 a 46

The appropriate amides and trifluorohydrate of triethylamine (1 equivalent) in tetrahydrofuran (5 ml) was stirred at room temperature for 2 days. Then the mixture is concentrated in vacuo and the residue was treated with methanolic ammonia and evaporated (x 3), leaving a foam that was collected in dichloromethane: methanol: 0.88 ammonia, 90: 10: 1, filtered and then purified by column chromatography on silica gel, eluting with dichloromethane: methanol: 0.88 ammonia, 90: 10: 1, providing the title compound in the form of a film that it was dissolved in methanol, evaporated (x 3), then suspended in diethyl ether and evaporated (x 3), producing a colored solid White.

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166

167

168

169

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Examples 51 a 55

The following compounds, of general formula shown below, were prepared using a procedure  similar to that described for example 3. The starting material adequate was treated with 1-1.1 equiv. from Triethylamine Trifluorhydrate at room temperature for 18-72 hours.

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170

171

Example 56 3 - {(2 R ) -2 - [(2 R ) -2- (3-Formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] propyl} - N - [2- (4-hydroxy-phenyl) -2- methylpropyl] benzamide

172

The title compound was prepared from product of preparation 38, using a procedure similar to of examples 38-50, in the form of a glass of brown color (35 mg, 31%)

1 H NMR (400 MHz, CD 3 OD) δ: 1.03 (3H, d), 1.27 (6H, s), 2.56-2.90 (4H, m), 3.45 (2H, s), 4.55-4.58 (1H, m), 6.67-6.72 (3H, m), 6.85-6.87 (1H, m), 7.19-7.26 (5H, m), 7.38 (1H, s), 7.43 (1H, d), 7.91 (d), 8.21 (s), 8.51 (s); LRMS APCI m / z 506 [M + H] +.

Example 57 N - {5 - [(1 R ) -2 - ((1 R ) -2- {3- [3- (3,4-Dihydro-1 H -isoquinolin-2-yl) -3-oxopropyl] phenyl} -1-methylethyl-amino) -1-hydroxyethyl] -2-hydroxyphenyl} formamide

173

The title compound was prepared from product of preparation 138, using a procedure similar to of examples 38-50, in the form of a glass of brown color (35 mg, 31%)

1 H NMR (400 MHz, CD 3 OD) δ: 1.00-1.05 (3H, m), 2.48-2.92 (11H, m), 3.59 (1H, t), 3.73 (1H, t), 4.54-4.65 (3H, m), 6.75-7.18 (10H, m), 7.97 (s), 8.28 (d), 8.56 (d); LRMS APCI m / z 502 [M + H] +

The capacity of the compounds of formula (1) to act as potent agonists of β2 mediating, so Thus, smooth muscle relaxation can be determined by the Measurement of the adrenergic receptor stimulation effect beta-2 in field-stimulated contraction Electric strips of guinea pig trachea.

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Guinea pig trachea

Male guinea pigs are sacrificed Dunkin-Hartley (475-525 g) per asphyxiation with CO2 and exanguination of the femoral artery and Isolate the trachea. Four preparations of each animal are obtained, starting the dissection immediately below the larynx and taking 2.5 cm of trachea length. The part of the trachea is open by cutting the cartilage opposite the tracheal muscle and then cut cross sections, of a width of 3-4 cartilage rings. The preparations of the resulting strips are suspended in 5 ml organ baths using cotton threads tied through the cartilage bands upper and lower. The strips are balanced, stretched, during 20 minutes in a modified Ringer Krebs buffer (Sigma K0507) that Contains 3 µM lndomethacin (Sigma I7378), 10 µM Guanetidine (Sigma G8520) and 10 µM Atenolol (Sigma A7655), are heated to 37 ° C and gasified with 95% O 2/5% CO 2, before apply an initial tension of 1 g. The preparations are allowed balance for 30-45 more minutes, time during which they are re-stressed (up to 1 g) twice at 15 minute intervals. Changes in tension are recorded and controlled by isometric transducers Conventionals coupled to a data collection system (customized for Pfizer). After the balance of tension, the tissues undergo electric field stimulation (ECE) using the following parameters: voltages of 10 s every 2 minutes, pulse width 0.1 ms, 10 Hz and maximum voltage just (25 Volts) continuously during the experiment. The ECE of the nerves post-ganglionic cholinergic in the trachea produces single-phase contractions of the smooth muscles and it Record the height of the contraction. Organ baths are constantly infuse with the Ringer Krebs buffer described previously by means of a peristaltic pump system (flow rate pump 7.5 ml / minute) during the experiment, with the exception of that when a beta-2 agonist is added from the present invention, the pump stops during the time of the cumulative dosage in the bathroom and starts again after reach the maximum response during the elimination period.

