JP4054366B2 - Compounds useful for the treatment of diseases - Google Patents

Description

  The present invention has the general formula:

(Wherein R ¹ , R ² , n and Q ¹ have the meanings shown below)
Β2 agonists, as well as methods for the preparation of such derivatives, intermediates used for their preparation, compositions containing them and their use.

  The adrenergic receptor is a member of the large G protein-coupled receptor superfamily. The adrenergic receptor subfamily is itself divided into α and β subfamilies, with the β subfamily consisting of at least three receptor subtypes: β1, β2, and β3. These receptors exhibit differential expression patterns in tissues of various mammalian systems and organs. β2 adrenergic (β2) receptors are expressed primarily in smooth muscle cells (eg, vascular, tracheal, uterine or intestinal smooth muscle), whereas β3 adrenergic receptors are expressed primarily in adipose tissue (and thus β3 agonists may have the potential to be useful in the treatment of obesity and diabetes), and β1 adrenergic receptors are expressed primarily in heart tissue (thus β1 agonists are mainly used as inotropic agents).

  The pathophysiology and treatment of airway disease has been extensively documented (referenced by Barnes, PJ Chest, 1997, 111: 2, pp 17S-26S and Bryan, SA et al, Expert Opinion on investigational drugs, 2000 9: 1, pp 25-42), so only a brief overview is included herein to provide some background information.

  Glucocorticosteroids, anti-leukotrienes, theophylline, chromones, anticholinergics and β2 agonists are currently used to treat allergic and non-allergic airway diseases such as asthma and chronic obstructive airway disease (COPD) Make up a class of drugs. Treatment guidelines for these diseases include inhaled β2 agonists that act both short-term and long-term. Β2 agonists that act in the short term, that is, act immediately, are used for “emergency” bronchodilation, while the long acting form provides sustained relief and is used as maintenance therapy.

  Bronchodilation is mediated through the activation of β2 adrenergic receptors expressed on airway smooth muscle cells, resulting in relaxation and thereby bronchodilation. Thus, as a functional antagonist, β2 agonists can prevent and reverse the effects of all bronchoconstrictors, including leukotriene D4 (LTD4), acetylcholine, bradykinin, prostaglandins, histamine and endothelin. Since β2 receptors are very widely distributed in the respiratory tract, β2 agonists may also affect other types of cells that play a role in asthma. For example, it has been reported that β2 agonists are thought to stabilize mast cells. Inhibiting the release of bronchoconstrictors appears to be the reason why β2 agonists block bronchoconstriction induced by allergens, exercise and cold. Furthermore, β2 agonists inhibit cholinergic neurotransmission in the human respiratory tract, which can lead to reduced cholinergic reflex bronchoconstriction.

  In addition to the airways, β2 adrenergic receptors are also expressed in other organs and tissues, so β2 agonists, such as the agents described in the present invention, can be used in other diseases, such as but not limited to diseases of the nervous system, For the treatment of preterm birth, congestive heart failure, depression, inflammatory and allergic skin diseases, psoriasis, proliferative skin diseases, glaucoma, and conditions where it is advantageous to reduce gastric hyperacidity, especially gastric and peptic ulceration It is also confirmed that it may be applied.

  However, many β2 agonists have side effects (muscle tremors) mainly due to their low selectivity, or effects on β2 adrenergic receptors expressed outside the respiratory tract, caused by high systemic exposure. Their use is limited because of their tachycardia, palpitations and restlessness. Therefore, there is a need for improved drugs of this class.

  Thus, there remains a need for new β2 agonists that have suitable pharmaceutical aspects, for example for potency, selectivity, action properties and / or duration of pharmacodynamic properties. In this context, the present invention relates to novel β2 agonists.

  EP0654534 B1 and EP0939134 B1 are compounds of the formula (XI):

The preparation method is disclosed. These compounds are disclosed as anti-obesity and anti-diabetic agents with specific β3 activity.
US 5,561,142 is the following formula

EP 0236624 is a compound of the following formula:

Which have anti-obesity and / or anti-hyperglycemic activity combined with good selectivity without cardiac side effects.

  The present invention relates to a compound of the general formula (1):

Wherein the group of (CH ₂ ) _n —C (═O) Q ¹ takes 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 and -Q ¹ below:

A group selected from 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, and -A is a C ₃ -C ₁₀ cycloalkyl, by two one or more carbon atoms carbon atoms or more than it optionally of the cycloalkyl, Preferably bridged by 1, 2, 3 or 4 carbon atoms, O-phenyl-pyrazolyl, 5- to 10-membered heterocyclic group, optionally aromatic, O, S or N A C ₁ -C ₄ alkyl or O-C ₁ -C ₄ alkyl, or a group of formula

Is replaced with
^{-R 3, R 4, R 5} , R 6 and ^{R 7} have the same or different, _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,
Selected from COOR ⁹ , SO ₂ NR ⁹ R ¹⁰ , CONR ⁹ R ¹⁰ , NR ⁹ 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 ^* represents a bond to a carbonyl group;
Or, where appropriate, for pharmaceutically acceptable salts and / or isomers thereof, tautomers, solvates or isotopic variations thereof,
However, when n is 0, Q ¹ is not —NHCH ₃ , and when n is 1 or 2, 1) Q ¹ is ^* —NH—C ₁ -C ₄ alkyl, or ^* —N ( R ⁸⁾ a ^-Q 2 -A, a wherein a is -C ₃ -C ₁₀ cycloalkyl, 2 carbon atoms or more of the cycloalkyl of more than one or optionally carbon Bridged by atoms,
-O-phenyl-pyrazolyl,
A 5- to 10-membered heterocyclic group, optionally aromatic, including 1, 2, 3 or 4 heteroatoms selected from O, S or N, optionally C ₁ -C Substituted with ₄ alkyl or O-C ₁ -C ₄ alkyl, and the heterocyclic group is other than pyridyl,
-Group of formula

Wherein one of R ³ to R ⁷ is CN, SOR ⁹ , SO ₂ R ⁹ , phenyl, O-phenyl, S-phenyl, SO ₂ -morpholinyl, or O— (CH ₂ ) ₃ — Pyrrolidinyl and / or
2) When ^one of R ¹ and R ² is H, the other is not CH ₃ .

  The compounds of formula (1) are β2 receptor agonists, are particularly useful for the treatment of diseases and / or conditions mediated by β2, and show good efficacy, especially when administered via the inhalation route. It was discovered this time.

  The term “potential” in the present invention means that formula (1) indicates the potency of an agonist for the β2 receptor, which is less than 10 nM as measured by the cell-based assay described herein. To do.

  Preferably the compounds of the present invention are selective agonists of the β2 receptor. Preferably, the compounds of the present invention exhibit agonistic potency at the β2 receptor, which is at least about 100 times higher than the value for β3 receptor and at least about 500 times higher than the value for β1 receptor.

In the general formula (1) herein above, C ₁ -C ₄ alkyl and C ₁ -C ₄ alkylene are straight or branched groups containing 1, 2, 3 or 4 carbon atoms. Show. This also means that when these groups have substituents or are present as substituents of other radicals, for example O- (C ₁ -C ₄ ) alkyl radicals, S- (C ₁ -C ₄ ) alkyls. Radicals, etc. . . Also applies. Examples of suitable (C ₁ -C ₄ ) alkyl radicals are methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl. . . It is. Examples of suitable O- (C ₁ -C ₄ ) alkyl radicals are methoxy, ethoxy, n-propyloxy, iso-propyloxy, n-butyloxy, iso-butyloxy, sec-butyloxy, tert-butyloxy. . . It is.

More of or two carbon atoms, C ₃ -C ₁₀ cycloalkyl which are crosslinked with optionally one or more carbon atoms include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, bicyclo [3.1.1] heptane, bicyclo [2.2.1] heptane, bicyclo [2.2.2] octane. Preferred cycloalkyl groups are cyclohexyl and adamantyl.

  Examples of 5- to 10-membered heterocyclic groups which are optionally aromatic and include 1, 2, 3 or 4 heteroatoms independently selected from O, S or N are morpholinyl, pyrrolidinyl, piperidyl, Piperazinyl, thienyl, isothiazolyl, oxazolyl, pyridyl, pyrimidyl, oxazolyl, isoxazolyl, thiazolyl, furanyl, imidazolyl, pyrazolyl, pyrrolyl, pyridazinyl, pyrazinyl, triazolyl, tetraazolyl, oxadiazolyl, triazinyl, indolyl, quinolyl, oxafurolyl, benzofuranyl, benzofuranyl Phthalazinyl, benzothiazolyl, benzoxazolyl, benzisothiazolyl, benzisoxazolyl, benzimidazolyl, indazolyl, and benzotriazolyl.

Preferred heterocyclic groups are pyrrolidinyl, pyridyl, pyrimidyl, quinolyl, isoquinolyl, benzoimidazolyl, and benzofuranyl.
Preferably said heterocyclic group contains 1 or 2 heteroatoms selected from O, S or N. More preferably, said heterocyclic group contains 1 or 2 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, the free bond of the phenyl group, for example the following structural formula

Means that the phenyl can be substituted at the meta or para position.
Compound of formula (1)

Can be prepared using conventional methods, for example, by the methods described below, wherein Q ¹ , Q ² , A and n are as defined above for compounds of formula (1) unless otherwise noted. As defined.

  The amide derivative of formula (1) is an acid of formula (2):

An amine of the formula

Wherein R ⁸ , Q ² , A, p and R ³ to R ⁶ are as described above for the compound of formula (1)
May be prepared by coupling with.

  Coupling generally involves adding an excess of the amine as an acid acceptor to a conventional coupling agent (eg 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, or N, N′-dicyclohexane). Hexylcarbodiimide), optionally in the presence of a catalyst (eg 1-hydroxybenzotriazole hydrate or 1-hydroxy-7-azabenzotriazole) and optionally a tertiary amine base (eg N-methylmorpholine). , Triethylamine or diisopropylethylamine). The reaction is carried out in a suitable solvent such as pyridine, dimethylformamide, tetrahydrofuran, dimethyl sulfoxide, dichloromethane or ethyl acetate at a temperature comprised between 10 ° C. and 40 ° C. (room temperature) for 1-24 hours. You can.

  The amine may be obtained from commercial sources or prepared from commercially available materials by conventional methods well known to those skilled in the art (eg reduction, oxidation, alkylation, protection, deprotection, etc.). Either.

  The acid of formula (2) is the corresponding ester of formula (4):

Wherein Ra is a suitable acid protecting group, preferably a (C ₁ -C ₄ ) alkyl group including but not limited to methyl and ethyl)
From the ester may be prepared without modification of the rest of the molecule according to any method known to those skilled in the art for preparing acids from esters. For example, the ester can be prepared with an aqueous acid or base (eg hydrochloric acid, potassium hydroxide, sodium hydroxide or lithium hydroxide), optionally in one or a mixture of solvents (eg water, 1,4-dioxane). , Tetrahydrofuran / water) at a temperature comprised between 20 ° C. and 100 ° C. for 1 to 40 hours.

  The ester of formula (4) is an amine of formula (5):

(Wherein Ra and n are as defined above)
A bromide of formula (6):

May be prepared by reacting with.
In a typical method, the amine of formula (5) is combined with the bromide of formula (6), optionally in one or a mixture of solvents (eg dimethyl sulfoxide, toluene, N, N-dimethylformamide, acetonitrile). In the presence of a suitable base (eg triethylamine, diisopropylethylamine, potassium carbonate) at a temperature comprised between 80 ° C. and 120 ° C. for 12 to 48 hours.

  The bromide of formula (6) is an ester of formula (7):

From the ester according to any method known to those skilled in the art for preparing alcohols without modification of the rest of the molecule.
In a typical method, the ester of formula (7) is reduced with borane-dimethyl sulfide complex in tetrahydrofuran at reflux for 2 hours.

  The alcohol of formula (7) may be prepared as either (R) or (S) enantiomer according to methods well described in the literature (Tetrahedron Letters 1994, 35 (50), 9375).

  The amine of formula (5) is the corresponding protected amine of formula (8):

[Wherein Ra and n are as defined above, Rb and Rc represent any suitable substituent such that HNRbRc is a chiral amine (eg Rb may be hydrogen, Rc may be α-methyl May be benzyl)]
May be prepared as either enantiomer of (R) or (S), provided that the bond between N and Rb, and the bond between N and Rc are standard methods, such as textbooks, for cleaving the nitrogen protecting group. TW GREENE, Protective Groups in Organic Synthesis, A. Wiley-Interscience Publication, 1981 can be easily cleaved to give the free amine of formula (5).

  The amine of formula (8) is an amine of formula HNRbRc, a ketone of formula (9):

(Wherein Ra, Rb, Rc and n are as defined above)
May be prepared as a single diastereomer by reaction with
In a typical method, a chiral intermediate is obtained from the reaction of a ketone of formula (9) with an amine of formula HNRbRc, which in turn is converted to a suitable reducing agent (eg, sodium cyanoborohydride of formula NaCNBH ₃ , or Reduction with the formula Na (OAc) ₃ BH sodium triacetoxyborohydride), optionally in the presence of a desiccant (eg molecular sieve, magnesium sulfate) and optionally in the presence of an acid catalyst (eg acetic acid). The amine of formula (8) is obtained as a mixture of diastereomers. The reaction is generally carried out in a solvent such as tetrahydrofuran or dichloromethane at a temperature comprised between 20 ° C. and 80 ° C. for 3 to 72 hours. The resulting product is then converted to the hydrochloride salt and selectively crystallized from a suitable solvent or mixture of solvents (eg, isopropanol, ethanol, methanol, diisopropyl ether, or diisopropyl ether / methanol) Formula (8) is obtained as a single diastereomer.

  The ketone of formula (9) (where n = 1) is an aryl halide of formula (10) via palladium:

(Wherein Ra is as defined above, and Hal represents a halogen atom including but not limited to bromo and iodo)
May be prepared by coupling with enolate or enolate equivalents.

In a typical method, an aryl halide of formula (10) is prepared by isopropenyl acetate together with tri-n-butyltin methoxide of formula Bu ₃ SnOMe with a suitable palladium catalyst (formula Pd (OAc) ₂ / P (o- Tol) in the presence of ₃ palladium acetate / tri-ortho-tolylphosphine) and reacting with tin enolate produced in-situ by treatment in a non-polar solvent (eg toluene, benzene, hexane). Preferably the reaction is carried out at a temperature comprised between 80 ° C. and 110 ° C. for 6 to 16 hours.

  The aryl halide of formula (10) is a corresponding acid of formula (11):

(In the formula, Hal is as defined above)
Can be obtained without modification of the rest of the molecule according to any method known to those skilled in the art for preparing esters from acids.

  In a typical process, the acid of formula (11) is combined with an alcohol solvent of formula RaOH (wherein Ra is as defined above) together with a temperature between 10 ° C. and 40 ° C. At room temperature) for 8 to 16 hours.

The acid of formula (11) is a commercial product.
The amine of formula (5), where R ¹ and R ² are both the same C ₁ -C ₄ alkyl, has the following scheme:

(Wherein R ¹ , R ² and R ³ are as defined above)
May be prepared according to
In an exemplary method, an ester of formula (12) is reacted with an “activated” alkyl (an organometallic alkyl such as R ² MgBr, R ² MgCl, or R ² Li) to produce the method described above. Used to obtain the corresponding tertiary alcohol of formula (13).

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

Alternatively, an amine of formula (5) where R ¹ and R ² are both the same C ₁ -C ₄ alkyl and n = 0 can be represented by the following scheme:

(Wherein R ¹ , R ² and Ra are as defined above)
May be prepared according to
In an exemplary method, the ester of formula (14) is reacted with an “activated” alkyl (an organometallic alkyl such as R ² MgBr, R ² MgCl, or R ² Li) to produce the method described above. To obtain the corresponding tertiary alcohol of formula (15).

  The tertiary alcohol of formula (15) is then treated with an alkyl nitrile (eg acetonitrile, chloroacetonitrile) in the presence of an acid (eg sulfuric acid, acetic acid) to give the protected intermediate, which in turn is The intermediate is cleaved using standard methods for cleaving nitrogen protecting groups, such as those described in textbooks, to give bromoamine (16).

  The resulting bromoamine (16) is combined with a suitable palladium catalyst (eg, [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II)) as a solvent in a carbon monoxide atmosphere as a solvent such as MeOH, EtOH, EtOH. ) At high temperature (100 ° C.) and high pressure (100 psi) to give the ester of formula (5).

  The ketone of formula (9) where n = 2 is an alkene of formula (17):

May be prepared by reduction of
In a typical method, a solution of an olefin of formula (17) in a suitable solvent (eg methanol, ethanol, ethyl acetate) is treated with a palladium catalyst (eg 10% palladium / carbon) and optionally under a hydrogen atmosphere. Stir at high pressure (eg 60 psi) at a temperature between room temperature and 60 ° C. for 8-24 hours.

  The alkene of formula (17) is an aryl halide of formula (18):

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

The ketone of formula (18) is a commercial product.
The amine of formula (5) in which R ¹ and R ² are both H and n is 1 has the following scheme:

(Wherein R ¹ , R ² and Ra are as defined above)
May be prepared according to
In a typical process, the acid of formula (19) is preferably reduced to the corresponding alcohol (20) in the presence of an ester. This reaction may be performed by forming an acyl imidazole or may be mixed with an anhydride and then reduced with sodium borohydride or another suitable reducing agent.

  The primary alcohol of formula (20) is then converted to a leaving group such as mesylate, tosylate, bromide or iodide and replaced with a suitable amine nucleophile. Preferred nucleophiles are azide ions that can then be reduced to primary amines via hydrogenation or triphenylphosphine. Other nucleophiles can include ammonia or alkylamines such as benzylamine or alkylamines, after which the alkyl group is cleaved to give the amine.

  For some of the steps in the process for preparing compounds of formula (1) described hereinabove, protecting a potentially reactive functional group that is not desired to react and thus cleaving the protecting group May be required. In such cases, protected radicals that do not cause any chemical reaction can be used. Specific methods of protection and deprotection, for example those described by TW GREENE (Protective Groups in Organic Synthesis, A. Wiley-Interscience Publication, 1981) or by PJ Kocienski (Protecting groups, Georg Thieme Verlag, 1994) Can be used.

Alternatively, compounds of general formula (1) can also be prepared according to the following scheme:
In which R ¹ , R ² , Ra, Rb, Rc, n and Q ₁ are as defined above.

PG is a suitable bulky hydroxyl protecting group, preferably TBDMS.
PG ′ is a suitable hydroxyl protecting group such as benzyl.
In a typical method, the acid of formula (21) is obtained by hydrolysis of the ester of formula (8). This reaction may be carried out with an aqueous acid or base (eg hydrochloric acid, potassium hydroxide, sodium hydroxide or lithium hydroxide), optionally in a solvent or solvent mixture (eg water, 1,4-dioxane, tetrahydrofuran / water). Achieving by treating for 1 to 40 hours at a temperature including between 20 ° C. and 100 ° C. in the presence.

  Amides of formula (22) are prepared by coupling an acid of formula (21) with an appropriate amine of formula (3), (3 ′) or (3 ″). With an excess of the amine as a body, conventional coupling agents (eg 2-chloro-1,3-dimethylimidazolidinum hexafluorophosphate, 1- (3-dimethylaminopropyl) -3-ethyl Carbodiimide hydrochloride, or N, N′-dicyclohexylcarbodiimide), optionally in the presence of a catalyst (eg 1-hydroxybenzotriazole hydrate or 1-hydroxy-7-azabenzotriazole) and desired A tertiary amine base such as N-methylmorpholine, triethylamine or N, N-diisopropyl The reaction is carried out in a suitable solvent such as pyridine, N, N-dimethylformamide, tetrahydrofuran, dimethyl sulfoxide, dichloromethane or ethyl acetate at a temperature comprised between 10 ° C. and 40 ° C. (At room temperature) for 1-24 hours.

  Said amine (3), (3 ′) or (3 ″) can be obtained from commercial sources or from conventional materials known to those skilled in the art (eg reduction, oxidation, alkylation, protection, Or may be prepared by deprotection etc.).

  The amine of formula (23) uses standard methods for cleaving nitrogen protecting groups, such as those found in textbooks, TW GREENE (Protective Groups in Organic Synthesis, A. Wiley-Interscience Publication, 1981). Can be prepared.

  When Rb or Rc = α-methylbenzyl, a typical deprotection method includes a suitable palladium catalyst (eg 20% palladium hydroxide / carbon) in a suitable solvent (eg methanol, ethanol, ethyl acetate). A solution of a protected amine of formula (22) with a suitable hydrogen donor, for example ammonium formate or formic acid, at a temperature between 25 ° C. and elevated temperature for 1-4 hours. Accompanied by.

