TW200533351A - Compounds for the treatment of diseases - Google Patents

Abstract

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

Description

200533351 (1) IX. Description of the invention [Technical field to which the invention belongs]

The present invention relates to a yS 2 agonist of the general formula (1):

Among them, R, R, n, and Q have meanings that are not described below, and a method for preparing these derivatives, a composition including these derivatives, and uses of these derivatives. [Prior art] Adrenaline receptors are members of a large family of G-protein coupled receptors. The adrenergic receptor subfamily itself is further subdivided into the ^ and ^ subfamilies, where the Θ-subfamily includes at least three receptor subtypes: ySl, / S2, and yS3. These receptors exhibit different phenotypes in the tissues and organs of mammals. The / 3 2 adrenergic (/ 3 2) receptor is mainly expressed in smooth muscle cells (eg, smooth muscle such as blood vessels, bronchial tubes, urethra, or small intestine), while the point 3 adrenergic receptor is mainly expressed in adipose tissue ( So / 3 agonists are potentially useful for treating obesity and diabetes) and / 3 1 adrenergic receptors are mainly expressed in cardiac tissue (so / 5 agonists are mainly used as cardiac stimulants). The pathology and treatment of respiratory diseases have been extensively reviewed in the literature (see, for example, Barnes, PJ Chest, 1 997, 1] 1: 2 pp 178- 26 8 and Bryan, SA et al., Expert Opinion on (2 ) (2) 200533351 investigational drugs, 2000, 9 · 1? Pp 25-42) Therefore, only a brief description is provided here to provide some background information. Glucocorticoids, anti-white-three-flame, tea test, Crom ones, anticholinergics, and Θ 2 agonists constitute current treatments for allergic and non-allergic respiratory diseases such as asthma and chronic obstructive respiratory disease (CPD) Type of drug used. Treatment programmes for these diseases include short-term and long-term acting inhaled Θ 2 agonists. A short-acting, fast-starting Stone 2 agonist is used to `` rescue 〃 bronchiectasis, while a long-acting form provides continuous relief and is used for maintenance treatments. Bronchiectasis is mediated by the agonist mechanism of the 0 2 adrenergic receptor expressed on airway smooth muscle cells, resulting in relaxation and bronchiectasis. Therefore, as a functional antagonist, Θ 2 agonists can block and reverse all bronchoconstrictive substances, including leukotriene D4 (LTD4), acetylcholine, angiotensin, prostaglandin, histamine, and endothelin. Effect. Because the / 3 2 receptor is so widely distributed in the respiratory tract, cold 2 agonists may also affect other cell types that have a role in asthma. For example, it has been reported that 02 agonists may stabilize mast cells. Inhibition of the release of bronchoconstrictive substances may be the reason why 2 agonists block bronchoconstriction induced by allergens, movement and cold air. In addition, $ 2 agonists inhibit cholinergic neurotransmission in the human respiratory tract, which may lead to reduced cholinergic reflex bronchoconstriction. In addition to the respiratory tract, it is also determined that Θ 2 adrenergic receptors will also be expressed in other organs and tissues. Therefore Θ 2 agonists, such as those described in the present invention, can be used for the treatment of other diseases, such as Limited to Nerve-6- (3) 200533351 system, premature birth, congestive heart failure, depression, inflammatory and allergic skin Peptic ulcer. However, there are multiple / 3 2 agonists that may be adversely affected by their low selection rate or driven by high systemic exposure and are mainly caused by mediators acting on the point 2 adrenergic receptors acting outside the respiratory tract ( Muscle tremor, tachycardia, palpitations, restlessness) limit their usefulness. # Therefore, for those who have the appropriate pharmaceutical form, such as in terms of potency, selectivity, pharmacokinetics, or duration of action, novel agonists still need to exist. [Summary of the Invention] The present invention relates to compounds of the general formula (1):

OH

'ΧΎν (〇Η2) ηχ Q1

R1 R2 ⑴ ch2oh ο where (CH2) n — c (= ο) Qi group is in meta or para position, —R! And R2 are independently selected from Η and C] —C4 alkyl; —η is 0, 1 Or 2; --Q1 is selected from ^ 4 200533351

And * — NR8— Q2 — A or * — NR8— Q3 groups, where —p is 1 or 2 and q is 1 or 2; —Q2 is a single bond or C with an OH substituent as appropriate! —C4 alkyl; —R8 is fluorene or C! —C4 alkyl; —Q3 is a C! Alkyl group containing NR9R1 (), OR9 or phenoxy substituent as appropriate, —A is selected from:. C3-C1G cycloalkyl, which is optionally bridged with one or more, preferably 1, 2, 3 or 4 carbon atoms, and optionally contains a hydroxy substituent. A 5- to 6-membered heterocyclic group, optionally aromatic, containing 1 or 2 heteroatoms from 0, N.S, and optionally 1 or 2 selected from C! -C4 alkyl, benzyl And cyclopropylmethyl substituents or R3 R4

, D quinolinyl or iso-8- (5) (5) 200533351 quinolinyl;-R3, R4, V, 1 ^ and r7 are the same or different and are selected from H, c!-C4 alkane OH9, SR9, SOR9, S02R9, halo, CN, CF3, OCF3, S02NR9R10, COOR9, CONR9R10, NR9R10, NHCOR] () and optionally phenyl with OH substituents; -R9 and R1 () Is the same or different and is selected from Η or (^ 一 (: 4alkyl) -R11 is selected from Η or ΟΗ, and -R12 and R13 are the same or different and are selected from Η ; As the case may be C-C4 alkyl group containing a substituent of OR9; C (= 〇) NH2; C (= 0) CH3, N (CH3) C (O) CH3; C (= 〇) 〇R9; as appropriate A phenyl group containing a halogen substituent; a pyridyl group containing a CN substituent, as appropriate; and a π-substituted group containing a C] —C 4 radical; and a * table for a carbonyl contact; or 'if appropriate 'They are pharmaceutically acceptable salts and / or isomers, tautomers, solvates or isotopic variants. Compounds of formula (1) are agonists of the yS 2 receptor, and can be shown in particular by 'Excellent efficacy', especially when administered by inhalation In the treatment of 2-mediated diseases and / or symptoms. Herein in the above general formula (1), C] -C 4 alkyl and c] -C 4 alkyl groups contain 1, 2, 3 or 4 carbons. A straight or branched group of atoms. Ci—C6 alkyl groups are straight or branched groups containing 1, 2, 3, 4, 5, or 6 carbon atoms. This also applies to those groups that carry substituents or serve as other radicals When it is a substituent, for example, 0- (C) -C4) alkyl radical, s- (C] -C4) alkyl radical, etc., suitable for -9- (6) (6) 200533351 When (C1- C4) Examples of alkyl radicals are methyl, ethyl, n-propyl'isopropyl, n-butyl, isobutyl, second butyl, third butyl, etc .. Suitable 0— (Cl—C4) Examples of alkyl radicals are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, second butoxy and third butoxy ... of which 2 C3-C1G cycloalkyl groups optionally having one or more carbon atoms bridged with one or more carbon atoms include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl , Bicyclic [3 · 1 · 1] heptane, bicyclic [2 · 2 · 1] heptane, bicyclic [2 · 2 · 2] Xin Yuan. The preferred cyclohexyl radicals are cyclohexyl and adamantyl. '' Contains 1 or 2 heteroatoms selected from 0, N or S, as appropriate, 5 or 6 members Non-limiting examples of heterocyclylfluorene are morpholinyl, pyrrolidinyl, piperidinyl, piperinyl, pyrazolyl, thienyl, furyl, imidazolyl, isothiazolyl, thiazolyl, isoxazolyl , Dfazolyl, pyridyl, and pyrimidinyl. Preferably, the heterocyclic group contains one nitrogen, two nitrogens, or one hydrogen and one oxygen atom. Preferred aromatic 5- to 6-membered heterocyclic groups are pyrazolyl and pyrido. Preferred non-aromatic 5- to 6-membered heterocyclic groups are morpholinyl, pyrrolidinyl, -D amidyl, and hydrazone. Finally, the halo group is selected from halogen atoms in the group consisting of fluoro, chloro, bromo and iodine, in particular fluoro or chloro. In the following, the free bond on the phenyl group is one of the following structures,

-10- (7) 200533351 means that the phenyl group may have a substituent at the meta or para position. Compound of formula (1)

Can be prepared using traditional procedures, such as the following exemplary methods

Unless otherwise stated, Q1, Q2, R1, R2, A, and η are all defined in the foregoing for the compound of formula (1). The amide derivative of formula (1) can be obtained by combining the acid of formula (2): 〇Η

ΗΟ 〜N F ch2oh ο

And other amine coupling made. The coupling is usually carried out in excess of the amine as an acid acceptor, using a conventional coupling agent (for example, 1- (3-dimethylaminopropyl)-3-1 (1) 200533351 monoethyl Carbodiimide hydrochloride or N, N / -dicyclohexylcarbodiimide), as appropriate in the presence of a catalyst (eg, 1-hydroxybenzotriti hydrate or 7-hydroxy-7-nitrogen Heterobenzotriazole), and optionally in the presence of a third amine base (eg, N-methylmorpholine, triethylamine, or diisopropylethylamine). The reaction can be carried out in a suitable solvent such as pyridine, N, N-dimethylformamide, tetrahydrofuran, dimethylasyl, dichloromethane or ethyl acetate, and include temperatures between 10 ° C and 4 (TC (Room temperature) for a period of 1 to 24 hours. The amines may be commercially available or may be made from commercially available materials using conventional methods well known to those skilled in the art (for example, by reduction, oxidation, alkylation, Transition metal media coupling, protection, deprotection, etc ...).

The acid of formula (2) can be obtained from the corresponding formula < OH

4) Esters are made of: (4) (CH2) 〇Ra τ 〇_ where Ra is a suitable acid protecting group, preferably (C) -c4) alkyl, including, but not limited to, methyl and ethyl Which can be prepared without changing the rest of the molecule according to any method known to those skilled in the art * for preparing acids from esters. For example, it may be treated with an acid or alkaline aqueous solution (eg, hydrogen chloride, potassium hydroxide, sodium hydroxide, or lithium hydroxide), and optionally a solvent or a solvent mixture (eg, water, 1,4-dioxane, tetrahydrofuran). / Water), the vinegar is hydrolyzed for a period of 1 to 72 hours at a temperature comprised between 20 ° C and 100 ° C. Ester of formula (4) can be via amine of formula (5):-12- (9) 200533351

R1 R2 (CH2) 〇Ra

Where Ra and n are as defined above; reacted with the epoxide of formula (6) to obtain:

CH2〇H In a typical procedure, the amine of formula (5) is optionally in the presence of a solvent or a solvent mixture (such as dimethyl arylene, toluene, N, N-dimethylformamide, acetonitrile), and Reacts with an epoxide of formula (6) in the presence of a suitable base (eg, triethylamine, diisopropylethylamine, potassium carbonate) at a temperature between 80 ° C and 1 2 (TC) 丨2 to 48 hours. Epoxides of formula (6) can be prepared according to those disclosed in US-4031108. Φ In the case of amines of formula (5), where R1 is Me and R2 is R, the Preparation of (R) or (S) mirror isomers by amines of formula (7):

Where Ra and η are both as defined above and "and any suitable substituents in the Rc table make NHRbRc a one-handed minor amine (eg, Rb may be hydrogen and Rc may be α-methylmethyl)", but its restrictions For the bond between N and Rb and between N and RC, the method of cutting off the nitrogen protecting group can be used, for example, in reference book ', -13- (10) 200533351

Protective Groups in Organic Synthesis " Third Edition by T. W. Greene and P. G. M. Wuts, John Wiley and Sons Inc., 1 999, can easily be cut into free (5) amines. An amine of formula (7) can be prepared as a single non-mirromeric isomer by reacting an amine of formula HNRbRc with a ketone of formula (8):

Among them, Ra, Rb, Rc and η are those defined above. In a typical procedure, the reaction of a ketone of formula (8) with an amine of formula HNRbRc results in a handful of intermediates which can be converted to a suitable reducing agent such as sodium cyanoborohydride of formula NaCNBH3, Acetyloxyborohydride), if necessary, is reduced in the presence of a desiccant (for example, molecular sieve., Magnesium sulfate) and optionally in the presence of an acid catalyst (for example, acetic acid) to obtain a formula (as a non-image isomer mixture) 7) Amine. The reaction is usually carried out in a solvent such as tetrahydrofuran or dichloromethane at a temperature between 20 ° C and 80 ° C for 3 to 72 hours. The resulting product is then converted into the hydrochloride salt and selectively crystallized from a suitable solvent-solvent mixture (eg, isopropanol, ethanol, methyl ether, isopropyl • ether, or isopropyl ether / methanol) to give a single non- Mirror image difference ▲ One of the structures (7). The ketone of formula (8) at ηdi1 can be made via the palladium medium coupling of an aryl halide of formula (9) with an enolate or an enol equivalent:

〇 Where Ra is as defined above and Hal represents a halogen atom, which includes, but is not limited to, -14- (11) (11) 200533351 is limited to bromine and iodine. In a typical procedure, an aryl halide of formula (9) and tin enolate produced in situ by treating isopropenyl acetate with tri-n-butyltin methoxide of formula BwSnOMe are in a suitable palladium catalyst ( In the presence of palladium acetate / tri-o-tolylphosphine of the formula Pd (OAc) 2./P(〇-Tol) 3, it is reacted in a non-polar solvent (such as toluene, benzene, hexane). Preferably, the reaction is performed at a temperature between 80 ° C and 110 ° C for 6 to 16 hours. The aryl halide of formula (9) can be obtained by acidifying the corresponding formula (10): X > yoh (10), where Hal is the former definition; wherein, it is based on the well-known from those skilled in the art. Any method of making esters from acids is performed without modifying the rest of the molecule. In a typical procedure, an acidic solvent of formula (10) and an alcoholic solvent of formula RaOH, where Ra is as defined above, and a temperature (room temperature between 10 ° C and 40 ° C in the presence of an acid such as hydrogen chloride) ) For 8 to 16 hours. Formula (100) acids are commercial products. The amine of formula (5), in the case where R 1 and R 2 are both C! -C4 alkyl, can be prepared according to the following reaction procedure: -15- (12) 200533351 Reaction procedure 1

(5) where R1, R2 and Ra are all defined above. φ In a typical procedure, an ester of formula (1 1) is reacted with an activated fluorenyl alkyl group (organometallic alkyl group such as R2MgBr, R2MgCl, or R2Li) using the above method to obtain a corresponding third alcohol of formula (1 2). . The third alcohol of formula (12) is then treated with an alkyl nitrile (e.g. acetonitrile, chloroacetonitrile) in the presence of an acid (e.g. sulfuric acid, acetic acid) to obtain a protected intermediate, which is in turn used to cut off the nitrogen protecting group Standard methods such as those mentioned in textbooks are cut off. The resulting amines are then acidified using the methods described herein to give amines of formula (5). Alternatively, the amine of formula (5) in the case where R 1 and R 2 are both c 1-c 4 alkyl and η = 0 can be prepared according to the following reaction procedure: -16- (13) 200533351 Reaction procedure 2

• Br

Wherein R1, R2 and Ra are defined as above. In a typical procedure, an ester of formula (1 3) is reacted with an `` activated amidinyl group (organometallic alkyl group such as R2MgBr, R2MgCl or R2Li) using the above method to obtain the corresponding triol such as formula (1 4). . The triol of formula (1 4) is then treated with an alkyl nitrile (such as acetonitrile, chloroacetonitrile) in the presence of an acid (such as sulfuric acid, acetic acid) to obtain a protected intermediate, which is in turn used to cut off the nitrogen protecting group. The standard method is, for example, cutting off under those mentioned in the textbook to obtain bromoamine (1 5). Use a suitable palladium catalyst (eg [1, 1/1 bis (diphenylphosphino) ferrocene] dichloropalladium (II)) and use RaO Η as a solvent (eg MeOH, EtOH) under high temperature (l 〇 ° C) and pressure (100 p si) treatment of the obtained bromoamine (15) to obtain an ester of formula (5). The ketone of ndi2 in formula (8) can be prepared by reducing the ene of formula (16) Get

(16) In a typical procedure, a palladium catalyst is used (for example, 10% Pd / -17- (14) (14) 200533351 c) 'Under the hydrogen environment, if necessary, a high pressure (such as 60 P si), A solution of an olefin of formula (6) in a suitable solvent (such as methanol, ethanol, ethyl acetate) at a temperature between room temperature and 60 ° C. The olefin of formula (1 6) can be prepared by the coupling of an activated olefin with the jiuba mediator of the aryl halide of formula (丨 7):

In a typical procedure, an aryl halide (17) and a vinyl ester (such as methyl acrylate) are reacted on a suitable palladium catalyst (such as the formula Pd (PPh3) 4 tetrakis (triphenylphosphine) palladium ( ), In the presence of palladium acetate / tri-o-tolylphosphine of formula Pd (OAc) 2 / P (o-tol) 3 or (diphenylphosphino) ferrocene palladium chloride of formula dppfPdCl2) in a suitable solvent (Such as acetonitrile, N, N-dimethylformamide, toluene), if necessary in the presence of a base such as triethylamine, 'coupled at a temperature between 40 ° C and 1 10 ° C 8 to 2 4 hour. (17) _ is a commodity. Alternatively, a compound of formula (1) can be prepared by reacting a bromide of formula (6) with an amine of formula (] 8):

Wherein R], R2, and n are the same as those defined for the compound of formula (1), unless otherwise stated.

In a typical procedure, the amine of formula (18) and the bromide of formula (6) are optionally in a solvent or a solvent mixture (such as dimethylformamide, toluene, N, N -18- (15) 200533351 ~ dimethylformate Methylformamide, acetonitrile), if necessary, at a suitable base (eg, triethylamine, diisopropylethylamine, potassium phosphate) at a temperature between 80 ° C and 120 ° C 1 2 to 48 hours. Formula (18) can be obtained via an acid of formula (19) incorporating an appropriate amine protecting group P1:

〇 Coupling with amines of formula NHR8 — Q2 — A and NHR8 — Q3 to prepare:

The coupling is usually in the presence of an excess of the amine as an acid acceptor, using a conventional coupling agent (eg, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride Or N, -dicyclohexylcarbodiimide), optionally a catalyst (eg, 1-hydroxybenzotriazole hydrate or 1-hydroxy-7-azabenzotriazole), and optionally a third This is done in the presence of an amine base such as N-methylmorpholine, triethylamine or diisopropylethylamine. The reaction can be carried out in a suitable solvent such as pyridine, dimethylformamide, tetrahydrofuran, dimethylasyl, dichloromethane or ethyl acetate, and between 10-19- (16) 200533351 C and 40. At a temperature between C (room temperature) for a period of} — 2 4 hours. The amine is commercially available or commercially available materials can be used in conventional methods well known to those skilled in the art (eg, reduction, oxidation, alkylation, transition metal-media couple σ, δ 蒦, deprotection, etc ... ..) be prepared. Acids of formula (19) can be prepared from the corresponding esters of formula (5). Acids in which R1 and R2 are both d-c4 alkyl groups in formula (19) can be prepared from the ester (5) added with an appropriate amine protecting group p i before or after the acid formation:

(5) (CH2) n ^ 〇Ra

T 〇 where Ra is a suitable acid protecting group, preferably (Cl — c4) alkyl, which includes, but is not limited to, methyl and ethyl; among them, the acid is prepared from an ester by the well known to those skilled in the art Without changing any method of the rest of the molecule. For example, an acid or alkaline aqueous solution (eg, hydrogen chloride, potassium hydroxide, sodium hydroxide, or lithium hydride) can be used, optionally a solvent or a solvent mixture (eg, water, 1 ^ 4 dioxane, tetrahydrofuran / water ) In the presence, the ester is hydrolyzed for a period of 1 to 40 hours at a temperature between 20 ° C and 100 ° C. An amine of formula (7) in the case where both R 1 and R 2 are A 'can be prepared according to the following reaction procedure: -20-(17) 200533351 Reaction procedure 3

X (CH2) n 〇Ra (21) ~ (CH2) n 〇Ra fork

Among them, R1, R2, and Ra are all defined in the foregoing. In a typical procedure 'is the first reduction of the acid of formula (M) to the corresponding alcohol (2 1) in the presence of an ester. This reaction can be carried out by forming fluorenimidazole or mixed anhydride 'and then reducing it with sodium borohydride or any suitable reducing agent.

