TW200531959A - Formamide derivatives 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

200531959 IX. Description of the invention: [Technology Xuan collar weaving belonging to the invention] The present invention relates to a "synergist of the following general formula:

0 5 wherein R, R, n, and Q1 have the meanings indicated below; and a method for preparing and using a composition containing the compound and a derivative thereof. Adrenergic receptors are members of the general family of receptors that couple large G proteins. The subfamily of adrenergic receptors can be divided into α and β subfamilies, and the β 10 subfamily consists of at least 3 receptor subtypes (βΐ, β2, and β3. These receptors are found in many mammalian systems and organs There are different expression patterns in tissues. Β2 adrenergic (β2) receptors are mainly expressed in smooth muscle cells (such as the smooth muscle of blood vessels, bronchial tubes, uterus or intestines), while β3 adrenergic receptors are mainly It is expressed in adipose tissue (therefore, β3 synergists have the potential to use 15 to treat obesity and diabetes), and βΐ adrenergic receptors are mainly expressed in cardiac tissue (thus, βΐ synergists are mainly used as hearts Stimulants). The pathophysiology and treatment of respiratory diseases have been extensively reviewed in the literature (for reference, see Barnes, P. J. Chest, 1997, 20 111: 2, ppl7S-26S; Bryan, SA, et al., Expert Opinion on investigational drug (2005, 9: 1, pp25-42), therefore, only a brief Overview to provide Some background information. 5

Glucocorticoids, anti-leukotrienes, tea test, cromones, anticholinergics and β2 synergists are now used to treat allergic and non-allergic airway diseases such as asthma and chronic Obstructive airway disease (COPD)). Treatment strategies for these diseases include both short-acting and long-acting inhaled β2 synergists. Short-acting effect starts quickly 10 15

20 β2 synergists can be used to "rescue, bronchiectasis, however, long-acting forms can provide continuous relief and are used as maintenance therapy. Bronchodilators can be expressed via adrenaline 爿 b expressed in airway smooth muscle cells. Agonism is transmitted, and the 1-unit is thus bronchiectasis. Therefore, β2 synergists can be used as a functional anti- ^ to prevent and completely change all bronchoconstriction substances (including leukotriene D4 ^ TD4), B Bleeding test, bradykinin, prostaglandin, histamine, and endothelin). De-n ^ equivalents are so widely distributed in the ah channel, so β2 cells. For example, ringing plays a role in asthma. The release agent of other types of fine-tightening substances can stabilize obese cells. Inhibiting the bronchial air inducement "is the principle of how pottery agents block allergens, sports, and cold human airways ^ trachea contraction. In addition, pottery agents can inhibit hormone reflex ^ hormonal nerve material, which can reduce the bile test. In addition to airway, t σ # in other organs', established ρ2 adrenergic receptors will also show, And, therefore, β2 synergists (such as those described in the present invention 200531959) have been applied to treat other diseases such as (but not limited to) the nervous system, premature birth, congestive heart failure, depression, inflammatory and Allergic skin disease, psoriasis, proliferative skin disease, glaucoma; and it can be excellently applied to the condition of reducing gastric acidity (especially on the stomach and peptic ulcer). However, many β2 synergists are used because of their low selectivity, or because of high systemic exposure, and the transmission of negative side effects (muscle tremor, heartbeat) driven primarily by the action of β2 adrenergic receptors, which are expressed outside the airway Speeding, palpitations, restlessness). Therefore, there is a need to improve this type of medicine. Therefore, there is still a need for novel β2 synergists with appropriate pharmacological profiles (e.g., in terms of potency, selectivity, pharmacokinetics, or duration of action). In this context, the invention relates to a novel β2 synergist. Various formamidine derivatives have been revealed. For example, us 15 2004/0006112 reveals a compound of the following formula that is effective as a β2 synergist:

US 2003/0229058 discloses a selective β2 synergist of the formula: 7 200531959 R13

However, the aforementioned amidine derivatives do not show a pharmacological profile that can be used as a drug that can effectively treat β3-regulated diseases and / or symptoms such as allergic and non-allergic airway diseases; especially by inhalation . • 5 [Abstract] The present invention relates to a compound of the general formula (1):

ΗΝ Ο ^ -Η where (CHA-CtC ^ Q1 group is at the meta or para position;

-R1 and R2 are each independently selected from fluorene and CrC4 alkyl; 10 -η is 0, 1 or 2; -Q1 is a group selected from:

R5 where ρ is 1 or 2 and q is 1 or 2, the group may be optionally connected by a carbon atom bridge 200531959,

And * -Nr8-q2-a group, in which Q2 is a CVW alkyl group, R8 may be a fluorene or CrC4 alkyl group and A may be a phenyl group, a C3_Cig ring alkyl group, and the ring alkyl group may be optionally selected from-or more (Preferably i, 2, 3, or 4) carbon atoms, tetrachloropropanyl, "primidyl, tetrahydrothipiperanyl, or the following groups:

R3 R4

-R, R, R, R6 and r7 may be the same or different, and may be selected from the group consisting of H, CrQ alkyl, OR9, SR9, Sor9, so2R9, _, cd, cd, 9, CF3, 〇CF3, S02NR9R10, co-NR9R10, NR9R10, NHCOR10 and phenyl optionally substituted with 1 to 3 groups selected from the group consisting of OR9, _ and CrC4; -R9 and R1G may be the same or different, and Selected from fluorene or C] _C4 alkyl; and * represents a position attached to several groups; 15 or, if appropriate, a pharmaceutically acceptable salt thereof and / or its isomers, tautomers, solvates Or isotopic variants. The compound of formula (1) is a synergist of the β2 receptor, which is particularly useful for the treatment of diseases and / or symptoms regulated by β3, and it can show excellent efficacy, especially when it is administered via the inhalation route. In the above general formula (1), "c4c4alkyl and crc4alkylene represent a straight or branched chain group containing 1, 2, 3 or 4 carbon atoms. If they carry a substituent or serve as This also applies to substituents of other groups, such as in 50- (CrC4) alkyl, SO ^ -Q) alkyl, etc. Examples of suitable (CVQ) alkyl groups are methyl, ethyl, n-propyl , Isopropyl, n-butyl, isobutyl, secondary butyl, tertiary butyl ... Examples of suitable 0- (CrC4) alkyl groups are methoxy, ethoxy, n-propoxy , Isopropoxy, n-butoxy, isobutoxy, secondary butoxy, and tertiary butoxy ... 10 2 or more carbon atoms C3- optionally bridged by one or more carbon atoms C1G cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, adamantyl, bicyclo [3.1.1] heptane, bicyclo [2.2.1] heptane, bicyclo [2.2. 2] Octane. The preferred cycloalkyl radicals are cyclohexyl and adamantine. In the end, the radical represents a halogen atom selected from the 15 group consisting of fluorine, gas, bromine and iodine, especially fluorine or gas. In the following, the free bond on the phenyl group (such as below Column structure):

This means that the phenyl group may be substituted at the meta or para position. 20 Compound of formula (1): 10 200531959

(CH2> n \ / Qi V 〇⑴ can be prepared using conventional procedures, such as using the methods set forth below, where Q1, Q2, R1, R2, A, and η are as previously defined for the compound of formula (1) (Unless otherwise stated). The amidine derivative of formula (1) can be obtained by letting the acid of formula (2):

NHCHO (2) and formula NHR8-Q2-A (3)

R5

R4R5

6 R or (3-

6 R Η

(3J amine is prepared by combining. This mixture is usually in excess of the amine (as an acid acceptor) 10, with a conventional coupling agent (for example, 1- (3-dimethylaminopropyl)- 3-ethylcarbodiimide hydrochloride, N, N'-dicyclohexylcarbodiimide or hexafluorophosphate 0- (1Η-benzotriazol-1-yl) -N, N, N ', N'-tetramethyl saw), selective to the presence of a catalyst (such as 1-hydroxybenzotriazole hydrate or 1-hydroxy-7-acylbenzotriazole), and to a tertiary amine base (such as N-methylmorpholine, triethylamine 11 200531959 or diisopropylethylamine). The reaction can be performed in a suitable solvent (such as pyridine, dimethylformamide, tetrahydrofuran, dimethyl Sulfonium, mono-alkane, or ethyl acetate), at a temperature of 10. (: to 4 (TC temperature (room temperature)). Butan, 24 the amine (3), (3,), ( 3 ,,) or (3 ,,,) are commercially available, or can use conventional methods (such as reduction, oxidation, therapy, transition metal transfer coupling, protection, To protect, etc.), commercially available The acid was prepared to give substances of formula (2) may be prepared from the formula (4) of the ester pertinence:

15 where Ra is a suitable acid-protecting group, preferably benzyl or (^ 4) alkyl: it includes (but is not limited to) methyl and ethyl; according to anyone already skilled in the art of age 2 The method uses s to prepare acids without modifying the remainder of the molecule. For example, this solution can be treated with an aqueous solution (such as vaporized chlorine, gaseous potassium oxide, sodium hydroxide, lithium oxide), and selectively hydrolyzed κ for 40 hours at a temperature between 20 C and 100 C. In addition, when the right is the base, the cool may be in the presence of a suitable catalyst (such as oxidation on carbon or gas! Bar on the stone anoresis), in a suitable solvent (methanol, ethanol, said in 曱 酉The milk in the seed) is hydrogenated at a temperature of 2G ° C to 5Gt: in an atmosphere of hydrogen for 1 to 48 hours. 12 20 200531959 The ester of formula (4) can be obtained by letting the amine of formula (5):

(5) (CH2) n-ORa

T Ό where Ra and η are as previously defined; prepared by reacting with a bromide of formula (6):

5 In a typical procedure, the amine of formula (5) and the bromide of formula (6) are selectively selected from solvents or solvent mixtures (e.g., dioxin, toluene, N, N-dimethylformamide, In the presence of acetonitrile), the reaction is selectively performed in the presence of a suitable test (such as triethylamine, diisopropylethylamine, potassium carbonate) at a temperature of 80 ° C to 120 ° C for 12 to 48 hours. 10 The bromide of formula (6) can be prepared according to the method disclosed in "Organic Process Research and Development, 1998, 2, 96-99". An amine of formula (5) (wherein R1 is Me and R2 is Η) can be prepared as a (R) or (S) mirror image from a corresponding protected amine of formula ⑺:

Where Ra and η are as previously defined; Rb and Rc represent any suitable substituents so that HNRbRc is a pair of palm amines (for example, Rb can be hydrogen and RC can be 13 15 200531959 α-benzyl benzyl) 'its limitations Provided that the bonds between N and Rb and N and Rc can be easily cleaved using standard methods of cleaving nitrogen protecting groups to provide free amines of formula (5), such as in the textbook "Organic Synthesis of Protecting Groups" Regiment "(third edition 'by those found in tw. Greene and PGM. Wms, John Wiley and Sons Inc., 1999).

The amine of formula (7) can be prepared as a single non-mirromeric isomer by reacting the amine of formula HNRbRc with a ketone of formula (8):

Where ~, and ^ are as previously defined. 10

In a typical procedure, the reaction of a ketone of formula (8) with an amine of formula HNRbRc can produce a neutral intermediate, which can in turn be selected from a suitable reducing agent (e.g., sodium cyanohydride of formula NaCNBH3 or Na (〇Ac) Sodium triethoxylate is selectively reduced in the presence of a desiccant (such as molecular sieves, sulfate sulphate) and optionally in the presence of an acid catalyst (such as acetic acid) to provide a formula for the moon woman such as It is a mixture of non-mirror isomers. The reaction is usually performed in a solvent (such as tetrachloromethane or dichloromethane) at a temperature of 2G ° C to 80 ° C for 3 to 7 ^ hours. Then, the resulting product is converted into hydrochloric acid or nitrate, and a solvent or solvent mixture (e.g., isopropanol, ethyl acetate, ethanol, methyl alcohol, ethyl alcohol, methyl ethyl alcohol, ethyl alcohol, propyl ether, or propyl ether), which has a suitable portability. Diisopropyl ether / methanol) to provide (7) as a non-mirromeric isomer. (_) Of formula (8) can be combined with the halogenated square group of formula (9) by combining the transfers (where Ra is as previously defined and the Guango epitope atom, 20 200531959 which includes ( But not limited to) bromine and iodine):

ORa (9) is prepared with enolate or its equivalent. In a typical procedure, a halogenated aryl of formula (9) and an enol tin (which is generated in situ by treating isopropyl acetate with 5 by treating tri-n-butyltin with methanol of formula Bi ^ SnOMe) is appropriate. It is reacted in a non-polar solvent (such as toluene, benzene, and hexane) in the presence of an acetic acid catalyst (acetic acid / tri-o-tolylphosphine of the formula Pd (OAC) 2 / P (〇-T〇l) 3). The reaction is preferably performed at a temperature of 80 to 110 ° C for 6 to 16 hours. 0 A halogenated aryl of formula (9) can be obtained by esterifying a corresponding acid of formula (丨 〇): &

15 points. Where Hal is as previously defined; it is prepared from an acid according to any method already well known to those skilled in the art, without modifying the remainder of the molecule. In a typical procedure, the acid of formula 与 and formula _ Alcoholic solvents (where Ra is as defined in VII) are reacted in the presence of an acid (such as hydrogenated hydrogen) at a temperature of up to 40 ° C (room temperature) for 8 to 16 hours. Furthermore, the acid of formula (e.g., cesium or carbonic acid) is reacted with fluorene (e.g., methane, desertified 20 benzyl) 'in a suitable solvent (such as N, N-dimethylphosphonium amine). , At 1 (rc to 15 200531959 40 ° C (room temperature), for 1 to 20 hours. The acid of formula (10) is a commercial product. The amine of formula (5) (wherein R1 And R2 are both CrC4 alkyl): Method 1

(5) where R1, R2 and Ra are as previously defined. In a typical procedure, the ester of formula (11) is reacted with an "activated" alkyl (organometallic alkyl such as R2MgBr, R2MgCl or 10 R2Li) using the method described above to provide the phase of formula (12) Compliant tertiary alcohol. Then, the tertiary alcohol of formula (12) is treated with calcined nitrile (eg, acetonitrile, chloroacetonitrile) in the presence of an acid (eg, sulfuric acid, acetic acid) to provide a protected intermediate, which in turn uses a standard cutting method (Such as those mentioned in textbooks) to cut off the nitrogen protecting group. The method described herein is then used to esterify the resulting amino acid to provide an amine of formula (5). Furthermore, the amine of formula (5) (wherein R1 and R2 are both CrC4 alkyl and n = 0) can be prepared according to the following method: 16 200531959 Method 2

(13) (14)

Where R1, R2 and Ra are as previously defined.

10

15 In the & order in the code, the method described above is used to react the formula (3) vinegar with a red-activated thiol (organometallic fluorenyl group, such as r2m, r2m, or R2Li) to provide formula (4) The tertiary alcohol of the formula (14) is then treated with fluorenyl nitrile (e.g., ethyl chloride, chloroethylchol) in the presence of an acid such as sulfuric acid, acetic acid to provide a trusted intermediate. Substances in turn use standard cleavage methods, such as those mentioned in textbooks, to cleave nitrogen protecting groups to provide bromoamine (15). In an oxidation-inhibiting environment, use RaOH (for example, MeOH, EtOH, benzyl alcohol) as a solvent or a solvent (such as dmf), at a high temperature (ιo C) and pressure (100 pS1), in a suitable manner. Catalysts (for example, m (dibenzylphosphino) bis (cyclopentadiene) ferrous] digas peak), handlebars, U, -bis (diphenylphosphino) bis (cyclopentadiene) Sub-, tris (di-alkylene) di & (0), 2,2, -bis (diphenylphosphino H, 1, · naphthyl dichloro_)) to treat the bromine amine produced (15) to provide the g intent of formula (5). The hydrazone of formula (16) can be prepared by reducing the hydrazone of formula (16) (which is called ... 17 200531959).

In a typical procedure, a palladium catalyst (eg, 10% palladium on activated carbon) is used to treat an olefin solution of formula (16) in a suitable solvent (eg, methanol, ethanol, ethyl acetate), and Stir in a hydrogen environment, optionally at elevated pressure (eg 60 psi), from room temperature to 6 (rc temperature 8-24 hours. Activated olefins can be coupled to the formula ( 17) to halogenate an aryl group to prepare an olefin of formula (16):

In a typical procedure, the aryl group of (17) and a vinyl ester (such as methyl acrylate) are mixed with a suitable palladium catalyst (for example, the formula Pd (pph3) 4 quat (tribenphosphine)) ( 0), acetic acid of formula Pd (OAc) 2 / P (0-Tol) 3 vaporizes / tri-o-phosphonium phenylphosphine or (diphenylphosphino) bis (cyclopentadiene) ferrous group of formula dppfPdCl2 (Ii) in the presence of 'in a suitable solvent (such as acetonitrile, dimethylformamide, methylbenzyl)' in the presence of a selective test (such as triethylamine), at a temperature of up to ii ° C, coupling 8 To 24 hours. The ketone of formula (17) is a commercial product. Furthermore, the compound of formula (1) can be prepared by reacting a bromide of formula (6) with an amine of formula (18);

20 where R, R, Q1 and η are as defined for the compound of formula (1) (unless otherwise stated in 200531959). In a typical procedure, an amine of formula (18) and a bromide of formula (6) are selectively selected from a solvent or a solvent mixture (e.g., difluorenimidine, toluene, N, N-dimethylformamide). , Acetonitrile), in the presence of a suitable base (such as triethyl 5 amine, diisopropylethylamine, potassium carbonate), at a temperature of 80 ° C to 120 ° C, the reaction for 12 to 48 hours . By coupling a formula (19) incorporating a suitable amine protecting group P1

10 and formula NHR8-Q2-A (3),

15 to prepare donkey amines of formula (18). The reclining is usually in excess of the amine (as an acid acceptor) with a conventional coupling agent (eg, 1- (3-diamidinoaminopropyl) -3-ethylcarbodiimide Hydrochloric acid or N, N'-dicyclohexylcarbodiimide), selectivity in the presence of a catalyst (such as 1-hydroxybenzotriazole hydrate or 1-hydroxy-7-acylbenzotriazole), and selection In the presence of a tertiary amine base (such as N-methylmorpholine, triethylamine or diisopropylethylamine). The reaction can be carried out in a suitable solvent such as pyridine, N, N-dimethylformamidine, tetrahydrofuran, difluorenylenesulfonium, dioxane, or ethyl acetate at a temperature of 10 ° C to 40 ° C. The temperature is between 19 200531959 degrees (room temperature), and it takes -24 hours. > The amines, (3,), (3 ,,), and (3 ,,,) are commercially available, or can use conventional methods (such as reduction, Oxidation, calcination, transition metal transfer, protection, deprotection, etc.), prepared from commercially available materials. The corresponding ester of formula (5) can be used to prepare an acid of formula (19). An acid of formula (19) can be prepared from the vinegar (5) doped with an appropriate amine protecting group 1 > 1 (this can be before or after acid formation) (wherein R1 and R2 are both crc4fluorenyl groups) : ^

Where Ra is a suitable acid-protecting group, preferably (Cl_C4) alkyl (which includes (but is not limited to) methyl and ethyl); from esters according to any method already well known to those skilled in the art To make an acid without modifying the remainder of the molecule. For example, the ester can be selected from a solvent or a solvent mixture (e.g., water, 1, 4) by an aqueous solution of an acid or base (e.g., hydrogen gas, potassium hydroxide, sodium hydroxide, or lithium hydroxide). -Dipyridine, tetrahydrofuran / water), hydrolysis treatment at a temperature of 20 ° C to 100 ° C for 1 to 40 hours. The amine of formula (5) (wherein R1 and R2 are both H) can be prepared according to the following method: 20 20 200531959

Where R, R2 and Ra are as previously defined. In a typical procedure, it is preferred that the acid of formula (20) is reduced to an alcohol (21) corresponding to phase 5 in the presence of an ester. This can be done by forming fluorenimidazole or a mixed anhydride, followed by reduction with sodium hydride or another suitable reducing agent. This first alcohol of formula (21) is then converted to a leaving group (such as a scopolite, tosylate, bromide or iodide) and substituted with a suitable amine nucleophile group. A preferred nucleophile is an azide ion, which can then be reduced to a primary amine via weathering or triphenylphosphine. Another nucleophilic group may include an oxygen or alkynyl group (such as "tripropylamine"), which is then left over to provide the amine.

〇 to prepare the ammonium amine (25) of formula 22, and then let the compound of formula 22 and a protected 21 200531959 vinylamine (such as N-vinylphthalimide) in a suitable catalyst (such as palladium (II) acetate ) And phosphines (such as tribenzylphosphine, tri-o-tolylphosphine) in the presence of a base (such as n, n-diisopropylethylamine) in a solvent (such as N, N-dimethylphosphonium) Hydrazine, acetonitrile), at 20. (: To 120. (: reaction temperature between 1 to 48 hours and 5 hours. Then, the dilute hydrocarbon of formula 23 can be reduced to the calcination of formula 24 using standard hydrogenation conditions and the standard protecting group removal method can be used to The protective phthalocyanine subgroup is removed. The amine of formula 25 can be reacted with the desert of formula 6 using the conditions outlined previously to provide a compound of formula 1. For the compound of formula (1) described above, In some steps of the preparation method, it is necessary to protect potentially reactive functional groups that do not want to react and, as a result, to cut off the hydrazone protecting group. In this example, any compatible protecting group can be used. In particular It can be used, for example, by D.W. Greeney and RGM · Wachthorn (protective groups in organic synthesis, John Willy and Songs, 1999) or by P.J. Kocienski (protective group (Georg 15 Thieme Verlag, 1994) described the protection and deprotection methods described above. The reactions described above and the preparation of the novel starting materials used in the Cochrane method are all known. And suitable for its performance or preparation of reagents and reaction conditions, and is used for separation The procedure for the desired product will be fairly well known to those skilled in the art by reference to the uranium examples and the examples and preparations so far. 20 Similarly, it can be obtained according to a number of fairly well-known methods, such as, for example, crystallization or chromatographic methods. Purify the compound of formula (1) and intermediates for its preparation. Subgroups of compounds of formula (1) containing the following substituents are preferred: Q1 is preferably a * -NH-Q2-A group, where a is cyclohexyl Or adamantyl. 22 200531959 Q is preferably the following:

Wherein R3, R4, R5 and R6 are Η Q is the following preferably: R3 R4

Where one of r3 to r6 is 0] 9 [and other R3

Q1 is preferably a * -nh-q2-a group, where A is the following group R3 R4

R7, R6, R11, R, R, R, and R may be the same or different, and may be selected from Η, CVC, ⑽, sr9, so9, so2R9, tooth base, CN, ⑺2R9, CF3, 〇cf3, so2NrV, and connr9r1. , Nen 9r1G, NH⑺Ri0 and phenyl which is optionally substituted with 1 to 3 groups selected from or9, halo and Crc4 alkyl groups, and its limitation is that at least 2 of R3 to r7 are H, of which Han 9 And r10 23 10 200531959 may be the same or different and are selected from fluorene or CrC4 alkyl. Q1 is more preferably a * -NH-Q2-A group, where A is the following group:

Wherein R3, R4, R5, R6 and R7 may be the same or different, and may be selected from Η, 5 OH, CH3, OCH3, OCF3, OCH2-CH3, SCH3, N (CH3) 2, n (c = o) ch3 , C (= o) nh2, cooch3, so2ch3, S02NH2, halo, CN, CF3, and phenyl optionally substituted with OH, which are limited to at least two of R3 to R7 being fluorene. Embodiment L] 1 10 In a preferred embodiment, A is the following group:

Wherein one of R3 to R7 is OH or phenyl substituted with OH. In a preferred embodiment, A is the following group:

R5 15 wherein one of R3 to R7 is OH or phenyl substituted with OH, and the other is selected from 24 200531959 hydrazone, Cl or CH3, which is restricted to that at least two of R3 to R7 are H. A is preferably a naphthyl group which is optionally substituted with 0Η. A is preferably a naphthyl group substituted with OH. Among the above compound groups, the following substituents are particularly preferred: Q2 is · <: Η2_,-(CH2) 2 ·,-(CH2) 3-, · 〇Η2-(: (<: Η3) 2- or -C (CH3) 2- 'and -CH2- or-(CH2) 2 are preferred. R is fluorene or CrQ alkyl and R2 is CrC4 alkyl. R1 is fluorene or CH3 and R2 is fluorene or CH3.

η is 0 or 1. 10 R1 is Η and R2 is CH3 and η is 0 or 1. R1 is CH3, R2 is CH3, and η is 0 or 1. Compounds of the formula VII as described in the Examples section hereafter N-benzyl-2- (3- {2-[(2R) _2_ (3_methylamidoaminoamenthylbenzyl 15hydroxyethylamine) Group] _2_methylpropyl} phenyl) acetamidamine;