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Experimental protocol to evaluate potency and effectiveness

After equilibrium for ECE (stimulation by electric field), the peristaltic pump stops and the preparations "are primed" with a single dose of isoprenaline 300 nM (Sigma 15627) to establish a maximum response in terms of inhibition of the contractile response to ECE. Later Eliminate isoprenaline for a period of 40 minutes. Behind the priming and recovery by elimination, a standard curve is performed for isoprenaline in all tissues (Curve 1 isoprenaline) by a cumulative addition in embolada to the bathroom using semilogarithmic increases in concentration. The interval of concentration used is 1 e-9 at 1 e / 3 e-6 M. At the end of the curve of isoprenaline, the preparations are washed again for 40 minutes before starting a second curve, both for the isoprenaline (as internal control) as for an agonist of beta-2 according to the present invention. The beta-2 agonist responses are expressed as percent inhibition of the ECE response. The data for the beta-2 agonist normalize expressing the inhibition as a percentage of the maximum inhibition induced by Isoprenaline in Curve 1. The EC_ {5O} value for the agonist of beta-2 according to the present invention is refers to the concentration of compound necessary to produce the Half the maximum effect. The data for the agonist of beta-2 according to the present invention is express therefore as the relative potency for isoprenaline defined by the relationship (EC_ {50} of the agonist of beta-2) / (EC50 of isoprenaline).

Confirmation of functional activity mediated by beta-2

The agonist activity of beta-2 of the test compounds is confirmed using the protocol previous, however, before building the curve for the agonist of beta-2 according to the present invention, the Preparations are pre-incubated (for a minimum of 45 minutes) with ICI 118551 300 nM (a selective antagonist of β2) which in the case of a beta-mediated effect gives as result a shift to the right of the curve of dose response of the test compound.

According to another alternative, the power of agonist for the β2 receptor of the compounds of formula (1) it can also be determined by measuring the concentration of the compound in accordance with the present invention necessary to produce the half of the maximum effect (EC50) for the β2 receptor.

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Compound Preparation

Stock solution of the compound is diluted in DMSO (dimethyl sulfoxide) 10 mM / 100% up to the maximum dose required in 4% DMSO. This maximum dose is used to construct a curve of 10 point semilogarithmic dilution, all in 4% DMSO. How pattern in each experiment was used Isoprenaline (Sigma, I-5627) and for control wells in each license plate. Data were expressed as% response to Isoprenaline

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Cell culture

CHO cells (hamster ovary) Chinese) that recombinantly expressed the adrenergic receptor human β2 (from Kobilka et al, PNAS 84: 46-50, 1987, and Bouvier et al, Mol Pharmacol 33: 133-139 1988 CHOh? 2) in MEM / NUT MIX F12 of Dulbeccos (Gibco, 21331-020) supplemented with fetal bovine serum at 10% (Sigma, F4135; lot 90K8404 Exp. 09/04), 2 mM glutamine (Sigma, G7513), 500 µg / ml of geneticin (Sigma, G7034) and 10 µg / ml of puromycin (Sigma, P8833). The cells were seeded to provide approximately 90% confluence for the test.