  The compound of the formula (1) can be obtained by reacting the amine (23) with the bromide of the formula (6). In a typical manner amine (23) and bromide (6) are optionally combined with a suitable solvent (eg toluene or xylene) and a suitable tertiary amine base (eg N-methylmorpholine, triethylamine or N, N-diisopropyl). In the presence of ethylamine) at elevated temperatures for 18-48 hours.

  For some of the steps in the process for preparing compounds of formula (1) described hereinabove, a potentially reactive hydroxyl function that is not desired to react is protected and consequently cleaved. It may be necessary. In such cases, protected radicals that do not cause any chemical reaction can be used. Specific methods of protection and deprotection, for example those described by TW GREENE (Protective Groups in Organic Synthesis, A. Wiley-Interscience Publication, 1981) or by PJ Kocienski (Protecting groups, Georg Thieme Verlag, 1994) Can be used.

  The above reactions and the preparation of the new starting materials used in the previous methods are all in accordance with the prior art, isolating the appropriate reagents and reaction conditions for their practice or preparation, and the desired product. Methods for this will be well understood by those skilled in the art by reference to literature precedents and the examples and preparations herein.

In addition, the compounds of formula (1) as well as intermediates for their preparation can also be purified according to various well-known methods such as crystallization or chromatography.
A compound of formula (1), wherein -R ¹ and R ² are independently selected from H and C ₁ -C ₄ alkyl;
-N is 0, 1 or 2 and -Q ¹ below:

A group selected from 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, and -A is crosslinked by C ₃ -C ₁₀ a cycloalkyl, two one or more carbon atoms carbon atoms or more than it optionally of the cycloalkyl Or a group of the following formula:

And
^{-R 3, R 4, R 5} , R 6 and ^{R 7} have the same or different, _H, C 1 -C ₄ ^{alkyl, OR 9, SR 9, SOR} 9, SO 2 R 9, halo, Selected from 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 linking group to a carbonyl group;
Or, where appropriate, pharmaceutically acceptable salts and / or isomers thereof, tautomers, solvates, or isotopic variations thereof,
However, when n is 0, Q ₁ is not —NHCH ₃ , and when n is 1 or 2,
1) Q ¹ is ^* —NH—C ₁ -C ₄ alkyl, or ^* —N (R ⁸ ) -Q ² -A, wherein A is C ₃ -C ₁₀ cycloalkyl, Two or more carbon atoms are optionally bridged by one or more carbon atoms, and / or 2) when ^one of R ¹ and R ² is H, the other is Preferably it is not CH ₃ .

Preferred ^* _-NH-C 1 -C ₄ alkyl is NH- isopropyl.
Preferred compounds of formula (1) are those wherein Q ¹ is ^* -N (R ⁸ ) -Q ² -A, wherein A is C ₃ -C ₁₀ cycloalkyl, Preferred is cyclohexyl or adamantyl, in which one or more carbon atoms are optionally bridged by one or more carbon atoms.

More preferably, n is 1, Q ² is CH ₂ or a single bond, A is a C ₃ -C ₁₀ cycloalkyl, wherein two or more carbon atoms of the cycloalkyl are optionally 1 Bridged by one or more carbon atoms, preferably cyclohexyl or adamantyl.

Other preferred compounds of formula (1) are those wherein n is 0.
Preferably n is 0 and Q ¹ is a group of the formula

Wherein Q ² is a single bond or C ₁ -C ₄ alkylene, R ⁸ is H, A is naphthyl or the following group

Wherein R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are the same or different and are 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 equally;
Wherein R ⁹ and R ¹⁰ are the same or different and are selected from H or C ₁ -C ₄ alkyl, and ^* represents a linking moiety to a carbonyl group.

Preferably Q ¹ is 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, A is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, Naphthyl or a group of formula

In which R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are as defined above.
Preferably A is a group of the formula

In which R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are H, C ₁ -C ₄ alkyl, OR ⁹ , SR ⁹ , Cl, F, CF ₃ , OCF ₃ , COOR ⁹ , SO ₂ selected from NR ⁹ R ¹⁰ and at least two of R ³ to R ⁷ represent H;
In which 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 are 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 are 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.
Q ² is preferably 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₎ - is selected from.

Preferably n is 0 or 1.
In the above compound groups, the following substituents are preferred:
R ¹ and R ² are both CH ₃ , or R ¹ is H, R ² is CH ₃ or CH ₂ —CH ₃ , or R ¹ and R ² are both H.

Particularly preferred are compounds of formula (1) as described herein in the Examples section below:
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- (hydroxymethyl) phenyl] Ethyl} amino) propyl] phenyl} acetamide;
2- {3-[(2R) -2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) propyl] phenyl} -N-isopropylacetamide ;
N-cyclopentyl-2- {3-[(2R) -2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) propyl] phenyl} acetamide ;
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-cyclobenzyl) -2- {3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methyl Propyl] 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-dimethylethyl) amino ] -1-hydroxyethyl} -2- (hydroxymethyl) phenol;
N- [2-Fluoro-5- (trifluoromethyl) benzyl] -2- {3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) 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- (hydroxymethyl) phenyl] Ethyl} amino) -2-methylpropyl] phenyl} acetamide;
N- [2-Chloro-5- (trifluoromethyl) benzyl] -2- {3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) 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- (hydroxymethyl) phenyl] Ethyl} amino) -2-methylpropyl] phenyl} acetamide;
N- [2- (4-chlorophenyl) ethyl] -3- {2-[(2R) -2-hydroxy-2- (4-hydroxy-3-hydroxy-methylphenyl) ethylamino] -2-methylpropyl} 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-trifluoromethyl Phenyl) 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-naphthalen-2-yl- Ethyl) benzamide;
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-hydroxy-2- (4-hydroxy-3-hydroxymethylphenyl) -ethylamino] -2-methylpropyl} -N- (2-methyl-2-phenylpropyl) Benzamide;
N- (4-chlorobenzyl) -3- {2-[(2R) -2-hydroxy-2- (4-hydroxy-3-hydroxy-methylphenyl) 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- (hydroxymethyl) 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-phenylpropyl) benzamide ;
4-[(1R) -2-({(1R) -2- [3- (3,4-dihydroisoquinolin-2 (1H) -ylcarbonyl) phenyl] -1-methylethyl} amino) -1-hydroxy Ethyl] -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-pyrrolidine-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- (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- ( 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-phenylpropyl) benzamide ;
3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] -N- (2-phenylethyl) 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-methoxy Phenyl) 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-phenoxy Phenyl) 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-methyl Pyridin-2-yl) ethyl] benzamide;
3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] -N- [2- (2-methoxy Phenyl) 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-methyl Propyl] 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- (hydroxymethyl) phenyl] Ethyl} amino) -2-methylpropyl] benzamide;
3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] -N- (2-mesitylethyl) benzamide;
N- [2- (2,6-difluoro-3-methylphenyl) ethyl] -3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] Ethyl} amino) -2-methylpropyl] benzamide;
N- [2- (6-Chloro-2-fluoro-3-methylphenyl) ethyl] -3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) Phenyl] ethyl} amino) -2-methylpropyl] benzamide;
N- [2- (2-Chloro-6-fluoro-3-methylphenyl) ethyl] -3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) 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-methylpropyl] benzamide ;
N- (2-chlorobenzyl) -3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] benzamide ;
N- [2- (4,6-Dimethylpyrimidin-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- (3-methyl Pyridin-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-methyl Propyl] 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-hydroxy Phenyl) -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- (hydroxymethyl) phenyl] Ethyl} amino) -2-methylpropyl] benzamide;
N- [2- (4-hydroxy-2,5-dimethylphenyl) ethyl] -3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) 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- (pyridine -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-hydroxy Phenyl) propyl] benzamide;
3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] -N- [2- (3-methyl Phenyl) ethyl] benzamide;
3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] -N- [2- (6-methoxy Pyridin-3-yl) ethyl] benzamide;
3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] -N- [3- (3-methoxy Phenyl) propyl] benzamide;
N- [3- (4-Chlorophenyl) propyl] -3- {2-[(2R) -2-hydroxy-2- (4-hydroxy-3-hydroxymethylphenyl) ethylamino] -2-methylpropyl} benzamide ;
3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] -N- {2- [4- ( 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 present invention, it is generally preferred for the compound of formula (1) that the (CH ₂ ) _n —C (═O) Q ¹ group is in the meta position.
The compound of formula (1) may also be converted into a pharmaceutically acceptable salt if desired. In particular, these pharmaceutically acceptable salts of the compound of formula (1) include these acid addition and basic salts (including disalts).

  Suitable acid addition salts are formed from acids that form non-toxic salts. Examples include acetate, adipate, aspartate, benzoate, besylate, bicarbonate / carbonate, bisulfate / sulfate, borate, camsylate, citrate, cyclamic acid Salt, edisylaate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride / chloride, odor Hydrohalide / bromide, hydroiodide / iodide, hydrogen phosphate, isethionate, D- and L-lactate, malate, maleate, malonate, mesylate, methyl Sulfate, 2-naphthylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogen, phosphate / dihydrogen phosphate, pyroglutamate , Saccharinate, stearin Acid salts, succinates, tannates, D- and L-tartrate, 1-hydroxy-2-naphthoate, tosylate, and xinafoate.

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

Acid and base hemisalts may also be formed, for example hemisulphate and hemicalcium salts.
For a summary of suitable salts, see Stahl and Wermuth, Handbook of Pharmaceutical Salts: Properties, Selection, and Use, Wiley-VCH, Weinheim, Germany (2002).

The pharmaceutically acceptable salts of the compound of formula (1) can be prepared by the following three methods:
(I) by reacting the compound of formula (1) with the desired acid or base;
(Ii) by removing an acid or base labile protecting group from a suitable precursor of the compound of formula (1), or a suitable cyclic precursor, such as a lactone or lactam, to the desired acid or base Or (iii) conversion from one salt of a compound of formula (1) to another by reaction with a suitable acid or base, or a suitable ion exchange column By means;
May be prepared by one or more of the following.

  All three reactions are typically performed in solution. The resulting salt may precipitate out and be collected by filtration or may be recovered by evaporation of the solvent. The degree of ionization of the resulting salt can vary from completely ionized to hardly ionized.

  The compounds of the invention may exist in both unsolvated and solvated forms. The term “solvate” is intended to refer to a molecular complex comprising a compound of the present invention and one or more pharmaceutically acceptable solvent molecules, such as the molecular chemistry stoichiometric amount of ethanol. , Used herein. The term “hydrate” is used when the solvent is water.

Included within the scope of this invention are clathrate-like complexes, i.e. drug-host inclusion complexes, in which, contrary to the solvates described above, the drug and host are stoichiometric. Present in non-stoichiometric or non-stoichiometric amounts. Also included are drug complexes containing two or more organic and / or inorganic components, which may be stoichiometric or non-stoichiometric amounts. The resulting complex may be ionized, partially ionized, or non-ionized. For a summary of such complexes, see J Pharm Sci, 64 (8), 1269-1288 (August 1975) by Haleblian.

In the following description, all references to compounds of formula (1) include their salts, solvates and complexes, and solvates and complexes of their salts.
The compounds of the present invention include all their polymorphs and crystalline forms, their prodrugs and isomers as defined herein below (including optical isomers, geometric isomers and tautomers) As well as compounds of formula (1) as defined herein before, including radiolabeled compounds of formula (1).

  As indicated, so-called “prodrugs” of the compounds of formula (1) are also within the scope of the present invention. Certain derivatives of the compound of formula (1), which may thus have little or no pharmacological activity on their own, are those having the desired activity when administered in the body or on the body surface. The compound (1) can be converted, for example, by cleavage by hydrolysis. Such derivatives are called “prodrugs”. More information on the use of prodrugs can be found in 'Pro-drugs as Novel Delivery Systems', Vol. 14, ACS Symposium Series (T. Higuchi and W. Stella) and 'Bioreversible Carriers in Drug Design', Pergamon Press, 1987 (E B Roche, American Pharmaceutical Association).

  Prodrugs according to the present invention are known to those skilled in the art as “pro-moieties”, for example as described in “Design of Prodrugs” by H. Bundgaard (Elsevier, 1985). Can be prepared by substituting the appropriate functionalities present in the compound of formula (1).

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), the ester, for example, the hydrogen of the carboxylic acid functional group of the compound of formula (1) is (C ₁ -C _8). ) Compounds replaced by alkyl;
(Ii) when the compound of formula (1) contains an alcohol functional group (—OH), the ether, eg the hydrogen of the alcohol functional group of the compound of formula (1), is (C ₁ -C ₈ ) alkanoyl A compound replaced by oxymethyl; and (iii) the compound of formula (1) contains a primary or secondary amino functional group (—NH ₂ or —NHR, wherein R is not H) If so, a compound in which one or both of the amides, for example one or both of the amino functional hydrogens of the compound of formula (1), are replaced by (C ₁ -C ₈ ) alkanoyl.

Additional examples of groups that can be substituted according to the foregoing examples and other types of prodrugs may be found in the aforementioned references.
Furthermore, certain compounds of formula (1) may themselves act as prodrugs of other compounds of formula (1).

Also included within the scope of the present invention are metabolites of compounds of formula (1), that is, compounds formed in vivo upon administration of the drug. Some examples of metabolites according to the present invention include:
(I) when the compound of formula (1) contains a methyl group, its hydroxymethyl derivative (—CH ₃ → —CH ₂ OH);
(Ii) when the compound of formula (1) contains an alkoxy group, its hydroxy derivative (—OR → —OH);
(Iii) when the compound of formula (1) contains a tertiary amino group, its secondary amino derivative (—NR ¹ R ² → —NHR ¹ or —NHR ² );
(Iv) when the compound of formula (1) contains a secondary amino group, its primary (amino) derivative (—NR ¹ → —NH ₂ );
(V) when the compound of formula (1) contains a phenyl moiety, its phenol derivative (-Ph → -PhOH); and (l). (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 can exist as two or more stereoisomers. Where the compound of formula (1) contains an alkenyl or alkenylene group, geometric cis / trans (or Z / E) isomers are possible. Tautomeric isomerism “tautomerism” can occur when a compound contains, for example, keto, or when structural isomers are interconvertible via a low energy barrier in an oxime group or aromatic moiety. This may take the form of proton tautomerism in compounds of formula (1) containing for example imino, keto or oxime groups, or so-called valence tautomerism in compounds containing aromatic moieties. Is possible. Thus, a single compound may exhibit more than one type of isomerism.

  Included within the scope of the invention are all stereoisomers, geometries, of compounds of formula (1), including compounds exhibiting more than one type of isomerism, and mixtures of one or more thereof. Isomeric and tautomeric forms are mentioned. Further included are acid addition or base addition salts in which the counter ion is optically active, such as d-lactate or l-lysine, or a racemate, such as dl-tartrate or dl-arginine.

The cis / trans isomers may be separated by conventional techniques well known to those skilled in the art, for example, chromatography and fractional crystallisation.
Prior art techniques for the preparation / isolation of individual enantiomers include chiral synthesis from appropriate optically pure precursors, or racemates (or salts or salts using, eg, chiral high pressure liquid chromatography (HPLC)). Including resolution of racemic derivatives).

  Alternatively, the racemate (or racemic precursor) may be reacted with a suitable optically active compound, such as an alcohol, or an acid or base if the compound of formula (1) contains an acidic or basic moiety For example, it may be reacted with tartaric acid or 1-phenylethylamine. The resulting mixture of diastereomers is separated by chromatography and / or fractional recrystallization, and one or both of the diastereoisomers is converted to the corresponding pure enantiomer (s) by methods well known to those skilled in the art. You can do it.

  The chiral compounds of the present invention (and their chiral precursors) can be chromatographed on asymmetric resins, typically HPLC, with a volume ratio of 0-50% isopropanol, typically 2-20%, And enantiomerically enriched using a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing 0 to 5% alkylamine, typically 0.1% diethylamine. ) Form. The enriched mixture is obtained by concentration of the eluate.

  Stereoisomeric aggregates may be separated by conventional techniques known to those skilled in the art-see, for example, "Stereochemistry of Organic Compounds" by E. L. Eliel (Wiley, New York, 1994).

In accordance with one aspect of the invention, the (R, R) -stereoisomer of the following formula, wherein R ¹ is hydrogen, R ² is C ₁ -C ₄ alkyl, preferably methyl, and n And Q ¹ are generally preferred as defined above:

In which n and Q ¹ are as defined above for the compound of formula (1).
The present invention relates to all pharmaceuticals in which one or more atoms have the same atomic number but the atomic mass or mass number is replaced by an atom that is different from the atomic mass or mass number predominantly found in nature. Containing a radioactively labeled compound of formula (1).

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

Certain isotope-labelled compounds of Formula (1), such as those incorporating a radioactive isotope, are useful in drug and / or substrate tissue distribution studies. The radioactive isotopes tritium, ie ³ H, and carbon-14, ie ¹⁴ C, are particularly useful for this purpose in view of their ease of incorporation and ease of detection.

Heavier isotopes such as deuterium, i.e. substituted by ^{2 H,} the stability of greater metabolic, certain therapeutic advantages resulting from the need for example increased in vivo half-life or reduced dosage In some situations, it may be more desirable.

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

  The compound of formula (1) labeled with an isotope is generally written according to conventional techniques known to those skilled in the art or together with a reagent labeled with a suitable isotope instead of the unlabeled reagent used previously. It can be prepared by methods analogous to those described in the Examples and Preparation section.

Pharmaceutically acceptable solvates of the in accordance with the invention, the solvent of crystallization which may be substituted with isotope, for example D _{2 O,} d 6 _- acetone, those which are d _6-DMSO.
The compounds of formula (1), their pharmaceutically acceptable salts and / or derived forms are valuable pharmaceutically active compounds that involve or act on the β2 receptor. Suitable for the treatment and prevention of many disorders that are thought to induce benefits, especially allergic and non-allergic airway diseases, but also other diseases such as but not limited to nervous system, premature birth, congestive heart failure, depression It is also suitable for the treatment of inflammatory and allergic skin diseases, psoriasis, proliferative skin diseases, glaucoma diseases and conditions where it is advantageous to reduce gastric hyperacidity, in particular gastric and duodenal ulcers.

  The compounds of formula (1) and their pharmaceutically acceptable salts and derived forms as described above are therapeutic and / or prophylactic for animals according to the invention, preferably for mammals and especially for humans. Can be administered as a medicament. These may be administered as such, administered as a mixture with each other, or in addition to the usual pharmaceutically harmless excipients and / or additives, as an active ingredient at least one compound of formula (1), its medicament Can be administered in the form of a pharmaceutical preparation containing a pharmaceutically acceptable salt and / or an effective dosage in an induced form.

  The compounds of formula (1), their pharmaceutically acceptable salts and / or derived forms can be lyophilized, spray dried or evaporated to form solid pieces, powders or crystalline or amorphous materials. A film may be provided. Microwave or radiation frequency drying may be used for this purpose.

  The compounds of formula (1), their pharmaceutically acceptable salts and / or derivatized forms may be administered alone or in combination with other agents, generally one or more pharmaceutically It will be administered as a formulation with acceptable excipients. The term “excipient” is used herein to refer to any ingredient other than the compound of the invention. The choice of excipient will to a large extent depend on the particular mode of administration.

  The compounds of the present invention may be administered orally. Oral administration may involve swallowing, so the compound will enter the gastrointestinal tract, or buccal or sublingual administration may be used where the compound enters the bloodstream directly from the mouth.

  Formulations suitable for oral administration include solid formulations such as tablets, particles, capsules containing liquids or powders, lozenges (including those filled with liquids), chewable chews, multiparticulates and nanoparticles, gels, Includes solid solutions, liposomes, films, ovules, sprays as well as liquid formulations.

  Liquid formulations include suspensions, solutions, syrups and elixirs. Such formulations may be used as fillers in soft or hard capsules, typically a carrier such as water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil, and one or more Includes many emulsifiers and / or suspending agents. Liquid formulations may also be prepared, for example, by redissolving a sachet solid.

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

  For tablet dosage forms, depending on dose, the drug may be manufactured 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 the drug, tablets generally contain a disintegrant. Examples of disintegrants are sodium starch glycolate, sodium carboxymethylcellulose, carboxymethylcellulose calcium, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methylcellulose, microcrystalline cellulose, hydroxypropyl cellulose substituted with lower alkyl, starch, pre-gelatin Starch, and sodium alginate. In general, disintegrants should be included from 1% to 25%, preferably 5% to 20% by weight of the dosage form.