N- (3,4-dimethylbenzyl) _2_ (3_ {2 [(2R) _2_ (3_ fluorenyl via phenyl R via ethylamino] benzyl propyl} phenyl group I 叩-(4-Gasbenzyl)] __ Biography "Qianji it; benzyl" -2-Ethylamino] -2-methylpropyl} benzylamine; daggeryl 20 is called (2 German Benzyl) ⑷ · Η2 · [Called Indioylamine | Cyclophenyl A via Ethylamino] Hydroxypropyl} benzylamine; group < 3- {2 [(2R) _2_ ( 3-methylamidinoamino via phenyl) yl] -2-methylpropyl is called naphthylethyl) benzylamine amine / ylamine 3- {2- [called 2 '(3. Silk knee 4, ylphenyl) _2, hex ~ 25 200531959 radical] -2-methylpropyl} -N- [2- (4-methylphenyl) ethyl] benzamide; N- [2 -(2,6-diamidinophenyl) ethyl] -3- {2-[(2R) -2- (3-methylamidoamino-4-merylphenyl) -2-viaethyl Amine] -2-methylpropyl} benzamide; N- [2- (2,3-diamidinophenyl) ethyl] -3- {2-[(2R) -2- (3 -Formamylamine 5-yl-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropylbenzidine; 3- {2-[(2R) -2- (3- Formamidoamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-amidopropyl} -N- [2- (4-hydroxy-2,3-dimethylphenyl) Ethyl] benzamidine; 3- {2-[(2R) _ 2- (3-methylfluorenylamino-4-hydroxyphenyl) -2 · hydroxyethylamine 10-yl] _2_fluorenylpropyl} -1 [2- (4-methoxyphenyl) ethyl] Benzamidine; 3- {2-[(2R) -2- (3-methylamidoamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl 丨- N-phenethyl-phenylhydrazine; N-cyclohexylfluorenyl-3- {2-[(2R) -2- (3-methylamidoamino-4-hydroxyphenyl) -2-hydroxyethyl Aminoamino] -2-methylpropyl} benzamide; 15 N- [5-((lR) -2- {l, l-dimethyl-2- [3- (piperidine-1- Carbonyl) phenyl] ethylamino} -1-hydroxyethyl) -2-hydroxyphenyl] formamidine; 3- {2-[(2R) -2- (3-fluorenylamino-4 -Ethylphenyl) -2-Ethylamino] -2-fluorenylpropyl N- [2- (3-trifluoromethylphenyl) ethyl] benzidine; 3- {2 -[(2R) -2- (3-methylfluorenylamino-4-hydroxyphenyl) -2-hydroxyethylamine 20-yl] -2_fluorenylpropyl} _N_ (3-phenylpropyl) Benzamidine; 3- {2-[(2R) -2- (3-amidinoamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-amidinopropyl 丨- N-inden-2-yl benzamidine; 3- {2-[(2R) -2- (3-formamidoamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2 -Fluorenylpropylbenzene N- (2-pyridin-2-ylethyl) benzamide; 26 200531959 3- {2-[(2R)- 2- (3-methylamidoamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-amidopropyl} -sense [2- (4-aminosulfonylphenyl) ethyl Group] benzamidine; N- (4-diamidinoaminobenzyl) -2- (3-{(2R) -2-[(2R) -2- (3-methylamidinoamino-4 -Hydroxyphenyl) -2-hydroxyethylamino] propyl} phenyl) acetamidamine; 5 N- [5- (2-{(lR) -2- [3- (3,4-dihydro -1H-isoxoline-2-carbonyl) -phenyl] -1,1-difluorenyl-ethylamino} -1-hydroxyethyl) -2-hydroxyphenyl] formamidine; 3- { 2-[(2R) -2- (3-methylaminoamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropylpropyl N- (4'-hydroxybiphenyl 3--3-methylmethyl) benzamidine; • 3- {2-[(2R) -2- (3-formamidoamino-4-hydroxyphenyl) -2-hydroxyethylamine 10 group] 2-Amidinopropan *}-N- [2- (4-hydroxy-2,5-diamidinophenyl) ethyl] benzamide; 3- {2-[(2R) -2- ( 3-Methylmethylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropylpropyl N- [2- (4-hydroxy-3-methylphenyl) ethyl ] Benzamidine; N- (4-Ethylaminoaminobenzyl) -2- (3-{(2R) -2-[(2R > 2- (3-methylamido15amino-4- Ethylphenyl) -2-Ethylamino] propyl} phenyl) amine, 4-{[2- (3-{(2R) -2-[(2R) -2- (3-methyl醯 基4-Hydroxyphenyl) -2-hydroxy®ethylamino] propyl} phenyl) acetoamido] fluorenyl} benzamide; N-adamantane-1-yl-3- {2 -[(2R) -2- (3-methylamidoamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} benzidine; 20 3- {2 -[(2R) -2- (3-methylamidoamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-amidopropyl} yl-pentyl-1-ylmethyl ) Aminobenzoate, 3- {2-[(2R) -2- (3-methylaminoamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropylpropyl N -(4-hydroxy-3,5-difluorenylbenzyl) benzamide; 3- {2-[(2R) -2- (3-methylamidinoamino-4-hydroxyphenyl) -2 -Hydroxyethylamine 27 200531959 group] -2-fluorenylpropyl}-! ^-(6-Cyclo-naphthyl-2-ylfluorenyl) benzamide; N- (3,6-digas -2-hydroxybenzyl) -3- {2-[(2R) -2- (3-fluorenylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-fluorenylpropane } Benzylamine; N- (3,4-Difluorenylbenzyl) -2- (3- {2-[(2R) -2- (3-methylamidinoamino-4-5 hydroxybenzene ) -2-hydroxyethylamino] ethyl} phenyl) acetamidamine; 3- {2-[(2R) -2- (3-fluorenylamino-4-merylphenyl)- 2-Ethylamino] -2-methylpropyl} -N- [2- (4-Ethylphenyl) -2-methylpropyl] Formamidine; 3- {2-[(2R) -2- (3-formylamino-4-merylphenyl) -2-merethylamino] -2-methylpropyl}-] ^-(4'- | ^ ylbiphenyl-4-ylmethyl) benzoate; 10 N-adamantyl-1-yl-2- (3-{(2R) -2-[(2R) -2 -(3-formylamino-4-hydroxyphenyl) -2-hydroxyethylamino] propyl} phenyl) acetamidamine; N- [5- (2- {2- [3- (10 _々-Tricyclo [6 · 3 · 1 · 0 * 2,7 *] dodec-2 (7), 3,5-tris-di-10-weiyl) phenyl] -1,1-dimethyl Ethylamino} -1_Ethyl) -2-Ethylphenyl] -fluorenylamine; 15 2- (3-{(2R) -2-[(2R) _2- (3-methylamino) Amino-4-Ethylphenyl) -2-Ethylamino] propyl} phenyl) -N- (4'-hydroxybiphenyl-3-ylmethyl) acetamide; 4- {[ 2- (3- {2-[(2R) -2- (3-fluorenylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-fluorenylpropyl} phenyl) -Ethenylamino] fluorenyl} benzyl benzoate; 20 2- (3-{(2R) -2-[(2R) -2- (3 · methylamidoamino-4-hydroxyphenyl ) -2-hydroxyethylamino] -2-fluorenylpropyl} phenyl) -N- (4-trifluoromethoxy-benzyl) acetamidinium; N- (2-Ga-4 · Benzyl) -N-ethyl-2- (3-((2R) -2 · [(2R) -2- (3-methylamidoamino-4-hydroxyphenyl) -2-hydroxyethyl Aminoamino] -2-fluorenylpropyl} Group) 28 200531959 Ethylamine; N- (2-chloro-4-hydroxybenzyl) -2- (3-{(2R) -2-[(2R) -2- (3-methylfluorenylamino- 4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropylphenylphenyl) acetamide; 5 2- (3- {(2R) -2-[(2R) -2- (3-fluorenylamino-4-merylphenyl) -2-lightethylamino] propyl} phenyl) -N- (4-meryl-3,5-dimethylcarbyl) Ammonium acetate, 2- (3-{(2R) -2-[(2R) -2- (3-methylaminoamino-4-hydroxyphenyl) -2-hydroxyethylamino] propyl} benzene ) -N- (2- | ^ iylqin-1-ylmethyl) amine, N- (5-chloro-2-hydroxybenzyl) -2- (3-{(2R) -2- [ (2R) -2- (3-methylfluorenyl 10 amino-4-¾phenylphenyl) -2-Ethylamino] propyl} phenyl) acetamide, N- (3,5-Digas 2-hydroxybenzyl) -2- (3-{(2R) -2-[(2R) -2- (3-fluorenylamino-4-hydroxybenzyl) -2-hydroxyethylamino ] Propyl} phenyl) acetamidamine; 2- (3-{(2R) -2-[(2R) -2- (3-methylaminoamino-4-merylphenyl) -2-light Ethylamino] propyl} phenyl) -N- (6-¾Qin-2-ylmethyl) amine, 15 2- (3-{(2R) -2-[(2R) -2- (3-Methylmethylamino-4-hydroxyphenyl) -2-hydroxyethylamino] propyl} benzyl) -N- (4'-Ethylbiphenyl-4-ylmethyl) ethylamine , N- (4-gas -Fluorenyl) -2- (3- {2-[(2R) -2- (3-formylamino-4 -lightylphenyl) -2-hydroxyethylamino] -2-fluorenylpropanyl } -Phenyl) -acetamidamine; 2- (3- {2-[(2R) -2- (3-methylaminoamino-4-hydroxyphenyl) -2-hydroxyethyl 20 amino ] -2-methylpropyl} -benzyl) -N- (4-methylsulfonyl-benzyl) -acetamidamine; 2- (3- {2-[(2R) -2- (3- Formamidoamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} -phenyl) -N- (4-methylsulfanyl-fluorenyl) -ethyl Styramine, 2- (3- {2-[(2R) -2- (3-methylamidoamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-amidopropyl} -Phenyl) -N- (4-dioxoyl-carbyl) -amine, 29 200531959 2- (3- {2-[(2R) -2- (3-methylamidoamino-4- Hydroxyphenyl) -2-hydroxyethylamino] -2-fluorenylpropyl} phenyl) -N- (4'-technyl-biphenyl-4-ylmethyl) acetamide; N- [2 -(5-Gas-2-hydroxyphenyl) -ethyl] -3- {2-[(2R) -2- (3-methylamido-5amino-4-hydroxyphenyl) -2-hydroxyethyl Aminoamino] -2-amidinopropyl} -benzimidamine; 2- (3- {2-[(2R) -2- (3-amidinoamino-4-hydroxyphenyl) -2 -Hydroxyethylamino] -2-amidinopropyl} phenyl) -N- (4'-hydroxybiphenyl-3-ylmethyl) -acetamidamine; 3- {2-[(2R)- 2- (3-methylamino 4-Hydroxyphenyl) -2-hydroxyethylamine 10-yl] -propyl} -N- [2- (4-: ¾phenylphenyl) -2-methylpropyl] -benzoic acid amine, N -(2-chloro-4-hydroxybenzyl) -2- (3-{(2R) -2-[(2R)-(2R) -2- (3-methylphenylamino-4-¾ylbenzene ) -2-Ethylamino] propyl} phenyl) ethylamine, N- [2- (5-Gas-2-hydroxybenzyl) -ethyl] -3- {2-[(2R ) -2- (3-methylamidoamino-4-¾phenylphenyl) -2-¾ethylamino] -2-methylpropyl} benzylamine, 15 3- {2-[( 2R) -2- (3-fluorenylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -propyl} -N- [2- (4-hydroxyphenyl) -2-fluorene Propyl] phenylbenzidine; 2- (3- {2-[(2R) -2- (3-fluorenylamino-4-hydroxyphenyl) _2_hydroxyethylamino] -2- Fluorenylpropyl} phenyl) -N- (tetrazol-σsane-4-yl) amine, N- (5-chloro-2-hydroxybenzyl) -2- (3- {2-[( 2R) -2- (3-fluorenylamino 20-4--4-ylphenyl) -2-¾ethylamino] -2-methylpropyl} phenyl) ethoxyamine, and N- { 5-[(lR) -2-((lR) -2- {3- [3- (3,4-dihydro-1H-isofluorin-2-yl) -3-oxopropyl] phenyl } -1-methylethylamino) -1-hydroxyethyl] -2-hydroxybenzyl} fluorenamine. According to one aspect of the present invention, compounds of formula (1) in which the (CHA-CpCOQ1 group is at meta position 30 200531959 are generally preferred. The pharmaceutically acceptable salts of the compounds of formula (1) include their acid additions and bases Poetry Series 0 Suitable acid power 0 Salts can be formed from acids capable of forming non-toxic salts. 5 examples include acetate, adipate, aspartate, benzoate, benzoate page salt , Carbonic acid salt, bisulfate, bisulfate / sulfate, delete salt, camphor phyllate, citrate, cyclic salt (CyClamate), ethylene diacetate, ethyl sulfonate (esylate), formate, fumarate, glucoheptanoate, gluconate, glucuronate, hexafluorophosphate, hibenZate 10, hydrochloric acid / gas, hydrobromic acid / Bromide, hydroiodic acid / iodide, hydrogen phosphate, isethionate, D • and L_lactate, malate, cis-butene monosalt, malonate, mesylate , Methylsulfate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, oxalate, palmitate, paraben, phosphate / hydrogen, Acid salt / dihydrogen phosphate, pyroglutamate salt, 15 gluconate salt, stearate salt, succinate salt, tanninate salt, D- and L-tartrate salt, 1-methyl-2-naphthalene Samarate, tosylate and xinafoate salts. Suitable salts can be formed from tests that can form non-toxic salts. Examples include inscriptions, arginine, festival, dance, Cholestyramine, diethylamine, glycolamine, 20glycine, lysine, lyme, meglumine, alcoholamine, potassium, sodium, tromethamine and zinc salts. Acids and tests can also be formed Semi-salts, such as hemi-sulphate and hemi-calcium. See Stahl and Wermuth's Handbook of Pharmaceutical Salts · Properties, Selection and Use, (Willie VCH, Wen Weinheim, Germany 31 200531959, 2002) to review suitable salts. One or more of three methods can be used to prepare the double salt of Xile that is a compound of formula (1): (1) let (1) The compound reacts with the desired acid or base; 5 (11) Removes an acid or base labile protecting group from a suitable precursor of the compound of formula (1); or uses the desired acid or base to Ring a suitable cyclic precursor (eg, lactone or lactam); or (111) react with a suitable acid or base or use a suitable ion exchange column to convert a salt of a compound of formula (1) Conversion to another. Wang. P Both reactions are typically performed in solution. The salt produced can be precipitated and collected by filtration, or it can be recovered by evaporation of the solvent. The degree of ionization in the produced salt can be determined from It changes from fully ionized to almost unionized. The compounds of the present invention can exist in both unsolvated and solvated forms. The name "solvate" as used herein is described as a molecular complex of 15 which contains The compound of the invention and a stoichiometric amount of one or more westernly acceptable solvent molecules (eg, ethanol). When the solvent is water, the name "hydrate" is used. Complexes included within the scope of the present invention are, for example, clathrate compounds, drug-host inclusion complexes (which are related to the aforementioned solvates In comparison, the drug 20 can be present in a stoichiometric or non-stoichiometric amount with the host.) Also included is a complex of the drug that contains two or more stoichiometric or non-stoichiometric amounts of organic and / or inorganic Component. The resulting complex can be ionized, partially ionized, or unionized. A review of this complex can be found in j pharm Sci, M (8), 1269-1288 (by Haleblian 32) 200531959 (August 1975)). After that, all references of the compound of formula (I) include references to their salts, solvates and complexes, and solvates and complexes of their salts. Compounds include compounds of formula (1) as defined above, 5 including all their polymorphs and crystal shapes, their prodrugs and isomers as defined thereafter (including optical, geometrical and tautomeric variants Structure) and isotope Calibration compounds of formula (1). As noted, so-called "prodrugs of compounds of formula (I)" are also within the scope of the invention. Therefore, certain derivatives of the compound of formula (I) themselves have little or no pharmacological activity. When administered into or on the body, they are converted (for example, by cleavage by hydrolysis) to have desired properties. The desired activity is a compound of formula (I). Such derivatives are referred to as "prodrugs." Further information on the use of prodrugs can be found in "Prodrugs as Novel Delivery Systems, Volume 14, ACS Forum Series", (T Higuchi ) And W Stella); 15 and "Bioreversible carriers in drug design", Pergamon Press, 1987 (ed. EB Roche, American Medical Association) (American Pharmaceutical Association). Prior to the present invention, the drug body can be replaced by the presence of 20 in the formula (I), for example, by a part that is already known as a "prodrug part" by those skilled in the art. ), As described by Bundgaard, for example in "Design of Prodrugs" (Elsevier, 1985). Prodrugs according to the invention Some examples include: ⑴ When the compound of formula 包含 contains a monocarboxylic acid functional group (-COOH), 33 200531959 its ester, for example, the hydrogen of the ferulic acid functional group of the compound of formula (1) is replaced by a (CVCs) alkyl group. Compounds; (ii) when the compound of formula (1) contains an alcohol function In the case of (-OH), its ether, for example, a compound in which the hydrogen of the alcohol functional group of the compound of the formula (1) is replaced with a (CrC6) alkoxymethyl 5 group; and (iii) when the compound of the formula (1) contains When the primary or secondary amine functional group (-NH2 or -NHR, where RiH) is used, the amine is, for example, one example is one or two hydrogens of the amine functional group of the compound of formula (1). Alkyl groups substituted compounds. 10 Further examples of substitution groups according to the previous examples and examples of other prodrug forms can be found in the aforementioned references. Furthermore, certain compounds of formula (1) themselves It can act as a prodrug of other compounds of formula (1). Also included within the scope of the present invention are the prodrugs of the compounds of formula (1), that is, in the living body after administration of the drug Some examples of the metabolites according to the present invention include: (i) When a compound of formula (1) includes a methyl group, its methylol derivative (-CH3 + -CH2OH): (ii) when the formula (1) When the compound includes an alkoxy group, its hydroxy derivative 20 (-OR + -OH); (iii) When the compound of the formula (1) When a tertiary amine group is included, its secondary amine derivative (-NR1R2 " > -NHR1 or -NHR2); (iv) When the compound of formula (1) includes a secondary amine group, its primary derivative (- nhr】->-nh2); 34 200531959

(V) a phenol derivative (-Ph ^ -PhOH) when the compound of formula (1) includes a phenyl moiety; A (vi) a carboxylic acid derivative of a compound of formula (1) (-CONH2 this COOH). 5 Compounds of formula (I) containing one or more asymmetric carbon atoms may exist as two or more stereoisomers. If the compound of formula (I) includes alkenyl or dilute groups, there may be geometric cis / trans (or Z / E) isomers. Homogeneous isomers of tautomers can occur if structural isomers can undergo interconversion through low energy barriers (the "2 isomerization phenomenon"). This may take the form of a proton isomeric form in a compound of the formula 0) 1 0 containing, for example, an imine, keto or oxime group, or a so-called valence homogeneity in a compound containing an aromatic moiety. . It is followed that a single compound may have more than one type of isomeric. Also included within the scope of the present invention are all stereoisomers, geometric isomers and tautomeric forms of compounds of formula (I), including compounds having more than -15 isomeric forms and one or more Multiple mixtures. It also includes counter-ions with optically active acid additions or base salts, such as cardiolactate or lysine, or racemates, such as tartrate or dl-arginine. Available to those skilled in the art Well-known conventional techniques (e.g., chromatography and partial crystallization) to separate cis / trans isomers. 20 Conventional techniques used to prepare / separate individual mirrors include palladium synthesis from a suitable optically pure drive; or the use of palladium high pressure liquid chromatography (HLPC) to resolve racemates, for example. Salt (or salt or derivative on the night ° Bu Jie Xuan salt). ^ Furthermore, the racemic salt (or a racemic precursor) can be reacted with a suitable optically active compound (eg, an alcohol); or an example of a compound of formula (i) that includes an acidic or basic moiety In reaction with acids or bases (such as tartaric acid or phenylethylamine). The non-mirromeric isomers produced can be separated by chromatographic analysis and / or partial crystallization, and one or both of the non-mirromeric isomers can be converted into conformance using methods already known to those skilled in the art. Pure mirror. The palmitic compound of the present invention (and its palmitic precursor) can be subjected to chromatographic analysis (typically HLPC). On an asymmetric resin, a hydrocarbon (typically heptane or hexane) containing 0 to 50% isopropyl alcohol (typically 2 to 20%) and 0 to 5% by volume of alkynylamine (typically 0.1% diethylamine). The form of the structure. Concentrating the eluate provides this rich mixture. According to the present invention, R is hydrogen and R2 is Ci_c. Generally, it is possible to use conventional techniques well known to those skilled in the art to separate the stereoisomers. Refer to the total σΕσ__ called "organic" Stereochemistry of compounds "(Wiley, New York, 1994). 15

In one aspect, the (R, R) stereoisomer of the following formula (wherein the group (methyl is preferred), minus (^ as defined above)

All of the daggers and bacons are medically available for 20 compounds, and the 冋 and 冋 sites are labeled li-. 'Atoms are replaced by atoms with the same number of atoms] 36 200531959, but their atomic weights or masses or mass numbers are different. Examples of isotopes in the compounds which are often predominant in nature are the I number and the amidine, au ^ Examples of isotopes in the compounds include isotopes of amidine, such as 2h and I carbon, such as leaf amidine and%; chlorine, such as 36C1; failure, such as%; E, such as 123m and 125n nitrogen, such as% and, 5N; oxygen, such as 150, 70, and% (such as thorium and sulfur, such as.

10 Certain isotopically-labeled compounds of formula (e.g., those incorporating radioisotopes) are useful in drug and / or matrix tissue distribution studies. For this purpose, the radioisotope europium (i.e., 3H) and carbon 14 (i.e., HC) are particularly useful, considering their easy incorporation and prepared detection equipment. Substituting heavier isotopes (such as 2H) for some therapeutic advantages' can produce greater metabolic stability, while, for example, can increase half-life in vivo or can reduce dosage requirements, so in some cases it is more good. 15 Replaced with positron-emitting isotopes (such as nc, Uf, [50], and [3n). You can then use matrix tomography (Eτ) research towels to check matrix receptor occupancy.

20 Isotopically-labeled compounds of formula (I) can generally be made using conventional techniques already known to those skilled in the art, or using methods similar to those described in the accompanying examples and preparations, using appropriately isotopically-labeled compounds. Reagents were prepared in place of previously used uncalibrated reagents. Pharmaceutically acceptable solvates according to the present invention include those in which the crystalline solvent can be substituted with isotopes, such as D20, d6-acetone, d6-DMSO. Compounds of formula (1), their pharmaceutically acceptable salts and / or derivative forms are useful pharmaceutically active compounds which are suitable for the treatment and prevention of many 37 200531959 stimuli containing β2 receptors or this amount of money The beneficiary diseases are allergic and non-allergic airway diseases) 'but it can also treat other diseases such as (but not limited to) the nervous system, premature birth, and congestive heart failure. Dermatosis, major / some; and it can be excellently applied in the condition of lowering gastric acidity (especially :: stomach :: two ulcers). The compound of the present invention intended to be used as medicine can be administered in crystals or with body products . They can be obtained by methods such as precipitation, crystallization, cold-drying, non-drying, drying, or hair drying, and are, for example, solid plugs, powders, and thin films. Microwave or radio wave drying can be used for this purpose. 3) They can be administered alone or in combination with one or more other compounds of the invention, or in combination with one or more other drugs (or if any combination thereof). Generally, they will be administered in a combination with one or more pharmaceutically acceptable excipients. The term "excipient" as used herein is described as any ingredient other than the compound of the present invention. The choice of excipient will depend to a large extent on factors such as the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the form of administration. Pharmaceutical compositions suitable for delivering the compounds of the present invention and methods for their preparation will be readily apparent to those skilled in the art. This composition and its preparation method can be found, for example, in "Remington, s sciences,", 19th edition (Mark Publishing Company, 1995). 0 The compound of the present invention can be administered orally Oral administration can include swallowing to allow the compound to enter the gastrointestinal tract, or it can be administered orally or sublingually, directly into the blood at 38 200531959 ° sigma compound. Formulas suitable for oral administration Includes solid formulations, such as lozenges; capsules containing microparticles, liquids, or powders; lozenges (including liquid fillings); chewables; multi- and nanoparticle; gels; solid solutions; lipid particles; films (including 5 mucus Adhesives); ovoid bodies; medicinal mists; and liquid formulations. Liquid formulations include suspensions, solutions, syrups, and medicinal solutions. This formulation can be used as a filler in soft or hard capsules, and it typically contains a load Agents (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 reconstituted into solids Prepared, for example, from fragrant powder. The compounds of the present invention can also be used in a fast-dissolving, fast-disintegrating administration form, such as the expert claims described in therapeutic patents (Expert 〇pinioon in Therapeutic Patents), (6), 981 -986 (consisting of Liang and Chen (2001)). 15 For a bolus form, the drug may consist of a dosage form ranging from 1% to 80% by weight, and more It is typically in the form of 5% to 60% by weight of Agent I. In addition to the drug, the bonding agent usually includes a disintegrant. Examples of disintegrants include sodium starch glycolate, sodium carboxymethyl cellulose Calcium Carboxymethyl Cellulose, Croscarmellose Sodium, Cross-linked 20 Polyvinylpyrrolidone (⑽spovidone), Polyvinylpyrrolidone, Methyl Cellulose, Microcrystalline Cellulose, Short-chain alkyl substituted hydroxypropyl cellulose, starch, pre-gelatinized starch, and sodium alginate. Generally, the disintegrant will contain a working weight of 1 ° /. To 25% by weight, preferably 5 By weight to a dosage form of 20% by weight. Binders are usually used to award lozenges Cohesive properties of the square. Suitable binding agents for 39 200531959 include microcrystalline cellulose, gelatin, sugars, polyethylene glycols, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, hydroxypropyl cellulose And hydroxypropyl fluorenyl cellulose. Lozenges may also contain diluents such as lactose (monohydrate, spray-dried monohydrate, anhydrous and the like), mannitol, xylitol, dextrose Sugar, sucrose, sorbitol, microcrystalline cellulose, starch and dibasic calcium phosphate dihydrate. Lozenges can also optionally contain surfactants such as sodium lauryl sulfate and polysorbate 80; and glidants, Such as silica and talc. When present, the surfactant may be 0.2% to 5% by weight of the lozenge; and the glidant may be 0.2% to 1% by weight of the lozenge. Lozenges also typically contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearate, and a mixture of magnesium stearate and sodium lauryl sulfate. The amount of the lubricant is usually from 0.25% to 10% by weight of the tablet, preferably from 0.5% to 3% by weight. 15 Other possible ingredients include antioxidants, colorants, flavoring agents, preservatives and taste masking agents. A typical lozenge contains up to about 80% of a drug, about 10% to about 90% by weight of a binding agent, about 0% to about 85% by weight of a diluent, and about 2% to about 10% by weight of disintegration. Agent and from about 0.25% to about 10% by weight of a 20 lubricant. The lozenge mixture can be compacted directly or by a roller to form a lozenge. In addition, the lozenge mixture or part of the mixture may be wetted, dried or melted into granules, melted or coagulated, or extruded before being tabletted. The final formulation may include one or more layers and may be coated or uncoated; it may even be encapsulated. 40 200531959 Lozenge formulations in "Medicinal Forms: Lozenges, Book 1" (by Lieberman and Lachman, Marcel Dekker) , N · Υ ·, Ν · Υ ·, 1980 (ISBN 0-8247-6918-X)). 5 Consumable oral film for human or veterinary use is typically a soft soluble or water-swellable Film taking form, which can be quickly dissolved or mucoadhesive; and typically contains a compound of the formula, a film-forming polymer, a coupling agent, a solvent, a humectant, a plasticizer, a stabilizer or an emulsifier, a viscosity modifier And solvents. Certain components of the formula can perform more than one function. The compound of formula (1) is soluble or insoluble in water. Water-soluble compounds typically contain 1% to 80% by weight of solutes. , More typically from 20% to 50% by weight. Less soluble compounds may contain a larger proportion of the composition, typically up to 88% by weight of the solute. Furthermore, the compound of formula VII may be as small as 15 In the form of granules.

The 忒 4 film-forming polymer may be selected from natural polysaccharides, proteins, or synthetic hydrocolloids, and typically exists in the range of 至 to 1% by weight, and more typically in the range of 30 to 80% by weight. Other possible ingredients include antioxidants, colorants, fragrances and odorants, preservatives, saliva stimulants, coolants, co-solvents (including oils), agents, bulking agents, anti-foaming agents, surface actives Agent and taste masking agent. Films according to the present invention can typically be prepared by evaporating and drying thin aqueous films that have been applied to a container or a carrier or paper. This can be done in drying and drying (typically-turn-on coater dryer), or by 41 200531959 cold / east drying or vacuuming. Solid formulations for oral administration can be formulated for immediate and / or modified spoon release. Modified release formulations include delayed, sustained, pulsed, controlled, targeted, and programmed release. 5 A suitably modified release formulation useful for the purposes of the present invention is described in U.S. Patent No. 6,106,864. Details of other suitable release technologies (such as high energy dispersions, infiltration and coated particles) can be found on the Pharmaceutical Technology Line of Verma et al., 25 (2), M4 ( 2001). The use of chewing gum to achieve controlled release is described in WO 00/35298. The compounds of the invention can also be administered directly to the bloodstream, to muscles or to internal organs. Suitable parenteral administration methods include intravenous, intraarterial, intraperitoneal, intrathecal, indoor, intraurethral, intrasternal, intramuscular, and intramuscular. Suitable devices for parenteral administration include needle (including microneedle) 15 syringes, needleless syringes, and infusion technology. * Secret intestinal formulas are typically water-containing, which can include formulations (such as salts, carbohydrates) and buffers (preferably pHa3 to 9); however, they can be more appropriately formulated for this application It is a sterile non-aqueous solution or: A dry form that can be used in combination with a suitable vehicle (such as sterile, non-pyrogenic water). Moxibustion can be easily achieved by preparing the parenteral formula in a sterile state using standard medical techniques already known to those skilled in the art (e.g., pull freeze-drying). ^ Appropriate formulations can be used (such as "Turning enhancer Bing Zeng 42 200531959 plus the solubility of a compound of formula ⑴ used in the preparation of parenteral solutions. Parenteral formulations can be formulated immediately and Modified release. Modified release formulations include delayed, sustained, pulsed, controlled, standard 5 and stylized release. Therefore, the compounds of the present invention can be formulated for use in implanted reservoirs. Solid, semi-solid, or thixotropic liquid for administration (which provides modified release of the active compound). Examples of this formulation include drug-coated graft molds and poly (dl-lactic-co-glycolol (pGLA ) Microspheres. _ Luming's compound can be administered topically to the silk membrane of the skin, that is, 10 skin or transdermal. Typical formulations that can be used for this purpose include gels, hydrogels, lotions, solutions, creams, Ointment, spray powder, dressing, sponge-like substance, film, skin patch, vaginal flat, implant, sponge, fiber, Zhiyue V and microemulsion. Lipids can also be used. Typical carriers include alcohol, Water, mineral oil, liquid petrolatum, white soft Paraffin, glycerol, polyethylene glycol, and propylene glycol. 15 Penetration enhancers can be incorporated, see, for example, J. Pharm Sci, 88 (10), 955-958, Finnin and jyjorgan (1999) October). And micro-needle or needle-free (for example, powder injection m, / 〇:. ^ ΧΤΜ ^ ^ ^ ^ ώ L β Other methods of local administration include electroporation, iontophoresis Injection method, sonic penetration method (Ph_phGresis), ultrasonic penetration method (_Gph duck is) 2〇 (Bioject) 1M, etc.) injection delivery.

丨 Han / I manage the release of CC buy. Modified, pulsed, controlled, target and Chengwu compounds of the present invention can also be administered intranasally or by inhalation, typically from 43 200531959 dry powder inhalers (alone, as a mixture, such as a dry mixture with lactose) ) Or as mixed component particles (eg, mixed with a phospholipid (such as lecithin)); or as from a pressurized container, pump, sprayer, nebulizer (preferably using electrodynamic fluid Mechanics (electrohydrodynamics) to produce fine atomizers) or sprayers (which can be used with or without suitable propellants such as 1,1,1,2, tetrafluoroethane or 1,1, 1,2,3,3,3-heptafluoropropane)) aerosol spraying. For intranasal use, the powder may contain a bioadhesive, such as polychitosan or cyclodextrin. • The pressurized container, pump, sprayer, atomizer or sprayer 10 comprises a solution or suspension containing a compound of the invention, which contains, for example, ethanol, an aqueous solution of ethanol or another suitable for dispersion As a solvent, a solubilizing or expanding release agent, a propellant; and an optional surfactant, such as sorbitan trioleate, oleic acid or oligolactic acid. Prior to use in dry powder or suspension formulations, the drug product can be micronized to a size suitable for inhalation delivery (typically less than 5 microns). This can be achieved by any suitable milling method, such as spiral jet milling, fluidized bed ® jet milling, supercritical fluid treatment to form nano particles, high pressure homogenization, or spray drying. Capsules (for example, made from gelatin or hydroxypropyl 20 methyl cellulose), blister and cartridge for use in an inhaler or insufflator can be formulated to contain a powder mixture containing a compound of the present invention, suitably Powder base (such as lactose or starch) and performance modifiers (such as 1-leucine, mannitol or magnesium stearate). The lactose may be in the form of anhydrous or monohydrate, the latter being preferred. Other suitable excipients include glucosan, glucose, maltose, sorbitol, xylitol, 44 200531959 fructose, sucrose and sucrose. A suitable solution formulation that can be used in a nebulizer using electrohydrodynamics to produce a fine mist can include from 1 microgram to 20 milligrams of a compound of the invention per drive, and its drive volume can vary from 1 microliter To 100 5 μl. A typical formulation may include a compound of formula (I), propylene glycol, sterile water, ethanol, and sodium chloride. Other solvents that can be used instead of propylene glycol include glycerol and polyethylene glycol. Appropriate flavorings (such as menthol and L-menthol) or sweeteners (such as saccharin or saccharin sodium) can be added to those formulations of the present invention intended for inhalation / intranasal administration. Inhalation / intranasal formulations can be formulated for immediate and / or modified release, such as using PGLA. Modified release formulations include delayed, sustained, pulsed, controlled, targeted, and programmed release. In the case of dry powder inhalants and aerosols, the dosage unit may be determined by a valve that delivers a metered amount. Units according to the invention will typically be arranged to be administered in a metered dose or "smoke" which contains 0.001 mg to 10 mg of a compound of formula (I). A full day dose typically ranges from 0.001 mg to 40 mg, which can be administered in a single dose or more often in divided doses throughout the day. 20 The compound of formula (1) is particularly suitable for administration by inhalation. The compounds of the invention can be administered rectally or vaginally, for example, in the form of suppositories, vaginal suppositories or enemas. Cocoa butter is a traditional suppository base, but different substitutes may be used where appropriate. Rectal / vaginal formulations can be formulated for immediate and / or modified release 45 200531959 controlled, release. Modified release formulations include delayed, sustained, pulsed, and programmed release. The compound of the present invention can also be directly administered to the eyes or ears. The formula 10 15 is the drop of isotonic pressure, adjusted by pH, and no g salt solution. Other formulations suitable for eye and ear administration include tinctures, creams, or gelatins (such as absorbable gel sponges, collagen), bio-incompatible materials (such as polysiloxane) implants, and vaginal tablets. , Lenses and microparticles or small capsules (such as niosomes or lipid particles). Polymers can be incorporated together (polyacrylic acid, polyvinyl alcohol, hyaluronic acid, cellulose polymers (such as human bipropyl fluorenyl cellulose, hydroxyethyl cellulose or fluorenyl cellulose), or heteropoly = Polymers (for example, gelangum) and preservatives (such as benzyl ammonium chloride). This formulation can also be delivered by iontophoresis. Eye / ear formulations can be formulated for immediate and / or modified release. Modified release formulations include delayed, sustained, pulsed, controlled, targeted or programmed release. The compounds of the present invention can be combined with soluble macromolecular entities such as cyclodextrin and its suitable derivatives or polyethylene glycol-containing polymers to improve the solubility in any of the aforementioned modes of administration, Dissolution rate, taste masking, bioavailability and / or stability. For example, drug-cyclodextrin complexes have been found to be useful for most dosage forms and routes of administration. Both inclusion and non-inclusion complexes can be used. In addition to being directly incompatible with the drug, cyclodextrin can be used as a co-additive, that is, as a carrier, diluent, or solubilizer. The most commonly used for these purposes are α-, β- and γ-cyclodextrin, examples of which can be found in International Patent Application No. 46 200531959 WO 91/11172, WO 94/02518, and WO 98/55148. Since it is desired to administer a combination of active compounds (for example, for the purpose of treating a particular disease or condition), it is also within the scope of the present invention to conveniently include in the form of a sachet suitable for co-administration of the composition Combining two or more pharmaceutical compositions (at least one of which includes a compound according to the invention). This sachet of medicine contains two or more individual pharmaceutical compositions, at least one of which includes a compound of formula (I) according to the present invention; and a tool, such as a container, divider bottle, or Separate box 10 15 20 packs. Examples of such sachets are blister packs which are well known for packaging lozenges, gels. 〃々 :: 月 月 之 药 展 is particularly suitable for administering different dosage forms (eg, ^ formula), and administering the individual 2 branch of the composition at unrelated dose intervals. For correction, ^ will be included for pure guides and m gastric palpation can be provided. ^ For administration to humans *, the range of ± is typically _ milligrams of ㈣⑽'s compound = total dose. For example, the venous%, although flat or divided according to the music mode, is outside the typical range provided by the article. Judgment of Health These agents have an average weight of about 65%. Doctors can easily determine the weight loss; human patients up to 7G kg and the elderly) dose. Objects outside this range (such as young children, in order to avoid doubt, treat, alleviate and preventative treatment in this article. The "treatment" listed includes reference to another specific embodiment of the rule 47 200531959. The compound or a pharmaceutically acceptable salt, derivative form or composition thereof may also be used in combination with a group of other therapeutic drugs to be co-administered to a patient to obtain some particularly desired therapeutic end results, such as treatment Pathophysiology related 5 disease courses, including (but not limited to): (i) bronchoconstriction, sacral inflammation, rupture (iv) tissue destruction, (v) signs and symptoms (such as dyspnea, cough). Two or more other therapeutic drugs can also be a compound of formula (I) or a pharmaceutically acceptable salt, derivative form or composition thereof, or one or more β2 synergists already known in the art. More typically, The second and more 10 therapeutic drugs will be selected from different types of therapeutic drugs. As used herein, the names "co-administration," "co-administration," and "combined with" refer to the formula ⑴ The compound and-or more other therapeutic agents are intended to refer to and determine the reference and include the following: • The combination of the compound of formula (1) and the therapeutic agent is administered to a patient in need of treatment at the same time. When these components are formulated together into a single dosage form and the components are released to the patient at the same time on the shell; • The combination of the compound of formula (1) and the therapeutic agent is administered substantially simultaneously to the treatment in need Patients, when these components are formulated into individual dosage forms with each other and are used by the patient at substantially the same point in time, the 20 components will therefore be released to the patient at substantially the same point in time; The combination of the compound of formula (1) and the therapeutic agent is sequentially administered to patients in need of treatment. When these components are formulated into individual dosage forms with each other, the patients have a significant time between each administration. When the interval method is used several times in a row, these components will be released to the patient at substantially different time points; 48 200531959; and • the combination of the compound of formula (1) and the therapeutic agent is sequentially administered to the required The patient to be treated, when these components are formulated together in a single dosage form and they will release the components in a controlled manner, they can therefore occur simultaneously, continuously, at the same and / or different time points by the patient 5 And / or partially overlapping administration; each of which can be administered by the same or different routes. Others that can be used in combination with the compound of formula (1) or a pharmaceutically acceptable salt, derivative form or composition thereof Suitable examples of therapeutic drugs include, but are by no means limited to: (a) 5-lipoxygenase (5 丄 〇) inhibitors or 5-lipoxygenase-activated protein (FLAP) antagonists; (b) white Trienol antagonists (LTRA), including antagonists LTB4, LTC4, ltd4, and lte4; 15 ⑷ histamine receptor antagonists, including HI and H3 antagonists; (d) α for decongestive use-and- α2-Adrenergic Receptor Agents Vascular Tightening Agents that mimic sympathetic effects; 0) M3 receptor antagonists or anti-parasympathetic agents of scopolamine; (0 PDE inhibitors, such as PDE3, PDE4, and PDE5 inhibitors 20 (g) Theophylline; (h) Sodium cromoglycate; (0COx inhibitor, no Both selective and selective COX-1 or COX-2 inhibitors (NSAID); 〇) oral and inhaled glucocorticoids; 49 200531959 (к) monoclonal antibody activity against endogenous inflammatory entities; ( i) anti-tumor necrosis factor (anti-TNF-α) agents; (m) adhesion molecule inhibitors, including VLA-4 antagonists; (η) kallikrein-Bi and B2-receptor antagonists; 5 (〇) Immunosuppressants; (P) inhibitors of matrix metalloproteinases (MMPs); (q) tachykines NK !, NK2 & NK3 receptor antagonists; (R) elastase inhibitors; (S) adenylate A2a receptor synergists; 10⑴UK urinary hormone inhibitors; (u) compounds that act on dopamine receptors, such as D2 synergists; (v) modulators of the NFkP pathway, such as IKK inhibitors; (w ) Regulators of cytokine signaling pathways, such as p38 MAP kinase or syk kinase; 15 (X) agents that can be classified as mucolytics or cough suppressants; (y) antibiotics; (z) HDAC inhibitors; and (аа) PI3 kinase inhibitor. According to the invention, the compound of formula (1) is preferably combined with the following: 20-H3 antagonist;-M3 receptor antagonist of scopolamine;-PDE4 inhibitor;-glucocorticoid;-adenylate A2a receptor Isoforms; 50 200531959 _ Regulators of cytokine signaling pathways, such as p 3 8 M AP kinase or syk kinase; or leukotrisin antagonists (LTRA), including the antagonists LTB4, LTC4, LTD4 and LTE4. 5 A compound of formula (1) according to the present invention is more preferably combined with:-glucocorticoids, especially inhaled glucocorticoids with reduced systemic side effects, including prednisone, prednisone, 9- Defluorinated skin easily, C: K pine, beclamethasone dipropionate, destructible% (1311 < ^ 〇1 ^ (^), fluticasone propionate, cicrel 10 And t (ciclesonide) and mometasone furoate (mometasone fuRcate); or-M3 receptor antagonists or anti-sympathetic agents, especially ipratropium salts , In other words bromide; tiotropium salts, in other words evolution; Dongxiao 〇xitr〇pium salts, in other words bromide; perenzepine and telenzepine 15 It should be noted that all references to treatment in this article include treatment, alleviation And preventive treatment. The instructions followed are all about the therapeutic application of the compound of formula (1). The compound of formula (1) has the ability to interact with the β2 receptor, so it has a wide range of therapeutic applications (such as It will be further described below), because the β2 receptor plays an important role in the physiology of all lactating animals. Therefore, 'a further aspect of the present invention relates to a compound of formula (1) or a pharmaceutically acceptable salt thereof, Derived forms or compositions that can be used to treat diseases, disorders, and symptoms that include the beta 2 receptor. More particularly, the invention also relates to compounds or complexes of formula (1) that can be used to treat disorders & Symptoms: Medically acceptable salts, derived forms / selected from the group consisting of: • What type is being broadcast, — — Asthma or pathogenic asthma, special M 9 Asthma due to miscellaneous buckle consisting of the following members: allergic asthma, allergic asthma, irritable gas mouths, non-allergic sclerosis, allergic bronchial IgE transmission of trachea Asthma, privileged Imayama, and essential asthma, true asthma, asthma, asthma, internal asthma caused by a physical disorder in the disease, sexual asthma caused by factors, Idiopathic asthma of unknown or unknown „Brother non-allergic asthma, bronchial asthma, emphysema asthma, exercise two, sexual asthma, allergies« severe asthma, cold money-induced asthma, occupational asthma, «, Infectious asthma caused by fungal, protozoan or viral infections, non-allergic asthma, primary asthma, wheezing syndrome = and bronchiolitis; 15 • chronic or acute bronchoconstriction, chronic bronchitis, Small tracheal obstruction and emphysema; • no obstructive or inflammatory airway disease of any type, pathogen, or pathogenesis, especially chronic obstructive or inflammatory airway disease selected from the members of the group consisting of : Eosinophilic Pneumonia, Chronic Obstructive Pulmonary Disease 20 (COPD), COPD including chronic bronchitis, emphysema, or dyspnea associated with or not associated with COPD, characterized by irreversible coPD, progressive Tracheal obstruction, adult respiratory distress syndrome (ARDS), allergic exacerbation of airway reactions caused by other medications, and airway diseases related to pulmonary hypertension, 52 200531959 • No matter what type, etiology or pathogenesis of bronchitis, especially Bronchitis selected from members of the group consisting of: acute bronchitis, acute laryngotracheobronchitis, peanut bronchitis, catarrhal bronchitis, hissing bronchitis, dry bronchitis, infectious asthma 5 bronchitis, productive bronchitis, staphylococcal or streptococcal bronchitis, and alveolar bronchitis; • acute lung injury; • bronchiectasis, regardless of type, etiology or pathogenesis, especially Bronchiectasis from a member of the group consisting of: columnar bronchiectasis, cystic bronchiectasis, spinning Shaped bronchiectasis, fine bronchiectasis, cystic bronchiectasis, dry bronchiectasis and follicular bronchiectasis shape. A still further aspect of the present invention also relates to the use of a compound of formula (1) or a pharmaceutically acceptable salt, derivative form or composition thereof, which can be used to make a medicament having β2 synergistic activity. In particular, the present invention relates to the use of a compound of formula (1) or a pharmaceutically acceptable salt, derivative form or composition thereof for the manufacture of a disease and / or symptom capable of being treated with β2-modulation (especially the above-mentioned Diseases and / or symptoms). Accordingly, the present invention provides a method of treating a mammal, including a human, which is of particular interest and can be an effective amount of a compound of formula 20 (1) or a pharmaceutically acceptable salt, derivative form or composition thereof. More specifically, the present invention provides a method of particular interest that can be used to treat β2-regulated diseases and / or symptoms (especially the diseases and / or symptoms listed above) in mammals, including humans, comprising: An effective amount of a compound of formula (1), a pharmaceutically acceptable salt and / or derivative thereof of 53 200531959 is administered to the mammal. The following examples illustrate the preparation of compounds of formula (I): Preparation 1: (3-ethoxyepimethylphenyl) ethyl acetate H3C \ ^ 〇ηχτ 〇 / CH3 5 will be 2,2 '-(1, 3. Phenyl) diacetic acid (10.0 g, 51 mmol) was dissolved in ethanol (100 liters), and the solution was treated dropwise with ethyl chloride (2.5 ml). The reaction mixture was stirred under reflux for 18 hours and cooled down in real time. The residue was mixed in ethyl acetate (100 ml) and extracted with a sodium carbamate bath (3 x 50 ml) and brine (3 x 50 ml). The organic phase was dried (MgS04), concentrated in the air, and the residue was triturated with pentagon to yield the product (11.8 g). HNMR (CDC13, 400 ΜΗζ) δ: 1.31 (6Η, t), 3.65 (4Η, S) '4.20 (4Η, q), 7.24-7 · 36 (4Η, m); LRMS ESI m / z 251 [M + H] + 15 Preparation 2: (3 · ethoxy county methylbenzyl) acetic acid

