CN1764648A

CN1764648A - hydroxamid acid derivatives as histone deacetylase (HDAC) inhibitors

Info

Publication number: CN1764648A
Application number: CN 200480006212
Authority: CN
Inventors: 浦野泰治; 佐藤茂树; 石桥直树; 上条一纪
Original assignee: Yamanouchi Pharmaceutical Co Ltd
Current assignee: Fujisawa Pharmaceutical Co Ltd; Yamanouchi Pharmaceutical Co Ltd
Priority date: 2003-01-13
Filing date: 2004-01-13
Publication date: 2006-04-26

Abstract

A compound of following formula (I) or salts thereof, are disclosed, wherein R1 is N-heterocycle optionally substituted by one or more proper substituents, R2 is amidoxyl, R3 is hydrogen or a proper substituent, L1 is (CH2)n optionally substituted by one or more proper substituents (wherein n is an integer of 0-6), wherein one or more methylene can be replaced by proper heteroatom, L2 is low-grade alkenylidene. The compound can be used as a histone deacetylase inhibitor.

Description

Hydroxamic acid derivs as histone deacetylase (HDAC) inhibitor

Technical field

The present invention relates to the compound of useful as drug, and the pharmaceutical composition that comprises this compound.

Background technology

Known histone deacetylase (below be also referred to as HDAC) plays significant feature transcribing of expressing of regulatory gene in the mechanism, can induce the excessive acetylize of histone and influence genetic expression.Therefore, it can be used as therapeutic or preventive medicine is used for the disease that gene unconventionality expression causes, for example inflammatory conditions, diabetes, diabetic complication, homozygote thalassemia, fibrosis, cirrhosis, acute promyelocytic leukemia (APL), organ-graft refection, autoimmune disorder, protozoal infections, tumour etc.

WO 01/38322 discloses the histone deacetylase inhibitor that following formula is represented:

Cy-L ¹-Ar-Y ¹-C(O)-NH-Z

Wherein

Cy is cycloalkyl, aryl, heteroaryl or heterocyclic radical, and it all can be chosen wantonly separately and be substituted;

L ¹Be-(CH ₂) _m-W-, wherein m is the integer of 0-4, W is selected from-C (O) NH-,-S (O) ₂NH-etc.;

Ar is optional substituted arylidene, and it is chosen wantonly with aryl, hetero-aromatic ring etc. and condenses;

Y ¹Be the saturated alkylidene group of chemical bond or straight or branched, wherein said alkylidene group can be chosen wantonly and be substituted;

Z be selected from anilino, pyridyl, thiadiazolyl group and-O-M (wherein M is the acceptable positively charged ion of H or medicine).

WO 02/22577 discloses as the following hydroxamic acid ester cpds of deacetylase inhibitors or the acceptable salt of its medicine:

Wherein

R ¹Be H, halogen or straight chain C ₁-C ₆Alkyl;

R ₂Be selected from H, C ₁-C ₁₀Alkyl, C ₄-C ₉Cycloalkyl, C ₄-C ₉Heterocyclylalkyl, C ₄-C ₉Heterocyclylalkyl alkyl, cycloalkylalkyl, aryl, heteroaryl etc.;

R ₃And R ₄Identical or different, independent is H, C ₁-C ₆Alkyl, acyl group or amido, or

R ₃And R ₄Represent C=O, C=S etc. with the carbon that they connected, or

R ₂Connected nitrogen and R ₃Connected carbon forms C together ₄-C ₉Heterocyclylalkyl, heteroaryl, many heteroaryls, non-aromatic adoption heterocycle, or blended aryl and the poly-heterocycle of non-aryl;

R ₅Be selected from H, C ₁-C ₆Alkyl etc.;

N, n ₁, n ₂And n ₃Identical or different, independently be selected from 0-6, work as n ₁During for 1-6, each carbon atom can be chosen wantonly independent of R ₃And/or R ₄Replace;

X and Y are identical or different, independently are selected from H, halogen, C ₁-C ₄Alkyl etc.

Summary of the invention

The present invention relates to the novel cpd of useful as drug, and the pharmaceutical composition that comprises this compound.

More specifically, the present invention relates to that the histone deacetylase activity is had effective inhibiting compound.

The present inventor also finds, histone deacetylase inhibitor, and for example formula (I) compound (hereinafter referred to as compound [I]) has effective immunosuppressive action and effective antitumour effect.Therefore, histone deacetylase inhibitor such as compound [I] can be used as the activeconstituents of immunosuppressive drug and antitumor drug, also can be used as the activeconstituents that is used for following treatment of diseases or preventive medicine: inflammatory conditions, diabetes, diabetic complication, homozygote thalassemia, fibrosis, cirrhosis, acute promyelocytic leukemia (APL), organ-graft refection, autoimmune disorder, protozoal infections, tumour etc.

Therefore, a target of the present invention provides and has treatment and prevent the bioactive compound of above-mentioned disease.

Another target of the present invention provides the pharmaceutical composition of the compound [I] that comprises as activeconstituents.

The present invention also another target provide histone deacetylase inhibitor for example compound [I] in treatment with prevent purposes in the above-mentioned disease.

The present invention also another target provides commodity package, and this commodity package comprises the pharmaceutical composition that contains compound [I] and appended written document, and this written document illustrates that described pharmaceutical composition can maybe should be used for the treatment of or prevent above-mentioned disease.

Therefore, the invention provides:

[1] following formula (I) compound or its salt:

Wherein

R ¹Be optional to be contained the N heterocycle by what one or more suitable substituent replaced,

R ²Be hydroxylamino,

R ³Be hydrogen or suitable substituents,

L ¹Be to choose wantonly to be replaced-(CH by one or more suitable substituent ₂) _n-(wherein n is the integer of 0-6), wherein one or more methylene radical can be replaced by suitable heteroatoms,

L ²It is lower alkenylene.

[2] compound or its salt of above-mentioned [1], wherein

R ¹Be to contain the N heterocycle by following various expression:

Or

Wherein

R ⁴Be hydrogen or be selected from following group

It is (1) optional by the low alkyl group of two (rudimentary) alkylaminos or hydroxyl replacement,

(2) lower alkoxy,

(3) the optional aryl that is selected from the substituting group replacement of halogen, low-grade alkane acidyl, low alkyl group alkylsulfonyl, lower alkoxy and two (rudimentary) alkylamino,

(4) low-grade alkane acidyl,

(5) elementary alkoxy carbonyl,

(6) aryl carbonyl,

(7) aryl (rudimentary) alkoxyl group,

(8) the optional substituting group list that is selected from low alkyl group, low-grade alkane acidyl and cycloalkyl replaces or dibasic amino,

(9) halo (rudimentary) alkyl,

(10) aryloxy,

(11) optional aryl (rudimentary) alkyl that is replaced by hydroxyl,

(12) carboxyl,

(13) nitro,

(14) cyano group,

(15) halogen,

(16) heteroaryl,

(17) the optional non-aromatic heterocyclic that is replaced by low alkyl group,

(18) hydroxyl,

(19) (rudimentary) alkyl sulfonyl-amino formyl radical,

(20) non-aromatic heterocyclic carbonyl;