  Binders are generally used to impart agglomeration properties to tablet formulations. Suitable binders include microcrystalline cellulose, gelatin, sugar, polyethylene glycol, natural and synthetic rubbers, polyvinylpyrrolidone, pregelatinized starch, hydroxypropylcellulose, and hydroxypropylmethylcellulose. Tablets are also diluents such as lactose (monohydrate, spray dried monohydrate, anhydride, etc.), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch, and dibasic calcium phosphate dihydrate Including things.

  Tablets may also optionally include surface active agents, such as sodium lauryl sulfate and polysorbate 80, and glidants, such as silicon dioxide and talc. When added, the surfactant may be included from 0.2% to 5% by weight of the tablet and the lubricant may be included from 0.2% to 1% by weight of the tablet.

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

Other possible ingredients include antioxidants, colorants, flavoring agents, preservatives, and taste masking agents.
Illustratively, the tablet may comprise up to about 80% drug, about 10% to about 90% binder, about 0% to about 85% diluent, about 2% to about 10% disintegration. And about 0.25 wt.% To about 10 wt.% Lubricant.

  A blend of tablet ingredients is compressed directly or by a roller and formed into tablets. Blends of tablet ingredients or portions of the blend may be wet, dry or melt granulated, melt coagulated, or extruded prior to tableting. The final formulation may contain one or more layers and may or may not be coated; it may be encapsulated.

Tablet formulation is discussed in Pharmaceutical Dosage Forms: Tblets, Vol. 1 (Marcer Dekker, New York, 1980) by H. Lieberman and Lachman.
Consumable oral films for human or veterinary use are typically flexible, water-soluble or water-swelling thin film dosage forms that are either rapidly dissolving or mucoadhesive. Well, typically it includes a compound of formula (1), a film-forming polymer, a binder, a solvent, a wetting agent, a plasticizer, a stabilizer or emulsifier, a viscosity modifier, and a solvent. Some components of the formulation may perform more than one function.

  The compound of formula (1) may be water-soluble or insoluble. Water soluble compounds typically include 1% to 80% by weight of the solute, more typically 20% to 50% by weight of the solute. Less soluble compounds may be included in a greater proportion of the composition, typically up to 88% by weight of the solute. Alternatively, the compound of formula (1) may be in the form of multiparticulate beads.

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

  Other possible ingredients include antioxidants, colorants, flavoring and flavor enhancers, preservatives, salivary stimulants, cooling agents, co-solvents (including oils), relaxation agents, fillers, antifoaming agents, Contains surfactant and taste masking agent.

  Films according to the present invention are typically prepared by evaporating and drying a thin aqueous film coated on a peelable backing support or paper. This preparation can be done in a drying oven or tunnel, typically in combination with a coater drier, or by lyophilization or vacuum.

  Solid formulations for oral administration may be formulated for immediate release and / or modified release. Modified release formulations include delayed release, sustained release, pulsed release, controlled release, release to target, and programmed release.

  Suitable modified release formulations for the purposes of the present invention are described in US Pat. No. 6,106,864. For details on other suitable release technologies, such as high energy dispersions, and osmotic and coated particles, see Pharmaceutical Technology On-line, 25 (2), 1-14 (2001) by Verma et al. You will find it. The use of chewing gum to achieve controlled release is described in WO 00/35298.

  The compounds of the present invention may also be administered directly into the bloodstream, intramuscularly or into internal organs. Suitable methods for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, and subcutaneous. Suitable devices for parenteral administration include syringes with needles (including fine needles), needleless syringes, and infusion techniques.

  Parenteral administration is typically an aqueous solution that may contain excipients such as salts, carbohydrates and buffering agents (preferably pH 3-9), but depending on the application, as a sterile non-aqueous solution or as appropriate A more suitable formulation may be formulated as a dry form for use with a non-toxic vehicle, such as sterile, pyrogen-free water.

Preparation of parenteral formulations under sterile conditions, such as by lyophilization, may be readily accomplished using standard pharmaceutical techniques known to those skilled in the art.
The solubility of the compound of formula (1) used in the preparation of parenteral solutions may be increased by the use of appropriate formulation techniques, such as techniques incorporating solubility enhancers.

  Formulations for parenteral administration may be formulated to be immediate and / or modified release. Modified release formulations include delayed release, sustained release, pulsed release, controlled release, release to target, and programmed release. Accordingly, the compounds of the present invention may be formulated as solid, semi-solid, or thixotropic liquids for administration as an implanted depot that provides a modified release of the active compound. Examples of such formulations include drug-coated stents and PGLA dl lactic / glycolic acid copolymer (PGLA) microspheres.

  The compounds of the present invention may also be administered topically to the skin or mucosa, ie dermally or transdermally. Typical formulations for this purpose are gels, hydrogels, lotions, solutions, creams, ointments, sprays, dressings, foams, films, skin patches, cachets, implants, sponges, fibers (fibre), bandage, and microemulsion. Liposomes may also be used. Typical carriers include alcohol, water, mineral oil, liquid paraffin, white petrolatum, glycerin, polyethylene glycol, and propylene glycol. Penetration enhancers may be incorporated-see, for example, J Pharm Sci, 88 (10), 955-958 (October 1999) by Finnin and Morgan.

  Other methods of topical administration include delivery by electroporation, iontophoresis, phonophoresis, sonophoresis, and fine needle injection or needleless injection (eg Powderject®, Bioject®, etc.) including.

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

  The compounds of the invention may also be administered intranasally or by inhalation, typically from a dry powder inhaler, in the form of a dry powder (eg, alone, as a mixture, eg, in a dry blend with lactose, or of mixed ingredients As particles, for example either phospholipids, eg mixed with phosphatidylcholine), or a suitable high pressure gas, eg 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3 -Can be administered as an aerosol spray from pressurized containers, pumps, sprays, atomizers (preferably atomizers with electric convection to produce a fine spray) or nebulizers with or without heptafluoropropane . For use in the nasal cavity, the powder may include a bioadhesive agent, such as chitosan or cyclodextrin.

  Pressurized containers, pumps, sprays, atomizers, or nebulizers are, for example, ethanol, aqueous ethanol, or suitable alternatives for the dispersion, dissolution or release of active ingredients, high pressure gas as solvent (one or A) or an optional surfactant, including solutions or suspensions of the compound (s) of the invention, including sorbitan trioleate, oleic acid or oligolactic acid.

  Prior to use in a dry powder or suspension formulation, the drug product is micronised to a particle size suitable for delivery by inhalation (typically less than 5 microns). This may be achieved by any suitable comminuting method, such as spiral jet mill, fluid bed jet mill, supercritical fluid processing to form nanoparticles, homogenization at high pressure, or spray drying.

  Capsules (eg, made of gelatin or hydroxypropylmethylcellulose), blisters and cartridges for use in inhalers or insufflators are compounds of the invention, suitable powder bases such as lactose or starch, and substances that modify performance, such as -It may be formulated to contain a powder mixture of leucine, mannitol or magnesium stearate. Lactose may be in anhydrous or monohydrate form, preferably the latter. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose, and trehalose.

  A suitable solution formulation for use in an atomizer using electroconvection to produce a fine spray may contain 1 μg to 20 mg of the compound of the invention per actuation, with the actuation volume varying from 1 μl to 100 μl. You can do it. A typical formulation may include a compound of formula (1), propylene glycol, sterile water, ethanol, and sodium chloride. Alternative solvents that may be used in place of propylene glycol include glycerol and polyethylene glycol.

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

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

  In the case of dry powder inhalers and aerosols, the dosage unit is determined by a valve that delivers the measured amount. Units according to the invention are adjusted to administer a measured dose or “push”, typically containing 0.001 mg to 10 mg of the compound of formula (1). The overall daily dose will typically range from 0.001 mg to 40 mg, which may be administered in a single dose or, more generally, in divided doses throughout the day. .

The compounds of formula (1) are particularly suitable for administration by inhalation.
The compounds of the present invention may be administered rectally or vaginally, for example, in the form of a suppository, pessary, or enema. Cocoa butter is a traditional suppository base, but various alternative materials may be used if appropriate.

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

  The compounds of the present invention may also be administered directly to the eye or ear, typically in the form of finely divided suspensions or solution droplets in sterile isotonic pH adjusted saline. Other formulations suitable for ophthalmic and ear administration are ointments, in vivo degradable (absorbable gel sponge, collagen) and non in vivo degradable (eg silicon) implants, cachets, lenses, and Particulate or vesicular systems such as niosomes or liposomes. Polymers such as cross-linked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, cellulose polymers such as hydroxypropylmethylcellulose, hydroxyethylcellulose, or methylcellulose, or heteropolysaccharide polymers such as gellan gum can be incorporated with preservatives such as benzalkonium chloride. Good. Such formulations may also be delivered by iontophoresis.

  Formulations for ocular / ear drop administration may be formulated for immediate release and / or modified release. Modified release formulations include delayed release, sustained release, pulsed release, controlled release, release to target, or programmed release.

  The compounds of the present invention may be used in any of the aforementioned modes of administration, so that soluble polymeric substances may be used for the purpose of improving their solubility, dissolution rate, taste masking, bioavailability, and / or stability, For example, it may be conjugated to cyclodextrin and suitable derivatives thereof, or polyethylene glycol-containing polymers.

  For example, drug-cyclodextrin complexes have been found to be generally useful for most dosage forms and administration routes. Both inclusion and non-inclusion compounds may be used. As an alternative to a direct complex containing the drug, cyclodextrin may be used as an auxiliary additive, ie as a carrier, diluent, or solubilizer. The most commonly used for these purposes are alpha-, beta-, and gamma-cyclodextrins, examples of which are described in international patent applications WO 91/11172, WO 94/02518 and WO 98. You may find it in / 55148.

  Two or more pharmaceutical compositions (at least one of which is at least one) only if it is desirable to administer a combination of active compounds, eg, for the purpose of treating a particular disease or condition It is within the scope of the present invention that the compounds according to the present invention may be conveniently combined in the form of a kit suitable for the combined use of the composition.

  Thus, the kit of the present invention holds two or more separate pharmaceutical compositions (of which at least one contains a compound of formula (1) according to the present invention) and said composition separately Means, for example containers, divided bottles, divided foil parcels. An example of such a kit is the common blister pack used for the packaging of tablets, capsules and the like.

  The kit of the invention is particularly suitable for administering different dosage forms, eg parenterally, for administering separate compositions at different dosing intervals, or for titrating separate compositions from each other. To assist compliance, the kit typically includes a package insert for administration and may be provided with a so-called memory aid.

  For administration to human patients, the total daily dose of the compounds of the invention will typically range from 0.001 mg to 5000 mg, depending of course on the mode of administration. For example, an intravenous daily dose may only require from 0.001 mg to 40 mg. The total daily dose may be administered in single or divided doses and may deviate from the typical ranges set forth herein at the physician's discretion.

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

To avoid confusion, the term “treatment” as used herein includes referring to treatment for cure, alleviation, and prevention.
In accordance with another aspect of the present invention, the compound of formula (1) or a pharmaceutically acceptable salt, derivatized form or composition thereof may also be used in combination with one or more additional patients. Combinations of therapeutic agents include, but are not limited to, signs and symptoms such as (i) bronchoconstriction, (ii) inflammation, (iii) allergy, (iv) tissue destruction, (v) shortness of breath, cough In the treatment of a physiologically relevant disease process, it can be used to obtain the end result of any particularly desirable treatment. The second and more additional therapeutic agents may also be a compound of formula (1) or a pharmaceutically acceptable salt, derivatized form or composition thereof, one known to those skilled in the art Or more β2 agonists may be used. More typically, the second and more therapeutic agents will be selected from different classes of therapeutic agents.

As used herein, the terms “in combination”, “in combination” and “in combination” with respect to a compound of formula (1) and one or more other therapeutic agents mean: Exactly mentioned and intended to include:
Co-administration of the combination of compound (s) of formula (1) and therapeutic agent (s) to a patient in need of treatment, wherein the components are at substantially the same time Formulated into a single dosage form that releases the ingredients to the patient,
Substantially simultaneous administration of the combination of compound (s) of formula (1) and therapeutic agent (s) to a patient in need of treatment, wherein the components are substantially the same Formulated separately in separate dosage forms taken by the patient at a time, wherein the components are released to the patient at substantially the same time,
Continuous administration of the combination of compound (s) of formula (1) and therapeutic agent (s) to a patient in need of treatment, wherein the components are Are formulated separately from each other in separate dosage forms taken at significant time intervals between each administration, in which case the components are released to the patient at substantially different times; and Continuous administration of the combination of compound (s) of formula (1) and therapeutic agent (s) to a patient in need thereof, wherein the components are administered in a controlled manner. Formulated in a single dosage form to be released, in which case the components are administered by the patient at the same time and / or at different times, simultaneously, sequentially and / or in duplicate,
In these cases, each portion may be administered either by the same route or by different routes.

Suitable examples of other therapeutic agents that may be used in combination with the compound (s) of formula (1) or pharmaceutically acceptable salts, derivatized forms or compositions thereof include: In no way is this limited:
(A) a 5-lipoxygenase (5-LO) inhibitor or a 5-lipoxygenase activating protein (FLAP) antagonist,
(B) leukotriene antagonists (LTRA), including antagonists of LTB ₄ , LTC ₄ , LTD ₄ and LTE ₄ ;
(C) a histamine receptor antagonist comprising H1 and H3 antagonists,
(D) an α ₁ -and α ₂ -adrenergic receptor agonist vasoconstrictor sympathomimetic for use as a decongestant;
(E) a muscarinic M3 receptor antagonist or anticholinergic agent,
(F) PDE inhibitors, such as inhibitors of PDE3, PDE4 and PDE5,
(G) theophylline,
(H) sodium cromoglycate,
(I) COX inhibitors (NSAIDs), both non-selective and selective COX-1 inhibitors or COX-2 inhibitors,
(J) Oral and inhalation glucocorticosteroids such as DAGR (dissociated agonists of the corticoid receptor)
(K) a monoclonal antibody active against the presence of endogenous inflammation;
(L) an anti-tumor necrosis factor (anti-TNF-α) drug,
(M) an adhesion molecule inhibitor comprising a VLA-4 antagonist,
(N) a kinin-B ₁ and B ₂ receptor antagonist,
(O) immunosuppressant,
(P) an inhibitor of matrix metalloprotease (MMP),
(Q) tachykinin NK ₁ , NK ₂ and NK ₃ receptor antagonists,
(R) an elastase inhibitor,
(S) an adenosine A2a receptor agonist,
(T) an inhibitor of urokinase,
(U) a compound acting at a dopamine receptor, such as a D2 agonist,
(V) a modulator of the NFκβ pathway, such as an IKK inhibitor,
(W) modulators of cytokine signaling pathways, such as p38 MAP kinase, syk kinase, or JAK kinase inhibitors (x) agents that can be classified as mucopolysaccharide degradation or antitussive,
(Y) antibiotics,
(Z) an HDAC inhibitor, and (aa) a PI3 kinase inhibitor.

According to the invention, the compound of formula (1) and the following agents:
An H3 antagonist,
A muscarinic M3 receptor antagonist,
-PDE4 inhibitors,
-Glucocorticosteroids,
An adenosine A2a receptor agonist,
- modulators of cytokine signaling pathways, including, for example, p38MAP kinase or antagonists of syk kinase -LTB _{4, LTC 4,} LTD ₄ and LTE _4, leukotriene antagonists (LTRA),
The combination with is preferable.

According to the invention, the compound of formula (1) and the following agents:
Inhaled glucocorticosteroids with reduced systemic side effects, including glucocorticosteroids, in particular prednisone, prednisolone, flunisolide, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone propionate, ciclesonide, and mometasone furoate, Or-a muscarinic M3 receptor antagonist or anticholinergic agent comprising in particular ipratropium salt, i.e. bromide, tiotropium salt, i.e. bromide, oxitropium salt, i.e. bromide, perenzepine, and telenzepine,
The combination with is more preferable.

  It is to be appreciated that all references herein to treatment include treatment for cure, alleviation, and prevention. The following description relates to therapeutic applications in which compounds of formula (1) may be placed.

  The compound of formula (1) has the ability to interact with the β2 receptor, whereby the β2 receptor is responsible for all mammalian physiology as described further below. Having an essential role.

Accordingly, a further aspect of the present invention is a compound of formula (1), or a pharmaceutically acceptable salt thereof, derived form, for use in the treatment of diseases, disorders, and conditions involving the β2 receptor. Or it relates to a composition. More specifically, the present invention also provides a compound of formula (1), or a pharmaceutically acceptable salt thereof, for use in the treatment of diseases, disorders, and conditions selected from the group consisting of: Related to the induced form or composition: i.e. via any type, etiology or pathogenesis asthma, especially atopic asthma, non-atopic asthma, allergic asthma, atopic bronchial IgE Asthma, bronchial asthma, essential asthma, true asthma, intrinsic asthma caused by pathophysiological disorders, extrinsic asthma caused by environmental factors, essential cause of unknown or unknown cause Asthma, non-atopic asthma, bronchitis asthma, emphysematous asthma, exercise-induced asthma, allergen-induced asthma, cold-induced asthma, occupational asthma, bacteria, fungi, protozoa, or wi Infective asthma caused by infection of the scan, non-allergic asthma, incipient (incipient) asthma, infants with wheezing (wheezy infant) syndrome asthma that is a member selected from the group consisting of, and bronchiolitis,
Chronic or acute bronchoconstriction, chronic bronchitis, small airway obstruction, and emphysema,
Obstructive or inflammatory airway diseases of any type, etiology or pathology, in particular chronic eosinophilic pneumonia, chronic obstructive pulmonary disease (COPD), COPD including chronic bronchitis, emphysema or breathing with or without COPD Group consisting of COPD characterized by difficulty, additional reversibility, progressive airway obstruction, adult respiratory distress syndrome (ARDS), exacerbation of airway hyperresponsiveness as a result of other medications, and airway disease associated with pulmonary hypertension An obstructive or inflammatory airway disease, which is a more selected member,
Bronchitis of any type, etiology or pathology, in particular acute bronchitis, acute laryngotracheal bronchitis, bronchitis with arachidic acid, catarrhal bronchitis, clonal bronchitis, dry bronchitis, infectious asthmatic bronchitis Bronchitis, a member selected from the group consisting of sputum bronchitis, staphylococcal or streptococcal bronchitis, and vesicular bronchitis,
Acute lung injury,
Bronchiectasis of any type, etiology or condition, in particular columnar bronchiectasis, saccular bronchiectasis, fusiform bronchiectasis, capillary bronchiectasis, cystic bronchiectasis, dry bronchiectasis And bronchiectasis being a member selected from the group consisting of follicular 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 medicament having β2 agonist activity. In particular, the invention relates to β2-mediated diseases and / or conditions, in particular the diseases and / or conditions listed above, of the compounds of formula (1), or pharmaceutically acceptable salts, derived forms or compositions thereof. Or relates to the use for the manufacture of a medicament for the treatment of a condition.

