KR20070026420A - Phenylethanolamine derivatives as beta-2 agonists - Google Patents

Abstract

The invention relates to compounds of formula (1) and to processes for the preparation of, intermediates used in the preparation of, compositions containing and the uses of, such derivatives. The compounds according to the present invention are useful in numerous diseases, disorders and conditions, in particular inflammatory, allergic and respiratory diseases, disorders and conditions. ® KIPO & WIPO 2007

Description

Phenylethanolamine derivatives as beta-2 agonists {PHENYLETHANOLAMINE DERIVATIVES AS BETA-2 AGONISTS}

The present invention relates to β2 agonists of the formula and to methods of preparing such derivatives, intermediates used in the preparation of such derivatives, compositions containing such derivatives and the use of such derivatives.

<Formula (1)>

In said formula, R <^1> , R <^2> , n and Q <^1> have the meaning shown below.

Adrenaline receptors are members of large G-protein coupled receptors. The adrenaline receptor subfamily is itself divided into the α and β subgroups, and the β subgroup consists of at least three receptor subtypes: β1, β2 and β3. These receptors exhibit differential expression patterns in tissues and organs of various tissue systems in mammals. β2 adrenergic (β2) receptors are mainly expressed in smooth muscle cells (eg, blood vessels, bronchus, uterus or intestinal smooth muscle), while β3 adrenergic receptors are mainly expressed in adipose tissue (hence, β3 agonists are obese and Β1 adrenergic receptors are mainly expressed in cardiac tissue (hence the β1 agonist is mainly used as cardiac agents).

Pathophysiology and treatment of airway diseases are described in Barnes, PJ Chest, 1997, 111: 2, pp 17S-26S and Bryan, SA et al, Expert Opinion on investigational drugs, 2000, 9: 1, pp25-42. ], And a brief summary will be included herein to provide some background.

Glucocorticosteroids, anti-leukotriene, theophylline, chromone, anticholinergic and β2 agonists currently constitute a group of drugs used to treat allergic and nonallergic airway diseases such as asthma and chronic obstructive airway disease (COPO). . Treatment guidelines for these diseases include both fast-acting and sustained inhalation β2 agonists. Fast-acting fast-acting β2 agonists are used to “recover” bronchial dilatation, while persistent forms provide sustained relief and are used as sustained therapy.

Bronchodilation is mediated through the hyperactivity of β2 adrenergic receptors expressed on airway smooth muscle cells, which leads to relaxation and thereby bronchodilation. Thus, β2 agonists as functional antagonists can prevent and reverse the effects of all bronchoconstrictors, such as leukotriene D4 (LTD4), acetylcholine, bradykinin, prostaglandin, histamine and endothelin. Because β2 receptors are very widely distributed in the airways, β2 agonists may also affect other types of cells that play a role in asthma. For example, there have been reports that β2 agonists can stabilize mast cells. Inhibition of release of bronchial contractile material may be a way for the β2 agent to block bronchial contraction induced by allergens, exercise and cold air. Furthermore, β2 agonists inhibit cholinergic neurotransmission in human airways, which can reduce choline-reflective bronchial contraction.

In addition to the airways, β2 adrenergic receptors are also expressed in other organs and tissues, and thus β2 agonists such as those described herein have other diseases (eg, nervous system disease, premature pain, congestive heart failure, depression, inflammatory). And conditions that are beneficial in lowering allergic skin diseases, psoriasis, proliferative skin diseases, glaucoma and acidity of the stomach, in particular but not limited to gastric and peptic ulcers.

However, many β2 agonists are caused by low selectivity or high systemic exposure, and due to harmful side effects (muscle tremor, tachycardia, palpitations, restlessness) that are mediated through action on β2 adrenergic receptors expressed outside the airways Its use is limited. Therefore, there is a need for improved drugs belonging to this group.

Thus, there remains a need for novel β2 agonists with suitable pharmacological profiles, for example in terms of efficacy, selectivity, duration of action and / or pharmacokinetic properties. In this context, the present invention relates to novel β2 agonists.

EP 0654534 B1 and EP 0939134 B1 disclose methods for the preparation of compounds of formula (XI).

<Formula XI>

These compounds are disclosed as anti-obesity and antidiabetic agents with specific β3 activity.

US 5,561,142 discloses selective β 3 agonists of the formula:

EP 0236624 discloses compounds of the following formula with good selectivity with anti-obesity and / or antihyperglycemic activity and without cardiac side effects.

The present invention relates to a compound of formula (1) or, if appropriate, a pharmaceutically acceptable salt thereof and / or an isomer, tautomer, solvate or isotopic variant thereof.

<Formula (1)>

Wherein the (CH ₂ ) _n -C (= 0) Q ¹ group is in the meta or para position,

R ¹ and R ² are independently selected from H and C ₁ -C ₄ alkyl,

n is 0, 1 or 2,

Q ¹

, ^*-NH-C₁-C₄알킬, 및 ^*-N(R⁸)-Q²-A 기로부터 선택되는 기이며, 여기서

, ^* -NH-C ₁ -C ₄ alkyl, and ^* -N (R ⁸ ) -Q ² -A group, wherein

-Q ² is a single bond or C ₁ -C ₄ alkylene,

R ⁸ is H or C ₁ -C ₄ alkyl,

-p is 1 or 2,

-A is C ₃ -C ₁₀ Cycloalkyl (two or more carbon atoms of said cycloalkyl are optionally crosslinked by one or more carbon atoms, preferably one, two, three or four carbon atoms), O-phenyl-pyrazolyl, 5-10 member Heterocyclic groups (comprising 1, 2, 3 or 4 heteroatoms selected from O, S or N, optionally aromatic, optionally substituted with C ₁ -C ₄ alkyl or OC ₁ -C ₄ alkyl ), Or a group of the formula

R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are the same or different and H, C ₁ -C ₄ alkyl, OR ⁹ , SR ⁹ , SOR ⁹ , SO ₂ R ⁹ , halo, CN, CF ₃ , OCF ₃ , phenyl, O-phenyl, S-phenyl, SO ₂ -morpholinyl, O- (CH ₂ ) ₃ -pyrrolidinyl, COOR ⁹ , SO ₂ NR ⁹ R ^1O , CONR ⁹ R ¹⁰ , NR ⁹ Selected from R ¹⁰ and NHCOR ¹⁰ ;

R ⁹ and R ¹⁰ are the same or different and are selected from H or C ₁ -C ₄ alkyl and * indicates the point of attachment to the carbonyl group,

Provided that if n is 0, Q ¹ is not -NHCH ₃ and if n is 1 or 2:

1) Q ¹ is ^* -NH-C ₁ -C ₄ alkyl, or ^* -N (R ⁸ ) -Q ² -A, where A is

C ₃ -C ₁₀ cycloalkyl, wherein at least two carbon atoms of said cycloalkyl are optionally crosslinked by at least one carbon atom,

O-phenyl-pyrazolyl,

5 to 10 membered heterocyclic groups (comprising 1, 2, 3 or 4 heteroatoms selected from O, S or N, optionally aromatic, optionally C ₁ -C ₄ alkyl or OC _1- Substituted with C ₄ alkyl, said heterocyclic group being other than pyridyl),

-Groups of the formula

(In the above formula,

R ³ To R ⁷ One is CN, SOR ⁹ , SO ₂ R ⁹ , phenyl, O-phenyl, S-phenyl, SO ₂ -morpholinyl or O- (CH ₂ ) ₃ -pyrrolidinyl);

2) If one of R ¹ and R ² is H, the other is not CH ₃ .

It has now been found that compounds of formula (1) are agonists of the β2 receptor, are particularly useful for treating β2-mediated diseases and / or conditions, and show good efficacy, especially when administered via the inhalation route.

In the present invention, the term "effective" means that the compound of formula (1) exhibits agonist efficacy on β2 receptor, which is less than 10 nM as measured by the cell based assay described herein.

Preferably, the compounds of the present invention are selective agents of the β2 receptor. Preferably, the compounds of the present invention exhibit agonist efficacy on the β2 receptor, which is at least about 100 fold for the β3 receptor and at least about 500 fold for the β1 receptor.

In formula (1), C ₁ -C ₄ alkyl and C ₁ -C ₄ Alkylene represents a straight or branched group containing 1, 2, 3 or 4 carbon atoms. This also applies when they have substituents or appear as substituents in other radicals, for example O- (C ₁ -C ₄ ) alkyl radicals, S- (C ₁ -C ₄ ) alkyl radicals and the like. Examples of suitable (C ₁ -C ₄ ) alkyl radicals are methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl and the like. Examples of suitable O- (C ₁ -C ₄ ) alkyl radicals are methoxy, ethoxy, n-propyloxy, iso-propyloxy, n-butyloxy, iso-butyloxy, sec-butyloxy and tert-butyloxy And so on.

C ₃ -C ₁₀ cycloalkyl wherein two or more carbon atoms are optionally crosslinked by one or more carbon atoms is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, bicyclo [3.1.1] heptane, Bicyclo [2.2.1] heptane, bicyclo [2.2.2] octane. Preferred cycloalkyl groups are cyclohexyl and adamantyl.

Examples of 5 to 10 membered heterocyclic groups (comprising 1, 2, 3 or 4 heteroatoms independently selected from O, S or N and optionally aromatic) are morpholinyl, pyrrolidinyl, py Ferridyl, piperazinyl, thienyl, isothiazolyl, oxazolyl, pyridyl, pyrimidyl, oxazolyl, isoxazolyl, thiazolyl, furanyl, imidazolyl, pyrazolyl, pyrrolyl, pyridazinyl, Pyrazinyl, triazolyl, tetrazolyl, oxdiazolyl, triazinyl, indolyl, quinolyl, isoquinolyl, benzofuranyl, quinazolyl, quinoxalyl, phthalazinyl, benzothiazolyl, benzoxazolyl, benziso Thiazolyl, benzisoxazolyl, benzimidazolyl, indazolyl and benzotriazolyl.

Preferred heterocyclic groups are pyrrolidinyl, pyridyl, pyrimidyl, quinolyl, isoquinolyl, benzoimidazolyl and benzofuranyl.

Preferably, the heterocyclic group contains one or two heteroatoms selected from O, S or N. More preferably, the heterocyclic group contains one or two nitrogen atoms.

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

In the following, a free bond on a phenyl group, as in the structure below, means that the phenyl can be substituted in the meta or para position.

The compounds of formula (1) can be prepared using conventional procedures such as the following exemplary methods, wherein Q ¹ , Q ² , A and n are previously defined for compounds of formula (1) unless otherwise indicated As it is.

<Formula (1)>

Amide derivatives of formula (1) include the acid of formula (2) and the formula NH ₂ -C ₁ -C ₄ alkyl, -NH (R ⁸ ) -Q ₂ -A,

과 커플링함으로써 제조될 수 있다.

It can be produced by coupling with.

<Formula (2)>

Wherein R ⁸ , Q ² , A, p and R ³ to R ⁶ are as defined above for the compound of formula (1).

Coupling is generally optionally performed in the presence of a catalyst (eg 1-hydroxybenzotriazole hydrate or 1-hydroxy-7-azabenzotriazole), optionally with a tertiary amine base (eg, In the presence of N-methylmorpholine, triethylamine or diisopropylethylamine, in excess of this amine as acid acceptor, conventional coupling agents (e.g., 1- (3-dimethylaminopropyl) -3- Ethylcarbodiimide hydrochloride or N, N'-dicyclohexylcarbodiimide). The reaction is carried out in a suitable solvent such as pyridine, dimethylformamide, tetrahydrofuran, dimethylsulfoxide, dichloromethane or ethyl acetate at a temperature comprising between 10 ° C. and 40 ° C. (room temperature) for 1-24 hours. Can be.

The amines can be prepared from commercially available or commercially available materials by conventional methods well known to those skilled in the art (eg, reduction, oxidation, alkylation, protection, deprotection, etc.).

The acid of formula (2) can be prepared from the corresponding ester of formula (4), according to any method well known to those skilled in the art, which prepares the acid from the ester without modifying the rest of the molecule.

Wherein Ra is a suitable acid protecting group, preferably a (C ₁ -C ₄ ) alkyl group (eg, but not limited to methyl and ethyl). For example, the ester may optionally be a solvent or mixture of solvents (eg, water, 1,4-dioxane, tetrahydrofuran / water) at a temperature comprising between 20 ° C. and 100 ° C. for 1-40 hours. It can be hydrolyzed by treatment with an aqueous acid or base (eg hydrochloric acid, potassium hydroxide, sodium hydroxide or lithium hydroxide) in the presence of.

Esters of formula (4) can be prepared by the reaction of amines of formula (5) with bromide of formula (6).

Wherein Ra and n are as defined above.

In a typical procedure, the amine of formula (5) may optionally be a suitable base (eg, triethylamine, diisopropylethylamine, potassium carbonate) at a temperature comprising between 80 ° C. and 120 ° C. for 12 to 48 hours. Is reacted with bromide of formula (6), optionally in the presence of a solvent or mixture of solvents (eg dimethyl sulfoxide, toluene, N, N-dimethylformamide, acetonitrile).

Bromides of formula (6) can be prepared from esters of formula (7) according to any method well known to those skilled in the art for preparing alcohols from esters without modifying the rest of the molecule.

In a typical procedure, the ester of formula (7) is reduced to borane dimethylsulfide complex in reflux tetrahydrofuran for 2 hours.

Alcohols of formula (7) can be prepared as (R) or (S) enantiomers, according to methods well described in Tetrahedron Letters 1994, 35 (50), 9375.

The amines of formula (5) can be prepared as (R) or (S) enantiomers from the corresponding protected amines of formula (8).

Wherein R a and n are as defined above and R b and R c represent any suitable substituent such that HNR b R c is a chiral amine, wherein the bonds between N and R b and between N and R c are intended to cleave a nitrogen protecting group. Easily cleaved using standard methodologies (eg, methodologies found in textbooks [TW GREENE, Protective Groups in Organic Synthesis, A. Wiley-Interscience Publication, 1981]) to provide free amines of formula (5) have.

The amine of formula (8) can be prepared as a single diastereomer by reaction of an amine of formula HNRbRc with a ketone of formula (9).

Wherein Ra, Rb, Rc and n are as defined above.

In a typical procedure, the reaction of the ketone of formula (9) with the amine of formula HNRbRc results in a chiral intermediate, which in turn is optionally in the presence of an acid catalyst (eg acetic acid), optionally a desiccant (eg molecular sieve). , Reduced by a suitable reducing agent (eg, sodium cyanoborohydride of formula NaCNBH ₃ or sodium triacetoxyborohydride of formula Na (OAc) ₃ BH) in the presence of magnesium sulfate) Amine is provided as a mixture of diastereomers. The reaction is generally carried out in a solvent such as tetrahydrofuran or dichloromethane at a temperature comprising between 20 ° C. and 80 ° C. for 3 to 72 hours. The resulting product is then converted to a hydrochloride salt and selectively crystallized from a suitable solvent or mixture of solvents (eg isopropanol, ethanol, methanol, diisopropyl ether or diisopropyl ether / methanol) (8) As a single diastereomer.

Ketones of formula (9) wherein n is 1 can be prepared by palladium mediated coupling of an aryl halide of formula (10) with an enolate or an enolate equivalent.

Wherein Ra is as defined above and Hal represents a halogen atom (eg, but not limited to bromo and iodo).

In a typical procedure, the aryl halides of formula (10) are palladium acetate / tri- of suitable palladium catalyst (Pd (OAc) ₂ / P (o-Tol) _{3 in} a nonpolar solvent (e.g. toluene, benzene, hexane). In the presence of ortho-tolylphosphyl), isopropenyl acetate is treated with tri-n-butyltin methoxide of the formula Bu ₃ SnOMe to react with tin enolate produced in situ. Preferably, the reaction is carried out at a temperature comprising between 80 ° C. and 110 ° C. for 6-16 hours.

The aryl halide of formula (10) is obtained by esterification of the corresponding acid of formula (11), according to any method well known to those skilled in the art for preparing esters from acids without modifying the rest of the molecule. Can lose.

Wherein Hal is as defined above.

In a typical procedure, the acid of formula (11) is an alcoholic solvent of formula RaOH, wherein Ra is as defined above, in the presence of an acid such as hydrogen chloride at a temperature between 10 ° C. and 40 ° C. (room temperature) for 8-16 hours. React with

Acids of formula (11) are commercial products.

Amines of formula (5), wherein R ¹ and R ² are both C ₁ -C ₄ alkyl, can be prepared according to the following scheme.

Wherein R ¹ , R ² and Ra are as defined above.

In a typical procedure, the ester of formula (12) is reacted with an "activated" alkyl (organic metal alkyl such as R ² MgBr, R ² MgCl or R ² Li) using the method described above, Corresponding tertiary alcohol of 13).

The tertiary alcohol of formula (13) is then treated with alkyl nitrile (eg acetonitrile, chloroacetonitrile) in the presence of an acid (eg sulfuric acid, acetic acid) to provide a protected intermediate This is again cleaved using standard methodology for cleaving nitrogen protecting groups such as those mentioned in textbooks. The resulting amino acid is then esterified using the method described herein to provide the amine of formula (5).

Alternatively, amines of formula (5), wherein R ¹ and R ² are both C ₁ -C ₄ alkyl and n is 0 can be prepared according to the following scheme.

Wherein R ¹ , R ² and Ra are as defined above.

In a typical procedure, the ester of formula (14) is reacted with "activated" alkyl (eg, organic metal alkyl, such as R ² MgBr, R ² MgCl or R ² Li) using the method described above to give formula (15) To the corresponding tertiary alcohol.

The tertiary alcohol of formula (15) is then treated with alkyl nitrile (eg acetonitrile, chloroacetonitrile) in the presence of an acid (eg sulfuric acid, acetic acid) to provide a protected intermediate This, in turn, is cleaved using standard methodology for cleaving nitrogen protecting groups such as those mentioned in textbooks to provide bromo amines (16).

The resulting bromo amine 16 is obtained by using RaOH as a solvent at elevated temperature (100 ° C.) and elevated pressure (100 psi) (eg, MeOH, EtOH), under a carbon monoxide atmosphere, using a suitable palladium catalyst (eg, [1] , 1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II)) to give the amine of formula (5).

Ketones of formula (9) wherein n is 2 can be prepared by reduction of alkenes of formula (17).

In a typical procedure, an olefin solution of formula (17) in a suitable solvent (eg methanol, ethanol, ethyl acetate) is treated with a palladium catalyst (eg 10% palladium on charcoal) and room temperature for 8-24 hours. And at a temperature between 60 ° C., optionally under elevated pressure (eg, 60 psi), under a hydrogen atmosphere.

Alkenes of formula (17) may be prepared by palladium mediated coupling of activated olefins with aryl halides of formula (18).

In a typical procedure, aryl halide 18 is a suitable solvent (eg, acetonitrile, N, N, at temperatures between 40 ° C. and 110 ° C. for 8 to 24 hours, optionally in the presence of a base such as triethylamine. Suitable palladium catalyst (eg, tetrakis (triphenylphosphine) palladium (0) of formula Pd (PPh ₃ ) ₄ , formula Pd (OAc) ₂ / P (o-tol) in dimethylformamide, toluene) ₃ is coupled with a vinyl ester (eg methyl acrylate) in the presence of palladium acetate / tri-ortho-tolylphosphine or (diphenylphosphino) ferrocenyl palladium chloride of the formula dppfPdCl ₂ .

Ketones of formula (18) are commercial products.

Amines of formula (5), wherein R ¹ and R ² are both H and n is 1, can be prepared according to the following scheme.

Wherein R ¹ , R ² and Ra are as defined above.

In a typical procedure, the acid of formula (19) is preferentially reduced to the corresponding alcohol (20) in the presence of an ester. This can be done by the formation of acyl imidazole or mixed anhydride followed by reduction with sodium borohydride or other suitable reducing agent.

The primary alcohol of formula (20) is then converted to a leaving group such as mesylate, tosylate, bromide or iodide and substituted with a suitable amine nucleophile. Preferred nucleophiles are azide ions, which can later be reduced via hydrogenation to primary amines or to triphenylphosphine. Other nucleophiles may include ammonia or alkylamines such as benzylamine or alkylamines, followed by cleavage of the alkyl groups to provide amines.

In some steps of the process for the preparation of the compound of formula (1) described above, it may be necessary to protect potentially reactive functional groups which do not wish to react and eventually cleave the protecting groups. In such cases, any commercially available protective radical can be used. In particular, TW GREENE, Protective Groups in Organic Synthesis , A. Wiley-Interscience Publication, 1981] or [PJ Kocienski, Protecting protection and deprotection methods such as those described in groups , Georg Thieme Verlag, 1994] can be used.

Alternatively, the compound of formula (1) may also be prepared according to the following scheme.

Wherein R ¹ , R ² , Ra, Rb, Rc, n and Q ₁ are as defined above.

PG is a bulky suitable hydroxy-protecting group, preferably TBDMS. PG 'is a suitable hydroxyl protecting group such as benzyl.

In a typical procedure, the acid of formula (21) is obtained by hydrolysis of the ester of formula (8). It is aqueous at temperatures including between 20 ° C. and 100 ° C. for 1-40 hours, optionally in the presence of a solvent or mixture of solvents (eg, water, 1,4-dioxane, tetrahydrofuran / water). By treatment with an acid or base (e. G., Hydrogen chloride, potassium hydroxide, sodium hydroxide or lithium hydroxide).

Amides of formula (22) are prepared by coupling an acid (21) with an amine of suitable formula (3), (3 ′) or (3 ″). Coupling is generally, optionally a tertiary amine base. (E.g., N-methylmorpholine, triethylamine or N, N-diisopropylethylamine), optionally in the presence of a catalyst (e.g., 1-hydroxybenzotriazole hydrate or 1-hydroxy In the presence of -7-azabenzotriazole), conventional coupling agents (e.g., 2-chloro-1,3-dimethylimidazolidinum hexafluorophosphate, 1- (3-dimethylaminopropyl) -3 -Ethylcarbodiimide hydrochloride or N, N'-dicyclohexylcarbodiimide) is carried out in excess of this amine as acid acceptor The reaction is carried out at 10 ° C. and 40 ° C. (room temperature for 1-24 hours). At a temperature comprising) suitable solvents, for example pyridine, N, N-dimethylformamide, tetrahydrate Furan, it can be carried out in dimethylsulfoxide, dichloromethane or ethyl acetate.

The amines (3), (3 ') or (3 ") are commercially available, or conventional methods well known to those skilled in the art from commercially available materials (e.g., reduction, oxidation, alkylation, protection, desorption). Protection and the like).

Amines of formula (23) are described in textbooks [T.W. GREENE. Protective Groups in Organic Synthesis. A. Wiley-Interscience Publication, 1981, such as those found in standard methodology for cleaving nitrogen protecting groups.

If Rb or Rc is α-methylbenzyl, a typical deprotection procedure is carried out in the presence of a suitable palladium catalyst (eg 20% palladium hydroxide on charcoal) at a temperature between 25 ° C. and elevated temperature for 1-4 hours, In a suitable solvent (eg methanol, ethanol, ethyl acetate), treatment of the protected amine solution of formula (22) with a suitable hydrogen donor, for example ammonium formate or formic acid, is involved.

The compound of formula (1) can be obtained by reaction of the amine (23) with bromide of formula (6). In a typical procedure, the amines 23 and bromide 6 are optionally heated under elevated temperatures for 18-48 hours, optionally with a suitable solvent (eg toluene or xylene) and a suitable tertiary amine base (eg N-methylmo In the presence of polyline, triethylamine or N, N-diisopropylethylamine).

In some steps of the process for preparing compounds of formula (1) described above, it may be necessary to protect potentially reactive hydroxyl functionalities that are not desired to react and eventually cleave the protecting groups. In such cases, any commercially available protective radical can be used. In particular, TW GREENE, Protective Groups in Organic Synthesis , A. Wiley-Interscience Publication, 1981] or [PJ Kocienski, Protecting protection and deprotection methods such as those described in groups , Georg Thieme Verlag, 1994] can be used.

All of the reactions and preparation methods of the novel starting materials used in the foregoing methods are conventional, as well as the appropriate reagents and reaction conditions for using or preparing them, as well as the procedures for isolating the desired product are described in the literature and in the examples herein. And it will be known to those skilled in the art with reference to the preparation method.

In addition, the compounds of formula (1), as well as intermediates for their preparation, can be purified by various known methods, for example crystallization or chromatography.

R ¹ and R ² are independently selected from H and C ₁ -C ₄ alkyl,

n is 0, 1 or 2,

Q ¹

, ^*-NH-C₁-C₄알킬, 및 ^*-N(R⁸)-Q²-A 기로부터 선택되는 기이며, 여기서

, ^* -NH-C ₁ -C ₄ alkyl, and ^* -N (R ⁸ ) -Q ² -A group, wherein

-Q ² is a single bond or C ₁ -C ₄ alkylene,

R ⁸ is H or C ₁ -C ₄ alkyl,

-p is 1 or 2,

-A is C ₃ -C ₁₀ Cycloalkyl (two or more carbon atoms of said cycloalkyl are optionally crosslinked by one or more carbon atoms), pyridyl, or a group of the formula

R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are the same or different and H, C ₁ -C ₄ alkyl, OR ⁹ , SR ⁹ , SOR ⁹ , SO ₂ R ⁹ , halo, CN, CF ₃ , OCF ₃ , COOR ⁹ , SO ₂ NR ⁹ R ¹⁰ , CONR ⁹ R ¹⁰ , NR ⁹ R ¹⁰ , NHCOR ¹⁰ ;

R ⁹ and R ¹⁰ are the same or different and are selected from H or C ₁ -C ₄ alkyl, and * represents a point of attachment to the carbonyl group or, if appropriate, pharmaceutically acceptable Salts and / or isomers, tautomers, solvates or isotopic variants thereof are preferred,

Provided that if n is 0, Q ¹ is not -NHCH ₃ and if n is 1 or 2:

1) Q ¹ is ^* -NH-C ₁ -C ₄ alkyl, or ^* -N (R ⁸ ) -Q ² -A, where A is C ₃ -C ₁₀ cycloalkyl (at least 2 carbon atoms of said cycloalkyl) Is optionally crosslinked by one or more carbon atoms);

2) If one of R ¹ and R ² is H, the other is not CH ₃ .

Preferred ^* -NH-C ₁ -C ₄ alkyl is NH-isopropyl.

Preferred compounds of formula (1) are those in which Q ¹ is ^* -N (R ⁸ ) -Q ² -A, wherein A is C ₃ -C ₁₀ cycloalkyl, wherein at least two carbon atoms of the cycloalkyl are optionally at least one carbon source Crosslinked by means), preferably cyclohexyl, or adamantyl.

More preferably, n is 1, Q ₂ is CH ₂ or a bond and A is C ₃ -C ₁₀ cycloalkyl, wherein at least two carbon atoms of said cycloalkyl are optionally crosslinked by at least one carbon atom , Preferably cyclohexyl, or adamantyl.

Other preferred compounds of formula (I) are those in which n is zero.

Preferably, n is 0, Q ¹ is a group of the formula

또는 ^*-N(R⁸)-Q²-A이고, Q²는 단일 결합 또는 C₁-C₄ 알킬렌이고, R⁸은 H이고, A는 나프틸 또는

Or ^* -N (R ⁸ ) -Q ² -A, Q ² is a single bond or C ₁ -C ₄ alkylene, R ⁸ is H, A is naphthyl or

이고,

ego,

R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are the same or different and H, C ₁ -C ₄ alkyl, OR ⁹ , SR ⁹ , SOR ⁹ , SO ₂ R ⁹ , halo, CF ₃ , OCF ₃ , COOR ⁹ , SO ₂ NR ⁹ R ¹⁰ , CONR ⁹ R ¹⁰ , NR ⁹ R ¹⁰ , NHCOR ¹⁰ , wherein at least two of R ³ to R ⁷ are H,

R ⁹ and R ¹⁰ are the same or different and are selected from H or C ₁ -C ₄ alkyl, and * indicates the point of attachment to the carbonyl group.

Preferably Q ¹ is

또는 ^*-N(R⁸)-Q²-A 기이고, Q²는 단일 결합 또는 C₁-C₄ 알킬렌이고, R⁸은 H 또는 C₁-C₄ 알킬이고, A는 시클로프로필, 시클로부틸, 시클로펜틸, 시클로헥실, 시클로헵틸, 아다만틸, 나프틸 또는 하기 화학식의 기이고,

Or a ^* -N (R ⁸ ) -Q ² -A group, Q ² is a single bond or C ₁ -C ₄ alkylene, R ⁸ is H or C ₁ -C ₄ alkyl, A is cyclopropyl, cyclo Butyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, naphthyl or a group of formula

R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are as defined above.

Preferably, A is a group of the formula

R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are derived from H, C ₁ -C ₄ alkyl, OR ⁹ , SR ⁹ , Cl, F, CF ₃ , OCF ₃ , COOR ⁹ , SO ₂ NR ⁹ R ¹⁰ And at least two of R ³ to R ⁷ represent H, R ⁹ and R ¹⁰ are the same or different and are selected from H or C ₁ -C ₄ alkyl.

Preferably, R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are the same or different and H, CH ₃ , OH, OCH ₃ , SCH ₃ , OCH ₂ CH ₃ , Cl, F, CF ₃ , OCF ₃ , COOH, SO ₂ NH ₂ , and at least two of R ³ to R ⁷ represent H.

Preferably, R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are the same or different and H, CH ₃ , OH, OCH ₃ , OCH ₂ CH ₃ , Cl, F, CF ₃ , OCF ₃ . COOH, SO ₂ NH ₂ and at least three of R ³ to R ⁷ represent H.

Preferably, R ⁸ is H, methyl or ethyl, more preferably H.

Preferably, Q ² is a bond, -CH ₂ -,-(CH ₂ ) ₂ -,-(CH ₂ ) _3- , -C (CH ₃ ) ₂ -CH _2- , -CH ₂ -C (CH ₃ ) _2- , and -CH (CH ₃ )-.

Preferably, n is 0 or 1.

In the above groups of compounds, the following substituents are preferred:

R ¹ and R ² are both CH _3, or

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

Especially preferred are the compounds of formula (1) below, as described in the Examples section of the present application.