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Testing method

25 µl / each dose well was transferred of the compound to cAMP-Flashplate® (NEN, SMP004B), with 1% DMSO as baseline controls and 100 nM lsoprenaline as maximum controls This was diluted 1: 2 by adding 25 µl / well of PBS. The cells were trypsinized (0.25% Sigma, T4049), were washed with PBS (Gibco, 14040-174) and resuspended in stimulation buffer (NEN, SMP004B) to provide 1x10 6 CHOhB2 cells / ml. The compounds are incubated with 50 µl of cells / well for 1 hour. The cells were then lysed by the addition of detection buffer 100 µl / well (NEN, SMP004B) containing <125> I-cAMP 0.18 / ml (NEN, NEX-130) and plates were incubated at temperature atmosphere for 2 more hours. The amount of 125 I-cAMP bound to the Flashplate® was quantified using a TopCount NXT (Packard), normal counting efficiency for 1 minute Dose response data were expressed. as the% activity of lsoprenaline and were adjusted using a Four parameter sigmoid adjustment.

Therefore it has been discovered that compounds of formula (1) according to the present invention that illustrated in examples 1 to 57 above show an EC50 of the cAMP of β2 less than 5 nM.

Claims (24)

1. A compound of general formula (1), 174 in which the group (CH 2) n -C (= O) Q 1 is at the target position or for,

-

R1 and R2 are selected independently between H and alkyl C 1 -C 4;

-

n is 0, 1 or 2;

-

Q1 is a selected group between,

175

where p is 1 or 2 and q is 1 or 2, said group being optionally linked by a carbon atom,

176

and a group * -NR 8 -Q 2 -A, in which Q 2 is a C 1 -C 4 alkylene, R 8 is H or C 1 -C 4 alkyl and A is pyridyl, C 3 -C 10 cycloalkyl, said alkyl being optionally bonded by one or more carbon atoms, tetrahydropyranyl, piperidinyl, tetrahydrothiopyranyl or a group

177

-

R 3, R 4, R 5, R 6 and R 7 are the same or different and are selected from H, alkyl C 1 -C 4, OR 9, SR 9, SOR 9, SO 2 R 9, halo, CN, CO 2 R 9, CF 3, OCF 3, SO 2 NR 9 R 10, CONR 9 R 10, NR 9 R 10, NHCOR 10 and phenyl optionally substituted with 1 to 3 groups selected from OR9, halo and alkyl C_ {1} -C_ {4}

-

R 9 and R 10 are the same or different and are selected from H or alkyl C_ {1} -C_ {4} and * represents the junction point to the carbonyl group;

or, when appropriate, its salts and / or isomers, tautomers, solvates or pharmaceutically isotopic variations acceptable.

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2. A compound according to claim 1, in which Q1 is a group * -NH-Q2 -A, in which A is cyclohexyl or adamantyl. 3. A compound according to claim 1, in which Q1 is a group * -NH-Q2 -A, in which A is a group 178 in which R 3, R 4, R 5, R 6 and R 7 are the same or different and are selected between H, C 1 -C 4 alkyl, OR 9, SR 9, SOR 9, SO 2 R 9, halo, CN, CO 2 R 9, CF 3, OCF 3, SO 2 NR 9 R 10, CONR 9 R 10, NR 9 R 10, NHCOR 10 and optionally substituted phenyl with 1 to 3 groups selected from OR9, halo and alkyl C_ {1} -C_ {4} with the condition that at least 2 from R 3 to R 7 are equal to H; wherein R 9 and R 10 are the same or different and are selected from H or alkyl C_ {1} -C_ {4}.

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4. A compound according to claim 3, in which Q1 is a group * -NH-Q2 -A, in which A is a group 179 in which R 3, R 4, R 5, R 6 and R 7 are the same or different and are selected between H, OH, CH 3, OCH 3, OCF 3, OCH_ {2} -CH_ {3}, SCH 3, N (CH 3) 2, N (C = O) CH 3, C (= O) NH 2, COOCH 3, SO 2 CH 3, SO 2 NH 2, CN, halo, CF 3 and phenyl optionally substituted with OH

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5. A compound according to claim 1, in which A is a group 180 in which one of R 3 to R 7 is OH or phenyl substituted with OH

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6. A compound according to claim 1, wherein A is naphthyl optionally substituted with OH.