The first alcohol of formula (2 1) is then converted and left off, such as methanesulfonate, tosylate, bromide or iodide, and replaced with an appropriate amine nucleophile. A preferred nucleophile is an azide ion, which is then reduced to the first amine via hydrogenation or with diphenylphosphine. Alternative nucleophiles may include ammonia or aminylamines such as benzylamine or allylamine, and the alkyl group is then cut off to form the amine. For some of the steps included in the above method of preparing the compound of formula (1), it may be necessary to protect a potentially reactive functional group that is not desired to be reacted, and the protective group may be cleaved later. In this case, any compatibility protecting group can be used. In particular, τ · W. Greene and PGM Wuts (Protective Groups in Organic Synthesis, John Wiley and Sons inc ·, 1 9 9 9) or P · J. K ocienski (Protective gro iip s, G eo rg Thieme V e rl ag, 1 9 9 4), and protection -21-(18) 200533351 and amine protection method. All of the above reactions and preparations of the novel starting materials used in the aforementioned methods are customary and the appropriate reagents and reaction conditions for their implementation or preparation, as well as the procedures used to isolate the desired products, can be referred by those skilled in the art The literature precedents and the examples and preparation examples herein are well known. In addition, the compound of the formula (1) and the intermediate used for its preparation can be purified according to various well-known methods such as crystallization or chromatography.

In a preferred embodiment of the present invention, Q2 is a single bond. In a preferred embodiment of the present invention, A is selected from the group consisting of morpholinyl, pyrrolyl, piperidinyl, piperidinyl, or pyrazolyl, and these groups optionally contain a methyl substituent. In a preferred embodiment of the present invention, A is selected from pyrazolyl containing one or two C] -c4 alkyl substituents as appropriate. In a preferred embodiment of the present invention, Q1 is *-NR8-Q3.

In a preferred embodiment of the present invention, Q 1 is a base selected from the following:

-22- (19) 200533351 its Φ (ch2). A c (= 〇) Q group is in meta or para position-R1 and R2 are independently selected from Cl-C4: 1: complete group;

And *-nr 'A, where p is 1 or 2, one (52 is C! — C4 extension

Q Yuanji, R8 is Η or Ci — C4 Yuanji and A is Houyiji; C 3 C]. Cycloalkyl, the ring base is bridged with 1, 2, 3, or 4 carbon atoms as needed. Tetrahydrofluoranyl, piperidinyl, tetrahydrothiopiperanyl, or the following radicals

R5

—R3, R4, R5, R6 and R7 are the same or different and are selected from the group consisting of: H, C] -C4 alkyl, OR9, SR9, SOR9, S02R9, halo, CN, CF3, 〇 CF3, S02NR9R10, COOR9, CONR9R10, NR9RIG, NHCOR1 () and optionally a phenyl group containing an OH substituent;-R9 and R1 () are the same or different and are selected from}! Or C!-C4 alkyl and -A table of carbonyl contacts; or, where appropriate, their pharmaceutically acceptable salts and / or isomers, tautomers, solvates, or isotopic variations. The compounds of the formula (1) containing the following substitutions are all preferred: -23- (20) 200533351 Preferably, Q1 is a * -NH-Q2-A group, where A is cyclohexyl or adamantyl. Preferably, Q 1 is the following

R3, R4, R5, and R6 are all Η.

Preferably, Q1 is * —NH— Q2 — Α group, where A is a group of the formula

Where R3, R4, r5, ruler 6 and R7 are the same or different and are selected from the group consisting of h, Cl-C4 alkyl, OR9, SR9, SOR9, S02R9, halo, CF3, OCF3, S02NR9R] G, CONR9RiG, NR9R] G, NHCOR] 0 and phenyl, but

The restriction is that at least two of R3 to R7 are equal to Η; wherein R9 and RI () are the same or different and are selected from C] -C4 alkyl. More preferably, Q1 is a * —NH— Q2 — A group, where A is a group of the formula

Wherein R3, R4, R5, R6 and R7 are the same or different and are selected from the group consisting of Η, OH, oh3, och2-ch3, sch3, halo, preferably Cl or F, cf3,

However, the restriction is that at least two of R3 to R7 are equal to H -24- (21) 200533351. Among the above compound groups, the following substituents are particularly preferred: Q2 is —CH2—, — (C Η 2 ) 2—, one (C Η 2) 3—, or body, — (CH3) 2—, preferably —CH2. R] is 11 or (: 1-C4 alkyl and R2 is < ^-1 (: 4 alkyl. More preferably, Ri is η or CH3 and R2 is CH3. Η is 1. R1 is Η and R2 is CH3 And η is 1. • R] is CH3, R2 is CH3, and η is 1. The following compounds that can be prepared according to the methods disclosed herein are all preferred: N —benzyl—2— {3-[2— ( {2-Hydroxy-2- [5-Hydroxy-6- (hydroxymethyl) pyridine-2-yl] ethyl 丨 amino) -2-methylpropyl] phenyl} acetamide; Ν-cyclopropyl -2— 丨 3-[2-({2-Hydroxy-2- [5 —Hydroxy-1— (hydroxymethyl) pyridine-2-yl] ethyl 丨 amino)-2 # -methylpropyl ] Phenyl 丨 acetamidine; 2-{3-[2-— ({2-hydroxyfluoren-2- (5-hydroxy-6- (hydroxymethyl) pyridin-2-yl] ethyl} amino)- 2-methylpropyl] phenyl} —N— [(1R, 2S) — 2— (hydroxymethyl) cyclohexyl] acetamide; 2-{3— [2— ({2 —hydroxyl 2— [5-Hydroxy-6- (Ethylmethyl) pyridine-2-yl] Ethyl 丨 Amino) -2-Methylpropyl] phenyl 丨 —N — (3- Phenyl-4-methylpropylacetamidine; 2-{3— [2-({2-Hydroxy-2-[5-Hydroxy-6- (-25- (22) (22) 200533351 hydroxymethyl) Pyridinyl-2-yl] ethyl 丨 amino) -2-methylpropyl] phenyl} — N — (pyridin-2-ylmethyl) acetamidamine; 2 — {3— [2 — ({2 1-Cycloyl 2- [5-Cycloyl-6- (Hydroxymethyl) pyridine- 2 -yl] ethyl} amino) -2-methylpropyl] phenyl} —N- (2-morpholine 4-4-ylethyl) acetamidamine; 2 — {3 1 [2— ({2-Cyclo-2— [5 -Cyclo-6— (hydroxymethyl) pyridine—2-yl] ethyl} Amine)-2 -methylpropyl] phenyl-N-isopropylacetamidamine; N-(4-chlorobenzyl) -2-2- {3— [2— ({2 — 经 基 —2 — [5-hydroxy-6- (hydroxymethyl) pyridine-2-yl] ethyl 丨 amino) -2-methylpropyl] phenyl} ethylamine; N— [2- (dimethylamino) Ethyl] 2-{3-[2-({2 -Hydroxy-2-[5 -Hydroxy-6-(hydroxymethyl) pyridine-2 -yl] ethyl} amino)-2 -methyl Propyl] phenyl 丨 ammonium amine; N — [2 — (diethylamino) ethyl] — 2 — {3 — [2 — ({2 —hydroxyl 2 — [5 —hydroxyl 6 — (hydroxyl (Methyl) pyridine- 2-yl] ethyl} amino) -2-methylpropyl] phenyl} acetamidamine; N- [3- (dimethylamino) propyl] -2—3- [2— {2--Cyclo-2— [5—Cyclo-6- (Cyclomethyl) D is more than B-Cycloyl] ethyl} amino) —2-methylpropyl] phenyl丨 Acetylamine; 2- 丨 3-[2— ({2-Cytoxy-2— [5 —Cyclo-6- (hydroxymethyl) pyridine-2-yl] ethyl 丨 amino)-2- Methylpropyl] phenyl 丨 N-pentylacetamide; 2 — {3 — [2 — ({2 —Ethyl 2 — [5 — _Amidyl 6 — (-26- (23) 200533351 hydroxymethyl) pyridine- 2-yl] ethyl} amino) -2-methylpropyl] phenyl) -N- (2-pyrrolidin-1-ylethyl) -ethylamidine; N- (2,4 —dichlorobenzyl) —2— {3— [2— ({2-Hydroxy-2— [5—Ethyl-6— (Ethylmethyl)]) Base} Amine group) 2-methylpropyl] phenyl} acetamidine; N— (3,4-dichlorobenzyl) —2— {3— [2— ({2 —hydroxyl 2 — [5 — Hydroxy-6- (hydroxymethyl) pyrimidin-2-yl] ethyl

} Amino} -2-methylpropyl] phenyl) acetamide; 2 {{3— [2 — ({2 aridyl-2— [5-aradyl-6— (hydroxymethyl) pyridine— 2-yl] ethyl} amino) -2-methylpropyl] phenyl} -N- (4-oxybenzyl) acetamidamine; N — (2 —Ethylethyl) — 2 — { 3-[2-({2-tauchi-2— [5-hydroxy-6- (hydroxymethyl) pyridine-2-yl] ethyl} amino) -2-methylpropyl] phenyl} ethyl Hydrazine; 2- {3— [2- ({2- laughter to 2--2- [5-meryl-6- (hydroxymethyl) pyridine- 2-yl] ethyl} amino)-2-methyl Propyl] phenyl} —N-propylacetamidamine; 2- {3-[2— ({2-hydroxy-2— [5-hydroxy-6— (hydroxymethyl) pyrimidin-2-yl ] Ethyl 丨 amino) -2-methylpropyl] phenyl} —N— (3-methoxypropyl) acetamide; N —cyclobutyl—2— {3— [2— ({ 2-hydroxy-2— [5-hydroxy-6- (hydroxymethyl) pyridine D-di-2-yl] ethyl} amino) -2 2-methylpropyl] phenyl 丨 acetamidine; 2— { 3 — [2 ({2 —Shoe base 2— [5 —Sheep to base 6— (-27- (24) (24) 200533351 hydroxymethyl) pyridine—2-yl] ethyl} amino) —2-methyl Propyl] phenyl} —N— [(1R) — 1— (1-naphthyl) ethyl} acetamidamine; N — 2,3 — —amino —1 Η — £ 卩 —1 —yl — 2 — {3 — [2 — ({2 —Cyclo-2— [5—Cyclo-6— (stilbyl to methyl)) 0 to [1N—2 —yl] ethyl} amino) —2—A Propyl] phenyl} acetamidamine; 2-{3— [2— ({2-hydroxy-2— [5-hydroxy-6— (hydroxymethyl) pyridine-2-yl] ethyl} amino} ) 2-methylpropyl] phenyl} — Ν — [2 — (1 -methylpyridin-2-yl) ethyl] acetamidamine; Ν — (4-dibenzyl) — 2 — {3 — [2— ({2-—Methoxy-2— [5-hydroxy-6- (hydroxymethyl) pyridine—2-yl] ethyl} amino) —2-methylpropyl] phenyl} ethyl alcohol Amine; 2-{3— [2— ({2-Hydroxy-2— [5-Hydroxy-6- (hydroxymethyl) pyridine- 2-yl] ethyl} amino) -2-methylpropyl] Phenyl} — Ν (4-Phenylbutyl) acetamide; 2- {3- [2— ({2-hydroxy-1-2- [5-hydroxy-6- (hydroxymethyl) pyridine-2-yl] ethyl} amine )-2 -methylpropyl] phenyl} -N- (3-methoxybenzyl) acetamide; Ν-(3-ethoxypropyl)-2-{3-[2-( {2-Hydroxy-2— [5-Hydroxy-6- (hydroxymethyl) pyridine-2-yl] ethyl} amino) -2-methylpropyl] phenyl} acetamidamine; 2— {3 — [2- ({2-Hydroxy-2— [5-Hydroxy-6- (hydroxymethyl) pyridine-2-yl] ethyl} amino) -2-methylpropyl] phenyl} —N— (3,4,5-dimethoxy dry group) acetamide; -28- (25) (25) 200533351 2— {3— [2— ({2-Ceryl-2— [5 —Ceryl-1 6-(hydroxymethyl) pyridine mono-2-yl] ethyl} amino) -2-methylpropyl] phenyl} —N— (4-mono (trifluoromethyl) benzyl] acetamidamine; 2 — {3— [2— ({2-Hydroxy-2— [5-Hydroxy-6- (hydroxymethyl) pyridine-2-yl] ethyl} amino) -2-methylpropyl] phenyl} —N— 2- (trifluoromethyl) benzylacetamidamine; N— (3,5-dimethoxybenzyl) —2— {3— [2— ({2 —Ceryl-2— [5—Ceryl A 6- (via methyl) D ratio n-a 2-yl] ethyl} amino)-2-methylpropyl] phenyl} acetamide; 2- {3— [2— ({ 2-hydroxy-2— [5-hydroxy-6— (hydroxymethyl) pyridine-2-yl] ethyl} amino) -2-methylpropyl] phenyl} —N— (2-phenoxy Ethyl) ethyl amine; 2- {3— [2— ({2-hydroxy-2— [5-hydroxy-6— (hydroxymethyl) pyridine-2-yl] ethyl} amino) —2— Methylpropyl] phenyl} — N — [(1 S) — 2 —Ethyl-1 monomethylethyl) acetamidine 2 — {3 — [2-({2 —hydroxyl 2 — [ 5-hydroxy-6- (hydroxymethyl) pyridine- 2-yl] ethyl} amino) -2-methylpropyl] phenyl} -N- [(1S) — 1- (hydroxymethyl)- 2-methylpropyl] acetamide; 2- {3— [2— ({2-hydroxy-2— [5-hydroxy-6- (hydroxymethyl) pyridine-2-yl] ethyl} amino ) A 2-A Propyl] phenyl} — N — [(1S, 2S) — 1 — (hydroxymethyl) 2-methylbutyl] acetamide; -29- (26) (26) 200533351 N [(1R ) — 1 —benzyl — 2 —hydroxyethyl) — 2 — {3— [2 — 2 —hydroxyl 2 — [5 —hydroxyl 6 — (hydroxymethyl) pyridine 2 -yl] ethyl} amine A) 2-methylpropyl] phenyl} acetamide; 2- {3 — [2 — ({2 —Cyclo-2— [5 —Cyclo-6— (hydroxymethyl) pyridine—2 —Yl] ethyl} amino) —2-methylpropyl] phenyl 丨 —N — [(1R) — 1 ((hydroxymethyl) propyl] acetamidamine, 2— {3— [2— ({2-Cyclo-2— [5—Cyclo-6— (hydroxymethyl) pyridine—2-yl] ethyl} amino) —2—methylpropyl] phenyl} — N— [ (1S) — 1- (hydroxymethyl) -2,2-dimethylpropyl] acetamide; N — [(1S) —2-cyclohexyl-1— (hydroxymethyl) ethyl] -2 — (3— [2— ({2 -Cycloyl-2— [5 —Cycloyl-6- (Cyclomethyl) pyridine—2-yl] ethyl 丨 amino) —2-methyl Propyl] phenyl} ethanamine; N — [(1 S 5 2 R) — 2 —invitation — 2 '3 — • chloro-1H —section —1 —yl] — 2 — {3- 〔2— ({2-Hydroxy-2— [5-Hydroxy-6- (hydroxymethyl) pyrimidine- 2-yl] ethyl 丨 amino)-2-methylpropyl] phenyl} acetamidine; 2— {3— [2— ({2-Hydroxy-2— [5-Hydroxy-6- (hydroxymethyl) pyridine-2-yl] ethyl} amino) -2-methylpropyl] phenyl}- N- (2-propoxyethyl) acetamide; N — (4-hydroxycyclohexyl) —2 — {3-[2 — ({2 —hydroxyl 2 — [5 —hydroxyl 6 — (hydroxyl (Methyl) pyridine- 2-yl] ethyl-30- (27) (27) 200533351} amino) -2-methylpropyl] phenyl} acetamidamine; 2— {3— [2— ({ 2-Hydroxy-2— [5-hydroxy-6- (hydroxymethyl) pyridine-2-yl] ethyl 丨 amino) -2-methylpropyl] phenyl} -N- (3-propoxy (Propyl) acetamide; N — ethyl — N —. (2 — via ethyl) — 2 — {3 — [2 — ({2 —hydroxyl 2 — [5 —hydroxyl 6 — (hydroxymethyl base Amidin-2-yl] ethyl} amino) -2-methylpropyl] phenyl 丨 acetamidamine; 1— ({3— [2— ({2 —hydroxy — 2 — [5 —hydroxy — 6 — (Aminomethyl) di-D-A 2 -yl] ethyl} amino)-2 -methylpropyl] phenyl} piperidine-4 -carboxamide; 6 — {2— [(2 — {3-[2- (4-Ethylsulfanyl piperazine- 1-yl)-2-ketoethyl] phenyl 丨 -1,1-dimethylethyl) amino] 1-hydroxyethyl Group 丨 2-(hydroxymethyl) D than pyridine-3-alcohol; 6-{2-[(2-{3-[2-(3,4-dihydroxyisoline-2 (1H)-group )-2-ketoethyl] phenyl} — 1,1 -dimethylethyl) amino] -1 -hydroxyethyl} -2-(hydroxymethyl) pyridin-3-ol; N-section —2— {3 — [2— ({2 —Cyclo-2— [5 —Cyclo-6— (hydroxymethyl) pyridine—2—yl] ethyl] amino) —2—methylpropane Phenyl] phenyl N-methylacetamide; 6 — {1—Ethyl — 2 — {[(2-{2 — [4 — (2 —Ethylethyl)) — # 1 — Base 2-ketoethyl} phenyl) -1 '1-dimethylethyl) amino] -1 2- (hydroxymethyl) pyridine-3-one; 6- {2 — {[2— (3— [2 -— (4 -— (4-chlorophenyl) —4—31— (28) (28) 200533351] Once the group is determined, the group is a single group) — 2-ketoethyl] phenyl) —1, 1-dimethylethyl) amino] -1,1-hydroxyethyl)-(hydroxymethyl) pyridine- 3-ol; 6- {2— {[1,1-dimethyl-2— {3— [2- (4-methylpiperidine-1, 1-yl)-2-ketoethyl] phenyl) ethyl) amino] -1, 1-hydroxyethyl]-2- (hydroxymethyl) pyridine-3 —Alcohol; 2— {3-[2— ({2-Hydroxy-2— [5-Hydroxy-6— (Cyclomethyl) -Hydroxy-2-yl] —Ethyl} Amine)) Propyl] phenyl} —N —methyl —N — (2-phenylethyl) acetamide; 6 — {2 — [1,1— — • methyl — 2— {3— [2 — Axyl-2-(4-pyridine-2 -ylpiperidine-1 -yl) ethyl] phenyl) amino] -1 -hydroxyethyl) -2-(hydroxymethyl) pyridine-3 — Alcohol; N — [3- (Dimethylamino) -propyl]-2— {3— ({2-Hydroxy-2— [5—Hydroxy-6- (hydroxymethyl) pyridine—2-yl] Ethyl} amino) -2-methylpropyl] phenyl 丨 N-methylacetamidamine; N— (2-—Ethylethyl) —2— {3— [2— ({2— 经A 2- [5-hydroxy-6- (hydroxymethyl) pyridin-2-yl] ethyl} amino group)-2-methylpropyl] phenyl 丨 N-propylpropylamine; N- [2— (diethylamino) ethyl] —2— {3— [2— ({2 —hydroxyl 2-(5 -hydroxyl 6-(hydroxymethyl) pyridine 2 -yl) -ethyl } Amino) -2-methylpropyl] phenyl} —N—methylacetamidin; 6— {2-{(1,1-dimethyl-2— {3— [2- (4 — Methyl-1,4-diazepine-1] 1-yl) -2-ketoethyl] phenyl) amine-32- (29) (29) 200533351 group] -1 1-hydroxyethyl) -1 2 — (Hydroxymethyl) pyridine 3-alcohol; 6 — [2 — ({1,1 — monomethyl 2 — [3 — (morphine 4 —yl — 2-ketoethyl] phenyl)) (Ethyl) amino)-1 -hydroxyethyl) -2-(hydroxymethyl) pyridine -3 -ol; 6-[2-({1,1-dimethyl-2-[3-(2- Morpholine 4-yl-2-ketoethyl] phenyl) ethyl} amino) -1-hydroxyethyl) -2- (hydroxymethyl) pyridine-3-ol; 2- {3— [ 2- ({2-Hydroxy-2— [5-Hydroxy-6- (hydroxymethyl) pyridine- 2-yl] ethyl} amino) -2-methylpropyl] phenyl} —N-methyl —N— [(IS) —1-Phenylethyl] acetamidamine, 6— [2— ({1,1, dimethyl-1—2— [3— (2-keto-2—piperidine —1 —ylethyl) phenyl] ethyl} amino) -1 1-hydroxyethyl) -2— (hydroxymethyl) pyridine-3—alcohol; 6— (1—meryl 2— {[2- (3— {2 -— ((3R) —3-hydroxypyrrole—1-yl) —2-ketoethyl—phenyl] —1,1—dimethylethyl) amino} ethyl) — 2 — (hydroxymethyl) pyridine-3 alcohol; 6 — (1 —Cyclo-2 — {[2 — (3 — {2 — [3 R) — 3 —hydroxypiperidine-1 Group) —2 —ketoethyl 丨 phenyl) —1,1 —dimethylethyl] amino group (ethyl) —2 — (hydroxymethyl) pyridine-3 —alcohol; 6 — {2- [ (2— {3— [2- (4-Ethylfluorenyl-1,4-diazepine-1, 1-yl) -2-ketoethyl] phenyl} 1,1,1-dimethylethyl ) Amine]-1 via ethyl ethyl 丨 2-(transmethyl methyl) D ratio than 3-alcohol; -33- (30) (30) 200533351 6-(1 -hydroxy-2-{〔 2- (3- (2- (4- (hydroxymethyl) piperidine-1-yl)-2-ketoethyl} phenyl) -1,1-dimethylethyl] amino} ethyl )-2-(hydroxymethyl) pyridine-3 -alcohol N— [1 ({3-—2- ({2-hydroxy-2— (5-hydroxy-6- (hydroxymethyl) pyridine 2-yl ] Ethyl} amino) -2 -methylpropyl] phenyl} ethylfluorenyl) pyrrolidine-3 -yl} -N -methylacetamidine; 2 1 {3 — [2 1 ({2 once 2- (5—Ethyl-6— (hydroxymethyl) pyridine—2-yl] ethyl} amino) —2-methylpropyl] phenyl} —N— (2-methoxyethyl base ) -N-propylacetamidamine; N-ethyl-2— {3— [2— ({2 —Cycloyl-2— (5-Cetyl-6— (hydroxymethyl)) — pyridine-2 —Yl] ethyl} amino) -2-methylpropyl] phenyl} ethenyl) —N— (2-methoxyethyl) acetamidine; N— [3 (dimethylamino) One 2,2-dimethylpropyl] one 2- {3- [2— ({2-meridyl-2— (5-meryl-6- (merylmethyl) pyridin-2-yl] ethyl [Amino group]-2-methylpropyl] phenyl} ethanamide; N— [3-fluoro-5— (trifluoromethyl) benzyl] —2— 丨 3— [2 — 2 —hydroxyl 2- (5-hydroxy-6- (hydroxymethyl) pyridine-2-yl] ethyl 丨 amino) -2-methylpropyl] phenyl} ethyl_amine; 2- {3-—2- ({2-Hydroxy-2- (5-hydroxy-6- (hydroxymethyl) pyridine- 2-yl] ethyl} amino) -2-methylpropyl] -34- (31) (31) 200533351 Phenyl} — N— [(IS) — 1- (methylidene) -3 -methylbutyl] acetamidine; 2 — {3— [2 — ({2 —phosphino-2-(5 -Chemotactic 6- (hydroxymethyl .) Pyridine-2-yl] ethyl} amino) -2-methylpropyl] phenyl} -N- [(IS) — 2-hydroxy-1 1-phenylethyl] acetamidamine, N, N —diethyl — 2 — {3— [2 — ({2 —Hydroxy-2 — (5 —Hydroxy-6-(hydroxymethyl) pyridine —2 —yl] ethyl} amino) — 2 —methyl Propyl] phenyl} ethanamide; 2 — {3 — [2 — ({2 —Cyclo-2 — (5 —Cyclo-6- (hydroxymethyl) pyridine 2-yl] ethyl} Amine group) 2-methylpropyl] phenyl} — N — 1 Η —pyrazole —5 —ylacetamide; 2 — {3- [2— ({2 —hydroxy-2 — (5-hydroxy -6- (hydroxymethyl) pyridine- 2-yl] ethyl 丨 amino) -2-methylpropyl] phenyl} — Ν — (5 —methyl-iH — D ratio — 3 —yl ) Acetyl 3-A; N— (cyclohexylmethyl) —2— {3— [2— ({2-Hydroxy-2 — (5-Hydroxy-6 — (Hydroxymethyl) pyridine 2-yl]) } Amino} -2-methylpropyl] phenyl 丨 acetamidine; 4 — ({3 — [2-({2-mesityl 2-(5-mesityl 6-(hydroxyl Methyl) pyridine- 2-yl] ethyl) amino)-2 -methylpropyl] phenyl 丨 ethenyl) piperidine-1 ethyl carboxylate; N — (5 —chlorine ratio One 2-base) one 2- {3— [2— ({2 —hydroxy-2 — (5-hydroxy-6 — (hydroxymethyl) pyridine — 2-yl] ethyl} amino) — 2-methyl Propyl] phenyl} ethanamide; -35- (32) (32) 200533351 2 — {3-[2— ({2 —Ethyl — 2 — (5 -Ethyl — 6-(hydroxymethyl ) Pyridine-2-yl] ethyl 丨 amino) -2-methylpropyl] phenyl} (6-methylsulfonyl than D-di-2-yl) ethoxyamine; 2 — {3— [2— ({2 —Cyclo-2— (5—Cyclo-6— (hydroxymethyl) pyridine—2-yl] ethyl} amino) —2—methylpropyl] phenyl}} — N— (3 —Methylpyridine—2 —yl] acetamidamine; 2 — {3 — [2— ({2 —Crystalline—2— (5 -Crystalline-6— (hydroxymethyl) pyridine—2—yl]) } Amino}-2 -methylpropyl] phenyl} -N -iso-D-quinoline-1 1 -ethylacetamide; NH — (4,6 —methyl group than a 2-methyl group) 2 — {3 _ [2 — ({2-Hydroxy-2— (5-Hydroxy-6— (Hydroxymethyl) cyclohexyl-2—yl] ethyl} amino) —2-Methylpropyl] benzene Acetylamine; 2- {3— [2— ({2-hydroxy-2- (5-hydroxy-6- (hydroxymethyl) pyridine-2-yl] ethyl} amino)-2-methyl Propyl] phenyl} -N— (2-methoxybenzyl) acetamidine; Ν — [(1S) —1—dry radical—2—Ethylethyl] —2- {3 — [2 — 2 —Hydroxy-2 — (5 · -Hydroxy-6 — (hydroxymethyl) pyridine—2-yl] ethyl} amino) —2-methylpropyl] phenyl} acetamidine> Ν— (1-Ethyl-1Hydroxy — 1-Hydroxy-D) — 2— {3— 〔2 — ({2 —Hydroxy-2 — (5-Hydroxy-6— (Hydroxymethyl) pyridine—2— Group] ethyl 丨 amino) -2-methylpropyl] phenyl} ethanamide; Ν— (1,3-dimethyl-1 1-oxazole- 5-yl)-2— {3 1 [ 2-2 -hydroxyl 2-(5 -hydroxyl 6-(hydroxymethyl) > 36- (33) (33) 200533351 pyridin-2-yl] ethyl} amine ) 2-methylpropyl] phenyl} acetamide; N— 2— {3 — [2 — ({2-Cyclo-2— (5-Hydroxy-6— (Hydroxymethyl) hexidine) -2 -yl] ethyl} amino)-2 -methylpropyl] phenyl} ethyl amine; 1-({3-[2-({2- 6- (hydroxymethyl) pyridine- 2-yl] ethyl} amino) -2-methylpropyl] phenyl} acetamidine) -L-proline amine; 6- {2 — [(2 — {3 — [2 -— (5-Amino-3—Secondary 1H—pyrazole-1—1-yl) —2-ketoethyl] phenyl} —1,1—dimethylethyl ) Amine group] 1 1 hydroxyethyl 丨 2 2-(hydroxymethyl) amidin 3 3 alcohol; 2 — {3 — [2 — ({2 aridyl group 2 — (5 — acyl group 6 — (Hydroxymethyl) pyridine- 2-yl] ethyl} amino) -2-methylpropyl] phenyl} — N — [(1 S) — 1 —phenylethyl] acetamidine; N — (3,4 — mono · methylfluorenyl) — 2 — (3 — {2 — [2 —controller — 2 — (5 —hydroxyl 6 — (methyl via methyl)) —Yl] ethyl} amino) -2-methylpropyl} phenyl] acetamidamine; N— [2- (4-chlorophenyl) ethyl] —2— (3 — {2— [2 Once the group is 2- (5—the group is 6- (Methyl)), the ratio of D is π—2- group] ethyl 丨 amino group)-2-methylpropyl] phenyl 丨 acetamidine; 6 — {2 — [(2 — {3 — (2 — (1'4 a > oxo-8-aerospiro [4.5] decyl-8-yl) -1 2-ketoethyl] phenyl} phenyl 1,1-Dimethylethyl) amino] -1,1-Ethylethyl} -1,2- (Ethylmethyl-37- (34) (34)