N-cycloheptyl-2- {3-[(2R) -2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) propyl ] Phenyl} acetamide;

N- (cyclohexylmethyl) -2- {3-[(2R) -2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} Amino) propyl] phenyl} -N-methylacetamide;

N-[(1S) -1-cyclohexylethyl] -2- {3-[(2R) -2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxy Methyl) phenyl] ethyl} amino) propyl] phenyl} acetamide;

2- {3-[(2R) -2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) propyl] phenyl} -N Isopropylacetamide;

N-cyclopentyl-2- {3-[(2R) -2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) propyl ] Phenyl} acetamide;

N- (cyclobutylmethyl) -2- {3-[(2R) -2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} Amino) propyl] phenyl} acetamide;

N- (cyclopentylmethyl) -2- {3-[(2R) -2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} Amino) propyl] phenyl} acetamide;

N-cyclohexyl-2- {3-[(2R) -2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) propyl ] Phenyl} acetamide;

N-cyclobutyl-2- {3-[(2R) -2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) propyl ] Phenyl} acetamide;

N- (cyclohexylmethyl) -2- {3-[(2R) -2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} Amino) propyl] phenyl} acetamide;

N- (cyclopropylmethyl) -2- {3-[(2R) -2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} Amino) propyl] phenyl} acetamide;

N- (cycloheptylmethyl) -2- {3-[(2R) -2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} Amino) propyl] phenyl} acetamide;

N-1-adamantyl-2- {3-[(2R) -2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} Amino) propyl] phenyl} acetamide;

N- (1-adamantylmethyl) -2- {3-[(2R) -2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl ] Ethyl} amino) propyl] phenyl} acetamide;

N-2-adamantyl-2- {3-[(2R) -2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} Amino) propyl] phenyl} acetamide;

N- (2-cyclohexylethyl) -2- {3-[(2R) -2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] Ethyl} amino) propyl] phenyl} -N-methylacetamide;

N-cycloheptyl-2- {3-[(2R) -2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) propyl ] Phenyl} -N-methylacetamide;

N-cyclohexyl-N-ethyl-2- {3-[(2R) -2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl } Amino) propyl] phenyl} acetamide;

N- (2-cyclohexylethyl) -2- {3-[(2R) -2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] Ethyl} amino) propyl] phenyl} acetamide;

N- (4-chlorobenzyl) -2- {3-([2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] phenyl} acetamide;

N- (2,6-dimethoxybenzyl) -2- {3-([2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl } Amino) -2-methylpropyl] phenyl} acetamide;

N-benzyl-2- {3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] Phenyl} acetamide;

4-{(1R) -2-[(2- {3- [2- (3,4-dihydroisoquinolin-2 (1H) -yl) -2-oxoethyl] phenyl} -1,1-dimethyl Ethyl) amino] -1-hydroxyethyl} -2- (hydroxymethyl) phenol;

N- [2-fluoro-5- (trifluoromethyl) benzyl] -2- {3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxy Oxymethyl) phenyl] ethyl} amino) -2-methylpropyl] phenyl} acetamide;

N- (2,6-dichlorobenzyl) -2- {3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino ) -2-methylpropyl] phenyl} acetamide;

2- {3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] phenyl} -N -[2- (methylthio) benzyl] acetamide;

N- (2,3-dimethylbenzyl) -2- {3-([2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} Amino) -2-methylpropyl] phenyl} acetamide;

2- {3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] phenyl} -N -[3- (trifluoromethyl) benzyl] acetamide;

N- [4-chloro-3- (trifluoromethyl) benzyl] -2- {3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxy Methyl) phenyl] ethyl} amino) -2-methylpropyl] phenyl} acetamide;

N- [2-chloro-5- (trifluoromethyl) benzyl] -2- {3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxy Methyl) phenyl] ethyl} amino) -2-methylpropyl] phenyl} acetamide;

N- [3,5-bis (trifluoromethyl) benzyl] -2- {3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl ) Phenyl] ethyl} amino) -2-methylpropyl] phenyl} acetamide;

N- [3-fluoro-5- (trifluoromethyl) benzyl] -2- {3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxy Oxymethyl) phenyl] ethyl} amino) -2-methylpropyl] phenyl} acetamide;

N- [2- (4-chlorophenyl) ethyl] -3- {2-[(2R) -2-hydroxy-2- (4-hydroxy-3-hydroxymethylphenyl) ethylamino] -2-methyl Propyl} benzamide;

3- {2-[(2R) -2-hydroxy-2- (4-hydroxy-3-hydroxymethylphenyl) -ethylamino] -2-methylpropyl} -N- [2- (4-methylphenyl) Ethyl] benzamide;

3- {2-[(2R) -2-hydroxy-2- (4-hydroxy-3-hydroxymethylphenyl) -ethylamino] -2-methyl-propyl} -N- [2- (4-tri Fluoromethylphenyl) ethyl] benzamide;

N- [2- (3,4-dichlorophenyl) ethyl] -3- {2-[(2R) -2-hydroxy-2- (4-hydroxy-3-hydroxymethylphenyl) ethylamino] -2 -Methyl-propyl} -benzamide;

N- [2- (3,4-dimethylphenyl) ethyl] -3- {2-[(2R) -2-hydroxy-2- (4-hydroxy-3-hydroxymethylphenyl) -ethylamino]- 2-methylpropyl} benzamide;

3- {2-[(2R) -2-hydroxy-2- (4-hydroxy-3-hydroxymethyl-phenyl) ethylamino] -2-methyl-propyl} -N- (2-naphthalene-2 -Yl-ethyl) benzamide;

N- (1,1-dimethyl-2-phenylethyl) -3- {2-[(2R) -2-hydroxy-2- (4-hydroxy-3-hydroxymethylphenyl) -ethylamino] -2 -Methylpropyl} benzamide;

3- {2-[(2R) -2-hydroxy-2- (4-hydroxy-3-hydroxymethylphenyl) -ethylamino] -2-methylpropyl} -N- (2-methyl-2-phenyl Propyl) benzamide;

N- (4-chlorobenzyl) -3- {2-[(2R) -2-hydroxy-2- (4-hydroxy-3-hydroxymethylphenyl) ethylamino] -2-methylpropyl} benzamide;

N- (2,6-dimethoxybenzyl) -2- {3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} Amino) ethyl] phenyl} acetamide;

N- (3,4-dichlorobenzyl) -2- {3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino ) Ethyl] phenyl} acetamide;

N-benzyl-2- {3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) ethyl] phenyl} acetamide ;

N- (2,3-dihydro-1H-inden-2-yl) -2- {3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxy Oxymethyl) phenyl] ethyl} amino) ethyl] phenyl} acetamide;

2- {3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) ethyl] phenyl} -N- (2- Phenylethyl) acetamide;

2- {3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) ethyl] phenyl} -N- (3- Phenylpropyl) acetamide;

N-benzyl-3-[(2R) -2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) propyl] benzamide;

N- (3,4-dichlorobenzyl) -3-[(2R) -2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} Amino) propyl] benzamide;

N- [2-fluoro-5- (trifluoromethyl) benzyl] -3-[(2R) -2-({(2R) -2-hydroxy-2- [4-hydroxy-3- ( Hydroxymethyl) phenyl] ethyl} amino) propyl] benzamide;

N- (2,6-dimethoxybenzyl) -3-[(2R) -2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl } Amino) propyl] benzamide;

N- [2- (4-chlorophenyl) ethyl] -3-[(2R) -2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl ] Ethyl} amino) propyl] benzamide;

N- (2,3-dihydro-1H-inden-2-yl) -3-[(2R) -2-({(2R) -2-hydroxy-2- [4-hydroxy-3- ( Hydroxymethyl) phenyl] ethyl} amino) propyl] benzamide;

3-[(2R) -2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) propyl] -N- (2-phenyl Ethyl) benzamide;

3-[(2R) -2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) propyl] -N-[(1R) -1-phenylethyl] benzamide;

3-[(2R) -2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) propyl] -N- (3-phenyl Propyl) benzamide;

4-[(1R) -2-({(1R) -2- [3- (3,4-dihydroisoquinoline-2 (1H) -ylcarbonyl) phenyl] -1methylethyl} amino) -1 Hydroxyethyl] -2- (hydroxymethyl) phenol;

N- (2,3-dimethylbenzyl) -3-[(2R) -2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} Amino) propyl] benzamide;

N- (5,6-diethyl-2,3-dihydro-1H-inden-2-yl) -3-[(2R) -2-({(2R) -2-hydroxy-2- [4 -Hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) propyl] benzamide;

N- (4-chlorobenzyl) -3-[(2R) -2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) Propyl] benzamide;

3-[(2R) -2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) propyl] -N-phenylbenzamide;

N- [4- (aminosulfonyl) benzyl] -3-[(2R) -2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] Ethyl} amino) propyl] benzamide;

N- [2- (3-fluorophenyl) ethyl] -3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} Amino) -2-methylpropyl] benzamide;

3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] -N- (2-py Rollidin-1-ylethyl) benzamide;

N- [2- (2,6-dichlorophenyl) ethyl] -3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl } Amino) -2-methylpropyl] benzamide;

N- (2,3-dihydro-1H-inden-2-ylmethyl) -3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl ) Phenyl] ethyl} amino) -2-methylpropyl] benzamide;

N- (2- {4-[(butylamino) carbonyl] phenyl} ethyl) -3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxy Methyl) phenyl] ethyl} amino) -2-methylpropyl] benzamide;

3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] -N- {2- [ 2- (phenylthio) phenyl] ethyl} benzamide;

N- (2-cyclohexylethyl) -3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2- Methylpropyl] benzamide;

3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] -N- (3-phenyl Propyl) benzamide;

3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] -N- (2-phenyl Ethyl) benzamide;

N- [2- (3,6-dichloro-2-methylphenyl) ethyl] -3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) Phenyl] ethyl} amino) -2-methylpropyl] benzamide;

N- [2- (5-chloro-2-methoxyphenyl) ethyl] -3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) Phenyl] ethyl} amino) -2-methylpropyl] benzamide;

3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] -N- [2- ( 3-methoxyphenyl) ethyl] benzamide;

N- [2- (3-ethoxyphenyl) ethyl] -3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} Amino) -2-methylpropyl] benzamide;

3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] -N- {2- [ 4- (3-pyrrolidin-1-ylpropoxy) phenyl] ethyl} benzamide;

3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] -N- {2- [ 2- (3-pyrrolidin-1-ylpropoxy) phenyl] ethyl} benzamide;

3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] -N- {2- [ 3- (3-pyrrolidin-1-ylpropoxy) phenyl] ethyl} benzamide;

N- [2- (4-chlorophenyl) ethyl] -N-ethyl-3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl ] Ethyl} amino) -2-methylpropyl] benzamide;

2- {3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] phenyl} -N -(3-pyrrolidin-1-ylpropyl) acetamide;

N- (cycloheptylmethyl) -2- {3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2 -Methylpropyl] phenyl} acetamide;

N-1-adamantyl-2- {3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2 -Methylpropyl] phenyl} acetamide;

N-benzyl-2- {3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] Phenyl} -N-methylacetamide;

N- [2- (4-fluorophenyl) ethyl] -3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} Amino) -2-methylpropyl] benzamide;

3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] -N- [2- ( 4-phenoxyphenyl) ethyl] benzamide;

N- [2- (4-ethoxyphenyl) ethyl] -3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} Amino) -2-methylpropyl] benzamide;

N- [2- (4-ethylphenyl) ethyl] -3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino ) -2-methylpropyl] benzamide;

3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] -N- [2- ( 6-methylpyridin-2-yl) ethyl] benzamide;

3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] -N- [2- ( 2-methoxyphenyl) ethyl] benzamide;

Methyl 4-[({3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] benzoyl } Amino) methyl] benzoate;

N- [4- (dimethylamino) benzyl] -3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino)- 2-methylpropyl] benzamide;

N- {2- [3-fluoro-4- (trifluoromethyl) phenyl] ethyl} -3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (Hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] benzamide;

N- [2- (3-fluoro-4-methylphenyl) ethyl] -3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl ] Ethyl} amino) -2-methylpropyl] benzamide;

N- [2- (2,3-difluoro-4-methylphenyl) ethyl] -3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxy Methyl) phenyl] ethyl} amino) -2-methylpropyl] benzamide;

3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] -N- (2-mesh Tilethyl) benzamide;

N- [2- (2,6-difluoro-3-methylphenyl) ethyl] -3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxy Methyl) phenyl] ethyl} amino) -2-methylpropyl] benzamide;

N- [2- (6-chloro-2-fluoro-3-methylphenyl) ethyl] -3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxy Oxymethyl) phenyl] ethyl} amino) -2-methylpropyl] benzamide;

N- [2- (2-chloro-6-fluoro-3-methylphenyl) ethyl] -3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxy Oxymethyl) phenyl] ethyl} amino) -2-methylpropyl] benzamide;

N- [2- (5-fluoro-2-methylphenyl) ethyl] -3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl ] Ethyl} amino) -2-methylpropyl] benzamide;

N- {2- [3-fluoro-5- (trifluoromethyl) phenyl] ethyl} -3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (Hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] benzamide;

3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] -N- {2- [ 2- (trifluoromethyl) phenyl] ethyl} benzamide;

3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] -N- [2- ( 2,4,5-trimethylphenyl) ethyl] benzamide;

3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] -N- (2-pyridine -2-ylethyl) benzamide;

N- [2- (1H-benzimidazol-2-yl) ethyl] -3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) Phenyl] ethyl} amino) -2-methylpropyl] benzamide;

3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] -N- {2- [ 4- (morpholin-4-ylsulfonyl) phenyl] ethyl} benzamide;

N- [2- (3-chloro-2-hydroxyphenyl) ethyl] -3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) Phenyl] ethyl} amino) -2-methylpropyl] benzamide;

N- [4-fluoro-2- (trifluoromethyl) benzyl] -3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) Phenyl] ethyl} amino) -2-methylpropyl] benzamide;

N- (3-chlorobenzyl) -3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methyl Propyl] benzamide;

N- (2-chlorobenzyl) -3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methyl Propyl] benzamide;

N- [2- (4,6-dimethylpyrimidin-2-yl) ethyl] -3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxy Methyl) phenyl] ethyl} amino) -2-methylpropyl] benzamide;

3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] -N- [2- ( 3-methylpyridin-2-yl) ethyl] benzamide;

N- [2- (2-chlorophenyl) ethyl] -3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino ) -2-methylpropyl] benzamide;

N- [2- (1-adamantyl) ethyl] -3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} Amino) -2-methylpropyl] benzamide;

3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] -N- [2- ( 1-naphthyl) ethyl] benzamide;

N- [2- (2,6-dimethylphenyl) ethyl] -3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl } Amino) -2-methylpropyl] benzamide;

3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] -N- {2- [ 4- (methylthio) phenyl] ethyl} benzamide;

N- [2- (5-chloro-2-fluorophenyl) ethyl] -3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) Phenyl] ethyl} amino) -2-methylpropyl] benzamide;

N- [2- (2-chloro-4-fluorophenyl) ethyl] -3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) Phenyl] ethyl} amino) -2-methylpropyl] benzamide;

3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] -N- [2- ( 4-methoxy-2,5-dimethylphenyl) ethyl] benzamide;

N- [2- (2,3-dichlorophenyl) ethyl] -3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl } Amino) -2-methylpropyl] benzamide;

3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] -N- [2- ( 4-methoxy-2,3-dimethylphenyl) ethyl] benzamide;

N- (2-biphenyl-4-ylethyl) -3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino ) -2-methylpropyl] benzamide;

N- [2- (2,4-dimethylphenyl) ethyl] -3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl } Amino) -2-methylpropyl] benzamide;

N- [2- (2,3-dimethylphenyl} ethyl] -3- [2-({(2R} -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl } Amino) -2-methylpropyl] benzamide;

3- [2-({(2R} -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl} phenyl] ethyl} amino} -2-methylpropyl] -N- {2- [ 3- (trifluoromethyl) phenyl] ethyl} benzamide;

N- [2- (4-chloro-2-fluorophenyl) ethyl] -3- [2-({(2R} -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) Phenyl] ethyl} amino) -2-methylpropyl] benzamide;

N- (2,5-dimethylbenzyl) -3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2 -Methylpropyl] benzamide;

N- (3,4-dichlorobenzyl) -3- {3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino ) -2-methylpropyl] phenyl} propanamide;

3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] -N- {2- [ 4- (trifluoromethoxy) phenyl] ethyl} benzamide;

3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] -N- [2- ( 4-hydroxyphenyl) -2-methylpropyl] benzamide;

3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl} phenyl] ethyl} amino) -2-methylpropyl] -N- [2- ( 4-hydroxy-3-methylphenyl) ethyl] benzamide;

N- [2- (4-hydroxy-2,3-dimethylphenyl) ethyl] -3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxy Methyl) phenyl] ethyl} amino) -2-methylpropyl] benzamide;

N- [2- (4-hydroxy-2,5-dimethylphenyl) ethyl] -3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxy Methyl) phenyl] ethyl} amino) -2-methylpropyl] benzamide;

N- (3,4-dichlorobenzyl) -2- {3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino ) -2-methylpropyl] phenyl} acetamide;

N- (3,5-dichlorobenzyl) -2- {3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino ) -2-methylpropyl] phenyl} acetamide;

2- {3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] phenyl} -N -(Pyridin-2-ylmethyl) acetamide;

N-ethyl-3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] -N- (3-phenylpropyl) benzamide;

3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] -N- [3- ( 4-hydroxyphenyl) propyl] benzamide;

3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] -N- [2- ( 3-methylphenyl) ethyl] benzamide;

3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] -N- [2- ( 6-methoxypyridin-3-yl) ethyl] benzamide;

3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] -N- [3- ( 3-methoxyphenyl) propyl] benzamide;

N- [3- (4-chlorophenyl) propyl] -3- {2-[(2R) -2-hydroxy-2- (4-hydroxy-3-hydroxymethylphenyl) ethylamino] -2-methyl Propyl} benzamide;

3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] -N- {2- [ 4- (1H-pyrazol-1-yl) phenoxy] ethyl} benzamide;

N- [2- (3,4-difluorophenyl) ethyl] -3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl ] Ethyl} amino) -2-methylpropyl] benzamide;

3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] -N- (2-quinoline -5-ylethyl) benzamide; And,

N- [3- (2-ethyl-2,3-dihydro-1-benzofuran-5-yl) propyl] -3- [2-({(2R) -2-hydroxy-2- [4- Hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] benzamide.

According to one aspect of the invention, compounds of formula (1) in which the (CH ₂ ) _n -C (= 0) Q ¹ group is in the meta position are generally preferred.

Compounds of formula (1) may also optionally be modified with pharmaceutically acceptable salts. In particular, pharmaceutically acceptable salts of compounds of formula (1) include their acid additions and base salts (including disalts).

Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include acetates, adipates, aspartates, benzoates, besylates, bicarbonates / carbonates, bisulfates / sulfates, borates, chamlates, citrates, cyclamates, disylates, acyls Latex, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hebenzate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, hydrogen Phosphates, isethionates, D- and L-lactates, maleates, maleates, malonates, mesylates, methylsulfates, 2-lead silicates, nicotinates, nitrates, orotates, oxalates, palmitates , Pamoate, phosphate / hydrogen, phosphate / phosphate dihydrogen, pyroglutamate, saccharide, stearate, succinate And it includes carbon carbonate, D- and L- tartrate, 1-hydroxy-2-naphthoate tosylate and Xi seizure benzoate salt.

Suitable base salts are formed from bases which form non-toxic salts. Examples include aluminum, arginine, benzatin, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, melglumine, olamine, potassium, sodium, tromethamine and zinc salts.

Hemisalts of acids and bases, such as hemisulphate and hemicalcium salts, may also be formed.

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

Pharmaceutically acceptable salts of compounds of formula (1) may be prepared by one or more of the following three methods.

(i) a method of reacting a compound of formula (1) with a desired acid or base;

(ii) removing the acid- or base-labile protecting group from a suitable precursor of the compound of formula (1) or ring-opening a suitable cyclic precursor such as lactone or lactam with the desired acid or base; or

(iii) A process for converting one salt of a compound of formula (1) to another by reaction with a suitable acid or base, or using a suitable ion exchange column.

All three reactions are typically carried out in solution. The resulting salt may precipitate out and be collected by filtration or may be recovered by solvent evaporation. The degree of ionization of the resulting salt can vary from complete ionization to almost non-ionization.

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

Inclusion compounds, ie complexes such as drug-host inclusion complexes in which the drug and host are present in stoichiometric or non stoichiometric amounts, unlike the solvates mentioned above, are included within the scope of the invention. Also included are drug complexes containing two or more organic and / or inorganic components, which may be in stoichiometric or non stoichiometric amounts. The resulting complex can be ionized, partially ionized, or non-ionized. For a description of such complexes, see Haleblian, J Pharm Sci, 64 (8), 1269-1288 (August 1975).

As used herein, the compound of formula (1) includes salts, solvates and complexes thereof and solvates and complexes thereof.

Compounds of the invention include compounds of formula (1) as defined herein, including all polymorphs and crystal habits thereof, prodrugs and isomers thereof as defined herein (including optical, geometric and tautomers) and Isotope-labeled compounds of formula (1).

As indicated, so-called 'prodrugs' of compounds of formula (1) are also within the scope of the present invention. Thus, certain derivatives of the compounds of formula (1), which may themselves have little or no pharmacological activity, are formulated to have the desired activity when administered into or onto the body, for example by hydrolytic cleavage ( It can be converted into the compound of 1). Such derivatives are called 'prodrugs'. Further information on the use of prodrugs can be found in Pro-drugs as Novel Delivery Systems, Vol. 14, ACS Symposium Series (T. Higuchi and W. Stella) and 'Bioreversible Carriers in Drug Design', Pergamon Press, 1987 (ed. E. B Roche, American Pharmaceutical Association).

Prodrugs according to the present invention are for example suitable for functional groups present in compounds of formula (1), as described in, for example, "Design of Prodrugs" by H. Bundgaard (Elsevier, 1985). It can be prepared by substituting certain residues known to those skilled in the art as 'pro-moiety'.

Some examples of prodrugs according to the present invention include the following.

(i) When the compound of formula (1) contains a carboxylic acid functional group (-COOH), its ester, for example if desired, the hydrogen of the carboxylic acid functional group of the compound of formula (1) ₁ -C ₈ ) alkyl substituted compound;

(ii) When the compound of formula (1) contains an alcohol functional group (-OH), the hydrogen of the ether, for example the alcohol functional group of the compound of formula (1), is (C ₁ -C ₆ ) alkanoyloxy Compound substituted with methyl; And

(iii) when the compound of formula (1) contains a primary or secondary amino functional group (-NH ₂ or NHR, wherein R is not H), the amides thereof, for example of the compound of formula (1) A compound in which one or two hydrogens of an amino functional group are substituted with (C ₁ -C ₁₀ ) alkanoyl.

Further examples of substituents according to the above examples and examples of other prodrug types can be found in the abovementioned references.

Moreover, certain compounds of formula (1) may themselves act as prodrugs of other compounds of formula (1).

Metabolites of the compounds of formula (1), ie compounds formed in vivo upon drug administration, are also included within the scope of the present invention. Some examples of metabolites according to the present invention include the following.

(i) when the compound of formula (1) contains a methyl group, its hydroxymethyl derivative (-CH _3-- CH ₂ OH);

(ii) when the compound of the formula (1) contains an alkoxy group, its hydroxy derivative (-OR-> -OH);

(iii) where the compound of formula (1) contains a tertiary amine group, its secondary amine derivative (-NR ¹ R ^2- > -NHR ¹ or -NHR ² );

(iv) where the compound of formula (1) contains a secondary amino group, its primary derivative (-NHR ^1- > -NH ₂ );

(v) where the compound of formula (1) contains a phenyl moiety, a phenol derivative thereof (-Ph--PhOH); And

(vi) When the compound of the formula (1) contains an amide group, its carboxylic acid derivative (-CONH ₂ → COOH).

Compounds of formula (1) containing one or more asymmetric carbon atoms may exist as two or more stereoisomers. If the compound of formula (1) contains an alkenyl or alkenylene group, cis / trans (or Z / E) geometric isomers are possible. Tautomerism (tautomerism) may occur if the compound contains, for example, a keto, or if the structural isomers are interconvertible through an oxime group or a low energy barrier of an aromatic moiety. This can take the form of, for example, proton tautomerization in compounds of formula (1) containing imino, keto, or oxime groups, or so-called valence tautomerization in compounds containing aromatic moieties. A single compound will be able to exhibit two or more types of isomerization.

All stereoisomeric, geometric isomeric and tautomeric forms of the compounds of the formula (1), including compounds showing two or more types of isomerization, and mixtures of one or more thereof, are included within the scope of the present invention. Also included are acid addition or base salts in which the counterion is optically active, for example d -lactate or l -lysine, or racemates such as dl -tartrate or dl -arginine.

Cis / trans isomers can be separated by conventional techniques well known to those skilled in the art, such as chromatography and fractional crystallization.

Conventional techniques for the preparation / isolation of individual enantiomers include racemics (or racemics of salts or derivatives) using chiral synthesis from optically pure suitable precursors or, for example, using chiral high pressure liquid chromatography (HPLC). Sieve).

Alternatively, racemates (or racemic precursors) are suitable optically active compounds, such as alcohols, or acids such as tartaric acid or 1-phenylethylamine when the compound of formula (1) contains an acidic or basic moiety. Or with a base. The resulting diastereomeric mixtures can be separated by chromatography and / or fractional crystallization, either or both of the diastereomers being converted to the corresponding pure enantiomer (s) by methods well known to those skilled in the art.

The chiral compounds (and chiral precursors thereof) of the invention comprise 0 to 50% by volume, typically 2 to 20% by volume of isopropanol and 0 to 5% by volume of alkylamine, typically 0.1% by volume of diethylamine. It can be obtained in enantiomer-concentrated form using chromatography on an asymmetric resin, typically HPLC, with a mobile phase consisting of hydrocarbons, typically heptane or hexane. Concentration of the eluent allows for a concentrated mixture.

Stereoisomeric solid racemic mixtures can be separated by conventional techniques known to those skilled in the art (see, eg, "Stereochemistry of Organic Compounds" by E. L. Eliel (Wiley, New York, 1994)).

According to one aspect of the invention, R ¹ is hydrogen and R ² is C ₁ -C ₄ Alkyl, preferably methyl, and n and Q ¹ are generally preferred (R, R) -stereoisomers of the formulas as defined above.

Wherein n and Q ¹ are as defined above for the compound of formula (1).

The present invention includes all pharmaceutically acceptable, isotopically labeled compounds of one or more valence atomic numbers of formula (1), substituted by atoms having the same atomic weight or mass number than atomic weight or mass number prevailing in nature.

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

Certain isotopically labeled compounds of formula (1), for example those incorporating radioisotopes, are useful for drug and / or matrix tissue distribution studies. Radioisotope tritium, ie ³ H, and carbon-14, ie ¹⁴ C, are useful for this purpose in view of ease of incorporation and an easy detection method.

Substitution with heavy isotopes, such as deuterium, i.e. ² H, enables certain therapeutic advantages resulting from better metabolic stability, eg, increased in vivo half-life or reduced dose requirements, and may therefore be desirable in some cases. have.

Substitution with positron emitting isotopes, such as ¹¹ C, ¹⁸ F, ¹⁵ O and ¹³ N, may be useful in positron emission tomography (PET) studies to investigate substrate receptor occupancy.

Isotope labeled compounds of formula (1) generally use the appropriate examples and preparation methods using suitable isotopically labeled reagents in place of the non-labeled reagents used previously or by conventional techniques known to those skilled in the art. It may be produced by the same method as the method described in.

Include those in acetone, d ₆ -DMSO - solvate, pharmaceutically acceptable according to the invention is that the solvent of crystallization may be isotopically substituted, for example D ₂ O, d _6.

Compounds of formula (1), pharmaceutically acceptable salts and / or derived forms thereof, involve β2 receptors or their hyperactivity, in particular allergic and nonallergic airway diseases, as well as other diseases (eg For example, there are conditions that are beneficial for lowering nervous system diseases, premature colic, congestive heart failure, depression, inflammatory and allergic skin diseases, psoriasis, proliferative skin diseases, glaucoma and acidity, especially stomach and peptic ulcers, Valuable pharmaceutical active compounds suitable for the treatment and prevention of numerous disorders that may be beneficial in the treatment of, but not limited to).

As mentioned above, the compounds of formula (1) and their pharmaceutically acceptable salts and derived forms are, according to the invention, for the treatment and / or prophylaxis in animals, preferably in mammals, in particular in humans. It can be administered as a medicine. They are themselves, in admixture together, or as active ingredients, as well as conventional dosages, as well as effective dosages of one or more compounds of formula (1), pharmaceutically acceptable salts and / or derived forms thereof. And in the form of pharmaceutical formulations containing harmless excipients and / or additives.

The compound of formula (1), pharmaceutically acceptable salts and / or derived forms thereof may be freeze dried, spray dried, or evaporated to dry to provide a solid plug, powder, or membrane of crystalline or amorphous material. Microwave or high frequency drying may be used for this purpose.

Compounds of formula (1), pharmaceutically acceptable salts and / or derivatives thereof may be administered alone or in combination with other drugs, generally in combination with one or more pharmaceutically acceptable excipients Will be administered as an agent. The term "excipient" is used herein to describe any ingredient other than the compound of the present invention. The choice of excipient will vary greatly depending on the particular mode of administration.

The compounds of the present invention can be administered orally. Oral administration may involve a sore throat so that the compound enters the gastrointestinal tract, or may be administered buccally or sublingually such that the compound enters the blood stream directly from the mouth.

Formulations suitable for oral administration include solid formulations such as capsules containing tablets, particulates, liquids, or powders, lozenges (including liquid-filled forms), chewing agents, multi- and nano-particulates, Gels, solid solutions, liposomes, membranes, orbs, sprays and liquid formulations.

Liquid formulations include dispersants, solutions, syrups and elixirs. Such formulations can be used as fillers in soft or hard capsules, and typically include carriers such as water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or suitable oils, and one or more emulsifiers and / or suspending agents. It may include. Liquid formulations can also be prepared by, for example, reconstitution of a solid from a sachet.

The compounds of the present invention may also be used in fast-soluble, fast disintegrating dosage forms such as those described in Expert Opinion in Therapeutic Patents, 11 (6), 981-986, by Liang and Chen (2001).

In tablet dosage forms, depending on the dosage, the drug may comprise from 1% to 80% by weight of the dosage form, more typically from 5% to 60% by weight of the dosage form. In addition to drugs, tablets generally contain a disintegrant. Examples of disintegrants include sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methyl cellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropyl Cellulose, starch, pregelatinized starch and sodium alginate. Generally, the disintegrant will comprise from 1% to 25% by weight, preferably from 5% to 20% by weight of the dosage form.

Binders are generally used to impart tack to tablet formulations. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycols, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, hydroxypropyl cellulose and hydroxypropyl methylcellulose. The tablets also contain diluents such as lactose (monohydrate, spray dried monohydrate, anhydride, etc.), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dibasic calcium phosphate dihydrate. do.

Tablets also optionally include surfactants such as sodium lauryl sulfate and polysorbate 80, and glidants such as silicon dioxide and talc. If present, the surface active agent may comprise from 0.2% to 5% by weight of the tablet and the glidant may comprise from 0.2% to 1% by weight of the tablet.

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

Other possible ingredients include antioxidants, colorants, flavors, preservatives and taste masking agents.

