HK1096379A1 - Sulfonamide derivatives for the treatment of diseases - Google Patents

Description

Sulfonamide derivatives for the treatment of diseases

Technical Field

The present invention relates to beta 2 agonists of the general formula:

wherein R is¹、R²N and Q¹Have the meanings indicated below, and to processes for the preparation of, compositions containing and the uses of, these derivatives.

Background

Adrenoceptors are members of the large superfamily of G-protein coupled receptors. The adrenoceptor subfamily is itself divided into α and β subfamilies, and the β subfamily is composed of at least 3 receptor subtypes: β 1, β 2 and β 3. These receptors display different expression patterns in tissues of various systems and organs in mammals. The β 2 adrenergic (β 2) receptor is predominantly expressed in smooth muscle cells (e.g., vascular, bronchial, uterine or intestinal smooth muscle), while the β 3 adrenergic receptor is predominantly expressed in adipose tissue (and therefore β 3 agonists may be useful in the treatment of obesity and diabetes) and the β 1 adrenergic receptor is predominantly expressed in cardiac tissue (and therefore β 1 agonists are predominantly used as cardiac stimulants).

The pathophysiology and treatment of airway diseases has been extensively reviewed in the literature (references see Barnes, p.j.chests, 1997, 111: 2, pages 17S-26S and Bryan, s.a. et al, Expert Opinion on experimental drugs, 2000, 9: 1, pages 25-42) and therefore only a brief summary will be included herein to provide some background information.

Glucocorticoids, anti-leukotrienes, theophylline, cromones, anticholinergics, and β 2 agonists constitute a current class of drugs for the treatment of allergic and non-allergic airway diseases such as asthma and Chronic Obstructive Pulmonary Disease (COPD). Therapeutic guidelines for these diseases include both short-and long-acting inhaled β 2 agonists. Short-acting, rapid-acting β 2 agonists are used to "rescue" bronchodilation, while long-acting forms provide sustained relief and are used as maintenance therapy.

Bronchiectasis is mediated via agonism of the β 2 adrenergic receptors expressed on airway smooth muscle cells, which leads to relaxation and thus bronchiectasis. Thus, as a functional antagonist, β 2 agonists prevent and reverse the effects of all bronchoconstrictor-inducing substances, including leukotriene D4(LTD4), acetylcholine, bradykinin, prostaglandins, histamine, and endothelin. Because β 2 receptors are so widely distributed in the airways, β 2 agonists can also affect other types of cells that play a role in asthma. For example, β 2 agonists have been reported to stabilize mast cells. The inhibitory effect on the release of bronchoconstrictor substances may be how beta 2 agonists block bronchoconstriction induced by allergens, exercise and cold air. In addition, β 2 agonists inhibit cholinergic neurotransmission in the human airways, which causes bronchoconstriction of the reduced cholinergic-reflex.

In addition to these airways, it has also been established that β 2 adrenoceptors are also expressed in other organs and tissues and therefore β 2 agonists, such as those described in the present invention, may have utility in the treatment of other diseases such as (but not limited to) neurological diseases, premature labor, congestive heart failure, depression, inflammatory and allergic skin diseases, psoriasis, proliferative skin diseases, glaucoma and in physiological conditions having the advantage of reducing gastric acidity, particularly in stomach and peptic ulcers.

However, many β 2 agonists are limited in use due to their low selectivity or adverse side effects (muscle tremor, cardiac tachycardias, palpitations, restlessness) caused by high systemic exposure and mediated through the action primarily on β 2 adrenergic receptors expressed outside the airways. There is therefore a need for such improved agents.

Thus, there remains a need for novel β 2 agonists with appropriate pharmacological properties (e.g. in terms of potency, pharmacokinetics or duration of action). In this connection, the present invention relates to novel β 2 agonists.

Various sulfonamide derivatives have been disclosed. For example, WO 02066250 discloses compounds of the formula useful as β 3 agonists, which are selective over β 2:

wherein m may be 2, R₁Can be H, OH or NR₅SO₂R₅(R₅Is H or C₁-C₆Alkyl), Z may be a bond, R₂Can be H or C₁-C₆Alkyl radical, R₄Can be C₁-C₆Alkyl, B may be phenyl, Y is C₁-C₆Alkyl and a may be phenyl.

WO 02/000622 discloses selective β 3 agonists of the formula:

wherein R is¹May be phenyl substituted by hydroxy and alkylsulfonylamino, X₁May be a bond, R²Can be hydrogen, R³Is hydrogen or hydroxyalkyl, X₂Can be CH₂，X₃Is a bond, O or NH and R⁴Is a cyclic group.

Other sulfonamide derivatives are also disclosed in US5,776,983 as β 3 agonists, and they are more specifically of the formula:

wherein R is¹Can be CH₃，R²Can be OH, R⁶Can be H, R³Can be H or alkyl, R⁴Can be H, alkyl, R⁵Can be H, R⁵' may be C (O) NR⁶R⁶', wherein R⁶And R⁶' may be H or lower alkyl.

However, none of the above sulfonamide derivatives have shown β 2 agonist activity and pharmacological properties, enabling their use as effective medicaments for the treatment of β 2-mediated diseases and/or physical complaints, in particular allergic and non-allergic airway diseases or other diseases such as those listed previously.

Disclosure of Invention

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

wherein (CH)₂)_n-C(＝O)Q¹The radicals being in the meta or para position, R¹And R²Independently selected from H and C₁-C₄Alkyl, n is 0, 1 or 2 and Q¹Is a group selected from:

and the group-NR⁸-Q²-A, wherein p is 1 or 2, Q²Is C optionally substituted by OH₁-C₄Alkylene radical, R⁸Is H or C₁-C₄Alkyl and A is pyridyl optionally substituted with OH, C optionally substituted with OH₃-C₇Cycloalkyl radicals, or radicals

Wherein R is³、R⁴、R⁵、R⁶And R⁷Are the same or different and are selected from H, C₁-C₄Alkyl, OR⁹、SR⁹Halo, CN, CF₃、OCF₃、COOR⁹、SO₂NR⁹R¹⁰、CONR⁹R¹⁰、NR⁹R¹⁰、NHCOR¹⁰And optionally 1 to 3 selected from OR⁹Halo and C₁-C₄A phenyl group substituted with a group of an alkyl group,

wherein R is⁹And R¹⁰Are identical or different and are selected from H or C₁-C₄Alkyl and denotes the point of attachment to the carbonyl group;

wherein the group Q¹Substituted with at least one hydroxyl group;

or, if appropriate, their pharmaceutically acceptable salts and/or isomers, tautomers, solvates or isotopic variations thereof.

The compounds of formula (1) are agonists of the β 2 receptor and are particularly useful for the treatment of β 2-mediated diseases and/or physical discomfort by exhibiting excellent efficacy, particularly when administered via the inhaled route.

In the above general formula (1), C₁-C₄Alkyl and C₁-C₄Alkylene represents a straight-chain or branched group comprising 1, 2, 3 or 4 carbon atoms. If they have substituents or occur as substituents of other groups, e.g. in O- (C)₁-C₄) Alkyl radical, S- (C)₁-C₄) Alkyl, and the like are also applicable. Suitably (C)₁-C₄) Examples of alkyl groups are methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, tert-butyl. Suitably (C)₁-C₄) Examples of alkoxy groups are methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy and t-butoxy.

C₃-C₇Cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Preferred is C₃-C₇Cycloalkyl is substituted with OH.

Finally, halo represents a halogen atom chosen from fluorine, chlorine, bromine and iodine, in particular fluorine or chlorine.

In the following, the free bonds on the phenyl groups, for example in the following structures,

meaning that the phenyl group may be substituted in the meta or para position.

A compound of formula (1)

Can be prepared using conventional procedures, for example, by the following illustrative method, wherein R¹、R²、Q¹And n is as defined for the compound of formula (1) above, unless otherwise specified.

The amide derivative of the formula (1) can be produced by coupling an acid of the formula (2) or a salt thereof

And formula NHR⁸-Q²-A(3)，

To (3) is prepared.

The coupling is generally carried out with an excess of the amine as acid acceptor, with a conventional coupling agent (e.g. 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride or N, N' -dicyclohexylcarbodiimide), optionally in the presence of a catalyst (e.g. 1-hydroxybenzotriazole hydrate or 1-hydroxy-7-azabenzotriazole), and optionally in the presence of a tertiary amine base (e.g. N-methylmorpholine, triethylamine or diisopropylethylamine). The reaction may be carried out in a suitable solvent such as pyridine, dimethylformamide, tetrahydrofuran, dimethylsulfoxide, dichloromethane or ethyl acetate, and at a temperature between 10 ℃ and 40 ℃ (room temperature) for a period of time ranging from 1 to 24 hours.

The amines (3), (3') or (3 ") are commercial products or can be prepared from commercial starting materials by conventional methods known to those skilled in the art (e.g., reduction, oxidation, alkylation, transition metal-mediated coupling, protection, deprotection, etc.).

The acid of formula (2) may be prepared from the corresponding ester of formula (4) according to any method known to those skilled in the art for preparing acids from esters:

wherein Ra is a suitable acid protecting group, preferably (C)₁-C₄) Alkyl groups, which include (but are not limited to) methyl and ethyl groups, without altering the rest of the molecule. For example, the ester may be hydrolysed by treatment with an aqueous solution of an acid or base (e.g. hydrogen chloride, potassium hydroxide, sodium hydroxide or lithium hydroxide), optionally in the presence of a solvent or mixture of solvents (e.g. water, propionitrile, 1, 4-dioxane, tetrahydrofuran/water) at a temperature between 20 ℃ and 100 ℃ for 1 to 40 hours.

Esters of formula (4) can be prepared by reacting an amine of formula (5):

wherein Ra and n are as defined above, with a bromide of formula (6):

the reaction of (1).

In a typical procedure, an amine of formula (5) is reacted with a bromide of formula (6), optionally in the presence of a solvent or mixture of solvents (e.g. dimethylsulfoxide, toluene, N-dimethylformamide, propionitrile, acetonitrile), optionally in the presence of a suitable base (e.g. triethylamine, diisopropylethylamine, potassium carbonate, potassium bicarbonate) at a temperature between 80 ℃ and 120 ℃ for 12 to 48 hours.

The bromides of formula (6) can be prepared according to the method of WO 02/06258 (page 36, example 14 a).

Alternatively, esters of formula (4), wherein n ═ 1, can be prepared from bromides of formula (7):

in a typical procedure, a bromide of formula (7) is treated with a suitable palladium catalyst (e.g., [1, 1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (II)) under an atmosphere of carbon monoxide using RaOH (e.g., MeOH, EtOH) as a solvent at elevated temperature (100 ℃) and pressure (up to 100psi) to yield an ester of formula (4).

An amine of formula (5) wherein R₁Is Me and R₂For H, the (R) or (S) enantiomer can be prepared from the corresponding protected amine of formula (8):

wherein Ra and N are as defined above and Rb and Rc represent any suitable substituent such that HNRbRc is a chiral amine (e.g., Rb can be hydrogen and Rc can be α -methylbenzyl), provided that the bonds between N and Rb and N and Rc can be readily cleaved using standard methods of cleaving nitrogen protecting groups (see, e.g., textbook t.w. green, protecting groups in organic synthesis, methods of a. viss-international scientific press, 1981) to yield the free amine of formula (5).

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

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

In a typical procedure, the reaction of a ketone of formula (9) with an amine of formula HNRbRc results in a chiral intermediate, which in turn is reacted with a suitable reducing agent (e.g., of formula NaCNBH)₃Sodium cyanoborohydride or of the formula Na (OAc)₃Sodium triacetoxyborohydride of BH), optionally in the presence of a drying agent (e.g., molecular sieve, magnesium sulfate) and optionally in the presence of an acid catalyst (e.g., acetic acid) to yield a mixture of diastereomers of the amine of formula (8). The reaction is typically carried out in a solvent such as tetrahydrofuran or dichloromethane at a temperature between 20 ℃ and 80 ℃ for 3 to 72 hours. The resulting product is then converted to the hydrochloride salt and selectively crystallized from an appropriate solvent or solvent mixture (e.g., isopropanol, ethanol, methanol, diisopropyl ether or diisopropyl ether/methanol) to yield the single diastereomer of (8).

Ketones of formula (9) wherein n ═ 1 can be prepared by aryl halides of formula (10):

wherein Ra is as defined above and Hal represents a halogen atom, including but not limited to bromine and iodine, with an enolate or enolate equivalent.

In a typical procedure, an aryl halide of formula (10) is reacted over a suitable palladium catalyst (of the formula Pd (OAc))₂/P(o-Tol)₃) In the presence of palladium acetate/tri-o-tolylphosphine in a non-polar solvent (e.g. toluene, benzene, hexane) with a catalyst of the formula Bu₃SnOMe's methoxylated tri-n-butyltin treatment of prenyl acetate treatment to generate in situ alkenesAnd (3) carrying out tin alcoholate reaction. Preferably, the reaction is carried out at a temperature between 80 ℃ and 110 ℃ for 6 to 16 hours.

The aryl halide of formula (10) may be obtained by esterification of the corresponding acid of formula (11) according to any method known to those skilled in the art for the preparation of esters from acids:

wherein Hal is as defined above without altering the rest of the molecule.

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

The acid of formula (11) is commercially available.

An amine of formula (5) wherein R¹＝R²Alkyl, can be prepared according to the following scheme:

scheme 1

Wherein R is¹、R²And Ra is as defined above.

In a typical procedure, using the above-described method, the ester of formula (12) is reacted with an "activated" alkyl (organometallic alkyl such as R)²MgBr、R²MgCl or R²Li) to produce the corresponding tertiary alcohol of formula (13).

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

Or, an amine of formula (5) wherein R¹＝R²＝C₁-C₄Alkyl and n ═ 0, can be prepared according to the following scheme:

scheme 2

Wherein R is¹、R²And Ra is as defined above.

In a typical procedure, using the above-described method, an ester of formula (14) is reacted with an "activated" alkyl (organometallic alkyl such as R)²MgBr、R²MgCl or R²Li) to produce the corresponding tertiary alcohol of formula (15).

The tertiary alcohol of formula (15) is then treated with an alkylnitrile (e.g. acetonitrile, chloroacetonitrile) in the presence of an acid (e.g. sulfuric acid, acetic acid) to yield a protected intermediate which is in turn cleaved using standard methods of cleaving the nitrogen protecting group such as those mentioned in textbooks to yield the bromoamine (16).

The resulting bromoamine (16) is treated with a suitable palladium catalyst (e.g., [1, 1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (II)) under an atmosphere of carbon monoxide using RaOH as a solvent (e.g., MeOH, EtOH) at elevated temperature (100 ℃) and pressure (100psi) to yield the ester of formula (5).

Ketones of formula (9) wherein n ═ 2 can be prepared by reduction of olefins of formula (17):

in a typical procedure, a solution of the alkene of formula (17) in a suitable solvent (e.g. methanol, ethanol, ethyl acetate) is treated with a palladium catalyst (e.g. 10% palladium on charcoal) and stirred under an atmosphere of hydrogen, optionally at elevated pressure (e.g. 60psi), at a temperature between room temperature and 60 ℃ for 8-24 hours.

The olefin of formula (17) can be prepared by palladium mediated coupling of an activated alkene with an aryl halide of formula (18):

in a typical procedure, the aryl halide (18) is reacted with a vinyl ester (e.g., methyl acrylate) over a suitable palladium catalyst (e.g., of the formula Pd (PPh)₃)₄Tetrakis (triphenylphosphine) palladium (0) of formula Pd (OAc)₂/P(o-tol)₃Palladium acetate/tri-o-tolylphosphine or of the formula dppfppdcl₂In the presence of a suitable solvent (e.g. acetonitrile, N-dimethylformamide, toluene), optionally in the presence of a base such as triethylamine, at a temperature between 40 ℃ and 110 ℃ for 8 to 24 hours.

The ketones of formula (18) are commercial products.

An amine of formula (5) R¹And R²All are H, and can be prepared according to the following scheme:

scheme 3

Wherein R is¹、R²And Ra is as defined above.

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

The primary alcohol of formula (20) is then converted to a leaving group such as mesylate, tosylate, bromide or iodide and displaced with an appropriate amine nucleophile. Preferred nucleophiles are azide ions, which can then be reduced to a primary amine via hydrogenation or triphenylphosphine. Alternative nucleophiles may include ammonia or alkylamines such as benzylamine or allylamine and subsequent cleavage of the alkyl group to provide the amine.

In a typical procedure, a compound of formula (I), wherein R¹And R²All methyl and n is 1, by reacting a compound of formula (21) in the presence of a conventional coupling agent, e.g. 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride or dicyclohexylcarbodiimide in a suitable solvent, e.g. pyridine, dimethylformamide and dimethylacetamide, optionally in the presence of an organic base, e.g. Hunig's base, and an additive, e.g. 1-hydroxybenzotriazole

Where X is H, K, Na, Li and possibly an organic amine base or other metal salt, with the appropriate compound of the formula NHR⁸-Q²-A(3)

So as to obtain a compound of formula (1):

wherein R is¹And R²Is methyl and n is 1.

The compound of formula (21) can be prepared by reacting a compound of formula (22)

Wherein X is H, Na, Li or K and possibly an organic amine or other metal salt, in the presence of a suitable solvent such as methanol, IPA, THF and water and in the presence of a suitable catalyst such as palladium hydroxide on carbon or palladium on carbon.

The compound of formula (22) can be prepared by reacting a compound of formula (23)

With M-OH, wherein M is selected from Na, K or Li, optionally in the presence of a suitable solvent such as propionitrile, tetrahydrofuran or dioxane, preferably propionitrile.

The compound of formula (23) may be obtained by deprotecting a compound of formula (24) using a deprotecting agent such as tetrabutylammonium fluoride, HF or triethylamine trihydrofluoride in the presence of a suitable solvent such as propionitrile.

Said compound of formula (24) can be prepared by reacting a compound of formula (la) at a temperature between 50 ℃ and 150 ℃ in the presence of a suitable solvent such as propionitrile, THF, toluene, ethyl acetate, acetonitrile, propionitrile, dioxane, DMF, DMSO, and optionally in the presence of a base such as sodium bicarbonate, potassium bicarbonate, Hunig's base or triethylamine

With a compound of the formula

Reacting for 12 to 36 hours.

For some of the steps of the process described herein above for the preparation of compounds of formula (1), it may be necessary to protect possible reactive functional groups which are not intended to react and thus to cleave the protecting group. In this case, any compatible protecting group may be used. In particular, methods of protection and deprotection such as those described by t.w.greene (protective group in organic synthesis, a. viss-international scientific press, 1981) or by p.j.kocienski (protective group, Georg ThiemeVerlag, 1994) can be used.

All the reactions and preparations of the novel starting materials described above for the aforementioned processes are conventional and the procedures for their performance or preparation of the appropriate reagents and reaction conditions and isolation of the desired products will be well known to those skilled in the art with reference to literature precedents and the examples and preparations herein.

Likewise, the compounds of formula (1) as well as intermediates used in their preparation may be purified according to various well-known methods, such as, for example, crystallization or chromatography.

Preferably Q²is-CH₂-、-(CH₂)₂-、-(CH₂)₃-、(C(CH₃)₂)-、-(CH₂)₄-or- (CH)₂OH))-。

Preferably, Q¹Is composed of

Wherein R is₃、R₄、R₅And R₆One is OH and the other is H.

Preferably, Q¹Is composed of

Wherein R is₃、R₄、R₅And R₆One is OH and the other is H.

Preferably, Q¹Is a group-NR⁸-Q²-A, wherein R⁸Is H, CH₃Or CH₂CH₃，Q²Is C₁-C₄Alkylene and a is naphthyl substituted by one hydroxy.

Preferably, Q¹Is a group-NR⁸-Q²-A, wherein R⁸Is H, CH₃Or CH₂CH₃，Q²Is C₁-C₄Alkylene and A is a group

Wherein R is³、R⁴、R⁵、R⁶And R⁷One is OH and the others are the same or different and are selected from H, C₁-C₄Alkyl, OR⁹、SR⁹Halo, CF₃、OCF₃、SO₂NR⁹R¹⁰、CONR⁹R¹⁰、NR⁹R¹⁰、NHCOR¹⁰With the proviso that R³To R⁷At least 2 of (a) is equal to H; wherein R is⁹And R¹⁰Are the same or differentAnd is selected from H or C₁-C₄An alkyl group.

