TW200534846A - Compounds useful 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

200534846 IX. Description of the invention: [Technical field to which the invention belongs] The present invention relates to a / 52 activator of the following general formula

HO

R1, R2, η, and Q1 all have the meanings indicated below,

And a method for preparing such derivatives, for preparing their intermediates, compositions containing them, and uses thereof. [Prior art] Adrenaline receptors are members of the large G-protein coupled receptor superfamily. The adrenergic receptor subgroups themselves are divided into Wan subgroups, of which the dot subgroups are composed of at least three receptor subtypes: say, say, and 戽. These receptors display differential expression patterns in the tissues and organs of mammals. / 32 Adrenergic receptors are mainly expressed in smooth muscle cells (such as blood g, bronchial organs, uterus or intestinal smooth muscle), while negative adrenergic receptors are mainly expressed in adipose tissue (hence the term Motility agents can potentially be used to treat obesity and diabetes), and adrenergic receptors are mainly expressed in heart tissue (hence milk activators are mainly used as cardiac stimulants). The pathophysiology and treatment of airway diseases have been extensively reviewed in the literature (for research materials, see Bames, pj Chest, 1997, 111: 2, pages 17S-26S 'and Bryan, SA, et al., Research Expert opinion on medicines, 2000, 9: 丨, pages 25_42), so here is only a brief excerpt to provide some background information. 99200 200534846 Corticosteroids, anti-leukotriene, parent-, talent, test, tryptamine, anti-biliary test, and / 52 activator, which constitute the current ° 〆 * 苒 or the purpose for the treatment of allergies The meaning of sexual and non-allergic airway diseases, such as the treatment guidelines for asthma and chronic obstructive airway disorders include short-acting and long-acting inhalation handsome = both. The short-acting rapid-acting β-activator system is W Rescue " Bronchial = Large ', however, the long-acting form provides long-lasting relief and is used as maintenance therapy.

The bronchiectasis is a mediator of adrenaline receptors that is known to be present on lice smooth muscle cells. It causes relaxation and is therefore an enlarged branch of milk. Therefore, as a functional antagonist, activators are said to prevent the effects of all bronchial constrictor substances, including Baisanxian: D4 (LTD4), acetylcholine, angiotensin, prostaglandin, Histamine and endothelin. Because the receptor system is so widely distributed in the airways, stimulants can also affect other cell types that play a role in asthma. For example, activators have been reported to stabilize mast cells. Inhibition of the release of tracheal constrictor substances' can be a way of how an activator can block the narrowing of the trachea caused by allergens, exercise and cold air. Furthermore, deep activators can inhibit cholinergic neurotransmission in the human airway, which may cause reduced cholinergic_reflex bronchoconstriction. In addition to the J airway, it has also been established that adrenergic receptors are also expressed in other organs and tissues, and thus become stimulants. For example, the adrenergic receptors described in the present invention have application in the treatment of other diseases. Diseases such as but not limited to neurological diseases, premature birth, congestive heart failure, depression, inflammatory and allergic skin diseases, psoriasis, proliferative skin diseases, glaucoma, and low monthly prevalence of 99200 200534846 Symptoms of interest 'especially stomach and peptic ulcer. However, many / 32 activators are limited in their use due to their low selectivity or adverse side effects, which are driven by high systemic exposure, and are mainly caused by blazed epinephrine that appears outside the airway The mediator of the role of the receptor (muscle shock, tachycardia, palpitations, can't sleep). Therefore, improved medicaments are needed in this category.

Therefore, there is still a need for novel cheering activators, which have an appropriate pharmacological action state, such as in terms of efficacy, selectivity, duration of action, and / or medicinal properties. In this connection, the present invention relates to novel activators. EP 0654534 Β1 and EP 0939134 Β1 are revealed—a method for preparing a compound of formula: R1 OZ R6

These 4 compounds have been revealed as anti-obesity and anti-diabetic agents having specific 3 activity. US 5,561,142 series reveals that the following formula is said to be selective activator OH R4 chch2n rjj-s〇2 (CH2) plant R7 (R1) n R3 I7 R6 r0-x ~ chcho-n- EP0236624 discloses the compound of the formula OH R1 R2

_ (CH2) n-Y

R4—R5 R3 99200 200534846 It has anti-obesity and / or anti-hyperglycemia activity, and it has good selective combination with cardiac side effects. [Summary of the Invention] The present invention relates to a compound of general formula ⑴:

Q1 (1) φ where (CH ^ -CpCOQ1 group is in meta or para position, -R1 and R2 are independently selected from Η and Ci-q alkyl, -η is 0, 1 or 2, and -Q1 is optional From the group: R3 R4 R3

-Q2 is a single bond or cvc4 alkylene group, -R8 is only or (^-(: 4 alkyl group, * ρ is 1 or 2, and -A is C3 -Ci cycloalkyl group, 2 of the cycloalkyl group) Carbon atoms or more, optionally bridged by one or more carbon atoms, preferably by one, two, three, or four carbon atoms, alpha phenyl 4 azolyl, 5 to 10 membered heterocyclic groups A group, optionally aromatic, containing one, two, three, or four heteroatoms selected from 0, S, or N, optionally substituted with a CVQ alkyl group or 0 & 7 4 99200 200534846 alkyl group, or the following formula Group

-圮, 114, 115, 116, and 117 are the same or different, and are selected from 11, (: 1 _ (: 4 alkyl, OR9, SR9, SOR9, S02R9, halo, CN, Cf3, ο%, phenyl 〇-phenyl, S-phenyl, Sormorpholinyl, 〇 (CH2) 3-tetrahydropyrrolyl,

COOR9, S02NR9R10, co-NR9R10, NR9r10, and NHCOR10; -R9 is the same or different from Rio and is selected from the alkyl group, and * represents the point of attachment to the carbonyl group; or, if appropriate, its pharmaceutically acceptable salt And / or isomers, tautomers, solvates or isotopic variations, with the proviso that when η is 0, then Q1 is not _NHCH3, and when 11 is 1 or 2, then: 1) Q1 is * -ΝΗΑ -C4 alkyl or * -N (R8) -Q2 -A, where a is -4 (10¾ alkyl, and the cycloalkyl has 2 or more carbon atoms, depending on the circumstances Or bridges of more than one carbon atom, -0-phenyl-esigma, 5 to 10 membered heterocyclic groups, optionally aromatic, containing one, two, three or four selected from 0, S or Ν Heteroatom, optionally substituted by Ci_c4 alkyl or O-Ci-C4 alkyl, the heterocyclic group is not pyridyl, the following formula is 99200 • 10 · 200534846

CN, SOR9, S02R9, phenyl, 0-phenyl, S-phenyl, S02-morpholinyl or 0- (CH2) 3-tetrahydrop-pyrrolyl, and / or 2) When R1 and R2 When one is Η, the other is not CH3.

It has been found that the compound of formula (1) is an agonist of the / 32 receptor, which is particularly useful for treating diseases and / or symptoms of the medicament, and shows good efficacy, especially when administered via the inhalation route. In the present invention, the term "effective" means that the compound of formula (I) shows an agonist potency of an antagonistic receptor, which is less than 10 nM when measured by a cell-based assay as described herein. . The compounds of the invention are preferably selective agonists for the / 32 receptor. The compound of the present invention preferably exhibits a stimulant effect on a receptor-forming agent, which is at least about 100 times higher than that of a calendar receptor and at least about 500 times higher than that of a milk receptor. In the above general formula (1), 'q-C: 4-alkyl group and q-C4-alkyl group represent a linear or branched group containing 1, 2, 3, or 4 carbon atoms. This also applies if it is substituted or substituted with other groups, such as in alkyl, S- (Ci-C4) alkyl, and the like. Examples of suitable (Ci_C4) alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, second-butyl, second-butyl ... Examples of suitable 0-%-C: 4) alkyl groups are methoxy, ethoxy, n-propyloxy, isopropoxy, n-butyloxy, isobutoxy, second- Butoxy and tertiary-butoxy ... 99200 -11-200534846 two or more carbon atoms are C3 -Ci cycloalkyl groups which are bridged by one or more carbon atoms as appropriate. Cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl , Cycloheptyl, auranyl, bicyclo [3.u] heptane, bicyclo [221] heptane, bicyclo [2.2.2] octane. Preferred cycloalkyls are cyclohexyl and auryl. 5- to 10-membered heterocyclic groups, optionally aromatic, containing one, two, two, or four heteroatoms independently selected from 0, S, or N, examples of which are morpholinyl, tetrahydropyrrolyl, Hexahydropyridyl, hexahydropyridyl, thienyl, isothiazolyl, oxazolyl, pyridyl, pyrimidinyloxazolyl, isoxazolyl, pyrazolyl, furyl, imidazolyl, pyrazolyl, Pyrrolyl, dacrotyl, pyrargyl, triazolyl, tetrazolyl, amidazolyl, trigenyl, indolyl, quinolinyl, isofluorinyl, benzofuranyl, quinazolyl, Fluorenyl, pyrenyl, benzothiasalyl, benzodecyl, benzoiso, fluorenyl, benzoisofluorenyl, benzimidazolyl, indazolyl, and benzotriazolyl. Preferred heterocyclic groups are tetrahydropyrrolyl, pyridyl, pyrimidinyl, quinolinyl, isoquinolinyl, benzimidazolyl and benzofuranyl. The hetero group group preferably contains one or two hetero atoms selected from 0, s or N. The heterocyclic group more preferably contains one or two nitrogen atoms. Finally, the _ group means an atom selected from the group consisting of a fluoro group, a chloro group, a bromo group, and an iodine group, especially a fluoro group or a gas group. In the following, a free state bond on a phenyl group, such as in the following structure, means that the benzyl group may be substituted at the meta or para position. Compound of formula (1) 99200 -12- 200534846

It can be made using conventional procedures, such as by the following illustrative method, where Ql, Q2, A, and n are as defined above for the compound of formula VII, unless otherwise mentioned.

Derivatives of formula amines can be obtained by making the acid of formula (2): QH

(ch2) 〇ΗΤ (2) is made by coupling with an amine of the formula NHrCVC4 and amine of _NH (R8) -Q2-A,

This coupling system is generally used in excess of the amine as an acid acceptor, and conventionally uses aW (e.g. 1- (3-_methylaminopropyl) _3_ethylcarbodiimide hydrochloride or N , N a cyclohexyl rabbit diimide) 'as appropriate in the presence of a catalyst (eg, benzylbenztriazole hydrate or __ hydroxyfazepine benzotriazole), and optionally a tertiary amine base (eg, Ν -Methylmorpholine, triethylamine or diisopropylethylamine). The reaction can be carried out in a suitable solvent, such as echinium, dimethylformamide, tetrahydrofuran, dimethylarsine, dichloromethane or ethyl acetate, and at a temperature between 10 ° C and 40 ° C (room temperature). Next, proceed for a period of 1-24 hours. 99200 -13- 200534846 a fe is made from commercially available materials, whether it is commercially available, or can be hunted and cooked by the artist (for example, reduction of knowledge, customary protection, etc.). ㈣ 、 Removal Formula (2) 酉 夂 can be made from its corresponding formula ester:

Among them, Ra is a suitable acid protecting group, preferably (CrQ) alkyl, which includes, but is not limited to, methyl and ethyl. According to any method known to those skilled in the art, acids can be prepared from esters without the rest of the molecule. Partial modification. For example, an ester can be made to exist in an aqueous acid or base (eg, hydrogen chloride, potassium hydroxide, sodium hydroxide, or hydroxide) 'optionally in a solvent or solvent mixture (eg, water, dioxolane, tetrahydrofuran / water). The temperature is between 20 ° C and 100 ° C. (: At a temperature of between 1 and 40 hours for hydrolysis. Ester of formula (4) can be obtained by formula (5) amine:

Where Ra and η are as defined above, and reacted with the bromide of formula ⑹ to make:

Br ⑹ HO 99200 -14- 200534846 In a typical procedural order, the formula amine and the formula ⑹ bromide are used, as appropriate,> cereal or lozenge mixtures (such as dimethylphosphine, methylbenzene, ν, ν · In the presence of dimethylformamide, acetonitrile, and optionally a suitable base (such as triethylamine, diisopropylethylamine, potassium carbonate), at a temperature between 8 (rc and 12 (rc) The reaction time is from 12 to 48 hours.

The alcohol is prepared from the ester according to any method known to those skilled in the art without modifying the rest of the molecule. In a typical procedure, the sulfonium ester is sulfonated with a borane to the methane complex in tetrahydrofuran under reflux for 2 hours. Formula methanol can be prepared according to the method described in the literature (Tetrahedron Letters 1994, 35 (50), 9375), whether it is (R) or palmarium isomers. The amine of formula (5) can be made from its corresponding formula ⑻ protected amine, whether it is ⑻ or ⑸ palm isomers ...

Rc

(8) ', Ra and n are as defined above, and Rb and Rc represent any appropriate substitution of the 99200 -15-200534846 group' so that HNRbRc is a para-amino amine (for example, Rb may be hydrogen and Rc may be α- Methylbenzyl), provided that the bond between n and the site and between N and Rc can be easily cleaved 'to obtain the free-form amine of formula (5), using standard operating methods for cleaving nitrogen protecting groups, such as in textbooks TWGREENE, Protective group for organic synthesis, published by A. Wiley-Interscience, 1981. Formula fluorene can be made into a single diastereomer by the reaction of amine HNRbRc amine with formula fluorenone:

Where Ra, Rb, Rc and η are as defined above. ⑼ In a typical procedure, the reaction of a ketone of formula (9) with an amine of formula

Or digas methane is conducted at a temperature between 20 ° C and 80 ° C for 3 to 72 hours. Then, the formed product is converted into its hydrochloride, and the sodium cyanoborohydride or the formula Na (0Ac) 3BH sodium triethoxylate borohydride is appropriately dissolved, as appropriate, depending on the desiccant (for example, molecular sieve, sulfuric acid Reduction in the presence of magnesium), and optionally in the presence of an acid catalyst (such as acetic acid), yields amidine, which is a mixture of diastereomers. This reaction is generally in a solvent, such as tetrahydrofuran ethanol, methanol, diisopropyl ether, or crystals, to obtain (8), which is a single diastereomeric W or> cereal mixture (such as isopropanol, diisopropyl Ether / methanol) selectively binds the isomers. A ketone of formula (9), where η = ι, can be obtained by the formula (1) aryl halide: 99200 -16 · 200534846 〇Ra (10) wherein Ra is as defined above, and Hal represents a southern atom. It includes, but is not limited to, molyl and moth-based, and is made by coupling the medium with a dilute or enol equivalent. In Xiang Dian's private order, the formula aryl dentate and dilute tin alcohol (produced on the spot by treating isopropyl acetate with the formula BU3SnOMe trimethoxy-n-butyl tin acetate) were obtained in Properly place a catalyst (palladium acetate / tri-o-tolylphosphine of formula pd (〇Ac) 2 / ρ (〇_τ〇1) 3) in a non-polar solvent (such as toluene, benzene, hexane)中 反应。 In the reaction. The reaction is preferably carried out at a temperature between 80 ° and n ° rc for 6 to 16 hours. An aryl iS compound of formula (10) can be obtained by esterification of its corresponding acid of formula (u):

Among them, Hal is as defined above. According to any method familiar to the artist, the ester is prepared from an acid without modifying the rest of the molecule. In a typical procedure, an acid of formula (11) and an alcoholic solvent of formula RaOH are used, where Ra is as defined above, in the presence of an acid, such as hydrogen chloride, between 10 ° C and 40 C (room temperature). The reaction was carried out at a temperature of 8 to 16 hours. The acid of formula (11) is a commercial product. Amine of formula (5), wherein R1 and R2 are the same q-C4 alkyl group, and can be prepared according to the following formula 99200-17-17200534846:

R2 and Ra are as defined above. ⑸ where R1

In a typical procedure, using the above method, the ester of formula (12) is reacted with an "activated alkyl group (organometallic alkyl group, such as r2 MgBr, r2 MgCl, or R2 Li) to obtain the corresponding formula ( 13) tertiary alcohol. Then, the tertiary alcohol of formula (13) is treated with a trinitrile (eg, ethyl acetate, chloroethoxy) in the presence of an acid (eg, sulfuric acid, acetic acid) to obtain a protected intermediate, In turn, the standard nitrogen splitting protective group is used to do the tricks, such as described in the textbook, to split it. Then, using the amino ester of Dunke in this article, the amino esterification is obtained to obtain the amine of formula (5) The method of 乂 makes the formed or amine of formula (5), in which both Han 1 and Chi 2 are η = 0, and can be made according to the following scheme: ",, the same Ci <: 4 alkyl group, stand 99200

Formula 2

(15)

〇Ra (5) -18- 200534846 wherein R1, R2 and Ra are as defined above. In a typical procedure, the above method is used to react an ester of formula (M) with an "activated" alkyl group (organometallic alkyl group, such as R2MgBr, to obtain the corresponding tertiary alcohol of formula (15) Then, the tertiary alcohol of formula (15) is treated with a benzyl group (such as ethyl wax and ethyl chloride) in the presence of an acid (such as sulfuric acid and acetic acid) to obtain a protected intermediate, which is sequentially used to split nitrogen. Standard methods of protecting groups, such as those described in textbooks, are split to obtain bromoamine (16). The formed bromoamine (16) is treated with a suitable palladium catalyst (for example [^ 广 双 (dibenzene Phosphinyl) dicyclopentadiene iron] dichloropalladium (11)), in a carbon oxide atmosphere, using RaOH as a solvent (eg, MeOH, EtOH) 'at high temperature (100 ° C) and pressure (100psi) It is processed to obtain an ester of formula (5). Ketone of formula (9), where n = 2 can be made by the reduction of an olefin of formula (π):

(17)

In a typical procedure, a solution of an olefin of formula (17) in a suitable solvent (e.g. methanol, ethanol, ethyl acetate) is treated with a palladium catalyst (e.g. 10% palladium / carbon) and exposed to hydrogen atmosphere. Then, as appropriate, under high pressure (for example, 60 psi), stir at room temperature and 60 ° C for 8-24 hours. The olefin of formula (17) can be made by the coupling of an activated olefin with the palladium of the aryl dentate of formula (18): 3 Ya% Hal (18) 99200 -19- 200534846 In a typical procedure, the The aryl compound (18) and vinyl ester (for example, methyl acrylate) are mixed with (0) and Pd (〇Ac) 2 in a suitable palladium catalyst (for example, triphenylphosphine of formula Pd (PPh3) 4). / P (〇-tol) 3 of palladium acetate / tri-o-tolylphosphine or (diphenylphosphino) dicyclopentadiene iron-based vaporizer of formula dppfPdCl2 in the presence of a suitable solvent (such as acetonitrile , N, N_dimethylformamide, toluene), depending on the presence of the case, such as triethylamine, coupling for 8 to 24 hours at a temperature between 4 (rc and U (rc). Formula ( 18) Ketone is a commercial product. Formula amidine, in which both are fluorene and ruler 2 and η is 1, can be made according to the following diagram:

〇Ra wherein R, R2 and Ra are as defined above. In a typical procedure, the acid of formula (19) is preferentially reduced to its corresponding alcohol (20) in the presence of an ester. This can be done by the formation of fluorenimidazole or mixed anhydride and subsequent reduction using sodium borohydride or another suitable reducing agent. The formula (20) -grade alcohol is then converted to a leaving group, such as methanesulfonate, toluene V, acid salt, desert, or hardened substance, and replaced with an appropriate amine nucleophilic group. The preferred nucleophilic group is an azide ion, which can then be reduced to a primary amine by hydrogenation of 99200-20-20200534846 or triphenylphosphine. Alternative nucleophiles may include ammonia or alkylamines, such as amidine or allylamine, and subsequent splitting of the alkyl group to obtain the amine. For some steps of the above-mentioned method of preparing compounds of formula VII, it may be necessary to protect potentially reactive functional groups that are not expected to react, and therefore to cleave the protecting group. In this case, any compatible protecting group may be used. In particular, the protection and removal protection methods described, for example, by T.w. Greene (protective group for organic synthesis, published by A. Wiley-Interscience, 1981) or P.J. Kocienski (protective group, Georg Thieme Verlag, 1994) can be used. Alternatively, the compound of the general formula ⑴ can also be prepared according to the following scheme: wherein ^^^^ ruler rib / ^ and 仏 are as defined above.

99200 -21-200534846

Rc

Rb R1

(8) Scheme 4

ORa

Rc

OH (21)

PG is a suitable bulky hydroxy protecting group, and preferably TBDMS PG1 is a suitable hydroxy protecting group, such as benzyl. In a typical procedure, the acid of formula (21) is obtained by the hydrolysis of the hydrazone ester. This is done by using an aqueous acid or base (such as hydrogen chloride, potassium hydroxide, sodium hydroxide or lithium hydroxide), as appropriate, or a solvent or solvent mixture (such as water, 1,4-dioxolane, tetrahydrofuran / water) In the presence, it can be achieved for a period of 1 to 40 hours at a temperature between fenta and ⑺❽ ° c. The amidine of formula (22) is prepared by combining an acid amidine with a suitable formula (D), amidine or amidine. This coupling system is generally in excess of the amine as an acid acceptor: with conventional coupling agents (such as 2-hexafluorophosphoric acid 2-amino-stilbyl-based tetraleptic file, 99200 -22- 200534846 1- (3-dimethylamine) Aminopropyl) -3-ethylcarbodiimide hydrochloride or n, n, _dicyclohexylcarbodiimide), depending on the catalyst (eg μhydroxybenzotriazole hydrate or 1- Hydroxy-7-nitrobenztriazole), and optionally a tertiary amine base such as N-methylmorpholine, triethylamine or N, N-diisopropylethylamine. The reaction can be carried out in a suitable solvent such as pyridine, N, N-dimethylformamide, tetrahydrofuran, dimethyl sulfoxide, methane or ethyl acetate, and between i (rc and 40 C (room temperature) Under the temperature, 丨 _ 24 hours period. Ammonium (3) (3) or (3. It is either commercially available or can be cooked by the art

The conventional methods (such as reduction, oxidation, alkylation, protection, removal of protection, etc.) that are known to the user are made from commercially available materials. The amine of formula (23) can be made using the standard method of the nitrogen protective group, for example, in the textbook T.W. Greene, the protective group for organic synthesis, published by Wiley_Intersd_, found in 1981. When Rb or Rc = a methylmethyl group, a typical removal protection procedure involves a solution of the protected amine of formula (22) in a suitable solvent (eg, methanol, ethanol, ethyl acetate) with an appropriate hydrogen donor, For example, ammonium formate or formamidine, in the presence of a suitable saturated catalyst (such as 20% hydroxide hydroxide / charcoal), at a temperature between pit and high temperature, for 1-4 hours. Oral hydrazone compounds can be obtained by reacting the amine (23) with a hydrazone bromide of formula. In a typical procedure, the amine (23) and phosphonium bromide can be used, as appropriate, in an appropriate solvent (such as toluene or xylene) and an appropriate tertiary amine base (such as N-fluorenyl horse & 4 'diethylamine or (N'N • diisopropylethylamine), heated together at high temperature for 18-48 hours. Regarding some of the steps of the above-mentioned method for preparing the compound of the formula (I), it may be necessary to protect the potentially reactive hydroxy functional group of the undesired reaction, and therefore the cracking of the protecting group. In this case, any compatible protecting group may be used. In particular, 'protection and removal as described by TW Greene (protective group for organic synthesis, published by A-Wiley-Interscience, 1981) or RJ. Kocienski (protective group, Georg Thieme Verlag, 1994) can be used Protection method. All of the above reactions and the preparation of novel starting materials used in the aforementioned methods are customary, and the appropriate reagents and reaction conditions for their operation or preparation, as well as procedures for isolating the desired product, are familiar to the artist's reference literature conventions and Examples and preparations for this are known. The compound of formula (I) and the intermediates used in its preparation can also be purified according to various conventional methods, such as crystallization or chromatography. A compound of formula (1), wherein -R1 and R2 are independently selected from fluorene and CrC4 alkyl, -η is 0, 1, or 2, and -Q1 is a group selected from:

(NIKVQ alkyl and group * -N (R8) -Q2_A, where -Q2 is a single bond or c! -C4 secondary alkyl group, -R8 is HSCVQ alkyl, 2 or more carbon atoms of the cycloalkyl group P is 1 or 2, and -A is a C3 -Ci ring alkynyl group. The ring has 99200-24-200534846 rings, which is optionally bridged by one or more carbon atoms, pyridyl, or a group of the formula R3 R4

-R, R, R5, R6 and are the same or different, and are selected from η, q -C4 alkyl, OR9, SR9, SOR9, S02R9, halo, CN, CF3, OCF3, COOR9, S02NR9R10, coNR9R10 , NR9R10, NHCOR10; R5 or R7 R6 -R9 is the same as or different from R10, and is selected from H or Cl_c4 alkyl, and * represents the point of attachment to several groups; or if appropriate ', it is pharmaceutically acceptable Salt and / or isomer, tautomer, solvate or isotope modification, with the proviso that when n is 0, then Q1 is not -NHCH3, and when η is 1 or 2, then: DQ is a * solen CVC4 alkyl group or * -N (R8) fA, where A is a cycloalkyl group, depending on the situation, one or more groups, two or more carbon atoms of the cycloalkyl group, the carbon atoms are bridged: Friends / or

Is better. A preferred * -NH-Ci alkyl is NH-isopropyl. Preferred compounds of formula 1 are the following compounds, wherein A is C3 -Ci < and Q1 is * -n (r8) -q2-a.

99200 -25-200534846. More preferably, η is 1, 〇4 is CH2 or a bond, and a is a C3-C10 cycloalkyl group, and the cycloalkyl group has two 1-solid atoms or more. Or a plurality of carbon atoms are bridged, preferably fluorene is 1% hexyl or gold steel alkyl. Other preferred compounds of formula (I) are those in which 11 is 0. Preferably, n is 0 and Q1 is a group of the formula R3 R4 R3

Or, N (R) Q A, where Q2 is a single bond or C1 (4 times calcined, r8 is fluorene, and A is naphthyl, or

The same, and is selected from the group consisting of H, CrC4 alkyl, CF3, 0cf3, COOR9, NHCOR10, wherein R3 to R7

Among them, 3, 114, 115, 116, and 1 ^ are the same or not, OR9, SR9, SOR9, S02R9, tooth S〇2 NR9 R1 〇, CONR9 R10, NR9 R1 〇, at least two are equal to h; where R% Rl. Is the same or different 'and is selected from the group alkynyl, and represents a point of attachment to a carbonyl group. Q1 is better

99200 -26- 200534846 group * -N (R8) -Q2-A, where Q2 is a single bond or Ci_C4 alkylene group, and R8 is H or

R7 R6 C! &Amp; alkyl, and A is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, auryl, fluorenyl, or a group of formula 113, 114, 115, 116 and 117 are as defined above. A car parent is a group of the formula R3 R4 R7 R6, F, CF3, 〇CF3, COOR9, S02NR9R10, and at least two of r3 to R7 represent Η 'where R9 and Ri0 are the same or different, and are selected from Only or. ! -C4 Burning base. Preferably, 113, 114, 115, 116, and 117 are the same or different and are selected from the group consisting of Η, CH3, OH, och3, sch3, OCH2CH3, α, F, CF3, 0CF3, COOH, S02NH2, and r3 At least two of R7 represent h. Preferably, 113, 114, ^ 5, 1 ^ and 1 ^ are the same or different, and are selected from the group consisting of Η, CH3, OH, 〇CH3, 〇CH2CH3, α, F, CF3, 〇CF3, COOH, S 〇2NH2, and at least three of R3 to R7 represent H. R8 is preferably fluorene, methyl or ethyl, and more preferably H. Q2 is preferably selected from a bond, _CH2-, _ (CH2) 2-, _ (cH2) 3-, -C (CH3) 2-CH2-, -CH2-C (CH3) 2-, and -CH ( CH3)-. 99200 -27- 200534846 η is preferably 0 or 1. Among the above compound groups, the following substituents are preferred: R1 and R2 are both CH3, or R1 is Η, and R2 is CH3 or CH2-CH3, or R1 and R2 are both Η. Particularly preferred are the compounds of formula (1) as described in the following paragraphs of the examples, meaning ... N-cycloheptyl-2- {3-[(2R) -2-({(2R) -2-hydroxy · 2- [4-Hydroxy-3_ (hydroxymethyl) phenyl] ethyl} amino) propyl] phenyl} acetamidamine; Ν- (cyclohexylmethyl) -2- {3-[(2R ) -2 _ ({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) propyl] phenyl} -N-methylacetamide ; N-[(1S) -1-cyclohexylethyl] -2- {3-[(2R) -2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl ) Phenyl] ethyl} amino) propyl] phenyl} acetamidamine; 2- {3-[(2R) -2-({(2R) -2-hydroxy-2- [4-hydroxy- 3- (hydroxymethyl) phenyl] ethyl} amino) propyl] phenylbenzene N-isopropylacetamide; N-cyclopentyl-2- {3-[(2R) -2- ( {(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) propyl] phenyl} acetamidamine; N- (cyclobutylmethyl)- 2- {3-[(2R) -2-({(2R) -2-hydroxy-2- [4-hydroxy ((hydroxyfluorenyl) phenyl] ethyl} amino) propyl] phenyl} ethyl Donkey amine; N- (cyclopentylmethyl) -2- {3-[(2R) -2-({(2R) -2-hydroxy-2- [4-hydroxyl (hydroxymethyl) phenyl] Ethyl} amino) propyl] phenyl} acetamidine; N-cyclohexyl-2- {3-[(2R) -2-({(2R)- 2-Ethyl-2- [4-hydroxy-3- (Ethyl) phenyl] ethyl} amino) propyl] phenyl} ethanamine; N-cyclobutyl-2- {3- [ (2R) -2-({(2R) _2-hydroxy-2- [4-hydroxy ((hydroxymethyl) benzyl] ethyl} amino) propyl] phenyl} ethanamide; 99200 • 28- 200534846 N- (cyclohexylmethyl) -2- {3-[(2R) -2-({(2R) -2-hydroxy-2- [4-hydroxy ((hydroxymethyl) phenyl) ethyl) Amine) propyl] phenyl} acetamidine; N- (cyclopropylmethyl) -2- {3-[(2R) -2-({(2R) -2-hydroxy-2- [4- Hydroxy ((hydroxymethyl) phenyl] ethyl} amino) propyl] phenyl} ethanamine; N- (cycloheptylmethyl) -2- {3-[(2R) -2 _ ({( 2R) -2-hydroxy_2- [4-hydroxyl (hydroxymethyl) phenyl] ethyl} amino} propyl] phenyl} acetamidamine; N-1-goldenyl-2- { 3-[(2R) -2-({(2R) -2-Cycloyl-2- [4-Cycloyl-3- (Methyl) phenyl] ethyl} amino) propyl] phenyl} Ethylamine; • N_ (l-goldenylmethyl) -2- {3-[(2R) -2-({(2R) -2-myl-2- [4-merylmethyl) Phenyl] ethyl} amino) propyl] phenyl} acetamidamine; N-2-adamantyl-2- {3-[(2R) _2-({(2R) -2-hydroxy-2 -[4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) propyl] phenyl} acetamidamine; N- (2- Hexylethyl) -2- {3-[(2R) -2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) Propyl] phenyl} -N-methylacetamidine; N-cycloheptyl-2- {3-[(2R) -2-({(2R) -2-hydroxy-2- [4-hydroxy- 3- (hydroxymethyl) benzene I-yl] ethyl} amino) propyl] phenyl} -N-fluorenylacetamidine; N-cyclohexyl-N-, ethyl-2- {3-[( 2R) -2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) propyl] phenyl} acetamidamine; N- (2-cyclohexylethyl) -2_ {3-[(2R) -2-({(2R) _2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amine )] Propyl] phenyl} ethanesulfonylamine; N- (4-pyridyl) -2- {3- [2-({(2R) -2-Cycloyl-2- [4-Cycloyl-3 -(Methyl) phenyl] ethyl} amino) -2-methylpropyl] phenyl} acetamidamine; N- (2,6-dioxofluorenyl) -2- {3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-fluorenylpropyl] phenyl} ethanil ; 99200 -29- 200534846 N-fluorenyl-2- {3- [2-({(2R) _2-hydroxy-2- [4-hydroxy-3- (methyl) phenyl] ethyl} amino group ) -2-methylpropyl] phenyl} ethanedonylamine; 4-{(111) -2-[(2_ {3- [2- (3,4-dihydroisoisoquinol-2 (111) -Base) -2-West Ethyl] phenyl} -1,1 · dimethylethyl) amino] -1-hydroxyethyl} -2- (hydroxymethyl) phenol; N- [2-fluoro-5-5- (trifluoro Fluorenyl) benzyl] -2_ {3- [2-({(2R) _2-hydroxy-2_ [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methyl Propyl] phenyl} acetamidamine; N- (2,6-diaminobenzyl) -2- {3- [2-({(2R) -2-hydroxy-2- [4-hydroxy each (hydroxyl (Methyl) phenyl] ethyl} amino) -2 • fluorenylpropyl] phenyl} acetamidamine; 2- {3- [2-({(2R) -2-hydroxy-2- [4- Hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] phenylbenzene N- [2- (methylthio) methyl] ethylamidine; N- (2 , 3-Difluorenylfluorenyl) _2- {3- [2-({(2R) -2-hydroxy_2- [4-hydroxy_3- (hydroxyfluorenyl) phenyl] ethyl} amino) 2-methylpropyl] phenyl} ethanamine; 2- {3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] Ethyl} amino) _2_methylpropyl] phenyl} -N- [3- (trifluoromethyl) benzyl] acetamidine; N- [4-airyl-3- (trifluoromethyl) Benzyl] -2- {3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methyl Propyl] phenyl} acetamidamine; N- [2-airyl-5- (trifluoromethyl) benzyl] -2- {3- [2-({(2R) -2-hydroxy- 2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-fluorenylpropyl] phenyl} acetamidamine; N- [3,5-bis (trifluoromethyl) (Benzyl) benzyl] -2- {3- [2-({(2R) -2-hydroxy1 [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methyl Propyl] phenyl} acetamidine; N- [3-fluoroyl-5- (trifluorofluorenyl) benzyl] -2_ {3- [2-({(2R) -2-hydroxy-2- [ 4-Hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) · 2-methylpropyl] phenyl} acetamidamine; Ν- [2- (4-aminophenyl) ethyl] Each {2-[(2R) -2_hydroxy-2- (4-hydroxy each hydroxy-fluorenylphenyl) ethylamino] -2-methylpropyl} benzamide; 99200 -30- 200534846 3 -{2-[(2R) -2-Ethyl-2- (4-Ethyl-3-Ethylmethylphenyl) -Ethylamino] -2-methylpropyl} -N- [2- ( 4-methylphenyl) ethyl] benzamide; 3- {2-[(2R) -2-hydroxy-2- (4-hydroxy-3-hydroxymethylphenyl) -ethylamino] form Propyl} -N- [2- (4-trifluoromethylphenyl) ethyl] phenylhydrazine; N- [2- (3,4-dichlorophenyl) ethyl] -3- {2-[(2R) -2-Ethyl-2- (4-Ethyl-3-Ethylmethylphenyl) ethylamino] -2-methyl-propyl} -benzamide; N- [2- (3,4-dimethylphenyl) ethyl] -3- {2-[(2R) -2-hydroxy-2- (4-hydroxy-3-hydroxymethyl Phenyl) -ethylamino] -2-methylpropyl} benzidine; M2-[(2R) -2-hydroxy_2- (4-hydroxy-3-hydroxymethyl_phenyl) ethylamine Methyl] -2-methyl-propylbenzene N- (2-fluoren-2-yl · ethyl) benzamide; N- (l, l-diamidino-2-phenylethyl) -3 -{2-[(2R) -2-hydroxy-2_ (4-hydroxy-3-hydroxy-methylphenyl) -ethylamino] -2-fluorenylpropyl} benzamide; 3- {2 -[(2R) -2-Ethyl-2- (4-Ethyl-3-Ethenylbenzyl) -ethylamino] -2-methylpropyl} -N- (2-fluorenyl-2 -Phenylpropyl) benzamide; N- (4-airbenzyl) -3- {2-[(2R) -2 · hydroxy-2- (4-hydroxy-3-hydroxy-methylphenyl) ) Ethylamino] -2-methylpropyl} phenylhydrazine; N- (2,6-dimethoxybenzyl) -2- {3- [2-({(2ΙΙ) · 2-hydroxy -2- [4-Hydroxy-3- (hydroxyamido) phenyl] ethyl} amino) ethyl] phenyl} ethylamidoamine; N- (3,4-dichlorobenzyl) -2- { 3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxyfluorenyl) phenyl] ethyl} amino) ethyl] phenyl} ethanamide; N- Benzyl-2- {3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxyfluorenyl) phenyl] ethyl} amino) ethyl] phenyl} Acetylamine; N- (2,3-dihydro-1H-inden-2-yl) -2- {3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxyl ) Phenyl] ethyl} amino) ethyl] phenyl} ethanamide; 99200 -31-200534846 2- {3- [2-({(2R) -2-hydroxy-2- [4-hydroxy -3- (hydroxymethyl) phenyl] ethyl} amino) ethyl] phenyl} -N- (2-phenylethyl) ethylamine; 2- {3- [2-({(2R ) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) ethyl] phenyl} -N- (3-phenylpropyl) acetamide; N-benzyl-3-[(2R) -2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) propyl] Benzidine; N- (3,4-dichlorobenzyl) -3-[(2R) -2-({(2R > 2-hydroxy-2- [4-hydroxy_3- (hydroxymethyl) Phenyl] ethyl} amino) propyl] benzidine; N-[> fluoro-5_ (trifluoromethyl) methyl] -3-[(2R) _2-({(2R) _2 -Hydroxy · 2 · [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) propyl] benzamide; N- (2,6-dimethoxybenzyl) -3 -[(2R) -2-({(2R) -2-hydroxy-2- [4-hydroxy-3_ (hydroxymethyl) phenyl] ethyl} amino) propyl] benzamide; Ν- [2 · (4-Gaphenyl) ethyl] -3-[(2R) _2-({(2R) _2-hydroxy-2- [4-hydroxy-3- (hydroxyfluorenyl) phenyl] ethyl } Amino) propyl] benzamide; N- (2,3-dimur-1H-in-2-yl) -3-[(2R)- 2-({(2R) -2-Cycloyl-2- [4-Cycloyl-3- (Methyl) phenyl] ethyl} amino) propyl] benzidine; 3-[(211 ) -2-({(2Min) -2-Cycloyl-2- [4-Cycloyl-3- (Methyl) phenyl] ethyl} amino) propyl] -N- (2-benzene Ethyl) benzamidine; 3-[(2R) -2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino ) Propyl] -N-[(1R) -1-phenylethyl] benzidine; 3-[(2R) -2-({(2R) -2-hydroxy-2- [4-hydroxy- 3- (hydroxymethyl) phenyl] ethyl} amino) propyl] -N- (3-phenylpropyl) benzidine; 4-[(lR) -2-({(lR)- 2- [3- (3,4-dihydroisoquinoline-2 (1H) -ylcarbonyl) phenylH-fluorenylethyl} amino) small hydroxyethyl] -2- (hydroxymethyl) phenol ; 99200 • 32 · 200534846 N- (2,3-dimethylfluorenyl) _3-[(2R) -2-({(2R) -2-hydroxy-2- [4_hydroxy-3- (hydroxymethyl Group) phenyl] ethyl} amino) propyl] benzamide; N- (5,6-diethyl-2,3-difluoren-1H-inden-2-yl) -3-[( 2R) -2-({(2R) -2-hydroxy-2- [4-hydroxy_3- (hydroxymethyl) phenyl] ethyl} amino) propyl] benzidine; N- (4 -Benzyl) -3-[(2R) -2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) propyl Benzamidine ; 3-[(2R) -2-({(2R) -2-hydroxy-2- [4 · hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) propyl] -N_benzene Benzamidine; N- [4- (aminosulfonyl) fluorenyl] -3-[(2R > 2-({(2R) -2-hydroxy-2- [4-hydroxy-3- ( Methyl) phenyl] ethyl} amino) propyl] benzamide; N- [2- (3-fluorophenyl) ethyl] -3- [2-({(2R) -2- Hydroxy-2- [4-hydroxy-3_ (hydroxymethyl) phenyl] ethyl} amino) -2-fluorenylpropyl] benzidine; 3_ [2-({(2R) _2_hydroxy- 2- [4-Hydroxy-3- (hydroxyfluorenyl) phenyl] ethyl} amino) -2-methylpropyl] -N- (2-ε9nitropyrrolo-1-ylethyl) benzene Methylamine; Ν- [2- (2,6-difluorophenyl) ethyl] -3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl Group) phenyl] ethyl} amino) -2-methylpropyl] benzamide; N- (2,3-dihydro-1inden-2-ylmethyl) -3- [2- ({(2R) -2-hydroxy-2- [4-hydroxy_3- (transmethyl) phenyl] ethyl} amino) -2-fluorenylpropyl] benzidine; N- (2 -{4-[(butylamino) carbonyl] phenyl} ethyl) -3- [2-({(2R) -2-hydroxy_2- [4-hydroxy-3_ (hydroxyfluorenyl) phenyl ] Ethyl} amino) -2-methylpropyl] benzidine; 3- [2-({(2R) -2-hydroxy-2 · [4-hydroxy-3_ (via methyl ) Phenyl] ethyl} aminomethylpropyl] -N- {2- [2- (phenylthio) phenyl] ethyl} phenylhydrazine; Ν- (2-cyclohexylethyl)- 3- [2-({(2R) -2-Cycloyl-2- [4-Cycloyl-3- (Methyl) phenyl] ethyl} amino) -2 · fluorenylpropyl] phenylhydrazone Hydrazine; 99200 -33 · 200534846 3- [2-({(2R) -2-hydroxy-2- [4-hydroxy ((hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl ] -N- (3-phenylpropyl) benzoic acid amine; 3- [2-({(2R) -2_hydroxy-2- [4_hydroxy-3- (hydroxymethyl) phenyl] ethyl } Amine) _2-methylpropyl] -N- (2-phenylethyl) benzamide; N- [2- (3,6-Digas_2_methylphenyl) ethyl]- 3_ [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] benzamide; N- [2- (5-Gasyl-2-methoxyphenyl) ethyl] -3- [2-({(2R) -2-hydroxy-2- [4-hydroxyl- (hydroxymethyl) benzene Methyl] ethyl} amino) -2-methylpropyl] benzidine ) Phenyl] ethyl} amino) _2 · methylpropyl] -N- [2- (3-methoxyphenyl) ethyl] benzamide; N- [2- (3 • ethoxybenzene ) Ethyl] -3- [2-({(2R) -2-hydroxy-2- [4-hydroxy · 3- (hydroxymethyl) Phenyl] ethyl} amino) -2-methylpropyl] benzamine; 3- [2-({(2R) -2-hydroxy · 2- [4-hydroxy-3- (hydroxymethyl ) Phenyl] ethyl} amino) -2-methylpropyl] -N- {2- [4- (3-tetrahydroex 1: lo-1-ylpropoxy) phenyl] ethyl} Benzamidine; 3- [2-({(m) -2-hydroxy_2_ [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-amidinopropyl] -N- {2- [2 "(3-tetrahydrop-bilo-1-ylpropoxy) phenyl] ethyl} phenylphosphonate; 3- [2-({(2R) -2-hydroxy -2- [4-Hydroxy (hydroxyhydroxy) phenyl] ethyl} amino) -2-fluorenylpropyl] -N- {2- [3- (3-tetrahydroρbilo-1- Propylpropoxy) phenyl] ethyl} benzamide; N- [2- (4-Gaphenyl) ethyl] -N-ethyl-3- [2-({(2R) -2- Hydroxy-2- [4-hydroxy-3- (hydroxyfluorenyl) phenyl] ethyl} amino) -2-fluorenylpropyl] benzidine; 2- {3- [2-({(2R ) -2-hydroxy-2- [4-hydroxy ((hydroxyfluorenyl) phenyl] ethyl} amino) -2- 99200 -34- 200534846 methylpropyl] phenyl} -N- (3-tetra Chloropyr-1-ylpropyl ethyl amine; N- (cycloheptylmethyl) -2- {3- [2-({(2R) -2-hydroxy-2- [4-hydroxyκ Via methyl) phenyl] ethyl} amino) -2-methylpropyl] phenyl} ethylamine; N-1-gold -2- {3- [2-({(2R) -2-Ethyl-2- [4- |% yl-3- (Ethylmethyl) phenyl] ethyl} amino) -2-methyl Propyl] phenyl} acetamidamine; N-methyl-2- {3- [2 _ ({(2R) _2-Cycloyl-2- [4-hydroxy-3- (methyl) phenyl) ethyl } Amino} -2-methylpropyl] phenyl} -N-methylacetamide; N- [2- (4-fluorophenyl) ethyl] _3- [2-({(2R) 2-Cycloyl-2- [4-Cyclo-3_ (Methyl) phenyl] ethyl} amino) -2-methylpropyl] benzamide; 3- [2-({( 2R) -2-Cycloyl-2- [4-Cycloyl 3- (Methyl) phenyl] ethyl} amino) _2_methylpropyl] -N- [2- (4-phenoxy Phenyl) ethyl] benzamide; Ν- [2- (4-ethoxyphenyl) ethyl] -3- [2-({(2R) -2-Ethyl-2- [4- Ethyl-3- (transmethyl) phenyl] ethyl} amino) -2-methylpropyl] benzamide; N- [2- (4-ethylphenyl) ethyl] -3 -[2-({(2R) -2-Cycloyl-2- [4-Cycloyl-3_ (f-Cyl) phenyl] ethyl} amino) -2-methylpropyl] benzamide ; 3- [2 _ ({(2R) -2-Cycloyl-2- [4-Cycloyl-3- (Methyl) phenyl] ethyl} amino) -2-methylpropyl] -N -[2- (6-Methyl ton-2-yl) ethyl] benzamide; 3- [2-({(2R) -2-Cycloyl-2- [4-Cycloyl-3- (Methyl) phenyl] ethyl} amino) -2- Propyl] -N- [2- (2-methoxyphenyl) ethyl] benzidine; 4-[({3- [2-({(2R) -2-Ceryl-2- [ 4-Ethyl-3-((methyl) phenyl] ethyl} amino) -2-fluorenylpropyl] benzylidene} amino) fluorenyl] benzoic acid ethyl ester; Ν · [4- ( Dimethylamino) methyl] -3- [2-({(2R) -2-Cycloyl-2- [4 · Cycloyl-3- (fluorenyl) phenyl] ethyl} amino)- 2-methylpropyl] benzamine; N- {2- [3-fluoroyl-4- (trifluoromethyl) phenyl] ethyl} _3- [2-({(2R) -2- Hydroxy-2- [4- 99200 -35- 200534846 hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] benzidine; N- [2- (3 -Fluoro-4-methylphenyl) ethyl] -3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (methyl) phenyl] ethyl} Amine) -2-methylpropyl] benzidine; N- [2- (2,3_difluoro_4_methylphenyl) ethyl] -3- [2 _ ({(2R) -2 -Hydroxy-2_ [4-hydroxy-3- (transmethyl) phenyl] ethyl} amino) -2 · methylpropyl] benzidine; H2-({(2R) _2_ergyl_ 2- [4-Cyridyl-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] -N- (2-trimethylethyl) benzamide; N -[2- (2,6-difluoro-3-methylphenyl) ethyl] -3- [2-({(2R) _2-hydroxy-2- [4- -3- (transmethyl) phenyl] ethyl} amino) -2-methylpropyl] benzamide; N- [2- (6 • amino · 2-fluoro-3-methyl Phenyl) ethyl] -3_ [2-({(2R) _2_hydroxy-2- [4-hydroxy-3- (hydroxyfluorenyl) phenyl] ethyl} amino} > 2-methylpropyl Group] benzamidine; N- [2- (2-Gas-6-fluoro-3-methylphenyl) ethyl] -3- [2-({(2R) -2-hydroxy-2 -[4-hydroxy ((hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] benzamide; N- [2- (5-fluoro-2-methylphenyl ) Ethyl] -3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (methyl) phenyl] ethyl} amino} > 2-methylpropyl ] Benzamidine; N- {2- [3-fluoroyl-5- (trifluoromethyl) phenyl] ethyl} -3- [2 _ ({(2R) -2- meridyl-2- [ 4-hydroxy-3- (hydroxyfluorenyl) phenyl] ethyl} amino) -2-methylpropyl] benzamide; 3- [2-({(2R) -2-hydroxy-2- [ 4-hydroxy ((hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] -N- {2- [2- (trifluorofluorenyl) phenyl] ethyl} benzidine Amine; 3- [2-({(2R) -2-Cycloyl-2-[4-Cyclo each (methyl) phenyl] ethyl} amino} > 2-methylpropyl] sun [ 2- (2,4,5_trimethylbenzyl) ethyl] benzolamine; 3- [2-({(2R) -2- meridyl-2- [4_ meridyl-3- (Amidino) phenyl] ethyl} amino) -2 · fluorenylpropyl] -N- (2 ^ pyridin-2-ylethyl) benzidine; Ν- [2- (1Η- Benzimidazol-2-yl) ethyl] -3- [2-({(2R) -2-hydroxy-2- [4-hydroxy99200 -36 · 200534846 -3- (hydroxymethyl) phenyl] ethyl Yl} amino) -2-methylpropyl] benzidine; 3- [2-({(2R) -2-syl-2--2-methyl-4- (methyl) benzene [Ethyl] ethyl} amino) _2 • methylpropyl] -N- {2- [4- (morpholineglacialsulfonyl) phenyl] ethyl} benzamide; N- [2- (3-Amino-2-hydroxyphenyl) ethyl] -3- [2-({(2R) -2-hydroxy_2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl } Amino) -2-methylpropyl] benzidine; N- [4-fluoro-2- (trifluoromethyl) benzyl] -3- [2-({(2R) -2- Hydroxy-2_ [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] benzidine; N- (3-aminobenzyl) -3- [ 2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) benzyl] ethyl®yl} amino) -2-methylpropyl] benzidine; N -(2-Gazynzyl) -3- [2-({(2R) _2-hydroxy-2- [4-hydroxy: (hydroxymethyl) benzyl] ethyl} amino) -2-methylpropane Group] benzamidine; N- [2- (4,6-dimethylpyrimidin-2-yl) ethyl] -3- [2-({ (2R) _2-hydroxy-2- [4-Cycloyl-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] benzidine; 3- [2- ( {(2R) _2-Ethyl_2- [4 · Ethyl-3- (Ethyl) phenyl] ethyl} amino) methylpropyl] -N- [2- (3-methylpyridine -2-yl) ethyl] phenylhydrazine; ^ aerophenyl) ethyl] -3- [2-({(2R) -2-Cycloyl-2- [4-Cycloyl-3_ (Cyclomethyl Group) phenyl] ethyl} amine 棊) -2-methylpropyl] benzamide; N- [2- (l-adamantyl) ethyl] -3- [2-({(2R ) -2-hydroxy-2- [4-hydroxy (methyl) phenyl] ethyl} amino) -2-methylpropyl] benzidine; 3- [2-({(2R)- 2-Ethyl-2- [4-Ethyl-3- (Ethyl) phenyl] ethyl} aminomethylpropyl] -N- [2- (l-Qinyl) ethyl] benzyl Amine ) Phenyl] ethyl} amino) -2-methylpropyl] benzidine; 3- [2-({(2R) -2-hydroxy-2- [4-hydroxy ) Phenyl] ethyl} amino) methyl 99200 -37- 200534846 propylpropyl] -N- {2- [4_ (methylthio) phenyl] ethyl} benzamide; N- [2- ( 5-amino-2-fluorophenyl) ethyl] -3- [2-({(2R) -2-hydroxy-2- [4_ ) Phenyl] ethyl} amino) -2-methylpropyl] phenylhydrazine; N- [2- (2-amino-4-fluorophenyl) ethyl] -3- [2- ( {(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] benzamide; 3- [2- ({(2R) -2-hydroxy-2- [4-hydroxy · 3 · (hydroxymethyl) phenyl] ethyl} amino) -2 • methylpropyl] -N- [2- (4- Methoxy-2,5-dimethylphenyl) ethyl] benzamide; Ν- [2- (2,3-difluorophenyl) ethyl] -3- [2-({(2R ) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-fluorenylpropyl] benzamide; 3- [2-({( 2R) -2-hydroxy-2- [4-hydroxy_3- (hydroxymethyl) phenyl] ethyl} amino) -2_fluorenylpropyl] -N_ [2_ (4_methoxy_2 , 3-dimethylphenyl) ethyl] benzidine; N- (2-biphenyl-4 · ylethyl) _3- [2-({(2R) -2-hydroxy-2- [4 -Hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] benzamide; N- [2- (2,4-dimethylphenyl) ethyl ] -3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] benzyl Fermented amine Jing Jia Phenyl] phenyl] ethyl}} amino) -2-methylpropyl] benzidine; 3- [2-({(2R) -2-Cycloyl-2- [4-Cycloyl-3- (Methyl) phenyl] ethyl} amino) -2-methylpropyl] -N- {2- [3- (trifluorofluorenyl) phenyl] ethyl} benzamide; Ν- [ 2- (4-Gas-2-fluorophenyl) ethyl] -3- [2-({(2R) -2-hydroxy-2- [4-Cyclo-3- (hydroxyfluorenyl) phenyl ] Ethyl} amino) -2-fluorenylpropyl] benzamide; N- (2,5-dimethylbenzyl) -3- [2-({(2R) _2 · hydroxy_2- [4-Hydroxy-3- (hydroxymethyl) benzyl] ethyl} amino) -2-methylpropyl] benzidine; N- (3,4-diamino) -3- { 3_ [2-({(2R) -2-Cycloyl_2- [4-Cycloyl-3- (Cyclomethyl) benzyl 99200 -38- 200534846yl] ethyl} amino) -2-methylpropane Phenyl] phenyl} propanamine; 3- [2-({(2R) _2_hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methyl Propyl] -N- {2- [4- (trifluoromethoxy) phenyl] ethyl} benzamide; 3- [2-({(2R) -2-hydroxy-2- [4 -Hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] -N- [2- (4-hydroxyphenyl) -2-amidinopropyl] benzoyl Amidoamine; 3- [2-({(2R) -2-hydroxy-2- [4-hydroxy_3- (transmethyl) phenyl] ethyl} amino) · 2-methyl Propyl] -N- [2- (4-Cyclo-3-methylphenyl) ethyl] benzamide; Ν- [2- (4-hydroxy_2,3_dimethylphenyl) Ethyl] -3- [2-({(2R) -2-Hydroxy-2- [4-Hydroxy (hydroxymethyl) phenyl] ethyl} amino) -2 • methylpropyl] Benzamidine; N- [2- (4-hydroxy · 2,5-diamidinophenyl) ethyl] -3- [2-({(2R) -2 · hydroxy_2_ [4_hydroxy each (Hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] benzamide; N- (3,4-dichlorobenzyl) -2- {3- [2-({ (2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-fluorenylpropyl] phenyl} acetamidamine; N- (3 , 5-Diazino) -2- {3- [2-({(2R) -2-Cycloyl-2- [4-Cycloyl-3- (methyl) benzyl] ethyl} amino ) -2-methylpropyl] phenyl} acetamidine; 2- {3- [2-({(2R) -2-Cycloyl-2- [4-Cycloyl-3- (Cyclomethyl ) Phenyl] ethyl} amino group> 2-methylpropyl] phenyl:}-N- (pyridin-2-ylfluorenyl) acetamidinium; N-ethyl-3- [2-({ (2R) -2-hydroxy_2_ [4_hydroxy-3- (hydroxyfluorenyl) phenyl] ethyl} amino) -2-fluorenylpropyl] -N- (3-phenylpropyl) benzene Formamidine; 3- [2-({(2R) -2-hydroxy-2- [4-hydroxyl (hydroxymethyl) phenyl] ethyl} amino) · 2 · methyl Group] -N- [3- (4-phenyl) propyl] benzidine; 3- [2-({(2R) -2-Cycloyl_2- [4-Cycloyl Group) phenyl] ethyl} amino) _2_fluorenylpropyl] -N- [2- (3-methylphenyl) ethyl] benzidine; 3- [2-({(2R > 2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methyl 99200 -39- 200534846 propylpropyl] -N- [2 · (6-methoxy P is more than fluoren-3-yl) ethyl] benzylamine; Ethyl} aminomethylpropyl] -N- [3- (3-methoxyphenyl) propyl] benzamide; N- [3- (4-Gaphenyl) propyl] -3- {2-[(2R) -2-Ethyl-2- (4-Ethyl-3-Ethylmethylphenyl) ethylamino; 1-2-methylpropyl} benzidine; 3- [ 2-({(2R) -2-meryl-2- [4-hydroxy-3- (methylol) phenyl] ethyl} aminomethylpropyl] -N- {2- [4- ( 1Η- ^ 嗤 -1-yl) phenoxy] ethyl} benzamide; N_ [2- (3,4-diphenylphenyl) ethyl] -3- [2-({(2R)- 2-Ethyl-2- [4-hydroxy-3-fluorenylmethyl] phenyl] ethyl} amino) -2-methylpropyl] benzidine; 3- [2-({(2R ) -2-hydroxy-2- [4-hydroxy-3- (methyl) phenyl] ethyl} amino) _2 · methylpropyl] -N- (2-junin-5-yl Base) benzylamine; and N- [3- (2-ethyl-2,3-dihydro-1-benzocrean-5-yl) propyl] -3- [2-({(2R ) -2-Ethyl-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino > 2-methylpropyl] benzamide. According to an aspect of the present invention, the compound of formula (0ί2) ηΤ (= 0) (^ in the meta position is generally better. The compound of formula 亦 may also be converted into a pharmaceutically acceptable salt according to circumstances. Specific In other words, such pharmaceutically acceptable salts of the compounds of formula (I) include their acid addition and base salts (including double salts). Appropriate acid addition salts are acids made from non-toxic salts. Examples include acetate , Adipate, aspartate, benzoate, benzoate, bicarbonate / diprate, acid sulfate / sulfate, rotten salt, camphor sulfonate, citrate, Cyclohexylamine sulfonate, ethanedisulfonate, ethanesulfonate, formate, fumarate, glucoheptanoate, gluconic acid 99200 • 40- 200534846 salt, aldehyde furoic acid Salt, hexafluorophosphate, n-dioxane, hydrochloride / gas, hydrobromide / bromide, hydroiodate / iodide, hydrophosphate, isethionate, D- and L-lactate, malate, maleate, malonate, methanesulfonate, fluorenyl sulfate, 2-naphthalenesulfonate, nicotinate , Nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrophosphate, pyroglutamate, sucrose, stearate, Succinate, tannate, and L_tartrate, μ-hydroxynaphthoate, toluoate, and ecsinafer salt. Suitable alkali salts are prepared from non-toxic salts. Examples include Shao, arginine, benzathine, calcium'choline, diethylamine, glycolamine, glycine, lysine, meglumine, meglumine, oleylamine, bell, sodium, Butanetriolamine and zinc salts. It can also form half salts of acids and bases, such as hemisulfates and hemicalcium salts. For a review of suitable salts, see Stahl and Wermuth, Handbook of Pharmaceutical Salts: Sex Shellfish, Selection and Use, Wiley-VCH, Weinheim, Germany (2002). A pharmaceutically acceptable salt of a compound of formula (I) can be made by one or more of three methods: (i) by reacting a compound of formula (1) with a desired acid or base; ⑼ by removing the acid from the appropriate precursor of the compound of formula 或 or the labile protecting group 'or by using the desired acid or base, The precursors are ring-opening, such as lactones or lactams; or (iii) by converting one salt of a compound of formula VII to another by reacting with a suitable acid or base, or using a suitable ion exchange column. The three reactions are typically carried out in solution. The salt formed is precipitated at 99200 -41-200534846 years of age, and can be recovered by evaporation, collection, or evaporation of the solvent. The degree of ionization in the formed salt can be changed. From fully ionized to almost non-ionized. The present compound can exist in both unsolvated and solvated forms. The term "solvate" is used herein to describe the inclusion of a compound of the invention with One or more pharmaceutically acceptable solvent molecules such as molecular complexes of ethanol. The term " hydrate " is used when the solvent is water.