Exemplary tablets include up to about 80% drug, about 10% to about 90% by weight binder, about 0% to about 85% by weight diluent, about 2% to about 10% by weight disintegrant, and about It contains 0.25 wt% to about 10 wt% lubricant.

Tablet blends may be compressed directly or by roller to form tablets. The tablet blend or portion of the blend may alternatively be wet-, dry-, or melt-granulated, melt condensed, or extruded prior to tableting. The final formulation may comprise one or more layers and may or may not be coated; It may also be encapsulated.

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

Consumable oral membranes for human or veterinary use are typically flexible, water-soluble or water-swellable thin film dosage forms that can quickly dissolve or adhere to mucosa, and are typically compounds of formula (1), membrane-forming polymers, binders, solvents, humectants , Plasticizers, stabilizers or emulsifiers, viscosity modifiers and solvents. Some components of the formulation may perform one or more functions.

The compound of formula (1) may be water soluble or water insoluble. Water soluble compounds typically comprise 1% to 80% by weight, more typically 20% to 50% by weight of the solute. Low soluble compounds may comprise a higher proportion of the composition, typically up to 88 wt% of the solute. Alternatively, the compound of formula (1) may exist in the form of multiparticulate beads.

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

Other possible ingredients include antioxidants, colorants, flavors and flavor enhancers, preservatives, saliva stimulants, coolants, cosolvents (including oils), softeners, extenders, antifoams, surfactants and taste masking agents.

Membranes according to the invention are typically prepared by evaporating to dry an aqueous thin film coated onto a peelable backing support or paper. This can be done in a drying oven or tunnel, typically a combined coater dryer, or by freeze drying or vacuum.

Solid preparations for oral administration may be formulated to be immediate and / or controlled release. Controlled release formulations include delayed release, sustained release, pulsed release, controlled release, target release, and program release.

Controlled-release preparations suitable for the purposes of the present invention are described in US Pat. 6, 106, 864. Details of other suitable release techniques, such as high energy dispersion and osmotic and coated particles, are described in Pharmaceutical Technology On-line, 25 (2), 1-14, by Verma et. al (2001). The use of chewing gum to achieve controlled release is described in WO 00/35298.

The compounds of the invention can also be administered directly into the bloodstream, into muscle, or into internal organs. Suitable methods for parenteral administration include intravenous, intraarterial, intraperitoneal, intradural, intraventricular, urethral, intrasternal, intracranial, intramuscular and subcutaneous administration. Apparatuses suitable for parenteral administration include needle (including microneedle) syringes, needleless syringes, and infusion techniques.

Parenteral preparations are typically aqueous solutions that may contain excipients such as salts, carbohydrates, and buffers (preferably buffered to pH 3-9), but in some applications they may be combined with a suitable vehicle such as sterile water without pyrogen. It may be formulated more suitably as a sterile non-aqueous solution or dried form to be used together.

The preparation of parenteral preparations under sterile conditions, for example by lyophilization, can be readily carried out using standard pharmaceutical techniques well known to those skilled in the art.

The solubility of the compound of formula (1) used to prepare parenteral solutions can be increased by the use of suitable formulation techniques, for example by the incorporation of solubility enhancers.

Formulations for parenteral administration may be formulated to be immediate and / or controlled release. Controlled release formulations include delayed release, sustained release, pulsed release, controlled release, target release, and program release. Thus, the compounds of the present invention may be formulated as solid, semisolid, or thixotropic liquid forms to be administered as implanted reservoirs that provide controlled release of the active compound. Examples of such formulations include drug coated stents and PGLA poly ( dl -lactic-coglycolic) acid (PGLA) microspheres.

The compounds of the invention may also be administered topically, ie dermal or transdermal, to the skin or mucosa. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, spray powders, dressings, foams, membranes, skin patches, wafers, implants, sponges, fibers, bandages and microemulsions. Include. Liposomes can also be used. Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol. Penetration enhancers can be incorporated (see, eg, J Pharm Sci, 88 (10), 955-958 by Finnin and Morgan (October 1999)).

Other topical methods of administration include electroporation, iontophoresis, sonophoresis, sonotherapy, and delivery by injection without microneedle or needles (eg Powderject ™, Bioject ™, etc.). do.

Formulations for topical administration may be formulated to be immediate and / or controlled release. Controlled release formulations include delayed release, sustained release, pulsed release, controlled release, target release, and program release.

The compounds of the invention also typically contain a dry powder from a dry powder inhaler (either alone as a mixture (eg, as a dry blend with lactose) or as mixed component particles (eg, phospholipids such as phosphatidylcholine). ), Or as an aerosol spray from a pressurized vessel, pump, spray, nebulizer (preferably an electrohydrator using electrohydrodynamics to produce fine mist), or a nebulizer, to be administered intranasally or by inhalation. And may or may not use a suitable propellant, such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane. For intranasal use, powders may include bioadhesives such as chitosan or cyclodextrins.

Pressurized vessels, pumps, sprays, nebulizers, or nebulizers can be used, for example, of the active propellant (s) as ethanol, aqueous ethanol, or solvents and optional surfactants such as sorbitan trioleate, oleic acid, or oligolactic acid. Solutions or suspensions of the compound (s) of the invention, including other materials suitable for dispersion, solubilization, or prolonged release.

Prior to use as a dry powder or suspension formulation, the drug product is micronized to a size (typically less than 5 microns) suitable for inhalation delivery. This can be done by any suitable grinding method, for example, spiral jet milling, fluidized bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenization, or spray drying.

Capsules for use in an inhaler or insufflator (for example, a gel prepared from the Latin or hydroxypropylmethylcellulose), blisters (blister) and the cartridge base a suitable powder, such as the present invention compound, lactose or starch and l - It may be formulated to contain a powder mix of performance modifiers such as isoleucine, mannitol, or magnesium stearate. Lactose may be in anhydride or monohydrate form, preferably the latter. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose.

Solution formulations suitable for use in nebulizers using electrohydraulics to produce fine mist may contain from 1 μg to 20 mg of the compound of the invention per operation and the working volume may vary from 1 μl to 100 μl. Typical formulations may include a compound of formula (1), propylene glycol, sterile water, ethanol and sodium chloride. Other solvents that may be used instead of propylene glycol include glycerol and polyethylene glycol.

Suitable flavoring agents such as menthol and levomenthol, or sweetening agents such as saccharin or saccharin sodium can be added to the formulations of the invention intended for inhalation / intranasal administration.

Formulations for inhalation / intranasal administration may be formulated to be immediate and / or controlled release using, for example, PGLA. Controlled release formulations include delayed release, sustained release, pulsed release, controlled release, target release, and program release.

For dry powder inhalers and aerosols, the dosage unit is determined using a valve that delivers a metered amount. Unit doses according to the invention are typically arranged to administer metered doses or “puffs” containing from 0.001 mg to 10 mg of the compound of formula (1). The total daily dose will typically be in the range of 0.001 mg to 40 mg, which may be administered in a single dose, or more usually as a divided dose for a day.

Compounds of formula (1) are particularly suitable for inhalation administration.

The compounds of the invention can be administered rectally or vaginally, for example in the form of suppositories, pessaries, or enemas. Cocoa butter is a traditional suppository base, but various other materials may be used as appropriate.

Formulations for rectal / vaginal administration may be formulated to be immediate and / or controlled release. Controlled release formulations include delayed release, sustained release, pulsed release, controlled release, target release, and program release.

The compounds of the present invention may also be administered directly to the eyes or ears, typically in the form of drops of micronized suspensions or solutions in isotonic pH-adjusted sterile saline. Other formulations suitable for ocular and ear administration include ointments, biodegradable (eg, absorbent gel sponges, collagen) and non-biodegradable (eg, silicone) implants, wafers, lenses and particulate or vesicular systems, For example niosom or liposome. Crosslinked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, cellulose polymers such as hydroxypropylmethylcellulose, hydroxyethylcellulose, or methyl cellulose, or heteropolysaccharide polymers such as gellan gum are polymers such as benzalkonium chloride It can be incorporated with preservatives such as. Such agents can also be delivered by iontophoretic therapy.

Formulations for eye / ear administration may be formulated to be immediate and / or controlled release. Controlled release formulations include delayed release, sustained release, pulsed release, controlled release, target release or program release.

The compounds of the present invention may be used in combination with cyclodextrins and suitable derivatives or polyethylene glycol-containing polymers to improve solubility, dissolution rate, taste masking, bioavailability and / or stability in using any of the above mentioned modes of administration. Can be combined with the same soluble macromolecule.

Drug-cyclodextrin complexes are found to be generally useful, for example in most dosage forms and routes of administration. Both inclusion and non-inclusion complexes may be used. As an alternative to direct complexation with the drug, cyclodextrin may be used as an auxiliary additive, i.e. as a carrier, diluent, or solubilizer. Most commonly used for these purposes are alpha-, beta- and gamma-cyclodextrins, examples of which can be found in International Patent Applications Nos. WO 91/11172, WO 94/02518 and WO 98/55148.

For example, for the purpose of treating a particular disease or condition, since it may be desirable to administer a combination of active compounds, two or more pharmaceutical compositions, one or more of which contain a compound according to the present invention, may It is within the scope of the present invention to be easily combined in the form of a kit suitable for coadministration.

Thus, the kits of the present invention comprise two or more separate pharmaceutical compositions, one or more of which contain a compound of formula (1) according to the present invention, wherein the method of separately retaining the compositions is, for example, a container , Split bottle, or split foil packet. Examples of such kits are familiar foam packs used for the packaging of tablets, capsules and the like.

The kit of the invention is particularly suitable for administering different dosage forms, for example parenteral dosage forms, in order to administer separate compositions at different dosage intervals or to titrate separate compositions against each other. To aid in compliance, kits typically contain instructions for administration and may provide a so-called memory aid.

In administration to human patients, the total daily dose of the compounds of the invention is typically in the range of 0.001 mg to 5000 mg, depending on the mode of administration. For example, a daily intravenous dose may require only 0.001 mg to 40 mg. The total daily dose may be administered in single or divided doses and, at the physician's discretion, may be outside the typical range given herein.

These dosages are based on the average human subject having a weight of about 65 kg to 70 kg. The physician will readily be able to determine the dosage for subjects whose weight is outside this range, such as infants and the elderly.

For the avoidance of doubt, the term “treatment” as used herein includes referring to healing, alleviation and preventive measures.

According to another embodiment of the present invention, the compound of formula (1), or a pharmaceutically acceptable salt, inducible form or composition thereof, is also used in combination with one or more additional therapeutic agents to be coadministered to a patient, Physiologically relevant disease processes include, but are not limited to, signs and symptoms such as (i) bronchial contraction, (ii) inflammation, (iii) allergies, (iv) tissue destruction, (v) shortness of breath, cough Some specific desired therapeutic outcomes, such as treatment. The second and more additional therapeutic agents may also be a compound of Formula (1), or a pharmaceutically acceptable salt, derived form or composition thereof, or one or more β2 agents known in the art. More typically, the second and more therapeutic agents will be selected from different therapeutic groups.

As used herein, the terms “co-administered”, “co-administered” and “combined” are intended to mean the compound of formula (1) and one or more other therapeutic agents, including Wherein each part can be administered by the same or different routes.

When the compound (s) of formula (1) and the therapeutic agent (s) are formulated together into a single dosage form which releases the components substantially simultaneously to a patient in need of such treatment, Simultaneous administration to the patient

If the compound (s) of formula (1) and the therapeutic agent (s) are formulated separately from one another, into separate dosage forms taken substantially simultaneously by the patient in need of such treatment, such combinations of such ingredients To the patient at substantially the same time, after which the components are released to the patient at substantially the same time.

The compound (s) of formula (1) and the therapeutic agent (s) are separately formulated into separate dosage forms that are taken at consecutive times (with significant time intervals between each dose) by the patient in need of treatment. When administered, such combination of such ingredients is sequentially administered to the patient, after which the ingredients are released to the patient at substantially different times.

When the compound (s) of formula (1) and the therapeutic agent (s) are formulated together into a single dosage form which releases the components in a controlled manner, such combinations of such components are sequentially administered to the patient, Then they are administered to the patient at the same and / or different times simultaneously, consecutively, and / or in parallel

Suitable examples of other therapeutic agents that can be used in combination with the compound (s) of Formula (1), or their pharmaceutically acceptable salts, derived forms, or compositions include, but are not limited to:

(a) a 5-lipoxygenase (5-LO) inhibitor or a 5-lipoxygenase activating protein (FLAP) antagonist,

(b) leukotriene antagonists (LTRA) such as LTB ₄ , LTC ₄ , LTD ₄ , and LTE ₄ ,

(c) histamine receptor antagonists such as H1 and H3 antagonists,

(d) α ₁ -and α ₂ -adrenoreceptor agonists vasoconstrictors sympathomimetic agents, for decongestant use,

(e) muscarinic M3 receptor antagonists or anticholinergic agents,

(f) PDE inhibitors, such as PDE3, PDE4 and PDE5 inhibitors,

(g) theophylline,

(h) sodium chromoglycate,

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

(j) oral and inhaled glucocorticosteroids such as DAGR (dissociated agonists of corticosteroid receptors),

(k) monoclonal antibodies active against endogenous inflammatory entities,

(l) anti-tumor necrosis factor (anti-TNF-α) agents,

(m) adhesion molecule inhibitors, such as VLA-4 antagonists,

(n) kinin-B ₁ -and B ₂ -receptor antagonists,

(o) immunosuppressants

(p) matrix metalloprotease (MMP) inhibitors,

(q) tachykinin NK ₁ , NK ₂ and NK ₃ receptor antagonists,

(r) elastase inhibitors,

(s) adenosine A2a receptor agonists,

(t) urokinase inhibitors,

(u) compounds acting on dopamine receptors, such as D2 agonists,

(v) NFκβ pathway modulators such as IKK inhibitors,

(w) cytokine signaling pathway modulators such as p38 MAP kinase, syk kinase or JAK kinase inhibitors,

(x) drugs that can be classified as mucolytic or antitussives,

(y) antibiotics,

(z) HDAC inhibitors, and

(aa) PI3 kinase inhibitors.

According to the present invention, a combination of the compound of the formula (1) with the following is preferable.

-H3 antagonists,

Muscarinic M3 receptor antagonists,

PDE4 inhibitors,

-Glucocorticosteroids,

Adenosine A2a receptor agonists,

Cytokine signaling pathway modulators, for example p38 MAP kinase or syk kinase, or

Leukotriene antagonists (LTRA), for example LTB ₄ , LTC ₄ , LTD ₄ , and LTE ₄ .

According to the present invention, a combination of the compound of formula (1) with the followings is more preferred.

Glucocorticosteroids, especially inhaled glucocorticosteroids with low systemic side effects, for example prednisone, prednisolone, flunisolid, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone propionate, cycl Resonide, and mometasone furoate, or

Muscarinic M3 receptor antagonists or anticholinergic agents, for example in particular epratropium salts, ie bromide, triotropium salts, ie bromide, oxytropium salts, ie bromide, ferrenzepine, and tellenezepine.

It is to be understood that all treatments herein refer to healing, alleviation and prophylaxis. The following description relates to therapeutic applications in which the compounds of formula (1) will be used.

Compounds of formula (1) have the ability to interact with β2 receptors and, due to the essential role played by β2 receptors in the physiology of all mammals, have a wide range of therapeutic applications as further described below. .

Therefore, a further aspect of the invention relates to a compound of formula (1), or a pharmaceutically acceptable salt, derived form or composition thereof, for use in treating diseases, disorders, and conditions in which the β2 receptor is involved. More specifically, the invention also relates to a compound of formula (1), or a pharmaceutically acceptable salt, inducible form or composition thereof, for use in treating a disease, disorder, and condition selected from the group consisting of will be.

-Asthma (regardless of type, etiology, or pathogenesis), especially atopic asthma, nonatopic asthma, allergic asthma, atopic bronchial IgE-mediated asthma, bronchial asthma, native asthma, true asthma, endogenous asthma caused by pathophysiological disorders Exogenous asthma caused by environmental factors, unexplained or inflexible native asthma, viatopic asthma, bronchial asthma, aerobic asthma, exercise induced asthma, allergen induced asthma, cold induced asthma, occupational asthma, bacteria, fungi, protozoa Or asthma, a member selected from the group consisting of infectious asthma, nonallergic asthma, early asthma, infant wheezing syndrome and bronchiolitis caused by viral infection,

Chronic or acute bronchial contraction, chronic bronchitis, small respiratory tract obstruction, and embolism,

COPD including obstructive or inflammatory airway disease (regardless of type, etiology, or pathogenesis), especially chronic eosinophilic pneumonia, chronic obstructive pulmonary disease (COPD), chronic bronchitis, pulmonary pneumothorax, or COPD that is not associated with COPD Obstructive or inflammatory airway disease, a member selected from the group consisting of COPD characterized by irreversible progressive airway obstruction, adult respiratory distress syndrome (ARDS), exacerbation of airway hyperactivity following other drug therapy, and airway disease associated with pulmonary hypertension,

Bronchitis (regardless of type, etiology, or pathogenesis), especially acute bronchitis, acute laryngeal bronchitis, arachid bronchitis, catarrhal bronchitis, croup bronchitis, dry bronchitis, infectious asthmatic bronchitis, wet bronchitis, staphylococcus or streptococcus Bronchitis, which is a member selected from the group consisting of cous bronchitis and alveolar bronchitis,

-Acute lung injury,

Bronchiectasis (regardless of type, etiology, or pathogenesis), particularly members selected from the group consisting of cylindrical bronchiectasis, cystic bronchiectasis, spindle bronchiectasis, capillary bronchiectasis, cystic bronchiectasis, dry bronchiectasis and vesicular bronchiectasis Bronchiectasis.

A still further aspect of the present invention also relates to the use of a compound of formula (1), or a pharmaceutically acceptable salt, derived form or composition thereof, for the manufacture of a drug having β 2 agonist activity. In particular, the present invention provides a compound of formula (1) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating β2 mediated diseases and / or conditions, in particular the diseases and / or conditions listed above, It relates to the use of the derived form or composition.

As a result, the present invention provides a very interesting method of treating a mammal, including a human, with an effective amount of a compound of formula (1), or a pharmaceutically acceptable salt, derived form or composition thereof. More precisely, the present invention relates to β2-mediated diseases of mammals, including humans, comprising administering to the mammal an effective amount of a compound of formula (1), a pharmaceutically acceptable salt thereof and / or an inducible form thereof; and It provides a very interesting way to treat (or) conditions, in particular the diseases and / or conditions listed above.

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

Example 1: N-cycloheptyl-2- {3-[(2R) -2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl } Amino) propyl] phenyl} acetamide

Ammonium fluoride (98 mg, 2.64 mmol) was stirred at room temperature, in stirred 2- {3-[(2R) -2-({(2R) -2-{[in methanol (3 ml) and water (1.5 ml)). tert-butyl (dimethyl) silyl] oxy} -2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) propyl] phenyl} -N-cycloheptylacetamide (formulation 1) (150 mg , 0.26 mmol) was added to the solution at one time. The reaction was heated at 40 ° C. for 18 hours and then cooled to room temperature. The solvent is removed in vacuo, the residue is dissolved in ethyl acetate (30 ml) and water (20 ml), the organic layer is separated, washed with brine (10 ml), dried (magnesium sulfate) and solvent Was removed in vacuo to yield a clear oil. This was purified by flash column chromatography on silica gel eluting with dichloromethane: methanol: ammonia (90: 10: 1 by volume) to afford the title compound as a white foam (87 mg).

Example 2: N- (cyclohexylmethyl) -2- {3-[(2R) -2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) Phenyl] ethyl} amino) propyl] phenyl} -N-methylacetamide

2- {3-[(2R) -2-({(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- [4-hydroxy-3] using the method of Example 1 Prepared from-(hydroxymethyl) phenyl] ethyl} amino) propyl] phenyl} -N- (cyclohexyl methyl) -N-methylacetamide (Preparation 2) to give the title compound as a white foam.

Example 3: N-[(1S) -1-cyclohexylethyl] -2- {3-[(2R) -2-({(2R) -2-hydroxy-2- [4-hydroxy-3 -(Hydroxymethyl) phenyl] ethyl} amino) propyl] phenyl} acetamide

2- {3-[(2R) -2-({(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- [4-hydroxy-3] using the method of Example 1 Prepared from-(hydroxymethyl) phenyl] ethyl} amino) propyl] phenyl} -N-[(1S) -1-cyclohexylethyl] acetamide (Preparation 3) to give the title compound as a white foam.

Example 4: 2- {3-[(2R) -2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) propyl] Phenyl} -N-isopropylacetamide

2- {3-[(2R) -2-({(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- [4-hydroxy-3] using the method of Example 1 Prepared from-(hydroxymethyl) phenyl] ethyl} amino) propyl] phenyl-N-isopropylacetamide (formulation 4) to give the title compound as a white foam.

Example 5: N-cyclopentyl-2- {3-[(2R) -2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl } Amino) propyl] phenyl} acetamide

2- {3-[(2R) -2-({(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- [4-hydroxy-3] using the method of Example 3 Prepared from-(hydroxymethyl) phenyl] ethyl} amino) propyl] phenyl} -N-cyclopentylacetamide (Formulation 5) to afford the title compound as a white foam.

Example 6: N- (cyclobutylmethyl) -2- {3-[(2R) -2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) Phenyl] ethyl} amino) propyl] phenyl} acetamide

2- {3-[(2R) -2-({(2R) -2-{[tert-butyl (dimethyl) silyl] oxy] -2- [4-hydroxy-3] using the method of Example 1 Prepared from-(hydroxymethyl) phenyl] ethyl} amino) propyl] phenyl} -N (cyclobutylmethyl) acetamide (preparation method 6) to afford the title compound as a white foam.

Example 7: N- (cyclopentylmethyl) -2- {3-[(2R) -2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) Phenyl] ethyl} amino) propyl] phenyl} acetamide

2- {3-[(2R) -2-({(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- [4-hydroxy-3] using the method of Example 1 Prepared from-(hydroxymethyl) phenyl] ethyl} amino) propyl] phenyl} -N- (cyclopentylmethyl) acetamide (form 7) to afford the title compound as a white foam.

Example 8: N-cyclohexyl-2- {3-[(2R) -2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl } Amino) propyl] phenyl} acetamide

2- {3-[(2R) -2-({(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- [4-hydroxy-3] using the method of Example 1 Prepared from-(hydroxymethyl) phenyl] ethyl} amino) propyl] phenyl} -N-cyclohexylacetamide (formulation 8) to afford the title compound as a white foam.

Example 9: N-cyclobutyl-2- {3-[(2R) -2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl } Amino) propyl] phenyl} acetamide

2- {3-[(2R) -2-({(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- [4-hydroxy-] using the method of Example 1 Prepared from 3- (hydroxymethyl) phenyl] ethyl} amino) propyl] phenyl} -N-cyclobutylacetamide (formulation 9) to afford the title compound as a white foam.

Example 10 N- (cyclohexylmethyl) -2- {3-[(2R) -2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) Phenyl] ethyl} amino) propyl] phenyl} acetamide

2- {3-[(2R) -2-({(2R) -2-[{tert-butyl (dimethyl) silyl] oxy} -2- [4-hydroxy-3 using the method of Example 1 Prepared from-(hydroxymethyl) phenyl] ethyl} amino) propyl] phenyl} -N- (cyclohexylmethyl) acetamide (formulation 10) to give the title compound as a yellow foam.

Example 11: N- (cyclopropylmethyl) -2- {3-[(2R) -2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) Phenyl] ethyl} amino) propyl] phenyl} acetamide

2- {3-[(2R) -2-({(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- [4-hydroxy-3] using the method of Example 1 Prepared from-(hydroxymethyl) phenyl] ethyl} amino) propyl] phenyl} -N- (cyclopropylmethyl) acetamide (11) to afford the title compound as a white foam.

Example 12 N- (cycloheptylmethyl) -2- {3-[(2R) -2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) Phenyl] ethyl} amino) propyl] phenyl} acetamide

2- {3-[(2R) -2-({(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- [4-hydroxy-3] using the method of Example 1 Prepared from-(hydroxymethyl) phenyl] ethyl} amino) propyl] phenyl} -N- (cycloheptylmethyl) acetamide (formulation 12) to afford the title compound as a white foam.

Example 13: N-1-adamantyl-2- {3-[(2R) -2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) Phenyl] ethyl} amino) propyl] phenyl} acetamide

N-1-adamantyl-2- {3-[(2R) -2-({(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2 using the method of Example 1 Prepared from-[4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) propyl] phenyl} acetamide (formulation 13) to afford the title compound as a white foam.

Example 14 N- (1-adamantylmethyl) -2- {3-[(2R) -2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxy Oxymethyl) phenyl] ethyl} amino) propyl] phenyl} acetamide

N- (1-adamantylmethyl) -2- {3-[(2R) -2-({(2R) -2-{[tert-butyl (dimethyl) silyl] oxy] oxy using the method of Example 1 } -2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) propyl] phenylacetamide (formulation 14) to give the title compound as a white foam.

Example 15 N-2-adamantyl-2- {3-[(2R) -2-((2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl ] Ethyl} amino) propyl] phenylacetamide

N- (1-adamantylmethyl) -2- {3-[(2R) -2-((2R) -2-{[tert-butyl (dimethyl) silyl] oxy} using the method of Example 1 2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) propyl] phenylacetamide (formulation 15) gave the title compound as a white foam.

Example 16: N- (2-cyclohexylethyl) -2- {3-[(2R) -2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxy Methyl) phenyl] ethyl} amino) propyl] phenyl} -N-methylacetamide

Using the method of Example 1 2- {3-[(2R) -2-({(2R) -2- [tert-butyl (dimethyl) silyl] oxy-2- [4-hydroxy-3- ( Prepared from hydroxymethyl) phenyl] ethyl} amino) propyl] phenyl} -N- (2-cyclohexylethyl) -N-methylacetamide (formulation 16) to give the title compound as a white foam.

Example 17: N-cycloheptyl-2- {3-[(2R) -2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl } Amino) propyl] phenyl} -N-methylacetamide

2- {3-[(2R) -2-({(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- [4-hydroxy-3] using the method of Example 1 Prepared from-(hydroxymethyl) phenyl] ethyl} amino) propyl] phenyl} -N-cycloheptyl-N-methylacetamide (Formulation 17) to afford the title compound as a white foam.

Example 18 N-cyclohexyl-N-ethyl-2- {3-[(2R) -2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl ) Phenyl] ethyl} amino) propyl] phenyl} acetamide

2- {3-[(2R) -2-({(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- [4-hydroxy-3] using the method of Example 1 Prepared from-(hydroxymethyl) phenyl] ethyl} amino) propyl] phenyl} -N-cyclohexyl-N-ethylacetamide (formulation 18) to give the title compound as a white foam.

Example 19 N- (2-cyclohexylethyl) -2- {3-[(2R) -2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxy Methyl) phenyl] ethyl} amino) propyl] phenyl} acetamide

2- {3-[(2R) -2-({(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- [4-hydroxy-3] using the method of Example 1 Prepared from-(hydroxymethyl) phenyl] ethyl} amino) propyl] phenyl-N- (2-cyclohexylethyl) acetamide (formulation 19) to give the title compound as a white foam.

Example 20 N- (4-chlorobenzyl) -2- {3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl } Amino) -2-methylpropyl] phenyl} acetamide

{3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methyl according to the procedure used for Formulation 1 Propyl] phenyl} acetic acid (Formulation 50) and the appropriate amine gave the title compound as white foam.

Example 21 N- (2,6-dimethoxybenzyl) -2- {3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) Phenyl] ethyl} amino) -2-methylpropyl] phenyl} acetamide

{3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methyl according to the procedure used for Formulation 1 Propyl] phenyl} acetic acid (Formulation 50) and the appropriate amine gave the title compound as white foam.

Example 22 N-benzyl-2- {3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2 -Methylpropyl] phenyl} acetamide

{3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methyl according to the procedure used for Formulation 1 Propyl] phenyl} acetic acid (Formulation 50) and the appropriate amine gave the title compound as white foam.

Example 23: 4- (1R) -2-[(2- {3- [2- (3,4-dihydroisoquinolin-2 (1H) -yl) -2-oxoethyl] phenyl} -1, 1-dimethylethyl) amino] -1-hydroxyethyl} -2 (hydroxymethyl) phenol

{3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methyl according to the procedure used for Formulation 1 Propyl] phenyl} acetic acid (Formulation 50) and the appropriate amine gave the title compound as white foam.

Example 24 N- [2-fluoro-5- (trifluoromethyl) benzyl] -2- {3- [2-({(2R) -2-hydroxy-2- [4-hydroxy- 3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] phenyl} acetamide

{3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methyl according to the procedure used for Formulation 1 Propyl] phenyl} acetic acid (Formulation 50) and the appropriate amine gave the title compound as white foam.

Example 25 N- (2,6-dichlorobenzyl-2- {3- [2-({(2R-2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl } Amino-2-methylpropyl] phenyl} acetamide

{3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methyl according to the procedure used for Formulation 1 Propyl] phenyl} acetic acid (Formulation 50) and the appropriate amine gave the title compound as white foam.

Example 26: 2- {3- [2-({(2R} -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl} phenyl] ethyl} amino) -2-methylpropyl] Phenyl} -N- [2 (methylthio) benzyl] acetamide

{3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methyl according to the procedure used for Formulation 1 Propyl] phenyl} acetic acid (Formulation 50) and the appropriate amine gave the title compound as white foam.

Example 27 N- (2,3-dimethylbenzyl) -2- {3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl ] Ethyl} amino) -2-methylpropyl] phenyl} acetamide

{3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methyl according to the procedure used for Formulation 1 Propyl] phenyl} acetic acid (Formulation 50) and the appropriate amine gave the title compound as white foam.

Example 28: 2- {3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] Phenyl} -N- [3- (trifluoromethyl) benzyl] acetamide

{3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methyl according to the procedure used for Formulation 1 Propyl] phenyl} acetic acid (Formulation 50) and the appropriate amine gave the title compound as white foam.

Example 29: N- [4-Chloro-3- (trifluoromethyl) benzyl] -2- {3- [2-({(2R)-2-hydroxy-2- [4-hydroxy- 3- (hydroxymethyl) phenyl] ethyl} amino) -2} acetamide

{3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methyl according to the procedure used for Formulation 1 Propyl] phenyl} acetic acid (Formulation 50) and the appropriate amine gave the title compound as white foam.

Example 30 N- [2-Chloro-5- (trifluoromethyl) benzyl) -2- {3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3 -(Hydroxymethyl) phenyl) ethyl} amino) -2-methylpropyl) phenyl} acetamide

{3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methyl according to the procedure used for Formulation 1 Propyl] phenyl} acetic acid (Formulation 50) and the appropriate amine gave the title compound as white foam.