More preferably, Q¹Is a group-NH-Q²-A, wherein Q²is-CH₂-、-(CH₂)₂-、-(CH₂)₂-、-(CH₂)₄-、-CH₂-C(CH₃)₂) -, preferably Q²is-CH₂-, and A is a group

Wherein R is³、R⁴、R⁵、R⁶And R⁷One is OH and the others are the same or different and are selected from H, OH, CH₃、OCH₂-CH₃、SCH₃Halo, CF₃、OCF₃With the proviso that R³To R⁷At least 2 of (a) is equal to H.

Preferably, wherein Q¹Is a group-NR⁸-Q²-A, wherein R⁸Is H, CH₃Or CH₂CH₃，Q²Is C₁-C₄Alkylene and A is a group

Wherein R is³、R⁴、R⁵、R⁶And R⁷One is phenyl substituted with OH and the other is H.

In the above group of compounds, the following substituents are particularly preferred:

R¹is H or C₁-C₄Alkyl and R²Is C₁-C₄An alkyl group. More preferably, R¹Is H or CH₃And R is²Is CH₃。

n is 0 or 1. More preferably n is 1.

R¹Is H, R²Is CH₃And n is 1.

R¹Is CH₃，R²Is CH₃And n is 1.

Particularly preferred are compounds of formula (1) as described in the examples section below, that is:

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

n- [ (4' -hydroxybiphenyl-4-yl) methyl ] -2- (3- {2- [ ((2R) -2-hydroxy-2- { 4-hydroxy-3- [ (methylsulfonyl) amino ] phenyl } ethyl) amino ] -2-methylpropyl } phenyl) acetamide;

n- (4-chloro-2-hydroxybenzyl) -2- (3- {2- [ ((2R) -2-hydroxy-2- { 4-hydroxy-3- [ (methylsulfonyl) amino ] phenyl } ethyl) amino ] -2-methylpropyl } phenyl) acetamide;

n- (4-hydroxy-3, 5-dimethylbenzyl) -2- (3- {2- [ ((2R) -2-hydroxy-2- { 4-hydroxy-3- [ (methylsulfonyl) amino ] phenyl } ethyl) amino ] -2-methylpropyl } phenyl) acetamide;

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

2- (3- {2- [ ((2R) -2-hydroxy-2- { 4-hydroxy-3- [ (methylsulfonyl) amino ] phenyl } ethyl) amino ] -2-methylpropyl } phenyl) -N- [ (6-hydroxy-2-naphthyl) methyl ] acetamide;

n- [ (4' -hydroxybiphenyl-3-yl) methyl ] -2- (3- {2- [ ((2R) -2-hydroxy-2- { 4-hydroxy-3- [ (methylsulfonyl) amino ] phenyl } ethyl) amino ] -2-methylpropyl } phenyl) acetamide;

n- [ (3' -hydroxybiphenyl-3-yl) methyl ] -2- (3- {2- [ ((2R) -2-hydroxy-2- { 4-hydroxy-3- [ (methylsulfonyl) amino ] phenyl } ethyl) amino ] -2-methylpropyl } phenyl) acetamide;

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

n- (3, 5-dichloro-2-hydroxybenzyl) -N-ethyl-2- (3- {2- [ ((2R) -2-hydroxy-2- { 4-hydroxy-3- [ (methylsulfonyl) amino ] phenyl } ethyl) amino ] -2-methylpropyl } phenyl) acetamide;

2- (3- {2- [ ((2R) -2-hydroxy-2- { 4-hydroxy-3- [ (methylsulfonyl) amino ] phenyl } ethyl) amino ] -2-methylpropyl } phenyl) -N- [ (6-hydroxy-1-naphthyl) methyl ] -N-methylacetamide;

n- [ (2' -hydroxybiphenyl-3-yl) methyl ] -2- (3- {2- [ ((2R) -2-hydroxy-2- { 4-hydroxy-3- [ (methylsulfonyl) amino ] phenyl } ethyl) amino ] -2-methylpropyl } phenyl) acetamide;

n- (2-hydroxy-5- { (1R) -1-hydroxy-2- [ (2- {3- [2- (6-hydroxy-3, 4-dihydroisoquinolin-2 (1H) -yl) -2-oxoethyl ] phenyl } -1, 1-dimethylethyl) amino ] ethyl } phenyl) methanesulfonamide;

2- (3- {2- [ ((2R) -2-hydroxy-2- { 4-hydroxy-3- [ (methylsulfonyl) amino ] phenyl } ethyl) amino ] -2-methylpropyl } phenyl) -N- [4- (4-hydroxyphenyl) butyl ] acetamide;

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

n- (2-chloro-4-hydroxybenzyl) -2- (3- {2- [ ((2R) -2-hydroxy-2- { 4-hydroxy-3- [ (methylsulfonyl) amino ] phenyl } ethyl) amino ] -2-methylpropyl } phenyl) acetamide;

n- (3, 5-dichloro-4-hydroxybenzyl) -2- (3- {2- [ ((2R) -2-hydroxy-2- { 4-hydroxy-3- [ (methylsulfonyl) amino ] phenyl } ethyl) amino ] -2-methylpropyl } phenyl) acetamide;

n- (2, 3-dichloro-4-hydroxybenzyl) -2- (3- {2- [ ((2R) -2-hydroxy-2- { 4-hydroxy-3- [ (methylsulfonyl) amino ] phenyl } ethyl) amino ] -2-methylpropyl } phenyl) acetamide;

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

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

n- (2-chloro-4-hydroxybenzyl) -N-ethyl-2- (3- {2- [ ((2R) -2-hydroxy-2- { 4-hydroxy-3- [ (methylsulfonyl) amino ] phenyl } ethyl) amino ] -2-methylpropyl } phenyl) acetamide;

n- (2-chloro-4-hydroxybenzyl) -2- (3- {2- [ ((2R) -2-hydroxy-2- { 4-hydroxy-3- [ (methylsulfonyl) amino ] phenyl } ethyl) amino ] -2-methylpropyl } phenyl) -N-methylacetamide;

n- (3-fluoro-5-hydroxybenzyl) -2- (3- {2- [ ((2R) -2-hydroxy-2- { 4-hydroxy-3- [ (methylsulfonyl) amino ] phenyl } ethyl) amino ] -2-methylpropyl } phenyl) -N-methylacetamide;

n- [ (2' -hydroxybiphenyl-2-yl) methyl ] -2- (3- {2- [ ((2R) -2-hydroxy-2- { 4-hydroxy-3- [ (methylsulfonyl) amino ] phenyl } ethyl) amino ] -2-methylpropyl } phenyl) acetamide;

n- [ (3' -hydroxybiphenyl-2-yl) methyl ] -2- (3- {2- [ ((2R) -2-hydroxy-2- { 4-hydroxy-3- [ (methylsulfonyl) amino ] phenyl } ethyl) amino ] -2-methylpropyl } phenyl) acetamide;

n- (4-hydroxy-2, 6-dimethylbenzyl) -2- (3- {2- [ ((2R) -2-hydroxy-2- { 4-hydroxy-3- [ (methylsulfonyl) amino ] phenyl } ethyl) amino ] -2-methylpropyl } phenyl) acetamide;

n- (2-hydroxy-5- { (1R) -1-hydroxy-2- [ (2- {3- [2- (7-hydroxy-3, 4-dihydroisoquinolin-2 (1H) -yl) -2-oxoethyl ] phenyl } -1, 1-dimethylethyl) amino ] ethyl } phenyl) methanesulfonamide;

n- (2-hydroxy-5- { (1R) -1-hydroxy-2- [ (2- {3- [2- (5-hydroxy-3, 4-dihydroisoquinolin-2 (1H) -yl) -2-oxoethyl ] phenyl } -1, 1-dimethylethyl) amino ] ethyl } phenyl) methanesulfonamide;

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

2- (3- {2- [ ((2R) -2-hydroxy-2- { 4-hydroxy-3- [ (methylsulfonyl) amino ] phenyl } ethyl) amino ] -2-methylpropyl } phenyl) -N- [ (1S) -2-hydroxy-1-phenylethyl ] acetamide;

n- [ (3' -hydroxybiphenyl-4-yl) methyl ] -2- (3- {2- [ ((2R) -2-hydroxy-2- { 4-hydroxy-3- [ (methylsulfonyl) amino ] phenyl } ethyl) amino ] -2-methylpropyl } phenyl) acetamide;

n- [ (2' -hydroxybiphenyl-4-yl) methyl ] -2- (3- {2- [ ((2R) -2-hydroxy-2- { 4-hydroxy-3- [ (methylsulfonyl) amino ] phenyl } ethyl) amino ] -2-methylpropyl } phenyl) acetamide;

n- [ (4' -hydroxybiphenyl-4-yl) methyl ] -3- {2- [ ((2R) -2-hydroxy-2- { 4-hydroxy-3- [ (methylsulfonyl) amino ] phenyl } ethyl) amino ] -2-methylpropyl } benzamide;

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

n- [ (4' -hydroxybiphenyl-3-yl) methyl ] -3- {2- [ ((2R) -2-hydroxy-2- { 4-hydroxy-3- [ (methylsulfonyl) amino ] phenyl } ethyl) amino ] -2-methylpropyl } benzamide;

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

n- [2- (4-hydroxy-2, 3-dimethylphenyl) ethyl ] -3- {2- [ ((2R) -2-hydroxy-2- { 4-hydroxy-3- [ (methylsulfonyl) amino ] phenyl } ethyl) amino ] -2-methylpropyl } benzamide; and the combination of (a) and (b),

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

According to one aspect of the invention, preference is generally given to compounds of formula (1) in which (CH)₂)_n-C(＝O)Q¹The groups are in the meta position.

Pharmaceutically acceptable salts of the compounds of formula (1) include acid addition and base salts thereof.

Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include acetate, aspartate, benzoate, benzenesulfonate, bicarbonate/carbonate, bisulfate/sulfate, borate, camphorsulfonate, citrate, edisylate, ethylsulfonate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, oxybenzoyl benzoate, hydrochloride/chloride, hydrobromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, methanesulfonate, methylsulfate, naphthenate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogenphosphate/dihydrogenphosphate, saccharinate, stearate, dihydrogenphosphate, saccharinate, dihydrogenphosphate, stearate, dihydrogenphosphate, dihydrogensulfate, camphorate, Succinate, tartrate, tosylate and trifluoroacetate and 1-hydroxy-2-naphthoate (xinafoate).

Suitable base salts are formed from bases which form non-toxic salts. Examples include aluminum salts, arginine salts, benzathine salts, calcium salts, choline salts, diethylamine salts, dialcohol salts, glycine salts, lysine salts, magnesium salts, N-methylglucamine salts, ethanolamine salts, potassium salts, sodium salts, tris salts and zinc salts. Hemisalts of acids and bases, e.g., hemisulfate and hemicalcium salts, may also be formed.

For a review of the appropriate salts, see Stahl and Wermuth, handbook of pharmaceutically acceptable salts: properties, selection and uses "(Vis-VCH, We inheim, Germany, 2002).

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

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

(ii) by removal of acid-or base-labile protecting groups from the appropriate precursor of the compound of formula (1) or by ring opening of the appropriate ring precursor (e.g., lactone or lactam) using the desired acid or base; or

(iii) The salt of the compound of formula (1) is converted to another salt by reaction with an appropriate acid or base or via an appropriate ion exchange column.

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

The compounds of the present invention may exist in unsolvated as well as solvated forms. The term "solvate" is used herein to describe a molecular complex comprising a compound of the invention and a stoichiometric amount of one or more pharmaceutically acceptable solvent molecules (e.g., ethanol). When the solvent is water, the term "hydrate" is used.

Included within the scope of the invention are complexes such as clathrates, drug-matrix (host) inclusion complexes wherein the drug and matrix are present in stoichiometric or non-stoichiometric amounts, as opposed to solvates as described above. Also included are complexes of drugs comprising two or more organic and/or inorganic components in stoichiometric or non-stoichiometric amounts. The resulting complex may be ionized, partially ionized, or not. For an overview of these complexes, see Haleblian J Pharm Sci, 64(8), 1269-.

All references below to compounds of formula (1) include references to salts, solvates and complexes thereof and references to solvates and complexes of salts thereof.

The compounds of the present invention include compounds of formula (1) as defined above, including all polymorphs and crystal habit thereof as defined below, prodrugs thereof and isomers thereof (including optical, geometric and tautomeric isomers) and isotopically-labeled compounds of formula (1).

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

Prodrugs according to the invention may be prepared, for example, by substituting the appropriate functional group present in a compound of formula (1) with certain moieties known to those skilled in the art, such as, for example, the moieties described in "Design of produgs" (Elsevier, 1985) by h.

Examples of some prodrugs according to the invention include:

(i) in the case where the compound of formula (1) contains a carboxylic acid function (-COOH), esters thereof, for example, wherein the hydrogen of the carboxylic acid function of the compound of formula (1) is replaced by (C)₁-C₈) An alkyl-substituted compound;

(ii) in the case where the compound of formula (1) comprises an alcoholic function (-OH), ethers thereof, for example, wherein the hydrogen of the alcoholic function of the compound of formula (1) is replaced by (C)₁-C₆) Alkanoyloxymethyl-substituted compounds; and

(iii) the compounds in formula (1) contain primary or secondary amino functions (-NH)₂or-NHR, where R.noteq.H), amides thereof, for example, where, as the case may be, the hydrogen of one or both amino functions of the compound of formula (1) is replaced by (C)₁-C₁₀) Alkanoyl substituted compounds.

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

Furthermore, certain compounds of formula (1) may themselves be useful as prodrugs of other compounds of formula (1).

Also included within the scope of the present invention are metabolites of the compounds of formula (1), i.e., compounds formed in vivo upon administration of the drug. Some examples of metabolites according to the invention include

(i) In case the compound of formula (1) contains a methyl group, the hydroxymethyl derivative thereof (-CH)₃→-CH₂OH)：

(ii) In the case where the compound of formula (1) contains an alkoxy group, a hydroxyl derivative thereof (-OR → -OH);

(iii) in the case where the compound of formula (1) contains a tertiary amino group, a secondary amino group derivative thereof (-NR)¹R²→-NHR¹or-NHR²)；

(iv) In the case where the compound of formula (1) contains a secondary amino group, its primary amino derivative (-NHR)¹→-NH₂)；

(v) In case the compound of formula (1) contains a phenyl moiety, its phenolic derivative (-Ph → -PhOH); and

(vi) in the case where the compound of formula (1) contains an amido group, the carboxylic acid derivative thereof (-CONH)₂→COOH)。

The compounds of formula (1) containing one or more asymmetric carbon atoms may exist as two or more stereoisomers. In the case where the compound of formula (1) contains an alkenyl or alkenylene group, geometric cis/trans (or Z/E) isomers are possible. In the case of structural isomers that can be interconverted via a low energy barrier, tautomerism ('tautomerism') can occur. This may take the form of proton tautomerism in compounds of formula (1) containing, for example, imino, keto, or nitrile groups, or so-called valence tautomerism in compounds containing aromatic moieties. It follows from this that: a single compound may exhibit more than one type of isomerism.

Included within the scope of the present invention are all stereoisomers, geometric isomers and tautomeric forms of the compounds of formula (1), including compounds exhibiting more than one type of isomerism and mixtures of one or more thereof. Also included are acid addition or base salts in which the counterion is optically active, e.g., d-lactate or 1-lysine, or racemic, e.g., d 1-tartrate or d 1-arginine.

The cis/trans isomers may be separated by conventional techniques well known to those skilled in the art, for example, chromatography and fractional crystallization.

Conventional techniques for the preparation/separation of individual enantiomers include chiral synthesis from appropriate optically pure precursors or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral High Pressure Liquid Chromatography (HPLC).

Alternatively, the racemate (or racemic precursor) may be reacted with an appropriate optically active compound (e.g. an alcohol) or, in the case of compounds of formula (1) containing an acidic or basic moiety, an acid or base such as tartaric acid or 1-phenylethylamine. The resulting diastereomeric mixtures can be separated by chromatography and/or fractional crystallization and one or both of the diastereomers can be converted to the corresponding pure enantiomers by methods well known to those skilled in the art.

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

Stereoisomeric crystal groups may be isolated by conventional techniques known to those skilled in the art-see, e.g., e.l. eliel, "stereochemistry of organic compounds" (vis, new york, 1994).

According to one aspect of the invention, preference is generally given to the (R, R) -stereoisomer of the formula, wherein R is¹Is hydrogen and R²Is C₁-C₄Alkyl, preferably methyl, and n and Q¹As defined above:

the present invention includes all pharmaceutically acceptable isotopically-labelled compounds of formula (1) wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number which predominates in nature.

Examples of isotopes suitable for inclusion in compounds of the invention include isotopes of hydrogen, for example²H and³H. isotopes of carbon, e.g.¹¹C、¹³C and¹⁴isotopes of C, chlorine, e.g.³⁶Isotopes of Cl, fluorine, e.g.¹⁸Isotopes of F, iodine, e.g.¹²³I and¹²⁵i, isotopes of nitrogen, e.g.¹³N and¹⁵isotopes of N, oxygen, e.g.¹⁵O，¹⁷O and¹⁸isotopes of O, phosphorus, e.g.³²Isotopes of P and sulfur, e.g.³⁵S。

Certain isotopically-labeled compounds of formula (1), for example those into which a radioisotope is incorporated, are useful in drug and/or matrix tissue distribution studies. The radioactive isotope tritium, that is,³h, and carbon-14, that is,¹⁴c, in view of their ease of incorporationThe detection method is rapid and is particularly useful for this purpose.

The metal ions are separated from the metal ions by heavier isotopes such as deuterium, that is,²h substitution may provide certain therapeutic advantages resulting from greater metabolic stability, such as increased half-life or reduced dosage requirements in vivo and, therefore, may be preferred in certain circumstances.

The isotope being emitted, e.g.¹¹C、¹⁸F、¹⁵O and¹³positron substitution of N can be used in Positron Emission Tomography (PET) studies to examine occupancy of matrix receptors.

Isotopically-labelled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying examples and preparations using a suitable isotopically-labelled reagent in place of the non-isotopically-labelled reagent employed previously.

Pharmaceutically acceptable solvates according to the invention include those in which the solvent of the crystallization may be isotopically substituted, e.g. D₂O，d₆-acetone, d₆-solvates of DMSO.

The compounds of formula (1), pharmaceutically acceptable salts and derivatives thereof, are valuable pharmaceutically active compounds which are suitable for the treatment and prophylaxis of a number of conditions in which the β 2 receptor is involved or in which agonism of this receptor may induce a benefit, particularly allergic and non-allergic airway diseases, as well as other diseases such as, but not limited to, nervous system, premature labour, congestive heart failure, depression, inflammatory and allergic skin diseases, psoriasis, proliferative skin diseases, glaucoma and conditions in which there is a reduction in gastric acidity, particularly the treatment of gastric and peptic ulcers.

The compounds of the invention for pharmaceutical use may be administered as crystalline or amorphous products. They can be obtained as solid plugs, powders or films by methods such as precipitation, crystallization, freeze drying, spray drying, or evaporative drying. Microwave or radio frequency drying may be used for this purpose.

They may be administered alone or in combination (or in any combination) with one or more compounds of the invention or with one or more other drugs. Typically, they will be administered in a formulation in combination with one or more pharmaceutically acceptable excipients. The term "excipient" is used herein to describe any ingredient that is not a compound of the present invention. The choice of excipient will depend in large part on factors such as the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.

Pharmaceutical compositions suitable for delivery of the compounds of the invention and methods for their preparation will be apparent to those skilled in the art. These compositions and their preparation can be found, for example, in Remington's Pharmaceutical Sciences, 19 th edition (Mack publishing company, 1995).

The compounds of the invention may also be administered directly into the bloodstream, into muscle, or into internal organs. Suitable methods for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intracerebroventricular, intraurethral, intrasternal, intracranial, intramuscular, and subcutaneous. Suitable devices for parenteral administration include needle (including microneedle) type injectors, needleless injectors and infusion techniques.

Parenteral formulations are typically aqueous solutions which may contain excipients such as salts, carbohydrates and buffers (preferably to a pH of from 3 to 9), but, for some applications, they may be more suitably formulated as sterile nonaqueous solutions or in dry form to be used in conjunction with a suitable carrier, e.g. sterile pyrogen-free water.

Preparation of parenteral formulations under sterile conditions, for example, by freeze-drying, can be readily accomplished using standard pharmaceutical techniques well known to those skilled in the art.