R ⁵Be hydrogen or be selected from low alkyl group and the group of aryl (rudimentary) alkyl,

R ⁶, R ⁷And R ⁸Each is hydrogen or low alkyl group naturally,

R ⁹For hydrogen or be selected from following group

(1) the optional low alkyl group that is replaced by two (rudimentary) alkylamino,

(2) the optional aryl that is replaced by lower alkoxy,

(3) (rudimentary) alkoxy carbonyl,

(4) cyano group,

It is (5) optional by the replacement of (rudimentary) alkyl list or dibasic formamyl,

(6) halogen,

(7) (rudimentary) alkyl-carbonyl,

(8) aryl carbonyl,

(9) ring (rudimentary) alkyl,

R ¹⁰Be hydrogen or be selected from following group

(1) (rudimentary) alkyl-carbamoyl,

(2) two (rudimentary) alkyl-carbamoyl,

(3) the optional aryl that is replaced by halogen,

(4) (rudimentary) alkoxy carbonyl,

(5) carboxyl,

(6) non-aromatic heterocyclic carbonyl,

(7) halogen,

(8) optional (rudimentary) alkyl that is replaced by hydroxyl, (rudimentary) alkoxyl group, non-aromatic heterocyclic, aryl, two (rudimentary) alkylamino or halogen,

(9) adamantyl,

R ¹¹Be hydrogen or aryl (rudimentary) alkyl, wherein aryl moiety is replaced by lower alkoxy,

R ¹²Be hydrogen or be selected from the optional low alkyl group that is replaced by halogen and the group of aryl,

R ¹³Be hydrogen or be selected from low alkyl group and the group of aryl,

R ¹⁴Be hydrogen or low alkyl group,

R ²Be hydroxylamino,

R ³Be hydrogen or lower alkoxy,

L ¹Be to choose wantonly by one or more substituting groups that are selected from low alkyl group and aryl (rudimentary) alkyl to replace-(CH ₂) _n-(wherein n is 1-5), one of them methylene radical can be replaced by Sauerstoffatom,

L ²It is vinylene.

[3] compound of above-mentioned [2], wherein

R ¹Be following formula represent contain the N annelated heterocycles:

R wherein ⁴And R ⁵Separately such as in above-mentioned [2] definition.

[4] compound or its salt of above-mentioned [3], wherein

R ⁴And R ⁵The hydrogen of respectively doing for oneself,

R ²Be hydroxylamino,

R ³Be hydrogen,

L ¹Be-CH ₂-,

L ²It is vinylene.

[5] compound of above-mentioned [2], wherein

R ¹Be following formula represent contain the N heterocycle:

R wherein ⁹, R ¹⁰And R ¹¹Separately such as in above-mentioned [2] definition.

[6] compound or its salt of above-mentioned [5], wherein

R ⁹Be hydrogen or the optional aryl that is replaced by lower alkoxy,

R ¹⁰Be hydrogen or the optional aryl that is replaced by halogen,

R ¹¹Be hydrogen,

R ²Be hydroxylamino,

R ³Be hydrogen,

L ¹Be-CH ₂-,

L ²It is vinylene.

[7] following formula: compound or its salt

Or

[8] have the compound or its salt of following formula (I '):

Wherein

R ¹Be optional to be contained the N annelated heterocycles by what one or more suitable substituent replaced,

R ²Be hydroxylamino,

R ³Be hydrogen or suitable substituents,

L ²It is lower alkenylene.

[9] compound or its salt of above-mentioned [8], wherein

R ¹Be following formula represent contain the N annelated heterocycles:

Or

Wherein

R ⁴Be hydrogen or be selected from following group

(1) low alkyl group,

(2) lower alkoxy,

(4) low-grade alkane acidyl,

(5) elementary alkoxy carbonyl,

(6) aryl carbonyl,

(7) aryl (rudimentary) alkoxyl group,

(9) halo (rudimentary) alkyl,

(10) aryloxy,

(11) optional aryl (rudimentary) alkyl that is replaced by hydroxyl,

(12) carboxyl,

(13) nitro,

(14) cyano group,

(15) halogen,

(16) heteroaryl,

R ⁶, R ⁷And R ⁸Respectively do for oneself hydrogen or low alkyl group,

R ²Be hydroxylamino,

R ³Be hydrogen or lower alkoxy,

L ¹Be to choose wantonly by one or more substituting groups that are selected from low alkyl group and aryl (rudimentary) alkyl to replace-(CH ₂) _n-(wherein n is 1 or 2), one of them methylene radical can be replaced by Sauerstoffatom,

L ²It is vinylene.

[10] have following formula (compound or its salt of I "):

Wherein

R ²Be hydroxylamino,

L ¹Be to choose wantonly to be replaced-(CH by one or more suitable substituent ₂) _n-(wherein n is the integer of 0-6),

L ²It is lower alkenylene.

[11] compound or its salt of above-mentioned [10], wherein

R ¹Be following formula represent contain the N annelated heterocycles:

Or

Wherein

R ⁴Be hydrogen or be selected from low alkyl group and the group of aryl;

R ⁵Be hydrogen or be selected from low alkyl group and the group of aryl (rudimentary) alkyl;

R ²Be hydroxylamino,

L ¹Be to choose wantonly by aryl (rudimentary) alkyl to replace-(CH ₂) _n-(wherein n is 1 or 2),

L ²It is vinylene.

In the above-claimed cpd, the compound of general formula (I ') (compound [I ']) and (I ") (compound [I "]) expression is also included within the scope of compound of general formula (I) expression.Below " compound [I] " also comprise " compound [I '] " and " compound [I "] ".

Above-claimed cpd and salt thereof can prepare by disclosed method among process illustrated in the following reaction process or preparation scheme and the embodiment.

In the description more than this specification sheets and subsequently, suitable example and explanation that the present invention has a mind to be included in the various definition in its scope are explained as follows in detail.

Below in the process, compound [I-1] and [I-2] are included in the scope of compound [I], and compound [II-A], [II-B], [II-C], [II-C '], [II-D], [II-E], [II-F], [II-G], [II-H], [II-I], [II-J], [II-K], [II-L], [II-M] and [II-N] are included in the scope of compound [II].

Process A

Process B

Process C

Process D

Process E

Process F

Process G

Process H

Process I

Process J

Step K

Step L

Step M

Step N

Wherein

R ¹, R ², R ³, R ⁴, R ⁵, R ⁶, R ⁷, R ⁸, R ⁹, R ¹⁰, R ¹¹, R ¹², R ¹³, R ¹⁴With

L ¹Define the same,

Each halogen naturally of Hal and Hal ',

L ¹' be that one of them carbon atom is by R ⁵(R wherein ⁵Define the same) L that replaces ¹,

R ¹⁵And R ¹⁶Each is low alkyl group (for example containing the alkyl of 1-6 carbon atom such as methyl, ethyl, propyl group, butyl, the tertiary butyl, amyl group, hexyl etc.) naturally, perhaps R ¹⁵, R ¹⁶Form non-aromatic heterocyclic with the nitrogen that is connected with them, one or more carbon are optional in the described heterocycle is replaced (for example piperidino-(1-position only), morpholino etc.), R by one or more heteroatomss that are selected from oxygen, nitrogen and sulphur ^aIt is hydroxy-protective group.