Example 31 N- [3,5-bis (trifluoromethyl) benzyl) -2- {3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (Hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] phenyl} acetamide

{3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2- according to the procedure used in Formulation 1 Methylpropyl] phenyl} acetic acid (Formulation 50) and the appropriate amine gave the title compound as a white foam.

Example 32 N- [3-fluoro-5- (trifluoromethyl) benzyl] -2- {3- [2-({(2R) -2-hydroxy-2- [4-hydroxy- 3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] phenyl} acetamide

{3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methyl according to the procedure used for Formulation 1 Propyl] phenyl} acetic acid (Formulation 50) and the appropriate amine gave the title compound as white foam.

Example 33 N- [2- (4-chlorophenyl) ethyl] -3- {2-[(2R) -2-hydroxy-2- (4-hydroxy-3-hydroxy-methylphenyl) ethylamino ] -2-methylpropyl} benzamide

3- {2-[(2R) -2- (tert-butyldimethylsilanyloxy) -2- (4-hydroxy-3-hydroxymethyl-phenyl) in methanol (3 ml) and water (1.7 ml) Ethylamino] -2-methylpropyl} -N- [2- (4-chlorophenyl) ethyl] benzamide (formulation 38) (470 mg, 0.77 mmol) and ammonium fluoride (280 mg, 7.70 mmol) were 18 hours Heated to 43 [deg.] C. The solvent was removed in vacuo and the product was purified by flash column chromatography on silica gel eluting with dichloromethane: methanol: ammonia (95: 5: 0.5 volume ratio). The resulting compound was taken up in methanol and evaporated (x3) to give a white foam (320 mg). A small sample was recrystallized (hexane: ethyl acetate) to give a white solid (mp 139-140 ° C).

Example 34: 3- {2-[(2R) -2-hydroxy-2- (4-hydroxy-3-hydroxymethylphenyl) ethylamino] -2-methylpropyl} -N- [2- (4 -Methylphenyl) ethyl] benzamide

3- {2-[(2R) -2- (tert-butyldimethylsilanyloxy) -2- (4-hydroxy-3-hydroxymethyl-phenyl) ethylamino]-using the method of Example 33- Prepared from 2-methylpropyl} -N- [2- (4-methylphenyl) ethyl] benzamide (Formulation 39) to afford the title compound as a white foam.

Example 35: 3- {2-[(2R) -2-hydroxy-2- (4-hydroxy-3-hydroxymethylphenyl) ethylamino] -2-methyl-propyl} -N- [2- ( 4-trifluoromethylphenyl) ethyl] benzamide

3- {2-[(2R) -2- (tert-butyldimethylsilanyloxy) -2- (4-hydroxy-3-hydroxymethyl-phenyl) ethylamino]-using the method of Example 33- Prepared from 2-methyl-propyl} -N- [2- (4-trifluoromethylphenyl) ethyl] benzamide (formulation 40) to afford the title compound as a white foam.

Example 36 N- [2- (3,4-dichlorophenyl) ethyl] -3- {2-[(2R) -2-hydroxy-2- (4-hydroxy-3-hydroxymethylphenyl) ethyl Amino] -2-methyl-propyl} -benzamide

3- {2-[(2R) -2- (tert-butyldimethylsilanyloxy) -2- (4-hydroxy-3-hydroxymethyl-phenyl) ethylamino]-using the method of Example 33- Prepared from 2-methyl-propyl} -N- [2- (3,4-dichlorophenyl) ethyl] benzamide (Formulation 41) to afford the title compound as a white foam.

Example 37: N- [2- (3,4-dimethylphenyl) ethyl] -3- {2-[(2R) -2-hydroxy-2- (4-hydroxy-3-hydroxymethylphenyl)- Ethylamino] -2-methylpropyl} benzamide

3-2-[(2R) -2- (tert-butyldimethylsilanyloxy) -2- (4-hydroxy-3-hydroxymethyl-phenyl) ethylamino] -2 using the method of Example 33. Prepared from -methyl-propyl} -N- [2- (3,4-dimethylphenyl) ethyl] benzamide (formulation 42) to afford the title compound as a white foam.

Example 38: 3- {2-[(2R) -2-hydroxy-2- (4-hydroxy-3-hydroxymethyl-phenyl) ethylamino] -2-methyl-propyl} -N- (2 -Naphthalen-2-yl-ethyl) benzamide

3- {2-[(2R) -2- (tert-butyldimethylsilanyloxy) -2- (4-hydroxy-3-hydroxymethyl-phenyl) ethylamino]-using the method of Example 33- Prepared from 2-methyl-propyl} -N- (2-naphthalen-2-ylethyl) benzamide (Form 43) to afford the title compound as a white foam.

Example 39: N- (1,1-dimethyl-2-phenylethyl) -3- {2-[(2R) -2-hydroxy-2- (4-hydroxy-3-hydroxy-methylphenyl)- Ethylamino] -2-methylpropyl} benzamide

3- {2-[(2R) -2- (tert-butyldimethylsilanyloxy) -2- (4-hydroxy-3-hydroxymethyl-phenyl) ethylamino]-using the method of Example 33- Prepared from 2-methyl-propyl} -N- (1,1-dimethyl-2-phenyl-ethyl) benzamide (44) to afford the title compound as a white foam.

Example 40: 3- {2-[(2R) -2-hydroxy-2- (4-hydroxy-3-hydroxymethylphenyl) -ethylamino] -2-methylpropyl} -N- (2-methyl -2-phenylpropyl) benzamide

3- {2-[(2R) -2- (tert-butyldimethylsilanyloxy) -2- (4-hydroxy-3-hydroxymethylphenyl) ethylamino] -2- using the method of Example 33. Prepared from methylpropyl} -N- (2-methyl-2-phenylpropyl) -benzamide (Formulation 45) to afford the title compound as a white foam.

Example 41 N- (4-chlorobenzyl) -3- {2-[(2R) -2-hydroxy-2- (4-hydroxy-3-hydroxy-methylphenyl) ethylamino] -2-methyl Profile} benzamide

3-{(2R) -2- [2- (tert-butyldimethylsilanyloxy) -2- (4-hydroxy-3-hydroxymethyl-phenyl) ethylamino]-using the method of Example 33- Prepared from 2-methylpropyl} -N- (4-chlorobenzyl) benzamide (Formulation 46) to afford the title compound as a white foam.

Example 42 N- (2,6-dimethoxybenzyl) -2- {3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) Phenyl] ethyl} amino) ethyl] phenyl} acetamide

{3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) ethyl] phenyl} according to the procedure used for Formulation 1 Prepared using acetic acid (51) and the appropriate amine to afford the title compound as a white foam.

Example 43 N- (3,4-dichlorobenzyl) -2- {3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl ] Ethyl} amino) ethyl] phenyl} acetamide

{3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) ethyl] phenyl} according to the procedure used for Formulation 1 Prepared using acetic acid (51) and the appropriate amine to afford the title compound as a white foam.

Example 44 N-benzyl-2- {3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) ethyl] Phenyl} acetamide

{3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) ethyl] phenyl} according to the procedure used for Formulation 1 Prepared using acetic acid (51) and the appropriate amine to afford the title compound as a white foam.

Example 45 N- (2,3-dihydro-1 H-inden-2-yl) -2- {3- [2-({(2R) -2-hydroxy-2- [4-hydroxy -3- (hydroxymethyl) phenyl] ethyl} amino) ethyl] phenyl} acetamide

{3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) ethyl] phenyl} according to the procedure used for Formulation 1 Prepared using acetic acid (51) and the appropriate amine to afford the title compound as a white foam.

Example 46: 2- {3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) ethyl] phenyl} -N -(2-phenylethyl) acetamide

{3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) ethyl] phenyl} according to the procedure used for Formulation 1 Prepared using acetic acid (51) and the appropriate amine to afford the title compound as a white foam.

Example 47: 2- {3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) ethyl] phenyl} -N -(3-phenylpropyl) acetamide

{3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) ethyl] phenyl} according to the procedure used for Formulation 1 Prepared using acetic acid (51) and the appropriate amine to afford the title compound as a white foam.

Example 48 N-benzyl-3-[(2R) -2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) propyl ] Benzamide

3-[(2R) -2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) propyl] benzoic acid in DMF (2 ml) Formulation 59 (116 mg, 0.22 mmol) in triethylamine (62 μl, 0.45 mmol), benzylamine (29 μl, 0.27 mmol), HOBt (33 mg, 0.25 mmol) and WSCDI (47 mg, 0.25 mmol) ) Was added and the resulting solution was stirred for 18 hours at room temperature. The solvent was removed in vacuo and the residue was partitioned between saturated aqueous sodium hydrogen carbonate solution (5 ml) and dichloromethane / methanol (95/5) (10 ml). The aqueous layer was separated and extracted with additional dichloromethane / methanol (95/5) (4 × 10 ml). The combined organic layers were dried (sodium sulfate), filtered and evaporated in vacuo. The resulting oil was purified by flash column chromatography on silica gel eluting with dichloromethane: methanol: 880 ammonia (90: 10: 1 volume ratio) to afford the title compound as a white foam (70 mg).

Example 49: N- (3,4-dichlorobenzyl) -3-[(2R) -2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) Phenyl] ethyl} amino) propyl] benzamide

3-[(2R) -2 ({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) propyl] following the procedure used for preparation 49] Prepared using benzoic acid (Formulation 59) and the appropriate amine to afford the title compound as a white foam.

Example 50: N- [2-fluoro-5- (trifluoromethyl) benzyl] -3-[(2R) -2-({(2R) -2-hydroxy-2- [4-hydroxy -3- (hydroxymethyl) phenyl] ethyl} amino) propyl] benzamide

3-[(2R) -2 ({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) propyl] following the procedure used for preparation 49] Prepared using benzoic acid (Formulation 59) and the appropriate amine to afford the title compound as a white foam.

Example 51 N- (2,6-dimethoxybenzyl) -3-[(2R) -2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl ) Phenyl] ethyl} amino) propyl] benzamide

3-[(2R) -2 ({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) propyl] following the procedure used for preparation 49] Prepared using benzoic acid (Formulation 59) and the appropriate amine to afford the title compound as a white foam.

Example 52 N- [2- (4-Chlorophenyl) ethyl] -3-[(2R) -2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxy Oxymethyl) phenyl] ethyl} amino) propyl] benzamide

3-[(2R) -2 ({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) propyl] following the procedure used for preparation 49] Prepared using benzoic acid (Formulation 59) and the appropriate amine to afford the title compound as a white foam.

Example 53: N- (2,3-dihydro-1H-inden-2-yl) -3-[(2R) -2-({(2R) -2-hydroxy-2- [4-hydroxy -3- (hydroxymethyl) phenyl] ethyl} amino) propyl] benzamide

3-[(2R) -2 ({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) propyl] following the procedure used for preparation 49] Prepared using benzoic acid (Formulation 59) and the appropriate amine to afford the title compound as a white foam.

Example 54: 3-[(2R) -2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) propyl] -N- (2-phenylethyl) benzamide

3-[(2R) -2 ({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) propyl] following the procedure used for preparation 49] Prepared using benzoic acid (Formulation 59) and the appropriate amine to afford the title compound as a white foam.

Example 55: 3-[(2R) -2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) propyl] -N- [(1R) -1-phenylethyl] benzamide

3-[(2R) -2 ({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) propyl] following the procedure used for preparation 49] Prepared using benzoic acid (Formulation 59) and the appropriate amine to afford the title compound as a white foam.

Example 56: 3-[(2R) -2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) propyl] -N- (3-phenylpropyl) benzamide

3-[(2R) -2 ({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) propyl] following the procedure used for preparation 49] Prepared using benzoic acid (Formulation 59) and the appropriate amine to afford the title compound as a white foam.

Example 57: 4-[(1R) -2-({(1R) -2- [3- (3,4-dihydroisoquinoline-2 (1H) -ylcarbonyl) phenyl] -1-methylethyl } Amino) -1-hydroxyethyl] -2- (hydroxymethyl) phenol

3-[(2R) -2 ({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) propyl] following the procedure used for preparation 49] Prepared using benzoic acid (Formulation 59) and the appropriate amine to afford the title compound as a white foam.

Example 58: N- (2,3-dimethylbenzyl) -3-[(2R) -2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) Phenyl] ethyl} amino) propyl] benzamide

3-[(2R) -2 ({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) propyl] following the procedure used for preparation 49] Prepared using benzoic acid (Formulation 59) and the appropriate amine to afford the title compound as a white foam.

Example 59: N- (5,6-diethyl-2,3-dihydro-1 H-inden-2-yl) -3-[(2R) -2-({(2R) -2hydroxy- 2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) propyl] benzamide

3-[(2R) -2 ({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) propyl] following the procedure used for preparation 49] Prepared using benzoic acid (Formulation 59) and the appropriate amine to afford the title compound as a white foam.

Example 60: N- (4-chlorobenzyl) -3-[(2R) -2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] Ethyl} amino) propyl] benzamide

3-[(2R) -2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) propyl] benzoic acid in DMF (3 ml) (Formula 59) Triethylamine (111 μl, 0.79 mmol), 4-chlorobenzylamine (39 μl, 0.32 mmol), and HBTU (110 mg, 0,29 mmol) were added to the (120 mg, 0.27 mmol) solution. The resulting solution was stirred for 18 hours at room temperature. The solvent was removed in vacuo and the residue was purified by flash column chromatography on silica gel eluting with dichloromethane: methanol: 880 ammonia (change from 93: 7: 0.7 to 90: 10: 1 by volume). The title compound was obtained as a white foam (97 mg).

Example 61: 3-[(2R) -2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) propyl] -N- Phenylbenzamide

3-[(2R) -2 ({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) propyl, following the procedure used in Example 60 ] Prepared with benzoic acid (Formulation 59) and the appropriate amine to afford the title compound as a white foam.

Example 62 N- [4- (aminosulfonyl) benzyl] -3-[(2R) -2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxy Methyl) phenyl] ethylamino) propyl] benzamide

3-[(2R) -2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) following the procedure used in Example 60 Propyl] benzoic acid (Formula 59) and suitable amines were substituted and substituted with dichloromethane: methanol: 880 ammonia (85: 15: 2 volume ratio) as eluent to afford the title compound as a white foam.

Example 63: N- [2- (3-fluorophenyl) ethyl] -3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) Phenyl] ethyl} amino) -2-methylpropyl] benzamide

3- [2-({(2R) -2-([tert-butyl (dimethyl) silyl) oxy} -2- [4-hydroxy-3- (hydroxy) in methanol (12 ml) and water (2 ml) Oxymethyl) phenyl) ethyl} amino) -2-methylpropyl] -N- [2- (3-fluorophenyl) ethyl) benzamide (Formulation 157) (343 mg, 0.58 mmol) and ammonium fluoride (213 mg , 5.76 mmol) was stirred at rt for 42 h. The solvent was removed in vacuo and the residue was purified by column chromatography on silica gel eluting with dichloromethane: methanol: 0.88 ammonia (100: 0: 0 to 90: 10: 1). The appropriate fractions were concentrated in vacuo and the residue was azeotropically distilled (x2) in ethanol to give a white solid. This solid was then recrystallized from ethanol / water and dried under vacuum to give the title compound as very pale yellow crystals (52% yield, 144 mg).

Examples 64-78

The following compounds having the formula shown below were prepared by using a suitable starting material and ammonium fluoride by a method similar to that described in Example 63. The reaction mixture was warmed to 40 ° C. until thin layer chromatography analysis showed that all starting materials were consumed.

Example 65: The compound was further purified by trituration with diethyl ether.

Example 72 Purification by column chromatography using an ISCO ^® silica cartridge, eluting with 100: 0 to 90: 10: 1 dichloromethane: methanol: 0.88 ammonia.

Example 75: Elution with 100: 0: 0 to 90: 10: 1 dichloromethane: methanol: 0.88 ammonia using a 4g RediSep® silica cartridge, followed by 100: 0: 0 to 80:20 Ethyl acetate: methanol: 2: 2 purified by column chromatography, eluting with ammonia.

Example 78: The crude compound was further purified by trituration with diethyl ether.

Example 79

N- [2- (4-chlorophenyl) ethyl] -N-ethyl-3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl ] Ethyl} amino) -2-methylpropyl] benzamide

Using a method similar to Example 33, 3- [2-({(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- [4-hydroxy-3- (hydroxymethyl The title compound was prepared as a colorless solid at 61% yield from) phenyl] ethyl} amino) -2-methylpropyl] -N- [2- (4-chlorophenyl) ethyl] -N-ethylbenzamide (Formulation 110). .

Example 80

2- {3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] phenyl} -N -(3-pyrrolidin-1-ylpropyl) acetamide

Using a method similar to Example 33, 2- {3- [2-({(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- [4-hydroxy-3- ( The title compound was prepared from hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] phenyl} -N- (3-pyrrolidin-1-ylpropyl) acetamide (Formulation 109). In addition the crude residue in dichloromethane: eluting with methanol (80: 20), Bio teji (Biotage) ^® by amino purified by column chromatography over silica gel, with 54% yield of the title compound was obtained as a colorless gum.

Example 81

N- (cycloheptylmethyl) -2- {3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxy methyl) phenyl] ethyl} amino) -2 -Methylpropyl] phenyl} acetamide

Using a method similar to Example 33, 3- [2-({(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- [4-hydroxy-3- (hydroxymethyl The material was prepared as a colorless solid in 69% yield from) phenyl] ethyl} amino) -2-methylpropyl] -N- [2- (4-chlorophenyl) ethyl] -N-ethylbenzamide (Formulation 110).

Example 82

N-1-adamantyl-2-{(3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino)- 2-methylpropyl] phenyl} acetamide

Using a method similar to Example 33, N-1-adamantyl-2- {3- [2-({(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- [ The title compound was prepared as white foam in 41% yield from 4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] phenyl} acetamide (Formulation 152).

Example 83

N-benzyl-2- {3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] Phenyl} -N-methylacetamide

Using a method similar to Example 33, N-benzyl-2- {3- [2-({(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- [4-hydroxy The title compound was prepared as a colorless solid in 75% yield from 3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] phenyl} -N-methylacetamide (Formulation 156).

Example 84

N- [2- (4-fluorophenyl) ethyl] -3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} Amino) -2-methylpropyl] benzamide

3- {2-[(2R) -2- (tert-butyldimethylsilanyloxy) -2- (4-hydroxy-3-hydroxymethyl-phenyl) in N, N-dimethylacetamide (1 mL) O- (1H-benzotriazol-1-yl) -N in ethylamino] -2-methylpropyl} benzoic acid (Formulation 37) (90 mg, 0.19 mmol) and N, N-dimethylacetamide (0.5 mL), A solution of N, N ', N'-tetramethyluronium hexafluorophosphate (61 mg, 0.16 mmol) was added to 4-fluorophenethylamine (33 mg, 0.19 in N, N-dimethylacetamide (0.5 mL). mmol) was added to the solution. The resulting mixture was stirred at rt for 72 h. The solvent was removed in vacuo and the residue was partitioned between dichloromethane (4 mL) and saturated sodium hydrogen carbonate solution (1 mL). The mixture was then filtered through a phase separation tube and the organic solution was concentrated in vacuo. Ammonium fluoride (70 mg, 1.9 mmol) was added to the residue suspension in methanol (2 mL) and water (1 mL) and the mixture was stirred at rt for 72 h. The reaction mixture was then concentrated in vacuo and the residue was purified by column chromatography on silica gel, eluting with dichloromethane: methanol: 0.88 ammonia of 100: 0: 0 to 91: 9: 1 and triturated with diethyl ether. Treatment yielded 45 mg of the title compound in 50% yield.

Examples 85-91

3- {2-[(2R) -2- (tert-Butyldimethylsilanyloxy) -2- (4-hydroxy-3-hydroxymethyl-phenyl) ethylamino] -2-methylpropyl} benzoic acid (Formulation 37) and the appropriate amine starting material, to prepare the following compounds having the formula shown below by methods analogous to those described in Example 84. Amines were either commercially available or prepared as described in Formulations 69-108.

After addition of ammonium fluoride, Examples: 89, 90 and 91 were warmed at 50 ° C. for 18 hours.

Example 92

N- [2- (4-ethoxy-3-methoxyphenyl) ethyl] -3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl ) Phenyl] ethyl} amino) -2-methylpropyl] benzamide

3- {2-[(2R) -2- (tert-butyldimethylsilanyloxy) -2- (4-hydroxy-3-hydroxymethyl-phenyl) ethyl in N, N-dimethylacetamide (1 mL) Amino] -2-methylpropyl} benzoic acid (Formulation 37) (90 mg, 0.19 mmol) and 0- (1H-benzotriazol-1-yl) -N, N in N, N-dimethylacetamide (0.5 mL), A solution of N ', N'-tetramethyluronium hexafluorophosphate (61 mg, 0.16 mmol) was added to 4-ethoxy-3-methoxyphenethylamine (37 mg, in N, N-dimethylacetamide (0.5 mL). 0.19 mmol) in the solution. The resulting mixture was stirred at rt for 72 h. The solvent was removed in vacuo and the residue partitioned between dichloromethane (4 mL) and saturated sodium hydrogen carbonate solution (1 mL). The mixture was then filtered through a phase separation tube and the organic solution was concentrated in vacuo. The residue was dissolved in dimethylsulfoxide (700 μl), triethylamine trihydrofluoride (30 μl, 0.19 mmol) was added and the mixture was stirred at rt for 72 h. The reaction mixture was then purified directly by HPLC using Phenomenex Luna C18 system, eluting with water / 0.05% diethylamine: acetonitrile from 5: 95 to 95: 5, 30% yield. To give the title compound (30.9 mg).

Examples 93-112

3- {2-[(2R) -2- (tert-Butyldimethylsilanyloxy) -2- (4-hydroxy-3-hydroxymethyl-phenyl) ethylamino] -2-methylpropyl} benzoic acid (Formulation 37) and the appropriate amine amine starting materials, the following compounds having the formula shown below were prepared by methods analogous to those described in Example 92. Amines were either commercially available or prepared as described in Formulations 69-108.

Example 102 {2- [2- (trifluoromethyl) phenyl] ethyl} amine can be prepared as described in WO 2003093231.

Example 106 4-[[4- (2-aminoethyl) phenyl] sulfonyl] -morpholine is commercially available from the Scientific Exchange Product List (K-046583).

Example 107 An amine precursor (2- (2-aminoethyl) -6-chlorophenol) can be prepared as described in DE1959898.

Example 108: Crude compound was purified by HPLC eluting with water / acetonitrile / trifluoroacetic acid (5: 95: 0.1): acetonitrile using a Phenomenex Luna C18 system at 95: 5 to 5: 95 Purification isolated the trifluoroacetic acid salt of the desired product.

Examples 109 and 110: Purified by HPLC eluting with crude compound Phenomenex Luna C18 system and eluting with 85: 15-15: 85 water / 0.1% formic acid: acetonitrile / 0.1% formic acid.

Example 113

N- [2- (2-chlorophenyl) ethyl] -3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino ) -2-methylpropyl] benzamide

3- [2-({(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2- A mixture of methylpropyl] -N- [2- (2-chlorophenyl) ethyl] benzamide (Formulation 118), (147 mg, 0.24 mmol) and triethylamine trihydrofluoride (39 μl, 0.24 mmol) Stirred at room temperature. The mixture was then concentrated in vacuo and the residue was purified by column chromatography on silica gel, eluting with dichloromethane: methanol: 0.88 ammonia in 100: 0: 0 to 95: 5: 0.5. The appropriate fractions were evaporated under reduced pressure and the residue was azeotropically distilled with methanolic ammonia to give 75 mg of the title compound as a colorless solid in 77% yield.

Examples 114-128

Using the appropriate starting materials and triethylamine trihydrofluoride, the following compounds were prepared having the formula shown below in a similar manner as described in Example 113. The reaction was monitored by tlc analysis and stirred for 18-72 hours at room temperature.

Example 129

N- (3,4-dichlorobenzyl) -3-{(3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} Amino) -2-methylpropyl] phenyl} propanamide

Using a method similar to Example 113, 3- {3- [2-({(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- [4-hydroxy-3- ( The title compound was prepared as a white foam in 71% yield from hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] phenyl} -N- (3,4-dichlorobenzyl) propanamide (Formulation 145).

Example 130

3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] -N- {2- [ 4- (trifluoromethoxy) phenyl] ethyl} benzamide

3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2 in N, N-dimethylformamide (5 mL) -Methylpropyl] benzoic acid (Formulation 140) (100 mg, 0.28 mol), 2- (4-trifluoromethoxyphenyl) ethylamine (US20020082454A1, p2), (46 mg, 0.28 mmol), 1- (3-dimethylaminopropyl A mixture of) -3-ethylcarbodiimide hydrochloride (43 mg, 0.28 mol), 1-hydroxybenzotriazole hydrate (35 mg, 0.28 mmol) and triethylamine (60 μL, 0.45 mmol) for 20 hours at room temperature Stirred at. The reaction mixture was then concentrated in vacuo and the residue dissolved in dichloromethane. The solution was then washed with saturated sodium carbonate solution and brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with dichloromethane: methanol: 0.88 ammonia from 100: 0:95 to 5: 1, 79 mg of the title compound as a white powder in 51% yield.

Examples 131 to 137

Using the appropriate acid and amine starting materials, the following compounds having the formula shown below were prepared in a similar manner as described in Example 130. Amines were either commercially available or prepared as described in Formulations 69-108.

Example 131 An amine precursor (4- (2-amino-1, 1-dimethylethyl) phenol) is described in Acta Chem. Scand. 8, 1203, 1207; 1954].

Examples 138-147

3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] benzoic acid (agent 140), ( 0.2 M in dimethylacetamide / 3.75% triethylamine, 225 μl, 45 μmol), suitable amine (0.2 M in dimethylacetamide / 3.75% triethylamine, 150 μl, 30 μmol) and 0- (1H-benzotriazole A mixture of -1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate (0.2M in dimethylacetamide, 225 μl, 45 μmol) was stirred at 60 ° C. for 3 days. The reaction mixture was then concentrated in vacuo, redissolved in dimethylsulfoxide (300 μl) and stirred at room temperature for 30 minutes. The mixture was further diluted with dimethylsulfoxide (50 μl) and water (100 L) and stirred at room temperature for 1 minute, then using a Phenomenex Luna C18 system, using 95: 5 to 5: 95 water / aceto Nitrile / diethylamine (5: 95: 0.05): Purified by HPLC eluting with acetonitrile to afford the desired compound.

Example 138 N-ethyl-3-phenylpropylamine is described in J. Med. Chem. 34, 248; 1991 may be prepared as described.

Example 141 6-methoxy-3-pyridineethanamine is described in Drug Design and Discovery, 10, 35; 1993).

Example 143 2- [4- (pyrazol-1-yl) phenoxy] ethylamine can be prepared as described in W02002032897, p55.

Example 146 5-Quinolineethanamine is described in J. Med. Chem., 28, 1803-10; 1985, as described herein.

Formulation 1: 2- {3-[(2R) -2-({(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- [4-hydroxy-3- (hydroxymethyl ) Phenyl] ethyl} amino) propyl] phenyl} -N-cycloheptylacetamide

(3-{(2R) -2-[(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- (4-hydroxy-3) in N, N-dimethylformamide (4 ml) -Hydroxymethyl-phenyl) -ethylamino] -propyl} -phenyl) -acetic acid (formulation 20) (250 mg, 0.45 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (94 mg , 0.49 mmol), a solution of hydroxybenzotriazole monohydrate (66 mg, 0.49 mmol) with triethylamine (0.12 ml, 0.89 mmol) and cycloheptylamine (56 mg, 0.49 mmol) and the resulting suspension was nitrogen Stir at room temperature for 18 hours under air. The solvent was removed in vacuo and the residue partitioned between ethyl acetate (10 ml) and saturated aqueous sodium bicarbonate (10 ml). The organic phase was separated and the aqueous phase further extracted with ethyl acetate (2x10 ml). The combined organic extracts were washed with water (5 ml), brine (5 ml), dried (with sodium sulfate) and the solvent removed in vacuo. The residue was purified by flash column chromatography on silica gel, eluting with dichloromethane: methanol: 880 ammonia (95: 5: 0.5 by volume) to give the title compound (150 mg) as a pale yellow oil.

Formulation 2: 2- {3-[(2R) -2-({(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- [4-hydroxy-3- (hydroxymethyl ) Phenyl] ethyl} amino) propyl] phenyl} -N- (cyclohexylmethyl) -N-methylacetamide

(3-{(2R) -2-[(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- (4-hydroxy-3-hydroxymethyl-phenyl) -ethylamino] Prepared by the method used in Formulation 1 with -propyl} -phenyl) -acetic acid (Formulation 20) and the appropriate amine, to give the title compound as a colorless oil.

Formulation 3: 2- {3-[(2R) -2-({(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- [4-hydroxy-3- (hydroxymethyl ) Phenyl] ethyl} amino) propyl] phenyl} -N-[(1S) -1-cyclohexylethyl] acetamide

(3-{(2R) -2-[(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- (4-hydroxy-3-hydroxymethyl-phenyl) -ethylamino] Prepared by the method used in Formulation 1 with -propyl} -phenyl) -acetic acid (formulation 20) and the appropriate amine to give the title compound as a colorless oil.

Formulation 4: 2- {3-[(2R) -2-({(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- [4-hydroxy-3- (hydroxymethyl ) Phenyl] ethyl} amino) propyl] phenyl} -N-isopropylacetamide

(3-{(2R) -2-[(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- (4-hydroxy-3-hydroxymethyl-phenyl) -ethylamino] Prepared by the method used in Formulation 1 with -propyl} -phenyl) -acetic acid (Formulation 20) and the appropriate amine, to give the title compound as a colorless oil.

Formulation 5: 2- (3-[(2R) -2-({(2R) -2-([tert-butyl (dimethyl) silyl] oxy) -2- [4-hydroxy-3- (hydroxymethyl ) Phenyl] ethyl} amino) propyl] phenyl} -N-cyclopentylacetamide

(3-{(2R) -2-[(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- (4-hydroxy-3-hydroxymethyl-phenyl) -ethylamino] Prepared by the method used in Formulation 1 with -propyl} -phenyl) -acetic acid (Formulation 20) and the appropriate amine, to give the title compound as a colorless oil.

Formulation 6: 2- {3-[(2R) -2-({(2R) -2-{[tert-butyl (dimethyl) silyl] oxy-2- [4-hydroxy-3- (hydroxymethyl) Phenyl] ethyl} amino) propyl] phenyl} -N- (cyclobutylmethyl) acetamide

(3-{(2R) -2-[(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- (4-hydroxy-3-hydroxymethyl-phenyl) -ethylamino] Prepared by the method used in Formulation 1 with -propyl} -phenyl) -acetic acid (Formulation 20) and the appropriate amine, to give the title compound as a colorless oil.