The solubility of the compounds of formula (1) used in the preparation of parenteral solutions can be increased by using appropriate formulation techniques, for example the incorporation of solubility enhancers.

Formulations for parenteral administration may be formulated as immediate and/or modified formulations. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted, and programmed release. The compounds of the present invention may therefore be formulated as solids, semi-solids, or thixotropic liquids for administration in an implanted depot providing modified release of the active compound. Examples of such formulations include drug-coated stents and poly (d 1-lacto-co-ethanolic) acid (PGLA) microspheres.

The compounds of the present invention may also be administered topically, i.e., dermally or transdermally, to the skin or mucosa. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibers, bandages, and microemulsions. Liposomes may also be used. Typical carriers include alcohols, water, mineral oil, liquid paraffin, white petrolatum, glycerin, polyethylene glycol, and propylene glycol. Penetration enhancers may be incorporated-see, for example, JPharm Sci, 88(10), 955-958 by Finnin and Morgan (10 months 1999).

Other means of topical administration include by electroporation, iontophoresis, phonophoresis, sonophoresis (sonophoresis) and microneedles or needleless (e.g. Powderject)^TM、Bioject^TMEtc.) injection delivery.

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

The compounds of the invention may also be administered intranasally or by inhalation, typically in the form of a dry powder (either alone, in a mixture, e.g., a dry blend with lactose, or in mixed component particles, e.g., mixed with a phospholipid, e.g., phosphatidylcholine) from a dry powder inhaler or as an aerosol spray from a pressurized container, pump, nebulizer, atomizer (preferably one that produces a fine mist using electrohydrodynamics), or nebulizer, with or without the use of a suitable propellant, e.g., 1, 1, 1, 2-tetrafluoroethane or 1, 1, 1, 2, 3, 3, 3-heptafluoropropane. For intranasal use, the powder may comprise a bioadhesive, for example, chitosan or cyclodextrin.

A pressurized container, pump, nebulizer, atomizer, or nebulizer contains a solution or suspension of a compound of the invention comprising, for example, ethanol, aqueous ethanol, or a suitable substitute for dispersion, dissolution, or extended release of the active ingredient, a propellant as a solvent, and optionally a surfactant, such as sorbitan trioleate, oleic acid, or oligomeric lactic acid.

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

Capsules (made, for example, from gelatin or hydroxypropylmethyl cellulose), blisters and cartridges for use in an inhaler or insufflator may be formulated containing a powder mix of a compound of the invention, a suitable powder base such as lactose or starch and a performance enhancing agent such as 1-leucine, mannitol or magnesium stearate. Lactose can be in anhydrous or monohydrate form, the latter being preferred. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose.

Solution formulations suitable for use in nebulizers that generate fine mist using electrohydrodynamic force may comprise 1 microgram to 20 milligrams of the compound of the invention per drive and the drive volumes may vary from 1 microliter to 100 microliters. Typical formulations may comprise 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 saccharin sodium, may be added to these formulations of the present invention intended for inhalation/intranasal administration.

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

In the case of dry powder inhalers and aerosols, the dosage unit is determined by the valve delivering a metered amount. The units according to the invention are typically configured to administer a metered dose or "puff comprising from 0.001 mg to 10 mg of a compound of formula (1). The total daily dose may typically range from 0.001 mg to 40 mg, which may be given as a single dose or, more usually, as divided doses throughout the day.

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

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

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

The compounds of the invention may also be administered directly to the eye or ear, typically in the form of drops of micronized suspension or solution in isotonic, pH-adjusted, sterile saline. Other formulations suitable for ocular and otic administration include ointments, biodegradable (e.g., absorbable gel sponges, collagen) and non-biodegradable (e.g., silicone) implants, wafers, lenses, and particles or vesicle systems, such as nonionic surfactant vesicles (niosomes) or liposomes. Polymers such as crosslinked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, cellulosic polymers, e.g., hydroxypropyl methylcellulose, hydroxyethyl cellulose, or methyl cellulose, or heteropolysaccharide polymers, e.g., gellan gum, may be incorporated with preservatives, such as benzalkonium chloride. These formulations can also be delivered by iontophoresis.

Formulations for ocular/otic administration may be formulated as immediate and/or modified release formulations. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted, or programmed release.

The compounds of the invention may be combined with soluble macromolecular entities such as cyclodextrins and suitable derivatives thereof or polyethylene glycol containing polymers in order to improve their solubility, dissolution rate, taste masking, bioavailability and/or stability for any of the above modes of administration.

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

Since it may be necessary to administer a combination of active compounds, for example for the purpose of treating a particular disease or physical discomfort, two or more pharmaceutical compositions within the scope of the present invention, at least one of which comprises a compound according to the invention, may conveniently be combined in the form of a kit suitable for simultaneous administration of the compositions.

The kit of the invention thus comprises two or more separate pharmaceutical compositions, at least one of which comprises a compound of formula (1) according to the invention, and means for separately retaining the compositions, such as a container, a separate bottle, or a separate foil pouch. Examples of such kits are the usual blister packs used for packaging tablets, capsules and the like.

The kit of the invention is particularly suitable for administration of different dosage forms, e.g. parenterally, for administration of these separate compositions at different dosage intervals, or for titration of the compositions separately from one another. To aid in compliance, the kit typically contains instructions and may have so-called memory aids.

For administration to a human patient, 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 need only be from 0.001 mg to 40 mg. The total daily dose may be administered in single or divided doses and may fall outside the typical ranges given herein, with the discretion of the physician.

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

For the avoidance of doubt, reference herein to "treatment" includes curative, palliative and prophylactic treatment.

According to another embodiment of the invention, the compound of formula (1), or a pharmaceutically acceptable salt, derivative form or composition thereof, may also be used in combination with one or more additional therapeutic agents intended to be co-administered to a patient for the purpose of achieving some particularly desirable therapeutic end result, such as treatment of pathophysiologically relevant disease processes, including, but not limited to, (i) bronchoconstriction, (ii) inflammation, (iii) allergy, (iv) tissue destruction, (v) signs and symptoms such as apnea, cough. The second and more additional therapeutic agents may also be a compound of formula (1), or a pharmaceutically acceptable salt, derivative form, or composition thereof, or one or more beta 2 agonists known in the art. More typically, the second and more therapeutic agents will be selected from different classes of therapeutic agents.

As used herein, the terms "co-administration", "co-administered" and "in combination with" when referring to a compound of formula (1) and one or more other therapeutic agents are intended to mean and indeed mean and include the following:

the combination of the compound of formula (1) and the therapeutic agent is administered simultaneously to a patient in need of treatment, when the ingredients are formulated together in a single dosage form that releases the ingredients to the patient at substantially the same time,

the combination of the compound of formula (1) and the therapeutic agent is administered substantially simultaneously to a patient in need of treatment when the ingredients are formulated separately from each other into separate dosage forms which are taken by the patient at substantially the same time whereupon the ingredients are released to the patient at substantially the same time;

the combination of the compound of formula (1) and the therapeutic agent is administered sequentially to a patient in need of treatment when these ingredients are formulated separately from each other into separate dosage forms which are taken by the patient at successive times over a significant time interval between each administration, whereupon the ingredients are released to the patient at substantially different times; and

the combination of the compound of formula (1) and the therapeutic agent is administered sequentially to a patient in need of treatment, when these ingredients are formulated together in a single dosage form that releases the ingredients in a controlled manner, so that they are taken simultaneously, sequentially, and/or overlappingly by the patient at the same and/or different times,

wherein each moiety may be administered by the same or different route.

Suitable examples of other therapeutic agents that may be used in combination with a compound of formula (1), or a pharmaceutically acceptable salt, derivative form or composition thereof, include (but are in no way limited to):

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

(b) leukotriene antagonists (LTRAs) including LTB₄、LTC₄、LTD₄And LTE₄The antagonist of (a) or (b),

(c) histamine receptor antagonists, including H1 and H3 antagonists,

(d) alpha for decongestant use₁-and α₂-an adrenoceptor agonist vasoconstrictive sympathomimetic agent,

(e) muscarinic M3 receptor antagonists or anticholinergic agents,

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

(g) the content of the theophylline is determined,

(h) the content of the sodium cromoglycate is as follows,

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

j) oral and inhaled glucocorticoids, e.g. DAGR (dissociative agonists of corticoid receptors)

(k) A monoclonal antibody directed against an endogenous inflammatory entity,

(l) Anti-tumor necrosis factor (anti-TNF-alpha) agents,

(m) adhesion molecule inhibitors, including VLA-4 antagonists,

(n) kinin-B₁-and B₂-an antagonist of a receptor,

(o) an immunosuppressive agent, wherein,

(p) inhibitors of Matrix Metalloproteinases (MMPs),

(q) tachykinin NK₁、NK₂And NK₃(ii) an antagonist of a receptor,

(r) an inhibitor of an elastase,

(s) adenosine A2a receptor agonists,

(t) an inhibitor of urokinase,

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

(v) modulators of the NF kappa beta pathway, such as IKK inhibitors,

(w) modulators of cytokine signaling pathways such as p38MAP kinase, syk kinase, or JAK kinase inhibitors,

(x) Agents that can be classified as mucolytic or antitussive, and

(y) an antibiotic.

Further preferred according to the invention is the combination of a compound of formula (1) with:

-an antagonist of H3, and,

-a muscarinic M3 receptor antagonist,

-a PDE4 inhibitor which is,

-a glucocorticoid in a form of a complex of two,

-an adenosine A2a receptor agonist,

a cytokine signaling pathway modulator, such as p38MAP kinase or syk kinase, or,

leukotriene antagonists (LTRAs) including LTB₄、LTC₄、LTD₄And LTE₄An antagonist of (1).

Further preferred according to the invention is the combination of a compound of formula (1) with:

glucocorticoids, in particular inhaled glucocorticoids with reduced systemic side effects, including prednisolone, flunisolide, triamcinolone acetonide, beclomethasone propionate, budesonide, fluticasone propionate, cericlone and mometasone furoate, or

Muscarinic M3 receptor antagonists or anticholinergic agents include in particular ipratropium salts, i.e. bromide, tiotropium salts, i.e. bromide, oxitropium salts, i.e. bromide, pelamipine and telenzepine.

It is to be understood that all treatments mentioned herein include curative, palliative and prophylactic treatments. The following description relates to potentially suitable therapeutic applications of the compounds of formula (1).

The compounds of formula (1) have the ability to interact with the β 2 receptor and thus have a wide range of therapeutic applications, as further described below, because of the fundamental role played by the β 2 receptor in the physiology of all mammals.

Accordingly, another aspect of the present invention is directed to compounds of formula (1), or pharmaceutically acceptable salts, derivatives or compositions thereof, for use in the treatment of diseases, disorders and physical conditions in which the β 2 receptor is involved. More particularly, the present invention also relates to compounds of formula (1), or pharmaceutically acceptable salts, derived forms or compositions thereof, for use in the treatment of diseases, disorders and physical discomfort selected from the group consisting of:

asthma of any type, etiology or pathogenesis, in particular asthma selected from allergic asthma, non-allergic asthma, allergic bronchial IgE-mediated asthma, bronchial asthma, idiopathic asthma, true asthma, intrinsic asthma caused by pathophysiological disorders, extrinsic asthma caused by environmental factors, idiopathic asthma of unknown or non-obvious cause, non-allergic asthma, bronchitis asthma, inflammatory asthma, exercise-induced asthma, allergen-induced asthma, cold-air induced asthma, occupational asthma, infectious asthma caused by bacterial, fungal, animal or viral infections, non-allergic asthma, incipient asthma, infant asthma syndrome and bronchiolitis,

chronic or acute bronchoconstriction, chronic bronchitis, obstruction of the small airways and emphysema,

obstructive or inflammatory airway diseases of any type, etiology or pathogenesis, in particular selected from chronic eosinophilic pneumonia, Chronic Obstructive Pulmonary Disease (COPD), COPD including chronic bronchitis, emphysema or dyspnea with or without involvement in COPD, COPD characterized by irreversible progressive airway obstruction, Adult Respiratory Distress Syndrome (ARDS), exacerbations of airway hyperactivity occurring after other drug treatment and airway diseases associated with pulmonary hypertension,

bronchitis of any type, etiology or pathogenesis, in particular bronchitis selected from acute bronchitis, acute laryngotracheobronchitis, arachidic bronchitis, catarrhal bronchitis, croupus bronchitis, dry bronchitis, infectious asthmatic bronchitis, proliferative bronchitis, staphylococcal or streptococcal bronchitis and alveolar bronchitis,

the risk of acute lung injury is high,

bronchiectasis of any type, etiology or pathogenesis, in particular bronchiectasis selected from the group consisting of cylindrical bronchiectasis, saccular bronchiectasis, spindle bronchiectasis, saccular bronchiectasis, dry bronchiectasis and follicular bronchiectasis.

In another aspect, the invention is also directed to the use of a compound of formula (1), or a pharmaceutically acceptable salt, derivative form or composition thereof, in the manufacture of a medicament having β 2 agonist activity. In particular, the present invention relates to the use of a compound of formula (1), or a pharmaceutically acceptable salt, derivative form or composition thereof, in the manufacture of a medicament for the treatment of a β 2 mediated disease and/or physical discomfort, in particular the diseases and/or physical discomfort listed above.

As a result, the present invention provides a method of particular interest for treating mammals, including humans, with an effective amount of a compound of formula (1), or a pharmaceutically acceptable salt, derivative form or composition thereof. More specifically, the present invention provides a method of particular interest for the treatment of β 2-mediated diseases and/or physical ailments, particularly the diseases and/or physical ailments listed above, in a mammal, including a human, which comprises administering to said mammal an effective amount of a compound of formula (1), a pharmaceutically acceptable salt and/or derivative form thereof.

Detailed Description

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

preparation 1: 2, 2' - (1, 3-phenylene) diacetic acid diethyl ester

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

¹HNMR(CDCl₃，400MHz)δ：1.31(t，6H)，3.65(s，4H)，4.20(q，4H)，7.24-7.36(m，4H)ppm

MS (electrospray): m/z 251[ M + H]⁺

Preparation 2: [3- (2-oxo-propyl) -phenyl ] -acetic acid ethyl ester

A solution of the diester from preparation 1 (44.3 g, 177 mmol) and 2, 2' - (1, 3-phenylene) diacetic acid (59.2, 308 mmol) in ethanol (24 ml) and dioxane (290 ml) was treated dropwise with 12M hydrochloric acid (4.9 ml, 58.8 mmol). The reaction mixture was stirred at reflux for 18 hours, cooled and concentrated to low volume. The reaction mixture was diluted with toluene (125 ml) and the resulting slurry was filtered. The filtrate and residue were concentrated in vacuo and dissolved in water and basified with sodium bicarbonate to neutral pH. The mixture was diluted with ethyl acetate (200 ml) and the organic layer was separated and washed with sodium bicarbonate solution (5 × 30 ml) and saturated aqueous sodium chloride solution (50 ml). The combined aqueous extracts were acidified to pH 3 with 6M hydrochloric acid and extracted with diethyl ether (3 × 30 ml). The organics were combined, dried (magnesium sulfate) and concentrated in vacuo. Trituration of the residue with pentane gave 10.8 g of the title compound as a colourless solid.

¹HNMR(CD₃OD，400MHz)δ：1.25(t，3H)，3.60(m，2H)，3.63(m，2H)，4.15(q，2H)，7.18-7.32(m，4H)ppm

MS (electrospray): m/z 245[ MNa ]]⁺

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

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

¹HNMR(CDCl₃，400MHz)δ：1.22(6H，s)，2.75(2H，s)，3.63(2H，s)，7.12-7.30(4H，m)。

MS(ESI)：m/z 209[M+H]⁺

Preparation 4: {3- [2- (2-chloro-acetylamino) -2-methyl-propyl ] -phenyl } -acetic acid

2-Chloroacetonitrile (8.8 mL, 140 mmol) was added to a solution of the alcohol from preparation 3 (16.0 g, 70 mmol) in acetic acid (33 mL). The resulting solution was cooled to 0 ℃, treated with concentrated sulfuric acid (33 ml), and the reaction mixture was gradually warmed to room temperature. After 4 hours the reaction mixture was poured into ice and basified with solid sodium carbonate. The solution was extracted with ethyl acetate (2 × 500 ml) and the combined organic extracts were dried (magnesium sulfate) and concentrated in vacuo to give the title product as a colorless solid (19.0 g).

¹HNMR(CDCl₃，400MHz)δ：1.36(s，6H)，3.02(s，2H)，3.62(s，2H)，3.95(s，2H)，6.19(m，1H)，7.06-7.31(m，4H)ppm。

MS (electrospray): m/z 282[ M-H]^-

Preparation 5: [3- (2-amino-2-methyl-propyl) -phenyl ] -acetic acid methyl ester

A solution of the amide from preparation 4 (5.1 g, 18 mmol), thiourea (1.6 g, 21 mmol) and acetic acid (18 ml) in ethanol (80 ml) was heated to reflux under a nitrogen atmosphere for 16 h. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated in vacuo, the residue was dissolved in methanol (150 ml), saturated with hydrogen chloride gas and the resulting solution was heated to reflux for 16 h. The mixture was concentrated in vacuo and the residue partitioned between ethyl acetate (200 ml) and 5% aqueous sodium carbonate (200 ml). The organic phase was washed with brine (100 ml), dried (magnesium sulfate) and concentrated in vacuo. The residue was purified by passage over a strong cation exchange resin eluting with methanol and then ammonia in 2M methanol to elute the product. The eluate was concentrated in vacuo to give the title compound as a yellow oil, 2.68 g.

¹HNMR(CDCl₃，400MHz)δ：1.14(s，6H)，2.68(s，2H)，3.62(s，2H)，3.69(s，3H)，7.08-7.16(m，3H)，7.23-7.27(m，1H)ppm。

MS (electrospray): m/z 222[ M + H]⁺

Preparation 6: n- {2- (benzyloxy) -5- [ (1R) -2-bromo-1-hydroxyethyl ] phenyl } sulfamide

A solution of (1R) -1- [ 3-amino-4- (benzyloxy) phenyl ] -2-bromoethanol (org. process Research and Development, 1998, 2, 96) (30.8 g, 95.6 mmol) in dichloromethane (300 ml) was treated with pyridine (9.3 ml, 115 mmol). The resulting solution was cooled to 5 ℃ and a solution of methanesulfonyl chloride (7.8 ml, 100.7 mmol) in dichloromethane (10 ml) was added dropwise. The mixture was stirred at 5 ℃ for another 30 minutes and then allowed to warm gradually to room temperature over a period of 16 hours. The reaction mixture was washed with 2N hydrochloric acid (110 ml) and the organic phase was separated, dried (magnesium sulfate) and the solvent removed in vacuo to yield an orange oil. The residue was crystallized from hot toluene (100 ml) to give the title compound as a pale pink solid (33.7 g).

¹HNMR(DMSOd₆，400MHz)δ：2.93(s，3H)，3.52-3.66(m，2H)，4.74(m，1H)，5.19(s，2H)，7.11(d，1H)，7.19-7.22(m，1H)，7.33-7.36(m，2H)，7.40-7.43(m，2H)，7.56(d，2H)，8.95(s，1H)ppm。

MS (electrospray): m/z 398/400[ M-H]^-

Preparation 7: n- [2- (benzyloxy) -5- ((1R) -2-bromo-1- { [ tert-butyl (dimethyl) silyl ] oxy } ethyl) phenyl ] methanesulfonamide

A solution of preparation 6 bromide (21.5 g, 53.7 mmol) in N, N-dimethylformamide (125 ml) was treated with imidazole (4.16 g, 75.2 mmol) and tert-butyl (dimethyl) silyl chloride (9.73 g, 64.5 mmol) and the resulting solution was stirred at room temperature for 16 h. The reaction mixture was diluted with ethyl acetate (200 ml) and washed with water (2 × 100 ml). The aqueous phases were combined and extracted with ethyl acetate (100 ml). The combined organic extracts were washed with 2N hydrochloric acid (100 ml), dried (magnesium sulfate) and reduced in vacuo. The residue was suspended in pentane: ethyl acetate (200 ml, 1: 1 by volume) and the solvent was evaporated. The residue was triturated with additional pentane: ethyl acetate (200 ml, vol 1: 1) and the resulting solid filtered off and dried in vacuo to give the title compound as a colourless solid (23.7 g).