In said process A, B, C, D, E, F, G, H, I, J, K, L, M and N, process that each initial compounds can be for example prepares in the scheme to be set forth according to this specification sheets or mode similarly are prepared.

For example, the process that can be set forth by preparation scheme 1,2,3 and 4 respectively of compound (A-1), (A-2), (A-3), (A-4) obtains; Compound (B-1), (B-2) and the process that (B-3) can be set forth by preparation scheme 6,7 and 8 respectively obtain; Compound (C-1), (C-1 ') can obtain by the process that preparation scheme 10 is set forth; Compound (C-2) and the process that (C-3) can be set forth by preparation scheme 11 and 12 respectively obtain; The process that compound (C-2 ') and (C-3 ') can be set forth by preparation scheme 23 and 24 respectively obtains; Compound (D-1) and the process that (D-2) can be set forth by preparation scheme 20 and 21 respectively obtain; Compound (E-1) can obtain by the process that preparation scheme 35 is set forth; Compound (F-1), (F-2), (F-3), (F-4) and the process that (F-5) can be set forth by preparation scheme 127,128,129,130 and 131 respectively obtain; Compound (G-1) and the process that (G-2) can be set forth by preparation scheme 195 and 196 respectively obtain; Compound (H-1), (H-2) and the process that (H-3) can be set forth by preparation scheme 204,206 and 201 respectively obtain; Compound (I-1) and the process that (I-2) can be set forth by preparation scheme 212 and 219 respectively obtain; Compound (J-1) can obtain by the process that preparation scheme 226 is set forth; Compound (K-1) can obtain by the process that preparation scheme 293 is set forth; Compound (L-1) can obtain by the process that preparation scheme 294 is set forth; Compound (M-1) and the process that (M-2) can be set forth by preparation scheme 101 and 102 respectively obtain; Compound (N-1) and the process that (N-2) can be set forth by preparation scheme 233 and 249 respectively obtain.The process that compound [II-A], [II-B], [II-C], [II-C '], [II-D], [II-E], [II-F], [II-G], [II-H], [II-I], [II-J], [II-K], [II-L], [II-M] and [II-N] can for example be set forth by preparation scheme 5,9,13,25,22,39,132,197,208,222,191,282,284,103 and 189 respectively obtains.

The compounds of this invention [I] can for example obtain from compound [II] according to disclosed method among following process or the embodiment.

Process 1

Process 2

R wherein ¹, R ³, L ¹, L ²And R ^aDefine the same.

Process 1

Compound [I-1] obtains by the hydroxyl deprotection that makes compound [II] in the presence of acid, is acid salt.

This acid comprises hydrogen chloride solution (for example hydrogenchloride is dissolved in solvent such as methyl alcohol, diox, ethyl acetate, diethyl ether etc.), acetate, tosic acid, boric acid etc.

Optional one or more suitable solvents that use are in order to deprotection.This solvent comprises methyl alcohol, ethanol, ethyl acetate, diox, diethyl ether, acetate etc.

Temperature of reaction is unimportant, and reaction is being carried out under the condition that is cooled to heat usually.

This process is an illustration with embodiment 1,58 etc.

Process 2

Compound [I-2] obtains with alkali reaction by making above-claimed cpd [I-1] (it is the acid salt additive salt), is free form.

Suitable alkali comprises sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium bicarbonate aqueous solution, potassium bicarbonate aqueous solution, aqueous sodium hydroxide solution etc.

Optional this reaction uses one or more suitable solvents in order to deprotection.This solvent comprises methyl alcohol, ethanol, ethyl acetate, diox, diethyl ether, acetate etc.

This process is an illustration with embodiment 116 grades.

In addition, compound [I-2] can be converted into suitable salt by ordinary method or the illustrated method (for example embodiment 113,118,119,120,123 etc.) of this specification sheets, and described salt is also included within the scope of the invention.

Compound [I] can be a salt, and this is also included within the scope of the invention.For example, when having basic group such as amino in the molecule, salt is that illustration is (for example with the mineral acid example hydrochloric acid with the acid salt, Hydrogen bromide, the salt of sulfuric acid etc., with organic acid such as methylsulfonic acid, Phenylsulfonic acid, the 4-toluenesulphonic acids, camphorsulfonic acid ([(1S for example, 4R)-7,7-dimethyl-2-oxo two rings [2.2.1] heptan-1-yl]) methylsulfonic acid or its enantiomorph etc.), fumaric acid, toxilic acid, amygdalic acid, citric acid, Whitfield's ointment, propanedioic acid, pentanedioic acid, the salt of succsinic acid etc.) etc., when having acidic-group such as carboxyl in the molecule, salt is that illustration is (for example with metal such as lithium with the subsalt, sodium, potassium, calcium, magnesium, the salt of aluminium etc. is with the salt of amino acid such as Methionin etc.) etc.

In addition, the solvate of compound [I] such as hydrate, ethanol compound etc. are also included within the scope of the present invention.

When compound [I] when having steric isomer, this isomer is also included within the scope of the present invention.

Term " halogen ", " halo " and " Hal " comprise fluorine, chlorine, bromine and iodine separately.

Term " heteroatoms " comprises nitrogen-atoms, Sauerstoffatom and sulphur atom.

Except as otherwise noted, the term " lower " means 1-6 that uses in this a specification sheets carbon atom.

Suitable " one or more " comprise digital 1-6, preferred 1-3.

Suitable " low alkyl group " comprises the straight or branched alkyl that contains 1-6 carbon atom, as methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group, tert-pentyl, neo-pentyl, hexyl, isohexyl etc.

Suitable " ring (rudimentary) alkyl " comprises the cycloalkyl that contains 3-6 carbon atom, as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl etc.

Suitable " lower alkoxy " comprises the straight or branched alkoxyl group that contains 1-6 carbon atom, as methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert.-butoxy, pentyloxy, uncle's pentyloxy, neopentyl oxygen, hexyloxy, different hexyloxy etc.

Suitable " low-grade alkane acidyl " comprises formyl radical and alkyloyl; wherein moieties is the straight or branched alkyl that contains 1-6 carbon atom, as ethanoyl, ethyl carbonyl, propyl group carbonyl, sec.-propyl carbonyl, butyl carbonyl, isobutyl-carbonyl, sec-butyl carbonyl, tertiary butyl carbonyl, amyl group carbonyl, tert-pentyl carbonyl, neo-pentyl carbonyl, hexyl carbonyl, isohexyl carbonyl etc.