Formulation 7: 2- {3-[(2R) -2-({(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- [4-hydroxy-3- (hydroxymethyl ) Phenyl] ethyl} amino) propyl] phenyl} -N- (cyclopentylmethyl) acetamide

(3-{(2R) -2-[(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- (4-hydroxy-3-hydroxymethyl-phenyl) -ethylamino] Prepared by the method used in Formulation 1 with -propyl} -phenyl) -acetic acid (Formulation 20) and the appropriate amine, to give the title compound as a colorless oil.

Formulation 8: 2- {3-[(2R) -2-({(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- [4-hydroxy-3- (hydroxymethyl ) Phenyl] ethyl} amino) propyl] phenyl} -N-cyclohexylacetamide

(3-{(2R) -2-[(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- (4-hydroxy-3-hydroxymethyl-phenyl) -ethylamino] Prepared by the method used in Formulation 1 with -propyl} -phenyl) -acetic acid (Formulation 20) and the appropriate amine, to give the title compound as a colorless oil.

Formulation 9: 2- {3-[(2R) -2-({(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- [4-hydroxy-3- (hydroxymethyl ) Phenyl] ethyl} amino) propyl] phenyl} -N-cyclobutylacetamide

(3-{(2R) -2-[(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- (4-hydroxy-3-hydroxymethyl-phenyl) -ethylamino] Prepared by the method used in Formulation 1 with -propyl} -phenyl) -acetic acid (Formulation 20) and the appropriate amine, to give the title compound as a colorless oil.

Formulation 10: 2- {3-[(2R) -2-({(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- [4-hydrate Roxy -3- ( Hydroxymethyl ) Phenyl ] Ethyl} amino) propyl] Phenyl } -N- ( Cyclohexylmethyl ) Acetamide

(3-{(2R) -2-[(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- (4-hydroxy-3-hydroxymethyl-phenyl) ethylamino]- Propyl} -phenyl) -acetic acid (Formulation 20) and the appropriate amine were used and prepared by the method used in Preparation 1 to give the title compound as a white foam.

Formulation 11: 2- {3-[(2R) -2-({(2R) -2 {[tert-butyl (dimethyl) silyl] oxy} -2- [4-hydroxy-3- (hydroxymethyl) Phenyl] ethyl} amino) propyl] phenyl} -N- (cyclopropylmethyl) acetamide

(3-{(2R) -2-[(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- (4-hydroxy-3-hydroxymethyl-phenyl) -ethylamino] -Propyl} -phenyl) -acetic acid (Formulation 20) and the appropriate amine were used and prepared by the method used in Preparation 1 to give the title compound as a white foam.

Formulation 12: 2- {3-[(2R) -2-({(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- [4-hydroxy-3- (hydroxymethyl ) Phenyl] ethyl} amino) propyl] phenyl} -N- (cycloheptylmethyl) acetamide

(3-{(2R) -2-[(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- (4-hydroxy-3-hydroxymethyl-phenyl) -ethylamino] -Propyl} -phenyl) -acetic acid (Formulation 20) and the appropriate amine were used and prepared by the method used in Preparation 1 to give the title compound as a white foam.

Formulation 13: N-1-adamantyl-2- {3-[(2R) -2-({(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- [4-hydrate Hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) propyl] phenyl} acetamide

(3-{(2R) -2-[(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- (4-hydroxy-3-hydroxymethyl-phenyl) -ethylamino] -Propyl} -phenyl) -acetic acid (Formulation 20) and the appropriate amine were used and prepared by the method used in Preparation 1 to give the title compound as a white foam.

Alternative

N-1-adamantyl-2- {3-[(2R) -2-({(2R) -2- [4- (benzyloxy) -3- (hydrate) using a method analogous to that of Formulation 25 The title compound was prepared as a colorless foam in 91% yield from oxymethyl) phenyl] -2-hydroxyethyl} amino) propyl] phenyl} acetamide (Formulation 164).

Formulation 14: N- (1-adamantylmethyl) -2- {3-[(2R) -2-({(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- [ 4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) propyl] phenyl} acetamide

(3-{(2R) -2-[(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- (4-hydroxy-3-hydroxymethyl-phenyl) -ethylamino] -Propyl} -phenyl) -acetic acid (Formulation 20) and the appropriate amine were used and prepared by the method used in Preparation 1 to give the title compound as a white foam.

Formulation 15: N-2-adamantyl-2- {3-[(2R) -2-({(2R) -2 {[tert-butyl (dimethyl) silyl] oxy) -2- [4-hydroxy -3- (hydroxymethyl) phenyl] ethyl) amino) propyl] phenyl} acetamide

(3-{(2R) -2-[(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- (4-hydroxy-3-hydroxymethyl-phenyl) -ethylamino] -Propyl} -phenyl) -acetic acid (Formulation 20) and the appropriate amine were used and prepared by the method used in Preparation 1 to give the title compound as a white foam.

Formulation 16: 2- {3-[(2R) -2-({(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- [4-hydroxy-3- (hydroxymethyl ) Phenyl] ethyl} amino) propyl] phenyl} -N- (2-cyclohexylethyl) -N-methylacetamide

(3-{(2R) -2-[(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- (4-hydroxy-3-hydroxymethyl-phenyl) -ethylamino] Prepared by the method used in Formulation 1 with -propyl} -phenyl) -acetic acid (Formulation 20) and the appropriate amine to afford the title compound as a white foam.

Formulation 17: 2- {3-[(2R) -2-({(2R) -2-{(tert-butyl (dimethyl) silyl] oxy} -2- [4-hydroxy-3- (hydroxymethyl) ) Phenyl] ethyl} amino) propyl] phenyl} -N-cycloheptyl-N-methylacetamide

(3-{(2R) -2-[(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- (4-hydroxy-3-hydroxymethyl-phenyl) -ethylamino] -Propyl} -phenyl) -acetic acid (Formulation 20) and the appropriate amine were used and prepared by the method used in Preparation 1 to give the title compound as a white foam.

Formulation 18: 2- {3-[(2R) -2-({(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- [4-hydroxy-3- (hydroxymethyl ) Phenyl] ethyl} amino) propyl] phenyl} -N-cyclohexyl-N-ethylacetamide

(3-{(2R) -2-[(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- (4-hydroxy-3-hydroxymethyl-phenyl) -ethylamino] -Propyl} -phenyl) -acetic acid (Formulation 20) and the appropriate amine were used and prepared by the method used in Preparation 1 to give the title compound as a white foam.

Formulation 19: 2- {3-[(2R) -2-({(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- [4-hydroxy-3- (hydroxymethyl ) Phenyl] ethyl} amino) propyl] phenyl} -N- (2-cyclohexylethyl) acetamide

(3-{(2R) -2-[(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- (4-hydroxy-3-hydroxymethyl-phenyl) -ethylamino] -Propyl} -phenyl) -acetic acid (Formulation 20) and the appropriate amine were used and prepared by the method used in Preparation 1 to give the title compound as a white foam.

Formulation 20: (3-{(2R) -2-[(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- (4-hydroxy-3-hydroxymethyl-phenyl)- Ethylamino] -propyl} -phenyl) -acetic acid

Methyl (3-{(2R) -2-[(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- (4-hydroxy-3-hydroxy) in tetrahydrofuran (40 ml) Methyl-phenyl) -ethylamino] -propyl} -phenyl) -acetate (Formulation 21) (7.04 g, 14.43 mmol) solution was treated with lithium hydroxide (28.9 ml of 1M aqueous solution, 28.9 mmol) and the reaction was carried out at room temperature for 16 hours. Stirred for a while. Hydrochloric acid (28.9 ml of 1M aqueous solution, 28.9 mmol) was added and then tetrahydrofuran was removed in vacuo. The remaining water layer was decanted and the residue was washed with additional water (10 ml). The residue was redissolved in methanol (30 ml) and the solvent removed in vacuo to yield the title compound (5.95 g) as a colorless foam that was used without further purification.

Formulation 21: Methyl (3-{(2R) -2-[(2R) -2 {[tert-butyl (dimethyl) silyl] oxy} -2- (4-hydroxy-3-hydroxymethyl-phenyl)- Ethylamino] -propyl} -phenyl) -acetate

Methyl (3-{(2R) -2-[(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- (4- [benzyloxy] -3-hydroxy) in ethanol (50 ml) Methyl-phenyl) -ethylamino] -propyl} -phenyl) -acetate (Formulation 22) (5.27 g, 9.12 mmol) and a suspension of 10% palladium (1.00 g) on carbon for 16 hours under hydrogen atmosphere at room temperature (60 psi ) Was stirred. The catalyst was filtered through arbocel and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with dichloromethane: methanol: 880 ammonia (change from 96: 4: 0.4 to 95: 5: 0.5 by volume) to give the title of a pale yellow oil used without further purification. Compound (1.99g) was obtained.

Formulation 22: Methyl (3-{(2R) -2-[(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- (4- [benzyloxy] -3-hydroxymethyl- Phenyl) -ethylamino] -propyl} -phenyl) -acetate

[2- (benzyloxy) -5-((1R) -2-bromo-1-{[tert-butyl (dimethyl) silyl] oxy} ethyl) phenyl] methanol (formulation 23) in dichloromethane (130 ml) ( 12.5 g, 27.7 mmol) and a solution of methyl {3-[(2R) -2-aminopropyl] phenyl} acetate (formulation 25) (11.5 g, 55.4 mmol) were heated to 90 ° C. to allow the dichloromethane to evaporate. . The resulting melt was left at 90 ° C. for an additional 16 hours. The reaction mixture was cooled to room temperature and purified by flash column chromatography on silica gel eluting with dichloromethane: methanol: 880 ammonia (change to 98: 2: 0.2 to 97: 3: 0.3, volume ratio) to give the title compound as a white oil ( 12.1 g) was obtained.

Formulation 23: [2- (benzyloxy) -5-((1R) -2-bromo-1-{[tert-butyl (dimethyl) silyl] oxy} ethyl) phenyl] methanol

Borane dimethylsulfide complex (42.4 ml 10M solution in tetrahydrofuran, 424 mmol) was added to methyl 2- (benzyloxy) -5-((1R) -2-bromo-1-{[in tetrahydrofuran (1600 ml). was added dropwise to a solution of tert-butyl (dimethyl) silyl] oxy} ethyl) benzoate (formulation 24), (91.0 g, 189 mmol). The resulting mixture was then heated to reflux for 2 hours, then cooled to 0 ° C. and quenched with methanol (270 ml). The mixture was allowed to stir at room temperature for 16 hours and then the solvent was removed in vacuo. The residue was partitioned between dichloromethane (500 ml) and water (500 ml). The aqueous phase was separated and extracted with dichloromethane (500 ml) and the combined organic extracts were washed with saturated aqueous sodium chloride (500 ml), dried (with magnesium sulfate) and the solvent removed in vacuo. The residue was purified by flash column chromatography on silica gel eluting with cyclohexane: ethyl acetate (change from 100: 0 to 80:20, volume ratio) to give the title compound (68.7 g) as a colorless oil.

Formulation 24: Methyl 2- (benzyloxy) -5-((1R) -2-bromo-1-{[tert-butyl (dimethyl) silyl] oxy} ethyl) benzoate

Methyl 2- (benzyloxy) -5-[(1R) -2-bromo-1-hydroxyethyl] benzoate (71.05 g, 195 mmol) in N, N-dimethylformamide (270 ml), imidazole (18.52 g, 272 mmol), tert-butyldimethylsilyl chloride (32.23 g, 214 mmol) and 4- (N, N-dimethylamino) pyridine (0.44 g, 3.6 mmol) were allowed to stir at room temperature under nitrogen atmosphere for 24 hours. . The solvent was removed in vacuo and the residue was partitioned between ethyl acetate (500 ml) and water (500 ml). The organic phase was separated and washed with 2N hydrochloric acid (twice with 500 ml), saturated aqueous sodium bicarbonate (500 ml twice) with saturated sodium chloride (500 ml), dried (with magnesium sulfate) and the solvent removed in vacuo to give the title compound as a colorless oil (91.0). g) was obtained.

Formulation 25: Methyl {3-[(2R) -2-aminopropyl] phenyl} acetate

Methyl [3-((2R) -2-{[(1R) -1-phenyl-ethyl] -amino} -propyl) -phenyl] -acetate hydrochloride (formulation 26) (7.69 g, 22 mmol) and ammonium formate (6.94 g, 110 mmol) was heated to 75 ° C. in the presence of 20% palladium hydroxide (Pd (OH) ₂ / C, 2.00 g) on charcoal. After 90 minutes the reaction mixture was cooled to room temperature, filtered through arbocell and the filtrate was concentrated in vacuo. The residue was partitioned between dichloromethane (100 ml) and 880 ammonia (100 ml) and the organic phase was separated. The aqueous phase was extracted with dichloromethane (100 ml) and the combined organic extracts were dried (with magnesium sulfate) and reduced in vacuo to afford the title compound (4.78 g) as a colorless oil.

Formulation 26: Methyl [3-((2R) -2-{[(1R) -1-phenyl-ethyl] -amino} -propyl) -phenyl] -acetate hydrochloride

Methyl [3- (2-oxopropyl) phenyl] acetate in dichloromethane (400 ml) (Formulation 27) (8.5 g, 41.2 mmol), (R) -α-methyl benzylamine (4.8 ml, 37.2 mmol), sodium tria A solution of cetoxyborohydride (11.6 g, 56 mmol) and acetic acid (2.2 ml, 38 mmol) was stirred for 48 hours at room temperature. The reaction mixture was quenched by the addition of saturated aqueous sodium bicarbonate (200 ml) and allowed to stir until boiling stops. The organic phase was separated and the aqueous phase extracted with dichloromethane (100 ml). The combined organic extracts were dried (with magnesium sulfate) and reduced in vacuo. Purification by flash column chromatography eluting with dichloromethane: methanol: ammonia (99: 1: 0.1-95: 5: 0.5 by volume) yielded a 4: 1 mixture of diastereomers of light yellow oil (R, R are given). Got it. Treatment with hydrogen chloride (1M solution in 40 ml of methanol, 40 mmol) followed by three successive crystallizations (diisopropylether / methanol) gave the title compound (5.68 g) as a white crystalline solid.

Formulation 27: Methyl [3- (2-oxopropyl) phenyl] acetate

Tributyltin methoxide (28.3 ml, 98 mmol), formulation 28 (15.0 g, 65 mmol), isopropenyl acetate (10.8 ml, 98 mmol), palladium (II) acetate (750 mg, 3.30 mmol) and tri-ortho-tolylphosphate Fins (2.0 g, 6.5 mmol) were stirred together at 100 ° C. for 5 hours under nitrogen in toluene (75 ml). After cooling the reaction was diluted with ethyl acetate (150 ml) and 4M aqueous potassium fluoride solution (90 ml) and stirred for 15 minutes. The mixture was filtered through arbocell and the organic phase was separated and reduced in vacuo. The residue is purified by flash column chromatography on silica gel eluting with a solvent gradient that changes from diethyl ether: pentane (0: 100 to 25: 75, volume ratio) to dichloromethane (12.6 g). Got.

Formulation 28: Methyl (3-bromophenyl) acetate

Acetyl chloride (0.7 ml, 9.3 mmol) was added slowly to a solution of (3-bromophenyl) -acetic acid (20.0 g, 93 mmol) in methanol (500 ml) under 0 ° C. nitrogen and the reaction was gradually warmed to room temperature over 5 hours. It was made. The solvent was removed in vacuo and the residual oil was redissolved in dichloromethane, dried (with sodium sulfate) and concentrated in vacuo to afford the title compound (20.6 g) as a colorless oil.

Formulation 29: 1- (3-bromophenyl) -2-methylpropan-2-ol

Methylmagnesium bromide (3M solution in diethyl ether, 51.6 ml, 155 mmol) was dried at 0 ° C. of 1- (3-bromo-phenyl) propan-2-one (15.0 g, 70 mmol) in diethyl ether (200 ml). It was added slowly to the solution. The resulting mixture was left for 3 hours, then cooled to 0 ° C. and slowly quenched with saturated aqueous ammonium chloride solution. The organic phase was washed with brine and dried (with sodium sulfate). The yellow oil was then purified by column chromatography on silica gel eluting with dichloromethane: pentane: methanol (90: 5: 5 volume ratio) to give a light yellow oil (13.26 g).

Formulation 30: N- [2- (3-bromophenyl) -1,1-dimethylethyl] -2chloroacetamide

Stirring of chloroacetonitrile (6.63 ml, 105 mmol) at room temperature in 1- (3-bromophenyl) -2-methylpropan-2-ol) (Formulation 29) (12.0 g, 52.Ommol) in acetic acid (25 ml) To the prepared solution. The resulting solution was cooled to 0 ° C. and concentrated sulfuric acid was added keeping the temperature at <10 ° C. The resulting solution was allowed to stir for 1 hour and then poured onto ice and basified by addition of solid calcium carbonate. The product was extracted with ethyl acetate (2x500ml), the combined organics were washed with water (50ml), dried (with sodium sulfate) and the solvent removed in vacuo to afford the title compound (16.08g) as an orange solid.

Formulation 31: 2- (3-Bromophenyl) -1,1-dimethylethylamine

N- [2- (3-bromophenyl) -1,1-dimethylethyl] -2-chloroacetamide (Formulation 30) (32.0 g, 105 mmol), thiourea (9.60 g, 126 mmol) in ethanol (250 ml) And a solution of acetic acid (50 ml) was heated to reflux overnight. The reaction mixture was cooled to rt and filtered, the filtrate was concentrated in vacuo and basified with aqueous sodium hydroxide solution (1H, 450 ml). The product was extracted with dichloromethane (2x500ml) and the combined organics were washed with brine (50ml), dried (with sodium sulfate) and the solvent removed in vacuo to give the title compound (23g) as a black oil.

Formulation 32: [2- (3-Bromophenyl) -1,1-dimethylethyl] carbamic acid tert-butyl ester

Treatment of 2- (3-bromophenyl) -1,1-dimethylethylamine (Formulation 31) (5.0 g, 22 mmol) 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), the combined organics were dried (with sodium sulfate) and the solvent was removed in vacuo. The crude was purified using a cation exchange column (methanol followed by 2M ammonia in methanol) and then purified by flash column chromatography on silica gel eluting with dichloromethane to give the title compound (7.23 g) as a brown oil.

Formulation 33: 3- (2-tert-butoxycarbonylamino-2-methylpropyl) benzoic acid methyl ester

[2- (3-Bromophenyl) -l, 1-dimethylethyl] carbamic acid tert-butyl ester (Formulation 32) (7.0 g, 21 mmol), [1,1'-bis (diphenyl) in methanol (250 ml) A solution of phosphino) ferrocene] dichloropalladium (II) (1.74 g, 2.1 mmol) and triethylamine (5.94 ml, 43 mmol) was heated at 100 ° C. under 100 psi carbon monoxide for 12 h. The reaction mixture was filtered through arbocell and the filtrate was concentrated in vacuo and then purified by flash column chromatography on silica gel eluting with dichloromethane: pentane (50:50 by volume) to afford the title compound (3.76 g) as a yellow solid. Got it.

Formulation 34: 3- (2-amino-2-methylpropyl) benzoic acid methyl ester

A solution of 3- (2-tert-butoxycarbonylamino-2-methylpropyl) benzoic acid methyl ester (Formulation 33) (1.6 g, 5.2 mmol) in dichloromethane (160 ml) with trifluoroacetic acid (13.6 ml) The treatment was allowed to warm to room temperature over 2 hours. The solvent was removed in vacuo and the product was purified by cation exchange chromatography (methanol followed by 2M ammonia in methanol) to give the title compound (1.06 g) of amber oil.

Formulation 35: 3- {2-[(2R) -2- (4-Benzyloxy-3-hydroxymethylphenyl) -2- (tert-butyldimethyl-silanyloxy) ethylamino] -2-methylpropyl} benzoic acid Methyl ester

3- (2-amino-2-methylpropyl) benzoic acid methyl ester (Formulation 34) (1.36 g, 6.60 mol) in acetonitrile (10 ml), [2- (benzyloxy) -5-((1R) -2- Bromo-1-{[tert-butyl (dimethyl) silyl] oxy} ethyl) phenyl] methanol (formulation 23) (2.96 g, 6.60 mmol), sodium iodide (980 mg, 6.60 mmol) and diisopropylethylamine (3.44 ml, 19.7 mmol) was heated to reflux for 48 h under a nitrogen atmosphere. Then the solvent was removed in vacuo, saturated aqueous sodium hydrogen carbonate solution (20 ml) was added and the product extracted with ethyl acetate (3 × 30 ml). The combined organics were washed with brine (3x20ml), dried (with sodium sulfate) and the solvent removed in vacuo. The residue was purified by flash column chromatography on silica gel eluting with dichloromethane: methanol: ammonia (95: 5: 0.5 by volume) to give the title compound, which was dissolved in diethyl ether and evaporated (x3). White foam (1.70 g) was obtained.

Formulation 36: 3- {2-[(2R) -2- (tert-Butyldimethylsilanyloxy) -2- (4-hydroxy-3-hydroxymethyl-phenyl) ethylamino] -2-methylpropyl} Benzoic acid methyl ester

3- {2-[(2R) -2- (4-benzyloxy-3-hydroxymethylphenyl) -2- (tert-butyldimethyl-silanyloxy) ethylamino] -2-methylpropyl in methanol (50 ml) } Benzoic acid methyl ester (Formulation 35) (2.12 g, 3.70 mmol) and palladium on carbon (10%, 300 mg) were hydrogenated at room temperature and 60 psi for 18 hours. The reaction mixture was filtered through arbocell and the filtrate was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel eluting with dichloromethane: methanol: ammonia (95: 5: 0.5 volume ratio) A compound was obtained, which was dissolved in diethyl ether and evaporated to give (x3) a white foam (1.50 g).

Formulation 37: 3- {2-[(2R) -2- (tert-Butyldimethylsilanyloxy) -2- (4-hydroxy-3-hydroxymethyl-phenyl) ethylamino] -2-methylpropyl} Benzoic acid

3- {2-[(2R) -2- (tert-Butyldimethylsilanyloxy) -2- (4-hydroxy-3-hydroxymethyl-phenyl) ethylamino] -2-methylpropyl} benzoic acid methyl ester Formulation 36 (1.50 g, 3.08 mmol), aqueous sodium hydroxide solution (5M, 3.07 ml, 15.0 mmol), water (2 ml) and dioxane (20 ml) were stirred at room temperature for 18 hours. The solvent was removed in vacuo and the residue was dissolved in water (30 ml) and acidified with aqueous hydrochloric acid (1N, 15.38 ml). The resulting white precipitate was filtered and dried for 72 h in vacuo to yield the title compound (1.28 g) as a white solid.

Formulation 38: 3- {2-[(2R) -2- (tert-Butyldimethylsilanyloxy) -2- (4-hydroxy-3-hydroxymethyl-phenyl) ethylamino] -2-methylpropyl} -N- {2- (4-chlorophenyl) ethyl] benzamide

2- (4-chlorophenyl) ethylamine (164 mg, 1.06 mmol) was dissolved in 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (203 mg, 1.06 mol), 3- in dichloromethane (30 ml). {2-[(2R) -2- (tert-Butyldimethylsilanyloxy) -2- (4-hydroxy-3-hydroxymethyl-phenyl) ethylamino] -2-methylpropyl} benzoic acid (formulation 37) (500 mg, 1.06 mmol), 1-hydroxybenzotriazole hydrate (160 mg, 1.06 mmol) and triethylamine (440 μl, 3.20 mmol) were added. The resulting solution was stirred under nitrogen for 48 hours. The solvent is removed in vacuo and the residue is taken up in ethyl acetate (30ml), washed with water (20ml), sodium hydrogen carbonate (0.5M, 2x20ml), brine (2x20ml), then dried (with sodium sulfate) and the solvent is dried. Removed in vacuo. The residue was purified by flash column chromatography on silica gel eluting with dichloromethane: methanol: ammonia (95: 5: 0.5 by volume) to afford the title compound, which was dissolved in methanol and evaporated and then diluted with diethyl ether. Dissolve and evaporate to give a white foam (480 mg).

Formulation 39: 3- {2-[(2R) -2- (tert-Butyldimethylsilanyloxy) -2- (4-hydroxy-3-hydroxymethyl-phenyl) ethylamino] -2-methylpropyl} -N- [2- (4-methylphenyl) ethyl] benzamide

3- {2-[(2R) -2- (tert-Butyldimethylsilanyloxy) -2- (4-hydroxy-3-hydroxymethyl-phenyl) ethylamino] -2-methylpropyl} benzoic acid (Formulation 37) and by the method used in Formulation 38 using the appropriate amine to afford the title compound as a white foam.

Formulation 40: 3- {2-[(2R) -2- (tert-Butyldimethylsilanyloxy) -2- (4-hydroxy-3-hydroxymethyl-phenyl) ethylamino] -2-methyl-propyl } -N- [2- (4-trifluoromethylphenyl) ethyl] benzamide

3- {2-[(2R) -2- (tert-Butyldimethylsilanyloxy) -2- (4-hydroxy-3-hydroxymethyl-phenyl) ethylamino] -2-methylpropyl} benzoic acid (Formulation 37) and by the method used in Formulation 38 using the appropriate amine to afford the title compound as a white foam.

Formulation 41: 3- {2-[(2R) -2- (tert-Butyldimethylsilanyloxy) -2- (4-hydroxy-3-hydroxymethyl-phenyl) ethylamino] -2-methyl-propyl } -N- [2- (3,4-dichlorophenyl) ethyl] benzamide

3- {2-[(2R) -2- (tert-Butyldimethylsilanyloxy) -2- (4-hydroxy-3-hydroxymethyl-phenyl) ethylamino] -2-methylpropyl} benzoic acid (Formulation 37) and by the method used in Formulation 38 using the appropriate amine to afford the title compound as a white foam.

Formulation 42: 3- {2-[(2R) -2- (tert-Butyldimethylsilanyloxy) -2- (4-hydroxy-3-hydroxymethyl-phenyl) ethylamino] -2-methyl-propyl } -N- [2- (3,4-dimethylphenyl) ethyl] benzamide

3- {2-[(2R) -2- (tert-Butyldimethylsilanyloxy) -2- (4-hydroxy-3-hydroxymethyl-phenyl) ethylamino] -2-methylpropyl} benzoic acid (Formulation 37) and by the method used in Formulation 38 using the appropriate amine to afford the title compound as a white foam.

Formulation 43: 3- {2-[(2R) -2- (tert-Butyldimethylsilanyloxy) -2- (4-hydroxy-3-hydroxymethyl-phenyl) ethylamino] -2-methyl-propyl } -N- (2-naphthalen-2-yl-ethyl) benzamide

3- {2-[(2R) -2- (tert-Butyldimethylsilanyloxy) -2- (4-hydroxy-3-hydroxymethyl-phenyl) ethylamino] -2-methylpropyl} benzoic acid (Formulation 37) and by the method used in Formulation 38 using the appropriate amine to afford the title compound as a white foam.

Formulation 44: 3- {2-[(2R) -2- (tert-Butyldimethylsilanyloxy) -2- (4-hydroxy-3-hydroxymethyl-phenyl) ethylamino] -2-methyl-propyl } -N- (1,1-dimethyl-2-phenyl-ethyl) benzamide

3- {2-[(2R) -2- (tert-Butyldimethylsilanyloxy) -2- (4-hydroxy-3-hydroxymethylphenyl) ethylamino] -2-methylpropyl} benzoic acid (formulation 37) And by the method used in Formulation 38 using the appropriate amine to afford the title compound as a white foam.

Formulation 45: 3- {2-[(2R) -2- (tert-Butyldimethylsilanyloxy) -2- (4-hydroxy-3-hydroxymethylphenyl) ethylamino] -2-methylpropyl} -N -(2-methyl-2-phenylpropyl) -benzamide

3- {2-[(2R) -2- (tert-Butyldimethylsilanyloxy) -2- (4-hydroxy-3-hydroxymethyl-phenyl) ethylamino] -2-methylpropyl} benzoic acid (Formulation 37) and by the method used in Formulation 38 using the appropriate amine to afford the title compound as a white foam.

Formulation 46: 3-{(2R) -2- [2- (tert-butyldimethylsilanyloxy) -2- (4-hydroxy-3-hydroxymethyl-phenyl) ethylamino] -2-methylpropyl} -N- (4-chlorobenzyl) benzamide

3- {2-[(2R) -2- (tert-Butyldimethylsilanyloxy) -2- (4-hydroxy-3-hydroxymethyl-phenyl) ethylamino] -2-methylpropyl} benzoic acid (Formulation 37) and by the method used in Formulation 38 using the appropriate amine to afford the title compound as a white foam.

Formulation 47: [3- (2-Amino-2-methyl-propyl) -phenyl] -acetic acid ethyl ester

{3- [2- (2-Chloro-acetylamino) -2-methyl-propyl] -phenyl} -acetic acid (Formulation 48) (5.1 g, 18 mmol), thiourea (1.6 g, 21 mmol) in ethanol (80 ml) And a solution of acetic acid (18 ml) was heated to reflux for 16 h under a nitrogen atmosphere. The reaction mixture was cooled down and filtered. The filtrate was reduced in vacuo, the residue was dissolved in ethanol (150 ml), saturated with hydrogen chloride gas and the resulting solution heated to reflux for 16 h. The solvent was reduced in vacuo and the residue was partitioned between ethyl acetate (200 ml) and 5% aqueous sodium carbonate (200 ml). The organic extract was washed with saturated sodium chloride (100 ml), dried (with sodium sulfate) and reduced in vacuo. The residue was purified with strong cation exchange resin, eluted with methanol and then eluted with 2N ammonia in methanol to elute the product. The eluent was concentrated in vacuo to afford the title compound (2.68 g, 63%) as a yellow oil.

Formulation 48: {3- [2- (2-Chloro-acetylamino) -2-methyl-propyl] -phenyl} -acetic acid

Concentrated sulfuric acid (21 ml) was added [3- (2-hydroxy-2-methyl-propyl) -phenyl] -acetic acid (formulation 49) (10.6 g, 51.0 mmol) and chloroacetonitrile in glacial acetic acid (16 ml) at 0 ° C. (4.8 ml, 76.0 mmol) was added dropwise. The reaction was allowed to warm to rt and poured on ice water (500 ml) after 2 h. The aqueous was extracted with ethyl acetate (2x250ml) and the combined organics were washed with brine (50ml), dried (with sodium sulfate) and the solvent removed in vacuo to afford the title compound (14.0g) as a golden oil.

Formulation 49: [3- (2-hydroxy-2-methyl-propyl) -phenyl] -acetic acid

Methyl magnesium chloride (3M solution in 51 ml tetrahydrofuran, 153 mmol) was added to esters (11.6 g, 51 mmol) in tetrahydrofuran (300 ml) under 0 ° C. nitrogen (International Journal of Peptide and Protein Research, 1987, 29 (3)). 331) dropwise to the stirred solution. The reaction was allowed to warm to room temperature overnight to form a thick white precipitate which was then carefully added water (50 ml) and 2N hydrochloric acid (80 ml). The aqueous was extracted with ethyl acetate (2x300ml) and the combined organics were washed with brine (50ml), dried (with sodium sulfate) and the solvent removed in vacuo to afford the title compound (11.2g) as a golden oil.