¹HNMR(CDCl₃，400MHz)δ：-0.07(s，3H)，0.11(s，3H)，0.89(s，9H)，2.91(s，3H)，4.80-4.83(m，1H)，6.80(bs，1H)，6.98(d，1H)，7.12(d，1H)，7.36-7.44(m，5H)，7.52-7.54(m，1H)ppm。

Alternative preparation method to preparation 7:

a solution of preparation 6 bromide (10 g, 24.98 mmol) was dissolved in DCM (20 ml, 2 ml/g) and then imidazole (4.58 g, 37.47 mmol, 1.5 equivalents) was added followed by TBDMSiCl (5.27 g, 34.97 mmol, 1.4 equivalents). The reaction mixture was heated to reflux for 1 hour and then cooled to 30 ℃. The mixture was diluted with isopropyl acetate (80 ml, 8 ml/g) and then quenched with 2M HCl (50 ml, 5 ml/g) and vigorously stirred for 10 minutes. The phases were separated and the organic phase was washed with water (50 ml, 5 ml/g). The volume of the organic phase was then reduced to 25-30 ml at 45 ℃ under reduced pressure. The solution was then cooled to room temperature and a suspension formed quickly and stirred at room temperature for 30 minutes. Heptane (20 ml, 2 ml/g) was then added over 10 minutes and the suspension was cooled to 5-10 ℃ and stirred for 1 hour. The suspension was then filtered and washed with heptane (2 × 10 ml) on filter paper. The resulting filter cake was dried in a vacuum oven at 50 ℃ for 12 hours to yield the title compound as a white solid (11.05 g, 86% yield).

¹HNMR(CDCl₃，400MHz)δ：-0.07(s，3H)，0.11(s，3H)，0.89(s，9H)，2.91(s，3H)，4.80-4.83(m，1H)，6.80(bs，1H)，6.98(d，1H)，7.12(d，1H)，7.36-7.44(m，5H)，7.52-7.54(m，1H)ppm。

Preparation 8: (3- {2- [ ((2R) -2- {4- (Phenylmethoxy) -3- [ (methylsulfonyl) amino ] phenyl } -2-hydroxyethyl) amino ] -2-methylpropyl } phenyl) acetic acid methyl ester

The bromide of preparation 7 (36.0 g, 70.8 mmol) and the amine of preparation 5 (36.0 g, 153 mmol) were heated at 85 ℃ for 72 hours. The reaction mixture was cooled to room temperature and purified by column chromatography on silica gel eluting with pentane: ethyl acetate (50: 50 by volume) to give the title product as a pale yellow oil (37.2 g).

¹HNMR(CDCl₃，400MHz)δ：-0.15(s，3H)，0.00(s，3H)，0.83(s，9H)，1.01(s，3H)，1.04(s，3H)，2.57-2.97(m，7H)，3.59(s，2H)，3.68(s，3H)，4.68-4.72(m，1H)，5.09(s，2H)，6.79(bs，1H)，6.95(d，1H)，7.04-7.21(m，7H)，7.37-7.44(m，5H)，7.56(d，1H)ppm。

MS(APCI)：m/z 655[M+H]⁺

Preparation 9: (3- {2- [ ((2R) -2- { [ tert-butyl (dimethyl) silyl ] oxy } -2- { 4-hydroxy-3- [ (methylsulfonyl } amino ] phenyl } ethyl) amino ] -2-methylpropyl } phenyl) acetic acid methyl ester

Preparation 8a solution of benzyl protected alcohol (36.8 g, 56 mmol) in ethanol (550 ml) was treated with ammonium formate (16.0 g, 254 mmol) and 20% palladium hydroxide on carbon (1.5 g). The resulting suspension was heated to 85 ℃ for 2 hours. After 2 hours, an additional 20% palladium hydroxide on carbon (1.0 g) was added and heating continued for 1 hour. The reaction mixture was cooled to room temperature, filtered and the solvent removed in vacuo. The residue was partitioned between ethyl acetate (500 ml) and 2N aqueous ammonia (100 ml). The organic phase was separated, dried (magnesium sulfate) and the solvent removed in vacuo. The residue was purified by column chromatography on silica gel eluting with dichloromethane: methanol: 0.88 ammonia (95: 5: 0.5 by volume) to give the title product as a pale yellow oil (20.6 g).

¹HNMR(400MHz，CDCl₃)δ：-0.17(s，3H)，-0.05(s，3H)，0.80(s，9H)，1.07(s，3H)，1.09(s，3H)，2.66-2.91(m，7H)，3.62(d，2H)，3.69(s，3H)，4.71-4.74(m，1H)，6.58(d，1H)，6.88(dd，1H)，7.05-7.14(m，3H)，7.21-7.25(m，1H)，7.30(s，1H)ppm。

MS (electrospray): m/z 565[ M + H]⁺

Preparation 10: (3- {2- [ (2R) -2- (tert-butyl-dimethyl-silanyloxy) -2- (4-hydroxy-3-methanesulfonylamino-phenyl) -ethylamino ] -2-methyl-propyl } -phenyl) -acetic acid

The ester of preparation 9 (20.6, 36 mmol) was dissolved in tetrahydrofuran (150 ml) and the solution was treated dropwise with 1M aqueous lithium hydroxide (72 ml, 72 mmol). The reaction mixture was stirred at room temperature for 72 hours. The reaction mixture was neutralized and concentrated to low volume by adding 1M hydrochloric acid (72 ml, 72 mmol). The aqueous phase was decanted and the residue was washed with water (2 × 50 ml). The residue was redissolved in tetrahydrofuran (50 ml) and toluene (50 ml) and the solvent was removed in vacuo to give the title compound as a light brown foam (20.17 g).

¹HNMR(400MHz，CD₃OD)δ：-0.14(s，3H)，0.07(s，3H)，0.83(s，9H)，1.32(m，6H)，2.93(m，5H)，3.23(m，2H)，3.54(m，2H)，4.94(m，1H)，6.91(d，1H)，7.03-7.16(m，3H)，7.26(m，2H)，7.60(m，1H)ppm。

MS (electrospray): m/z 236[ M + H ] +

Preparation of 5 a: [3- (2-amino-2-methyl-propyl) -phenyl ] -acetic acid ethyl ester

A mixture of the amide from preparation 4 (151.4 g, 534 mmol), thiourea (48.7 g, 640 mmol) and acetic acid (303 ml) in ethanol (1.5 l) was heated to reflux under a nitrogen atmosphere for 5 h. The reaction mixture was cooled to room temperature and the suspension was concentrated in vacuo. The residue was azeotroped with toluene (2 × 900 ml) and then treated with ethanol (1.5 l) and stirred for 1 hour. The solid precipitate was removed by filtration and the filtrate was cooled in an ice bath, treated with 98% sulfuric acid (227 ml) and stirred at room temperature for 1 hour. The solution was concentrated in vacuo to remove most of the ethanol and adjusted to pH9 using aqueous sodium bicarbonate. The solid precipitate was removed by filtration and washed with water (300 ml) then ethyl acetate (1.0 l). The combined biphasic filtrate and wash layers were separated and the aqueous layer was re-extracted with ethyl acetate (1.0 l +500 ml). The combined ethyl acetate extracts were dried over magnesium sulfate, filtered and concentrated in vacuo to give the title compound as a brown oil (89.5 g).

¹HNMR(d₆-DMSO，400MHz)δ：0.99(s，6H)，1.16(t，3H)，2.59(s，2H)，3.61(s，2H)，4.06(q，2H)，7.06(m，3H)，7.21(m，1H)

Preparation 5 b: [3- (2-amino-2-methyl-propyl) -phenyl ] -acetic acid ethyl ester, di-p-toluoyl-1-tartrate

A solution of the amine from preparation 5a (124.9 g, 531 mmol) in acetonitrile (1.0 l) was treated with a solution of di-p-toluoyl-1-tartaric acid (194.8 g, 504 mmol) in acetonitrile (750 ml). The resulting slurry was stirred for 3 hours and the solid precipitate was isolated by filtration and washed with acetonitrile (2 × 250 ml) to yield the title compound as a white solid (210 g).

¹HNMR(d₆-DMSO，400MHz)δ：1.13(s，6H)，1.17(t，3H)，2.34(s，6H)，2.78(s，2H)，3.63(s，2H)，4.06(q，2H)，5.61(s，2H)，7.02(d，2H)，7.15(d，1H)，7.25(m，5H)，7.80(d，4H)。

Preparation 5 c: [3- (2-amino-2-methyl-propyl) -phenyl ] -acetic acid ethyl ester

A solution of potassium carbonate (37.90 g, 274.22 mmol) in water (213 ml) was added to a suspension of preparation 5b (42.62 g, 68.56 mmol) in propionitrile (213 ml) and stirred until all solids were dissolved. The phases were then separated and the propionitrile phase was washed with water (107 ml). The volume of the solution was reduced under reduced pressure to about 30 ml to give a solution of the title compound in propionitrile. Samples were removed and concentrated to dryness to give weight analyte and yield was shown to be 81%.

¹HNMR(d₆-DMSO，400MHz)δ：0.99(s，6H)，1.16(t，3H)，2.59(s，2H)，3.61(s，2H)，4.06(q，2H)，7.06(m，3H)，7.21(m，1H)。

Preparation of 8 a: (3- {2- [ ((2R) -2- { [ tert-butyl (dimethyl) silyl ] oxy } -2- { 4-benzyloxy-3- [ (methylsulfonyl) amino ] phenyl } ethyl) amino ] -2-methylpropyl } phenyl) acetic acid ethyl ester

N- [2- (benzyloxy) -5- ((1R) -2-bromo-1- ([ tert-butyl (dimethyl) silyl ] oxy } ethyl) phenyl ] methanesulfonamide (14.34 g, 27.88 mmol) was added to a preparation of a solution of 5c (13.12 g, 55.75 mmol) in propionitrile (15 ml.) the mixture was then heated at reflux for 3 days the solution was diluted with propionitrile (55 ml) and cooled to 20-25 ℃ and the solution was washed with 1M HCl (aq) (70 ml) then water (35 ml) and taken directly to the next step, assuming 100% yield.

Preparation of 9 a: (R) -2- (3- {2- [ 2-hydroxy-2- (4-benzyloxy-3-methanesulfonylaminophenyl) ethylamino ] -2-methylpropyl } phenyl) acetic acid ethyl ester

Triethylamine trihydrofluoride (9.1 ml, 8.99 g, 55.76 mmol) was added to a solution of preparation 8a (18.64 g, 27.88 mmol) in propionitrile (72 ml). The solution was stirred at 20-25 ℃ for 3 hours. The solution was then washed with 5M NH₃(aqueous solution) (72 ml) the reaction was stopped, stirred for 10 min and the phases were separated. The propionitrile solution was then washed with water (72 ml) and the solution was directly taken to the next step, assuming 100% yield.

Preparation 10 a: (R) -2- (3- {2- [ 2-hydroxy-2- (4-benzyloxy-3-methanesulfonylaminophenyl) ethylamino ] -2-methylpropyl } phenyl) acetic acid

A solution of sodium hydroxide (6.69 g, 167.28 mmol) in water (72 ml) was added to a solution of preparation 9a (15.47 g, 27.88 mmol) in propionitrile (72 ml). The biphasic mixture was then stirred vigorously for 3 hours. The phases were separated and the aqueous phase was washed with fresh propionitrile (72 ml) and then diluted with 1, 4-dioxane (72 ml). The pH of the solution was then adjusted to pH 6-7 by adding 37% w/w HCl (aq) and the resulting suspension was stirred for one hour. The suspension was then filtered and washed with water on filter paper and then dried to give the title compound as an off-white solid (13.55 g, 92% over 3 steps).

¹HNMR(400MHz，CD₃OD)δ：1.33(s，3H)，1.35(s，3H)，2.89(s，3H)，2.96(s，2H)，3.06-3.19(m，2H)，3.50(s，2H)，4.50(m，1H)，5.22(s，2H)，7.08(d，1H)，7.13(d，1H)，7.19(s，1H)，7.24(t，2H)，7.27(d，1H)，7.31(d，1H)，7.38(t，2H)，7.48(d，2H)，7.49(s，1H)ppm。

Preparation 10 b: (R) -2- (3- {2- [ 2-hydroxy-2- (4-hydroxy-3-methanesulfonylaminophenyl) ethylamino ] -2-methylpropyl } phenyl) acetic acid sodium salt

A solution of sodium hydroxide (1.40 g, 35.05 mmol) in water (100 ml) was added to prepare a suspension of 10a (18.46 g, 35.05 mmol) in methanol (600 ml). The mixture was hydrogenated over 20 wt% palladium hydroxide on carbon at 150psi and 60 ℃ for 5 hours. The mixture was filtered to remove catalyst residue and then the volume was reduced to 100 ml under reduced pressure. The mixture was distilled under reduced pressure and left to stand at a fixed volume of acetonitrile. The resulting suspension was filtered and washed with acetonitrile on filter paper and then dried to provide the title compound as an off-white solid (15.34 g, 95%).

¹HNMR(400MHz，CD₃OD)δ：1.07(s，3H)，1.09(s，3H)，2.70(s，2H)，2.73-2.81(m，2H)，2.87(s，3H)，3.44(s，2H)，4.60-4.63(m，1H)，6.84(d，1H)，6.92(d，1H)，7.04(d，1H)，7.11(s，1H)，7.14(d，1H)，7.15(t，1H)，7.34(s，1H)ppm。

The compound of formula 10b may then be reacted with a suitable compound of formula NHR in the presence of a conventional coupling agent such as 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride or dicyclohexylcarbodiimide in a suitable solvent such as pyridine, dimethylformamide or dimethylacetamide⁸-Q²-A(3)

The amine of (2) is reacted.

So as to obtain a compound of formula (1):

wherein R is¹And R²Is methyl and n is 1.

Preparation 11: 1- (3-bromophenyl) -2-methylpropan-2-ol

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

¹HNMR(400MHz，CDCl₃)δ：1.22(s，6H)，1.42(bs，1H)，2.74(s，2H)，7.15(m，2H)，7.40(m，2H)ppm。

Preparation 12: n- [2- (3-bromophenyl) -1, 1-dimethylethyl ] -2-chloroacetamide

Chloroacetonitrile (6.63 ml, 105 mmol) was added at room temperature to a stirred solution of the alcohol of preparation 11 (12.0 g, 52.0 mmol) in acetic acid (25 ml). The resulting solution was cooled to 0 ℃ and concentrated sulfuric acid (25 ml) was added, maintaining the temperature < 10 ℃. The resulting solution was stirred for 1 hour, then poured into ice and basified by addition of solid potassium carbonate. The product was extracted with ethyl acetate (2 × 500 ml), the organics combined and washed with water (50 ml), dried (sodium sulfate) and the solvent removed in vacuo to afford the title compound as an orange solid (16.08 g).

¹HNMR(400MHz，CDCl₃)δ：1.37(s，6H)，3.02(s，2H)，3.94(s，2H)，6.17(bs，1H)，7.03-7.08(d，1H)，7.11-7.13(t，1H)，7.26(s，1H)，7.32-7.39(d，1H)ppm。

LRMS (electrospray) M/z 306[ M + H ]]⁺

Preparation 13: [2- (3-bromophenyl) -1, 1-dimethylethyl ] amine

A solution of the amide from preparation 12 (32.0 g, 105 mmol), thiourea (9.60 g, 126 mmol) and acetic acid (50 ml) in ethanol (250 ml) was heated to reflux overnight. The reaction mixture was cooled to room temperature and filtered, the filtrate was concentrated in vacuo and basified with aqueous sodium hydroxide (1M, 450 ml). The product was extracted with dichloromethane (2 × 500 ml) and the combined organics were washed with brine (50 ml), dried (sodium sulfate) and the solvent removed in vacuo to provide the title compound as a black oil (23 g).

¹HNMR(400MHz，CDCl₃)δ：1.12(s，6H)，1.84(bs，2H)，2.62(s，2H)，7.08-7.16(m，2H)，7.32-7.36(m，2H)ppm。

LRMS (electrospray) M/z 228[ M + H ]]⁺

Preparation 14: n- [2- (benzyloxy) -5- ((1R) -2- { [2- (3-bromophenyl) -1, 1-dimethylethyl ] amino } -1-hydroxyethyl) phenyl ] methanesulfonamide

The amine of preparation 13 (5.04 g, 22.3 mmol) was dissolved in dichloromethane (20 ml) and treated with N- [2- (benzyloxy) -5- ((1S) -2-bromo- ([ tert-butyl (dimethyl) silyl ] oxy) ethyl) -phenyl ] methanesulfonamide (WO 02/06258, page 36, example 14a) (11.90 g, 45.0 mmol). The resulting solution was heated at 90 ℃ until the solvent evaporated and then stirred at 90 ℃ for another 16 hours. The reaction mixture was cooled to room temperature and the residue was purified by column chromatography on silica gel eluting with pentane: ethyl acetate (90: 10) to give the title product as a brown oil (8.36 g).

¹HNMR(CD₃OD，400MHz)δ：-0.14(s，3H)，0.04(s，3H)，0.84(s，9H)，1.10(s，3H)，1.13(s，3H)，2.87(s，3H)，2.67-2.90(m，4H)，4.73-4.77(m，1H)，5.25(s，2H)，7.12-7.23(m，4H)，7.36-7.48(m，6H)，7.53-7.55(m，2H)ppm。

MS (electrospray): m/z 661/663[ M + H ]]⁺，683/685[M+H]⁺

Preparation 15: 3- {2- [ ((2R) -2- {4- (benzyloxy) -3- [ (methylsulfonyl) amino ] phenyl } -2- { [ tert-butyl (dimethyl) silyl ] oxy } ethyl) amino ] -2-methylpropyl } benzoic acid methyl ester

Preparation 14 of a solution of bromide (8.36 g, 12.6 mmol), (1, 1' -bis (diphenylphosphino) ferrocene) dichloropalladium (II) (1.03 g, 1.26 mmol) and triethylamine (3.5 ml, 25.1 mmol) in methanol was heated at 100 ℃ for 16 h under 100psi of carbon monoxide. The reaction mixture was cooled to room temperature, filtered and the solvent removed in vacuo. Purification by column chromatography on silica gel eluting with dichloromethane: methanol: 0.88 ammonia (90: 10: 1) gave the title compound as an orange oil, 7.79 g (with trace contamination of catalyst residues).

¹HNMR(400MHz，CD₃OD)δ：-0.17(s，3H)，0.00(s，3H)，0.80(s，9H)，1.12(m，3H)，1.15(s，3H)，2.67-2.92(m，3H)，3.96(s，3H)，4.73-4.77(m，1H)，5.24(s，2H)，7.11(d，1H)，7.19(dd，1H)，7.36-7.48(m，6H)，7.54(d，2H)，7.91-7.93(m，2H)ppm。

MS (electrospray) M/z 641[ M + H ]]⁺，663[M+Na]⁺

Preparation 16: 3- {2- [ ((2R) -2- { [ tert-butyl (dimethyl) silyl ] oxy } -2- { 4-hydroxy-3- [ (methylsulfonyl) amino ] phenyl } ethyl) amino ] -2-methylpropyl } benzoic acid methyl ester

Prepared from the ester of preparation 15 using the method of preparation 7 to give the title compound as a colourless oil.

¹HNMR(400MHz，CD₃OD)δ：-0.21(s，3H)，-0.05(s，3H)，0.75(s，9H)，1.08(s，3H)，1.12(s，3H)，2.62-2.88(m，7H)，3.92(s，3H)，4.64-4.69(m，1H)，6.84(d，1H)，7.03(dd，1H)，7.35-7.36(m，1H)，7.39-7.42(m，2H)，7.87-7.89(m，2H)ppm。

MS (electrospray) M/z 551[ M + H ]]⁺，573[M+Na]⁺

Preparation 17: 3- {2- [ ((2R) -2- { [ tert-butyl (dimethyl) silyl ] oxy } -2- { 4-hydroxy-3- [ (methylsulfonyl) amino ] phenyl } ethyl) amino ] -2-methylpropyl } benzoic acid

Prepared from the ester of preparation 16 using the method of preparation 8 to give the title compound as a colorless solid.