  As a result, the present invention provides a particularly interesting method for treating mammals, including humans, with an effective amount of a compound of formula (1), or a pharmaceutically acceptable salt, derived form or composition thereof. provide. More particularly, the present invention comprises administering to a mammal, including a human, an effective amount of a compound of formula (1), a pharmaceutically acceptable salt thereof and / or a derived form thereof. Provided are particularly interesting methods for treating β2 mediated diseases and / or conditions in animals, particularly 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 added to 2- {3-[(2R) -2-({(2R) -2-{[tert-butyl] in methanol (3 ml) and water (1.5 ml). (Dimethyl) silyl] oxy} -2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) propyl] phenyl} -N-cycloheptylacetamide (Preparation Example 1) (150 mg, 0.26 mmol) To the stirring solution was added in one portion at room temperature. The reaction was heated at 40 ° C. for 18 hours and then allowed to cool 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) and dried (magnesium sulfate) Was removed in vacuo to give a clear oil. This material was purified by flash column chromatography on silica gel eluting with dichloromethane: methanol: ammonia (90: 10: 1 volume ratio) to give 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- (hydroxymethyl) phenyl] ethyl} Amino) propyl] phenyl} -N- (cyclohexylmethyl) -N-methylacetamide (Preparation Example 2) was prepared using the method for Example 1 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- (hydroxy) Methyl) phenyl] ethyl} amino) propyl] phenyl} acetamide

  2- {3-[(2R) -2-({(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} Prepared from amino) propyl] phenyl} -N-[(1S) -1-cyclohexylethyl] acetamide (Preparation Example 3) using the method for Example 1 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- (hydroxymethyl) phenyl] ethyl} Prepared from amino) propyl] phenyl} -N-isopropylacetamide (Preparation Example 4) using the method for Example 1 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- (hydroxymethyl) phenyl] ethyl} Prepared from amino) propyl] phenyl} -N-cyclopentylacetamide (Preparation Example 5) using the method for Example 3 to give 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- (hydroxymethyl) phenyl] ethyl} Prepared from amino) propyl] phenyl} -N- (cyclobutylmethyl) acetamide (Preparation Example 6) using the method for Example 1 to give 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- (hydroxymethyl) phenyl] ethyl} Prepared from amino) propyl] phenyl} -N- (cyclopentylmethyl) acetamide (Preparation Example 7) using the method for Example 1 to give 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- (hydroxymethyl) phenyl] ethyl} Prepared from amino) propyl] phenyl} -N-cyclohexylacetamide (Preparation Example 8) using the method for Example 1 to give 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-3- (hydroxymethyl) phenyl] ethyl} Prepared from amino) propyl] phenyl} -N-cyclobutylacetamide (Preparation Example 9) using the method for Example 1 to give 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- (hydroxymethyl) phenyl] ethyl} Prepared from amino) propyl] phenyl} -N- (cyclohexylmethyl) acetamide (Preparation Example 10) using the method for Example 1 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- (hydroxymethyl) phenyl] ethyl} Prepared from amino) propyl] phenyl} -N- (cyclopropylmethyl) acetamide (Preparation Example 11) using the method for Example 1 to give 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- (hydroxymethyl) phenyl] ethyl} Prepared from amino) propyl] phenyl} -N- (cycloheptylmethyl) acetamide (Preparation Example 12) using the method for Example 1 to give 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- [4-hydroxy-3- (hydroxy) Prepared from methyl) phenyl] ethyl} amino) propyl] phenyl} acetamide (Preparation Example 13) using the method for Example 1 to give the title compound as a white foam.

Example 14: N- (1-adamantylmethyl) -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-{[tert-butyl (dimethyl) silyl] oxy} -2- [4-hydroxy-3 Prepared from-(hydroxymethyl) phenyl] ethyl} amino) propyl] phenyl} acetamide (Preparation Example 14) using the method for Example 1 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] phenyl} acetamide

  N-2-adamantyl-2- {3-[(2R) -2-({(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- [4-hydroxy-3- (hydroxy) Prepared from methyl) phenyl] ethyl} amino) propyl] phenyl} acetamide (Preparation Example 15) using the method for Example 1 to give the title compound as a white foam.

Example 16: N- (2-cyclohexylethyl) -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- (hydroxymethyl) phenyl] ethyl} Prepared from amino) propyl] phenyl} -N- (2-cyclohexylethyl) -N-methylacetamide (Preparation Example 16) using the method for Example 1 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- (hydroxymethyl) phenyl] ethyl} Prepared from amino) propyl] phenyl} -N-cycloheptyl-N-methylacetamide (Preparation Example 17) using the method for Example 1 to give 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- (hydroxymethyl) phenyl] ethyl} Amino) propyl] phenyl} -N-cyclohexyl-N-ethylacetamide (Preparation Example 18) was prepared using the method for Example 1 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- (hydroxymethyl) phenyl] Ethyl} amino) propyl] phenyl} acetamide

  2- {3-[(2R) -2-({(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} Amino) propyl] phenyl} -N- (2-cyclohexylethyl) acetamide (Preparation Example 19) was prepared using the method for Example 1 to give the title compound as a white foam.

Example 20: N- (4-cyclobenzyl) -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-methylpropyl] according to the method used for Preparation Example 1 Prepared using phenyl} acetic acid (Preparation Example 50) and the appropriate amine to give the title compound as a 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-methylpropyl] according to the method used for Preparation Example 1 Prepared using phenyl} acetic acid (Preparation Example 50) and the appropriate amine to give the title compound as a 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-methylpropyl] according to the method used for Preparation Example 1 Prepared using phenyl} acetic acid (Preparation Example 50) and the appropriate amine to give the title compound as a 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-methylpropyl] according to the method used for Preparation Example 1 Prepared using phenyl} acetic acid (Preparation Example 50) and the appropriate amine to give the title compound as a white foam.

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

  {3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] according to the method used for Preparation Example 1 Prepared using phenyl} acetic acid (Preparation Example 50) and the appropriate amine to give the title compound as a 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-methylpropyl] according to the method used for Preparation Example 1 Prepared using phenyl} acetic acid (Preparation Example 50) and the appropriate amine to give the title compound as a 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-methylpropyl] according to the method used for Preparation Example 1 Prepared using phenyl} acetic acid (Preparation Example 50) and the appropriate amine to give the title compound as a 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-methylpropyl] according to the method used for Preparation Example 1 Prepared using phenyl} acetic acid (Preparation Example 50) and the appropriate amine to give the title compound as a 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-methylpropyl] according to the method used for Preparation Example 1 Prepared using phenyl} acetic acid (Preparation Example 50) and the appropriate amine to give the title compound as a white foam.

Example 29: 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

  {3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] according to the method used for Preparation Example 1 Prepared using phenyl} acetic acid (Preparation Example 50) and the appropriate amine to give the title compound as a white foam.

Example 30: 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

  {3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] according to the method used for Preparation Example 1 Prepared using phenyl} acetic acid (Preparation Example 50) and the appropriate amine to give the title compound as a 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-methylpropyl] according to the method used for Preparation Example 1 Prepared using phenyl} acetic acid (Preparation Example 50) and the appropriate amine to give 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- (hydroxy) Methyl) phenyl] ethyl} amino) -2-methylpropyl] phenyl} acetamide

  {3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] according to the method used for Preparation Example 1 Prepared using phenyl} acetic acid (Preparation Example 50) and the appropriate amine to give the title compound as a 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 (Preparation Example 38) (470 mg, 0.77 mmol) and ammonium fluoride (280 mg, 7.70 mmol) were added at 43 ° C. For 18 hours. 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 dissolved in methanol and evaporated (× 3) 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] -2-methylpropyl} -N- [2 Prepared from-(4-Methylphenyl) ethyl] benzamide (Preparation Example 39) using the method of Example 33 to give 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] -2-methyl-propyl} -N- [ Prepared from 2- (4-trifluoromethylphenyl) ethyl] benzamide (Preparation Example 40) using the method of Example 33 to give 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) ethylamino]- 2-methyl-propyl} -benzamide

  3- {2-[(2R) -2- (tert-butyldimethylsilanyloxy) -2- (4-hydroxy-3-hydroxymethyl-phenyl) ethylamino] -2-methyl-propyl} -N- [ Prepared from 2- (3,4-dichlorophenyl) ethyl] benzamide (Preparation Example 41) using the method of Example 33 to give 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-methyl-propyl} -N- [ Prepared from 2- (3,4-dimethylphenyl) ethyl] benzamide (Preparation Example 42) using the method of Example 33 to give 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-naphthalene- 2-yl-ethyl) benzamide

  3- {2-[(2R) -2- (tert-butyldimethylsilanyloxy) -2- (4-hydroxy-3-hydroxymethyl-phenyl) ethylamino] -2-methyl-propyl} -N- ( Prepared from 2-naphthalen-2-yl-ethyl) benzamide (Preparation Example 43) using the method of Example 33 to give 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] -2-methyl-propyl} -N- ( Prepared from 1,1-dimethyl-2-phenyl-ethyl) benzamide (Preparation Example 44) using the method of Example 33 to give 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-methylpropyl} -N- (2- Prepared from methyl-2-phenylpropyl) benzamide (Preparation Example 45) using the method of Example 33 to give 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-methylpropyl} Benzamide

  3-{(2R) -2- [2- (tert-butyldimethylsilanyloxy) -2- (4-hydroxy-3-hydroxymethyl-phenyl) ethylamino] -2-methylpropyl} -N- (4 Prepared from -chlorobenzyl) benzamide (Preparation Example 46) using the method of Example 33 to give 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

  According to the method used for Preparative Example 1, {3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) ethyl] phenyl} acetic acid ( Prepared using Preparation 51) and the appropriate amine to give 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

  According to the method used for Preparative Example 1, {3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) ethyl] phenyl} acetic acid ( Prepared using Preparation 51) and the appropriate amine to give 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

  According to the method used for Preparative Example 1, {3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) ethyl] phenyl} acetic acid ( Prepared using Preparation 51) and the appropriate amine to give the title compound as a white foam.

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

  According to the method used for Preparative Example 1, {3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) ethyl] phenyl} acetic acid ( Prepared using Preparation 51) and the appropriate amine to give 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

  According to the method used for Preparative Example 1, {3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) ethyl] phenyl} acetic acid ( Prepared using Preparation 51) and the appropriate amine to give 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

  According to the method used for Preparative Example 1, {3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) ethyl] phenyl} acetic acid ( Prepared using Preparation 51) and the appropriate amine to give 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 (preparation) in DMF (2 ml) Example 59) To a solution of (116 mg, 0.22 mmol), triethylamine (62 [mu] l, 0.45 mmol), benzylamine (29 [mu] l, 0.27 mmol), HOBt (33 mg, 0.25 mmol) and WSCDI (47 mg, 0.25 mmol) And the resulting solution was stirred at room temperature for 18 hours. The solvent was removed in vacuo and the residue was partitioned between saturated aqueous sodium bicarbonate (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 eluted by dichloromethane: methanol: 880 ammonia (90: 10: 1, volume ratio) by flash column chromatography on silica gel to give 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] benzoic acid according to the method used for Example 48 Prepared using the acid (Preparation 59) and the appropriate amine to give 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] benzoic acid according to the method used for Example 48 Prepared using the acid (Preparation 59) and the appropriate amine to give 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] benzoic acid according to the method used for Example 48 Prepared using the acid (Preparation 59) and the appropriate amine to give the title compound as a white foam.

Example 52: N- [2- (4-chlorophenyl) ethyl] -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 according to the method used for Example 48 Prepared using the acid (Preparation 59) and the appropriate amine to give 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] benzoic acid according to the method used for Example 48 Prepared using the acid (Preparation 59) and the appropriate amine to give 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] benzoic acid according to the method used for Example 48 Prepared using the acid (Preparation 59) and the appropriate amine to give 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] benzoic acid according to the method used for Example 48 Prepared using the acid (Preparation 59) and the appropriate amine to give 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] benzoic acid according to the method used for Example 48 Prepared using the acid (Preparation 59) and the appropriate amine to give the title compound as a white foam.

Example 57: 4-[(1R) -2-({(1R) -2- [3- (3,4-dihydroisoquinolin-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] benzoic acid according to the method used for Example 48 Prepared using the acid (Preparation 59) and the appropriate amine to give 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] benzoic acid according to the method used for Example 48 Prepared using the acid (Preparation 59) and the appropriate amine to give the title compound as a white foam.

Example 59: 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

3-[(2R) -2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) propyl] benzoic acid according to the method used for Example 48 Prepared using the acid (Preparation 59) and the appropriate amine to give 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 (preparation) in DMF (3 ml) Example 59) To a solution of (120 mg, 0.27 mmol), triethylamine (111 μl, 0.79 mmol), 4-chlorobenzylamine (39 μl, 0.32 mmol), and HBTU (110 mg, 0.29 mmol) were added to give The solution was stirred at room temperature for 18 hours. The solvent is removed in vacuo and the residue is eluted by flash column chromatography on silica gel with dichloromethane: methanol: 880 ammonia (changing from 93: 7: 0.7 to 90: 10: 1, volume ratio). To give the title compound 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] benzoic acid according to the method used for Example 60 Prepared using the acid (Preparation 59) and the appropriate amine to give the title compound as a white foam.

Example 62: N- [4- (aminosulfonyl) 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 according to the method used for Example 60 Prepared using acid (Preparation 59) and the appropriate amine, replacing dichloromethane: methanol: 880 ammonia (85: 15: 2, volume ratio) as eluent to give 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- (hydroxymethyl)] in methanol (12 mL) and water (2 mL) Phenyl] ethyl} amino) -2-methylpropyl] -N- [2- (3-fluorophenyl) ethyl] benzamide (Preparation Example 157) (343 mg, 0.58 mmol), and ammonium fluoride (213 mg, 5.76 mmol) ) At room temperature for 42 hours. The solvent was removed in vacuo and the residue was purified by column chromatography on silica gel eluting with dichloromethane: methanol: 0.88 ammonia, 100: 0: 0 to 90: 10: 1. Appropriate fractions were concentrated in vacuo and the residue azeotroped in ethanol (x2) to give a white solid. The solid was then recrystallized with ethanol / water and dried under vacuum to give the title compound as very pale yellow crystals in 52% yield, 144 mg.

Examples 64-78
The following compounds of the general formula shown below were prepared by methods similar to those described for Example 63 using the appropriate starting materials and ammonium fluoride. The reaction mixture was warmed to 40 ° C. until thin layer chromatography analysis showed that all starting material was consumed.

Example 65 : The compound was further purified by trituration with diethyl ether.
Example 72 : Purified by column chromatography using an ISCO® silica cartridge, eluting with dichloromethane: methanol: 0.88 ammonia, 100: 0 to 90: 10: 1.

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

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

  The title compound is 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 (Preparation Example 110) was used in the same manner as in Example 33 to give a colorless solid in a yield of 61%. Prepared.

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

  The title compound is 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 (Preparation Example 109) was prepared using a method similar to that of Example 33. The crude product was further purified by column chromatography on Biotage® amino silica gel, eluting with dichloromethane: methanol, 80:20, to give the title compound as a colorless viscous material in 54% yield. .

Example 81
N- (cycloheptylmethyl) -2- {3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl ] Phenyl} acetamide

  The title compound is 2- {3- [2-({(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl } Amino) -2-methylpropyl] phenyl} -N- (cycloheptylmethyl) acetamide (Preparation Example 151) using a method similar to that of Example 33 to yield 69% as a white foam. Prepared.

Example 82
N-1-adamantyl-2- {3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] phenyl } Acetamide

  The title compound is N-1-adamantyl-2- {3- [2-({(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- [4-hydroxy-3- ( Prepared as a white foam in 41% yield from hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] phenyl} acetamide (Preparation Example 152) using a method similar to that of Example 33 did.

Example 83
N-benzyl-2- {3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] phenyl}- N-methylacetamide

  The title compound is 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 (Preparation Example 156) prepared as a colorless solid in 75% yield using a method similar to that of Example 33. did.

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) ethylamino] in N, N-dimethylacetamide (1 mL) -2-methylpropyl} benzoic acid (Preparation Example 37) (90 mg, 0.19 mmol), and O- (1H-benzotriazol-1-yl) in N, N-dimethylacetamide (0.5 mL) A solution of —N, N, N ′, N′-tetramethyluronium hexafluorophosphate (61 mg, 0.16 mmol) was added to 4-fluorophenethylamine (33 mg, 0 mL) in N, N-dimethylacetamide (0.5 mL). .19 mmol) solution. The resulting mixture was stirred at room temperature for 72 hours. The solvent was removed in vacuo and the residue was partitioned between dichloromethane (4 mL) and saturated sodium bicarbonate 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 a suspension of the residue in methanol (2 mL) and water (1 mL) and the mixture was stirred at room temperature for 72 hours. The reaction mixture was then concentrated in vacuo and the residue was eluted by column chromatography on silica gel with dichloromethane: methanol: 0.88 ammonia (100: 0: 0 to 91: 9: 1, volume ratio). Purification followed by trituration with diethyl ether gave the title compound in 50% yield, 45 mg.

Examples 85-91
The following compounds of the general formula shown below are prepared according to methods similar to those described for Example 84 3- {2-[(2R) -2- (tert-butyldimethylsilanyloxy) -2- ( Prepared using 4-hydroxy-3-hydroxymethyl-phenyl) ethylamino] -2-methylpropyl} benzoic acid (Preparation Example 37) and the appropriate amine as starting materials. Amines were either commercially available or were prepared as described in Preparative Examples 69-108.

Upon addition of the fluorinated amine, Examples 89, 90 and 91 were warmed to 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) ethylamino] in N, N-dimethylacetamide (1 mL) -2-methylpropyl} benzoic acid (Preparation Example 37) (90 mg, 0.19 mmol), and O- (1H-benzotriazol-1-yl) in N, N-dimethylacetamide (0.5 mL) A solution of —N, N, N ′, N′-tetramethyluronium hexafluorophosphate (61 mg, 0.16 mmol) was added to 4-ethoxy-3-methoxyphenethylamine in N, N-dimethylacetamide (0.5 mL). (37 mg, 0.19 mmol) was added to the solution. The resulting mixture was stirred at room temperature for 72 hours. The solvent was removed in vacuo and the residue was partitioned between dichloromethane (4 mL) and saturated sodium bicarbonate 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 dimethyl sulfoxide (700 μL), triethylamine trihydrofluoride (30 μL, 0.19 mmol) was added and the mixture was stirred at room temperature for 72 hours. The reaction mixture was then purified directly by HPLC using a Phenomenex Luna C18 system, eluting with water / 0.05% diethylamine: acetonitrile, 5:95 to 95: 5 to yield the title compound. Obtained at 30% (30.9 mg).

Examples 93-112
The following compounds of the general formula shown below are prepared according to methods similar to those described for Example 92 in 3- {2-[(2R) -2- (tert-butyldimethylsilanyloxy) -2- ( Prepared using 4-hydroxy-3-hydroxymethyl-phenyl) ethylamino] -2-methylpropyl} benzoic acid (Preparation Example 37) and the appropriate amine as starting materials. Amines were either commercially available or prepared as described in Preparative Examples 69-108.

Example 102 : {2- [2- (trifluoromethyl) phenyl] ethyl} amine can be prepared as described in WO2003092931.
Example 106 : 4-[[4- (2-Aminoethyl) phenyl] sulfonyl] -morpholine is commercially available from the Scientific Exchange Product List (K-046583).

Example 107 : The amine precursor (2- (2-aminoethyl) -6-chlorophenol) can be prepared as described in DE 1959898.
Example 108 : Crude compound eluted by HPLC using a Phenomenex Luna C18 system with water / acetonitrile / trifluoroacetic acid (5: 95: 0.1): acetonitrile, 95: 5 to 5:95. Purified and isolated the trifluoroacetate salt of the desired product.

Examples 109 to 110 : Crude compounds were purified by HPLC using a Phenomenex Luna C18 system, eluting with water / 0.1% formic acid: acetonitrile / 0.1% formic acid, 85:15 to 15:85. did.

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-methylpropyl ] -N- [2- (2-chlorophenyl) ethyl] benzamide (Preparation Example 118), (147 mg, 0.24 mmol), and triethylamine trihydrofluoride (39 μL, 0.24 mmol) were mixed at room temperature for 3 days. Stir. The mixture is then concentrated in vacuo and the residue is purified by column chromatography on silica gel, eluting with dichloromethane: methanol: 0.88 ammonia, 100: 0: 0 to 95: 5: 0.5. did. Appropriate fractions were evaporated under reduced pressure and the residue azeotroped with methanolic ammonia to give the title compound as a colorless solid in 77% yield, 75 mg.

Examples 114-128
The following compounds of the general formula shown below were prepared in a manner similar to that described for Example 113 using the appropriate starting materials and triethylamine trihydrofluoride. The reaction was monitored by tlc analysis and stirred at room temperature for 17-72 hours.

Example 129
N- (3,4-dichlorobenzyl) -3- {3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2 -Methylpropyl] phenyl} propanamide

  The title compound is 3- {3- [2-({(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl } Amino) -2-methylpropyl] phenyl} -N- (3,4-dichlorobenzyl) propanamide (Preparation Example 145) using a method similar to that of Example 113 as a white foam. It was prepared at a rate of 71%.

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-methylpropyl in N, N-dimethylformamide (5 mL) ] Benzoic acid (Preparation Example 140) (100 mg, 0.28 mmol), 2- (4-trifluoromethoxyphenyl) ethylamine (US20020082454A1, p2) (46 mg, 0.28 mmol), 1- (3-dimethylaminopropyl)- A mixture of 3-ethylcarbodiimide hydrochloride (43 mg, 0.28 mmol), 1-hydroxybenzotriazole hydrate (35 mg, 0.28 mmol), and triethylamine (60 μL, 0.45 mmol) was stirred at room temperature for 20 hours. The reaction mixture was then concentrated in vacuo and the residue was dissolved in dichloromethane. The solution was then washed with saturated sodium carbonate solution and 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, 100: 0: 0 to 95: 5: 1 to give the title compound as a white powder in 51% yield. Obtained at 79 mg.