Suitable " elementary alkoxy carbonyl " comprises that wherein moieties is the alkoxy carbonyl that contains the straight or branched alkyl of 1-6 carbon atom, as methoxycarbonyl, ethoxy carbonyl, propoxycarbonyl, isopropoxy carbonyl, butoxy carbonyl, isobutoxy carbonyl, sec-butoxy carbonyl, tert-butoxycarbonyl, pentyloxy carbonyl, tert-pentyloxy carbonyl, neopentyl oxygen carbonyl, hexyloxy carbonyl, different hexyloxy carbonyl etc.

Suitable " halo (rudimentary) alkyl " comprises the low alkyl group that is replaced by 1-3 halogen atom, as a chloromethyl, dichloromethyl, trichloromethyl, a methyl fluoride, difluoromethyl, trifluoromethyl, a brooethyl, two brooethyls, trisbromomethyl, a chloroethyl, Dichloroethyl, three chloroethyls, a fluoro ethyl, two fluoro ethyls, trifluoroethyl etc.

Suitable " lower alkenylene " comprises the straight or branched alkenylene that contains 1-6 carbon atom, as vinylene, 1-methyl vinylidene, 2-methyl vinylidene, 1-propenylidene, 2-propenylidene, 2-methyl isophthalic acid-propenylidene, 2-methyl-2-propenylidene, 1-crotonylidene, 2-crotonylidene, 3-crotonylidene, 1-inferior pentenyl, 2-inferior pentenyl, 3-inferior pentenyl, 4-inferior pentenyl, the inferior hexenyl of 1-, the inferior hexenyl of 2-, the inferior hexenyl of 3-, the inferior hexenyl of 4-, the inferior hexenyl of 5-etc.The suitable lower alkenylene that is used for L2 is for example vinylene, 1-methyl vinylidene, 2-methyl vinylidene etc.

Suitable " aryl " comprises C ₆-C ₁₆Aryl such as phenyl, naphthyl, anthryl, pyrenyl, phenanthryl, Azulene base etc.

Suitable " aryloxy " comprises C ₆-C ₁₆Aryloxy is as phenoxy group, naphthyloxy, anthracene oxygen base, pyrene oxygen base, luxuriant and rich with fragrance oxygen base, Azulene oxygen base etc.

Suitable " aryl (rudimentary) alkyl " comprises phenyl (C ₁-C ₆) alkyl such as benzyl, styroyl, phenyl propyl, phenyl butyl, phenyl hexyl etc., naphthyl (C ₁-C ₆) alkyl such as naphthyl methyl, naphthyl ethyl, naphthyl propyl group, naphthyl butyl, naphthyl amyl group, naphthyl hexyl etc.

Suitable " aryl carbonyl " comprises that wherein aryl moiety is C ₆-C ₁₆The aryl carbonyl of aryl is as phenylcarbonyl group (benzoyl), naphthyl carbonyl, anthryl carbonyl, pyrenyl carbonyl, phenanthryl carbonyl, Azulene base carbonyl etc.

Suitable " aryl (rudimentary) alkoxyl group " comprises phenyl (C ₁-C ₆) alkoxyl group such as benzyloxy, benzene oxyethyl group, phenyl propoxy-, phenyl butoxy, phenyl hexyloxy etc., naphthyl (C ₁-C ₆) alkoxyl group such as naphthyl methoxyl group, naphthyl oxyethyl group, naphthyl propoxy-, naphthyl butoxy, naphthyl pentyloxy, naphthyl hexyloxy etc.

Suitable " amino " comprises unsubstituted amino and is selected from the replacement of substituting group list or dibasic amino of low alkyl group, low-grade alkane acidyl and cycloalkyl, as N-(C ₁-C ₆Alkyl) amino (for example N-methylamino, N-ethylamino, N-propyl group amino, N-normal-butyl amino, N-isobutylamino, N-tertiary butyl amino etc.), N-(C ₁-C ₆Alkanoylamino (for example N-acetylamino, N-ethyl carbonylamino, N-propyl group carbonylamino, N-normal-butyl carbonylamino, N-isobutyl-carbonylamino, N-tertiary butyl carbonylamino etc.), N-(C ₃-C ₆Cycloalkyl amino (for example N-cyclopropyl amino, N-cyclobutyl amino, N-cyclopentyl amino, N-cyclohexyl amino etc.), N, N-two (C ₁-C ₆Alkyl) amino (for example N, N-dimethylamino, N, N-diethylamino, N-ethyl-N-methylamino etc.) etc.

Suitable " choose wantonly and replaced or dibasic formamyl by the low alkyl group list " comprises formamyl; Wherein moieties is N-(rudimentary) alkyl-carbamoyl that contains the alkyl of 1-6 carbon atom, as N-methylamino formyl radical, N-ethylamino formyl radical, N-propyl group formamyl, N-butyl formamyl, N-isobutylamino formyl radical, N-tertiary butyl formamyl, N-amyl group formamyl, N-neo-pentyl formamyl, N-isopentyl formamyl, N-hexyl formamyl etc.; Wherein moieties is the N that respectively contains the alkyl of 1-6 carbon atom; N-two (rudimentary) alkyl-carbamoyl; as N; the N-formyl-dimethylamino; N; N-diethylamino formyl radical; N; N-dipropyl formamyl; N; N-dibutylamino formyl radical; N; N-diisobutyl formamyl; N; N-two-tertiary butyl formamyl; N; N-diamyl formamyl; N; N-di neo-pentyl formamyl; N; N-diisoamyl formamyl; N, N-dihexyl formamyl; N-ethyl-N-methylamino formyl radical; N-methyl-N-propyl group formamyl; N-butyl-N-methylamino formyl radical; N-methyl-N-isopropyl butyl formamyl etc.

" heteroaryl " includes 5-14 annular atoms, shares πDian Zi and also contain 1-4 heteroatomic group that is selected from nitrogen, oxygen, sulphur in circular permutation except that carbon atom.Suitable " heteroaryl " comprises thienyl, benzothienyl, furyl, benzofuryl, dibenzofuran group, pyrryl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidyl, indyl, quinolyl, isoquinolyl, quinoxalinyl, tetrazyl, oxazolyl, thiazolyl, isoxazolyl etc.

" heteroaryl " in " heteroaryl (rudimentary) alkyl " and " (rudimentary) alkyl " respectively to " heteroaryl " and " (rudimentary) alkyl " in illustrative similar.Suitable " heteroaryl (rudimentary) alkyl " comprises pyridylmethyl, pyridyl ethyl, quinolyl methyl etc.

Two " (rudimentary) alkyl " in " (rudimentary) alkyl-carbonyl (rudimentary) alkyl " separately to " (rudimentary) alkyl " in illustrative similar.Suitable " (rudimentary) alkyl-carbonyl (rudimentary) alkyl " comprises ethanoyl methyl, ethyl carbonyl methyl etc.

" non-aromatic heterocyclic " comprises and contains 5-14 annular atoms, and also contain 1-3 heteroatomic group that is selected from nitrogen, oxygen, sulphur except that carbon atom.Suitable " non-aromatic heterocyclic " comprises pyrrolidyl, pyrazolidyl, imidazolidyl, isoxazole alkyl, isothiazole alkyl, piperidyl (for example piperidino-(1-position only) etc.), piperazinyl, morpholinyl (for example morpholino etc.), thio-morpholinyl (for example thiomorpholine generation etc.) etc.