Do esters need to be designated?

Formulation 50: {3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] phenyl} acetic acid

Ethyl {3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] phenyl} acetate (formulations 68) and the method used in Formulation 20 to give the title compound as a cream solid.

Formulation 51: {3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) ethyl] phenyl} acetic acid

Using ethyl {3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) ethyl] phenyl} acetate (formulation 52) And prepared by the method used in Formulation 20 to obtain the title compound as a white solid.

Formulation 52: Ethyl {3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) ethyl] phenyl} acetate

Ethyl {3- [2-({(2R) -2- [4- (benzyloxy) -3- (hydroxymethyl) phenyl] -2-hydroxyethyl} amino) ethyl] phenyl} acetate (formulation 53) Was prepared by the method used in Formulation 21 to give the title compound as an orange oil.

Formulation 53: Ethyl {3- [2-({(2R) -2- [4- (benzyloxy) -3- (hydroxymethyl) phenyl] -2-hydroxyethyl} amino) ethyl] phenyl} acetate

Ethyl (3- {2-[((2R) -2- [4- (benzyloxy) -3- (hydroxymethyl) phenyl] -2-{[tert-butyl) in methanol (15 ml) and water (10 ml) A solution of (dimethyl) silyl] oxy} ethyl) amino] ethyl} phenyl) acetate (formulation 54) (2.39 g, 4.14 mmol) was treated with ammonium fluoride (1.53 g, 41.4 mmol) and the reaction was 40 ° C. for 16 h. Heated to. Methanol was removed in vacuo and the aqueous residue was extracted with dichloromethane (3x50ml). The combined organics are dried (with sodium sulfate) and the solvent is dried in vacuo and the residue is eluted with silica gel: eluting with dichloromethane: methanol: 880 ammonia (change from 97: 3: 0.3 to 95: 5: 0.5 by volume ratio). Purification by flash column chromatography gave the title compound (1.90 g) as an orange gum.

Formulation 54: Ethyl (3- (2-[((2R) -2- [4- (benzyloxy) -3- (hydroxymethyl) phenyl] -2-{[tert-butyl (dimethyl) silyl] oxy} Ethyl) amino] ethyl} phenyl) acetate

[2- (benzyloxy) -5-((1R) -2-bromo-1-{[tert-butyl (dimethyl) silyl] oxy} ethyl) phenyl] methanol (formulation 23) and ethyl [3- (2 -Aminoethyl) phenyl] acetate (Formulation 58) was used and prepared by the method used in Formulation 22 to give the title compound as a yellow oil.

Formulation 55: Ethyl [3- (2-hydroxyethyl) phenyl] acetate

Carbonyl diimidazole (5.11 g, 31.5 mmol) in ester in tetrahydrofuran (100 ml) under nitrogen at room temperature (International Journal of Peptide and Protein Research, 1987, 29 (3), 331) (7.00 g, 31.5 mmol) was added to the stirred solution in one portion. The reaction was stirred for 2 hours, water (26 ml) was added and the reaction cooled to 0 ° C. Sodium borohydride (6.00 g, 0.15 mmol) was then added in portions and the reaction was allowed to warm to room temperature with continued stirring over 2 hours. Ethyl acetate (300 ml) was added followed by dropwise addition of 2N aqueous hydrochloric acid (20 ml). The organic layer was separated and the aqueous was extracted with ethyl acetate (2x75ml), the combined organics were dried (with sodium sulfate) and the solvent was removed in vacuo to give a white solid which was ethyl acetate: phenane (50: 50, volume ratio). Purification by flash column chromatography on silica gel eluting with) afforded the title compound (4.60 g) as a colorless oil.

Formulation 56: Ethyl (3- {2-[(methylsulfonyl) oxy] ethyl} phenyl) acetate

Methane sulfonyl chloride (2.78 g, 24.3 mmol) was added ethyl [3- (2-hydroxyethyl) phenyl] acetate (formulation 55) (4.60 g, 22.1 mmol) and triethyl in dichloromethane (250 ml) under 0 ° C. nitrogen. To the solution of amine (3.40 ml, 24.3 mmol) was added dropwise. The reaction was allowed to warm to gal room temperature in 1 h and washed with saturated aqueous sodium hydrogen carbonate (75 ml). The aqueous was washed with dichloromethane (2x100ml) and the combined organics were washed with water (25ml), dried (with sodium sulfate) and the solvent removed in vacuo to give the title compound (6.2 g) as a colorless oil.

Formulation 57: Ethyl [3- (2-azidoethyl) phenyl] acetate

Sodium azide (2.82 g, 43.3 mmol) was added ethyl (3- {2-[(methylsulfonyl) oxy] ethyl} phenyl) acetate (Form 56) in N, N-dimethylformamide (400 ml) at room temperature (6.20). g, 21.7 mmol) was added to the stirred solution in one portion. The reaction was heated at 60 ° C. for 1 hour then allowed to cool to room temperature and the solvent removed in vacuo. Ethyl acetate (200ml) and water (75ml) were added and the organics were separated, the aqueous was washed with ethyl acetate (2x100ml) and the combined organics were evaporated in vacuo to yield an oil which was then ethyl acetate: phenane (5 Purified by flash column chromatography on silica gel eluting with (95: volume ratio) to give the title compound (4.65 g) as a colorless oil.

Formulation 58: ethyl [3- (2-aminoethyl) phenyl] acetate

Triphenylphosphine (3.88 g, 23.3 mmol) was stirred of ethyl [3- (2-azidoethyl) phenyl] acetate (formulation 57) (3.88 g, 16.6 mmol) in tetrahydrofuran (100 ml) at room temperature under nitrogen. To the prepared solution at one time. The reaction was stirred for 18 hours, water (5 ml) was added and the reaction heated at 50 ° C. for 4 hours, the reaction was cooled to room temperature and the solvent removed in vacuo. The residue was dissolved in saturated aqueous sodium hydrogen carbonate (40 ml) and the aqueous extracted with dichloromethane (3 × 50 ml). The combined organics were dried (with sodium sulfate), the solvent removed in vacuo and purified by flash column chromatography on silica gel eluting with dichloromethane: methanol (95: 5, volume ratio) to give the title compound as a colorless oil (3.11 g). )

Formulation 59: 3-[(2R) -2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) propyl] benzoic acid

Methyl 3-[(2R) -2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) propyl in tetrahydrofuran (35ml) ] To a solution of benzoate (formulation 60) (5.12 g, 14.24 mmol) was added an aqueous lithium hydroxide solution (1M, 29 ml, 29 mmol) and the solution was allowed to stir at room temperature for 18 hours. Aqueous hydrochloric acid (1M, 29 ml, 29 mmol) was added and the tetrahydrofuran / water was removed in vacuo to yield the title compound (5.87 g) as an off-white solid, used without further purification.

Formulation 60: Methyl 3-[(2R) -2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) propyl] benzoate

Methyl 3-[(2R) -2-({(2R) -2- [4- (benzyloxy) -3- (hydroxymethyl) phenyl] -2-hydroxyethyl} amino) propyl in ethanol (100ml) ] Benzoate (Formulation 61) (6.83 g, 15.2 mmol) and a suspension of 10% palladium on carbon (683 mg) were stirred for 18 h under room temperature hydrogen atmosphere (60 psi). The catalyst was filtered through arbocell and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with dichloromethane: methanol: 880 ammonia (change from 95: 5: 0.5 to 90: 10: 1 in volume ratio) to give the title compound as a pale yellow gum (5.12 g). Got.

Formulation 61: Methyl 3-[(2R) -2-((2R) -2- [4- (benzyloxy) -3- (hydroxymethyl) phenyl] -2-hydroxyethyl) amino) propyl] benzoate

Methyl 3-{(2R) -2-[((2R) -2- [4- (benzyloxy) -3- (hydroxymethyl) phenyl] -2-{[in methanol (180 ml) and water (60 ml) A solution of tert-butyl (dimethyl) silyl] oxy} ethyl) amino] propyl} benzoate (formulation 62) (10 g, 17.74 mmol) and ammonium fluoride (6.57 g, 177 mmol) was heated at 40 ° C. for 18 hours. Methanol was removed in vacuo and the remaining aqueous layer was extracted with dichloromethane (2x100 ml). The combined organic layer was dried (with sodium sulfate), filtered and evaporated in vacuo. The resulting oil was purified by flash column chromatography on silica gel eluting with dichloromethane: methanol: 880 ammonia (95: 5: 0.5, volume ratio) to give the title compound (6.83 g) as a pale yellow gum.

Formulation 62: Methyl 3-{(2R) -2-[((2R) -2- [4- (benzyloxy) -3- (hydroxymethyl) phenyl] -2-{[tert-butyl (dimethyl) silyl ] Oxy} ethyl) amino] propyl} benzoate

2- (benzyloxy) -5-((1R) -2-bromo-1-{[tert-butyl (dimethyl) silyl] oxy} ethyl) phenyl] methanol (formulation 23) in dichloromethane (70 ml) (9.23 g, 20.5 mmol) and methyl {3-[(2R) -2-aminopropyl] phenyl} acetate (formulation 63) (8.48 g, 40.9 mmol) were heated to 90 ° C. and the dichloromethane was allowed to evaporate. The resulting melt was placed at 90 ° C. for an additional 18 hours. The reaction mixture was cooled to room temperature and purified by flash column chromatography on silica gel eluting with dichloromethane: methanol: 880 ammonia (change from 98: 2: 0.2 to 97.5: 2.5: 0.25, volume ratio) to give the title compound of orange oil ( 10 g) was obtained.

Formulation 63: Methyl {3-[(2R) -2-aminopropyl] phenyl} acetate

Methyl [3-((2R) -2-{[(1R) -1-phenyl-ethyl] -amino} -propyl) -phenyl] -acetate (Formulation 64) in ethanol (200 ml) (13.65 g, 40.9 mmol) And a solution of ammonium formate (12.9 g, 204 mol) was heated to reflux in the presence of 20% palladium hydroxide (Pd (OH) ₂ / C, 1.36 g) on charcoal. After 3 hours the reaction mixture was cooled to room temperature, filtered through arbocell and the filtrate was concentrated in vacuo. The residue was partitioned between dichloromethane (200 ml) and 880 ammonia (100 ml) and the organic phase was separated. The aqueous layer was extracted with additional dichloromethane (3 × 100 ml) and the combined organic extracts were washed with brine (100 ml), dried (with sodium sulfate) and reduced in vacuo to afford the title compound (8.48 g) as a pale yellow oil.

Formulation 64: Methyl [3-((2R) -2-{[(1R) -1-phenyl-ethyl] -amino} -propyl) -phenyl] -acetate hydrochloride

Methyl [3- (2-oxopropyl) phenyl] acetate in dichloromethane (1500 ml) (Formulation 65) (45.3 g, 236 mmol), (R) -α-methyl benzylamine (27.6 ml, 214 mmol), sodium triacetoxy A solution of borohydride (68.1 g, 321 mmol) and acetic acid (14.7 ml, 257 mmol) was stirred at rt for 18 h. Saturated aqueous sodium bicarbonate (600 ml) was added to quench the reaction mixture and allow to stir until boiling stops. The organic phase was separated and the aqueous phase extracted with additional dichloromethane (2x100 ml). The combined organic extracts were washed with brine (100 ml), dried (with sodium sulfate), filtered through celite and then reduced in vacuo. The oil was dissolved in methanol (200 ml), treated with 1 M hydrogen chloride in methanol (300 ml) and then reduced in vacuo to give a 4: 1 mixture of diastereomers of the hydrochloride salt (R, R is given). Twice (diisopropylether / methanol) gave the title compound (27.3 g) as a colorless crystalline solid.

Formulation 65: Methyl [3- (2-oxopropyl) phenyl] acetate

Tributyltin methoxide (80.3 ml, 279 mmol), methyl 3-bromobenzoate (53.5 g, 249 mmol), isopropenyl acetate (39.4 ml, 358 mm), palladium (II) acetate (2.6 g, 11.6 mmol) and Tri- o -tolylphosphine (7.1 g, 23.2 mmol) was stirred together in toluene (350 ml) for 18 h under 100 ° C. nitrogen. After heating, the reaction was treated with 4M aqueous potassium fluoride solution (560 ml) and stirred for 2 hours. The resulting mixture was diluted with additional toluene (200 ml), filtered through celite and the filter pad washed with ethyl acetate. The organic phase was separated, dried (with sodium sulfate) and reduced in vacuo. The residue was purified by flash column chromatography on silica gel eluting with ethyl acetate: pentane (changes from 10: 90 to 20: 80, volume ratio) to give the title compound (45.3 g) as an orange oil.

Formulation 66: Ethyl (3- {2-[((2R) -2- [4- (benzyloxy) -3- (hydroxymethyl) phenyl) -2- [tert-butyl (dimethyl) silyl] oxy} ethyl ) Amino] -2-methylpropyl} phenyl) acetate

[2- (benzyloxy) -5-((1R) -2-bromo-1-{[tert-butyl (dimethyl) silyl] oxy} ethyl) phenyl] methanol (formulation 23) and [3- (2- Prepared using the method amino-2-methyl-propyl) -phenyl] acetic acid ethyl ester (Formulation 47) and used in Formulation 22 to give the title compound as a yellow oil.

Formulation 67: Ethyl {3- [2-({(2R) -2- [4- (benzyloxy) -3- (hydroxymethyl) phenyl] -2-hydroxyethyl} amino) -2-methylpropylphenyl }acetate

Ethyl (3- {2-[((2R) -2- [4- (benzyloxy) -3- (hydroxymethyl) phenyl] -2-{[tert-butyl (dimethyl) silyl] oxy} ethyl) amino ] -2-methylpropyl} phenyl) acetate (formulation 66) was prepared by the method used in preparation 53 to obtain the title compound of the oil.

Formulation 68: Ethyl {3- (2-({(2R) -2-hydroxy-2- (4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] phenyl} acetate

Ethyl {3- [2-({(2R) -2- [4- (benzyloxy) -3- (hydroxymethyl) phenyl] -2-hydroxyethyl} amino) -2-methylpropyl] phenyl} acetate Formulation 67 was used and prepared by the method used in preparation 21, to obtain the title compound as a colorless oil.

Formulation 69:

2- (3-Fluoro-4-trifluoromethyl-phenyl) -ethylamine

Chlorotrimethylsilane (2 mL, 16 mmol) was added dropwise to lithium borohydride (2M in tetrahydrofuran, 4 mL, 8 mmol). Then a solution of 3-fluoro-4- (trifluoromethyl) phenylacetonitrile (312 mg, 4 mmol) in tetrahydrofuran (2 mL) was added at 0 ° C. and the mixture was allowed to stir for 24 hours while warming to room temperature. . The mixture was then diluted with methanol (20 mL) and concentrated in vacuo. The residue was taken up in 20% potassium hydroxide solution (20 mL), concentrated with dichloromethane (3x20 mL) and the combined organic solutions were dried over magnesium sulfate and concentrated in vacuo. The residue was purified using column chromatography, eluting with methanol and then eluting with 1M ammonia in methanol, using an Isolute® SCX-2 cartridge to give an oily residue. The oil was treated with diethyl ether to give 485 mg of the title compound in 59% yield.

Formulation 70:

2- (5-Chloro-2-methoxy-phenyl) -ethylamine

Using the method analogous to that of Formulation 69, the title compound was prepared in 52% yield from (5-chloro-2-methoxy-phenyl) acetonitrile (W02004039377, p40).

Formulations 71-79

The following compounds, of the formula shown below, were prepared using an appropriate phenylacetonitrile starting material and by a method analogous to that described in Formulation 69. Unless stated otherwise, R ³ to R ⁷ are hydrogen.

Formulation 79: Compounds were purified using sulfonic acid functionalized lantern.

Formulation 80

2- (4-Chloro-phenyl) -N-ethyl-acetamide

4-chlorophenyl acetic acid (1 g, 5.88 mmol) in dichloromethane (30 mL), ethylamine (2M in tetrahydrofuran, 5.88 mL, 11.76 mmol), 1-hydroxybenzotriazole hydrate (90 mg, 5.88 mmol), 1 A mixture of-(3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1.13 g, 5.88 mmol), and triethylamine (1.78 g, 17.64 mmol) was stirred at rt for 18 h. The mixture was then diluted with 1M sodium hydroxide solution (30 mL) and the aqueous layer was extracted with dichloromethane (30 mL). The combined organic solution was washed with 1M hydrochloric acid and brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with 100: 0 to 90:10 dichloromethane: methanol to give 443 mg of the title compound as a colorless solid in 37% yield.

Formulation 81

[2- (4-Chloro-phenyl) -ethyl] -ethyl-amine hydrochloride

A mixture of 2- (4-chloro-phenyl) -N-ethyl-acetamide (Formulation 80), (437 mg, 2.22 mmol) and borane tetrahydrofuran complex (1M, 8.88 mL, 8.88 mmol) in tetrahydrofuran was 18 Heated to reflux for hours. The cooled reaction mixture was then diluted with methanol (5 mL) and 12M hydrochloric acid (2 mL) and heated to reflux for another 1 hour. The mixture was cooled to rt and concentrated in vacuo. The residue was treated with ethyl acetate to give 403 mg of the title compound as a colorless solid in 99% yield.

Formulation 82

2- (4-Methylsulfanyl-phenyl) -ethylamine

A solution of 4- (methylthio) phenylacetonitrile (828 mg, 5.08 mmol) in tetrahydrofuran (10 mL) was added dropwise to lithium aluminum hydride (1M in tetrahydrofuran, 5.6 mL, 5.6 mmol) and the mixture at 0 ° C. Stir for 1 hour. Additional lithium aluminum hydride (1M in tetrahydrofuran, 5.6 mL, 5.6 mmol) was added and the mixture was stirred at rt for 18 h and then heated to reflux for 1 h. The reaction mixture was cooled to 0 ° C., 1M sodium hydroxide solution (3 mL) was added dropwise and stirring continued for an additional 1 hour. The mixture was then filtered through Celite ^® , washed with ethyl acetate and the filtrate was washed with 1M sodium hydroxide solution. The organic solution was then loaded onto an Isolute ^® SCX cartridge, washed with methanol and eluted with 1M ammonia in methanol. The relevant fractions were concentrated in vacuo and the residue was purified by column chromatography on silica gel eluting with dichloromethane: methanol: 0.88 ammonia in 100: 0: 0 to 95: 5: 0.5 to give 18% yield of the title compound of the yellow oil. 154 mg was obtained.

Formulation 83

(4-hydroxy-3-methyl-phenyl) -acetonitrile

Boron tribromide (1M in dichloromethane, 6.2 mL, 6.2 mmol) was added to a solution of 4-methoxy-3-methylphenylacetonitrile (0.2 g, 1.24 mmol) in dichloromethane (10 mL) and cooled to -78 ° C. The reaction mixture was stirred at this temperature for 1 hour and then at room temperature for 2 hours. The mixture was then cooled back to −78 ° C., diluted with sodium hydrogen carbonate solution and allowed to warm to room temperature. The organic layer was separated, washed with brine, dried over sodium sulfate and concentrated in vacuo to yield 0.16 g of the title compound as a white solid in 87% yield.

Formulation 84

(4-hydroxy-2,5-dimethyl-phenyl) -acetonitrile

The title compound was prepared as a colorless solid with 60% yield from (4-methoxy-2,5-dimethylphenyl) acetonitrile using a method similar to that of Formulation 83.

Formulation 85

(4-hydroxy-2,3-dimethyl-phenyl) -acetonitrile

The title compound was prepared as a colorless solid with 94% yield from (4-methoxy-2,3-dimethyl-phenyl) acetonitrile using a method similar to that of Formulation 83.

Formulation 86

2- (4-methoxy-2,5-dimethyl-phenyl) -ethylamine

Of 2M methanolic ammonia (10mL) (4- methoxy-2,5-dimethyl-phenyl) acetonitrile (200mg, 1.14mmol) and Raney ^® nickel (Raney ^® nickel) hydrogen gas in the mixture of (50mg) 60psi Stir at room temperature for 18 hours. TLC analysis showed that not all of the starting material was consumed, so additional Rayney® nickel in 2M methanolic ammonia (10 mL) was added. The reaction mixture was stirred for an additional 18 hours at room temperature under 60 psi of hydrogen gas and then filtered through Arbocel ^® . The filtrate was concentrated in vacuo and the residue was purified by column chromatography on silica gel eluting with dichloromethane: methanol: 0.88 ammonia in 100: 0: 0 to 90: 10: 1 to give a title of light brown solid in 38% yield. 98 g of compound was obtained.

Formulation 87

2- (4-methoxy-2,3-dimethyl-phenyl) -ethylamine

Using a method similar to that of Formulation 86, the title compound of the clear oil was prepared in 93% yield from (4-methoxy-2,3-dimethyl-phenyl) -acetonitrile.

Formulation 88

4- (2-amino-ethyl) -2-methyl-phenol

Using a method similar to that of Formulation 86, the title compound of the clear oil was prepared in 85% yield from (4-hydroxy-3-methylphenyl) acetonitrile (Formulation 83).

Formulation 89

4- (2-amino-ethyl) -2,5-dimethyl-phenol

The title compound was prepared in 73% yield from (4-hydroxy-2,5-dimethyl-phenyl) acetonitrile (Formulation 84) using a method analogous to that of Formulation 86.

Formulation 90

4- (2-amino-ethyl) -2,3-dimethyl-phenol

Using a method similar to that of Formulation 86, the title compound was prepared as a colorless solid in 95% yield from (4-hydroxy-2,3-dimethyl-phenyl) -acetonitrile (Formulation 85).

Formulation 91

2- (2,3-dimethyl-phenyl) -ethylamine

Of 2,3-dimethylphenylacetonitrile ([J. Org Chem, 51 (26), 5157-60; 1986]), (190 mg, 1.31 mmol) and Raney ^® nickel (100 mg) in 2 M methanolic ammonia (5 mL). The mixture was stirred for 4 days under 50 psi of hydrogen gas. The mixture was then filtered through arbocell and concentrated in vacuo to give 130 mg of the title compound as a solid in 66% yield.

Formulation 92

2- (2,3-Dichloro-phenyl) -ethylamine

A solution of 2,3-dichlorophenylacetonitrile (0.5 g, 2.7 mmol) in diethyl ether (5 mL) was added to lithium aluminum hydride (1M in diethyl ether, 2.7 mL, 2.7 mmol) and aluminum trichloride (359 mg, 2.7 mmol) in cold ice solution. The mixture was stirred at rt for 2.5 h and then quenched with 1 M sodium hydroxide solution (5 mL). The mixture was stirred for an additional 30 minutes and filtered through Celite ^® . The filtrate layer was separated and the organic solution was concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with 100: 0: 0 to 95: 5: 0.5 of dichloromethane: methanol: 0.88 ammonia to give 135 mg of the title compound as a clear oil in 26% yield.

Formulation 93

2- (5-Chloro-2-fluoro-phenyl) -ethylamine

Sodium borohydride (1.73 g, 45.51 mmol) was added 5-chloro-2-fluorophenylacetonitrile (1.04 g, 6.15 mmol) and cobalt (II) chloride hexahydrate (2.18 g, 9.22 mmol) in methanol (30 mL). The solution was added in portions and the mixture was stirred at room temperature for 3 hours. The suspension was then filtered through Celite ^® and concentrated in vacuo to partition the residue into 1M hydrochloric acid (40 mL) and dichloromethane (40 mL). The aqueous layer was separated, basified to pH 11 with 1M ammonia solution and extracted with dichloromethane (2 × 40 mL). The combined organic solution was washed with brine (30 mL), dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with dichloromethane: methanol: 0.88 ammonia in 100: 0: 0 to 98: 2: 0.2 to give 350 mg of the title compound as a yellow oil in 33% yield.

Formulation 94

2- (2-Chloro-4-fluoro-phenyl) -ethylamine

Using a method similar to that of Formulation 93, the title compound was obtained as light brown oil in 46% yield from 2-chloro-4-fluorophenylacetonitrile.

Formulation 95

2- (4-Chloro-2-fluoro-phenyl) -ethylamine

Using the method analogous to that of Formulation 93, the title compound was prepared from 4-chloro-2-fluorophenylacetonitrile. It was purified using the Isco SCX ^® (Isco SCX ^®) which was eluted with methanol and the crude compound eluted with 1M methanolic ammonia cartridge. The appropriate fractions were concentrated in vacuo and the residue was further purified by column chromatography on silica gel eluting with 95: 5: 0.3 of dichloromethane: methanol: 0.88 ammonia to give the title compound as a pale yellow oil in 29% yield.

Formulation 96

(2,3-Dihydro-benzofuran-2-yl) -methanol

A solution of meta-chloroperbenzoic acid (96.4 g, 335 mmol) in dichloromethane (500 mL) was added to a cold ice solution of 2-allylphenol (30 g, 224 mmol) in dichloromethane (1 L) and the mixture was stirred at 0 ° C. for 30 minutes. Stirred and stirred at rt for 18 h. The reaction mixture was then cooled back to 0 ° C., quenched with 2M sodium hydroxide solution (700 mL) and stirred for 30 minutes. The organic layer was then separated, dried over magnesium sulfate and concentrated in vacuo to yield a yellow oil. The oil was purified by HPLC using Chiralpak AD 250 * 4.6mm column and eluent as hexanes: isopropanol (90: 10) to afford the title compound.

Formulation 97

2,3-dihydro-1-benzofuran-2-ylmethyl 4-methylbenzenesulfonate

p-toluenesulfonyl chloride (26.7 g, 140 mol) is added to a solution of (2,3-dihydro-benzofuran-2-yl) -methanol (formulation 96) (21 g, 140 mmol) in pyridine (400 mL) and the mixture Was stirred at room temperature for 4 days. The reaction mixture was then concentrated in vacuo and the residue was azeotropically distilled with toluene, diluted with ethyl acetate (500 mL) and washed with 2M hydrochloric acid (2x300 mL). The organic solution was dried over magnesium sulfate and concentrated in vacuo to give a brown oil. The oil was treated with cyclohexane to give 33.5 g of the title compound as a white solid in 79% yield.

Formulation 98

2-ethyl-2,3-dihydro-benzofuran

Methyl lithium (1.6 M in diethyl ether, 313 mL, 500 mmol) was added to a solution of copper (I) iodide (47.6 g, 250 mmol) in diethyl ether (750 mL) at -70 ° C. The solution was then allowed to warm to -10 ° C and stirred for 30 minutes. The mixture was then added to a solution of 2,3-dihydro-1-benzofuran-2-ylmethyl 4-methylbenzenesulfonate (Formula 97) (15.2 g, 50 mmol) in diethyl ether (500 mL) and the reaction mixture Was stirred at -40 ° C for 1 hour and stirred at room temperature for 2 hours. The mixture was then cooled to −70 ° C. and quenched with 10% ammonium chloride solution (750 mL) and 2M hydrochloric acid (50 mL), diluted with 0.88 ammonia (100 mL) and stirred for 18 h. The reaction mixture was extracted with diethyl ether (3x500 mL) and the organic solution was dried over magnesium sulfate and concentrated in vacuo to afford 7.25 g of the title compound as a brown oil in 98% yield.

Formulation 99

(+) And (-) 5-bromo-2-ethyl-2,3-dihydro-benzofuran

N-bromosuccinimide (8.66 g, 48.6 mmol) was added to a solution of 2-ethyl-2,3-dihydro-benzofuran (formulation 98) in dichloromethane (70 mL) and the mixture was stirred at room temperature for 18 hours. I was. The mixture was then diluted with dichloromethane (200 mL) and washed with water (200 mL) and sodium meta-bisulfite (200 mL). The organic solution was dried over magnesium sulfate and concentrated in vacuo to afford a yellow oil which was purified by HPLC using Chiralcel OJ 250 * 20 mm column and eluent with hexanes: isopropanol (95: 5) as the first mirror image of the title compound. Isomers were obtained. Further elution gave 2.95 g of the second isomer of the title compound.

Formulation 100

Di-tert-butyl [3- (2-ethyl-2,3-dihydro-1-benzofuran-5-yl) propyl] imidodicarbonate

N, N-bis-Boc-N-allylamine (2.99 g, 11.6 mmol) was azeotropically distilled with toluene (2x50 mL) and then dissolved in tetrahydrofuran (12 mL). The solution was cooled to 0 ° C. and 9-borabicyclo [3.3.1] nonane dimer (0.5M in tetrahydrofuran, 46.5 mL, 23.2 mmol) was added and the mixture was stirred at 0 ° C. for 3 hours. 5-Bromo-2-ethyl-2,3-dihydro-benzofuran (formulation 98, enantiomer 2), (2.9 g, 12.8 mmol), tripotassium phosphate in N, N-dimethylformamide (12 mL) 7.7 mL, 23.2 mmol) and a mixture of [1,1'-bis (diphenylphosphino) ferrocene] palladium (II) chloride (4.74 mg, 0.58 mmol) were added and the reaction mixture was stirred at rt for 18 h. The reaction was then quenched with 2M sodium hydroxide solution (30 mL) and water (10 mL) and stirred for 1 h at room temperature. The mixture was then extracted with diethyl ether, dried over magnesium sulfate and concentrated in vacuo. The residue was suspended in 25: 75 ethyl acetate: petroleum ether, filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with 7: 93 ethyl acetate: petroleum ether to give 2.15 g of the title compound as a clear oil in 46% yield.

Formulation 101

3- (2-ethyl-2,3-dihydro-benzofuran-5-yl) -propylamine hydrochloride

Di-tert-butyl [3- (2-ethyl-2,3-dihydro-1-benzofuran-5-yl) propyl] imidodicarbonate in hydrochloric acid (4M in dioxane, 20 mL) (Formulation 100), A solution of (2.19 g, 5.4 mmol) was stirred at rt for 18 h. The reaction mixture was then concentrated in vacuo to afford the title compound in quantitative yield.

Formulation 102

tert-butyl (2- {4-[(butylamino) carbonyl] phenyl} ethyl) carbamate

4- {2-[(tert-butoxycarbonyl) amino] ethyl} benzoic acid (22.2 g, 83.6 mmol) (EP0836839, p60) carbonyldiimidazole (21.36 g, 131.7 mmol) in dichloromethane (600 mL), And a mixture of N, N-diisopropylethylamine (20 mL, 115.1 mmol) was stirred at room temperature for 2 hours. Then ⁿ butylamine (10 mL, 101.18 mmol) was added and the mixture was stirred for an additional 18 hours at room temperature. The reaction mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate and washed with 10% citric acid (2x50 mL), saturated sodium hydrogen carbonate solution (200 mL), water (200 mL) and brine (200 mL). The organic solution was dried over sodium sulfate and concentrated in vacuo to give a creamy powder. The powder was purified by column chromatography on silica gel eluting with 99: 1 dichloromethane: methanol to give 17.5 g of the title compound in 65% yield.