Examples 131-137
The following compounds of the general formula shown below were prepared by methods similar to those described for Example 130, using the appropriate acid and amine as starting materials. Amines were either commercially available or were prepared as described in Preparative Examples 69-108.

Example 131 : An amine precursor (4- (2-amino-1,1-dimethylethyl) phenol) can be prepared as described in Acta Chem. Scand. 8, 1203, 1207; 1954.

Examples 138 to 147

  3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] benzoic acid (Preparation Example 140) (dimethylacetamide /3.75% 0.2M in triethylamine, 225 μL, 45 μmol), suitable amine (dimethylacetamide / 0.2M in 3.75% triethylamine, 150 μL, 30 μmol), and O- (1H-benzotriazole- A mixture of 1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate (0.2 M in dimethylacetamide, 225 μL, 45 μmol) was stirred at 60 ° C. for 3 days. The reaction mixture was then concentrated in vacuo, redissolved in dimethyl sulfoxide (300 μL) and stirred for 30 minutes at room temperature. The mixture was further diluted with dimethyl sulfoxide (50 μL) and water (100 μL), stirred at room temperature for 1 minute, and then by HPLC using a Phenomenex Luna C18 system with water / acetonitrile / diethylamine (5: 95: 0. 05): Acetonitrile, eluting with 95: 5 to 5:95 and purified to give the desired compound.

Example 138 : N-ethyl-3-phenylpropylamine can be prepared as described in J. Med. Chem., 34, 248; 1991.
Example 141 : 6-methoxy-3-pyridineethanamine can be prepared as described in Drug Design and Discovery, 10, 35; 1993.

Example 143 : 2- [4- (Pyrazol-1-yl) phenoxy] ethylamine can be prepared as described in WO20020332897, p55.
Example 146 : 5-Quinolineethanamine can be prepared as described in J. Med. Chem., 28, 1803-10; 1985.

Preparation Example 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 (Preparation Example 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 The turbid liquid was left stirring at room temperature under a nitrogen atmosphere for 18 hours. The solvent was removed in vacuo and the residue was partitioned between ethyl acetate (10 ml) and saturated aqueous sodium bicarbonate (10 ml). The organic phase was separated and extracted from the aqueous phase with additional ethyl acetate (2 × 10 ml). The combined organic extracts were washed with water (5 ml), brine (5 ml), dried (sodium sulfate) and the solvent removed in vacuo. The residue was purified by flash column chromatography on silica gel eluting with dichloromethane: methanol: 880 ammonia (95: 5: 0.5, volume ratio) to give the title compound as a pale yellow oil ( 150 mg).

Preparation Example 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

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

Preparation Example 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

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

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

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

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

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

Preparation Example 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

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

Preparation Example 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

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

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

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

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

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

Preparation Example 10: 2- {3-[(2R) -2-({(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- [4-hydroxy-3- (hydroxymethyl) Phenyl] ethyl} amino) propyl] phenyl} -N- (cyclohexylmethyl) acetamide

  According to the method used for Preparation 1, (3-{(2R) -2-[(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- (4-hydroxy-3-hydroxymethyl) Prepared using -phenyl) -ethylamino] -propyl} -phenyl) -acetic acid (Preparation Example 20) and the appropriate amine to give the title compound as a white foam.

Preparation Example 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

  According to the method used for Preparation 1, (3-{(2R) -2-[(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- (4-hydroxy-3-hydroxymethyl) Prepared using -phenyl) -ethylamino] -propyl} -phenyl) -acetic acid (Preparation Example 20) and the appropriate amine to give the title compound as a white foam.

Preparation Example 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

  According to the method used for Preparation 1, (3-{(2R) -2-[(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- (4-hydroxy-3-hydroxymethyl) Prepared using -phenyl) -ethylamino] -propyl} -phenyl) -acetic acid (Preparation Example 20) and the appropriate amine to give the title compound as a white foam.

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

  According to the method used for Preparation 1, (3-{(2R) -2-[(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- (4-hydroxy-3-hydroxymethyl) Prepared using -phenyl) -ethylamino] -propyl} -phenyl) -acetic acid (Preparation Example 20) and the appropriate amine to give the title compound as a white foam.

Alternative Method The title compound was prepared from N-1-adamantyl-2- {3-[(2R) -2-({(2R) -2- [4- (benzyloxy) -3- (hydroxymethyl) phenyl]- Prepared as a colorless foam in 91% yield from 2-hydroxyethyl} amino) propyl] phenyl} acetamide (Preparation Example 164) using a method similar to that of Preparation Example 25.

Preparation Example 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

  According to the method used for Preparation 1, (3-{(2R) -2-[(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- (4-hydroxy-3-hydroxymethyl) Prepared using -phenyl) -ethylamino] -propyl} -phenyl) -acetic acid (Preparation Example 20) and the appropriate amine to give the title compound as a white foam.

Preparation Example 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

  According to the method used for Preparation 1, (3-{(2R) -2-[(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- (4-hydroxy-3-hydroxymethyl) Prepared using -phenyl) -ethylamino] -propyl} -phenyl) -acetic acid (Preparation Example 20) and the appropriate amine to give the title compound as a white foam.

Preparation Example 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

  According to the method used for Preparation 1, (3-{(2R) -2-[(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- (4-hydroxy-3-hydroxymethyl) Prepared using -phenyl) -ethylamino] -propyl} -phenyl) -acetic acid (Preparation Example 20) and the appropriate amine to give the title compound as a white foam.

Preparation Example 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

  According to the method used for Preparation 1, (3-{(2R) -2-[(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- (4-hydroxy-3-hydroxymethyl) Prepared using -phenyl) -ethylamino] -propyl} -phenyl) -acetic acid (Preparation Example 20) and the appropriate amine to give the title compound as a white foam.

Preparation Example 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

  According to the method used for Preparation 1, (3-{(2R) -2-[(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- (4-hydroxy-3-hydroxymethyl) Prepared using -phenyl) -ethylamino] -propyl} -phenyl) -acetic acid (Preparation Example 20) and the appropriate amine to give the title compound as a white foam.

Preparation Example 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

  According to the method used for Preparation 1, (3-{(2R) -2-[(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- (4-hydroxy-3-hydroxymethyl) Prepared using -phenyl) -ethylamino] -propyl} -phenyl) -acetic acid (Preparation Example 20) and the appropriate amine to give the title compound as a white foam.

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

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

Preparation Example 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-] in ethanol (50 ml) Hydroxymethyl-phenyl) -ethylamino] -propyl} -phenyl) -acetate (Preparation 22) (5.27 g, 9.12 mmol), and 10% palladium / carbon (1.00 g) under hydrogen atmosphere (60 psi) And stirred at room temperature for 16 hours. The catalyst was filtered off 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 (changing from 96: 4: 0.4 to 95: 5: 0.5, volume ratio) to give the title Was obtained as a pale yellow oil (1.99 g) which was used without further purification.

Preparation Example 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 (Preparation Example 23) in dichloromethane (130 ml) A solution of (12.5 g, 27.7 mmol) and methyl {3-[(2R) -2-aminopropyl] phenyl} acetate (Preparation Example 25) (11.5 g, 55.4 mmol) was heated to 90 ° C. Dichloromethane was evaporated. 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 with dichloromethane: methanol: 880 ammonia (change from 98: 2: 0.2 to 97: 3: 0.3, volume ratio). Elution and purification gave the title compound as a white oil (12.1 g).

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

  Borane dimethylsulfide complex (10M solution in tetrahydrofuran 42.4 ml, 424 mmol) was converted to methyl 2- (benzyloxy) -5-((1R) -2-bromo-1-{[tert-butyl] in tetrahydrofuran (1600 ml). (Dimethyl) silyl] oxy} ethyl) benzoate (Preparation Example 24) (91.0 g, 189 mmol) was added dropwise. Next, the obtained mixture was heated and refluxed for 2 hours, then cooled to 0 ° C., and the reaction was stopped with methanol (270 ml). The mixture was left stirring at room temperature for 16 hours, after which 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 solution (500 ml), dried (magnesium sulfate) and the solvent removed in vacuo. The residue was purified by flash column chromatography on silica gel eluting with cyclohexane: ethyl acetate (changed from 100: 0 to 80:20, volume ratio) to give the title compound (68.7 g) as a colorless oil. Got as.

Preparation 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), imidazole (18.52 g, N, N-dimethylformamide (270 ml) 272 mmol), tert-butyldimethylsilyl chloride (32.23 g, 214 mmol), and 4- (N, N-dimethylamino) pyridine (0.44 g, 3.6 mmol) were stirred at room temperature under a nitrogen atmosphere. Stirred for 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, washed with 2N hydrochloric acid (2 times 500 ml), saturated aqueous sodium bicarbonate (2 times 500 ml), saturated sodium chloride (500 ml), dried (magnesium sulfate), solvent removed in vacuo, The title compound was obtained as a colorless oil (91.0 g).

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

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

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

  Methyl [3- (2-oxopropyl) phenyl] acetate (Preparation 27) (8.5 g, 41.2 mmol), (R) -α-methylbenzylamine (4.8 ml, 37.37) in dichloromethane (400 ml). 2 mmol), sodium triacetoxyborohydride (11.6 g, 56 mmol) and acetic acid (2.2 ml, 38 mmol) were stirred at room temperature for 48 hours. The reaction was stopped by adding saturated aqueous sodium bicarbonate (200 ml) to the reaction mixture and allowed to stir until boiling was complete. The organic phase was separated and extracted from the aqueous phase with dichloromethane (100 ml). The combined organic extracts were dried (magnesium sulfate) and concentrated in vacuo. Purify by flash column chromatography eluting with dichloromethane: methanol: ammonia (99: 1: 0.1 to 95: 5: 0.5, volume ratio) to obtain a 4: 1 mixture of diastereomers (mainly R , R) was obtained as a pale yellow oil (8.71 g). After treatment with hydrogen chloride (1M solution in methanol 40 ml, 40 mmol), three successive crystallizations (diisopropyl ether / methanol) gave the title compound as a white crystalline solid (5.68 g).

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

  Tributyltin methoxide (28.3 mg, 98 mmol), Preparation 28 (15.0 g, 65 mmol), Isopropenyl acetate (10.8 ml, 98 mmol), Palladium (II) acetate (750 mg, 3.30 mmol) and Tri-ortho- Tolylphosphine (2.0 g, 6.5 mmol) was combined in toluene (75 ml) and stirred at 100 ° C. under nitrogen for 5 hours. After cooling, the reaction mixture 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 arbocel and the organic phase was separated and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a gradient varying from diethyl ether: pentane (0: 100 to 25:75, volume ratio) to dichloromethane to give the title compound as a pale yellow oil. Obtained (12.6 g).

Preparation Example 28: Methyl (3-bromophenyl) acetate

  Acetyl chloride (0.7 ml, 9.3 mmol) was added slowly to a solution of (3-bromo-phenyl) -acetic acid (20.0 g, 93 mmol) in methanol (500 ml) at 0 ° C. under nitrogen. Was allowed to warm slowly to room temperature over 5 hours. The solvent was removed in vacuo and the residual oil was redissolved in dichloromethane, dried (sodium sulfate) and concentrated in vacuo to give the title compound as a colorless oil (20.6 g).

Preparation Example 29: 1- (3-Bromophenyl) -2-methylpropan-2-ol)

  Methyl magnesium bromide (3M solution in diethyl ether, 51.6 ml, 155 mmol) was added to 1- (3-bromo-phenyl) propan-2-one (15.0 g, dry diethyl ether (200 ml)). 70 mmol) was added slowly at 0 ° C. The resulting mixture was allowed to stand for 3 hours, cooled to 0 ° C., and slowly quenched with a saturated aqueous ammonium chloride solution. The organic phase was washed with brine and dried (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 pale yellow oil (13.26 g). ).

Preparation Example 30: N- [2- (3-Bromophenyl) -1,1-dimethylethyl] -2-chloroacetamide

  Chloroacetonitrile (6.63 ml, 105 mmol) was added to 1- (3-bromophenyl) -2-methylpropan-2-ol) (Preparation Example 29) (12.0 g, 52.0 mmol) in acetic acid (25 ml). To the stirred solution was added at room temperature. The resulting solution was cooled to 0 ° C. and concentrated sulfuric acid (25 ml) was added keeping the temperature <10 ° C. The resulting solution was left stirring for 1 hour, then poured onto ice and made alkaline by adding solid potassium carbonate. The product is extracted with ethyl acetate (2 × 500 ml), the organic phases are combined, washed with water (50 ml), dried (sodium sulfate), the solvent removed in vacuo and the title compound as an orange solid Obtained (16.08 g).

Preparation Example 31: 2- (3-Bromophenyl) -1,1-dimethylethylamine

  N- [2- (3-Bromophenyl) -1,1-dimethylethyl] -2-chloroacetamide (Preparation 30) (32.0 g, 105 mmol), thiourea (9.60 g) in ethanol (250 ml) 126 mmol) and acetic acid (50 ml) were heated to reflux overnight. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated in vacuo and made alkaline with aqueous sodium hydroxide (1M, 450 ml). The product was extracted with dichloromethane (2 × 500 ml) and the combined organic solution was washed with brine (50 ml), dried (sodium sulfate) and the solvent removed in vacuo to give the title compound as a black oil As 23 g.

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

  2- (3-Bromophenyl) -1,1-dimethylethylamine (Preparation 31) (5.0 g, 22 mmol) was added with di-tert-butyl bicarbonate (5.26 g, 24 mmol) in dichloromethane (50 ml). Treated and stirred for 20 hours. The reaction mixture was washed with water (50 ml), the combined organic solution was dried (sodium sulfate) and the solvent was removed in vacuo. The crude product material was purified using a cation exchange column (methanol followed by 2M ammonia in methanol) followed by flash column chromatography on silica gel eluting with dichloromethane to give the title compound Was obtained as a brown oil (7.23 g).

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

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

Preparation Example 34: 3- (2-Amino-2-methylpropyl) benzoic acid methyl ester

  A solution of 3- (2-tert-butoxycarbonylamino-2-methylpropyl) benzoic acid methyl ester (Preparation Example 33) (1.6 g, 5.2 mmol) in dichloromethane (160 ml) at 0 ° C. was added to trifluoroacetic acid. (13.6 ml) and 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 as an amber oil (1.06 g).

Preparation Example 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 (Preparation Example 34) (1.36 g, 6.60 mmol), [2- (benzyloxy) -5-((1R ) -2-Bromo-1-{[tert-butyl (dimethyl) silyl] oxy} ethyl) phenyl] methanol (Preparation Example 23) (2.96 g, 6.60 mmol), sodium iodide (980 mg, 6.60 mmol) And diisopropylethylamine (3.44 ml, 19.7 mmol) were heated to reflux for 48 hours under a nitrogen atmosphere. The solvent was then removed in vacuo, saturated aqueous sodium bicarbonate (20 ml) was added and the product was extracted with ethyl acetate (3 × 20 ml). The combined organic solution was washed with brine (3 × 20 ml), dried (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 volume ratio) to give the title compound. The purified product was dissolved in diethyl ether and evaporated (x3) to give a white foam (1.70 g).

Preparation Example 36: 3- {2-[(2R) -2- (tert-butyldimethylsilanyloxy) -2- (4-hydroxy-3-hydroxymethyl-phenyl) ethylamino] -2-methylpropyl} benzoate 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 (Preparation 35) (2.12 g, 3.70 mmol) and palladium / carbon (10%, 300 mg) were hydrogenated at room temperature and 60 psi for 18 hours. The reaction mixture was filtered through arbocel, the filtrate was concentrated in vacuo, and the residue was eluted by flash column chromatography on silica gel with dichloromethane: methanol: ammonia (95: 5: 0.5 volume ratio). To give the title compound, which was dissolved in diethyl ether and evaporated (x3) to give a white foam (1.50 g).

Preparation Example 37: 3- {2-[(2R) -2- (tert-butyldimethylsilanyloxy) -2- (4-hydroxy-3-hydroxymethyl-phenyl) ethylamino] -2-methylpropyl} benzoic acid acid

  3- {2-[(2R) -2- (tert-butyldimethylsilanyloxy) -2- (4-hydroxy-3-hydroxymethyl-phenyl) ethylamino] -2-methylpropyl} benzoic acid methyl ester ( Preparation Example 36) (1.50 g, 3.08 mmol), aqueous sodium hydroxide (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 off and dried in vacuo for 72 hours to give the title compound as a white solid (1.28 g).

Preparation Example 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 added to 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (203 mg, 1.06 mmol), 3- {2-[(2R) -2- (tert-butyldimethylsilanyloxy) -2- (4-hydroxy-3-hydroxymethyl-phenyl) ethylamino] -2-methylpropyl} benzoic acid (Preparation Example 37) (500 mg, 1.06 mmol), 1-hydroxybenzotriazole hydrate (160 mg, 1.06 mmol), and triethylamine (440 μl, 3.20 mmol) were added to a mixture. The resulting solution was stirred for 48 hours under nitrogen. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate (30 ml) and washed with water (20 ml), sodium bicarbonate (5.0 M, 2 × 20 ml), brine (2 × 20 ml) and dried ( Sodium sulfate), the solvent was removed in vacuo. The residue was purified by flash column chromatography on silica gel eluting with dichloromethane: methanol: ammonia (95: 5: 0.5 volume ratio) to give the title compound. The resulting material was dissolved in methanol and evaporated, then dissolved in diethyl ether and evaporated to give a white foam (480 mg).

Preparation Example 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 according to the method used for Preparation 38 Prepared using -methylpropyl} benzoic acid (Preparation Example 37) and the appropriate amine to give the title compound as a white foam.

Preparation Example 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 according to the method used for Preparation 38 Prepared using -methylpropyl} benzoic acid (Preparation Example 37) and the appropriate amine to give the title compound as a white foam.

Preparation Example 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 according to the method used for Preparation 38 Prepared using -methylpropyl} benzoic acid (Preparation Example 37) and the appropriate amine to give the title compound as a white foam.

Preparation Example 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 according to the method used for Preparation 38 Prepared using -methylpropyl} benzoic acid (Preparation Example 37) and the appropriate amine to give the title compound as a white foam.

Preparation Example 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 according to the method used for Preparation 38 Prepared using -methylpropyl} benzoic acid (Preparation Example 37) and the appropriate amine to give the title compound as a white foam.

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

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

Preparation Example 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 according to the method used for Preparation 38 Prepared using -methylpropyl} benzoic acid (Preparation Example 37) and the appropriate amine to give the title compound as a white foam.

Preparation Example 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 according to the method used for Preparation 38 Prepared using -methylpropyl} benzoic acid (Preparation Example 37) and the appropriate amine to give the title compound as a white foam.

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

  {3- [2- (2-Chloro-acetylamino) -2-methyl-propyl] -phenyl} -acetic acid (Preparation Example 48) (5.1 g, 18 mmol) in ethanol (80 ml), thiourea (1. A solution of 6 g, 21 mmol) and acetic acid (18 ml) was heated to reflux for 16 hours under a nitrogen atmosphere. The reaction mixture was cooled and filtered. The filtrate was concentrated in vacuo, the residue was dissolved in ethanol (150 ml), saturated with hydrogen chloride gas, and the resulting solution was heated to reflux for 16 hours. The solvent was concentrated 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 (sodium sulfate) and concentrated in vacuo. The residue was passed through a strong cation exchange resin with methanol followed by 2N ammonia in methanol to elute the product. The eluate was concentrated in vacuo to give the title compound as a yellow oil (2.68 g, 63%).

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

  Concentrated sulfuric acid (21 ml) was added to [3- (2-hydroxy-2-methyl-propyl) -phenyl] -acetic acid (Preparation 49) (10.6 g, 51.0 mmol) and chloroacetonitrile in glacial acetic acid (16 ml). (4.8 ml, 76.0 mmol) was added dropwise at 0 ° C. The reaction was allowed to warm to room temperature and poured into ice water (500 ml) after 2 hours. Extract from this aqueous solution with ethyl acetate (2 × 250 ml), wash the combined organic solution with brine (50 ml), dry (sodium sulfate) and remove the solvent in vacuo to give the title compound as a golden oil. Obtained as material (14.0 g).

Preparation Example 49: [3- (2-Hydroxy-2-methyl-propyl) -phenyl] -acetic acid

A stirred solution of methylmagnesium chloride (3M solution in tetrahydrofuran 51 ml, 153 mmol) in ester (11.6 g, 51 mmol) (International Journal of Peptide and Protein Research, 1987, 29 (3), 331) in tetrahydrofuran (300 ml). Was added dropwise at 0 ° C. under nitrogen. The reaction was allowed to warm to room temperature overnight to form a thick white precipitate, then water (50 ml) and 2N hydrochloric acid (80 ml) were carefully added. Extract from this aqueous solution with ethyl acetate (2 × 300 ml), wash the combined organic solution with brine (50 ml), dry (sodium sulfate) and remove the solvent in vacuo to give the title compound as a golden oil. Obtained as material (11.2 g).