Comprise contain N annelated heterocycles such as indyl suitable " containing the N heterocycle " in " optional contained the N heterocycle by what one or more substituting groups replaced ", pseudoindoyl, indolyl, benzimidazolyl-, quinolyl, isoquinolyl, indazolyl, the benzotriazole base, quinoxalinyl, (for example imidazo [4 for imidazopyridyl, 5-c] pyridyl etc.), imidazolidine and pyridyl (for example 4,5,6,7-tetrahydrochysene [4,5-c] pyridyl etc.), 7-azabicyclic [2.2.1] heptyl, 3-azabicyclic [3.2.2] nonyl, (for example pyrido [3 for the pyridine-imidazole base, 2-d] imidazolyl, pyrido [4,3-d] imidazolyl etc.), azepine benzimidazolyl-etc., and contain N hetero-aromatic ring such as imidazolyl, thiazolyl, pyrazolyl oxazolyl etc.

Particularly, preferably choose the N heterocycle that contains that is replaced by substituting group shown in one or more R1 wantonly and comprise, for example the group shown in the following formula:

With

R wherein ⁴, R ⁵, R ⁶, R ⁷, R ⁸, R ⁹, R ¹⁰, R ¹¹, R ¹², R ¹³, R ¹⁴Define the same.

Above various in, suitable R ⁴It is hydrogen or following group: (1) low alkyl group (for example methyl, ethyl, propyl group, sec.-propyl, butyl, amyl group, hexyl etc.); (2) lower alkoxy (for example methoxyl group, oxyethyl group, propoxy-, butoxy, pentyloxy, hexyloxy etc.); (3) the optional aryl (for example phenyl, 4-p-methoxy-phenyl, 4-ethoxyl phenenyl, 4-acetylphenyl, 4-(N, N-dimethylamino) phenyl, 4-fluorophenyl, 4-methyl sulphonyl phenyl etc.) that is selected from the substituting group replacement of halogen, low-grade alkane acidyl, low alkyl group alkylsulfonyl, lower alkoxy and two (rudimentary) alkylamino; (4) low-grade alkane acidyl (for example ethanoyl etc.); (5) elementary alkoxy carbonyl (for example methoxycarbonyl etc.); (6) aryl carbonyl (for example benzyloxycarbonyl group etc.); (7) aryl (rudimentary) alkoxyl group (for example benzyloxy etc.); (8) the optional substituting group list that is selected from low alkyl group, lower alkoxy and cycloalkyl replaces or dibasic amino (for example amino, N, N-dimethylamino, N, N-diethylamino, N-propyl group carbonylamino, N-cyclopentyl amino etc.); (9) halo (rudimentary) alkyl (for example trifluoromethyl etc.); (10) aryloxy (for example phenoxy group etc.); (11) optional aryl (rudimentary) alkyl that is replaced by hydroxyl (for example hydroxyphenyl methyl etc.); (12) carboxyl; (13) nitro; (14) cyano group; (15) halogen (for example fluorine, chlorine, bromine etc.); (16) heteroaryl (for example thienyl, tetrazyl, pyridyl etc.); (17) the optional non-aromatic heterocyclic (for example 4-picolyl (piperadinyl), morpholino, piperidino-(1-position only) etc.) that is replaced by low alkyl group; (18) hydroxyl; (19) (rudimentary) alkyl sulfonyl-amino formyl radical (for example methyl sulphonyl formamyl etc.); (20) non-aromatic heterocyclic carbonyl (for example tetramethyleneimine-1-base carbonyl etc.).In addition, (for example pyridyl (rudimentary) alkyl such as pyridylmethyl etc., low alkyl group-carbonyl (rudimentary) alkyl (for example ethanoyl methyl etc.) etc. also can be used for R to heteroaryl (rudimentary) alkyl ⁴

Above various in, suitable R ⁵Be hydrogen or be selected from following group: low alkyl group (for example methyl, ethyl, propyl group, butyl etc.), aryl (rudimentary) alkyl (for example benzyl, styroyl etc.), heteroaryl (rudimentary) alkyl (for example pyridyl (rudimentary) alkyl such as pyridylmethyl etc.) and lower alkylcarbonyl (rudimentary) alkyl (for example ethanoyl methyl etc.).Preferred R ⁵Be hydrogen or be selected from low alkyl group and the group of aryl (rudimentary) alkyl.

Above various in, suitable R ⁶, R ⁷And R ⁸Each is hydrogen or low alkyl group (for example methyl, ethyl, propyl group, butyl etc.) naturally.

Above various in, suitable R ⁹It is hydrogen or following group: (1) optional low alkyl group that is replaced by two (rudimentary) alkylamino (for example dimethyl aminoethyl etc.); (2) the optional aryl (for example phenyl, o-methoxyphenyl, m-methoxyphenyl, p-methoxyphenyl etc.) that is replaced by lower alkoxy; (3) (rudimentary) alkoxy carbonyl (for example methoxycarbonyl etc.); (4) cyano group; (5) the optional replacement by (rudimentary) alkyl list or dibasic formamyl (for example formamyl, N, N-formyl-dimethylamino, N-sec.-propyl formamyl etc.); (6) halogen (for example chlorine, bromine etc.); (7) (rudimentary) alkyl-carbonyl (for example ethanoyl etc.); (8) aryl carbonyl (for example benzoyl etc.); (9) ring (rudimentary) alkyl (for example cyclohexyl etc.) etc.

Above various in, R ¹⁰Shown suitable substituent is hydrogen or following group: (1) (rudimentary) alkyl-carbamoyl (for example N-methylamino formyl radical etc.); (2) two (rudimentary) alkyl-carbamoyl (for example N, N-formyl-dimethylamino etc.); (3) the optional aryl that is replaced by halogen (for example phenyl, rubigan, to fluorophenyl etc.); (4) (rudimentary) alkoxy carbonyl (for example methoxycarbonyl, ethoxy carbonyl etc.); (5) carboxyl; (6) non-aromatic heterocyclic carbonyl (for example piperidino carbonyl etc.); (7) halogen (for example chlorine etc.); (8) optional (rudimentary) alkyl that is replaced by hydroxyl or (rudimentary) alkoxyl group, non-aromatic heterocyclic, aryl, two (rudimentary) alkylamino or halogen (for example methylol, methoxymethyl, piperidino-(1-position only) methyl, morpholino methyl, N, N-dimethylaminomethyl, trifluoromethyl etc.) and (9) adamantyl etc.

Above various in, R ¹¹Shown suitable substituent is hydrogen or aryl (rudimentary) alkyl (for example p-methoxyphenyl methyl etc.) of being replaced by lower alkoxy of aryl moiety etc. wherein.

Above various in, R ¹²Shown suitable substituent is hydrogen or the group that is selected from low alkyl group (for example methyl etc.), the optional aryl (for example phenyl, rubigan etc.) that is replaced by halogen etc.