Preparation 1 (443 g, 177 mmol) of hydrochloric acid (12M, 4.9 ml, 58.8 mmol) in ethanol (24¾L) and dioxin (290 ml) dropwise A solution of 2,2 '-(l, 3-phenylene) diacetic acid (59.2 g, 308 mmol). The reaction mixture was stirred under reflux for 18 hours before cooling to 20 portions, and concentrated to a low volume. The reaction mixture was diluted with toluene (125 ml) and the resulting slurry was filtered. The filtrate was concentrated in vacuo, the residue was mixed in water and basified with sodium bicarbonate until the pH was neutral. The mixture was diluted with ethyl acetate (200 ml), the organic layer was separated and washed with sodium bicarbonate solution (5 x 30 ml) and brine (50 ml). The combined aqueous aqueous extract was acidified to pH 3, 5 with 6M hydrogen acid and extracted with diethyl ether (3 x 30 mL). Combine organics, dry (MgS04) and concentrate in vacuo. The residue was triturated with pentagon to give a colorless solid (10.8 g).

] H NMR (CD3OD, 400 ΜΗζ) δ: 1.25 (3H, t), 3.60 (2Η, ® m), 3.63 (2Η, m), 4.15 (2Η, q), 7.18- 7.32 (4Η, m); LRMS 10 ESI m / z 245 [M + Na] + Preparation 3: [3- (2-Ethyl-2-methylpropyl) phenyl] acetic acid

Vaporized magnesium (51 mL, 3M solution in tetrahydrofuran, 153 mmol) was added dropwise to Preparation 2 (11.6 g, 51 μmol) in nitrogen at 0 ° C under nitrogen International Journal of Peptide and Protein Research

Journal of Peptide and Protein Research), 1987, 29 (3), 331) in a stirred solution in tetrahydrofuran (300 ml). The reaction was allowed to warm to room temperature overnight to form a thick white precipitate, and then water (50 mL) and 2N hydrogen acid (80 mL) were carefully added. Water 20 was extracted with ethyl acetate (2x300 ml), and the combined organics were washed with cereal and brine (50 liters), dried (sodium sulfate), and the solvent was removed in vacuo to provide the title as a golden oil. Compound (11.2 g). hNMRCCDCh '400 ΜΗζ) δ: 1.22 (6Η, s), 2.75 (2Η, 55 200531959 s), 3.63 (2Η, s), 7.12-7.30 (4Η, m); LRMS ESI m / z 2〇9 [Μ + Η] Preparation 4: (3- {2-[(Gasinoethyl) amino] -2-methylpropyl} phenyl) acetic acid

5 Add tritium acetonitrile (8.8 mL, 140 mmol) to a solution of Preparation 3 (16.0 g, 70 mmol) in acetic acid (33 mL) and cool to tritium. Treat the resulting solution with concentrated sulfuric acid (33 mL) and allow it to gradually warm to room temperature. After 4 hours, the reaction mixture was poured onto ice and assayed with solid carbonate. The solution was extracted with ethyl acetate (2x500 ml), the combined organic extracts were dried (MgS04) and concentrated in vacuo to provide the title product as a colorless solid (19.0 g). bNMR ^ CDCb, 400 ΜΗζ) δ: 1.36 (6H, s), 3.02 (2Η, s), 3.62 (2Η, s), 3.95 (2Η, 20s), 6.19 (1Η, m ), 7.06-7.31 (4Η, m); • 15 LRMS ESI m / z 282 [MH] 'Preparation 5: [3- (2-amino-2-methylpropyl) phenyl] acetic acid acetic acid vinegar

Under a nitrogen atmosphere, heat a solution of Preparation 4 (5.1 · g, 18 mmol), thiourea (1-6 grams, 21 mmol) in acetic acid (18 mL) in ethanol (80 mL) and heat for 20 hours. To reflux for 16 hours. The reaction mixture was allowed to cool to room temperature, filtered and the filtrate was concentrated in vacuo. The residue was dissolved in ethanol (150 ml), saturated with 56 200531959 hydrogen chloride gas and the resulting solution was heated to reflux for 16 hours. The mixture was concentrated in vacuo, and ethyl acetate (200 ml) and 5% aqueous sodium carbonate (200 ml) were added. The organic phase was washed with brine (100 mL), dried (MgSCU) and concentrated in vacuo. A strong cation exchange resin was used to purify the 5 residues (methanol, then 2M ammonia solution in methanol) to provide a yellow oil (2.68 g). hNMRCCDCh, 400 ΜΗζ) δ: 1.14 (6Η, s), 2.68 (2Η, s), 3.62 (2Η, s), 3.69 (3Η, s), 7.08-7 · 16 (3Η , M), 7.23-7 · 27 (1Η, m); LRMS ESI m / z 222 [M + Η] + 10 to prepare 6: [3- (2-tertiary butoxycarbonylaminoamidinopropyl) ) Phenyl] methyl acetate

Η30γ〇H3d 3 ch3 At 0-5 C, add a solution of di-tert-butyl tartarate (8.19 g, 38.0 mmol) in digas methane (40 ml) to methane in digas (60 ml) • A solution of 5 (8.4 g, 38.0 mmol) in 15 and triethylamine (5.2 ml, 3800 mmol) was prepared. The mixture was heated to RT and stirred overnight. The solvent was removed, the residue was treated with a sodium carbonate solution and extracted with ethyl acetate (3x30 ml). Wash the combined organic layers with water (3x20 mL) and dry (NajO4). The product was purified by chromatographic analysis (0-80% ethyl acetate in hexane) to yield a 20-color oil, which was dissolved in diethyl ether (x3) and evaporated (10.0 g) . iHNMR ^ CDCh, 400 ΜΗζ) δ: 1.26 (6Η, s), 1.46 (9Η, s) '2.97 (2Η's), 3.60 (2Η, 25s), 3.68 (3Η , S), 4.26 (1Η, bs), 7.05-7 · 07 (2Η, m), 7.13-7 · 17 (1Η, m), 7.22-7 · 26 (1Η, 57 200531959

Preparation 7: [3- (2-tertiary butoxycarbonylamino-2-methylpropyl) phenyl] acetic acid

At RT, prepare 6 (7.45 g, 23.0 mmol), sodium hydroxide 5 solution (5M, 4.6 ml, II 5 mmol), Twenty Hills (30 ml), and water ( 8 liters) for 18 hours. The solvent was removed and the material was dissolved in water, cooled and acidified to pH 3 with hydrochloric acid (2M). The product was extracted with ethyl acetate (3x30 mL), and the organics were washed with brine (3x30 mL) and dried (Na2SO4). The resulting oil was dissolved in diethyl ether and evaporated to give a colorless gum (70 g). 10 lHNMR (CD3OD, 400 MHz) δ: 1.23 (6H, s), L48 (9H, s), 2.96 (2 ，, S), 3.57 (2Η, s), 7.04-7 · 〇6 (2η, m), 7 · 11-7 · 13 (1Η, m), 7 · 18-7 · 22 (1Η, m); LRMS APCI m / z 308 [M + H] + Preparation 8: (2- {3-[(3,4-Dichlorobenzylaminofluorenyl) fluorenyl] benzyl} _u_dimethyl-15yl-ethyl) aminophosphonic acid tert-butyl ester

Add 3,4-Diaminobenzylamine (1.30 mL, 9.76 mmol) to Preparation 7 (3.00 g, 9.76 mmol), hydroxybenzotriazole hydrate (1% g, penmol) , 1- (3-dimethylaminopropylethylcarbodiimide (187 g, 9.76 mmol) and tri (1.50 g, 9.76 diacidimide diethylamine hydrochloride (4.07 ml , Η · 2 mmol), and the resulting solution was stirred at RT for 18 hours. The solvent was removed, and the crude material was mixed with ethyl acetate (50 ml) and water (30 ml) ), Sodium carbonate solution (2x30 ml), brine (30 ml), hydrogen acid (0.5M, 2x30 ml) and brine (30 ml), and then dried (Na2S04). Milled with diethyl ether (3.1 5 g) The resulting white solid was crushed. HNMRCCDCb, 400 MΗζ) δ: 1.25 (6H, s), 1.45 (9Η, s), 2.97 (2Η, s), 3.62 (2Η, s), 4. · 22 (1Η, bs), 4.34 (2Η, d), 5.78 (1Η, bs), 6.99-7 · 01 (1Η, dd), 7.04 (1Η, s), 7.07 -7 · 09 (1Η, d), 7.12-7.14 (1Η, d), 7.22 (1Η, d), 7.27 (1Η, 10 d), 7.32 (1Η, d); LRMS APCI m / z 465 [Μ + Η] + Preparation 9: (2- {3-[(3,4-Difluorenylbenzylaminofluorenyl) methyl] phenyl} -1,1-difluorenyl-ethyl) aminocarboxylic acid tert-butyl ester

Prepared using the acid from Preparation 7, the method described in Preparation 8, and 3,4-dimethylbenzylamine. hNMRCCDCh, 400 ΜΗζ) δ: 1.19 (6H, s), 1.46 (9Η, s), 2.20 (6Η, d), 2.95 (2Η, s), 3.59 (2Η, s), 4.15 (1Η, bs), 4.32 (2Η, d), 5.59 (1Η, bs), 6.86-6 · 93 (2Η, m), 7.02-7 · 06 (3Η, 20 m ), 7.13-7 · 15 (1Η, d), 7.23-7 · 27 (1Η, m) ;. LRMS APCI m / z 425 [M + H] + Preparation 10: 2- [3- (2-Amino-2-methylpropyl) phenyl] -N- (3,4-diaminobenzyl) 59 200531959 Ethylamine

Preparation of 8 (3.0 g '6.50 mol) in Erzhi Can (5 liters) was treated with hydrogenated gas (4M in Erzhixian, 20 ml), leaving the resulting solution at 5 under 117 Stir for 18 hours. The solvent was removed, the compound was redissolved in methanol (X2) and evaporated. The resulting gum was suspended in diethylscale and evaporated to give a white solid (2.7 g). mp (ethyl acetate-methanol) 214-216 (dec) ° C. hNMRCCDgOD ′ 400 ΜΗζ) δ: 1.33 (6H, s), 2.90 (2Η, ίο S), 3.59 (2Η, s), 4.35 (2Η, s), 7.13_719 (3Η, m),

7.24-7 · 27 (1Η, m) '7.31-7.38 (2Η'm), 7.42 (1Η, d) ;. LRMS ESI m / z 365 [M + H] + dimethylbenzyl) Preparation 11: 2- [3- (2-Amino-2-amidinopropyl) benzyl] _n_ (3,4_ acetamidine

15

H NMR (CD3OD, 400 MΗζ) δ: ΐ · 32 (6Η, s), 2 2i (6h s), 2.89 (2Η, s), 3.56 (2Η, s), 4.29 (2H, s), 6.95-7 · 05 (3η m), 7.14-7 · 16 (2Η'm), 7.24-7 · 26 (ΐΗ, m), 7.31-7 · 35 (1η 20 m); 60 200531959 LRMS ESI m / z 325 [M + H] Preparation 12: N- {2 · Benzyloxy-5-[( 1 R) -2- Mo (tertiary butyl dimethyl sulfonyloxy) ethyl] phenyl} fluorenamine

N- [2-benzyl-5- (2-bromo-1-hydroxyethyl) phenyl] in N2, N, N-dimethylformamide (25 ml) at RT Formamide (Research and Development of Organic Methods, 1998, 2, 96-99) (4.12 g, 11.8 mmol) was added to a solution of vaporized tert-butyldimethylsilyl (3.50 g, 23.2 mmol) ), Flavor saliva (1.90 g, 27.9 mmol) and 4- (diamidoamino) pyridine (40 mg, 33 μmol). The resulting solution was stirred at RT overnight, the solvent was removed and the product was mixed with ethyl acetate (70 ml). The organics were washed with water (100 ml) and the aqueous phase was extracted with ethyl acetate (20 ml). The combined organics were washed with hydrochloric acid (2M, 50 mL), brine (100 mL) and dried (Mgs04). The crude product was purified by color chromatography (5-25% ethyl acetate in pentane) to give a colorless oil (5.7 g). NMR (CDC13, 400 ΜΗζ) δ: -0.08 to -0.05 (3H, m), 0.09-0 · 11 (3Η, s), 0.89-0 · 90 (9Η, m ), 3.38-3_55 (2Η, m), 3.78-3 · 84 (1Η 'm)' 5.06-5.11 (2H, m), 6.90-6 · 97 (1Η, m), 7 · 03-7 · 12 (1Η 'm)' 7.24 (m), 7.36-7 · 43 (5Η, m), 7.67-7.78 (m), 7.88 (d), 8.74 (d); 61 20 200531959 LRMS APCI m / z 464/466 [M + H] + Preparation 13: 2- (3- {2-[(2R) -2- (4-benzyloxy-3-methylamidoaminophenyl) _2- (Tertiary butyl-difluorenylsilyloxy) ethylamino] -2-methylpropyl} benzyl) -N- (3,4-diaphthyl) ethenylamine

5 ^ At 90 ° C, prepare 12 (500 mg, 1.08 mmol) and 10 (780 mg, 216 mmol) with heating and stir for 24 hours. After cooling, the material was dissolved in methanol and evaporated. The material was suspended in diethyl ether and the precipitate was filtered off. The filtrate was evaporated and the material was purified by chromatography (0-5% methanol in 10 digas methane), then suspended in diethyl ether (x3) and evaporated to produce a sponge-like substance ( 425 mg). 4 NMR (CD3OD, 400 ΜΗζ) δ: · 0 · 20 to -0 · 18 (3Η, m), -0 · 04 to 0 · 00 (3Η, m), 0 · 78-0 · 81 (9Η, m ), 1.01-1 · 03 (3Η, m), 1.05 (3Η, bs), 2.62-2 · 74 (3Η, m), 2.83-2 · 88 (1Η, m), 15 3.52 (2Η, d), 4.31 (2Η, s), 4.68-4.71 (1m, m), 5.17-5 · 19 (2 m, m), 7.00-7 · 23 (7Η , M), 7.29-7 · 41 (5Η, m), 7.44-7 · 49 (2Η, m), 8.57 (S); LRMS ESI m / z 748 [Μ + Η] +; HRMS C41H51Cl2N304Si 748.3099 [M + H] +, found 748.3066. 20 Preparation 14: 2- (3- {2-[(2R) -2- (4-benzyloxy-3-fluorenylaminophenyl) _2- (tertiary-butyl-difluorenylsilyloxy) ) Ethylamino] -2-methylpropyl} benzene 62 200531959 group) -N- (3,4-dimethylbenzyl) ethylamine

Prepared using amidine from Preparation 13, bromide from Preparation 12, and the method described in Preparation 11. 5 iHNMRCCDCh, 400 ΜΗζ) δ: -0.17, -0.16 (3H, 2x s), -0.05 to -0.01 (3Η, m), 0 · 78 · 0 · 82 (9Η, m), 0 · 97- 1.01 (6Η, m), 2.19 (3Η, s), 2.20 (3Η, s), 2.56-2 · 90 (4Η, m), 3.54-3.63 (2H, m), 4 · 28-4 · 35 (2Η, m), 4.67-4 · 74 (1Η, m), 5.06-5 · 09 (2Η, m), 5.58-5.62 and 5.99-6 · 03 (1Η, m), 6.87-7 · 25 (9Η, m), 10 7 · 35-7 · 44 (5Η, m), 7.68-7 · 79 (1Η, m), 8.30 (d), 8.43 ( d), 8.71 (S), 8.74 (S); LRMS ESI m / z 748 [M + H] +; HRMS C43H57N304Si 708.4191 [M + H] +, found 708.4156. Preparation 15: N-benzyl-2- (3- {2-[(2R) -2- (tertiary-butyldimethylsilyloxy 15-yl) -2- (3-methylamidoamino-4- Hydroxyphenyl) ethylamino] -2-fluorenylpropyl} phenyl) ethanil

63 200531959 Preparation of 13 (100 mg, 134 μmol) and palladium on carbon (10%, 20 mg) for 6 hours at 50 psi / RT in methanol (10 ml). The mixture was filtered through an "auxiliary filter" and the solvent was removed. This material was suspended in a sodium bicarbonate solution and extracted with ethyl acetate (30 ml). The organic layer was washed with sodium bicarbonate solution, brine (2 × ml) and dried (Na2S04). The resulting material was suspended in diethyl ether (x3) and evaporated to produce a thin film (24 mg). bNMRCCDsOD, 400 ΜΗζ) δ: -0.19 (3H, s), -0.02 (3Η, s), 0.79 (9Η, s), 1.04 (3Η, s), 1.07 (3Η, s), 2.62-2.89 (4Η, 10 m), 3.48-3 · 56 (2Η, dd), 4.35 (2Η, s), 4.61 (1Η, bs), 4.69-4 · 72 ( 1Η, m), 5.17-5 · 19 (2Η, m), 6.79-6 · 85 (1Η, m), 6.91-6 · 94 (1Η, m), 7.04-7 · 06 (1Η, m), 7.11-7 · 28 (7Η, m), 8.12 (1Η, d), 8.27, 8.59 (1Η, 2χ s); LRMS ESI m / z 590 [Μ + Η] +; 15 HRMS C34H47N304Si 590.3402 [M + H] +, found 590.3409. Preparation 16: 2- (3- {2-[(2R) -2- (tertiary-butyldimethylsilyloxy) -2- (3-methylamidoamino-4-hydroxyphenyl) ethylamine Group] -2-methylpropyl} phenyl) -N- (3,4-dimethylbenzyl) acetamide

〇 64 20 200531959 Prepared using amidamine from Preparation 14 and the method described in Preparation 15. The product was purified by chromatography (0-3.5% methanol in dioxane + 0.3% ammonia) to give a sponge-like substance (85 mg). 4 NMR (CD3OD, 400 ΜΗζ) δ: -0.20 to -18 (3H, m), 5 -0.03-0 · 00 (3Η, m), 0 · 79-0 · 81 (9Η, m), 1.02 -1 · 05 (6Η, m), 2.19 (3Η, s), 2.20 (3Η, s), 2.61-2 · 73 (3Η, m), 2.83-2 · 88 (1Η , M), 3.46 (2Η, dd), 4.27 (2Η, s), 4.65 (1Η, dd), 6.78-7 · 22 (8Η, m), 8.12 (d), 8.27 (s), 8.59 (s); LRMS ESI m / z 618 [M + H] +; 0 1HRMS C36H51N304Si 618.3722 [M + H] +, found 6181370. Preparation 17: (3-Bromophenyl) acetic acid acetate. At 0C, under nitrogen, ethyl acetate (07 mL, 93 mmol) was slowly added to methanol (500). (3-mL-phenyl) acetic acid (200 g, 93¾ mol) in methanol, and the reaction was gradually heated to room temperature for more than 5 hours. The solvent was removed in vacuum 'and the residual oil was redissolved in dichloromethane, dried over sodium sulfate and concentrated in vacuo to provide the title compound as a colorless oil (20.6 g). 201HNMR (400MHz, CDCl3) ": 3.59 (2H, s), 3.70 (3H,) 7.17-7.24 (2Η, m), 7.37_7 · 45 (2Η, m); LRMS ESI m / z 253 [M + Na] + Preparation 18: [3- (2-Phenoxypropyl) benzyl] methyl acetate 65 200531959

At 100 ° C, tributyltin methanol (28.3 ml, 98 mmol), the product of Preparation 17 (15.0 g, 65 mmol), isopropenyl acetate (10.8 ml, 98 mmol), acetic acid Palladium (Π) (750 mg, 3.30 mmol) and tris-methyl-5 benzylphosphine (2.0 g, 6.5 mmol) were stirred in toluene (75 mL) for 5 hours. After cooling, the reaction was diluted with ethyl acetate (150 ml) and 4M aqueous potassium fluoride solution (90 ml) and stirred for 15 minutes. The mixture was filtered through Arbocel®, the organic phase was separated and concentrated in vacuo. Then, the residue was purified in a silica gel using column chromatography, and diethyl ether: pentane from 0: 100 to 25: 75 1 0, followed by dichloromethane to provide the title compound. For a pale yellow oil, the yield is 94% (12.6 g). bNMRGOO MHz, CDC13): δ: 2.15 (3H, s), 3.61 (2Η, s), 3.69 (5Η, s), 7.10-7 · 13 (2Η, m), 7.19 (1Η, d), 7.30 (1Η, t); LRMS ESI: m / ζ229 [M + Na] + 15 to prepare 19: [3 _ ((2R) -2-{[(iR > i-phenylethyl] amine Propyl) -propyl) -phenyl] methyl acetate hydrochloride

The product of preparation a (8.5 g '41.2 mol) in dichloromethane (400 ¾ liter), (R) -a-methylbenzylamine (4.8 ml, 37 · 2) were stirred at room temperature. 20 mol), sodium triacetoxyborohydride (11.6 g, 56 mol) and a solution of acetic acid (2.2 liters '38 mol) for 48 hours. A saturated sodium bicarbonate solution (20066 200531959 ml) was added to stop the reaction mixture, and stirring was continued until effervescence ceased. Eight + related to two Qi? Ie Qi Sheng) Extraction of n-separate water, and then continue to check the organic solution and kiss in a vacuum towel. Chromatography: Purification with quotient: 1: 0: 1 to 95: 5: 5 · 2 dichloromethane: methanol ^ leaching, can provide a non-mirrored isomer mixture of 4 · · 1 ( R, R is main) = is a pale yellow oil (8.71 g). Treatment with hydrogenated gas (40 ml, "in methanol = solution, 40 mmol) followed by three successive crystallizations (diisopropyl_alcohol) provided the title compound as a white crystalline solid. Rate, 5.68 g. 〇'101HNMR (400 MHz, CD3OD): δ: 1.18 (3Η, d), i 68 (3h d), 2 nose 2.66 (1Η, m), 3.15- 3.26 (1Η, m), 3.25-3 · 3〇 (1η, m) 3.31 (3H's) '3.62 (2Η, s), 4.59 (1Η, q), 6.99-7 · 〇2 (2Η, m) '7.17 (1Η' m) '7.25-7 · 28 (1Η, m), 7.48-7 · 52 (5Η, m); LRMS ESI m / z 312 [M + H] + 15 Preparation 20: {3-[(2R) -2-aminopropyl] phenyl} methyl acetate

, CH 3 in the presence of 20% palladium hydroxide on activated carbon (200 g), the product of Preparation 19 (7.69 g, 22 mmol) and ammonium formate (6.94 g, 110 mmol) The solution was heated to 75 ° C. After 90 minutes, the reaction mixture was cooled to 20 to warm, filtered through Aposir® and the filtrate was concentrated in vacuo. The residue was partitioned between methane (100 ml) and 0.888 ammonium chloride) and the phases were separated. The aqueous phase was extracted with dichloromethane (100 ml), the combined organic solution was dried over magnesium sulfate and concentrated in vacuo to obtain a certain yield of the title 67 200531959 compound as a colorless oil (4.78 g) . NMR (400 MHz, CD3OD): δ: 1.06 (3Η, d), 2.57-2 · 67 (2Η, m), 3.05-3 · 12 (1Η, m), 3.63 (2Η , S), 3.67 (3Η, s), 7.09-7 · 13 (3Η, m), 7.23-7 · 27 (1Η, t); LRMS ESI m / z 208 5 [M + H ] + Preparation 21: (3-{(2R) -2-[(tertiary butoxycarbonyl) amino] propyl} phenyl) acetic acid methyl ester

From the product of Preparation 20 and di-tert-butyl dicarboxylic acid, the title compound was prepared using a method similar to Preparation 6 in the case of a yellow oil with a yield of 97%. HNMR (400 MHz, CD3C13): δ: 1.07 (3Η, d), 1.43 (9Η, s), 2.61 (1Η, dd), 2.81 (1Η, dd), 3.60 (2Η, s), 3.69 (3Η, s), 3.89 (1Η, bs), 4.36 (1Η, bs), 7.06-7 · 19 (3Η, m), 7.22-7.27 ( 1Η, m); LRMS APCI m / z 306 [M-Η] · φ 15 Preparation 22: (3-{(2R) -2 _ [(tertiary butoxycarbonyl) amino] propyl} phenyl) acetic acid