200533351) pyridine-3-ol; and N— (2-mercapto; yl) —2— (3-hydroxy-2— (5-hydroxy-6— (hydroxymethyl 3 ethylamino] propyl) phenyl) phenyl ) Acetylamine; N —fluorenyl — 2 — (3 — {(2 R) — 2 (5 —Cyclo-6- (Cyclomethyl) Hydroxyl — 2yl —phenyl) ethanyl); N — (3,4-dimethylbenzyl) —2— [2-hydroxy-2— (5-hydroxy-6— (co-yl] ethylamino] propyl} phenyl) ethanamide; N— (2,5-Dimethylbenzyl) —2 —— [2-Hydroxy-2— (5-Hydroxy-6— (Cycloyl) —2— (3 — {(2 R) — 2 — [2-methyl-6- (hydroxymethyl) pyridin-2-yl] e) acetamidine; 2 — (3 — {(2 R) — 2— [2-methyl-6— (hydroxymethyl) Pyridyl-2-yl] ethylamino N- (2-methoxybenzyl) acetamidamine; N- (2-ethoxybenzyl) -2- (3- 2-hydroxy-2-2- (5 — Hydroxy-6- (hydroxymethyl) ethylamino] propyl 丨 phenyl) acetamidamine; N— (3,4-dichlorobenzyl) —2— (3 [2-hydroxy-2— (5 — Hydroxy-6- (hydroxy ^ yl) ethylamino] propyl 丨 phenyl) acetamide, and {2 — [(2R)-2 I) pyrimidin-2-yl]-[2-hydroxy-2- 1-yl] ethylamino] propyl (3- — ((2R) — 2 丨 methyl) pyridine — 2 (3 — {(2R)-2 —methylmethyl) pyridine — 2 hydroxy — 2 — (5-hydroxyamine Yl] propyl 丨 phenyl-2- (5-propyl-] propyl 丨 phenyl)-{(2R)-2-[yl) pyrimidine- 2 -yl-{(2 R) — 2 —: Methyl) pyridine 2 — -38- (35) (35) 200533351 N— (2-chloro-6-fluorobenzyl) —2- (3— {(2R)-2— [2-hydroxy-2— (5-Hydroxy-6-hydroxymethylpyridine-2-yl] ethylamino] propyl 丨 phenyl) acetamide. According to one aspect of the present invention, it is usually preferred to be (CH2) n in formula (1). — C (= 〇) Q1 is a compound in the meta position. Pharmaceutically acceptable salts of the compound of formula (1) include acid addition salts and test salts. Appropriate acid addition salts are those which form non-toxic salts. Acid formed. Examples include acetate, adipate, aspartate, benzoate, benzenesulfonate Acid salt, bicarbonate / carbonate, bisulfate / sulfate, borate, camphorsulfonate, citrate, cyclohexylsulfonate, ethanedisulfonate, ethanesulfonate, formate, Fumarate, gluceptate, gluconate, gluconate, hexafluorodiskate, hibenzate, hydrochloride / chloride, hydrobromic acid Salt / bromide, hydroiodate / iodide, hydrogen phosphate, isethionate, D- and L-lactate, malate, maleate, malonate, methanesulfonic acid Salt, methyl sulfate, 2 ~ naphthalene sulfonate, nicotinic acid salt, nitrate, lactate, oxalate, palmitate, dihydroxycetate, phosphate ^ / hydrogen salt, phosphate / Dihydrogen phosphate, pyrogluconate, gluconate, stearate, succinate, tannate, D- and L-alcoholates, 1-hydroxy-2-naphthoate, Tosylate and xinafoate. Appropriate base salts are formed from bases which form non-toxic salts. Examples include salt, osmium, ft fe: acid salt, benzathine, brocade, bile test, -39-(36) 200533351 diethylamine, di amine 1 (amine), glycine , Lysine, magnesium, meglumine, n-amine, potassium, sodium, trimethylolamine and zinc. It is also possible to form acid and base hemi-salts, such as hemi-sulphate and hemi-salt. For comments on appropriate salts, see Handbook of Pharmaceutical Salts: Properties, Selection, and Usby. Stahl and Wermuth (Wiley- VCH, Weinheim, Germany, 20 G 2) pharmaceutically acceptable salts of compounds of formula (1) can be prepared by one or more of the following three methods: (1) by combining a compound of formula (1) with Desirable acid or base reactions; (ii) via removal of acid- or base-stability protecting groups from appropriate precursors of the compound of formula (1) or via appropriate cyclic precursors such as lactones or lactams' Ring opening using a desired acid or base; or • () converting one salt of a compound of formula (1) to another salt by using the appropriate acid or base or using an appropriate ion exchange 'mediator reaction. All two reactions are typically performed in solution. The resulting salt can be collected by filtration or recovered by evaporation of the solvent. The degree of ionization of the resulting salt may vary from fully ionized to almost non-ionized. The compounds of the invention may exist in both unsolvated and solvated forms. The term 'solvate' is used herein to describe a molecular complex comprising a compound of the invention and a stoichiometric amount of one or more pharmaceutically acceptable molecules of a solvent, such as ethanol. The term ', hydrate' is used when the solvent is -40-(37) 200533351 water. _ The scope of the present invention also includes, for example, clathrates and drug-host inclusion complexes, in which, in contrast to the aforementioned solvates, the drug and the host system are calculated in a stoichiometric or non-chemical manner The amount exists. Also included are pharmaceutical complexes containing two or more organic and / or inorganic components in stoichiometric or non-stoichiometric amounts. The resulting complex may be ionized, partially ionized, or unionized. For a review of these complexes, see Haleblian's].? 1 ^ 1 * 111.3〇 ^ 5 6 4 (8), 1 269-1288 (August 1975) ° In the following, all references to compounds of formula (1) include their salts, solvates and complexes and their References to solvates and complexes of salts. The compounds of the present invention include compounds of formula (1) as defined above, including all polymorphs and crystal inertias thereof, and their prodrugs and isomers (including optics, geometry, and interconversions) as defined below Isomers) and isotopically labeled compounds of formula (1). # As noted, the so-called `` prodrugs '' of compounds of formula (1) are also included within the scope of the present invention. In this way, derivatives of certain compounds of formula (1), which may themselves have little or no pharmacological activity, may be converted into compounds of formula (1) with desirable activity when administered into or on the body, for example, Obtained by hydrolysis. These derivatives are referred to as '' prodrugs ''. For further information on the use of prodrugs, refer to, Pro-drugs as Novel Delivery Systems, Vo 1. 14, ACS Symposium (T. Higuchi and W. Stella) and ', Bio reversible Carriers in Drug Design in Drug Design ", P ergam 〇n -41-(38) 200533351

Press, 1 9 8 7 (ed. E. B Roche, American Pharmaceutical Association). The prodrug according to the present invention can be replaced, for example, by using a molecule known to those skilled in the art that can be used as a 'promoter' (moleties) to replace the appropriate functional group contained in the compound of formula (1). And made as described in, for example, Design of Prodrugs "by Η. Bundgaard (Elsevier, 1 9 8 5). # Examples of certain prodrugs according to the invention include: (i) in formula (1 ) Where the compound contains a monocarboxylic acid functional group (monoCOOH), it is an ester, for example, a compound in which the hydrogen of the residual acid functional group of the compound of formula (1) is replaced by (C) -C8) alkyl; Π) In the case where the compound of formula (1) contains an alcohol functional group (monoOH), it is an ether, for example, wherein the hydrogen of the alcohol functional group of the compound of formula (1) is (C! -C4) alkanoyloxy And (iii) in the case where the compound of formula (1) carries a first or second amine functional group (—N 或 2 or —NHR, where R is Η), The amidine, for example, 'as appropriate, one or two hydrogens contained in the amine functional group of the compound of the formula (1) is used (c!-CI 〇) The obtained compound is substituted. For other examples of the substituents according to the foregoing examples and other prodrug examples, refer to the aforementioned reference materials. Furthermore, some compounds of formula (1) may themselves be prodrugs of other compounds of formula (!). Also included in the scope of the present invention are metabolites of compounds of formula (1), also -42-(39) (39) 200533351, ie compounds formed in vivo (invi ν) after taking a drug. Metabolism according to the present invention Some examples of compounds include (i) in the case where the compound of formula (1) contains a methyl group, its hydromethyl derivative (“CH3 — — C Η 2 〇Η); (π) in formula (1) In the case where the compound contains an alkoxy group, it is a hydroxyl derivative thereof (-0 R—-〇 Η); (i Π) In the case where the compound of the formula (1) contains a third amine group, it is a second amine group Derivatives (a NR ^ R2-NHR1 or a NHR2); (iv) in the case where the compound of formula (1) contains a second amine group, its first amine derivative (a NHR1-NH2); ν) In the case where the compound of formula (1) includes a phenyl moiety, its phenol derivative (—ph — — PhOH); and (vi) in the case where the compound of formula (1) includes a monoamine group, it is a residual acid derivative (—CONH2- > — C00H). Contains one or more asymmetric carbons Atomic compounds of formula (1) may exist as two or more stereoisomers. In the case where the compound of formula (1) contains an alkenyl or alkenyl group, there may be geometric cis / trans (or Z / E) Isomers. In the case where structural isomers can be converted to each other through a low energy barrier, tautomerism tautomers may occur). This may be in the form of a proton tautomer in a compound of formula (1) containing, for example, an imine, keto, or oxime group, or a so-called valence tautomerism in a compound containing an aromatic moiety. Sex. Therefore, a single compound may exhibit more than one type of isomerism. Also included within the scope of the present invention are all stereoisomeric -43-(40) (40) 200533351 compounds, geometric isomers and tautomeric forms of the compounds of formula (i), including compounds exhibiting more than one isomerism, and A mixture of one or more of them. Also included are those whose counterions are optically active acid addition salts or base salts, such as d-lactate or 1-lysine, or those that are racemic, such as dl-lactate or dl-spermine acid. The cis / trans isomers can be separated using conventional techniques well known to those skilled in the art, such as chromatography and fractional crystallization. Conventional techniques for the preparation / isolation of individual mirror isomers include chiral synthesis or use of appropriate optically pure precursors, for example, chiral high pressure liquid chromatography (HP LC) Or the racemate of the derivative). Alternatively, the racemate (or racemic precursor) may be combined with a suitable optically active compound, for example, an alcohol, or, in the case where the compound of formula (1) contains an acidic or basic moiety, with an acid or A base such as tartaric acid or 1-phenylethylamine is reacted. The resulting non-mirromeric isomers can be separated by chromatography and / or fractional crystallization or one or two non-mirromeric isomers can be converted into the corresponding pure mirror isomers by means well known to those skilled in the art. The chiral compounds of the present invention (and their chiral precursors) can be chromatographed, typically HPLC, on an asymmetric resin to include hydrocarbons, typically heptane or hexane, containing 0 to 50 volumes %, Typically 2% to 20% isopropyl ester 'and mobile phase from 0 to 5% by volume, typically 0.1% of diethylamine to obtain the image-enriched isomeric form. Concentration of the eluate provides the rich mixture. One-body isomeric crystalline groups (c. 〇ng I 〇merates) can be separated by conventional techniques known to those skilled in the art (44) (41) 200533351, for example, "Stereochemistry of Organic Compounds ^ by EL" Eliel (

Wiley, New York, 1 994). According to one aspect of the present invention, in the following formula (R, R)-stereoisomers, R1 is hydrogen and R2 is C? -C4 alkyl, preferably methyl, and η is Q]

The ones defined above are usually the better ones.