Formulation 103

4- (2-aminoethyl) -N-butylbenzamide hydrochloride

Using a method similar to formulation 101, the title compound of white powder was prepared in 84% yield from tert-butyl (2- {4-[(butylamino) carbonyl] phenyl} ethyl) carbamate (Formulation 102). .

Formulation 104

[4- (3-Pyrrolidin-1-yl-propoxy) -phenyl] -acetonitrile

1- (3-chloropropyl) pyrrolidine ([J. Am. Chem. Soc., 77, 2270; 1955]) (133 g, 0.9 mol), acetonitrile (1 L), 4-hydroxybenzonitrile (100 g , 0.75 mol) and cesium carbonate (256 g, 0.78 mol) were stirred at 45 ° C. for 18 hours. The reaction mixture was then concentrated in vacuo and the residue partitioned between ethyl acetate (800 mL) and water (800 mL). The aqueous layer was separated and extracted with ethyl acetate (800 mL) and the combined organic solutions were washed with water (500 mL) and extracted with 2M hydrochloric acid (2x600 mL). The acidic solution was basified to pH 8-9 with 40% potassium hydroxide solution and extracted with ethyl acetate (800 mL). The aqueous solution was then further basified to pH 10-11 with 40% potassium hydroxide solution and extracted with ethyl acetate (800 mL). The combined organic solution was dried over sodium sulfate, filtered through a pad of silica and concentrated in vacuo to yield 150 g of the title compound as a red oil in 79% yield.

Formulation 105

2- [4- (3-Pyrrolidin-1-yl-propoxy) -phenyl] -ethylamine

Of [4- (3-pyrrolidin-1-yl-propoxy) -phenyl] -acetonitrile (Formulation 104), (1 g, 4.1 mmol) and Raney ^® nickel (100 mg) in 2 M methanolic ammonia (35 mL) The mixture was stirred at 50 ° C. for 6 hours under 60 psi of hydrogen gas. TLC analysis showed that not all of the starting material was consumed, so additional Rainey ^® nickel (200 mg) was added to the reaction mixture and heating continued for 5 hours. Further Rayni ^® nickel (200 mg) was added and subsequent mixture was stirred at 50 ° C. for 3 hours as there was still starting material in subsequent TLC analysis. The reaction mixture was then filtered through Arbocel ^® and concentrated in vacuo to yield a yellow oil. The oil 85: 15: 1.5 to 80:20: dichloromethane 2: methanol: 0.88 4g ready to ammonia eluting with chef ^® (RediSep ^®) was obtained in 16% yield purified by column chromatography using a silica cartridge 160mg Got.

Formulation 106

[2- (3-Pyrrolidin-1-yl-propoxy) phenyl] -acetonitrile

Using a method similar to that of Formulation 104, 58% from 2-hydroxy-benzeneacetonitrile ([J. Org. Chem .; 66, 3435; 2001]) and 1- (3-chloropropyl) pyrrolidine To yield the title compound as a light brown gum.

Formulation 107

2- [2- (3-Pyrrolidin-1-yl-propoxy) -phenyl] -ethylamine

Using a method similar to that of Formulation 69, the title compound was prepared in 48% yield from the product of Formulation 106.

Formulation 108

{2- [3- (3-pyrrolidin-1-ylpropoxy) phenyl] ethyl} amine

Using the method analogous to that of Formulation 69, the title compound was prepared from [3- (3-pyrrolidine-l-ylpropoxy) phenyl] acetonitrile (170 mg, 0.70 mmol). The crude compound is then further purified by column chromatography using 4 g Redicept ^® silica cartridge, eluting with 100: 0: 0 to 80: 20: 2, dichloromethane: methanol: 0.88 ammonia to give the desired product in 30% yield. Got it.

Formulation 109

3- {2-[(2R)-(tert-Butyl-dimethyl-silanyloxy) -2- (4-hydroxy-3-hydroxymethyl-phenyl) -ethylamino] -2-methyl-propyl}- N- (3-Pyrrolidin-1-yl-propyl) -benzamide

1- (3-aminopropyl) pyrrolidine (38 μl, 0.30 mmol) was added to 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (79 mg) in N, N-dimethylformamide (4 mL). , 0.41 mmol), 3- {2-[(2R) -2- (tert-butyldimethylsilanyloxy) -2- (4-hydroxy-3-hydroxymethyl-phenyl) ethylamino] -2-methyl Propyl} benzoic acid (formulation 37) (130 mg, 0.28 mol), 1-hydroxybenzotriazole hydrate (40 mg, 0.29 mmol) and N, N-diisopropylethylamine (210 μl, 1.49 mmol) were added. . The resulting solution was stirred for 9 days at room temperature and after 9 days TLC analysis showed that the starting material still remained. Then further 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (79 mg, 0.41 mmol), 1-hydroxybenzotriazole hydrate (40 mg, 0.29 mmol) and N, N-diiso Propylethylamine (210 μl, 1.49 mmol) was added and stirring continued for 2 days at room temperature. The solvent was removed in vacuo and the residue partitioned between ethyl acetate (25 mL) and saturated sodium hydrogen carbonate solution (20 mL). The organic solution was separated, dried (with sodium sulfate) and concentrated in vacuo to give an orange oil. The oil was purified by flash column chromatography on silica gel eluting with 100: 0: 0 to 75: 25: 2 dichloromethane: methanol: 0.88 ammonia to give 70 mg of the title compound as a glass in 43% yield.

Formulation 110

3- [2-({(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2- Methylpropyl] -N- [2- (4-chlorophenyl) ethyl] -N-ethylbenzamide

Using a method similar to that of Formulation 109, 3- {2-[(2R) -2- (tert-butyldimethylsilanyloxy) -2- (4-hydroxy-3-hydroxymethyl-phenyl) ethyl The title compound as a white solid was prepared in 43% yield from amino] -2-methylpropyl} benzoic acid (Formulation 37) and [2- (4-chloro-phenyl) -ethyl] -ethyl-amine hydrochloride (Formulation 81). .

Formulation 111

3- [2-({(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- [4-hydroxy-3- (hydroxyl methyl) phenyl] ethyl} amino) -2- Methylpropyl] -N- (2-pyrrolidin-1-ylethyl) benzamide

1- (2-aminoethyl) pyrrolidine (83 μl, 0.63 mmol) to 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (122 mg) of N, N-dimethylformamide (5 mL) , 0.63 mol), 3- {2-[(2R) -2- (tert-butyldimethylsilanyloxy) -2- (4-hydroxy-3-hydroxymethyl-phenyl) ethylamino] -2-methyl Propyl} benzoic acid (formulation 37) (200 mg, 0.42 mmol), added to a mixture of 1-hydroxybenzotriazole hydrate (63 mg, 0.47 mmol) and N, N-diisopropylethylamine (88 μl, 0.63 mmol) It was. The resulting solution was stirred for 18 hours at room temperature. The solvent was removed in vacuo and the residue partitioned between ethyl acetate (50 mL) and saturated sodium hydrogen carbonate solution (10 mL). The aqueous layer was separated and reextracted with dichloromethane (30 mL), the combined organic solutions were dried (with sodium sulfate) and concentrated in vacuo to afford a yellow oil. The oil was purified by flash column chromatography on silica gel eluting with 100: 0: 0 to 75: 25: 2 dichloromethane: methanol: 0.88 ammonia to afford the title compound as a pale yellow solid.

Formulations 112-138

The following compound which is a chemical formula shown below is 3- {2-[(2R) -2- (tert-butyldimethylsilanyloxy) -2- (4-hydroxy-3-hydroxymethyl-phenyl) ethylamino]- Prepared in a similar manner as described for Formulation 38 using 2-methylpropyl} benzoic acid (Formulation 37) and the appropriate amine starting material. The reaction was monitored via TLC analysis and stirred at room temperature for 18-72 hours.

Formulation 115: 2- (2-phenylsulfanyl-phenyl) -ethylamine is described in Collection of Czechoslovak Chemical Communications, 54 (7), 1995-2008; 1989].

Formulation 116: Concentrate the appropriate fractions in vacuo and elute with 100: 0 to 80: 20 ethyl acetate: pentane and then by column chromatography on amino silica gel eluting with 100: 0 to 80: 20 dichloromethane: methanol. It was further purified.

Formulation 139

Methyl 3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] benzoate

3- {2-[(2R) -2- (tert-butyldimethylsilanyloxy) -2- (4-hydroxy-3-hydroxymethyl-phenyl) ethylamino in methanol (20 mL) and water (5 mL) ] -2-methylpropyl} benzoic acid methyl ester (formulation 36), (4.0 g, 8.21 mmol) and ammonium fluoride (3.04 g, 82.Ommol) were heated at 40 ° C. for 18 hours. The reaction mixture was then concentrated in vacuo and the residue was purified by column chromatography on silica gel eluting with dichloromethane: methanol: 0.88 ammonia of 100: 0: 0 to 90: 10: 0.1 to give a white foam in 81% yield. 2.42 g of the title compound were obtained.

Formulation 140

3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] benzoic acid

3- {2- [2-hydroxy-2- (4-hydroxy-3-hydroxymethyl-phenyl) -ethylamino] -2-methyl-propyl} in tetrahydrofuran (20 mL) and water (20 mL) A mixture of benzoic acid methyl ester (Formulation 139) (2.35 g, 6.32 mmol) and lithium hydroxide (303 mg, 12.64 mmol) was stirred at room temperature for 3 days. The reaction mixture was then concentrated in vacuo and the residue diluted with water and acidified with 1M hydrochloric acid (12 mL). The mixture was stirred at rt for 2 h and then concentrated in vacuo. The crude residue was used for the next reaction without further purification.

Formulation 141

3- [3- (2-tert-butoxycarbonylamino-2-methyl-propyl) -phenyl] -acrylic acid benzyl ester

[2- (3-Bromophenyl) -1,1-dimethylethyl] carbamic acid tert-butylester (formulation 32), (2 g, 6.09 mmol), benzyl acrylate (2 g, 12.19) in acetonitrile (100 mL) , A mixture of palladium (II) acetate (204 mg, 0.91 mmol), tri-p-tolyl phosphite (556 mg, 1.83 mmol) and triethylamine (2.12 mL, 15.22 mmol) was heated to reflux for 48 hours. The reaction mixture was then concentrated in vacuo and the residue was purified by column chromatography on silica gel eluting with ethyl acetate: pentane to give 2.23 g of the title compound as a pale yellow oil in 90% yield.

Formulation 142

3- [3- (2-Amino-2-methyl-propyl) -phenyl] -acrylic acid benzyl ester

3- [3- (2-tert-butoxycarbonylamino-2-methyl-propyl) -phenyl] -acrylic acid benzyl ester (Formulation 141), (2.23 g, 5.45 mmol), and tri in dichloromethane (10 mL) The mixture of fluoroacetic acid (5 mL) was stirred at rt for 1 h. The mixture was then concentrated in vacuo and the residue was diluted with sodium hydrogen carbonate solution (10 mL) and extracted with ethyl acetate (3x20 mL). The combined organic solution was dried over magnesium sulfate and concentrated in vacuo to yield the title compound as a yellow oil in quantitative yield.

Formulation 143

Benzyl-3- (3- {2-[((2R) -2- [4- (benzoyloxy) -3- (hydroxymethyl) phenyl] -2-{[tert-butyl (dimethyl) silyl] oxy} Ethyl) amino] -2-methylpropyl} phenyl) acrylate

[2- (benzyloxy) -5-((1R) -2-bromo-1-{[tert-butyl (dimethyl) silyl] oxy} ethyl) phenyl] methanol (formulation 23) (800 mg, 1.77 mmol) and A mixture of 3- [3- (2-amino-2-methyl-propyl) -phenyl] -acrylic acid benzyl ester (formulation 142), (1.10 g, 3.55 mmol) was stirred at 90 ° C. for 18 hours. The reaction mixture was then cooled to rt, diluted with diethyl ether (40 mL) and stirred for 4 h. The resulting precipitate was filtered off, washed again with diethyl ether and the filtrate was concentrated in vacuo to give a brown oil. Purification of the oil by column chromatography on silica gel eluting with dichloromethane: methanol: 0.88 ammonia gave 300 mg of the title compound in 25% yield.

Formulation 144

3- {3- [2-({(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] phenyl} propanoic acid

Ammonium formate (139 mg, 2.20 mmol) and palladium (II) hydroxide (50 mg) were added to 3- (3- {2- [2- (4-benzyloxy-3-hydroxymethyl-phenyl) in ethanol (10 mL). ) -2- (tert-butyl-dimethyl-silanyloxy) -ethylamino] -2-methyl-propyl} -phenyl) -acrylic acid benzyl ester (Formulation 143), (300 mg, 0.44 mmol) and added to a mixture Was heated to reflux for 30 minutes. The reaction mixture was then cooled, filtered through Arbocel ^® and concentrated in vacuo to yield 200 mg of the title compound in 90% yield.

Formulation 145

3- {3- [2-({(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] phenyl} -N- (3,4-dichlorobenzyl) propanamide

Using a method similar to that of Formulation 38, 3- {3- [2-({(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- [4-hydroxy-3- The title compound as a clear oil was prepared in 64% yield from (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] phenyl} propanoic acid (Formulation 144) and 3,4-dichlorobenzylamine.

Formulation 146

[3- (2-Amino-2-methyl-propyl) -phenyl] -acetic acid methyl ester

Acetyl chloride (154.5 g, 1.97 mol) was dissolved in methanol (350 mL) {3- [2- (2-chloro-acetylamino) -2-methyl-propyl] -phenyl} -acetic acid (formulation 48), (20 g, 0.66 mol) solution and the mixture was heated to reflux for 18 hours. The reaction mixture was then concentrated in vacuo to give 154.5 g of the title compound as a brown oil in 87% yield.

Formulation 147

Methyl (3- {2-[((2R) -2- [4- (benzyloxy) -3- (hydroxymethyl) phenyl] -2-{[tert-butyl (dimethyl) silyl] oxy} ethyl) amino ] -2-methylpropyl} phenyl) acetate

[2- (benzyloxy) -5-((1R) -2-bromo-1-{[tert-butyl (dimethyl) silyl] oxy} ethyl) phenyl] methanol in dimethylsulfoxide (7.5 mL) (Formulation 23 ), (3.4 g, 7.5 mmol), [3- (2-amino-2-methylpropyl) phenyl] acetic acid (agent 146), (1.7 g, 7.5 mmol) and N, N-diisopropylethylamine (1.4 mL, 8 mmol) was stirred at 90 ° C. for 28 h. The reaction mixture was then cooled, diluted with ethyl acetate and washed with water. The organic solution was then dried over magnesium sulfate, concentrated in vacuo and the residue purified by column chromatography on silica gel eluting with ethyl acetate: pentane at 66: 33 to give 2.2 g of the title compound as a colorless oil in 50% yield. Got it.

Formulation 148

(3-{(2-[((2R) -2- [4- (benzyloxy) -3- (hydroxymethyl) phenyl] -2-{[tert-butyl (dimethyl) silyl] oxy} ethyl) amino ] -2-methylpropyl} phenyl) acetic acid

Lithium hydroxide solution (1M in water, 16.2 mL, 16.2 mmol) was dissolved in tetrahydrofuran (49 mL) and methanol (17 mL) in methyl (3- {2-[((2R) -2- [4- (benzyloxy)- 3- (hydroxymethyl) phenyl] -2-{[tert-butyl (dimethyl) silyl] oxy} ethyl) amino] -2-methylpropyl} phenyl) acetate (formulation 147), (4.80 g, 8.1 mmol) The solution was added and the mixture was stirred at rt for 18 h. The reaction mixture was then concentrated in vacuo and the residue diluted with water and acidified to pH 7 with 1M hydrochloric acid. The resulting precipitate was filtered and washed with water to give 4.37 g of the title compound as a pale yellow solid in 94% yield.

Formulation 149

2- (3- {2-[((2R) -2- [4- (benzyloxy) -3- (hydroxymethyl) phenyl] -2-{[tert-butyl (dimethyl) silyl] oxy} ethyl) Amino] -2-methylpropyl} phenyl) -N- (cycloheptylmethyl) acetamide

Using a method similar to that of Formulation 38, (3- {2-[((2R) -2- [4- (benzyloxy) -3- (hydroxymethyl) phenyl] -2-{[tert-butyl (Dimethyl) silyl] oxy} ethyl) amino] -2-methylpropyl} phenyl) acetic acid (Formulation 148) and cycloheptane methylamine gave the title compound as a white solid in 97% yield.

Formulation 150

N-1-adamantyl-2- (3- {2-[((2R) -2- [4- (benzyloxy) -3- (hydroxymethyl) phenyl] -2-{[tert-butyl ( Dimethyl) silyl] oxy} ethyl) amino] -2-methylpropyl} phenyl) acetamide

Using a method similar to that of Formulation 38, (3- {2-[((2R) -2- [4- (benzyloxy) -3- (hydroxymethyl) phenyl] -2-{[tert-butyl The title compound as a yellow oil was prepared in 71% yield from (dimethyl) silyl] oxy} ethyl) amino] -2-methylpropyl} phenyl) acetic acid (Formulation 148) and 1-adamantylamine.

Formulation 151

2- {3- [2-({(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] phenyl} -N- (cycloheptylmethyl) acetamide

Using a method similar to that of Formulation 144, 2- (3- {2-[((2R) -2- [4- (benzyloxy) -3- (hydroxymethyl) phenyl] -2-{[tert The title compound of yellow oil was prepared in 96% yield from -butyl (dimethyl) silyl] oxy} ethyl) amino] -2-methylpropyl} phenyl) -N- (cycloheptylmethyl) acetamide (Formulation 149).

Formulation 152

N-1-adamantyl-2- {3- [2-({(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- [4-hydroxy-3- (hydroxy Methyl) phenyl] ethyl} amino) -2-methylpropyl] phenyl} acetamide

Using a method similar to that of Formulation 144, N-1-adamantyl-2- (3- {2-[((2R) -2- [4- (benzyloxy) -3- (hydroxymethyl) The title compound as a white solid was prepared in 73% yield from phenyl] -2-{[tert-butyl (dimethyl) silyl] oxy} ethyl) amino] -2-methylpropyl} phenyl) acetamide (Formulation 150).

Formulation 153

Methyl {3- [2-({(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino)- 2-methylpropyl] phenyl} acetate

Using a method similar to that of Formulation 21, methyl (3- {2-[((2R) -2- [4- (benzyloxy) -3- (hydroxymethyl) phenyl] -2-{[tert- The title compound as a brown oil was prepared in 80% yield from butyl (dimethyl) silyl] oxy} ethyl) amino] -2-methylpropyl} phenyl) acetate (Formulation 147).

Formulation 154

{3- [2-((2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2- Methylpropyl] phenyl} acetic acid

Methyl {3- [2-({(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- [4-hydroxy-3- (hydroxymethyl)) in tetrahydrofuran (50 mL) A mixture of phenyl] ethyl} amino) -2-methylpropyl] phenyl} acetate (formulation 153), (5 g, 10 mmol) and lithium hydroxide (1M in water, 30 mL, 30 mmol) was stirred at room temperature for 48 hours. The reaction mixture was then acidified with 1M hydrochloric acid (30 mL), concentrated in vacuo, the residue treated with water and azeotropic distillation (x3) with methanol to give 4.1 g of the title compound as a white solid in 84% yield.

Formulation 155

2- {3- [2-({(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] phenyl} -N- (3-pyrrolidin-1-ylpropyl) acetamide

Using a method analogous to that of Formulation 38, {3- [2-({(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- [4-hydroxy-3- (hydroxy The title compound was prepared in 16% yield from oxymethyl) phenyl] ethyl} amino) -2-methylpropyl] phenyl} acetic acid (Formulation 154).

Formulation 156

N-benzyl-2- {3- [2-({(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- [4-hydroxy-3- (hydroxymethyl) phenyl] Ethyl} amino) -2-methylpropyl] phenyl} -N-methylacetamide

Using a method analogous to that of Formulation 38, {3- [2-({(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- [4-hydroxy-3- (hydroxy The title compound was prepared in 55% yield from oxymethyl) phenyl] ethyl} amino) -2-methylpropyl] phenyl} acetic acid (Formulation 154) and N-benzylmethylamine.

Formulation 157

3- [2-({(2R) -2- [tert-butyl (dimethyl) silyl] oxy} -2- [4-hydroxy-3- (hydroxyl methyl) phenyl] ethyl} amino) -2-methyl Propyl] -N- [2- (3-fluorophenyl) ethyl] benzamide

3- {2-[(2R) -2- (tert-Butyldimethylsilanyloxy) -2- (4-hydroxy-3-hydroxymethyl-phenyl) ethylamino] -2-methylpropyl} benzoic acid (Formulation 37) A mixture of (473 mg, 1 mmol) and O- (1H-benzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate (379 mg, 1 mmol) was added to N, To a solution of 3-fluorophenethylamine (139 mg, 1 mmol) in N-dimethylacetamide (6 mL) was added and the mixture was stirred at rt for 18 h. The solvent was removed in vacuo and the residue was redissolved in dichloromethane (100 mL) and washed with saturated sodium hydrogen carbonate solution (3x20 mL) and brine (10 mL). The organic solution was then dried over sodium sulfate, concentrated in vacuo and the residue purified by column chromatography on silica gel eluting with dichloromethane: methanol: 0.88 ammonia from 100: 0: 0 to 90: 10: 1. The appropriate fractions were then concentrated in vacuo and the residue was redissolved in ethyl acetate, washed with saturated sodium hydrogen carbonate solution, dried over sodium sulfate and concentrated in vacuo to give 343 mg of the title compound in 52% yield.

Formulation 158

3- [2-({(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2- Methylpropyl] -N- [2- (5-chloro-2-methoxyphenyl) ethyl] benzamide

3- {2-[(2R) -2- (tert-butyldimethylsilanyloxy) -2- (4-hydroxy-3-hydroxymethyl-phenyl) ethyl in N, N-dimethylacetamide (8 mL) Amino] -2-methylpropyl} benzoic acid (agent 37) (400 mg, 0.85 mmol), O- (1H-benzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluor A mixture of lophosphate (320 mg, 0.85 mmol), triethylamine (225 μl, 1.6 mmol) and 2- (5-chloro-2-methoxy-phenyl) -ethylamine (formulation 70), (64 mg, 0.85 mmol) Was stirred for 18 hours at room temperature. The solvent was removed in vacuo and the residue was partitioned between dichloromethane (4 mL) and saturated sodium hydrogen carbonate solution (1 mL). After drying the organic solution over magnesium sulfate, concentrated in vacuo and the residue was 90: 10: 1 to 80: 20: dichloromethane 2: MeOH: the ISCO companion ^® (Companion ^®) silica cartridge eluting with 0.88 ammonia Purification using gave the title compound in 22% yield.

Formulation 159

3- [2-({(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2- Methylpropyl] -N- [2- (3-ethoxyphenyl) ethyl] benzamide

Using a method similar to that of Formulation 158, 3- {2-[(2R) -2- (tert-butyldimethylsilanyloxy) -2- (4-hydroxy-3-hydroxymethyl-phenyl) ethyl The title compound was prepared in 67% yield from amino] -2-methylpropyl} benzoic acid (Formulation 37) and 3-ethoxyphenethylamine.

Formulation 160

3- [2-({(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2- Methylpropyl] -N- [2- (3-methoxyphenyl) ethyl] benzamide

Using a method similar to that of Formulation 158, 3- {2-[(2R) -2- (tert-butyldimethylsilanyloxy) -2- (4-hydroxy-3-hydroxymethyl-phenyl) ethyl The title compound was prepared in 98% yield from amino] -2-methylpropyl} benzoic acid (Formulation 37) and 3-methoxyphenethylamine.

Formulation 161

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

Lithium hydroxide solution (1M in water, 90 mL, 90 mmol) was dissolved in methanol (200 mL) methyl [3-((2R) -2-{[(1R) -1-phenyl-ethyl] -amino} -propyl) -phenyl] -To a solution of acetate hydrochloride (Formulation 26), (13.5 g, 43.5 mmol) and the mixture was stirred at rt for 18 h. 1M hydrochloric acid (90 mL) was then added to the reaction mixture and methanol was removed in vacuo. The resulting precipitate was filtered and washed with a mixture of water (20 mL) and 20:80 ethanol / diethyl ether to give 11.8 g of the title compound as a solid in 91% yield.

Formulation 162

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

1-adamantylamine (5.44 g, 36 mmol) and triethylamine (15 mL, 108 mol) were added to [3-((2R) -2-{[(1R) -1-phenylethyl] amino in dichloromethane (200 mL). } Propyl) phenyl] acetic acid (formulation 161), (10.7 g, 36 mmol) was added to the solution. Then 2-chloro-1,3-dimethylimidazolidinium hexafluorophosphate (10 g, 36 mmol) was added and the mixture was stirred at room temperature for 2 hours. The reaction mixture was washed with water and the organic solution was dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with 95: 5: 0.5 of dichloromethane: methanol: 0.88 ammonia to give 17.6 g of foam product in quantitative yield.

Formulation 163

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

Using a method similar to that of Formulation 25, N-1-adamantyl-2- [3-((2R) -2-{[(1R) -1-phenylethyl] amino} propyl) phenyl] acetamide The title compound was prepared in 92% yield from (Formulation 162).

Formulation 164

N-1-adamantyl-2- {3-[(2R) -2-({(2R) -2- [4- (benzyloxy) -3- (hydroxymethyl) phenyl] -2-hydroxy Ethyl} amino) propyl] phenyl} acetamide

[2- (benzyloxy) -5-((1R) -2-bromo-1-{[tert-butyl (dimethyl) silyl] oxy} ethyl) phenyl] methanol (formulation 23), (900 mg, 2 mmol) and A mixture of N-1-adamantyl-2- {3-[(2R) -2-aminopropyl] phenyl} acetamide (Formulation 163), (1.3 g, 4 mmol) was heated at 90 ° C. for 24 hours. The reaction mixture was then cooled to room temperature and the crude product was purified by column chromatography on silica gel eluting with 95: 5: 0.5 dichloromethane: methanol: 0.88 ammonia to yield 1.16 g of the title compound as a pale foam in 83% yield. Got it.

Abbreviation

TBDMS = tert-butyl (dimethyl) silyl

In vitro activity of the compound of formula (1)

By acting as an potent β2 agonist, the ability of the compound of formula (1) to mediate smooth muscle relaxation can be determined by measuring the effect of beta-2 adrenergic receptor stimulation on the electric field stimulation contraction of the guinea pig bronchial strip.

Guinea pig bronchus

Dunkin - a Hartley (Dunkin-Hartley) male guinea pigs (475-525 g) CO ₂ Blood loss from asphyxia and femoral artery was killed and bronchus was isolated. Four specimens were obtained from each animal and a 2.5 cm long bronchus was obtained starting dissection just below the larynx. The cartilage on the other side of the bronchial muscles was cut open to open the bronchial section, and then the transverse sections of 3-4 cartilage rings were cut. The resulting strip specimens were suspended in a 5 ml organ bath using cotton yarn tied through the upper and lower cartilage bands. Strips were in modified Krebs Ringer buffer (Sigma K0507) containing 3 μM indomethacin (Sigma I7378), 10 μM guanetidine (Sigma G8520) and 10 μM atenolol (Sigma A7655). No tension was applied for 20 minutes, equilibrated, heated at 37 ° C. and filled with 95% O ₂ /5% CO ₂ gas followed by the initial tension of 1 g. Samples were equilibrated for an additional 30-45 minutes during which time they were again tensioned twice (at 1 g) at 15 minute intervals. Changes in tension were recorded and monitored through a standard isotonic transducer connected to a data-collection system (designed conventionally in Pfizer). After the tension reached equilibrium, the tissues were subjected to electric field stimulation (EFS) using the following parameters: continued for 10 seconds every 2 minutes during the experiment, 0.1 ms pulse width, 10 Hz and nearly- Maximum voltage (25 volts). Single-phase contraction of smooth muscle was observed in cholinergic nerves after ganglion among bronchus and the height of single contraction was recorded. Except for the addition of the beta-2 agonist of the present invention, the Krebs Ringer buffer described above was constantly injected throughout the experiment using a peristaltic pump system (pump flow rate 7.5 ml / min), at which time the pump The reactor stopped while the volume of the bath was accumulating and returned to operation after reaching the maximum response during the wash period.

Experimental protocol for evaluation of efficacy and efficiency

After equilibration for EFS, the peristaltic pump stopped and the sample was primed with a single dose of 300 nM isoprenin (Sigma I5627) to generate the maximum response regarding the inhibition of the contractile EFS response. It was then washed with isoprenaline over 40 minutes. After priming and wash recovery, a standard curve for isoprenal was performed on all tissues by adding cumulative bolus to the bath with concentration increasing by half of the log (isoprelinin curve 1). The concentration range used was 1 ^e-9 to 1 ^e / 3 ^e-6 M. After the isoprenin curve was formed, the sample was washed again with isoprenin (internal control) or beta-2 agonist of the present invention for 40 minutes before the second curve was generated. Beta-2 agonist responses were expressed as percent inhibition of the EFS response. Data on beta-2 agonists were normalized by expressing inhibition as a percentage of the maximum inhibition induced by isoprenin in curve 1. EC ₅₀ values for the beta-2 agonists of the invention refer to the concentration of compound required to represent half the maximum effect. The data of the beta-2 agonists of the present invention were then expressed as relative potency against isoprenin, defined as the ratio (EC ₅₀ beta-2 agonist) / (EC ₅₀ isoprenin).

Confirmation of Beta-2 Mediated Functional Activity

The beta-2 agonist activity of the test compound was confirmed using the above protocol, except that before plotting the beta-2 agonist of the invention, the right side of the test compound dose response curve in the case of beta-2 mediated effects Samples were pre-incubated (for at least 45 minutes) with 300 nM ICI 118551 (selective β ₂ antagonist) indicating migration.

According to another alternative, the agonist efficacy of the β2 receptor of the compound of formula (1) can also be determined by measuring the concentration of the compound of the invention which is required to show half the maximum effect (EC ₅₀ ) on the β2 receptor.

Compound manufacturing

10 mM / 100% DMSO (dimethylsulfoxide) stock of the compound was diluted to the highest required dose in 4% DMSO. These highest doses are all used to generate a 10-point semi-log dilution curve, at 4% DMSO. Isoprelinin (Sigma, I-5627) was used as the standard for all experiments and control wells on each plate. Data are expressed in% isoprenal response.