Prepare a mixture of 21 (8.31 g, 27.1 mmol) and lithium hydroxide> cereal (1M in water, 54 mL, 54 mmol) in tetrahydrofuran (100 mL) at room temperature with stirring for 20 hours. . The reaction mixture was then concentrated in vacuo and the aqueous residue solution was acidified to pH 2 with 2M hydrogen acid. The mixture was then extracted with ethyl acetate (3x75 ml) and the combined organic solution was washed with brine (100 ml), dried over magnesium sulfate, and concentrated in vacuo to obtain the compound of the title 68 200531959, as A yellow oil, 82% yield (6.50 g). bNMRGOO MHz, CDC13): δ: 1.07 (3Η, d), 1.40 (9Η, s), 2.61 (1Η, dd), 2.77-2 · 88 (1Η, bs), 3. · 62 (2Η, s), 3.89 (1Η, bs), 4.39 (1Η, bs), 7.07-7 · 16 (3Η, m), 7.22-7 · 27 (1Η, m) ; 5 LRMS APCI m / z 292 [Μ-Η] * Preparation 23 · (3-{(2R) -2-[(tertiary butoxyweiyl) amino] propyl} phenyl) acetic acid acetate

• At room temperature, the product of Preparation 22 (6.30 g, 21.5 mmol), 1- (3-10 dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (4 · 14 G, 21.5 mmoles), 1-hydroxybenzotriazole hydrate (3.30 g, 21.5 mmoles) and triethylamine (4.85 ml, 43 mmoles) were stirred in methane (100 ml) ) In 10 minutes. Then, benzyl alcohol (2.2 ml, 21.5 mmol) was added and the mixture was stirred at room temperature for 18 hours. The reaction 15 mixture was then diluted with dichloromethane (50 ml), washed with sodium bicarbonate solution (100 ml) and brine (100 ml), dried over magnesium sulfate and concentrated in vacuo. The title compound was obtained as a clear oil, 50% yield, 4.16 g. NMR (400 MHz, CDC13): δ: 1.04 (3H, d), 1.44 (9Η, s), 2.59 (1Η, dd), 2.81 (1Η, dd), 3.64 (2Η, s), 3.87 (1Η, 20 bs), 4.34 (1Η, bs), 5.13 (2Η, s), 7.07-7.11 (2Η, m), 7.13 (1Η, bd ), 7.22-7 · 27 (1Η, m), 7.29-7 · 38 (5Η, m); LRMS APCI m / z 382 [MH] '69 200531959 Preparation 24 · {3-[(2R) -2-aminopropyl] phenyl} benzyl acetate

Hydrogenated gas (4M in Mount Erhuang, 5.43 ml, 21.72 mmol) was forced into the product of Preparation 23 in Ershan (50 ml) (4 16 g, 10% mmol 5 mole) The solution was stirred at room temperature for 72 hours. The solvent was removed in vacuo and the residue was dissolved in digas methane and washed with sodium bicarbonate solution (50 mL) and brine (50 mL). Then, the organic / cereal solution was dried over magnesium sulfate and concentrated in vacuo to obtain the title compound as a yellow oil with a yield of 93% (2.85 g). 10 lHN] V [R (400MHZ, CDC13): δ: 1.09 (3H, d), 1.55 (2Η, bs) '2.48 (1Η' dd) '2.66 (1Η , Dd), 3.10-3.18 (1Η, m), 3.65 (2Η, s), 5.17 (2Η, s), 7.09-7 · 13 (2Η, m), 7.14 -7 · 18 (1Η, bd), 7.24-7.38 (6Η 5 m); LRMS APCI m / z 284 [MH] 'Preparation 25: (3-{(2R) -2-[((2R) -2- [4- (benzyloxy) -3- (methylamidoamino) benzene 15yl] A [tertiary butyl (dimethyl) carboxyl] oxy} ethyl) amino] -propyl} Phenyl) benzyl donate

From the products of Preparation 12 and Preparation 24, a method similar to Preparation 3 was used to prepare the title compound, as a brown oil, with a yield of 25/0. 200531959 LRMS APCI m / z 667 [M + H] + Preparation 26: {3-[(2R) -2-(((2R) -2-{[tertiary butyl (difluorenyl) lithium alkyl] Oxygen} -2- [3- (methylaminoamino) -4-merylphenyl] ethyl} amino) propyl] phenyl} acetic acid

The product of Preparation 25 (851 mg, 1.27 mmol) and 10% Pd / C (50 mg) were suspended in methanol; the mixture was stirred at 60 psi of hydrogen at room temperature for 72 hours. Then, the reaction mixture was filtered through an auxiliary filter and the filtrate was concentrated in vacuo to obtain the title product as a brown sponge-like substance, yield 94%, 580 mg. NMR (400 MHz, CDC13): δ: -0.09 (3H, s), 0.08 (3Η, s), 0.88 (9Η, s), 1.12, 1.24 (3Η, 2xd), 2 · 07-2 · 82 (2Η, m), 2.99 (1Η, dd), 3.18 (1Η, dd), 3.60 (2Η, s), 4.16-4 · 22 (1Η, m) , 4.97-5 · 07 (1Η, m), 6.87 (1Η, d), 6.99-7 · 32 (6Η, m), 15 7.93 (S), 8.17 (d), 8.33 (s ); LRMS APCI m / z 487 [M + ΗΓ Preparation 27 ·· 2- {3-[(2R) -2-(((2R) -2-{[tertiary butyldimethyl) silyl] oxygen } -2- [3- (methylamidoamino) -4-hydroxyphenyl] ethyl) amino) propyl} phenyl) -N- [4- (dimethylamino) benzyl] ethyl Phenylamine 71 200531959

Prepare the product (100 mg, 206 μmol), hydroxybenzotriazole hydrate (32 mg, 206 μmol) in N, N-monofluorenamide (2 mL). Ear), 1- (3-monomethylaminopropyl) -3-ethylcarbodiimide hydrochloride (5 milligrams, 206M moles) and triethylamine (58 microliters, 412 micromoles) ) The mixture was stirred at room temperature for 10 minutes. Then, 4-renylaminoaminobenzylamine (31 μg, 206 μmol) was added and the mixture was stirred at room temperature for 20 hours. Then, the solvent was removed in vacuo and the residue was diluted with dichloromethane, washed with sodium bicarbonate solution (20¾ liters) and brine (20 ml), dried over magnesium sulfate, and concentrated in the air to obtain The title compound, as a brown gum, yields 100/0, 131 mg. NMR (400 MHz, CDC13): 〇17 (3Η, s), 〇⑻ (3H, s), 0.83 (9Η, s), 1.08 (3Η, m), 2. 8 (K3 · 〇〇 (1〇η, m), 3.47 (1Η, m), 3.66 (2H, m), 4.23 (2Η, m), 5.48 (1Η, m), 6.66 (1Η, 15 d), 6.70-7 · 23 (10Η, m), 7.97 (m), 8.27 (s); LRMS Apci heart 504 [M + H] 'Preparations 28 to 29 The products from Preparation 26 and appropriate Amine, using a method similar to that described in Preparation 27, to prepare the following compounds shown in the following formula. The reaction was monitored using 20TLC analysis, and stirred at room temperature for 18-72 hours. 72 200531959

HN, ^ H τ number Qi Data yield 28 LRMS APCI m / z 632 [M-ΗΓ 99% 29: LRMS APCl m / z 6618 {M-ΗΓ 99% Preparation 28: Ν- [4- (aminofluorenyl ) Phenyl] acetamide can be prepared as described in Med. Chem., 46, 3116, 2003. Preparation 29: 4- (Aminomethyl) benzamide can be prepared as described in WO 5 02085860 p239. Preparation 30: [3-((2R) -2-{[((1R) -1-phenylethyl] amino} propyl) phenyl) acetic acid

Bell hydroxide> Valley solution (1M in water, 90 ml, 90 millimoles) was added to the product of Preparation 19 (〇3.50 grams, 43.5 millimoles in methanol (200¾ liters)) ) In the grain solution, Ya was allowed to stir the mixture at room temperature for 18 hours. Then, fresh wind lactic acid (90¾ liters) was added to the reaction mixture and methanol was removed in vacuo to filter out the resulting precipitate and water (20 ml) and ethanol / diethyl ether (20: 80) The mixture was washed to obtain the title compound as a solid, 91% yield, 11.8 g. 73 200531959 h NMRGOO MHz, CD3OD) δ: 1.16 (3Η, d), 1.62 (3Η, d), 2.66-2 · 62 (1Η, m), 3.13-3 · 26 (2Η, m), 3.46 (2Η, s), 4.48-4 · 56 (1Η, q), 6.92 (1Η, d), 7.19 (1Η, s), 7.18-7 · 22 (2Η, m), 7.45-7.52 (5Η, m); LRMS ESI m / z 298 [M + H] + 5 Preparation 31: Nl-adamantyl-2- [3-((2R) -2-{[(lR) -l-phenylethyl] amino} propyl) phenyl] ethylamine

1-adamantylamine (5.44 g, 36.0 mmol) and triethylamine (15 mL, 108 mmol) were added to dioxane (200 mL) to make a product of 10 (10.7 g, 36.0 mol). Then, hexafluoroscale acid gas-1,3-difluorenimidazole tablet (10.0 g, 36.0 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was washed with water, the organic solution was dried over magnesium sulfate and concentrated in vacuo. Purification of glutamate residues on silica gel by column chromatography was performed with dichloromethane calcination of 9 5 · 5 · 0 · 5: methanol: 0.88 ammonia, and a certain yield of 15 was obtained. The product, as a sponge-like substance, 17.6 grams. bNMRGOOMHz, CD3OD) S: 0.89 (3H, d), 1.35 (3Η, d), 1-65-1 · 75 (6Η, m), 1.98 (6Η, m), 2.04 (3Η, m) ), 2.37-2 · 42 (1Η, dd), 2.65-2 · 74 (1Η, m), 2.95-3 · 〇〇 (1Η, dd), 3.36 (2Η, s), 3 98 (1Η, q), 6.89 (1Η, d), 6.98 (1Η, s), 7.09 (1η, 20d), 7.17 (1Η, t), 7.22-7 · 27 (1Η, m), 7.30-7 · 38 (4Η, m); LRMS ESI m / z 431 [M + H] + 74 200531959 Preparation 32: N · 1-adamantyl_2- {3- [(2R) -2-aminopropyl] phenyl} • acetamidamine

From Preparation 31, a method similar to Preparation 20 was used to prepare the title compound, as a solid, yield 92%. 5 NMR (400 MHz, CD3OD) δ: 1.09 (3H, d), 1.66-1.72 (6Η, m), 2.00 (6Η, m), 2.03 (3Η, m), 2.58 -2 · 70 (2Η, m),

3 · 10 · 3 · 16 (1Η, q), 3.40 (2Η, s), 7.05-7 · 28 (4Η, m); LRMS ESI m / z 327 [M + H] + Preparation 33: 2- (3 _ {(2R) -2-[((2r) -2- [3- (acetamido) _4_ (benzyloxy) benzyl 10]]-2-{[secondary butyl (dimethyl Base) Shibakanyl] oxy} ethyl) amino] propylbutanyl

Preparation of 15% mixture of ^% mg, 1.5 mmol) and 32 (978 mg, 30 mmol) of product prepared by heating in methane (0.5 ml) at 90 ° C. 5 Minutes to evaporate methane. Then, the reaction mixture (if it is a melt) is heated at 90 ° C. for 18 hours before cooling to room temperature. Then, the crude product was purified on a silica gel by column chromatography, and was extracted with 98: 2: 2 dioxane: methanol: 0.88 ammonia to obtain the title compound as an off-white sponge. Like substance, yield 59%, 630 mg. 75 200531959 NMR (400 MHz, CD3OD) δ: -0 · 18 (3Η, s), 0.00 (3Η, s), 0.83 (9Η, s), 1.05-1.08 (d, 3H), 1 · 66-1 · 72 (6Η, m), 2.00 (6Η, m), 2.02 (3H, m), 2.52-2.71 (3H, m), 2.84-2 · 96 (2Η, m), 3 · 36-3 · 41 (2Η, m), 4.68-4 · 72 (1Η, m), 5.20 (2Η, s), 6.92-7 · 18 (6Η, m), 7.30-7.50 (5H, m), 8.22 (m), 8.36 (s), 8.54 (s); LRMS ESI m / z 710 [M + H] +

Preparation 34: N-adamantane-1-yl-2- (3- {2-[(2R) -2-(((2R) -2- (tertiary-butyldimethylsilyloxy) -2- (3-fluorenylamino-4-hydroxyphenyl) ethylamino} propyl) phenyl} acetamidamine

From the product 33, a method similar to that of Preparation 20 was used to prepare the title compound in a certain amount of yield as a transparent sponge-like substance. 4 NMR (400 MHz, CD3OD) δ: -0.17 (3H, s), 0.00 (3Η, s), 0.83 (9Η, s), 1.04-1.06 (d, 3Η), 1.69-1 · 70 (6Η, m), 15 2 · 00 (6Η, m), 2.03 (3Η, m), 2.52-2 · 70 (3Η, m), 2.88-2 · 94 (2Η, m), 3.37-3 · 38 (2Η, m), 4.64-4 · 69 (1Η, m), 6.92-7 · 18 (6Η, m), 8.00 (lH, d), 8.30 (s), 8.56 (s); LRMS ESI m / z 620 [M + Η] + Preparation 35: 1 · (3-bromophenyl) -2-methylpropan-2-ol)

Br

76 200531959 At 0 ° C, slowly add methylmagnesium bromide (3M solution in diethyl ether, 5ΐ · 6 mL 'millimoles) to the dry diethyl ether (200 mL). 1- (3-Bromo-phenyl) propan-2-one (15.0 g, 70 mmol) and the mixture was stirred for 3 hours. Then, the reaction mixture was cooled down again, and the reaction was slowly stopped with a saturated aqueous ammonium chloride solution. The organic solution 'was washed with brine, dried over sodium sulfate and concentrated in vacuo. Then, the residual yellow oil was purified on Shixi gel by tube analysis method, and it was extracted with dioxane: pentanyl: methanol, 90: 5: 5 to obtain a pale yellow oil, yield 83%, 13 26 grams. 10 iHNMRGOO MHz, CDC13) δ: 1.22 (6Η, s), 1.42 (1H, bs), 2.74 (2Η, s), 7.15 (2Η, m), 7.40 (2Η, m) Preparation 36: N- [2_ (3-Bromophenyl) -1,1 · dimethylethyl] ammonium acetamide

At room temperature, acetonitrile (6.63 ml, 105 mmol) was added to a solution of the product of Preparation 35 (12.0 g, 52.0 mmol) in acetic acid (25 ml). The resulting solution was cooled to o ° c and concentrated sulfuric acid (25 ml) was added 'however the temperature was maintained below 1 o ° c. The resulting solution was left and stirred for 1 hour, then poured onto ice and tested by adding solid carbonate. The product was extracted with ethyl acetate (2x500 ml) and the combined organic solution was washed with water (50 ml) 20, dried over sodium sulfate, and concentrated in vacuo to obtain the title compound in a fixed yield, such as It is a solid of color, 16.0 g. WNMRGOO MHz, CDC13) δ: 1.37 (6Η, S), 3.02 (2Η, 77 200531959 S), 3.94 (2Η, s), 6.17 (1H, bs), 7.08-7 · 03 (1Η, d), 7.10-7.13 (1H, t), 7.26 (1Η, s), 7.39-7.32 (lHd,); LRMS ESI m / z 306 [M + H] +; Micro analysis: required for C12H15BrClNO : C 47.32; H 4.96; N 4.60; Found C 47 · 26; H 4.87; N 4.65 5 Preparation 37: 2- (3-bromophenyl) -1,1-dimethylethylamine

The solution of Preparation 36 (32.0 g, 105 mmol), thiourea (9.60 g, 126 mmol), and acetic acid (50 mL) in ethanol (250 mL) was heated to reflux overnight. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated in vacuo 10, basified with aqueous sodium hydroxide (1M, 450 ml) and extracted with dichloromethane (2 x 500 ml). The combined organic solution was washed with brine (50 ml), dried over sodium sulfate and concentrated in vacuo to obtain the title compound as a black oil, 96% yield, 23 g. ] ΗΝΙΙ (400 ΜΗζ, CDC13R 1.12 (6H, s), 1.84 (2Η, 15 bs), 2.62 (2Η, s), 7.16-7 · 08 (2Η, m), 7.36 · 7.32 (2Η, m); LRMS ESI m / z 228 [M + Η] + Preparation 38: [2- (3-bromophenyl) -1 dimethylethyl] aminotricarboxylic acid tert-butyl ester

The product of Preparation 37 (5.0 g, 22 mmol) was treated with di-tert-butyl dicarbonate (5.26 20 g, 244 mole) in methane (50 ml) and stirred for 20 hours. The reaction mixture was washed with water (50 ml), the combined organic solutions were dried over sodium sulfate and concentrated in vacuo. A cation exchange tube 78 200531959 column was used to purify the crude product material (methanol, followed by 2M ammonia in methanol), followed by flash column chromatography on a silica gel, and eluting with dichloromethane to obtain a certain amount. The title compound was obtained in a yield of 7.23 g as a brown oil. bNMRGOO MHz, CDC13) δ: 1.27 (6Η, s), 1.50 (9H, s), 2.97 (2Η, s), 4.24 (1Η, bs), 7.05 (1Η, d), 7 · 15-7 · 11 (1Η, t), 7.30 (1Η, s), 7.35 (1Η, d); LRMS ESI m / z 350 [Μ + ΝΗ4] + Preparation 39: benzyl 3- {2 -[(Tertiary butoxycarbonyl) amino] -2-methylpropyl} benzoic acid

10 The product of Preparation 38 (3.9 g, 12 mmol), [U, -bis (diphenylphosphino) bis (cyclopentadiene) ferrous] dichloropalladium in benzyl alcohol (60 ml) (11) A solution of (1.00 g, 1.3 mmol) with triethylamine (3.3 ml, 24 mmol) was heated to 100 ° C for 5 hours at 100 psi carbon monoxide. The reaction mixture was cooled and then filtered through abocilium and the filtrate was concentrated in vacuo. The residue was dissolved in ethyl acetate, and washed with sodium nitrite solution (50 ml) and brine (2 x 50 ml). The organic solution was then dried over sodium sulfate and concentrated in vacuo to provide a dark oil. This oil was purified on a Shixi gel by column chromatography, and it was extracted with 100: 0 to 84: 16 hexane: ethyl acetate to obtain 20 to obtain the title compound. If it is a pale yellow oil, the yield 61%, 2.81 grams. ] H NMR (400 MHz 9 CDC13) δ: 1.25 (6H 5 s) ^ 1.45 (9H 5 s), 3.05 (2H, s), 4.22 (1H, bs), 5.35 (2Η, s), 7 · 32 · 7 · 48 (7Η, m), 7.86 (1Η, s), 7.93-7 · 97 (1Η, m) 79 200531959 Preparation 40: 3- (2-amino-2-methylpropane) Benzyl benzoate hydrochloride

HC1 was prepared from the product of Preparation 39 using a method similar to that of Preparation 24. The title compound was prepared as a white solid with a yield of 91%. 5 iHNMRGOO MHz, CD3OD) δ: 1.33 (6H, s), 2.98 (2Η,

s), 5.37 (2Η, s), 7.31-7.53 (7Η, m), 7.93 (1Η, s), 8.00 · 8 · 04 (1Η, m); LRMS APCI m / z 284 [Μ + Η] + Preparation 41: 3- {2-[((2R) -2- [4- (benzyloxy) -3 · (methylamidoamino) phenyl] -2-{[tri Butyl (dimethyl) silyl] oxy} ethyl) amino] -2-methylpropyl} benzene 10 benzyl gallate

The product of Preparation 40 (1.81 g, 6.38 mmol), Preparation 12 (2.96 g, 6.38 mmol), and potassium carbonate (1.76 g, 12.8 mmol) were added in dimethylsulfine (10 ml). The mixture was heated at 95 ° C for 40 hours. The 15 reaction mixture was cooled, then diluted with water (250 ml) and extracted with ethyl acetate (3 x 50 ml). The combined organic solution was washed with sodium bicarbonate solution (50 ml) and brine (2 x 50 ml), dried over sodium sulfate and concentrated in vacuo to provide an orange oil. This oil was purified on a Shixi gel by column chromatography with 50:50 dioxane: hexane, followed by 100: 0 to 98: 2 dichlorohydrazone 80 200531959 calcination: methanol. Appropriate German fractions were evaporated under reduced pressure, and the residue was further purified on a silica gel using column chromatography, eluting with dichloromethane: methanol from 100: 0 to 98: 2 to provide One yellow gum. The gum was allowed to azeotrope with diethyl phospholipid) to obtain the title compound, as a yellow gum, yield 20%, 0835 g. 4 NMR (400 MHz, CDC13): δ: -0.15 to -0.17 (3H, m), -0.03 (3Η, s), 0 · 79-0 · 82 (9Η, s), ι · 〇ι ( 3Η, s), 1.04 (3Η, s), 2.62-2 · 86 (4Η, m), 4.66-4 · 74 (1Η, m), 5.06-5 · 07 (2Η , M), 5.36 (2Η, s), 6.88 (1Η, d), 7.01-7 · 05 (1Η, m), 10 7.27-7.50 (12H'm) '7.74 (lH, m ), 7.87-7.96 (2H, m), 8.39 (s), 8.40 (s), 8.76 (s), 8.78 (s); LRMS APCI m / z 667 [Μ + ΗΓ Preparation 42: 3_ [2 _ ({( 211) -2 _ {[tertiary butyl (dimethyl) lithium alkyl] oxo 2— [3 ((fluorenylamino) -4-hydroxyphenyl] ethyl} amino) -2-methyl Propyl] phenylbenzoic acid

15 From the product of Preparation 41, a method similar to 26 was used to prepare the title compound. The crude product was then azeotroped with diethyl ether (χ3) to obtain the title compound as a pale yellow solid with a yield of 97%. b NMR (400 MHz, CD3OD): δ: -0.12 (3H, s), 0.05 (3Η, s), 0.81 (9Η, s), 1.24 (6Η, s), 2.98 (2Η, dd), 3.26-3 · 30 (2Η, 20 m), 4.91 (1Η, t), 6.89 (1Η, d), 7.02 (1Η, m), 7.37-7 · 49 (2Η, m), 7.85 (1Η, bs), 7.93-7 · 96 (1Η, d), 8.11 (s, 1Η), 8.32 (s), 81 200531959 8.61 (s); LRMS ESI m / z 487 [M + H] " Preparation 43: (4_Ceryl_2,5 · dimethylphenyl) acetonitrile

A solution of (4-methoxy-2,5-dimethylphenyl) 5acetonitrile (0.5 g, 2.9 mmol) in dichloromethane (10 ml) was cooled to -80 ° C And treated with boron tribromide (1M in dichloromethane, 14.3 ml, 14.3 mmol). The reaction mixture was stirred at -80 ° F for another 30 minutes, and then it was warmed to room temperature for more than 2 hours. The reaction mixture was quenched with a saturated sodium bicarbonate solution (20 ml) and the organic layer was separated. The organic solution was washed with brine (20 ml), dried over sodium sulfate 10 and concentrated in vacuo to obtain a light brown solid. Purify by column chromatography on Shixi gel, and elute with ethyl acetate 20:80 to 33 · 67: pentamidine to obtain the title compound, as a colorless solid, dispersed at 60% in In mineral oil, the yield was 0.28 g. NMR (400 MHz, CD3OD) δ: 2.13 (3H, s), 2.23 (3H, 15 s) " 3.66 (2Η, s), 6.60 (1Η, s), 6.98 (1Η, s) ); LRMS ESI m / z! 6〇 [M-Η] " l44 · (4-¾-2-2,3-difluorenyl-benzyl) acetonitrile

The title compound was prepared from (4-methoxy-2,3-dimethyl-benzyl) acetonitrile using a method similar to that of Preparation 20 43. The yield was a colorless solid with a yield of 82 200531959 94%.

] Η NMR (400 MHz, CDC13) δ: 2.2 (3Η, s), 2.24 (3 ·, s), 3.62 (2Η, s), 6.64 (1Η, d), 7.03 (17, d); LRMS APCI m / z 160 [MH], 5 Preparation 45: (4-hydroxy-3-methylphenyl) acetonitrile

The title compound was prepared from (4-methoxy-3-methylphenyl) acetonitrile using a procedure similar to that of Preparation 43 as a pale yellow solid. 10 bNMRGOO MHz, CDC13) δ: 2.25 (3Η, s), 3.65 (2Η, s), 4.98 (1Η, bs), 6.76 (1Η, d), 7.01 (1Η, d) ), 7.07 (1Η, s); LRMS ESI m / z 146 [M-ΗΓ Preparation 46: 4- (2-aminoethyl) -2,5-dimethylphenol

A solution of the product of Preparation 43 (0.28 g, 1.74 mmol) was hydrogenated in ethanol (15 15 ml) over Raney nickel (0.1 g, 50% w / w) at 60 psi for 16 hours. . Then, the reaction mixture was filtered and the residue was purified using a cationic exchange resin at true $ 0m, and the title compound was obtained by eluting with methanol at a concentration of 1 乂 in methanol to obtain the title compound. ] ΗNMIL (400 MHz, CD3OD) δ: 2 · ΐ1 (3Η 'S)' 2.19 (3Η's), 2.63-2 · 67 (2Η, m), 2.72-2.76 (2H, 2) ' 6.54 (1Η, S), 83 20 200531959 6.81 (1Η, s); LRMS ESI m / z 166 [M + H] Preparation 47: 4- (2-amino-ethyl) -2,3 -Difluorenyl-phenol

From the product of Preparation 44, the method similar to Preparation 46 was used to prepare the title compound as a colorless solid with a yield of 95%.

W NMR (400 MHz, CDC13) δ: 6.78 (1H, d), 6.55 (1Η, d), 2.75-2.68 (4Η, m), 2.19 (3Η, s), 2.12 ( 3Η, s); LRMS APCI m / z 166 [Μ + Η] + Preparation 48: 4- (2-aminoethyl) -2-methylphenol

From the product of Preparation 45, a method similar to Preparation 46 was used to prepare the title compound, as a colorless oil. 4 NMR (400 MHz, CD3OD) δ: 2.15 (3H, s), 2.60-2.64 (2Η, m), 2.79-2 · 83 (2Η, m), 6.66 (d, 1Η), 6.82 ( 1Η, d), 6.90 (1Η, s); LRMS ESI m / z 152 [M + Η] + Preparation of 49: (3-iodobenzyl) amino phosphonium tert-butyl ester

Treatment of 3-iodobenzylamine hydrochloride (4.95 g, 18 4 mmol) with triethylamine (3.1 ml, 22 mmol) and di-tert-butyl dicarbonate 84 200531959 (4.40 g, 20 mmol) (Mole) in a dipyridine (100 ml) suspension, and the resulting solution was shaken at room temperature for 1.5 hours. Then, 2M hydrochloric acid (30 ml) and water (30 ml) were used to> gastric lavage reaction compound 'dried on sodium sulfate and reduced in a vacuum, agricultural 5 to obtain a certain amount of yield The title compound as a colorless solid, 6.43 g. NMR (400 MHz, CDC13) δ: 1.46 (9Η, s), 4.21 · 4 30 (2Η, m), 4.79-4 · 89 (1Η, bs), 7.06 (1Η, dd ), 7.25 (1Η, d), 7.60 (1Η, d), 7.63 (1Η, s); LRMS ESI m / z 332 [M-Η] -l0 Preparation 50: [(4 ' -Hydroxybiphenyl-3-yl) methyl] carbamic acid tert-butyl ester

The product of Preparation 49 (0.75 g, 2.25 millimoles' hydroxyphenylboronic acid (0.62 grams, 4.50 millimoles) in dimethylformamide (14 mL) was treated with a 2M aqueous solution of sodium carbonate (4 mL). ) And ι, ι, -bis (dibenzylidene 15-based) di (cyclopentadiene) ferrous palladium (11) (0.11 g, 0.14 mmol) solution at 80 C The resulting mixture was heated for 16 hours. The solvent was removed in vacuum, and the residue was purified on silica gel by column chromatography. The residue was extracted with 25:75 ethyl acetate: pentane to obtain a quantitative product. Rate of the title compound, as a pale pink crystalline solid, 0.73 g. 20] H NMR (400 MHz, CDC13) δ: 1.47 (9Η, s), 4.33441 (2Η, m), 4. · 87-4 · 94 (1Η, bs), 6.89 (2Η, d), 7.21 (1Η, d), 7.37 (1Η, dd), 7.43-7 · 45 (4Η, m) ; LRMS ESI m / z 298 [Μ-Η]-85 200531959 Preparation 51: 3 '-(aminofluorenyl) biben-4-ol hydrochloride

The product of Preparation 50 (0.73 g, 2.43 mmol) was treated with 4M hydrochloric acid (6 "ml, 24.3 mmol) in di-nf, and the resulting solution was stirred at room temperature. 3 hours. The reaction mixture was then concentrated in vacuo to obtain the title compound as a colorless solid. NMR (400 MHz, CD3OD) δ: 4.17 (2H, s), 6.87 (2Η, d), 7.34 (1Η, d), 7.45-7 · 50 (3Η, m), 7.61 (1Η , D), 7.65 (1Η, s); LRMS ESI m / z 198 [Μ-Η] _ 10, Preparation of 52 · 2-Chrysyl-1-Qinamine

η2ν Before adding 0.88 ammonia (6 ml), at room temperature, stir 2-hydroxy_ 丨 _naphthoic acid (5.0 g, 26.6 mmol), and carbonize 1- (3-diamidoaminopropylethyl) A solution of diamidine hydrochloride (5.6 g, 29.2 mmol) with 1-hydroxybenzyltrioxane (3 95 15 g '29.2 mmol) in tetrahydrofuran (70 ml) for 30 minutes. The resulting suspension was stirred at room temperature for 2 hours. The reaction mixture was then filtered, the filtrate was diluted with water (80 ml) and extracted with ethyl acetate (4 x 80 ml). Water (2 x 50 ml) and brine (50 Ml) The combined organic extracts were washed, dried over sodium sulfate and concentrated in vacuo to provide an orange oil. 20 The oil was purified on a silica gel using column chromatography to 95: 5: 0.5 Di 86 200531959 Chloropane: methanol: 0.880 ammonia, the title compound can be obtained, as a pink solid, yield 37%, 1.83 g.] HNMR (400 MHz, CDC13) δ: 6.11-6 · 35 (2Η, bs), 7.17 (1Η, d), 7.36 (1Η, dd), 7.54 (1Η, dd), 7.79 (1Η, d), 7.84 (1Η, 5 d), 8.22 (1Η, d), 11.70-11 · 88 (188 bs); LRMS ESI m / z 186 [M-Η] 'Preparation 53: 3,5-gas -N- ethyl-2-hydroxybenzamide Amides

The title compound was prepared from 3,5-dichloro-2-hydroxybenzoic acid and ethylamine using a method similar to that for the preparation of 52 10, and the title compound was obtained as a pale yellow solid. NMR (400 MHz, CDC13) δ: 1.28 (3Η, t), 3.47-3.54 (2Η, m), 6.29-6 · 36 (1Η, bs), 7.27 (1Η, d), 7.48 ( 1Η, d); LRMS ESI m / z 232 [M-ΗΓ ® 15 Preparation 54: 4- (Aminofluorenyl) -2,6-dimethylphenol hydrochloride

A solution of borane in tetrahydrofuran (1M in tetrahydrofuran, 27.1 ml, 27.1 mmol) was added dropwise to 3,5-dimethyl-4-hydroxybenzonitrile (1.0 g, 6.79 mmol). The solution in tetrahydrofuran (70 ml) was heated under reflux for 20 hours at 20 ° C. The reaction mixture was cooled to room temperature, treated with 87 200531959 6N hydrogen acid (20 mL) and heated under reflux for another% minutes. The reaction mixture was then cooled to room temperature and the solvent was removed in vacuo. The residue was purified using strong cationic cross-linked lipids, and was eluted with methanol followed by 2M ammonia in methanol to provide a light-colored oil. ，, treat this oil with 1M 5 hydrogen chloride (2G ml) in methanol and concentrate the reaction mixture in vacuo to obtain the title compound in the ratio m, as a pale yellow solid, 1.12 g. 4 NMR (400 MHz, CDCl3) δ: 2.22 (6Η, s), 3 75 (2H, s), 6.90 (2Η, s). 10 Preparation 55: 2- (aminomethyl) -4-chlorophenol hydrochloride