The present invention includes all pharmaceutically acceptable isotopically-labeled compounds of formula (1), in which one or more atoms are atomic or mass atomic atoms having the same atomic order but different from the main atomic mass or mass number in nature The replacement. Examples of isotopes suitable for inclusion in the compounds of the present invention include hydrogen isotopes, such as 2Η and 3Η; carbon isotopes, such as 14C; chlorine isotopes, such as 3 6 C 1; fluorine isotopes, such as] 8 F; iodine isotopes, such as] 231 And 1251; nitrogen isotopes, such as I3n and 15n; oxygen isotopes, such as 150, 170, and 180; phosphorus isotopes, such as 32p; and sulfur isotopes, such as 3 5 S. Certain isotopically-labeled compounds of formula (1), such as those incorporated with radioisotopes, can be used in drug and / or tissue distribution studies. Radioactive deuterium, i.e., 3H, and carbon-tritium, i.e., from their easy incorporation and convenient detection means, are particularly useful for this purpose. Substitution with heavier isotopes such as deuterium, ie 2H, can provide some of the therapeutic advantages of greater metabolic stability derived from Geng -45-(42) 200533351, such as bioassay, or reduced dose requirements' and therefore In some cases, positron emission isotope, such as 1] C, 18F, generation can be used for positron emission local anatomy (PET) 硏 receptor receptor occupancy. Isotopically-labeled compounds of formula (1) are generally prepared by techniques known in the art or similarly in the appended Examples and Preparations using appropriate isotopically-labeled agents instead of previously used ones. Pharmaceutically acceptable solvated crystalline solvents according to the present invention are substituted with isotopes, such as D20, d6 DMSO. The compounds of formula (1), their pharmaceutically acceptable derivative forms, are all useful pharmaceutically active compounds, which involve the / 32 receptor or the treatment and prevention of disorders in which this receptor agonism can induce disorders, particularly Allergic and non-disease, but also can be used in the treatment of other diseases, such as nervous system, premature delivery, congestive heart failure, depression; skin diseases, psoriasis, proliferative skin diseases, glaucoma gastric acidity, favorable symptoms, In particular, the compounds of the present invention which are intended for pharmaceutical use for gastric and peptic ulcers can be administered in the form of amorphous products. They can be obtained by methods such as precipitation, drying, spray drying, or evaporation drying, in the form of powder, or film. Microwave or RF drying methods can be used. 150 and 13N, which are used in the study to explore the unlabeled pharmaceuticals including the acetone, d6-salts, and / or a variety of allergic properties suitable for its benefit 5 through the procedures described in this technique. Respiratory tracts such as, but not limited to, inflamed and allergic eyes and those with reduced ulcers. Use its crystal form or crystallization, freezing, for example, solid blocks for this purpose. -46- (43) 200533351 They can be taken alone or in combination with one or more other compounds of the present invention or in combination with one or more other drugs (or any combination of them). Generally, they are administered as a formulation in combination with one or more pharmaceutically acceptable excipients. The term `` excipient '' is used herein to describe any ingredient other than the compound of the invention. The choice of excipients is largely determined by factors such as the particular method of administration, the effect of the excipients on solubility and stability, and the nature of the dosage form. The pharmaceutical composition suitable for the delivery of the compounds of the present invention and their preparation methods are easily understood by those skilled in the art. These compositions and their preparation methods can be referred to, for example, "Remington's Pharmacutical Science", 19th Edition (Mack Publishing Company, 1995). The compounds of the present invention can be administered orally. Oral administration can include swallowing so that the compounds enter the gastrointestinal Or by buccal or sublingual medication, allowing the compound to enter the bloodstream directly from the mouth. Φ Formulations suitable for oral administration include solid formulations such as tablets, capsules containing granules, liquids or powders) , Lozenges (including those filled with liquids), chews, multi-type and nano-type granules, gels, solid solutions, liposomes, films, ovoids, sprays and liquid formulations. Liquids Formulations include suspensions, solutions, syrups, and formulations. Such formulations can be used as fillings in soft or hard capsules and typically include carriers such as water, ethanol, polyethylene glycol, Propylene glycol, methyl cellulose, or a suitable oil, and one or more emulsifiers and / or suspending agents. Liquid formulations can also be prepared by reconstituting a solid, for example, from a drug pack, -47- (44 ) (44) 200533351. The compounds of the present invention can also be used in fast-dissolving, fast-disintegrating dosage forms, such as in Expert Opinion in Therapeutic Patents, 11 (6), 981-986, by Liang and Chen (2001). When used in a tablet form, depending on the dosage, the drug may occupy from 1% to 80% by weight of the dosage form, and more typically from 5% to 60% by weight of the dosage form. In addition to the drug, tablets Agents usually include a disintegrant. Examples of disintegrants include sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, cross-linked polyvinyl pyrrolidone, polyethylene 1: 1 ratio of ketocolone, methylcellulose, microcrystalline cellulose, low carbon number of keto-substituted hydroxypropyl cellulose, starch, pregelatinized starch, and sodium alginate. Generally, disintegrants are Occupies the dosage form from 1% to 25% by weight, preferably from 5% to 20% by weight. Binders are generally used to impart cohesive properties to tablet formulations. Suitable binders include microcrystalline cellulose, gelatin , Sugar, polyethylene glycol, natural and synthetic gums, polyethylene Pyrrolidone, pregelatinized starch, hydroxypropyl cellulose, and hydroxypropyl methyl cellulose. Tablets may also contain diluents such as lactose (-hydrate, spray-dried-hydrate, anhydrous, and the like), Mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch, and phosphate dibasic calcium dihydrate. Tablets can also include surfactants as needed, such as sodium lauryl sulfate and polysorbate Ester 80 (poly sorbate 80), and glidant s such as silica and talc. When contained, the surfactant may occupy from 0.2 to 5% by weight of the tablet, and the glidant may occupy from 0.2 to 48- (45) 200533351 to 1% by weight of the tablet. Tablets also typically include lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and a magnesium stearate / sodium lauryl sulfate mixture. The lubricant usually occupies from 0.5 to 10% by weight of the tablet, preferably from 0.5 to 3% by weight. Other possible ingredients include antioxidants, colorants, flavoring agents, preservatives and taste masking agents. • Exemplary tablets contain up to about 80% of the drug, from about 10% to about 90% by weight of a binder, from about 0% to about 85% by weight of a diluent, and from about 2% by weight to about 10% by weight of a disintegrant, and from about 0.25% to about 10% by weight of a lubricant. Tablet blends can be compressed directly or with a roller to form tablets. Alternatively, the tablet blend or a portion of the blend may be wet one, dry one, or melt granulated, coagulated, or extruded to form a tablet. The final formulation can include one or more layers and can be coated or uncoated, which can even be glue-sealed. Tablets are said to be formulated in Pharmaceutical Dosage Forms: Tablets, Vol. 1, by Η Lieberman and L. Lachman (Marcel Dekker, New York, 198 0). Consumable oral films for human or veterinary use are typically flexible, water-soluble or water-swellable film dosage forms that are rapidly soluble or mucoadhesive and typically include a compound of formula (1), a film-forming polymer, Binders, solvents, humectants, plasticizers, stabilizers or emulsifiers, viscosity modifiers and solvents. Certain ingredients of the formulation may perform more than one function. The compound of formula (1) may be water-soluble or water-insoluble. Water-soluble compounds -49- (46) (46) 200533351 The compounds typically occupy solutes from 1% to 80% by weight, more typically from 20% to 50% by weight. The less soluble compound ' occupies a greater proportion of the composition, typically up to 88% by weight of the solute. Alternatively, the compound of formula (1) may be in the form of multi-granular beads. The film-forming polymer may be selected from natural polysaccharides, proteins, or synthetic hydrocolloids and typically has a content in the range of 0.01 to 99% by weight, and more typically 30 to 80% by weight. Other possible ingredients include antioxidants, colorants, flavors and flavor enhancers, preservatives, saliva stimulants, coolants, co-solvents (including oils), lubricants, swelling agents, defoamers, surfactants And taste masking agent. The film according to the present invention is typically prepared by evaporating and drying an aqueous film solution coated on a peelable backing carrier or paper. This can be done in a drying oven or tunnel dryer, typically a combination coater dryer, or via freeze drying or vacuum. Solid formulations for oral use can be formulated for immediate and / or adjusted release. Modified release formulations include delayed-, sustained-, pulse-, controlled-, target-guided, and programmed release. Suitable modified release formulations for the purposes of the present invention are described in U.S. Patent Nos. 6,106; 8 64. For other suitable release technologies, such as high-energy dispersing and penetrating and coating particles, refer to Pharmaceatical Technology On-line, 25 (2) 5 1 · 14, by Verma et al (2001). The use of chewing gum to achieve controlled release is described in WO 00/3 52 98. 0-50- (47) (47) 200533351 The compounds of the present invention can also be directly administered to the bloodstream, muscle, or internal organs. Inside. Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, indoor, intraurethral, intrasternal, intracranial, intramuscular, and subcutaneous. Suitable devices for parenteral administration include needle (including microneedle) syringes, needleless syringes, and infusion techniques. Parenteral formulations are typically aqueous solutions, which may contain excipients such as salts, sugars, and buffers (preferably to ρ Η 値 from 3 to 9), but, for some applications, they may be more Appropriately formulated as a sterile non-aqueous solution or in dry form for use with a suitable vehicle such as sterile, pyrogen-free water. Under sterile conditions, for example, the preparation of parenteral formulations via freeze-drying can be used in this technique. Standard pharmaceutical techniques are well known to those skilled in the art. The solubility of a compound of formula (1) used in the preparation of parenteral solutions can be increased by using appropriate formulation techniques, such as the incorporation of solubility enhancers. Formulations for parenteral administration can be formulated for immediate release and / or modified release. Modified release formulations include delayed-, sustained-, pulse-, controlled-, target-directed and programmed-controlled releases. As such, the compounds of the present invention can be formulated as solid, semi-solid, or shaken liquids for administration in the form of a depot to provide controlled release of the active compound. Examples of such formulations include drug-coated stents and poly (dl-lactic-co-glycolic acid) (PGLA) microspheres. The compounds of the invention can also be applied topically to the skin or mucous membranes, that is, -51-(48) (48) 200533351, percutaneously or transdermally. Typical formulations used for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, wine powders, dressings, foam tinctures, films, skin patches, medicated facial patches, implants, sponges , Fibers, bandages and microemulsions. Microlipids can also be used. Typical carriers include alcohol, water, mineral oil, liquid paraffin oil, white paraffin oil, glycerin, polyethylene glycol, and propylene glycol. It is possible to infuse budding enhancers—see, Pharn Sci, 88 (10); 955-958, by Finnin and Morgan (October 1999). Other local administration methods include via electroporation, iontophoresis, phonophoresis, sonar electroosmosis (s ο η 〇ph 〇resis) and microneedle or needleless injection (such as Po wderj ect ™, Bioject ™, etc.). Formulations for topical administration can be formulated for immediate and / or adjusted release. Modified release formulations include delayed-, sustained-, pulse-one, controlled-, target-guided, and programmed release. The compounds of the present invention may also be administered intranasally or by inhalation, typically in the form of a dry powder (alone, or in the form of a mixture, e.g., a dry blend with lactose, or as particles of a mixed ingredient, e.g., with a phospholipid Substances such as phosphatidylcholine blends) are administered from a dry powder inhaler, or in the form of an aerosol spray from a pressure vessel, pump, sprayer, sprayer (preferably a sprayer using a galvanostat to produce fine powder) ), Or a sprayer, with or without a suitable spray base such as 1,1,1,2, tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane. For intranasal use, the powder may include a bioadhesive, such as chitosan or cyclodextrin. Pressure vessels, pumps, sprayers, sprayers, or sprayers containing the present invention-52- (49) (49) 200533351 A solution or suspension of a compound which includes' for example, ethanol, an aqueous ethanol solution, or a suitable Alternative agents for dissolving or prolonging the release of actives, aerosol bases as solvents, and optional surfactants, such as sorbitan trioleate, oleic acid, or oligolactic acid. Prior to use in dry powder or suspension formulations, the drug product is micronized or sized to be suitable for delivery via inhalation (typically less than 5 microns). This can be done by appropriate honing methods such as spiral jet honing, fluid bed jet honing, supercritical fluid treatment to form nano particles, high pressure homogenization, or spray drying. Capsules for use in inhalers or insufflators (made from, for example, gelatin or hydroxypropyl methylcellulose), foamers' and pharmacies can be formulated to contain the compounds of the invention, suitable powder bases such as Powder mixture of lactose or starch and performance modifiers such as 1-leucine, mannitol, or magnesium stearate. The custard may be anhydrous or in the form of a monohydrate, preferably the latter. Other suitable excipients include polydextrose, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose. A suitable solution formulation in a sprayer that uses electrodynamic mechanics to produce a fine mist may contain from 1 microgram to 20 milligrams of a compound of the invention per actuation and the actuation volume may be from 1 microliter to 100 microliters. Typical formulations may include compounds of formula (1), propylene glycol, sterile water, ethanol and sodium chloride. Alternative solvents that can be used in place of propylene glycol include glycerin and polyethylene glycol. Suitable flavouring agents ' such as menthol and L-menthol, or sweeteners, such as saccharin or sodium saccharin, can be added to the formulations of the present invention intended for inhalation / intranasal administration. -53- (50) (50) 200533351 Formulations for inhalation / intranasal administration may be formulated using 'e.g.' PGLA, formulated or immediate and / or adjusted release. Modified release formulations include delayed—continuous one, pulse one, control one, target guided one, and programmed release. In the case of dry powder inhalers and aerosols, the dosage unit is determined using a valve that delivers a given amount. Units according to the invention are typically delivered by women's clothing-a given dose from 0.001 mg to 10 mg or a "puff" compound of formula (1). The entire daily dose is typically in the range of 0.001 mg to 40 mg, and this can be given in a single dose, or more often in several divided doses throughout the day. Compounds of formula (1) are particularly suitable for inhaled administration. The compounds of the invention can be administered rectally or vaginally, for example, in the form of suppositories, pessaries, or enemas. Cocoa butter is a conventional suppository base, but there are a number of alternatives that can be used appropriately. Formulations for rectal / vaginal administration can be formulated for immediate and / or modified release. Modified release formulations include delayed-, sustained-, pulse-one, control-one, target-guided, and program-controlled release-types. The compounds of this invention can also be administered directly to the eyes or ears, typically in the form of droplets of a micronized suspension or solution in isotonic, pH-adjusted sterile saline. Other formulations suitable for the eye and for administration include ointments, biodegradable (such as absorbable gel sponges, collagen) and non-biodegradable (such as silicone) implants, tablets, lenses and granules or vesicles 'Like systems' such as nonionic surfactant microcapsules (niosome) or microliposome. Polymers such as cross-linked polyacrylic acid, polyvinyl acid, hyaluronic acid, fibers -54- (51) 200533351 quality polymers, such as hydroxypropyl methyl cellulose, hydroxyethyl cellulose, or methyl cellulose Or heteropolysaccharide polymers, such as gel an • gum, can be blended with preservatives such as benzyl ammonium chloride. These formulations can also be delivered via iontophoresis. Formulations for administration and / or administration can be formulated for immediate and / or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, target-guided-, or programmed-release. • The compounds of the present invention can be compounded with soluble macromolecules, such as cyclosaccharin and its appropriate derivatives, or polymers containing polyethylene glycol to improve their solubility, dissolution rate, taste masking, bioavailability and / Or stability for any of the above modes of administration. For example, the 'drug-cyclodextrin complex has been found to be commonly used in most dosage forms and routes of administration. Both inclusive and non-inclusive types can be used. As an alternative to direct compounding with drugs, cyclodextrin can be used as an auxiliary additive, that is, as a carrier, diluent, or solubilizer. The most commonly used for this purpose are / 3- and 7-cyclodextrin, examples of which can be found in International Patent Applications Nos. WO 91/11172, WO 94/02 5 18 and W 098/55148. Since it may be appropriate to administer an active ingredient combination for the purpose of, for example, treating a particular disease or symptom, within the scope of the present invention, two or more pharmaceutical compositions may be conveniently incorporated, at least one of which contains a compound of the present invention. Or, they can be combined into a set of suitable compositions for common administration. As such, the kit of the present invention includes two or more separate pharmaceutical compositions, at least one of which contains a compound of formula (1) of the present invention, and a tool for separately holding the composition such as -55- (52) 200533351, such as a container, Separate bottles, or separate foil packages. An example of this is the familiar blister pack for packaging tablets, capsules, and the like. The kit of the present invention is particularly suitable for administration of different dosage forms, for example, parenteral dosage forms' for administration of separated compositions at different administration intervals, or titration of compositions separated from each other. To help with compliance, the kits typically include medication guidelines and can be supplemented with so-called memory aids. φ To be administered to a human patient, the total daily dose of the compound of the present invention is typically in the range of 0.001 mg to 5000 mg, of course, depending on the mode of administration. For example, a daily intravenous dose may only require from 0.00 mg to 40 mg. The total dose per dose can be administered in a single dose or in divided doses and at the discretion of the physician. It falls outside the typical range given herein. These doses are based on an average human patient with a body weight of about 65 kg to 70 kg. Doctors can successfully determine the weight of patients outside this range, such as the dosage for infants and the elderly. # For the avoidance of doubt, this article's reference to 'therapeutic treatment' includes both curative treatment 'and standard treatment and preventative treatment. According to another specific embodiment of the present invention, the compound of formula (1), or a pharmaceutically acceptable salt, derivative form or composition thereof, may also be combined with one or more additional therapeutic agents for co-administration to a patient to obtain certain special desirability. Therapeutic end results such as the treatment of pathophysiology-related disease processes, including but not limited to (i) bronchoconstriction, (ii) inflammation, (iii) allergic, (iv) tissue destruction, (v) signs and symptoms such as Asthma and cough. The second and more additional treatments may also be a compound of formula (1), or -56- (53) 200533351 thereof, a scientifically acceptable salt, derivative form or composition, or one or more techniques. Known stone 2 agonist. More typically, the second and more therapeutic agents are selected from different classes of therapeutic agents. As used in the text, the terms ', co-administration,', co-administration and combination, when referring to a compound of formula (I) and one or more other therapeutic agents, are intended to mean, and indeed refer to, and Including the following: • The combination of a compound of formula (1) and a therapeutic agent is simultaneously administered to a patient in need of Φ treatment, and these ingredients are formulated together into a single dosage form to release the ingredients to the patient at substantially the same time , • The combination of the compound of formula (1) and a therapeutic agent is administered to a patient in need of treatment at the same time, and the ingredients are formulated separately from each other and the dose is taken by the patient at substantially the same time, and thereafter These 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 to the patient in need of treatment in sequence, and these ingredients are formulated separately from each other. Dosage form 'is given to the patient at consecutive times with a significant time interval between each administration', after which the ingredients are released to the patient at substantially different times, and (1) These combinations of compounds and therapeutic agents are sequentially administered to patients in need of 'these ingredients are formulated together into a single dosage form' which releases these ingredients in a controlled manner, and thereafter they are all in the same Each of these parts can be administered to the patient simultaneously, continuously and / or overlapping at different times and can be administered via the same or different routes. -57- (54) (54) 200533351 Suitable examples of other therapeutic agents that can be used in combination with a compound of formula (1), or a pharmaceutically acceptable salt, derivative form or composition thereof include, but are not limited to: ( a) 5-lipoxygenase (5-L0) inhibitor or 5-lipoxygenase activating protein (FLAP) antagonist, (b) leukotriene antagonists (LTRAS) including LTB4, LTC4, LTD4 and Antagonism of LTE4! J, (c) Histamine receptor antagonists include Η! And H3 antagonists, (d) α!-And α 2-adrenergic receptor agonist vasoconstrictor sympathomimetic for decongestion (E) A muscarinic M3 receptor antagonist or an anticholinergic agent, (f) PDE inhibitors such as PDE3, PDE4, and PDE5 inhibit J Qi! 1, (g) theophylline, (h) sodium cromoglycate, (i) COX inhibitors include non-selective and selective cox-1 or COX-2 inhibitors (NSAIDs), (j) orally and Inhaled glucocorticoids, such as DAGR (dissociation agonist of the corticoid receptor), (k) monoclonal antibody active against endogenous inflammatory entities, (1) anti-TNF —Α) agents, (m) adhesion molecule inhibitors include VLA-4 antagonists, (η) kallikrein / 3 1 — and / 3 2 —receptor antagonists, (0) immunosuppressants, (P) Matrix metalloproteinase (MMMPs) inhibitor, -58- (55) (55) 200533351 (q) tachykinin NK1 'and NK3 receptor antagonists, (r) elastase inhibitor (S) adenosine A2a receptor agonists, (t) urokinase inhibitors, (u) compounds that act on dopamine receptors, such as 02 agonists' (v) NF «pathway modulators, such as IKK inhibition Agents, (w) modulators of the cytokine signaling pathway, such as p3 8 MAP kinases, syk kinases, or JAK kinase inhibitors, (X) can be classified as mucus solvents or only The drug agent, and (y) Antibiotics, (z) H D A C inhibitor, and (aa) P13 kinase inhibitors. According to the present invention, a compound of formula (1) is preferably combined with the following: a H3 antagonist, a pentoxine M3 receptor antagonist, and a PDE4 inhibitor. j, a glucocorticosteroid, an adenosine A 2 a receptor agonist, an interleukin signaling pathway modulator such as p3 8 MAP kinase or syk kinase, or leukotriene antagonists (LTRAs) including LTB4, LTC4, LTD4 and LTE4 antagonize together! > 59- (56) 200533351 According to the present invention, it is more preferable that the compound of formula (1) can be combined with the following group: _ a glucocorticosteroid, especially an inhaled glucocorticosteroid with reduced systemic side effects, Including prednisone, prednisolone, flunisolid, triamcinolone acetonide, beclomethasone dirpro-pionate, budesonide (Budis ο nide •), fluticasone propionate (fluticasone), ciclesonide, and mometasone furoate, or a muscarinic M 3 receptor antagonist or an antiscopolamine, Including, in particular, anti-acetylcholine (ipratr opiate) salts, that is, bromide; tiotrpium (tiotrpium) salts, that is, bromide; oxytropin (〇xitrOpium) salts, also That is, bromide; perenzepine, and telenzepine 〇φ should also be understood, all references to treatment in this article include curative, standard and preventive treatment. The following description relates to therapeutic applications in which compounds of formula (IX) can be placed. The compound of formula (1) has the ability to interact with the / 32 receptor, thereby having a range of therapeutic applications, as described below, because the 々2 receptor plays an essential role in the physiology of all mammals The reason. Therefore, another aspect of 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 treatment of diseases, disorders, and symptoms involving the two receptors. More specifically, -60- (57) (57) 200533351 The present invention also relates to diseases, disorders of the compound of formula (1), or a pharmaceutically acceptable salt, derivative form or composition thereof selected from the group , And the use in the treatment of symptoms. • Asthma of any type, etiology, or pathogenesis, especially selected from the group consisting of ectopic wheezing, non-ectopic wheezing, allergic wheezing, ectopic bronchial IgE — vector wheezing, bronchial wheezing, Spontaneous wheezing, true wheezing, internal wheezing due to pathological disorders, spontaneous wheezing of unknown or insignificant origin, non-ectopic wheezing, bronchial wheezing, emphysema Asthma, exercise-induced asthma, allergen-induced asthma, cold-air-induced asthma, occupational asthma, infectious asthma caused by bacterial, fungal, protozoan, or viral infection, non-allergic asthma Asthma, primary asthma, wheezing baby syndrome and bronchiolitis in the group consisting of: • chronic or acute bronchoconstriction, chronic bronchitis, small airway obstruction, and emphysema, • any type, etiology , Or pathogenesis of obstructive or inflammatory airway diseases, especially selected from chronic eosinophilic pneumonia, chronic obstructive pneumonia disease (COPD), including chronic bronchitis, emphysema, or related or unrelated to COPD Dyspnea C Ο PD COPD, adult respiratory distress syndrome (ARDS) with characteristics of irreversible, progressive airway obstruction, increased weight of airway activity caused by other drug treatments, and airway diseases related to pulmonary hypertension One of the members of obstructive or inflammatory airway disease, • Three types of bronchitis of any type, etiology or pathogenesis, especially selected from acute bronchitis, acute laryngotracheitis, peanut bronchitis, mucosa > 61-(58) (58) 200533351 Bronchitis, floating bronchitis, dry bronchitis, infectious asthmatic bronchitis, productive bronchitis, staphylococcal or streptococcal bronchitis, and pulmonary bronchitis, • acute lung injury, • any Type, disease source, or pathogenesis of bronchiectasis, especially selected from the group of columnar bronchiectasis, cystic bronchiectasis, spindle bronchiectasis, capillary bronchiectasis, cystic bronchiectasis, dry bronchiectasis and follicular bronchiectasis One of the groups constitutes bronchiectasis. The present invention also relates to a compound of formula (1), Or the use of a pharmaceutically acceptable salt, derivative form or composition thereof for the manufacture of a medicament having P 2 agonistic activity. In particular, the present invention relates to a compound of formula (1), or a pharmaceutically acceptable salt, derivative form or composition thereof, for the treatment of A 2 -mediated diseases and / or symptoms, in particular the diseases and / or symptoms listed above. Uses in the manufacture of medicines. For this reason, the present invention provides a useful method for treating mammals, including humans, using an effective amount of a compound of formula (1) 'or its musically acceptable salt, derivative form or composition. More precisely, the present invention provides a particularly useful method for treating lactation, including / 5 2-vector diseases and / or symptoms of humans, especially the diseases and / or symptoms listed above, including using an effective amount of formula (1 ) A compound, a pharmaceutically acceptable salt and / or derivative thereof for administration to the mammal. The following examples illustrate the preparation of compounds of formula (1): -62-(59) (59) Preparation