¹HNMR(400MHz，CD₃OD}δ：-0.14(s，3H)，0.04(s，3H)，0.82(s，9H)，1.23(s，3H)，1.24(s，3H)，2.88-2.96(m，5H)，3.00-3.14(m，2H)，4.83-4.87(m，1H)，6.89(d，1H)，7.07(dd，1H)，7.24-7.26(m，1H)，7.32(t，1H)，7.37(s，1H)，7.82(s，1H)，7.86(d，1H)ppm。

MS (electrospray) M/z 537[ M + H ]]⁺，559[M+Na]⁺

Preparation of 18-53

Preparation of the appropriate carboxylic acid 10 or 17(0.15 mmol), 1-hydroxybenzotriazole hydrate (22 mg, 0.16 mmol), a solution of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (34 mg, 0.18 mmol) and N-ethyldiisopropylamine (130 μ l, 0.73 mmol) in N, N-dimethylformamide (2 ml) was treated with the appropriate amine (0.23 mmol) and the reaction mixture was shaken at room temperature for 18 h. The reaction mixture was concentrated in vacuo and the residue partitioned between dichloromethane (3 ml) and water (1 ml). The phases were separated and the organic layer was washed with brine (1 ml), dried (sodium sulfate) and concentrated in vacuo. The residue was purified by column chromatography eluting on silica gel with dichloromethane: methanol: 0.88 ammonia (98: 2: 0 to 94: 6: 0.5 by volume) to give the desired product.

Alternatively, the following methods may be used for the synthesis of 18 to 53:

a solution of the appropriate carboxylic acid from preparation 10 or 17 (5.08 mmol) in N, N-dimethylformamide (60 ml) was treated with 1-hydroxybenzotriazole hydrate (0.755 g, 5.59 mmol), the appropriate amine (5.08 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1.07 g, 5.59 mmol) and triethylamine (1.49 ml, 10.67 mmol). The resulting suspension was stirred at room temperature for 18 hours. The solvent was removed in vacuo and the residue partitioned between dichloromethane (100 ml) and saturated aqueous sodium bicarbonate (50 ml). The organic and aqueous phases were separated and extracted with dichloromethane: methanol (95: 5 by volume, 2X 20 ml). The combined organic extracts were separated, washed with saturated aqueous sodium chloride (100 ml), dried (sodium sulfate), and the solvent was removed in vacuo. The residue was purified by column chromatography eluting on silica gel with dichloromethane: methanol: 0.88 ammonia (95: 5: 0.5 by volume) to give the desired compound.

Preparation 54: n- (4-bromophenylmethyl) -2- (3- {2- [ ((2R) -2- { [ tert-butyl (dimethyl) silyl ] oxy } -2- { 4-hydroxy-3- [ (methylsulfonyl) amino ] phenyl } ethyl) amino ] -2-methylpropyl } phenyl) -acetamide

Prepared using the method of preparation 18 using the acid from preparation 10 and (4-bromobenzyl) amine to give a yellow gum of the title compound.

¹HNMR(400MHz，CDCl₃)δ：-0.18(s，3H)，0.00(s，3H)，0.81(s，9H)，1.02(s，3H)，1.04(s，3H)，2.61-2.72(m，4H)，2.83(s，3H)，3.53(s，2H)，4.33(s，2H)，4.65-4.70(m，1H)，6.83-6.86(d，1H)，7.00-7.44(m，10H)ppm。

MS (electrospray) M/z 720[ M + H ]]⁺，742[M+H]⁺

Preparation 55: 2- (3- {2- [ ((2R) -2- { [ tert-butyl (dimethyl) silyl ] oxy } -2- { 4-hydroxy-3- [ (methylsulfonyl) amino ] phenyl } ethyl) amino ] -2-methylpropyl } phenyl) -N- [ (3' -hydroxybiphenyl-4-yl) methyl ] acetamide

A solution of the bromide from preparation 56 (0.50 g, 0.70 mmol), (3-hydroxyphenyl) boronic acid (0.19 g, 1.4 mmol), (1, 1' -bis (diphenylphosphino) ferrocene) dichloropalladium (II) (36 mg, 0.04 mmol) in N, N-dimethylformamide (8 ml) was treated with 2M aqueous sodium carbonate (2 ml) and the resulting suspension was heated to 80 ℃ for 16 h. The reaction mixture was cooled to room temperature and the solvent was removed in vacuo. The residue was azeotroped with toluene (50 ml), redissolved in ethyl acetate (50 ml) and neutralized with 1N aqueous hydrochloric acid (to pH 7). The organic and aqueous layers were separated and extracted with additional ethyl acetate (2 × 50 ml). The combined organic extracts were washed with water (100 ml), saturated aqueous sodium chloride (100 ml), dried (sodium sulfate) and the solvent removed in vacuo to give an orange gum (515 mg), which was used without further purification.

¹HNMR(400MHz，CD₃OD)δ：-0.13(s，3H)，0.04(s，3H)，0.84(s，9H)，1.11(s，3H)，1.13(s，3H)，2.74-2.97(m，7H)，3.55-3.63(m，2H)，4.42-4.45(m，2H)，4.73-4.76(m，1H)，6.89-6.94(m，3H)，7.15-7.30(m，9H)，7.41(d，1H)，7.51(s，1H)，7.53(s，1H)ppm。

MS (electrospray) M/z 732[ M + H ]]⁺，754[M+H]⁺

Preparation 56: 2- (3- {2- [ ((2R) -2- { [ tert-butyl (dimethyl) silyl ] oxy } -2- { 4-hydroxy-3- [ (methylsulfonyl) amino ] phenyl } ethyl) amino ] -2-methylpropyl } phenyl) -N- [ (2' -hydroxybiphenyl-4-yl) methyl ] acetamide

Prepared from (2-hydroxyphenyl) boronic acid using the method of preparation 55 to yield the title compound as a brown oil.

¹HNMR(400MHz，CD₃OD)δ：-0.13(s，3H)，0.04(s，3H)，0.84(s，9H)，1.12(s，3H)，1.14(s，3H)，2.72-2.99(m，7H)，3.58-3.61(m，2H)，4.43-4.45(m，2H)，4.74-4.78(m，1H)，6.78-6.81(m，1H)，6.90-6.92(m，1H)，7.02-7.10(m，2H)，7.15-7.39(m，8H)，7.41(d，1H)，7.53(s，1H)，7.55(s，1H)ppm。

MS (electrospray) M/z 755[ M + H ]]⁺

Preparation 57: 2-hydroxy-1-naphthamides

A solution of 2-hydroxy-1-naphthoic acid (5.0 g, 26.6 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (5.6 g, 29.2 mmol) and 1-hydroxybenzotriazole (3.95 g, 29.2 mmol) in tetrahydrofuran (70 ml) was stirred at room temperature for 30 minutes, 0.880NH was added₃(6 ml). The resulting suspension was stirred at room temperature for 2 hours. The reaction mixture was filtered and the filtrate was diluted with water (80 ml) and extracted with ethyl acetate (4 × 80 ml). The combined organic extracts were washed with water (50 ml × 2), saturated aqueous sodium chloride (50 ml), dried (sodium sulfate) and the solvent was removed in vacuo to yield an orange oil. Purification by column chromatography on silica gel eluting with dichloromethane: methanol: 0.880 ammonia 95: 5: 0.5 gave the title compound as a pink solid (1.83 g).

¹HNMR(400MHz，CDCl₃)δ：6.11-6.35(bs，2H)，7.17(d，1H)，7.36(dd，1H)，7.54(dd，1H)，7.79(d，1H)，7.84(d，1H)，8.22(d，1H)，11.70-11.88(bs，1H)ppm。

MS (electrospray) M/z 186[ M-H ]]^-

Preparation 58: 6-hydroxy-2-naphthamides

A solution of 6-hydroxy-2-naphthoic acid (1.88 g, 9.99 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (2.11 g, 10.98 mmol), 1-hydroxybenzotriazole (1.48 g, 10.98 mmol) and ammonium carbonate (4.80 g, 49.95 mmol) in N, N-dimethylformamide (70 ml) was stirred under nitrogen at room temperature for 3 days. The solvent was removed in vacuo and the residue partitioned between saturated aqueous sodium bicarbonate (50 ml) and ethyl acetate (6 × 50 ml). The combined organic extracts were washed with water (25 ml), saturated aqueous sodium chloride (25 ml), dried (sodium sulfate) and the solvent removed in vacuo. The solid was absorbed on silica gel and purified by column chromatography eluting on silica gel with dichloromethane: methanol: 0.880 ammonia (95: 5: 0.5 to 90: 10: 1) to give the title compound as a pale yellow solid (1.1 g).

¹HNMR(400MHz，CD₃OD)δ：7.14(d，1H)，7.15(s，1H)，7.79(d，1H)，7.83(d，2H)，8.32(s，1H)ppm。

MS (electrospray) M/z 186[ M-H ]]^-

Preparation 59: 1- (aminomethyl) -2-naphthol

A solution of borane in tetrahydrofuran (19.23 ml of a 1M solution, 19.23 mmol) was added dropwise under a nitrogen atmosphere to a solution of the amide from preparation 57 (0.90 g, 4.81 mmol) in tetrahydrofuran (10 ml). The reaction was then heated to reflux for 2 hours. The solution was cooled, treated with 6M hydrochloric acid (10 ml) and refluxed for another 2 hours. The resulting suspension was cooled and pH adjusted by the addition of 0.880NH₃Adjusted to pH9 and extracted with ethyl acetate (50 ml × 3). The combined organic extracts were washed with saturated aqueous sodium chloride (20 ml), dried (sodium sulfate) and the solvent removed under reduced pressure.Purification by column chromatography on silica gel eluting with dichloromethane: methanol: 0.880 ammonia (95: 5: 0.5 to 90: 10: 1) gave the title compound as a pink solid (0.19 g).

¹HNMR(400MHz，CD₃OD)δ：4.41(s，2H)，7.07(d，1H)，7.23(1H，dd)，7.43(dd，1H)，7.66(d，1H)，7.72(d，1H)，7.87(d，1H)ppm。

MS (electrospray) M/z 174[ M + H ]]⁺，172[M-H]^-

Preparation 60: 6- (aminomethyl) -2-naphthol

Prepared according to the procedure of preparation 59 using the amide from preparation 58.

¹HNMR(400MHz，CD₃OD)δ：3.91(s，2H)，7.03-7.08(m，2H)，7.36(dd，1H)，7.61(d，1H)，7.66(d，1H)，7.69(s，1H)ppm。

MS (electrospray) M/z 172[ M-H ]]^-

Preparation 61: (3-Iodophenylmethyl) carbamic acid tert-butyl ester

A suspension of 3-iodobenzylamine hydrochloride (4.95 g, 18.4 mmol) in dichloromethane (100 ml) was treated with triethylamine (3.1 ml, 22 mmol) and di-tert-butyl dicarbonate (4.40 g, 20 mmol) and the resulting solution was stirred at room temperature under a nitrogen atmosphere for 1.5 hours. The reaction mixture was washed with 2M hydrochloric acid (30 ml), water (30 ml), dried (sodium sulfate), and the solvent was removed in vacuo to give the title compound as a colorless solid (6.43 g).

¹HNMR(400MHz，CDCl₃)δ：1.46(s，9H)，4.21-4.30(m，2H)，4.79-4.89(bs，1H)，7.06(dd，1H)，7.25(d，1H)，7.60(d，1H)，7.63(s，1H)ppm。

MS (electrospray) M/z 332[ M-H]^-，356[M+Na]⁺

Preparation 62: (2-Bromobenzyl) carbamic acid tert-butyl ester

Prepared from 2-bromobenzylamine using the procedure of preparation 61 to yield the title compound as a colorless solid.

¹HNMR(400MHz，CD₃OD)δ：1.50(s，9H)，4.33(s，2H)，7.18-7.22(m，1H)，7.35-7.38(m，2H)，7.59(d，1H)ppm。

MS (electrospray) M/z 308/310[ M + Na ]]⁺

Preparation 63: [ (4' -Hydroxybiphenyl-3-yl) methyl ] carbamic acid tert-butyl ester

The iodide from preparation 61 (0.75 g, 2.25 mmol), 4-hydroxyphenylboronic acid (0.62 g, 4.50 mmol), 1' -bis (diphenylphosphino) ferrocenylpalladium (II) chloride (0.11 g, 0.14 mmol), a solution in N, N-dimethylformamide (14 ml) was treated with 2M aqueous sodium carbonate (4 ml) and the resulting mixture was heated at 80 ℃ under a nitrogen atmosphere for 16 hours. The solvent was removed in vacuo and the residue was purified by column chromatography on silica gel eluting with ethyl acetate: pentane (1: 3) to give the title compound as a pale pink crystalline solid (0.73 g).

¹HNMR(400MHz，CDCl₃)δ：1.47(s，9H)，4.33-4.41(m，2H)，4.87-4.94(bs，1H)，6.89(d，2H)，7.21(d，1H)，7.37(dd，1H)，7.43-7.45(m，4H)ppm。

MS (electrospray) M/z 298[ M-H ]]^-，322[M+Na]⁺

Preparation of 64: [ (2' -Hydroxybiphenyl-3-yl) methyl ] carbamic acid tert-butyl ester

Prepared from iodide of preparation 61 and 2-hydroxyboronic acid using the procedure of preparation 63 to yield the title compound as a colorless solid.

¹HNMR(400MHz，CDCl₃)δ：1.46(s，9H)，4.38(d，2H)，4.90(bs，1H)，5.24(bs，1H)，6.97-7.01(m，2H)，7.22-7.47(m，6H)ppm。

MS (electrospray) M/z 322[ M + Na ] +

Preparation 65: [ (2' -Hydroxybiphenyl-2-yl) methyl ] carbamic acid tert-butyl ester

Prepared from the bromide of preparation 62 and 2-hydroxyboronic acid using the method of preparation 63 to yield the title compound as a colorless solid.

¹HNMR(400MHz，CD₃OD)δ：1.46(s，9H)，4.15(d，2H)，6.91-6.96(m，2H)，7.10(dd，1H)，7.17-7.41(m，5H)ppm。

MS (electrospray) M/z 298[ M-H ]]^-

Preparation 66: [ (3' -Hydroxybiphenyl-2-yl) methyl ] carbamic acid tert-butyl ester

Prepared from the bromide of preparation 62 and 3-hydroxyboronic acid using the method of preparation 63 to yield the title compound as a colorless solid.

¹HNMR(400MHz，CD₃OD)δ：1.48(s，9H)，4.21(s，2H)，6.76-6.83(m，3H)，7.21-7.43(m，5H)ppm。

MS (electrospray) M/z 298[ M-H ]]^-

Preparation 67: [ (3' -Hydroxybiphenyl-3-yl) methyl ] carbamic acid tert-butyl ester

Prepared from iodide of preparation 61 and 3-hydroxyphenylboronic acid using the procedure of preparation 63 to give the title compound as a brown gum.

¹HNMR(400MHz，CDCl₃)δ：1.48(s，9H)，4.37(d，2H)，4.86-4.91(bs，1H)，6.82(dd，1H)，7.04(t，1H)，7.11(d，1H)，7.24-7.30(m，2H)，7.36(t，1H)，7.43(d，1H)，7.45(d，1H)ppm。

MS (electrospray) M/z 298[ M-H ]]^-，597[2M-H]^-

Preparation 68: 3' - (aminomethyl) -biphenyl-4-ol

The phenol from preparation 63 (0.73 g, 2.43 mmol) was treated with 4M HCl in dioxane (6 ml, 24.3 mmol) and the resulting solution was stirred at room temperature for 3 hours. The solvent was removed in vacuo to yield the title compound as a colorless solid.

¹HNMR(400MHz，CD₃OD)δ：4.17(s，2H)，6.87(d，2H)，7.34(d，1H)，7.45-7.50(m，3H)，7.61(d，1H)，7.65(s，1H)ppm。

MS (electrospray) M/z 198[ M-H]^-，200[M+H]⁺

Preparation 69: 3' - (aminomethyl) biphenyl-3-ol

Prepared from the phenol of preparation 67 using the method of preparation 68 to give a brown gum of the title compound.

¹HNMR(400MHz，CD₃OD)δ：4.17(s，2H)，6.80(dd，1H)，7.04(t，1H)，7.08-7.11(m，1H)，7.26(t，1H)，7.41(d，1H)，7.50(t，1H)，7.63(d，1H)，7.69(s，1H)ppm。

MS (electrospray) M/z 198[ M-H]^-，200[M+H]⁺

Preparation 70: 3' - (aminomethyl) biphenyl-2-ol

Prepared from the phenol of preparation 63 using the method of preparation 68 to give the title compound as a colorless solid.

¹HNMR(400MHz，CD₃OD)δ：4.19(s，2H)，6.93-6.97(m，2H)，7.19-7.23(m，1H)，7.31(d，1H)，7.41(dd，1H)，7.50-7.53(m，1H)，7.65-7.69(m，2H)ppm。

MS (electrospray) M/z 200[ M + H ]]⁺

Preparation 71: 2' - (aminomethyl) biphenyl-2-ol

Prepared from preparation 65 using the method of preparation 68 to give the title compound as a colorless solid.

¹HNMR(400MHz，CD₃OD)δ：4.03(s，2H)，6.99-7.04(m，2H)，7.19(dd，1H)，7.30-7.34(m，2H)，7.50-7.58(m，3H)ppm。

MS (electrospray) M/z 200[ M + H ]]⁺

Preparation of 72: 2' - (aminomethyl) biphenyl-3-ol

Prepared from preparation 66 using the method of preparation 68 to give the title compound as a colorless solid.

¹HNMR(400MHz，CD₃OD)δ：4.15(s，2H)，6.79-6.84(m，2H)，6.88-6.91(m，1H)，7.31-7.35(m，1H)，7.37-7.40(m，1H)，7.48-7.54(m，2H)，7.56-7.60(m，1H)ppm。

MS (electrospray) M/z 200[ M + H ]]⁺

Preparation 73: (4- { [ tert-butyl (dimethyl) silyl ] oxy } phenyl) acetonitrile

A solution of (4-hydroxyphenyl) acetonitrile (6.01 g, 45.1 mmol) in N, N-dimethylformamide (60 ml) was treated with imidazole (3.81 g, 58.6 mmol), tert-butyldimethylsilyl chloride (7.49 g, 49.6 mmol) and N, N-dimethylaminopyridine (20 mg) and the resulting solution was stirred at room temperature under a nitrogen atmosphere for 16 hours. The reaction mixture was diluted with water (200 ml) and extracted with ethyl acetate (200 ml × 2). The combined organic extracts were washed with saturated aqueous sodium chloride (200 ml), dried (sodium sulfate) and the solvent removed in vacuo. Purification by column chromatography on silica gel eluting with ethyl acetate: pentane (0: 100 to 10: 90) gave the title compound as a pale yellow oil (9.44 g).

¹HNMR(400MHz，CDCl₃)δ：0.19(s，6H)，0.97(s，9H)，3.66(s，2H)，6.82(d，2H)，7.17(d，2H)ppm。

MS(APCI)m/z 265[M+NH₄]⁺

Preparation 74: 2- (4- { [ tert-butyl (dimethyl) silyl ] oxy } phenyl) -2-methylpropanenitrile

A solution of the nitrile from preparation 73 (5.62 g, 22.7 mmol), methyl iodide (3.11 ml, 50 mmol), and 18-crown-6 (1.5 g, 5.6 mmol) in anhydrous tetrahydrofuran (300 ml) was cooled to-78 ℃ under a nitrogen atmosphere. Potassium tert-butoxide (50 ml of a 1M solution in tetrahydrofuran, 50 mmol) was added dropwise over 20 minutes and the reaction mixture was then gradually warmed to room temperature. After 2 hours the reaction was cooled again to-78 ℃ and stopped by adding saturated aqueous ammonium chloride (200 ml) and allowed to warm to room temperature. The resulting solution was extracted with ethyl acetate (300 ml × 2), the combined organics were dried (sodium sulfate) and the solvent was removed in vacuo. Purification by column chromatography eluting on silica gel with ethyl acetate: pentane (0: 100 to 10: 90) gave the title compound as a colourless oil (4.75 g).

¹HNMR(400MHz，CDCl₃)δ：0.19(s，6H)，0.97(s，9H)，1.68(s，6H)，6.82(d，2H)，7.30(d，2H)ppm。

MS(APCI)m/z 293[M+NH₄]⁺

Preparation 75: [2- (4- { [ tert-butyl (dimethyl) silyl ] oxy } phenyl) -2-methylpropyl ] amine

A solution of the nitrile from preparation 74 (0.75 g, 2.7 mmol) in diethyl ether (5 ml) was added dropwise to a cold (0 ℃) solution of lithium aluminum hydride in diethyl ether (2.98 ml of a 1M solution). The resulting solution was stirred at 0 ℃ for 3 hours and then quenched by the addition of water (0.1 ml), 2N aqueous sodium chloride (0.1 ml) and additional water (0.3 ml). The resulting suspension was filtered and the filtrate was concentrated in vacuo. Purification by column chromatography eluting on silica gel with dichloromethane: methanol: 0.880 ammonia (97: 3: 0.5 to 93: 7: 0.5) gave the title compound as a colourless oil (0.52 g).