The title compound was prepared from 5-air-2-hydroxybenzonitrile using a method similar to that described in Preparation 54. ] HNMR (400 MHz, CDC13) δ: 4.08 (2Η, s), 6.87 (1Η, 15 d) '7.27 (1Η, d), 7.35 (1Η, s); LRMS APCI m / z 156 [Μ-Η] _ Preparation 56: 4,-(Aminomethyl) biphenyl-4-ol hydrochloride

The title compound was prepared from 4'-hydroxybiphenyl-4-carbonitrile using a method similar to that of Preparation 54. 20 NMR (400 MHz, CD3OD) δ: 4.10 (s, 2H), 6.83 (d, 2H), 7.44-7.46 (m, 4H), 7.60 (d, 2H). 88 200531959 Preparation 57: 1- (aminomethyl) -2-naphthol

10 15 Add a solution of borane (19.23 ml of a 1M solution, 19.23 mmol) in tetrahydrofuran dropwise to the amidine (0.90 g, 4.81 mmol) from Preparation 52 in tetrahydrofuran (10 ml) The solution was then heated under reflux for 2 hours. The solution was cooled, treated with HCl (10 ml) and heated under reflux for another 2 hours. The resulting suspension was cooled to room temperature, 0.88 ammonia was added to adjust the pH to pH 9 and extracted with ethyl acetate (3x50 ml). The combined organic solution (20 ml) was washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified on a silica gel by column chromatography, and the title compound was eluted with 95: 5: 0.5 to 90 ... 10: 1 dichloromethane: methanol: 0.88 ammonia. As a pink solid, the yield is 23%, 0.19 g. NMR (400 MHz, CD3OD) δ: 4.41 (2H, s), 7.07 (1Η, d), 7.23 (dd, 1Η), 7.43 (1Η, dd), 7.66 (1Η, d), 7.72 (1Η, d), 7.87 (1Η, d); LRMS ESI m / z 174 [M + Η] + clothing 58 · 2,4-dichloro-6-[(ethylamino) fluorenyl Fan

A solution of the product of Preparation 53 (0.77 g, 3.29 mmol) in tetrahydrofuran (10 ml) was cooled to 0 ° C and the sintered-tetrahydrofuran complex (1M in tetrahydrofuran, 9.9 ml, 9.9 Millimoles). The resulting solution 89 20 200531959 was heated to a temperature of more than 20 minutes, and then heated under reflux for 16 hours. The reaction was cooled to 0 c and the reaction was stopped by adding methanol. The resulting solution was heated to room temperature for more than 2 hours and then concentrated in vacuo. The remaining residue was dehydrated in dichloromethane (40 ml) and washed with water (2 x 100 ml), brine (10 ¾ liters), dried over sodium sulfate and reduced in vacuo to provide one, Color oil. The oil was purified on a Shixi gel by column chromatography, and the title compound was obtained by eluting with 2: 2 to 5.95 methanol: dioxane to obtain the title compound as a colorless solid with a yield of 74. %, 0.53 g. iHNMR (400 MHz, CDC13) δ: 1 · ΐ7 (3Η, t), 2 72 (2H, 10❾), 3.98 (2Η, s), 6.86 (1Η, d), 7.23 (1Η, d) The following compounds can be prepared from the product of Preparation 42 and the appropriate amine using a method similar to that described in Preparation 27 to prepare the following compounds shown by the following general formula. The reaction is monitored by TLC analysis and stirred at room temperature. 18_72 hours. 15 90 200531959

G

No. Qi Data Yield 59 t TH NMR (400MHz, CD3OD) δ: -0Λ9 (3H, s), -0.04 (3H, s), 0.78 (9H, s), 1.08 (3H, s), 1.10 (3H, s), 2.65-2.85 (4H, m), 2.89 (2H, t), 3.57 (2H, t), 4.67 (1H, dd), 6.79 (1H, d), 6.93 (1H, dd), 7.21-7.37 (6H, m) f 7.59-7.65 (2H, m), 8.08 (1H, d), 8.29 (s); LRMS ESI m / z 624 [_] + 21% 60 ch3 sound H 1H NMR (400MHz, CDCl3) δ: -0.23 (3H, s), -0.09 (3H, s), 0.71 (9H, s), 1.06 (3Hf s), 1.08 (3H, s), 2.18 (3H, s), 2.26 (3H, s ), 2.60-2.82 (4H, m) f 2.90-2.94 (2H, m), 3.61-3.71 (2H, m), 4.61- 4.65 (1H, m), 6.29-6.33 (1H, m), 6.62- 6 , 64 (1H, m), 6.85-6.89 (2H, m) f 6.96 (1H, d), 7.18 〇H, s), 7.27-7.32 (2H, m), 7.40-7.42 (1H, m), 7.78 (1H, s), 8.23 (1H, s), 9,62 (1 H, bs) LRMS APCI m / z 634 [MH] * 56% 61 ^ ~ HN ~ 'LRMS APCi m / z 668 [M + H ] + 88% 91 200531959

62 \ LRMS APCI m / z 668 [M + H] + 48% 63 Η3 ° γ ^^ 〇Η ΗΝ CH LRMS APC1 m / z 634 [M + H] + 77% 64 r rcCH3 \ LRMS APC—1 m / z 620 [M + Hf 96% 65 oS3 LRMS APCI m / z 642 [M + H] + 91% 66 j6t LRMS APC! m / z 620 [M + H] + 95% 67 Cl yS LRMS APCI m / z 660 [M + H wide 89% 68 / j0r LRMS APCI m / z 642 [M + Hf 91% preparation 60: purified by column chromatography using a 12 g Redisep® cartridge, 96: 4: 0.3 dichloromethane: methanol: 0.88 ammonia stripping 5 Preparation 62: Further azeotropy (x3) with diethyl ether to obtain the desired product Preparation 68: 6- (aminofluorenyl) 2-naphthol can be prepared as described in US 20040204455, pl9 92 200531959 Preparation 69: 3- [2-({(2R) -2-{[tertiary butyl (dimethyl) lithium alkyl]] Oxygen} -2 · [3- (formylamino) -4-hydroxyphenyl] ethyl} amino > 2-methylpropyl] -N- [2- (4-hydroxyphenyl) -2 -Methylpropyl] benzidine

5 4 (2-Monthestyl-1,1--methylethyl) age hydrochloric acid {Acta Chem.

Scand. 8 '1203, 1207; 1954}, (41 mg, 0.21 mmol) was added to the product of Preparation 42 (100 mg, 0.2 μmol), hexafluoro acid 0- (1 Benzotriazol-1-yl) _N, N, ν ,, ν, _tetramethylsaw (78 mg, 0.2 μmol) with triethylamine (35 μl, 0.4 mmol) A mixture of 10% dimethylformamide (3 ml) 10 was stirred, and the mixture was stirred at room temperature for 18 hours. Then, the solvent was removed in vacuo and the residue was mixed in ethyl acetate, and washed with a saturated sodium bicarbonate solution (3 x 20 ml) and brine (3 x 20 ml). Then, the organic solution was dried over sodium sulfate and concentrated in vacuo to obtain the title compound as a brown sponge-like substance with a yield of 54%. 15 LRMS APCI m / z 634 [M + H] + Preparations 70 to 76 The product from Preparation 42 and appropriate _ can be used to describe the method in Preparation 69 to prepare the TLC analysis shown in the following formula to monitor the reaction and The following compounds are shown at μ at room temperature. Use to mix for 18-72 hours. 93 20 200531959

Number Qi Data Yield 70 LRMS APCI m / z 668 [M + Hf 96% 71 LRMS APCI m / z 620 [Μ + ΗΓ 89% 72 LRMS APCI m / z 642 [M + H] + 84% 73 Η〇αα LRMS APCI m / z 626 [Μ + ΗΓ 96% 74 LRMS APCI m / z 660 [M + H] + 83% 75 ^ ατ LRMS APCI m / z 642 [M + Hf 99% 76 ην / _Ο ^ Ο ~ 0η i LRMS APCI m / z 668 [M + Hf 80% Preparation 77: 2,2 '-(1,3-phenylene) diethyl acetate

94 200531959 Ethyl chloro (12.5 ml, 175 mmol) was added to a suspension of 2,2,2,3,1-diphenyl) diacetic acid (50.0 g, 260 mmol) in ethanol (500 ml) The resulting solution was heated under reflux for 16 hours. The reaction was then cooled to room temperature and the solvent was removed in vacuo. The residue was distributed between a saturated aqueous solution of sodium bicarbonate 5 (300 ml) and ethyl acetate (500 ml). The organic phase was separated and washed with water (200 ml) and brine (300 ml), dried over sodium sulfate and concentrated in vacuo to obtain the title compound in a certain yield, as a pale yellow oil, 63.5 g. iHNM ^ CDCU, 400 ΜΗζ) δ: 1.31 (6Η, t), 3.65 (4Η, 10 S) '4.20 (4Η, q), 7.24-7 · 36 (4Η, m); LRMS ESI m / z 251 [M + H] + Preparation 78: [3- (2-oxo-propyl) phenyl] -ethyl acetate

Diacetate from Preparation 77 (44.3 g, 177 mmol) and 2,2,-(1,3-phenylene) di were treated dropwise with 12M hydrogen acid (4.9 ml, 58.8 mmol). Acetic acid (59.2 g, 308 mmol) in ethanol (24 ml) and twentieth mountain (290 ml). The reaction mixture was stirred under reflux for 18 hours, cooled to warm and concentrated in vacuo. The reaction / complex was then diluted with toluene (125 ml) and the resulting slurry was filtered. The filtrate was concentrated in vacuo and the residue was mixed in water and basified with sodium bicarbonate until the pH was neutral. The mixture was diluted with ethyl acetate (200 ml), and the organic layer was separated and washed with sodium bicarbonate solution (5 x 30 ml) and brine (50 ml). The combined extract aqueous solution was acidified with 6M hydrochloric acid to pH 3, and extracted with diethyl ether (3x30 mL). The combined organic solution was dried over magnesium sulfate and concentrated in vacuo. The residue was triturated with pentagon to obtain the title compound as a colorless solid in a yield of 27% '10.8 g. 4 NMR (CD3OD, 400 ΜΗζ) δ: 1.25 (3Η, t), 3.60 (2Η, 5 m), 3.63 (2Η, m), 4.15 (2Η, q), 7.18 · 7 · 32 (4Η, m); LRMS ESI: m / z245 [M + Na] + Preparation 79: [3- (2_Ethylfluorenyl-propyl) _phenyl] -acetic acid

At 0 ° C, methyl chloride (51 mL, 3M 10 solution in tetrahydrofuran, 153 mmol) was added dropwise to the product of Preparation 78 (11.6 g, 51 mmol) (Win International Journal of Peptide and Protein Research, 1987, 29 (3), 331) a stirred solution in tetrahydrofuran (300 ml). The reaction was then heated to a thermostat to form a thick white precipitate, and then water (50 mL) and 2N hydrogen acid (80 mL) were carefully added. The aqueous layer was separated and extracted with ethyl acetate φ 15 (2x300 ml). The combined organic solution was washed with brine (50 ml), dried over sodium sulfate and concentrated in vacuo to obtain a certain amount of the standard compound 'as a golden oil, 11.2 g. hNMRCCDCh, 400 ΜΗζ) δ: 1.22 (6Η, S), 2.75 (2Η, s) '3.63 (2Η, s), 7.12-7 · 30 (4Η, m); LRMS ESI m / z 209 20 [M + H] + Preparation 80: {3- [2- (2-chloro-ethylamido) -2-amidino-propyl] -phenylbutanoic acid

96 200531959 A solution of the product of Preparation 79 (16.0 g, 70 mmol) was added in 2-acetonitrile (8.8¾ liters' 140¾ mols) in acetic acid (% ml). The resulting solution was cooled to 0 ° C, treated with concentrated sulfuric acid (33 ml), and the reaction mixture was gradually heated to room temperature. After 4 hours, the reaction mixture was poured onto ice 5 and basified with solid sodium carbonate. The solution was extracted with ethyl acetate (2x500 ml), the combined organic extract solution was dried over magnesium sulfate and concentrated in vacuo to obtain the title product as a colorless solid, yield 96%, 9.0 g . bNMRCCDCh, 400 ΜΗζ) δ 1.36 (6H, s), 3.02 (2Η, 10 s), 3.62 (2Η, S), 3.95 (2Η, s), 6.19 (1Η, m), 7.06-7 · 31 (4Η, m); LRMS ESI m / z 282 [M-Η] 'Preparation 81 · [3- (2-Amino-2_methyl-propyl) _ Phenylρ methyl acetate

Under reflux, a solution of the product 80 (51 g, 18 mmol), thiourea 15 (1.6 g '21 mmol), and a solution of acetic acid (18 mL) in ethanol (80 mL) was heated for 16 hours. . The reaction mixture was then cooled to room temperature and filtered. The effluent was concentrated in vacuo and the residue was dissolved in methanol (mL) and saturated with nitrogen chloride gas. The resulting solution was heated to reflux for 16 hours. The compound was concentrated in vacuo and the residue was distributed between ethyl acetate (200 ml) and a 5% aqueous solution of 20 sodium carbonate (200 ml). The organic phase was washed with brine (100 ml) and concentrated in a vacuum towel on the claws. · Strong cation exchange resin to purify the residue, and then elute with methanol followed by ammonia solution in methanol. It can be used as a yellow oil. Yield: 2,5 g. 97 200531959 bNMRCCDCh, 400 μ ζ) δ: 1.14 (6Η, s), 2.68 (2Η, s), 3.62 (2Η, s), 3.69 (3Η, s), 7.08-7 · 16 (3Η, m), 7.23-7 · 27 (1Η, m); LRMS ESI m / z 222 [M + Η] + Preparation 82: (3- {2-[(tertiary butoxyl)) Amine] methylpropyl} phenyl) 5 ethyl acetate • From the product of Preparation 81 using a method similar to Preparation 49 to prepare the title compound, the title compound can be obtained as a colorless oil with a yield of 81%. WNM ^ CDCb, 400 ΜΗζ) δ: 1.25 (6H, s), L45 (9H, 10 s), 2.95 (2Η, s), 3.60 (2Η, s), 3.70 (3Η, s) , 4 25 (1Η, bs), 7 · 02-7 · 06 (2Η, m), 7 · 15 (1Η, d), 7 25 (m, called; lrms ㈣ m / z 344 [M + Na] + Preparation 83: (3- {2-[(Tertiary butoxyepiyl) aminomethylpropyl} phenyl) acetic acid

A 5M sodium hydroxide solution (4.6 ml 'n mmol) was forcefully poured into the preparation of the product (7.45 g, 23 mmol) in Twenty Hills (30 ml) and water (8 ml) The solution 'and stir the mixture at room temperature for 18 hours. Then, the reaction mixture was concentrated in vacuo, the residue was dissolved in water and acidified with 2M hydrogen to 20 to pH 3, and then the mixture was extracted with Methylen (3 x 30 ml) and washed with brine. The combined organic solution (ml) was dried over sulphur and dried in a vacuum under 98 200531959 to provide an oil. This oil was then co-folated with diethyl to obtain the title compound as a colorless gum, yield 99%, 7.0 g. NMR (CDC13, 400 ΜΗζ) δ: 1.25 (6H, s), 1.50 (9Η, s), 2.95 (2Η, s), 3.55 (2Η, s), 3.65 (s, 1Η) , 7 · 05 (2Η, m), 5 7 · 10 (1Η 'd)' 7 · 20 (1Η, m), 7.25 (1Η, m) Preparation 84: (3- {2-[(third order Butoxycarbonyl) amino] _2_fluorenylpropyl 丨 phenyl) benzyl acetate

j〇 Add carbonate shavings (6.03 g, 18.6 mmol) to the product of Preparation 83 (5.7 g, 18.6 mmol) in N, N-dimethylformamide (40 ml). The solution was stirred at room temperature for 1 hour. The reaction mixture was then concentrated in vacuo and the residue was dissolved in N, N-dimethylformamide (80 ml) and treated with benzyl bromide (3 "8 g, I8.6 mmol) And incubate for 3 hours at room temperature. The mixture was then filtered and concentrated in vacuo, and the residue was dissolved in ethyl acetate (60 ml), washed with brine (60 ml), dried over mash and concentrated in vacuo to The title compound was obtained as a color oil, 76% yield, 5.6 g. 6 hNMRCCDCb, 400 ΜΗζ) δ: 1.25 (6H, s), 1 49 (9 s) '2.98 (2Η' s) '3.65 (2Η' s), 4.30 (s, 1Η), 5.14 ( 2¾ 20 7 · 06-7 · 10 (2Η, d), 7.15-7.20 (1H, m), 7.22 · 7 · 39 (6Η, 'S)' LRMS ESI m / z 396 [MH] ') Preparation 85: [3- (2-Amino-2-methylpropyl) phenyl] benzyl acetate 99 200531959

Trifluoroacetic acid (30 ml) was added to the product of Preparation 84 (5.6 g, 4 mmol) and the mixture was stirred at room temperature for 18 hours. Then, the reaction mixture was concentrated in vacuo, the residue was diluted with methane (100 ml) and basified with a saturated sodium bicarbonate solution (300 ml). The organic layer was separated, washed with brine, dried over magnesium sulfate and concentrated in vacuo to obtain the title compound as a yellow oil with a yield of 76%. bNMRCCDCh, 400 ΜΗζ) δ: 1.10 (6Η, s), 1.50 (9H, s), 2.64 (2Η, s), 3.66 (2Η, s), 5.13 (2Η, s), 7 · 07-7 · 12 (2Η, d), 10 7 · 14_7 · 18 (1Η, m), 7.22_7 · 38 (6Η, m); LRMS ESI m / z 298 [Μ + Η] + Preparation 86: (3- {2-[((2R > 2- [4- (benzyloxy) -3- (fluorenylamino) phenyl] -2-{[secondary butyl monomethyl) crushed ] Oxy} ethyl) amino] -2-methylpropyl} benzyl) benzyl acetate

15 From the products of Preparations 12 and 85, the title compound was prepared in a similar manner to that of Preparation 13 in 55% yield. 4 NMR (400 MHz, CDC13) δ: · 0 · 20 (3Η, m), -0 · 06 (3Η, s), 0 · 78 (9Η, s), 0 · 925 (3Η, s), 0 · 95 (3Η, s), 2.53-2 · 77 (4Η, m) '3.57 (2Η, s), 4.61-4 · 68 (1Η, m), 5.0 · 1-5 · 02 (2Η, m), 100 200531959 5.06 (2Η, s), 6.84-6 · 87 (1Η, m), 6.97-7 · 36 (14Η, m), 7.62-7 · 70 (1Η, m) , 8.33-8 · 35 (1Η, m), 8.34 (s), 8.67 (s), 8.70 (s); LRMS ESI m / z 681 [M + H] · Preparation 87: {H2-({( 2R) -2 _ {[tertiary butyl (dimethyl) lithium alkyl] oxy} 1 [3. 5 (methylamino) -4-hydroxyphenyl] ethyl} amino) -2- Methylpropyl] phenyl}

From the product of Preparation 86, a method similar to Preparation 26 was used to prepare the title compound with a yield of 93%. NMR (400 MHz, CDC13) δ: -0.06 (3H, s), 〇05 (3Η, 10 s) '0 · 88 (9Η's)' 1 · 00 (3Η's) '1 · 〇4 (3Η, s), 2.58-2.88 (4Η, m), 3.58 (2Η, s), 4.64-4.67 (1Η, m), 6.88 · 6 · 90 (1Η, m), 6.95-6 · 98 (1Η, m), 7.07-7 · 27 (5Η, m), 8.04-8.05 (d), 8.25 (s), 9.55 (bs); LRMS ESI m / z 501 [ M + H] * Preparation 88 · Ga-N-ethyl-5-mercaptobenzamide

From 2-chloro-5-hydroxybenzoic acid and ethylamine, the title compound was prepared in a similar manner to that used in Preparation 52 as a colorless solid. ] H NMR (400 MHz, CDC13) δ: 1.22 (3H, t), 3.42-3.49 101 200531959 (2H 'm), 6.48_6 · 52 (1Η, m), 6.80 (1Η, dd), 7 · 13 (1Η, d) 7.38 (1Η, d); LRMS ESI m / z 200 [M + H] + Preparation of 89: 4-chloro-3-[(ethylamino) methyl] phenol

From the product of Preparation 88, the method of Preparation 57 was used to prepare the title compound 'as a colorless solid. NMR (400 MHz, CD3OD) δ: 1.15 (3Η, t), 2.68 (2H, q), 3.79 (2Η, s), 6.67-6 · 70 (1Η, m), 6.84 (1Η, d), 7.16 (1Η, d). Preparation of 90: 4-{[tertiary butyl (difluorenyl) silyl) oxy] chlorobenzaldehyde

10 15 'Stir 2-air-4-transylbenzene (5.0 g, 32 mmol) at room temperature, secondary butyl (monomethyl) stone sintered base gas (5.3 g, 35 mmol) Moore), taste. Sit (2.9 g, 45 mmol) and N, N-dimethylaminopyridine. Solution (10 mg) in N, N-dimethylformamide (40 ml) for 16 hours. The solvent was removed in vacuo and the residue was distributed between ethyl acetate (100 ml) and water (000 ml). The organic phase was separated, washed with brine (50 ml), dried over sodium sulfate and concentrated in vacuo. Purified on a silica gel by column chromatography and eluted with 75:25 to 0.33 pentane: ethyl acetate to obtain the title compound, such as a helmet-colored oil, yield 75%, 6.50 g . … NMR (400 MHz, CDC13) δ: 0.25 (6Η, s), 〇97 (9h, s), 102 20 200531959 6 · 80 (1Η, dd), 6.87 (1Η, d), 7. · 84 (1Η, d), 10 · 32 (1Η, s) Preparation 91: Ν- (4-{[tertiary butyl (difluorenyl) lithium alkyl] oxo-2-chlorobenzyl) propan-2 -Dilute-1-amine

ch3ch3 〇 ~ Si—έ ~ € 3 ch3ch3 was treated with sodium triethoxylate borohydride (7.6 g, 35.6 mmol) from the aldehyde (6.50 g, 24.0 mmol) from preparation 90 and allylamine A solution of 1.51 g, 26.4 mmol in dioxane (60 ml) was stirred at room temperature for 16 hours. A saturated sodium bicarbonate solution (50 ml) was added and the organic layer was separated. The organic solution was washed with brine (50 ¾ liters), dried (sodium sulfate) and concentrated in 10 vacuum to provide a yellow oil. The oil was purified on a silica gel by column chromatography, and the title compound was eluted with 75 ·· 25 to 67: 33 amyl acetate: ethyl acetate to obtain the title compound as a colorless oil with a yield of 38%. , 2.80 grams. ! H NMR (400 MHz, CDC13) δ: 0.19 (6H, s), 0.97 (9Η, s), 1.84 (1Η, bs), 3.26 (2Η, d), 3.81 ( 2Η, s), 5.12 (1Η, 15 dd), 5.20 (1Η, dd), 5.88-5 · 98 (1Η, m), 6.71 (1Η, dd), 6.85-6 · 86 (1Η, d), 7.24 (1Η, d); LRMS ESI m / z 312 [M + Η] + Preparation 92: (4-{[tertiary butyl (difluorenyl) lithium alkyl] Oxo-2-chlorobenzyl) amine

Under reflux, the product of 91 (2.8 g, 9.0 mmol) was prepared by heating, di20 methyl barbituric acid (7.0 g, 45 mmol) and tetrakis (triphenylphosphine) (0) ( 0.10 g, 0.08 mmol) in dichloromethane (80 ml) for 4 hours. The solution was cooled 103 200531959, then concentrated in vacuo and the residue was distributed between ethyl acetate (50 ml) and 1N aqueous sodium hydroxide solution (50 ml). The organic layer was separated, washed with brine (50 mL), dried over sodium sulfate and concentrated in vacuo. The residue was purified on a silica gel by column chromatography, and the title compound was obtained by diluting with dichloromethane: methanol: 0.880 and dichloromethane: methanol: 0.880 from 98: 2: 0 to 95: 5: 5 0.5. Oil, 70% yield, 1.70 g. NMR (400 MHz, CDC13) δ: 0.19 (6H, s), 0.97 (9Η, s), 1.89 (2Η, s), 3.85 (2Η, s), 6.70 (1Η, dd), 6.85-6.86 (1Η, dd), 7.21 (1Η, d) 10 Preparations 93 to 95 The products similar to those described in Preparation 27 can be used to prepare products from Preparation 87 and appropriate amines to prepare The following compounds shown by the following formulae were prepared. The reaction was monitored by TLC analysis and stirred at room temperature for 18-72 hours.

No.〇1 Data yield 93 / = Λ 0-CH T NMR (400MHz, CD3OD) δ: -0.18 (3H, s), -0Ό7 (3H, s), 0.75 (9H, s), 1.01 (3H, s ), 1.04 (3H, s), 2.59-2.83 (4H, m), 3.56-3.58 (2H, m), 3.89 (3H, s), 4.41-4.53 (2H, m), 4.63-4.66 (1H, m ), 6.80-6.82 (1HT m), 6.95-6.98 (1H, m), 7.03-7.05 (1H, m), 7.09-7.11 (2H, m), 7.21-7.26 (4H, m), 7.93-7.69 ( 2H, d); LRMS ESI m / z 648 [M + H] + 41% 104 200531959 94 HO \ 1H NMR (400MHz, CD3OD) δ: -0.21 to-43% η3Ά 0.16 (3H, m), -0.04- 0.01 (3H, m), 0.76-0.83 (9H, m), 1.02-1.09 (9H, m), 2.61- 2.77 (3H, m), 2.84-2.92 (1H, m), 3.32-3.38 (2H, m ), 3.70t 3.81 (2H, 2xs), 4.55, 4.63 (2H, 2xs), 4.66, 4.72 (1H, m), 6.62-6.69 (1H, m), 6.78-6.87 (2H, m), 6.90-6.96 (1H, m), 6.99-7.26 (5H, m), 8.07-8.10 (1H, s), 8.29 (s), 8.60 (s); LRMS APCI m / z 668 [M + H] + 95 ^ NMR ( 400MHz, CD3〇D) δ: -0.25 54% hn \ = / v___Lr 1 (3H, s), -0.09 (3H, s), 0.73 (9H, m), 0.97 ▼ (3H, s), 0.99 (3H , s), 2: 56-2.83 (4H, m), 3.47-3.48 (2H, m), 4.31 (2Ht s), 4.59-4.63 (1H, m), 6.73 -7.41 (15H, m), 8.08 (s), 8.21 (s), 8.57 (s); LRMS ESI m / z 682 [M + H 广 制造 96: 2- {3- [2-({(2R) -2-{[tertiary butyl (dimethyl) silyl] oxy} -2- [3- (methylamino) -4-hydroxyphenyl] ethyl} amino) -2-methyl Propyl] phenyl} -N- (2-chloro-4-hydroxybenzyl) acetamidamine

〇 From the products of Preparations 87 and 92, a method similar to that of Preparation 27 was used to prepare the title compound. The yield was 62% in the case of a colored sponge. 105 200531959 bNMRGOO MHz, CD3OD) δ: -0 · 19 (3Η, s), -0.03 (3Η, s), 0 · 79 (9Η, s), 1.01-1 · 10 (6Η, m) , 2.62-2 · 76 (3Η, m), 2.85 (1Η, m), 3.37-3 · 92 (2Η, m), 4.34 (2Η, s), 4.66 (1Η , M), 6.62 (1H, m), 6.78-6 · 82 (2Η, m), 6.91 (1Η, m), 7.02_7 · 23 (5Η, m), 8.09 face 8.11 (1Η, m), 8.27 (s), 8.59 (s); LRMS APCI m / z 640 [M + H] + Preparation 97: 2- (3-bromophenyl) -N- (3,4-dimethylbenzyl ) Acetamide

The title compound was prepared from 3,4-difluorenylbenzylamine and 3-bromophenylacetic acid using a method similar to that of Preparation 10 27 as a white solid with a yield of 93%. HNMR (400 MHz, CDC13) δ: 2.20 (6Η, s), 3.50 (2Η, s), 4.30 (2Η, d), 5.80 (1Η, 10brs), 7.60- 7.80 (7Η, m); LRMS ESI 332 [M] + Preparation 98: N- (3,4-dimethylbenzyl) -2- {3-[(E) -2 · (1,3- Dioxo-1,3-dihydro 15 -2Η-isoindole_2-yl) vinyl] phenyl} ethanamine

The product of Preparation 97 (5.0 g, 15 mmol) was heated in acetonitrile (35 mL) under reflux, N-vinylphthalimide (2.62 g, 15.1 mmol), 106 200531959 di-o-toluene Phosphine (473 g, 1.55 mmol), acetic acid (98 mg, 0.4 mg) and N, N-diisopropylethylamine (30 ml, 172 mmol) for 16 hours Shou. The reaction mixture was then cooled to room temperature and the precipitate was filtered off. Then, the solid was dissolved in digas methane, activated carbon was added, and the solution was filtered through a plug of sirens. The filtrate was concentrated in vacuo and the residue was recrystallized from hot -chloromethane / methanol to obtain the title compound as a yellow solid, 55% yield, 3.5 g. ] ΗΝΜΙΙ (400 MHz, CDC13) δ: 2.20 (6H, s), 3.80 (2 ，, s), 4.30 (26, d), 6.0 (1Η, brs), 6.90 (2H, m), 7 · 01 (1Η, 10 m), 7.18 (1Η, m), 7.26-7 · 40 (4Η, m), 7.56-7 · 61 (1Η, m), 7.75 (2Η, m), 7 · 88 (2Η, m) Preparation of 99: Ν- (3,4-dimethylbenzyl) winter {3- [2- (1,3-dioxo-1,3-dihydroisosigmadol) b Phenyl] phenyl> ethanamine

The product of Preparation 98 (3.3 g, 7.7 mmol) and 10% palladium on carbon (1 g) were suspended in ethanol, and the mixture was stirred at 50 psi of hydrogen at room temperature for 16 hours. The reaction mixture was then filtered through abocilium, washed with ethanol and the filtrate was concentrated in vacuo to obtain the title product as a yellow solid, 52% yield, 1.7 g. 107 200531959 hNMRGOO MHz, CDC13) δ: 2.20 (6Η, s), 2.95 (2Η, t), 3.60 (2Η, s), 3.90 (2Η, t), 4.39 (2Η , D), 5.95 (1Η, brs), 6.90-7 · 20 (8Η, m), 7.60-7 · 70 (3Η, m) Preparation of 100: 2- [3- (2-amine Ethyl) phenyl] -N- (3,4-dimethylbenzyl) -acetamidamine

Hydrazine monohydrate (6 ml, 123.6 mmol) was added to a suspension of the product of Preparation 99 (3.5 g, 8.2 mmol) in ethanol (125 ml), and the mixture was heated under reflux for 4 hours. The reaction mixture was then cooled to room temperature and filtered. The filtrate was concentrated in vacuo and the residue was purified on silica gel 10 using column chromatography. The title compound was obtained by diluting with 95: 5: 1 dichloromethane: methanol: 088 ammonia, yield 57. ° /. , 1.4 grams. H NMR (400 MHz, CD3OD) δ: 2.18 (6H, s), 2.73 (2Η, m) '2.86 (2Η, m), 3.50 (2Η, s), 4.25 (2 (, s) , 6.87-7 · 25 (7Η, m); LRMS ESI 297 [M + Η] + 15 Preparation 101: 2- (3- {2-[((2R) -2- [4- (benzyloxy) ) -3- (methylamidoamino) phenyl] -2 _ {[tertiary butyl (dimethyl μ alkyl; | oxy} ethyl) amino] ethyl) phenyl) -N · ( 3,4-Difluorenylbenzyl) acetamide

108 200531959 From the products of Preparation 12 and Preparation 100, the title compound was prepared in a similar manner to that of Preparation 33 if the product was a yellow oil with 37% yield. ] HNMR (400 MHz, CD3OD) δ: · 0 · 18 (3Η, s), -0 · 03 (3Η, s), 0 · 80 (9Η, s), 2.20 (6Η, m), 2 · 80 (4Η, m), 3.40 (2Η, 5 m), 3.50 (2Η, s), 4.25 (2Η, s), 4.76 (1Η, m), 5.18 (2Η, s), 6.85-7 · 45 (15Η, m), 8.23 (s), 8.30 (s); LRMS ESI 680 [M + H] + Preparation 102: 2- {3- [2 _ ({(2R) -2-{[tertiary butyl (dimethyl) silyl] oxy} -2- [3- (fluorenylamino) -4-hydroxybenzyl] ethyl} amino) ethyl] benzene 10 } -N- (3,4-dimethylbenzyl) acetamide

〇 From the product of Preparation 101, a method similar to that of Preparation 20 was used to prepare the title compound. If it was a white sponge-like substance, the yield was 83%. NMR (400 MHz, CD3OD) δ: -0.18 (3H, s), -0.05 (3 Η, 15 s), 0.81 (9 Η, s), 2.18 (6H, m), 2.80 ( 4Η, m), 3.29 (2Η, m), 3.51 (2Η, s), 4.25 (2Η, s), 4.70 (1Η, m), 6.80 (1Η, d), 6.91-7 · 20 (9Η, m), 8.03 (s), 8.25 (s); LRMS ESI 590 [M + H] + 109 200531959 Preparation 103 to 110 The product from Preparation 87 and the appropriate amine can be used. The following compounds shown by the following formula were prepared similar to the method described in Preparation 27. The reaction was monitored by TLC analysis and stirred at room temperature for 18-72 hours.