200533351 [Embodiment] A suspension of ethoxycarbonylmethylphenyl) ethyl acetate 0, / 3-phenylene) diacetic acid (50 g) is added to ethanol (500 ml). (12 · 5 ml, 175 mmol) and heat the resulting solution to reflux 16 / 丄 to cool the reaction to room temperature and remove the solvent in vacuo. The residue was partitioned between saturated sodium bicarbonate (300 ml) and ethyl acetate (500 ml). The phases were extracted with water (200 ml), saturated sodium chloride (300 ml), water (Na 2 S 04), and the solvent was removed in vacuo to give the title (63.5 g) as a pale yellow oil. 】 H NMR (CDC13, 400MHz) (5: 1.31 (6H, t), (4H, s), 4.20 (4H 'q)' 7.24-7.36 (4H 5 m) MS (EFI): m / z251 [M + H] +, 260 chlorine (hours. After carbonic acid is organic, the compound is 3.65

Preparation 2: (3-ethoxycarbonylmethylphenyl) acetic acid

HO for preparation 1 (44 · 3 g, 177 mmol) and 2, 2 /-(monophenyl) diacetic acid (59.2 g, 308 mmol) in acetic acid (liter) and dioxane The solution in (290 ml) was treated dropwise with hydrochloric acid I, 4.9 ml, 58.8 mmol. The reaction mixture was stirred at reflux for half 18 hours before cooling and concentrating the volume. The reaction mixture was diluted with toluene (mL) and the resulting slurry was filtered. The filtrate was reduced from 24 millimeters to 12 millimeters (125 air-concentrated -63- (60) (60) 200533351) and the residue was dissolved in water and basified with sodium bicarbonate until ρ ρ neutral. The mixture was ethyl acetate (200 ml) was diluted, and the organic layer was separated and washed with a sodium bicarbonate solution (5 X 30 ml) and a saturated aqueous sodium chloride solution (50 ml). The water extract of Hexi was acidified with 6M hydrochloric acid to pH 3 and extraction with ether (3 x 30 ml). The organic layer was combined, dehydrated (MgSO 4) and concentrated in vacuo. The residue was decanted with pentane to give the title compound as a colorless solid (1 0.8 g).] H NMR (CD3OD, 400MHz) 5: 1.25 (3H, t), 3.60 (2H, m), 3.63 (2H, m), 4.15 (2H, q)? 7.18- 7.32 (4H, m). MS (EFI): m / z 245 〔MNa〕 + Preparation 3: [3- (2-Hydroxy-2-methylpropyl) phenyl] acetic acid

A solution of Preparation 2 (6.85 g, 32 mmol) in ether (100 ml) was cooled to 0 ° C and dissolved in methylmagnesium bromide / ether (3 M, 23.5 ml, 70.0) Millimoles). The reaction mixture was allowed to gradually warm to room temperature. After 2 hours, the reaction was quenched by the addition of a saturated ammonium chloride solution (200 mL). The organic phase was separated, washed with brine (100 mL), dehydrated (MgSO 4) and concentrated in vacuo. Purification by column chromatography (4 0 —} 00% dichloromethane / pentane) gave the title compound (6.23 g) as a colorless oil. NMR (CDC13, 400MHz) δ: 1.22 (6Η, s), 2.75 (2Η, s), 3.63 (2Η, s), 7.] 2-7.30 (4 Η, m). ≫ 64- (61) 200533351 MS (EFI): 209 [M + Η] Preparation 4: {3- —2- (2-chloroacetamido) -2-methylpropyl

2-chloroacetonitrile (8.8 ml, 140 mmol) was added to a solution of Preparation 3 (16.0 g, 70 mmol) in acetic acid (33 ml). The resulting solution was cooled to 0 ° C, treated with concentrated sulfuric acid (33 ml), and the reaction mixture was gradually warmed to room temperature. After 4 hours, the reaction mixture was poured onto ice and basified with sodium carbonate. The solution was extracted with ethyl acetate (2 × 500 ml) and the combined organic extract was dehydrated (MgSO4) and concentrated in vacuo to give the title compound (19.0 g) as a colorless solid. JH NMR (CDC13, 400MHz) 5: 13 · 6 (6H, s), 3.02 (2H, s), 3.62 (2H, s), 3.95 (2H, s), 6.19 (1Η, m), 7.06- 7.3 1 (4H, m). MS (electrospray): m / z282 [M—H] — Preparation 5: [3- (2-Amino-2-methylpropyl) phenyl] methyl acetate

H.N

A solution of Preparation 4 (5.1 g, 18 mmol), thiourea (1.6 g, 21 mmol), and acetic acid (8 mL) in ethanol (80 mL) was placed under nitrogen. Heat to reflux for 16 hours. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated in vacuo, the residue was dissolved in methanol (] 50 ml) -65- (62) 200533351, saturated with hydrogen chloride gas and the resulting solution was heated to reflux for 16 hours. The mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate (200 mL) and 5% sodium carbonate solution (200 mL). The organic phase was extracted with brine (100 ml), dehydrated (Mg S04) and concentrated in vacuo. The residue was purified with a strong cation exchange resin (methanol, then a 2M chlorine / methanol solution). The eluate was concentrated in vacuo to give the title compound (2.68 g) as a yellow oil. NMR (CDC13, 400MHz) 5: 1 · 1 4 (6 Η, s), 2 · 6 8 (2H, s), 3.62 (2H, s), 3.69 (3H, s), 7.08-7.16 (3 H, m), 7 · 2 3 — 7.2 7 (1 H, m) o MS (electron): m / z 2 2 2 〔M + H〕 + Preparation 6: (3— {2— 〔2— (2, 2 —dimethyl-1 4 H — [1, 3

] Dioxadioxo [5,4-b] Hou d-6-yl) _2 monohydroxyethylamino]-2-methylpropyl} phenyl) ethyl acetate

OH

Put 2,2-dimethyl-6-oxiranyl-4H ~ [1,3] dioxadiene [5,4-b] pyridine (2.24 g, 10.82 mmol) and prepare Product 5 (2.39, 10.82 mmol) was heated to 90 ° C in Dimethoate (20 ml) for 24 hours. The reaction mixture was dissolved in ethyl acetate (200 mL), extracted with saturated brine (4 × 50 mL), and dehydrated (MgSO4). The crude product was purified by chromatography (0-methanol / dichloro-66- (63) (63) 200533351 methane + 1% chlorine) to obtain a standard oil (1.96 g). NMR (CD3OD, 400MHz) 5: 1.12 (6H, s), 1.55 (6H, s), 2.76 (2H, d), 2.82-2.89 (lH, m), 3.10 (lH, d), 3.60 (2H , S), 3.67 (3H, s) ^ 4.72- 4.79 (lH, bs), 7.05--7.10 (4H, m), 7.21-7.29 (2 H, m) 〇MS (EFI): m / z429 〔M + H〕 +

Preparation 7: (3— {2-—2-Cyclo-2— (5-Cyclo-6—Cyclomethylpyridine—2-yl) ethylamino] —2-methylpropyl} phenyl) Acetic acid dihydrochloride

Preparation 6 (2.16 g, 5.05 mmol) / tetrahydrofuran (30 mL) was treated with lithium hydroxide (1M, 10.1 ml, 10.09 mmol) and stirred at room temperature for 20 hours. Hydrochloric acid (1M, 20 ml, 20.0 mmol) was added and stirring was continued for 2 hours, then at 60 ° C for one hour. The solvent was removed in vacuo and the material was applied to an SCX column (methanol to 2M NH3 / methanol) and purified by chromatography (0-20% methanol / dichloromethane + 1% ammonia) to give a yellow oil. It was dissolved in tetrahydrofuran (5 ml), treated with lithium hydroxide (1M 2.72 ml, 2.72 mmol) and stirred at room temperature for 3 days. The reaction mixture was neutralized with hydrochloric acid (1M, 2.72 ml, 2.72 mmol) and the solvent was removed. Lithium hydroxide (1M, 2.72 ml, 2.72 mmol) was added and the mixture was stirred at room temperature for 20 hours. The reaction mixture was neutralized with hydrochloric acid (4M'di-67- (64) 200533351 oxetane, 1 ml, 4 mmol) to obtain a yellow glass (62 9 mg). 4 NMR (CD3OD, 400MHz) accounted for: 1.85 (6 Η's) (2H, s), 3.35 (lH, dd), 3.6 (lH, dd), 2H, s), 4.77 (2H , S), 5.01-5.05 (lH, m) — 7.26 (3H, m), 7.29 — 7.38 (2H, m), 7.45 — 1 H, m). MS (electrospray): m / z375 [M + H] + Preparation 8: (3-bromophenyl) methyl acetate and removed, 3.05 3.63 (, 7. 1 4 7.50 (

Br

ch3

To (3-bromophenyl) acetic acid (20.0 g, 93 mmol) · (500 ml) was slowly added acetamidine (9 · 3 mmol) under nitrogen and the reaction was allowed to proceed. The solvent was removed gradually over 5 hours to room temperature and the remaining oil was redissolved in dichloromethane 'with sulfur water and concentrated in vacuo to give the title compound (20.6 g) as a colorless oil. NMR (400 MHz , CDC13) (5: 3.59 (2H, s) (3H, s), 7.17— 7.24 (2H, m), 7.37—7.45 () ° LRMS ESI m / z 253 [M + Na] + Preparation 9: [3- (2-ketopropyl) phenyl] methyl acetate / methanol (0.7 mmol. Sodium vacuum removal, 3.7 0 2H, m -68- (65) 200533351 h3c

ch3

Tributyltin Methoxide (28.3 ml, 98 mM), | (15.0 g, 65 mM), isopropenyl acetate (10.8 mM), palladium (II) acetate (750 mg , 3.30 mmoles) o-Tolylphosphine (2.0 g, 6.5 mmoles) were stirred together in toluene () at 100 ° C for 5 hours. After cooling, the reaction was diluted with 160 ml of acetic acid) and 4M aqueous potassium fluoride solution (90 ml) and stirred for 15 minutes. The mixture was filtered through Arbo cel ® and the organic phase was separated and concentrated. Then it was purified by column chromatography on silica gel with diethyl ether: pentane to 25:75, followed by dichloromethane, and eluted to obtain a pale yellow oily compound with a yield of 94% (12 · 6 g). ] H NMR (400MHz, CDC13) (5: 2.15 (3H, s) (2H, s), 3.69 (5H, s), 7.10-7.13 (2H, 7.19 (1H, d)), 7.30 (1H, t ). LRMS ESI: m / z 229 [M + Na] + Preparation 10: [3- ((2R) — 2— {[((1R) — 1-phenyl] amino] propyl) phenyl) phenyl] methyl acetate Hydrochloride ^ Prepare 8 liters, 98 and 2-75 ml ethyl acetate (and stir in vacuum 0-100 title, 3.61 ethyl

The product of Preparation 9 (8.5 g, 4 1.2 mmol), (R monomethylbenzylamine (4.8 ml, 37.2 mmol), sodium triacetamidine oxide (1 1.6 g, 5 6 millimoles) and acetic acid (2.2 ml, 3 8) —a base shed ammonia millole-69- (66) (66)

200533351) when the solution in dichloromethane (400 ml) was stirred at room temperature. The mixture was quenched by adding saturated sodium bicarbonate solution (200 ml) and stirred until foaming ceased. The aqueous phase was separated and extracted with 100 ml of dichloromethane. The combined organic solution was then concentrated by dehydrating with magnesium sulfate. On sand gel, dichloromethane: methanol: ammonia, 9 9: to 9 5: 5: 0 · 5 was eluted and purified by column chromatography to obtain non-mirror images, mainly R, R) 4: 1 The mixture was a pale yellow oil (8.7) with hydrogen chloride (40 ml, 1 M, methanol solution, 40 mmol). Then, three consecutive crystallizations (isopropyl ether / methanol) gave the title compound as a white body, 50% yield, 5.68 g.] H NMR (400MHz, CD3OD) (5: 1.1. 8 (3 Η, d) (3H, d), 2.60-2.66 (lH, m), 3.15-3.26 ( ), 3.25— 3.30 (lH, m), 3.31 (3H, s)-3.62 s), 4.59 (lH, q), 6.99—7.02 (2Η, η), 7. · m), 7.25-7.28 (lH, m), 7.48—7.52 (5Η, LRMSESIm / z312 [M + H] + Preparation 11: {3-[(2R) — 2-aminopropyl] phenyl} ethyl 〇, ch3 The solution of 10 products (7.69 g, 22 mmol) and formic acid formic acid, 110 mmol was prepared in 20% palladium hydroxide / carbon (2. In the presence of heating to 7 5 ° C After 90 minutes, the reaction mixture was cooled, filtered through Arbocel® and the filtrate was concentrated in vacuo. The residue methane (100 ml) was mixed with 0.8 8 Ammonia (] 00 ml) was separated and mixed with -70- and 4 8 small reaction mixed with methane (water and true 1: 0.1 structure (t g). Treatment, crystalline solid> 1.68 1H, m (2H, 1 7 (1 methyl acetate (6.94 g)) was separated into a dichloromethane (67) 200533351 phase. The aqueous phase was extracted with dichloromethane (100 ml) and the organic solution was dehydrated with magnesium sulfate. And concentrated in vacuo to give the title compound as a colorless oil in full yield (4.78 g).] H NMR (400MHz ^ CD3OD) δ: 1.06 (3Η, d), 2.57—2.67 (2H, m), 3.05—3.12 (lH, m), 3.63 (2H, s), 3.67 (3H, s), 7.09-7.13 (3H, m), 7.23-7.27 (1H, t).