¹HNMR(400MHz，CDCl₃)δ：0.18(s，6H)，0.97(s，9H)，1.00(bs，2H)，1.25(s，6H)，2.73(s，2H)，6.78(d，2H)，7.16(d，2H)ppm。

MS(APCI)m/z 280[M+H]⁺

Preparation of 76: 4- (aminomethyl) -2, 6-dimethylphenol hydrochloride

A solution of borane in tetrahydrofuran (27.1 ml of a 1M solution, 27.1 mmol) was added dropwise to a solution of 3, 5-dimethyl-4-hydroxybenzonitrile (1.0 g, 6.79 mmol) in tetrahydrofuran (70 ml) and the resulting solution was heated to reflux under a nitrogen atmosphere for 16 h. The reaction was cooled to room temperature and treated with 6N hydrochloric acid (20 ml) and refluxed for another 30 minutes. The reaction mixture was cooled to room temperature and the solvent was removed in vacuo. The product was purified using a strong cation exchange resin eluting with methanol followed by 2M aqueous ammonia in methanol to yield the title compound as an orange oil. The oil was treated with 1M hydrogen chloride in methanol (20 ml) and the solvent was removed in vacuo to give the title compound as a pale yellow solid (1.12 g).

¹HNMR(400MHz，CDCl₃)δ：2.22(s，6H)，3.75(s，2H)，6.90(s，2H)。

Preparation 77: 2- (aminomethyl) -4-chlorophenol hydrochloride

Prepared from 5-chloro-2-hydroxybenzonitrile using the procedure described in preparation 76.

¹HNMR(400MHz，CDCl₃)δ：4.08(s，2H)，6.87(d，1H)，7.27(d，1H)，7.35(s，1H)。

MS(APCI)m/z 156[M-H]^-，158[M+H]⁺

Preparation 77: 4' - (aminomethyl) biphenyl-4-ol hydrochloride

Prepared from 4' -hydroxybiphenyl-4-carbonitrile using the procedure described in preparation 76.

¹HNMR(400MHz，CD₃OD)δ：4.10(s，2H)，6.83(d，2H)，7.44-7.46(m，4H)，7.60(d，2H)ppm。

Preparation of 79: 3, 5-dichloro-N-ethyl-2-hydroxybenzamide

Prepared from 3, 5-dichloro-2-hydroxybenzoic acid and ethylamine using the method of preparation 57 to give the title compound as a pale yellow solid.

¹HNMR(400MHz，CDCl₃)δ：1.28(t，3H)，3.47-3.54(m，2H)，6.29-6.36(bs，1H)，7.27(d，1H)，7.48(d，1H)ppm。

MS (electrospray) M/z 232[ M-H ]]^-

Preparation 80: 2, 4-dichloro-6- [ (ethylamino) methyl ] phenol

A solution of the amide from preparation 79 (0.77 g, 3.29 mmol) in tetrahydrofuran (10 ml) was cooled to 0 ℃ and treated with borane-tetrahydrofuran complex (9.9 ml of a 1M solution in tetrahydrofuran, 9.9 mmol). The resulting solution was warmed to room temperature over 20 minutes and then heated to reflux for 16 hours. The reaction mixture was cooled to 0 ℃ and stopped by adding methanol (until effervescence ceased). The resulting solution was warmed to room temperature over 2 hours and then the solvent was removed in vacuo. The residue was dissolved in dichloromethane (40 ml) and washed with water (10 ml × 2), saturated aqueous sodium chloride (10 ml), dried (sodium sulfate) and reduced in vacuo to yield a colorless oil. Purification by column chromatography on silica gel eluting with dichloromethane: methanol (98: 2 to 95: 5) gave the title compound as a colourless solid (0.53 g).

¹HNMR(400MHz，CDCl₃)δ：1.17(t，3H)，2.72(q，2H)，3.98(s，2H)，6.86(d，1H)，7.23(d，1H)ppm。

Preparation 81: 6-hydroxy-N-methyl-N-1-naphthamides

Prepared from 6-hydroxy-1-naphthoic acid and methylamine using the method of preparation 57 to give the title compound as a light orange solid.

¹HNMR(400MHz，CD₃OD)δ：2.97(s，3H)，7.10-7.14(m，2H)，7.34-7.40(m，2H)，7.73(dd，1H)，8.04(d，1H)ppm。

Preparation 82: 5- [ (methylamino) methyl ] -2-naphthol

Prepared from the amide of preparation 81 using the method of preparation 80 to yield the title compound as a pale pink solid.

¹HNMR(400MHz，CD₃OD)δ：2.48(s，3H)，4.14(s，2H)，7.11-7.14(m，2H)，7.25(d，1H)，7.33(t，1H)，7.59(d，1H)，7.94(d，1H)ppm。

MS (electrospray) M/z 186[ M-H ]]^-，188[M+H]⁺

Preparation 83: 3-hydroxy-5- (trifluoromethyl) benzamide

Prepared from 3-hydroxy-5- (trifluoromethyl) benzoic acid using the method of preparation 58 to give the title compound as a pale yellow solid.

¹HNMR(400MHz，CD₃OD)δ：7.18(t，1H)，7.50(t，1H)，7.60-7.61(m，1H)ppm。

MS (electrospray) M/z 204[ M-H]^-

Preparation 84: 3- (aminomethyl) -5- (trifluoromethyl) phenol

Prepared from the amide of preparation 83 using the method of preparation 80 to yield a pale yellow oil of the title compound.

¹HNMR(400MHz，CD₃OD)δ：3.81(s，2H)，6.91(s，1H)，6.98(s，1H)，7.09(s，1H)ppm。

MS (electrospray) M/z 192[ M + H ]]⁺

Preparation 85: 3- (aminomethyl) -5-chlorophenol

Prepared from 3-chloro-5-hydroxybenzonitrile using the procedure of preparation 76 to give the title compound as a pale yellow solid.

¹HNMR(400MHz，CD₃OD)δ：3.69(s，2H)，6.65(d，2H)，6.79(t，1H)ppm。

MS (electrospray) M/z 158[ M + H ]]⁺

Preparation 86: 3- [ (acetylamino) methyl ] -5-chlorophenyl acetate

A solution of preparation 85 amine (700 mg, 4.46 mmol) in tetrahydrofuran (20 ml) was treated with triethylamine (1.3 ml, 8.9 mmol) and acetyl chloride (0.64 ml, 8.9 mmol). The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered and the filtrate was reduced in vacuo to yield the title compound as a colorless solid (1.07 g).

¹HNMR(400MHz，CDCl₃)δ：2.15(s，3H)，2.27(s，3H)，3.71-3.75(m，1H)，4.38-4.41(m，2H)，6.92(s，1H)，7.02(s，1H)，7.13(s，1H)ppm。

MS (electrospray) M/z 264[ M + Na ]]⁺

Preparation 87: n- (3-chloro-5-hydroxybenzyl) acetamide

Preparation 86 a solution of the diacetate (1.07 g, 4.44 mmol) in methanol (10 ml) was treated with sodium methoxide (30 mg, 0.55 mmol) and the resulting mixture was stirred at room temperature for 6 hours. The solvent was removed in vacuo and the residue was purified by column chromatography on silica gel eluting with ethyl acetate to pentane (1: 1 to 1: 0) to give the title compound as a yellow solid (0.78 g).

¹HNMR(400MHz，CDCl₃)δ：2.05(s，3H)，4.33(d，2H)，6.08-6.14(m，1H)，6.73(d，2H)，6.79(t，1H)ppm。

MS (electrospray) M/z 200[ M + H ]]⁺

Preparation 88: 3-chloro-5- [ (ethylamino) methyl ] phenol

Prepared from the amide of preparation 87 (0.75 g, 3.76 mmol) using the method of preparation 59 to yield the title compound as a colorless solid (0.48 g).

¹HNMR(400MHz，CD₃OD)δ：1.14(t，3H)，2.71(q，2H)，3.25-3.27(m，1H)，3.72(s，2H)，6.66-6.68(m，2H)，6.79(s，1H)ppm。

MS (electrospray) M/z [ M-H ]]^-

Preparation 89: 4- { [ tert-butyl (dimethyl) silyl ] oxy } -2-chlorobenzaldehyde

A solution of 2-chloro-4-hydroxybenzaldehyde (5.0 g, 32 mmol), tert-butyl (dimethyl) silyl chloride (5.3 g, 35 mmol), imidazole (2.9 g, 45 mmol) and N, N-dimethylaminopyridine (10 mg) in N, N-dimethylformamide (40 ml) was stirred at room temperature under nitrogen atmosphere for 16 hours. The solvent was removed in vacuo and the residue partitioned between ethyl acetate (100 ml) and water (100 ml). The organic phase was separated, washed with saturated aqueous sodium chloride (50 ml), dried (sodium sulfate) and reduced in vacuo. Further purification by column chromatography eluting on silica gel with pentane: ethyl acetate (3: 1 to 2: 1) gave the title compound as a colourless oil (6.50 g).

¹HNMR(400MHz，CDCl₃)δ：0.25(s，6H)，0.97(s，9H)，6.08(dd，1H)，6.87(d，1H)，7.84(d，1H)，10.32(s，1H)ppm。

Preparation 90: n- (4- { [ tert-butyl (dimethyl) silyl ] oxy } -2-chlorophenylmethyl) prop-2-en-1-amine

A solution of the aldehyde (6.50 g, 24.0 mmol) from preparation 89 and allylamine (1.51 g, 26.4 mmol) in dichloromethane (60 ml) was treated with sodium triacetoxyborohydride (7.6 g, 35.6 mmol) and the resulting suspension was stirred at room temperature for 16 h. Saturated aqueous sodium bicarbonate (50 ml) was added and the organic phase was separated. The organic phase was washed with saturated aqueous sodium chloride (50 ml), dried (sodium sulfate) and the solvent removed in vacuo to give a yellow oil. Purification by column chromatography on silica gel eluting with pentane: ethyl acetate (3: 1 to 2: 1) gave the title compound as a colourless oil (2.80 g).

¹HNMR(400MHz，CDCl₃)δ：0.19(s，6H)，0.97(s，9H)，1.84(bs，1H)，3.26(d，2H)，3.81(s，2H)，5.12(dd，1H)，5.20(dd，1H)，5.88-5.98(m，1H)，6.71(dd，1H)，6.85-6.86(d，1H)，7.24(d，1H)ppm。

MS (electrospray) M/z 312[ M + H ]]⁺

Preparation 91: 4- [ (allylamino) methyl ] -2, 6-dichlorophenol

Prepared from 3, 5-dichloro-4-hydroxybenzaldehyde and allylamine using the method of preparation 90 to give the title compound as a colorless oil.

¹HNMR(400MHz，DMSO_d6)δ：3.11(d，2H)，3.50(s，2H)，5.06(d，1H)，5.16(d，1H)，5.77-5.90(m，1H)，7.10(s，2H)ppm。

MS (electrospray) M/z 232/234[ M + H ]]⁺

Preparation 92: (4- { [ tert-butyl (dimethyl) silyl ] oxy } -2-chlorophenylmethyl) amine

A solution of the amine from preparation 91 (2.8 g, 9.0 mmol), dimethyl barbituric acid (7.0 g, 45 mmol) and tetrakis (triphenylphosphine) palladium (0) (0.10 g, 0.08 mmol) in dichloromethane (80 ml) was heated to reflux for 4 h. The cooled solution was reduced under vacuum and the residue was partitioned between ethyl acetate (50 ml) and 1N aqueous sodium hydroxide (50 ml). The organic phase was separated, washed with saturated aqueous sodium chloride (50 ml), dried (sodium sulfate) and reduced in vacuo. Further purification by column chromatography eluting on silica gel with dichloromethane: methanol: 0.880 ammonia (98: 2: 0 to 95: 5: 0.5) gave the title compound as a colourless oil (1.70 g).

¹HNMR(400MHz，CDCl₃)δ：0.19(s，6H)，0.97(s，9H)，1.89(s，2H)，3.85(s，2H)，6.70(dd，1H)，6.85-6.86(dd，1H)，7.21(d，1H)ppm。

Preparation 93: (4- { [ tert-butyl (dimethyl) silyl ] oxy } benzyl) methylamine

Prepared from the aldehyde and methylamine of preparation 89 using the method of preparation 90 to give the title compound as a yellow oil.

¹HNMR(400MHz，CDCl₃)δ：0.23(s，6H)，1.00(s，9H)，2.50(s，3H)，3.93(s，2H)，6.70-6.73(m，1H)，6.76(d，1H)，7.20(d，1H)ppm。

MS (electrospray) M/z 286/288[ M + H ]]⁺

Preparation 94: 4- (aminomethyl) -2, 6-dichlorophenol barbiturate

Prepared from the amine from preparation 91 using the method of preparation 92 to yield the barbiturate salt of the title compound.

¹HNMR(400MHz，DMSO_d6) δ: 2.60-4.40 (broad multiplet, 2H), 3.03(s, 6H), 3.93(s, 2H), 7.49(s, 2H) ppm.

MS (electrospray) M/z 192/194[ M + H ]]⁺

Preparation 95: 4- { [ tert-butyl (dimethyl) silyl ] oxy } -2, 3-dichlorobenzaldehyde

Prepared according to the procedure for preparation 89 from 2, 3-dichloro-4-hydroxybenzaldehyde to give the title compound as a yellow oil.

¹HNMR(400MHz，CDCl₃)δ：0.29(s，6H)，1.04(s，9H)，6.88(d，1H)，7.76(d，1H)，10.32(s，1H)ppm。

Preparation 96: n- (4- { [ tert-butyl (dimethyl) silyl ] oxy } -2, 3-dichlorobenzyl) prop-2-en-1-amine

Prepared according to preparation 90 using allylamine and the aldehyde from preparation 95 to yield the title compound as a colorless oil.

¹HNMR(400MHz，CDCl₃)δ：0.20(s，6H)，1.01(s，9H)，3.25(d，2H)，3.82(s，2H)，5.10(dd，1H)，5.18(dd，1H)，5.85-5.93(m，1H)，6.76(d，1H)，7.13(d，1H)ppm。

MS (electrospray) M/z 346/348[ M + H ]]⁺

Preparation 97: (4- { [ tert-butyl (dimethyl) silyl ] oxy } -2, 3-dichlorobenzyl) amine

Prepared according to preparation 92 using the amine from preparation 96 to yield the title compound as a colorless oil.

¹HNMR(400MHz，CD₃OD)δ：0.23(s，6H)，1.03(s，9H)，3.92(s，2H)，6.77(d，1H)，7.12(d，1H)ppm。

Preparation 98: 4- { [ tert-butyl (dimethyl) silyl ] oxy } -1-naphthaldehyde

Prepared according to the procedure for preparation 89 from 2, 3-dichloro-4-hydroxybenzaldehyde to give the title compound as a brown solid.

¹HNMR(400MHz，CDCl₃)δ：0.36(s，6H)，1.10(s，9H)，6.94(d，1H)，7.56(dd，1H)，7.68(dd，1H)，7.86(d，1H)，8.27(dd，1H)，9.30(dd，1H)，10.21(s，1H)ppm。

Preparation 99: n- [ (4- { [ tert-butyl (dimethyl) silyl ] oxy } -1-naphthyl) methyl ] prop-2-en-1-amine

Prepared according to preparation 90 using allylamine and aldehyde from preparation 98 to yield a yellow oil of the title compound.

¹HNMR(400MHz，CDCl₃)δ：0.30(s，6H)，1.11(s，9H)，1.97(bs，1H)，3.39(d，2H)，4.17(s，2H)，5.16(dd，1H)，5.25(dd，1H)，5.95-6.05(m，1H)，6.82(d，1H)，7.32(d，1H)，7.47-7.57(m，2H)，8.07(d，1H)，8.25(d，1H)ppm。

MS (electrospray) M/z 328[ M + H ]]⁺，655[2M+H]⁺

Preparation of 100: [ (4- { [ tert-butyl (dimethyl) silyl ] oxy } -1-naphthyl) methyl ] amine

Prepared according to preparation 92 using the amine from preparation 99 to give the title compound as a colorless oil.

¹HNMR(400MHz，CDCl₃)δ：0.28(s，6H)，1.09(s，9H)，2.31(bs，2H)，4.24(s，2H)，6.80(d，1H)，7.27(t，1H)，7.46-7.55(m，4H)，8.00(d，1H)，8.25(d，1H)。

Preparation 101: 3-hydroxy-N-methyl-5- (trifluoromethyl) benzamide

Prepared from 3-hydroxy-5- (trifluoromethyl) benzoic acid and methylamine using the method of preparation 58 to give the title compound as a light orange solid.

¹HNMR(400MHz，CD₃OD)δ：2.99(s，3H)，7.14(s，1H)，7.43(s，1H)，7.52(s，1H)ppm。

MS (electrospray) M/z 218[ M-H]^-

Preparation 102: 3- [ (methylamino) methyl ] -5- (trifluoromethyl) phenol

Prepared from the amide of preparation 101 using the method of preparation 59 to yield the title compound as a colorless solid.

¹HNMR(400MHz，CD₃OD)δ：2.41(s，3H)，3.75(s，2H)，6.93(s，1H)，6.98(s，1H)，7.09(s，1H)ppm。

MS (electrospray) M/z 206[ M + H ]]⁺

Preparation 103: 4- (aminomethyl) -3, 5-dimethylphenol

Prepared from 4-hydroxy-2, 6-dimethylbenzonitrile using the procedure of preparation 76 to give the title compound as a colorless solid.

¹HNMR(400MHz，D₂O)δ：2.09(s，6H)，3.90(s，2H)，6.95(s，2H)ppm。

Preparation 104: (4-hydroxy-2, 5-dimethylphenyl) acetonitrile

A solution of (4-methoxy-2, 5-dimethylphenyl) acetonitrile (0.5 g, 2.9 mmol) in dichloromethane (10 ml) was cooled to-80 ℃ and treated with a solution of boron tribromide in dichloromethane (14.3 ml of a 1M solution, 14.3 mmol). The reaction mixture was stirred at-80 ℃ for another 30 minutes and then gradually warmed to room temperature over a period of 2 hours. The reaction mixture was quenched with saturated aqueous sodium bicarbonate (20 ml) and the organic phase was separated. The organic phase was washed with saturated aqueous sodium chloride (20 ml), dried (sodium sulfate) and the solvent removed in vacuo to yield a light brown solid. Purification by column chromatography eluting on silica gel with ethyl acetate: pentane (1: 4 to 1: 2) gave the title compound as a pale solid (0.28 g).

¹HNMR(400MHz，CD₃OD)δ：2.13(s，3H)，2.23(s，3H)，3.66(s，2H)，6.60(s，1H)，6.98(s，1H)ppm。

MS (electrospray) M/z 160[ M-H [)]^-

Preparation 105: (4-hydroxy-2, 3-dimethylphenyl) acetonitrile

Prepared from (4-methoxy-2, 3-dimethylphenyl) acetonitrile using the procedure of preparation 104 to give the title compound as a pale yellow solid.

¹HNMR(400MHz，CDCl₃)δ：2.20(s，3H)，2.24(s，3H)，3.62(s，2H)，4.91(bs，1H)，6.64(d，1H)，7.03(d，1H)ppm。

MS (electrospray) M/z 160[ M-H [)]^-

Preparation 106: (4-hydroxy-3-methylphenyl) acetonitrile

Prepared from (4-methoxy-3-methylphenyl) acetonitrile using the procedure of preparation 104 to give the title compound as a pale yellow solid.

¹HNMR(400MHz，CDCl₃)δ：2.25(s，3H)，3.65(s，2H)，4.98(bs，1H)，6.76(d，1H)，7.01(d，1H)，7.07(s，1H)ppm。

MS (electrospray) M/z 146[ M-H]^-

Preparation 107: 4- (2-aminoethyl) -2, 5-dimethylphenol

A solution of the nitrile from preparation 104 (0.28 g, 1.74 mmol) in ethanol (15 mL) was hydrogenated over Raney nickel (0.1 g, 50% w/w) at 60psi for 16 h. The reaction mixture was filtered and the solvent was removed in vacuo. The residue was purified by strong cation exchange resin with methanol and then with non-basic impurities eluting with 1M aqueous ammonia in methanol to yield the title compound as a colorless oil.