Need to name the ester?
Preparation Example 50: {3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] phenyl} acetic acid

  According to the method used for Preparation 20, ethyl {3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl ] Phenyl} acetate (Preparation Example 68) to give the title compound as a cream solid.

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

  According to the method used for Preparation 20, ethyl {3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) ethyl] phenyl} acetate Prepared using (Preparation Example 52) to give the title compound as a white solid.

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

  According to the method used for Preparation Example 21, ethyl {3- [2-({(2R) -2- [4- (benzyloxy) -3- (hydroxymethyl) phenyl] -2-hydroxyethyl} amino) ethyl] Prepared using phenyl} acetate (Preparation Example 53) to give the title compound as an orange oil.

Preparation 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-] in methanol (15 ml) and water (10 ml). A solution of butyl (dimethyl) silyl] oxy} ethyl) amino] ethyl} phenyl) acetate (Preparation Example 54) (2.39 g, 4.14 mmol) was treated with ammonium fluoride (1.53 g, 41.4 mmol). The reaction was heated to 40 ° C. for 16 hours. Methanol was removed in vacuo and extracted from the aqueous residue with dichloromethane (3 × 50 ml). The combined organic solution is dried (sodium sulfate), the solvent is removed in vacuo, and the residue is purified by flash column chromatography on silica gel with dichloromethane: methanol: 880 ammonia (97: 3: 0.3 to 95: 5). Elution at: 0.5, volume ratio) to give the title compound as an orange gum (1.90 g).

Preparation Example 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 (preparation example) according to the method used for preparation example 22. 23), and ethyl [3- (2-aminoethyl) phenyl] acetate (Preparation Example 58) to give the title compound as a yellow oil.

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

  Carbonyldiimidazole (5.11 g, 31.5 mmol) was stirred into an ester (International Journal of Peptide and Protein Research, 1987, 29 (3), 331) (7.00 g, 31.5 mmol) in tetrahydrofuran (100 ml). To the solution was added in one portion at room temperature under nitrogen. The reaction was stirred for 2 hours, water (26 ml) was added and the reaction was 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 for 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 extracted from the aqueous phase with ethyl acetate (2 × 75 ml), the combined organic solution was dried (sodium sulfate) and the solvent was removed in vacuo to give a white solid. This was purified by flash column chromatography on silica gel eluting with ethyl acetate: pentane (50:50, volume ratio) to give the title compound as a colorless oil (4.60 g).

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

  Methanesulfonyl chloride (2.78 g, 24.3 mmol) was added to ethyl [3- (2-hydroxyethyl) phenyl] acetate (Preparation 55) (4.60 g, 22.1 mmol) and triethylamine (dichloromethane (250 ml)). 3.40 ml, 24.3 mmol) was added dropwise at 0 ° C. under nitrogen. The reaction was allowed to warm to room temperature over 1 hour and washed with saturated aqueous sodium bicarbonate (75 ml). The aqueous solution was washed with dichloromethane (2 × 100 ml) and the combined organic solution was washed with water (25 ml), dried (sodium sulfate) and the solvent removed in vacuo to give the title compound as a colorless oil. (6.2 g).

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

  Sodium azide (2.82 g, 43.3 mmol) was added to ethyl (3- {2-[(methylsulfonyl) oxy] ethyl} phenyl) acetate (Preparation Example 56) in N, N-dimethylformamide (400 ml) ( 6.20 g, 21.7 mmol) was added in one portion at room temperature. 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 (200 ml) and water (75 ml) were added, the organic solution was separated, the aqueous solution was washed with ethyl acetate (2 × 100 ml), and the combined organic solutions were evaporated in vacuo to give an oil. This was purified by flash column chromatography on silica gel, eluting with ethyl acetate: pentane (5:95, volume ratio) to give the title compound as a colorless oil (4.65 g).

Preparation 58: Ethyl [3- (2-aminoethyl) phenyl] acetate

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

Preparation 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] benzoate (35 ml) in tetrahydrofuran (35 ml) Preparation 60) To a solution of (5.12 g, 14.24 mmol) was added aqueous lithium hydroxide (1M, 29 ml, 29 mmol) and the solution was left stirring 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 give the title compound as an off-white solid (5.87 g), which was used without further purification.

Preparation 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) phenyl] -2-hydroxyethyl} amino) propyl in ethanol (100 ml) A suspension of benzoate (Preparation 61) (6.83 g, 15.2 mmol) and 10% palladium / carbon (683 mg) was stirred at room temperature under an atmosphere of hydrogen (60 psi) for 18 hours. The catalyst was filtered off 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 (changing from 95: 5: 0.5 to 90: 10: 1, volume ratio) to give the title compound Was obtained as a pale yellow viscous substance (5.12 g).

Preparation 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 (Preparation 62) (10 g, 17.74 mmol) and ammonium fluoride (6.57 g, 117 mmol) was heated at 40 ° C. for 18 hours. did. Methanol was removed in vacuo and extracted from the remaining aqueous layer with dichloromethane (2 × 100 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 (95: 5: 0.5, volume ratio) to give the title compound (6.83 g) Was obtained as a pale yellow viscous substance.

Preparation Example 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 (Preparation Example 23) in dichloromethane (70 ml) A solution of (9.23 g, 20.5 mmol) and methyl {3-[(2R) -2-aminopropyl] phenyl} acetate (Preparation Example 63) (8.48 g, 40.9 mmol) was heated to 90 ° C. Dichloromethane was evaporated. The resulting melt was left at 90 ° C. for an additional 18 hours. Cool the reaction mixture to room temperature and change by flash column chromatography on silica gel changing dichloromethane: methanol: 880 ammonia (98: 2: 0.2 to 97.5: 2.5: 0.25, volume ratio To give the title compound (10 g) as an orange oil.

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

Methyl [3-((2R) -2-{[(1R) -1-phenyl-ethyl] -amino} -propyl) -phenyl] -acetate (Preparation Example 64) (13.65 g) in ethanol (200 ml) 40.9 mmol) and ammonium formate (12.9 g, 204 mmol) were heated to reflux in the presence of 20% palladium hydroxide / carbon (Pd (OH) _{2 /} C, 1.36 g). After 3 hours, the reaction mixture was cooled to room temperature, filtered through arbocel, 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. Extract from the aqueous phase with further dichloromethane (3 × 100 ml) and wash the combined organic extracts with brine (100 ml), dry (sodium sulfate) and concentrate in vacuo to give the title compound (8.48 g) Was obtained as a pale yellow oil.

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

  Methyl [3- (2-oxopropyl) phenyl] acetate (Preparation 65) (45.3 g, 236 mmol), (R) -α-methylbenzylamine (27.6 ml, 214 mmol), trichloromethane (1500 ml) A solution of sodium acetoxyborohydride (68.1 g, 321 mmol) and acetic acid (14.7 ml, 257 mmol) was stirred at room temperature for 18 hours. The reaction was stopped by adding saturated aqueous sodium bicarbonate (600 ml) to the reaction mixture and allowed to stir until boiling was complete. The organic phase was separated and extracted from the aqueous phase with additional dichloromethane (2 × 100 ml). The combined organic extracts were washed with brine (100 ml), dried (sodium sulfate) and concentrated in vacuo through celite. This oil was dissolved in methanol (200 ml), treated with 1M hydrochloric acid in methanol (300 ml), concentrated in vacuo, and a 4: 1 mixture of diastereomers (mainly R, R) was converted to off-white hydrochloric acid. Obtained as a salt. Two successive crystallizations (diisopropyl ether / methanol) gave the title compound (27.3 g) as a colorless crystalline solid.

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

Tributyltin methoxide (80.3 mg, 279 mmol), methyl 3-bromobenzoate (53.5 g, 249 mmol), isopropenyl acetate (39.4 ml, 358 mmol), palladium (II) acetate (2.6 g, 11.6 mmol) and Tri- O- tolylphosphine (7.1 g, 23.2 mmol) was combined in toluene (350 ml) and stirred at 100 ° C. under nitrogen for 18 hours. After cooling, the reaction solution 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 was washed with ethyl acetate. The organic phase was separated, dried (sodium sulfate) and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate: pentane (change from 10:90 to 20:80, volume ratio) to give the title compound (45.3 g) as an orange oil Obtained as material.

Preparation Example 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 (preparation example) according to the method used for preparation example 22. 23) and [3- (2-Amino-2-methyl-propyl) -phenyl] -acetic acid ethyl ester (Preparation Example 47) to give the title compound as a yellow oil.

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

  According to the method used for Preparation 53, ethyl (3- {2-[((2R) -2- [4- (benzyloxy) -3- (hydroxymethyl) phenyl] -2-{[tert-butyl (dimethyl ) Silyl] oxy} ethyl) amino] -2-methylpropyl} phenyl) acetate (Preparation Example 66) to give the title compound as an oil.

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

  According to the method used for Preparation 21, ethyl {3- [2-({(2R) -2- [4- (benzyloxy) -3- (hydroxymethyl) phenyl] -2-hydroxyethyl} amino) -2 -Methylpropyl] phenyl} acetate (Preparation Example 67) to give the title compound as a colorless oil.

Preparation Example 69
2- (3-Fluoro-4-trifluoromethyl-phenyl) -ethylamine

  Chlorotrimethylsilane (2 mL, 16 mmol) was added dropwise to lithium borohydride (2M solution in tetrahydrofuran, 4 mL, 8 mmol). A solution of 3-fluoro-4- (trifluoromethyl) phenylacetonitrile (312 mg, 4 mmol) in tetrahydrofuran (2 mL) was then added at 0 ° C. and the mixture was left to stir for 24 hours while simultaneously warming to room temperature. The mixture was then diluted with methanol (200 ml) and concentrated in vacuo. The residue was dissolved in 20% potassium hydroxide solution (20 mL) and extracted with dichloromethane (3 × 20 mL), the combined organic solution was dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography using an Isolute® SCX-2 cartridge eluting with methanol followed by 1M ammonia in methanol to give an oily residue. This oil was triturated with diethyl ether to give the title compound in 59% yield, 485 mg.

Preparation Example 70
2- (5-Chloro-2-methoxy-phenyl) -ethylamine

  The title compound was prepared in 52% yield from (5-chloro-2-methoxy-phenyl) acetonitrile (WO2004039377, p40) using a method similar to that of Preparation 69.

Preparation Examples 71 to 79
The following compounds of the general formula shown below were prepared in a manner similar to that described for Preparation 69, using the appropriate starting material phenylacetonitrile. Unless otherwise stated, R ³ to R ⁷ are hydrogen.

Preparative Example 79: The compound was purified using sulfonic acid functionalized lanterns.
Preparation Example 80
2- (4-Chloro-phenyl) -N-ethyl-acetamide

4-Chlorophenylacetic acid (1 g, 5.88 mmol) in dichloromethane (30 mL).
), Ethylamine (2M solution in tetrahydrofuran, 5.88 mL, 11.76 mmol), 1-hydroxybenzotriazole hydrate (90 mg, 5.88 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride A mixture of (1.13 g, 5.88 mmol) and triethylamine (1.78 g, 17.64 mmol) was stirred at room temperature for 18 hours. The mixture was then diluted with 1M sodium hydroxide solution (30 mL) and extracted from the aqueous phase 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 dichloromethane: methanol, 100: 0 to 90:10, to give the title compound as a colorless solid in 37% yield, 443 mg.

Preparation Example 81
[2- (4-Chloro-phenyl) -ethyl] -ethyl-amine hydrochloride

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

Preparation Example 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 solution in tetrahydrofuran, 5.6 mL, 5.6 mmol) and mixed. The solution was stirred at 0 ° C. for 1 hour. Additional lithium aluminum hydride (1M solution in tetrahydrofuran, 5.6 mL, 5.6 mmol) was added and the mixture was stirred at room temperature for 18 hours and then heated at reflux for 1 hour. The reaction mixture was cooled to 0 ° C., 1M sodium hydroxide solution (3 mL) was added dropwise and stirring was continued for an additional hour. The mixture was then filtered through Celite®, rinsed with ethyl acetate, and the filtrate was washed with 1M sodium hydroxide solution. The organic solution was then placed on an Isolute® SCX cartridge, washed with methanol and eluted with 1M ammonia in methanol. The relevant fractions are concentrated in vacuo and the residue is purified by column chromatography on silica gel, eluting with dichloromethane: methanol: 0.88 ammonia, 100: 0: 0 to 95: 5: 0.5. The title compound was obtained as a yellow oil in a yield of 18% and 154 mg.

Preparation Example 83
(4-Hydroxy-3-methyl-phenyl) -acetonitrile

  Boron tribromide (1M solution 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), − 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 again to −78 ° C., diluted with sodium bicarbonate 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 give the title compound as a white solid in 87% yield, 0.16 g.

Preparation Example 84
(4-Hydroxy-2,5-dimethyl-phenyl) -acetonitrile

  The title compound was prepared from (4-methoxy-2,5-dimethylphenyl) acetonitrile as a colorless solid in a yield of 60% using the same method as in Preparation Example 83.

Preparation Example 85
(4-Hydroxy-2,3-dimethyl-phenyl) -acetonitrile

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

Preparation Example 86
2- (4-Methoxy-2,5-dimethyl-phenyl) -ethylamine

  A mixture of (4-methoxy-2,5-dimethyl-phenyl) -acetonitrile (200 mg, 1.14 mmol) and Raney® nickel (50 mg) in 2M methanolic ammonia (10 mL) was added to 60 psi of hydrogen gas. The mixture was stirred at room temperature for 18 hours. Since Tlc analysis showed that all starting material was not consumed, additional Raney® nickel (50 mg) in 2M methanolic ammonia (10 mL) was added. The reaction mixture was stirred under hydrogen gas 60 psi for an additional 18 hours at room temperature 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, 100: 0: 0 to 90: 10: 1 to give the title compound. Obtained as a pale brown solid in 38% yield, 98 mg.

Preparation Example 87
2- (4-Methoxy-2,3-dimethyl-phenyl) -ethylamine

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

Preparation Example 88
4- (2-Amino-ethyl) -2-methyl-phenol

  The title compound was prepared from (4-hydroxy-3-methylphenyl) -acetonitrile (Preparation Example 83) as a clear oil in 85% yield using a method similar to that of Preparation 86. .

Preparation Example 89
4- (2-Amino-ethyl) -2,5-dimethyl-phenol

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

Preparation Example 90
4- (2-Amino-ethyl) -2,3-dimethyl-phenol

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

Preparation Example 91
2- (2,3-Dimethyl-phenyl) -ethylamine

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

Preparation Example 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 solution in diethyl ether, 2.7 mL, 2.7 mmol) and aluminum trichloride. (359 mg, 2.7 mmol) was added to an ice-cold solution. The mixture was stirred at room temperature for 2.5 hours and then quenched with 1M sodium hydroxide solution (5 mL). The mixture was stirred for an additional 30 minutes and filtered through Celite®. The filtrate was phase separated and the organic solution was concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with dichloromethane: methanol: 0.88 ammonia, 100: 0: 0 to 95: 5: 0.5 to give the title compound as a clear oil. Yield 26%, obtained in 135 mg.

Preparation Example 93
2- (5-Chloro-2-fluoro-phenyl) -ethylamine

  Sodium borohydride (1.73 g, 45.51 mmol) was added to 5-chloro-2-fluorophenylacetonitrile (1.04 g, 6.15 mmol) and cobalt (II) chloride hexahydrate (2 mL) in methanol (30 mL). .18 g, 9.22 mmol) was added in portions and the mixture was stirred at room temperature for 3 hours. The suspension was then filtered through Celite®, concentrated in vacuo, and the residue was partitioned between 1M hydrochloric acid (40 mL) and dichloromethane (40 mL). The aqueous phase was separated, made alkaline 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, 100: 0: 0 to 98: 2: 0.2 to yield the title compound as a yellow oil. Obtained at a rate of 33%, 350 mg.

Preparation Example 94
2- (2-Chloro-4-fluoro-phenyl) -ethylamine

  The title compound was prepared from 2-chloro-4-fluorophenylacetonitrile as a pale brown oil in a yield of 46% using a method similar to that of Preparation 93.

Preparation Example 95
2- (4-Chloro-2-fluoro-phenyl) -ethylamine

  The title compound was prepared from 4-chloro-2-fluorophenylacetonitrile using a method similar to that of Preparation 93. The crude compound was purified using an Isco SCX® cartridge, eluting with methanol followed by 1M methanolic ammonia. The appropriate fractions are concentrated in vacuo and the residue is further purified by column chromatography on silica gel eluting with dichloromethane: methanol: 0.88 ammonia, 95: 5: 0.3 to give the title compound. Obtained as a pale yellow oil in 29% yield.

Preparation Example 96
(2,3-dihydro-benzofuran-2-yl) -methanol

A solution of meta-chloroperbenzoic acid (96.4 g, 335 mmol) in dichloromethane (500 mL) is added to an ice-cooled solution of 2-allylphenol (30 g, 224 mmol) in dichloromethane (1 L) and the mixture is added to 0 mL. Stir at 30 ° C. for 30 minutes and at room temperature for 18 hours. The reaction mixture was then cooled again 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 give a yellow oil. The oil was purified by HPLC using a Chiralpak AD 250 ^* 4.6 mm column and hexane: isopropanol (90:10) as eluent to give the title compound.

Preparation Example 97
2,3-dihydro-1-benzofuran-2-ylmethyl 4-methylbenzenesulfonate

  p-Toluenesulfonyl chloride (26.7 g, 140 mmol) was added to a solution of (2,3-dihydro-1-benzofuran-2-yl) -methanol (Preparation Example 96) (21 g, 149 mmol) in pyridine (400 mL). In addition, the mixture was stirred at room temperature for 4 days. The reaction mixture was then concentrated in vacuo and the residue azeotroped with toluene, diluted with ethyl acetate (500 mL) and washed with 2M hydrochloric acid (2 × 300 mL). The organic solution was dried over magnesium sulfate and concentrated in vacuo to give a brown oil. After trituration of this oil in cyclohexane, the title compound was obtained as a white solid in 79% yield, 35.5 g.

Preparation Example 98
2-Ethyl-2,3-dihydro-benzofuran

  Methyl lithium (1.6M solution 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 (Preparation 97) (15.2 g, 50 mmol) in diethyl ether (500 mL) and the reaction mixed. The solution was stirred at −40 ° C. for 1 hour and at room temperature for 2 hours. The mixture was then cooled to -70 ° C., 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 hours. Extract from the reaction mixture with diethyl ether (3 × 500 mL), dry the organic solution over magnesium sulfate and concentrate in vacuo to give the title compound as a brown oil in 98% yield, 7.25 g. I got it.

Preparation Example 99
(+) And (−) 5-bromo-2-ethyl-2,3-dihydro-benzofuran

N-bromosuccinimide (8.66 g, 48.6 mmol) is added to a solution of 2-ethyl-2,3-dihydro-benzofuran (Preparation 98) in dichloromethane (70 mL) and the mixture is stirred at room temperature for 18 hours. did. 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 give a yellow oil. The oil was purified by HPLC using a Chiralpak OJ 250 ^* 20 mm column and hexane: isopropanol (95: 5) as eluent to give the first enantiomer of the title compound. Further elution provided 2.95 g of the second isomer of the title compound.

Preparation Example 100
Di-tert-butyl [3- (2-ethyl-2,3-dihydro-1-benzofuran-5-yl) propyl] imide dicarbonate

  N, N-Bis-Boc-N-allylamine (2.99 g, 11.6 mmol) was azeotroped with toluene (2 × 50 mL) and then dissolved in tetrahydrofuran (12 mL). The solution was cooled to 0 ° C., 9-borobicyclo [3.3.1] nonane dimer (0.5 M solution in tetrahydrofuran, 46.5 mL, 23.2 mmol) was added and the mixture was stirred at 0 ° C. for 3 hours. Stir for hours. 5-Bromo-2-ethyl-2,3-dihydro-benzofuran (Preparation 98, Enantiomer 2) (2.9 g, 12.8 mmol), tripotassium phosphate (7) in N, N-dimethylformamide (12 mL). 7 mL, 23.2 mmol) and [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) chloride (4.74 mg, 0.58 mmol) are added and the reaction mixture is allowed to reach room temperature for 18 hours. Stir. The reaction was then quenched with 2M sodium hydroxide solution (30 mL) and water (10 mL) and stirred at room temperature for 1 hour. The mixture was then extracted with diethyl ether, dried over magnesium sulfate and concentrated in vacuo. The residue was suspended in ethyl acetate: petroleum ether, 25:75, filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with ethyl acetate: petroleum ether, 7:93 to give the title compound as a clear oil in 46% yield, 2.15 g.