LRMS ESI m / z 208 〔M + H〕 +

Preparation 12: (3— {(2R) — 2— [2— (2,2—monomethyl-4H — [1 5 3] monooxa-coordination [5 5 4 — b] 6-yl) -2-hydroxyethylamino] propyl 丨 phenyl) methyl acetate

OH

Φ From the product of preparation 1 and 2,2-dimethyl-6-oxiranyl-4H- [1,3] dioxadiene [5,4-b] pyridine, use similar preparation of 6 Method The title compound was prepared as a brown oil (1.35 g, 42%). O] H NMR (CD3OD 400 MHz) 5: 1.06 (3H, d), 1.52 (6H, s), 2.56-2.7 5 (3H, m), 2.83-3.04 (2H, m), 3.61 / 3.67 (3 Η, 2χ s), 4.66—4.71 (1Η, m), 4.74 / 4.78 (2H, 2x, s), 7.04— 7.30 ( 6H, m). LRMS APCI m / z 4 1 5 [Μ + Η] + -71-(68) 200533351 Preparation 13: (3- 丨 (2R) — 2-—2-hydroxy-2— (5-hydroxy-6-hydroxymethyl) -Pyridinyl-2-yl) ethylamino] propyl} phenyl) acetic acid hydrochloride

Preparation 12 (1.35 g, 3.26 mmol) / tetrahydrofuran (20 ml) was treated with lithium hydroxide (1 M, 6.52 ml, 6.52 mmol) and stirred at room temperature for 40 hours. Add hydrochloric acid (1M, 20 mL, 20.0 mmol) and continue stirring at 60 ° C for 2 hours. Evaporation in vacuo gave a brown glassy substance (2.94 g, > 100%). ! H NMR (CD3OD, 400MHz) 5: 1.28 (3H, 2x d), 2.75-2.84 (1H, m), 3.26 -3.34 (1 H, m), J. JJ — 3.67 (5H, m), 4.97 ( 2H, s), 5.36 (1 H, dt), 7. 1 7 -7.24 (3H, m), 7.80 (1H, dt) 5 • 7.8 8-7.9 5 (2 H, m) ° LRMS APCI m / z 361 〔M + H〕 + Example 1: N— (3'4 — monochloro dry group) — 2 — (3 — {2 — (2 —hydroxyl 2 — (5 —hydroxyl 6 —hydroxymethyl) Pyridyl-2 -yl) ethylamino]-2-methylpropyl phenyl) acetamido HO.

-72-(69) 200533351 The preparation 7 (150 mg, 3 4 2 micromolar, crude), [[(3-dimethylaminopropyl) -3-ethylcarbodicarbamide Imine hydrochloride (65 mg '342 micromoles), triphenylbenzotriazole hydrate (53 mg, 342 micromoles), and triethylamine (93 microliters, 684 micromoles) After stirring in N-dimethylformamide (5 ml) for 10 minutes, 3,4-dichlorobenzyl ester (60 mg, 3 4 2 micromoles) was added, and the resulting solution was stirred at room temperature 2 0 hour. The solvent was removed and the product was dissolved in dichloromethane (20 ml), extracted with saturated sodium bicarbonate (20 ml), brine (2 x 30 ml) and dehydrated (M g S 04). The product was purified twice by chromatography (0-10% methanol / dichloromethane + 1% ammonia) to give a yellow glass (15 mg). ] H NMR (CD3OD, 400MHz) < 5: 1.04 (3H, s), i.05 (3H, s), 2.68 (2H, dd), 2.91 (lH, dd), 3.00 (1, dd) , 3.47 (2H, s), 4.25 (2H, s), 4.63 (2H, s), 4.67 (lH, dd), 7.00-7.34 (9H, m). MS (AP CI): m / z 532/533/534 〔M + H〕 + Example 2: N— (3,4-dimethylbenzyl) —2— (3— {2— [2 —hydroxyl 2- (5-hydroxy-6-hydroxymethylpyridine-2-yl) ethylamino] -2-methylpropyl} phenyl) acetamidamine

A pale yellow foam was prepared by using 3,4-dimethylbenzylamine by the procedure described in Example 1. ] H NMR (CD 3 OD, 400 MHz) δ: 1.07 (3Η, s), 1.08 -73- (70) 200533351

(3H, s), 2.18 (3H, s), 2.19 (3H, s), 2.70 (2H, dd), 2.91 (lH, dd), 2.99 (lH, dd), 3.52 (2H, s), 4.27 ( 2H, s), 4.69 (2H, s), 4.71 (lH, dd), 6.89-7.25 (9H, m). MS (APCI): m / z492 [M + H] + Example 3: N—Cyclohexylmethyl-2— (3 — {2 — [2 —Hydroxy-1 2

Mono (5-hydroxy-6-hydroxymethylpyridine-2-yl) -ethylamino] -2-methylpropyl} phenyl) acetamide

A pale yellow foam was obtained by using cyclohexylmethylamine following the procedure described in Example 1. ! H NMR (CD3OD, 400MHz) 5: 0 · 8 1-0.9 4 (2 Η, m), 1.09 (3H, s), 1.1 (3H, s), 1.14-1.27 (4Η,

m), 1.84—1.86 (lH, m), 1.59-1.72 (4H, m), 2.71 (2H, dd), 2.91-30.5 (4H, m), 3.47 (2H, s), 4.70 (2H, s) , 4.72 (1H, dd), 7.05 (1H, d), 7.12- 7.26 (5H, m). MS (APCI): m / z470 [M + H] + Example 4: N- [2- (4-chlorophenyl) ethyl] -2- (3-{2 a (5-Cycloyl-6-Cyclomethyl-D-Cyclobutyral 2-yl] -2-methylpropyl 丨 phenyl) acetamidamine-74- 200533351

A pale yellow foam was obtained by using 4-chlorophenylethylamine following the procedure described in Example 1. NMR (CD3OD, 400MHz) (5: 1.09 (3Η, s), 1.11 (3H, s), 2.69-2.80 (4H, m), 2.91 (lH, dd), 3.00 (lH, dd), 3.39 ( 2H, t), 3.43 (2H, s), 4.70

(2H, s), 4_72 (lH, dd), 7.05-7.14 (6H, m), 7.17-7.26 (4H, m). MS (APCI): m / z 512/513/514 〔M + H〕 + Example 5: N— (2-hydroxybenzyl) —2— (3— {(2R)-2 — [2 —hydroxyl— 2- (5-hydroxy-6-hydroxymethylpyridine-2-yl) ethylamino] propyl} phenyl) acetamidamine

From the product of Preparation 13 and 2-aminomethylphenol, the title compound was prepared as a pale yellow foam (28 mg) using a method similar to that in Example 1. NMR (CD3OD, 400MHz) ο: 1.06 / 1.07 (3 Η ^ 2χ d), 2.5 · 6— 2.66 (lH, m), 2.72-2.81 (lH, m) ^ 2.86 -3 · 09 (3Η, m) , 3 · 5 2/3. 5 3 (2 Η, 2 χ s), 4.3 2 / 4.3 3 (2 Η, 2 χ s), 4 · 69/4 · 70 (2Η, 2 χ s), 4 · 70— 4 · 74 (1Η, m), 6.70 — 6 · 7 8 (2 Η, m), 7 · 0 1 — 7.2 5 (8 Η, m). -75- (72) 200533351 MS (APCI): m / z466 [M + H] Example 6: N-benzyl-2— (3— {(2R)-2— [2-hydroxy-1 2 — (5 —Hydroxy-6-hydroxymethylpyridine-2-yl) ethylamino] propyl} phenyl) acetamidamine

From the Preparation 13 product and benzylamine, the title compound was prepared in a similar manner to that described in Example 1. ] H NMR (CD3OD, 40 0MHz) < 5: 1.0 5/1 / 1.06 (3 Η, 2 xd), 2.56-2.66 (lH, m), 2.70-2.80 (lH, m), 2.84- 3.10 (3H, m), 3.52 / 3.53 (2H, 2x s), 4.35 / 4.36 (2H, 2x s), 4.68 / 4.69 (2H, 2x s), 4.70— 4.73 (1H, m), 7.02— 7.28 (11H, m). MS (APCI): m / z450 〔M + H〕 +

Example 7: N — (3,4 dimethylbenzyl) — 2 — (3 — {(2R) — 2 — [2 — (2 —hydroxy — 2 — (5-hydroxy-6 —hydroxymethyl) Monopyridine-2-yl) monoethylamino] propyl} acetamidamine

HO

I The title compound was prepared in a similar manner to that described in Example 1 from the preparation of the 13 product and 3,4-dimethylbenzylamine. -76- (73) 200533351 1 H NMR (CD3OD, 400MHz) δ: 1 · 0 6/1 · 0 7 (3 Η, 2 xd), 2 · 1 9 / 2.20 (6H, 2x s), 2 · 5 5-2 · 6 6 (1H, m), 2.70— 2.80 (lH, m), 2.84— 3.10 (3H, m), 3.50 / 3.51 (2H, 2x s), 4.2 8 / 4.2 9 (2H, 2x s ), 4 · 6 7/4 · 6 8 (2 H, 2xs), 4.70—4.73 (lH, m), 6.88-7.28 (9H, m) 〇MS (APCI): m / z478 〔M + H ] +

Example 8: N— (2,5-dimethylbenzyl) —2— (3 -— ((2R) —2— [2-hydroxy-2— (5-hydroxy-6-hydroxymethylpyridine—2 —Yl) ethylamino] propyl} phenylethyl) acetamidamine

From the Preparation 13 product and 2,5-dimethylbenzylamine, the title compound was prepared in a similar manner to that described in Example 1.

NMR (CD3OD, 400MHz) δ: 1.06 / 1.07 (3 Η, 2 xd), 2.18 (3Η, 2x s), 2.21 (3H, 2x s), 2.56-2.66 (lH , M), 2.70— 2.80 (lH, m), 2.82-3.08 (3H, m), 3.51 / 3.52 (2H, 2x s), 4.30 / 4.31 (2H, 2x s), 4.68 / 4.69 (2H, 2xs) , 4.70—4.73 (lH, m), 6.90—7 · 2 6 (9 H, m). MS (APCI): m / z 4 7 8 [M + H] + Example 9: 2— (3— {(2R) —2— [2 —hydroxyl—2— (5 — -77- (74) 200533351 Hydroxy-6-hydroxymethylpyridine- 2-yl) ethylamino] propyl} phenyl) -N- (2-methoxybenzyl) acetamidamine

From the product of Preparation 13 and: 2-methoxybenzylamine, the title compound was prepared in a similar manner to that described in Example 1. ] H NMR (CD 3 0 D, 400MHz): 1.05 / 1 .06 (3H, 2 xd), 2.56-2.66 (1H, m), 2. 70-2. 8 0 (1H, m), 2. 8 1 — 3 · 10 (3H, m), 3.5 1/5. 3, 52 (2H, 2 xs), 3 • 78 (3 H, s), 4 · 36/4 · 37 (2H, 2 xs), 4.68 / 4 • 69 (2H, 2 xs), 4. 69-4.74 (1 H, m), 6. 79-6.84 (1H, t), 6.90 (1H d), 7.02 — 7 .27 ( 8 H, m) o MS (APCI): m / z 480 〔M-f Η] 4

Example 10: N- (2-ethoxybenzyl) -2- (3-((2R) -2-2- [2-hydroxy-1-2- (5-hydroxy-6-hydroxymethylpyridine-2-yl ) Ethylamino] propyl 丨 phenyl) Ethylamine

From the Preparation 13 product and 2-ethoxybenzylamine, the title compound was prepared in a similar manner to that described in Example 1. ] H NMR (CD3OD, 400MHz) ο: 1.06 / 1.0 7 (3 2, 2χ d), 1.34 (3H, t), 2.56-2.66 (lH, m), 2.70—2.80 -78- (75) (75)

200533351 (1Η, η), 2.8 2-3.10 (3Η, m) s), 4.02 (2H, q), 4.3 4 / 4.3 5 (2H (2H, 2xs), 4.70-4.74 ( lH, m, t), 6.88 (1H, d), 7.01 — 7.24 (MS (APCI): m / z 494 [M + H] 4 Example 11: N— (3,4—dichlorobenzyl) — -2-[2-Hydroxy-2— (5- • 3.5 4 / 3.5 5 (2 H, 2x, 2x s), 4.70 / 4.71), 7.03-7.2 2 (1 H 8 H, m) o 2- ( 3 — {(2R) -hydroxy-6-hydroxymethylpropyl} phenyl) acetamidine-pyridine-2-yl) ethylamino] amine

The title compound was prepared from the method for preparing the 1 3 product and 3,4 dichlorobenzylamine 1. ] H NMR (CD3OD, 400MHz) 5:), 2.56—2.66 (lH, m), 2.70—2-3 — 3.0 (3H, m), 3.54 / 3.55 (2 Η, 2Η, 2χ s), 4.70 / 4.7 1 (2Η, 2χ s) m), 7.03-7.22 (7H, m) »7.36 1 Η, d) MS (APCI): m / z 5 1 8 [M + H] Example 12: N- (2-chloro-6-fluorobenzyl))-2- [2-hydroxy-2— (, using similar to Example .06 / 1.07 (3H, 2x s 80 (lH, m), 2.81! Χ s), 4.3 4 / 4.3 5 (, 4.70 — 4.74 (1Η, 1H, d), 7.45 1 (—2— (3-{(2 R 5—hydroxy-6-hydroxymethyl-79- (76) (76) 200533351 Glulamidine-2-yl) ethylamino] propyl] phenyl) acetamidamine

From the product of Preparation 13 and 2-chloro-6-fluorobenzylamine, the title compound was prepared in a similar manner to that described in Example 1. NMR (CD3OD '400MHz) 5: 1 · 0 6/1 · 0 7 (3 Η, 2 xs) 2.5 5-2.63 (1 H ^ m), 2.70-2.80 (lH, m), 2 · 82 -3 · 10 (3H, m), 3.4 7 / 3.4 8 (2H, 2x s), 4.54 / 4.5 5 (

2H, 2x s), 4.69-4 · 70 (2Η, 2x s), 4.70-4.73 (1 H, ni), 7.00-7.34 (9H, m) 〇MS (APCI): m / z502 [M + H] + The compound of formula (1) acts as a potent / 3 2 agonist and thus the ability of mediator smooth muscles to relax can be measured by measuring the effect of the 3/2 adrenergic receptor stimulation on the electric field-stimulated contraction of guinea pig trachea strips. Guinea pig trachea Male, Dunkin-Hartley guinea pigs (475-525 g) were killed by asphyxiation with C02 and bleeding from the femoral artery, and the trachea was isolated. Four preparations were obtained from each animal, dissected starting immediately under the throat and a 2.5 cm trachea was taken. The tracheal segment is cut through the cartilage from the opposite side of the trachea muscle, and a cross section of 3-4 cartilage ring width is cut out. The obtained strip-shaped preparation was suspended in a 5 ml organ trough by using a cotton thread fastened with cartilage bands passing through the upper and lower ends. Place the strips in a 3 M indomethacin (I n d o me t h a c i n) (-80- (77) (77) 200533351

Sigma 1 7 3 7 8), 10 M Guanethidine (Sigma G 8 5 2 0) and 10 // M Atenolol (S i g m a A 7 6 5 5)

Krebs Ringer buffer (Sigma K05 07), equilibrated under heating at 37 ° C and aerated with 95% 02/5% C02. After decompression for 20 minutes, an initial tension of 1 g was applied. The preparations were allowed to equilibrate for another 30-40 minutes, during which they were stretched (to 1 g) twice more at 15-minute intervals. Changes in tension are recorded and identified through a standard isometric transducer coupled to a data collection system (customer of Pfizer). After tension equilibrium, the tissue was subjected to electric field stimulation (EFS) using the following parameters: a 10-second string every 2 minutes, a pulse width of 0.1 ms, 10 Hz, and just the maximum voltage (25 volts) (continuously throughout the experiment) ). EFS applied to bile-induced nerves after ganglia in the trachea resulted in single-phase contraction of smooth muscle and recorded twitch height. In the whole experiment, the above-mentioned Krebs Ringer buffer was continuously injected into the organ trough by using a pumping system (pump flow rate of 7.5 ml / min). However, when the stone 2 agonist of the present invention was added, The pump was stopped for a period of time, and the washout period was started again after the maximum response was recorded. After the balance between EFS and the experimental procedure for the evaluation of power and benefits, the peristaltic pump was stopped and a single dose of 300 nM isopren aline (Sigma 15627) vv was used to prime these preparations. To establish the maximum response in terms of inhibition of contractile EFS response. Isoproterenol was then washed out over a period of 40 minutes. After initial administration and washout recovery, a standard curve for isoproterenol was performed on all tissues using cumulative bolus addition of the tank using a semi-log concentration-81-(78) (78) 200533351 ( Isoprenaline curve 1). The concentration range used is Γ_ 9 to le / 3e-6M. At the end of the isoproterenol curve, the preparation was washed again for 40 minutes before the second curve was started. This can be for isoproterenol (as an internal control) or for the 02 agonist of the invention, and for the β 2 agonist. The response table is the percentage of EF S response suppression. Data for the / 32 agonist are normalized by expressing the inhibition as the percentage of maximal inhibition induced by isoprenaline in curve 1. The ε C 5 0 5 of this invention without 2 agonists refers to the concentration of the compound required to produce half the maximum effect. Then the data table of the present invention's / 3 2 agonists is expressed as the relative potency to isoproterenol in the ratio (eC 502 2 agonist) / (EC 50 isoproterenol). Determination of yS 2 Mediator Functional Activity The test compound's / 3 2 agonist activity was determined using the procedure described above, but before constituting the / 3 2 agonist curve of the present invention, ICI 1 3 8 5 5 1 (--A selective 々2 antagonist) pre-soaked the preparation (minimum 45 minutes), which caused the dose response curve of the test compound to be shifted to the right in the case of yS 2 mediator effect. According to another alternative, the agonist potency of the compound of formula (1) on the / 32 receptor can also be determined by measuring the concentration of the compound of the invention (EC5G) required to produce a half-maximum effect on the / 32 receptor. Compound Preparation Dilute the compound's 10 μM 100% D M S 0 (dimethylformamide) stock solution -82- (79) 200533351 to the highest required dose in 4% DMSO. Use this highest dose to construct a 10-point half-one log dilution curve, all in 4% DMSO. Isoproterenol (Sigma, 1-562 7) was used as a standard in each experiment and control well slot on each plate. Data are reported as% isoproterenol response. Cell culture

CH0 (vole ovary) cells that recombinably express human Θ 2 adrenergic receptors (available from Kobilka et al., PNAS 84: 46-5 0, 19 8 7 and Bouvier et al.? Mol Pharmacol 33: 1 3 3-1 3 9 1 9 8 8 CHOh / 3 2) is supplemented with 10% fetal bovine blood pupa (Sigma, F4135, Lot 90K8 4 04 Exp 09/04), 2 mM glucosamine (Sigma, G7513), 500 micrograms / ml of geneticin G418 sulfate (Sigma, G7034) and 10 micrograms / ml of Puromycin (Sigma, P8833) were grown in Dulbeccos MEM / NUT MIX F12 (Gibco, 21331-020). The cell line was inoculated and cultured to about 90% confluence for the test method used in the test. The compound transfer agent of each dose of 25 microliters / hole 6? 4? -Flashplate ® (NEN, SMP004B), within 1 0% DMS0 was used as the bottom control and 100 μM isoproterenol was used as the largest 値 control sample. Dilute this 1: 2 by adding 25 μl / well of PBS. Cells were trypsinized (0.25%, Sigma, T4049), washed with (Gibco, -83- (80) (80) 200533351 1 4 040-1 74), and resuspended in stimulation buffer (NEN, SMP004B ) To obtain 1 X 106 cells / ml CHOh cold 2. Warmly immerse the compound at 50 μl / well for one hour. Then add 100 μl / well of detection buffer (NEN, SMP004B) (internal 0.18 // Ci / ml of 1251 — cAMP (NEN, NEX — 1 30)) to lyse the cells and place the plates in Let warm for 2 hours at room temperature. Topcount NXT (Packard) was used to quantitatively determine the amount of 125I-c AMP bound to Flashplate® with a normal counting efficiency of 1 minute. The dose-response data sheet was% isoproterenol activity and was matched using a 4-parameter sigmoidalfit. It was thus found that the compounds of the formula (1) (Examples 1 to 12) of the present invention showed a cold 2 c A M P E C 50 below 5 n M.