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7. A compound according to any one of claims 1 to 6, wherein Q2 is -CH 2 -, - (CH 2) 2 -, - (CH 2) 3 -, -CH 2 -C (CH 3) 2 - or -C (CH 3) 2 -. 8. A compound according to claim 7, wherein Q 2 is -CH 2 -. 9. A compound according to claim 1, in which Q1 is 181 in which R_ {3}, R_ {4}, R 5 and R 6 are H. 10. A compound according to any one of claims 1 to 9, wherein R1 is H or alkyl C 1 -C 4 and R 2 is alkyl C_ {1} -C_ {4}. 11. A compound according to the claim 10, wherein R 1 is H or CH 3 and R 2 is H or CH 3. 12. A compound according to the claim 1 to 11, wherein n is 0 or 1. 13. The stereoisomer (R, R) of a compound of according to any one of claims 1 to 12. 14. A compound according to any one of claims 1 to 13, wherein the group (CH 2) n -C (= O) Q 1 is at the target position 15. A compound according to the claim 1 selected from the group consisting of N -Benzyl-2- (3- {2 - [(2 R ) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} phenyl) acetamide; N - (3,4-Dimethylbenzyl) -2- (3- {2 - [(2 R ) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} phenyl) acetamide; N - [2- (4-Chlorophenyl) ethyl] -3- {2 - [(2 R ) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} ben-
zamide; N - [2- (2-Chlorophenyl) ethyl] -3- {2 - [(2 R ) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} ben-
zamide; 3- {2 - [(2 R ) -2- (3-Formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} - N - (2-naphthalen-1-ylethyl) benzamide; 3- {2 - [(2 R ) -2- (3-Formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} - N - [2- (4-methylphenyl) ethyl] benzamide; N - [2- (2,6-Dimethylphenyl) ethyl] -3- {2 - [(2 R ) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methyl-propyl} benzamide ; N - [2- (2,3-Dimethylphenyl) ethyl] -3- {2 - [(2 R ) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methyl-propylbenzamide; 3- {2 - [(2 R ) -2- (3-Formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} - N - [2- (4-hydroxy-2,3-dimethylphenyl) ethyl ]benzamide; 3- {2 - [(2 R ) -2- (3-Formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} - N - [2- (4-methoxyphenyl) ethyl] benzamide; 3- {2 - [(2 R ) -2- (3-Formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} - N -phenethyl-benzamide; N- Cyclohexylmethyl-3- {2 - [(2 R ) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} benzamide;