No. Qi Data Yield 103 1H NMR (400MHz, CD3OD) δ: -0.25 (3H, s), -0,08 (3H, s), 0.73 (9H, s), 0.97 (3H, s), 0,99 (3H, s), 2.37 (3H, s), 2.56-2.83 (4H, m), 3.39-3.45 (2H, m), 4.24 (2H, s), 4.60-4.63 (1H, m), 6.73 -6.79 (1H, m), 6.85 (1H, dd), 6.97 (1H, d), 7.03 (1H, s), 6.97-7.16 (6H, m), 8.04 (d), 8.21 (s), 8.53 ( s); LRMS ESI m / z 658 [M + H] _ 66% 104 F rrVF nH NMR (400MHz, CDCI3) δ: -0.24 (3H, s), ^ 0.08 (3H, s), 0.74 (9H, s ) t 0.98 (3H, s), 1.00 (3H, s), 2.57-2.83 (4H, m), 3.48 (2H, m), 4.37 (2H, s), 4.60-4.63 (1H, m), 6.73 ( 1H, d), 6.85 (1H, dd), 6.99-7.17 (5H, m), 7.32 (2H, d), 7.49 (2H, d), 8.04 (d), 8.22 (s), 8.52 (s); LRMS APCI m / z 658 [M + H] + 55% 110 200531959

105 1H NMR (400MHz, CDCI3) δ: -0.17 (3H, s), -0.06 (3H, s), 0.76 (9H, s), 1.01 (3H, s), 1.03 (3H, s), 2.59 -2.83 (4H, m), 3.56-3.68 (2H, dd), 4.45-4.49 (2H, m), 4.64-4.67 (1H, m), 6.84-6.86 (1H, m), 6.95 (8H, m) , 7.55-7.57 (2H, m), 8.17 (d), 8.63 (s); LRMS ESI m / z 615 [M + H] + 19% 106 1H NMR (400MHz, CDCb) δ: -0.16 (3H, s ), -0.06 (3H, s), 0.77 (9H, s), 1.00 (3H, s), 1.04 (3H, s), 2.57-2.85 (4H, m), 2.53-3.67 (2H, dd), 4.40 (2H, m), 4 64-4.67 (1H, m), 6.80 (1H, m), 6.96 (1H, m), 7.02 (7H, m), 7.32-7.34 (2H, m), 8.17 ⑼, 8.74 (s); LRMS APCI m / z 674 [Μ + ΗΓ 52% 107 ^ a: 1H NMR (400MHz, CD3OD) δ: -0.26 (3H, s), 0.10 (3H, s) f 0.72 (9H , s), 0.93 (3H, s), 0.95 (3H, s), 2.49-2.79 (4H, m), 3.46-3.47 (2H, m), 4.33 (2H, s), 4.58-4.61 (1H, m )? 6.72-7.48 (15H, m), 8.04 (1H, d), 8.21 (s), 8.52 (s); LRMS APCI m / z 682 [M + H] + 72% 108: IX 1H NMR (400MHz , CD3OD) δ: -.024 (3H, s), -0.08 (3h, s), 0.74 (9H, s), 0.99 (3H, s), 1.02 (3H, s), 2.59-2.87 (4H, m ), 3.47 (2H, m), 4.2 3 (2H, s), 4.62-4.65 (1H, m), 6.65 (1H, d), 6.74 (1H, d), 6.90-6.95 (1H, m), 7.01-7.07 (3H, m), 7.10 ( 1H, s), 7.14-7.24 (2H, m), 8.05 (1H, d), 8.22 (s), 8.53 (s); LRMS APCI m / z 640 [M + H] + 43% 111 200531959 109 1H NMR (400MHz, CD30D) δ: -0,24 (3H, s), -0.08 (3H, s), 0.73 (9H, s), 1.00 (3H, s) r 1.02 (3H, s), 1.45-1.56 ( 2H, m), 2.01-2.04 (2H, m), 2.53-2.84 (8H, m), 3.38 (2H, s), 3.58 (1H, s), 4.60-4.63 (1H, m), 6.73 (1H, d), 6.85 (1H, dd), 6.97 (1H, d), 7.05-7.14 (3H, m), 8.04 (1H, d), 8.24 fs), 8.53 (s); LRMS APCI m / 2 598 (M + H] + 110 ίΗ NMR (400MHz, CD30D) δ: -0.18 (3H, s), -0,02 (3H, s), 0.80 (9H, s), 1.05 (3H, s), 1,07 ( 3H, s), 2.61-2.91 (4H, m), 3.08 (3H, s), 3.55 (2H, d), 4.45 (2H, s), 4.66 (2H, dd), 6.79 (IK, d), 6.91 (1H, dd), 7.05 (1H, d), 7.13 (1H, s), 7.15-7.25 (3H, m), 7.45 (2H, d), 7.85 (2H, d), 8,10 (1H, d), 8.28 (s), 8.60 (s); LRMS APCI m / z 668 [M + H] +

Preparations 111 to 119 To 1- (3-monomethylaminopropyl) -3-ethylcarbodiimide hydrochloride (40 μg, 205 μmol) was added to Preparation 42 (100 mg, 206 Micromolar), tribenzamide (32 mg, 205 micromolar), and triethylamine (0.55 microliter 412U molar) in a gaseous tofu (2 ml), then For amine ⑽ U Mo Er) 'Asian: |: Wen the axis of the mixture. The solvent was then removed in the air, and the ethyl acetate was removed from the residue, washed with sodium bicarbonate solution (20 ml) and brine (20 ml), dried (Na2S04), and shrunk in vacuo to leave a Although floating in a thin film of -7 g ~ ethyl ether (χ3) to obtain a sponge-like substance. 112

200531959

S

No. Qi Data Yield 111 LRMS ESI m / z 590 [M + Hf 81% 112 LRMS APCI m / z 582 [M + H] + 74% 113 LRMS APCI m / z 554 [M + H] " 94% 114 'HN Ο LRMS APCI m / z 658 [M + H] + 87% 115 LRMS APCI m / z 604 [M + Hf 83% 116 χβ LRMS APCI m / z 602 [Μ + ΗΓ 89% 117 if) LRMS APCI m / z 591 [M + H] " 74% 118 LRMS APCI m / z 620 [M + H] + 90% 119 LRMS APCI m / z 669 [M + Hf 80% 120 * .CD LRMS APCI m / z 602 {M + Hf 92% 121 * / HNiQ LRMS APCI… / z 620 [M + H] + 38% * No evaporation from diethyl ether 113 200531959 Preparation 122: N- {5-[(2R) -2- {2 -[3- (10-acyl-tricyclo [6 · 3 · 1 · 0 * 2,7 *] dodec-2 (7), 3,5-triene-10-carbonyl) phenyl] _U-di Fluorenylethylamino} -1_ (tertiary butyldimethylsilyloxy) ethyl] -2-hydroxybenzyl} formamidine

The title compound was prepared using 104-tricyclo [6 · 3 · 1 · 0 * 2,7 *] dodec-2 (7), 3,5-triene using a method similar to Preparation 69. LRMS APCI m / z 628 [M + H] + Preparation 123: 3- {2-[(2R) -2_ (tertiary butyldimethylsilyloxy) _2_ (3-methylsynylamino-4- Ethylphenyl) ethylamino] -2-methylpropylb-n- [2- (5-Ga • 2-hydroxyphenyl) ethyl] benzidine

The title compound was prepared in a similar manner to 2- (2-aminoethyl) -4-anhydride. LRMS APCI m / z 640 [M + H] + Preparations 124 to 128 This amine (412 μmol) was added to Preparation 42 (200 mg, 412 μmol 114 200531959 ears), via benzotrisalazine Hydrate (63 mg, 412 micromolar) m-di-yl-molyl-propyl) -3-ethylcarbodiimide hydrochloride (π mg, Micro- and Triethylamine_ml, 824 micromol The quinone 'in dichloromethane (2 ml) and the mixture was allowed to halve at room temperature for 18 hours. Then, the solvent was removed in vacuo and the residue was diluted with ethyl acetate, washed with sodium bicarbonate solution: 2 ml) and brine (> 20 ml), and dried. The crude product was purified on a silica gel by color chromatography, and was extracted with 99 7: 03 methylene chloride: 0.88 ammonia. The appropriate age and residue were evaporated under reduced M and concentrated in vacuo. The resulting white sponge-like substance was suspended in diethylamine 10 and evaporated.

Number Qi Data Yield 124 ~ X ^ Ch3 ch3 NMR (400MHz, CDCI3) δ: -0.23 (3H, s), -0.09 (3H, s), 0.69 (9H, s), 1.07 (3H, s), 1.08 (3H, s), 2.27 (3H, s), 2.29 (3H, s), 2.60-2.82 (4H, m), 2.98 (2H, t), 3,64-3.73 (2H, m), 4.61-4.65 (1H, m), 6.39 (1H, m), 6.84-7.42 (10H, m), 7.80 (1H, s), 8.24 (1H, s), 9.70-9.80 (m); LRMS APCI m / z 619 [ M + H] + 63% 115 200531959

125 Cl 1H NMR (400MHz, CDCI3) δ: -0.23 (3H, s), -0.09 (3H, s), 0.70 (9H, s), 1.02 (3H, s), 1.04 (3H, s), 2.60- 2.79 (4H, m), 3.09-3.12 (2H, t), 3.74-3.79 (2H, m), 4.58-4.60 (1H, m), 6.35-6.39 (1H, m), 6.88 (1H, d), 6.94 (1Hf d), 7.10 (1H, s), 7.20-7.34 (4H, m) f 7.38-7.42 (2H, m), 7.76 (1H, s), 8.24 (1H, s), 9.76 (1H, s ); LRMS APCI m / 2 624 [M + Hf 70% 126 ch3 1H NMR (400MHz, CDCI3) δ: -0.22 (3H, s), -0.09 (3H, s), 0.71 (9H, s), 1.20 ( 3H, s), 1.22 (3H, s), 2.34 (6H, s), 2.61-2.78 (4H, m), 3.00 (2H, t), 3.56-3.60 (2H, m), 4.59-4.62 (1H, m), 6.39-6.43 (1H, m), 6.86 (1H, d), 6.96-7.07 (3H, m), 7.16 (1H, s), 7.28-7.33 (2HT m), 7.42 (1H, d), 7.77 (1H, s), 8.24 (1H, s), 9.65 (1H, s); LRMS APCI m / z 618 [M + H] + 96% 127 j0T .ch3 'H NMR (400MHz, CDCI3) δ: > 0.23 (3H, s), -0.09 (3H, s), 0.70 (9H, s), 1.04 (3H, s), 1.05 (3H, s) f 2.33 (3H, s), 2.61-2.76 (4Hf m ), 2.88-2.92 (2H, t), 3.67-3.74 (2H, m), 4.57-4.60 (1H, m), 6.25-6.29 (1H, m), 6.88 (1Ht d), 6.98 (1H, d) , 7Ό9-7.33 (7H, m), 7.75 (1H, s >, 8.23 (1H, s), 9.82 (1H, s); LRMS APCI m / z 604 [M + H] + 73% 116 200531959 128 ---------Ή NMR (400MHz, CDCI3) δ: -0.23 (3Η, s), -0 · 10 (3Η, s), 0.68 (9Η, s), 1.03 (3Η, s), 1.04 (3Η, s), 2.59-2.76 (4Η, m ), 3.42-3.48 (2Η, m), 3.80-3.94 (2Η, m), 4.58-4.61 (1Η, m), 6.30-6.34 (1H, m), 6.89 (1H, d), 6.98 (1H, d ), 7.10 (1H, s), 7.23-7,60 (6H, m), 7.75 (1H, s), 7.77 (1H, d), 8.15 (1H, d), 8.18 (1H, d), 9.77 ( 1H, s); LRMS APCI m / z 640 [M + H] + 19% Preparation of 129: 3- (2-f oxo-propyl) benzoic acid fluorenyl ester

Under 100 ° C, under nitrogen, tributyltin methanol (80.3 ml, 279 mol), methyl bromide benzate (53.5 g, 249 mmol), isopropyl diacetate (39.4 ml, 358 mmol), acetic acid (π) (2.6 g, 11.6 mmol) and monomethylphosphine (7.1 g, 23.2 mmol) in toluene (350 ml) Stir for 18 hours. After cooling, the reaction was treated with a bell fluoride solution (4M, 560 ml) and stirred for 2 hours. The resulting 10 mixture was diluted with another xylene (200 ml) and filtered through Celite®, and the filter pad was washed with ethyl acetate. The organic phase was separated, dried (sodium sulfate) and reduced in vacuo. The residue was purified by chromatographic method 7 and washed with ethyl acetate: pentane at 10:90 to 20:80 to give the title compound (45.3 g) as a color oil. ] H NMR (_ MHz, CDC13) δ: 2.18 (3Η, s), 3.75 (2Η, 15, ^ s) '3.91 (3Η, s), 7.43-7 · 37 (2Η , M), 7.87 (1Η, s), 7 gw ·% 117 200531959 (1H'd); LRMS ESI m / z 215 [M + Na] +, 191 [M-Η]. Ester hydrochloride Preparation of no: H (2R) -2-((1RH-phenylethylamino) propyl) benzylformate

The title compound was prepared in Preparation 129 using a method similar to Preparation 19 to provide the title compound (27.3 g) as a colorless crystalline solid. NMR (400 MHz, CD3OD) δ: 1.17-1 · ΐ6 (3Η, ... 1 · 71-1 · 69 (3Η, d), 2 · 71-2 · 65 (1Η, dd), 3.25- 3.19 (ΐΗ, m) 3.43-3 · 38 (1Η, dd), 3.90 (3Η, s), 4.68-4 · 63 (1Η, q) 7.35-7 · 33 ( 1Η, d), 7.45-7 · 42 (1Η, dd), 7.55-7 · 49 (5Η, 7.75 (1Η, s), 7.92-7 · 90 (1Η, d)) Preparation 131: {3-[(2R) -2-aminopropyl] phenyl} formyl acetate

The title compound was prepared in Preparation 130 using a method similar to Preparation 20 to provide the title compound (8.48 g) as a pale yellow oil. ] H NMR (400 MHz, CDC13) δ ·· 1.14-U2 (3H, d), 2.64-2 · 59 (1Η, dd), 2.78-2 · 73 (1Η, dd), 3.26 -3 · ΐ7 (1Η, m), 3.90 (3Η, s), 7.38-7 · 34 (2Η, m), 7.90-7 · 87 (2Η, m); LRMs ESI m / z 194 [M + H] + Preparation 132: 3-((2R) -2-tertiary butoxycarbonylaminopropyl) benzylcarboxylic acid 118 20 200531959

The mixture of Preparation 131 (5.00 g, 26.0 mmol), di-tert-butyl diferrate (6.22 g, 28.5 mmol) and sodium bicarbonate (4.35 g, 52 mmol) was stirred at 1, 4 -Two humens (100 ml) and water (10 ml) in a mixture for 205 hours. The solvent was removed and the material was distributed between ethyl acetate (200 ml) and hydrogen acid (2M '100¾ liters). The organics were washed with brine (100 ml) and dried (MgS04). The solvent was removed, leaving a white solid (7.12 g, 93%).

iHNMRGOO MHz, CD3OD) δ: 1.09 (3H, d), 1.35 (9Η, s), 2.73-2 · 79 (2Η, m), 3.76-3 · 83 (1Η, m), 3 · 89 (3Η, s), 10 6 · 54 (1Η, d), 7.26-7 · 46 (2Η, m), 7.84-7 · 87 (2Η, m); LCMS

Rt 4.53 min m / z 294 [M + Η] + Preparation 133 · 3-((2R) -2-tertiary butoxyepiaminopropyl) benzoic acid 3 ch3 0 ch3 Stir to prepare 132 (7.10 G, 24.3 mmol) and a mixture of lithium hydroxide (1.00 M, 15 500.0 ml, 50.0 mmol) in tetrahydrofuran (100 ml) for 20 hours. The reaction mixture was diluted with ethyl acetate (250 ml) and acidified to pH 2 with hydrochloric acid (2M). The aqueous phase was re-extracted with ethyl acetate (150 ml), and the combined organics were washed with brine (300 ml) and dried (MgS04). Transition and solvent removal provided 5.53 g (82%) of the title compound. 20 1h NMR (400 MHz, CD3OD) δ: 1 · 10 (3Η, d), 1.36 (9Η, s), 2.82-2 · 81 (2Η, m), 3.77-3 · 84 (1Η, m ), 7.35-7 · 45 (2Η, m), 7.84-7 · 89 (2Η, m); LRMS APCI m / z 278 [Μ-Η] · 119 200531959 Preparation 134: 3-((2R ) -2-tertiary butoxyweilylaminopropyl) benzyl benzyl g

Carbonation planer (6.50 g, 19.8 mmol) in water (10 ml) was added to preparation 133 (5.50 g, 19.8 5 mmol) in N, N-dimethylformamide (50 ml). ) Solution, and the resulting mixture was stirred at room temperature for 1 hour. Then, benzyl bromide (3.42 g, 19.8 mmol) was added and the mixture was stirred for 20 hours. Ethyl acetate (50 ml) was added and the suspension was filtered. The filtrate was washed with saturated brine (1000 ml) and dried (MgS04). Filtration and removal of the solvent left 7.20 g of the title compound. 10 NMR (400 MHz, CD3OD) δ: 1.09 (3H, d), 1.32 (9Η, s), 2.74 (2Η, d), 2.75-2 · 83 (1Η, m), 5. · 34 (2Η, s), 7.29-7 · 40 (4Η, m), 7.43-7 · 47 (3Η, m), 7.85-7 · 90 (2Η, m); LRMS APCI m / z 270 [M-BOC] + Preparation 135: Benzyl 3-((2R) -2-aminopropyl) benzoate

Treatment with trifluoroacetic acid (35 ml) prepared 134 (7.20 g, 19.0 mmol), and the mixture was left to stir for 20 hours. Remove the trifluoroacetic acid in vacuum and add dioxane (175 ml). The mixture was assayed with saturated sodium bicarbonate (150 ml) and washed with sodium hydroxide (1M, 50 ml). The combined organics were washed with brine (150 20 ml) and dried (MgS04) to leave a colored oil (3.70 g, 72%). NMR (400 MHz, CD3OD) δ: 1.04 (3H, d), 2.66 (2Η, 120 200531959 d), 3.05 (1Η, dt), 5.33 (2Η, s), 7.28 -7 · 44 (7Η, m), 7.86-7.90 (2H, m); LRMS APCI m / z 270 [M + H] + Preparation 136: 3-{(2R) -2-[(2R) -2- (4-Benzyloxy-3-fluorenylaminophenyl) -2- (tertiary-butyldimethylsilyloxy) ethylamino] propyl} benzoic acid methyl 5-ester

Preparation 135 (3.70 g, 13.8 mmol) and Preparation 12 (3.20 g, 6.9 10

Millimolar) to 90 ° C for 26 hours. The mixture was cooled and diluted with dichloromethane (100 ml). The organics were washed with saturated sodium bicarbonate (200 mL) and concentrated in vacuo. This crude material was purified (x2) using chromatographic analysis, and extracted with ethyl acetate: heptane from 0: 100 to 40:60 to give 20 g (52%) of the title compound. LRMS APCI m / z 270 [M + H] + Preparation 137: 3-{(2R) _2-[(2R) -2_ (tertiary-butyldimethylsilyloxy) _2_ (3-methylamidoamino) -4-Hydroxyphenyl) ethylamino] propyl} benzoic acid

Preparation of 136 (20 g, 3.1 mmol) with OH in 60 ml of methanol hydrogenated at 60 psi / RT and palladium on carbon (10%, 205 mg) for 20 hours. An ammonia solution (2M, 50 ml) in methanol was added and the mixture was shaken for 2 minutes. After 121 15 200531959, the mixture was filtered through an auxiliary filter, washed with an ammonia solution (2M '250¾ liters) in methanol, and the resulting organics were concentrated to produce a dark green solid. The crude product was purified by chromatographic analysis, and it was eluted with 100: 0: 0 to 75: 20: 5 dioxane: methanol: 0.88 ammonia to produce the standard 5 title compound, such as a dark Green solid (131 mg). 4 NMR (400 MHz, DMSO-d6) δ: -0.18 (3H, s), -〇06 (3Η, s), 0.77 (9s, s), 0.98 (3), d), 2.61 -2 · 68 (2Η, m), 2.65-2 · 73 (2Η, m), 2.80-2.86 (1Η, m), 4.56-4 · 6〇 (ιη, m), 6.75 ( 1Η, d), 6.81 (1Η, dd), 7.83 (2Η, d), 7.70-7 · 75 (2Η, 10 m) '8.00 (d)' 8.25 (s), 9.53 (s); LRMS APCI m / z 473 [Μ + Η] + Preparation 138: 3-((2R) -2-[(2R) -2- (tertiary butyldimethylsilyloxy) -2_ (3- 曱 醯Aminoamino-4-hydroxyphenyl) ethylamino] propylbenzene N- [2- (4-alkylphenyl) -2-fluorenylpropyl] phenylamine

15 As 4- (2-amino-1,1-diamidoethyl) phosphonium hydrochloride (Octa (^ 〇16111.8〇 & 11 (18, 120.3, 1207; 1954)), use similar The title compound was prepared by the method of Preparation 27.! H NMR (400 MHz, CD3OD) δ> 0 · 24 (3Η, s), -0 · 08 (3Η, s), 0.76 (9Η, s), 0 · 99 (3Η, d), 1.28 (6Η, s), 2.54-2 · 92 (5Η, 20 m), 3.46 (2Η, s), 4.60-4.63 (1Η, m), 6.66 -6 · 70 (3Η, m), 6.77-6 · 80 (1Η, dd), 7.20-7.34 (4Η, m), 7.45 (1Η, s), 7.50 (1Η, 122 200531959 d) ' 7.92-7 · 93 (1Η, d), 8.21 (s), 8.55 (s); LRMS APCI m / z 620 [M + H] + Preparation 139: (2E) -3- [3- (2- Oxypropyl) phenyl] methyl acrylate

5 Under reflux, in a nitrogen atmosphere, heat 3-bromophenylacetone (50.0 g, 235 mmol), ethyl acrylate (0.4 g, 469 mmol), palladium acetate (11) ( A solution of 7.9 g '35 .2 mmoles), tri-o-tolylphosphine (214 g, 70.4 mmoles) and triethylamine (82 ml) in acetonitrile (900 ml) for 16 hours. The reaction mixture was cooled to room temperature and the solvent was removed in vacuo. Purified using flash 10 column chromatography, extracting with 90:10 to 70:30 pentane: ethyl acetate ' to provide the title compound as an orange oil (54 · 3 g). NMR (400 MHz, CD3OD) δ: 2.15 (3Η, s), 3.70 (2Η, s), 3.77 (3Η, s), 6.43-6 · 39 (1Η, d), 7.20 -7 · 18 (1Η, d), 7.34,7 · 31 (2Η, t), 7.41, 7.39 (1Η, d), 7.66-7 · 62 (1Η, d); 15 LRMS ESI : m / ζ 241 [M + Na]., 217 [M-Η], Preparation of 140: 3- [3- (2-Pendoxypropyl) benzyl] propanoic acid methyl ester.

Prepared according to the procedure used in Preparation 26 using Preparation 139 to provide the title compound as a light colored oil. 20 NMR (400 MHz, CD3OD) δ: 2.14 (3Η, s), 2.64-2.60 (2Η, t), 2.96-2 · 92 (2Η, t), 3.66 (5Η, s ), 7.05-7 · 04 (2Η, d), 7.11-7 · 09 (1Η, d), 7.27-7 · 23 (1Η, q); LRMS ESI m / z 243 123 200531959 [ M + Na] +, 219 [MH], Preparation 141 · [3-((2R) -2-{[(lR) -l-benzyl-ethyl] amino} propyl) phenyl] methyl propionate Ester hydrochloride

5 Prepared according to the procedure used for Preparation 19 using Preparation 140 to provide the title compound as a white crystalline solid. NMR (400 MHz, CD3OD) δ: 1.18-1 · 16 (3Η, d), 1.71-1.69 (3Η, d), 2.62-2 · 56 (3Η, m), 2.89-2 · 85 (2Η, t), 3.20-3 · 12 (1Η, m), 3.34-3 · 29 (1Η, m), 3.61 (3Η, s), 10 4 64-4 · 59 (1Η, q), 6.92-6 · 91 (2Η, d), 7.12-7 · 10 (1Η, d), 7.23-7 · 19 (1t, t) , 7.54_7.47 (5Η, m); LRMS ESI m / z 326 [M + H] +. Preparation 142: 3- {3-[(2R) -2-((lR) -1-phenylethylamino) propyl] phenylpropanoic acid

15 Stir preparation 141 (3.25 g, 8.98 mmol) in 1,4-dioxane (40 mL) with water (40 mL) and sodium hydroxide (5M, 9.0 mL, 45.0 mmol) 18 hours. The solvent was removed in vacuo and the material was dissolved in water and acidified to pH 6 with hydrochloric acid (2M) and allowed to solidify for more than 18 hours. Twenty solids were removed by tearing and dried in vacuum (1.0 g, 36%). The filtrate was concentrated, tetrahydrofuran was added and the mixture was filtered and read. The filtrate was evaporated to leave a sponge-like substance suspended in 124 200531959 ethyl ether (x3) to produce a colorless sponge-like substance (1.96 g, 70%). hNMRGOOMHz, CD3OD) 5: 1.13 (3H, d), 1.62 (3Η, d), 2.42 (2H, t), 2.55-2 · 64 (1Η, m), 2.84 (2Η, t) , 3.08-3.42 5 (2H, m), 4.46-4.52 (1Η, m), 6.86 (1Η, d), 6.98 (1H, s), 7.11-7.22 (2H, m), 7 · 45-7 · 52 (5Η, m); LCMS APCI m / z 312 [M + H] + Preparation 143: l- (3,4-dihydro-1H-isofluorin-2-yl) -3- {3-[(2R) -2-((lR) -1-phenylethylamino) propyl] phenyl} propan-1-one

10 Preparation of chloro-1,3-diamidinoimidazoline hexafluorophosphate (1.75 g, 6.27 mmol) in dichloroarsine (80 ml) 142 (1.95 g, 6.27 mmol) , Triethylamine (2.62 ml, 19.0 mmol), leave the resulting solution and stir for 3 hours. The solvent was removed and the residue was mixed in ethyl acetate, washed with saturated sodium bicarbonate (3x20 ml), brine (3x20 ml) and dried (Na2S04). 15 After filtering and removing the solvent, the material was purified by chromatographic analysis, and was stripped with 99.7: 〇: 0.3 to 96.7: 3: 0.3 of digas methane: methanol: 0.88 ammonia. The product (x3) was evaporated from diethyl ether to give a half solid (23 g, 86%). ] ΗΝΜΙΙ (400 MHz, CDC13) δ: 0 · 88 (3Η, d), 1.30 (3Η, d), 2.42-2 · 50 (1), m), 2.64-2 · 98 (8Η M), 3.55-3.62 (1Η, 20m), 3.78-3.96 (2Η, m), 4.51 (1Η, s), 4.72 (1Η, s), 6.88-7 · 38 (13Η, m); LCMS APCI m / ζ 427 [M + Η] + Preparation I44: 3- [3-((2r) -2-aminopropyl) phenyl]] _ (3 , Cardiodihydro] Η_iso 喳 lin-2-yl) c- 酉 with 125 200531959

Preparation 143 (2.20 g, 5.16 mmol), ammonium formate (1.63 g, 26.0 mmol), and palladium hydroxide (500 mg) were heated in ethanol (40 ml) and stirred at 70 ° C 4 hours. The mixture was filtered through an auxiliary filter and the solvent was removed. Chromatographic analysis was used to purify the material, diluting with dichloromethane: methanol: 0.88 ammonia in 99.7: 0: 0.3 to 94.7: 5: 0.3 to evaporate (x3) from diethyl ether to produce a colorless oil ( 1.26 g, 76%). NMR (400 MHz, CDC13) δ: Rota isomer i.10 /; L11 10 15 (3H, 2x d), 2.43-2 · 48 (1Η, m), 252 · 62-2 · 76 (3Η , M), 2.78-2 · 86 (2Η, m), 2.96-3 · 02 (2Η, m), 3.08-3 · 18 (1Η, m), 3.58 (1Η, t ), 3.81 (1Η, t), 4.553 / 4 · 73 (2Η, 2xs), 6.98-7 · 24 (8Η, m); LCMS APCI m / z 323 [M + H] + Preparation 145: N- {2-benzyloxy-5-[(lR) -l- (tertiary-butyldimethylsilyloxy) -2-((1 Magic-2- {3_ [3- (3, 4-dihydro_111-iso.quinolin-2-yl) -3-oxo-propyl] benzyl} -1-l-fluorenylethylamino) ethyl] phenyl} phosphonate

The title compound (216 mg, 67%) was prepared using Preparation 144 and Preparation 12 in a similar manner to Preparation 136. ] HNMR (400 MHz, CD3OD) δ: Rotamer_〇19 (3H, s), -.G1 (3H, s), G.82 (9H, s), G.98-1.04 (3H, s), 2 48_2% 126 20 200531959 (11H, m), 3.57-3.62 / 3 · 72-3 · 76 (2Η, m), 4 · 53-4 · 70 (3Η, m), 5 · 18 (2Η, m), 6.87-6 · 97 (3Η, m), 6.99-7.18 (7H, m), 7.28-7 · 39 (3Η, m), 7.45-7 · 60 ( 2Η, m), 8.20 (d), 8.31 (d); LCMS APCI m / z 707 [M + H] + Preparation 146: N- {5-[(lR) -l- (tertiary butyl dimethyl Silyloxy) -2-((lR) -2- {3- [3- (3,4-diaza-1 hydrazone-isoquatidine-2-yl) -3-oxo-propyl] Phenyl} -1 _methylethylamino) ethyl] -2-hydroxyphenyl} formamidine

Prepared using ammonium from Preparation 145 and the method described in Preparation 15 to produce a brown sponge-like substance (280 mg, 100%). ] HNMR (400 MHz, CD3OD) 5: Rotamer-0 · 14 (3Η, s), -0.03 (3Η, s), 0.84 (9Η, s), 1.08-1 · 12 (3Η, m), 2.54-3.20 (11Η, m), 3.60-3 · 65/3 · 74-3 · 77 (2Η, 2χ t), 4.56-4.66 (2Η, 2x s), 4.78-4.84 (1H, m), 6.80_7 · 24 (1Η, m), 8.10 (s), 8.3 l (s); LCMS APCI m / z 617 [M + H] + Example 1: N-benzyl- 2- (3- {2-[(2R) -2- (3-methylaminoamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} phenyl) Acetamide