Preparation Example 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] imide dicarbonate (Preparation Example 100) in hydrochloric acid (4M solution in dioxane, 20 mL) ( 2.19 g, 5.4 mmol) was stirred at room temperature for 18 hours. The reaction mixture was then concentrated in vacuo to give the title compound in quantitative yield.

Preparation Example 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, 131.131) in dichloromethane (600 mL). 7 mmol), 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 (2 × 50 mL), saturated sodium bicarbonate 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 cream colored powder. The powder was purified by column chromatography on silica gel eluting with dichloromethane: methanol, 99: 1 to give the title compound in 65% yield, 17.5 g.

Preparation Example 103
4- (2-Aminoethyl) -N-butylbenzamide hydrochloride

  The title compound was obtained from tert-butyl (2- {4-[(butylamino) carbonyl] phenyl} ethyl) carbamate (Preparation Example 102) using a method similar to that of Preparation Example 101 as a white powder, yield 84 %.

Preparation Example 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), 4-hydroxybenzonitrile (100 g, 0. 1) in acetonitrile (1 L). 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 was 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 solution was washed with water (500 mL) and extracted with 2M hydrochloric acid (2 × 600 mL). The acidic solution was made alkaline to pH 8-9 with 40% potassium hydroxide solution and extracted with ethyl acetate (800 mL). The aqueous solution was then made alkaline with pH 10-11 using 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 give the title compound as a red oil in 79% yield, 150 g.

Preparation Example 105
2- [4- (3-Pyrrolidin-1-yl-propoxy) -phenyl] -ethylamine

  [4- (3-Pyrrolidin-1-yl-propoxy) -phenyl] -acetonitrile (Preparation 104) (1 g, 4.1 mmol) and Rany® nickel (2 mL) in 2M methanolic ammonia (35 mL). 100 mg) was stirred for 6 hours at 50 ° C. under 60 psi of hydrogen gas. Since Tlc analysis showed that all starting material was not consumed, additional Raney® nickel (200 mg) was added to the reaction mixture and heating was continued for 5 hours. Tlc analysis again showed starting material still present so additional Raney® nickel (200 mg) was added and the mixture was stirred at 50 ° C. for 3 h. The reaction mixture was then filtered through Arbocel® and concentrated in vacuo to give a yellow oil. This oil was purified by column chromatography using 4 g RediSep® silica cartridge, eluting with dichloromethane: methanol: 0.88 ammonia, 85: 15: 1.5 to 80: 20: 2. The title compound was obtained in 160% yield, 160 mg.

Preparation Example 106
[2- (3-Pyrrolidin-1-yl-propoxy) -phenyl] -acetonitrile

  The title compound was prepared from 2-hydroxy-benzeneacetonitrile (J. Org. Chem .; 66, 3435; 2001) and 1- (3-chloropropyl) pyrrolidine using a method similar to that of Preparation 104. As a light brown viscous substance, it was prepared in a yield of 58%.

Preparation Example 107
2- [2- (3-Pyrrolidin-1-yl-propoxy) -phenyl] -ethylamine

  The title compound was prepared from the product of Preparation 106 using a method similar to that of Preparation 69 in 48% yield.

Preparation Example 108
{ 2- [3- (3-Pyrrolidin-1-yl-propoxy) phenyl] ethyl} amine

  The title compound was prepared from [3- (3-pyrrolidin-1-ylpropoxy) phenyl] acetonitrile (170 g, 0.70 mmol) using a method similar to that of Preparation 69. The crude compound was then purified by column chromatography using a 4 g RediSep® silica cartridge, eluting with dichloromethane: methanol: 0.88 ammonia, 100: 0: 0 to 80: 20: 2, The desired product was obtained in 30% yield.

Preparation Example 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, 0.30 mmol) in N, N-dimethylformamide (4 mL). 41 mmol), 3- {2-[(2R) -2- (tert-butyldimethylsilanyloxy) -2- (4-hydroxy-3-hydroxymethyl-phenyl) ethylamino] -2-methylpropyl} benzoic acid Preparation Example 37 Added to a mixture of (130 mg, 0.28 mmol), 1-hydroxybenzotriazole hydrate (40 mg, 0.29 mmol) and N, N-diisopropylethylamine (210 μL, 1.49 mmol). The resulting solution was stirred for 9 days at room temperature, after which tlc analysis showed that starting material still remained. Then additional 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (79 mg, 0.41 mmol), 1-hydroxybenzotriazole hydrate (40 mg, 0.29 mmol) and N, N-diisopropylethylamine (210 μL, 1.49 mmol) was added and stirring was continued at room temperature for 2 days. The solvent was removed in vacuo and the residue was partitioned between ethyl acetate (25 mL) and saturated sodium bicarbonate solution (20 mL). The organic solution was separated, dried (sodium sulfate) and concentrated in vacuo to give an orange oil. The oil was purified by flash column chromatography on silica gel eluting with dichloromethane: methanol: 0.88 ammonia, 100: 0: 0 to 75: 25: 2 to give the title compound as a glassy material. Yield 43%, 70 mg.

Preparation Example 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

  The title compound is 3- {2-[(2R) -2- (tert-butyldimethylsilanyloxy) -2- (4-hydroxy-3-hydroxymethyl-phenyl) ethylamino] -2-methylpropyl} Using benzoic acid (Preparation Example 37) and [2- (4-chloro-phenyl) -ethyl] -ethyl-amine hydrochloride (Preparation Example 81) as a white solid, using a method similar to that of Preparation Example 109 In a yield of 43%.

Preparation Example 111
3- [2-({(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl ] -N- (2-pyrrolidin-1-ylethyl) benzamide

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

Preparation Examples 112 to 138
The following compounds of the general formula shown below are prepared according to methods similar to those described for Preparation 38, starting materials 3- {2-[(2R) -2- (tert-butyldimethylsilanyloxy)- Prepared using 2- (4-hydroxy-3-hydroxymethyl-phenyl) ethylamino] -2-methylpropyl} benzoic acid (Preparation Example 37) and the appropriate amine. The reaction was monitored by tlc analysis and stirred at room temperature for 18-72 hours.

Preparation 115 : 2- (2-Phenylsulfanyl-phenyl) -ethylamine can be prepared as described in Collection of Czechoslovak Chemical Communications, 54 (7), 1995-2008;

Preparative Example 116 : Concentration of appropriate fractions in vacuo, and the residue further purified by column chromatography on amino silica gel in ethyl acetate: pentane, 100: 0 to 80:20, followed by dichloromethane: methanol, 100: Purified by eluting from 0 to 80:20.

Preparation Example 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 (Preparation Example 36) (4.0 g, 8.21 mmol) and ammonium fluoride (3.04 g, 82.0 mmol) were heated at 40 ° C. for 18 hours. The reaction mixture was then concentrated in vacuo and the residue was eluted by column chromatography on silica gel eluting with dichloromethane: methanol: 0.88 ammonia, 100: 0: 0 to 90: 10: 0.1. Purification gave the title compound as a white foam in 81% yield, 2.42 g.

Preparation Example 140
3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] benzoic acid

  Methyl 3- {2- [2-hydroxy-2- (4-hydroxy-3-hydroxymethyl-phenyl) -ethylamino] -2-methyl-propyl} benzoate in tetrahydrofuran (20 mL) and water (20 mL) A mixture of ester (Preparation Example 139) (235 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 was diluted with water and acidified with 1M hydrochloric acid (12 mL). The mixture was stirred at room temperature for 2 hours and then concentrated in vacuo. The crude product residue was used in subsequent reactions without further purification.

Preparation Example 141
3- [3- (2-tert-Butoxycarbonylamino-2-methyl-propyl) -phenyl] -acrylic acid benzyl ester

  [2- (3-Bromophenyl) -1,1-dimethylethyl] carbamic acid tert-butyl ester (Preparation Example 32) (2 g, 6.09 mmol), benzyl acrylate (2 g, 12.12 mL) in acetonitrile (100 mL). 19), palladium (II) acetate (204 mg, 0.91 mmol), tri-p-tolylphosphite (556 mg, 1.83 mmol) and triethylamine (2.12 mL, 15.22 mmol) Heated under reflux for 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 the title compound as a pale yellow oil, 90% yield, 2%. Obtained at .23 g.

Preparation Example 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 (Preparation Example 141) (2.23 g, 5.45 mmol) in dichloromethane (10 mL); And a mixture of trifluoroacetic acid (5 mL) was stirred at room temperature for 1 hour. The mixture was then concentrated in vacuo and the residue was diluted with sodium bicarbonate solution (10 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic solution was dried over magnesium sulfate and concentrated in vacuo to give the title compound as a yellow oil in quantitative yield.

Preparation Example 143
Benzyl-3- (3- {2-[((2R) -2- [4- (benzyloxy) -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 (Preparation Example 23) (800 mg, 1.77 mmol) , And 3- [3- (2-amino-2-methyl-propyl) -phenyl] -acrylic acid benzyl ester (Preparation Example 142) (1.10 g, 3.55 mmol) was stirred at 90 ° C. for 18 hours did. The reaction mixture was then cooled to room temperature, diluted with diethyl ether (40 mL) and stirred for 4 hours. The resulting precipitate was filtered off, rinsed with diethyl ether, and the filtrate was concentrated in vacuo to give a brown oil. The oil was purified by column chromatography on silica gel eluting with dichloromethane: methanol: 0.88 ammonia to give the title compound in 25% yield, 300 mg.

Preparation Example 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 (Preparation Example 143) (300 mg, 0.44 mmol) in solution and mixed The solution was heated under reflux for 30 minutes. The reaction mixture was then cooled, filtered through Arbocel® and concentrated in vacuo to give the title compound in 90% yield, 200 mg.

Preparation Example 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

  The title compound is 3- {3- [2-({(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl } Amino) -2-methylpropyl] phenyl} propanoic acid (Preparation Example 144) and 3,4-dichlorobenzylamine using a method similar to that of Preparation Example 38 as a clear oil, 64% yield Prepared.

Preparation Example 146
[3- (2-Amino-2-methyl-propyl) -phenyl] -acetic acid methyl ester

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

Preparation Example 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 (preparation) in dimethyl sulfoxide (7.5 mL) Example 23) (3.4 g, 7.5 mmol), [3- (2-amino-2-methylpropyl) phenyl] acetic acid (Preparation Example 146) (1.7 g, 7.5 mmol) and N, N-diisopropylethylamine A mixture of (1.4 mL, 8 mmol) was stirred at 90 ° C. for 28 hours. The reaction mixture was then cooled, diluted with ethyl acetate and washed with water. The organic solution is then dried over magnesium sulfate, concentrated in vacuo, and the residue is purified by column chromatography on silica gel eluting with ethyl acetate: pentane, 66:33 to give the title compound as colorless. Obtained as an oily substance, yield 50%, 2.2 g.

Preparation Example 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 aqueous solution, 16.2 mL, 16.2 mmol) was added to methyl (3- {2-[((2R) -2- [4- (benzyl) in tetrahydrofuran (49 mL) and methanol (17 mL). Oxy) -3- (hydroxymethyl) phenyl] -2-{[tert-butyl (dimethyl) silyl] oxy} ethyl) amino] -2-methylpropyl} phenyl) acetate (Preparation Example 147) (4.80 g, 8 0.1 mmol) and the mixture was stirred at room temperature for 18 hours. The reaction mixture was then concentrated in vacuo and the residue was diluted with water and acidified to pH 7 with 1M hydrochloric acid. The resulting precipitate was filtered off and washed with water to give the title compound as a pale yellow solid in 94% yield, 4.37 g.

Preparation Example 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

  The title compound is (3- {2-[((2R) -2- [4- (benzyloxy) -3- (hydroxymethyl) phenyl] -2-{[tert-butyl (dimethyl) silyl] oxy} Prepared as a white solid in 97% yield from ethyl) amino] -2-methylpropyl} phenyl) acetic acid (Preparation Example 148) and cyclopentanemethylamine using a method similar to that of Preparation Example 38.

Preparation Example 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

  The title compound is (3- {2-[((2R) -2- [4- (benzyloxy) -3- (hydroxymethyl) phenyl] -2-{[tert-butyl (dimethyl) silyl] oxy} Prepared as a yellow oil in 71% yield from ethyl) amino] -2-methylpropyl} phenyl) acetic acid (Preparation Example 148) and 1-adamantylamine using a method similar to that of Preparation 38 .

Preparation Example 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

  The title compound is 2- (3- {2-[((2R) -2- [4- (benzyloxy) -3- (hydroxymethyl) phenyl] -2-{[tert-butyl (dimethyl) silyl] Yield 96 as a yellow oil from oxy} ethyl) amino] -2-methylpropyl} phenyl) -N- (cycloheptylmethyl) acetamide (Preparation Example 149) using a method similar to that of Preparation 144 %.

Preparation Example 152
N-1-adamantyl-2- {3- [2-({(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- [4-hydroxy-3- (hydroxymethyl) phenyl] Ethyl} amino) -2-methylpropyl] phenyl} acetamide

  The title compound is N-1-adamantyl-2- (3- {2-[((2R) -2- [4- (benzyloxy) -3- (hydroxymethyl) phenyl] -2-{[tert- From butyl (dimethyl) silyl] oxy} ethyl) amino] -2-methylpropyl} phenyl) acetamide (Preparation Example 150) using a method similar to that of Preparation Example 144 as a white solid in 73% yield Prepared.

Preparation Example 153
Methyl {3- [2-({(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2- Methylpropyl] phenyl} acetate

  The title compound is methyl (3- {2-[((2R) -2- [4- (benzyloxy) -3- (hydroxymethyl) phenyl] -2-{[tert-butyl (dimethyl) silyl] oxy). } Ethyl) amino] -2-methylpropyl} phenyl) acetate (Preparation Example 147) was prepared in 80% yield as a brown oil using a method similar to that of Preparation Example 21.

Preparation Example 154
{3- [2-({(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methyl Propyl] phenyl} acetic acid

  Methyl {3- [2-({(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- [4-hydroxy-3- (hydroxymethyl) phenyl] in tetrahydrofuran (50 mL) A mixture of ethyl} amino) -2-methylpropyl] phenyl} acetate (Preparation Example 153) (5 g, 10 mmol) and lithium hydroxide (1M aqueous solution, 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 was triturated with water and azeotroped with methanol (x3) to give the title compound as a white solid, Yield 84% and 4.1 g.

Preparation Example 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

  The title compound is {3- [2-({(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino ) -2-Methylpropyl] phenyl} acetic acid (Preparation Example 154) and 1-pyrrolidinepropanamine using a method similar to that of Preparation 38 in 16% yield.

Preparation Example 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

  The title compound is {3- [2-({(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino ) -2-methylpropyl] phenyl} acetic acid (Preparation Example 154) and N-benzylmethylamine, using a similar method to that of Preparation 38, with a yield of 55%.

Preparation Example 157
3- [2-({(2R) -2-{[tert-butyl (dimethyl) silyl] oxy} -2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl ] -N- [2- (3-Fluorophenyl) ethyl] benzamide

  3- {2-[(2R) -2- (tert-butyldimethylsilanyloxy) -2- (4-hydroxy-3-hydroxymethyl-phenyl) ethylamino] -2-methylpropyl} benzoic acid (Preparation Example 37) (473 mg, 1 mmol) and a mixture of O- (1H-benzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate (379 mg, 1 mmol) , N-dimethylacetamide (6 mL) was added to a solution of 3-fluorophenethylamine (139 mg, 1 mmol) and the mixture was stirred at room temperature for 18 hours. The solvent was removed in vacuo and the residue was redissolved in dichloromethane (100 mL) and washed with saturated sodium bicarbonate solution (3 × 20 mL) and brine (10 mL). The organic solution is then dried over sodium sulfate and concentrated in vacuo, and the residue is purified by column chromatography on silica gel in dichloromethane: methanol: 0.88 ammonia, 100: 0: 0 to 90: 10: 1. Eluted and purified. The appropriate fraction is then concentrated in vacuo and the residue is redissolved in ethyl acetate, washed with saturated sodium bicarbonate solution, dried over sodium sulfate and concentrated in vacuo to yield the title compound in yield. Obtained at 52%, 343 mg.

Preparation Example 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) ethylamino in N, N-dimethylacetamide (8 mL) ] -2-Methylpropyl} benzoic acid (Preparation Example 37) (400 mg, 0.85 mmol), and O- (1H-benzotriazol-1-yl) -N, N, N ′, N′-tetramethyluro Mixing of hexahexafluorophosphate (320 mg, 0.85 mmol), triethylamine (225 μL, 1.6 mmol) and 2- (5-chloro-2-methoxy-phenyl) -ethylamine (Preparation Example 70) (64 mg, 0.85 mmol) The solution was stirred at room temperature for 18 hours. The solvent was removed in vacuo and the residue was partitioned between dichloromethane (4 mL) and saturated sodium bicarbonate solution (1 mL). The organic solution is then dried over magnesium sulfate and concentrated in vacuo, and the residue is used with an ISCO Companion® silica cartridge using dichloromethane: methanol: 0.88 ammonia, 90: 10: 1 to 80:20. The product was purified by eluting at 2: to give the title compound in 22% yield.

Preparation Example 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

  The title compound is 3- {2-[(2R) -2- (tert-butyldimethylsilanyloxy) -2- (4-hydroxy-3-hydroxymethyl-phenyl) ethylamino] -2-methylpropyl} Prepared from benzoic acid (Preparation Example 37) and 3-ethoxyphenethylamine in a yield of 67% using the same method as in Preparation Example 158.

Preparation Example 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

  The title compound is 3- {2-[(2R) -2- (tert-butyldimethylsilanyloxy) -2- (4-hydroxy-3-hydroxymethyl-phenyl) ethylamino] -2-methylpropyl} Prepared from benzoic acid (Preparation Example 37) and 3-methoxyphenethylamine in a yield of 98% using the same method as that of Preparation Example 158.

Preparation Example 161
[3-((2R) -2-{[(1R) -1-phenylethyl] amino} propyl) phenyl] acetic acid

  Lithium hydroxide solution (1M aqueous solution 90 mL, 90 mmol) was added to methyl [3-((2R) -2-{[(1R) -1-phenyl-ethyl] -amino} -propyl) -phenyl in methanol (200 mL). ] -Acetate hydrochloride (Preparation Example 26) (13.5 g, 43.5 mmol) was added and the mixture was stirred at room temperature for 18 hours. 1M hydrochloric acid (90 mL) was then added to the reaction mixture and the methanol was removed in vacuo. The resulting precipitate was filtered off and washed with water (20 mL) and a mixture of ethanol / diethyl ether, 20:80 to give the title compound as a solid in 91% yield, 11.8 g.

Preparation Example 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 mmol) were added to [3-((2R) -2-{[(1R) -1-phenylethyl] amino} propyl in dichloromethane (200 mL). ) Phenyl] acetic acid (Preparation Example 161) (10.7 g, 36 mmol) was added to the solution. Then 2-chloro-1,3-dimethylimidazolidinum 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 dichloromethane: methanol: 0.88 ammonia, 95: 5: 0.5, to give the product as a foam in quantitative yield, 17.6 g. I got it.

Preparation Example 163
N-1-adamantyl-2- {3-[(2R) -2-aminopropyl] phenyl} acetamide

  The title compound was prepared from N-1-adamantyl-2- [3-((2R) -2-{[(1R) -1-phenylethyl] amino} propyl) phenyl] acetamide (Preparation Example 162). Using a method similar to that of 25, it was prepared as a solid in 92% yield.

Preparation Example 164
N-1-adamantyl-2- {3-[(2R) -2-({(2R) -2- [4- (benzyloxy) -3- (hydroxymethyl) phenyl] -2-hydroxyethyl} amino) Propyl] phenyl} acetamide

  [2- (benzyloxy) -5-((1R) -2-bromo-1-{[tert-butyl (dimethyl) silyl] oxy} ethyl) phenyl] methanol (Preparation Example 23) (900 mg, 2 mmol), and A mixture of N-1-adamantyl-2- {3-[(2R) -2-aminopropyl] phenyl} acetamide (Preparation Example 163) (1.3 g, 4 mmol) was heated at 90 ° C. for 24 hours. The reaction mixture is then cooled to room temperature and the crude product is purified by column chromatography on silica gel eluting with dichloromethane: methanol: 0.88 ammonia, 95: 5: 0.5 to give the title compound Was obtained as a pale foam in a yield of 83% and 11.6 g.