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N - [5 - ((1 R ) -2- {1,1-Dimethyl-2- [3- (piperidine-1-carbonyl) phenyl] ethylamino} -1-hydroxyethyl) -2-hydroxyphenyl] formamide; 3- {2 - [(2 R ) -2- (3-Formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} - N - [2- (3-trifluoromethylphenyl) ethyl] benzamide; 3- {2 - [(2 R ) -2- (3-Formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} - N - (3-phenylpropyl) benzamide; 3- {2 - [(2 R ) -2- (3-Formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} - N -indan-2-ylbenzamide; 3- {2 - [(2 R ) -2- (3-Formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} - N - (2-pyridin-2-ylethyl) benzamide; 3- {2 - [(2 R ) -2- (3-Formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} - N - [2- (4-sulfamoylphenyl) ethyl] benzamide; N - (4-Dimethylaminobenzyl) -2- (3 - {(2 R ) -2 - [(2 R ) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] propyl} phenyl) acetamide; N - [5- (2 - {(1 R ) -2- [3- (3,4-Dihydro-1H-isoquinoline-2-carbonyl) -phenyl] -1,1-dimethyl-ethylamino} -1-hydroxyethyl ) -2-hydroxyphenyl] formamide; 3- {2 - [(2 R ) -2- (3-Formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} - N - (4'-hydroxybiphenyl-3-yl-methyl) benzamide 3- {2 - [(2 R ) -2- (3-Formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} - N - [2- (4-hydroxy-2,5-dimethylphenyl) ethyl ]benzamide; 3- {2 - [(2 R ) -2- (3-Formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} - N - [2- (4-hydroxy-3-methyl-phenyl) ethyl ]benzamide; N - (4-Acetylaminobenzyl) -2- (3 - {(2 R ) -2 - [(2 R ) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] propyl} phenyl) acetamide; 4 - {[2- (3 - {(2 R ) -2 - [(2 R ) -2- (3-Formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] propyl} phenyl) acetylamino] methyl} benzamide; N -Adamantan-1-yl-3- {2 - [(2 R ) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} benzamide; 3- {2 - [(2 R ) -2- (3-Formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} - N - (2-hydroxy-naphthalen-1-ylmethyl) benzamide; 3- {2 - [(2 R ) -2- (3-Formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} - N - (4-hydroxy-3,5-dimethylbenzyl) benzamide; 3- {2 - [(2 R ) -2- (3-Formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} - N - (6-hydroxy-naphthalen- N -2-ylmethyl) benzamide; N - (3,6-Dichloro-2-hydroxybenzyl) -3- {2 - [(2 R ) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methyl-propyl} benzamide; N - (3,4-Dimethylbenzyl) -2- (3- {2 - [(2 R ) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] ethyl} phenyl) acetamide; 3- {2 - [(2 R ) -2- (3-Formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} - N - [2- (4-hydroxyphenyl) -2-methylpropyl] benzamide; 3- {2 - [(2 R ) -2- (3-Formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} - N - (4'-hydroxybiphenyl-4-yl-methyl) benzamide; N -Adamantan-1-yl-2- (3 - {(2 R ) -2 - [(2 R ) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] propyl} phenyl) acetamide; N - [5- (2- {2- [3- (10-Aza-tricycle [6.3.1.0 * 2.7 *] dodeca-2 (7), 3,5-triene-10-carbonyl) phenyl] - 1,1-dimethylethylamino} -1-hydroxyethyl) -2-hydroxyphenyl] -formamide; 2- (3 - {(2 R ) -2 - [(2 R ) -2- (3-Formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] propyl} phenyl) - N - (4'-hydroxybiphenyl-3- ilmethyl) acetamide; 4 - {[2- (3- {2 - [(2 R ) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} methyl ester
phenyl) -acetylamino] methyl} benzoic;