-84-

Claims (1)

200533351 (1) Scope of patent application R1 R2 compounds of formula (1) OH (CH2) n vQ1 〇) where the (CH2) n — C (= Ο) Q1 group is in the meta or para position—R1 and R2 are independently selected from Η and C] —C4 alkyl, —η is 0 , 1 or 2 and R12 ★ ——Ν Ν——R12 * —Ν Ν——R12 • Ν Ν ★ —Ν or * NR8 — Q3, where —ρ is 1 or 2 and q is 1 or 2 —Q2 is a single key or as the case may be C! -C4 alkylene group with OH substituent—R8 is 1 ^ or C! —C4 alkyl group, and 9n 1 〇Q3 is G—C6 courtyard group containing NRyR OR9 or phenoxy substituent as appropriate. Selected from: -85- (2) 200533351. c3—CIQ cycloalkyl, the cycloalkyl is optionally bridged with 1 or 2, 3 or 4 carbon atoms, and optionally contains a hydroxy substituent; A 5- to 6-membered heterocyclic group, optionally aromatic, containing 1 or 2 heteroatoms selected from 0, N, or S, and optionally 1 or 2 selected from C! -C4 alkyl, benzyl And cyclopropylmethyl substituents or Quinolinyl or isoquinolinyl—R3, R4, R5, 6 and r7 are the same or different and are selected from H, C! -C4 alkyl, OR9, SR9, SOR9, S02R9, halo, CN , CF3, 〇CF3, so2nr9r10, COOR9, CONR9R10, NR9R10, NHCOR1G and optionally phenyl with OH substituents;-R9 and R1 () are the same or different and are selected from Η or c] -C4 alkyl Among them, -R1] is selected from Η or OH, and -R12 and R13 are the same or different and selected from 视; as the case may be Ci-C4 alkyl group containing OR9 substituent; C (= 〇) nH2 ; C (= 0) CH3, n (ch3) c (= CH3; c (= 〇) 〇R9; phenyl with halogen substituents as appropriate; pyridyl with CN substituents as appropriate; and C with optionally 1-C 4 radix π-phenyl di-D-group; and-* indicates a carbonyl contact; or, if appropriate, their pharmaceutically acceptable salts and / or isomers, tautomers Substances, solvates or isotopic variants. -86- (3) 200533351 2 · The compound according to item 1 of the scope of patent application, where Q2 is a single bond. 3 · The compound according to item 1 of scope of patent application, where A Morpholinyl Pyrrolidinyl, piperidinyl, piperidinyl, or pyrazolyl, these groups optionally contain a monomethyl substituent. 4 · The compound according to item 1 of the scope of patent application, wherein A is selected from the group consisting of one or Pyrazolyl with two C! -C4 alkyl substituents. 5 · Compound according to item 1 of the scope of patent application, where Q 1 is * NR8 — Q3 〇6 · Compound according to item 1 of the scope of patent application, wherein (CH2) n — C (二 〇) — {^ Meta or para, one of R1 and R2 is independently selected from Η and (:)-0: 4 alkyl; -η is 0, 1 or 2-Q1 is a group selected from And * — NR8 ~ q2—a, where ρ is 1 or 2, (^ is d—0: 4 alkylene, R8 is Η or C] —c4 alkyl and A is pyridyl; C3 — C1G cycloalkyl The cycloalkyl group is optionally bridged with 1, 2, 3, or 4 carbon atoms, tetrahydropiperanyl, piperidinyl, tetrahydrothiopiperanyl, or the following group -87- (4) 200533351 R5 —R3, R4, R5, R6, and R7 are the same or different and are: H, C] —C4 alkyl, OR9, SR9, SOR9, CN, CF3, 〇CF3, S02NR9R10, CONR9 NHCORI (), and as appropriate Phenyl group of OH substituent;-R9 and R1G are the same or different and are selected from the hydrazone or C to carbonyl junction, or, where appropriate, their pharmaceutically acceptable tautomers of salts , Solvates, or isotopic variations. 7. Compound according to item 6 of the scope of patent application *-Q2-A group, in which Λ is cyclohexyl or diamond. 8 · Compound Q2-group A according to scope of patent application, in which A is selected from the following formulae From the following S02R9, halo, R10, NR9R10, 1-C4 alkyl and * table and / or isomers, wherein Q1 is alkyl. Where Q1 is Wherein R3, R4, R5, R6 and R7 are the same or phase-converted-C4 courtyard, OR9, SR9, SOR9, S〇2R '' OCF3, SO2NR9R] 0, COOR9, C〇n ^ 5 NHC 0 R] G and Phenyl, but its limiting condition is R 3 and is at least two selected from the group consisting of hydrazone, C group, CN, CF3, 〇〇, NR9R10, etc. -88- (5) (5) 200533351 where R9 and R1C) are Those who are the same or different and are selected from Η or C] -C4 alkyl. 9. The compound according to item 6 of the scope of patent application, wherein Q2 is -C Η 2-,-(C Η 2) 2-,-(C Η 2) 3-, or-(CH3) 2-〇 Where R3 'R4, R5 and R6 are all Η. η. The compound according to any one of claims 1 to 10 of the scope of patent application, wherein Ri is CH3 and R2 is CH3. 1 2. A compound according to any one of claims 1 to 10 in the scope of patent application, wherein n is 0 or 1. 1 3. — (R, R) -stereoisomers of compounds of any one of claims 1 to 10 in the scope of patent application. 14. The compound according to any one of the items 1 to 10 of the scope of patent application, wherein the (CH2) n-C (= 〇) Q1 group is at the meta position. 1 5. The compound according to item 1 of the scope of patent application, which is selected from the group consisting of: N-Carkey-2 — {3— [2— ({2 — 经 基 —2 — [ 5-Cyclo-6- (hydroxymethyl) pyridin-2-yl] ethyl 丨 amino) -2-methylpropyl] phenyl} acetamidamine; N-cyclopropyl-2-2- {3- [2- ({2-Methyl-2— [5-Hydroxy-6- (hydroxymethyl) pyridine-2-yl] ethyl} amino)-2 -89- (6) (6) 200533351 monomethylpropane Phenyl] acetomethylamine; 2-{3— [2— ({2-hydroxy-2— [5-hydroxy-6— (hydroxymethyl) pyridine-2-yl] ethyl} amino) — 2-methylpropyl] phenyl} —N— [(1R, 2S) — 2- (hydroxymethyl) cyclohexyl] acetamide; 2— {3— [2— ({2 —hydroxy-2— [5-Hydroxy-6- (hydroxymethyl) pyridine-2-yl] ethyl} amino) -2-methylpropyl] phenyl} —N— (3-morpholine-4-ylpropyl) Acetylamine; 2- {3— [2— ({2-Hydroxy-2— [5-Hydroxy-6- (hydroxymethyl) pyridine- 2-yl Ethyl} amino) -2-methylpropyl] phenyl} — N — (D ratio of 2-methyl-2-ethylmethyl) ethylamine; 2 — {3— [2— ({2 —hydroxyl 2-[5-Hydroxy-6- (hydroxymethyl) pyridin-2-yl] ethyl} amino) -2-methylpropyl] phenyl}-N- (2-morpholine 4-yl Ethyl) acetamide; 2- {3— [2— ({2-hydroxy-2— [5-hydroxy-6— (hydroxymethyl) pyridine-2-yl] ethyl} amino) —2— Methylpropyl] phenyl-N-isopropylacetamidamine; N — (4-chlorochloroyl) — 2 — {3 — [2 — ({2 —Ceryl — 2 — [5 —Hydroxy-6] — (Hydroxymethyl) pyridine-2-yl] ethyl 丨 amino) -2-methylpropyl] phenyl} acetamidamine; N — [2- (dimethylamino) ethyl] -2— {3 — [2— ({2—Hydroxy-2— [5-Hydroxy-6- (hydroxymethyl) pyridine-2-yl] ethyl} amino) —2—methylpropyl] phenyl 丨 B Hydrazine; N— [2- (monoethylamino) ethyl] —2— {3— [2— ({-90- (7) (7) 200533351 2 -hydroxy-2 — — 5-hydroxy 6- (hydroxymethyl) pyridine- 2-yl] ethyl} amino) -2-methylpropyl] phenyl 丨 acetamidine; N- [3- (dimethylamino) propyl] -2 — {3— 〔2— ({2 —Cycloyl-2— [5 —Cyclo-6— (Cyclomethyl) PϋΠa—2—yl] ethyl} amino) —2-methylpropyl ] Phenyl} ethanamide; 2 — {3 — [2 — (丨 2 —Cyclo-2 — [5 —Cyclo-6 — (hydroxymethyl) pyridine 2-yl] ethyl} amino) -2-methylpropyl] phenyl} -N -pentylacetamide; 2- {3-[2— ({2 -hydroxy-2-[5 -hydroxyl 6-(hydroxymethyl) pyridine- 2-yl] ethyl} amino) -2-methylpropyl] phenyl) -N- (2-pyrrolidin-1-ylethyl) monoacetamide; Ν- (2,4-dichloro Benzyl) — 2 — {3 — [2 — ({2 —taucyl 2 — [5 —hydroxyl 6 — (hydroxymethyl) amidinyl 2 —yl] ethyl} amino) — 2 —methyl Propyl] phenyl} ethanamide; Ν— (3,4-dichlorobenzyl) —2— {3— [2— ({2—hydroxyl—2— 5-hydroxy-6- (hydroxymethyl) 0-pyridine-2-yl] ethyl} amino) -2-methylpropyl] phenyl} acetamide; 2- {3 — [2— ({ 2-Ethyl-2--2- [5-Ethyl-6- (hydroxymethyl) pyridine- 2-yl] ethyl} amino) -2-methylpropyl] phenyl} — N- (4-oxy Benzyl) acetamidine; N— (2-—Ethylethyl) —2— {3— [2— ({2 —Cytoxy-2— [5 —Hydroxy-6— (hydroxymethyl) pyridine— 2-yl] ethyl} amino) -2-methylpropyl] phenyl acetomethylamine; 2 — {3 — [2 — ({2 — ^ yl — 2 — [5 —yl — 6 — (-91-(8) (8) 200533351 hydroxymethyl) pyridine-2-yl] ethyl 丨 amino) -2-methylpropyl] phenyl} —N-propylacetamidamine; 2— { 3— [2— ({2-Cyclo-2— [5-Cyclo-6- (hydroxymethyl) pyridine-2-yl] ethyl 丨 amino) -2-methylpropyl] phenyl} -N— (3-methoxypropyl) acetamide; N-cyclobutyl—2— {3— [2- ({2 —Hydroxy-2-2- [5 —Hydroxy-6 — (Hydroxy Methyl) pyridin-2-yl] ethyl} amino) -2 2-methylpropyl] phenyl} acetamidamine; 2- {3— [2- ({2 -hydroxy-2— [5 — Hydroxy-6- (hydroxymethyl) pyridine-2-yl] ethyl} amino) -2-methylpropyl] phenyl} — N — [(1R) -1 1- (1-naphthyl) ethyl } Ethylamine; N — 2, 3 — Monoammonium — 1 Η — £ 卩 1 — 1 — 2 — {3 — [2 — ({2—Branyl — 2 — [5 —Branyl — 6 — ( (Methyl group) 0 to 0 to give 2- 2-]] ethyl} amino)-2-methylpropyl] phenyl} acetamide; 2- {3— [2— ({2- — 2— [5—Ethyl-6— (hydroxymethyl) pyridine—2-yl] ethyl 丨 amino) —2—methylpropyl] phenyl} — Ν— [2— (1-methylpyridine -2-yl) ethyl] acetamidamine; Ν— (4-fluorobenzyl) —2— {3- 〔2— ({2-hydroxy-2 2- [5-hydroxy-6— (hydroxymethyl) Pyridine-2-yl] ethyl} amino) -2-methylpropyl] benzylamine, 2— {3 — [2— ({2 —Cyclo-2 — [5 —Cydro 6- (hydroxymethyl) pyridine- 2-yl] ethyl 丨 amino) -2-methylpropyl] phenyl} —N- (4-phenylbutyl) acetamidamine; -92- (9 ) (9) 200533351 2-{3— [2— ({2 —Cyclo-2— [5 —Cyclo-6— (hydroxymethyl) pyridine—2-yl] ethyl 丨 amino) —2 — Methylpropyl] phenyl} -N- (3-methoxybenzyl) acetamidamine; N-(3-ethoxypropyl) -2-{3 — [2— ({2 —heteroyl -2-[5-via 6-(transmethyl) D ratio π-2 -yl] ethyl} amino)-2-methylpropyl] phenyl} acetamidine; 2 — { 3- [2— ({2-Cycloyl-2— [5-Cyclo-6- (hydroxymethyl) pyridine-2-yl] ethyl} amino) -2-methylpropyl] phenyl} — N— (3,4,5-trimethoxybenzyl) acetamidamine; 2— {3 — [2— ({2-Cyclo-2— [5 —Cyclo-6— (hydroxymethyl) Pyridin-2-yl] ethyl} amino) -2 methylpropyl] phenyl} —N- (4-mono (trifluoromethyl) benzyl] acetamidamine; 2 — 丨 3 — [2 — ({2 — sheep to A 2- 2- [5- via 6- (hydroxymethyl) pyridine- 2-yl] ethyl} amino)-2-methylpropyl] phenyl} -N- [2- (trifluoromethyl ) Benzylacetamide; N — (3,5 —dimethoxybenzyl) — 2 — {3— [2— ({2 monohydroxy — 2 — [5-hydroxy — 6 — (hydroxymethyl) 0-pyridine-2-yl] ethyl} amino) -2-methylpropyl] phenyl} acetamidamine; 2 — {3— [2- ({2 —Ceryl — 2 — [5 —Ceryl -6- (hydroxymethyl) pyridine- 2-yl] ethyl 丨 amino) -2-methylpropyl] phenyl} — N- (2-phenoxyethyl) ethylamine, 2- {3— [2— ({2-Hydroxy-2— [5-Hydroxy-6- (hydroxymethyl) pyridine-2-yl] ethyl 丨 amino)-2-methylpropyl] phenyl}} (1S) — 2-hydroxy-1-methylethyl) acetamide-93- (10) (10) 200533351 2— 丨 3— [2— ({2 —Crystalline—2— [5 —Crystalline -6- (hydroxymethyl) pyridine- 2-yl] ethyl} amino) -2-methylpropyl] phenyl} -N — [(1S) —1-— A 2-methylpropyl] acetamidamine; 2 — {3 — [2 — ({2 —Cycloyl — 2 — [5 —, 6 — (hydroxymethyl) pyridine — 2-yl] ethyl } Amino} -2-methylpropyl] phenyl} —N— [(1S, 2S) — 1— (chain methyl) -2-methylbutyl] acetamidamine; N [(1R ) — 1-benzyl-2-hydroxyethyl) -2— {3-— 2- 2-hydroxy-2 — [5-hydroxy-6- (hydroxymethyl) Dttidine-2-yl] ethyl} Amine) -2-methylpropyl] phenyl} ethanamide; 2- {3 — [2— ({2 —Ethyl — 2 — [5 —Ethyl — 6 — (hydroxymethyl) pyridine — 2-yl] ethyl} amino) -2-methylpropyl] phenyl} -N- [(1R) — 1- (hydroxymethyl) propyl] acetamido 2— {3— [2— ({2-Cycloyl-2- [5-Cyclo-6- (hydroxymethyl) pyridine- 2-yl] ethyl} amino) -2-methylpropyl] phenyl 丨 N- [( 1S) — 1- (hydroxymethyl) -2,2-dimethylpropyl] acetamide; N-1 (1S) — 2-cyclohexyl-1— (hydroxymethyl) ethyl] —2— {3— [2 -— ({2-Hydroxy-2— [5-Hydroxy-6- (hydroxymethyl) pyridine-2-yl] ethyl 丨 amino) —2-methylpropyl] phenyl 丨 acetamidine; -94- (11) (11) 200533351 N— [(1S, 2R) — 2 —Hydroxy-2,3- —1—yl] —2— {3-[2 — ({2 —Cycloyl-6— (hydroxymethyl)) -2-yl] ethyl} ylpropyl] phenyl} acetamidamine; 2- {3 -— [2 -— ({2-hydroxy-2— [f hydroxymethyl) pyridine-2-yl] ethyl} Amine) -phenyl} -N— (2-propoxyethyl) acetamidamine; N— (4-hydroxycyclohexyl) —2 — {3 —I group — 2 — [5 —hydroxyl 6 — (Hydroxymethyl) D ratio is steeper} Amine) -2-methylpropyl] phenyl} acetamidamine; 2- {3-—2- ({2-Hydroxy-2-2- [5-hydroxymethyl) Pyridin-2-yl] ethyl} amino) -phenyl} -N- (3-propoxypropyl) acetamidamine; N-ethyl-N- (2-hydroxyethyl) -2- { 2-hydroxy-1 2- [5-hydroxy-6- (hydroxymethyl] ethyl} amino) -2-methylpropyl] phenyl} 1 — ({3 — [2 — ({2 — _ to 2- (hydroxymethyl) pyridine-2-yl] ethyl} amino)] phenyl 丨 piperidine-4 monocarboxamide; 6 — {2 — [(2 — {3 — [2 (4-Ethyl) -2-ketoethyl] phenyl} -1,1-diE] -1Hydroxyethyl 丨 2-2 ((hydroxymethyl) pyridine) 15 6 — {2 — [(2 — {3 — (2 — (3,4--2 (] H) —yl) —2 —fluorenylethyl] phenyl} — • nitro-1 1 Η —mu j5 -2 — [5 —Zhao Jiamine A) 2-methyl-hydroxy-6- (2-methylpropyl] [2- — {{2 -hydroxy: a 2-yl] ethyl; mono-hydroxy-6-(2-methylpropyl]- {3-〔2 — (Amino) pyrimidine—2—acetamidamine; [5 —Hydroxy-6—2—methylpropylamidinopiperidine 1 —Aminoethyl) amino — 3- Alcohol; -dihydroxyisoD-quinoline-1, 1 -dimethyl-95- (12) (12) 200533351 ylethyl) amino]-1 -hydroxyethyl 丨 -2-(hydroxymethyl) pyridine- 3-alcohol; N-benzyl-2— {3— [2— ({2-hydroxy-2— [5-hydroxy-6— (hydroxymethyl) Dttidine-2—yl] ethyl] amino) -2 -methylpropyl] phenyl 丨 N-methylacetamide; 6- {1- meridian-2-{[(2 — {2— [4— (2 — (Ethylethyl) -piperyl-1-yl] -2-ylethyl-2-phenyl) -1,1-dimethylethyl) amino] -2— (hydroxymethyl) pyridine-3— Ketones; 6— {2 — {[2 -— (3-—2- (4 -— (4-chlorophenyl) —4-hydroxypiperidine—1-yl) —2—ketoethyl] phenyl) — 1,1 dimethylethyl) amino] -1 1-tether ethyl) -2- (transmethyl) D-pyridine-3 alcohol; 6 — {2 — {[1 '1 — 1 Methyl-2 — {3 — [2 — (4-methylpiperazine-1—yl) —2—ketoethyl] phenyl) ethyl) amino] —1—hydroxyethyl] —2— (Hydroxymethyl) pyridine 