Above various in, R ¹³Shown suitable substituent is hydrogen or the group that is selected from low alkyl group (for example methyl etc.), aryl (for example phenyl etc.) etc.

Above various in, R ¹⁴Shown suitable substituent is hydrogen or low alkyl group (for example methyl etc.) etc.

Be used for L ¹" (CH ₂) _n-" in suitable " n " be the integer of 0-6, preferred 1 or 2."-(CH ₂) _n-" optional by replacements such as one or more suitable substituents such as low alkyl group (for example methyl, ethyl, propyl group, butyl, amyl group, hexyl etc.), lower alkoxy (for example methoxyl group, oxyethyl group, propoxy-, butoxy, pentyloxy, hexyloxy etc.), aryl (rudimentary) alkyl (for example benzyl etc.).In addition, one or more methylene radical (for example a methylene radical etc.) can be by suitable heteroatoms (for example Sauerstoffatom etc.) displacement.

The present invention is used for L ¹Suitable " (CH ₂) _n-" for example comprise-CH ₂-,-(CH ₂) ₂-,-CH (CH ₃)-,-CH ₂-O-,-(CH ₂) ₃-,-(CH ₂) ₃-O-,-(CH ₂) ₄-O-,

Deng.

Suitable " hydroxy-protective group " is as follows:

Low alkyl group (for example methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, amyl group, hexyl etc.), preferable methyl; Lower alkoxy (rudimentary) alkyl (for example methoxymethyl etc.); Lower alkoxy (rudimentary) alkoxyl group (rudimentary) alkyl (for example 2-methoxy ethoxy methyl etc.);

Wherein optional aryl (rudimentary) alkyl that is replaced by one or more suitable substituent of aryl moiety (for example benzyl (Bn), to methoxy-benzyl,, to dimethoxy-benzyl etc.), preferred benzyl; Optional aryl (rudimentary) alkoxyl group (rudimentary) alkyl that is replaced by one or more suitable substituent of aryl moiety (for example benzyloxymethyl, to methoxyl group benzyloxy ylmethyl etc.) wherein;

(rudimentary) alkylthio (rudimentary) alkyl (for example methylthiomethyl, ethylmercapto group methyl, rosickyite ylmethyl, iprotiazem ylmethyl, butylthio methyl, isobutyl sulfenyl methyl, own sulfenyl methyl etc.) etc., preferred methylthiomethyl;

Three replace silyl as three (rudimentary) alkyl silyl (for example trimethyl silyl, triethylsilyl, tributyl silyl, t-butyldimethylsilyl, tri-tert silyl etc.), low alkyl group diaryl silyl (for example methyldiphenyl base silyl, ethyl diphenylmethyl silylation, propyl group diphenylmethyl silylation, t-butyldiphenylsilyl (TBDPS) etc.) etc., preferred t-butyldimethylsilyl (TBDMS) and t-butyldiphenylsilyl;

Heterocyclic group (for example THP trtrahydropyranyl etc.);

The following stated acyl group [for example aliphatic acyl such as low-grade alkane acidyl (for example ethanoyl, propionyl, valeryl etc.); Aromatic acyl group (for example benzoyl (Bz), toluyl, naphthoyl, fluorenyl carbonyl etc.);

Lower alkoxycarbonyl (for example methoxycarbonyl, ethoxy carbonyl, propoxycarbonyl, isopropoxy carbonyl, butoxy carbonyl, isobutoxy carbonyl, tert-butoxycarbonyl, pentyloxy carbonyl, hexyloxy carbonyl etc.) etc.;

Wherein aryl moiety is chosen aryl (rudimentary) alkoxy carbonyl (for example benzyloxycarbonyl, bromo-benzyloxycarbonyl etc.) that is replaced by one or more suitable substituent wantonly;

Low alkyl group alkylsulfonyl (for example methyl sulphonyl, ethylsulfonyl etc.);

Lower alkoxy alkylsulfonyl (for example methoxyl group alkylsulfonyl, oxyethyl group alkylsulfonyl etc.);

Aryl (rudimentary) alkyloyl (for example phenyl acetyl, phenyl propionyl, phenyl butyryl radicals, phenyl isobutyryl, phenyl pentanoyl, phenyl caproyl, naphthyl ethanoyl, naphthyl propionyl, naphthyl acyl group, naphthyl isobutyryl, naphthyl pentanoyl, naphthyl caproyl etc.);

Aryl (rudimentary) enoyl-such as aryl (C ₃-C ₆) enoyl-(for example phenyl acryloyl, phenyl crotonoyl, phenyl methacryloyl, phenyl pentenoyl, phenyl hexenoyl, naphthyl acryl, naphthyl enoyl-, naphthyl methacryloyl, naphthyl pentenoyl, naphthyl hexenoyl etc.) etc.;

Low-grade alkenyl (for example vinyl, allyl group etc.); Deng.

The preferred hydroxy-protective group of the present invention is for example THP trtrahydropyranyl, trimethyl silyl, t-butyldimethylsilyl etc.

Below abbreviation also is used for this specification sheets: Boc (tert-butoxycarbonyl); HOBT or HOBt (I-hydroxybenzotriazole); WSCD (1-ethyl-3-(3 '-dimethylamino-propyl)-carbodiimide); DMF (N, dinethylformamide); Aq. (aqueous solution); Me (methyl); MeOH (methyl alcohol); Et (ethyl); EtOH (ethanol); TBu (tertiary butyl); TsCl (Tosyl chloride); Ac (ethanoyl); AcOH (acetate); AcOEt (ethyl acetate); AcONH ₄(ammonium acetate); Ph (phenyl); DIEA (diisopropylethylamine); THP (tetrahydropyrans); THF (tetrahydrofuran (THF)) and TFA or TFAOH (trifluoroacetic acid).

Test method

Be the validity of explanation The compounds of this invention [I], below provided the pharmacology test result of representative compounds of the present invention.

Test 1: the mensuration of histone deacetylase inhibitor activity

The partial purification of human histone deacetylase, [ ³H] preparation and the active analysis of histone deacetylase of ethanoyl histone carry out as follows according to the method for propositions such as Yoshida basically.

The partial purification of human histone deacetylase

From HTL Jurkat cell partial purification human histone deacetylase.With Jurkat cell (5 * 10 ⁸Individual cell) is suspended in the HDA damping fluid that 40ml is made up of 15mM potassiumphosphate, pH7.5,5% glycerine and 0.2mM EDTA.After the homogenate, centrifugal (35,000 * g, 10 minutes) collecting cell nuclear is supplemented with 1M (NH at 20mL ₄) ₂SO ₄Same buffer in homogenate.The heavy-gravity homogenate is carried out supersound process, and centrifugal (35,000 * g, 10 minutes) clarification is by with (NH ₄) ₂SO ₄Concentration be increased to 3.5M deacetylase be precipitated out.Sedimentary protein is dissolved in the HDA damping fluid of 10mL and and dialyses with 4 liters of identical damping fluids.Then the dialyzate application of sample is arrived with identical damping fluid equilibrated DEAE Mierocrystalline cellulose (Whatman DE52) post (on 25 * 85mm), with 300mL linear gradient NaCl (0-0.6M) wash-out.The histone deacetylase activity is unimodal to be occurred between 0.3 to 0.4M NaCl.