¹HNMR(400MHz，CD₃OD)δ：2.11(s，3H)，2.19(s，3H)，2.63-2.67(m，2H)，2.72-2.76(m，2H)，6.54(s，1H)，6.81(s，1H)ppm。

MS (electrospray) M/z 166[ M + H ]]⁺

Preparation 108: 4- (2-aminoethyl) -2, 3-dimethylphenol

Prepared from the nitrile of preparation 105 using the method of preparation 107 to give the title compound as a colourless oil.

¹HNMR(400MHz，CD₃OD)δ：2.12(s，3H)，2.19(s，3H)，2.68-2.75(m，4H)，6.55(d，1H)，6.78(d，1H)ppm。

MS (electrospray) M/z 166[ M + H ]]⁺

Preparation 109: 4- (2-aminoethyl) -2-methylphenol

Prepared from the nitrile of preparation 106 using the method of preparation 107 to give the title compound as a colourless oil.

¹HNMR(400MHz，CD₃OD)δ：2.15(s，3H)，2.60-2.64(m，2H)，2.79-2.83(m，2H)，6.66(d，1H)，6.82(d，1H)，6.90(s，1H)ppm。

MS (electrospray) M/z 152[ M + H ]]⁺

Examples 1 to 38

The appropriate protected alcohol (0.075 mmol) was dissolved in ethanol (4 ml) and the solution treated with a solution of ammonium fluoride (16 mg, 0.43 mmol) in water (300 μ l). The reaction mixture was then stirred at 50 ℃ for 18 hours and allowed to cool to room temperature. If the solid product precipitated, the reaction mixture was filtered and washed with methanol: water (2 ml, 1: 1 by volume) to give the title compound. If no product precipitated, the reaction mixture was concentrated in vacuo and the residue was purified by column chromatography on silica gel eluting with dichloromethane: methanol: 0.88 aqueous ammonia 98: 2: 0 to 95: 5: 0.5 to 90: 10: 1 to give the title product.

Alternatively, the following methods may be used for the syntheses of examples 1 to 38:

a solution of the appropriate protected alcohol (2.87 mmol) in methanol (80 ml) was treated with a solution of ammonium fluoride (1.06 g, 28.7 mmol) in water (53 ml) and the resulting mixture was heated at 40 ℃ for 16 h. The reaction was cooled to room temperature and filtered, washed with a mixture of water and methanol (1: 1, 3X 10 ml by volume), methanol (2X 10 ml). The solid was dried in vacuo to yield the desired compound.

Example 1: 2- (3- {2- [ ((2R) -2-hydroxy-2- [ 4-hydroxy-3- [ (methylsulfonyl) amino ] phenyl } ethyl) amino ] -2-methylpropyl } phenyl) -N- (4-hydroxy-3-methoxybenzyl) acetamide

Preparation 18(0.075 mmol) was dissolved in ethanol (4 ml) and the solution was treated with a solution of ammonium fluoride (16 mg, 0.43 mmol) in water (300 μ l). The reaction mixture was then stirred at 50 ℃ for 18 hours and allowed to cool to room temperature. The reaction mixture was concentrated in vacuo and the residue was purified by column chromatography on silica gel eluting with dichloromethane: methanol: 0.88 aqueous ammonia 98: 2: 0 to 95: 5: 0.5 to 90: 10: 1 to give the title product as a colorless solid.

¹HNMR(CD₃OD，400MHz)δ：1.04(s，3H)，1.06(s，3H)，2.68-2.90(m，7H)，3.53(s，2H)，3.74(s，3H)，4.23(m，2H)，4.62(m，1H)，6.67(m，2H)，6.77(m，1H)，6.85(d，1H)，7.01-7.22(m，6H)，7.37(m，1H)ppm。

MS (electrospray) M/z 572[ M + H ]]⁺

Example 2: n- [ (4' -hydroxybiphenyl-4-yl) methyl ] -2- (3- {2- [ ((2R) -2-hydroxy-2- { 4-hydroxy-3- [ (methylsulfonyl) amino ] phenyl } ethyl) amino ] -2-methylpropyl } phenyl) acetamide

Preparation 19(0.075 mmol) was dissolved in ethanol (4 ml) and the solution was treated with a solution of ammonium fluoride (16 mg, 0.43 mmol) in water (300 μ l). The reaction mixture was then stirred at 50 ℃ for 18 hours and allowed to cool to room temperature. The reaction mixture was filtered and the solid washed with methanol: water (2 ml, 1: 1 by volume) to give the title compound as a colorless solid.

¹HNMR(400MHz，DMSO_d6)δ：0.90(s，3H)，0.92(s，3H)，2.56(s，2H)，2.62-2.65(m，2H)，2.88(s，3H)，3.43(s，2H)，4.25(2H，d)，4.40-4.43(m，1H)，6.80-6.82(m，3H)，6.96-7.01(m，2H)，7.07-7.10(m，2H)，7.14-7.18(m，2H)，7.23(d，2H)，7.42-7.48(m，4H)，8.47(t，1H)。

MS (electrospray) M/z 618[ M + H ]]⁺

Example 3: n- (4-chloro-2-hydroxybenzyl) -2- (3- {2- [ ((2R) -2-hydroxy-2- { 4-hydroxy-3- [ (methylsulfonyl) amino ] phenyl } ethyl) amino ] -2-methylpropyl } phenyl) acetamide

Preparation 20(0.075 mmol) was dissolved in ethanol (4 ml) and the solution was treated with a solution of ammonium fluoride (16 mg, 0.43 mmol) in water (300 μ l). The reaction mixture was then stirred at 50 ℃ for 18 hours and allowed to cool to room temperature. The reaction mixture was filtered and washed with methanol: water (2 ml, 1: 1 by volume) to give the title compound as a colorless solid.

¹HNMR(400MHz，DMSO_d6)δ：0.90(s，3H)，0.91(s，3H)，2.56(s，2H)，2.59-2.67(m，2H)，2.88(s，3H)，3.44(s，2H)，4.16(s，2H)，4.40-4.43(m，1H)，6.76-6.81(m，2H)，6.96-7.18(m，8H)8.42(s，1H)。

MS (electrospray) M/z 574[ M-H ]]^-，576[M+H]⁺

Example 4: n- (4-hydroxy-3, 5-dimethylbenzyl) -2- (3- {2- [ ((2R) -2-hydroxy-2- { 4-hydroxy-3- [ (methylsulfonyl) amino ] phenyl } ethyl) amino ] -2-methylpropyl } phenyl) acetamide

Preparation 21(0.075 mmol) was dissolved in ethanol (4 ml) and the solution was treated with a solution of ammonium fluoride (16 mg, 0.43 mmol) in water (300 μ l). The reaction mixture was then stirred at 50 ℃ for 18 hours and allowed to cool to room temperature. The reaction mixture was filtered and washed with methanol: water (2 ml, 1: 1 by volume) to give the title compound as a colorless solid.

¹HNMR(400MHz，DMSO_d6) δ: 0.90(s, 3H), 0.91(s, 3H), 2.08(s, 6H), 2.55(s, 2H), 2.62-2.65(m, 2H), 2.88(s, 3H), 3.83(s, 2H partially obscured by H2O), 4.05(d, 2H), 4.40-4.43(m, 1H), 6.71(s, 2H), 6.81(d, 1H), 6.95-7.01(m, 2H), 7.05-7.09(m, 2H), 7.13-7.18(m, 2H), 8.28-8.31(t, 1H).

Example 5: 2- (3- {2- [ ((2R) -2-hydroxy-2- { 4-hydroxy-3- [ (methylsulfonyl) amino ] phenyl } ethyl) amino ] -2-methylpropyl } phenyl) -N- [ (2-hydroxy-1-naphthyl) methyl ] acetamide

Preparation 22(0.075 mmol) was dissolved in ethanol (4 ml) and the solution was treated with a solution of ammonium fluoride (16 mg, 0.43 mmol) in water (300 μ l). The reaction mixture was then stirred at 50 ℃ for 18 hours and allowed to cool to room temperature. The reaction mixture was concentrated in vacuo and the residue was purified by column chromatography on silica gel eluting with dichloromethane: methanol: 0.88 aqueous ammonia 98: 2: 0 to 95: 5: 0.5 to 90: 10: 1 to give the title product as a colorless solid.

¹HNMR(400MHz，DMSO_d6)δ：0.86(s，3H)，0.87(s，3H)，2.46-2.68(m，4H)，2.90(s，3H)，3.40(s，2H)，4.41-4.47(m，1H)，4.63(d，2H)，6.83(d，1H)，6.94-7.05(m，4H)，7.11-7.16(m，2H)，7.19(s，1H)，7.27(t，1H)，7.40(t，1H)，7.72(d，1H)，7.79(d，1H)，7.88(d，1H)，8.48-8.52(bs，1H)。

MS (electrospray) M/z 590[ M-H ]]^-

Example 6: 2- (3- {2- [ ((2R) -2-hydroxy-2- { 4-hydroxy-3- [ (methylsulfonyl) amino ] phenyl } ethyl) amino ] -2-methylpropyl } phenyl } -N- [ (6-hydroxy-2-naphthyl) methyl ] acetamide

Preparation 23(0.075 mmol) was dissolved in ethanol (4 ml) and the solution was treated with a solution of ammonium fluoride (16 mg, 0.43 mmol) in water (300 μ l). The reaction mixture was then stirred at 50 ℃ for 18 hours and allowed to cool to room temperature. The reaction mixture was filtered and washed with methanol: water (2 ml, 1: 1 by volume) to give the title compound as a colorless solid.

¹HNMR(400MHz，DMSO_d6)δ：0.90(s，3H)，0.92(s，3H)，2.49-2.68(m，4H)，2.89(s，3H)，3.44(s，2H)，4.34(d，2H)，4.40-4.43(m，1H)，6.80(d，1H)，6.96-7.17(m，7H)，7.23(d，1H)，7.51(s，1H)，7.58(d，1H)，7.61(d，1H)，8.50(dd，1H)。

MS (electrospray) M/z 590[ M-H ]]^-，592[M+H]⁺，614[M+Na]⁺

Example 7: n- [ (4' -hydroxybiphenyl-3-yl) methyl ] -2- (3- {2- [ ((2R) -2-hydroxy-2- { 4-hydroxy-3- [ (methylsulfonyl) amino ] phenyl } ethyl) amino ] -2-methylpropyl } phenyl) acetamide

Preparation 24(0.075 mmol) was dissolved in ethanol (4 ml) and the solution was treated with a solution of ammonium fluoride (16 mg, 0.43 mmol) in water (300 μ l). The reaction mixture was then stirred at 50 ℃ for 18 hours and allowed to cool to room temperature. The reaction mixture was filtered and washed with methanol: water (2 ml, 1: 1 by volume) to give the title compound as a colorless solid.

¹HNMR(400MHz，DMSO_d6)δ：0.88(s，3H)，0.90(s，3H)，2.66-2.54(m，4H)，2.88(s，3H)，3.43(s，2H)，4.29(d，2H)，4.39-4.43(m，1H)，6.79-6.82(m，3H)，6.96-7.01(dd，2H)，7.07-7.17(m，5H)，7.27-7.31(dd，1H)，7.36-7.41(m，4H)，8.52(dd，1H)ppm。

MS (electrospray) M/z 618[ M + H ]]⁺

Example 8: n- [ (3' -hydroxybiphenyl-3-yl) methyl ] -2- (3- {2- [ ((2R) -2-hydroxy-2- { 4-hydroxy-3- [ (methylsulfonyl) amino ] phenyl } ethyl) amino ] -2-methylpropyl } phenyl) acetamide

Preparation 25(0.075 mmol) was dissolved in ethanol (4 ml) and the solution was treated with a solution of ammonium fluoride (16 mg, 0.43 mmol) in water (300 μ l). The reaction mixture was then stirred at 50 ℃ for 18 hours and allowed to cool to room temperature. The reaction mixture was filtered and washed with methanol: water (2 ml, 1: 1 by volume) to give the title compound as a colorless solid.

¹HNMR(400MHz，DMSO_d6)δ：1.16(s，6H)，2.85(s，2H)，2.92(s，3H)，2.96-3.03(m，2H)，3.57(s，2H)，4.42(s，2H)，4.77-4.79(m，1H)，6.74(d，1H)，6.90(d，1H)，6.95-6.97(m，2H)，7.09-7.27(m，7H)，7.32(t，1H)，7.41-7.42(m，3H)ppm。

MS (electrospray) M/z 618[ M + H ]]⁺，6401[M+Na]⁺，616[M-H]^-

Example 9: 2- (3- {2- [ ((2R) -2-hydroxy-2- { 4-hydroxy-3- [ (methylsulfonyl) amino ] phenyl } ethyl) amino ] -2-methylpropyl } phenyl) -N- [2- (4-hydroxyphenyl) -2-methylpropyl ] acetamide

Preparation 26(0.075 mmol) was dissolved in ethanol (4 ml) and the solution was treated with a solution of ammonium fluoride (16 mg, 0.43 mmol) in water (300 μ l). The reaction mixture was then stirred at 50 ℃ for 18 hours and allowed to cool to room temperature. The reaction mixture was concentrated in vacuo and the residue was purified by column chromatography on silica gel eluting with dichloromethane: methanol: 0.88 aqueous ammonia 98: 2: 0 to 95: 5: 0.5 to 90: 10: 1 to give the title product as a colorless solid.

¹HNMR(400MHz，DMSO_d6)δ：0.91(s，3H)，0.92(s，3H)，1.11(s，6H)，2.56(s，2H)，2.64-2.66(m，2H)，2.89(s，3H)，3.15(s，2H)，3.35(s，2H)，4.42-4.45(m，1H)，6.65(d，2H)，6.81(d，1H)，6.94-7.03(m，4H)，7.07-7.14(m，3H)，7.18(s，1H)，7.60(t，1H)。

MS(APCI)m/z 582[M-H]^-，584[M+H]⁺

Example 10: n- (3, 5-dichloro-2-hydroxybenzyl) -N-ethyl-2- (3- {2- [ ((2R) -2-hydroxy-2- { 4-hydroxy-3- [ (methylsulfonyl) amino ] phenyl } ethyl) amino ] -2-methylpropyl } phenyl) acetamide

Preparation 27(0.075 mmol) was dissolved in ethanol (4 ml) and the solution was treated with a solution of ammonium fluoride (16 mg, 0.43 mmol) in water (300 μ l). The reaction mixture was then stirred at 50 ℃ for 18 hours and allowed to cool to room temperature. The reaction mixture was filtered and washed with methanol: water (2 ml, 1: 1 by volume) to give the title compound as a colorless solid.

¹HNMR(400MHz，CD₃OD) δ: 1.05-1.16(m, 9H), 2.70-2.96(m, 7H), 3.32 and 3.34(2t, 2H), 3.74 and 3.83(2s, 2H), 4.56 and 4.58(2s, 2H), 4.64-4.66(m, 1H), 6.85(dd, 1H), 7.01-7.26(m, 7H), 7.36(dd, 1H).

MS (electrospray) M/z 637[ M-H ]]^-

All reactions were carried out under a nitrogen atmosphere unless otherwise indicated.

Abbreviations

TBDMS ═ tert-butyl (dimethyl) silyl

IPA: isopropanol (I-propanol)

THF: tetrahydrofuran (THF)

s ═ singlet

d is doublet

ddd-doublet

t is triplet

q is quartet

m is multiplet

broad unimodal such as NH or OH

The ability of the compounds of formula (1) to act as potent beta 2 agonists and thus mediate smooth muscle relaxation can be determined by determining the effect of beta-2 adrenergic receptor stimulation on the electric field-stimulated contraction of guinea pig tracheal strips.

Guinea pig trachea

Male, Dunkin-Hartley guinea pigs (475-₂Asphyxiated and bled and the trachea isolated from the femoral artery. Four preparations were obtained from each animal, dissection was started immediately below the larynx and a 2.5 cm long trachea was removed. The tracheal tube segment was opened by cutting the cartilage opposite the tracheal muscle and then cut into transverse segments, 3-4 cartilage rings wide. The resulting long strip preparation was suspended in a 5 ml organ bath using cotton thread tied to the upper and lower cartilage strips. These strips were equilibrated in modified Krebs Ringer buffer (SigmaK0507) containing 3. mu.M indomethacin (Sigma 17378), 10. mu.M guanethidine (Sigma G8520) and 10. mu.M atenolol (Sigma A7655), relaxed, 20 minutes, heated at 37 ℃ and with 95% O₂/5％CO₂Inflated and then applied an initial tension of 1 gram. The preparations were allowed to equilibrate for another 30-45 minutes, during which time they were strained two more times (to 1 gram) at 15 minute intervals. The changes in tension are recorded and monitored via a standard, isometric transducer connected to a data-collection system (specifically designed by Pfizer). After the tonometric balancing, these tissues were subjected to Electric Field Stimulation (EFS) using the following parameters: 10s wave trains (trains), 0.1ms pulse width, 10Hz and just maximum voltage (25 volts) were continuously applied every 2 minutes throughout the experiment. EFS of the postganglionic cholinergic nerve in the trachea causes monophasic contraction of smooth muscle and records twitch height. Throughout the experiment, except when the beta-2 agonist according to the invention was added, the organ bath was constantly perfused with the above Krebs Ringer buffer via a peristaltic pump system (pump flow rate 7.5 ml/min), then the pump was stopped at the time of cumulative dose to the bath and reached during the washout periodAfter the maximum reaction, it is started again.

Experimental protocols to assess efficacy and efficacy

After equilibration to the EFS, the peristaltic pump was stopped and a single dose of 300nM isoproterenol (Sigma 15627) "injected (printed)" preparation to establish the maximal response based on inhibition of the systolic EFS response. Isoproterenol was then washed out over 40 minutes. After infusion and washout recovery, a standard curve of isoproterenol was plotted on all tissues (isoproterenol curve 1), via cumulative, bolus addition to the bath, using semilogarithmic increments of concentration. The concentration range used was 1^e-9To 1^e/3^e-6And M. At the end of the isoproterenol curve, the preparation was washed again for 40 minutes before starting the second curve for isoproterenol (as internal control) or the beta-2 agonist according to the invention. Beta-2 agonist response is expressed as percent inhibition of EFS response. Data for beta-2 agonists are normalized by expressing inhibition as a percentage of the maximum inhibition induced by isoproterenol in curve 1. EC of beta-2 agonists according to the invention₅₀Values refer to the concentration of compound required to produce half-maximal effect. Thus the data for the beta-2 agonists according to the invention are represented by (EC)₅₀The relative potency of isoproterenol as defined by the β -2 agonist)/(EC 50 isoproterenol) indicates.

Confirmation of beta-2 mediated functional Activity

The β -2 agonist activity of the test compounds was confirmed using the protocol described above, however, prior to establishing a curve for a β -2 agonist according to the invention, the preparation was preincubated (minimum 45 minutes) with 300nMICI 118551 (selective β 2 antagonist), which produced a shift in the right of the test compound dose response curve in physical discomfort of the β -2 mediated effect.

According to another alternative, the agonist potency of the β 2 receptor of the compound of formula (1) may also be increased by producing half maximal Effect (EC) at the β 2 receptor₅₀) According to the needDetermination of the concentration of the compound of the invention.

Preparation of compounds

Compound stocks of 10 mM/100% DMSO (dimethyl sulfoxide) were diluted in 4% DMSO to the maximum dose required. This maximum dose was used to establish a 10-point semilog dilution curve, all in 4% DMSO. Isoproterenol (Sigma, 1-5627) was used as a standard in each experiment and as a control well on each plate. Data are expressed as% isoproterenol response.

Cell culture

CHO (Chinese hamster ovary) cells recombinantly expressing the human β 2 adrenergic receptor (obtained from Kobilka et al, PNAS 84: 46-50, 1987 and Bouvier et al, MolPharmacol 33: 1988CHOh β 2133-139) were cultured in Dulbeccos MEM/NUT MIX F12(Gibco, 21331-020) supplemented with 10% fetal bovine serum (Sigma, F4135, lot No. 90K8404Exp 09/04), 2mM glutamine (Sigma, G7513), 500. mu.g/ml geneticin (Sigma, G7034) and 10. mu.g/ml puromycin (Sigma, P8833). Cells were seeded to achieve approximately 90% confluency (confluency) for testing.