Those included in the scope of the present invention are complexes, such as clathrates and drug-host storage complexes, in which drugs and wounds are very different from the solvates mentioned previously in stoichiometric or non-stoichiometric The amount exists. Also included is a drug complex ' which contains two or more organic and / or inorganic ingredients ' which may be in a stoichiometric or non-stoichiometric amount. The complex formed may be ionized, partially ionized, or unionized. About this composite

Pharm Sci5 64 (8), 1269-1288, Haleblian (1975 ^ August). All subsequent references to compounds of formula IX include references to salts, solvates and complexes thereof, as well as solvates and complexes to salts thereof. The compounds of the present invention include compounds of formula (I) as defined above, including all polymorphs and crystal forms thereof as defined below, prodrugs and isomers thereof (including optical, geometric, and tautomeric isomers), And compounds of formula (I) identified by isotopes. As noted, the so-called "prodrugs" of compounds of formula ⑴ are also within the scope of the present invention. Therefore, 99200 -42- 200534846 may itself have little or no pharmacological activity. Derivatives of certain compounds of formula (1) Substances, when administered into or on the body, 'can be converted, for example, by hydrolysis to a compound of formula ⑴ having the desired activity. Such derivatives are referred to as "prodrugs". For further information on the use of prodrugs, see "Prodrugs as Novel Delivery Systems,", Volume 14, ACS Series (T. Higuchi and W. Stella), and ', Bioreversible Carriers in Drug Design ", Pergamon Press, 1987 (ed. EB Roche, American Medical Association). Prodrugs according to the present invention can be produced, for example, in such a manner that the appropriate functional groups present in the compound of formula (1) are known to those skilled in the art as, certain partial groups of "pre-groups" Replacements, such as those described in "Design of Prodrugs," H. Bundgaard (Elsevier, 1985). Some examples of prodrugs according to the present invention include: (1) In the case where the compound of formula VII contains a carboxylic acid functional group (-C00H), its vinegar ', for example, where the hydrogen system of the carboxylic acid function of compound of formula IX is Ci_c8) Compounds that are substituted by a radical; ⑻ Where the compound of formula (1) contains an alcohol functional group (_〇H), it is an ether, for example, where the hydrogen system of the alcohol functional group of the fluorene compound is (Ci -C6) alkane Compounds substituted with ethoxyfluorenyl groups; and (111) in the case where the compound of formula (1) contains a primary or secondary amine functional group (_NH2 or -NHR 'where R is H), for example, among them A compound in which one or two (as the case may be) hydrogen of the compound of formula ⑴ is replaced by a (cardio-cardio) alkanoyl group. For other examples of alternative groups and other prodrug types based on the scripture examples, see the references mentioned above. 99200 -43- 200534846 Furthermore, some compounds of formula VII can themselves be used as prodrugs of other compounds of formula IX. Also included within the scope of the present invention are the metabolites of compounds of formula (I), meaning compounds that are formed in vivo after drug administration. Some examples of the metabolites according to the present invention include (i) in the case where the compound of formula 甲基 contains a methyl group, its hydroxymethyl derivative (-CH3 -CH2OH): ⑼ the compound of formula (1) contains an alkoxy group In this case, it is a hydroxy derivative (-OR -OH); (iii) In the case where the compound of the formula VII contains a tertiary amine group, it is a secondary amine derivative (-NR1 R2 -NHR1 or -NHR2) (IV) in the case where the compound of formula VII contains a secondary amine group, it is a primary derivative (-NHRi_NH2); (v) in the case where the compound of formula IX contains a phenyl moiety group, it is derived from its phenol (-Ph_PhOH); and (I) · (νι) In the case where the compound of formula 醯 contains an amine group, its carboxylic acid derivative (_CONH2 COOH) 〇 Formula of one or more asymmetric carbon atoms ⑴ Compounds can exist as two or more stereoisomers. In the case where the compound of formula VII contains a dilute or subdilute group, it may be a geometric cis / trans (or Z / E) isomer. In the case of compounds containing, for example, keto structural isomers which can be converted into each other by a lower oxime group or an aromatic moiety, the energy barrier tautomerism isomerism (" tautomerism) Can exist. It may take the form of a proton tautomerism in a compound of formula ⑴ containing, for example, an imine, keto or oxime group, or in a compound containing a partial group of aromatic 99200-44-200534846, the so-called valence Bond tautomerism. As a result, a single compound can exhibit more than one type of isomerism. Included within the scope of the present invention are all stereoisomers, geometric isomers, and tautomeric forms of the compound of formula (I), including compounds that exhibit more than one type of isomerism and mixtures of one or more thereof. Also included are acid additions or base salts, where the counter ion is optically active, such as lactate or 1-lysine, or racemic, such as tartaric acid or di-arginine.

Cis / trans isomers can be separated by conventional techniques familiar to the artist, such as chromatography and fractional crystallization. Conventional techniques for the preparation / isolation of individual palmar isomers, including the synthesis of palmars from appropriate optically pure precursors, or the analysis of racemates (or racemates of salts or derivatives), For example, palladium high pressure liquid chromatography (HPLC) is used. Alternatively, a racemate (or a racemic precursor) can be reacted with a suitable optically active compound, for example, ㈣, or in the case where the compound of formula 含有 contains an acidic or experimental moiety, with an acid or base such as tartaric acid Or 丨 _phenylethylamine reaction. The diastereomeric mixtures formed can be separated by chromatography and / or fractional crystallization, and one or both of the diastereomers can be converted into their corresponding pure counterparts by means known to skilled artisans. Isomers. The palmitic compounds of the present invention (and their palmar precursors) can be obtained in isomerically enriched forms using palm chromatography, typically HPLC, on asymmetric resins, with mobile phases, including hydrocarbons, typically It is heptane or hexane, and isopropanol with a volume ratio of 0 to 50% is typically 2% to 20%, and alkylamine with a volume ratio of 0 to 5% is typically 0.1% diethyl alcohol. amine. The eluent was concentrated to obtain a mixture rich in 99200 -45- 200534846. Stereochemistry that is familiar with conventional techniques known to the artist ", E. L. Elie Uwiiey, New Stereoisomeric dense polymers can be borrowed-see, for example, '' Organic Compound York, 1994). According to one aspect of the present invention, the following formula _ • stereoisomers, where! ^ Is

Wind 'and R2 is Cl_C4 alkyl, preferably methyl, and both η and Q1 are as defined above', which is generally better:

Wherein η and Qi are as defined above for the compound of formula (I). The present invention includes all pharmaceutically acceptable compounds of formula (a) of the formula (I), in which one or more atomic systems have the same atomic order, but the atomic mass or mass number is different from the predominantly atomic mass or Atomic substitution of mass numbers. Examples of suitable isotopes to be added to the compounds of the present invention include the following isotopes, hydrogen, such as 2H and 3H, carbon, such as " c, 13c, and 14 (:, gas, tongue, such as C1, fluorine, such as 18ρ, hindrance, such as 123 Workers and 125 workers, nitrogen, such as N and 15N, oxygen, such as 15, 17 and 18, phosphorus, such as 32p, and sulfur 'such as 3 5 S. Certain compounds of formula (1) are identified by isotopes, For example, those who incorporate radioactive isotopes can be used in the study of the distribution of drugs and / or tissues. Radioactive 14 isotopes of rhenium, meaning 3H, and carbon-14, meaning 14C, are easy to incorporate 99200 -46- 200534846 and The immediate method of the test is especially suitable for this project from 4 shi '. &Quot; ^ Isotopes instead of' such as H, which means 2h, can obtain some of the therapeutic advantages caused by the greater metabolic sex, such as Increasing the in vivo half-life, or reducing the dose requirements, and therefore may be better in some cases. Replacement with positron emission isotopes, such as LLC, 18F, 150n, etc. can be used for positron emission surface morphology_) research To view acceptances. Isotopically labeled compounds of formula ⑴ can be generally identified by narrowing down to conventional techniques known to the artist, or by methods similar to those described in the accompanying Example: Preparation, using appropriate isotopically labeled compounds. Reagents, made in place of previously unlabeled reagents. The pharmaceutically acceptable solvating solvents according to the present invention may be substituted isotopically, such as D20, d :: ketone, d6-DMSO. 6 The compound C is 'a pharmaceutically acceptable salt and / or a pharmaceutically active compound in a form that is valuable', which is suitable for the treatment and prevention of many secondary and secondary receptors or the catalysing agents of this receptor. Diseases that can cause benefits: 'especially allergic and non-allergic airway diseases, and also treat them ^ such as but not limited to neurological diseases, premature birth, congestive heart failure: a! Health and allergic skin diseases, Psoriasis, proliferative skin disease, bruising ^ and symptoms that are beneficial in reducing gastric acidity, especially the stomach and stomach ★ The compound of formula (I) above and its pharmaceutically acceptable salts and derivatives 99200 -47- 200534846 According to the present invention, it is preferably administered to animals, preferably mammals, and in particular to humans, as a medicine for treatment and / or prevention. It may itself be in a mixture with each other, seven-kill # & in-or in the form of W Le formulations with active ingredients in medicine, the pharmaceutical preparation in addition to conventional medicine and innocuous excipients and / or The additive has at least one compound of formula (I), its pharmaceutically acceptable salt and / or derivative form. _Compounds whose pharmaceutically acceptable salts and / or derived forms may be

Beam-dried for 1 mist or evaporative drying to provide crystalline or amorphous solid pillars, pick-up charge @, 戍 溥 Μ. Microwave or RF drying is available for this project. '' The compound of formula (1), its pharmaceutically acceptable salt and / or derived form can be administered alone or in combination with other drugs, and is usually administered in a formulation accompanied by one or more acceptable excipients. The term " excipient " is used in the text to describe ingredients other than the compounds of the present invention. The choice of excipients will depend to a large extent on the particular mode of administration. The compounds of the invention can be administered orally. Oral administration may involve swallowing so that the chemistries enter the gastrointestinal tract, or may be administered by cheek or sublingual, whereby the compound enters the bloodstream directly from the mouth. y π Oral rent ... 々 'say goodbye, capsules containing microparticles, liquids or powders' lozenges (including liquid filling chews, multiple- and nano-microparticles, gels, solid solutions, microlipids, Films, ovules, sprays and liquid formulations., Liquid formulations include suspensions, are used as solutions in soft or hard capsules, syrups and elixirs. Such formulations can be filled with fillers and typically include a carrier, for example 99200 -48- 200534846 such as water, ethanol, polyethylene glycol, propylene glycol, methyl cellulose or suitable oils, and one or more emulsifiers and / or suspending agents. Liquid formulations can also be made by solids such as from sachets. The compound of the present invention can also be used in a fast-dissolving, fast-disintegrating dosage form, for example, as described in Liang and Chen's expert opinion on the treatment patent 11 (6), 981-986, (2001). About tablets The dosage form depends on the dosage. The drug may constitute 1% to 80% by weight of the dosage form, and more typically 5% to 60% by weight of the dosage form. In addition to drugs, tablets generally contain disintegrants. Disintegrants Examples, including starch Sodium glycolate, sodium carboxymethylcellulose, calcium carboxymethylcellulose, sodium carboxymethylcellulose, crospovidone, polyvinyl tetrahydropyrrolidone, methylcellulose, microcellulose Crystalline cellulose, low-carbon alkyl substituted propyl cellulose, starch, pregelatinized starch, and sodium alginate. Generally, the disintegrant will constitute 1% to 25% by weight of the dosage form, preferably It is 5 weight% to 20% by weight. Binders are generally used to impart the bonding quality to tablet formulations. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyethylene Tetrahydropyrrolidone, pregelatinized starch, hydroxypropyl cellulose and hydroxypropyl methyl cellulose. Tablets may also contain diluents such as lactose (monohydrate, spray-dried monohydrate, anhydrous, etc.) , Mannitol, xylitol, sucrose, anthocyanin, microcrystalline cellulose, bactericidal and dibasic calcium phosphate dihydrate. Tablets may also contain surfactants such as lauryl sulfate Sodium polycyanoic acid with purpose 80 'and dosage, such as dioxin And talc. When stored ^ 99200 -49- 200534846, the 'surfactant can account for 0.2 to 5% by weight of the tablet, and the glidant can account for 0.2 to 0/0 to i% by weight of the tablet. Tablets also typically contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and a mixture of magnesium stearate and sodium lauryl sulfate. Lubricants are generally It is 0.25% to 10% by weight of the tablet, preferably 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% drug, about 10% to about 90% by weight binder 'about 0% by weight / 0 to about 85% by weight diluent, about 2% by weight / 0 to about 10% by weight A disintegrant, and about 0.25 to about 10% by weight of a lubricant. The tablet blend can be compressed directly or by a roller to form a tablet. The tablet admixture or part of the admixture may alternatively be moistened, dried- or melted to granulate, melted to solidify, or extruded before compression. The final formulation may include one or more layers and may be coated or uncoated; it may even be encapsulated. The formulation of tablets is discussed in Pharmaceutical Dosage Forms · Tablets, Volume i, H. Liebem ^ and L. Lachman (Mqrcel Dekker, New York, 1980). Consumable oral film for human or veterinary use, typically a soft, water-soluble or water-swellable film dosage form that dissolves quickly or is mucoadhesive, and typically contains a compound of formula (1), a film-forming polymerization Body, adhesive, solvent, humectant, plasticizer, stabilizer or emulsifier, viscosity modifier and solvent. One of the ingredients in this formula can be used for one or more functions. The compound of formula (I) may be water-soluble or insoluble. The water-soluble compound typically accounts for 1% to 80% by weight of the solute, and more typically 2G% to 5099200-50-200534846 t / o. More insoluble compounds, ^ j account for a large proportion of the composition, typically> gluten up to 88% weight / 0, or 1 wu person times, the compound of formula (1) can be multiple microparticle beads form. The film-forming polymer may be selected from natural polyacetic acid, protein, or synthetic hydrocolloids, and is typically present in a range of 0.01 to 99% by weight, and more typically in a range of 30 to 80% by weight.

Other possible ingredients include antioxidants, colorants, flavor and flavor enhancers, preservatives, saliva stimulants, coolants, co-solvents (including oils, lubricants, bulking agents, defoamers, surfactants Agents and taste masking agents. The films according to the invention are typically made by evaporative drying of an aqueous film coated on a peelable backing carrier or paper. This can be 'typically' in a dry flood box or tunnel For combined coater dryers, or by freeze-drying or evacuation. Solid formulations for oral administration can be formulated for immediate and / or modified release. Modified release formulations include delayed ... continuous ... pulse ... controlled-, target-targeted and stylized release. Suitable modified release formulations for the purposes of this invention are described in US Patent 6,106,864. Details of other suitable release techniques, such as high-energy dispersions And penetrating and coating particles can be found in online medical technology 25 (2), l-14, Vermaf, _). The use of chewing gum to achieve controlled release is described in WO 00/35298. The compounds of the invention can also be administered directly into the bloodstream, muscle or internal organs. Appropriate methods for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, indoor, intraurethral, intrasternal, intracranial, intramuscular, and dermal 99200 -51-200534846. Appropriate devices for parenteral administration, including G needles (including microneedles), syringes, needleless syringes, and perfusion techniques. Parenteral formulations are typically aqueous solutions, which may contain nutrients such as sleep, carbohydrates, and buffers. Agent (preferably 3 to 9), but for this application, it can be more suitably formulated into a sterile non-aqueous solution, or in a dry form to be used with an appropriate vehicle such as sterile pyrogen-free water.

Parenteral formulations are prepared under aseptic conditions, e.g., by cold; dry, and can be easily accomplished using standard pharmaceutical techniques familiar to those skilled in the art. The solubility of a compound of formula (I) used in parenteral solution preparation can be increased by appropriate formulation techniques, such as by incorporating a solubility enhancer. Formulations for parenteral administration can be formulated for immediate and / or modified release. Revised release formulas include delayed release, sustained release, pulse release, controlled release, and programmed release. Thus, the compounds of the present invention can be formulated as solid, semi-solid, or thixotropic liquid 'for administration in an implanted reservoir, providing a modified release of the active compound. Examples of such formulations include drug-coated stents and PGLA poly (dl-lactic-co-glycolic acid) (PGLA) microspheres. The compounds of the invention can also be administered topically to the skin or mucous membranes, i.e., dermal or transdermal. Typical formulations for this project include gels, hydrogels, lotions, solutions, creams, ointments, dusters, dressings, vesicles, films, skin patches, tablets, implants, sponges , Fiber, bandages and microemulsions. Microlipids can also be used. Typical carriers include alcohol, water, mineral oil, liquid petrolatum, ash oil, glycerin, polyethylene glycol, and propylene glycol. / Permeability enhancers can be incorporated by reference, e.g., J Pharm, 88 (10), 955 milk 8

Finnin and Morgan (October 1999). 99200 -52- 200534846 Other methods of topical administration include delivery by electroporation, iontophoresis, electroporation, acoustic transdermal electroosmosis, and microneedle or needleless (eg PoowijectTM, BiojectTM, etc.) injection delivery. Formulated for topical administration. Revised formula, target targeting and stylized release. Can be deployed for immediate and / or modified release, including delayed-, continuous-, pulsed-, controlled-

The compounds of the present invention can also be administered in a μ-hour form, or by inhalation, typically in the form of a dry powder (whether alone, as a mixture, such as in dry lactose 4 & For example, phosphorus and biliary test mix), self-drying powder inhaler, or aerosol mouth mist, self-pressurized trough chestnut f atomizer, atomizer (preferably using electrohydrodynamics to generate fine mist mist) Carburetor) or atomizer, with or without appropriate propellant, such as 1,1,1'2 · tetrafluoroethane or i-based propane. It ' s powder for intranasal use may contain bioadhesives, such as chitosan or cyclodextrin. Pressurized containers, pumps, sprays, atomizers or atomizers each contain a solution or 'liquid' of a compound of the invention, containing, for example, ethanol, an aqueous solution of ethanol, or suitable for dispersing, solubilizing, or prolonging the release of the active. Substitute agent, as the advancing agent M, and selected surfactants, such as anthocyanin trioleate, oleic acid or lactic acid. Prior to use in dry powder or suspension formulations, the drug product is micronized to a size suitable for transmission by inhalation (typically less than 5 microns). This can be achieved by any suitable comminution method, such as spiral jet milling, fluid bed jet milling, supercritical fluid treatment to form nanoparticle, high pressure homogenization or spray drying 99200 -53. 200534846 mist drying. Capsules (made from, for example, gelatin or hydroxypropyl methylcellulose), foaming agents, and cartridges for inhalers or insufflators can be formulated into powder mixtures containing the compounds of the present invention, suitable powder bases such as lactose Or starch, and performance modifiers such as 1-leucine, mannitol or magnesium stearate. Lactose may be anhydrous or in the form of a monohydrate, the latter being preferred. Other suitable excipients include dextran, glucose, maltose, anthocyanin, xylitol, fructose, sucrose and trehalose. Suitable solution formulation for use in nebulizers that use electrokinetic kinetics to generate fine mists. Each actuation can contain from 1 microgram to 20 milligrams of the compound of the invention, and the activation volume can be changed from 1 microliter to 100 micrometers. Rise. A typical formulation may include a compound of formula VII, propylene glycol, sterile water, ethanol, and sodium gasification. Alternative solvents for propylene glycol, including glycerol and polyethylene glycol. Appropriate flavoring agents, such as scopolamine and levulinate, or sweeteners, such as saccharin or saccharin sodium, can be added to the formulations of the present invention for inhalation / intranasal administration. Formulations for inhalation / intranasal administration may use, for example, PGLA, which is formulated upon release and / or modified for release. Revised release formulas include delayed_, sustained_, pulse-, controlled_, targeted and programmed release. In the case of dry powder inhalers and aerosols, the dosage unit is a valve that transmits a metered amount. The unit according to the invention is typically arranged to be administered in a metered dose ' or a " blown gas " The entire daily dosage is typically in the range of mg to 40 milligrams' which can be administered in a single dose, or more commonly throughout the day 99200-54-200534846 are administered in discrete doses. Compounds of formula (1) are particularly suitable for administration by inhalation. The compounds of the invention may be administered rectally or vaginally, for example, in the form of a test agent, a pessary, or an enema. Cocoa butter is a traditional test agent base: a variety of alternatives can be used, as appropriate. Rectal / vaginal formulations can be formulated for immediate and / or modified release. Revised release formula ’includes delayed-, sustained-, pulsed -... controlled-, targeted, and programmed release.

The compounds of the present invention can also be administered directly to the eyes or ears, typically in the form of micronized suspensions or solutions in sterile saline at a pH equal to < 4 >. Other formulations suitable for eye and ear administration, including ointments, biodegradable (such as absorbable gel sponges, collagen), and bio-non-degradable (such as polysilicone oxygen) implants, flat sheet lenses and Microparticles or vesicle-like systems, such as neoplasms or liposomes. Polymers, such as cross-linked polyacrylic acid, polyvinyl alcohol, hyaluronic acid 'cellulose polymers, such as propyl cellulose, M ethyl cellulose or methyl cellulose, or heteropolycholesteric polymers, such as Glue paste glue can be mixed with preservatives, such as chlorinated oxygen. This formulation can also be transferred by ion transfer. Formulations for eye / ear administration can be formulated for immediate and / or modified release. Revised release formulas include delayed, continuous, pulsed, controlled-, targeted, or programmed release. Body wall moonning "may not be combined with a soluble macromolecule body, the macromolecule = bad dextrin and its appropriate derivative or a polymer containing polyethylene glycol 1 ~ mi solution rate, taste masking, bioavailability and / Or An 99200 • 55- 200534846 qualitative, for use in any of the aforementioned modes of administration. For example, drug-cyclodextrin complex systems have been found to be generally applicable to most dosage forms and routes of administration. Can be used Both central and non-inclusion complexes. As an alternative to direct compounding with drugs, cyclodextrin can be used as an auxiliary additive. The use of the agent means that it is used as a diluent, diluent or solubilizer. The purpose is α., Fen and cyclodextrin, examples of which can be found in the international patent applications WO 91/11172, WO94 / 02518 and WO98 / 55l48. Since it may be desirable to administer a combination of active compounds, for example In order to achieve the treatment of a particular disease or symptom, within the scope of the present invention, two or more pharmaceutical compositions, at least one of which contains a compound according to the present invention, may suitably be combined in a composition suitable for co-administration of these compositions. Kit form U 'The kit of the present invention contains a medicament of the medical group, one of which contains a compound of the formula (I) according to the present invention, and an individual: a device holding the composition', such as a container, a differentiated bottle, or a divided : Packet. An example of such a kit is the familiar bubble packaging for packaging tablets, capsules, etc. The kit of the present invention is particularly suitable for administration of different dosage forms, such as parenteral, to individual compositions at ^: dose intervals, Or titrate individual substances towards each other. To help compliance, kits typically include instructions for administration and can be provided with so-called memory aids. For administration to human patients, the total daily dose of a compound of the invention is typically ο · Within the range of milligrams to 5000 milligrams, of course, depending on the mode of administration, for example, an intravenous dose may require only _ milligrams to 40 milligrams. 99200 -56- 200534846 The total daily dose may be in a single or separate dose It can be administered, and it can fall outside the typical range given in the doctor's judgment. These dosages are based on general human patients with a body weight of about 65 kg to 70 kg. It will be easy to determine the dosage for patients whose weight falls outside this range, such as infants and the elderly. To avoid confusion, the term "treatment" in this article includes the term cure, relief, and preventive treatment. According to In another specific embodiment of the present invention, the compound of formula (I) or a pharmaceutically acceptable salt, derived form or composition thereof can also be used in combination with one or more other therapeutic agents for co-administration to a patient, In order to obtain some specific desired end results of treatment, such as the treatment of pathophysiologically related disease processes, including but not limited to ① bronchoconstriction, inflammation, anaphylaxis, (iv) tissue destruction, (V) signs and Symptoms such as breathlessness, coughing. The second and more other therapeutic agents may also be compounds of formula (I), or a pharmaceutically acceptable salt, derived form or composition thereof, or—or more than one of these techniques. Known as / 32 activator. More typically, the second and more therapeutic agents are selected from different types of therapeutic agents. The terms " co-administration ", " co-administration " and " combined administration " as used herein refer to a compound of formula (1) and / or other therapeutic agents, which means, and indeed Allegations and include the following: • simultaneous administration of such a combination of a compound of formula 治疗 and a therapeutic agent to a patient in need of treatment, when such ingredients are-formulated into a single dosage form, and the disease is administered at substantially the same time The patient releases the ingredient, /, • For patients in need of treatment, the compound of formula _ is administered substantially simultaneously _ 99200 -57- 200534846 This combination of therapeutic agents 'when such ingredients are formulated separately from each other into individual dosage forms' It is taken by the patient at substantially the same time, so the ingredient is released to the patient at substantially the same time. • For patients in need of treatment, the compound of formula (1) and the therapeutic agent are successively administered. This combination, when such ingredients are formulated separately from each other into individual dosage forms, 'is taken by the patient in continuous time, with a significant time interval between administrations, so the ingredients are at substantially different times To Release of the patient; and • For patients in need of treatment, successively administering such a combination of a compound of formula (1) and a therapeutic agent, when such ingredients are formulated together into a single dosage form, they release the ingredient in a controlled manner Therefore, it is administered by the patient jointly, continuously and / or overlapping at the same and / or different time, each part of which can be administered by the same or different routes. Other therapeutic agents that can be combined with a compound of formula (1) or a pharmaceutically acceptable salt, derivative form or composition thereof, suitable examples include, but are not limited to, ⑻5- 爿 Fatty oxidase (5- LO) inhibitor or 5-lipoxygenase-activated protein (FLAP) deactivator, (b) leukotriene antagonists (LTRA), including LTB4, LTC4, LTD4 & LTE4 antagonists, ⑹ histamine receptor Antagonists, including sigma and% antagonists, () α ″ α 2 -adrenergic receptor activator vasoconstrictor sympathomimetics' for decongestion purposes, muscarinic 3 receptor antagonists or antibiliary Alkaline agents, (f) PDE inhibitors, such as PDE3, PDE4, and PDE5 inhibitors, 99200 -58- 200534846 (g) Theophylline, ⑻ clomamor sodium gluconate, (l) cox inhibitors, non-selective And selective COX-1 or COX-2 inhibitors (NSAE)), ① oral and inhaled corticosteroids, such as DAGR (dissociator of corticoid receptors), ⑻ active against endogenous inflammatory bulk Monoclonal antibodies, ⑴ antitumor necrosis factor (anti-TNF-α) agents, (m) adhesion molecule inhibitors, including VLA-4 antagonists, ⑻ Kallikrein 7 and B2-receptor antagonist, ⑻ immunosuppressant, (P) inhibitor of interstitial metalloproteinase (MMP), (q) tachykinin nk !, nk2 & nk3 receptor antagonist, 00 elasticity Protease inhibitors, ⑻ adenosine A2a receptor activators, (0 urokinase inhibitors, ⑻ compounds that act on dopamine, receptors, such as D2 activators, (v) modulation of the NF / c / 5 pathway Preparations, such as ικκ inhibitors, (w) modulators of cytokine signaling pathways, such as p38 MAP kinase, syk kinase, or JAK kinase inhibitors, ⑻ can be classified as mucopolysaccharide decomposers or anti-cough agents, ( y) antibiotics, (z) HDAC inhibitors, and (aa) PI3 kinase inhibitors. 99200 -59- 200534846 According to the present invention, a compound of formula (I) is preferably combined with the following: -h3 antagonist, -muscarine M3 receptor antagonists, PDE4 inhibitors, corticosteroids, adenosine A2a receptor activators, modulators of cytokine signaling pathways, such as p38 MAP kinase or syk kinase, or leukotriene Antagonists (LTRA), including LTB4, LTC4, LTD4, and LTE4 antagonists. The combination of the compound of formula (1) with the following is further preferred:-Corticosteroids, especially inhaled corticosteroids with reduced systemic side effects, including prednisone, prednisone hydrochloride, flunisolide, propyl S Assimilated fluoride via dehydropilusol, clodsone dipropionate, bacteroides, fluticasone propionate, ciclesonide and mometasone furoate, or -Muscarinic M3 receptor antagonists or anticholinergics, including in particular ipratropium salts, meaning bromide, tiotropium salts, meaning desertification, oak Oxitropium salt, which means bromide, perenzepine and telenzepine. It should be understood that all references to treatment in this context include cure, relief, and preventive treatment. The following description relates to therapeutic applications of 99200 -60-200534846 to which compounds of formula IX can be administered. The compounds of formula (I) have the ability to interact with receptors, and thus have a wide range of therapeutic applications as described further below, due to the essential role that receptors play in the physiology of all mammals. Therefore, a further aspect of the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt, derived form or composition thereof, for the treatment of diseases, disorders and symptoms involving the / 22 X body. More specifically, the invention also relates to a compound of formula (1), or a pharmaceutically acceptable salt, derived form or composition thereof, for use in the treatment of diseases, disorders and symptoms, selected from the group consisting of: Type, etiology or pathogenesis of asthma, especially the asthma of the following members, selected from the group consisting of ectopic asthma, non-ectopic asthma, allergic asthma, asthma mediated by ectopic bronchial IgE, bronchial asthma, spontaneous Asthma, true asthma, endogenous asthma due to pathophysiology, exogenous asthma due to environmental factors, spontaneous asthma due to unknown or non-obvious causes, non-ectopic asthma, bronchitis asthma, emphysema asthma , Asthma caused by exercise, asthma caused by allergens, asthma caused by cold air, occupational asthma, infectious asthma caused by bacterial, fungal, protozoan or viral infection, non-allergic asthma, initial asthma, Wheezing infant signs and bronchial bronchitis, • chronic or acute bronchoconstriction, chronic bronchitis, small airway obstruction, and emphysema, Type, etiology or pathogenesis of obstructive or inflammatory airway diseases, especially those of the following members, are selected from 99200 -61-200534846 including chronic eosinophilic pneumonia, chronic obstructive pulmonary disease (COPD), including and COPD with or without associated chronic bronchitis, emphysema, or dyspnea COPD is characterized by COPD with irreversible, progressive airway obstruction, adult dyspnea syndrome (ARDS), and airway passage caused by other medications Exacerbation of high responsiveness and airway diseases associated with pulmonary hypertension, • bronchitis of any type, etiology, or pathogenesis, especially bronchitis of the following members, selected from the group consisting of acute bronchitis, Acute laryngotracheal bronchitis, arachis bronchitis, catarrhal bronchitis, Grubb bronchitis, dry bronchitis, infectious asthmatic bronchitis, sputum bronchitis, staphylococcus Or streptococcal bronchitis and alveolar bronchitis, • acute lung injury, • bronchiectasis regardless of the type, etiology or pathogenesis,枝 The tracheal dilatation of the following members is selected from the group consisting of cylindrical branch tracheal dilatation, cystic branch tracheal expansion, spindle-shaped branch tracheal expansion, microvascular stem branch tracheal expansion and filter branch tracheal expansion, gallbladder branch tracheal expansion, and vesicular branch trachea. expansion. Or pharmaceutically acceptable

Yet another aspect of the present invention relates to a salt, a derivatized form, or a composition that is acceptable for a compound of formula (1) in a drug. The drug has / 32 activator activity. In particular, 99200 -62-200534846 Therefore, the present invention provides a method of treating eight mammals (including humans) of interest, which uses an effective amount of a compound of formula (I), or a scientifically acceptable salt thereof Derived form or composition. More specifically, the present invention provides a particularly interesting method of treating vector-borne diseases and / or symptoms in mammals, including humans, in particular as listed above = diseases and / or symptoms, including The mammal administers an effective amount of a tritified person, a pharmaceutically acceptable salt thereof, and / or a derived form. σ [Embodiment] The following examples illustrate the preparation of compounds of formula IX: Example 1: Ν-cycloheptyl-2_ {3 _ [(2R) -2 _ ({(2R) ihydroxy_2cahydroxy_3 • ( Methyl) phenyl] ethyl} amino) propyl] phenyl} ethanil

Add ammonium fluoride (98 mg, 2.64 mmol) in one portion at room temperature

(Hydroxymethyl) phenyl] ethyl} amino) propyl] phenyl} _N_cycloheptylacetamidamine (Preparation 1) (150 mg, 0.26 mmol) in methanol (3 ml ) And stirred solution in water (1.5 ml). The reaction was heated at 40 t for 18 hours and then allowed to cool to room temperature. The solvent was removed in vacuo, and the residue was dissolved in ethyl acetate (30 mL) and water (20 mL). The organic layer was separated, washed with brine (100 mL), dried (MgSO4), and dried in vacuo. The solvent was removed and a clear oil was produced. It was purified by flash column chromatography on Shixijiao, and dissolved with 99200-63-200534846 gas methane: methanol: ammonia (90: 10: 1 volume ratio) to obtain the title compound as a white foam (87 Mg). 1H NMR (400MHz, CD3 OD): 5 = 7.25-7.00 (6H, m), 6.85 (1H, d), 4.58 (3Η, m), 3.80 (1Η, m), 3.40 (2Η , S), 2.95 (2Η, m), 2.75 (2Η, m), 2.58 (1Η, m), 1.83 (2H, m), 1.70-1.40 (10H, m), 1.05 (3H, d ) ppm · LRMS (electrospray): m / z [M + Na] +477, [Μ-ΗΓ453. Example 2: N- (cyclohexylmethyl) -2- {3-[(2R) -2- ( {(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) propyl] phenyl} -N-methylacetamide

Using the method of Example 1, prepared from 2- {3 _ [(2R) -2 _ ({(2R) -2-{[Third-butyl (dimethyl) suprylalkyl] oxy} -2- [4-Hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) propyl] phenyl} -N- (cyclohexylfluorenyl) -N-methylacetamide (Preparation 2), obtained The title compound is a white vesicle. 1H NMR (400MHz, CD3 OD): 5 = 7.21 (2H, m), 7.0 (4H, m), 6.68 (1H, d), 4.61 (3Η, m), 3.71 (2Η , S), 3.31 (2Η, m), 3.20 (2Η, m), 2.91 (5Η, m), 2.71 (2H, m), 2.60 (1H, m), 1.70 (5H , M), 1.22 (4H, m), 1.04 (3H, d), 0.95 (2H, m) ppm. LRMS (electrospray): m / z [M + H] +469, [M + Na] + 491 · Example 3: N-[(1S) -1-cyclohexylethyl] -2_ {3-[(2R) -2-(((2R) -2_hydroxy_2_ [4_hydroxy-3- (Hydroxyfluorenyl) phenyl] ethyl} amino) propyl] phenyl} ethanamide 99200 -64- 200534846

OH

Using the method of Example 1, prepared from 2- {3-[(2R) -2-({(2R) -2-{[Third-butyl (dimethyl) silyl] oxy] 2- [ 4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) propyl] phenyl} _N _ [(1S) small cyclohexylethyl] acetamidamine (Preparation 3) to obtain the title compound as White foam. 1H NMR (400MHz, CD3 OD): 5 = 7.20 (4H, m), 7.01 (2H, dd), 6.71 (1H, d), 4.60 (3H, m), 3.62 (1H, m), 3.48 (1H, d), 3.41 (1H, d), 2.85 (2H, m), 2.63 (2H, m), 2.58 (1H, dd), 1.60 (5H, m), 1.40- 1.02 (10H, m), 0.93 (2H, m) ppm. LRMS (electrospray): m / z [M + H] +469, [M + Na] +491.

Example 4: 2- {3-[(2R) -2-({(2R) _2-hydroxy_2 · [4-hydroxy-3_ (hydroxymethyl) phenyl] ethyl} amino) propyl] benzene Isopropylacetamidamine OH

Using the method of Example 1, prepared from 2- {3-[(2R) -2-({(2R) -2-{[Third-butyl ('monofluorenyl) crushed alkyl] oxy}- 2- [4-Ethyl-3- (transmethyl) phenyl] ethyl} amino) propyl] phenyl} -N-isopropylacetamidamine (Preparation 4) to give the title compound as white Bubble beads. 1H NMR (400MHz, CD3 OD): δ = 7.22 (1H3 d) 5 7.18-7.16 (1H, d) 5 7.12-7.10 (1H, d), 7.07 (1H, s), 7.04-6.99 (2H, t) , 6.71-6.69 (1H, d), 4.63-4.60 (3H, m), 3.97-3.90 (1H5 m) 3 3.41 (2H3 s)? 2.98-2.93 (1H, q), 2.91-2.86 (1H, dd) 5 2.74- 99200 -65 · 200534846 2 · 70 (2H, dd), 2.60-2.55 (1H, dd), 1.13-Ul (6H, d), 1.08-1.07 (3H, d) ppm. LRMS (electrospray): m / z [M + H] +401, [Μ_Η] · 399 ·

Example 5: N-cyclopentyl-2- {3-[(2R) -2-({(2R) -2-hydroxy_2- [4-hydroxy-3_ (hydroxymethyl) phenyl] ethyl} Amine) propyl] phenyl} acetamidine OH

Using the method described in Example 3, prepared from 2- {3-[(2R) -2-({(2R) -2-{[third-butyl (dimethyl) silyl] oxy] 2- [ 4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) propyl] phenyl} -N-cyclopentylacetamidamine (Preparation 5) to give the title compound as a white foam. 1H NMR (400MHz, CD3OD): δ = 7.22 (1Η? D)? 7.18-7.16 (1Η, d), 7.11-7 · 09 (1H, d), 7.06 (1H, s), 7.04-6.98 ( 2H, t), 6.71-6_69 (1H, d), 4.63-4.60 (3¾ m), 4.10-4.04 (1H, m), 3.42 (2H, s) 5 2.98-2.93 (1H, q) 5 2.90 -2.85 (1H? Dd), 2.74-2.69 (2H, dd) 5 2.60-2.55 (1H, dd)? 1.94-1.86 (2H, m), 1.73-1.65 (2H, m), 1.62-1.54 (2H, m), 1.47-1.39 (2H, m), 1.08-1.07 (3H, d) ppm. LRMS (electrospray): m / z [M + H] +427, [MH] -425 · CHN analysis ·· Measured value C, 68.48%, H, 8.20%, N, 6.35%; C25H34N204 + 0.66Η2 O requires C, 68.49%, H, 8.12%, N, 6.39%. Example 6: N- (cyclobutylmethyl ) -2- {3-[(2R) _2-({(2R) _2-hydroxy_2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) propyl] phenyl Acetamidine 99200 -66- 200534846

OH

HO〆

Using the method of Example 1, prepared from 2- {3-[(2R) -2-({(2R) -2-{[third-butyl (dimethyl) silyl] oxy}} 2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) propyl] phenyl} -N- (cyclobutylmethyl) acetamide (Preparation 6) to obtain the title compound as a white foam Bedding.

1H NMR (400MHz, CD3 OD): δ = 7.22 (1H3 d)? 7.18-7.16 (1H, d), 7.12-7.10 (1H, d), 7.07 (1H, s), 7.04-6 · 99 ( 2H, t), 6.71-6.69 (1H, d), 4.62-4.59 (3¾ m), 3.44 (2H, s), 3.18-3.17 (2H, d), 2.97-2.92 (1H, q), 2.90 -2.85 (1H, dd), 2.73-2.69 (2H, dd), 2.60-2.55 (1H, dd), 2.50-2.43 (1H, m), 2.04-1.97 (2H, m), 1.92-1.78 (2H, m), 1.72-1.63 (2H, m), 1.08-1.06 (3H, d) ppm. LRMS (electrospray): m / z [M + H] +427, [Μ-Η] · 425 · CHN analysis : Measured value C, 68.24%, Η, 8.09%, N, 6.39%; C25H34N204 + 0.75Η2 O requires C, 68.23%, H, 8.13%, N, 6.37%. Example 7: N- (cyclopentane Methyl) -2- {3-[(2R) _2 _ ({(2R) _2_hydroxy_2 · [4_hydroxy-3 · (transmethyl) phenyl] ethyl-yl} amino) propyl ] Phenyl} acetamide

Using the method of Example 1, prepared from 2_ {3-[(m) -2 _ ({(2R) -2-{[Third · butyl (dimethyl) silyl] oxy] 2- [4- Hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) propyl] phenyl} -N- (cyclopentylmethyl) acetamide (Preparation 7) to obtain the title 99200 -67 · 200534846 Compound as a white foam. 1H NMR (400MHz, CD3 OD): δ = 7.22 (1H? D), 7.19-7.17 (1H, d) 5 7.12-7.11 (1H, d), 7.08 (1H, s), 7.04-7.00 (2H, t ), 6.71-6.69 (1H, d), 4.63-4.60 (3¾ m), 3.44 (2H, s), 3.10-3.08 (2H, d), 2.98-2.94 (1H, q), 2.90-2.85 ( 1H, dd), 2.74-2.70 (2H, dd), 2.60-2.55 (1H, dd), 2.07-2.00 (1H, m), 1.73-1.66 (2H, m), 1.62-1 · 46 (4H, m ), 1 · 22-1 · 12 (2H, m), 1.08-1.07 (3H, d) ppm. LRMS (electrospray): m / z [M + H] +441, [MH] -439.

CHN analysis: Measured values C, 69 · 12%, H, 8.19%, N, 6.26%; C26H36N204 + 0 · 62Η20, C, 69.13%, H, 8.31%, N, 6.20%. Example 8: N_ Cyclohexyl-2- {3-[(2R) -2 _ ({(2R) -2_hydroxy-2- [4_hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) propyl] Phenyl} acetamide

OH

Using the method described in Example 1, prepared from 2- {3-[(2R) -2-({(2R) -2-{[Third-butyl (dimethyl) oxetyl] oxy] 2 -[4-Hydroxy ((hydroxymethyl) phenyl] ethyl} amino) propyl] phenyl-}-N-cyclohexylacetamidamine (Preparation 8) to obtain the title compound as a white foam. 1H NMR (400MHz, CD3OD): δ = 7.22 (1Η5 d), 7.19-7.17 (1Η, d), 7.12-7 · 10 (1H, d), 7.07 (1H, s), 7.04-6.99 (2H, t ), 6.71-6.69 (1H, d), 4.64-4.60 (3¾ m), 3.64-3.56 (1H, m), 3.42 (2H, s), 3.00_2 · 94 (1H, q), 2.91- 2.86 (1H, dd), 2.76-2.72 (2H, dd), 2.61-2.56 (1H, dd), 1.86-1.80 (2H, m), 1.75-1.70 (2H, m), 1.65-1.59 (lH, m ), 1.38-1.28 (2H, m), 1.25-1.15 (3H, m), 1.09-1.07 (3H, d) 99200 -68- 200534846 ppm. LRMS (electrospray): m / z [M + H] +441, [Μ-ΗΓ439. CHN analysis: measured values C, 6S.49%, H, 8.27%, N, 6.14%; c26H36N204 + 0.85H2O requires C, 68.50%, H, 8.34%, N , 6.14% ·

Example 9: N_cyclobutyl-2- {3 _ [(2R) -2-({(2R) -2-hydroxy_2_ [4-hydroxy-3_ (methylol) phenyl] ethyl} amino ) Propyl] phenyl} acetamidoOH

Using the method of Example 1, made from 2_ {3-[(2R) -2-({(2R) -2-{[Third-butyl (dimethyl) silyl] oxy} -2-} 4-Hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) propyl] phenylbutylethylamine (Preparation 9) 'The title compound was obtained as a white foam. 1H NMR (400MHz, CD3OD): δ = 7.21 (1Η, d) 5 7.18-7.16 (1Η, d), 7.11-7.09 (1H, d), 7.06 (1H, s), 7.03-6.98 (2H, t) , 6.70-6.68 (1H, d), 4.62-4.59 (3¾ m), 4.294.21 (1H, m), 3.40 (2H, s), 2.88-2.43 (1H, q), 2.90-2.85 (1H, dd ), 2.73-2.68 (2H, m), 2.61-2.56 (1H? Dd), 2.29-2.21 (2H, m), 1.98-1.89 (2H, m) 5 1.76-1.66 (2H, m), 1.08-1.07 (3H, d) ppm. LRMS (electrospray): m / z [M + H] +413, [Μ-Η] _411 · CHN Analysis: Measured value C, 67.18%, H, 7.75%, N , 6.51%; C24H32N204 + 0 · 93Η2〇 need C, 67.15%, H, 7.95%, N, 6.53%. Example 10: N- (cyclohexylmethyl) _2- {3-[(2R) -2-({ (2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) propyl] phenyl} ethanamine 99200 -69- 200534846

Using the method described in Example 1, prepared from 2- {3 _ [(2R) _2-({(2R) -2-{[Third-butyl (dimethyl) silyl] oxyalkyl] oxybutane 2- [ 4-hydroxy-3-fluorenylmethyl) phenyl] ethyl} amino) propyl] phenyl} -N- (cyclohexylmethyl) acetamidamine (Preparation 10) to obtain the title compound as a yellow foam Thing.

1H NMR (400MHz, CD3 OD): 5 = 7.21-7.20 (1H, m), 7.18-7.16 (1H, d), 7.11-7.09 (lH, d), 7.06 (lH, s), 7.02-6.98 (2H , T), 6.70-6.68 (lH, d), 4.61-4.58 (3H, m), 3.44 (2H, s), 2.99_2 · 98 (2H, d), 2.94-2.83 (2H, m) , 2.71-2.67 (2H, q,), 2.58-2.53 (1H, dd), 1.70-1.60 (5H, m), 1.49-1 · 40 (1H, m), 1.26-U2 (3H, m) , 1.06-1.05 (3H5 d) 5 0.93-0.83 (2H, m) ppm. LRMS (electrospray): m / z [M + H] +455, [M + Na] +477, [Μ-Η] · 453 · CHN analysis: measured values C, 70.07%, H, 8.50%, N, 6.17%; C27H38N204 + 0.45Η2 O requires C, 70.09%, H, 8.47%, N, 6.05%.

Example 11: N- (cyclopropylmethyl) -2- {3-[(2R) -2-({(2R) -2-hydroxy-2- [4-hydroxy_3- (hydroxymethyl) benzyl Group] ethyl} amino) propyl] phenyl} ethanil

Using the method of Example 1, prepared from 2- {3-[(2R) -2-({(2R) -2-{[third-butyl (dimethyl) silyl] oxy} -2- [4-hydroxy-3- (hydroxyfluorenyl) phenyl] ethyl} amine 99200 -70- 200534846 based) propyl] phenyl} -N- (cyclopropylmethyl) acetamidamine (Preparation 11), The title compound was obtained as a white foam. 1H NMR (400MHz, CD3 OD): 5 = 7.21-7.16 (2H, m), 7.12-7.10 (1H, d), 7.07 (1H, s), 7.02-6.98 (2H, m), 6.70-6.68 (1H , D), 4.61-4.58 (3H, m), 3.45 (2H, s), 3.03-3.01 (2H, d), 2.95_2 · 83 (2H, m), 2.71-2.67 (2H, m) , 2.59-2.54 (1H, m), 1.07-1.06 (3H, d), 0.97-0.90 (1H, m), 0.48-0.43 (2H, q,), 0.19-0.15 (2H, q,) ppm. LRMS (Electrospray): m / z [M + H] +413, [M + Na] +435, [Μ-Η] · 411 ·

CHN analysis: Measured values C, 67.85%, H, 7.82%, N, 6.48%; C24H32N204 + 0.70H2 O requires C, 67.80%, H, 7.92%, N, 6.59%. Example 12: N- (Ring Heptylmethyl) -2- {3-[(2R) -2-({(2R) -2-hydroxy-2_ [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) Propyl] phenyl} ethanil

OH

HO〆 «Jo Using the method of Example 1, made from 2- {3-[(2R) -2-({(2R) -2-{[third-butyl (difluorenyl) silyl] oxy } -2- [4-hydroxy_3- (hydroxymethyl) benzyl] ethyl} amino) propyl] phenyl} -N- (cycloheptylmethyl) acetamide (Preparation 12), obtained The title compound is a white swimmer. 1H NMR (400MHz, CD3 OD): 5 = 7.24-6.95 (6H, m), 6.72-6.69 (1H, d), 4.62 (2H, s), 4.62-4.59 (1H, m), 3.26 (2H, s), 3.00-2.97 (2H, d), 2.98-2.54 (m, 5H), 1.70-1.02 (m, 13H), 1.05 (3H, d) ppm. LRMS (electrospray): m / z [M + H] +469. 99200 -71-200534846

Example 13: N_l-Au- steel alkyl-2- {3 _ [(2R) -2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl } Amino) propyl] phenyl} acetamidine OH

Using the method of Example 1, made from N-1-aussinoalkyl-2- {3-[(2R) -2-({(2R) -2-{[third-butyl (dimethyl) Silyl] oxy} -2- [4-hydroxy_3- (hydroxymethyl) phenyl] ethyl} amino) propyl] phenyl} acetamidamine (Preparation 13) to give the title compound as white Bubble beads. 1H NMR (400MHz, CD3 OD): δ = 7.22-6.96 (6H, m), 6.68-6.65 (1H, d), 4.63-4.59 (3H, m), 3.38 (2H, s), 2.98_2 · 92 (1H, q), 2.88-2 · 54 (4H, m), 2-02 (3H, s), 2.00 (6H, s), 1.68 (6H, s), 1.05-1.03 ( 3H, d) ppm. LRMS (electrospray): m / z [Μ_Η] · 491. Example 14: N- (l-Au steel alkylmethyl) -2- {3-[(2R) -2- ({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) propyl] phenyl} acetamidine

Using the method of Example 1, made from N- (l-gold steel alkylfluorenyl) -2- {3-[(2R) -2-({(2R) -2-{[third-butyl ( Dimethyl) silyl] oxy} -2- [4-hydroxyl (hydroxymethyl) phenyl] ethyl} amino) propyl] phenyl} acetamidamine (Preparation 14) to obtain the title compound, It is a white bubble. 99200 -72- 200534846 1H NMR (400MHz, CD3 OD): 5 = 7.22-7.12 (5H, m), 7.06-7.00 (1H, t), 6.72-6.70 (1H, d), 4 · 62-4 · 59 (1H, m), 4.61 (2H, s) 5 3.46 (2H, s), 2.98-2.92 (1H, q), 2.91-2.54 (6H, m), 2.90 (3H, s), 1.68-1.56 (6H , M), 1.42 (6H, s), 1.06 -1.04 (3H? D) ppm. LRMS (electrospray): m / z [M + H] +507, [M + Na] +529.