127 200531959 Preparation 15 (24 mg, 40 μmol), formic acid (0.5 ml), tetrahydrofuran (5 ml) and water (0.5 ml) were heated to 90 ° C for 18 hours. Add another portion of formic acid (0.5 mL) and tetrahydrofuran (5 mL) and continue heating for another 18 hours. The solvent was removed and the product was purified by chromatography ((M0% methanol in dichloromethane + 0.3% ammonia). The product was dissolved in methanol (χ3) and evaporated (10 mg). H NMR (CD3OD, 400 ΜΗζ) δ: 1.05-1.09 (6Η, Π1), 2.69-2.78 (2Η, m), 2.78-2.83 (1Η, m), 2.87-2.93 (1Η, m), 3.53 (2Η, s), 4.35 (2Η, s), 4.65 (1Η, dd), 6.82-6 · 86 (1Η, 10 m), 6.99 (1Η , Dd), 7.03-7 · 06 (1Η, m), 7.13-7 · 28 (7Η, m), 8.08 (d), 8.28 (s), 8.55 (s), 8.61 (s); MS (APCI) m / ζ 476 [M + H]; HRMS C28H33N304 476.2544 [M + H] + Found 476.2533. Example 2: N- (3,4-dimethylbenzyl) -2- (3- { 2-[(2R) -2- (3-methylamidoamino 15-4-hydroxy-phenyl) -2-hydroxyethylamino] -2-amidopropyl} phenyl) acetamidamine

Prepared using amidine from Preparation 16 and the method described in Example 1. NMR (CD3OD, 400 ΜΗζ) δ: 1.05-1 · 08 (6Η, m), 2.18 (3Η, s), 2.19 (3Η, s), 2.67-2 · 94 (4Η, m), 3.52 (2Η, 20 s), 4.27 (2Η, s), 4.62 (1Η, dd), 4.65 (1Η, dd), 6.81-7 · 06 (6Η ' m), 7.12-7.24 (3Η, m), 8.07 (d), 8.27 (s), 8.55 (s), 8.61 (s). 128 200531959 MS (APCI) m / z 504 [M + H] +; HRMS C30H37N30 04 504.2857 [M + H] + found 504.2842. Example 3: N- [4- (dimethylamino) benzyl] -2] 3 _ [(2ΙΙ) · 2-({(2Κ) _2- [3_ (fluorenylamino) -4-hydroxybenzene Yl] -2-hydroxyethyl} amino) propyl] phenyl} 5 acetamido f3

A mixture of the product of Preparation 27 (131¾ g, 0.21 mmol) in trihydrofuran (2 ml) and triethylamine hydrogen trifluoride (16 µl, 010 mmol) was stirred at room temperature for 3 days. Then, the mixture was concentrated in vacuo and the residue was purified on Shixi gel using 10 column chromatography, and washed with 100: 0: 0 to 90: 10 ·· 1 dioxane: methanol: 0.88 ammonia. The title compound was obtained as a brown sponge-like substance with a yield of 36% and 18 mg. H NMR (400 MHz 'CDC13) δ: 1.07 (3H, m), 2.57 (1Η, dd), 2.67-2 · 76 (2Η, m), 2.85-2 · 99 (2Η, m ), 2.87 (6Η, s), 15 3.47 (1Η'm), 4.23 (2Η, s), 4.68 (1Η, dd), 6.67-6 · 71 (2Η, m), 6.77-6 · 79 (2Η, d), 6.90 (1Η, m), 6.97-7.70 (m, 6Η), 7.97 (d), 8.27 (s), 8.35 (s); LRMS APCI m / z 619 [M + H]-f Examples 4 to 12 The following compounds shown by the following general formula can be prepared using a method similar to that described in Example 3. At room temperature, the appropriate starting material is treated with 1-1.1 equivalents of triethylamine trifluoride gas for 18-72 hours. 129 200531959

Number Qi Data Yield 4 TH NMR (400MH2, CD3CI3) δ: 1.00 (3H. D), 2.09 (3H, s) f 2.55 (1H, dd) t 2.64-271 (2H, m), 2.83-2.93 (2H , m), 3.13 (m · H) · 49 (2fVs), 4.30 (2H, s), 4.64-4.69 (1H, m), 6.76 (1H, dX 6.89 (1Hf dd), 6,98 (1Ht d) , 7.06 (1H, m), 7.09-7.19 (4H, m), 7.45 (2H, d), 7,99 (d), 8.03 (s), 8.28 (s), 8.35 (s); LRMS APGI m / z 517 [Μ-ΗΓ 17% 5 Η NMR (400MHz, CD3CI3) δ: 1.09 (3H, d), 2.60 (1H, dd), 2.74-2.82 (2H, m), 2.90-2.96 (1H, m), 3.00-3.08 (1H, m), 3.53 (2H, s), 4.40 (2H, s), 4.61 (1H · dd) · 6.78 (1H, d), 6.91 (1H, dd), 7.02 (1H, d) , 7.08-7.10 (1H, m), 7.12-7.25 (3H, m), 7.29 (2H, d), 7 J8 (2H, d), 7.99 (d), 8.28 (s), 8.56 (s) LRMS APCI m / z 503 [MH] · 12% * 6-~ HN— '' H NMR (400MHz, CD3OD) δ: 1.05, 1.07 (3H, d) f 2.54-3.06 (5H, m), 3.53 (2H, s ), 4.40 (2H, s), 4,60-4.65 (1H, m), 6.80 ^ 7.42 (14H, m), 8.00 (1H, s), 8.27 (s), 8.59 (s); LRMS APCI m / z 554 [M + Hf 10% * 7 9h3 xX〇H NMR (400MHz, CD3OD) δ: 1.07, 1.08 (3H, d), 2.14 (6H, s), 2.54-3.02 (5H, m), 3.47 (2H , s), 4.18 (2H, m), 4.56 ^ 4.64 (1H, m) 6.76-7.22 (8H, m), 7.97 (1H, s), 8.27 (s), 8.56 (s); LRMS APCI m / z 506 [M + H] + 31% 130 200531959 〇1H NMR (400MHz, CD3OD) δ: 0.96, 38% Η 0.97 (3H, d), 2.42-2.84 (5H, m), 3.46 * 1J (2H, s) , 4.54 ^ 4.60 (1HS m), 4.78 (2H, s), 6.76-7,40 (8H, m), 7.66-7.74 (3H, m), 7.85-7.91 (1H, m), 7.96 (1H, s ), 8.27 (s), 8.54 (s); LRMS ARC! M / z * 9 528 [M + Hf Η ί ^ ΊΓΥα nH NMR (400MHz, CD3OD) δ: 1.07, 25% Her 1.08 (3H, d), 2.58-3.00 (5H, m), 3.51 (2H, s), 4.29 (2H, s), 4.58-4.64 (1H, m), 6.71-7.23 (9H, m), 7.96 (1H, s), W 8.28 (s), 8.56 (s); LRMS APCI m / z * 1Π 512 [M + H] + 1 UC) He I ^ NMR (400MHz, CD3OD) δ: 1.09, 24% yS 1.10 (3H, d) f 2.58 ^ 3.04 (5H, m), 3.52 (2H, s), 4.32 (2H, s), 4.60-4.64 (1H, m), 7.05-7.24 (8H, m), 7.97 (1H, s), 8.29 (s ), 8.57 (s); LRMS APCI m / z 546 [M + H] + * 11 '----- 1H NMR (400MHz, CD3OD) δ: 1.02, 30% JN, 1.04 (3H, d), 2.54 -2.94 (5H, s), 3.52 (2H, s), 4.45 (2H, s), 4.55 ^ .60 (1Hr ❿ m), 6.76-7.29 (9H, m), 7.53-7.61 (3H, m), 7.96 (1H, s), 8.28 ( s), 8.55 (s); LRMS APCI m / z 528 [Μ + ΗΓ * 12 TVTVoh ΊΗ NMR (400MHz, CD3〇D) δ: 1.05, 35% I w ^ 1.06 (3H, d), 2.46-2.98 ( 5H, m), 3.51 (2H, s), 4.36 (2H, s), 4.52-4.60 (1H, m), 6.75-7.25 (10H, m), 7.39-7.47 (4HS m), 7.96 (1H, s ), 8.27 (s), 8.54 (s); LRMS APCI m / z 554 [M + H] + * Purified on silica gel using gelatin chromatography (Hydroxane: methanol. 88 ammonia stripping), the crude compound was azeotroped with 2M methanol ammonia. This is followed by further azeotropy in methanol (x3) and diethyl ether (x3) to obtain the desired product, as a white solid. 131 200531959 Examples 13 to 23 The following compounds shown by the following general formula can be prepared using a method similar to that described in Example 3. The appropriate starting material is treated with 1-1.1 equivalents of triethylamine trifluoride at room temperature for 18-72 hours.

Number Qi Data Yield 13 1H NMR (400MHz, CD3OD) δ: 1.09, 1.10 (3H, 2xs), 1.14, 1Λ6 (3H, 2xs), 2.76-3.04 (6H, m), 3.56 (2H, m), 4.67 (1H, dd), 6.84 (1H, d), 7.02 (1H, m), 7.20-7.28 (4H, m), 7.33-7Λ0 (2H, m), 7.60-7.67 (2H, m), 8.12 (1H , d), 8.29 (s), 8.64 (s); LRMS ESI m / z 534 [M + Naf 65% 14 < Η3 H3c, ^ k ^ 0H TH NMR (400MHz, CD3〇D) δ: 1Ό6 ( 3H, s), 1.13 (3H, s), 2.10 (3H, s), 2.21 (3H, s), 2.70-3.02 (6H, m), 3.51 (2H, t), 4_62 · 4 · 68 (1H, m), 6.79-6.81 (1H, m), 6.82-6.87 (2H, m), 7.01-7.07 (1H, m), 7.31-7.39 (2H, m), 7.69 (2H, m), 8.09 (1H, s), 8.29 (s), 8.63 * (s); LRMS APCI m / z 520 [M + H] + 90% * 15-~~ HN— 'ίΗ NMR (400MHz, CO3OD) δ: 1.06 (3H , s), 1.12 (3H, s), 2.72-2.98 (4H, m), 4.58-4.67 (3H, m), 6.77-7.00 (4H, m), 7.16-7.73 (10H, m), 8.04 (1H , s), 8.27 (s), 8.59 (s); LRMS APCI m / z 554 [M + H] + 39% 132 200531959

16 I 1H NMR (400MHz, CD3〇〇) δ; 1.06 (3H, s>, 1.13 (3H, s), 2.72-3,00 (4H, m) t 4.54-4.70 (3H, m), 6J8 -6.86 (3H, m), 6.97.6.99 (1H, d), 7.34-7.58 (8HT m), 7.71-7.76 (2H, m), 8.05 (1H, s), 8.27 (s), 8.59 (s) ; LRMS APCi m / z 554 [M ^ H] + 41% M7 i ^ NMR (40DMHZ, CD3OD) δ: 1.09 (3H, s), 1,16 (3H, s), 2 · ^^ 2.21 (3H, s), 2.75-3.06 (6Ht m), 3,45 ^ 3.51 (2H, m), 4.66-4.71 (1H, m), 6.53 (1H, s), 6,83-6,88 (3H, m) , 7.02-7.04 (1H, m), 7.32 ^ 7.41 (2H, m), 7.63-7 · 68 (2H, m), 8 '”(s), 8,63 (s); LRMS APCI m / z 520 [M Shikuang 40% " 18 jQC〇hi 1H NMR (400MHz, GD30D) δ: 1.06 (3H, s), 1.13 (3H, s), 2.13 (3H, s) r 2.71-3.00 ( 6H, m), 3.47-3.56 (2H, m), 4.64.4.69 (1H, m), 6.63-6.65 (1H, m), 6.83-7.39 (6H, m), 7.60-7.69 (2H, m), 8.09 (1H, s), 8.29 (s) r 8.63 (s); LRMS APCI m / z 5D6 [M + H wide 43% * 19 ηγχ9 HO% NMR (400MHz, CD3OD) δ: 109 (3H, s), 1.14 (3H, s), 2J7-3.00 (4H, m), 4.63-4.67 (1H, m), 4.98 (2H, s), 6.38-6.40 (1H, m), 6.81-6,83 (1H, m ), 7.12-7.14 (1H, d), 7,26-7.48 (5H, m), 7JO-7. 78 (4H, m), 8.06 (1Hf s), 8.28 (s), 8.60 (s); LRMS APC) m / z 528 [M + Hf 33% 133 200531959

* 20 CH-1H NMR (400MHz, GD3OD) 6: 1.09 (3H, s), 1.15 (3H, s), 2.17 (6H, s), 2,75-3.00 (4H, m), 4.37-4.46 (2H , m), 4.64-4.82 (1H, m) v 6.79-6.82 (1H, m), 6.91 (2H, s), 6,97-7.01 (1H, m), 7.33-7.40 (2H, m) y 7.68 -7.74 {2H, m), 8.05 (1H, s), β.28 {$}, 8.61 (s |; LRMS APCI m / z 5Q6 [M + H] 4 48% ★ 21 OI TH NMR {400MHz, CD3OD ) δ; 1.13 (3H, s), 1.18 (3H, s), 2.80-3.06 (4H, m), 4.52 (2H, m), 4.64-4.77 (1H, m), 6,82-6,84 ( 1H, m), 7.00-7.25 (3H, m), 7.39-7.44 (2H, m), 7.73 ^ 7.78 (2H, m), 8.08 (1H, S), 8.29 ($), 8.62 (s); UmS APGI m / z 546 [M + H] + 20% * 22 ^ χα0Η TH NMR (400MHz, CD3OD) δ: 1.07 (3Ht s), 1.13 (3H s) r 2J3-2.98 (4H, m), 4.63-4.76 (3H, m), 6.75-6.78 (1H, m): 6.95-7.05 (3H, m), 7.33-7,40 (3H, m), 7,60-7.80 (5H, m), 8,04 ( 1H, s), 8,26 (s), 8,60 (s); LRMS APCI m / z 528 [M + H] + 62% i 23 I h3c qh3 TH NMR (400MHz, CD3OD) 6: 1.07 (3H , s), 1,11 (3H, s), 1.33 (6H, s), 274-2.96 (4H, m), 3,52 (2H, s), 4.56-4 JO (2H, m), 6J2- 6 J4 (1H, d), 6.82 ^ 6.84 (1H, d) t 7,04 (1H, m), 7,20-7.36 (4H, m), 7.49-7. 57 (2H, m) 8.06 C1Ht s), 8.29 (s), 8J3 (s); LRMS APCI m / z 520 [M + Hf 35% Example 14: For azeotropy with 2M methanol ammonia before purification. * Before purification on silica gel using column chromatography (extracted with digas methane: methanol: 0.88 ammonia at 90: 10: 1), the crude product compound was azeotroped with 2M methanol methanol. This is followed by further azeotroping in methanol (x3) 5 and diethyl ether (x3) to obtain the desired product, as a white solid. 134 200531959 Examples 24 to 27 The following compounds shown by the following general formula can be prepared using a method similar to that described in Example 3. At room temperature, the appropriate starting material is treated with 1-1.1 equivalents of triethylamine trifluoride for 18-72 hours.

OH

No. Qi Data Yield 24 I 1H NMR (400MHz, CDaOD) δ: 1.01 (3H, s), 1.03 (3H, s), 2.63-2.87 (4H, m), 3.52 (2H, s), 3.84 (3H, s), 4.38 (2H, s), 4,56-4.60 (1H, m), 6J8-6.80 (1H, m), 6.94-6.97 (1H, m), 7.00-7.02 (1H, m), 7.11- 7.20 (4H, m), 7.26 ^ 7,29 (2H, m), 7.87-7.89 (2H, d), 7.98-7.99 (d), 8.21 (s), 8.54 (s); LRMS ESI m / z 534 (Μ + ΗΓ 75% 25 HO Η = εΛ 0 nH NMR (400MHz, CDCI3) δ: 0.96-1.04 (9H, m), 2.60-2.88 (4H, m), 3.16-3.33 (2H, m), 3.66, 3.79 (2H, 2xs), 4.61, 4.66 (2H, 2xs), 4.64, 4.79 (1H, m), 6.56 (1H, m), 6.73-6.79 (2H, m), 6.92-7.19 (6H, m), 7.98 (1H, m), 8.23 (s), 8.65 (s); LRMS APCI m / z 554 [M + H] + 41% 26 1 1H NMR (400MHz, CDCI3) δ: 0.98 (3H, s), 1.00 (3H, s), 2.61-2.84 (4H, m), 3.48 (2H, s), 4.30 (2H, s), 4.54-4.57 (1H, m), 6J5-6.77 (3H, m), 6.91-6.94 (1H, m), 6.96-6.99 (1H, m), 7.08-7.18 (6H, m), 7.33-7.40 (4H, m), 7.98 (s), 8.21 (s), 8.56 (s); LRMS ESI m / z 568 [M + H] 4 93% 135 5 200531959 27 rrOH 1H NMR (400MHz, CD3OD) δ: 1.05 44% α (3Η, s), 1.08 (3Η, s), 2. 66-2.93 (4H, m), 3.52 (2H, m), 4.34 (2H, s), 4.61 (1H, m), 6.81 (1H, m), 6.79 (1H, d), 6.81 (1H, d) , 6.99-7.22 (6H, m), 8.06 (1H, d), 8.28 (s), 8.61 (s); LRMS ARC! M / 2 526 [M + H] + Example 28 ·· N-adamantyl- 2- {3-[(2r) -2 _ ({(2R) _2_ [3_ (methylamidoamino) phenyl] -2-hydroxyethyl} amino) propyl] benzyl} acetamidamine

5 The product of Preparation 34 (500 mg, 0.81 mmol) and ammonium fluoride (200 mg, 5.4 mmol) were heated in methanol (5 ml) and water (1.5 ml) at 40 ° C. Ear) mixture for 18 hours. Then, the reaction mixture was concentrated in vacuo, and the residue was purified on a silica gel by column chromatography, and extracted with dichloromethane: methanol: 0.88 ammonia of 90 ·· 10 ·· 0.1, and The title compound was obtained as 10 in the form of a sponge, with a yield of 84% and 347 mg. iH NMR (400 MHz, CD30D) δ: 1.05-110 (m, 3H), 1.64-1.74 (6Η 'm)' 1.98_2 · 03 (9Η, m), 2.36- 2.98 (5Η, m), 3.36 (2Η, s), 4.46-4 · 60 (1Η, m), 6.46-7.20 (6Η, m), 7.96 (1Η, s) , 8.28 (s), 8.56 (s), LRMS ESI m / z 506 [M + H] +! 5 Example 29: Called 3,4-dimethylbenzyl (methylamidoamino) -4-hydroxybenzene Phenyl] -2-hydroxyethyl} amino) ethyl] phenyl 丨 acetamidamine 136 200531959

OH

From the product of Preparation 102, a method similar to that of Example 4-12 was used to prepare the title compound as a solid. bNMRGOO MHz, CD30D): 2.20 (6Η, m), 3.00 (2Η, 5 m), 3.18 (2Η, m), 3.28 (2Η, m), 3.56 (2Η, s ), 4.28 (2Η, s), 4.81 (1Η, m), 6.81 (1H, d), 6.98 (2Η, m), 7.05 (2Η, m), 7.20 (4Η M), 7.30 (1Η, t), 8.10 (s), 8.30 (s); LRMS ESI 476 [M + H] + Examples 30 to 37 10 can be prepared using methods similar to those described in Example 3 The following compounds are shown by the following formulas. At room temperature, the appropriate starting material is treated with 1-1.1 equivalents of triethylamine trifluoride for 18-72 hours.

OH

〇 Number Qi data yield 30, ja, NMR (400MHz, CD3〇D) δ: 0 ^ 4 (3Η, s), 0.97 (3Η, s), 2.33 (3H, s), 2.56 ^ 2.81 (4H, m ) t 3.43 (2H, s), 4.21 (2H, s), 4.52-4.55 (1H, m), 6.73 (1H, m), 6.89-6.95 (2H, m), 7.03-7.13 (7H, m), 7,98 (d), 8.19 (s), 8.52 (s); LRMS ESI m / z 522 [Μ + ΗΓ 26% 137 200531959

31, ^ C ^ F 1H NMR (400MHz, CD3〇D) δ: 0.99 (3H, s), 1.01 (3H, s), 2.60-2.85 (4H, m), 3.49 (2H, s), 4.36 (2H , s), 4.54-4.59 (1H, m), 6.75 (1H, d), 6.92 (1H, dd), 6.98 (1H, d), 7.08-7.18 (3H, m), 7.31 (2H, d), 7.48 (2H, d), 8.00 (d), 8.22 (s), 8.64 (s); LRMS APCI m / z 544 [M + H] + 27% 32 NMR (400MHz, CD3OD) δ: 0.97 (3H, s ), 1.00 (3H, s), 2.59-2.86 (4H, m), 3.48 (2H, s), 4.34 (2H, s), 4.53-4.56 (1Hf m), 6.74 (1H, d), 6.92 (1H , d), 6.98 (1H, bd), 7.08-7.17 (3H, m), 7.29 (2H, d), 7.55 (2H, d), 8.00 (1H, d), 8.22 (s), 8.64 (s) ; LRMS ESI m / z 501 [M + Hf 38% 33 1 1H NMR (400MHz, CD3OD) δ: 1.00 (3H, s), 1.02 (3H, s), 2.62-2.86 (4H, m), 3 * 47 (2H, s), 4.30 (2H, s), 4.55-4.58 (1H, m), 6.82 (1H, d), 6.99 (1H, dd), 7.04 (1H, d), 7.14-7.23 (5H , m), 7.29 (1H, s), 7.31 (1H, s), 8.07 (1H, dO, 8.29 (s), 8.64 (s); LRMS APCI m / z 560 [M + H] + 49% 34 1H NMR (400MHz, CD3OD) δ: 0.93 (3H, s) 0.96 (3H, s), 2.51-2.83 (4H, m), 3.47 (2H, s), 4.34 (2H, s), 4.52-4.55 (1H , m), 6.73-6.76 (3H, m), 6.90-6.97 (2 H, m), 7.04-7.06 (2H, m) t 7.12-7.14 (2H, m), 7.20-7.33 (5H, m), 7.99 (1H, bs), 8.21 (s), 8.54 (s) ; LRMS APCI m / z 568 [M + H] + 82% 138 200531959

35 XX 屮 NMR (400MHz, CD3OD) δ: 0.99 (3Η, s), 1.01 (3Η, s), 2.61-2.86 (4Η, m), 3.47 (2H, s), 4.23 (2H, s), 4.55- 4.58 (1H, m), 6.64-6.66 (1H, m), 6.75-6.79 (1H, m), 6.92-7.16 (8H, m), 7.99 (1H, d), 8.22 (s), 8.54 (s) ; LRMS APCI m / z 526 [M + H] + 50% 36 " Os nH NMR (400MHz, CD3OD) δ: 1.02 (3H, s), 1.04 (3H, s), 1.44-1.55 (2H, m) , 2.00-2.04 (2H, m), 2.52-2.87 (8H, m), 2.39 (2H, s), 3.55-3.61 (1H, m), 4.56-4.59 (1H, m), 6.76 (1Ή, d) , 6.93-6.98 (2H, m), 7.07-7.16 (3H, m) f 8.00 (1H, d), 8.23 (s), 8.55 (s); LRMS APCI m / z 486 [M + H] + 40% 37 〇〇〇〇NMR (400MHz, CD3OD) δ: 1.06 (3H, s), 1.08 (3H, s), 2 67-2.95 (4H, m), 3.07 (3H, s), 3.56 (2H, s), 4.45 (2H, s), 4.60 (1H, dd), 6.81 (1H, d), 6.98 (1H, dd), 7.04 (1H, d), 7.14-7.25 (4H, m) t 7.44 (2H , d), 7.84 (2H, d), 8.06 (1H, d), 8.28 (s), 8.61 (s); LRMS APCI m / z 554 [M + H] + Examples 30 to 37 Stir at room temperature Appropriate amidine and triethylamine hydrogen trifluoride (1 equivalent) in tetrahydrofuran (5 ml) for 2 days. Then, the mixture was concentrated in vacuo, and the residue was treated with methanol ammonia and evaporated (χ3) to leave a sponge-like substance mixed in 90: 10: 1 dioxane: methanol: 0.88 ammonia and filtered. , And then purified by column chromatography on silica gel with 90: 10: 1 dichloromethane; methanol: 0.88 ammonia to elute to obtain the title compound, if it is a thin film, dissolve 139 200531959 in methanol It was neutralized and evaporated (x3), then suspended in diethyl ether and evaporated (x3) to give a white solid. r \ u

Ύ

Number Qi Actual yield 38 TH NMR (400MHz, GD3OD) δ: 1.07 (3H, s), 1.14 (3H, s), 2.73-3.00 (6H, m), 3.57-3.62 (2Ht m), 4.65 -4.70 (1H, m), 6.83 (1H, d), 7.01-7.05 (1H, m), 7.16-7.40 (7H, m), 7.61-7.67 (2H, m) 9 8.09 (1H, d), 8.29 (s), 8.63 (s) * LRMS APCI m / z 476 [M + H] + 52% 39 rH NMR (400MHz, CD3OD) δ: 0.94-1.34 (11H, m), 1.58-1.80 (6H, m) , 2,74-3.00 (4H, m), 3.14 · 3 · 30 (2H, m), 4.65-4.69 (1H, m), 6.83 (IH, d), 7.02-7.06 (1H, m), 7.32- 7.31 (2H, m), 7.37-7.73 (2H, m), 8.07 (1H, d), 8.30 (s), 8.63 (s); LRMS APCI m / z 468 [M + H] + 65% 40 1H NMR (400MHz, CD3OD) δ: 1.09 (3H, s), 1.11 (3H, s), 1.46-1.80 (6H, m), 2.76-2.95 (4H, m), 3.35 (2H, bs), 3, 69 (2H, bs), 4.62-4.65 (1H, m), 6.82 (1H, d), 6.99-7.02 (1H, m), 7.18-7.30 (3H, m), 7.33-7.37 (1H, m), 8.04 (1H, s), 8.29 (s), 8.63 (s); LRMS APCI m / z 438 [M + Hf 69% 140 200531959

41 FF 'H NMR (400MHz, CD3OD) δ: 1.04 (3H, s), 1.11 (3H, s), 2.69-3Ό3 (6H, m), 3.47 ^ 3.67 (2H, m), 4.63-4.67 ( 1H, m), 6.82 (1H, d), 7.00-7.06 (1H, m), 7.30-7.64 (8H, m), 8.08 (1H, s), 8.29 (s), 8.63 (s); LRMS APC) m / z 542 [M + H] + 52% 42 1H NMR (400MHz, CD3OD) δ: 1.05 (3H, s), 1.13 (3Hr s), 1.88-1.98 (2H, m), 2.64-2.80 (4H, m), 2.89-3.00 (2H, m), 3.38-3.46 (2H, m), 4.63-4.67 (1H, m) r 6.81 (1H, d), 6.98 ^ 7.08 (1H, m), 7.10-7.30 ( 5H, m), 7.30-7.40 (2H, m), 7.62-7.70 (2H, m), 8.08 (1H, s), 8.27 (s), 8.61 (s); LRMS APCI m / z 488 [Μ + ΗΓ 59% 43 1H NMR (400MHz, CD3OD) δ: 1.06 (3H, s), 1.13 (3H, s), 2.71-3.04 (8H, s), 4.50-4.80 (2H, m), 6.80 (1H, d) : 6.96-7.06 (1H, m), 7.11-7.20 (4H, m), 7.31-7.42 (2H, m), 7.68-7.71 (2H, m), 8.06 (1H, d), 8.27 (s), 8.61 (s); LRMS APCI m / z 488 [M + H] + 56% 44 iH NMR (400MHz, CD3〇D) δ: 1.04 (3H, s), 1.11 (3H, s), 2.70-2.97 (4H, m), 3.06 (2H, t), 3.71 (2H, t), 4.64-4.68 (1H, m), 6.82-6.86 (IH, m), 7.00-7.06 (1H, m), 7.19 ^ 7.38 (4H, m), 7.61-7.64 (2H, m), 7.72 (1H, t), 8.08 (1H, s), 8.28 (s), 8.45 (1H, d), 8.63 (s); LRMS APCI m / z 477 [M + Hf 62% 141 200531959

45 XT, 'H NMR (400MHz, CD3OD) δ: 1.05 (3H, s), 1.12 (3H, s), 2,70-3.00 (6H, m), 3.50-3.60 (2H, m), 3.74 (3H , s), 4.63-4.66 (1H, m), 6.80-6.86 (3H, m), 7.00-7.06 (1H, m), 7.12 (2H, d), 7.30-7.39 (2Hr m), 7.60-7.65 ( 2H, m), 8.09 (1H, s), 8.29 (s), 8.63 (s); LRMS APCI m / z 506 [M + H] + 28% 46 ^ wS〇, nh2 1H NMR (400MHz, CD3OD) δ : 1.13 (3H, s), 1.18 (3H, s), 2.75-3.06 (6H, m), 3.62 (2H, t), 4.68-4.75 (1H, m), 6.85 (1H, d), 7.03 (1H , d), 7.37-7.45 (4H, m), 7.62-7.70 (2H, m), 7.80 (2H, d), 8.12 (1H, s), 8.30 (s), 8.64 (s); LRMS APCI m / z 555 [M + Hf 27% 47 xo 1H NMR (400MHz, CD3OD) δ: 1.ΜΙ.24 (6H, m), 2.80-3.06 (7H, m), 3.80-3.84 (1H, bs), 3.93- 3.97 (1H, bs), 4.55-4.59 (1H, bs), 4.68-4.73 (1H, m), 6.87 (1H, dd), 7.00-7.15 (3H, m), 7.20-7.30 (2H, m), 7.82-7.87 (1H, m), 8.09 (1H, s), 8.28 (s), 8.63 (s); LRMS APCI m / z 488 [M + H] + 57% 48 ^ NMR (400MHz, CD3OD) δ: Λ ΛΑ (3H, s), 1.19 (3H, s), 1.74 (6H, s), 2.07 (3H, s), 2.15 (6H, s), 2.76-3.10 (4H, m), 4.56 (1H, bs ), 4.64-4.72 (1H, m), 6. 84 (1H, d), 7.03 (1H, d), 7.31-7.39 (2H, m), 7.58-7,62 (2H, m), 8.11 (1H, s), 8.30 (s), 8.63 (s) ; LRMS APCI m / z 506 [M + H] + 8% 142 200531959 49 — € P 1H NMR (400MHz, CD3OD) δ: 1.00-1.08 (6H, m), 2.00 (1H, d), 2.26-2.38 ( 1H, m), 2.63-3.30 (7H, m), 3.40-3.58 (2H, m), 4.46-4.56 (1H, d), 4.60-4.68 (1H, m), 6.58-6.68 (2H, m), 6.80-6.90 (1H, m), 6.96-7.34 (7H, m) t 8.08 (1H, s), 8.30 (s), 8.63 (s); LRMS APCI rri / z 514 [M + H] + 19% 50 'H NMR (400MHz, CD3OD) δ: 1.10 (3H, s), 1.14 (3H, s), 2.27.3.00 (6H, m), 3.57-3.60 (2H, t), 4.63-4.71 (1H, m) , 6.71 (1H, d), 6.82 (1H, d), 6.99-7.09 (3H, m), 7.32-7.39 (2H, m), 7.61-7.67 (2H, m), 8.08 (1H, s), 8.29 (s), 8.63 (s); LRMS APCI m / z 526 [M + H] + 17%

Examples 51 to 55 The methods similar to those described in Example 3 can be used to prepare the following compounds shown by the following general formula. At room temperature, the appropriate starting material is treated with 1-1.1 equivalents of triethylamine tris 5H2F for 18-72 hours.