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2- (3 - {(2 R ) -2 - [(2 R ) -2- (3-Formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} phenyl) - N - (4-trifluoromethoxy- benzyl) acetamide; N - (2-Chloro-4-hydroxybenzyl) - N -ethyl-2- (3 - {(2 R ) -2 - [(2 R ) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino ] -2-methylpropyl} phenyl) -cetamide; N - (2-Chloro-4-hydroxybenzyl) -2- (3 - {(2 R ) -2 - [(2 R ) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2- methylpropyl} -phenyl) acetamide; 2- (3 - {(2 R ) -2 - [(2 R ) -2- (3-Formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] propyl} phenyl) - N - (4-hydroxy-3,5 -dimethylbenzyl) acetamide; 2- (3 - {(2 R ) -2 - [(2 R ) -2- (3-Formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] propyl} phenyl) - N - (2-hydroxynaphthalen-1-ylmethyl ) acetamide; N - (5-Chloro-2-hydroxybenzyl) -2- (3 - {(2 R ) -2 - [(2 R ) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] propyl} phenyl ) acetamide; N - (3,5-Dichloro-2-hydroxybenzyl) -2- (3 - {(2 R ) -2 - [(2 R ) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] propyl } phenyl) acetamide; 2- (3 - {(2 R ) -2 - [(2 R ) -2- (3-Formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] propyl} phenyl) - N - (6-hydroxynaphthalen-2-ylmethyl ) acetamide; 2- (3 - {(2 R ) -2 - [(2 R ) -2- (3-Formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] propyl} phenyl) - N - (4'-hydroxybiphenyl-4- ilmethyl) acetamide; N - (4-Cyano-benzyl) -2- (3- {2 - [(2 R ) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} -phenyl) -acetamide ; 2- (3- {2 - [(2 R ) 2- (3-Formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} -phenyl) - N - (4-methanesulfonyl-benzyl) -acetamide; 2- (3- {2 - [(2 R ) -2- (3-Formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} -phenyl) - N - (4-methylsulfanyl-benzyl) -acetamide ; 2- (3- {2 - [(2 R ) -2- (3-Formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} -phenyl) - N - (4-trifluoromethyl-benzyl) -acetamide ; 2- (3- {2 - [(2 R ) -2- (3-Formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} phenyl) - N - (4'-hydroxybiphenyl-4-ylmethyl) acetamide; N - [2- (5-Chloro-2-hydroxyphenyl) -ethyl] -3- {2 - [(2 R ) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} -benzamide; 2- (3- {2 - [(2 R ) -2- (3-Formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} phenyl) - N -0 (4'-hydroxy-biphenyl-3 -ylmethyl) -acetamide; 3- {2 - [(2 R ) -2- (3-Formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -propyl} - N- [2- (4-hydroxyphenyl) -2-methyl-propyl] -benzamide ; N - (2-Chloro-4-hydroxybenzyl) -2- (3 - {(2 R ) -2 - [(2 R ) - (2 R ) -2- (3-formylamino-4-hydroxyphenyl) -2- hydroxyethylamino] propyl} phenyl) acetamide; N - [2- (5-Chloro-2-hydroxyphenyl) -ethyl] -3- {2 - [(2 R ) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} benzamide; 3- {2 - [(2 R ) -2- (3-Formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -propyl} -N- [2- (4-hydroxyphenyl) -2-methyl-propyl] benzamide; 2- (3- {2 - [(2 R ) -2- (3-Formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} phenyl) - N - (tetrahydro-thiopyran-4-yl) acetamide ; N - (5-Chloro-2-hydroxybenzyl) -2- (3- {2 - [(2 R ) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methyl-propyl} phenyl ) acetamide; Y, N - {5 - [(1 R ) -2 - ((1 R ) -2- {3- [3- (3,4-Dihydro-1 H -isoquinolin-2-yl) -3-oxopropyl] phenyl} -1-methylethylamino) -1-hydroxyethyl] -2-hydroxyphenyl} formamide. 16. N- (5-Chloro-2-hydroxybenzyl) -2- (3 - {(2R) -2 - [(2R) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] propyl} phenyl) acetamide  or a pharmaceutically acceptable salt or solvate thereof. 17. 2- (3 - {(2R) -2 - [(2R) -2- (3-Formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] propyl} phenyl) -N- (4-hydroxy-3,5-dimethylbenzyl ) acetamide  or a pharmaceutically acceptable salt or solvate thereof. 18. 2- (3 - {(2R) -2 - [(2R) -2- (3-Formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] propyl} phenyl) -N- (6-hydroxynaphthalen-2-ylmethyl) acetamide  or a pharmaceutically acceptable salt or solvate thereof. 19. 2- (3 - {(2R) -2 - [(2R) -2- (3-Formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] propyl} phenyl) -N- (4'-hydroxybiphenyl-4-ylmethyl) acetamide  or a pharmaceutically acceptable salt or solvate thereof. twenty. N- [2- (4-Chlorophenyl) ethyl] -3- {2 - [(2R) -2- (3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} benzamide  or a pharmaceutically acceptable salt or solvate thereof. 21. A pharmaceutical composition comprising at least an effective amount of a compound of formula (1) as described in any one of claims 1 to 20 or a salt or a pharmaceutically acceptable derivative thereof. 22. A compound of formula (1) as has been described in any one of claims 1 to 20 or a salt, a form or composition derived therefrom, pharmaceutically acceptable for use as a medicine. 23. The use of a compound of formula (1) as is described in any one of claims 1 to 20 or of a pharmaceutically derived salt, form or composition thereof acceptable, for the manufacture of a drug for the treatment of diseases, disorders and conditions selected from the group Constituted by:

?

asthma of any kind, etiology or pathogenesis, in particular asthma that is a member selected from the group consisting of atopic asthma, asthma no atopic, allergic asthma, IgE-mediated bronchial atopic asthma, asthma  bronchial, idiopathic asthma, true asthma, intrinsic asthma caused due to pathophysiological discomfort, extrinsic asthma caused by environmental factors, idiopathic asthma of unknown cause or not apparent, non-atopic asthma, bronchitic asthma, emphysematous asthma, exercise-induced asthma, allergen-induced asthma, asthma Cold air induced, occupational asthma, infectious asthma caused by infection by bacteria, fungi, protozoa or infection viral, non-allergic asthma, incipient asthma, childhood syndrome wheezing and bronchiolitis,

?

chronic bronchoconstriction or acute, chronic bronchitis, airway obstruction inferior and emphysema,

?

obstructive or inflammatory diseases of the respiratory tract or of any kind, etiology or pathogenesis, in particular an obstructive or inflammatory disease of the respiratory tract that is a member selected from the group consisting of chronic eosinophilic pneumonia, chronic obstructive pulmonary disease (COPD), COPD which includes chronic bronchitis, pulmonary emphysema or dipnea associated or not associated with COPD, COPD characterized by progressive, irreversible airway obstruction, adult respiratory distress syndrome (ARDS), aggravation of airway hyperreactivity as a result of other drug therapy and respiratory disease associated with pulmonary hypertension,

?

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

?

acute lung injury,

?

bronchiectasis of any type, etiology or pathogenesis in particular bronchiectasis which is a  selected member of the group consisting of bronchiectasis cylindrical, saculated bronchiectasis, fusiform bronchiectasis, capillary bronchiectasis, cystic bronchiectasis, dry bronchiectasis and follicular bronchiectasis.

24. Combination of a compound according to any of claims 1 to 20 with another agent (or agents) therapeutic selected from:

(to)

inhibitors of 5-lipoxygenase (5-LO) or antagonists of the 5-lipoxygenase activation protein (FLAP),

(b)

leukotriene antagonists (LTRA) including antagonists of LTB_4, LTC_ {4}, LTD_ {4} and LTE_ {4},

(C)

receptor antagonists histamine including H1 and H3 antagonists,

(d)

sympathomimetic agents agonist vasoconstrictors of the α1 adrenoceptors and α2 for decongestant use,

(and)

muscarinic receptor antagonists M3 or anticholinergic agents,

(F)

PDE inhibitors, for example, PDE3, PDE4 and PDE5 inhibitors,

(g)

theophylline,

(h)

sodium cromoglycate,

(i)

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

(j)

oral glucocorticosteroids e inhaled,

(k)

active monoclonal antibodies against endogenous inflammatory entities,

(l)

anti-factor agents tumor necrosis (anti-TNF-?),

(m)

adhesion molecule inhibitors including VLA-4 antagonists,

(n)

receptor antagonists quinine-B 1 and B 2,

(or)

immunosuppressive agents,

(p)

metalloprotease inhibitors of matrix (MPM),

(q)

receptor antagonists takinin NK 1, NK 2 and NK 3,

(r)

elastase inhibitors,

(s)

adenosine receptor antagonists A2a,

(t)

urokinase inhibitors

(or)

compounds that act on dopamine receptors, for example, D2 agonists,

(v)

route modulators NF??, For example, IKK inhibitors,

(w)

route modulators cytokine signaling such as MAP kinase p38 or syk kinase,

(x)

agents that can be classified as mucolytic or cough suppressant

(Y)

antibiotics,

(z)

HDAC inhibitors, e,

(aa)

P13 kinase inhibitors.