Example 15: N-2-gold steel alkyl-2- {3-[(2R) -2-({(2R) -2-hydroxy-2- [4-hydroxy-3_ (hydroxymethyl) phenyl] Ethyl} amino) propyl] phenyl} ethanilamine OH

Using the method of Example 1, made from N-2-gold steel alkyl-2- {3-[(2R) _2-({(2R) -2 _ {[third-butyl (difluorenyl) silyl group ] Oxy} -2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) propyl] phenyl} acetamidamine (Preparation 15) to obtain the title compound as a white foam . 1H NMR (400MHz, CD3 OD): δ = 7.24-7.10 (5H, m), 7.05-6.98 (1H, t), 6.70-6.68 (2H, d), 4.61 (2H, s), 4.62-4.58 (1H , M), 3.94 (1H, s), 3.54 (2H, s), 2.96-2.52 (5H, m), 1.96-1.75 (12H, m), 1.62-1.56 (2H, d), 1.05 -1.03 (3H, d) ppm. LRMS (electrospray): m / z [Μ-ΗΓ491 · Example 16: N_ (2-cyclohexylethyl) _2_ {3-[(2R) -2-({( 2R) -2 · hydroxy_2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) propyl] phenyl} -N-methylacetamide 99200 -73- 200534846 CH3 ΗΟ ^ Prepared from 2- {3-[(2R) -2-({(2R) -2-{[Third-butyl (monomethyl) pyridyl) oxy]} using the method of Example 1 -2- [4-Ethyl-3- (methyl) phenyl] ethyl} amino) propyl] phenyl} -N- (2-cyclohexylethyl) -N-methylacetamide (Preparation 16) to obtain the title compound as a white foam. 1H NMR (400MHz, CD3 OD): 5 = 7.23-7.00 (6H, m), 6.71-6.68 (1H, d), 4.61 (2H, s), 4.61-4.57 (lH, m), 3.71-3.68 (2H , M), 4.61-4_57 (lH, m), 3.71-3.68 (2H, m), 3.43-3.26 (2H, m), 2.97-2.52 (8H, m), 1.78-0.82 (13H, m), 1.08 -1.06 (3H, d) ppm. LRMS (electrospray): m / z [M + Na] +505, [Μ-Η] · 491. Example 17 · N-cycloheptyl_2- {3 _ [( 2R) -2-({(2R) -2-Ethyl-2_ [4_ peryl-3- (Ethyl) phenyl] ethyl} amino) propyl] phenylphenyl N-methylacetamidine amine

Using the method described in Example 1, prepared from 2_ {3-[(2R) -2-({(2R) -2-{[Third · butyl (monomethyl) crushed alkyl] oxy} -2- [4-Cyclo-3- (methyl) phenyl] ethyl} amino) propyl] phenylb N-cycloheptyl-N-fluorenylacetamidamine (Preparation 17) to obtain the title compound, It is a white foam. 1H NMR (400MHz, CD3 0D): 5 = 7.23-6.96 (6H, m), 6.72-6 · 64 (1H, dd), 4.62-4.60 (2Η, d), 4.61-4.58 (1Η, m) , 4.58-4.51 (0.5Η, m), 3.70-3.63 (0.5Η, 99200 -74 · 200534846 m), 3.75-3.67 (2H, d), 2.95-2.50 (5H, m), 2.82-2 · 78 (3H, d), 1.72-1.20 (12H, m), 1.02-1.00 (3H, 2d) ppm · LRMS (electrospray): m / z [M + Na] +491.

Example 18: N-cyclohexyl-N-ethyl-2- {3-[(2R) -2 _ ({(2R) _2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl]] Ethyl} amino) propyl] phenyl} ethanil

Using the method described in Example 1, prepared from 2- {3 _ [(2R) -2-({(2R) -2 _ {[Third-butyl (dimethyl) silyl] oxyalkyl] oxy-2- [ 4-hydroxy-3- (methyl) phenyl] ethyl} amino) propyl] phenyl} -N-cyclohexyl-N-ethylacetamidamine (Preparation 18) to give the title compound as white Foam.

1H NMR (400MHz, CD3 OD): δ = 7.25-6.98 (6H, m) 5 6.70-6.67 (1H, d), 4.61 (2H, s), 4.60-4.57 (1H, m), 3.72 (2H, s ), 3.65-3.61 (1H, m), 3.30-3.24 (2H, q), 2.95-2 · 50 (5H, m), 1.84-1.08 (10H, m), 1.12-1 · 08 ( 3H, t), 1.04-1.02 (3H, d) ppm. LRMS (electrospray): m / z [M + Na] + 491 ·

Example 19: N- (2-cyclohexylethyl) -2- {3-[(2R) -2 _ ({(2R) _2_hydroxy_2_ [4_hydroxy-3- (methyl) phenyl)] Ethyl} amino) propyl] phenyl} ethylamine OH

99200 -75- 200534846 Prepared from 2- {3-[(2R) -2-({(2R) -2-{[Third-Butyl (Dimethyl) Suptilyl) ] Oxy} _2- [4-hydroxy-3- (methyl) phenyl] ethyl} amino) propyl] phenylbenzene N- (2-cyclohexylethyl) acetamide (Preparation 19) The title compound was obtained as a white foam. 1H NMR (400MHz, CD3 OD): δ = 7.22-6.98 (6H, m), 6.68-6.66 (1H, d), 4.61 (2H, s), 4.6 (Μ · 58 (1H, m) , 3.42 (2H, s), 3.20-3.16 (2H, t), 2.96-2.56 (5¾ m), 1.73-1.60 (5H, m) 5 1.40-1.35 (2H, q), 1.30-1.12 (4H, m ), 1.07-1 · 05 (3H, d), 0.92-0.81 (2H, m) ppm.

LRMS (electrospray): m / z [M + Na] + 491 · Example 20: N- (4-chlorobenzyl) _2- {3- [2-({(2R) -2_hydroxy-2- [4-Hydroxy-3_ (methyl) phenyl] ethyl} amino) -2 • methylpropyl] phenyl} acetamidine

According to the procedure used for Preparation 1, {3- [2-({(2R) -2-hydroxy-2- [4-hydroxy ((hydroxymethyl) phenyl] ethyl} amino) _2_methyl) Propyl] phenyl} acetic acid (Preparation 50) was prepared with the appropriate amine to give the title compound as a white foam. 1H NMR (400MHz, CD3 OD) · δ = 7.37-7.36 (1Η, d), 7.32-7.17 (8H, m)? 7.13-7.11 (1H, d), 6.82-6.80 (1H, d), 4.75- 4.71 (1H, m), 4.70 (2H, s), 4.37 (2H, s), 3.58 (2H, s), 3.02_2.96 (1H, m), 2.93-2.89 (1H, m), 2.86- 2.78 (2H, m), 1.16 (3H, s), 1.14 (3H, s) ppm_ LRMS (electrospray): m / z [M + H] +497, [M + Na] +519, [Μ -Η] · 495. 99200 -76 · 200534846 Example 21: N_ (2,6_dimethoxyfluorenyl) _2_ {3_ [2-({(2R) _2-hydroxy-2- [4_hydroxy-3 -(Hydroxymethyl) phenyl] ethyl} amino) -2 • methylpropyl] phenyl} acetamidoCH. I 3

According to the procedure used for preparation 1, {3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2 -Methylpropyl] phenyl} acetic acid (Preparation 50) with the appropriate amine to give the title compound as a white foam. 1H NMR (400MHz, CD3OD): δ = 7.39-7.38 (1Η, d), 7.32-7.13 (6Η, m), 6.83-6.81 (1H, d), 6.66 (1H, s), 6.64 ( 1H, s), 4.80-4.77 (1H, m), 4.70 (2H, s), 4.46 (2H, s), 3.80 (6H, s), 3.52 (2H, s), 3.15 3.00 (2H, m), 2.88 (2H, m), 1.21 (3H, s), 1.20 (3H, s) ppm.

LRMS (electrospray): m / z [M + H] +523, [M + Na] +545, [MH] _521 · Example 22: N_ 爷 基 _2_ {3_ [2_⑽ 轻 基 · 2 and passing _3 · (Methyl) phenyl] ethyl} amino) -2-methylpropyl] phenyl 丨 acetamidine

According to the procedure used to prepare 1, use {3_ [2 _ ({(2R) winter hydroxyl 4 [4_hydroxy-3- (methylol) phenyl] ethyl} amino) _2_methylpropyl] benzene Methyl} acetic acid (Preparation 50) and the appropriate amine to give the title compound as a white foam. H NMR (400MHz, CD3OD): δ = 7.38-7.37 (1H5 d), 7.33-7.17 (9Η, m), 99200 -77- 200534846 7.12-7.11 (1H, m), 6.82-6.80 (1H, d), 4.75-4.72 (1H, dd), 4.70 (2H, s), 4.40 (2H, s), 3.58 (2H, s), 3.02-2.96 (1H, m), 2.93-2.89 (1H, m), 2.86-2.78 (2H, m), 1.16 (3H, s), 1.15 (3H, s) ppm. LRMS (Electrospray) ·· m / z [M + H] +463, [ M + Na] +485, [Μ-ΗΓ461 · Example 23: 4 _ {(lR) -2-[(2- {3_ [2- (3,4-diazaisoquinoline_2 (1H) _yl) _2_ketoethyl] phenyl} -1, l-dimethylethyl) amino] -1-transethyl} -2- (transmethyl)

According to the procedure used for preparation 1, {3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2 -Methylpropyl] phenyl} acetic acid (Preparation 50) with the appropriate amine to give the title compound as a white foam. 1H NMR (400MHz, CD3OD): 5 = 7.36-7.35 (1H, d), 7.29-7.24 (1H, m), 7.22-7.13 (5H, m), 7.12-7.09 (2H, m), 7.04-7.02 ( 1H, d), 6.80-6.78 (1H, m), 4.74 (1H? S), 4.71-4.66 (4H, m), 3.90-3.89 (2H, m), 3.86-3.82 (1H, m), 3.78- 3.75 (1H, m) 5 2.94-2.86 (2H, m), 2.81-2.66 (4H, m), 1.08-1.01 (6H, m) ppm. LRMS (electrospray): m / z [M + H] +489, [M + Na] +511, [Μ_ΗΓ487 · Example 24: N- [2-Fluoro-5- (trifluoromethyl) methyl] -2- {3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxyfluorenyl) phenyl] ethyl} amino) _2_methylpropyl] phenyl} ethanil

99200 -78- 200534846 According to the procedure used to prepare 1, use {3_ [2 _ ({(2R) 丨 Hydroxydong [4 · Hydroxy-3- (Methyl) phenyl; | ethyl} amino}> 2 _Methylpropyl] phenyl} acetic acid (Preparation 50) and the appropriate amine to give the title compound as a white foam. 1H NMR (400MHz, CD3 OD): δ = 7.62-7.58 (1H? M) 5 7.56-7.54 (1H? M), 7.33-7.32 (1H, d), 7.28-7.12 (5H, m), 7.08-7.06 (1H, d), 6.78-6.76 (1H, d), 4.70-4.67 ( 1H, m), 4.65 (2H, s), 4.46 (2H, s), 3.55 (2H, s), 2.96-2.91 (1H, m), 2.86-2.81 (1H, m), 2.80-2.72 (2H, m), 1.10 (3H, s), 1.09 (3H, s) ppm. LRMS (electrospray): m / z [m + H] +549, [M + Na] +571 , [Μ-ΗΓ547. Example 25: N_ (2,6-digas benzyl) -2_ {3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- ( Group) phenyl] ethyl} amino) -2-methylpropyl] phenyl} ethanil

According to the procedure used for preparation 1, {3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2 -Methylpropyl] phenyl} acetic acid (Preparation 50) was made with the appropriate amine to give the title compound as a white foam. 1H NMR (400MHz, CD3OD): δ = 7.45-7.43 (2Η, m), 7.39-7.38 (1Η5 d) 5 7.34-7.27 (2Η, m), 7.23-7.19 (3¾ m), 7.14-7.12 (1H, m), 6.83-6.81 (1H, d), 4.79-4.76 (1H, m), 4.71 (2H, s), 4.70 (2H, s), 3.55 (2H, s), 3.09-2.97 (2H, m), 2_88 (2H, s), 1.22 (3H, s), 1.21 (3H, s) ppm · LRMS (electrospray): m / z [M + H] +531, [M + Na] +553 , [Μ-ΗΓ529 · Example 26: 2- {3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino group) -2 • methylpropyl] phenyl} _N- [2 · (methylthio) benzyl] acetamide 99200 -79 · 200534846

OH

According to the procedure used to prepare 1, use {3- [2 < {(2R) _2_hydroxy-2- [4-hydroxy-3- (transmethyl) phenyl] ethyl} amino) _2_methyl Propyl] phenyl and acetic acid (Preparation 50) were prepared with the appropriate amine to give the title compound as a white foam. 1H NMR (400MHz, CD3 OD): δ = 7.36-7.10 (10H, m), 6.81-6.79 (1H, d), 4.73-4.69 (1H, m), 4.69 (2H, s), 4.47 (2H , S), 3.59 (2H, s), 2.99-2.94 (1H, m), 2.89-2.84 (1H, m), 2.81-2.76 (2H, m), 2.48 (3H, s), 1.15 (3H , S), U3 (3H, s) ppm. LRMS (electrospray): m / z [m + H] +509, [M + Na] +531, [Μ-Η] · 507 · Example 27: N- (2,3_dimethylbenzyl) _2- {3_ [2 _ ({(2R) _2-hydroxy_2- [4-hydroxy_3- (transmethyl) phenyl) ethyl} amino) _2 -Methylpropyl] phenyl} ethanamine

According to the procedure used to prepare 1, use {3_ [2-({(2R) _2-hydroxy-2- [4-hydroxy-3- (hydroxyfluorenyl) phenyl] ethyl} amino) -2-methyl Propyl] phenyl} acetic acid (Preparation 50) with the appropriate amine to give the title compound as a white foam. 1H NMR (400MHz, CD30D): δ = 7.37-7.36 (1H, m), 7.30-7.16 (4H, m), 7.12-7.01 (4H, m), 6.82-6.80 (1H, d), 4.74-4.71 ( 1H, m), 4.69 (2H, s), 4.40 (2H, s), 3.56 (2H, s), 3.01-2.96 (1H, m), 2.92-2.88 (1H, m), 2.86-2.77 ( 2H, m), 99200 -80- 200534846 2.29 (3H, s), 2.18 (3H, s), 1.16 (3H, s), 1.14 (3H, s) ppm. LRMS (electrospray): m / z [M + H] +491, [M + Na] +513, [Μ-ΗΓ489 · Example 28: 2- {3- [2-({(2R) -2_hydroxy-2_ [4-hydroxy-3 -(Hydroxymethyl) phenyl] ethyl} amino) · 2-methylpropyl] phenyl} -N- [3- (trifluoromethyl) methyl] ethylamine

According to the procedure used for Preparation 1, {3- [2-({(2R) _2-hydroxyl [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methyl Propyl] phenyl} acetic acid (Preparation 50) was prepared with the appropriate amine to give the title compound as a white foam. 1H NMR (400MHz, CD3 OD): δ = 7.56-7.47 (4H, m), 7.36-7.35 (1H3 m), 7.28-7.15 (4H, m), 7.11-7.09 (1H, d), 6.80-6.78 ( 1H, d), 4.73-4.69 (1H, m), 4.69 (2H, s), 4.47 (2H, s), 3_59 (2H, s), 2.99-2.94 (1H, m), 2.89-2 · 85 (1H, m), 2.84-2.75 (2H, m), U4 (3H, s), 1.13 (3H, s) ppm. LRMS (electrospray): m / z [M + H] +531 , [M + Na] +553, [Μ-ΗΓ529 · Example 29: N_ [4-Gasyl-3_ (trifluoromethyl) methyl]] _ 2- {3- [2 _ ({(2R) -2-hydroxy _2_ [4-hydroxy_3- (hydroxyfluorenyl) phenyl] ethyl} amino) -2-methylpropyl] phenyl} acetamidine

According to the procedure used for preparation 1, {3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2 -Methylpropyl] phenyl} acetic acid (Preparation 50) 99200 -81-200534846 and appropriate amine to give the title compound as a white foam. 1H NMR (400MHz, CD3 OD): 5 = 7.64-7.63 (1H, m), 7.54-7.52 (1H, m), 7.47-7.45 (1H, m), 7.34-7.33 (1H, m), 7.27_7 14 (4H, m), 7.09-7 · 08 (1H, d), 6.80-6.78 (1H, d), 4.71-4.67 (1H, m), 4.69 (2H, s), 4 · 43 (2H, s), 3.58 (2H, s), 2.96-2.91 (1H, m), 2.84-2.80 (1H, m), 2.81-2.72 (2H, m), U2 (3H, s), 1.09 (3H5 s) ppm. LRMS (electrospray): m / z [m + H] +565, [M + Na] +587, [MH] -563. Example 30: N- [2-Gas- 5- (trifluoromethyl) methyl] -2- {3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3_ (hydroxymethyl) phenyl] ethyl} amino Methylpropyl] phenyl} acetamidamine

According to the procedure used for Preparation 1, use {3- [2 _ ({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} aminomethylpropyl ;] Phenyl} acetic acid (Preparation 50) and appropriate amine to give the title compound as a white foam. 1H NMR (400MHz, CD30D): δ = 7.63-7.56 (3Η, m), 7.36-7.35 (1H5 d), 7.30-7.21 (3H, m), 7.18-7 · 16 (1H, dd), 7.12-7.11 (1H, d), 6.81-6.79 (1H, d), 4.73-4.69 (1H, m ), 4.69 (2H, s), 4.54 (2H, s), 3.62 (2H, s), 3.03-2.91 (1H, m), 2.89-2.84 (1H, m), 2.86-2.75 (2H , M), U4 (3H, s), 1 · 12 (3H, s) ppm · LRMS (electrospray): m / z [M + Hf565, [M + Na] +587, [Μ-ΗΓ563 ·· Example 31] : N- [3,5-bis (trifluoromethyl) methyl group] _2_ {3- [2 _ ({(2R) -2-Cycloyl-2_ [4-hydroxy-3- (hydroxyfluorenyl) phenyl ] Ethyl} Amine) _2_methylpropyl] Phenyl} Ethylamine 99200 -82- 200534846

According to the procedure used for Preparation 1, {3- [2-({(2R) -2-hydroxy-2- [4-hydroxy ((hydroxymethyl) phenyl] ethyl} amino) -2-methyl) Propyl] phenyl} acetic acid (Preparation 50) with the appropriate amine to give the title compound as a white foam.

1H NMR (400MHz, CD3 OD): 5 = 7.86-7.84 (3H, m), 7.35 (1H, s), 7.28- 7.15 (4H, m), 7.11-7.09 (1H, d), 6.81 -6 · 79 (1H, d), 4.71-4.68 (1H, m), 4.69 (2H, s), 4.54 (2H, s), 3_60 (2H, s), 2.96-2.91 (1H, m), 2.83-2.79 (1H, m), 2.80

-2.71 (2H, m), 1.10 (3H, s), 1.08 (3H, s) ppm. LRMS (electrospray): m / z [M + H] +599, [M + Na] +621, [ Μ-Η; Γ597 · Example 32: N_ [3_fluoro group_5- (trifluoromethyl); gib 2- {3_ [2-({(2R) _2hydroxy-2- [4- meridian group_ 3- (hydroxymethyl) phenyl] ethyl} amino) -2 • methylpropyl] phenyl} acetamidine

According to the procedure used to prepare 1, use {3 _ [; 2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (fluorenyl) phenyl] ethyl} amino) -2 _Amidinopropyl] phenyl and acetic acid (Preparation 50) were prepared with an appropriate amine, and the title compound was a white foam. 1H NMR (400MHz, CD3OD): § = 7.40 (1H, s), 7.36-7.16 (7H, m), 7.13- 99200 -83- 200534846 7 · 11 (1H, d), 6.82-6.80 (1H, d) , 4.74-4.69 (1H, m), 4.69 (2H, s), 4.47 (2H, s), 3.60 (2H, s), 3.01-2.94 (1H, m), 2.91-2.87 (1H, m) , 2.85-2.77 (2H, m), U5 (3H, s), 1.13 (3H, s) ppm. LRMS (electrospray): m / z [M + H] +549, [M + Na] +571, [MH] _547 · Example 33: N_ [2_ (4-Gaphenyl) ethyl] _3- {2-[(2R) -2_hydroxy-2_ (4 · hydroxy-3_hydroxy-methyl Phenyl) ethylamino] _2-methylpropyl} benzamine

Add 3- {2 _ [(2R) _2- (Third-butyldimethylsupalyloxy) -2- (4-Cycloyl-3_Cyclomethyl-phenyl) ethylamino]- N- [2- (4-Gaphenyl) ethyl] benzamide (Preparation 38) (470 mg, 0.77 mmol) and ammonium fluoride (280 mg, 7.70 mmol) Ear), heated to 43 ° C in formazan (3 ml) and water (1.7 ml) over 18 hours. The solvent was removed in vacuum, and the product was purified by flash column chromatography on silica gel, and dissolved in methane: methanol: ammonia (95: 5: 0.5 by volume). The formed compound was dissolved in methanol and evaporated (X3) to give a white foam ~ (320 mg). The small sample was recrystallized (hexane: ethyl acetate) to obtain a white solid (melting point: 139-140 ° C). 1H NMR (400MHz, CD3 OD) 5 = 7.64-7.60 (2H, m), 7.37-7.20 (7H, m), 7.11 (1H, dd), 6.74 (1H5 d), 4.68_4 · 65 (3H, m ), 3.57 (2H, m), 2.98-2.87 (4H, m), 2.77-2.70 (2H, m), U2 (3H, s), 1.05 (3H, s) · LRMS (electrospray) m / z 497 [M + H] +, 519 [M + Na] + Analytical calculated value (actual measured value) for C28H33C1N204 · 0 · 5 Η2〇0 · 3 C4H1 () 0 99200 -84- 200534846 C, 66.63 (66.39), Η, 6.95 (7.06), N, 5.31 (5.30)%. Example 34: 3- {2-[(2R) -2-hydroxy-2- (4-hydroxy-3_hydroxymethylphenyl) ) -Ethylamino] _2-methylpropylbenzene N- [2- (4-methylphenyl) ethyl] benzidine

Using the method of Example 33, prepared from 3- {2-[(2R) -2- (Third-butyldimethylsuccinyloxy) -2- (4-Ethyl-3-Ethylmethyl -Phenyl) ethylamino] -2-methylpropyl} -N- [2- (4-methylphenyl) ethyl] benzamide (Preparation 39) to give the title compound as a white foam Beads. 1H NMR (400MHz, CD3 OD) δ = 7.69-7.65 (2H, m) 5 7.37-7.30 (3H, m), 7.14-7.06 (5H, m), 6.75 (lH, d), 4.67-4.64 (3H, m), 3.59-3.54 (2H, m), 2.96-2.84 (4H, m), 2.77-2.69 (2H, m), 2.28 (3H, s), 1.11 (3H, s), 1.04 ( 3H, s) · LRMS (Electrospray) m / z 477 [M + H] +, 499 [M + Na] + Analytical calculated value for C29H36N204.0.5H200.3C4H1 () 0 (actual value) C5 71.42 ( 71.62), amidine, 7.94 (7.88), N, 5.52 (5.57)%. Example 35: 3- {2-[(2R) -2-hydroxy-2 · (4-hydroxy-3-hydroxyfluorenylphenyl) -Ethylamino] -2-methyl_propylfluorene 2_ (4-trifluoromethylphenyl) ethyl] benzidine

Using the method of Example 33, prepared from 3- {2-[(2R) -2- (Third-butyldimethyl 99200 -85- 200534846 silanesilyloxy) -2- (4-hydroxy-3-hydroxy Methyl-phenyl) ethylamino] -2-methyl-propyl} -N- [2- (4-trifluoromethylphenyl) ethyl] benzamide (Preparation 4), and The title compound is a white foam. 1H NMR (400MHz, CD3 OD) δ = 7.68-7.62 (1H, m) 5 7.61 (1H, bs), 7.66 (2H, d), 7.42 (2H, d), 7.38-7.30 (3H, m), 7.12 (lH, dd), 6.75 (lH, dd), 4.68-4.65 (1H), 4.65 (2H, s), 3.61 (2H, m), 3.00 (2H, t), 2.92 (1H, dd), 2.86 (1H, d), 2.73 (1H, dd), 2.69 (1H, d), U1 (3H, s), 1.04 (3H, s), LRMS (electrospray) m / z 531 [ M + H] + HRMS to C2 9 H3 4 F3 N2 04 531.2447 [M + H] + Found 531.2465 · Example 36: N- [2- (3,4-Digasphenyl) ethyl] -3_ { 2-[(2R) -2-hydroxy-2- (4 • hydroxy-3 · hydroxymethylphenyl) ethylamino] -2-methyl-propylbenzamide

Using the method of Example 33, prepared from 3- {2-[(2R) -2- (Third-butyldimethylsilyloxy) -2- (4-hydroxy-3-hydroxymethyl · benzene Group) Ethylamino] -2-methyl-propylbenzene N- [2- (3,4-difluorophenyl) ethyl] benzidine (Preparation 41) to give the title compound as a white foam Thing. 1H NMR (400MHz, CD3 OD) 5 = 7.62 (1H, d), 7.60 (1H, s), 7.42-7.40 (2H3 m), 7.38-7.31 (3H, m), 7.18-7 · 11 (2H , M), 6.75 (1H, d), 4.68-4.66 (1H), 4.65 (2H, s), 3.56 (2H, m), 2.86-2.97 (4H, m), 2.69-2.77 (2H , M), 1.11 (3H, s), 1.0 4 (3H5 s). LRMS (electrospray) m / z 531 [M + H] + 99200 • 86-200534846 HRMS for C28H33C12N204 531.1801 [M + H] + Found 531.1812. Example 37: N_ [2- (3,4_dimethylphenyl) ethyl] _3_ {2 _ [(2R) _2-hydroxy_2- (4_hydroxy-3-hydroxymethylphenyl) ) -Ethylamino] -2-methylpropyl} benzidine

Using the method of Example 33, prepared from 3- {2 _ [(2R) -2- (Third-butyldimethylsilyloxy) -2- (4-hydroxy_3-hydroxymethyl-phenyl ) Ethylamino] -2-methyl-propyl} -NP- (3,4-dimethylphenyl) ethyl] benzidine (Preparation 42), and the title compound 'is a white foam. . 1H NMR (400MHz, CD3 OD) δ = 7.63 (1H, m) 5 7.61 (1H, bs) 5 7.38-7.31 (3H, m), 7.12 (lH, dd), 7.02-6.99 (2H, m), 6.92 (lH, dd), 6.75 (lH, d), 4.67-4.64 (1H, m), 4.65 (2H, s), 3.53 (2H, t), 2.92 (1H, dd), 2.86 (1H, d), 2.82 (2H, t), 2.72 (1H, dd), 2.69 (1H, d), 2.20 (6H, s), 1.11 (3H, s), 1.04 (3H S) · LRMS (electrospray) m / z 491 [M + H] + for C3〇H39N2〇42HRMS 491.2905 [M + H] + found 491.2892. Example 38: 3] 2-[(2R) _2_ Hydroxy-2- (4-hydroxy-3-hydroxymethyl-phenyl) ethylaminobenzene 2-methylpropylfan_2_yl · ethyl) benzamine

Using the method of Example 33, prepared from 3- {2-[(2R) -2- (Third-butyldifluorene 99200 -87- 200534846 Keystone oxalyloxy) -2- (4-¾yl- 3-Methyl-phenyl) ethylamino] -2-methyl-propyl} -N- (2-tea-2-ylethyl) benzamide (Preparation 43) to give the title compound, It is a white foam. 1H NMR (400MHz? CD3OD) δ 7.80-7.75 (3Η, m), 7.68 (1Η, bs), 7.62 (1Η, m), 7.57 (1H, bs), 7.44-7.29 (6H, m), 7.12 (1H, dd), 6.75 (1H, d), 4.67-4.63 (1H, m), 4.66 (2H, s), 3.67 (2H, m), 3.06 (2H, t), 2.90 (1H , Dd), 2.82 (1H, d), 2.71 (1H, dd), 2.66 (1H, d), 1.08 (3H, s), 1.01 (3H, s). LRMS (electrospray) m / z 513 [M + H] +

HRMS for C3 2 H3 7N2 04 513.2748 [M + H] + Found 513.2726. Example 39: N- (l, l_dimethyl-2-phenylethyl) -3- {2 _ [(2R) _2 _Hydroxy_2- (4_hydroxy-3-hydroxy · methylphenyl) _ethylamino] -2-methylpropyl} benzamide

Using the method of Example 33, prepared from 3- {2-[(2R) -2- (Third-butyldimethylsilyloxy) -2- (4-hydroxy-3-hydroxyfluorenyl-benzene Group) ethylamino] -2-methyl-propyl} -N- (1,1-diamidino-2-phenyl-ethyl) benzidine (Preparation 44) to give the title compound as White foam. 1H NMR (400MHz, CD3 OD) 6 = 7.64 (1H, m), 7.60 (1H, bs), 7.35-7.27 (3H, m), 7.24-7.15 (5H, m), 7_06 (lH, dd), 6.72 (lH, d), 4.64 (2H, s), 4.64-4.61 (lH, m), 3.20 (lH, d), 3.12 (lH, d), 2.86 (lH, dd), 2-81 (lH, d), 2.73-2.69 (2H, m), 1.42 (3H, s), 1_39 (3H, s), 1.09 (3H, s), 1.05 (3H, s). LRMS (electrospray) m / z 491 [M + H] + 99200 • 88- 200534846 HRMS of C3 2 H3 7 N2 04 491.2905 [M + H] + Found 491.2885. Example 40: 3- {2-[(2R) -2-hydroxy-2_ (4-hydroxyl _3-Hydroxymethylphenyl) -ethylamino] -2-methylpropyl} s (2-methyl_2_phenylpropyl) benzidine

OH

Using the method of Example 33, prepared from 3- {2-[(2R) -2- (Third-butyldimethylsilyloxy) -2- (4-hydroxy-3-hydroxymethylphenyl) Ethylamino] -2-methylpropyl} -N- (2-methyl-2-phenylpropyl) -benzamide (Preparation 45) to give the title compound as a white foam. 1H NMR (400MHz5 CD3OD) δ 7.53 (1Η, m)? 7.60 (1Η, bs), 7.43 (1Η, dd), 7.34-7.28 (5H, m), 7.20-7.16 (1H, m), 7 · 10 ( 1H, dd), 6.74 (1H, d), 4.65 (2H, s), 4.65-4.61 (1H, dd), 3.57 (2H, s), 2.87 (1H, dd), 2.79 (1H, d), 2.75-2.69 (2H, m), 1.38 (6H, s), 1.07 (3H, s), 1.03 (3H, s). LRMS (electrospray) m / z 491 [M + H] + pair C3 〇H3 9 N2 04 HRMS 491.2905 [M + H] + Found 491.2897. Example 41: N- (4-Gasino) -3_ {2- 丨 (2R) -2-hydroxy-2- (4- Hydroxy-3-hydroxy · methylphenyl) ethylamino] -2_methylpropyl} benzidine

Using the method of Example 33, prepared from 3-{(2R) -2- [2- (Third-butyldimethyl 99200 -89- 200534846-based silyloxy) -2- (4-hydroxy-3- Hydroxymethyl-phenyl) ethylaminomethylpropion *}-N- (4-Arylidene) benzidine (Preparation 46) to give the title compound as a white foam. H NMR (400MHz, CD3 OD) δ = 7.74-7.70 (3H, m), 7.40-7.29 (7H, m) 5 7.07 (1H, dd), 6.71 (1H, d), 4.67-4.63 (1H, dd) , 4.63 (2H, s), 4.60 (2¾ dd), 2.96-2 · 88 (2H, m), 2.76-2.70 (2H, m), U2 (3H, s), 1.04 (3H ， S) · LRMS (electrospray) m / z 481/483 [M + H] + HRMS to C3 〇H3 2 C1N2 04 483.2045 [M + H] + Measured value 483.2038. Example 42: N_ (2,6 -Dimethoxybenzyl) _2_ {3_ [2-({(2R) _2-hydroxy_2- [4 · hydroxyl (hydroxymethyl) phenyl] ethyl} amino) ethyl] phenyl} Acetamide ch3

According to the procedure used to prepare 1, use {3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxyfluorenyl) phenyl] ethyl} amino) ethyl ] Phenyl} acetic acid (Preparation 51) was prepared with the appropriate amine and the title compound was found as a white foam. 1H NMR (400MHz, CD3 OD): (5 = 7.26-7.19 (3H, m), 7.11-7.07 (4H, m), 6.74-6.72 (1H, d), 6.61-6.59 (2H, d), 4 · 70-4_67 (1H, m), 4.63 (2H, s), 4.41 (2H, s), 3.75 (6H, s), 3.45 (2H, s), 2.91-2.75 (6H, m) ppm · LRMS (Electrospray): m / z [m + H] +495, [M + Na] +517, [Μ-ΗΓ493. CHN analysis: Measured value c, 66.15%, H, 6.89%, N, 5 · 53%; C28H34N206 + 0.75Η20. Requires C, 66.19%, H, 7.04%, N, 5.51%. 99200 -90- 200534846 Example 43: N_ (3,4-digas benzyl) -2- {3_ [2 -({(2R) _2-hydroxy_2- [4-hydroxy_3- (hydroxymethyl) phenyl] ethyl} amino) ethyl] phenyl} acetamidine

H0X

According to the procedure used for Preparation 1, use {3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) ethyl ] Phenyl} acetic acid (Preparation 51) with the appropriate amine to give the title compound as a white foam. 1H NMR (400MHz, CD3 OD): 5 = 7.43-7.41 (1H, d), 7.36-7.35 (1H, d), 7.26-7.23 (2H, m), 7.15-7.06 (5H, m), 6.74-6.72 (1H, d), 4.70-4.66 (1H, m), 4.63 (2H, s), 4.32 (2H, s), 3.53 (2H5 s), 2.94-2.75 (6H, m) ppm. LRMS (electrospray) : M / z [M + H] +503, [M + Na] +525, [Μ-Η] · 501 · CHN analysis: found C, 59.26%, H, 5.52%, N, 5 · 20%; c2 6 H2 8 N2 04 Cl2 + 1.35Η2〇 requires C, 59.17%, H, 5.86%, N, 5.31%. Example 44: N- N 基 -2_ {3_ [2- ( {(2R) -2-hydroxy-2_ [4-hydroxy-3_ (methylol) phenyl] ethyl} amino) ethyl] phenyl} acetamidamine

According to the procedure used to prepare 1, use {3- [2 _ ({(2R) -2_Hydroxydong [4 • hydroxy via methyl) phenyl] ethyl 丨 amino) ethyl] phenyl 丨 acetic acid (preparation 51) Made with the appropriate amine to give the title compound as a white foam. 99200 -91-200534846 1H NMR (400MHz, CD3 OD): 5 = 7.30-7 · 19 (7H, m), 7.15-7.14 (2H, m), 7.11-7.06 (2H, m), 6.74-6.72 (1H , d), 4.70-4.67 (1H, m), 4.63 (2H, s), 4.35 (2H, s), 3.52 (2H, s), 2.95-2.77 (6H, m) ppm · LRMS (EFI Fog): m / z [M + H] +435, [M + Na] +457, [MH] _433 · CHN analysis: Measured value C, 67.21%, H, 6.70%, N, 5.99% ; C26H3〇N204 + 0.45 CH2 Cl2 requires C, 67 · 20%, H, 6.59%, N, 5.93%. Example 45 · N- (2,3-diaza-ΙΗ- 印 _2-yl)- 2 · {3_ 丨 2 _ ({(2R) _2- | ^ yl-3- (methyl) phenyl) ethyl} amino) ethyl] phenyl} ethanil

According to the procedure used for Preparation 1, use {3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) ethyl ] Phenyl} acetic acid (Preparation 51) with the appropriate amine to give the title compound as a white foam. 1H NMR (400MHz, CD3 OD): δ = 7.26 (1H, s), 7.24-7.17 (3H, m), 7.13- 7.07 (6H, m), 6.74-6.72 (1H, d), 4.72-4.68 (1H , M), 4.63 (2H, s), 4.59-4.52 (1H, m), 3.45 (2H, s), 3.26-3 · 24 (1H, d), 3.22-3.20 (1H, d) , 2.97-2.79 (8H, m) ppm. LRMS (electrospray): m / z [M + H] +461, [M + Na] +483, [Μ-ΗΓ459 · CHN analysis: Found C, 65.30% , H, 6_57%, N, 5.57%; C28H32 N204 + 0.80 CH2C12 + 0.10H20 requires C, 65 · 23%, H, 6.42%, N, 5.28%. Example 46: 2- {3- [2 _ ({( 2R) -2_hydroxy-2_ [4-hydroxy_3_ (Methyl) phenyl Iethyl} amino) ethyl] phenyl} _N- (2-phenylethyl) acetamidine 99200 -92 -200534846

OH

HO, according to the procedure used for Preparation 1, using {3_ [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) ethyl Was made from phenyl] acetic acid (Preparation 51) and the appropriate amine to give the title compound as a white foam. 1H NMR (400MHz5 CD3 OD): δ = 7.27-7.26 (1H, d), 7.24-7.06 (10H, m) 5 6.74-6.72 (lH, d), 4.72-4.69 (lH, m), 4.64 (2H, s), 3.44-3.39 (4H, m), 3.00-2.92 (2H, m), 2.89-2.82 (4H, m), 2.79-2.75 (2H, t) ppm. LRMS (electrospray): m / z [ m + H] +449, [M + Na] +471, [Μ-Η] · 447 · CHN analysis: found C, 64 · 80%, H, 6.70%, N, 5 52%; c2 7 h3 2 N2 04 + 0.75 CH2 (¾ requires C, 65.07%, H, 6.59%, N, 5.47%. Example 47: 2_ {3_ [2 _ ({(2R) _2 · hydroxy_2- [4-hydroxy -3- (Methyl) phenyl] ethyl} amino) ethyl] benzylphenylpropyl) ethylamine

HO〆 uses {3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) according to the procedure used in Preparation 1) Ethyl] phenyl} acetic acid (Preparation 51) was prepared with the appropriate amine to give the title compound as a white foam. 1H NMR (400MHz5 CD3OD): δ = 7.25-7.19 (4Η5 m), 7.15-7.05 (7Η5 m), 6.74-6.72 (1Η, d), 4.69-4.64 (3Η, m), 3.47 (2H, s), 3.21_3.17 (2H, t), 2.96-99200 -93- 200534846 2.74 (6H, m), 2.60-2.56 (2H, t), 1.75-1.73 (2H, m) ppm. LRMS (electrospray): m / z [M + H] +463, [M + Na] +485, [MH] -461 · CHN analysis: measured values C, 68.54%, H, 7.17%, N, 5.80%; C28H34N204 +0.40 CH2C12 + 0.10H20 requires C, 68.45%, H, 7.08%, N, 5.62%. Example 48: N_benzyl_3 _ [(2R) -2-(((2R) -2-hydroxy_ 2- [4-hydroxy_3- (hydroxymethyl) phenyl] ethyl} amino) propyl] benzidine

In 3-[(2R) -2-({(2R) -2-hydroxy-2_ [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) propyl] benzoic acid (Preparation 59 ) (116 mg, 0.22 mmol) in a solution of DMF (2 ml), added triethylamine (62 µl, 0.45 mmol), benzylamine (29 µl 0.27 mmol), HOBt (33 mg, 0.25 mmol) and WSCDI (47 mg, 0.25 mmol), and the resulting solution was stirred at room temperature for 18 hours. The solvent was removed in vacuo and the residue was partitioned between a saturated aqueous sodium bicarbonate solution (5 ml) and dichloromethane / methanol (95/5) (10 ml). The water-layer was separated and extracted with another gaseous methane / methanol (95/5) (4 x 10 ml). The combined organic layers were dried (sodium sulfate), filtered, and evaporated in vacuo. The formed oil was purified by flash column chromatography on silica gel, and was dissolved in dichloromethane: methanol: 880 ammonia (90: 10: 1, volume ratio) to obtain the title compound as a white foam (70 mg ). 1H NMR (400MHz, CD3 OD): δ = 7.70-7.68 (1H, d), 7.66 (1H, s) 5 7.38-7.29 (6H, m), 7.26-7.21 (1H, m), 7.21 (1H, s) ), 7.03-7.01 (1H, d), 6.69-6.67 99200 -94- 200534846 (1H, d), 4.64-4.61 (1H, m), 4.61 (2H, s), 4.58 (2H, s), 3.05- 2.98 (1H, m), 2.92 -2.86 (1H, dd)? 2.84-2.79 (1H, dd) 5 2.75-2.71 (1H, dd), 2.68-2.63 (1H, dd), 1.10-1.08 (3H , d) ppm. LRMS (electrospray): m / z [M + H] +435, [M + Na] +457, [MH] -433 · CHN analysis: Found C, 69.79, H, 6.96, N, 6.37; C26H3ON204 + 0.7H20 requires C, 69.84, H, 7.08, N, 6.26. Example 49: N- (3,4-digas benzyl) -3 _ [(2R) -2-({( 2R) -2-hydroxy_2_ [4_hydroxy-3- (

Methyl) phenyl] ethyl} amino) propyl] benzamide OH

ci Cl According to the procedure used in Example 49, 3-[(2R) _2-({(2R) _2-hydroxy-2- [4 · hydroxy-3- (hydroxyfluorenyl) phenyl] ethyl} amino group ) Propyl] benzoic acid (Preparation 59) and the appropriate amine to give the title compound as a white foam. 1H NMR (400MHz, CD3 OD): δ = 7.69-7.67 (1H, d), 7.65 (1H, s), 7.51

(1H, s), 7.48-7 · 46 (1H, d), 7.36-7 · 27 (3H, m), 7.21 (1H, s), 7.03-7.02 (1H, d), 6.69- 6.66 (1H, d), 4.65-4.61 (1H, m), 4.61 (2H, s), 4.54 (2H, s), 3.02-2.97 (1H, m), 2.91-2.86 (1H5 dd) 5 2.83 -2.77 (1H, dd), 2.74-2.69 (1H, dd), 2.68-2.63 (1H, dd), 1.09-1.08 (3H, d) ppm. LRMS (electrospray): m / z [M + H] +503, [M + Na] +525, [Μ-ΗΓ501. Example 50: N- [2 · Fluoro-5- (trifluorofluorenyl) benzyl] -3 _ [(2R) -2-({( 2R) _2-hydroxy-2- [4-hydroxy ((hydroxymethyl) phenyl] ethyl} amino) propyl] benzidine amine 99200 -95- 200534846

OH

CH According to the procedure used in Example 49, 3-[(2R) -2-({(2R) -2-hydroxy_2- [4-Cyclomethyl) phenyl] ethyl 丨 amino) propyl ] Phenylic acid (Preparation 59) is suitable. Amine gas was formed into the 'and the title compound was a white bubble. 1H NMR (400MHz, CD3 OD): δ = 7.74-7.60 (4H, m), 7.38-7.29 (3H, m), 7.22 (1H, s), 7.04-7.02 (1H, d), 6.69-6.67 (1H , d), 4.67 (2H, s)? 4.67-4.61 (1H, m), 4.61 (2H, s), 3.04-2.99 (1H, m), 2.93-2.80 (2H, m), 2.76-2.71 (1H , m), 2.68-2.63 (1H, m), 1.09-1.08 (3H, d) ppm. LRMS (electrospray): m / z [m + H] +521, [M + Na] +543, [ Μ-ΗΓ 519 · 011 \ [Analysis: Measured value (:, 60.88, 11, 5.58, where 5.58; (: 27112 8 卩 41 ^ 204 + 0.7 H20 requires C, 60.83, H, 5.56, N, 5.25. Example 51 : N- (2,6c methoxybenzyl) _3 _ [(2R) -2-(((2R) -2_hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl) ethyl } Amino) propyl] benzidine

According to the procedure used in Example 49, 3-[(22) _2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) Propyl] phenylarsinic acid (Preparation 59) was prepared with the appropriate amine to give the title compound as a white foam. 1H NMR (400MHz5 CD3 OD): δ = 7.58-7.55 (2H5 m), 7.31-7.24 (3H, m) 5 99200 -96- 200534846 7 · 19 (1H, s), 7.00-6.98 (1H, dd), 6.68-6.64 (3H, m), 4.63 (2H, s), 4.63-4.58 (1H, m), 4_60 (2H, s), 3.84 (6H, s), 3.00-2.94 (1H, m ), 2.90-2.85 (1H, m), 2.78-2.61 (3H, m), 1.08-1.06 (3H, d) ppm. LRMS (electrospray): m / z [M + H] +495, [M + Na] +517, [Μ-ΗΓ493. CHN analysis: found C, 65.52, 52, 6.89, N, 5.43; C28H34N2O6 + 1.0H2O requires C, 65.61, H, 7.08, N, 5.46. Example 52: N- [2- (4-Gaphenyl) ethyl] -3-[(2R) -2-({(2R) -2-hydroxy-2- [4-hydroxy-3 · (hydroxymethyl) benzene ] Ethyl} amino) propyl] benzidine

According to the procedure used in Example 49, 3-[(2R) -2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino ) Propyl] benzoic acid (Preparation 59) and the appropriate amine to give the title compound as a white foam. 1H NMR (400MHz, CD3 OD): δ = 7.60-7.58 (1H, d), 7.54 (1H3 s), 7.35- 7.23 (7H, m), 7.04-7.01 (1H, dd), 6.70-6.68 (1H, d), 4.64-4.61 (1H, m), 4.61 (2H, s), 3.60-3: 57 (2H, t), 3.02-2.96 (1H, m), 2.92-2.87 (3H, m), 2.83 2.78 (1H, m), 2.75-2.71 (1H, dd), 2.66-2.61 (1H, dd), 1.09-1.08 (3H, d) ppm · LRMS (electrospray): m / z [M + H] +483, [M + Na] +505, [Μ-Η] · 481 · CHN analysis: measured values C, 65.90, H, 6.68, N, 5.55; C2 7 H3 丨 C1N2 04 + 0 · 5Η2 O requires C, 65.91, H, 6.56, N, 5.69. Example 53: N_ (2,3-dihydro-1H _ ^ _ 2-yl) _3 _ [(2R) -2-({(2R) -2-hydroxy-2- [4 -Hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) propyl] benzamide 99200 • 97- 200534846

According to the procedure used in Example 49, 3-[(2R) -2-({(2R) -2 · hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino ) Propyl] phenylarsinic acid (Preparation 59) and the appropriate amine to give the title compound as a white foam.

1H NMR (400MHz, CD3 OD): 3 = 7.66-7.63 (2H, m), 7.35-7.28 (2H, m), 7.22-7.21 (3H, m), 7.15-7.13 (2H, m), 7.03-7.02 (1H, dd), 6.70-6.68 (1H, d), 4.84-4.79 (lH, m), 4.64-4.60 (lH, m), 4.61 (2H, s), 3.37-3.30 (2H, dd), 3.03 -2.97 (3H, m), 2.92-2.87 (lH, m), 2.84-2.78 (lH, m), 2.76-2.71 (lH, m), 2.68-2.63 (1H, dd), 1.09-1.08 (3H, d) ppm. LRMS (electrospray): m / z [M + H] +461, [M + Na] +483, [MH] -459 · CHN Analysis: Measured value c, 7042, H, 6 87, N, 5 91; C2 8 H3 2 & 〇4 +0 9h2 〇 C, 70.54, H, 7.15, N, 5.88 are required. Example 54: 3-[(2R) _2-({(2R) _2- Hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) propyl] -N- (2-phenylethyl) benzamide

According to the procedure used in Example 49, 3-[(2R) -2 _ ({(2R) -2-hydroxy-2- [4-Cyclohydroxymethyl) phenyl] ethyl} amino) propyl] Made from benzoic acid (Preparation 59) and the appropriate amine to give the title compound as a white foam. 99200 -98- 200534846 1H NMR (400MHz, CD3 OD): δ = 7.60-7.58 (1H, d) 5 7.56 (1H, s), 7.35-7.17 (8H, m), 7.05-7.02 (1H, dd), 6.70-6.68 (1H, d) 5 4.64-4.60 (1H, m), 4.62 (2H, s), 3 · 61-3 · 57 (2H, t), 3 · 03_2 · 97 (1H, m), 2 · 93-2 · 87 (3H, m), 2.84-2.78 (1H, m), 2.77-2.71 (1H, m), 2.66-2.61 (1H, dd), 1.09-1.08 (3H, d) ppm. LRMS (Electrospray): m / z [M + H] +449, [M + Na] +471, [MH] _447 · CHN Analysis: Measured values C, 70.10, H, 7.16, N, 6.09; C27H32N2O4 + 0.75H2O requires C, 70.18, H, 7.31, N, 6.06. Example 55 · 3 _ [(2R) -2-({(2R) _2 · Cycloline_2- [4_Guji_3 · (Cyclomethyl ) Phenyl] ethyl} amino) propyl] -N _ [(1R) _1_phenylethyl] benzidine

HO〆 According to the procedure used in Example 49, 3 _ [(2R) -2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amine (Propyl) propyl] benzoic acid (Preparation 59) with the appropriate amine to give the title compound as a white foam. 1H NMR (400MHz, CD3 OD): δ = 7.67-7.64 (2H, m), 7.41-7.39 (2H, d), 7.34-7.28 (4Η, τη), 7.24-7.21 (2H, m) 5 7.02-7.00 (1H, dd), 6.68-6.66 (1H, d), 5.26-5.21 (lH, q), 4.63-4.60 (lH, m), 4.60 (2H, s), 3.03-2.99 (lH, m), 2.91 -2.86 (1H, dd), 2.83 · 2 · 78 (1H, dd), 2.74-2.70 (1H, dd), 2.69-2.63 (1H, dd), 1.57-1.55 (3H, d), 1.09- 1.08 (3H, d) ppm. LRMS (Electrospray): m / z [M + H] +449, [M + Na] +471, [Μ-ΗΓ447. (: Book analysis: Measured value (:, 68.96, 11, 7.07, > 1, 5.91; 0: 2711321 ^ 2〇4 + 1.2112〇 requires C, 68.97, H, 7.37, N, 5.96 99200 • 99- 200534846 Example 56: 3-[(2R) -2- ( {(2R) -2-hydroxy-2- 丨 4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) propyl] -N- (3-phenylpropyl) benzamide

According to the procedure used in Example 49, 3-[(2R) -2-({(2R) -2 · hydroxy-2- [4 · hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino ) Propyl] benzoic acid (Preparation 59) and the appropriate amine to give the title compound as a white foam. 1H NMR (400MHz, CD3 OD): δ = 7.63-7.61 (1H, d), 7.59 (1H, s), 7.35- 7.21 (7H, m), 7.16-7.13 (1H, m), 7.03-7.01 (1H , dd), 6.69-6.67 (1H, d), 4.61 (3H, m), 3.42-3.39 (2H, t), 3.00-2.96 (1H, q), 2.91-2 · 86 (1H, dd) , 2.81-2.76 (1H, dd), 2.74-2.61 (4H, m), 1.98-1.91 (2H, quintet), 1.09-1.07 (3H, d) ppm.

LRMS (electrospray): m / z [m + h] +463, [M + Na] +485, [MH; p461 · Example 57: 4-[(lR) _2-({(lR) _2- [ 3- (3,4_dihydroisopyridinoline-2 (1H) -ylidene) phenyl H_methylethyl} amino) _1_Ethyl] winter (Ethyl) Hope QH, 〇

According to the procedure used in Example 49, 3 _ [(2R) -2-({(2R) -2-hydroxy-2- [4 · Ethyl (hydroxymethyl) phenyl] ethyl} amino) propyl Benzyl] benzoic acid (Preparation 59) was prepared with Shida amine to give the title compound as a white foam. H NMR (400MHz, CD3 OD): 5 = 7.39-7.36 (1Η, m), 7.29-7.17 (6Η, m), 99200 • 100 · 200534846 7.12-7.01 (3H, m), 6.71_6 · 69 (1H , D), 4_62 (2H, s), 4.62-4.55 (2H, m), 3.96 (2H, s), 3.60-3.56 (1H, m), 3.11-2.64 (7H, m), U0-1.08 (3H , D) ppm. LRMS (electrospray): m / z [M + H] +461, [M + Na] +483, [Μ-Η; Η459 · CHN analysis: Measured value c, 71.65, H, 7 · 12, N, 6.39; C28H32N2O4 + 0.41H2O requires C, 71.87, H, 7.07, N, 5.99. Example 58: N- (2,3-dimethylbenzyl) -3-[(2R) -2- ({(2R) -2-hydroxy-2- [4-hydroxy_3- (hydroxymethyl) phenyl] ethyl} amino) propyl] benzidine

According to the procedure used in Example 49, 3-[(2R) -2-({(2R) winter hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) propyl Benzyl] phenylarsinic acid (Preparation 59) was prepared with the appropriate amine to give the title compound as a white foam. 1H NMR (400MHz, CD3 OD): δ = 7.68-7.66 (1H, d) 5 7.64 (1H, s), 7.36- 7.28 (2H, m), 7.21 (1H, d), 7.14-7.12 (1H, d ), 7.08-6.99 (3H, m), 6.68-6.68 (lH, d), 4.63-4.59 (lH, m), 4.61 (2H, s), 4.59 (2H, s), 3.04-2.99 (lH, q ), 2.92-2.89 (1H, dd), 2.83-2.79 (1H, dd), 2.75-2.71 (1H, dd), 2.69-2.64 (1H, dd), 2.30 (3H, s), 2.28 (3H, s ), 1.1M.09 (3H, d) ppm. LRMS (electrospray): m / z [M + H] +463, [M + Naf485, [MH] _461 · 01 > 1 Analysis: Measured value (: , 70.17, 11, 7.33, wind 5.90; 0: 2 81134 called 04 + 0.901120 requires C, 70.24, H, 7.54, N, 5.85. Example 59: N_ (5,6-diethyl-2,3-dihydro -1H_awn-2_yl) _3-[(2R) _2-(((2R) -2-hydroxy_2_ 丨 4_hydroxy 碁 _3 · (methyl) phenyl) ethyl} amino ) Propyl] benzamidine 99200 -101-200534846

According to the procedure used in Example 49, 3-[(2R) -2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino ) Propyl] benzoic acid (Preparation 59) was prepared with the appropriate amine to give the title compound as a white foam.

1H NMR (400MHz, CD3 OD): 5 = 7.65-7.63 (1H, d), 7.61 (1H, s), 7.34-7.26 (2H, m), 7.21 (1H, s), 7.03-7 · 01 (1H, m), 7.01 (2H, s), 6.69-6.67 (1H, d), 4.81 -4.77 (1H, dd), 4.63-4.60 (1H, m), 4.61 (2H, s), 3.31-3.26 (2H, dd), 3.03-2.99 (lH, q), 2.97-2.92 (2H, dd), 2.92-2.87 (lH, dd), 2.83-2.78 (lH, dd), 2.75- 2.71 (1H, dd), 2.68-2.61 (5H, m), 1.22-1.18 (6H, t), U0-1.09 (3H, d) ppm. LRMS (electrospray): m / z [M + H] +517, [M + Na] +539, [Μ-Η] · 515 · 0 ^ Analysis: Measured value (:, 72.58 ,: ", 7.80, 1 < [, 5.34; (: 32114 () ^ [204+ 0.71120 requires C, 72.62, H, 7.88, N, 5.29.

Example 60: N- (4-Arylidene) -3-[(2R) -2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl } Amino) propyl] benzidine

In 3-[(2R) -2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) propyl] benzoic acid (preparation 59) (120 mg, 0.27 mmol) in a solution of DMF (3 mmol 99200 -102- 200534846 liters) was added with triethylamine (111 μl, 0.79 mmol), 4-chloro Fluorenylamine (39 μl, 0.32 mmol) and HBTU (110 mg, 0.29 mmol), and the resulting solution was stirred at room temperature for 18 hours. The solvent was removed in vacuum, and the residue was purified by flash column chromatography on silica gel, and dissolved in methane: methanol: 880 ammonia (93: 7: 0.7 to 90: 10: 1, volume ratio). To give the title compound as a white foam (97 mg). 1H NMR (400MHz, CD3 OD): 5 = 7.70-7.68 (1Η, d), 7.66 (1Η, s), 7.38-

7.30 (6H, m), 7.23 (1H, d), 7.05-7 · 03 (1H, dd), 6.70_6 · 68 (1H, d), 4.67-4.64 (1H, dd), 4.62 (2H, s), 4.55 (2H, s), 3.15 · 3 · 07 (1H, m), 3.00_2 · 86 (2H, m), 2.82-2.78 (1H, dd), 2.72- 2.67 (1H, dd), 1.13-1.12 (3H, d) ppm.