Abbreviation TBDMS = tert-butyl (dimethyl) silyl
The ability of the compound of formula (1) to act as an active β2 agonist of the compound of formula (1) and thus mediate smooth muscle relaxation is the stimulation of the electric field of guinea pig tracheal strips. May be determined by measuring the effect of β2 adrenergic receptors on contraction by.

Guinea pig tracheal male Dunkin-Hartley guinea pigs (475-525 g) are killed by asphyxiation with CO ₂ , whole blood is taken from the femoral artery, and the trachea is isolated. An incision is started just below the larynx, and a 2.5 cm long trachea is collected to obtain four specimens from each animal. The trachea piece cuts and opens the cartilage on the opposite side of the tracheal muscle, and then cuts a piece laterally to the width of the 3-4 cartilage ring. The resulting strip specimen is suspended in a 5 ml organ bath using cotton thread tied through the upper and lower cartilage bands. Strips were equilibrated in a modified Krebs Ringer buffer (Sigma K0507) containing 3 μM indomethacin (Sigma I7378), 10 μM guanethidine (Sigma G8520), and 10 μM atenolol (Sigma A7655) for 20 minutes without tension. Heat at 37 ° C., introduce 95% O ₂ /5% CO ₂ gas and load the first 1 g of tension. The specimen is left to equilibrate for an additional 30-45 minutes, during which time tension (1 g) is again applied twice at 15 minute intervals. Changes in tension are recorded and monitored via a standard isometric transducer in conjunction with a data integration system (Pfizer custom design). After tension loading and equilibration, the tissue is subjected to electric field stimulation (EFS) using the following parameters: 10 s trains every 2 minutes, 0.1 ms pulse width, 10 Hz continuously throughout the experimental period. And just-maximal voltage (25 volts). Post-nodal cholinergic EFS in the trachea results in a uniphasic contraction of smooth muscle and the height of this twitch is recorded. When adding a beta 2 agonist according to the present invention to the organ tank, then stop the pump during cumulative administration to the tank and start it again for the washout period after the maximum response has been reached With the exception of the above, constant perfusion was performed with the Krebs Ringer buffer by a peristaltic pump system (pump flow rate 7.5 ml / min) throughout the experiment.

After equilibration to the experimental protocol EFS for efficacy and efficacy evaluation , the peristaltic pump is stopped and the sample is “primed” with a single volume of 300 nM isoprenaline (Sigma 15627) to produce contractile EFS. Establish maximum response with respect to inhibition of response. The isoprenaline is then washed out for 40 minutes. After recovery by priming and washout, a standard curve for isoprenaline (Isoprenaline Curve 1) is generated for all tissues by cumulative bolus addition to the bath by increasing the half log concentration. The concentration range to be used is 1 ^e-9 to 1 ^e / 3 ^e-6 M. At the end of the isoprenaline curve, the specimen is again washed for 40 minutes, and the creation of a second curve for either isoprenaline (as an internal control) or a beta 2 agonist according to the present invention begins. Beta 2 agonist response is expressed as a percentage of inhibition of the EFS response. Data for beta 2 agonists are normalized by expressing inhibition as a percentage of the maximum inhibition induced by isoprenaline in curve 1. The EC ₅₀ value of a beta 2 agonist according to the present invention refers to the concentration of compound required to obtain 1/2 of the maximum effect. Next, data for beta 2 agonists according to the present invention are expressed as relative potency for isoprenaline, defined by the ratio of (EC ₅₀ beta 2 agonist) / (EC ₅₀ isoprenaline).

Confirmation of Functional Activity via Beta-2 The beta2 agonist activity of the test compound is confirmed using the above protocol, but before the curve for the beta2 agonist according to the present invention is constructed, the sample is 300 nM ICI 118551. Pre-incubation (minimum 45 minutes) with (selective β ₂ antagonist), so that the dose response curve of the test compound in the case of an effect via beta-2 is shifted to the right.

According to another alternative method, the agonist potency of the compound of formula (1) with respect to the β2 receptor is also required to obtain a maximum effect of 1/2 on the β2 receptor (EC ₅₀ ). According to measurement of the concentration of the compound according to

Compound Preparation A 10 mM / 100% DMSO (dimethyl sulfoxide) stock of compound is diluted to the required top dose in 4% DMSO. This highest dose is used to generate a 10 point semi-log dilution curve in all 4% DMSO. Isoprenaline (Sigma, I-5627) was used as a standard in all experiments and for the control wells of each plate. Data were expressed as% of isoprenaline response.

Cell culture CHO (Chinese hamster ovary) cells (Kobilka et al., PNAS 84: 46-50, 1987 and Bouvier et al., Mol Pharmacol 33: 133-139 1988 CHOhβ2 expressing recombinant human β2 adrenergic receptors. More) 10% fetal bovine serum (Sigma, F4135, Lot 90K8404 Exp 09/04), 2 mM glutamine (Sigma, G7513), 500 μg / ml geneticin (Sigma, G7034), and 10 μg / ml puromycin ( The cells were cultured in Dulbeccos MEM / NUT MIX F12 (Gibco, 21331-020) supplemented with Sigma, P8833). Cells were seeded and approximately 90% confluency was obtained for testing.

Assay Method 25 μl / well of each dose of compound was transferred to a cAMP-Flashplate® (NEN, SMP004B) with 1% DMSO as a basal control and 100 nM isoprenaline as a maximal control. This was diluted 1: 2 by adding 25 μl / well PBS. Cells are trypsinized (0.25% Sigma, T4049), washed with PBS (Gibco, 14040-174), resuspended in stimulation buffer (NEN, SMP004B) and 1 × 10 ⁶ cells / ml CHOhB2 Got. Compounds were incubated for 1 hour in 50 μl / well cells. Subsequently, 100 μl / well of detection buffer (NEN, SMP004B) containing 0.18 μCi / ml ¹²⁵ I-cAMP (NEN, NEX-130) was added to dissolve, and the plate was further incubated at room temperature for 2 hours. The amount of ¹²⁵ I-cAMP bound to the Flashplate® was quantified using a Topcount NXT (Packard) with a normal counting efficiency of 1 minute. Dose-response data was expressed as% of isoprenaline activity and fitted by fitting to a sigmoidal curve of four parameters.

Thus, it was found that the tested compounds of formula (1) according to the invention exhibit a β2cAMP EC ₅₀ lower than 10 nM.
The following table shows the activity of the compounds of the invention:

Claims (24)

Compound of formula (1)

Wherein the (CH ₂ ) _n —C (═O) Q ¹ group takes 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 and -Q ¹ below:

A group selected from 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, and -A is a C ₃ -C ₁₀ cycloalkyl, more than, or two carbon atoms of the cycloalkyl is optionally by one or more carbon atoms Bridged; O-phenyl-pyrazolyl ; a 5- to 10-membered heterocyclic group, optionally aromatic, 1, 2, 3 or 4 complex selected from O, S or N Including atoms and optionally C ₁ -C ₄ alkyl or O—C ₁ -C ₄ alkyl, or a group of formula

Is replaced with
^{-R 3, R 4, R 5} , R 6 and ^{R 7} have the same or different, _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,
Selected from COOR ⁹ , SO ₂ NR ⁹ R ¹⁰ , CONR ⁹ R ¹⁰ , NR ⁹ 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 ^* represents a bond to a carbonyl group;
Or, where appropriate, their pharmaceutically acceptable salts and / or their stereoisomers, geometric isomers , tautomers, solvates or isotope- labelled compounds ,
However, when n is 0, Q ¹ is not —NHCH ₃ , and when n is 1 or 2, 1) Q ¹ is ^* —NH—C ₁ -C ₄ alkyl, or ^* —N ( R ⁸ ) —Q ² —A, wherein A is —C ₃ -C ₁₀ cycloalkyl, wherein two or more carbon atoms of the cycloalkyl are optionally one or more Bridged by carbon atoms,
-O-phenyl-pyrazolyl,
A 5- to 10-membered heterocyclic group, optionally aromatic, including 1, 2, 3 or 4 heteroatoms selected from O, S or N, optionally C ₁ -C Substituted with ₄ alkyl, or O—C ₁ -C ₄ alkyl, and the heterocyclic group is other than pyridyl,
-Group of formula

Wherein one of R ³ to R ⁷ is CN, SOR ⁹ , SO ₂ R ⁹ , phenyl, O-phenyl, S-phenyl, SO ₂ -morpholinyl, or O— (CH ₂ ) ₃ — Pyrrolidinyl and / or
2) The compound, wherein when one of R ¹ and R ² is H, the other is not CH ₃ .   A is C ₃ -C ₁₀ A cycloalkyl, optionally bridged by 2, 1, 3 or 4 carbon atoms with 2 or more carbon atoms of the cycloalkyl; O-phenyl-pyrazolyl; 5 to 10 membered heterocycle A cyclic group, optionally aromatic, including 1, 2, 3 or 4 heteroatoms selected from O, S or N and optionally C ₁ -C ₄ Alkyl or O-C ₁ -C ₄ Alkyl or a group of formula

The compound of claim 1, wherein the compound is substituted with Q ¹ is a group of the following formula

Wherein Q ² is a single bond or C ₁ -C ₄ alkylene, R ⁸ is H, and A is the following group

The compound of claim 1, wherein R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are as described in claim 1. Q ¹ is ^* a -N ^{(R 8) -Q} 2 -A group, groups of the formula wherein A is less

Where R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are 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;
Or different wherein ^{R 9} and ^{R 10} are the same, are selected from H or _C 1 -C ₄ alkyl, A compound according to claim 1 or 3. R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are the same or different and are H, CH ₃ , OH, OCH ₃ , SCH ₃ , OCH ₂ CH ₃ , Cl, F, CF ₃ , OCF 5. The compound of claim 4 , wherein the compound is selected from ₃ , COOH, SO ₂ NH ₂ , and at least two of R ³ to R ⁷ represent H. R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are the same or different and are H, CH ₃ , OH, OCH ₃ , SCH ₃ , OCH ₂ CH ₃ , Cl, F, CF ₃ , OCF _3, COOH, selected from _SO 2 NH _2, and at least three ^{R 7} from ^{R 3} represents H, compound of claim 5. The compound according to claim 1, wherein Q ¹ is ^* -N (R ⁸ ) -Q ² -A, wherein A is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or adamantyl. ^8. A compound according to any one of claims 1 to 7 , wherein R8 is H, methyl or ethyl. 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₎ - from selected, the compounds according to any one of claims 1 to 8. Q ¹ is the following group

The compound according to any one of claims 1 to 3, wherein The compound according to any one of claims 1 to 10 , wherein n is 0 or 1. The compound according to any one of claims 1 to 11 , wherein R ¹ is H and R ² is H or CH ₂ CH ₃ . The compound according to any one of claims 1 to 11 , wherein R ¹ is CH ₃ and R ² is CH ₃ . The following formula:

The compound of any one of Claims 1-13 represented by these. _{(CH 2) n -C (=} O) Q 1 group takes the position meta compound according to any one of claims 1 14. The following compounds 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- (hydroxymethyl) phenyl] Ethyl} amino) propyl] phenyl} acetamide;
2- {3-[(2R) -2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) propyl] phenyl} -N-isopropylacetamide ;
N-cyclopentyl-2- {3-[(2R) -2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) propyl] phenyl} acetamide ;
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-cyclobenzyl) -2- {3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methyl Propyl] 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-dimethylethyl) amino ] -1-hydroxyethyl} -2- (hydroxymethyl) phenol;
N- [2-Fluoro-5- (trifluoromethyl) benzyl] -2- {3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) 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- (hydroxymethyl) phenyl] Ethyl} amino) -2-methylpropyl] phenyl} acetamide;
N- [2-Chloro-5- (trifluoromethyl) benzyl] -2- {3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) 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- (hydroxymethyl) phenyl] Ethyl} amino) -2-methylpropyl] phenyl} acetamide;
N- [2- (4-chlorophenyl) ethyl] -3- {2-[(2R) -2-hydroxy-2- (4-hydroxy-3-hydroxy-methylphenyl) ethylamino] -2-methylpropyl} 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-trifluoromethyl Phenyl) 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-naphthalen-2-yl- Ethyl) benzamide;
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-hydroxy-2- (4-hydroxy-3-hydroxymethylphenyl) -ethylamino] -2-methylpropyl} -N- (2-methyl-2-phenylpropyl) Benzamide;
N- (4-chlorobenzyl) -3- {2-[(2R) -2-hydroxy-2- (4-hydroxy-3-hydroxy-methylphenyl) 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- (hydroxymethyl) 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-phenylpropyl) benzamide ;
4-[(1R) -2-({(1R) -2- [3- (3,4-dihydroisoquinolin-2 (1H) -ylcarbonyl) phenyl] -1-methylethyl} amino) -1-hydroxy Ethyl] -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-pyrrolidine-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- (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- ( 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-phenylpropyl) benzamide ;
3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] -N- (2-phenylethyl) 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-methoxy Phenyl) 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-phenoxy Phenyl) 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-methyl Pyridin-2-yl) ethyl] benzamide;
3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] -N- [2- (2-methoxy Phenyl) 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-methyl Propyl] 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- (hydroxymethyl) phenyl] Ethyl} amino) -2-methylpropyl] benzamide;
3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] -N- (2-mesitylethyl) benzamide;
N- [2- (2,6-difluoro-3-methylphenyl) ethyl] -3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] Ethyl} amino) -2-methylpropyl] benzamide;
N- [2- (6-Chloro-2-fluoro-3-methylphenyl) ethyl] -3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) Phenyl] ethyl} amino) -2-methylpropyl] benzamide;
N- [2- (2-Chloro-6-fluoro-3-methylphenyl) ethyl] -3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) 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-methylpropyl] benzamide ;
N- (2-chlorobenzyl) -3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] benzamide ;
N- [2- (4,6-Dimethylpyrimidin-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- (3-methyl Pyridin-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-methyl Propyl] 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-hydroxy Phenyl) -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- (hydroxymethyl) phenyl] Ethyl} amino) -2-methylpropyl] benzamide;
N- [2- (4-hydroxy-2,5-dimethylphenyl) ethyl] -3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) 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- (pyridine -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-hydroxy Phenyl) propyl] benzamide;
3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] -N- [2- (3-methyl Phenyl) ethyl] benzamide;
3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] -N- [2- (6-methoxy Pyridin-3-yl) ethyl] benzamide;
3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] -N- [3- (3-methoxy Phenyl) propyl] benzamide;
N- [3- (4-Chlorophenyl) propyl] -3- {2-[(2R) -2-hydroxy-2- (4-hydroxy-3-hydroxymethylphenyl) ethylamino] -2-methylpropyl} benzamide ;
3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] -N- {2- [4- ( 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- [ 2. The compound of claim 1 selected from the group consisting of 4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] benzamide. 17. A compound of formula (1) as claimed in any one of claims 1 to 16 , or a pharmaceutically acceptable salt, stereoisomer, geometric isomer, tautomer, solvate or isotope thereof. A process for the preparation of an element labeled compound comprising an acid of formula (2):

An amine of the formula

[Wherein R ⁸ , Q ² , A, p and R ³ to R ⁶ are as defined above for the compound of formula (1)]
Coupling with the method. 17. A compound of formula (1) as defined in any one of claims 1 to 16 , or a pharmaceutically acceptable salt, stereoisomer, geometric isomer, tautomer, solvate or isotope thereof. A pharmaceutical composition comprising a compound labeled with an element . 19. A pharmaceutical composition according to claim 18 , further comprising one or more pharmaceutically acceptable excipients and / or additives. 20. A pharmaceutical composition according to claim 18 or 19 for use in the treatment of diseases, disorders and conditions involving β2 receptors. The group consisting of:
Asthma of any type, etiology or pathology, in particular atopic asthma, non-atopic asthma, allergic asthma, asthma via atopic bronchial IgE, bronchial asthma, essential asthma, true asthma, pathophysiological disorder Endogenous asthma caused by environmental factors, extrinsic asthma caused by environmental factors, essential asthma of unknown or unclear causes, non-atopic asthma, bronchitis asthma, emphysematous asthma, exercise-induced asthma , Allergen-induced asthma, cold-induced asthma, occupational asthma, infectious asthma caused by bacterial, fungal, protozoan, or viral infection, non-allergic asthma, primary asthma, infants with wheezing Asthma, a member selected from the group consisting of syndrome, and bronchiolitis,
Chronic or acute bronchoconstriction, chronic bronchitis, small airway obstruction, and emphysema,
Obstructive or inflammatory airway diseases of any type, etiology or pathology, in particular chronic eosinophilic pneumonia, chronic obstructive pulmonary disease (COPD), COPD including chronic bronchitis, emphysema or breathing with or without COPD From the group consisting of COPD characterized by difficult, irreversible, progressive airway obstruction, adult respiratory distress syndrome (ARDS), exacerbation of airway hyperresponsiveness as a result of other medications, and airway disease associated with pulmonary hypertension Selected member, obstructive or inflammatory airway disease,
Bronchitis of any type, etiology or pathology, in particular acute bronchitis, acute laryngotracheal bronchitis, bronchitis with arachidic acid, catarrhal bronchitis, clonal bronchitis, dry bronchitis, infectious asthmatic bronchitis Bronchitis, a member selected from the group consisting of productive bronchitis, staphylococcal or streptococcal bronchitis, and alveolar bronchitis,
Acute lung injury,
Bronchiectasis of any type, etiology or condition, in particular columnar bronchiectasis, saccular bronchiectasis, fusiform bronchiectasis, capillary bronchiectasis, cystic bronchiectasis, dry bronchiectasis, and Bronchiectasis being a member selected from the group consisting of follicular bronchiectasis,
20. A pharmaceutical composition according to claim 18 or 19 for use in the treatment of a more selected disease, disorder and condition. A compound of formula (1) as defined in any one of claims 1 to 16 , or a pharmaceutically acceptable salt, stereoisomer, geometric isomer thereof for the manufacture of a medicament having β2 agonist activity , Tautomers, solvates or isotope-labelled compounds . A compound of formula (1) as defined in any one of claims 1 to 16 for the manufacture of a medicament for the treatment of diseases, disorders and conditions selected from the group as defined in claim 21. Or a pharmaceutically acceptable salt, stereoisomer, geometric isomer, tautomer, solvate or isotope labeled compound thereof . The compound according to any one of claims 1 to 16 , or a pharmaceutically acceptable salt, stereoisomer, geometric isomer, tautomer, solvate or isotope-labeled compound thereof, and :
(A) a 5-lipoxygenase (5-LO) inhibitor or a 5-lipoxygenase activating protein (FLAP) antagonist,
(B) leukotriene antagonists (LTRA), including antagonists of LTB ₄ , LTC ₄ , LTD ₄ and LTE ₄ ;
(C) a histamine receptor antagonist comprising H1 and H3 antagonists,
(D) an α ₁ -and α ₂ -adrenergic receptor agonist vasoconstrictor sympathomimetic for use as a decongestant;
(E) a muscarinic M3 receptor antagonist or anticholinergic agent,
(F) PDE inhibitors, such as inhibitors of PDE3, PDE4 and PDE5,
(G) theophylline,
(H) sodium cromoglycate,
(I) COX inhibitors (NSAIDs), both non-selective and selective COX-1 inhibitors or COX-2 inhibitors,
(J) oral and inhalation glucocorticosteroids, such as DAGR (dissociated agonists of the corticoid receptor),
(K) a monoclonal antibody active against the presence of endogenous inflammation;
(L) an anti-tumor necrosis factor (anti-TNF-α) drug,
(M) an adhesion molecule inhibitor comprising a VLA-4 antagonist,
(N) a kinin-B ₁ and B ₂ receptor antagonist,
(O) immunosuppressant,
(P) an inhibitor of matrix metalloprotease (MMP),
(Q) tachykinin NK ₁ , NK ₂ and NK ₃ receptor antagonists,
(R) an elastase inhibitor,
(S) an adenosine A2a receptor agonist,
(T) an inhibitor of urokinase,
(U) a compound acting at a dopamine receptor, such as a D2 agonist,
(V) a modulator of the NFκβ pathway, such as an IKK inhibitor,
(W) a modulator of a cytokine signaling pathway, such as a p38 MAP kinase, syk kinase, or JAK kinase inhibitor;
(X) drugs that can be classified as mucopolysaccharide degradation or antitussive,
(Y) antibiotics,
A pharmaceutical composition comprising a combination with (z) an HDAC inhibitor, and (aa) a therapeutic agent selected from PI3 kinase inhibitors.