[ ³ H] preparation of ethanoyl histone

For obtain [ ³H] substrate analyzed as histone deacetylase of the histone of ethanoyl mark, at 75cm ²In the flask 20mL RPMI-1640 substratum (is supplemented with 1 * 10 among the 10%FBS, penicillin (50 units/mL) and Streptomycin sulphate (50 μ g/mL)) ⁸Individual Jurkat cell and 300MBq[ ³H] sodium acetate in the presence of the 5mM Sodium propanecarboxylate at 5%CO ₂37 ℃ of incubations are 30 minutes in-95% air atmosphere, gather in the crops in the centrifuge tube (50mL), and 1000rpm collected in centrifugal 10 minutes, with the salt water washing of phosphate buffered once.With washed cell suspension in 15mL with ice-cooled lysis buffer (10mM Tris-HCl, 50mM sodium bisulfite, 1%Triton X-100,10mM MgCl ₂, 8.6% sucrose, pH6.5) in.After carrying out Dounce homogenate (30 vibrations), nucleus was collected by 1000rpm in centrifugal 10 minutes, successively with 15mL lysis buffer washing 3 times, with 15mL with ice-cooled lavation buffer solution (10mM Tris-HCl, 13mM EDTA, pH7.4) washing once.Granular precipitation makes it be suspended in 6mL with in the ice-cooled water with mixer, adds 68 μ l H to gained suspension ₂SO ₄To the concentration that reaches 0.4N.At 4 ℃ of following incubations after 1 hour, suspension is 15, and centrifugal 5 minutes of 000rpm obtains supernatant liquor and it is mixed with 60mL acetone.After being incubated overnight under-20 ℃, collect condensation product by micro centrifuge, air-dry, in-80 ℃ of preservations.

The active analysis of histone deacetylase

For carrying out standard analysis, with 10 μ l [ ³H] histone of ethanoyl mark joins the enzyme fraction of 90 μ l, and the gained mixture was 25 ℃ of following incubations 30 minutes.By the HCl that adds 10 μ l reaction is stopped.Discharge [ ³H] acetate 1mL ethyl acetate extraction, the solvent layer of getting 0.9mL joins in the toluene scintillation solution of 10mL, in order to measure radioactivity.

The active mensuration of test 2:T cytostatic agent

T lymphocyte blastogenesis test is carried out in microtiter plate, and each hole adds and contains 1.5 * 10 ⁵The 0.1mL RPMI-1640 substratum of individual Lewis rat spleen cells, described culture medium supplemented has 10% foetal calf serum (FBS), 50mM 2 mercapto ethanol, penicillin, and (100 units/mL) and Streptomycin sulphate (100 μ g/mL) wherein add concanavalin A (1 μ g/mL).Cell is at 5% CO ₂Wet environment in 37 ℃ of following incubations 72 hours.Through behind the incubation period, test compound is undertaken quantitatively by AlamarBlue (trade mark) analytical method the inhibition of T lymphocyte blastogenesis is active.Test sample is dissolved among the DMSO, further with RPMI-1640 substratum dilution and join in the culture.The activity of test compound is with IC ₅₀Expression.

These tests the results are shown in Table 1.

Table 1: the HDAC of The compounds of this invention suppresses active and T cell growth inhibiting activity

Embodiment Test 1: Test 2:
Embodiment Test 1: Test 2:	HDAC suppresses active t cell growth inhibitory activity IC ₅₀(nM) IC ₅₀(nM)
Compd E 1 28 69 compd Es 3 140 160 compd Es 5 96 310 compd Es 6 150 150

The pharmaceutical composition of the present invention that comprises histone deacetylase inhibitor such as compound [I] can be used as treatment of diseases or the preventive medicine that gene unconventionality expression causes, described disease is inflammatory conditions, diabetes, diabetic complication, homozygote thalassemia, fibrosis, cirrhosis, acute promyelocytic leukemia (APL), protozoal infections etc. for example.In addition, it also can be used as antineoplastic agent or immunosuppressor, in order to prevent organ-graft refection and autoimmune disorder, is exemplified below:

The rejection that causes by the transplanting of organ or tissue such as heart, kidney, liver, marrow, skin, cornea, lung, pancreas, small intestine, limbs, muscle, nerve, intervertebral disk, tracheae, sarcoplast, cartilage etc.;

Graft-vs-host reaction after the bone marrow transplantation;

Autoimmune disease such as rheumatoid arthritis, systemic lupus erythematous, struma lymphomatosa, multiple sclerosis, myasthenia gravis, type i diabetes etc.;

The infection that pathogenic micro-organism (for example Aspergillus fumigatus (Aspergillus fumigatus), sharp sickle spore (Fusariumoxysporum), star Trichophyton (Trichophyton asteroides) etc.) causes.

In addition, the pharmaceutical preparation of histone deacetylase inhibitor such as compound [I] also can be used for treatment or prevents following disease.

The cutaneous manifestations symptom of inflammatory or transition hyperproliferative skin disease or immunologically mediated disease (for example psoriasis, atopic dermatitis, contact dermatitis, eczematoid dermatitis, seborrheic dermatitis, lichen planus, pemphigus, bullous pemphigoid, epidermolysis bullosa, urticaria, vasodilation, vasculitis, erythema, skin eosinophilia, lupus erythematosus, acne, alopecia circumscripta etc.);

Eye autoimmune disorder (keratoconjunctivitis for example, vernal conjunctivitis, the uveitis relevant with Behcet, keratitis, herpetic keratitis, taper keratitis (conicalkeratitis), dystrophia epithelialis corneae, walleye, ocular pemphigus (ocularpremphigus), Mooren's ulcer, scleritis, Grave ' s illness in eye, Vogt-Koyanagi-Harada syndrome, keratoconjunctivitis sicca (dry eyes), vesicle, iridocyclitis, sarcoidosis, endocrine ophthalmopathy etc.);

Reversibility obstructive airway diseases [asthma (for example bronchial asthma, atopic asthma, intrinsic asthma, extrinsic asthma, dust asthma etc.), particularly chronic or obstinate asthma (for example tardy property asthma, air flue allergy etc.), bronchitis etc.];

Mucous membrane or vascular inflammation (for example stomach ulcer, ischemia or thrombotic blood vessel injury, ischemic enteropathy, enteritis, necrotizing enterocolitis, the damage of intestines relevant, the disease of leukotrienes B4 mediation etc.) with thermal burn;

Enteritis/allergy (for example coeliac disease, rectitis, Eosinophilic Gastroenteritis, mast cell disease, Crohn disease, ulcerative colitis etc.);

Show that symptom is away from GI food dependency anaphylactic disease (for example migraine, rhinitis, eczema etc.);

Kidney disease (for example interstitial nephritis, Goodpasture's syndrome, hemolytic uremic syndrome, diabetic nephropathy etc.);