LRMS (electrospray): m / z [m + H] +469, [M + Na] +491, [Μ-Μ] · 467 · Example 61: 3 _ [(2R) _2-({(2R) -2 -Hydroxy_2- [4_hydroxy_3_ (transmethyl) phenyl] ethyl} amino) propyl] -N_phenylbenzamide

According to the procedure used in Example 60, 3-[(2R) -2-({(2R) -2-hydroxy-2- [4-Cycloyl-3- (hydroxyamido) phenyl] ethyl} amino ) Propyl] benzoic acid (Preparation 59) and the appropriate amine to give the title compound as a white foam. 1H NMR (400MHz, CD3 OD): δ = 7.77-7.74 (2H, m) 5 7.69-7.67 (2H3 d), 7.41-7.33 (4H, m), 7.22 (lH, d), 7.16-7.12 (lH, t), 7.05-7_03 (lH, dd), 6.70-6 · 68 (1H, d), 4.66-4.61 (1H, m), 4.62 (2H, s), 3.09-3.04 (1H, m), 2.96-2.84 (2H, m), 2.79-2.69 (2H, m), 1.14-1.12 (3H, d) ppm. 99200 -103- 200534846 LRMS (electrospray): m / z [Μ + Η] +421 , [M + Na] +443, [Μ-ΗΓ419 CHN analysis: measured values c, 67.98, H, 6.64, N, 6.48; C25H2 8 N204 + 0.06 CH2Cl2 + 0.95H2O requires C, 67.99, H, 6.83, N, 6.33. Example 62: N- [4 ((Aminosulfonyl) ethynyl] -3-[(2R) -2-({(2R) -2-hydroxy · 2- [4_hydroxy_3- ( Chinyl) phenyl] ethyl} amino) propyl] benzylamine

According to the procedure used in Example 60, 3-[(22) _2-({(2R) -2 · hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) Propyl] benzoic acid (Preparation 59) and appropriate amines were substituted with methane: methanol: 880 ammonia (85 ·· 15 ·· 2, volume ratio) as the eluent to obtain the title compound as a white foam. Thing. 1H NMR (400MHz, CD3OD): 5 = 7.87-7.85 (2H, d), 7.71-7.69 (1H, d),

7.67 (1H, s), 7.53-7.50 (2H, d), 7.39-7.32 (2H, m), 7.23 (1H, d), 7.05-7.03 (1H, dd), 6.70-6.68 (1H , D), 4.67-4.65 (1H, m), 4.65 (2H, s), 4.62 (2H, s), 3.14-3.07 (1H, m >, 2.97-2.92 (1H, dd), 2.91-2.86 (1H, dd) 5 2.82-2.78 (1H, dd), 2.72-2.67 (1H, dd), 1.13_1 · 12 (3H, d) ppm. LRMS (electrospray): m / z [M + H ] +514, [M + Na] +536, [Μ-ΗΓ512. CHN analysis: measured values C, 56.26, H, 6.01, N, 7.45; C26H31N306S + 2.1H20 requires C, 56.63, H, 6.43, N, 7.62 Example 63 Ν- [2- (3 · Gabenyl) ethyl] _3- [2-({(2R) _2-Cycloyl-2- [4_Cycloyl_3- (Cyclomethyl) phenyl ] Ethyl} amino) -2-methylpropyl] benzamidine 99200 • 104 · 200534846

3- [2-({(2R) -2-{[Third · butyl (dimethyl) silyl] oxy group 2- [4-Cycloyl-3- (hydroxyfluorenyl) phenyl] Ethyl} aminomethylpropyl] -N_ [2- (3-fluorophenyl) ethyl] benzidine (Preparation 157) (343 mg, 0.58 mmol) and ammonium fluoride (213 Mg, 5.76 mmol), stirred in methanol (12 ml) and water (2 ml) at room temperature for 42 hours. The solvent was removed in vacuo and the residue was passed through a column on silica gel Analyze and purify with methane: methanol: 0.88 ammonia 100 :: 0 to 90: 10: 1. The appropriate fractions are concentrated in vacuo and the residue is azeotroped in ethanol (χ2), and A white solid was obtained. The solid was then recrystallized from ethanol / water and dried under vacuum to give the title compound as very pale yellow crystals, 52% yield, 144 mg. 1H NMR (400MHz, CD3 OD) δ : 7.63 (2H5 m), 7.38-7.23 (4H, m), 7.13 (1H, m), 7.05 (1H, m), 7.00 (1H, m), 6.91 (1H, m) 5 6.85 (1H, d) , 4.65 (3H, m), 3.59 (2H, m)? 2.96-2.84 (2H, m), 2.78-2.68 (2H, m), 1.10 (3H, s)? 1.04 (3H, s) ppm; LRMS ESI m / z 481 [M + H] + Examples 64 to 78 The following compounds having the general formula shown below were prepared by a method similar to that described in Example 63 using an appropriate starting material and ammonium fluoride. The reaction mixture was warmed to 40 ° C until TLC analysis shows that all starting materials have been consumed. 99200 -105- 200534846

Η〆HC OH h lyj H3C 〇h3 r 0 ^ 1 No. Qi Data yield 64 1H NMR (400MHz, CD3OD) δ: 7.78-7.71 (2H, m) 7.40-7.31 (3H, m), 7.15 (1H, m ), 6.76 (1H, m), 4.70-4.64 (3H, m), 3.62-3.50 (2H, m), 3.01-2.94 (2H, m), 2.76-2.63 (4H, m), 2.59-2.46 (4H , m), 1.78-1.65 (4H, m), 1.13 (3H, s), 1.01 (3H, s) ppm; LRMS APCI m / z 456 [M + H] + 65 rr Cl 1H NMR (400MHz, CD3OD) δ: 7.65 (2H, m) 7.37-7.29 (5H, m), 7.21-7.11 (2H, m), 6.77 (1H, m), 4.70-4.63 (3H, m), 3.66 (2H, m), 3.30 (2H, m), 2.96-2.69 (4H, m), 1.10 (3H, s), 1.05 (3H, s) ppm; LRMS APCI m / z 531 [M + H] + 81% 66 \ r ^ b 1H NMR (400MHz, CD3OD) δ: 7.64 (m, 2H), 7.40-7.30 (3H, m), 7.19-7.05 (5H, m), 6.75 (1H, m), 4.65 (3H, m), 3.42 (2H , m), 2.69-3.10 (9H, m), 1.14 (3H, s), 1.05 (3H, s) ppm LRMS APCI m / z 489 [M + H] + 35% 67 ^ 0 ^ NH ch3 1H NMR ( 400MHz, CD3OD) δ: 7.74 (2H, m), 7.66-7.59 (2H, m), 7.37-7.25 (5H, m), 7.13 (1H, m), 6.75 (1H, d), 4.65 (3H, m ), 3.62 (2H, m), 3.32 (2H, m), 3.00-2.68 (6H, m), 1.59 (2H, m), 1.39 (2H, m), 1.12 (3H, s), 1.04 (3H , s), 0.97 (3H, t) ppm LRMS APCI m / z 562 [M + H] + 31% 68 P s 1H NMR (400MHz, CD3OD) δ: 7.68- 7.56 (2H, m), 7.40-7.07 ( 13H, brm), 6.74 (1H, m), 4.86-4.74 (3H, m), 3.70-3.58 (2H, m), 3.11 (2H, m), 2.68- 2.95 (4H, m), 1.12 (3H, s), 1.06 (3H, s) ppm; LRMS APCI m / z 571 [M + H] + 34% 99200 -106- 200534846

69 f Strict 1H NMR (400MHz, CD3OD) δ: 7.66 (2H, m), 7.34 (3H, m), 7.13 (1H, m), 6.74 (1H, d), 4.67 (1H, d), 4.65 (2H, s), 3.42-3.34 (2H, m), 2.87-2.97 (2H, m), 2.70-2.77 (2H, m), 1.80-1.59 (5H, m), 1.47 (2H, q), 1.15 -1.30 (4H, m), 1.12 (3H, s), 1.05 (3H, s), 1.00-0.90 (2H, m) ppm LRMS ESI m / z469 [M + H] + 69% 70 1H NMR (400MHz, CD3OD) δ: 7.67 (2H, m), 7.39-7.32 (3H, m), 7.26-7.12 (6H, m), 6.75 (1H, d), 4.68-4.63 (3H, t), 3.43-3.38 (2H , m), 2.98-2.88 (2H, m), 2.76-2.64 (4H, m), 1.97-1.89 (2H, m), 1.12 (3H, s), 1.05 (3H, s) ppm; LRMS APCI m / z 477 [M + H] + 89% 71 N 1H NMR (400MHz, CD3〇D) δ: 7.64 (2H, m), 7.38-7.13 (9H, m), 6.76 (1H, d), 4.65 (3H, m), 3.60 (2H, m), 2.97-2.86 (4H, m), 2.76-2.70 (2H, m), 1.11 (3H, s), 1.05 (3H, s) ppm; LRMS APCI m / z 463 [ M + H] + 72% 72 l h3c, Cl Φ Cl 1H NMR (400MHz, CD3OD) δ: 7.68-7.63 (2H, m), 7.39-7.31 (3H, m), 7.25 (2H, m), 7.26- 7.19 (1H, m), 6.76 (1H, d), 4.69-4.64 (3H, m), 3.58-3.53 (2H, t), 3.23-3.18 (2H, m), 3.00-2.80 (2H, m), 2.71-2.69 (2H, t ), 2.47 (3H, s), 1.12 (3H, s), 1.06 (3H, s) ppm; LRMS ESI m / z 545 [M + H] + 16% 73 1 3 Cl 1H NMR (400MHz, CD3OD) δ: 7.61 (2H, m), 7.40-7.30 (3H, m), 7.20-7.10 (3H, m), 6.90 (1 H, d), 6.77 (1H, d), 4.75-4.60 (3H, m) , 3.80 (3H, s), 3.60-3.50 (2H, m), 3.00-2.80 (4H, m), 2.80-2.70 (2H, m), 1.95-1.15 (3H, m), 1.10 (3H, s) ppm 48% 74 1 V ^ K \ / ° h3c 1H NMR (400MHz, CD3〇D) δ: 7.75-7.65 (2H, m), 7.40-7.10 (6H, m), 6.80-6.70 (3H, m), 4.70-4.60 (3H, m), 3.67 (3H, s), 3.60-3.50 (2H, m), 3.00-2.70 (6H, brm), 1.15 (3H, s), 1.05 (3H, s) ppm; LRMS APCI 493 [M + H] + 10% 99200 -107- 200534846

75 'f -V 〇h3c' '1H NMR (400MHz, CD3OD) δ: 7.67-7.60 (2Η, m), 7.40-7.25 (3Hf m), 7.20-7.10 (2H, m), 6.80-6.70 (4H, m ), 4.70-4.60 (3H, m), 4.00-3.90 (2H, m), 3.63-3.53 (2H, m), 2.96-2.60 (6H, m), 1.40-1.30 (3H, m), 1.20-1.00 (6H, m) ppm; LRMS APCI 507 [MH] + 5% 76 〆α-0 1H NMR (400MHz, CD3〇D) δ: 7.70-7.60 (2H, m) 7.40-7.35 (3H, m), 7.20 -7.10 (3H, m), 6.90-6.70 (3H, m), 4.65-4.60 (3H, m), 4.10-4.00 (2H, m), 3.60-3.50 (2H, m), 3.00-2.80 (12H, m), 2.10 (2H, m), 1.95 (4H, m), 1.20 (3H, s), 1.17 (3H, s) ppm; LRMS APCI m / z 590 [M + H] + 77 Ϊ 'γ 1H NMR (400MHz, CD3OD) δ: 7.62 (2H, m), 7.36-7.29 (3H, m) 7.18-7.11 (3H, m), 6.90 (1H, m), 6.84 (1H, m), 6.74 (1H, m ), 4.66-4.62 (3H, m), 4.05-3.97 (2H, m), 3.61-3.57 (2H, m), 2.95-2.83 (4H, m), 2.65-2.76 (4H, m), 2.60 (4H , m), 2.04-1.92 (2H, m), 1.84-1.76 (4H, m), 1.09 (3H, s), 1.03 (3H, m) ppm; LRMS APCI m / z 590 [M + H] + 62 % 78 q χχχ〇: 〇1H NMR (400MHz, CD3〇D) δ: 7.65-7.61 (2H, m) 7.37-7.30 (3H, m), 7.18-7.12 (2H, m), 6.81- 6.72 (4H, m), 4.68-4.64 (3H, m), 3.96 (2H, m), 3.64-3.54 (2H, m), 2.96-2.85 (4H, m), 2.75-2.56 (8H, m), 2.00-1.93 (2H, m), 1.84-1.79 (4H, m), 1.10 (3H, s), 1.03 (3H, s) ppm; LRMS ESI m / z 590 [M + H] + 56% Example 65: The compound was further purified by trituration with diethyl ether. Example 72: Purification by column chromatography, using an ISCO® silicone cartridge, dissolving with dichloromethane ·· methanol · · 0.88 ammonia 100: 0 to 90: 10: 1. Example 75: Purification by column chromatography using a 4 g RediSep® silicone cartridge with dioxane: methanol: 0.88 ammonia 100: 0: 0 to 90: 10: 1, followed by ethyl acetate: methanol: 0.88 Ammonia 100: 0: 0 to 80: 20: 2 dissolves. 99200 -108- 200534846 Example 78 · The crude compound was further purified by trituration with ethyl scale. Example 79 N_ [2- (4-Gaphenyl) ethyl] _n_ethyl-3- [2-({(2R) -2-hydroxy_2- [4_hydroxy-3_ (light methyl) benzene Group] ethyl} amino) _2_methylpropyl] benzidine

The title compound was prepared from 3- [2-({(2R > 2-{[third-butyl (dimethyl) silyl] oxy] 2- [4-hydroxy_3 -(Hydroxyfluorenyl) phenyl] ethyl} amino) -2-fluorenylpropyl] -N- [2- (4-Gaphenyl) ethyl] -N-ethylbenzylamine (prepared 110), a colorless solid, 61% yield. 1H NMR (400MHz, CD3 OD) 7.30-7 · 10 (8H, m), 6.87 (2H, m), 6.73 (1H, d), 4.63 (3H, m), 3.71 (lH, m), 3-61 (lH, m), 3.50 (lH, m), 3.16 (lH, m), 3.01-2.69 (6H, m \ 1.29-1.26, 1.07-1.01 ( 9H, 2xm) ppm; LRMS APCI m / z 525 [M + H] + Example 80 2- {3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) Group) phenyl] ethyl} amino) -2-methylpropyl] phenyl} _N- (3-tetrahydropyrrole_1_ylpropyl) acetamidamine

The title compound was prepared from 2- {3- [2-({(2R) -2-{[Third-butyl (difluorenyl) silyxyl] oxy] oxy} -2- [4-Hydroxy-3- (hydroxyfluorenyl) benzene 99200 -109- 200534846 group] ethyl} amino) -2-methylpropyl] phenyl N- (3-tetrahydropyrrole small propyl) Acetamide (Preparation 109). The crude residue was further purified by column chromatography on Biotage® Aminite, and the title compound was obtained as a colorless gum with 54% yield by dissolving in dichloromethane · formazan 80:20. 1H NMR (400MHz, CD3 0D) 7.70-7.64 (2H, m), 7.40-7 · 30 (3H, m), 7.13 (1H, m), 6.75 (m, 1H), 4.69-4.64 ( 3H, m), 3.42 (2H, m), 3.00-2.90 (2H, m), 2.77-2.64 (2H, m), 2.60-2 · 50 (6H, m), 1.88-1.75 (6H , M), U2 (3H, s), 1.03 (s, 3H) ppm; LRMS APCI m / z 470 [M + H] + Example 81 Ν · (cycloheptylmethyl) -2_ {3- [2- ({(2R) -2-hydroxy-2_ [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] phenyl} acetamidine

OH

The title compound was prepared from 2- {3- [2-({(2R) -2-{[third-butyl (difluorenyl) suprylalkyl] oxy} -2. -[4-hydroxy-3- (hydroxyfluorenyl) phenyl] ethyl} amino) -2-methylpropyl] phenyl} -N- (cycloheptylfluorenyl) acetamidine (Preparation 151) , As a white foam, 69% yield. 1H NMR (400MHz, CD3 OD) δ: 7.65 (1H, m), 7.38 (1H, s)? 7.18-7.07 (4H, m), 6.90 (1H, d), 4.93-4.78 (1H, m), 4.04 (2H, m), 3.51 (2H, d), 3.18-3.07 (2H, m), 3.02-2.93 (4H, m), 1.72-1.36 (10H, m), 1.28 (6H, m), U9-1.07 (3H? M) ppm; LRMS ESI m / z 483 [M + H] + 99200 -110- 200534846 Example 82 Ν · 1-adamantyl-2_ {3_ 丨 2 _ ({(2R)- 2-hydroxy_2 · [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) _2_methylpropyl] phenyl} acetamidine

The title compound was prepared from N-1-adamantyl-2- {3- [2-({(2R) -2-{[third · butyl (dimethyl) stone) using a method similar to Example 33. Oxalyl] oxy} -2- [4 · Cycloyl • 3- (hydroxyfluorenyl) phenyl] ethyl} amino) -2-fluorenylpropyl] phenyl} acetamidine (Preparation 152) , As a white foam, 41% yield. 1HNMR (400MHz, CD3OD) 5: 7.19-7.12 (5H, m), 7.02 (1H, dd), 6.78 (1H, d), 4.65 (3H, m), 3_40 (2H, d), 2.97 (1H , M), 2.82 (1H, m), 2_78 (2H, dd), 2.03 (9H, m), 1.64 (6H, m), 1.05 (6H, dd) ppm; LRMS ESI m / z 507 [ M + H] + Example 83 N-Benzyl · 2- {3 · [2-({(2ί〇-2_hydroxy_2_ [4-hydroxy-3- (methyl) phenyl) ethyl} amine ) -2-methylpropyl] phenyl} -N-methylethanil

The title compound was prepared in a similar manner to that described in Example 33 and was prepared from N_fyl-2_ {3- [2-({(2R) -2 _ {[Third-butyl (dimethyl) silyl] oxy BU 2 as hydroxyl 99200 -Ill-200534846 -3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] phenyl BU N-methylacetamide (Preparation 156), as Colorless solid, 75% yield. 1H NMR (400MHz, CD3 OD) 5: 7.18 (11H, m), 6.75 (1H, m), 4.61 (5H, m), 3.80 (2H, m), 2.60-2.95 (7H, m), 1.01 (6H5 m) ppm; LRMS APCI m / z 477 [M + H] + Example 84 N- [2- (4_fluorophenyl) ethyl] _3- [2-({(2R) -2_hydroxy-2_ [ 4-hydroxy-3_ (hydroxymethyl) phenyl] ethyl} amino) -2 • methylpropyl] benzidine

3- {2-[(2R) -2- (Third-butyldimethylsilyloxy) -2 general hydroxyl hydroxymethyl-phenyl) ethylamino] -2-methylpropyl} Phenylacetic acid (Preparation 37) (90 mg, 0.19 mol) in Ν, Ν-dimethylacetamide (1 ml) and hexafluorophosphate 〇_ (1Η_benzo-1-1-yl ) -N, N, N, N'-tetramethylphosphonium (61 mg, 016 mmol) in ν, N-dimethylacetamide (0.5 ml), added to 4 • fluoro group A solution of phenethylamine (mg, 0.19 mmol) in N, N-dimethylacetamide (0.5 ml). The resulting mixture was stirred at room temperature for 72 hours. The solvent 'was removed in vacuo and the residue was separated between methane (4 ml) and a saturated sodium bicarbonate solution (1 ml). The mixture was then filtered through a phase separation tube and the organic solution was concentrated in vacuo. Ammonium fluoride (70 mg, ι9 mmol) was added to the float of the residue in methanol (2 ml) and water (1 ml), and the mixture was stirred at room temperature for 72 hours. The reaction 99200 -112- 200534846 was concentrated in vacuo, and the residue was purified by column chromatography on silica gel with methane: methanol: 0 · 88 ammonia 100: 0: 0 to 91: 9 ·· i Dissolved, followed by trituration, to obtain the title compound, 50% yield, 45 mg. 1H NMR (400MHz, CD3 OD) 5: 7.63 (2H, m), 7.40-7.30 (3H, m), 7.23 (2H, m), 7.14 (1H, m), 7.00 (2H, m), 6.75 (1H , D), 4.65 (3H, m), 3.58 (2H, m), 2.98-2.64 (6H, m), 1.11 (3H, s), 1.05 (3H, s) ppm; LRMS APCI m / z 481 [M + H] + Examples 85 to 91 The following compounds having the general formula shown below were prepared in a similar manner to that described in Example 84 using 3- {2-[(2R) -2- (third-but Dimethylsilyloxy) -2- (4-hydroxy-3- via methyl-phenyl) ethylamino] -2-methylpropyl} benzoic acid (Preparation 37) with appropriate amine starting material production. Amines are either commercially available or prepared as described in Preparations 69-108.

Number Q1 Data yield 85 σΐΝ I 1H NMR (400MHz, CD3OD) δ: 7.63 (2Η, m), 7.39-7.27 (5Η, m), 7.22 (2H, m), 7.13 (1H, m), 7.06 (1H , m), 6.98-6.85 (4H, m), 6.75 (1H, d), 4.65 (3H, m), 3.59 (2H, m), 2.96-2.66 (6H, m), 1.10 (3H, s), 1.03 (3H, s) ppm; LRMS APCI m / z 555 [M + H] + 58% 99200 -113- 200534846

86 87 88 89 90

H3C

N

1H NMR (400MHz, CD3OD) δ: 7.63 (2H, m), 7.39-7.27 (3H, m), 7.16-7.09 (3H, m), 6.84-6.72 (3H, m), 4.65 (3H, m), 3.99 (2H, q), 3.56 (2H, m), 2.96-2.80 (4H, m), 2.78-2.66 (2H, m), 1.35 (3H, t), 1.10 (3H, s), 1.05 (3H, s) ppm; LRMS APCI m / z 507 [M + H] + 45% 1H NMR (400MHz, CD3〇D) δ: 45% 7.63 (2H, m), 7.39-7.27 (3H, m), 7.16-7.07 (5H, m), 6.76 (1H, d), 4.65 (3H, m), 3.58 (2H, m), 2.96-2.83 (4H, m), 2.78-2.66 (2H, m), 2.59 (2H, q ), 1.19 (3H, t), 1.11 (3H, s), 1.05 (3H, s) ppm; LRMS APCI m / z 491 [M + H] + 1H NMR (400MHz, CD3OD) δ: 22% 7.66-7.59 (3H, m), 7.39-7.29 (3H, m), 7.15-7.08 (3H, m), 6.75 (1H, d), 4.65 (3H, m), 3.70 (2H, t), 3.04 (2H, t ), 2.99-2.83 (2H, m), 2.80-2.68 (2H, m), 2.49 (3H, s), 1.10 (3H, s), 1.03 (3H, s) ppm; LRMS APCI m / z 478 [M + H] + 1H NMR (400MHz, CD3OD) δ: 7.60 (2H, m), 7.42-7.10 (6Hf m), 6.90-6.70 (3H, d), 4.65 (3H, m), 3.75 (3H, s) , 3.50-3.60 (2H, m), 2.95-2.60 (6H, m), 1.15 (3H, s), 1.05 (3H, s) ppm; LRMS APCI m / z 493 [M + H] + 25% 1H NMR (400MHz, CD3OD) δ: 8.00-7.90 ( 2H, m), 7.80-7.70 (2H, m), 7.50-7.10 (6H, m), 6.80-6.70 (1H, m), 4.65 (3H, m), 3.90 (2H, s), 3.32 (3H, s), 2.80-3.00 (2H, m), 2.80-2.70 (2H, m), 1.17 (3H, s), 1.07 (3H, s) ppm; LRMS APCI m / z 507 [M + H] + 32% 99200 -114- 200534846 91 ch3 '1Η NMR (400MHz, CD3OD) δ: 52% I 7.80-7.60 (2H, m), 7.40-7.10 (6H,, N, ch3 m), 6.80-6.60 (3H, m) , 5.00-4.80 (3H, m), 4.60-4.40 (2H, m), 2.80-3.00 (6H, m), 2.80-2.60 (4H, m), 1.15 (3H, s), 1.05 (3H, s) ppm; LRMS APCI m / z 492 [M + H] + When ammonium fluoride was added, the examples: 89, 90 and 91 were warmed at 50 ° C for 18 hours. Example 92

Ν · [2_ (4_ethoxy_3_methoxyphenyl) ethyl] -3_ [2-({(2R) _2-hydroxy-2_ [4-hydroxy_3_ (hydroxymethyl) phenyl] Ethyl} amino) -2-methylpropyl] benzidine

3- {2 _ [(2R) -2- (Third-butyldimethylsilyloxy) -2- (4-Cyclo-3hydroxymethyl-phenyl) ethylamino] -2 -Methylpropyl} benzoic acid (Preparation 37) (90 mg, 0.19 mmol) in Ν, Ν · dimethylacetamide (1 ml) with hexafluorophosphate. (Ιη_benzotriazole) Small group) _N, N, N, N, N, -tetramethylphosphonium (61 mg, 0.16 mmol) in N, N-dimethylacetamidine (0.5 ml), added to 4- A solution of ethoxy-3-methoxyphenethylamine (37 mg, 0.19 mmol) in N, N-dimethylacetamide (0.5 ml). The resulting mixture was stirred at room temperature for 72 hours. The solvent was removed in vacuo and the residue was partitioned between dichloromethane (4 mL) and saturated sodium bicarbonate solution (1 mL). The mixture was then filtered through a phase separation tube and the organic solution was concentrated in vacuo. The residue was dissolved in dimethyl sulfoxide (700 µl) 'and triethylamine hydrogen trifluoride (30 µl 0.19 99200 • 115- 200534846 mmol) was added, and the mixture was stirred at room temperature for 72 hours. Next, the reaction mixture was purified directly by HPLC using Phenomenex Luna C18 system and dissolved in water / 0.05% diethylamine: acetonitrile 5:95 to 95: 5 to obtain the title compound in 30% yield (30.9 mg). 1H NMR (400MHz, CD3 OD) 5: 7.60-7.68 (2H, m), 7.39-7.29 (3H, m), 7.13 (1H, m), 6.85-6.81 (2H, m), 6.78-6.72 (2H, m), 4.67-4.62 (3H, m), 4.00 (2H, q), 3.75 (3H, s), 3.58 (2H, m), 2.98-2.64 (6H, m), 1.37 (3H, m t), 1.10 (3H, s), 1.03 (3H, s) ppm; LCMS m / z 537.28 [M + H] + Examples 93 to 112 The following compounds having the general formula shown below are similarly related by The method described in Example 92 using 3- {2-[(2R) -2- (third-butyldimethylsilyloxy) -2- (4-hydroxy-3-hydroxymethyl-phenyl ) Ethylamino] -2-methylpropyl} benzoic acid (Preparation 37) was prepared with the appropriate amine as the starting material. Amines are either commercially available or prepared as described in Preparations 69-108.

Number Q1 Data yield 93 1H NMR (400MHz, CD3OD) δ: 7.60 (3Η, m), 7.35 (3Η, m), 7.22 (2H, m), 7.13 (1H, m), 6.76 (1H, m), 4.64 (3H, m), 3.62 (2H, m) 2.92 (4H, m), 2.75 (2H, m), 1.10 (3H, s), 1.03 (3H, s) ppm; LRMS ESI m / z 549 (M + H] + 11% 99200 -116- 200534846

94

98

N 1H NMR (400MHz, CD3OD) δ: 7.62 (2H, m), 7.35 (3H, m), 7.10 (2H, m), 6.90 (2H, m), 6.75 (1H, m), 4.65 (3H, m ), 3.58 (2H, m), 2.90 (3H, m) 2.70 (3H, m), 2.20 (3H, s) 1.10 (3H, s), 1.03 (3H, s) ppm; LRMS APCI m / z 495 [ M + H] + 36%

H0C

N 1H NMR (400MHz, CD3OD) δ: 7.62 (2H, m), 7.32 (3H, m), 7.13 (1H, m), 6.90 (2H, m), 6.75 (1H, m), 4.65 (3H, m ), 3.60 (2H, m) 2.80 (6H, m), 2.22 (3H, s) 1.10 (3H, s), 1.05 (3H, s) ppm; LRMS APCI m / z 513 [M + H] + 63%

H3C \ ^^ / CH

N

N

Cl 99 〇H3

1H NMR (400MHz, CD3OD) δ: 7.69 (2H, m), 7.37 (3H, m), 7.15 (1H, m), 6.78 (3H, m), 4.63 (3H, m), 3.42 (2H, m) , 2.95 (4H, m), 2.74 (2H, m), 2.32 (6H, s), 2.20 (3H, s) 1.12 (3H, s), 1.05 (3H, s) ppm; LRMS APCI m / z 505 [ M + H] + 1H NMR (400MHz, CD3OD) δ: 7.60 (2H, m), 7.32 (3H, m), 7.10 (2H, m), 6.78 (2H, m), 4.63 (3H, m), 3.60 (2H, m), 2.66 (6H, m), 2.19 (3H, s) 1.10 (3H, s), 1.05 (3H, s) ppm; LRMS APCI m / z 513 [M + H] + 1H NMR (400MHz , CD3OD) δ: 7.62 (2H, m), 7.35 (3H, m), 7.10 (3H, m), 6.76 (1H, m), 4.65 (3H, m), 3.62 (2H, m) 3.14 (2H, m), 2.81 (4H, m), 2.19 (3H, s) 1.10 (3H, s), 1.05 (3H, s) ppm; LRMS APCI m / z 529 [M + H] + 1H NMR (400MHz, CD3OD) δ: 7.61 (2H, m), 7.32 (3H, m), 7.17 (2H, m), 6.93 (1H, m), 6.76 (1H, m), 4.65 (3H, m), 3.62 (2H, m) 3.17 (2H, m), 2.81 (4H, m), 2.32 (3H, s) 1.10 (3H, s), 1.05 (3H, s) ppm; LRMS APCI m / z 529 [M + H] + 80% 44 % 28% 64% 99200 -117- 200534846

100 101 102 103 104 105

CH

CH

1H NMR (400MHz, CD3OD) δ: 7.67-7.61 (2H, m), 7.40-7.32 (3H, m), 7.17 (2H, m), 6.93 (1H, m), 6.82 (1H, m), 6.76 ( 1H, m), 4.65 (3H, m), 3.62 (2H, m) 3.17 (2H, m), 3.00-2.64 (4H, m), 2.32 (3H, s) 1.10 (3H, s), 1.05 (3H , s) ppm; LRMS APCI m / z 529 [M + H] + Ή NMR (400MHz, CD3OD) δ: 7.60 (4H, m), 7.34 (4H, m), 7.25 (1H, m), 7.13 (1H , m), 6.75 (1H, m), 4.65 (3H, m), 3.63 (2H, m), 3.04 (2H, m), 2.81 (4H, m), 1.10 (3H, s), 1.05 (3H, s) ppm; LRMS APCI m / z 549 [M + H] + 1H NMR (400MHz, CD3OD) δ: 7.66 (3H, m), 7.50 (2H, m), 7.37 (4H, m), 7.13 (1H, m), 6.75 (1H, m), 4.65 (3H, m), 3.63 (2H, m), 3.11 (2H, m), 2.90 (2H, m), 2.75 (2H, m), 1.10 (3H, s ), 1.05 (3H, s) ppm; LRMS APCI m / z 531 [M + H] + 1H NMR (400MHz, CD3OD) δ: 7.66 (2H, m), 7.36 (3H, m), 7.15 (1H, m ), 6.88 (2H, m), 6.76 (1H, m), 4.65 (3H, m), 3.83 (6H, m), 3.50 (2H, m), 2.25 (3H, s), 2.14 (6H, m) , 1.10 (3H, s), 1.05 (3H, s) ppm; LRMS APCI m / z 505 [M + H] + 1H NMR (400MHz, CD3OD) δ: 8.44 (m, 1H) f 7.75 (m, 1H) , 7.64-7.60 (2H, m), 7.38-7.23 (5H, m) , 7.12 (1H, m), 6.76 (1H, m), 4.69-4.60 (3H, m), 3.73 (2H, m), 3.09 (2H, m), 2.98-2.65 (4H, m), 1.11 (3H , s), 1.04 (3H, s) ppm; LCMS m / z 464.29 [M + H] + Ή NMR (400MHz, CD3OD) δ: 7.67-7.61 (m, 2H), 7.50-7.43 (2H, m), 7.38-7.27 (3H, m), 7.20-7.10 (3H, m), 6.76 (1H, m), 4.69-4.64 (3H, m), 3.83 (2H, t), 3.20 (2H, t), 2.97- 2.61 (4H, m), 1.08 (3H, s), 1.01 (3H, s) ppm; LCMS m / z 503.23 [M + H] + 46% 35% 50% 38% 52% 19% 99200 -118- 200534846

106 \ 〇 < 〇 1H NMR (400MHz, CD3OD) δ: 7.68-7.46 (6H, m), 7.28-7.38 (3H, m), 7.11 (1H, m), 6.76 (1H, m), 4.67-4.62 (3H, m), 3.60-3.70 (6H, m), 3.03 (2H, t), 2.98-2.66 (8H, m), 1.10 (3H, s), 1.04 (3H, s) ppm; LCMS m / z 612.23 [M + H] + 25% 107 Cl 6 .OH LCMS m / z 513.17 [M + H] + 46% 108 ϊ 1H NMR (400MHz, CD3OD) δ: 7.81 (m, 2H), 7.60 (1H, m ), 7.49 (3H, m), 7.36 (2H, m), 7.20 (1H, m), 6.80 (1H, m), 4.84 (1H, m), 4.76 (2H, s), 4.65 (2H, m) , 3.20 (2H, m), 3.08 (2H, s), 1.34 (6H, m) ppm; LRMS APCI m / z 535 [M + H] + 33% 109 Cl 6. .1 1H NMR (400MHz, CD3OD) δ : 7.83-7.78 (m, 2H), 7.50-7.20 (8H, m), 6.90-6.80 (1H, d), 4.65 (2H, s), 4.58-4.50 (3H, m), 3.22-3.05 (4H, m), 1.40-1.25 (6H, m) ppm; LCMS m / z 483.2045 [M + H] + 45% 110 0 / 丨 N 1H NMR (400MHz, CD3〇D) δ: 7.82-7.78 (2H, m) , 7.45-7.20 (8H, m), 6.82-6.78 (1H, d), 4.90-4.80 (1H, s), 4.75-4.60 (4H, m), 3.25-3.05 (4H, m), 1.30-1.22 ( 6H, m) ppm; LCMS m / z 483.2045 [M + H] + 21% 99200 119- 200534846 111 1H NMR (400MHz, CD3OD) δ: 33% CH, I 〇 7 .65-7.61 (2H, m), 7.38-7.27 (3H, X m), 7.13 (1H, m), 7.09 (1H, s), 6.76 (1 Ϊ (1H, m), 4.68-4.62 (3H, m), 3.82 (2H, t), 3.13 (2H, t), 2.98-2.64 (4H, m), H3C N v ν '1.11 (3H, s), 1.04 (3H, s) ppm; LRMS APCI m / z 493.29 [M + H] + 112 1 8 2 LRMS APCI m / z 478.28 [M + H] + 25% Ah V, N, ch3 Example 102: {2- 「2- (trifluoromethyl) phenyl] Ethyl} amine can be prepared as described in WO 2003093231 Example 106: 4-"" 4- (2-Aminoethyl) phenyl] sulfonyl] -morpholine is commercially available from the Scientific Exchange Product List (K-046583) Example 107: Amine precursor (2- (2-aminoethyl) -6-phenol) can be prepared as described in DE1959898 Example 108: The crude compound is purified by HPLC using Phenomenex Luna C18 System, dissolve with water / acetonitrile / trifluoroacetic acid (5: 95: 0.1), acetonitrile 95: 5 to 5: 95, and separate trifluoroacetate of the desired product. Example 109 and 110: The crude compound was purified by HPLC using Phenomenex Luna C18 system with water / 0.1% formic acid: acetonitrile / 0.1% formic acid 85:15 to 15:85. Example 113 N- [2_ (2_Gaphenyl) ) Ethyl] -3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl Benzamidine 99200 -120- 200534846

3-[> ({(2R) -2 _ {[Third-butyl (dimethyl) oxetyl] oxy] 2- [4-hydroxy-3- (hydroxymethyl) phenyl] Ethyl} amino) -2 · methylpropyl] -N- [2- (2 · Gaphenyl) ethyl] benzamidine (Preparation 118) (147 mg, 0.24 mmol) and triethyl A mixture of amine hydrogen trifluoride (39 µl, 0.24 mmol) was stirred at room temperature for 3 days. Then, the mixture was concentrated in vacuo, and the residue was purified by column chromatography on silica gel, and was dissolved with methane: methanol: 0.88 ammonia 100: 0: 0 to 95: 5: 0.5. The appropriate fractions were evaporated under reduced pressure and the residue was azeotroped with methanolic ammonia to give the title compound as a colorless solid, 77% yield, 75 mg. 1H NMR (400MHz, CD3 OD) 5: 7.61 (2H, m), 7.37-7.29 (5H, m), 7.23-7.16 (2H, m), 7.12 (1H, dd), 6.74 (1H, d) , 4.66 (1H, m), 4.64 (2H, s), 3.63 (2H, m), 3.05 (2H, t), 2.96-2.84 (2H, t), 2.76-2.69 (2H, m), U〇 ( 3H, s), 1.04 (3H, s) ppm; LRMS ESI m / z 497 [M + H] + Examples 114 to 128 The following compounds having the formulas shown below-are similar to those described for Example 113 Method using appropriate starting materials and triethylamine trifluoride. The reaction was monitored and analyzed by TLC, and i8-72 hours were stirred at room temperature. OH η

99200 -121-200534846

Q1 Data Yield 114 N Η 1H NMR (400MHz, CD3OD) δ: 7.66 (2H, m), 7.38-7.31 (3H, m), 7.13 (1H, m), 6.75 (1H, d), 4.67 (1H , m), 4.65 (2H, d), 3.44-3.36 (2H, m), 2.99-2.88 (2H, m), 2.78-2.69 (2H, m), 1.94 (3H, s), 1.67-1.77 (6H , m), 1.58 (6H, m), 1.37 (2H, m), 1.12 (3H, s), 1.05 (3H, s) ppm; LRMS APCI m / z 521 [M + H] + 67% 115 r 1H NMR (400MHz, CD3OD) δ: 8.21 (1H, m), 7.85 (1H, m), 7.74 (1H, m), 7.65 (2H, m), 7.47 (2H, m), 7.39-7.31 (5H, m ), 7.14 (1H, dd), 6.75 (1H, m), 4.68 (1H, m), 4.64 (2H, d), 3.71 (2H, m), 3.39 (2H, m), 2.99-2.87 (2H, m), 2.79-2.70 (2H, m), 1.12 (3H, s), 1.05 (3H, s) ppm; LRMS APCI m / z 513 [M + H] + 50% 116 rf h3c 1H NMR (400MHz, CD3OD ) δ: 7.68-7.61 (2H, m), 7.36 (2H, m), 7.33 (1H, m), 7.14 (1H, dd), 6.96 (3H, m), 6.75 (1H, m), 4.67 (1H , m), 4.63 (2H, m), 3.47 (2H, m), 3.00-2.89 (4H, m), 2.77-2.71 (2H, m), 2.35 (6H, s), 1.13 (3H, s), 1.05 (3H, s) ppm; LRMS APCI m / z 491 [M + H] + 75% 117 1H NMR (400MHz, CD3OD) δ: 7.63 (2H, m), 7.37-7.31 (3H, m), 7.20- 7.12 (5 H, m), 6.74 (1H, m), 4.67 (1H, m), 4.65 (2H, d), 3.55-3.59 (2H, m), 2.97-2.85 (4H, m), 2.70-2.77 (2H, m), 2.42 (3H, s), 1.11 (3H, s), 1.05 (3H, s) ppm LRMS APCI m / z 509 [M + H] + 30% 118 IF Cl 1H NMR (400MHz, CD3〇D) δ: 7.61 (2H, m), 7.36-7.28 (4H, m), 7.21 (1H, m), 7.11 (1H, m), 7.02 (1H, m), 6.74 (1H, d), 4.65 (3H, m), 3.60 (2H, m), 2.96-2.84 (4H, m), 2.77-2.69 (2H, m), 1.10 (3H, s), 1.04 (3H, s) ppm; LCMS m / z515 [M] + 23% 99200 -12220052005846 119

1H NMR (400MHz, CD3OD) δ: 7.62 (2H, m), 7.30-7.37 (4H, m), 7.17 (1H, m), 7.11 (1H, dd), 6.96 (1H, m), 6.74 ( 1H, d), 4.67 (1H, m), 4.64 (2H, m), 3.61 (2H, m), 3.02 (2H, t), 2.96-2.85 (2H, m), 2.78-2.70 (2H, m) , 1.11 (3H, s), 1.04 (3H, s) ppm; LRMS APCI m / z 515 [M + H] + 45% 120

Ο CH, 1H NMR (400MHz, CD3OD) δ: 7.65 (2H, m), 7.38-7.31 (3H, m), 7.12 (1H, dd), 6.88 (1H, s), 6.75 (1H, d), 6.66 (1H, s), 4.67 (1H, m), 4.65 (2H, m), 3.77 (3H, s), 3.49 (2H, m), 2.98-2.87 (2H, m), 2.84-2.70 (4H, m ), 2.30 (3H, s), 2.08 (3H, s), 1.12 (3H, s), 1.05 (3H, s) ppm; LRMS ESI m / z 521 [M + H] + 52% 121

Ή NMR (400MHz, CD3OD) δ: 7.62 (2H, m), 7.38 (1H, dd), 7.32 (3H, m), 7.25 (1H, m), 7.19 (1H, m), 7.12 (1H, d) , 6.74 (1H, d), 4.68 (1H, m), 4.65 (2H, m), 3.68 (2H, m), 3.10 (2H, m), 2.96 (2H, m), 2.73 (2H, m), 1.11 (3H, s), 1.05 (3H, s) ppm; LRMS APCI m / z 531 [M + H] + 67% 122

CH, Ή NMR (400MHz, CD3OD) δ: 7.65 (1H, m) 7.63 (1H, m), 7.38-7.31 (3H, m), 7.13 (1H, dd), 6.95 (1H, s), 6.75 (1H , d), 6.67 (1H, d), 4.67 (1H, m), 4.65 (2H, m), 3.76 (3H, s), 3.49 (2H, m), 2.98-2.87 (4H, m), 2.79- 2.70 (2H, m), 2.25 (3H, s), 2.12 (3H, s), 1.12 (3H, s), 1.05 (3H, s) ppm LRMS ESI m / z 521 [M + H] + Microanalysis: C31H40N2O5 0.1 H2〇requires (%): C 71.27; H 7.76; N 5.36; found (%) C 70.87; H 7.36, N 5.36. 83% 123

1H NMR (400MHz, CD3OD) δ: 7.63 (1H, m), 7.60 (1H, bs), 7.57-7.50 (4H, m), 7.41-7.26 (8H, m), 7.11 (1H, m), 6.73 ( 1H, dd), 4.66-4.62 (3H, m), 3.69 (2H, t), 2.96-2.83 (4H, m), 2.75-2.67 (2H, m), 1.09 (3H, s), 1.02 (3H, s) ppm LRMS ESI m / z 539 [M + Na] + 74% 99200 -123- 200534846 124 V H3C > ^-3 1H NMR (400MHz, CD3〇D) δ: 7.65 (2H, m) 7.63 (2H, m), 7.39-7.30 (1H, d), 7.12 (1H, dd), 7.01 (1H, d), 6.95 (1H, bs), 6.88 (1H, d), 6.74 (1H, d), 4.69-4.63 (3H, m), 3.60 (2H, m), 2.98-2.85 (4H, m), 2.78-2.68 (2H, m), 2.29 (3H, s), 2.24 (3H, s), 1.11 (3H, s ), 1.04 (3H, s) ppm; LRMS ESI m / z 513 [M + Na] + 79% 125 J CH3 1H NMR (400MHz, CD3OD) δ: 7.65 (2H, m), 7.39-7.31 (3H, m ), 7.13 (1H, dd), 7.02-6.94 (3H, m), 6.75 (1H, d), 4.65 (3H, m), 3.64-3.60 (2H, m), 2.99-2.93 (3H, m), 2.88 (1H, m), 2.74 (1H, dd), 2.71 (1H, m), 2.26 (3H, s), 2.25 (3H, s), 1.12 (3H, s), 1.06 (3H, s) ppm LRMS APCI m / z 491 [M + H] + 58% 126 r 1H NMR (400MHz, CD3OD) δ: 7.66- 7.46 (6H, m), 7.33 (3H, m), 7.13 (1H, d), 6.75 (1H , d), 4.67 (3H, m), 3.66- 3.60 (2H, m), 3.04-2.85 (4H, m), 2.89-2.76 (2H, m), 1.11 (3H, s), 1.04 (3H, s) ppm LRMS APCI m / z 531 [M + H] + 79% 127 f F 1H NMR (400MHz, CDCI3) δ: 7.60 (2H, m), 7.36-7.26 (4H, m), 7.16-7.09 (3H, m), 6.75 (1H, d), 4.66 (3H, m), 3.83-3.57 (2H, m), 2.98-2.69 (6H, m), 1.10 (3H, s), 1.04 (3H, s) ppm; LRMS APCI m / z 515 [M + H] + 85% 128 ch3 1H NMR (400MHz, CD3OD) δ: 7.72 (2H, m) 7.39-7.32 (2H, m), 7.26 (1H, d), 7.11 (1H, bs), 7.09-7.03 (2H, dd), 6.95 (1H, d), 6.68 (1H, d), 4.63 (3H, m), 4.49 (2H, dd), 2.94-2.86 (2H, m), 2.73 (2H, dd), 2.29 (3H, s), 2.24 (3H, s), 1.11 (3H, s), 1.04 (3H, s) ppm; LRMS ESI m / z 499 [M + Na] + 44% Example 129

N- (3,4-Diaminobenzyl) -3- {3- [2-[{(2R) -2-hydroxy-2_ [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} Amine) _2_methylpropyl] phenyl} propanamine 99200 -124- 200534846 OH Ο

The title compound was prepared from 3- {3- [2-({(2R)-2- 2-[[Third-butyl (dimethyl) silidyl] oxyalkyl] oxybutan-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] phenyl} -N- (3,4-diaminobenzyl) propanamine (prepared 145) as a white foam in 71% yield.

1H NMR (400MHz, CD3 OD) δ: 7.38 (1H, d), 7.35 (2H, d), 7.08 (6H, m), 6.78 (1H, d), 5.61 (3H, m), 4.23 (2H, s), 2.95 (3H, m), 2.68 (3H, m), 2.58 (2H, t), 1.01 (6H, s) ppm; LRMS ESI m / z 545 [M + H] + Examples 130

3- [2 _ ({(2R) -2_hydroxy_2- [4-hydroxy_3- (transmethyl) phenyl] ethyl} amino) _2 · methylpropylbenzene N- {2_ [4_p Fluoromethoxy) phenyl] ethyl} benzamide

3- [2-({(2R) -2-hydroxy-2- [4-hydroxy each (methyl) phenyl] ethyl} amino) -2-methylpropyl] benzoic acid (Preparation 140 ) (100 mg, 0.28 mmol), 2- (4-trifluoromethoxyphenyl) ethylamine (US20020082454A1, page 2) (46 mg, 0.28 mmol), 1- (3-bis Methylaminopropyl) each ethylcarbodiimide hydrochloride (43 mg, 0.28 mmol), 1-hydroxybenzotriazole hydrate (35 mg, 028 mmol) and triethylamine ( 60 microliters (0.45 mmol) of N, N-dimethylformamidine (5 ml) 99200 -125- 200534846 was stirred at room temperature for 20 hours. The reaction mixture was then concentrated in vacuo and the residue was dissolved in digas methane. The solution was then washed with a saturated sodium carbonate solution and brine, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by column chromatography on silica gel and eluted with methane: methanol: 0.88 ammonia 100: 0: 0 to 95: 5: 1 to provide the title compound as a white powder, 51% yield, 79 mg . 1H NMR (400MHz? CD3 OD) ^: 7.63 (2H, m), 7.38-7.30 (5H, m), 7.17 (2H, m), 7.12 (1H, dd), 6.75 (1H, d), 4 66 (3H, m), 3.57 (2H, d), 2.99-2.85 (4H, m), 2.79-2.69 (2H, m), 1.12 (3H, s), 1.06 (3H, s) ppm; LRMS APCI m / z 547 [M + H] + Examples 131 to 137 The following compounds having the general formula shown below were made by a method similar to that described in Example 130 using appropriate acids and amine starting materials . Amines are

Either commercially available or prepared as described in Preparation 69-108. OH

99200126-200534846

Ref. 131 Q1

Data 1H NMR (400MHz, CD3OD) δ: 7.54 (1H, m), 7.50 (1H, m), 7.34-7.28 (3H, m), 7.25 (2H, m), 7.10 (1H, dd), 6.73 (3H , m), 4.62 (3H, m), 3.51 (2H, s), 2.92-2.87 (1H, m), 2.81 (1H, m), 2.76-2.70 (2H, m), 1.33 (6H, s), 1.08 (3H, s), 1.04 (3H, s) ppm; LRMS APCI m / z 507 [M + H] + yield 6% 132

1H NMR (400MHz, CD3OD) δ: 7.88-7.80 (3H, m), 7.63 (2H, m), 7.12 (1H, dd), 6.92 (1H, m), 6.84 (1H, dd), 6.75 (1H, d), 6.63 (1H, d), 4.67 (1H, m), 4.65 (2H, m), 3.51 (2H, m), 2.99-2.86 (2H, m), 2.78-2.70 (4H, m), 2.13 (3H, s), 1.12 (3H, s), 1.05 (3H, s) ppm; LRMS APCI m / z 493 [M + H] + 22% 133

1H NMR (400MHz, CD3OD) δ: 7.98 (2H, m), 7.43-7.36 (3H, m), 7.16 (1H, dd), 6.82-6.77 (2H, m), 6.52 (1H, d), 4.75 ( 1H, m), 4.66 (2H, m), 3.47 (2H, m), 3.07 (1H, m), 2.98 (2H, m), 2.92 (1H, m), 2.85 (2H, m), 2.24 (3H , s), 2.11 (3H, s), 1.23 (3H, s), 1.19 (3H, s) ppm; LRMS APCI m / z 507 [M + H] + 6% 134

1H NMR (400MHz, CD3OD) δ: 7.66 (2H, m), 7.40-7.34 (3H, m), 7.14 (1H, dd), 6.83 (1 H, s), 6.76 (1H, m), 6.50 (1H, d), 4.69 (1H, m), 4.66 (2H, s), 3.49 (2H, m), 3.04-2.98 (2H, m), 2.87 (1H, m), 2.82-2.77 (3H, m ), 2.22 (3H, s), 2.08 (3H, s), 1.17 (3H, s), 1.12 (3H, s) ppm; LRMS APCI m / z 507 [M + H] + 16%

99200 -127- 200534846 135 1Η NMR (400MHz, CD3〇D) δ: 7.41-7.05 (9Η, m), 6.78 (1Η, d), 4.65 (3Η, m), 4.36 (2H, s), 3.55 (2H , s), 2.87 (2H, m), 2.81-2.69 (2H, m), 1.12 (3H, s), 1.05 (3H, s) ppm; LRMS ESI m / z 531 [M + H] + 41% 136 Cl 1H NMR (400MHz, CD3〇D) δ: 7.34-7.03 (9H, m), 6.79 (1H, d), 4.63 (3H, m), 4.37 (2H, s), 3.54 (2H, s), 2.90 (2H, m), 2.81-2.64 (2H, m), 1.12 (3H, s), 1.05 (3H, s) ppm; LRMS ESI m / z 531 [M + H] + 24% 137 1H NMR (400MHz, CD3OD) δ: 8.42 (1H, d), 7.77 (1H, t), 7.31-7.04 (8H, m), 6.76 (1H, d), 4.62 (3H, m), 4.44 (2H, s), 3.59 ( 2H, s), 2.92-2.65 (4H, m), 1.06 (3H, s), 1.04 (3H, s) ppm; LRMS ESI m / z 464 [M + H] + 66% Example 131: Amine precursor ( 4- (2 • amino-1,1-dimethylethyl) phenol) can be C7 ^ m.

SamJ. 8, 1203, 1207; made as described in 1954 Examples 138 to 147

3- [2-({(2R), 2-hydroxy-2- [4-hydroxy-3- (hydroxyfluorenyl) phenyl] ethyl} amino) -2-methylpropyl] benzoic acid ( Preparation 140) (0.2 M in dimethylacetamide / 3.75% triethylamine, 225 μl, 45 μmol), appropriate amine (0.2M, in dimethylacetamide / 3.75% triethylamine) Ethylamine, 150 μl, 30 μmol) and 0- (1 fluorene-benzotriazole small hexafluorophosphate) -Fanfan%? ^-Tetrafluorenylfluorene (0.2 " Amine, 225 μl, 45 μmol) was stirred at 60 ° C. for 3 days. Then, the reaction mixture was concentrated in vacuo, redissolved in dimethylarsine (300 μl), and Stir for 30 minutes at warm temperature. Dilute the mixture with an additional dimethylphosphine 99200 -128- 200534846 (50 µl) and water (100 µl), stir at room temperature for one minute, then purify by HPLC using Phenomenex Luna C18 system, dissolving with water / acetonitrile / diethylamine (5: 95: 0.05): acetonitrile 95: 5 to 5:95 to obtain the desired compound.