Cell culture

CHO (Chinese) recombinantly expressing human β2 adrenergic receptor (from Kobilka et al., PNAS 84: 46-50, 1987) and Bouvier et al., Mol Pharmacol 33: 133-139 1988 CHOhβ2) Hamster Ovary cells were treated with 10% fetal bovine serum (Sigma, F4135, Lot 90K8404 Exp 09/04), 2 mM glutamine (Sigma, G7513), 500 μg / ml Geneticin (Sigma, G7034) and Growing in Dulbeccos MEM / NUT MIX F12 (Gibco, 21331-020) supplemented with 10 μg / ml puromycin (Sigma, P8833). The cells were seeded to obtain about 90% density for the test.

Method

25 μl / well of each compound dose was administered with cAMP-Flashplate® (NEN, SMP004B) with 1% DMSO as the basal control and 100 nM isoprenal as the max control. ). This was diluted 1: 2 by adding 25 μl / well PBS. Cells were treated with trypsin (0.25% sigma, T4049), washed with PBS (Zipco, 14040-174) and then resuspended in stimulation buffer (NEN, SMP004B) to give 1 × 10 ⁶ cells / ml CHOhB2. Compounds were incubated with 50 μl / well cells for 1 hour. Cells were then lysed by the addition of 100 μl / well detection buffer (NEN, SMP004B) containing 0.18 μCi / ml ¹²⁵ I-cAMP (NEN, NEX-130) and plates were incubated for an additional 2 hours at room temperature. The amount of ¹²⁵ I-cAMP bound to Flashplate® was quantified using Topcount NXT (Packard) with normal counting efficiency for 1 minute. Dose-response data was expressed in% of isoprenal activity and was fitted using four parameter sigmoidal fits.

It was found that the compound of formula (1) of the present invention tested showed β2 cAMP EC ₅₀ of less than 10 nM.

The following table shows the activity of the compounds of the present invention.

Claims (26)

A compound of formula (1) or a pharmaceutically acceptable salt thereof and / or an isomer, tautomer, solvate or isotopic variant thereof, as appropriate. <Formula (1)>

Wherein the (CH ₂ ) _n -C (= 0) Q ¹ group is in the meta or para position, R ¹ and R ² are independently selected from H and C ₁ -C ₄ alkyl, n is 0, 1 or 2, Q ¹

, ^* -NH-C ₁ -C ₄ alkyl, and ^* -N (R ⁸ ) -Q ² -A group, wherein -Q ² is a single bond or C ₁ -C ₄ alkylene, R ⁸ is H or C ₁ -C ₄ alkyl, -p is 1 or 2, -A is C ₃ -C ₁₀ Cycloalkyl (two or more carbon atoms of said cycloalkyl are optionally crosslinked by one or more carbon atoms, preferably one, two, three or four carbon atoms), O-phenyl-pyrazolyl, 5-10 member Heterocyclic groups (comprising 1, 2, 3 or 4 heteroatoms selected from O, S or N, optionally aromatic, optionally substituted with C ₁ -C ₄ alkyl or OC ₁ -C ₄ alkyl ), Or a group of the formula

R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are the same or different and H, C ₁ -C ₄ alkyl, OR ⁹ , SR ⁹ , SOR ⁹ , SO ₂ R ⁹ , halo, CN, CF ₃ , OCF ₃ , phenyl, O-phenyl, S-phenyl, SO ₂ -morpholinyl, O- (CH ₂ ) ₃ -pyrrolidinyl, COOR ⁹ , SO ₂ NR ⁹ R ^1O , CONR ⁹ R ¹⁰ , NR ⁹ Selected from R ¹⁰ and NHCOR ¹⁰ ; R ⁹ and R ¹⁰ are the same or different and are selected from H or C ₁ -C ₄ alkyl and * indicates the point of attachment to the carbonyl group, Provided that if n is 0, Q ¹ is not -NHCH ₃ and if n is 1 or 2: 1) Q ¹ is ^* -NH-C ₁ -C ₄ alkyl, or ^* -N (R ⁸ ) -Q ² -A, where A is C ₃ -C ₁₀ cycloalkyl, wherein at least two carbon atoms of said cycloalkyl are optionally crosslinked by at least one carbon atom, O-phenyl-pyrazolyl, 5 to 10 membered heterocyclic groups (comprising 1, 2, 3 or 4 heteroatoms selected from O, S or N, optionally aromatic, optionally C ₁ -C ₄ alkyl or OC _1- Substituted with C ₄ alkyl, said heterocyclic group being other than pyridyl), -Groups of the formula

In which R ³ To R ⁷ One is CN, SOR ⁹ , SO ₂ R ⁹ , phenyl, O-phenyl, S-phenyl, SO ₂ -morpholinyl or O- (CH ₂ ) ₃ -pyrrolidinyl); 2) If one of R ¹ and R ² is H, the other is not CH ₃ . The method of claim 1, Q ¹ is a group of the formula

Or ^* -N (R ⁸ ) -Q ² -A, Q ² is a single bond or C ₁ -C ₄ alkylene, R ⁸ is H, and A is

Is, R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are compounds as defined in claim 1. 3. The compound of claim 1, wherein Q ¹ is ^* —N (R ⁸ ) —Q ² —A, and A is a group of formula

R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are derived from H, C ₁ -C ₄ alkyl, OR ⁹ , SR ⁹ , Cl, F, CF ₃ , OCF ₃ , COOR ⁹ , SO ₂ NR ⁹ R ¹⁰ And at least two of R ³ to R ⁷ represent H, R ⁹ and R ¹⁰ are the same or different and are selected from H or C ₁ -C ₄ alkyl. 4. The compound of claim ³ , wherein R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are the same or different and H, CH ₃ , OH, OCH ₃ , SCH ₃ , OCH ₂ CH ₃ , Cl, F, CF ₃ , OCF ₃ , COOH, SO ₂ NH ₂ , wherein at least two of R ³ to R ⁷ represent H. The compound of claim 4, wherein R ³ , R ⁴ , R ⁵ , R ^6, and R ⁷ are the same or different, and H, CH ₃ , OH, OCH ₃ , SCH ₃ , OCH ₂ CH ₃ , Cl, F, CF _3. , OCF ₃ , COOH, SO ₂ NH ₂ , wherein at least three of R ³ to R ⁷ represent H. The compound of claim 1, wherein Q ¹ is ^* —N (R ⁸ ) —Q ² —A and A is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or adamantyl. The compound of any one of claims 1-6, wherein R ⁸ is H, methyl or ethyl. 8. The compound of claim 1, wherein Q ² is a bond, —CH ₂ —, — (CH ₂ ) ₂ —, — (CH ₂ ) ₃ —, —C (CH ₃ ) ₂ —CH ₂ -, -CH ₂ -C (CH ₃ ) _2- , and -CH (CH ₃ )-. The compound of claim 1 or 2, wherein Q ¹ is

Phosphorus compounds. The compound of claim 1, wherein n is 0 or 1. 11. The compound of any one of claims 1-10, wherein R ¹ is H and R ² is H or CH ₂ CH ₃ . The compound of claim 1, wherein R ¹ is CH ₃ and R ² is CH ₃ . The (R, R) -stereoisomer of the compound according to any one of claims 1 to 12. The compound of any one of claims 1-13, wherein the (CH ₂ ) _n -C (= 0) Q ¹ group is in the meta position. The method of claim 1, N-cycloheptyl-2- {3-[(2R) -2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) propyl ] Phenyl} acetamide; N- (cyclohexylmethyl) -2- {3-[(2R) -2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} Amino) propyl] phenyl} -N-methylacetamide; N-[(1S) -1-cyclohexylethyl] -2- {3-[(2R) -2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxy Methyl) phenyl] ethyl} amino) propyl] phenyl} acetamide; 2- {3-[(2R) -2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) propyl] phenyl} -N Isopropylacetamide; N-cyclopentyl-2- {3-[(2R) -2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) propyl ] Phenyl} acetamide; N- (cyclobutylmethyl) -2- {3-[(2R) -2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} Amino) propyl] phenyl} acetamide; N- (cyclopentylmethyl) -2- {3-[(2R) -2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} Amino) propyl] phenyl} acetamide; N-cyclohexyl-2- {3-[(2R) -2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) propyl ] Phenyl} acetamide; N-cyclobutyl-2- {3-[(2R) -2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) propyl ] Phenyl} acetamide; N- (cyclohexylmethyl) -2- {3-[(2R) -2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} Amino) propyl] phenyl} acetamide; N- (cyclopropylmethyl) -2- {3-[(2R) -2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} Amino) propyl] phenyl} acetamide; N- (cycloheptylmethyl) -2- {3-[(2R) -2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} Amino) propyl] phenyl} acetamide; N-1-adamantyl-2- {3-[(2R) -2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} Amino) propyl] phenyl} acetamide; N- (1-adamantylmethyl) -2- {3-[(2R) -2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl ] Ethyl} amino) propyl] phenyl} acetamide; N-2-adamantyl-2- {3-[(2R) -2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} Amino) propyl] phenyl} acetamide; N- (2-cyclohexylethyl) -2- {3-[(2R) -2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] Ethyl} amino) propyl] phenyl} -N-methylacetamide; N-cycloheptyl-2- {3-[(2R) -2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) propyl ] Phenyl} -N-methylacetamide; N-cyclohexyl-N-ethyl-2- {3-[(2R) -2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl } Amino) propyl] phenyl} acetamide; N- (2-cyclohexylethyl) -2- {3-[(2R) -2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] Ethyl} amino) propyl] phenyl} acetamide; N- (4-chlorobenzyl) -2- {3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino)- 2-methylpropyl] phenyl} acetamide; N- (2,6-dimethoxybenzyl) -2- {3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} Amino) -2-methylpropyl] phenyl} acetamide; N-benzyl-2- {3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] Phenyl} acetamide; 4-{(1R) -2-[(2- {3- [2- (3,4-dihydroisoquinolin-2 (1H) -yl) -2-oxoethyl] phenyl} -1,1-dimethyl Ethyl) amino] -1-hydroxyethyl} -2- (hydroxymethyl) phenol; N- [2-fluoro-5- (trifluoromethyl) benzyl] -2- {3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxy Oxymethyl) phenyl] ethyl} amino) -2-methylpropyl] phenyl} acetamide; N- (2,6-dichlorobenzyl) -2- {3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino ) -2-methylpropyl] phenyl} acetamide; 2- {3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] phenyl} -N -[2- (methylthio) benzyl] acetamide; N- (2,3-dimethylbenzyl) -2- {3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino ) -2-methylpropyl] phenyl} acetamide; 2- {3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] phenyl} -N -[3- (trifluoromethyl) benzyl] acetamide; N- [4-chloro-3- (trifluoromethyl) benzyl] -2- {3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxy Methyl) phenyl] ethyl} amino) -2-methylpropyl] phenyl} acetamide; N- [2-chloro-5- (trifluoromethyl) benzyl] -2- {3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxy Methyl) phenyl] ethyl} amino) -2-methylpropyl] phenyl} acetamide; N- [3,5-bis (trifluoromethyl) benzyl] -2- {3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl ) Phenyl] ethyl} amino) -2-methylpropyl] phenyl} acetamide; N- [3-fluoro-5- (trifluoromethyl) benzyl] -2- {3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxy Oxymethyl) phenyl] ethyl} amino) -2-methylpropyl] phenyl} acetamide; N- [2- (4-chlorophenyl) ethyl] -3- {2-[(2R) -2-hydroxy-2- (4-hydroxy-3-hydroxymethylphenyl) ethylamino] -2-methyl Propyl} benzamide; 3- {2-[(2R) -2-hydroxy-2- (4-hydroxy-3-hydroxymethylphenyl) -ethylamino] -2-methylpropyl} -N- [2- (4-methylphenyl) Ethyl] benzamide; 3- {2-[(2R) -2-hydroxy-2- (4-hydroxy-3-hydroxymethylphenyl) -ethylamino] -2-methyl-propyl} -N- [2- (4-tri Fluoromethylphenyl) ethyl] benzamide; N- [2- (3,4-dichlorophenyl) ethyl] -3- {2-[(2R) -2-hydroxy-2- (4-hydroxy-3-hydroxymethylphenyl) ethylamino] -2 -Methyl-propyl} -benzamide; N- [2- (3,4-dimethylphenyl) ethyl] -3- {2-[(2R) -2-hydroxy-2- (4-hydroxy-3-hydroxymethylphenyl) -ethylamino]- 2-methylpropyl} benzamide; 3- {2-[(2R) -2-hydroxy-2- (4-hydroxy-3-hydroxymethyl-phenyl) ethylamino] -2-methyl-propyl} -N- (2-naphthalene-2 -Yl-ethyl) benzamide; N- (1,1-dimethyl-2-phenylethyl) -3- {2-[(2R) -2-hydroxy-2- (4-hydroxy-3-hydroxymethylphenyl) -ethylamino] -2 -Methylpropyl} benzamide; 3- {2-[(2R) -2-hydroxy-2- (4-hydroxy-3-hydroxymethylphenyl) -ethylamino] -2-methylpropyl} -N- (2-methyl-2-phenyl Propyl) benzamide; N- (4-chlorobenzyl) -3- {2-[(2R) -2-hydroxy-2- (4-hydroxy-3-hydroxymethylphenyl) ethylamino] -2-methylpropyl} benzamide; N- (2,6-dimethoxybenzyl) -2- {3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} Amino) ethyl] phenyl} acetamide; N- (3,4-dichlorobenzyl) -2- {3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino ) Ethyl] phenyl} acetamide; N-benzyl-2- {3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) ethyl] phenyl} acet amides; N- (2,3-dihydro-1H-inden-2-yl) -2- {3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxy Oxymethyl) phenyl] ethyl} amino) ethyl] phenyl} acetamide; 2- {3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) ethyl] phenyl} -N- (2- Phenylethyl) acetamide; 2- {3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) ethyl] phenyl} -N- (3- Phenylpropyl) acetamide; N-benzyl-3-[(2R) -2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) propyl] benzamide; N- (3,4-dichlorobenzyl) -3-[(2R) -2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} Amino) propyl] benzamide; N- [2-fluoro-5- (trifluoromethyl) benzyl] -3-[(2R) -2-({(2R) -2-hydroxy-2- [4-hydroxy-3- ( Hydroxymethyl) phenyl] ethyl} amino) propyl] benzamide; N- (2,6-dimethoxybenzyl) -3-[(2R) -2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl } Amino) propyl] benzamide; N- [2- (4-chlorophenyl) ethyl] -3-[(2R) -2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl ] Ethyl} amino) propyl] benzamide; N- (2,3-dihydro-1H-inden-2-yl) -3-[(2R) -2-({(2R) -2-hydroxy-2- [4-hydroxy-3- ( Hydroxymethyl) phenyl] ethyl} amino) propyl] benzamide; 3-[(2R) -2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) propyl] -N- (2- Phenylethyl) benzamide; 3-[(2R) -2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) propyl] -N-[(1R) -1-phenylethyl] benzamide; 3-[(2R) -2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) propyl] -N- (3-phenyl Propyl) benzamide; 4-[(1R) -2-({(1R) -2- [3- (3,4-dihydroisoquinoline-2 (1H) -ylcarbonyl) phenyl] -1methylethyl} amino) -1 Hydroxyethyl] -2- (hydroxymethyl) phenol; N- (2,3-dimethylbenzyl) -3-[(2R) -2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} Amino) propyl] benzamide; N- (5,6-diethyl-2,3-dihydro-1H-inden-2-yl) -3-[(2R) -2-({(2R) -2-hydroxy-2- [4 -Hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) propyl] benzamide; N- (4-chlorobenzyl) -3-[(2R) -2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) Propyl] benzamide; 3-[(2R) -2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) propyl] -N-phenylbenzamide; N- [4- (aminosulfonyl) benzyl] -3-[(2R) -2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] Ethyl} amino) propyl] benzamide; N- [2- (3-fluorophenyl) ethyl] -3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} Amino) -2-methylpropyl] benzamide; 3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] -N- (2-py Rollidin-1-ylethyl) benzamide; N- [2- (2,6-dichlorophenyl) ethyl] -3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl } Amino) -2-methylpropyl] benzamide; N- (2,3-dihydro-1H-inden-2-ylmethyl) -3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl ) Phenyl] ethyl} amino) -2-methylpropyl] benzamide; N- (2- {4-[(butylamino) carbonyl] phenyl} ethyl) -3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxy Methyl) phenyl] ethyl} amino) -2-methylpropyl] benzamide; 3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] -N- {2- [ 2- (phenylthio) phenyl] ethyl} benzamide; N- (2-cyclohexylethyl) -3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2- Methylpropyl] benzamide; 3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] -N- (3-phenyl Propyl) benzamide; 3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] -N- (2-phenyl Ethyl) benzamide; N- [2- (3,6-dichloro-2-methylphenyl) ethyl] -3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) Phenyl] ethyl} amino) -2-methylpropyl] benzamide; N- [2- (5-chloro-2-methoxyphenyl) ethyl] -3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) Phenyl] ethyl} amino) -2-methylpropyl] benzamide; 3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] -N- [2- ( 3-methoxyphenyl) ethyl] benzamide; N- [2- (3-ethoxyphenyl) ethyl] -3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} Amino) -2-methylpropyl] benzamide; 3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] -N- {2- [ 4- (3-pyrrolidin-1-ylpropoxy) phenyl] ethyl} benzamide; 3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] -N- {2- [ 2- (3-pyrrolidin-1-ylpropoxy) phenyl] ethyl} benzamide; 3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] -N- {2- [ 3- (3-pyrrolidin-1-ylpropoxy) phenyl] ethyl} benzamide; N- [2- (4-chlorophenyl) ethyl] -N-ethyl-3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl ] Ethyl} amino) -2-methylpropyl] benzamide; 2- {3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] phenyl} -N -(3-pyrrolidin-1-ylpropyl) acetamide; N- (cycloheptylmethyl) -2- {3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2 -Methylpropyl] phenyl} acetamide; N-1-adamantyl-2- {3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2 -Methylpropyl] phenyl} acetamide; N-benzyl-2- {3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] Phenyl} -N-methylacetamide; N- [2- (4-fluorophenyl) ethyl] -3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} Amino) -2-methylpropyl] benzamide; 3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] -N- [2- ( 4-phenoxyphenyl) ethyl] benzamide; N- [2- (4-ethoxyphenyl) ethyl] -3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} Amino) -2-methylpropyl] benzamide; N- [2- (4-ethylphenyl) ethyl] -3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino ) -2-methylpropyl] benzamide; 3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] -N- [2- ( 6-methylpyridin-2-yl) ethyl] benzamide; 3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] -N- [2- ( 2-methoxyphenyl) ethyl] benzamide; Methyl 4-[({3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] benzoyl } Amino) methyl] benzoate; N- [4- (dimethylamino) benzyl] -3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino)- 2-methylpropyl] benzamide; N- {2- [3-fluoro-4- (trifluoromethyl) phenyl] ethyl} -3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (Hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] benzamide; N- [2- (3-fluoro-4-methylphenyl) ethyl] -3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl ] Ethyl} amino) -2-methylpropyl] benzamide; N- [2- (2,3-difluoro-4-methylphenyl) ethyl] -3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxy Methyl) phenyl] ethyl} amino) -2-methylpropyl] benzamide; 3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] -N- (2-mesh Tilethyl) benzamide; N- [2- (2,6-difluoro-3-methylphenyl) ethyl] -3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxy Methyl) phenyl] ethyl} amino) -2-methylpropyl] benzamide; N- [2- (6-chloro-2-fluoro-3-methylphenyl) ethyl] -3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxy Oxymethyl) phenyl] ethyl} amino) -2-methylpropyl] benzamide; N- [2- (2-chloro-6-fluoro-3-methylphenyl) ethyl] -3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxy Oxymethyl) phenyl] ethyl} amino) -2-methylpropyl] benzamide; N- [2- (5-fluoro-2-methylphenyl) ethyl] -3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl ] Ethyl} amino) -2-methylpropyl] benzamide; N- {2- [3-fluoro-5- (trifluoromethyl) phenyl] ethyl} -3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (Hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] benzamide; 3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] -N- {2- [ 2- (trifluoromethyl) phenyl] ethyl} benzamide; 3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] -N- [2- ( 2,4,5-trimethylphenyl) ethyl] benzamide; 3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] -N- (2-pyridine -2-ylethyl) benzamide; N- [2- (1H-benzimidazol-2-yl) ethyl] -3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) Phenyl] ethyl} amino) -2-methylpropyl] benzamide; 3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] -N- {2- [ 4- (morpholin-4-ylsulfonyl) phenyl] ethyl} benzamide; N- [2- (3-chloro-2-hydroxyphenyl) ethyl] -3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) Phenyl] ethyl} amino) -2-methylpropyl] benzamide; N- [4-fluoro-2- (trifluoromethyl) benzyl] -3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) Phenyl] ethyl} amino) -2-methylpropyl] benzamide; N- (3-chlorobenzyl) -3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methyl Propyl] benzamide; N- (2-chlorobenzyl) -3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methyl Propyl] benzamide; N- [2- (4,6-dimethylpyrimidin-2-yl) ethyl] -3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxy Methyl) phenyl] ethyl} amino) -2-methylpropyl] benzamide; 3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] -N- [2- ( 3-methylpyridin-2-yl) ethyl] benzamide; N- [2- (2-chlorophenyl) ethyl] -3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino ) -2-methylpropyl] benzamide; N- [2- (1-adamantyl) ethyl] -3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} Amino) -2-methylpropyl] benzamide; 3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] -N- [2- ( 1-naphthyl) ethyl] benzamide; N- [2- (2,6-dimethylphenyl) ethyl] -3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl } Amino) -2-methylpropyl] benzamide; 3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] -N- {2- [ 4- (methylthio) phenyl] ethyl} benzamide; N- [2- (5-chloro-2-fluorophenyl) ethyl] -3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) Phenyl] ethyl} amino) -2-methylpropyl] benzamide; N- [2- (2-chloro-4-fluorophenyl) ethyl] -3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) Phenyl] ethyl} amino) -2-methylpropyl] benzamide; 3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] -N- [2- ( 4-methoxy-2,5-dimethylphenyl) ethyl] benzamide; N- [2- (2,3-dichlorophenyl) ethyl] -3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl } Amino) -2-methylpropyl] benzamide; 3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] -N- [2- ( 4-methoxy-2,3-dimethylphenyl) ethyl] benzamide; N- (2-biphenyl-4-ylethyl) -3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino ) -2-methylpropyl] benzamide; N- [2- (2,4-dimethylphenyl) ethyl] -3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl } Amino) -2-methylpropyl] benzamide; N- [2- (2,3-dimethylphenyl} ethyl] -3- [2-({(2R} -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl } Amino) -2-methylpropyl] benzamide; 3- [2-({(2R} -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] -N- {2- [ 3- (trifluoromethyl) phenyl] ethyl} benzamide; N- [2- (4-chloro-2-fluorophenyl) ethyl] -3- [2-({(2R} -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) Phenyl] ethyl} amino) -2-methylpropyl] benzamide; N- (2,5-dimethylbenzyl) -3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2 -Methylpropyl] benzamide; N- (3,4-dichlorobenzyl) -3- {3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino ) -2-methylpropyl] phenyl} propanamide; 3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] -N- {2- [ 4- (trifluoromethoxy) phenyl] ethyl} benzamide; 3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] -N- [2- ( 4-hydroxyphenyl) -2-methylpropyl] benzamide; 3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl} phenyl] ethyl} amino) -2-methylpropyl] -N- [2- ( 4-hydroxy-3-methylphenyl) ethyl] benzamide; N- [2- (4-hydroxy-2,3-dimethylphenyl) ethyl] -3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxy Methyl) phenyl] ethyl} amino) -2-methylpropyl] benzamide; N- [2- (4-hydroxy-2,5-dimethylphenyl) ethyl] -3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxy Methyl) phenyl] ethyl} amino) -2-methylpropyl] benzamide; N- (3,4-dichlorobenzyl) -2- {3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} Amino) -2-methylpropyl] phenyl} acetamide; N- (3,5-dichlorobenzyl) -2- {3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino ) -2-methylpropyl] phenyl} acetamide; 2- {3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] phenyl} -N -(Pyridin-2-ylmethyl) acetamide; N-ethyl-3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] -N- (3-phenylpropyl) benzamide; 3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] -N- [3- ( 4-hydroxyphenyl) propyl] benzamide; 3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] -N- [2- ( 3-methylphenyl) ethyl] benzamide; 3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] -N- [2- ( 6-methoxypyridin-3-yl) ethyl] benzamide; 3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] -N- [3- ( 3-methoxyphenyl) propyl] benzamide; N- [3- (4-chlorophenyl) propyl] -3- {2-[(2R) -2-hydroxy-2- (4-hydroxy-3-hydroxymethylphenyl) ethylamino] -2-methyl Propyl} benzamide; 3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] -N- {2- [ 4- (1H-pyrazol-1-yl) phenoxy] ethyl} benzamide; N- [2- (3,4-difluorophenyl) ethyl] -3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl ] Ethyl} amino) -2-methylpropyl] benzamide; 3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] -N- (2-quinoline -5-ylethyl) benzamide; And, N- [3- (2-ethyl-2,3-dihydro-1-benzofuran-5-yl) propyl] -3- [2-({(2R) -2-hydroxy-2- [4- Hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] benzamide. The formula (1) according to any one of claims 1 to 15, comprising coupling an amine of formula (3), (3 '), or (3' ') with an acid of formula (2) To produce a compound or a pharmaceutically acceptable salt or derivative thereof. <Formula (2)>

<Formula (3)> N (R ⁸ ) -Q ² -A <Formula (3 ')>

<Formula (3 ")>

Wherein R ⁸ , Q ² , A, p and R ³ to R ⁶ are as defined above for the compound of formula (1). A pharmaceutical composition comprising at least an effective amount of a compound of formula (1) according to any one of claims 1 to 15 or a pharmaceutically acceptable salt or derivative thereof. The pharmaceutical composition according to any one of claims 1 to 15, further comprising one or more pharmaceutically acceptable excipients and / or additives. A compound of formula (1) according to any one of claims 1 to 15, or a pharmaceutically acceptable salt, derived form or composition thereof, for use as a medicament. A compound of formula (1) according to any one of claims 1 to 15 or a pharmaceutically acceptable salt, inducible form thereof, or the like for use in treating a disease, disorder, and condition in which a β2 receptor is involved. Composition. -Asthma (regardless of type, etiology, or pathogenesis), especially atopic asthma, nonatopic asthma, allergic asthma, atopic bronchial IgE-mediated asthma, bronchial asthma, native asthma, true asthma, endogenous asthma caused by pathophysiological disorders Exogenous asthma caused by environmental factors, unexplained or inflexible native asthma, viatopic asthma, bronchial asthma, aerobic asthma, exercise induced asthma, allergen induced asthma, cold induced asthma, occupational asthma, bacteria, fungi, protozoa Or asthma, a member selected from the group consisting of infectious asthma, nonallergic asthma, early asthma, infant wheezing syndrome and bronchiolitis caused by viral infection, Chronic or acute bronchial contraction, chronic bronchitis, small respiratory tract obstruction, and embolism, COPD including obstructive or inflammatory airway disease (regardless of type, etiology, or pathogenesis), especially chronic eosinophilic pneumonia, chronic obstructive pulmonary disease (COPD), chronic bronchitis, pulmonary pneumothorax, or COPD that is not associated with COPD Obstructive or inflammatory airway disease, a member selected from the group consisting of COPD characterized by irreversible progressive airway obstruction, adult respiratory distress syndrome (ARDS), airway hyperactivity exacerbated by other drug therapy, and airway disease associated with pulmonary hypertension , Bronchitis (regardless of type, etiology, or pathogenesis), especially acute bronchitis, acute laryngeal bronchitis, arachid bronchitis, catarrhal bronchitis, croup bronchitis, dry bronchitis, infectious asthmatic bronchitis, wet bronchitis, staphylococcus or streptococcus Bronchitis, which is a member selected from the group consisting of cous bronchitis and alveolar bronchitis, -Acute lung injury, Bronchiectasis (regardless of type, etiology, or pathogenesis), particularly members selected from the group consisting of cylindrical bronchiectasis, cystic bronchiectasis, spindle bronchiectasis, capillary bronchiectasis, cystic bronchiectasis, dry bronchiectasis and vesicular bronchiectasis A compound of formula (1) according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, for use in treating diseases, disorders, and conditions selected from the group consisting of phosphorus bronchiectasis, Inducible form or composition. Use of a compound of formula (1) according to any one of claims 1 to 15, or a pharmaceutically acceptable salt, derived form or composition thereof, for the manufacture of a drug having β2 agonist activity. A compound of formula (1) according to any one of claims 1 to 15, or a pharmaceutically acceptable thereof, for the manufacture of a medicament for the treatment of diseases, disorders, and conditions selected from the group as described in claim 21. The use of salts, solvates or compositions. A β2 agonist comprising treating a mammal, including a human, with an effective amount of a compound of formula (1) according to any one of claims 1 to 15, or a pharmaceutically acceptable salt, inducible form or composition thereof. To treat said mammal. The method of claim 24, wherein the disease, disorder or condition is selected from the group as described in claim 21. A compound according to any one of claims 1 to 15 (a) a 5-lipoxygenase (5-LO) inhibitor or a 5-lipoxygenase activating protein (FLAP) antagonist, (b) leukotriene antagonists (LTRA) such as LTB ₄ , LTC ₄ , LTD ₄ , and LTE ₄ , (c) histamine receptor antagonists such as H1 and H3 antagonists, (d) α ₁ -and α ₂ -adrenoreceptor agonists vasoconstrictors sympathomimetic agents, for decongestant use, (e) muscarinic M3 receptor antagonists or anticholinergic agents, (f) PDE inhibitors, such as PDE3, PDE4 and PDE5 inhibitors, (g) theophylline, (h) sodium chromoglycate, (i) non-selective and selective COX inhibitors COX-1 or COX-2 inhibitors (NSAIDs), (j) oral and inhaled glucocorticosteroids such as DAGR (dissociated agonists of corticosteroid receptors), (k) monoclonal antibodies active against endogenous inflammatory entities, (l) anti-tumor necrosis factor (anti-TNF-α) agents, (m) adhesion molecule inhibitors, such as VLA-4 antagonists, (n) kinin-B ₁ -and B ₂ -receptor antagonists, (o) immunosuppressants (p) matrix metalloprotease (MMP) inhibitors, (q) tachykinin NK ₁ , NK ₂ and NK ₃ receptor antagonists, (r) elastase inhibitors, (s) adenosine A2a receptor agonists, (t) urokinase inhibitors, (u) compounds acting on dopamine receptors, such as D2 agonists, (v) NFκβ pathway modulators such as IKK inhibitors, (w) cytokine signaling pathway modulators such as p38 MAP kinase, syk kinase or JAK kinase inhibitors, (x) drugs that can be classified as mucolytic or antitussives, (y) antibiotics, (z) HDAC inhibitors, and (aa) Combination of therapeutic agents selected from PI3 kinase inhibitors.