〇 143 200531959

No. Qi Data Yield 51 1H NMR (400MHz, CD3OD) δ: 1.04 (3H, s), 1,12 (3H, s), 2.24 (6Hf s), 2.69-3.01 (6H, m), 3.52-3.55 ( 2Hr m), 4.62-4.66 (1H, m), 6.82-6.84 (1H, m), 6.95-7.10 (4H, m), 7.31-7.37 (2H, m), 7.60-7.70 (2H, m), 8.09 (1H, s), 8.28 (s), 8.63 (s); LRMS APCI m / z 504 [Μ + ΗΓ 81% 52 C! RH NMR (400MHz, CD3〇D) δ: 1.04 (3H, s), 1.11 (3H, s), 2.69 ^ 2.96 (4H, m), 3.01-3.08 (2H, m), 3.61-3.66 (2H, m), 4.62-4.65 (1H, m), 6.82 (1H, d) t 7.00 -7,03 (1H, m), 7.16-7.21 (2H, m), 7.28-7.40 (4H, m), 7.61-7.65 (2H, m), 8.08 (1H, s), 8.28 (s), 8.63 (s); LRMS APCI m / z 510 [Μ + ΗΓ 79% 53 Η N1VIR (400MHz, CD3OD) δ: 1.05 (3H, s), 1.13 (3H, s), 2.34 (6H, s), 2.71-2.79 (2H, m), Z95-3.01 (4ht m), 3.43-3.49 (2H, m) f 4.64-4.67 91H, m), 6.83 (1H, d), 6.95-6.97 (3H, m), 7.02-7.08 (1H, m), 7.33-7.41 (2H, m), 7.67-7.73 (2H, m) f 8.12 (1H, s) f 8.29 (s), 8.63 (s); LRMS APCI m / z 504 [M + H] + 96% 54 J0T 'H— NMR (400MHz, CD3OD) δ: 1.04 (3H, s), 1.11 (3Hf s), 2.27 (3H, s), 2.69-2.98 (6H, m), 3.54 -3.60 (2H, m), 4.62-4.65 (1H, m), 6.82 (1H, d), 7.00-7.14 (5H, m), 7.30-7.38 (2H, m) f 7.59-7.67 (2H, m) , 8.08 (1H, s), 8.29 (s), 8.62 (s); LRMS APCI m / z 504 [M + H] + 86% 144 200531959 55 Γ ^ NMR (400MHz, CD3〇D) δ: 1.04 76 % 'HN (3H, s), 1.12 (3H, s), 2.68-3.02 (4H, light U m), 3.62-3.97 (2H, m), 3.70-3.74 (2H, • m) f 4.64-4.68 ( 1H, m), 6.83 (1H, d), *, V 7.02 (1H, d), 7.34-7.48 (6H, m), 7.62 (1H, s), 7.65-7.67 (1H, m), 7.72-7.76 (1H, m), 7.80-7.84 (1H, m), 8.18 (1H, s), 8.20 (1H, d), 8.29 (s), 8.62 (s); LRMS APCI m / z 526 [M + H] + Example 56: 3-{(2R) -2-[(2R) -2- (3-methylaminoaminoglacial hydroxyphenyl) -2-hydroxyethylamino] propyl} -N- [2 -(4-hydroxyphenyl) -2-methylpropyl] benzamide

5 From the product of Preparation 138, use a procedure similar to that in Example 38-50 to prepare the title compound as a brown glass (35 mg, 31%).

HNMR (400 MHz, CD3OD) δ: 1.03 (3Η, d), 1.27 (6Η, s), 2.56-2.90 (4Η, m), 3.45 (2Η, s), 4 · 55-4 · 58 (1Η, m), 6.67-6 · 72 (3Η, m), 6.85 · 6 · 87 (1Η, m), 7.19-7 · 26 (5Η, m ), 10 7 · 38 (1Η, s), 7.43 (1Η, d), 7.91 (d), 8.21 (s), 8.51 (s); LRMS APCI m / z 506 [M + H] + Example 57 : N- {5-[(lR) -2-((lR) -2- {3- [3- (3,4-dihydro_1H-isoquinolin-2-yl) -3-oxopropane Phenyl] phenyl} -l-fluorenylethylamino) -1-hydroxyethyl] -2-hydroxyphenyl} formamidine 145 200531959

From the product of Preparation 138, a method similar to that in Example 38-50 was used to prepare the title compound as a brown glass (35 mg, 31%). ] H NMR (400 MHz, CD3OD) δ: 1.00-1.05 (3Η, m), 5 2.48-2.92 (11Η, m), 3.59 (1Η, t), 3.73 (1Η, t) , 4.54-4 · 65 (3Η, m), 6.75-7 · 18 (10Η, m), 7.97 (s), 8.28 (d), 8.56 (d); LRMS APCI m / z 502 [M + H] + The compound of formula (1) acts as a potent β 2 synergist, so the ability to regulate the relaxation of smooth muscle can be measured by stimulating the contraction of electric field in guinea pig trachea strips, measuring 10 β 2 adrenergic receptors. Effect to measure. The guinea pig air camp uses CO2 asphyxiation to kill male Dimkin-Hartley guinea pigs (475-525 g), expels blood from the thigh arteries, and separates the trachea. Four preparations were obtained from each animal, and immediately underwent sub-throat dissection and removal of the 2.5 cm long trachea. The tracheal mass is opened by cutting cartilage relative to the trachea muscles, and then transect across 3-4 cartilage ring widths. A cotton thread was passed over the upper and lower cartilage bands, and the resulting strip preparation was suspended in a 5 ml organ trough. Modified Kleb's Residue containing 3 μM indomethacin (Sigma 17378), 1 μM guanethidine (Sigma G8520), and 10 μM Atenolol (Sigma 20 A7655) (Krebs Ringer) buffer (West

In Sigma (K0507), before applying an initial tension of 1 gram, heat and supply 95% 〇2 / 5 ° / 〇C〇2 gas at 37 ° C for 20 minutes to balance the strip 146 200531959 (not taut). The preparations were allowed to equilibrate for a further 30-45 minutes while they were tightened (to 1 g) twice at 15 minute intervals. Changes in tension are recorded and monitored via standard isometric transducers (custom-designed by Pfizer) linked to a data collection system. After maintaining the tension balance 5, the tissue was subjected to electric field stimulation (EFS) using the following parameters: conduction for 2 seconds every 2 minutes, pulse width of 0.1 microseconds, 10 Hz and continuous experiment length only maximum voltage (25 volts). Post-ganglion cholinergic neuronal EFS in the trachea causes a single-phase contraction of the smooth muscle and records the height of the retraction. Throughout this experiment, the organ trough was held for 10 minutes by an end-pump system (pump flow rate of 7.5 ml / min) and continued to be filled with the above-mentioned Krebslund buffer, except when the β2 synergist according to the present invention was added Time; then, the pump is stopped when cumulatively injected into the tank, and restarted at the washout period after reaching the maximum response. Experimental method for evaluation of strength and efficacy After maintaining EFS balance, stop the peristaltic pump and perfuse isoproterenol (Sigma 15627) with a single dose of 300 nM 15 ". The maximal response is established by inhibiting the contractible EFS response. Then, isopropyl [norepinephrine] is washed away for more than 40 minutes. After reperfusion and washing out, a semi-logarithmic increase in concentration is used, increasing gradually and in large quantities. To this slot, a standard curve for isopropyl [norepinephrine] (isopropyl [no]] 20 epinephrine curve) was performed on all tissues. The concentration range used was 9 to le / 3e_6M. At the end of the isopropyl [nor] adrenaline curve, the preparation of isopropyl [nor] adrenaline (as an internal control) or the second curve month of the β2 isoform according to the present invention 'was used to clean the preparations again. Preparation 40 minutes. The β2 synergist response is expressed as the percentage inhibition of the EFS response. This inhibition is normalized by expressing the inhibition as the percentage of the maximum inhibition induced by iso147 200531959 propyl [norepinephrine] in the curve. β2 equivalent The EC50 value of the β2 synergist according to the present invention refers to the concentration of the compound required to produce half of the maximum effect. Then, the information of the β2 synergist according to the present invention can be obtained from (EC% β2 synergist) / The ratio of (EC50 isopropyl [nor] adreno5 adrenaline) is defined and expressed as potency relative to isopropyl [nor] adrenaline. Confirmation of the functional activity regulated by β-2 was confirmed using the method described above Test compound β2 synergist activity; but 'before constructing the curve of β2 synergist according to the present invention, ICI 10 118551 (selective β2 antagonist, which can be used in the direction of the dose response curve of the test compound Cases of β-2 regulated effects in right shift) Pre-cultivation (minimum 45 minutes) of these preparations. According to another alternative example, half of the maximum effect on the β2 receptor can also be measured by measurement (EC 50). ) The required concentration of a compound according to the present invention is used to measure the potency of 15 β2 receptors of a compound of formula (1). The error of 1 compound ^ In 4% DMSO, the compound was 10 mM / 100 % DMSO (dihydrazine) to dilute to storage Top dose. Use this top dose to construct a 10:30 logarithmic dilution curve, all in 4% DMSO. In every 20 experiments and for control wells on each plate, use isopropyl [debrided] adrenal glands. (© Gamma, 1-5627) as standard. Data are expressed as% isoproterenol response.

IgJ cells were cultured in Dulbeccos MEM / NUT MIX F12 (Jeep 148 200531959 (Gibco), 21331-020), and CHO (Chinese Hamster Ovary) cells expressing human β2 adrenergic receptors were grown and recombined (From Kobilka et al., PNAS 84: 46-50, 1987; and Bouvier et al.,) Vj〇i

Pharmacol 33: 133-1391988 CHOhp2), 10% embryonic bovine blood 5 sera (sigma, F4135, lot number 90K8404 Exp 09/04), 2mM facial asparagine (sigma, G7513), 500 μg / ml genetic mold Supplemented with geneticin (sigma, G7034) and 10 μg / ml puromycin (sigma, P8833). Cells were seeded to provide approximately 90% of the clusters used for the experiments. Test Method 10 Pass 25 μl / well of each compound dose to cAMP-FlasHplate® (NEN, SMP004b) with 1% DMSO as the base control and 100 nM isopropyl [norepinephrine] as the Maximum control. Add 25 μl / well of PBS and dilute 1: 2. Trypsinized (0.25% Sigma, Ding 4049) cells, washed with PBS (Jeep Buckle, 14040-174) and resuspended in spinal stimulus buffer (NEN, SMP004b) to provide 1 x 106 cells / ml CHOhB2 The cells were cultured at 50 μl / well for 1 hour. Then, lyse the cells by adding 100 μl / well of 125I-cAMP (NEN, NEX-130) detection buffer (NEN, SMP004b) containing 0.18 uCi / ml, and incubate the plate at room temperature for another 2 hours . Topcoimt 20 NXT (Packard) was used to quantify the amount of 125i_cAMP adhered to the rapid plateau, and the normal counting efficiency was 1 minute. Dose response data are expressed as% isoproterenol adrenaline activity and fitted using a four-parameter sigmoid fit. Therefore, it has been found that the compound of formula (1) according to the present invention clarified in the above Examples 1 to 57 shows β2 cAMPEC50 below 5 nM. 149 200531959

I: Schematic description 3 (none) [Description of main component symbols] (none) 150

Claims (1)

200531959 10. Scope of patent application: 1. A compound of general formula (1): 0 where (CHA-CPCOQ1 group is at the meta or para position; -R1 and R2 are each independently selected from fluorene and CrC4 alkyl; -η is 0, 1 or 2; -Q1 is a group selected from: 10 R3 R4 R5 where P is 1 or 2 and q is 1 or 2, the group may be optionally bridged by one carbon atom; And * -NR8-Q2-A group, in which the alkylene group, "is ^^ or CrC4 alkyl group and A is pyridyl, C3-CiQ cycloalkyl group, the cycloalkyl group may be Tetrahydropiperanyl, piperidinyl, tetrahydrothiazyl 151 200531959 piperanyl or the following groups: R5 gas R7 氺 3, 114, 115, 116, and 117 may be the same or different, and may be selected from 11, CrC4 alkyl, OR9, SR9, SOR9, S02R9, halo, C02R9, 5 CF3, CN, ocf3, so2nr9r10 , CONR9R10, NR9R] 0, NHCOR1G and phenyl optionally substituted with 1 to 3 groups selected from OR9, halo and CrC4 alkyl groups; -R9 and R1G may be the same or different, and may be selected from HSQ -Q alkyl and * represent the attachment position of the carbonyl group; 10 or, if appropriate, a pharmaceutically acceptable salt thereof and / or an isomer, tautomer, solvate or isotope variant thereof. 2. For example, the compound in the scope of application for the patent, wherein Q1 is a * -NH-Q2-A group, where A may be cyclohexyl or adamantyl. 3. For example, the compound in the scope of patent application, wherein Q1 is a * -NH-Q2-A 15 group, where A may be the following group: R5 of which 113, 114, 5, 5, and 117 may be the same or different, and may be selected from 11, CrC4 alkyl, OR9, SR9, SOR9, S02R9, i-based, CN, C02R9, 152 200531959 CF3, 〇CF3, S02NR9R10, CONR9R] G, NR9R10, NHCOR10 and phenyl optionally substituted with 1 to 3 groups selected from OR9, halo and CrC4 alkyl groups, the limitation is that at least 2 of R3 to R7 are fluorene Wherein R9 and R10 may be the same or different, and may be selected from fluorene or CrC4 alkyl. 4. The compound according to item 1 of the scope of patent application, wherein Q1 is a * -nh-q2-a group, and A may be the following group: Wherein R3, R4, R5, R6 and R7 may be the same or different, and may be selected from Η, 10 OH, ch3, och3, ocf3, och2-ch3, sch3, N (CH3) 2, n (c = o) ch3 , C (= o) nh2, cooch3, so2ch3, S02NH2, CN, dentate, CF3, and phenyl optionally substituted with OH. 5. The compound according to item 1 of the patent application, wherein A may be the following group: Wherein one of R3 to R7 is OH or a benzyl group substituted with OH. 6. The compound according to item 1 of the application, wherein A is a naphthyl group optionally substituted with 0H. 7. If the compound in the first item of the scope of patent application, Q2 may be -CH2-, 153 200531959-(CH2) 2-,-(CH2) 3-, -CH2-C (CH3) 2- or -C (CH3 )2-. 8. For the compound in the scope of application for item 1, wherein Q2 is -CH2_. 9. For the compound in the scope of patent application, Q1 can be the following: Where R3, R4, R5 and R6 are Η. 10. The compound according to any one of claims 1 to 9, wherein R1 is fluorene or CrC4 alkyl and R2 is CrC4 alkyl. 11. The compound according to any one of claims 1 to 9, wherein R1 is Η or CH3 and R2 is Η or CH3. 10 12. The compound according to any one of claims 1 to 9, wherein n is 0 or 1013. The compound according to any one of claims 1 to 9, which is (R, R ) Stereoisomers. 14. The compound according to any one of claims 1 to 9 in which the 15 (CHA-CtC ^ Q1 group is in the meta position. 15. The compound according to any one of claims 1 to 9 in the patent , Where R1 is Η or CH3, R2 is Η or CH3, η is 0 or 1, and the (CHA-CpCOQ1 group is in the meta position. 16. If the compound of the scope of application for item 1 is selected from The group consisting of 20: N-benzyl-2- (3- {2-[(2R) -2- (3-fluorenylamino-4-hydroxybenzene 154 200531959 group) -2-Ethyl group Amine] -2-methylpropyl} phenyl) amine, N- (3,4-diamidinobenzyl) -2- (3- {2-[(2R) -2- (3-methyl Fluorenylamino-4-¾ylphenyl) -2-Ethylamino] -2-fluorenylpropyl} phenyl) acetamide, N- [2- (4-Gaphenyl) ethyl] -3- {2-[(2R) -2- (3-methylaminoamino 5-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} benzidine ; N- [2- (2-Gasphenyl) ethyl] -3-{2-[(2R) -2- (3 • Phenylamino-4-hydroxyphenyl) -2-hydroxyethyl Amine] -2-fluorenylpropyl} benzamide; 3- {2-[(2R) -2- (3-methylfluorenylamino-4-hydroxyphenyl) -2-hydroxyethylamine Yl] -2-methylpropyl} -N- (2-pentyl-1-ylethyl) Methylamine, 10 3- {2-[(2R) -2- (3-Aminomethylamino-4 -Ethylphenyl) -2-Ethylamino] -2-Aminopropylpropyl N- [2- (4-methylphenyl) ethyl] benzidine; N- [2- (2,6-dimethylphenyl) ethyl] -3- {2-[(2R) 2- (3-fluorenylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} phenylhydrazine; 15 N- [2- (2,3 -Dimethylphenyl) ethyl] -3- {2-[(2R) -2- (3-methylaminoamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2- Fluorenylpropylbenzidine; 3- {2-[(2R) -2- (3-methylfluorenylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-fluorenyl Propyl *}-N- [2- (4-hydroxy-2,3-difluorenylbenzyl) ethyl] 20 benzamidine; 3- {2-[(2R) -2- (3-formamidine Methylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-fluorenylpropion *}-N- [2- (4-methoxyoxybenzyl) ethyl] phenylhydrazine; 3- {2-[(2R) -2- (3-methylaminoamino-4-hydroxyphenyl) -2-hydroxyethyl 155 200531959 amino] -2-methylpropyl 丨 -N-benzene Ethyl-benzylamine; N-cyclohexylmethyl-3- {2-[(2R) -2- (3-fluorenylamino-4-hydroxyphenyl) -2-hydroxyethylamino ] -2-fluorenylpropyl} phenylhydrazine; N- [5-((lR) -2- {l, l-difluorenyl-2- [3- (σ唆 -1-Carbonyl) phenyl] 5 ethylamino} -1-transethyl) -2-transylphenyl] methylamine, 3- {2-[(2R) -2- (3 -Methylaminoamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl *}-N- [2- (3-trifluoromethylphenyl) ethyl] benzene Formamidine; 3- {2-[(2R) -2- (3-methylamidoamino-4-hydroxyphenyl) -2-hydroxyethyl10 amino] -2 -amidopropyl}- N- (3-Phenylpropyl) phenylamine, 3- {2-[(2R) -2- (3-methylaminoamino-4-hydroxyphenyl) -2-hydroxyethylamino ] -2-methylpropyl *}-N-inden-2-ylbenzylamine; 3- {2-[(2R) -2- (3-fluorenylamino-4-hydroxyphenyl)- 2-hydroxyethylamino] -2-methylpropyl} -N- (2- ^ 2--2-ethylethyl) benzamide, 15 3- {2-[(2R) -2- ( 3-methylfluorenylamino 4-hydroxyphenyl) -2-hydroxyethylamino] -2-fluorenylpropyl} -N- [2- (4-aminophenyl blue phenyl) ethyl ] Phenylamine amine; N- (4-dimethylaminobenzyl) -2- (3-{(2R) -2-[(2R) -2- (3-methyldonylamino-4- Controll phenyl) -2-Ethylamino] propyl} phenyl) ethyl 20 amine; N- [5- (2-{(lR) -2- [3- (3,4-dihydro -1H-isofluoroline-2-carbonyl) -phenyl] -1,1-difluorenyl-ethylamino} -1-perethyl) -2-merylphenyl] fluorenamine ; 3- {2-[(2R) -2- (3-Aminomethylamino-4-merylphenyl) -2-controlethyl 156 200531959 amino] -2-amidinopropyl *}-N -(4'-hydroxybiphenyl-3-ylmethyl) benzamidine; 3- {2-[(2R) -2- (3-fluorenylamino-4-merylphenyl) -2 -Ethylamino] -2-methylpropyl}-> 1- [2- (4-Ethyl-2,5-diamidinophenyl) ethyl] 5 Phenylamine; 3- {2-[(2R) -2- (3-methylfluorenylamino-4-hydroxyphenyl) -2-hydroxyethylamino] _2_methylpropyl} [2_ (4_hydroxylmethyl Phenyl) ethyl] benzamidine; N- (4-ethylamidinylamino) > 2- (3-{(2R) -2-[(2R) -2- (3-formaldehyde) Fluorenylamino-4-hydroxyphenyl) -2-hydroxyethylamino] propyl} phenyl) acetamidamine; 4-{[2_ (3-{(2R) -2-[(2R)- 2- (3_fluorenylamino_4. Meridylphenyl) -2-hydroxyethylamino] propyl} phenyl) ethenylamino; | methyl} benzidine; 5 N-adamantine Alkyl-1. 3-3- (2-[(2ΙΙ) -2- (3-methylaminoamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} Benzamidine; 3- {2-[(2R) -2- (3-methylamidoamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl}- 1 ^-(2-hydroxy-naphthyl-1-ylmethyl) benzamidine; > 3 -{2-[(2R) -2- (3-methylaminoamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl}-^ (4-hydroxy- 3,5-dimethylbenzyl) benzamidine; 3- {2-[(2R) -2- (3-methylamidoamino-4-hydroxyphenyl) -2-hydroxyethyl Yl] -2-methylpropyl} -N- (6-Cycyl-Qinyl-2-ylmethyl) benzyl 157 200531959 amine; N- (3,6-digas-2-hydroxybenzyl ) -3- {2-[(2R) -2- (3-fluorenylamino-4-merylphenyl) -2-merethylamino] -2-fluorenylpropyl} benzoic acid amine , N- (3,4-Difluorenylbenzyl) -2- (3- {2-[(2R) -2- (3-fluorenylamino 5-4-lightylphenyl) -2- ¾ethylamino] ethyl} phenyl) ethylamine, 3- {2-[(2R) -2- (3-methylamidoamino-4-hydroxyphenyl) -2-hydroxyethylamine Group] -2-methylpropyl} -N- [2- (4-¾ylphenyl) -2-methylpropyl] phenylhydrazine; 3- {2-[(2R) -2- ( 3-methylaminoamino-4 -controlylphenyl) -2-Ethyl10amino] -2-methylpropylbenzene N- (4'-hydroxybiphenyl-4-ylmethyl) benzene Formamidine; N-adamantane-1-yl-2- (3-{(2R) -2-[(2R) -2- (3-amidinoamino-4-hydroxyphenyl) -2- Hydroxyethylamino] propyl} phenyl) acetamidamine; Bis-2 (7), 15 3,5-bis fine-10-_carbonyl) phenyl] -1,1-dimethylethylamino} -1-transethyl) -2-hydroxyphenyl ] -Fluorenamine; 2- (3-{(2R) -2-[(2R) -2- (3-methylfluorenylamino-4-hydroxyphenyl) -2-triethylamino] propyl Yl) phenyl) -N- (4'-Ethylbiphenyl-3 -ylmethyl) acetamide; 20 4-{[2- (3- {2-[(2R) -2- (3- Fluorenylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -2-methylpropyl} phenyl) -acetamido] fluorenyl} fluorenyl benzoate; 2- (3-{(2R) -2-[(2R) -2- (3-methylamidoamino-4-hydroxyphenyl) -2-Ethylamino] -2-methylpropyl} benzene ) -N- (4-difluorofluorenyloxy 158 200531959 yl-carbyl) ethylamine, N- (2-chloro-4-hydroxybenzyl) -N-ethyl-2- (3-{( 2R) -2-[(2R) -2- (3-formylamino-4-merylphenyl) -2-¾ethylamino] -2-methylpropyl} phenyl) acetamidamine ; 5 N- (2-Chloro-4-hydroxybenzyl) -2- (3-{(2R) -2-[(2R) -2- (3-methylamidoamino-4-merylphenyl ) -2-Ethylamino] -2-methylpropyl} -phenyl) Ethylamine; 2- (3-{(2R) -2-[(2R) -2- (3-formamidine Amino-4-hydroxyphenyl) -2-¾ethylamino] propyl} phenyl) -N- (4-Cyclo-3,5-dimethylmethyl 10-yl) acetamidine Amine; 2- (3 _ {(2R) -2-[(2R) -2- (3-fluorenylamino-4-hydroxyphenyl) -2-hydroxyethylamino] propyl} phenyl) -N- (2-hydroxynaphthalene small methyl) acetochlor; N- (5-chloro-2-hydroxybenzyl) -2- (3-{(2R) -2-[(2R) -2- (3-fluorenylamino-4-hydroxyphenyl) -2-hydroxyethylamino] propyl} phenyl) ethanamine; N- (3,5-dichloro-2-merylbenzyl Yl) -2- (3-{(2R) -2-[(2R) -2- (3-methylaminoamino-4-hydroxyphenyl) -2-hydroxyethylamino] propyl} Phenyl) acetamidamine; 2- (3-{(2R) -2-[(2R) -2- (3-fluorenylamino-4-hydroxyphenyl 20-yl) -2-hydroxyethylamino ] Propyl} phenyl) -N- (6-hydroxynaphthalene-2-ylmethyl) acetamidamine; 2- (3-{(2R) -2-[(2R) -2- (3- 曱 醯Amino-4-hydroxyphenyl) -2-hydroxyethylamino] propyl} phenyl) -N- (4'-hydroxybiphenyl-4-ylfluorenyl) ethenamide; 159 200531959 N- (4-cyano-benzyl) -2- (3- {2-[(2R) -2- (3-fluorenylamino-4-hydroxyphenyl) -2-hydroxyethylamino]- 2-amidinopropyl} -phenyl) -acetamidamine; 2- (3- {2-[(2R) -2- (3-methylamidoamino-4-hydroxyphenyl) -2-hydroxy Ethylamino] -2-methylpropyl} -phenyl) -N- (4-xanthazolyl-carbyl) -acetic acid 5 amine; 2- (3- {2-[(2R)- 2- (3-Methylamino-4,4-methylphenyl) -2-methylethylamino] -2-methylpropyl} -phenyl) -N- (4-methylsulfanyl) ) -Acetamidamine; 2- (3- {2-[(2R) -2- (3-fluorenylamino-4-hydroxyphenyl) -2-hydroxyethyl 10-ylamino] -2- Methylpropyl} -phenyl) -N- (4-diaziridinyl-fluorenyl) -acetic acid amine; 2- (3- {2-[(2R) -2- (3-methylfluorenylamino) 4-hydroxyphenyl) -2-hydroxyethylamino] -2-fluorenylpropyl} phenyl) -N- (4'-hydroxy-biphenyl-4-ylfluorenyl) acetamidine; 15 N- [2- (5-chloro-2-hydroxyphenyl) -ethyl] -3- {2-[(2R) -2- (3-methylamidoamino-4-hydroxyphenyl) -2 -Hydroxyethylamino] -2-fluorenylpropyl benzamidine; 2- (3- {2-[(2R) -2- (3-formylamino-4-merylphenyl)) -2-Ethylamino] -2-methylpropyl} phenyl) -N- (4'-Ethylbiphenyl-3-ylmethyl) -20 acetamidine; 3- {2- [ (2R) -2- (3-fluorenylamino-4-hydroxyphenyl) -2-hydroxyethylamino] -propyl} -N- [2- (4-controlylphenyl) -2 -Fluorenylpropyl] -benzamide, N- (2-chloro-4-hydroxybenzyl) -2- (3-{(2R) -2-[(2R)-(2R) -2- ( 3-methylamidoamino-4-hydroxyphenyl) -2-hydroxyethylamino] propyl} phenyl) ethyl 160 200531959 fluorenamine; N- [2- (5- 2-Ethylphenyl) -ethyl] -3-{2-[(2R) -2- (3-Methylmethylamino-4-controlylphenyl) -2-Ethylamino] -2-Aminopropyl} benzylamidine; 5 3- {2-[(2R) -2- (3-Formamylamino-4-hydroxyphenyl) -2-hydroxyethylamino] _Propyl} -N- [2- (4-¾ylphenyl) -2-methylpropyl] -benzamide, 2- (3-{2-[(2R) -2- (3- Methylamino-4-methylphenyl) -2-ethylamino] -2-methylpropyl} phenyl) -N- (tetraazepine-4-yl) ethylamine, Ν_ (5-chloro-2-hydroxybenzyl) _2- (3- {2-[(2R) -2- (3-fluorenylamine 10-yl-4-hydroxyphenyl) _2_hydroxyethylamino ] -2-methylpropyl} phenyl) acetamide; and N- {5-[(lR) -2-((lR) -2- {3_ [3- (3,4-dihydro-1H -Isofluorin-2-yl) -3-lanthoxypropyl] phenyl} -1-fluorenylethylamino) -1-transethyl] -2-acylphenyl} fluorenamine. 15 17. A pharmaceutical composition comprising at least one effective amount of a compound of formula (1) as claimed in any one of claims 1 to 9 or a pharmaceutically acceptable salt or derivative thereof. 18. A compound of formula (1) or a pharmaceutically acceptable salt, derivative form, or composition thereof according to any one of claims 1 to 9 of the scope of patent application, which can be used as a pharmaceutical agent. 19. The use of a compound of formula (1) or a pharmaceutically acceptable salt, derivative form or composition thereof according to any one of claims 1 to 9 of the scope of patent application, which can be used to manufacture a therapeutic agent selected from the group consisting of Medications for diseases, conditions and symptoms of the following groups: 161 200531959 • Asthma of any type, pathogen or pathogenesis, especially asthma selected from the group consisting of: allergic asthma, non-allergic Allergic asthma, allergic asthma, asthma transmitted by allergic bronchial IgE, bronchial asthma, idiopathic asthma, idiopathic asthma, endogenous asthma caused by pathophysiology 5 disorders, external factors caused by environmental factors Asthma, idiopathic asthma of unknown or unknown cause, non-allergic asthma, bronchial asthma, emphysema asthma, exercise induced asthma, allergen induced asthma, cold air induced asthma, occupational asthma, Infectious asthma caused by bacterial, fungal, protozoan or viral infections, 10 non-allergic asthma, primary asthma, wheezing syndrome and bronchiole Ductitis; • chronic or acute bronchoconstriction, chronic bronchitis, small tracheal obstruction, and emphysema; • obstructive or inflammatory 15 airway diseases of any type, pathogen, or pathogenesis, especially selected from the following Obstructive or inflammatory airway disease of members of the group: chronic eosinophilic pneumonia, chronic obstructive pulmonary disease (COPD), COPD including chronic bronchitis, emphysema, or dyspnea associated with or not associated with COPD , Characterized by irreversible COPD, progressive tracheal obstruction, adult respiratory distress syndrome 20 (ARDS), allergic exacerbations of airway reactions caused by other medications, and airway diseases related to pulmonary hypertension; no matter what type, pathogen Or pathogenesis of bronchitis, especially bronchitis selected from members of the group consisting of: acute bronchitis, acute laryngotracheobronchitis, peanut bronchitis, catarrhal bronchitis 162 200531959 bronchitis, radioactive tube Inflammation, bronchitis wei, infectious asthmatic bronchitis, productive bronchitis, staphylococcal or strep Bronchiolitis and alveolar bronchus &. • Acute lung injury; • Bronchodilator-free, pathogenic or pathogenesis-related bronchiectasis, especially M-bronchodilators selected from the group consisting of: columnar bronchi Dilatation, cystic bronchiectasis, spinous bronchiectasis, bronchiectasis, cystic bronchiectasis, dry bronchiectasis, and vesicular bronchiectasis. 10 20. A method for treating Wei animals including humans with a β2 synergist, which comprises an effective amount of a compound of formula (1) such as any one of claims 1 to 9 or a medicine thereof To treat the mammal with an acceptable salt, derivative form, or composition. 21. A combination comprising 15 compounds as claimed in any one of claims 1 to 9 and other drugs selected from the group consisting of: (a) a 5-lipoxygenase (5-LO) inhibitor or 5-lipoxygenase activated protein (FLAP) antagonists; (b) leukotriene antagonists (LTRA), including antagonists LTB4, LTC4, LTD4, and LTE4; 20 (C) histamine receptor antagonists, including HI and H3 antagonists; (d) ocr and α2-adrenergic receptor synergists for decongestive use; vasoconstriction agents that mimic sympathetic nerve effects; (e) methamphetamine M3 receptor antagonists or Antiparasympathetic agents; ⑴ PDE inhibitors, such as PDE3, PDE4 and PDE5 inhibitors; 163 200531959 (g) Tea test; (h) sodium cromoglycate; (i) COX inhibitors, non-selective and selective COX- 1 or both COX-2 inhibitors (NSAID); 5 G) oral and inhaled glucocorticoids; (k) monoclonal antibody activity against endogenous inflammatory entities; (l) anti-tumor necrosis factor (anti-TNF -α) agents; (m) adhesion molecule inhibitors, including VLA-4 antagonists; (η) kinin-Bι- and B2-receptor antagonists; 10 (〇) immunosuppressants (P) inhibitors of matrix metalloproteinases (MMPs); (q) tachykines NK !, NK2 and NK3 receptor antagonists; (r) elastase inhibitors; (s) adenylate A2a receptor Agents; 15 ⑴UK urinary hormone inhibitors; (u) compounds acting on dopamine receptors, such as D2 synergists; (v) modulators of the NFKp pathway, such as IKK inhibitors; (w) cytokines emit signals Regulators of pathways, such as p38 MAP kinase or syk kinase; 20 (X) agents that can be classified as mucolytics or cough suppressants; (y) antibiotics; (z) HDAC inhibitors; and (aa) PI3 kinase inhibitors. 164 200531959 VII. Designated Representative Map: (1) The designated representative map in this case is: (). (2) Brief description of the component symbols in this representative picture: 8. If there is a chemical formula in this case, please disclose the chemical formula that can best show the characteristics of the invention: 4