No. Q1 data 138 shows LRMS ESI m / z 504.30 [M] + 139 r_Xr〇H LRMS ESI m / z 492.26 [M] + 140 LRMS ESI m / z 476.26 [M] + 141 I jfr. 、 1 LRMS ESI m / z 493.26 [M] + 142 〇 〇 / LRMS ESI m / z 506.28 [M] + 143 〇r / Cl LRMS ESI m / z 510.23 [MH] '144 N 〇People> LRMS ESI m / z 544.27 [M] + 99200 -129- 200534846 145 LRMS ESI m / z 498.23 [M] + 146 rx i Xj LRMS ESI m / z 513.26 [M] + 147 LRMS ESI m / z 546.31 [M] +

Example 138: N-ethyl-3-phenylpropylamine can be prepared as described in J. CTzem. 34, 248; 1991 Example 141: 6-methoxy-3-pyridineethylamine can be set up as ## It was found that Example 143 was prepared as described in 10, 35; 1993: 244- (say azol-1-yl) phenoxy] ethylamine can be prepared as described in WO2002032897, page 55. Example 146 ·· 5-edge Porphyrin ethylamine can be prepared as described in / M to CTzern., 28, 1803-10; 1985 to prepare 1: 2_ {3-[(2R) -2-({(2R) -2-{[第 第Tributyl (dimethyl) silyl] oxy} -2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) propyl] phenyl} -N-cycloheptyl Acetamide

Put (3-{(2R) -2-[(2R) -2-{[third-butyl (difluorenyl) silyl] oxy} -2- (4- 99200 -130- 200534846 via Methyl-phenyl) · ethylamino] _propylbuphenyl) _acetic acid (Preparation 20) (25 mg '0.45 mmol), 1- (3-dimethylaminopropyl) _3 _Ethylcarbodiimide hydrochloride (94 mg, 0.49 mmol), hydroxybenzotriazole monohydrate (66 mg, 0.49 mmol) at N, N-dimethylformamide (4 ml), treated with triethylamine (0.12 ml, 0.89 mmol) and cycloheptylamine (56 mg, 0.49 mmol), and the resulting suspension was allowed to stand at room temperature and It was left to stir under a nitrogen atmosphere for 18 hours. The solvent was removed in vacuo and the residue was partitioned between ethyl acetate (10 mL) and saturated aqueous sodium bicarbonate solution (10 mL). The organic phase was separated and the aqueous phase was extracted with additional ethyl acetate (2 x 10 mL). The combined organic extracts were washed with water (5 mL), brine (5 mL), dried (Na2SO4), and the solvent was removed in vacuo. The residue was purified by flash column chromatography on silica gel, and dissolved in methane: methanol: 880 ammonia (95: 5: 0.5 by volume) to obtain the title compound as a pale yellow oil (150 mg). 1H NMR (400MHz, CD3 OD): δ = 7.20-6.98 (6H, m), 6.68 (1H, d), 4.60 (3H, m), 3.80 (1H, m), 3.40 (2H, s), 2.85 ( 2H, m), 2.63 (2H, m), 2.58 (1H, m), 1.80 (2H, m), 1.75-1.40 (10H, m), 1.03 (3H, d), 0.83 (9H , S), 0 · 00 (3H, s), -0.20 (3H, s) ppm. LRMS (electrospray): m / z [M + H] +569. Preparation 2: 2- {3 _ [(2R) -2 _ ({(2R) _2-{[Third butyl (dimethyl) silyl] oxy} -2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) Propyl] phenyl} -N- (cyclohexylfluorenyl) -N-methylacetamide 99200 -131-200534846

HO

I According to the procedure used to prepare 1, use (3-{(2R) -2-[(2R) -2-{[Third-butyl (dimethyl) carboxanyl] oxy} -2- (4-Cyclo-3-methyl-phenyl) -ethylamino] -propyl} -phenyl) -acetic acid (Preparation 20) was prepared with the appropriate amine to give the title compound as a colorless oil. 1H NMR (400MHz, CD3 OD): δ = 7.20-6.95 (6H, m), 6.63 (1H, d) 5 4.60 (3H, m), 3.68 (2H, s), 3.20 (2H, m), 2.85 (5H, m), 2.63 (2H, m), 2.57 (1H, m), 1.60 (5H, m), 1.20 (4H, m), 1.03 (3H, d), 0.81 (11H, m) , 0.00 (3H, s), -0.21 (3H, s) ppm. LRMS (electrospray): m / z [M + H] +583. Preparation 3: 2_ {3 _ [(2R) _2 _ ({(2R ) _2 _ {[Third-butyl (dimethyl) dreamyl] oxy} _2- [4_hydroxy-3- (methyl) phenyl] ethyl} amino) propyl] phenyl N 7 1S) Small cyclohexylethyl] acetamide

According to the procedure used to prepare 1, use (3 _ {(2R)! [(2R) _24 [Third-butyl (dimethyl) silyxyl] oxy] 2- (4-meryl-3- Hydroxyfluorenylphenyl) -ethylamino] -propyl} -phenyl) -acetic acid (Preparation 20) was prepared with the appropriate amine to give the title compound as a colorless oil. 99200 -132- 200534846 1H NMR (400MHz, CD3 OD): δ = 7.20 (3H, m)? 7.03 (1H, s), 6.98 (2H, dd), 6.68 (1H, d), 4.60 (3H, m), 3.68 (1H, m), 3.42 (1H, d), 3.38 (1H, d), 2.85 (2H, m), 2.63 (2H, m), 2.58 ( 1H, dd), 1.65 (4H, m), 1.40-0.83 (13H, m) ppm · LRMS (electrospray): m / z [M + H] +583, [M + Na] +605, [Μ -ΗΓ582. Preparation 4: 2_ {3-[(2R) _2 _ ({(2R) -2 _ {[Third-butyl (dimethyl) silyl 1oxy} -2--2-4-hydroxy-3- (Hydroxymethyl) phenyl] ethyl} amino) propyl] phenylisopropylethylamine

OTBDMS

HO, according to the procedure used to prepare 1, using (3-{(2R) -2 _ [(2R) -2-{[Third-butyl (dimethyl) silyl] oxy} -2- (4-Ethyl-3-hydroxymethyl-phenyl) -ethylamino] -propyl} -phenyl) -acetic acid (Preparation 20) was prepared with the appropriate amine to give the title compound as a colorless oil. 1H NMR (400MHz, CD3 OD): δ = 7.19-7.15 (2H, m), 7.11-7.10 (1H5 d), 7.04 (1H, s), 6.99-6.96 (2H, t), 6.69-6.67 (1H, d), 4.71-4.67 (1H, dd), 4.65-4.58 (2H, m), 3: 96-3.90 (1H, m), 3.39 (2H, s), 2.93-2.84 (2H, m) 5 2.70- 2.62 (2H, m), 2.56-2_52 (1H, m), 1_12-1.11 (6H, d), 1.05-1.03 (3H, d), 0.83 (9H, s), -0.01 (3H, s) , -0.20 (3H, s) ppm. LRMS (electrospray): m / z [M + H] +515, [Μ-ΗΓ513 · Preparation 5: 2_ {3-[(2R) -2 _ ({(2R ) _2 _ {[Third-butyl (dimethyl) alkyl] oxy} _2- [4-hydroxy_3- (hydroxymethyl) phenyl] ethyl} amino) propyl] phenyl N-Cyclopentylacetamide 99200 -133-200534846

OTBDMS

HO〆 uses (3-{(2R) -2-[(2R) -2-{[Third-butyl (dimethyl) silyl] oxy} · 2_ (4-Ethyl-3-hydroxymethylphenyl) -ethylamino] -propyl} -phenyl) -acetic acid (Preparation 20) was prepared with the appropriate amine to give the title compound as a colorless oil.

1H NMR (400MHz, CD3OD): δ = 7.19 (1Η5 d), 7.17-7.15 (1Η, d), 7.11-7.09 (1H, d), 7.04 (1H, s), 6_99 · 6.95 (2H, t ), 6.69-6.67 (1H, d), 4.71-4.67 (1H, dd), 4.65-4.58 (2H, m), 4.10-4 · 04 (1H, m), 3.40 (2H, s), 2 · 92_2 · 84 (2H, m), 2.69-2.62 (2H, m), 2.56-2.51 (1H, m), 1.94-1.86 (2H, m), 1.73-1 · 65 (2H, m), 1.62-1.53 (2H, m), L47-1.39 (2H, m), 1.05-1.03 (3H, d), 0.83 (9H, s), -0.01 (3H, s), _0.20 (3H, s) ppm. LRMS (electrospray): m / z [M + H] +541, [Μ_Η] · 539. Preparation 6: 2- {3-[(2R) -2-({(2R) -2- { [Third-butyl (dimethyl) dreamyl] oxy] _2- [4-Cycloyl-3- (methylidyl) phenyl] ethyl} amino) propyl] phenyl} glutamine ( Cyclobutylmethyl) acetamide

H0X According to the procedure used for Preparation 1, (3-{(2r) -2-[(2r) _2 _ {[Third_butyl (monomethyl) silyl] oxy} -2} (4- The title compound was prepared from hydroxymethyl-phenyl-> ethylamino] -propyl} -phenyl) -acetic acid (Preparation 20) and the appropriate amine, 99200 -134- 200534846 as a colorless oil. 1H NMR (400MHz, CD3 OD): δ = 7.19-7.15 (2H, m)? 7.12-7.10 (1H, m)? 7.04 (lH, s), 7.00-6_96 (2H, m), 6.69-6.67 (lH, d ), 4.71_4.67 (lH, dd), 4.65-4.58 (2H, m), 3.43 (2H, s), 3.19-3.17 (2H, d), 2.93-2.85 (2H, m), 2.70- 2.62 (2H, m), 2.56_2.51 (1H, m), 2.48-2.43 (1H, m), 2.04-1.96 (2H, m), 1.90-1.78 (2H, m), 1.72-1.65 (2H , M), 1.05 · 1.03 (3H, d), 0.83 (9H, s), 0.00 (3H, s), -0.20 (3H5 s) ppm. LRMS (electrospray): m / z [M + H] +541, [Μ-Η] · 539 ·

Preparation 7: 2- {3 _ [(2R) -2 _ ({(2R) -2-{[Third-butyl (dimethyl) silyl] oxy}}-2- [4- mesityl-3- ( Methyl) phenyl] ethyl} amino) propyl] phenyl} -N_ (cyclopentylmethyl) acetamidine

OTBDMS

According to the procedure used to prepare 1, use (3-{(2R) -2 _ [(2R) -2-{[Third · butyl (dimethyl) silyxyl] oxy] 2_ (4- 3-Hydroxymethyl-phenyl) -ethylamino] -propyl} -phenyl) -acetic acid (Preparation 20) with the appropriate amine to give the title compound as a colorless oil. 1H NMR (400MHz, CD3OD): δ = 7.18 (1Η, s), 7.16-7.14 (1Η, d) 5 7.11-7 · 09 (1H, d), 7.04 (1H, s), 6.99-6 · 95 (2H, m), 6.68-6.66 (1H, d), 4.70-4.67 (1H, dd), 4.65-4.57 (2H, m), 3.43 (2H, s), 3.10-3.08 (2H , D), 2.93-2.85 (2H, m), 2.70-2.63 (2H, m), 2.56-2.51 (1H, m), 2.08-2.00 (1H, m), 1.74-1.67 (2H, m), 1.64 -1.50 (4H, m), 1.22-U4 (2H, m), 1.06-1.04 (3H, d), 0.84 (9H, s), 99200 -135- 200534846 0.01 (3H, s),- 0.18 (3H, s) ppm. LRMS (electrospray): m / z [M + H] +555, [Μ-ΗΓ554. Preparation 8: 2- {3-[(2R) _2-({(2R) _2-{[Third-butyl (dimethyl) silyl] oxy} -2- [4-Cyclo-3- (methyl) phenyl] ethyl} amino) propyl] phenyl Cyclohexylacetamide

OTBDMS

According to the procedure used for Preparation 1, (3-{(2R) -2-[(2R) -2-{[Third · butyl (dimethyl) silyl] oxy} -2- (4- Hydroxy-3-hydroxymethyl-phenyl) -ethylamino] -propyl} -phenyl) -acetic acid (Preparation 20) was prepared with the appropriate amine to give the title compound as a colorless oil. 1H NMR (400MHz, CD3 OD): δ = 7.19 (1Η? D), 7.17-7.15 (1Η, d), 7.11-7.09 (1H, d), 7.04 (1H, s), 6.99 · 6 95 (2H, t), 6.69-6.67 (1H, d), 4 · 7 (M · 67 (1H, dd), 4.65-4.58 (2H, m), 3.65-3.57 (1H, m), 3 · 40 (2H, s), 2.92-2.84 (2H, m), 2.69-2.61 (21 ^ 111), 2.56-2_51 (1H, m), 1.86_1 · 80 (2H, m), 1.75-1.70 (2H, m), 1.64-1.59 (1H, m), 1.39 · 1 · 28 (2H, m), 1.24-1.15 (3H, m), 1.05-1.03 (3H, d), 0.83 (9H, s), -0.01 (3H, s), -0.20 (3H, s) ppm. LRMS (electrospray): m / z [M + Hf555, [Μ-ΗΓ554. Preparation 9: 2- {3-[(2R ) _2-({(2R) _2 _ {[Third-butyl (dimethyl) silyl 1oxy} · 2_ [4-hydroxy-3- (methyl) phenyl 1ethyl} amino) Propyl] phenyl} -N-cyclobutylacetamide 99200 -136- 200534846

OTBDMS

According to the procedure used for preparation 1, (3-{(2R) -2-[(2R) -2-{[third-butyl (dimethyl) silyl] oxy} -2- (4- Hydroxy-3-hydroxymethyl-phenylethylamino] -propylbuphenyl) -acetic acid (Preparation 20) was prepared with the appropriate amine to give the title compound as a colorless oil.

1H NMR (400MHz, CD3 OD): δ = 7.19 (1Η5 d), 7.17-7.15 (1Η, d) 3 7.11-7.09 (1H, d), 7.03 (1H, s), 6.99-6 · 95 (2H, m), 6.68-6.66 (1H, d), 4.70-4.65 (1H, dd), 4.62-4.61 (2H, d), 4.29-4 · 21 (1H, m) , 3.39 (2H, s), 2.92-2.84 (2H, m), 2.68-2.61 (2H, m), 2.57-2 · 52 (1H, m), 2.29-2 · 21 (2H, m ), 1.98-1.87 (2H, m), 1.74-1.66 (2H, m), 1.0-5.0-3 (3H, d), 0.82 (9H, s), -0.01 (3H, s), -0.20 (3H, s) ppm. LRMS (electrospray): m / z [M + H] +527, [Μ-ΗΓ525. Preparation 10: 2- {3-[(2R) -2 _ ({(2R) _2 _ {[Third butyl (dimethyl) silyl] oxy

Group} _2- [4_hydroxy_3_ (hydroxymethyl) phenyl] ethyl} amino) propyl] phenyl (cyclohexylmethyl) acetamidamine

According to the procedure used for Preparation 1, (3-{(2R) -2-[(2R) -2-{[Third-butyl (dimethyl) oxetyl) oxy] 2- (4- Hydroxy-3-hydroxymethyl-phenyl) -ethylamino] -propyl 99200 -137- 200534846 phenylphenyl) -acetic acid (Preparation 20) and appropriate amines to give the title compound as a white bubble . 1H NMR (400MHz, CD3OD): δ = 7.18-7.14 (2Η? M), 7.11-7.09 (1Η, m), 7.03 (1H, s), 6.98-6.95 (2H, m), 6.68-6.66 ( 1H, d), 4.70-4.67 (1H, dd), 4.62-4.61 (2H, d), 3.43 (2H, s), 3.00-2.99 (2H, d), 2.91-2.84 (2H, m), 2.70-2.62 (2H, m), 2.55-2.50 (1H, m), 1.69-1.67 (5H, m), 1.49-1.43 (1H, m), 1.27-1.14 (3H, m), 1.05-1.03 (2H , M), 0.84 (9H, s), 0.01 (3H, s), -0.18 (3H, s) ppm. LRMS (electrospray): m / z [M + H] +569, [M + Na] +591, [Μ-ΗΓ567.

Preparation 11: 2- {3-[(2R) _2-({(2R) _2-{[Third · butyl (dimethyl) silyl] oxy}}-2- [4_ meridyl-3- (Methyl) phenyl] ethyl} amino) propyl] phenylphenyl N- (cyclopropylmethyl) acetamide

According to the procedure used to prepare 1, use (3-{(2R) _2-[(2R) -2-{[Third-butyl (dimethyl) lithium alkyl] oxy} -2- (4 -Hydroxy-3-hydroxymethyl-phenyl) -ethylamino] -propyl} -phenyl) -acetic acid (Preparation 20) with the appropriate amine to give the title compound as a white foam bed. 1H NMR (400MHz, CD3 OD): 5 = 7.15-7.07 (3H, m), 7.01 (1H, s), 6.95-6.92 (2H, m), 6.65-6.63 (1H, d), 4.66-4.63 (1H , m), 4.58-4.57 (2H5 d), 3.40 (2H, s), 3.00-2.98 (2H, d), 2.89-2.80 (2H, m), 2.65-2 · 57 (2H, m), 2.53-2.48 (1H, dd), 1.01-1.00 (3H, d), 0.93-0.87 (1H, m), 0.79 (9H, s), 0.44-0.40 (2H, q), 0.15-0.12 (2H, q ), -0.04 (3H, s), -0.24 (3H, s) ppm. 99200 -138- 200534846 LRMS (electrospray): m / z [M + H] +527, [M + Na] +549, [Μ-Η; Γ525 · Preparation 12: 2- {3-[(2R) -2 _ ({(2R) _2-{[Third-butyl (dimethyl) silyl] oxy] oxy} · 2 · [4_Hydroxy-3 · (Methyl) phenyl] ethyl} amino) propyl] phenylphenyl N_ (cycloheptylfluorenyl) acetamidine

OTBDMS

According to the procedure used for Preparation 1, (3-{(2R) -2-[(2R) -2-{[Third-butyl (dimethyl) suprylalkyl] oxybutanyl 2- (4 -Methyl-3-hydroxymethyl-phenyl) -ethylamino] -propylbuphenyl) -acetic acid (Preparation 20) and the appropriate amine to give the title compound as a white foam. 1H NMR (400MHz, CD3 OD): δ = 7.24-6.95 (6H, m), 6.70-6.67 (1H, d), 4.72-4.68 (1H, m), 4.67-4.58 (2H, m), 3.24 (2H , s), 3.02-2.99 (2H? d), 2.92- 2.50 (5H, m), 1.72-1.08 (13H, m), 1.06-1.04 (3H, d), 0.92 (9H, s), 0.00 (3H, s), -0.19 (3H, s) ppm. LRMS (electrospray): m / z [M + H] +583, [M + Na] +605. Preparation 13: Nl-Au-Steelalkyl _2- {3-[(2R) _2-({(2R) _2-{[Third · butyl (dimethyl) silyl] oxy] 2- [4-hydroxy-3- (hydroxymethyl ) Phenyl] ethyl} amino) propyl] phenyl} acetamidamine

OTBDMS

Η〆99200 -139- 200534846 According to the procedure used for preparation 1, (3-{(2R) -2-[(2R) -2-{[Third-butyl (dimethyl) silylyl] Oxy} -2- (4-hydroxy-3-hydroxymethyl-phenyl) _ethylamino] -propylbuphenyl) -acetic acid (Preparation 20) and the appropriate amine to give the title compound as White foam. 1H NMR (400MHz, CD3 OD): δ = 7.20-6.93 (6H, m), 6.68-6.65 (1H, d), 4.74-4.68 (lH, m), 4.65-4.58 (2H, m), 3.40 (s , 2H), 2.96-2.85 (m, 2H), 2.72-2.54 (3H, m), 2.04 (3H, s), 2.01 (6H, s), 1.70 (6H, s), 1.07-1.05 (3H , D), 0.85 (9H, s), 0.02 (3H, s), -0.19 (3H, s) ppm. LRMS (electrospray): m / z [Μ-ΗΓ605. Alternative method title compound Based on a method similar to Preparation 25, it is prepared from Nl-gold steel alkyl-2- {3-[(2R) -2-({(2R) -2- [4_ (sheepoxy) _3- (via methyl ) Phenyl] -2-Ethyl} amino) propyl] phenyl} acetamidamine (Preparation 164) as a colorless foam in 91% yield. Preparation 14: N- (l_gold steel alkylmethyl) -2- {3-[(2R) -2-({(2R) -2 _ {[third butyl (dimethyl) silyl] oxy Gyl 2- [4-hydroxy-3_ (hydroxymethyl) phenyl] ethyl} amino) propyl] phenyl} acetamidamine

According to the procedure used to prepare 1, use (3-{(2R) -2-[(2R) -2-{[Third-butyl (dimethyl) lithium alkyl] oxy} _2- (4 -Midyl-3-hydroxymethylphenyl) -ethylamino] -propylbuphenyl) -acetic acid (Preparation 20) and the appropriate amine to give the title compound as a white foam. 99200 -140- 200534846 1H NMR (400MHz, CD3 OD): δ = 7.22-6.96 (6H? M), 6.71-6.68 (1H? D), 4.75-4.67 (1H, m), 4.66-4.58 (2H, m ), 3_26 (2H, s), 2.88-2.50 (5H, m), 2.84 (2H, s), 1.90 (3H, s), 1.74-1.58 (6H, m), 1.44 (6H, s), 1.08- 1.06 (3H, d), 0_84 (9H, s), 0.01 (3H, s), -0.19 (3H, s) ppm. LRMS (electrospray): m / z [Μ-Η] · 619 · Preparation 15: N-2-gold steel alkyl_2- {3-[(2R) _2-({(2R) _2-{[third butyl (dimethyl) silyl] oxy} -2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) propyl] phenyl} acetamidine

OTBDMS

According to the procedure used for Preparation 1, (3-{(2R) -2-[(2R) -2-{[Third-butyl (dimethyl) suprylalkyl] oxybutanyl 2- (4 -Midyl-3-hydroxymethylphenyl) -ethylamino] -propyl} -phenyl) -acetic acid (Preparation 20) with the appropriate amine to give the title compound as a white bubble.

1H NMR (400MHz, CD3 OD): δ = 7.22-6.96 (6H, m), 6.70-6.68 (1H, d) 5 4.72-4.68 (1H, m), 4.67-4.58 (2H, m), 3.95 (1H , S), 3.52 (2H, s), 2.94-2.50 (5H, m), 1.96-1.78 (12H, m), 1.62-1.56 (2H, d), 1.05-1.03 (3H, d), 0.83 (9H , S), 0.00 (3H, s), -0.19 (3H, s) ppm. LRMS (electrospray): m / z [M_H] -605. Preparation 16: 2- {3-[(2R) -2 -({(2R) _2-{[Third.butyl (dimethyl) silyl] oxy} -2- [4-Cycloyl-3- (Methyl) phenyl] ethyl} amino ) Propyl] phenylphenyl N- (2-cyclohexylethyl) methylacetamide 99200 -141-200534846

OTRniWIQ

According to the procedure used to prepare 1, use (3-{(2R) -2-[(2R) _2-{[Third-butyl (dimethyl) silylyl] oxy} -2- (4 -Methyl-3_hydroxymethyl-phenyl) _ethylamino] -propyl} -phenyl) _acetic acid (Preparation 20) and the appropriate amine to give the title compound as a white foam. 1H NMR (400MHz, CD3 OD): δ = 7.22-6.98 (6H, m) 5 6.70-6.68 (1H, d), 4.75-4.71 (1H, m), 4.70-4 · 58 (2H, m) , 3.70-3 · 64 (2H, m), 3.45-3.37 (2H, m), 2.98-2.52 (8H, m), 1.80-0.80 (25H, m), 0.04 (3H, s), -0.19 (3H, s) ppm. LRMS (electrospray): m / z [M + H] +619. Preparation 17: 2- {3-[(2R) _2-({(2R) -2-{[第 第Tri-butyl (dimethyl) silyl ioxy} _2- [4-hydroxy-3_ (hydroxymethyl) phenyl] ethyl} amino) propyl] phenyl group N-cycloheptylmethyl Acetamide

According to the procedure used to prepare 1, use (3-{(2R) -2-[(2R) -2 _ {[Third-butyl (monomethyl) lithium alkyl] oxy} _2- (4- Benzyl-3-methylphenyl) -ethylamino] -propylphenyl) -acetic acid (Preparation 20) was prepared with the appropriate amine to give the title compound as a white foam. 1H NMR (400MHz, CD3 〇Ό): δ = 7.22-6.96 (6Η? M) 5 6.72-6.64 (1Η, dd) 5 4.72-4.65 (1H, m), 4 · 62-4 · 60 (2H, m) , 4.58-4.51 (0.5Η, m), 3.90-3 · 83 (0.5Η, 99200 -142- 200534846 m), 3.77 (lH, s), 3.66 (lH, s), 2.96-2.50 ( 5H, m), 2.82-2.78 (3H, d), 1.76-1 · 20 (12H, m), 1.06-1.04 (3H, dd), 0.82-0.80 (9H, 2s), 0.01-0 · 00 (3H, 2s), -0.18--0.19 (3H, 2s) ppm. LRMS (electrospray): m / z [M + H] +583, [M + Na] + 605 · Preparation 18: 2_ {3_ [(2R) _2-({(2R) _2- {丨 Third-butyl (dimethyl) silyl] oxy}}-2- [4-Cycyl-3- (methyl) phenyl)] Ethyl} amino) propyl] phenyl} -N-cyclohexyl-N-ethylacetamide

According to the procedure used to prepare 1, use (3-{(2R) -2-[(2R) -2-{[Third-butyl (monomethyl) lithium alkyl] milk group} _2- (4 -Benzyl-3- via methyl-phenyl) -ethylamino] -propylphenylphenyl) -acetic acid (Preparation 20) with the appropriate amine to give the title compound as a white foam. 1H NMR (400MHz, CD3 OD): δ = 7.25-6.94 (6H, m), 6.70-6.66 (1H, d), 4 · 72-4 · 68 (1H, m), 4.64A58 (2H, m), 3.73 (2H, s), 3.70-3.60 (1H, m), 3.73 (2H, s), 3.70-3.60 (1H, m), 3.30-3.24 (2H, q), 2.95-2.48 (5H, m ), 1.85-1.10 (10H, m), U2-1.08 (3H, t), 1.04-1.02 (3H, d), 0.92 (9H, s), 0.01 (3H, s), -0.20 (3H5 s ) ppm. LRMS (electrospray): m / z [M + H] + 605 · Preparation 19: 2- {3-[(2R) -2-({(2R) -2 _ {[third-butyl (Dimethyl) silyl] oxyphenyl 2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) propyl] phenylphenyl n_ (2-cyclohexylethyl) ethyl Lamine 99200 -143- 200534846

OTBDMS

According to the procedure used to prepare 1, use (3-{(2R) -2 _ [(2R) _2-{[Third-butyl (dimethyl) lithium alkyl] oxy} _2- (4- 3-Hydroxymethyl-phenyl) -ethylamino] -propyl} -phenyl) -acetic acid (Preparation 20) was prepared with the appropriate amine to give the title compound as a white foam. 1H NMR (400MHz, CD3 OD): δ = 7.22-6.96 (6H? M) 3 6.68-6.66 (1H5 d), 4.70-4.65 (1H, m), 4.64-4.58 (2H, m), 3.42 (2H, s) 5 3.21-3.17 (2H, t), 2.93-2.50 (5H, m)? 1.74-1.60 (5H, m), 1.39-1.34 (2H, q), 1.30-1.12 (4H, m), 1.04- 1.02 (3H, d), 0.96-0.91 (2H, m), 0.90 (9H, s), 0.00 (3H, s), -1.99 (3H, s) ppm · LRMS (electrospray ): M / z [M + Na] +605.

OTBDMS

Preparation 20: (3-{(2R) _2 _ [(2R) _2 _ {[third butyl (dimethyl) silyl] oxy}} _ 2- (4-lightyl_3_methyl-phenyl ) -Ethylamino] propylphenyl) _Acrylic acid will be (3-{(2R) -2 _ [(2R) -2 _ {[Third-butyl (dimethyl) lithium alkyl] oxy] 2 hydroxy-3-hydroxymethyl-phenyl) -ethylamino] -propylbuphenyl) _methyl acetate (Preparation 21) (7.04 g, 14.43 mmol) in tetrahydrofuran (40 ml) The solution was treated with lithium hydroxide (28.9 ml, 1 M aqueous solution, 28.9 mmol), and the reaction was left to stir at room temperature for 16 hours. Hydrochloric acid (28.9 ml, 1M in water, 28.9 mmol) was added 'and the tetrahydrosquench was removed in vacuo. The remaining aqueous layer was decanted from 99200 -144- 200534846 and the residue was washed with additional water (10 ml). The residue was redissolved in methanol (30 mL) and the solvent was removed in vacuo to obtain the title compound as a colorless foam (5.95 g), which was used without further purification. 1H NMR (400MHz, CD3 OD): 5 = 7.32 (1H5 s) 5 7.25-7.18 (2H, m) 5 7.13 (1H, s), 7.12-7.10 (1H5 d), 7.02-7.01 (1H, d), 6.79-6.77 (1H, d), 4.98-4.95 (1H, m), 4.65-4 · 64 (2H, d), 3.48 (2H, s), 3.48-3 · 43 (1H, m), 3.28-3 · 23 (1H, dd), 3.13-3.09 (1H, dd), 2.98-2 · 93 (1H, dd), 2.77-2.72 (1H, dd), 1.23-1.21 (3H, d), 0.86 (9H, s), 0.06 (3H, s), -0.13 (3H, s) ppm · LRMS (electrospray): m / z [m + H] +474, [ M + Na] +496, [Μ-Η] · 472. (^ Analysis: Measured values ::, 64.15%, 11,8.25%, wind 2.84%; 〇: 261130〇58 丨 +0.7 H2 O requires C , 64 · 22%, H, 8.37%, N, 2.88% · Preparation 21: (3-{(2R) -2-[(2R) -2-{[Third-butyl (dimethyl) silane Radical I

) _2_ (4_Ethyl_3_hydroxymethylphenyl) _ethylamino] -propylphenylphenyl > methyl acetate OTBDMS

HO〆 will be (3-{(2R) -2 _ [(2R) -2-{[third-butyl (dimethyl) silyl] oxy} -2--2- (benzyloxy) -3 -Amidino-phenyl) · Ethylamino > Propylphenylphenyl Methyl Acetate (Preparation 22) (5.27 g, 9.12 mmol) with 10% palladium / carbon (l.oo g) in ethanol (50 ml) of the suspension, stirred in a hydrogen atmosphere (60 psi) and room temperature for 16 hours. The catalyst was filtered through arbocel, and the filtrate was concentrated in vacuo. The residue was borrowed quickly on Shixi gum. Purified by column chromatography and dissolved in dioxane: methanol: 99200 -145- 200534846 880 ammonia (96: 4: 0.4 changed to 95 ·· 5: 0 · 5, volume ratio) to obtain the title compound, which was light. Yellow oil (1.99 g), used without further purification. 1H NMR (400MHz, CD3 OD): δ = 7.21-7.17 (2H, m), 7.11-7.09 (1H, d)? 7.03-6.98 (3H, m ), 6.69-6.67 (1H, d), 4.71-4.68 (1H, t), 4.62-4.61 (2H, d), 3.67 (3H, s), 3.59 (2H, s), 2.96-2.86 (2H, m), 2.69-2.55 (3H, m), 1.07-1.05 (3H, d), 0.82 (9H, s), -0.01 (3H, s), _0 · 20 (3H, s) ppm. LRMS (Electrospray): m / z [M + H] +488, [M + Na] +510, [M-ΗΓ486 Preparation 22: (3-{(1 2R) _2-[(2R) _2-{[third-butyl (dimethyl) silyl] oxy}} -(4_ [Masteroxy] _3 · Methyl-phenyl) _Ethylaminopropyl} • phenyl) _methyl acetate

OTBDMS

1 > (Ethyloxy) -5 _ ((lR) _2-bromoyl_1 _ {[third-butyl (dimethyl) lithium] oxy} ethyl) phenyl] methanol (Preparation 23 ) (12.5 g, 27.7 mmol) with {3-[(2R) aspartylpropyl] phenyl} acetic acid acetate (Preparation 25) (11.5 g, 55.4 mmol) (130 ml) was heated to 90 ° C, and the digas was evaporated. The resulting melt was left at 90 ° C. for another 16 hours. The reaction mixture was allowed to cool to room temperature, and purified by flash column chromatography on silica gel, and was dissolved in methane: methanol: 880 ammonia (98: 2: 0.2 to 97: 3: 0.3, volume ratio) and dissolved, and The title compound (12.1 g) was obtained as a white oil. -146- 1 H NMR (400MHz, CD3 OD): 5 = 7.47-7.45 (2H, m), 7.39-7.29 (4H, m), 7.19-7.15 (1H, t), 7.13-7 · 07 ( 2H, m), 7.03 (lH, s), 7.01-6.99 (lH, d), 6.93-2 99200 200534846 6.91 (1H, d), 5.12 (2H, s), 4.76-4.73 (1H, t), 4.67 -4.66 (2H, d), 3.66 (3H, s), 3.58 (2H, s), 2.95-2.80 (2H, m), 2.68-2.55 (3H, m), 1.06-1.05 (3H, d) , 0 · 83 (9H, s), 0 · 00 (3H, s), · 0 · 19 (3H, s) ppm · LRMS (electrospray): m / z [M + H] +578, [M + Na] +600. Preparation 23: [2- (Ethyloxy) -5 _ ((lR) -2_bromo-l-{[third-butyl (dimethyl) alkyl] oxy} ethyl ) Phenyl] methanol

OTBDMS

Add the sintered dimethyl sulfide compound (42.4 ml, iQM ✓ in tetrahydro sigma glutamate, Valley fluid, 424 millimoles) dropwise to 2- (Ethoxy) -5-((lR)- 2- Mo-1-{[Third-butyl (dimethyl) oxalyl] oxy} ethyl) methyl benzoate (Preparation 24) (91.0 g '189 Maomol) in four Hydrogen bite (1600 liters) in solution. The resulting mixture was then heated to reflux for 2 hours, then allowed to cool to 0 ° C, and then the reaction was quenched with methanol (270 mL). The mixture was left to stir at room temperature for 16 hours, and then the solvent was removed in vacuo. The residue was partitioned between dichloromethane (500 ml) and water (500 ml). The aqueous phase was separated and extracted with dioxane (500 ml), and the combined organic extracts were washed with a saturated aqueous sodium vaporized solution (500 ml), dried (MgSO4), and the solvent was removed in vacuo. The residue was purified by flash column chromatography on silica gel, and the title compound (68.7 g) was obtained by dissolving cyclohexane: ethyl acetate (100: 0 to 80:20, volume ratio). , Is a colorless oil. 1H NMR (400MHz, CDC13): 5-7.42-7.36 (5H, m) 5 7.29-7.25 (3H5 m) 5 99200 -147- 200534846 6.94 (1H, d), 5.12 (2H, s) , 4.84-4 · 81 (1H, m), 4.74 (2H, s), 3.48-3 · 40 (2H, m), 0.90 (9H, s), 0.11 (3H, s), -0 · 07 (3H, s) ppm. LRMS (Electrospray): m / z [M + Na] +473/475. Preparation 24 ·· 2- (Nyloxy) -5-((lR) _2 -Bromo small {[tertiary-butyl (dimethyl) dreamyl] oxy} ethyl) methyl benzoate

OTBDMS

Methyl 2- (benzyloxy) -5-[(lR) -2-bromo · 1-hydroxyethyl] benzoate (7105 g, 195 mmol), imidazole (18.52 g, 272 mmol) Moore), Gasified Tertiary Butyl Dimethyl Shixueyuan (32.23 g, 214 mmol) and 4- (N, N-dimethylamino) ρridine (0.44 g, 3.6 mmol) ) A solution in N, N-dimethylformamide (270 ml) was left to stir at room temperature under a nitrogen atmosphere for 24 hours. The solvent was removed in vacuo and the residue was partitioned between ethyl acetate (500 ml) and water (500 ml). The organic phase was separated and washed with 2N hydrochloric acid (2 times, 500 ml), saturated sodium bicarbonate aqueous solution (2 times 500 ml), saturated sodium gasification (500 ml), and dried (magnesium sulfate), and moved in vacuo The solvent was removed to give the title compound as a colorless oil (91.0 g). 1HNMR (400 MHz, CDC13): δ = 7.81 (1H, bs) 5 7.51-7.30 (6H, m), 7.01 (1H, d), 5.19 (2H, s), 4.85-4.82 (1H, m), 3.91 (3H, s), 3.48-3.39 (2H, m), 0.90 (9H, s), 0.11 (3H, s), -0.08 (3H, s) ppm. LRMS (electrospray): m / z [M + Na] +501/503. Preparation 25 · {3-[(2R) -2-aminopropyl] phenyl} methyl acetate 99200 -148- 200534846

[3-((2R) -2-{[(lR) -l-benzyl-ethyl] -amino} -propyl) _phenyl] _methyl acetate hydrochloride (Preparation 26) (7.69 G, 22 mmol) and ammonium formate (6.94 g, 110 mmol), heated to 75 ° in the presence of 20% palladium hydroxide / carbon (Pd (〇H) 2 / C, 2.00 g) C. After 90 minutes, the reaction mixture was cooled to room temperature, filtered through arbocel, and the filtrate was concentrated in vacuo. The residue was partitioned between dichloromethane (100 ml) and 880 ammonia (100 ml), and the organic phase was separated. The aqueous phase was extracted with methane (100 ml) and the combined organic extracts were dried (magnesium sulfate) and reduced in vacuo to give the title compound as a colorless oil (4.78 g). 1H NMR (400MHz3 CD3 OD): δ = 7.27-7.23 (1H, t), 7.13-7.09 (3H, m), 3.67 (3H, s), 3.63 (2H, s), 3.12-3.05 (1H, m), 2.67-2.57 (2H, m), 1.06 (3H, d) ppm. LRMS (electrospray): m / z [M + H] +208, [M + Na] +230. Preparation 26: [ 3-((2R) -2-{[(lR) -l-phenyl · ethyl] -amino} -propyl) _phenyl] _methyl acetate hydrochloride.

[3- (2-Ketopropyl) phenyl] acetic acid methyl ester (Preparation 27) (8.5 g, 41.2 mmol), (R) -a-methylbenzylamine (4.8 mL, 37.2 mmol) ), A solution of sodium triethoxyalkoxyborohydride (11.6 g, 56 mmol) and acetic acid (2.2 ml, 38 mmol) in dichloromethane (400 ml), and stirred at room temperature for 48 hours. The reaction mixture was quenched by adding 99200 -149- 200534846 to a saturated aqueous sodium bicarbonate solution (200 ml) and stirred until foaming ceased. The organic phase was separated and the aqueous phase was extracted with dichloromethane (100 mL). The combined organic extracts were dried (magnesium sulfate) and reduced in vacuo. Purified by flash column chromatography, and dissolved in digas: methanol: gas (99 · 1 · 0.1 to 95 · 5 · 0.5 volume ratio) to obtain a 4: 1 mixture of diastereomers (mainly R, R) is a pale yellow oil (8.71 g). Treatment with hydrogen chloride (40 ml of a 1 M solution in methanol, 40 mmol) followed by three successive crystallizations (diisopropyl / methanol) gave the title compound as a white crystalline solid (5.68 g). 1H NMR (400MHz, CD3 OD): δ = 7.52-7.48 (5H, m) 5 7.28-7.25 (1H, m), 7.18-7.16 (1H, m), 7.02-6.99 (2H, m), 4.59 (1H , q), 3.62 (2H, s), 3.30 (3H, s), 3.30-3 · 25 (1H, m), 3.26-3 · 15 (1H, m), 2.66-2.60 (1H, m) , 1.68 (3H, d), 1.18, (3H, d) ppm. LRMS (electrospray): m / z [M + H] +312, [M + Na] +334. Preparation 27: [3_ (2-Methoxypropyl) phenyl] methyl picanoate

Η ^ Trimethoxytin butyltin (28.3 ml, 98 mmol), Preparation 28 (15.0 g '65 mmol), Isopropenyl acetate (10.8 ml, mmol) , Palladium acetate (11) (750 mg, 3.30 mmol) and tri-o-tolylphosphine (2.0 g, 6.5 mmol) in toluene (75 ml), stir together at 10 (rc and nitrogen) 5 hours. After cooling, the reaction was diluted with ethyl acetate (150 ml) and 4M potassium fluoride > cereal (90 liters) and stirred for 15 minutes. The mixture was filtered through arbcd and the organic phase was separated , And reduced in vacuum. The residue was purified by flash column chromatography silica gel 99200 -150- 200534846, and the solvent was changed to dichloromethane with ether: pentane (0: 100 to 25: 75, volume ratio). The gradient solution dissolves to give the title compound as a pale yellow oil (12.6 g). 1H NMR (400 MHz, CDC13): δ = 7.30 (1Η, t), 7.19 (1H, d) 5 7.13 ^ 7.10 (2H, m ), 3.69 (5H, s), 3_61 (2H, s), 2.15 (3H, s) ppm. LRMS (electrospray): m / z [M + NH4] +224, [M + Na] +229. Preparation 28: (3-Bromophenyl) methyl acetate

At 0 ° C under nitrogen, acetamidine chloride (0.7 ml, 9.3 mmol) was slowly added to (3- > odorantyl) -acetic acid (20.0 g, 93¾ mole) in methanol (500 ml) of the solution and the reaction was allowed to gradually warm to room temperature over a period of 5 hours. The solvent was removed in vacuo, and the residual oil was re-dissolved in digas methane, dried (sodium sulfate) 'and concentrated in vacuo to give the title compound as a colorless oil (20.6 g). 1H NMR (400 MHz, CDC13): δ = 7.37-7.45 (2H, m), 7.24-7.17 (2H, m), 3.70 (3H, s), 3.59 (2H, s) ppm. LRMS (EFI Fog): m / z [M + Na] +253. Preparation 29: 1_ (3-bromophenyl) -2-methylpropan-2-ol)

Slowly add methylmagnesium bromide (3M solution in ethyl acetate, 51.6 ml, 155 mmol) to μρ-bromophenyl at 0 ° C (15 g, 7 (0 mmol) in a solution of anhydrous ether (200 ml). The resulting mixture was left at 99200 -151-200534846 for 3 hours, then cooled to, and the reaction was slowly quenched with a saturated gasification aqueous solution. The organic phase was washed with brine and dried (Na2SO4). Next, the yellow oil was purified by column chromatography on silica gel, and was dissolved in dichloromethane: pentane · methanol (90: 5 ·· 5 volume ratio) to obtain a light yellow oil (13.26 g). 1H NMR (400 MHz, CDC13) δ = 7.40 (2Η, m), 7.15 (2Η, m), 2.74 (2H, s), 1.42 (lH, bs), 1.22 (6H, s) ·

Preparation 30: N_ 丨 2- (3-bromophenylH, i-ditynoethyl) _2_gasacetamide H CH3 N, / 乂 a

CI " T

At room temperature, acetonitrile (6.63 mL, 105 mmol) was added to 1- (3-benzylphenyl) -2-methylpropan-2-ol) (Preparation 29) (12.0 g, 52.0 mmol) Ear) in a stirred solution in acetic acid (25 liters). The resulting solution was cooled to, and concentrated sulfuric acid (25 ml) was added, keeping the temperature < i0 ° C. The resulting solution was left to stir for 1 hour, then poured onto ice and basified by adding solid potassium carbonate. The product was extracted with ethyl acetate (2x500 ml), the organic materials were combined, washed with water (50 ml), dried (sodium sulfate), and the solvent was removed in vacuo to give the title compound as an orange solid (16.08 grams). 1H NMR (400 MHz, CDC13) 5 = 7.39-7.32 (1H, d), 7.26 (1H, s), 7.1-7.13 (1H, t), 7.08-7.03 (1H, d), 6.17 ( 1H, bs), 3.94 (2H, s), 3.02 (2H, s), 1.37 (6H, s). Calculated CHN for Ci 2 Hi 5 BrCINO (measured value): c, 47.32 (47.26), H, 4.96 (4.87), N, 4.60 (4.65). LRMS (electrospray) m / z 306 [M + H] + Preparation M: 2_ (3_bromophenyl) _1,1-di Methylethylamine 99200 -152- 200534846

Add N_ [2- (3-bromophenyl) -U-dimethylethyl] -2-chloroacetamide (Preparation 30) (32.0 g, 105 mmol), thiourea (9.60 g, 126 mmol) Mol) and acetic acid (50 ml) in ethanol (250 ml) were heated to reflux overnight. The reaction mixture was allowed to cool to room temperature and filtered, and the filtrate was concentrated in vacuo and basified with aqueous sodium hydroxide (1M, 450 ml). The product was extracted with methane (2x500 ml) and the combined organics were washed with brine (50 ml), dried (Na2SO4), and the solvent was removed in vacuo to give the title compound as a black oil (23 G). 1H NMR (400 MHz, CDC13) δ = 7.36-7.32 (2Η5 m), 7.16-7.08 (2Η, m), 2.62 (2Η, s), 1.84 (2Η, bs), 1.12 (6Η, s ). LRMS (electrospray) m / z 228 [M + H] + Preparation 32: [2- (3-bromophenyl) -1, l-dimethylethyl] amine methyl acid tert-butyl ester

Add 2- (3-bromophenyl) -1,1-dimethylethylamine (Preparation 3 to 50 g, 22 mmol) to dicarbonate in digas methane (50 ml). Butyl ester (5.26 g, 24 mmol) was treated and stirred for 20 hours. The reaction mixture was washed with water (50 mL), and the combined organics were dried (Na2SO4) and removed in vacuo. The crude material was purified using a cation-exchange column (methanol, followed by 2M ammonia in methanol), followed by purification by flash column chromatography on silica gel, and dissociated with gaseous hexane to give the title compound as a brown oil ( 7.23 99200 -153- 200534846 g). iHNMRGOOMHz'DCls) 5 = 7.35 (lH, d), 7.30 (lH, s), 7.15-7.11 (1H, t), 7.05 (1H, d), 4.24 (1H, bs), 2.97 (2H, s) ), 1.50 (9H, s), 1.27 (6H, s). LRMS (electrospray) m / z 350 [M + NH4] + Preparation 33: 3- (2-Third-butoxycarbonylamino) Methyl-2-methylpropyl) benzoate

[2- (3-Bromophenyl) -1,1 · dimethylethyl] aminomethyl acid tert-butyl ester (Preparation 32) (7.0 g, 21 mmol), [1, Γ- Bis (diphenylphosphino) dicyclopentadiene iron] Digas palladium (11) (1.74 g, 2.1 mmol) and triethylamine (5.94 mL, 43 mmol) in methanol (250 mL) The solution was heated to 100 ° C under 100 psi-carbon oxide for 12 hours. The reaction mixture was filtered through arbcel, and the filtrate was concentrated in vacuo, and purified by flash column chromatography on silica gel, and dissolved in dichloromethane: pentane (50:50 volume ratio) to give the title compound. As a yellow solid (3.76 g). 1H NMR (400 MHz, CDC13) δ = 7.92-7.90 (1Η, m), 7.82 (1H, s) 5 7.35-7.34 (2H, m), 4.24 (1H, bs), 3.90 (3H, s) , 3.05 (2H, s), 1.48 (9H, s), 1.26 (6H, s), LRMS (electrospray) m / z 208 [M + H-BOC] + Preparation 34: 3 -(2 · Amino-: 2-methylpropyl) phenyl benzoate

Methyl 3- (2-tert-butoxycarbonylamino_2-fluorenylpropyl) benzoate (Preparation 33) (1.6 g, 5.2 mmol) in methane (160 ml) The solution in) was treated with trifluoroacetic acid (13.6 ml) at 99200 -154- 200534846 0 ° C, and left to warm to room temperature for 2 hours. The solvent was removed in vacuo and the product was purified by cation exchange chromatography (methanol, followed by 2M ammonia in methanol) to give the title compound as an unsaturated oil (1.06 g). 1H NMR (400 MHz, CDC13) δ = 7.90-7.88 (1Η, m), 7.84 (1H, s), 7.36-7.35 (2H, m), 3_90 (3H, s), 2.71 (2H, s) , 1.67 (2H, bs), 1.12 (6H, s). LRMS (electrospray) m / z 208 [M + H] +

OTBDMS

Preparation 35: 3- {2-[(2R) -2- (4-Ethyloxy_3_hydroxymethylphenyl) _2_ (third_butyldimethyl-feveryloxy) ethylamino 】 -2-methylpropyl} benzoic acid g

Methyl 3- (2-amino-2-methylpropyl) benzoate (Preparation 34) (136 g, 660 mmol), [2- (benzyloxy) _5-((lR ) _2-Bromo-small {[Third-butyl (difluorenyl) lithium] oxy} ethyl) phenyl] methanol (Preparation 23) (2.96 g, 6.60 mmol), sodium selenate (980 mg, 6.60 mmol) and diisopropylethylamine (3.44 ml, 19.7 mmol), heated to reflux in acetonitrile (10 ml) under nitrogen atmosphere for 48 hours. The solvent was then removed in vacuo, and a saturated aqueous sodium bicarbonate solution (20 mL) was added, and the product was extracted with ethyl acetate (3x30 mL). The combined organics were washed with brine (3 x 20 mL), dried (Na2SO4), and the solvent was removed in vacuo. The residue was purified by flash column chromatography on silica gel, and the title compound was obtained by dissolving methane · methanol: ammonia (95: 5: 0.5 by volume) in digas, and the purified product was dissolved in ether, and Steaming 99200 -155- 200534846 hair (x3) yields white foam (1.70 g). 1H NMR (400 MHz, CDC13) δ = 7.89-7.84 (2Η, m) 5 7.44-7.21 (9Η, m), 6.88 (1H, d), 5.10 (2H, s), 4.73-4.69 (3H, m), 3.91 (3H, s), 2.83 · 2 · 62 (4H, m), 2.86 (1H, t), 1.05 (3H, s), 1_02 (3H, s), 0.79 (9H , S), -0.44 (3H, s), -0.19 (3H, s) · LRMS (electrospray) m / z 578 [M + H] +, 600 [M + Na] + Preparation 36: 3 -{2 _ [(2R) -2- (Third-butyldimethylsilyloxy) -2- (4-hydroxy-3-hydroxymethyl-phenyl) ethylamino] -2-methyl Propyl} methyl benzoate

OTBDMS

Make 3- {2-[(2R) -2- (4-benzyloxy-3 · hydroxymethylphenyl) -2- (third-butyldimethyl-silyl) in methanol (50 ml) (Oxy) ethylamino] -2-methylpropyl} benzoic acid methyl ester (Preparation 35) (2.12 g, 3.70 mmol) with palladium / carbon (100/0, 300 mg), Hydrogenated at room temperature and 60 psi for 18 hours. The reaction mixture was filtered through arbocel, and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel, and dissolved in methylene chloride: methanol: ammonia (95: 5: 0.5 volume ratio) The title compound was obtained, this material was dissolved in ether and evaporated (x3) to give a white foam (1.50 g). 1H NMR (400 MHz, CDC13) δ = 7.89-7.86 (1H, m), 7.82 (1H, bs), 7.33- 7.31 (2H, m), 7.13 (1H, dd), 6.96 (1H, d), 6.79 (1H, d), 4.81 (2H, dd), 4.66 (1H, dd), 3.91 (3H, s), 2.81-2.76 (1H, m), 2.67 (2H, dd), 2.58 (1H, dd), 1.06 (3H, s), 1.03 (3H, s), 0.79 (9H, s), -0.03 (3H, s), -0.19 (3H, s) · LRMS (electrospray) m / z 488 [M + H] +, 510 [M + Na] + 99200 • 156- 200534846 Preparation 37: 3- {2 _ [(2R) -2- (Third · butyldimethylsilyloxy) _2 -(4-side-3-hydroxymethyl-phenyl) ethylamino] methylpropyl 丨 benzoic acid OTBDMS J 1 ^

OH

3- {2-[(2R) -2- (Third-butyldimethylsilyloxy) _2- (4-hydroxy net hydroxymethyl-benzyl) ethylamino] _2_methylpropyl Methyl} benzylformate (Preparation 36) (150 g '3.08 mol), aqueous sodium hydroxide solution (5M, 3.07 ml, 15.0 mmol), water (2 liters), and dioxolane (2 〇mL), stir at room temperature for 18 hours. The solvent was removed in vacuo and the residue was dissolved in water (30 ml) and acidified with aqueous hydrochloric acid (1N, 15.38 ml). The formed white precipitate 'was filtered off and dried under vacuum for 72 hours to obtain the title compound as a white solid (1.28 g). 1H NMR (400MHz, CD3 OD) δ = 7.88 (1H, d), 7.81 (1H, bs), 7.38-7.28 (3H, m), 7.10 (1H, dd), 6.77 (1H, d), 4 · 92 (1H, m, part under solvent peak), 4.61 (2H, dd)? 3.23-3.12 (2H, m), 2.95 (2H, dd), 1.08 (6H, s), 0.81 (9H, s ), -0.04 (3H, s), -0.15 (3H, s). LRMS (electrospray) m / z 474 [M + H] + Preparation 38: 3- {2-[(2R) -2- ( Tert-butyldimethylsilyloxy) -2- (4-hydroxy-3_hydroxymethylphenyl) ethylamino] -2-methylpropyl} -fluorene [2- (4-Ga Phenyl) ethyl] benzamidine 99200 -157- 200534846

Add 2- (4-Gasphenyl) ethylamine (164 mg, 1.06 mmol) to 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (203 mg , 1.06 mmol), 3- {2-[(2R) -2- (third-butyldimethylsilyloxy) -2- (4-hydroxy-3-hydroxymethyl-benzene ) Ethylaminomethylpropyl} benzoic acid (Preparation 37) (500 mg, 1.06 mmol), 1-hydroxybenzotriazole hydrate (160 mg, 1.06 mmol) and triethylamine (440 Μl, 3.20 mmol) in a mixture of methane (30 ml). The resulting solution was stirred under nitrogen for 48 hours. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate (30 ml), washed with water (20 ml), sodium bicarbonate (0.5M, 2x20 ml), brine (2x20 ml), and dried ( Sodium sulfate), and the solvent was removed in vacuo. The residue was purified by flash column chromatography on silica gel, and the title compound was dissolved with methane: methanol · ammonia (95: 5: 0.5 volume ratio) to obtain the title compound, and the formed substance was dissolved in methanol, and Evaporate, then dissolve in ether and evaporate to give a white foam (480 mg). 1H NMR (400MHz, CD3 OD) δ = 7.64-7.60 (2H, m)? 7.36-7.19 (7H, m), 7.05 (1H, dd), 6.72 (1H, d), 4.71-4.67 ( 1H, m), 4.60 (2H, dd) 5 3.57 (2H, t), 2.93-2.61 (6H, m), 1.09 (3H, s), 1.06 (3H, s), 0.78 (9H, s),- 0.04 (3H, s), -0.22 (3H, s) · LRMS (electrospray) m / z 611 [M + H] +, 633 [M + Na] + 99200 -158- 200534846 Preparation 39: 3- { 2 -_- 2 · (Third-Butyldimethylcynyloxy) Wedding group-3-Methylphenyl) Ethylamino] _2_methylpropyl} Yang_ (4_ f-ylbenzene ) Ethyl] benzamidine

According to the procedure used to prepare 38, 3_ {2-[(2R) _2_ (Third · butyldifluorenylsilyloxy) -2- (4-hydroxy-3-hydroxymethyl-phenyl) ethyl Amino] -2-methylpropyl} phenylarsinic acid (Preparation 37) and the appropriate amine were used to give the title compound as a white foam. 1H NMR (400MHz, CD3 OD) δ = 7.65-7.61 (2H, m), 7.36-7.30 (2H, m), 7.27 (1H, d), 7.14-7.06 (5H, m), 6.72 (1H, d), 4.71-4.68 (1H, m), 4.60 (2H, dd), 3.54 (2H, t), 2.90-2.83 (3H, m), 2.70 (2H, dd), 2. · 61 (1H, dd), 2.28 (3H, s), 1.09 (3H, s), 1.05 (3H, s), 0.78 (9H, s), 0-04 (3H, s), -0.22 (1H, s). LRMS (electrospray) m / z 591 [M + H] +, 613 [M + Na] + Preparation 40: 3- {2-[(2R) -2- (third-but Dimethylsilyloxyhydroxy-3-hydroxymethyl · phenyl) ethylamino] _2_methyl-propylbenzene N- [2- (4_trifluoromethylphenyl)

Ethyl] benzidine OTBDMS

3

CF According to the procedure used to prepare 38, 3- {2 _ [(2R) -2- (Third-butyldimethyl 99200 -159- 200534846 based silyloxy) -2- (4-merylhydroxymethyl -Phenyl) ethylamino] 2-methylpropyl} benzoic acid (Preparation 37) and an appropriate amine to give the title compound as a white foam bed. 1H NMR (400 MHz, CDC13) 5 = 7.66 (2Η, d), 7.45 (1Η, m), 7.38 (1Η, s), 7.33 (2H, d), 7.29_7 · 22 (2H, m) , 7.07 (1H, dd), 6.88 (1H, dd), 6.75 (1H, dd), 6.15 (1H, t), 4.75 (1H3 dd), 4.57 (1H51), 3.73-3.68 ( 2H? M) 5 2.99 (2H, t), 2.76 (1H, dd), 2.65 (2H, s), 2.58 (1H, dd), 1.03 (3H, s), 1.00 (3H, s), 0.79 (9H, s), -0.05 (3H, s), -0.20 (3H, s).