3-ol; 2 — {3 — [2 — (丨 2-mesityl 2 — [5 —membrane-6 — (hydroxymethyl) pyridine — 2-yl] monoethyl } Amino} -2-methylpropyl] phenyl} —N —methyl—N — (2-phenylethyl) acetamidamine; 6 — {2 — [1,1 —_ ^ methyla 2 — {3 — [2 —Axyl — 2 — (4-pyridine — 2-ylpiperidine — 1 —yl) ethyl] phenyl) amine] — 1 — hydroxy Group) —2— (hydroxymethyl) pyridine—3-ol; N — [3- (dimethylamino) -propyl] —2— {3— ({2 — hydroxy—2-[5 —hydroxy— 6- (hydroxymethyl) pyridine-2-yl] ethyl} amino) -2-methylpropyl] phenyl 丨 N-methylacetamide; -96- (13) (13) 200533351 N — (2 —Hydroxyethyl) — 2 — {3— [2— ({2—Hydroxy-2— [5 —Hydroxy-6— (hydroxymethyl) pyridine—2-yl] ethyl} amino) -2-methylpropyl] phenyl} -N-propylpropanamide; N— [2- (diethylamino) ethyl] —2— {3— [2— ({2 —hydroxyl-2 — (5 —hydroxy-6— (hydroxymethyl) oxidine—2-yl] -ethyl} amino) —2-methylpropyl] phenyl 丨 N-methylacetamide; 6 — { 2 — {(1,1 —monomethyl-1 2 — {3 — [2 — (4-methyl-1,4-diazepine-1 1-yl) -2-phenylethyl] phenyl) Amine]-1 via ethyl group)-2-(transmethyl group) D ratio of a 3-alcohol; 6-[2-({1, 1, 1-^ methyl_ 2 — [3- — (Mulan-1, 4-Amino-2, 2-Ethyl)] phenyl) ethyl] amino) —1—Ethyl) —2— (hydroxymethyl) pyridine—3—alcohol; 6— [2— ({1,1-dimethyl-2— [3 -— (2—morpholine—4-yl—2-ethyl] phenyl) ethyl] amino) —1—methylethyl ) 2 — (hydroxymethyl) pyridin — 3 — alcohol; 2 — {3— [2— ({2 —hydroxyl 2 — [5 —hydroxyl 6 — (methylol) approved ^ 2 -Yl] ethyl} amino) -2-methylpropyl] phenyl 丨 N-methyl-N- [(1S) — 1-phenylethyl] acetamido 6 — [2 — ({ 1 '1' monomethyl — 2 — [3 — (2 —fluorenyl — 2 — 1-piperidine — 1 —ethylethyl) benzyl] ethyl 丨 amino) — 1 )-2-(hydroxymethyl) pyridine-3-alcohol; 6-(1-via 2-{[2 — (3 — {2-[(3 R) — 3--97- (14) (14 ) 200533351 hydroxypyrrole-1 monoyl) -2-ketoethyl} phenyl) -1,1-dimethylethyl) amino} ethyl) -2 2- (hydroxymethyl ) D than pyridinyl 3-alcohol; 6 — (1-hydroxy-2 — {[2— (3 — {2 — (3R) — 3 — hydroxypiperidine-1 —yl) — 2 — ketoethyl} Phenyl) -1,1-Dimethylethyl] amino} ethyl) -2— (Aminomethyl) 0 to 0—A 3-alcohol; 6— {2 — [(2 — {3 — [2 -— (4-Ethyl-1,4-—Aza-A—1—A)) — 2-Aminoethyl] phenyl} —1,1 —_ «methylethyl) amino] — 1 monohydroxyethyl} 2- 2- (hydroxymethyl) pyridine 3-alcohol; 6- (1-meryl-2— {[2— (3— {2— (4-methyl Pyridine-1 monoyl) -1 2-ketoethyl} phenyl) -1,1-dimethylethyl] amino} ethyl) 2 2- (hydroxymethyl) pyridine 3 -alcohol 9 N — [1 ({3-[2— ({2 —Cyclo-2— (5—Cyclo-6— (Cyclomethyl) D is more than 2-diyl] ethyl} amino) —2— Methylpropyl] phenyl} ethylfluorenyl) pyrrolidine-3-yl} —N-methylacetamidinylamine; 2 — {3— [2 — ({2-meryl — 2 — (5 —meryl 6-(hydroxymethyl) Pyridinyl-2-yl] ethyl} amino) -2-methylpropyl] phenyl} — N— (2-methoxyethyl) —N-propylacetamidamine; N —ethyl-2 — {3 — [2 — ({2 —Cyclo-2 — (5 —Cyclo-6— (hydroxymethyl) pyridine—2-yl] ethyl} amino) —2—methylpropyl] Phenyl} ethenyl) -N— (2-methoxyethyl) ethenamide; • 98- (15) (15) 200533351 N— [3 (dimethylamino) -1,2-dimethyl Propyl] 2-{3-[2-({2-hydroxy-2-(5-hydroxy-6-(hydroxymethyl) pyridine-2-yl] ethyl} amine)-2-methyl Propyl] phenyl} ethanamine; N— [3-fluoro-5— (trifluoromethyl) benzyl] —2— {3— [2 — ({2 —hydroxyl 2 — (5 —hydroxyl 6 — (hydroxymethyl) pyridine—2-yl] ethyl 丨 amino) —2-methylpropyl] phenyl} acetamidamine; 2- {3 — [2- ({2- — -2-(5-via a 6-(hydroxymethyl) pyridine-2-yl] ethyl 丨 amino)-2- methyl propyl] phenyl-a N-[(1 S) —1- (Hydroxymethyl) 3-methylbutyl] acetamide; 2- {3-[2— ({2 —Cyclo-2— (5—Cyclo-6— (Hydroxymethyl) Yl) pyridine mono-2-yl] ethyl} amino) 2-methylpropyl] phenyl} —N — [(1S) — 2 —Cyclo-1 monophenylethyl] acetamido N, N — _Ethyl 2 — {3 — [2 — ({2 —Ethyl — 2 — (5 —Hydroxy-6 — (hydroxymethyl) pyridine 2 -yl] ethyl —amino) — 2 — Methylpropyl] phenyl} amine acetic acid; 2 — {3 — [2— (2-acyl-2- (5-acyl-6— (hydroxymethyl) pyridine-2-yl] ethyl)} Amine)-2 -methylpropyl] phenyl 丨 N— 1 1 —pyrazole-5 —ylacetamidamine; 2-{3— [2— ({2 —Ethyl 2-(5 — Ethyl-6- (hydroxymethyl) pyridine-2-yl] ethyl} amino) -2-methylpropyl] phenyl 丨 N— (5-methyl-1 1 Η-pyrazole-1 3- ) Ethylamine; -99- (16) (16) 200533351 N— (cyclohexylmethyl) —2— {3— [2— (丨 2 —hydroxyl 2 — (5 —hydroxyl 6 — ( Methyl) amidinyl-2-yl] ethyl} amino) -2-methylpropyl] phenyl acetoamine; 4- ({3— [2- ({2-Hydroxy-2— ( 5-hydroxy-6- (hydroxymethyl) pyridine- 2-yl] ethyl} amino) -2-methylpropyl] phenyl} ethenyl) piperidine-1 monocarboxylic acid ethyl ester; N- (5-chloropyridine-2-yl) -2— {3— [2— ({2 — hydroxy-2-(5-hydroxy-6 — (hydroxymethyl) pyridine-2-yl] ethyl) amino} ) 2-methylpropyl] phenyl} acetamide; 2 — {3— [2— ({2 —Cyclo-2— (5 —Cyto-6— (hydroxymethyl) pyridine—2— Group] ethyl 丨 amino) -2-methylpropyl] phenyl} — N-(6-methylpyridine-2-yl) acetamidamine; 2 — {3 — [2 — ({2 — —2 — (5 —Shenyl — 6 — (hydroxymethyl) pyridine — 2 —yl] ethyl} amino) — 2 —methylpropyl] phenyl} — N — (3 —methylpyridine — 2-yl) acetamidamine; 2- {3— [2— ({2-meridyl-2- (5-meridyl-6- (hydroxymethyl) pyridine-2-yl] ethyl} Group)-2-methylpropyl] phenyl} —N-isoD-quinoline-1 1-methylacetamide; N— (4,6-dimethyldimethylpyridine-2—yl) —2— { 3— [2 —. ({2 —Hydroxy-2 — (5 -Hydroxy-6 — (hydroxymethyl) pyridine-2 2-yl] ethyl 丨 amino) -2-methylpropyl] phenyl} ethyl Hydrazine; 2 — {3 1 [2 — ({2 —taucyl — 2 — (5 —Cyclo-6— (hydroxymethyl) pyridine—2—yl] ethyl} amino) —2—methyl Propyl] phenyl 丨 N- (2-methoxybenzyl) acetamidamine; -100- (17) (17) 200533351 N — [(IS) — 1 —benzyl — 2 —hydroxyethyl] One 2- {3 — [2 — ({2-hydroxy-1 2-(5-hydroxy-1 6-(hydroxymethyl) pyridin-2-yl] ethyl} amino)-2-methylpropyl] benzene Ethylamine N — (1 —Ethyl — 1 Η — 5 —yl) — 2 — {3 — [2 1 ({2—hydroxyl 2 — (5 —hydroxyl 6 — (hydroxyl (Methyl) pyrimidin-2-yl] ethyl} amino) -2-methylpropyl] phenyl} acetamidamine; Ν— (1,3-dimethyl-1Η) Amidazol 5 -yl) 2-{3 1 [2-({2 -hydroxyl 2-(5 -hydroxyl 6-(hydroxymethyl) pyridine 2 -yl] ethyl) amino)-2 —Methylpropyl] phenyl} ethanamine; Ν — (3-chlorocarbyl) — 2 — {3 — [2 — ({2 —Ceryl — 2 — (5-hydroxy-6— (hydroxymethyl) ) Pyridin-2-yl] ethyl 丨 amino) -2-methylpropyl] phenyl} acetamidamine; 1- ({3-—2-({2-Cycloyl-2-(5- Via 6- (hydroxymethyl) pyridine- 2-yl] ethyl 丨 amino) -2-methylpropyl] phenyl} acetamidine) -L-proline amine; 6- {2- [(2- {3-—2- (5-amino-3—third-butyl-1—pyrazol-1-yl) —2—ketoethyl] phenyl} — 1, 1, 2-dimethyl Ethyl) amino]-1 -hydroxyethyl-1-(hydroxymethyl) pyridine-3 -ol; 2-{3-[2-({2 -hydroxy-2-(5- 6- (hydroxymethyl) pyridine- 2-yl] ethyl} amino) -2-methylpropyl] phenyl). -N-[(1 S)-1 -phenylethyl ] Ethylamine; -101-(18) (18) 200533351 N— (3,4-dimethylbenzyl) —2— (3— {2— [2 —hydroxyl 2 — (5 —hydroxyl 6 — (Hydroxymethyl) pyrimidin-2-yl] ethyl} amino) —2-methylpropyl 丨 phenyl] acetamidamine; N— [2- (4-chlorophenyl) ethyl] — 2- (3— {2- [2-hydroxy-2— (5-hydroxy-6— (hydroxymethyl) pyridine-2-yl] ethyl 丨 amino) -2-methylpropyl] phenyl} Acetylamine; 6- {2— [(2— {3— (2 — (1,4-dioxa-8-azaspiro [4.5] dec-8-yl) -2-ketoethyl] Phenyl 丨 -1,1-dimethylethyl) amino] -1-hydroxyethyl 丨 2- (hydroxymethyl) pyridine-3-ol; and N- (2-hydroxybenzyl) -2 — (3— {2-[(2R)-2 —Hydroxy-2 — (5-Hydroxy-6 — (Hydroxymethyl) Hexidine-2 —yl] Ethylamino] propylphenylphenyl) acetamidine ; N-benzyl-2— (3 -— ((2R) —2— [2-hydroxy-2— (5-hydroxy-6- (hydroxymethyl) pyridine-2-yl] ethyl Amine] propyl} phenyl) acetamidine; N— (3,4-dimethylbenzyl) —2— (3 -— ((2R) —2— [2-hydroxy—2— (5-hydroxy 6- (hydroxymethyl) pyridine-2 2-yl] ethylamino] propyl 丨 phenyl) acetamidamine; N— (2,5-dimethylbenzyl) —2— (3— {(2R )-2-[2-Hydroxy-2 — (5 -Hydroxy-6-(hydroxymethyl) pyridine 2 -yl] -2-(3-{(2 R)-2-[2 -Ethyl radical 2 -(5-Ethyl-6- (hydroxymethyl) pyridine-2-yl] ethylamino] propyl} phenyl) acetamidamine; -102- (19) (19) 200533351 2 ~ (3— { (2R) — 2— [2-Hydroxy-2— (5-Hydroxy-6- (hydroxymethyl) pyridine—2-yl] ethylamino] propyl} phenyl) —N— (2 ~ methoxy Benzyl) acetamidine; (2-ethoxybenzyl) -2— (3 -— ((2R) —2— [2-hydroxy ~ 2— (5-hydroxy-6- (hydroxymethyl) pyridine) —2 —yl] ethylamino] propyl} phenyl) acetamidamine; N ^ (3, 4-dichlorobenzyl) — 2 — (3-{(2R) — 2 — [2 — Hydroxy-2 mono (5-hydroxy-6- (hydroxymethyl) pyridine-2-yl] ethylamino] propyl} phenyl) acetamide, and (2-chloro-6-fluorobenzyl) -2— (3- {(2R)-2 [? ~~ hydroxy-2 (5-hydroxy-6-hydroxymethylpyridin-2-yl] ethylamino] propyl} phenyl) acetamidamine. 16 · A pharmaceutical composition for treating diseases, disorders, and symptoms, which comprises an effective amount of a compound of formula (1) in any one of claims 1 to 10 of the patent application scope or a pharmaceutically acceptable derivative derived therefrom Of salt. 17 · The compound according to any one of claims 1 to 10 of the scope of patent application, or a pharmaceutically acceptable salt or their composition derived therefrom, which is used as a medicinal product. 18 · A compound of any one of claims 1 to 10 of the scope of patent application, or a pharmaceutically acceptable salt or a composition derived therefrom, which is used to treat diseases and disorders selected from the following And symptoms of medicinal use: • Asthma of any type, etiology, or pathogenesis, especially selected from the group consisting of ectopic asthma, non-ectopic wheezing, allergic wheezing, and ectopic bronchial IgE — Vector wheezing, bronchial wheezing, spontaneous wheezing, true wheezing, -103- (20) 200533351 intrinsic wheezing, non-ectopic wheezing, branching, exercise induced by pathological disorders Asthma, allergic wheezing, occupational asthma, consisting of bacteria, true infectious asthma, non-allergic asthma syndromes, and bronchiolitis • Chronic or acute bronchoconstriction, and emphysema, • Any type, etiology, or disease, especially selected from chronic eosinophilic (C PD), including COPD with chronic bronchial irrelevant dyspnea; COPD of the characteristic of obstruction, adult suffocation "Other medical treatment centers Airway causing airway movement Diseases in the group of diseases, • Any type, the source or origin of which is acute bronchitis, acute laryngotracheobronchitis, floating bronchitis, dry bronchitis, productive bronchitis, glucose and pulmonary bronchitis, • acute lung injury, • any type, the source, or hair is selected from the group consisting of columnar bronchiectasis, cystic wheezing, autonomic bronchial wheezing, emphysema wheezing, wheezing, Cold-air-induced asthma, protozoa, or virus-induced wheezing, primary wheezing, wheezing in infants, wheezing, chronic bronchitis, small airway obstruction principle, obstructive or inflammatory airways Pneumonia, chronic obstructive pneumonia disease ^, emphysema or irreversible with COPD, progressive airway [distress syndrome (ARDS), due to excessive weight gain and blockage of one of the members associated with pulmonary hypertension] Principles of inflammatory or inflammatory airways Three bronchitis, especially bronchodilators based on principles of inflammation, arachis bronchitis, mucosal bronchitis, infectious asthma or streptococcal bronchitis, especially Bronchiectasis, fusiform bronchiectasis -104-- (21) 200 533 351, one of the group's bronchial capillary bronchiectasis, cystic bronchiectasis, dry bronchiectasis and follicular bronchiectasis constituted expansion. 19 · A composition of a compound according to any one of claims 1 to 10 and another therapeutic agent selected from the group consisting of: (a) a 5-lipoxygenase (5-LO) inhibitor or 5- Lipoxygenase activating protein (FLAP) antagonists, 鬌 (b) Leukotriene antagonists (LTRAS) including LTB4, LTC4, LTD4, and LTE4 antagonists! J, (c) Histamine receptor antagonists include H3 and H3 antagonists, (d) α!-And α 2-adrenergic receptor agonist, vasoconstrictor, sympathomimetic for decongestion, (e) muscarinic M3 receptor antagonist or anticholinergic agent, (f) PDE inhibition, all together! 1, female PDE3, P DE4 and PDE 5 j Qi! I, (g) tea test, (h) sodium cromoglycate, (i) COX inhibitors include non-selective and selective COX-1 or COX-2 inhibitors (NSAIDs), (j ) Oral and inhaled glucocorticoids, such as DAGR (dissociation agonist of the corticosteroid receptor), (k) monoclonal antibody actives against endogenous inflammatory entities, (1) anti-tumor necrosis factor ( anti — TNF-α) agents, (m) adhesion molecule inhibitors include VL Α-4 antagonists, (η) kinin! Yihe / 3 2 —receptor antagonist, -105- (22) 200533351 (〇) immunosuppressants, (P) matrix metalloproteinases (MMPs) inhibitors, (q) tachykinin NKi, NKdd NK3 Receptor antagonists, (r) elastase inhibitors, (s) adenosine A2a receptor agonists, (t) urokinase inhibitors, (u) compounds that act on dopamine receptors, such as d2 agonists, (v) NF «pathway modulators, such as IKK inhibitors, (w) modulators of the cytokine signaling pathway, such as p3 8 MAP kinase, syk kinase or jAk kinase inhibitors, (X) agents that can be classified as mucus solvents or antitussives, and (y) antibiotics. -106- 200533351 Qi Wuming said that the single abbreviation symbol table is the definitive drawing reference table of the original drawing table: the copy of the plan and the copy ^ \) y If there is a chemical formula in this case, please reveal the best display Inventive chemical formula: OH (CH2) n \ R1 R2 V ⑴ 〇