Measurement method

Transfer of 25 μ l/well of each dose of compound to cAMP-(NEN, SMP004B), 1% DMSO was used as the basal control and 100nM isoproterenol was used as the maximal control. This was diluted 1: 2 by the addition of 25. mu.l/well PBS. Cells were trypsinized (0.25% Sigma, T4049), washed with PBS (Gibco, 14040-containing 174) and resuspended in stimulation buffer (NEN, SMP004B) to 1X 10⁶Cells/ml CHOhB 2. The compounds were incubated with 50. mu.l/well of cells for 1 hour. Then by adding 100 microliter/well of 0.18. mu. Ci/ml¹²⁵Cells were lysed in I-cAMP (NEN, NEX-130) detection buffer (NEN, SMP004B) and the plates were incubated for another 2 hours at room temperature.¹²⁵I-cAMP binds toThe amount of (c) was quantified using Topcount NXT (Packard), normal calculation efficiency 1 minute. Dose-response data are expressed as% isoproterenol activity and fitted using a four-parameter S-fit curve.

It has thus been found that the compounds of formula (1) according to the invention, illustrated in the above examples 1 to 38, exhibit a β 2cAMP EC of between 0.02nM and 3.03nM₅₀. The following table illustrates the activity of the compounds of the invention:

examples	EC(nM)
		1	0.03
2	0.24
		3	0.02
6	0.16
		7	0.26
9	0.45
		13	0.08
15	0.09
		20	0.29

Claims (31)

1. A compound of the general formula (1),

wherein (CH)₂)_n-C(＝O)Q¹The radical being in the meta-or para-position, R¹And R²Independently selected from H and C₁-C₄Alkyl, n is 0, 1 or 2 and Q¹A group selected from:

and the group-NR⁸-Q²-A, wherein p is 1 or 2, Q²Is C optionally substituted by one hydroxy group₁-C₄Alkylene radical, R⁸Is H or C₁-C₄Alkyl and A is pyridyl optionally substituted with OH, C optionally substituted with OH₃-C₇Cycloalkyl radicals, or radicals

Wherein R is³、R⁴、R⁵，R⁶And R⁷Are the same or different and are selected from H, C₁-C₄Alkyl, OR⁹、SR⁹Halo, CN, CF₃，OCF₃、COOR⁹、SO₂NR⁹R¹⁰、CONR⁹R¹⁰、NR⁹R¹⁰、NHCOR¹⁰And optionally 1 to 3 selected from OR⁹Halo and C₁-C₄A phenyl group substituted with an alkyl group,

wherein R is⁹And R¹⁰Are identical or different and are selected from H or C₁-C₄Alkyl and denotes the point of attachment to the carbonyl group;

wherein the group Q¹Substituted with at least one hydroxyl group;

or, if appropriate, their pharmaceutically acceptable salts and/or isomers, tautomers, solvates or isotopic variations thereof.

2. A compound according to claim 1, wherein Q¹Is a group-NR⁸-Q²-A, wherein R⁸Is H, CH₃Or CH₂CH₃And A is naphthyl substituted by one hydroxy.

3. A compound according to claim 1, wherein Q¹Is a group-NR⁸-Q²-A, wherein R⁸Is H, CH₃Or CH₂CH₃And A is a group

Wherein R is³、R⁴、R⁵、R⁶And R⁷One is OH and the others are the same or different and are selected from H, C₁-C₄Alkyl, OR⁹、SR⁹Halo, CF₃、OCF₃、SO₂NR⁹R¹⁰、CONR⁹R¹⁰、NR⁹R¹⁰，NHCOR¹⁰With the proviso that R³To R⁷At least 2 of (a) is equal to H;

wherein R is⁹And R¹⁰Are identical or different and are selected from H or C₁-C₄An alkyl group.

4. A compound according to claim 3, wherein Q¹Is a group-NR-Q²A and A is a group

Wherein R is³、R⁴、R⁵、R⁶And R⁷One is OH and the others are the same or different and are selected from H, OH, CH₃、OCH₂-CH₃、SCH₃Halo, CF₃、OCF₃With the proviso that R³To R⁷At least 2 of (a) is equal to H.

5. A compound according to claim 1, wherein Q¹Is a group-NR⁸-Q²-A, wherein R⁸Is H, CH₃Or CH₂CH₃And A is a group

Wherein R is³、R⁴、R⁵、R⁶And R⁷One is phenyl substituted with OH and the other is H.

6. A compound according to any one of claims 1 to 5, wherein Q²is-CH₂-、(CH₂)₂-、(CH₂)₂-、-(CH₂)₃-、(C(CH₃)₂)-(CH₂)₄-or (CH)₂OH))-。

7. A compound according to claim 6, wherein Q²is-CH₂-。

8. A compound according to claim 1, wherein Q¹Is composed of

Wherein R is³、R⁴、R⁵And R⁶One is OH and the other is H.

9. A compound according to claim 1, wherein Q¹Is composed of

Wherein R is³、R⁴、R⁵And R⁶One is OH and the other is H.

10. A compound according to any one of claims 1 to 9, wherein R¹Is H or C₁-C₄Alkyl and R²Is C₁-C₄An alkyl group.

11. A compound according to claim 10, wherein R¹Is H or CH₃And R²Is CH₃。

12. The compound of claim 11, wherein n is 1.

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

14. A compound according to any one of claims 1 to 13, wherein (CH)₂)_n-C(＝O)Q¹The groups are in the meta position.

15. A compound according to claim 1 selected from

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

n- [ (4' -hydroxybiphenyl-4-yl) methyl ] -2- (3- {2- [ ((2R) -2-hydroxy-2- { 4-hydroxy-3- [ (methylsulfonyl) amino ] phenyl } ethyl) amino ] -2-methylpropyl } phenyl) acetamide;

n- (4-chloro-2-hydroxybenzyl) -2- (3- {2- [ ((2R) -2-hydroxy-2- { 4-hydroxy-3- [ (methylsulfonyl) amino ] phenyl } ethyl) amino ] -2-methylpropyl } phenyl) acetamide;

n- (4-hydroxy-3, 5-dimethylbenzyl) -2- (3- {2- [ ((2R) -2-hydroxy-2- { 4-hydroxy-3- [ (methylsulfonyl) amino ] phenyl } ethyl) amino ] -2-methylpropyl } phenyl) acetamide;

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

2- (3- {2- [ ((2R) -2-hydroxy-2- { 4-hydroxy-3- [ (methylsulfonyl) amino ] phenyl } ethyl) amino ] -2-methylpropyl } phenyl) -N- [ (6-hydroxy-2-naphthyl) methyl ] acetamide;

n- [ (4' -hydroxybiphenyl-3-yl) methyl ] -2- (3- {2- [ ((2R) -2-hydroxy-2- { 4-hydroxy-3- [ (methylsulfonyl) amino ] phenyl } ethyl) amino ] -2-methylpropyl } phenyl) acetamide;

n- [ (3' -hydroxybiphenyl-3-yl) methyl ] -2- (3- {2- [ ((2R) -2-hydroxy-2- { 4-hydroxy-3- [ (methylsulfonyl) amino ] phenyl } ethyl) amino ] -2-methylpropyl } phenyl) acetamide;

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

n- (3, 5-dichloro-2-hydroxybenzyl) -N-ethyl-2- (3- {2- [ ((2R) -2-hydroxy-2- { 4-hydroxy-3- [ (methylsulfonyl) amino ] phenyl } ethyl) amino ] -2-methylpropyl } phenyl) acetamide;

2- (3- {2- [ ((2R) -2-hydroxy-2- { 4-hydroxy-3- [ (methylsulfonyl) amino ] phenyl } ethyl) amino ] -2-methylpropyl } phenyl) -N- [ (6-hydroxy-1-naphthyl) methyl ] -N-methylacetamide;

n- [ (2' -hydroxybiphenyl-3-yl) methyl ] -2- (3- {2- [ ((2R) -2-hydroxy-2- { 4-hydroxy-3- [ (methylsulfonyl) amino ] phenyl } ethyl) amino ] -2-methylpropyl } phenyl) acetamide;

n- (2-hydroxy-5- { (1R) -1-hydroxy-2- [ (2- {3- [2- (6-hydroxy-3, 4-dihydroisoquinolin-2 (1H) -yl) -2-oxoethyl ] phenyl } -1, 1-dimethylethyl) amino ] ethyl } phenyl) methanesulfonamide;

2- (3- {2- [ ((2R) -2-hydroxy-2- { 4-hydroxy-3- [ (methylsulfonyl) amino ] phenyl } ethyl) amino ] -2-methylpropyl } phenyl) -N- [4- (4-hydroxyphenyl) butyl ] acetamide;

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

n- (2-chloro-4-hydroxybenzyl) -2- (3- {2- [ ((2R) -2-hydroxy-2- { 4-hydroxy-3- [ (methylsulfonyl) amino ] phenyl } ethyl) amino ] -2-methylpropyl } phenyl) acetamide;

n- (3, 5-dichloro-4-hydroxybenzyl) -2- (3- {2- [ ((2R) -2-hydroxy-2- { 4-hydroxy-3- [ (methylsulfonyl) amino ] phenyl } ethyl) amino ] -2-methylpropyl } phenyl) acetamide;

n- (2, 3-dichloro-4-hydroxybenzyl) -2- (3- {2- [ ((2R) -2-hydroxy-2- { 4-hydroxy-3- [ (methylsulfonyl) amino ] phenyl } ethyl) amino ] -2-methylpropyl } phenyl) acetamide;

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

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

n- (2-chloro-4-hydroxybenzyl) -N-ethyl-2- (3- {2- [ ((2R) -2-hydroxy-2- { 4-hydroxy-3- [ (methylsulfonyl) amino ] phenyl } ethyl) amino ] -2-methylpropyl } phenyl) acetamide;

n- (2-chloro-4-hydroxybenzyl) -2- (3- {2- [ ((2R) -2-hydroxy-2- { 4-hydroxy-3- [ (methylsulfonyl) amino ] phenyl } ethyl) amino ] -2-methylpropyl } phenyl) -N-methylacetamide;

n- (3-hydroxy-5- (trifluoromethyl) benzyl) -2- (3- {2- [ ((2R) -2-hydroxy-2- { 4-hydroxy-3- [ (methylsulfonyl) amino ] phenyl } ethyl) amino ] -2-methylpropyl } phenyl) -N-methylacetamide;

n- [ (2' -hydroxybiphenyl-2-yl) methyl ] -2- (3- {2- [ ((2R) -2-hydroxy-2- { 4-hydroxy-3- [ (methylsulfonyl) amino ] phenyl } ethyl) amino ] -2-methylpropyl } phenyl) acetamide;

n- [ (3' -hydroxybiphenyl-2-yl) methyl ] -2- (3- {2- [ ((2R) -2-hydroxy-2- { 4-hydroxy-3- [ (methylsulfonyl) amino ] phenyl } ethyl) amino ] -2-methylpropyl } phenyl) acetamide;

n- (4-hydroxy-2, 6-dimethylbenzyl) -2- (3- {2- [ ((2R) -2-hydroxy-2- { 4-hydroxy-3- [ (methylsulfonyl) amino ] phenyl } ethyl) amino ] -2-methylpropyl } phenyl) acetamide;

n- (2-hydroxy-5- { (1R) -1-hydroxy-2- [ (2- {3- [2- (7-hydroxy-3, 4-dihydroisoquinolin-2 (1H) -yl) -2-oxoethyl ] phenyl } -1, 1-dimethylethyl) amino ] ethyl } phenyl) methanesulfonamide;

n- (2-hydroxy-5- { (1R) -1-hydroxy-2- [ (2- {3- [2- (5-hydroxy-3, 4-dihydroisoquinolin-2 (1H) -yl) -2-oxoethyl ] phenyl } -1, 1-dimethylethyl) amino ] ethyl } phenyl) methanesulfonamide;

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

2- (3- {2- [ ((2R) -2-hydroxy-2- { 4-hydroxy-3- [ (methylsulfonyl) amino ] phenyl } ethyl) amino ] -2-methylpropyl } phenyl) -N- [ (1S) -2-hydroxy-1-phenylethyl ] acetamide;

n- [ (3' -hydroxybiphenyl-4-yl) methyl ] -2- (3- {2- [ ((2R) -2-hydroxy-2- { 4-hydroxy-3- [ (methylsulfonyl) amino ] phenyl } ethyl) amino ] -2-methylpropyl } phenyl) acetamide;

n- [ (2' -hydroxybiphenyl-4-yl) methyl ] -2- (3- {2- [ ((2R) -2-hydroxy-2- { 4-hydroxy-3- [ (methylsulfonyl) amino ] phenyl } ethyl) amino ] -2-methylpropyl } phenyl) acetamide;

n- [ (4' -hydroxybiphenyl-4-yl) methyl ] -3- {2- [ ((2R) -2-hydroxy-2- { 4-hydroxy-3- [ (methylsulfonyl) amino ] phenyl } ethyl) amino ] -2-methylpropyl } benzamide;

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

n- [ (4' -hydroxybiphenyl-3-yl) methyl ] -3- {2- [ ((2R) -2-hydroxy-2- { 4-hydroxy-3- [ (methylsulfonyl) amino ] phenyl } ethyl) amino ] -2-methylpropyl } benzamide;

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

n- [2- (4-hydroxy-2, 3-dimethylphenyl) ethyl ] -3- {2- [ ((2R) -2-hydroxy-2- { 4-hydroxy-3- [ (methylsulfonyl) amino ] phenyl } ethyl) amino ] -2-methylpropyl } benzamide; and the combination of (a) and (b),

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

N- [ (4' -hydroxybiphenyl-4-yl) methyl ] -2- (3- {2- [ ((2R) -2-hydroxy-2- { 4-hydroxy-3- [ (methylsulfonyl) amino ] phenyl } ethyl) amino ] -2-methylpropyl } phenyl) acetamide.

N- [ (4' -hydroxybiphenyl-3-yl) methyl ] -2- (3- {2- [ ((2R) -2-hydroxy ] -2- { 4-hydroxy-3- [ (methylsulfonyl) amino ] phenyl } ethyl) amino ] -2-methylpropyl } phenyl) acetamide.

2- (3- {2- [ ((2R) -2-hydroxy-2- { 4-hydroxy-3- [ (methylsulfonyl) amino ] phenyl } ethyl) amino ] -2-methylpropyl } phenyl) -N- [2- (4-hydroxyphenyl) -2-methylpropyl ] acetamide.

N- [ (3' -hydroxybiphenyl-3-yl) methyl ] -2- (3- {2- [ ((2R) -2-hydroxy-2- { 4-hydroxy-3- [ (methylsulfonyl) amino ] phenyl } ethyl) amino ] -2-methylpropyl } phenyl) acetamide.

N- (3, 5-dichloro-2-hydroxybenzyl) -N-ethyl-2- (3- {2- [ ((2R) -2-hydroxy-2- { 4-hydroxy-3- [ (methylsulfonyl) amino ] phenyl } ethyl) amino ] -2-methylpropyl } phenyl) acetamide.

21. A pharmaceutical composition comprising a compound of formula (1) according to any one of claims 1 to 5, or a pharmaceutically acceptable salt or solvate thereof, together with usual pharmaceutically harmless excipients and/or additives.

22. Use of a compound of formula (1) as defined in any one of claims 1 to 20, or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a medicament having β 2 agonist activity.

23. Use of a compound of formula (1) as defined in any one of claims 1 to 20, or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a medicament for the treatment of a disease, condition or physical discomfort selected from: asthma, chronic or acute bronchoconstriction, chronic bronchitis, small airway obstruction, emphysema, obstructive or inflammatory airway disease, bronchitis, acute lung injury and bronchiectasis.

24. The use of claim 23, wherein the disease, condition or disorder is selected from the group consisting of: allergic asthma, non-allergic asthma, allergic bronchial IgE-mediated asthma, bronchial asthma, idiopathic asthma, genuine asthma, intrinsic asthma caused by pathophysiological disorders, extrinsic asthma caused by environmental factors, idiopathic asthma of unknown or unobvious cause, non-allergic emphysema, bronchitis asthma, emphysema, exercise-induced asthma, allergen-induced asthma, cold air-induced asthma, occupational asthma, infectious asthma caused by bacterial, fungal, protozoal or viral infection, non-allergic asthma, incipient asthma, asthmatic acoustic infant syndrome, bronchiolitis, chronic eosinophilic pneumonia, Chronic Obstructive Pulmonary Disease (COPD), airways including chronic bronchitis, emphysema or dyspnea associated with or not associated with COPD, COPD characterized by irreversible progressive obstruction, COPD, Adult Respiratory Distress Syndrome (ARDS), exacerbation of airway hyperactivity following other drug therapy, airway diseases associated with pulmonary hypertension, acute bronchitis, acute laryngotracheobronchitis, arachidic bronchitis, catarrhal bronchitis, gluteal bronchitis, dry bronchitis, infectious asthmatic bronchitis, proliferative bronchitis, staphylococcal or streptococcal bronchitis, alveolar bronchitis, cylindrical bronchiectasis, cystic bronchiectasis, fusiform bronchiectasis, cystic bronchiectasis, dry bronchiectasis, and follicular bronchiectasis.

25. A process for the preparation of a compound of formula (1) as defined in any one of claims 1 to 20, comprising the steps of:

(a) reacting an acid of formula (2):

wherein R1, R2 and n are as defined in claim 1,

and a formula NR⁸-Q²-A(3)

In which R is³To R⁶，R⁸，Q²And A is as defined in claim 1,

(b) isolating the compound of formula (1).

26. A process for the preparation of a compound of formula (1) as claimed in claim 1, wherein R is¹And R²Is methyl and n is 1, comprising the following steps:

(a) reacting a compound of formula (21) in a suitable solvent in the presence of a conventional coupling agent, optionally in the presence of an organic base and additives

Where X is H, K, Na, Li and possibly an organic amine base or other metal salt, with the formula NHR⁸-Q²-A(3)，

To obtain said compound of formula (1);

(b) isolating the compound of formula (1).

27. The method of claim 26, wherein the compound of formula (21) is prepared by reacting a compound of formula (22),

wherein X is H, Na, Li or K and possibly an organic amine or other metal salt, in a suitable solvent and in the presence of a suitable catalyst.

28. The method of claim 27, wherein the compound of formula (22) is prepared by reacting a compound of formula (23)

With M-OH, wherein M is selected from Na, Li or K, optionally in the presence of a suitable solvent.

29. A process according to claim 28, wherein said compound of formula (23) is obtained by deprotecting a compound of formula (24) using a deprotecting agent in the presence of a suitable solvent.

30. The process of claim 29, wherein the compound of formula (24) is prepared by reacting a compound of formula (la) in the presence of a suitable solvent, and optionally in the presence of a base, at a temperature between 50 ℃ and 150 ℃

With a compound of the formula

Reacting for 12 to 36 hours.

31. A combination of a compound according to any one of claims 1 to 20 and a further therapeutic agent selected from:

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

(b) leukotriene antagonists (LTRAs),

(c) a histamine receptor antagonist which is selected from the group consisting of,

(d) alpha 1-and alpha 2-adrenoceptor agonists for decongestant use vasoconstrictor sympathomimetics,

(e) muscarinic M3 receptor antagonists or anticholinergic agents,

(f) a PDE inhibitor which is capable of inhibiting the activity of a compound,

(g) the content of the theophylline is determined,

(h) the content of the sodium cromoglycate is as follows,

(i) a COX inhibitor is used in the treatment of,

(j) the oral administration and inhalation of glucocorticoids,

(k) a monoclonal antibody directed against an endogenous inflammatory entity,

(l) Anti-tumor necrosis factor (anti-TNF-alpha) agents,

(m) an inhibitor of an adhesion molecule,

(n) kinin-B₁-and B₂-an antagonist of a receptor,

(o) an immunosuppressive agent, wherein,

(p) inhibitors of Matrix Metalloproteinases (MMPs),

(q) tachykinin NK₁、NK₂And NK₃(ii) an antagonist of a receptor,

(r) an inhibitor of an elastase,

(s) adenosine A2a receptor agonists,

(t) an inhibitor of urokinase,

(u) compounds which act on dopamine receptors,

(v) modulators of the NF kappa beta pathway,

(w) modulators of cytokine signaling pathways,

(x) Agents that can be classified as mucolytic or antitussive, and

(y) an antibiotic.