LRMS (electrospray) m / z 646 [M + H] + Preparation 41 ·· 3- {2 _ [(2R) -2- (Third-butyldimethylsilyloxy): (4 • hydroxy Each via methyl · phenyl) ethylamino] _2_methyl · propyl is called 2- (3,4_diphenylphenyl) ethyl] benzidine

According to the procedure used to prepare 38, 3- {2-[(2R) -2- (Third-butyldimethylsilyloxy) _2- (4-hydroxymethylol_phenyl) ethyl Amine > 2-methylpropyl} benzoic acid (Preparation 37) was prepared with the appropriate amine to give the title compound as a white foam. 1H NMR (400 MHz, CDC13) δ = 7.45 (1Η? D), 7.40-7.36 (2Η, m), 7.33 (1Η, d), 7.30-7.22 (2Η, m), 7.05 (2Η, m), 6 88 (1Η, dd), 6.75 (1Η, d), 6.17 (1H, t), 4.75 (1H, dd), 4.69 (1H, t), 3.63 (2H, m), 2.89 (1H, t), 2.76 (1H, dd), 2.66 (2H, s), 2.59 (1H, dd), 1.04 (3H, s), 1.00 (3H, s), 0.79 (9H, s), -0.05 99200 -160- 200534846 (3H, s), -0.20 (3H, s). LRMS (electrospray) m / z 646 [M + H] + Preparation 42: 3 -{2-[(2R) -2- (Third-butyldimethylsilyloxy) _2 (4-hydroxy-3-transmethyl-benzyl) ethylamino] _2_methyl-propyl BU N_ [2_ (3,4-: methylphenyl) ethyl] benzamidine

According to the procedure used to prepare 38, 3- {2-[(2R) _2- (Third-butyldimethylsilyloxy) -2- (4-hydroxy; hydroxymethyl-phenyl) ethyl Aminomethylpropyl} benzoic acid (Preparation 37) was prepared with the appropriate amine to give the title compound as a white foam. 1H NMR (400 MHz, CDC13) 5 = 7.43 (1H, d), 7.37 (1H, s), 7.20-7.27 (2H, m), 7.06-7.09 (2H, m), 7.01 (1H, s) , 6.94 (1H, d), 6.88 (1H, dd), 6.74 (1H, dd), 6.13 (1H, t), 4.75 (1H, dd), 4.59 (1H, t), 3.64 (1H, dd), 2.85 (1H, t), 2.77 (1H, dd), 2.65 (2H, s), 2.59 (1H, dd), 2.24 (3H, s), 2.23 (3H, s ), 1.03 (3H, s), 1.00 (3H, s), 0.79 (9H, s), -0.05 (3H, s), -0.20 (3H, s). LRMS (APCI) m / z 606 [ M + H] + Preparation 43: 3- {2-[(2R) _2- (Third · butyldimethylsilyloxy) -2- (4-hydroxy-3-hydroxymethyl · phenyl) Ethylamino] _2 · methyl-propyl tea-2-yl-ethyl) benzamidine 99200 -161- 200534846

MSHN / 13C

Alas, according to the procedure used to prepare 38, 3- {2 _ [(2R) -2- (third-butyldimethylsilyloxy) -2- (4-hydroxy-3-hydroxymethyl- Phenyl) ethylamino] -2-fluorenylpropyl} benzoic acid (Preparation 37) was prepared with the appropriate amine to give the title compound as a white foam. 1H NMR (400 MHz, CDC13) δ 7.77 (3Η, m) 5 7.67 (1Η, s), 7.48-7.35 (5H, m), 7.23-7.19 (2H, m), 7.06 (1H, dd), 7.37 ( 1H, dd), 6_74 (1H, d), 6.17 (1H, t), 4_74 (2H, dd), 4.67 (1H, t), 3.76 (2H, dd), 3.09 (2H, t), 2.75 (1H, dd), 2.62 (2H, s), 2_57 (1H, dd), 1.00 (3H, s), 0.97 (3H, s), 0.78 (9H, s), -0.05 ( 3H, s), -0.21 (3H, s). LRMS (electrospray) m / z 628 [M + H] + Preparation 44: 3- {2 _ [(2R) _2_ (third-butyldimethyl Silyloxy) -2- (4 • hydroxy: methyl-phenyl) ethylamino] _2_methyl-propylbenzene N_ (1,1ββ: methyl: phenyl_ethyl) benzidine amine

According to the procedure used to prepare 38, 3- {2-[(2R) -2- (Third-butyldimethylsilyloxy) -2- (4 • hydroxy_3_hydroxymethyl_benzene Group) Ethylamino] _2-fluorenylpropyl} phenylarsinic acid (Preparation 37) and appropriate amines to give the title compound as a white 99200 -162- 200534846 colored foam. 1H NMR (400 MHz, CDC13) δ = 7.43 (1H, m), 7.36 (1H, s), 7.31-7.13 (7H, m), 7.08 (1H, dd), 6.84 (1H, dd), 6 75 (1H, d), 5.70 (1H, s), 4.73 (2H, dd), 4.68 (1H, t), 3.10 (2H, dd), 2.77 (1H, dd), 2.65 (2H , S), 2.68 (1H, dd), 1.45 (3H, s), 1.44 (3H, s), 1.06, (3Η, s), 1.01 (3H, s), 0.79 (9H, s), _ 0 · 04 (3H, s), -0.21 (3H, s). LRMS (electrospray) m / z 605 [M + H] + Preparation 45: 3- {2-[(2R) _2- (Third · butyldimethylsilyloxy) -2- (4-hydroxy-3_hydroxymethylphenyl) ethylamino] -2 · methylpropyl} _N_ (2_methyl_2 (_Phenylpropyl) _ benzamidine

According to the procedure used to prepare 38, 3- {2-[(2R) -2- (third-butyldimethylsilyloxy) -2- (4-hydroxy-3-hydroxyfluorenyl-benzene Group) Ethylamino] -2-methylpropyl} phenylarsinic acid (Preparation 37) and the appropriate amine to give the title compound as a white foam. 1H NMR (400 MHz, CDC13) δ = 7.42-7.34 (4H, m), 7.29-7.15 (5H, m), 7.05 (1H, dd), 6.87 (1H, dd), 6.74 ( 1H, d), 5.73 (1H, t), 4.74 (2H, dd), 4.64 (1H, dd), 3.62 (2H, dd), 2.75 (1H, dd), 2.61 (2H, dd), 2.66 (1H, dd), 1.40 (6H, s), 1.00 (3H, s), 0.97 (3H, s), 0.79 (9H, s), -05 (3H, s), -0.20 (3H, s). LRMS (Electrospray) m / z 605 [M + H] + 99200 -163- 200534846 Preparation 46: 3 _ {(2R) _2- [2- (third_butyldimethylsilyloxy) _2- ( 4 • hydroxy • 3_hydroxymethyl_phenyl) ethylamino group 2.methylpropyl group N- (4-Arylidene) benzidine

According to the procedure used to prepare 38, 3- {2-[(2R) -2- (third-butyldimethylsilyloxy) -2- (4-hydroxy-3-hydroxymethyl-benzene Group) Ethylamino] -2-methylpropyl} phenylarsinic acid (Preparation 37) and the appropriate amine to give the title compound as a white foam. 1H NMR (400 MHz, CDC13) δ 7.55 = (1H, m), 7.49 (1H, m), 7.33-7.24 (4H, m), 7.06 (1H, dd), 6.88 (1H, dd), 6_74 (1H, d), 6.49 (1H, t), 4.73 (1H, dd), 4.57 (2H, dd), 2.75 (1H, dd), 2.66 (2H, s)? 2.66 (1H, dd), 1.04 ( 3H, s), 1.00 (3H, s), 0.78 (9H, s), -0.06 (3H, s), -0.21 (3H, s). LRMS (electrospray) m / z 597/599 [ M + H] +

Η3〇ν〇 group) -phenyl] -acetoacetate ethyl ester Preparation 47: [3- (2 • amino-2-methyl • propyl

Add {3- [2_ (2_Ga-acetamido) · 2 · methyl-propyl] -phenyl [acetic acid (Preparation 48) (5.1 g, 18 mol), thiourea (1.6 G, 21 mmol) and acetic acid (18 ml) in ethanol (80 ml), heated to reflux under a nitrogen atmosphere for 16 hours. The reaction mixture was cooled and filtered. The filtrate was reduced in vacuo, the residue was dissolved in ethanol (150 ml), saturated with hydrogenated hydrogen gas, and the resulting solution was heated to reflux for 16 hours. The solvent was reduced in the air to 99200-164-200534846, and the residue was separated between ethyl acetate (200 ml) and 5% aqueous sodium carbonate solution (200 ml). The organic extract was washed with saturated sodium gaseous (100 mL), dried (Na2SO4), and reduced in vacuo. The residue was purified by a strong cation exchange resin, and then dissolved in methanol and then 2N ammonia in methanol to dissolve the product. The eluent was concentrated in vacuo to give the title compound as a yellow oil (2.68 g, 63%). 1H NMR (400 MHz, CDC13): 5 = 7.29-7.04 (4H, m), 4.08 (2H, q), 3.64 (2H, s), 2.57 (2H, s), 1.18 (3H , T), 0_99 (6H, s) ppm · LRMS (electrospray): m / z [M + H] +236, [M + NH4] +258.

Preparation 48: {3- [2- (2-Gas-acetamido) -2 · methyl-propyl] -phenyl} -acetic acid was added dropwise at 0 ° C, concentrated sulfuric acid (21 ml) To [3- (2-hydroxy-2-methyl-propyl) -phenyl] -acetic acid (Preparation 49) (10.6 g, 51.0 mmol) with acetonitrile (4.8 mL, 76.0 mmol) on ice In acetic acid (16 ml). The reaction was allowed to warm to room temperature, and after 2 hours, was poured onto ice water (500 ml). The aqueous solution was extracted with ethyl acetate (2x250 mL), and the combined organic materials were washed with brine (50 mL), dried (Na2SO4), and the solvent was removed in vacuo to give the title compound as a golden oil (14.0 g ). 1H NMR (400 MHz, CDC13 δ = 7.31-7.06 (4Η, m), 6.19 (1Η, bs), 3.95 (2H, s), 3.62 (2H, s), 3.02 (2H, s), 1 · 36 (6H, s) ppm. LRMS (electrospray): m / z [MH] -282 / 284 · Preparation 49: [3- (2-Cyclo-2-methyl-propyl) _benzene Based) Acetic acid 99200 -165- 200534846

At 0 ° C and nitrogen, vaporized methylmagnesium (51 ml, 3m solution in tetrahydrofuran, 153 mmol) was added dropwise to the ester (11.6 g, 51 mmol) (International Peptide and Journal of Protein Research, 1987, 29 (3), 331) in a stirred solution in tetrahydrofuran (300 ml). The reaction was allowed to warm to room temperature overnight and formed a thick white precipitate, then water (50 mL) and 2N hydrochloric acid (1 mL) were carefully added. The aqueous solution was extracted with ethyl acetate (2x300 mL), and the combined organic materials were washed with brine (50 mL), dried (Na2SO4), and the solvent was removed in vacuo to obtain the title compound as a golden oil (11 · 2 g). 1H NMR (400 MHz, CDC13): δ = 7.30-7.12 (4Η, m), 3.63 (2Η, s), 2.75 (2H, s), 1.22 (6H, s) ppm. LRMS (electrospray): m / z [M + H] +209. Need to be named? Preparation 50 ·· {3_ [2 _ ({(2R) _2 · Hydroxy_2 and hydroxy々 (via methyl) phenyl] ethyl} amino) -2_methylpropyl] phenyl 丨 acrylic acid

According to the procedure used to prepare 20, {3_ [2-({(2Κ) · 2-hydroxy-2- [4-hydroxy-3- (methylol) phenyl] ethyl} aminomethylpropyl ] Phenyl 丨 ethyl acetate (Preparation 68) to give the title compound as a milky yellow solid. 1H NMR (400MHz5 CD3 OD): δ = 7.43-7.42 (1H, d), 7.37-7.22 (4H, m ) 5 99200 -166- 200534846 7.15-7.13 (lH, m), 6.85-6.83 (lH, d), 4.90-4.86 (lH, m), 4.71 (2H, s), 3.56-3 · 55 (2H, m ), 3.25-3.13 (2H, m), 3.05-2.98 (2H, m), 1.40 (3H, s), 1.38 (3H, s) ppm. LRMS (electrospray): m / z [ M + H] +374, [MH] _372 · Preparation 51: {3- [2 _ ({(2R) -2_hydroxy-2- [4_hydroxy-3_ (hydroxymethyl) phenyl] ethyl} amine ) Ethyl] phenyl} acetic acid

According to the procedure used to prepare 20, {3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) ethyl ] Phenyl} ethyl acetate (Preparation 52) to give the title compound as a white solid. 1H NMR (400MHz, CD3 OD): δ 7.26 (1H, d), 7.20-7.16 (1H, t), 7.09-6.97 (5H, m), 6.74-6_72 (1H, d), 4.68_4 · 65 (1H, m), 4.44 (2H, s), 3.42 (2H, s), 2.95 -2.71 (6H, m) ppm. LRMS (electrospray): m / z [M-Η] · 344 · Preparation 52: {3 '[2 _ ({(2R) -2-hydroxy_2- 丨 4-hydroxy_3_ (transmethyl) phenyl] ethyl} amino) ethyl] phenyl} acetic acid Ethyl ester

HO, according to the procedure used to prepare 21, using {3_ [2-({(2R) -2- [4- (benzyloxy) 3- (methylethyl) phenyl] -2-ethylethyl} amine (Ethyl) ethyl] phenyl} ethyl acetate (Preparation 99200 • 167-200534846 53) to obtain the title compound as an orange oil. 1H NMR (400MHz, CD3 OD): (5 7.25-7.20 (2H, m), 7.11-7.05 (4H, m), 6.73-6.71 (1H, d), 4.68-4.63 (3H, m), 4.15-4.09 (2H, m), 3.59 (2H, s), 2.89-2.71 (6H, m), 1.24-1.21 (3H, t) ppm. LRMS (electrospray): m / z [M + H] + 374, [Μ · Η] · 372.

Preparation 53: {3_ [2-({(2R) -2- [4- (Ethyloxy) -3_ (hydroxymethyl) phenyl] -2_isoethyl} amino) ethyl] phenyl} Ethyl acetate OH

The (3- {2 _ [((2R) -2- [4- (narrowoxy) -3- (hydroxymethyl) phenyl] -2-{[third-butyl (dimethyl) stone Alkyl] oxy} ethyl) amino] ethyl} phenyl) ethyl acetate (Preparation 54) (2.39 g, 4.14 mmol) in methanol (15 mL) and water (10 mL) Treat with ammonium fluoride (1.53 g, 41.4 mmol) and heat the reaction to 40 ° C for 16 hours. The methanol was removed in vacuo and the aqueous residue was extracted with methane (3 x 50 mL). The combined organics were dehydrated and dried (sodium sulfate), the solvent was removed in vacuo, and the residue was purified by flash column chromatography on silica gel with methane: methanol: 880 ammonia (97: 3: 2) 0.3 was changed to 95: 5: 0.5 (volume ratio) and the title compound was obtained as an orange gum (1.90 g).

1H NMR (400MHz, CD3 OD): δ = 7.45-7.34 (5H, m) 5 7.31-7.27 (1H, m), 7.24-716 (2H, m), 7.11-7.09 (3H, m), 2.96-2.94 (lH, d), 5.12 (2H, s), 4.72-4.68 (3¾ m), 4.15-4.09 (2H, m), 3.59 (2H, s), 2.91-2.74 (6H, m), 1.24-1.20 99200 -168- 200534846 (3H, t) ppm. LRMS (electrospray): m / z [M + H] +464, [Μ-ΗΓ462. Preparation 54: (3- {2-[((2R) -2 -[4_ (Ethyloxy) -3_ (hydroxymethyl) phenyl] _2-{[Third-butyl (dimethyl) dreamyl] oxy} ethyl) amino] ethyl} phenyl )Ethyl acetate

According to the procedure used for the preparation of 22, [2-(; oxy) -5-((lR) -2-bromo-H [third-butyl (dimethyl) silyl] oxy} Ethyl) phenyl] fluorenol (Preparation 23) and ethyl [3- (2-aminoethyl) phenyl] acetate (Preparation 58) to give the title compound as a yellow oil. 1H NMR (400MHz, CD3 OD): δ = 7.44-7.43 (2H5 d), 7.37-7.33 (3H, m), 7.30-7.27 (1H, t), 7.24-7.20 (1H, t), 7.15-7.08 ( 4H, m), 6.94-6.92 (1H, d), 5.10 (2H, s), 4.77-4.74 (1H, m), 4.67-4.66 (2H, d), 4.14-4.09 (2H, m), 3.58 (2H, s), 2.90-2.75 (5H, m), 2.66-2.62 (1H, m), 1.24-1.21 (3H, t), 0.78 (9H, s), -0.05 (3H, s) , -0.22 (3H, s) ppm. LRMS (electrospray): m / z [M + H] +578, [MH] _576 · Preparation 55: [3- (2-hydroxyethyl) phenyl] acetic acid Ethyl ester

Add carbonyldiimidazole (5.11 g, 31.5 mmol) to the subject at room temperature under nitrogen (International Journal of Skin and Protein Research, 1987, 29 (3) 331) (7.00 G '31.5¾ mol) in a tetrahydroscream (100 liters) of the infused solution 99200 -169- 200534846. The reaction was stirred for 2 hours, water (26 mL) was added, and the reaction was cooled to 0 ° C. Sodium hydride (600 g, ουmoles) was then added in portions, and the reaction was allowed to warm to room temperature with continued stirring for 2 hours. Ethyl acetate (300 ml) was added, followed by 2N aqueous hydrochloric acid solution (20 ml). The organic layer was separated and the aqueous solution was extracted with ethyl acetate (2x75 ml), and the combined organic matter was dried (Na2SO4) 'and the solvent was removed in vacuo to obtain a white solid' which was borrowed on Shixi gum Purify by column chromatography and dissolve with ethyl acetate: pentane (50:50, volume ratio) to obtain the title compound as a colorless oil (4.60 g). 1H NMR (400 MHz, CDC13): 5 = 7.28-7.24 (1H, m) 5 7.15-7.11 (3H, m) 5 4.17-4.08 (2H, m), 3.84-3.81 (2H, t), 3.59 (2H , s) 5 2.86-2.82 (2H, t), 1.29-1.23 (3H, t) ppm. LRMS (electrospray): m / z [M + Na] +231, [Μ-ΗΓ207. Manufacturing ^ 56: (3- {2-[(Methanesulfonyl) oxy] ethyl} phenyl) ethyl acetate

At 0 ° C. under nitrogen, gasified pinanesulfonium (2.78 g, 24.3 mmol) was added dropwise to [3- (2-hydroxyethyl) phenyl] ethyl acetate (Preparation 55) (4.60 G, 22.1 mmoles) and triethylamine (3.40 ml, 24.3 mmoles) in dioxane (250 ml). The reaction was allowed to warm to room temperature over 1 h and was washed with a saturated aqueous sodium bicarbonate solution (75 ml). The aqueous solution was washed with dichloromethane (2x100 ml), and the combined organic material was washed with water (25 ml), dried (sodium sulfate), and the solvent was removed in vacuo to obtain the title compound 99200 -170- 200534846 , Is colorless oil (6.2 grams). 1HNMR (400 MHz, CDC13δ = 7.29-7.25 (1Η51), 7.17-7.12 (3Η, t), 4.41- 4.38 (2Η, t), 4.16-4 · 10 (2Η, m), 3_58 (2Η , S), 3.04-3.00 (2Η, t), 2.81 (3Η, s), 1.26-1.22 (3H51) ppm. LRMS (electrospray): m / z [M + H] +578, [Μ -Η] _576 ·

Preparation 57: [3- (2-azidoethyl) phenyl] ethyl acetate N

At room temperature, sodium azide (2.82 g, 43.3 mmol) was added in one portion to (3_ {2-[(methylsulfonyl) oxy] ethyl} phenyl) acetate (preparation 56) (6.20 g, 21.7 mmol) in N, N-dimethylformamide (400 ml) with stirring > grains. The reaction was heated at 60 ° C for 1 hour, then allowed to cool to room temperature 'and the solvent was removed in vacuo. Ethyl acetate (200 ml) and water (75 ml) were added, and the organic matter was separated. The aqueous solution was washed with ethyl acetate (2 x 100 ml), and the combined organic matter was evaporated in vacuo to produce The oily substance was purified by flash column chromatography on silica gel, and then dissolved with ethyl acetate: pentanol (5:95, volume ratio) to obtain the title compound as a colorless oil (Tunfag). 1H NMR (400 MHz, CDC13): 5 = 7.27-7.23 (1H, t), 7.17-7.12 (3H, m), 4.15-4.06 (2H, m), 3.60 (2H, s), 3.51_3.47 ( 2H, t), 2.87-2.84 (2H, t), 1.24- 1.20 (3H, t) ppm. LRMS (electrospray): m / z [M + Na] +256, [Μ-Η; Γ232 · Preparation 58 · ethyl 丨 3- (2-aminoethyl) phenyl] acetic acid g

Η κι 99200 -171-200534846 Diphenylphosphine (3.88 g, 23.3 mmol) in one portion at room temperature under nitrogen.

The retentate was dissolved in a saturated aqueous sodium bicarbonate solution (40 ml), and water was extracted with methane (2 ml). The combined organics were dehydrated and dried (sodium sulfate). The solvent was removed in vacuo, and the residue was purified by flash column chromatography on silica gel, and dissolved in methane: methanol (95: 5, volume ratio). , And the title compound was obtained as a colorless oil (3 · ιm). 1H NMR (400 MHz, CDC13): 5 = 7.26-7.22 (1H, t), 7.13-7.08 (3H, t), 4.16- 4.11 (2H, m), 3.58 (2H, s), 2.96-2.93 (2H51 ), 2.74-2.71 (2H, t), 1.25-1.22 (3H, t) ppm. LRMS (electrospray): m / z [M + H] +208, [M + Na] +230, [Μ- Η] · 206 · Preparation 59: 3-[(2R) -2 _ ({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) propyl Benzoic acid

In methyl 3-[(2R) -2-({(2R) -2-hydroxy-2- [4 · hydroxy ((methyl) phenyl] ethyl} amino) propyl) benzoate (prepared 60) (5.12 g, 14.24 mmol) in a solution in tetrahydrofuran (35 ml), lithium hydroxide solution (1 M, 29 ml, 29 mmol) was added, and the solution was left at room temperature Stir for 18 hours. An aqueous solution of hydrochloric acid 99200 -172- 200534846 (1M, 29 ml, 29 mmol) was added, and tetrahydrofuran / water was removed in vacuo to obtain the title compound as an off-white solid (5.87 g), which was used without further purification. 1H NMR (400MHz, CD3 OD): 5 = 7.86-7.84 (1H, d), 7.82 (1H, s), 7.37- 7.30 (3H, m), 7.17-7.15 (1H, dd), 6.79-6.77 (1H , D), 4.89-4.85 (1H, m), 4.65 (2H, s), 3.60_3.50 (1H, m), 3.21-3.15 (3H, m), 2.84_2 · 78 (1H, dd), 1.25-1.23 (3H, d) ppm. LRMS (electrospray): m / z [M + H] +346, [M + Na] +368, [Μ · Η] · 344.

CHN analysis: measured values C5 50.29, H, 6.07, N, 3.07; Q 9 H2 3 N05 + 2.0LiCl + 1.3H20 requires C, 50.31, H, 5.69, N, 3.09. Preparation 60: 3 _ [(2R) _2_ ({(2R) _2-hydroxy_2_ [4_hydroxy_3- (hydroxymethyl) phenyl] ethyl} amino) propyl] methyl benzoate

HO

3-[(2R) -2 _ ({(2R) -2Uoxy) _3- (hydroxymethyl) phenyl] -2-Ethyl} amino) propyl] benzoic acid methyl ester (Preparation 61) (6.83 g, 152 mmol) and a suspension of 10% palladium / carbon (683 mg) in ethanol (100 ml), stirred at room temperature (60 psi) for 18 hours under hydrogen atmosphere hour. The catalyst was filtered through arbcei, and the filtrate was concentrated in the air. The residue was purified by flash column chromatography on silica gel, and the title compound was obtained by dissolving in one gas methyl alcohol · methanol: 880 ammonia (95: 5: 0.5 to 90: 10: 1, volume ratio) to obtain the title compound, which was light. Yellow gum (512 g). H NMR (400MHz, CD3 OD): § = 7.85-7.83 (1H5 m), 7.79 (1H, s), 7.36- 99200 -173- 200534846 7.35 (2H, m), 7.20 (1H, s), 7 · 02-6 · 99 (1H, dd), 6.68-6 · 65 (1H, d), 4.61-4.58 (1H, m), 4.60 (2H, s), 3_90 (3H, s), 2.97- 2.87 (2H, m), 2.80-2.62 (3H, m), 1.08-1.07 (3H, d) ppm. LRMS (electrospray): m / z [M + H] +360, [M + Na] + 382, [Μ-Η] · 358 Preparation 61: 3- 丨 (2R) -2-({(2R) -2- [4- (Ethyloxy) -3- (hydroxymethyl) phenyl] -2 -Hydroxyethyl}

Amino) propyl] methyl benzoate

Add H (2R) -2-[((2R) -2- [4_ (Ethyloxy) _3- (hydroxymethyl) phenyl] -2-{[Third-butyl (dimethyl) stone Alkyl] oxy} ethyl) amino] propyl} methyl benzoate (Preparation 62) (10 g, 17.74 mmol) with ammonium fluoride (6.57 g, 177 mmol) in formazan (180 Ml) and water (60 ml) and heated at 40 ° C for 18 hours. The methanol was removed in vacuo, and the remaining aqueous layer was extracted with methane (2 x 100 mL). The combined organic layers were dried (sodium sulfate), filtered, and evaporated in vacuo. The formed oil was purified on a silica gel by flash column chromatography, and dissolved in methane ~: methanol: 880 ammonia (95: 5: 0.5, volume ratio) to obtain the title compound (6.83 g) as Light yellow gum. 1H NMR (400MHz, CD3 OD): (5 = 7.83-7.82 (1H, d), 7.78 (1H, s), 7.47-7.45 (2H, m), 7.39-7.28 (6H, m), 7.11- 7.10 (1H, d), 6.89-6.87 (1H, d), 5.11 (2H, s), 4.65 (2H, s), 4.65-4.62 (1H, m), 3.88 (3H, s), 2.98-2.89 (2H, m), 2.79-2.64 (3H, m), 1.09-1.08 (3H, d) ppm. LRMS (electrospray): m / z [M + H] +450, [M + Na] +472, [MH] -448. 99200 -174- 200534846

Preparation 62: 3-{(2R) _2-[((2R) -2_ [4- (Ethyloxy) -3- (hydroxymethyl) phenyl] -2 · {[Third · butyl (dimethyl) Alkyl) alkyl] oxy} ethyl) amino] propyl} methyl benzoate OTBDMS

[2- (Ethyloxy) -5 _ ((lR) -2_amoyl small {[third butyl (dimethyl) oxetyl] oxy} ethyl) phenyl] methanol (Preparation 23 ) (9.23 g, 20.5 mmol) with {3-[(2R) -2-aminopropyl] phenyl} methyl acetate (Preparation 63) (8.48 g, 40.9 mmol) The solution in digas methane (70 ml) was heated to 90 ° C to evaporate the digas methane. The resulting melt was left at 90 ° C for another 18 hours. The reaction mixture was cooled to room temperature, purified by flash column chromatography on silica gel, and dissolved in digas methane ·· methanol: 880 ammonia (98: 2: 0.2 changed to 97.5: 2.5 ·· 0.25, volume ratio) The title compound (10 g) was obtained as an orange oil. 1H NMR (400MHz, CD3 OD): δ = 7.84-7.82 (1H, m), 7.79 (1H, s), 7.47-7.43 (2H, m), 7.39_7.30 (6H, m), 7.08-7.06 (1H, d), 6.89-6.86 (1H, d), 5.10 (2H, s), 4.74-4.71 (1H, t), 4.65-4.64 (2H, d), 3.88 (3H, s), 2.97-2.87 (2H, m), 2.69-2.68 (2H, d), 2.65_2 · 61 (1H, dd), 1.08_1.07 (3H, d), 0 · 80 (9H, s), -0.03 (3H , s) r0.21 (3H, s) ppm. LRMS (electrospray): m / z [M + H] +564, [M + Na] +586. Preparation 63: {3-[(2R) -2 -Aminopropyl] phenyl} methyl acetate.

[3-((2Ii) -2-{[(lR) -l-phenyl-ethyl] -aminopropylpropyl) -phenyl] • methyl acetate 99200 -175- 200534846 ester (Preparation 64) (13.65 g , 40.9 mmoles) and ammonium gallate (12.9 g, 204 mmoles) in ethanol (200 ml) under reflux at 20% palladium hydroxide / carbon (Pd (OH) 2 / C '1.36 g) in the presence of heat. After 3 hours, the reaction mixture was cooled to room temperature, filtered through arbocel, and the filtrate was concentrated in vacuo. The residue was partitioned between methane (200 ml) and 880 ammonia (100 ml), and the organic phase was separated. The aqueous phase was extracted with additional dichloromethane (3x100 mL), and the combined organic extracts were washed with brine (100 mL), dried (Na2SO4), and reduced in vacuo to give the title compound (8 48 g) as a pale yellow oil. 1H NMR (400 MHz, CDC13): 5 = 7.90-7.87 (2H, m), 7.38-7.34 (2H, m), 3.90 (3H, s) 5 3.26-3.17 (1H5 m) 5 2.78-2.73 (1H, dd), 2.64-2.59 (1H, dd), 1.14-1.12 (3H? d) ppm. LRMS (electrospray): m / z [M + H] + 194. Preparation 64: [3-((2R) -2-{[((lR) -l-phenylethylethylaminopropylpropyl) phenyl] methyl acetate salt phosphonium salt

Methyl 0 (2-ketopropyl) phenyl] acetate (Preparation 65) (45 · 3 g, 236 mmol), called methylmethylamine (27.6 ml, 214 mmol), triethyl A solution of sodium hydrogen hydride (68.1 g, 321 mmol) and acetic acid (147 ml, 257 mmol) in dichloromethane (1500 ml) at room temperature for -18 hours. The reaction mixture was quenched by adding a saturated aqueous sodium bicarbonate solution (600 ml) and stirred until foaming ceased. The organic phase was separated and the aqueous phase was extracted with 99200 -176- 200534846 the other two methane (2 x 100 ml). The combined organic extracts were washed with brine (100 ml), dried (Na2SO4), reduced through celite, and reduced in vacuo. This oil was dissolved in methanol (200 ml), treated with 1M gasification gas (300 liters) in methanol and reduced in vacuo to obtain a 4: 1 mixture of diastereomers (mainly R, R) as off-white hydrochloride. Two successive crystallizations (diisopropyl ether / methanol) were performed to obtain the title compound (27.3 g) as a colorless crystalline solid. 1H NMR (400MHz, CD3 OD): δ = 7.92-7.90 (1H5 d), 7.75 (1H, s) 5 7.55- 7.49 (5H, m), 7.45-7.42 (1H, dd), 7_35-7 · 33 ( 1H, d), 4.68_4 · 63 (1H, q), 3.90 (3H, s), 3.43-3 · 38 (1H, dd), 3.25-3.19 (1H, m), 2.71-2.65 (1H , Dd), 1.71-1.69 (3H, d), U7-1.16, (3H, d) ppm · Preparation 65: [3- (2-ketopropyl) phenyl] methyl acetate

Tributyltin methoxylate (80.3 ml, 279 mmol), methyl 3-benzylbenzoate (53.5 g, 249 mmol), isopropenyl acetate (39-4 ml, 358 mmol), vinegar Acid palladium (11) (2.6 g, 11.6 mmol) and tri-o-tolylphosphine (71 g, 23.2 mmol) at i00 ° C under nitrogen in toluene (350 ml) Stir for 18 hours. After cooling, the reaction was treated 'with a 4M potassium fluoride solution (560 ml) and stirred for 2 hours. The resulting mixture was diluted with additional toluene (200 ml), filtered through celite, and the filtrate was washed with ethyl acetate. The organic phase was separated, dried (sodium sulfate), and reduced in vacuo. The residue was purified by flash column chromatography on silica gel, and the title compound (45.3 g) was dissolved by dissolving with ethyl acetate 99200 • 177 · 200534846 ester: pentane (10:90, changed to 20:80, volume ratio). ), For orange oil. 1H NMR (400 MHz, CDC13): 5 = 7.95-7.93 (1H, d), 7.87 (1H, s), 7.43-7.37 (2H, m), 3.91 (3H, s), 3.75 (2H, s) ), 2.18 (3H, s) ppm. LRMS (electrospray): m / z [M + Na] +215, 191. Preparation 66: (3_ {2-[((2R) _2_ [4- ( Ethyloxy) -3- (hydroxymethyl) phenyl] -2-{[Third-butyl (dimethyl) dreamyl] oxy} ethyl) amino] -2-methylpropyl} Phenyl) ethyl acetate

OTBDMS

According to the procedure used to prepare 22, [2-(; oxy) -5-((lR) -2-bromo-l-1 _ {[third butyl (dimethyl) lithium alkyl] oxy} Ethyl) phenyl] methanol (Preparation 23) and [3- (2-amino-2-methyl-propyl) -phenyl] -ethyl acetate (Preparation 47) were prepared to give the title compound as Yellow oil.

1H NMR (400MHz, CD3 OD): 5 = 7.48-7.05 (11H, m), 7.04-6.96 (1H, d), 5.10 (2H, s), 4.80-4.74 (1H, m), 4.78-4.63 (2H , Q), 4.16-4.05 (2H, q), 3.60 (2H, s), 2.89-2.63 (2H, m), 2.70-2.62 (2H, m), 1.24-1 · 20 (3H, t) , 1.07-1.04 (6H, d), 0.81 (9H, s), 0.00 (3H, s), -0.18 (3H, s) ppm. LRMS (electrospray): m / z [M + H] +606, [Μ-Η] · 604. Preparation 67: {3- [2-({(2R) -2- [4- (Ethyloxy) (hydroxymethyl) phenyl] -2-hydroxyethyl} amino ) · 2-methylpropyl] phenyl} ethyl acetate 99200 -178- 200534846

OH

According to the procedure used to prepare 53, use (3- {2-[((2R) -2- [4- (benzyloxy) -3_ (methylol) phenyl] -2-{[third-but (Dimethyl) lithium alkyl] oxy} ethyl) amino] -2-methylpropyl} phenyl) ethyl acetate (Preparation 66) to give the title compound as an oil.

1H NMR (400MHz, CD3 OD): δ = 7.47-7.03 (11H, m), 6.98-6.95 (1H, d), 5.14 (2H, s), 4.68 (2H, s), 4.684.66 (1H , M), 4.15-4.10 (2H, q), 3.60 (2H, s), 2.90-2.64 (4H, m), 1.26-1.22 (3H, t), 1.08-1.05 (6H, d) ppm. LRMS ( Electrospray): m / z [M + H] +492, [Μ-ΗΓ490. Preparation 68: {3_ [2 _ ({(2R) _2-hydroxy-2 · [4 · hydroxy_3_ (via methyl) Phenyl] ethyl} amino) -2-methylpropyl] phenyl} ethyl acetate

OH

According to the procedure used to prepare 21, {3- [2-({(2R) -2- [4- (Ethyloxy) -3- (fluorenyl) benzyl] -2-¾ethyl} amine Methyl) -2-methylpropyl] phenyl] • acetic acid (Preparation 67) to give the title compound as a colorless oil. 1H NMR (400MHz, CD3 OD): δ = 7.30-7.02 (6H, m), 6.77-6.75 (1H, d), 4.62 (2H, s), 4.62-4.60 (lH, m), 4.17-4.09 (2H , Q), 3.65-3.50 (2H, m), 2.90-2 · 63 (4H, m), 1.14-UO (3H, t), 1.08-1.05 (6H, d) ppm. LRMS (electrospray): m / z [M + H] +402, [Μ-ΗΓ400. 99200 • 179 · 200534846 Preparation 69 2- (3-Fluoro-4-trifluoromethyl-phenyl) NK '

Amine Trimethylsilane (2 ml, 16 mmol) was added dropwise to lithium borohydride (2 M in tetrahydrofuran, 4 ml, 8 mmol). Then, at 0. (: Next, add a solution of 3-fluoro-based (trifluoromethyl) phenylacetonitrile (312 mg, 4 mmol) in tetrahydrofuran (2 ml), and stir the mixture for 24 hours while warming to room temperature. The mixture was then diluted with methanol (20 ml) and concentrated in vacuo. The residue was dissolved in a 2000/0 potassium hydroxide solution (20 ml) and extracted with methane (3 x 20 ml). The combined organic solution was dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography using an Isolute® SCX-2 cartridge with methanol, followed by 1M ammonia in methanol. An oily residue was obtained. The oil was triturated with ether to give the title compound, 59% yield, 485 mg. 1H NMR (400 MHz, CDC13) 5: 7.53 (1H, m), 7.08 (2H, m), 3.02 (2H, t) 2.82 (2H, t) ppm; LRMS APCI m / z 208 [M + H] + Preparation 70 2- (5-Gas-2-methoxy-phenyl) -ethylamine 0 / η3

Cl 99200-180- 200534846 The title compound was prepared from (5-chloro-2-methoxy-phenyl) acetonitrile (WO2004039377, page 40) using a similar procedure to Preparation 69, 52% yield. ^ NMRC ^ OMHz ^ CDC ^) δ: 7.11-7.00 (2H? M) 5 6.75-6.65 (1Η, m) 3.72 (3H, s), 2.90-2.80 (2H, m), 2.70-2.60 (2H, m ) ppm Preparation 71 to 79 The following compounds having the general formula shown below were prepared by a method similar to that described for Preparation 69 using the appropriate phenylacetonitrile starting material. Unless otherwise mentioned, R3 to R7 are hydrogen. „3

nh2 number data yield 71 R3 = H; r4 = f; r5 = ch3 1H NMR (400MHz, CDCI3) δ: 7.12 (1H, m), 6.90 (2H, m), 2.95 (2H, t) 2.70 (2H, t) 2.25 (3H, s) ppm; LRMS APCI m / z 154 [M + H] + 95% 72 r3 = F; r4 = f; r5 = ch3 1H NMR (400MHz, CDCI3) δ: 6.83 (2H, m ), 2.94 (2H, t) 2.78 (2H, t) 2.25 (3H, s) ppm; LRMS APCI m / z 172 [M + H] + 61% 73 r3 = ck3; r5 = ch3; r7 = ch3ch3 1H NMR (400MHz, CDCI3) δ: 6.84 (2H, m), 2.88-2.69 (4H, m) 2.30 (6H, s) 2.24 (3H, s) ppm; LRMS APCI m / z 163 [M + H] + 80% 74 r3 = F; r4 = ch3; r7 = f 1H NMR (400MHz, CDCI3) δ: 6.97 (1H, m), 6.75 (1H, m), 2.92 (2H, t) 2.82 (2H, t) 2.24 (3H , s) ppm; LRMS APCI m / z 172 [M + H] + 66% 75 r3 = F; r4 = ch3; r7 = ci 1H NMR (400MHz, CDCI3) δ: 7.05 (1H, m), 6.97 (1H , m), 2.96 (4H, m) 2.23 (3H, s) ppm; LRMS APCI m / z 228 [M + CH3CN] + 58% 99200 -181-200534846 76 r3 = CI; r4 = ch3; r7 = f 1H NMR (400MHz, CDCI3) δ: 7.14-6.99 (1H, m), 6.97-6.73 (1H, m), 3.07-2.83 (4H, m) 2.35 (3H, s) ppm; LRMS APCI m / z 228 [M + CH3CN] + 63% 77 r3 = H; r4 = f; r7 = ch3 1H NMR (400MHz, CD CI3) δ: 7.07 (1H, m), 6.83 (2H, m), 2.97 (2H, t), 2.78 (2H, m) 2.27 (3H, s) ppm; LRMS APCI m / z 154 [M + H] + 62% 78 r4 = F; r5 = h; r6 = cf3 1H NMR (400MHz, CDCI3) δ: 7.44-7.26 (1H, m), 7.09-6.86 (2H, m), 2.98-2.84 (2H, t) 2.72-2.84 (2H, t) ppm; LRMS APCI m / z 208 [M + H] + 53% 79 r3 = ch3; r4 = ch3; r7 = ch3 1H NMR (400MHz, CDCI3) δ: 6.98 (2H, m ), 2.95 (2H, m), 2.77 (2H, m), 2.25 (3H, s), 2.19 (6H, s) ppm; LRMS APCI m / z 164 [M + H] + 62% Preparation 79: Make compound Purification using sulfonic acid functionalized lanterns. Preparation 80 2- (4-Gasphenyl) -N-ethyl-acetamidamine

Add 4-nitrophenylacetic acid (1 g, 5.88 mmol), ethylamine (2M in tetrahydrofuran, 5.88 ml, 11.76 mmol), 1-hydroxybenzotriazole hydrate (90 mg, 5.88 mmol) Mol), 1- (3-Diamidopropyl) -3-ethylcarbodiimide hydrochloride (1.13 g, 5.88 mmol) and triethylamine (1.78 g, 17.64 mmol) Ear) A mixture in dichloromethane (30 ml) was stirred at room temperature for 18 hours. Then, the mixture was diluted with a 1 M sodium hydroxide solution (30 ml), and the aqueous layer was extracted with dichloromethane (30 ml). The combined organic solutions were washed with 1M hydrochloric acid and brine, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by column chromatography on silica gel and dissolved with dioxane: methanol 100: 90 to 90:10 to obtain the title compound as a colorless solid, 37% yield, 443 99200 -182- 200534846 Mg. 1H NMR (400 MHz, CDC13) 5 ·· 7.31-7.28 (2H, m), 7.27-7.24 (2H, m), 3.45 (2H, s), 3.18 (2H, m), 1.08 (3H, t) ppm; LRMS APCI m / z 198 [M + H] + Preparation 81 [2- (4-Gaphenyl) _ethyl] -ethyl-amine hydrochloride Η

Combine 2- (4-Gaphenyl) · N-ethyl-acetamidamine (Preparation 80) (437 mg, 2.22 mmol) with borane tetrahydrofuran complex (1M, 8.88 ml, 8.88 mmol) ) The mixture in tetrahydrofuran was heated at reflux for 18 hours. Then, the cooled reaction mixture was diluted with methanol (5 ml) and 12M hydrochloric acid (2 ml) and heated to reflux for another hour. The mixture was cooled to room temperature and concentrated in vacuo. The residue was triturated with ethyl acetate to provide the title compound as a colorless solid, 99% yield, 403 mg. 1H NMR (400 MHz, CDC13) 5: 7.35 (2Η, m), 7.27 (2Η, m), 3.22 (2Η, m), 3.05 (2H, q), 2.97 (2H, m) , 1.29 (3H, t) ppm; LRMS APCI m / z 184 [M + H] + Preparation 82 2- (4_methylphenyl-phenyl) -ethylamine

A solution of 4- (fluorenylthio) phenylacetonitrile (828 mg, 5.08 mmol) in tetrahydrofuran 99200 -183- 200534846 (10 ml) was added dropwise to lithium aluminum hydride (1M, 5.6 strokes in tetrahydrofuran). Liters, 5.6 millimoles), and the mixture was stirred under ^ small ^ additional aluminum hydride (1M, in tetrahydrofuran, 5.6 ml, 5.6 millimoles), and the mixture was stirred. Stir at room temperature for 18 hours, and then pull back ..., 1 j day guard. The reaction mixture was allowed to cool down, iM sodium hydroxide solution (3 ml) was added dropwise, and stirring was continued for another hour. The mixture was then filtered through Cdite®, washed with ethyl acetate, and the filtrate was washed with sodium hydroxide solution. Then, the organic solution was loaded onto an Isohite (g) scx cartridge, washed with methanol, and dissolved in 1M ammonia in methanol. The relevant fractions were concentrated in vacuo, and the residue was purified by column chromatography on silica gel with methane: methanol: 〇88 ammonia 100 ·· 〇: 〇 to 95: 5: 〇5, The title compound was obtained as a yellow oil, 18. Yield: 154 mg. 1H NMR (400 MHz, CDC13) 5: 7.20 (2H, m), 7.14 (2H, m), 2.84 (2H, m) 5 2.71 (2H, m), 2.43 (3H, s) ppm; LRMS APCI m / z 168 [M + H] + Preparation 83 (4-hydroxy-3-methylphenyl) _acetonitrile

Add the tribromide side (1M in digas, 6.2 ml, 6.2 mmol) to 4-methoxy-3-methylphenylacetonitrile (0.2 g, 1.24 mmol) in digas The solution in oxane (10 ml) was cooled to -78 ° C. The reaction mixture was stirred at this temperature for 1 hour and then at room temperature for 2 hours. Next, the mixture was cooled again to -78 ° C, diluted with a sodium bicarbonate solution, and allowed to warm to room temperature. The organic layer was separated, washed with brine, dried over sodium sulfate, and concentrated in vacuo at 99200-184-200534846 to give the title compound as a white solid, 87% yield, 0.6 g. 1H NMR (400 MHz, CDC13) 5: 7.07 (1H, s), 7.00 (1H, d) 5 6.76 (1H, d), 3.65 (2H, s), 2.25 (3H, s) ppm; LRMS APCI m / z 146 [MH]-Preparation 84 (4-hydroxy-2,5-dimethyl · phenyl) _acetonitrile

The title compound was prepared from (4-methoxy-2,5-monomethylphenyl) acetonitrile using a similar method to Preparation 83 as a colorless solid in 60% yield. 1H NMR (400 MHz, CDC13) δ: 6.98 (1Η, s), 6.60 (1H, s), 3.66 (2H, s), 2.25 (3H, s) 3 2.13 (3H, s) ppm; LRMS APCI m / z 160 [MH] * Preparation of 85 (4-hydroxy_2,3-dimethyl-phenyl) -acetonitrile

The title compound was prepared from (4-methoxy-2,3-difluorenyl-phenyl) -acetonitrile using a similar method to Preparation 83 as a colorless solid in 94% yield. 1H NMR (400 MHz, CDC13) δ: 7.03 (1H, d) 5 6.64 (1H? D), 3.62 (2H, s)? 2.24 (3H, s) 5 2.20 (3H, s) ppm; LRMS APCI m / z 160 [MH] 'Preparation 86 2- (4-methoxy-2,5-dimethyl-phenyl) -ethylamine 99200 -185- 200534846 CH'

^ CH

A mixture of (4-methoxy-2,5-dimethyl-phenylacetonitrile (200 mg, 114 mmol) and Raney® nickel (50 g) in 2M methanolic ammonia (10 ml) Stir at 60 psi hydrogen and room temperature for 18 hours. TLC analysis shows that not all starting materials have been consumed. Therefore, an additional 2M methanolic ammonia (10 ml) of Raney® nickel (50 mg) was added. The reaction was reacted The mixture was stirred at 60 psi hydrogen and room temperature for another 18 hours, and then filtered through A ^ ocd®. The filtrate was concentrated in vacuo and the residue was purified by column chromatography on silica gel with methane: methanol : 0.88 ammonia 100: 〇: 〇 to 90: 10: 1 dissolve to provide the title product as a light brown solid, 38% yield, 98 mg. 1H NMR (400 MHz, CDC13) δ: 6.87 (1Η, s), 6.68 (1H5 s), 3.77 (3H, s), 2.80 (2H, m), 2.69 (2H, m), 2.28 (3H, s), 2.10 (3H, s) ppm; LRMS APCI m / z 180 [M + H] + Preparation 87 2_ (4-Methoxy-2,3-dimethyl · phenyl) _ethylamine

The title compound of ch3 was prepared from (4-methoxy-2,3-difluorenyl-phenyl) -acetonitrile using a method similar to that of Preparation 86 as a transparent oil with a yield of 93%. 1H NMR (400 MHz, CDC13) δ: 6.96 (1H, d) 3 6.66 (1H, d) 5 3.80 (3H, s), 2.96-2.84 (2H, m), 2.81-2.73 (2H, m), 2 22 (3H, s), 2.17 (3H, s), 1.63 (2H, s) 99200 -186- 200534846 ppm; LRMS APCIm / z 180 [M + Hf Preparation 88 4- (2-amino · ethyl Group) -2-methyl " · fen

The title compound of ch3 was prepared from (4-hydroxy-3-fluorenylphenyl) acetonitrile (Preparation 83) using a similar method to Preparation 86, as a clear oil, 85% yield.

1H NMR (400 MHz5 CDC13) δ: 6.90 (1Η? S), 6.82 (1Η, d), 6.65 (1H, d), 2.83-2.79 (2H, m), 2.61 (2H, m), 2.15 (3H, s) ppm; LRMS APCI m / z 152 [M + H] + Preparation 89 4_ (2-amino-ethyl) -2,5-dimethyl-phenol

The title compound was prepared from (4-hydroxy-2,5-dimethyl-phenyl) -acetonitrile (Preparation 84) using a similar procedure to Preparation 86 as a solid in 73% yield. 1H NMR (400 MHz, CDC13) 5: 6.81 (1H, s), 6.54 (1H, s), 2.79-2.64 (4H, m), 2.19 (3H, s), 2.11 (3H, s) ppm; LRMS APCI m / z 166 [M + H] + Preparation 90 4- (2-amino-ethyl) _2,3-dimethyl-pan

99200 -187- 200534846 The title compound was prepared from (4_hydroxy_2,3_dimethyl-phenyl) _acetonitrile (Preparation 85) using a similar method to Preparation 86 and was a colorless solid in 95% yield. 1H NMR (400 MHz, CDC13) δ: 6.78 (1Η, d) 5 6.55 (1H, d), 2.75-2.68 (4H5 m), 2.19 (3H, s), 2.12 (3H, s) ppm; LRMS APCI m / z 166 [M + H] + Preparation 91

2- (2,3-dimethylphenyl) -ethylamine

Mix 2,3-dimethylphenylacetonitrile (j · c / zem, 51 (26), 5157-60; 1986) (190 mg, 1.31 mmol) with Raney® nickel (100 mg) at 2M The mixture in methanolic ammonia (5 ml) was stirred under 50 psi hydrogen for 4 days. The mixture was then filtered through Arbocel® and concentrated in vacuo to give the title compound as a solid, 66% yield, 130 mg. 1H NMR (400 MHz, CDC13) 5: 7.02-6.94 (3H, m), 2.26-2.13 (10H, m) ppm; LRMSESIm / zl50 [M + H] +

Preparation 92 2- (2,3_Digas-phenyl) -ethylamine

A solution of 2,3-difluorophenylacetonitrile (0.5 g, 2.7 mmol) in ether (5 ml) was added to lithium aluminum hydride (1M in ether, 2.7 ml, 2.7 mmol) ) In an ice-cold solution with aluminum trioxide (359 mg, 2.7 mmol). The mixture was stirred at room temperature for 2.5 hours, and then the reaction was quenched with a 1 M sodium hydroxide solution (5 mmol 99200 -188- 200534846 liters). The mixture was stirred for another 30 minutes and filtered through cdite (g). The filtrate layers were separated and the organic solution was concentrated in vacuo. The residue was purified by column chromatography on silica gel and eluted with methane: methanol: 088 ammonia 100: 0 · 0 to 95: 5: 0.5 to provide the title compound as a clear oil, 26% yield , 135 mg. 1H NMR (400 MHz, CDCim 7.38 (1H, ⑽, 7.27-7 19 (2H, of, 2 see (2H, m), 2.87 (2H, m) ppm; LRMS APCI m / z 190 [M + H] + Preparation 93 2- (5-Gas-2-fluorophenyl) -ethylamine

H2N, / Cl Sodium borohydride (1.73 g, 45.51 mmol) was added in portions to 5-amino-2-fluorophenylacetonitrile (1.04 g, 6.15 mmol) and cobalt vaporized ( 11) A solution of hexahydrate (218 g, 9.22 mmol) in methanol (30 ml), and the mixture was stirred at room temperature for 3 hours. The suspension was then filtered through cdite®, concentrated in vacuo, and the residue was separated between 1M hydrochloric acid (40 ml) and digasmethane (40 ml). The aqueous phase was separated, basified to pH 11 with a 1 M ammonia solution, and extracted with methane (2 x 40 mL). The combined organic solutions were washed with brine (30 liters)> strips', dried over sulfuric acid, and concentrated in vacuo. The residue was purified by column chromatography on silica gel, and then dissolved in dichloromethane: methanol: 0.88 ammonia 100: 0 to 98: 2: 0.2 to give the title compound as a yellow oil '33% yield, 350 mg. 1H NMR (400 MHz, CDC13) 5: 7.28 (1H5 m), 7.22 (1H, m)? 7.05 (1H3 m) 5 2.85 (2H, m) 5 2.77 (2H, m) ppm; LRMS APCI m / z 174 [M + H] + 99200 -189- 200534846 Preparation 94 2_ (2_Amino-4-aerophenyl) -ethylamine

The title compound was prepared from 2-amino-4-fluorophenylacetonitrile in a similar manner to Preparation 93 as a light brown oil, 46% yield. 1H NMR (400 MHz, CDC13) δ: 7.30 (1Η, dd), 7.17 (1H, dd), 6.99 (1H, m) 5 2.86 (4H5 m) ppm; LRMS APCI m / z 174 [M + H] + Preparation 95 2 · (4-Amino-2_fluorophenyl) -ethylamine

The title compound was prepared from 4-aminotofluorophenyl acetonitrile using a procedure analogous to Preparation 93. The crude compound was purified using an Isco SCX® cartridge, and then eluted with 1M methanolic ammonia. The appropriate eluate was concentrated in vacuo, and the residue was further purified by column chromatography on Shixijiao, and the title compound was obtained by dissolving it in Diqiyangyuan: methanol: 0.88 ammonia 95: 5: 0.3. Yellow oil, 29% yield. 1H NMR (400 MHz, CDC13) δ: 7.30 (1H, dd), 7.17 (1H, dd), 6.99 (1H, dt) 5 2.86 (4H, m) ppm; LRMS APCI m / z 174 [M + H] + Preparation of 96 (2,3-dihydro-benzofuran-2-yl) -methanol

99200 -190- 200534846 A solution of m-chloroperbenzoic acid (96.4 g, 335 mmol) in methane (500 ml) was added to 2-allylphenol (30 g, 224 mmol) In an ice-cold solution in digas-methane (1 liter), the mixture was stirred for 30 minutes and at room temperature for 18 hours. Then, the reaction mixture was cooled to 0 ° C again, the reaction was quenched with 2M sodium hydroxide solution (700 ml), and stirred for 30 minutes. Then, the organic layer was separated, dried over magnesium sulfate, and concentrated in vacuo to obtain a yellow oil. The oil was purified by HpLC using a Chiralpak AD 250 * 4.6 mm column and hexane: isopropanol (90:10) as the eluent to give the title compound. 'HNMRC ^ OMHz ^ CDCla) (5: 7.20-7.10 (2H, m) 5 6.85 (1H, m), 6.78 (1H, m), 4.90 (1H, m), 3.86 (1H, m) , 3.70 (1H, m), 3.30-3.20 (1H, m) 3.10 (1H, m) ppm Preparation 97

4-Benzenesulfonic acid methyl 2,3-diargon [μbenzofuran: methyl methyl esters Add p-toluenesulfonium (26.7 g, 14.0 mmol) to pyrene, 3_dihydro _ Benzofuranodyl) -methanol (Preparation 96) (21 g, 140 mmol) in a solution of pyridine (400 strokes), and the mixture was stirred at room temperature for 4 days. The reaction was then concentrated in vacuo and the residue was azeotroped with toluene, diluted with ethyl acetate (500 ml), and washed with 2M hydrochloric acid (2 x 300 ml). The organic solution was dried over magnesium sulfate and concentrated in vacuo to obtain a brown oil. Next 'trituration # in cyclohexyl to provide the title compound as white 99200 200534846 solid' 79% yield, 33.5 g. LRMS APCI m / z 305 [M + H] + Preparation 98 2_ethyl_2,3 · diargon-benzo-smell

At -70 ° C, methyl lithium (1.6M in diethyl ether, 313 ml, 500 mmol) was added to copper elfide (1) (47.6 g, 250 mmol) in diethyl ether (750 ml) Inside the solution. Then, the solution was warmed to -10 ° C and stirred for 30 minutes. Next, the mixture was added to 4-benzenesulfonic acid methyl 2,3-dihydro-1-benzofuran-2-yl methyl ester (Preparation 97) (15.2 g, 50 mmol) in diethyl ether (500). Ml), and the reaction mixture was stirred at -40 ° C for 1 hour and at room temperature for 2 hours. Then, the mixture was cooled to -70 ° C, and the reaction was quenched with a 10% gasified ammonium solution (750 ml) and 2M hydrochloric acid (50 ml), and diluted with 0.88 ammonia (100 ml). Stir for 18 hours. The reaction mixture was extracted with ethyl acetate (3 × 500 ml), and the organic solution was dried over magnesium sulfate and concentrated in vacuo to give the title compound as a brown oil, 98% yield, 7.25 g. Preparation 99

(+) And (_) 5-bromo-2-ethyl-2,3-diargon-benzofuran added N-bromosuccinimide (8.66 g, 48.6 mmol) to 2-ethyl Of a solution of phenyl-2,3-dihydro-benzofuran (Preparation 98) in dioxane (70 ml) and the mixture was stirred at room temperature for 18 hours. Then, the mixture was diluted with 99200-192-200534846 digas methane (200 ml), and washed with water (200 ml) and meta-acidic sodium sulfite (200 ml). The organic solution was dehydrated and dried over magnesium sulfate, and concentrated in vacuo to obtain a yellow oil, which was purified by HPLC using a 0 ± ^ 1 ^ 10; 250 * 20 mm column and hexane: isopropanol (95: 5) As a dissociating agent, a brother isomer of the standard compound is obtained. Further dissociation provided the second isomer of the title compound, 2.95 g. 1H NMR (400 MHz, CDC13) δ: 7.24 (1Η, m), 7.18 (1H, m) 5 6.62 (1H, d) 5 4.75 (1H, m), 3.30-3.20 (1H3 m) 5 2.92-2.80 ( 1H, m), 1.77-1.88 (1H, m), 1.75-1.65 (lH, m) 1.00 (3H, m) ppm Preparation of 100 [3_ (2-ethyl-2,3-monohydro-1-benzo唉 -5_yl) propyl] iminodicarbonate di_tertiary-butyl ester

N, N-Diallylamine (2.99 g, 1 L6 mmol) was azeotroped with toluene (2 x 50 ml) and then dissolved in tetrahydrofuran (12 ml). The solution was cooled to 0 ° C, 9-borabicyclo [3.3.1] nonane dimer (0.5M, '46 .5 ml in tetrahydrofuran, 23.2 mmol) was added, and the mixture was stirred at 0 ° C 3 hours. Add 5-bromoaspartyl-2,3-dihydro-benzofuran (Preparation 98, Para-isomer 2) (2.9 g, 12.8 mmol), Tripotassium phosphate (7.7 mL, 23.2 mmol) (Ear) and [1, Γ-bis (diphenylphosphino) dicyclopentadiene iron] vaporized palladium (11) (4.74 mg, 0.58 mmol ·) The mixture in amidine (12 ml) and the 99200-193-200534846 reaction mixture was stirred at room temperature for 18 hours. The reaction was quenched with 2M sodium hydroxide solution (ml) and water (10 ml) and allowed to stir at room temperature for 1 hour. Then, the mixture was extracted with diethyl ether, dried over magnesium sulfate, and shrunk in the air. The residue was suspended in ethyl acetate · petroleum scale 25:75, filtered, and the mash was concentrated in vacuo. The residue was purified by column chromatography on Shi Ximu, and the residue was dissolved in ethyl acetate: petroleum ether 7:93 to obtain the title compound as a transparent oil, 46% yield, 2.15 g. LRMS ESI m / z 428 [M + Na] +

Preparation 101 3- (2-Ethyl-2,3-diargon-benzobite-5_yl) -propionate

[3- (2-Ethyl-2,3-dihydro-1_benzocrean-5-1) propyl] fluorenimodicarbonate di-third-butyl ester (Preparation 100) (2.19 G, 5.4 millimoles) in hydrochloric acid (4M in dioxolane, 20 ml), and stirred at room temperature for 1 hour. The reaction mixture was then concentrated in vacuo to give the title compound in quantitative yield. 1H NMR (400 MHz, CDC13) δ: 7.00-6.85 (2Η, m), 6.60 (1Η, d), 4.75 (1H, m), 3.20 (1H, m), 2.97 (2H, m), 2.80 (1H, m), 2.60 (2H, m), 2.10-1.95 (2H, m), 1.90-1.60 (2H, m), 1.00 (3H, m) ppm Preparation of 102 (2_ {4-[(butylamine ) Carbonyl] phenyl} ethyl) aminocarboxylic acid tert-butyl ester Η

〇99200 -194- 200534846 4_ {2 _ [(Third-butoxycarbonyl) amino] ethyl} benzoic acid (η2g, 83.6 mmoles XEP0836839, page 60), carbonyldiimidazole (21.36g, 131.7 mmol) and a mixture of N, N-diisopropylethylamine (20 ml, 115.1 mmol) in methane (600 ml) and stirred at room temperature for 2 hours. Then, n-butylamine (10 ml, 101.18 mmol) was added, and the mixture was stirred at room temperature for another 18 hours. The reaction mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate and 10% citric acid (2x50 ml), saturated sodium bicarbonate solution (200 ml), water (200 ml) and brine ( 200 ml). The organic solution was dried over sodium sulfate and concentrated in vacuo to obtain a milky yellow powder. The powder was purified by column chromatography on silica gel, and dissolved in dioxane: methanol 99: 1 to obtain the title compound, 65% yield, 17.5 g.

LRMS Clixi / z 338.3 [M + NH4] +, melting point = 118 ° C Preparation 103 4- (2-aminoethyl) butyl benzamidine hydrochloride

The title compound was prepared from (2- {4-[(butylamino) carbonyl] phenyl} ethyl) aminocarboxylic acid tert-butyl ester (Preparation 102) using a similar method to Preparation 101, as a white powder, 84% yield. 1H NMR (400MHz, DMSO-d6) δ: 8.38 (1H, m), 8.04 (3H, m), 7.78 (2H, d), 7.34 (2H, d), 3.24 (2H, m), 3.06 (2H, m), 2.82 (2H, m), 1.46 (2H, m), 1.28 (2H, m), 0.886 (3H, t) ppm LRMS Cl m / z 221.2 [M + H] + 99200 -195- 200534846 Preparation 104 [4- (3_tetraazapyrrolobiyl-1-yl-propoxy) -phenylbutadiene

1- (3-aminopropyl) tetrahydropyrrole Zm. CAem · & c ·, 77, 2270; 1955) (133 g, 0.9 mol), 4-hydroxybenzonitrile (100 g, 0.75 mol) and carbonate shavings (256 g, 0.78 mol) in acetonitrile (1 liter), stirred at 45 ° C for 18 hours. The reaction mixture was then concentrated in vacuo and the residue was partitioned between ethyl acetate (800 mL) and water (800 mL). The aqueous layer was separated and extracted with ethyl acetate (800 ml), and the combined organic solution was washed with water (500 ml) and extracted with 2M hydrochloric acid (2 x 600 ml). The acidic solution was basified with 40% potassium hydroxide solution to pH 8-9, and extracted with ethyl acetate (800 mL). Next, the aqueous solution was further alkalized to a pH of 10-11 using a 40% potassium hydroxide solution, and extracted with ethyl acetate (800 ml). The combined organic solutions were dried over sodium sulfate, filtered through a pad of silica gel, and concentrated in vacuo to give the title compound as a red oil, 79% yield, 150 g. 1H NMR (400 MHz, CDC13) δ: 7.24 (2Η, d), 6.85 (2Η, d) 5 4.09-3.89 (2H, m), 3.75 (2H, s), 2.71-2.36 (6H, m) , 2 · 14-1 · 93 (2H, m), 1.89-1.65 (4H, m) ppm; LRMS APCI m / z 245 [M + H] + Preparation 105 2- [4 · (3-tetraazepine ratio Ming · _1_yl-propoxy) -phenyl] -ethylamine

99200 -196- 200534846 [4- (3-tetrahydrop-bilo-1-yl-propoxy) -phenyl] -acetonitrile (Preparation ι〇4) (ιg, 4.1 mmol) and A mixture of Raney®. (100 mg) in 2M methanolic ammonia (35 ml) was stirred at 60 psi hydrogen and 50 ° C for 6 hours. TLC analysis showed that not all starting materials had been consumed '. Therefore, another RaneyD nickel (200 gram) was added to the reaction mixture' and heating was continued for 5 hours. tlc analysis again showed that the starting material was still present, so additional Raney® nickel (200 mg) was added and the mixture was stirred at 50 ° C for 3 hours. The reaction mixture was then filtered through Arbocel® and concentrated in vacuo to obtain a yellow oil. The oil was purified by column chromatography, and 4 g of RediSep® Shixi gel cartridge was used to dissociate with methane: methanol: 0.88 ammonia 85: 15: 1.5 to 80 ·· 20: 2 to obtain the title compound, 16% Yield, 160 mg. 1H NMR (400 MHz, CDC13) 5: 7.10 (2H, d), 6.81 (2H, d), 4.10-4.00 (2H, m), 3.05_2 · 65 (10H, m), 2.25-2.14 ( 2H, m), 2.05_1.95 (4H, m) ppm; LRMS APCI m / z 249 [M + H] + Preparation 106 [2_ (3-tetrahydropyrrolidine-1 · yl-propoxy) -Phenyl] ethoxy

The title compound was prepared from 2-hydroxy-phenylacetonitrile (/ · Og ·; 66, 3435; 2001) and 1- (3-aminopropyl) tetrahydropyrrole using a similar method to Preparation 104, as a light brown gum, 58% yield. 1H NMR (400MHz, CD3 OD) 5: 7.33-7.25 (2H, m), 7.02-6.90 (2H, m), 4.12-4.09 (2H, m), 3.75 (2H, s), 2.76-2.72 ( 2H, m), 2.62-2.57 (4H, m), 2.09- 99200 -197- 200534846 2.02 (2H? M)? 1.87-1.78 (4H, m); LRMS APCI m / z 245 [M + H] + Preparation 107 2- [2- (3_tetrahydropyrrole-1-yl · propoxy) -phenyl] -ethylamine

The title compound was prepared from Preparation 106 in a similar manner to Preparation 69 in 48% yield. 1HNMR (400MHz, CD3OD) 5: 7.19-7.16 (2H, m), 6.92 (1H? M) 5 6.86 (1H, m), 4.06-4.02 (2H, m), 2.87-2.83 (2H, m), 2.80 -2.75 (2H, m), 2.71-2.67 (2H, m), 2.62-2.55 (4H, m), 2.07-2.00 (2H, m), 1.86-1.81 (4H, m); LRMS APCI m / z 249 [M + H] + Preparation of 108 {2- [3- (3-tetrahydropyrrole small propoxy) phenyl] ethyl} amine

The title compound was prepared from [3- (3-tetrahydropyrrolidinylpropoxy) phenyl] acetonitrile (170 mg, 0.70 mmol) using a similar procedure to that of Preparation 69. Then, the crude compound was further purified by column chromatography, and 4 g of RediSep® silica gel cartridge was used to dissociate with dioxane: methanol: 0.88 ammonia 100: 0: 0 to 80: 20: 2 to obtain the desired product. , 30% yield. 1H NMR (400MHz, CD3 OD) d: 7.23-7.19 (lH, m), 6.81-6.78 (3H, m), 99200 -198- 200534846 4.04-3.98 (2H, m), 2.99-2.95 (2H, m) , 2.81-2.77 (2H, m), 2.74-2 · 70 (2H, m), 2.66-2.62 (4H, m), 2.05-1.98 (2H, m), 1.87-1.82 (4H, m); LRMS APCI m / z 249 [M + H] + Preparation 109 3- {2 _ [(2R) · (Third · butyl-dimethyl-dream alkyloxy) -2- (4-hydroxy-3_ (Hydroxymethyl-phenyl) -ethylamino] -2-methyl-propyl} _N · (3-tetraazapyrrolo-1-yl-propyl) -benzyl

Add 1- (3-aminopropyl) tetrahydropi ratio (38 μl, 0.30 mmol) to 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide salt Acid salt (79 mg, 0.41 mmol), 3- {2-[(2R > 2- (third-butyldimethylsilyloxy) _2_ (4_hydroxy-3-viamethyl-benzyl ) Ethylamino] _2 · methylpropyl} benzoic acid (Preparation ^ 7) (130 mg '0.28 pen moles), 1-Acetylidetrisigma hydrate (40 mg, 0.29 mmol) Mol) and N, N-diisopropylethylamine (210 microliters, ι 49 mmol) in a mixture of N, N-dimethylformamide (4 ml). The resulting The solution was stirred at room temperature for 9 days. After this period of time, TLC analysis showed that the starting material remained. Then, another 1- (3-dimethylaminopropylethylcarbodiimide salt was added. Culture salt (79 mg, 0.41 mmol), μ-benzotrisialohydrate (40 mg, 0.29 mmol) and n, N-diisopropylethylamine (21 μl 1.49) Millimoles) and continued stirring at room temperature for 2 days. The solvent was removed in vacuo and the residue was taken up in ethyl acetate (25 ml) and saturated. Sodium bicarbonate solution (20 ml) was separated between 99200-199-200534846. The organic solution was separated, dried (sodium sulfate), and concentrated in vacuo to obtain an orange oil. The oil was borrowed on silicone Purification by flash column chromatography, dissociation with methane: methanol: 0.88 ammonia 100: 0: 75 to 75: 25: 2, provided the title compound as glass, 43% yield, 70 mg. 1H NMR (400MHz, CD3 OD) 5: 7.48 (2H, m) 5 7.40-7.31 (2H, m), 7.27 (1H, m), 7.07 (1H, dd), 6.74 (1H, d), 4.69 (1H, m), 4.64 (2H, m), 3.43 (2H, m), 2.90-2.50 (10H, m), 1.90-1.70 (6H, m), 1.11 (3H, s), 1.07 (3H, s), 0.79 (9H, s), -0.02 (3H, s), -0.21 (3H, s) ppm; LRMS APCI m / z 584 [M + H] + Preparation 110 3_ [2 _ ({(2R) _2_ {[Third-butyl (dimethyl) dreamyl] oxy group 2_ [4-Cycloyl-3- (methyl) phenyl] ethyl} amino) _2_methylpropyl]- Ν · [2- (4-Gasphenyl) ethyl] -N-ethylbenzidine

The title compound was prepared from 3- {2-[(2R) -2- (third-butyldimethylsilyloxy) -2- (4-hydroxy-3-hydroxyfluorene) using a method analogous to Preparation 109. -Phenyl) ethylamino] -2-methylpropyl} benzoic acid (Preparation 37) and [2- (4-Gaphenyl) -ethyl] -ethyl-amine hydrochloride (Preparation 81) , As a white solid, 43% yield. 1H NMR (400MHz, CD3 OD) 7.90-6 · 90 (10H, m), 6.72 (1H, d), 4.69 (1H, m), 4.63 (2H, m), 3.70 (1H, m), 3.61 (1H, m), 3.49 (1H, m), 3.10 (1H, m), 3.03-2.58 (6H, m), 1.29-1.26, 1.07 -1 · 01 (9H, 2xm), 0 · 82 (9H, s), 0.01 (3H, s), -0.18 (3H, s) ppm; LRMS APCI m / z 639 [M + H] + 99200 -200 -200534846 Preparation 111 3_ [2-({(2R) -2 _ {[Third-butyl (dimethyl) silyl] oxy}} _ 2- [4-hydroxy-3_ (methylidyl) phenyl)] Ethyl} amino) -2-methylpropyl] -N- (2-tetrahydroρbilo_1-ylethyl) benzidine

Add 1- (2-aminoethyl) tetrahydropyrrole (83 μl, 0.63 mmol) to 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (122 mg, 0.63 mmol), 3- {2-[(2R) -2- (third-butyldimethylsilyloxy) -2- (4-hydroxy-3 · hydroxyfluorenyl- Phenyl) ethylamino] -2-methylpropyl} benzoic acid (Preparation 37) (200 mg, 0.42 mmol), 1-hydroxybenzotriazole hydrate (63 mg, 0.47 mmol) ) And N, N-diisopropylethylamine (88 µl 0.63 mmol) in N, N-dimethylformamide (5 ml). The resulting solution was stirred at room temperature for 18 hours. The solvent was removed in vacuo and the residue was partitioned between ethyl acetate (50 mL) and saturated sodium bicarbonate solution (10 mL). The aqueous layer was separated and re-extracted with dichloromethane (30 mL), and the combined organic solutions were dried (sodium sulfate) and concentrated in vacuo to obtain a yellow oil. The oil was purified by flash column chromatography on silica gel, and the residue was dissolved in dichloromethane: methanol: 〇88 ammonia 100 ·· 0 ·· 0 to 75 ·· 25 ·· 2 to provide the title compound as a pale yellow color. solid. 1H NMR (400MHz, CD3 OD) δ: 7.69 (2Η, m), 7.40-7.31 (2Η, m), 7.26 (1H, m), 7.14-7.03 (1H, dd), 6.85 (1H, d) , 4.69 (1H, m), 4.62 (2H, m), 3.58 99200 -201-200534846 (2H, m), 2.89-2.59 (10H, m), 1.82-1.79 (4H, m), 1_12 (3H, s ), 1.07 (3H, s), 0.79 (9H, s), -0.01 (3H, s), -0.21 (3H, s) ppm; LRMS APCI m / z 570 [M + H] + Preparations 112 to 138 have The following compounds of the general formula shown below are prepared by a method similar to that described for Preparation 38 using 3- {2-[(2R) -2- (third-butyldimethylsilyloxy) -2 -(4-hydroxy-3-hydroxymethyl-phenyl) ethylamino] -2-methylpropyl} benzoic acid (Preparation 37) made with the appropriate amine starting material. The reaction is monitored by TLC analysis, and

Stir at room temperature for 18-72 hours.

No. Qi data 112 r 4 f Cl 1H NMR (400MHz, CD3OD) δ: 7.64 (2H, m) 7.37-7.28 (5H, m), 7.20 (1H, m), 7.08 (1H, m), 6.75 (1H, d), 4.72 (1H, m), 4.65 (2H, m), 3.68 (2H, m), 3.30 (2H, m), 2.95-2.60 (4H, m), 1.12 (3H, s), 1.08 (3H , s), 0.80 (9H, s), -0.02 (3H, s), -0.19 (3H, s) ppm; LRMS APCI m / z 645 [M + H] + 44% 113 r 1H NMR (400MHz, CD3OD ) δ: 7.65 (2H, m), 7.40-7.05 (8H, m), 6.75 (1H, m), 4.78-4.63 (3H, m), 3.46 (2H, m), 3.15- 2.70 (9H, m) , 1.15 (3H, s), 1.11 (3H, s), 0.79 (9H, s), -0.01 (3H, s), -0.20 (3H, s) ppm; LRMS APCI m / z 603 [M + H] + 16% 99200 202- 200534846

114 115 116 117

N

Cl

1H NMR (400MHz, CD3OD) δ: 7.75 (2H, m), 7.65 (2H, m), 7.40-7.25 (5H, m), 7.09 (1H, m), 6.73 (1H, m), 4.75-4.62 ( 3H, m), 3.62 (2H, m), 3.37 (2H, m), 3.02-2.62 (6H, m), 1.59 (2H, m), 1.41 (2H, m), 1.14-1.07 (6H, m) , 0.97 (3H, t), 0.79 (9H, s), -0.01 to -0.21 (6H, m) ppm; LRMS APCI m / z 22% 676 [M + H] + __ 1H NMR (400MHz, CD3OD) δ : 7.63 34〇 / 0 (2H, m), 7.25 (12H, m), 7.05 (1H, m), 6.73 (1H, m), 4.68 (3H, m), 3.62 (2H, m), 3.13 (2H , m), 2.80 (4H, brm), 1.08 (6H, m), 0.80 (9H, s), -0.05 (3H, s). -0.21 (3H, s) ppm LRMS ESI m / z 685 [M + H) + 1H NMR (400MHz, CD30D) δ: 7.63 3〇〇 / 0 (2H, m), 7.40-7.20 (5H, m), 7.10 (1H, m), 6.75 (1H, m), 4.62 (3H , m), 3.59 (2H, m), 3.22 (2H, m), 2.92-2.64 (4H, brm), 2.51 (3H, s), 1.10 (6H, m), 0.80 (9H, s), -0.02 (3H, s), -0.21 (3H, s) ppm; LRMS ESI m / z 659 [M + H] + 1H NMR (400MHz, CD30D) δ: 7.66 34〇 / 0 (2H, m), 7.34 (2H , m), 7.26 (1H, d), 7.07 (1H, m), 6.72 (1H, m), 4.69 (1H, m), 4.63 (2H, d), 3.39 (2H, t), 2.75 (3H, brm), 2.63 (1H, m), 1.81 (2H, m), 1.75-1.63 (3H, m), 1.52 (2H, m), 1.36 (1H, m), 1.28 (1H, m), 1.17-1.24 (2H, m), 1.11 (3H, s), 1.08 (3H, s), 1.03-0.92 (2H, m), 0.77 (9H, s), -0.05 (3H, s) -0.27 (3H, s) ppm LRMS ESI m / z 583 [M + H] + 99200 203-200534846

118 rn Cl 1H NMR (400MHz, CD3〇D) δ: 7.65 (2H, m), 7.38-7.31 (4H, m), 7.27 (1H, d), 7.20 (2H, m), 7.06 (1H, dd ), 6.72 (1H, d), 4.69 (1H, m), 4.63 (2H, d), 3.62 (2H, m), 3.07 (2H, t), 2.89-2.82 (2H, t), 2.79-2.71 ( 1H, m), 2.65 (1H, m), 1.10 (3H, s), 1.07 (3H, s), 0.78 (9H, s), -0.04 (3H, s) -0.21 (3H, s) ppm; LRMS ESI m / z 611 [M + H] + 38% 119 1H NMR (400MHz, CD3OD) δ: 7.66 (2H, m), 7.37-7.30 (2H, m), 7.26 (1H, m), 7.09-7.00 ( 1H, m), 6.72 (1H, d), 4.69 (1H, m), 4.63 (2H, d), 3.43-3.38 (2H, m), 2.83-2.89 (2H, m), 2.80-2.71 (1H, m), 2.61-2.65 (1H, m), 1.96 (3H, s), 1.68 (6H, m), 1.61 (6H, d), 1.42 (2H, m), 1.10 (3H, s), 1.07 (3H , s) 0.78 (9H, s), -0.04 (3H, s) -0.22 (3H, s) ppm; LRMS ESI m / z 635 [M + H] + 37% 120 r 1H NMR (400MHz, CD3OD) δ : 8.26 (1H, m), 7.86 (1H, m), 7.74 (1H, m), 7.64 (2H, m), 7.53 (1H, m), 7.46 (1H, m), 7.41-7.31 (4H, m ), 7.27 (1H, m), 7.06 (1H, dd), 6.73 (1H, m), 4.70 (1H, m), 4.63 (2H, d), 3.72 (2H, m), 3.40 (2H, t) , 2.90-2.70 (3H, m), 2.64 (1H, m), 1.09 (3H, s), 1.07 (3H, s), 0.78 (9H, s), -0.03 (3H, s), -0.21 (3H, s) ppm; LRMS ESI m / z 627 [M + H] + 24% 121 l HX f h3c 1H NMR (400MHz, CD3OD) δ: 7.67 (2H, m), 7.39-7.32 (2H, m), 7.27 (1H, m), 7.07 (1H, dd), 6.98 (3H, m), 6.72 (1H, m), 4.70 (1H, m), 4.63 (2H, d), 3.46 (2H, t), 2.99 (2H, m), 2.87 (2H, m), 2.73 (1H, m), 2.66 ( 1H, m), 2.39 (6H, s), 1.11 (3H, s), 1.09 (3H, s), 0.79 (9H, s), -0.03 (3H, s), -0.21 (3H, s) ppm; LRMS ESI m / z 605 [M + H] + 40% 99200 204- 200534846

122 1H NMR (400MHz, CD3OD) δ: 7.63 (2H, m), 7.35 (2H, m), 7.27 (1H, m), 7.17 (4H, m), 7.06 (1H, dd) 6.72 (1H, m) , 4.70 (1H, m), 4.63 (2H, d), 3.56 (2H, t), 2.87 (3H, m), 2.71 (2H, m), 2.64 (1H, m), 2.43 (3H, s), 1.09 (3H, s), 1.07 (3H, s), 0.78 (9H, s), -0.04 (3H, s), -0.22 (3H, s) ppm; LRMS ESI m / z 623 [M + H] + 46% 123 F CI 1H NMR (400MHz, CD3OD) δ: 7.62 (2Hf m), 7.34-7.27 (3H, m), 7.22 (2H, m), 7.03-7.09 (2H, m), 6.72 (1H, d ), 4.69 (1H, m), 4.63 (2H, m), 3.59 (2H, m), 2.96 (2H, m), 2.71 (2H, m), 2.63 (2H, m), 1.09 (3H, s) , 1.06 (3H, s), 0.78 (9H, s), -0.04 (3H, s), -0.21 (3H, s) ppm; LRMS APCI m / z 629 [M + H] + 61% 124 丨 1H NMR (400MHz, CD3OD) δ: 7.62 (2H, m), 7.34 (3H, m), 7.27 (1H, d), 7.18 (1H, m), 7.06 (1H, dd), 6.97 (1H, m), 6.72 (1H, d), 4.69 (1H, m), 4.63 (2H, m), 3.62 (2H, m), 3.04 (2H, t), 2.89-2.70 (3H, m), 2.61 (1H, m), 1.09 (3H, s), 1.07 (3H, s), 0.78 (9H, s), -0.04 (3H, s), -0.21 (3H, s) ppm; LRMS APCI m / z 629 [M + H] + 60% 125 Ν γ ch3 —vs ch3 ch3 1H NMR (400MHz, CD3OD) δ: 7.54-7.75 (2H, m), 7.42-7.24 (3H, m), 7.17-7.04 (1H, m), 6.98-6.83 (1H, dd), 6.79-6.64 (2H, m), 4.70 (1H, m), 4.63 (2H, d), 3.77 (3H, s), 3.51 (2H, t), 2.89-2.82 (4H, m), 2.79-2.71 (1H, m), 2.64 (1H, m ), 2.33 (3H, s), 2.09 (3H, s), 1.07 (6H, s), 0.78 (9H, s), -0.03 (3H, s), -0.21 (3H, s) ppm; LRMS ESI m / z 635 [M + H] + 19% 99200 205-200534846

1H NMR (400MHz, CD3OD) δ: 7.62 (2H, m) 7.44-7.14 (6H, m), 7.08 (1H, d), 6.73 (1H, d), 4.71 (1H, m), 4.60 (2H, m ), 3.68 (2H, m), 3.14 (2H, m), 2.93-2.58 (4H, m), 1.10 (3H, s), 1.07 (3H, s), 0.78 (9H, s), -0.04 (3H , s), -0.21 (3H, s) ppm; LRMS APCI m / z 645 [M + H] + 1H NMR (400MHz, CD3OD) δ: 7.65 (2H, m) 7.37-7.31 (2H, m), 7.27 (1H, d), 7.06 (1H, dd), 6.97 (1H, d), 6.73 (1H, d), 6.68 (1H, d), 4.73-4.68 (1H, m) f 4.60 (2H, m), 3.76 (3H, s), 3.49 (2H, m), 2.93-2.60 (6H, m), 2.28 (3H, s), 2.13 (3H, s), 1.10 (3H, s), 1.07 (3H, s) , 0.78 (9H, s), -0.04 (3H, s), -0.21 (3H, s) ppm LRMS APCI m / z 635 [M + H] + 1H NMR (400MHz, CD3OD) δ: 7.67-7.62 (2H , m), 7.59-7.52 (4H, dd), 7.42-7.36 (2H, dd), 7.35-7.26 (6H, m), 7.05 (1H, dd), 6.71 (1H, dd), 4.67 (1H, dd ), 4.60 (2H, dd), 3.61 (2H, t), 2.95 (2H, t), 2.83 (1H, dd), 2.70 (2H, dd), 2.60-2.65 (1H, m), 1.08 (3H, s), 1.06 (3H, s), 0.77 (9H, s), -0.05 (3H, s), -0.23 (3H, s) ppm; LRMS APCI m / z 653 [M + H] + Ή NMR (400MHz , CD3OD) δ: 7.65 (2H, m) 7.37-7.31 (2H, m ), 7.27 (1H, d), 7.06 (1H, dd), 7.03 (1H, d), 6.96 (1H, bs), 6.90 (1H, d), 6.72 (1H, d), 4.72-4.68 (1H, m), 4.60 (2H, m), 3.51 (2H, m), 2.91-2.84 (3H, m), 2.71 (2H, dd), 2.64 (1H, m), 2.33 (3H, s), 2.24 (3H , s), 1.10 (3H, s), 1.07 (3H, s), 0.78 (9H, s), -0.04 (3H, s), -0.22 (3H, s) ppm; LRMS APCI m / z 605 [M + H] + 67% 39% 43% 46% 99200 206- 200534846

130 h3c 1H NMR (400MHz, CD3OD) δ: 7.87-7.80 (2H, m), 7.38-7.30 (2H, m), 7.27 (1H, d), 7.06 (1H, dd), 7.02-6.94 (3H, m ), 6.72 (1H, d), 4.68 (1H, m), 4.60 (2H, m), 3.51 (2H, m), 2.94 (2H, m), 2.84 (1H, m), 2.71 (2H, dd) , 2.61 (1H, m), 2.29 (3H, s), 2.27 (3H, s), 1.10 (3H, s), 1.07 (3H, s), 0.78 (9H, s), -0.04 (3H, s) , -0.21 (3H, s) ppm; LRMS APCI m / z 605 [M + H] + 35% 131 μ Mw) 1H NMR (400MHz, CDCI3) δ: 7.44-7.38 (2H, m), 7.33-7.20 ( 7H, m), 7.06 (1H, d), 6.88 (1H, s), 6.75 (1H, d), 6.13-6.09 (1H, m), 4.82-4.60 (2H, m), 4.58 (1H, t) , 3.51-3.44 (2H, m), 2.84-2.55 (6H, m), 2.00-1.90 (2H, m), 1.04 (3H, s), 1.00 (3H, s), 0.79 (9H, s),- 0.05 (3H, s), -0.21 (3H, s) ppm; LRMS APCI m / z 592 [M + H] + 45% 132 rv " MO 1H NMR (400MHz, CDCI3) δ: 7.44 (1H, d) , 7.38 (1H, m), 7.32-7.22 (7H, m), 7.08 (1H, d), 6.88 (1H, s), 6.75 (1H, d), 6.14 (1H, m), 4.83-4.75 (2H , m), 4.59 (1H, t), 3.72-3.68 (2H, q), 2.92 (2H, t), 2.82-2.75 (1H, m), 2.65-2.56 (3H, m), 1.03 (3H, s ), 1.00 (3H, s), 0.79 (9H, s), -0.05 (3H, s), -0.20 (3H, s) ppm; LRMS APCI m / z 592 [M + H] + 45% 133 I 1H NMR (400MHz, CDCI3) δ: 7.51-7.39 (6H, m), 7.27 -7.23 (2H, m), 7.10 (1H, d), 6.89 (1H, s), 6.77-6.65 (1H, d), 6.16 (1H, m), 4.84-4.76 (2H, m), 4.62-4.58 (1H, t), 3.72-3.68 (2H, m), 2.99 (2H, t), 2.83-2.76 (1H, m), 2.66-2.58 (3H, m), 1.03 (3H, s), 1.00 (3H , s), 0.79 (9H, s), -0.04 (3H, s), -0.20 (3H, s) ppm; LRMS APCI m / z 645 [M + H] + 53% 99200 • 207- 200534846

134 F 1Η NMR (400MHz, CDCI3) δ: 7.45 (1Η, d), 7.39 (1Η, m), 7.29-7.23 (2Η, m), 7.20-7.06 (4Η, m), 6.90 (1H, s), 6.76 (1H, d), 6.19 (1H, m), 4.83-4.76 (2H, m), 4.59 (1H, t), 3.69-3.63 (2H, m), 2.99 (2H, m), 2.84-2.76 ( 1H, m), 2.66-2.60 (3H, m), 1.04 (3H, s), 1.01 (3H, s), 0.80 (9H, s), -0.04 (3H, s), -0.19 (3H, s) ppm; LRMS APCI m / z 629 [M + H] + 46% 135 Ηχ 1 CH3 1H NMR (400MHz, CD3OD) δ: 7.73 (2H, m) 7.40-7.33 (2H, m), 7.26 (1H, d) , 7.11 (1H, bs), 7.07-7.04 (2H, dd), 6.96 (1H, d), 6.71 (1H, d), 4.66 (2H, dd), 4.63 (2H, dd), 4.54 (2H, s ), 2.83 (1H, t), 2.72 (2H, dd), 2.61 (1H, dd), 2.32 (3H, s), 2.26 (3H, s), 1.11 (3H, s), 1.08 (3H, s) , 0.78 (9H, s), -0.06 (3H, s), -0.23 (3H, s) ppm; LRMS APCI m / z 591 [M + H] + 44% 136 0 1H NMR (400MHz, CD3OD) δ: 7.69-7.58 (2H, m) 7.39-7.03 (5H, m), 6.90- 6.68 (4H, m), 4.75-4.57 (3H, m), 3.62-3.49 (2H, m), 3.18-3.07 (2H, m), 2.91- 2.53 (10H, m), 2.05-1.90 (4H, m), 1.87-1.73 (2H, m), 1.11-1.06 (6H, m), 0.78 (9H, s), -0.05 (3H , s), -0.22 (3H, s) ppm ; LRMS APCI m / z 691 [M + H] + 2% 137 °. 1H NMR (400MHz, CD3OD) δ: 7.65-7.61 (2H, m), 7.34-7.30 (2H, m), 7.26 (2H, m), 7.17-7.15 (2H, m) 7.06 (1H, m), 6.93 (1H, m), 6.85 (1H, m), 6.73 (1H, m), 4.71-4.63 (3H, m), 4.06-4.02 (2H, m), 3.61-3.57 (2H, m), 2.96-2.58 (15H, m), 2.07-2.02 (2H, m), 1.84-1.79 (4H, m), 1.09-1.06 (6H, m), 0.79 (9H, s), -0.03 (3H, s), -0.21 (3H, s) ppm; LRMS APCI m / z 705 [M + H] + 78% 99200 -208-200534846 138 1Η NMR (400MHz, CD3OD) δ: 7.63 56% (2Η, m) 7.34-7.21 (3Η, m), 7.17 (1H, m), 7.07 (1H, m), 6.79-6.65 (4H, m), I (4.67-4.57 (3H, m), 3.95-3.92 (2H, m),) 3.57-3.53 (2H, m), 2.86-2.53 (12H, (m), 1.98-1.85 (2H, m), 1.82-1.70 (4H, 〇m), 1.04-1.01 (6H, m), 0.78 (9H, s) , -0.02 (3H, s), -0.20 (3H, s) ppm 115. 2- (2-phenylthio-phenyl) -ethylamine can be prepared according to Czechoslovak Chemical Communication Set 54 通信, 1995-2008; 1989 Made as described

Preparation 116: The appropriate fractions were concentrated in vacuo, and the residue was further purified by column chromatography on amine silica gel with ethyl acetate: pentane 100: 0 to 80:20, followed by methane: Methanol is dissolved from 100: 0 to 80:20. Preparation 139 3- [2-({(2R) _2-Hydroxy_2_ [4_Hydroxy-3- (transmethyl) phenyl] ethyl} amino) -2-methylpropyl] benzidine ester

3- {2 _ [(2R) -2- (Third-butyldimethylsilyloxy) -2_ (4-hydroxyaspartyl-phenyl) ethylamino] -2-methylpropane Methyl} benzoate (Preparation 36) (40 g, 8.21 mol) with ammonium fluoride (3.04 g, 82.0 mmol) in methanol (20 ml) and water (5 ml) The mixture was heated at 40 ° C for 18 hours. Then, the reaction mixture was concentrated in vacuo, and the residue was purified by column chromatography on silica gel with methane: methanol: 0.88 ammonia 100: 0: 90 to 90: 10: 0.1 to obtain The title compound was a white foam, 81% yield, 2.42 g. 99200 -209 · 200534846 1H NMR (400MHz, CD3 OD) 5: 7.87 (2H, m), 7.40 (2H, m), 7.29 (1H, m), 7.09 (1H, dd), 6.72 (1H, d), 4.69-4.61 (3H, m), 3.90 (3H, s), 2.90-2.73 (4H, m), 1.08 (3H, s), 1.06 (3H, s) ppm; LRMS ESI m / z 374 [M + H] + Preparation 140 3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (methylol) phenyl] ethyl} amino) -2 • methylpropyl] benzoic acid

3- {2- [2-Ethyl-2- (4-Ethyl-3-Ethylmethyl-phenyl) _Ethylamino] -2-methyl-propyl} -benzoic acid methyl ester (prepared 139) (2.35 g, 6.32 mmol) and lithium hydroxide (303 mg, 12.64 mmol) in tetrahydrofuran (20 ml) and water (20 ml) and stirred at room temperature for 3 days. The reaction mixture was then concentrated in vacuo and the residue was diluted with water and acidified with 1M hydrochloric acid (12 mL). The mixture was stirred at room temperature for 2 hours and then concentrated in vacuo. The crude residue was used in subsequent reactions without further purification. 1H NMR (400MHz, CD3 OD) 5: 7.87 (1H, m), 7.84 (1H, bs), 7.39-7.31 (3H, m), 7.19 (1H, dd), 6_79 (1H, d), 4.86 (1H M), 4.66 (2H, s), 3.22-3.11 (2H5 m), 3.02 (2H5 m) 5 1.32 (6H, s) ppm; LRMS ESI m / z 360 [M + H] + Preparation 141 3 -[3- (2-Third-butoxycarbonylamino-2-methyl-propyl) -phenyl] -propionic acid benzyl ester

99200 -210- 200534846 [2- (3-Bromophenyl) -l, l-dimethylethyl] amine methyl acid tert-butyl ester (Preparation 32) (2 g, 6.09 mmol), G g of acrylic acid, 12.19 g), palladium acetate (11) (204 mg, 0.91 mmol), tri-p-toluyl phosphite (556 mg, 1 β83 mmol) and triethylamine (2.12 Ml, 15.22 mmol) in acetonitrile (100 ml) and heated at reflux for 48 hours. Then, the reaction mixture was concentrated in vacuo, and the residue was purified by column chromatography on silica gel to obtain the title compound as a pale yellow oil, 90% Yield, 2.23 g. 1H NMR (400MHz, CD3 OD) δ: 7.75 (1H, d), 7.35 (7H, m), 7.20 (1H, d), 6.58 (1H, d), 6.00 (1H, brs), 5.20 (2H , S), 3.00 (2H, s), 1.43 (9H, s), 1.22 (6H, s) ppm; LRMS ESI m / z 310 [M + H] + Preparation 142 3 · [3_ (2-amino- 2-methylpropyl) -phenylphenyl acrylate

Combine 3-〇 (2-tert-butoxycarbonylamino 1methylbis) _phenyl] _benzyl acrylate (Preparation 141) (2.23 g, 5.45 mmol) with trifluoroacetic acid (5 ml) The mixture in digas methane (10 ml) was stirred at room temperature for 1 hour. The mixture was then concentrated in vacuo and the residue was diluted with sodium bicarbonate solution (ml) and extracted with ethyl acetate (3 x 20 ml). The combined organic solutions were dried over magnesium sulfate and concentrated in vacuo to give the title compound as a yellow oil in quantitative yield.

99200 -211-200534846 7.38 (7H, m), 6.60 (1H, brs), 5.23 (2H, s), 2.91 (2H, s), 1.30 (6H, s) ppm; LRMS ESI m / z 408 [MH] 'Preparation 143

3- (3- {2-[((2R) _2- [4- (Ethyloxy) _3_ (hydroxymethyl) phenyl]] _ 2 _ {[third-butyl (dimethyl) silyl] oxy } Ethyl) amino] -2-methylpropyl} phenyl) benzyl acrylate

[2- (Urooxy) -5-((lR) -2_bromoyl_1 _ {[Third-butyl (dimethyl) carboxyl] oxy} ethyl) phenyl] methanol (Preparation 23) (800 mg, 1.77 mmol) and 3- [3- (2-amino-2-methyl-propyl) -phenyl] -propionic acid benzyl ester (Preparation 丨 42) (1.10 G '3.55 mmol) was stirred at 90 ° C for 18 hours. Then, the reaction mixture was cooled to room temperature, diluted with diethyl ether (40 ml), and stirred for 4 hours. The formed precipitate was filtered off, washed with diethyl ether, and the filtrate was concentrated in vacuo to obtain a brown oil. Purify the oil by column chromatography on silica gel.

Dissolved in one gas methyl alcohol: methanol: 0.88 ammonia to provide the title compound, 25% yield, 300 mg-. 1H NMR (400MHz, CD3 OD) δ: 7.78 (1H, d), 7.38 (16H, m), 6.95 (1H, m), 6.58 (1H, d), 5.25 (2H, s), 5.04 (2H, s), 4.78 (1H, m), 4.64 (2H, m), 2.80 (2H, m), 2.68 (2H, m), 1 · 14 (3H, s), U0 (3H, s), 0.78 (9H, s), 0 · 03 (3H, s), -0.21 (3H, s) ppm; LRMS ESI m / z 680 [M + H] + 99200 -212- 200534846 Preparation 144 3_ {3_ [1 2 _ ({(2R) -2 _ {[Third butyl (dimethyl) fever group] oxy group 2 · [4-hydroxy-3- ( (Methyl) phenyl] ethyl} amino) -2 • methylpropyl] phenyl} propionic acid

Add ammonium formate (139 mg, 2.20 mmol) and palladium hydroxide (11) (50 mg) to 3- (3- {2- [2- (4-fluorenoxy-3-hydroxymethylphenyl) ) -2- (Third-Butyl-Dimethyl-Cyclosyloxy) -Ethylamino] -2-methyl-propyl} -phenyl) _Acrylic Acid T g (Preparation 143) ( 300 mg, 0.44 mmol) in ethanol (10 ml), and the mixture was heated at reflux for 30 minutes. The reaction mixture was then cooled, filtered through Arbocel®, and concentrated in vacuo to give the title compound, 90% yield, 200 mg.

99200 -213- 1 H NMR (400MHz, CD3 OD) 5: 7.30 (1H, s), 7.20 (1H, m), 7.18 (1H, d), 7.09 (2H, m), 7.00 (1H, d), 6.78 (1H, d), 4.88 (1H, m), 4.63 (2H, m), 3.11 (2H, m), 2.83 (4H, m), 2.48 (2H, m), 1 · 23 (6H, s), 0_81 (9H, s), _0.03 (3H, s), -0.18 (3H3 s) ppm; LRMS ESI m / z 502 [M + H] + Preparation 145 2 3- {3_ [2-({(2R) -2 _ {[Third-butyl (dimethyl) silyl] oxy] 2- [4-hydroxy: (hydroxymethyl) phenyl] ethyl} amino ) -2-methylpropyl] phenyl} -N · (3,4-diaminobenzyl) propanamine 200534846

The title compound was prepared from 3- {3- [2-({(2R) -2-{[third butyl (dimethyl) oxetyl) oxy] 2 [[ 4-hydroxy% hydroxymethyl) phenyl] ethyl} amino) -2-fluorenylpropyl] phenyl} propanoic acid (Preparation 144) and 3,4-digas benzylamine, a transparent oil, 64% Yield. 1H NMR (400MHz, CD3 OD) δ: 7.40 (3H, m), 7.18 (1H, m), 7.08 (5H, m), 6.78 (1H, d), 4.61 (3H, m), 4.23 (2H , s), 2.90 (3H, m), 2.60 (5H, m), 1.08 (3H, s), 1.04 (3H, s), 0.81 (9H, s), 0.00 (3H, s), -0.18 (3H, s) ppm; LRMS ESI m / z 659 [M + H] + Preparation of 146 [3- (2-amino-2-methyl-propyl) -phenyl methyl acetate

Add vaporized acetamidine (154.5 g, 1.97 moles) to {3- [2- (2-Gas-acetamido) -2-methyl-propanyl] -phenylacetic acid (Preparation 48) (20 g, 0.66 mol) in a solution of methanol (350 ml), and the mixture was heated under reflux for π hours. The reaction mixture was then concentrated in vacuo to give the title compound as a brown oil, 87% yield, 154.5 g. 1H NMR (300MHz, CDC13) 5: 7.22 (1Η, m), 7.18-7.05 (3Η, m), 3.71 (3Η, s), 3.58 (2H, s), 2.62 (2H, s), 1 · 12 (6H, s) ppm; GCMS m / z 206 [MH]-99200 -214- 200534846 Preparation 147 (3- {2-[(((2R) -2_ [4_ (Masteroxy) _3 (hydroxymethyl ) Benzyl] _2 {[Third butyl (dimethyl) fever group 1oxy} m group 丨 _2_methylpropyl} phenyl) methyl ester

[2- (Ethyloxy) -5-((lR) -2-bromoyl-1-{[tertiary-butyl (dimethyl) lithium] oxy} ethyl) phenyl] Formazan (Preparation 23) (3.4 g, 7.5 mmol), [3- (2-amino-2-methylpropyl) phenyl] acetic acid (Preparation 146) (1.7 g, 7.5 mmol) and N , N-: Isopropylethylamine (1.4 ml, 8 mmol) in dimethyl sulfoxide (7.5 ml), stirred at 90 ° C for 28 hours. Then, the reaction mixture was cooled, diluted with ethyl acetate, and washed with water. Next, the organic solution was dehydrated and dried with magnesium sulfate, concentrated in vacuo, and the residue was purified by column chromatography on silica gel, and then dissolved with ethyl acetate: pentane 66:33 to obtain the title compound as a colorless oil. , 50% yield, 2.2 g. 1H NMR (400 MHz, CDC13) δ: 7.44-7.31 (6Η, m), 7.30-7.19 (3Η, m), 7.13-7.05 (2H, m), 6.80 (1H, d), 4.75-4.66 (3H, m), 3.68 (3H, s), 3.59 (2H, s), 2.90-2.72 (4H, m), 1.22-1.09 (6H, m), 0.70 (9H, s), -0.06 (3H , S), -0.28 (3H, s) ppm Preparation 148 (3- {2-[((2R) -2_ [4_ (Ethyloxy) _3- (hydroxymethyl) phenyl] -2-{[第Tri-butyl (dimethyl) silyl] oxy} ethyl) amino] -2 · methylpropyl} phenyl) acetic acid 99200 -215- 200534846

Lithium hydroxide solution (1M in water, 16_2 ml, 16.2 mmol) was added to (3) 2-[((2R) -2- [4- (benzyloxy) -3- (hydroxymethyl) Phenyl] _2 _ {[Third-butyl (dimethyl) carboxanyl] oxy} ethyl) amino] _2-methylpropyl} phenyl) methyl acetate (Preparation 147) (4.80 g ' 8.1 mmol) in a solution of tetrahydrofuran (49 ml) and formazan (17 ml), and the mixture was stirred at room temperature for 18 hours. The reaction mixture was then concentrated in vacuo and the residue was diluted with water and acidified to pH 7 with 1M hydrochloric acid. The formed precipitate was filtered off and the bar was washed with water to give the title compound as a pale yellow solid, 94% yield, 4.37 g. ^ NMRC ^ OMH ^ DMSO- ^) 5: 7.45-7.38 (6H, m), 7.31 (2H, m), 7.13 (1H, m) 7.02 (3H, m), 5_04 (3H, m), 4.52 (2H, d), 3.52 (2H, d), 2.43 (2H, d), 3.37 (2H, d), 1.24 (6H, m), 0.78 (9H, s), 0.02 (3H, s) ), -0.92 (3H, s) ppm; LRMS ESI m / z 659 [M + H] + Preparation 149 2- (3- {2-[(((2R)-;? _ [4_ (爷 oxy) __ 3 -(Methyl) phenyl 2] [Third-butyl (dimethyl) dreamyl] oxy} ethyl) amino group 2-methylpropyl} phenyl) (cycloheptylmethyl Ethylamine

99200 -216- 200534846 2- [4- (fluorenyloxy) -3- (hydroxymethyl) phenyl] -2-{[third-butyl (dimethyl) silyl] oxy} ethyl) Amine] -2-methylpropyl} phenyl) acetic acid (Preparation 148) and cycloheptanemethylamine as a white solid in 97% yield. 1H NMR (400MHz, CD3 OD) 5: 7.72 (1H, dd), 7.44 (1H, d), 7.42 (2H, m), 7.38-7.21 (5H, m), 7.19 (1H, d), 7.07 (1H, d), 7.02 (1H, m), 5.08 (2H, d), 5.03 (1H, m), 4.71 (2H, d), 3.51 (2H, d), 3.03-2.96 (4H , M), 1.77-1.34 (13H, m), 1.28 (6H, m), 1.07 (2H, m), 0.93 (9H, s), 0.07 (3H, s), -0.92 (3H, s) ppm; LRMS ESI m / z 688 [M + H] +

Preparation of 150 N_l-gold steel alkyl_2_ (3- {2-[((2R) -2_ [4_ (Ethyloxy) -3- (hydroxymethyl) phenyl] -2-{[second-but (Monomethyl) fever group] oxy} ethyl) amino] _2_methylpropyl} phenyl) acetamidine

OTBDMS 〇 The title compound was prepared from (3- {2-[((2R) -2- [4- (benzyloxy), 3- (hydroxymethyl) phenyl] -2- {[Third-butyl (dimethyl) silyl] oxy} ethyl) amino] -2-methylpropyl} phenyl) acetic acid (Preparation 148) and 1-gold steel alkylamine are Yellow oil, 71% yield. 1H NMR (400MHz5 DMSO-d6) δ: 7.52 (3Η, m), 7.52-7.24 (4Η, m), 7.18-7 · 08 (2H, m), 7.07-6.98 (2H, m), 6.94 ( 1H, m), 5.09 (2H, d), 5.01 (1H, t), 4.66-4.61 (1H, m), 4.54 (2H, d), 3.25 (2H, d), 3.15 ( 1H, d), 2.59-2.43 (2H, m), 1.98-1.92 (3H, m), 1.87 (6H, m), 1.57 (6H, m), 0.96 (6H, dd), 0.79 (9H, d), 99200 -217- 200534846 -0 · 98 (3H, s), -0.93 (3H, s) ppm; LRMS ESI m / z 712 [M + H] + Preparation 151 2_ {3- [2- ({(2R) -2 _ {[Third-butyl (dimethyl) silyl] oxy}}-2_ [4-Hydroxy-3- (transmethyl) phenyl] ethyl} amino) · 2 · Methylpropyl] phenyl} -N- (cycloheptylmethyl) acetamide

The title compound was prepared from 2- (3- {2-[((2R) -2- [4- (fluorenyloxy) -3- (hydroxymethyl) phenyl] -2- {[Third-butyl (dimethyl) silyl] oxy} ethyl) amino] -2-methylpropyl} phenyl) -N- (cycloheptylmethyl) acetamide (prepared 149) as a yellow oil in 96% yield. 1H NMR (400MHz, CD3 OD) 5: 7.67 (1H, m), 7.18-7.04 (5H, m), 6.79 (1H, d), 4.92-4.84 (1H, m), 4.67 (2H, m), 3.51 (2H, d), 3 · 21-3 · 03 (2H, m), 3 · 02 (2H, m), 2_96 (2H, m), 1.86_1 · 38 (11H, m), 1.24 (6H, m), 1.21-U1 (2H, m), 0.82 (9H, s), 0.06 (3H, s), -0.39 (3H, s) ppm; LRMS ESI m / z 597 [M + H] + Preparation 152 N-l_Gold steel alkyl-2_ {3- [2-({(2R) -2-{[Third · butyl (dimethyl) silyl] oxy}} _ 2- [4_hydroxy_ 3- (Methyl) phenyl] ethyl} amino) _2_methylpropyl] phenyl} acetamidinium 99200 -218- 200534846

OTBDMS

The title compound was prepared from Nl-goldenyl alkyl 2- (3- {2-[((2K) _2 · [4- (mainoxy) _3- (transmethyl)) benzene using a similar method to prepare 144. Group] -2-{[Third-butyl (dimethyl) carboxanyl] oxy} ethyl) amino] -2-methylpropyl} phenyl) acetamide (Preparation 150), As a white solid, 73% yield. ^ NMRC ^ OMHz ^ DMSO- ^) 5: 7.42 (1H, m) 5 7.12 (1H5 d), 7.09-7.05 (1H, m), 7.03-6.95 (4H, m), 6.64 (1H, d) , 4.95 (1H, brs), 4.60 (1H, m), 4.42 (2H, d), 3.24 (2H, d), 2.75 (1H, d), 2.57 (2H, d), 1.97 (3H, m), 1_93 (6H, m), 1.57 (6H, m), 0.92 (6H, dd), 0.78 (9H, d), -0.03 (3H, s), -0.18 (3H, s) ppm; LRMS ESI m / z 621 [M + H] + Preparation 153 {3- [2 _ ({(2R) -2-{[Third-butyl (dimethyl) dreamyl] Oxy} _2_ [4_ mesitylhydroxymethyl) phenyl 1ethyl} amino) _2_methylpropyl] phenyl} acrylic acid

OTBDMS

The title compound was prepared from (3- {2-[((2R) -2-[4- (Wordoxy) -3- (hydroxyfluorenyl) phenyl] _2-{[第Tri-butyl (difluorenyl) lithium alkyl] oxy} ethyl) amino] -2-fluorenylpropyl} phenyl) methyl acetate (Preparation 147) as a brown oil, 80% yield . 1H NMR (400 MHz, CDC13) (5: 7.30-7.20 (2H, m), 7.19-7.00 (4H, m), 99200 • 219- 200534846 6.80 (lH, d), 4.75-4.66 (3H, m), 5.10 (2H, s), 3.68 (3H, s), 3.59 (2H, s), 2.85-2.62 (4H, m), 1.10-1.01 (6H, m), 0.80 (9H, s) , -0.02 (3H, s), -0.20 (3H, s) ppm Preparation 154 {3- [2-({(2R) _2-{[Third butyl (dimethyl) dream alkyl ] Oxyphenyl 2-acyl-3 (hydroxymethyl) phenyl] ethyl} amino) _2_methylpropyl] phenyl} acrylic acid

{3- [2-({(2R) -2-{[Third-butyl (dimethyl) sylalkyl] oxy} -2 apocytyl-3- (transmethyl) phenyl] ethyl Methyl} aminomethylpropyl] phenyl 丨 methyl acetate (Preparation 153) (5 g, 10 mmol) with lithium hydroxide in water, 30 mL, 30 mmol) in tetrahydrofuran (50 mL) The mixture was stirred at room temperature for 48 hours. Then, the reaction mixture was acidified with 1M hydrochloric acid (30 ml), concentrated in vacuo, and the residue was triturated with water and azeotroped with methanol (χ3) to give the title compound 'as a white solid, 84% yield Rate, 4.1 g. 1H NMR (400MHz, CD3 OD) δ: 7.39-7.31 (2H, m), 7.28 (1H, m), 7.20- 7. · 10 (3H, m), 6B (1H, d), 4.92-4.83 (1H , M), 4.65 (2H, m), 3.61 (2H, s), 3.34-3.24 (2H, m), 3.00 (2H, m), 1.33 (6H, s), 0.82 (9H, s ), 0.06 (3H, s), -0.12 (3H, s) ppm Preparation 155 2- {3_ [2 _ ({(2R) _2-{[Third-butyl (dimethyl) dreamyl] oxyl] oxy BU 2_ [4-Hydroxy-3- (methyl) phenyl] ethyl} amino) -2-fluorenylpropyl] phenyl BU N_ (3 · tetrahydropyrrole-1_ylpropyl) acetamidine Amine 99200 -220- 200534846

The title compound was prepared in a similar manner to Preparation 38 from {3- [2-({(2R > 2-{[Third-butyl (difluorenyl) suprylalkyl] oxyl-2-oxo-2- [4- Hydroxy-3- (fluorenyl) phenyl] ethyl} amino) -2-methylpropyl] phenyl} acetic acid (Preparation 154) and 1-tetrahydropyrrolylpropylamine, 16% yield.

^ NMRC ^ OMHz ^ CDC ^) 5: 7.20 (1H, m) 5 7.08-6.96 (3H, m), 6.85 (1H, m), 6.70 (1H, m), 6.58 (1H, m), 4 75 (2H, s), 4.64 (1H, m), 3.42 (2H, m), 3.24 (2H, m), 2.80 (1H, m), 2.62 (3H, m), 2 43 (6H, m), 1.68 (4H, m), 1.60 (2H, m), 1.00 (6H, s), 0.81 (9H, s), -0_05 (3H, s), -0.19 (3H, s) ppm Preparation of 156 N-benzyl_2- {3_ [2 _ ({(2R) -2 _ {[Third-Butyl (dimethyl) dreamyl] oxyl] oxo-2-oxo

Hydroxy ((hydroxymethyl) phenyl) ethyl} amino) -2-methylpropyl] phenylbenzene N-methylacetamide

The title compound was prepared using a similar method to Preparation 38 from {3- [2-({(2R) -2-{[fluorenedi-butyl (difluorenyl) sulfoxy] yl] oxy} _2- [4 -Ethyl ((methyl) phenyl] ethyl} amino) -2-fluorenylpropyl] phenyl} acetic acid (Preparation 154) with Benzylmethylamine, 55% yield. 99200 -221-200534846 1H NMR (400MHz, CD3 OD) δ: 7.55-7.01 (11H, m), 6J3 (1H, m), 4.63 (5H, m), 2.85 (2H, m), 2.80 (2H, m), 2.72 (1H, m), 2.68 (3H, m), 1.87 (1H, m), 1.03 (6H, m), 0 · 80 (9H, s), -0 · 00 (3H, s), -0.19 (3H, s) ppm Preparation 157 3- [2 _ ({(2R) _2 _ {[Third butyl (dimethyl) alkyl] oxy}}-2_ 丨 4 -Hydroxy-3_ (kisylmethyl) phenyl] ethyl} amino) -2-methylpropyl] -N- [2- (3-fluorophenyl) ethyl I benzamidine

3] 2 _ [(2R) _2- (Third-butyldimethylsilyloxy) -2- (4-Cycloyl-3-Cyclomethyl-phenyl) ethylamino] -2-form Propyl} benzoic acid (Preparation 37) (473 mg, 1 mmol) and hexafluoro phosphate (379 mg, 1 mmol) to a solution of 3-fluorophenylethylamine (139 mg '1 mmol) in N, N-dimethylacetamide (6 ml), The mixture was stirred at room temperature for 18 hours. The solvent was removed in vacuo, and the residue was redissolved in methane (100 mL) and washed with saturated sodium bicarbonate solution (3 x 20 mL) and brine (10 mL). Then, the organic solution was dehydrated and dried over sodium sulfate, concentrated in vacuo, and the residue was purified by column chromatography on silica gel with methane: methanol: 0.88 ammonia, 100: 0: 0 to 90:10: 1melt off. Next, the appropriate fractions were concentrated in vacuo, and the residue was redissolved in ethyl acetate, washed with saturated sodium bicarbonate solution, dried over sodium sulfate 'and concentrated in vacuo to give the title compound, 52% Yield, 343 99200 -222- 200534846 mg. 1H NMR (400MHz, CD3 OD) 5 ·· 7.65-7.62 (2H, m), 7.38-7.23 (4H, m), 7.09-6.99 (3H, m), 6.92 (1H, d), 6.74 (1H, d), 4_70 (1H, m), 4.65 (2H, m), 3.61 (2H, m), 2.96-2 · 60 (6H, m), U0 (3H, s), 1 · 07 (3H, s), 0.79 (9H, s), -0.03 (3H, s), -0.21 (3H5 s) ppm; LRMS ESI m / z 595 [M + H] + Preparation 158

3- [2 _ ({(2R) -2-{[Third-butyl (dimethyl) dreamyl] oxy}}-2- [4-Cycyl · 3 · (Methyl) phenyl) ethyl } Amino) -2-methylpropyl] -N- [2- (5-amino-2-methoxyphenyl) ethyl] benzidine

OTBDMS

ΗΟ〆〇Η〆 3- {2-[(2R) -2- (third-butyldifluorenylsilyloxy) _2_ (4_hydroxy-3- via methyl-phenyl) ethylamino ] -2-methylpropyl} benzoic acid (Preparation 37) (400 mg, 0-85 mmol), hexafluorophosphate 0- (ιη-benzotriazol-1-yl) -n, N, N ,, N, -tetramethylphosphonium (320 mg, 0.85 mmol), triethylamine (225 μl, 1.6 mmol) and 2- (5-amino-2-methoxy -Phenyl) -ethylamine (Preparation 70) (64 mg, 0.85 mmol) in N, N-monomethylacetamide (8 ml), stir at room temperature μ hour. The solvent was removed in vacuo and the residue was partitioned between dichloromethane (4 mL) and saturated sodium bicarbonate solution (1 mL). Then, the organic solution was dehydrated and dried with magnesium sulfate, concentrated in vacuo, and the residue was purified. Using an ISCO Companion® silicone cartridge, digas methane: methanol: 0 88 99200 • 223-200534846 ammonia 90: 10: 1 Dissolved to 80:20 ... 2 to give the title compound in 22% yield. 1H NMR (400MHz, CD3 OD) 5: 7.70-7.60 (2H, m), 7.50-7.38 (3H, m), 7.20_7.10 (3H, m), 6.95 (1H, d), 6.85 ( 1H, d), 4.95 (1H, s), 4.75-4 · 60 (2H, m), 3.81 (3H, s), 3.57 (2H, m), 3.10-2.90 (6H, m), 1_25 ( 6H, s), 0.82 (9H, s), -0.03 (3H, s), -0.16 (3H, s) ppm Preparation 159 3- [2 _ ({(2R) -2 _ {[Second-Butyl (Dimethyl) fever group] oxy group 2- [4-Cycloyl-3- (Methyl) phenyl] ethyl} amino) -2-methylpropyl] _N- [2- ( 3 • ethoxyphenyl) ethyl] benzene

The title compound was prepared from 3- {2-[(2R) -2-(Second-butylmonomethylsupalyloxy) -2- (4-mercapto-3) using a similar method to that used to prepare 158. -Methyl-phenyl) ethylamino] -2-methylpropyl} benzoic acid (Preparation 37) and 3-ethoxyphenethylamine, 67% yield. LRMS APCI m / z 621 [M + H] + Preparation 160 3- [2-({(2R) -2 _ {[Third butyl (dimethyl) alkyl] oxy group) Methyl) phenyl] ethyl} amino) -2_methylpropyl] _N_ [2-biphenyloxyphenyl) ethyl] benzidine amine 99200 -224 · 200534846

The title compound was prepared from 3- {2-[(2r) _2-(third-butyldifluorenylsilyloxy) _2_ (4-side Ihydroxymethyl_phenyl) using a similar method to that used to prepare 158. Ethylamino] -2-methylpropyl} benzoic acid (Preparation 3 is > Methoxyphenethylamine, 98 / 〇

LRMS ESI m / z 607 [M + H] + Preparation 161 [3-((2R) -2-{[(lRH-phenylethyl] amino} propyl) phenyl] acrylic acid

Lithium hydroxide solution (1M in water, 90 ml, 90 mmol) was added to [3-((2R) -2-{[(lR) -l-benzyl-ethyl] -amino}} (Propyl) _phenyl] • formamidine acetate hydrochloride (Preparation 26) (13.5 g, 43.5 mmol) in methanol (200 ml), and the mixture was stirred at room temperature for 18 hour. Then, 1M hydrochloric acid (90 liters) was added to the reaction mixture, and methanol was removed in vacuo. The formed precipitate was decanted and washed with water (20 ml) and a mixture of ethanol / ether 20:80 to obtain the title compound as a solid, 91% yield, 11.8 g. 1H NMR (400MHz, CD3 OD) 5 ·· 7.52-7.45 (5H, m), 7.22-7.18 (2H, m), 7.19 (1H, s), 6.92 (1H, d), 4.56_4 · 48 (1H, q), 3.46 (2H, s), 3.26-3.13 (2H, m), 99200 -225-200534846 2.66-2.62 (1H, m), 1.62 (3H, d), 1.16 (3H, d) ppm; LRMS ESI m / z 298 [M + H] + Preparation of 162 N-l_adamantyl_2- [3-((2R) -2-{[(lR) _l-benzene Ethyl] amino] propyl] phenyl] acetoamine

Add 1-goldenyl amine (5.44 g, 36 mmol) and triethylamine (15 mL, 108 mmol) to [3-((2R) -2-{[(lR)- l-phenylethyl] amino} propyl) phenyl] acetic acid (Preparation 161) (10.7 g, 36 mmol) in digas methane (200 ml). Then, 2-amino-1,3-dimethyltetrahydroimidazole hexafluorophosphate (10 g, 36 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was washed with water, and the organic solution was dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by column chromatography on silica gel and eluted with methane: methanol: 0.88 ammonia 95: 5: 0.5 to provide the product as a foam, quantitative yield, 17.6 g. 1H NMR (400MHz, CD3 OD) 5: 7.38-7.30 (4H, m), 7.27-7.22 (lH, m), 7.17 (1H, t), 7.09 (1H? D), 6.98 (1H, s), 6.89 (1H, d), 3.98 (1H, q), 3.36 (2H, s), 3.00-2.95 (1H, dd), 2.74-2.65 (1H, m), 2.42-2 · 37 (1H, dd) , 2.04 (3H, m), 1.98 (6H, m), 1.75-1.65 (6H, m), 1.35 (d, 3H), 0.89 (d, 3H) ppm; LRMS ESI m / z 431 [ M + Hf Preparation of 163 Nl-Gold Steel Alkyl-2- {3-[(2R) -2-aminopropyl] phenyl} ethylamine 99200 -226- 200534846

The title compound was prepared from N-1-gold steel alkyl-2- [3-((2R) _2-{[(lR) small phenylethyl] amino} propyl) benzene using a similar method to Preparation 25. Methyl] acetamide (Preparation 162) as a solid, 92% yield. 1H NMR (400MHz, CD3 OD) δ: 7.28-7.05 (4H, m), 3.40 (2H, s), 3.16-3.10 (1H, q), 2.70-2.58 (2H, m), 2.03 (3H, m) , 2.00 (6H, m), 1.72-1.66 (6H, m), 1.09 (d, 3H) ppm; LRMS ESI m / z 327 [M + H] +

Preparation 164

Nl-gold steel alkyl-2- {3-[(2R) -2-({(2R) _2- [4- (benzyloxy) -3 • (hydroxymethyl) phenyl] _2_Ethyl } Amino) propyl] phenyl} ethylamine OTBDMS

[2- (Benzyloxy) -5-((lR) -2-bromo small {[third-butyl (dimethyl) sylalkyl] oxy} ethyl) phenyl] fluorenol ( Preparation 23) (900 mg, 2 mmol) with N-1-adamantyl-2- {3 _ [(2R) -2-aminopropyl] phenyl} acetamide (Preparation 163) (1.3 G, 4 mmol), heated at 90 ° C for 24 hours. The reaction mixture was then allowed to cool to room temperature, and the crude product was purified by column chromatography on silica gel, and was dissolved in methane: methanol: 0.88 ammonia 95: 5: 0.5 to give the title compound as a light foam, 83 % Yield, 1.16 g. 1HNMR (400MHz, CD3OD) 5: 7.48-7.28 (6H, m), 7.17-6.72 (6H, m), 5.14 (2H, s), 4.78-4.74 (1H, m), 4.73-4.64 (m, 2H), 3.36 (2H, s), 2.95-2.84 99200 -227- 200534846 (2H, m), 2.70-2 · 63 (2H, m), 2.59-2.50 (1H, m), 2 · 03 (3H, m), 2.00 (6H, m), 1.70-1.64 (6H, m), 1.05 (3H, d), 0.84 (9H, s), 0.00 (3H, s), -0.18 (3H, s) ppm Abbreviation TBDMS = the activity of the tertiary-butyl (dimethyl) silyl hydrazone compound. Externally active compound of formula (1) acts as an effective / 52 activator and thus the ability of the smooth muscle of the medium to relax. It was measured by measuring the effect of / 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 CO2, and blood was drawn from the femoral artery, and the trachea was isolated. Four preparations were obtained from each animal, dissected from just below the throat, and a trachea of 2.5 cm in length was obtained. By removing the cartilage opposite the tracheal muscles, one piece of the trachea is opened 'and then several lateral slices of 3-4 cartilage ring widths are cut. The knotted preparation was suspended in a 5 ml organ bath using cotton threads passing above and below the cartilage band. Make the strips containing 3 indomethacin

(mdomethacm) (SigmaI7378), 10 // M guanethidine (sigmaG8520) and 10 // M fee 醯 c female (aten〇l〇l) (SigmaA7655) modified Krebs Ringer buffer (Sigma K0507) , Without tension after 20 minutes, at 37. It was heated below 0 ° and inflated at 95% 02/5% CO2, and then an initial tensile force of 1 g was applied. The preparation was allowed to equilibrate for another 30-45 minutes, during which time it was tightened (to 1 g) twice at 15-minute intervals. Changes in tension are recorded and monitored by standard isometric sensors (custom-designed by pflzer) connected to the data collection system. After the tension has reached equilibrium, the tissue is subjected to electric field stimulation (EFS) using the following 99200 • 228-200534846 parameters: a sequence of 10 seconds every 2 minutes, a pulse width of 0.1 milliseconds, 10 Hz and exactly the highest voltage (25 volts) Continuously throughout the length of the experiment. The EFS of the cholinergic nerves in the posterior ganglion in the trachea causes a single-phase contraction of smooth muscle and records the yanking height. Throughout the experiment, a peristaltic pump system (pumping flow rate of 7.5 ml / min) was used to continuously infuse the organ bath with the above-mentioned granules, but when the 2 activators according to the present invention were added, the pump was stopped and experienced Accumulate the time from medication to the bath and start again after reaching the maximum response after the washout period. An experiment to evaluate the efficacy and efficacy is to stop the peristaltic pump after reaching a balance with EFS, and to induce, prepare, and prepare a single dose of 300nM isoproterenol (SigmaI5627) to suppress the contraction of EFS response The biggest response. Then, isoproterenol was washed out over a period of 40 minutes. After induction, washing, and recovery, the standard curve for isoproterenol (isoproterenol curve 1) is a semi-logarithmic increase in concentration, which is performed on all tissues by adding accumulated clumps to the bath. The concentration range used was 丨 ❻ ... to 丨. / ^ 6 ". At the completion of the isoproterenol curve, the preparation was washed for another 40 minutes, and then the second curve was started, whether for isoproterenol ( As an internal control group) or according to the present invention, the 2 stimulator. The 2 stimulator response is expressed as the percentage inhibition of the EFS response. The data of each 2 activator is normalized by the inhibition X in The percentage of maximal inhibition caused by isoproterenol in curve 1 is shown. The EC50 value of the agonist 2 according to the present invention refers to the concentration of the compound required to produce half the maximum effect. Then, according to the present invention The data of End 2 activator is the drug relative to isoproterenol as defined by the ratio (EC "End 2 Activator) / (EC50 0 Isoprenol 99200 -229- 200534846 Epinephrine) Effective representation. Do the work of 2 media The / 3-2 activator activity of the test compound was confirmed using the above proposal, but before the / 3-2 activator curve according to the invention was established, the preparation was reacted with 300 nM ICI 118551 (optionally antagonist) is pre-cultured (minimum 45 minutes). This antagonist causes the dose-response curve of the test compound to shift to the right in the case of two mediators. According to another alternative, the formula ( 1) The agonist efficacy of the / 32 receptor of a compound can also be measured by measuring the concentration of the compound of the present invention required to produce one and a half maximal effects on the / 32 receptor (EC5Q). Compound Preparation Dilute the 10mMA00% DMSO (dimethylformite) stock solution of the compound in 4% DMSO to the highest required dose. This highest dose was used to construct a 10:30 logarithmic dilution curve, all in 4% DMSO. Isoproterenol (Sigma 1-5627) was used as a standard in each experiment and was used in control wells on each plate. Data are expressed as% isoproterenol response. Cell cultures reconstituted CHO (Chinese large cheek rat ovary) cells that express human red adrenergic receptors (available from Kobilka et al., PNAS 84: 46-50, 1987, and Bouvier et al., Mol Pharmacol 33: 133-139 1988 CHOh ^), supplemented with 10% bovine fetal serum (Sigma, F4135, lot number 90K8404 Exp 09/04), 2 mM glutamine (Sigma, G7513), 500 μg / ml based factor (Sigma, G7034) And 10 μg / ml Puromycin (Sigma, P8833) in Dulbeccos MEM / NUT mixture F12 (Gibco, 21331-020). Cells were seeded to obtain approximately 90% confluence for testing. 99200 • 230- 200534846 Detection method Transfer 25 μl / well of each dose of compound to cAMp-FlashPlate® (NEN, SMP004B), with 1% DMS0 as the basic control group, and 100 nM isoproterenol as the highest control group. Dilute it 1: 2 by adding 25 μl / well PBS. Cells were trypsinized (0.25% Sigma, T4049), washed with PBS (Gibco, 14040-174), and resuspended in stimulation buffer (NEN, SMP004B) to obtain 1 x 10 6 cells / ml CHOhB2. Compounds were incubated with 50 μl / well of cells for 1 hour. Then, the cells were lysed by adding 100 μl / well detection buffer (NEN, SMP004B) containing 0.18 // Ci / ml 125I-cAMP (NEN, NEX-130), and the plate was allowed to stand at room temperature. Incubate for another 2 hours. The amount of 12 51-cAMP, which has been incorporated into FlashPlate®, is quantified using Topcount NXT (Packard). The normal counting efficiency is over 1 minute. Dose-response data are expressed in% isoproterenol and are anastomosed using a four-parameter S-shaped anastomosis. Therefore, it has been found that the compounds of formula (I) according to the invention that have been tested show / 32 cAMPEC50 below: 10 nM. The following table illustrates the activity of the compounds of the invention: Example EC50 (nM) 1 0.143 14 0.0640 16 0.874 23 0.0800 24 0.150 46 0.838 62 0.444 99200 -231-200534846

63 0.0750 66 1.16 88 0.434 102 0.100 114 0.134 99 200 -232-

Claims (1)

200534846 10. Scope of patent application: 1. A compound of formula ⑴ Where (CHA-Ceow1 group is in meta or para position, -R1 and R2 are independently selected from fluorene and CrC4 alkyl group, -η is 0, 1 or 2, and Q1 is a group selected from: R3 R3 tNH-CVC: 4 alkyl and group * _N (R8) -Q2-A, where -Q2 is a single bond or CrC4 alkylene, -R8 is HiCVq alkyl, -P is 1 or 2, and -A is C3 cycloalkyl, 2 or more carbon atoms of the cycloalkyl are optionally bridged by one or more carbon atoms, preferably 1, 2, 3 or 4 gray atoms, The radical ^^ sigma is a 5 to ι membered heterocyclic group, optionally aromatic, containing one, two, three, or four heteroatoms selected from 0, S, or N, optionally by Ci- C4 alkyl or occ alkyl substituted, or a group of the formula 99200 200534846 -R3, R4, R5, R6 and R7 are the same or different and are selected from the group consisting of fluorene, q-C4 alkyl, OR9, SR9, SOR9, S02R9, halo, CN, CF3, OCF3, benzyl, 〇-benzene Group, S-phenyl, S02_morpholinyl, 0_ (CH2) 3-tetrahydropyrrolyl, COOR9, S02 NR9 R10, CONR9 R10, NR9 R10 and NHCOR10; -R9 is the same or different from Rio And is selected from H4Ci_C4 alkyl, and * represents the point of attachment to the carbonyl group; or, if appropriate, 'a pharmaceutically acceptable salt and / or isomer, tautomer, solvate, or isotopic modification, The condition is that when η is 0, then Q1 is not -NHCH3, and when n is i or 2, then: 1) Q1 is tNH-C! -C4 alkyl or * -N (R8) -Q2 A, where a is -C3-C1 () cycloalkyl, two or more carbon atoms of the cycloalkyl are optionally bridged by one or more carbon atoms, -0-phenyl than fluorenyl, -5 to 10-membered heterocyclic group, optionally aromatic, containing one, two, three or four heteroatoms selected from 0, S or N, optionally (^^^ alkyl or Oq -Q Alkyl substituted, the heterocyclic group is not pyridyl,-the group of the formula 99200 200534846 CN, SOR9, S02R9, phenyl, 0-phenyl, S-phenyl, S02-morpholinyl or 0- (CH2) 3-tetrahydropyrrolyl, and / or 2) When R1 and R2 When one is Η, the other is not CH3. 2_ The compound of claim 1, wherein Q1 is a group of the formula R3 Or * _N (R8) -Q2-A, where Q2 is a single bond or a cardiac alkylene group, R8 is Η, and Α is R5 where R3, R4, R5, R6 and R7 are as defined in claim 1. 3. The compound as claimed in claim 1, wherein Q1 is a group * -N (R8) _Q2-A, where A is a group of the formula 99200 200534846 F, CF3, 0CF3, COOR9, S02NR9R10, and at least two of R3 to R7 represent Η, where R9 and R10 are the same or different, and are selected from 11 or (^-(: 4 alkyl. 4. For example, the compound of claim 3, wherein ruler 3, 114, ruler 5, 116, and 117 are the same or different, and are selected from the group consisting of Η, CH3, OH, OCH3, SCH3, OCH2CH3, C1, F, CF3, 〇CF3, COOH , S02NH2, and at least two of R3 to R7 represent Η 〇5. The compound of claim 4, wherein 1 ^,: ^, 圮, 116 and 1 ^ are the same or different and are selected from Η, CH3, OH , OCH3, SCH3, OCH2CH3, C1, F, Ch, OCF3, COOH, S02NH2, and at least three of R3 to R7 represent H. 6. The compound of claim 1, wherein Q1 is * -N (R8) -Q2 -A, where A is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or auranyl. 7. A compound according to any one of 1 to 6, wherein R8 is Η , Methyl or ethyl 0 φ 8 · As in any one of the items 1 to 6 in which Q2 is selected from a bond, (¾ ...- (ch2) 2-,-(ch2) 3-, -c (ch3) 2-ch2 ·, -ch2-c (ch3) 2- and _ch (c h3): 9. The compound of claim 1, wherein Q1 is The compound of any one of items 1 to 6 from 10 to July, wherein η is 0 or 1 1011. If the compound of any one of members 1 to 6 is invited, where Ri is Η and R2 is Η 99200 200534846 or CH2 CH3. 12_ The compound of any one of claims 1 to 6, wherein R1 is CH3 and R2 is CH3. 13. A (R, R) · stereoisomer of a compound according to any one of claims 1 to 6. 14. The compound according to any one of claims 1 to 6, wherein the c (= 0) Q1 group is in the meta position. 15_ The compound of any one of claims 1 to 6, wherein η is 0 or 1, Ri is η or CH3, R2 is η, CH3 or CH2CH3, and the (CHA-Q ^ C ^ Q1 group is in between 16. The compound according to claim 1, which is selected from the group consisting of N-cycloheptyl-2- {3-[(2R) -2-({(2R) -2-hydroxy-2- [4-hydroxyl -3- (hydroxymethyl) phenyl] ethyl} amino) propyl] phenyl} ethanamide; N- (cyclohexylfluorenyl) -2- {3_ |; (2R) -2-({ (2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) benzyl] ethyl} amino) propyl] phenyl} -N-methylacetamide; N-[( 1S) Cyclohexylethyl] -2- {3-[(2R) -2-({(2R) -2-hydroxy-2 · [4_hydroxy-Mhydroxymethyl) phenyl}] ethyl} amine )] Propyl] phenyl} ethanamide; 2- {3-[(2R > 2 _ ({(2R) -2-hydroxy-2 · [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl } Amino} propyl] phenyl} -N-isopropylacetamidamine; N-cyclopentyl-2- {3-[(2R) -2-({(2R) -2-hydroxy-2 -[4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) propyl] phenyl} ethanamine; N- (cyclobutylmethyl) _2_ {3 _ [(2R) -2- ( {(2R) -2_hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) propyl] phenyl} acetamidamine; N- (cyclopentylmethyl )-2_{ 3-[(2R) _2-({(2R) -2-hydroxy · 2_ [4-hydroxy each (hydroxymethyl 99200 200534846) phenyl] ethyl} amino) propyl] phenyl} acetamidamine; N-cyclohexyl-2- {3 _ [(2R) -2-({(2R) -2-hydroxy-2_ [4-hydroxy-3- (hydroxymethyl) benzyl] ethyl} amino) propyl ] Phenyl} ethanamide; N-cyclobutyl-2- {3-[(2R) -2-({(2R) -2-hydroxy-2_ [4-hydroxy-3- (hydroxymethyl) benzyl Group] ethyl} amino) propyl] phenyl} acetamidamine; N- (cyclohexylmethyl) -2- {3-[(2R) -2-({(2R) -2-hydroxy-2 -[4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) propyl] phenyl} ethanamine; N- (cyclopropylmethyl) -2- {3-[(2R ) -2-({(2R) -2-hydroxy-2- [4-hydroxy (hydroxymethyl) phenyl] ethyl} amino) propyl] phenyl} acetamidamine; N- (cycloheptyl Methyl) -2- {3-[(2R) -2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) propyl Phenyl] phenyl} acetamidine; N_1-adamantyl-2- {3-[(2R) -2 _ ({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl ) Phenyl] ethyl} amino) propyl] phenyl} acetamidamine; N- (l-goldenylmethyl) -2- {3-[(2R) -2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) propyl] phenyl} Hydrazine; N-2-gold steel alkyl-2- {3-[(2R) -2-({(2R) -2-hydroxy-2- [4-hydroxy_3_ (hydroxymethyl) phenyl]] Ethyl} amino) propyl] phenyl} acetamidine; N- (2-cyclohexylethyl) -2- {3-[(2R) -2-({(2R) -2-hydroxy-2 -[4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) propyl] phenyl} -N-methylacetamidamine; N-cycloheptyl-2- {3-[( 2R) -2 _ ({(2R) -2-hydroxy-2- [4-hydroxy ((hydroxymethyl) benzyl] ethyl} amino) propyl) phenyl] phenylmethyl N-methylacetamide; N -Badhexyl-N-ethyl-2- {3-[(2R) -2-({(2R) -2- | ^ yl-2- [4 · Ethyl-3- (Ethyl) phenyl ] Ethyl} amino) propyl] phenyl} acetamidine; Ν- (2-ί ^ hexylethyl) -2- {3-[(2R) -2-({(2R) -2- | % Yl-2- [4-Ethyl-3- (Ethyl 99200 200534846 methyl) phenyl] ethyl} amino) propyl] phenyl} ethenylamine; N- (4-octyl) -2 -{3- [2-({(2R) -2_hydroxy-2- [4-hydroxy_3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] phenyl } Acetamidine; N- (2,6-dimethoxybenzyl) -2- {3- [2 _ ({(2R) _2-hydroxy-2- [4 · hydroxy_3- (hydroxymethyl) Phenyl] ethyl} amino) -2-methylpropyl] phenyl} acetamidamine; N-benzyl_2- {3- [2-({(2R) -2-hydroxy-2 -[4-hydroxy_3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] phenyl} acetamide; 4-{(lR) -2-[(2- {3_ [2- (3,4-dihydroisoquinoline-2 (1H) -yl) -2 • ketoethyl] phenyldimethylethyl) amino] -1 · Ethyl}- 2- (hydroxymethyl) phenol; N- [2-fluoroyl-5- (trifluoromethyl) fluorenyl] -2- {3- [2-({(2R) -2-hydroxy_2- [ 4 · Hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] phenyl} acetamidamine; N- (2,6-difluorofluorenyl) -2- {3- [2-({(2R) -2- ^ lyl-2- [4-Cycloyl-3- (Methyl) phenyl] ethyl} amino) -2-fluorenylpropyl] Phenyl} acetamide; 2- {3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2 -Methylpropyl] phenyl} -N- [2- (methylthio) benzyl] ethanamine; N- (2,3-dimethylmethyl) -2- {3- [2- ( {(2R) -2_Cycloyl-2- [4-Cycloyl-3- (Methyl) phenyl] ethyl} amino) -2-fluorenylpropyl] phenyl} ethanamide; 2 -{3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2 · methylpropyl] phenyl } · N- [3- (trifluoromethyl) hexyl] ethanamine; Ν- [4-chloro-3- (trifluoromethyl) benzyl] _2- {3- [2-({( 2R) -2_hydroxy-2_ [4 -Hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-fluorenylpropyl] phenyl} ethenamide; N- [2-Gasyl-5- (trifluoromethyl) Fluorenyl] -2- {3- [2-({(2R) -2-hydroxy · 2- [4-hydroxy-3- (hydroxyfluorenyl) phenyl] ethyl} amino) -2-methyl Propyl] phenyl} ethanamide; N- [3,5-bis (trifluorofluorenyl) benzyl] -2- {3- [2-({(2R) -2-hydroxy-2- [4 -Hydroxyl 99200 200534846 each (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] phenyl} acetamidamine; N- [3-fluoroyl-5- (trifluoromethyl) Benzyl] -2- {3- [2-({(2R) -2_hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methyl Propyl] phenyl} acetamidamine; N- [2- (4-Gaphenyl) ethyl] -3- {2-[(2R) -2-Isyl-2- (4-Isyl-3 -Ethyl-methylphenyl) ethylamino] -2-methylpropyl} benzamide; 3- {2-[(2R) -2-Ethyl-2- (4-Ethyl-3 -Via methylphenyl) -ethylamino] -2-methylpropylbenzene N- [2- (4-methylphenyl) ethyl] benzamide; 3- {2-[(2R) -2-hydroxy-2- (4-hydroxy-3-hydroxymethylphenyl) -ethylamino] -2-methyl-propyl} -N- [2- (4 · trifluoromethylphenyl) Ethyl] benzamidine; Ν- [2_ (3,4-difluorophenyl) ethyl] -3- {2-[(2R) -2-hydroxy-2- ( 4-hydroxy-3-hydroxymethylphenyl) ethylamino] -2-methyl-propyl} -benzamide; N- [2- (3,4-dimethylphenyl) ethyl] -3- {2-[(2R) -2-hydroxy-2- (4-hydroxy-3-hydroxymethylphenyl) -ethylamino] -2-methylpropyl} benzamide; 3- {2-[(2R) -2-hydroxy-2- (4-hydroxy-3 · hydroxymethyl-phenyl) ethylamino] -2-fluorenyl-propyl} -N_ (2-naphthalene-2- -Ethyl) benzamide; N- (l, l-dimethyl-2-phenylethyl) -3- {2-[(2R) -2_hydroxy-2- (4-hydroxy_ 3-hydroxy-fluorenylphenyl) -ethylamino] -2-methylpropyl} phenylhydrazine; 3- {2-[(2R) = 2-hydroxy-2- (4-hydroxy-3- Hydroxymethylphenyl) -ethylamino] -2-methylpropyl} -N- (2-methyl-2-phenylpropyl) phenylhydrazine; N- (4-pyridyl)- 3- {2-[(2R) -2-Ethyl-2- (4-Ethyl-3-Ethyl-methylphenyl) ethylamino] -2-fluorenylpropyl} benzamide; N- (2,6-dimethoxyethynyl) -2- {3- [2-({(2R) -2-Cycloyl-2- [4-Cycloyl-3_ (Cyclomethyl) phenyl ] Ethyl} amino) ethyl] phenyl} acetamidine; N- (3,4-dichlorofluorenyl) -2- {3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3_ (hydroxyfluorenyl) 99200 200534846 phenyl] ethyl} amino) ethyl] phenyl} acetamidinium; N_benzyl -2- {3- [2-({(2R) -2-hydroxy-2- [4-hydroxy · 3- (hydroxymethyl) phenyl] ethyl} amino) ethyl] phenyl} acetamidine Amine; N- (2,3-dihydro-1fluorene-inden-2-yl) -2- {3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxyl (Methyl) phenyl] ethyl} amino) ethyl] phenyl} acetamidamine; 2- {3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- ( Hydroxymethyl) phenyl] ethyl} amino) ethyl] phenyl} -N- (2-phenylethyl) acetamide; 2- {3- [2-({(2R) -2- Ethyl-2- [4-Ethyl-3- (transmethyl) phenyl] ethyl} amino) Ethyl] phenyl} -N- (3-phenylpropyl) acetamidamine; N- Benzyl-3-[(2R) -2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) benzyl] ethyl} amino) propyl] benzyl Fluorenamine; N- (3,4-difluorofluorenyl) -3 _ [(2R) -2-({(2R) -2-hydroxy-2- [4-hydroxy_3- (hydroxymethyl) phenyl ] Ethyl} amino) propyl] benzidine; N- [2-fluoro-5- (trifluorofluorenyl) benzyl] -3-[(2R) -2-({(2R) -2 -Hydroxy-2- [4 · hydroxy_3- (hydroxymethyl) phenyl] ethyl} amino) propyl] phenylhydrazine; Ν- (2,6-dimethoxyfluorenyl) -3 -[(2R) -2-({(2R) -2-hydroxy-2- [4-hydroxy_3- (hydroxyfluorenyl) phenyl] acetamidine} amino) propyl] benzamide; Ν - [2- (4-chlorophenyl) ethyl] -3-[(2R) -2-({(2R) -2 · hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl Group} amino) propyl] benzamide; N_ (2,3-dihydro-111_inden_2_yl) -3-[(2R) _2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxyfluorenyl) phenyl] ethyl} amino) propyl] benzidine; 3-[(2R) -2 _ ({(2R) -2-hydroxy-2- [ 4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) propyl] -N- (2-phenylethyl) benzamide; 3-[(2R) -2-({ (2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxyfluorenyl) phenyl] ethyl} amine 99200 200534846 group) propyl] -N-[(1R) -1_phenylethyl ] Benzamidine; 3-[(2R) -2-({(2R) -2-Cycloyl-2- [4-Cycloyl-3 ((methyl) phenyl] ethyl} amino) propyl) Phenyl] -N- (3-phenylpropyl) benzamide; 4-[(lR) -2-({(lR) -2- [3- (3,4-dihydroisobutan-2 (1H) -Michioyl) phenyl] -1-methylethyl} amino) -1-hydroxyethyl] -2- (hydroxymethyl) phenol; N- (2,3-dimethylbenzyl) Group) -3-[(2R) -2 _ ({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) propyl] benzyl Amine; N- (5,6-diethyl-2,3-dihydro-1H-inden-2-yl) -3-[(2R) -2-({(2R) -2-hydroxy-2- [4- 经 基 -3- (经Methyl) phenyl] ethyl} amino) propyl] benzidine; N- (4-chlorobenzyl) -3-[(2R) -2-({(2R) _2-hydroxy-2 · [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) propyl] benzidine; 3-[(2R) -2-({(2R) -2-Ethyl-2 -[4-Ethyl-3- (methyl) phenyl] ethyl} amino) propyl] -N-phenylbenzamide; N- [4- (aminosulfonyl) benzyl ] -3-[(2R) -2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) propyl] benzidine Amine; N- [2- (3-fluorophenyl) ethyl] -3- [2-({(2R) -2-Cycloyl-2- [4-Cycloyl-3- (fluorenyl) benzene [Ethyl] ethyl 丨 amino) -2-methylpropyl] benzidine; 3- [2-({(2R) -2-Cycloyl-2- [4-hydroxy-3- (Cyclomethyl ) Phenyl] ethyl} amino) _2_methylpropyl] -N- (2-tetra-rat Isπ each-1-ylethyl) benzylamine; Ν- [2- (2,6-di Phenyl) ethyl] -3- [2-({(2R) -2-Cycloyl_2- [4-Cycloyl-3- (fluorenyl) phenyl] ethyl} amino) -2 -Methylpropyl] benzidine; Ν- (2,3 · dihydro-1H-Memben-2-ylmethyl) -3- [2-({(2R) -2 · meridian · 2- [4-Ethyl-3- (hydroxyamido) phenyl] ethyl} amino) -2-amidopropyl] phenylhydrazine; N- (2- {4-[(butyl Amino) carboxyl] benzyl} ethyl) -3- [2-({(2R) -2-Ethyl-2- [4 · 99200 -ιο · 200534846 hydroxy-3- (hydroxymethyl) phenyl] Ethyl} amino) -2-methylpropyl] benzamide; 3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxyfluorenyl) phenyl ] Ethyl} amino) -2-methylpropyl] -N- {2- [2- (phenylthio) phenyl] ethyl} benzamide; Ν- (2-cyclohexylethyl) -3- [2-({(2R) -2-hydroxy-2- [4 · hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] benzidine Amine; 3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-amidinopropyl] -N -(3-phenylpropyl) benzidine; 3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amine (Yl) -2-fluorenylpropyl] -N- (2-phenylethyl) benzamide; N- [2- (3,6-digas-2-methylphenyl) ethyl]- 3- [2-({(2R) -2-hydroxy-2- [4-hydroxy ((hydroxymethyl) phenyl] ethyl} amino) · 2-fluorenylpropyl] phenylhydrazine; Ν -[2- (5-Gasyl-2-methyllactyl) ethyl] -3- [2-({(2R) -2- | ^ lyl-2- [4-deryl-3- ( Methyl) phenyl] ethyl} amino) -2-methylpropyl] benzamide; 3- [2-({(2R) -2-hydroxy -2- [4-hydroxy · 3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] -N- [2- (3-methoxyphenyl) ethyl] benzene Formamidine; N- [2- (3-ethoxyphenyl) ethyl] · 3- [2-({(2ΙΙ) -2-hydroxy-2- [4-hydroxy-3- (hydroxyfluorenyl) Phenyl] ethyl} amino) -2-methylpropyl] benzidine; 3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl ) Phenyl] ethyl} amino) -2-methylpropyl] -N- {2- [4- (3-tetrahydropyrrole-1-ylpropoxy) phenyl] ethyl} benzene Amine; 3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] -N -{2- [2- (3-tetrahydropyrrole-1_ylpropoxy) phenyl] ethyl} benzamide; 3- [2-({(2R) -2-hydroxy-2- [ 4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2- 99200 -11-200534846 methylpropyl] -N- {2- [3- (3-izg hydropyrrole small group Propoxy) phenyl] ethyl} benzamide; N_ [2- (4_Gaphenyl) ethyl] ethyl-3- [2-({(2R) -2-hydroxy-2- [4 -Hydroxy-3-fluorenylmethyl) phenyl] ethyl} amino) -2-methylpropyl] benzidine; 2- {3_ [2-({(2R) -2-hydroxy-2_ [ 4-hydroxy-3_ (hydroxymethyl) phenyl] ethyl} amino) -2-fluorenylpropyl] P-nitropyridin-1-ylpropyl) ethylamine; N- (cycloheptylmethyl) -2- {3- [2-({(2R) -2-hydroxy-2- [4-hydroxy -3- (hydroxyfluorenyl) phenyl] ethyl} amino) -2-methylpropyl] phenyl} ethanamide; N-1-adamantyl-2- {3- [2- ( {(2R) -2-hydroxy-2_ [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] phenyl} ethenylamine; N-fluorenyl -2- {3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-fluorenylpropyl] Phenyl} -N-methylacetamidamine; N- [2- (4-Gaphenyl) ethyl] -3- [2 _ ({(2R) -2_Ceryl-2- [4-Ceryl -3- (transmethyl) phenyl] ethyl} amino) -2-methylpropyl] benzamide; 3- [2-({(2R) -2-hydroxy-2- [4- Hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] -N- [2- (4-phenoxyphenyl) ethyl] benzamide; N -[2- (4-ethoxyphenyl) ethyl] -3- [2-({(2R) -2-Cycloyl-2- [4-Cyclo-3-((fluorenyl) phenyl)] Ethyl} amino) -2-methylpropyl] benzidine; N- [2- (4-ethylphenyl) ethyl] -3- [2-({(2R) -2- | ^ l-2--2- (4-Ethyl-3- (methyl) phenyl] ethyl} amino) -2-fluorenylpropyl] benzidine; 3- [2-({(2R ) -2-hydroxy -2- [4-hydroxy-3- (hydroxyfluorenyl) phenyl] ethyl} amino) _2_fluorenylpropyl] -N- [2- (6-methylpyridin-2-yl) ethyl] Benzamidine; 3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) · 2-methylpropyl]- Ν- [2- (2-methoxyphenyl) ethyl] benzamide; 99200 -12- 200534846 4-[({3- [2-({(2R) -2-hydroxy_2- [4 -Hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] benzylidene} amino) methyl] benzoic acid methyl ester; N- [4- (di (Methylamino) benzyl] _3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methyl Propyl] benzamide; N- {2- [3-fluoroyl-4- (trifluoromethyl) phenyl] ethyl} -3- [2-({(2R) -2-hydroxy-2 -[4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-fluorenylpropyl] phenylhydrazine; N- [2_ (3-fluoroyl-4-methylbenzene (Yl) ethyl] -3_ [2-({(2R) -2-hydroxy · 2- [4 · hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-fluorenylpropyl ] Benzamidine; N- [2- (2,3-difluoro-4-methylphenyl) ethyl] -3- [2-({(2R) -2-hydroxy-2- [4- Hydroxy-3- (methyl) phenyl] ethyl} amino) -2-methylpropyl] benzidine Amine; 3- [2-({(2R) _2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] -N- (2-Trimethylphenylethyl) benzidine; N- [2- (2,6-difluoro-3-methylphenyl) ethyl] -3- [2-({(2R) -2 _Hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] benzidine; N- [2- (6-amino- 2-fluoro-3-methylphenyl) ethyl] -3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (fluorenyl) phenyl] ethyl } Amino) -2-fluorenylpropyl] benzidine; N- [2- (2-Gasyl-6 · fluoro_3_fluorenylphenyl) ethyl] -3_ [2 _ ({( 2R) -2-hydroxyhydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] benzamide; N- [2- (5-fluoroyl-2- Methylphenyl) ethyl] -3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2- Methylpropyl] benzidine; N- {2- [3-fluoroyl-5- (trifluoromethyl) phenyl] ethyl} -3- [2-({(2R) -2-hydroxy 99200 -13- 200534846 -2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2 · methylpropyl] benzamide; 3- [2-({( 2R) -2-hydroxy-2- [4_hydroxy-3 · (hydroxymethyl) phenyl] ethyl} amino) _2_ methylpropyl ] -N- {2- [2- (trifluoromethyl) phenyl] ethyl} benzamide; 3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3 -(Hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] -N- [2- (2,4,5-trimethylphenyl) ethyl] benzamide; 3- [2-({(2R) -2_hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] -N- ( 2-pyridin-2-ylethyl) benzimidamine; Ν- [2- (1Η_benzimidazol-2-yl) ethyl] -3- [2-({(2R) -2-hydroxy- 2- [4 · hydroxy_3- (transmethyl) phenyl] ethyl} amino) -2-methylpropyl] benzamide; 3- [2-({(2R) _2-hydroxy- 2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) _2_methylpropyl] -N- {2- [4_ (morpholin-4-ylsulfonyl) benzene Phenyl] ethyl} benzamide; N- [2- (3-amino-2-hydroxyphenyl) ethyl] -3- [2-({(2R) -2-hydroxy-2_ [4- Hydroxy-3- (methyl) phenyl] ethyl} amino) -2-methylpropyl] benzamide; N- [4-fluoro-2- (trifluoromethyl) benzyl] -3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (methyl) phenylhydrazone] ethyl} amino) -2-methylpropyl] benzenehydrazone Amine; N- (3-chlorobenzyl) -3- [2-({(2R) -2-hydroxy-2- [4-hydroxy_3- (hydroxyfluorenyl) phenyl] ethyl } Amino) -2-methylpropyl] benzidine; N- (2-airbenzyl) -3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3 -(Hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] phenylhydrazine; N- [2- (4,6-dimethylpyrimidine_2_yl) ethyl] -3- [2-({(2R) -2-hydroxy-2 · [4-hydroxy-3- (hydroxyamido) phenyl] ethyl} amino) _2_methylpropyl] benzamide ; 3- [2-({(2R) -2-hydroxy-2- [4-hydroxy_3- (hydroxymethyl) phenyl] ethyl} amino) -2. 99200 -14- 200534846 methyl propyl Group] -N-〇 (3-methylpyridine Iyl) ethyl] benzamide; N- [2- (2-Gaphenyl) ethyl] -3- [2 _ ({(2R) -2 -Ethyl-2- [4-Ethyl-3- (transmethyl) phenyl] ethyl} amino) · 2 · methylpropyl] benzidine; N- [2- (l-gold Steel alkyl) ethyl] -3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) _2_methyl Propyl] benzidine; H2 _ ({(2R) -2 · hydroxy_2_ [4_hydroxy_3_fluorenylmethyl] phenyl] ethyl} amino group> 2-methylpropyl] _N- [2 -(1_fanyl) ethyl] benzidine, N- [2- (2,6-dimethylphenyl) ethyl] -3- [2-({(2R) -2-hydroxy- 2- [4-hydroxy-3- (hydroxyfluorenyl) phenyl] ethyl} amino) -2-methylpropane ] Benzamidine; 3- [2-({(2R) _2-hydroxy-2- [4-hydroxy-3-fluorenylmethyl) phenyl] ethyl} amino) _2_methylpropyl] -N -{2- [4- (methylthio) phenyl] ethyl} benzamide; N- [2- (5-Gas-2-fluorobenzyl) ethyl] -3- [2- ( {(2R) -2-hydroxy_2- [4-hydroxy-3- (hydroxyfluorenyl) phenyl] ethyl} amino) -2-methylpropyl] benzidine; N- [2_ ( 2-amino-4-fluorobenzyl) ethyl] -3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} Amine) -2-methylpropyl] benzidine; 3- [2-({(2R) _2-hydroxy_2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} Amine) -2-fluorenylpropyl] -N- [2- (4-methoxy-2,5 · dimethylphenyl) ethyl] benzamide; Ν- [2- (2, 3-difluorophenyl) ethyl] -3- [2-({(2R) _2-hydroxy_2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2 -Fluorenylpropyl] benzamide; 3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino)- 2-methylpropyl] · N- [2- (4-methoxy-2,3-dimethylphenyl) ethyl] benzidine; N- (2-biphenyl-4-ylethyl Group) -3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxyfluorenyl) phenyl] ethyl} amino) -2-methyl Group] benzamidine; N- [2- (2,4-dimethylphenyl) ethyl] _3_ [2-({(2R) -2-hydroxy-2- [4_hydroxy 99200 -15- 200534846 -3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] benzamide; N- [2- (2,3-dimethylphenyl) ethyl]- 3- [2-({(2R) -2-hydroxy · 2- [4- mesitylmethyl) phenyl] ethyl} amino) -2-methylpropyl] benzamide; [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) _2_methylpropyl] -N- {2- [3 -(Trifluoromethyl) phenyl] ethyl} benzamide; N- [2- (4-amino-2-fluorophenyl) ethyl] -3- [2-({(2R)- 2-hydroxy_2- [4-Cyclo-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] benzamide; Ν · (2,5-dimethyl Benzyl) -3- [2-({(2R) -2 · hydroxy-2- [4-hydroxyhydroxymethyl) phenyl] ethyl} amino) · 2-methylpropyl] benzidine Amine; Ν_ (3,4-diaziridinyl) -3- {3- [2-[{(2R) -2-hydroxy-2- [4-hydroxy-3_ (hydroxymethyl) phenyl] ethyl } Amino) -2-methylpropyl] phenyl} propanamine; 3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl ] Ethyl} amino) _2_methylpropyl] -N- {2- [4- (trifluoromethoxy) Group] ethyl} benzamide; 3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2 -Methylpropyl] -N- [2- (4-hydroxyphenyl) -2-methylpropyl] benzamide; 3- [2-({(2R) -2-hydroxy-2- [ 4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-fluorenylpropyl] -N- [2- (4-hydroxy-3-fluorenylphenyl) ethyl] benzene Formamidine; N- [2- (4-hydroxy-2,3-dimethylphenyl) ethyl] -3- [2-({(2R) -2-hydroxy-2_ [4-hydroxy-3 -(Hydroxymethyl) phenyl] ethyl} amino) -2-fluorenylpropyl] benzamide; N- [2- (4-hydroxy-2,5-difluorenylphenyl) ethyl ] _3- [2 _ ({(2R) -2-hydroxy-2- [4_hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] benzidine; N- (3,4-Diaminobenzyl) -2- {3- [2-({(2R) -2-hydroxy-2- [4-hydroxy! (Hydroxymethyl) phenyl] ethyl} amino) -2-fluorenylpropyl] benzyl} ethylamine, Ν- (3,5 · difluorofluorenyl) -2- {3- [2- ({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxyfluorenyl) 99200 -16-200534846 phenyl] ethyl} amino) -2-methylpropyl] phenyl} ethyl Amidoamine; 2- {3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropane Phenyl] phenylbenzene N- (pyridin-2-ylmethyl) acetamide; N-ethyl-3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- ( Hydroxymethyl) phenyl] ethyl} amino) -2-fluorenylpropyl] -N- (3-phenylpropyl) benzamide; 3- [2-({(2R) -2- Hydroxy-2- [4-hydroxy_3- (hydroxymethyl) phenyl] ethyl} amino) _2_methylpropyl] -N- [3- (4-hydroxyphenyl) propyl] benzidine Amine; 3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) _2_ ® methylpropyl] -N- [2- (3-methylphenyl) ethyl] benzidine; 3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl ] Ethyl} amino) _2 · methylpropyl] -N- [2- (6-methoxypyridin-3-yl) ethyl] benzamide; 3- [2-({(2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxyfluorenyl) phenyl] ethyl} amino -2_methylpropyl] -N- [3- (3-methoxyphenyl) propyl] phenylhydrazine; N- [3- (4-Gaphenyl) propyl] -3- {2- [(2R) -2-hydroxy-2- (4-hydroxy-3-hydroxymethylphenyl) ethylamino] -2-methylpropyl} benzamide; $ 3- [2-({( 2R) -2-hydroxy-2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] -N- {2- [4- (1Η- Pyrazole small group) phenoxy] ethyl} benzamide; Ν- [2- (3,4-difluorophenyl) ethyl] -3- [2-({(2R) -2-hydroxy _2_ [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] benzamide; 3- [2-({(2R) -2-hydroxy -2- [4-hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-fluorenylpropyl] -N- (2-fluorin-5-ylethyl) benzidine Amine; and N- [3- (2 · ethyl-2,3-dihydro-1-benzofuran-5-yl) propyl] -3- [2 _ ({(2R) -2_hydroxy-2- [4-Hydroxy-3- (hydroxymethyl) phenyl] ethyl} amino) -2-methylpropyl] benzidine. 99200 -17 · 200534846 17. A method for preparing a compound of formula (I), or a pharmaceutically acceptable salt or derivative thereof, as described in any one of claims i to 16 below, comprising the steps of Acid: OH Η (CH2) n OH 〇 (2) Coupling with amine of formula N (R8) -Q2_ACD, R3 R4 R3 w Λ -¾ κ (3 ,,) where R8, Q2, Α, ρ & R3 to R6 are as defined above for the compound of formula ⑴. Zhan 18. A pharmaceutical composition comprising at least an effective amount of a compound of formula 所述 as described in claim m, or a pharmaceutically acceptable salt or derivation thereof = a pharmaceutical composition of claim 18, which It further comprises one or both of excipients and / or additives. Preface • The compound of formula (I), or a pharmaceutically acceptable form or composition thereof, as claimed in claim 1, which is used as a medicament. I. Derivatized 21. A compound of formula (I), or a pharmaceutically acceptable form or composition thereof, as claimed, for use in the treatment of a disorder or condition involving a derivative. Physical diseases, 22. If requested, a compound of formula (I) or a pharmaceutically acceptable salt thereof, a derived form or a composition of -18-200534846, which is used to treat diseases, disorders, and symptoms, and is selected from: Asthma of this type, etiology or pathogenesis, especially the asthma of the following members, selected from the group consisting of ectopic asthma, non-ectopic asthma, allergic asthma, ectopic bronchial IgE-mediated asthma, bronchial asthma Spontaneous asthma, real asthma, endogenous asthma due to pathophysiology, exogenous asthma due to environmental factors, spontaneous asthma due to unknown or insignificant causes, non-ectopic asthma, bronchitis gas%, Emphysema, asthma caused by exercise, asthma caused by allergen, asthma caused by cold air, occupational asthma, infectious asthma caused by bacterial, fungal, protozoan or viral infection, non-allergic asthma, Early asthma, wheezing infant signs, and bronchial bronchitis, 'Chronic or acute bronchoconstriction, chronic bronchitis, small airway obstruction, and emphysema' No matter what type, etiology or pathogenesis of obstruction or inflammatory airway disease, especially the following members of the obstruction or inflammatory airway disease, are selected from the group consisting of chronic eosinophilic pneumonia, chronic obstructive pulmonary disease (COPD), including COPD COPD with or without associated chronic bronchitis, emphysema, or dyspnea, characterized by COPD with irreversible, progressive airway obstruction, adult dyspnea syndrome (ARDS), and airway crossing caused by other medications Deterioration of responsiveness and airway diseases associated with pulmonary hypertension, • Bronchiolitis regardless of type, etiology or pathogenesis, especially 99200 -19- 200534846 are bronchitis from the following members, selected from the group including acute Bronchitis, acute laryngotracheal bronchitis, arachis bronchitis, catarrhal bronchitis, Merubic bronchitis, dry bronchitis, infectious asthmatic bronchitis, sputum bronchial Inflammation, staphylococcus or keycocci bronchitis and alveolar bronchitis, • acute lung injury, • branches of any type, etiology or pathogenesis Tracheal dilatation, especially branch tracheal dilatation of the following members, is selected from the group consisting of cylindrical branch tracheal expansion, sac-like branch tracheal expansion, spindle-shaped branch tracheal expansion, microvascular branch tracheal expansion, gallbladder branch tracheal expansion, dry bronchiectasis and follicle Branch trachea dilatation. 23 · —Such as a request! The use of a compound of formula (I) or a pharmaceutically acceptable salt, a bamboo-derived form, or a composition according to any one of 16 to 16, which has a / 32 activator activity. 24. —Use of a compound of formula (I) or a pharmaceutically acceptable salt, solvate or composition thereof according to any one of claims 1 to 16 in the manufacture of a medicament for the treatment selected from the group consisting of Diseases, disorders and symptoms of the group described in 22. 25. A combination of a compound according to any one of claims 1 to 16 and a therapeutic agent selected from the group consisting of: ⑻ 5-lipoxygenase (5-LO) inhibitor or 5-lipoxygenase activating protein ( (FLAP) antagonists, (b) leukotriene antagonists (LTRA), including LTB4, LTC4, ah and their antagonists, 99200-20 · 200534846 (c) histamine styloid antagonists, including Hirschmann and H3 antagonists, ⑷ And-sympathetic agent with adrenergic receptor activator vasoconstrictor for depletion, muscarinic M3 receptor antagonist or anticholinergic agent, (f) PDE inhibitors, such as pDE3, Inhibitors of pDE4 and pDE5, (g) Theophylline, Scopolamine sodium grenate, (1) COX inhibitors' non-selective and selective cox-1 or cox-2 inhibitors • (NSAID ) Both, ① Oral and inhaled corticosteroids, such as DAGR (Corticoid Receptor Dissociator), (k) Monoclonal antibodies with activity against endogenous inflammatory bulk, (l) Anti-tumor necrosis factor ( Anti-^! ^^) agents, (m) adhesion molecule inhibitors, including antagonists, kinin-Bi- and B2-receptor antagonists, 0 Agents, (p) inhibitors of interstitial metalloproteinases (MMPs), tachykinins NK2, NK2 and NK3 receptor antagonists, (r) elastase inhibitors, (s) adenosine A2a receptor activators , ⑴ inhibitors of urokinase, ⑻ compounds that act on dopamine receptors, such as D2 activators, (v) modulators of the NF / c / 5 pathway, such as IKK inhibitors, (w) cytokines send messages Modulators of pathways, such as ρ38ΜΑρkinase, _ 99200 -21-200534846 Kinase or JAK kinase inhibitors, ⑻ can be classified as mucopolysaccharide decomposers or anti-cough agents, (y) antibiotics, (z) HDAC inhibitors, and (aa) PI3 kinase inhibitors. 99200 22- 200534846 VII. Designated representative map ... (I) The designated representative map of this case is: (none) (II) The component symbols of this representative map are briefly explained: 8. If there is a chemical formula in this case, please disclose the features that can best show the invention Chemical formula: (CH2) n people Q1 (1) 99200