Sacred disease (for example polymyositis, Ge-Ba syndromes, Meniere, polyneuritis, mononeuritis, cerebral infarction, presenile dementia, Parkinson's disease, amyotrophic lateral sclerosis (ALS), radiculopathy etc.);

Cerebral ischaemia disease (for example head injury, hematencephalon (for example subarachnoid hemorrhage, ICH etc.), cerebral thrombosis, cerebral embolism, asystolia, apoplexy, transient ischemia's outbreak (TIA), hypertensive encephalopathy etc.);

Endocrinopathy (for example hyperthyroidism, Exophthalmus goiter etc.);

Hematologic disease (for example simple cell substitution obstacle, aplastic anemia, hypoplastic anemia, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, granulopenia, pernicious anemia, megaloblastic anemia, red corpuscle take place and can not wait);

Skeletal diseases (for example osteoporosis etc.);

Respiratory tract disease (for example sarcoidosis, pulmonary fibrosis, idiopathic interstitial pneumonia etc.);

Dermatosis (for example dermatomyositis, ordinary leukodermia, ichthyosis simplex, photosensitization, cutaneous T cell lymphoma etc.);

Circulation system disease (for example arteriosclerosis, atherosclerosis, aortitis syndromes, polyarteritis nodosa, myocardosis etc.);

Collagen diseases (for example scleroderma, wegener's granuloma, Si Yegelun syndromes etc.);

Obesity;

Eosinophilic fasciitis;

Periodontal disease (for example gums, periodontal tissue, alveolar bone or dentine damage etc.);

Nephrotic syndrome (for example glomerulonephritis);

Male pattern alopecia disease, old alopecia;

Muscular dystrophy;

Pyoderma and Sai Zerui syndromes;

Chromosome abnormalty relative disease (for example mongolism etc.);

Addison's disease;

The disease of active oxygen mediation { organ damage [for example with preservation, transplanting, ischemic disease relevant organ (for example heart, liver, kidney, digestive tube etc.) ischemic cycle penaltys such as (for example thrombus disease, myocardial infarctions etc.)] for example;

Enteropathy (for example endotoxin shock, pseudomembranous colitis, medicine or radiation-induced colitis etc.);

Ephrosis (for example ischemic acute kidney insufficiency, chronic renal failure etc.);

Tuberculosis (for example poisoning that causes of lung's oxygen or medicine (for example paracort, bleomycin etc.), lung cancer, pulmonary emphysema etc.);

Illness in eye (for example cataract, iron storage diseases (ophthalmic siderosis), the retinitis, pigmentation (Pigmentosa), senile plaque, vitreum spot, corneal alkali are burnt etc.);

Dermatitis (for example erythema multiforme, linear immunoglobulin A bleb dermatitis, sclerotin dermatitis (cementdermatitis) etc.);

Other disease (disease that for example gingivitis, periodontitis, pyemia, pancreatitis and environmental pollution (for example atmosphere etc.), aging, carcinogenic substance, cancer metastasis, altitude sickness etc. are caused) }; Histamine release or leukotrienes C4 discharge the disease that causes;

Restenosis after coronary angioplasty and the tissue adhesion prevention;

Autoimmune disorder and inflammatory states (for example primary myxedema, autoimmunity atrophic gastritis, menopause in advance, male sterility, juvenile diabetes, pemphigus vulgaris, pemphigoid, sympatheticophthalmia, lens cause uveitis, special property leukopenia, active chronic hepatitis, congenital sclerosis, discoid lupus erythematosus, autoimmunity orchitis, sacroiliitis (for example being out of shape sacroiliitis etc.), the polychondritis etc. sent out);

Human immunodeficiency virus (HIV) infects, AIDS;

Anaphylaxis conjunctivitis;

Wound, burn, the perform the operation hypertrophic cicatrix that causes, keloid etc.

Therefore, pharmaceutical composition of the present invention can be used for treatment and prevention of liver disease [for example immunogenicity disease (for example chronic autoimmunity hepatic diseases such as autoimmune liver disease, primary biliary cirrhosis, sclerosing cholangitis etc.), liver are divided excision, acute severe hepatitis (for example toxin, viral hepatitis, shock, anoxic etc. cause necrosis), hepatitis B, non-A non-B hepatitis, liver cirrhosis, hepatic failure (for example fulminant hepatitis, tardy hepatitis, " urgency-chronic " hepatic failure (the acute hepatic failure of chronic hepatic diseases etc.) etc.) etc.].

Pharmaceutical composition of the present invention can pharmaceutical preparation form use, for example containing histone deacetylase inhibitor such as compound [I], and be fit in outside, the intestines or the organic or inorganic carrier of parenteral admin or solid, semisolid or the liquid form that vehicle is mixed together use as activeconstituents.Activeconstituents can for example mix with general nontoxicity, medicine acceptable carrier, forms the formulation of tablet, pill, capsule, suppository, solution, emulsion, suspensoid, injection, paste, liniment, eye drops, lotion, gelifying agent, emulsifiable paste and other any suitable use.

Can be used for carrier of the present invention and comprise that water, glucose, lactose, Sudan Gum-arabic, gelatin, N.F,USP MANNITOL, starch slurry, Magnesium Trisilicate, talcum powder, W-Gum, Keratin sulfate, colloidal silica, yam starch, urea and other are suitable for producing the carrier of solid, semisolid, liquid form preparation.In addition, also can make used additives, stablizer, thickening material, solubilizing agent, tinting material and perfume compound.

For this composition is applied to the mankind, preferably the mode by intravenously administrable, intramuscular administration, topical or oral administration gives, or gives by the intravascular stent that soaks into compound [1].The histone deacetylase inhibitor for example effective dosage of compound [I] treatment depends on each patient's to be treated age and physical appearance and changes thereupon, when a patient is treated, usually, under the intravenously administrable situation, every day, per kilogram human body body weight gave for example dosage of compound [1] of 0.01-10mg histone deacetylase inhibitor; Under the intramuscular administration situation, every day, per kilogram human body body weight gave for example dosage of compound [1] of 0.1-10mg histone deacetylase inhibitor; Under the oral administration situation, every day, per kilogram human body body weight gave for example dosage of compound [1] of 0.5-50mg histone deacetylase inhibitor, to treat.

When preparation said medicine formulation, compound [I] or its salt also can for example rapamycin, Mycophenolic Acid, Ciclosporin A, tacrolimus and brequinar sodium combine with other immunosuppressive substance.

Hereinafter the reaction in order to preparation The compounds of this invention [I] among each preparation scheme and the embodiment is described in detail.The present invention should not limited by following preparation scheme and embodiment by any way.

Preparation scheme 1

N to 4-iodophenyl acetate (1346mg), add in dinethylformamide (15mL) solution 2-aminophenyl t-butyl carbamate (1.07g), I-hydroxybenzotriazole (HOBT) (764mg), 1-ethyl-3-(3 '-dimethylamino-propyl) carbodiimide hydrochloride (1.08g), the gained mixture was stirred 3 hours at ambient temperature.Mixture is poured in the water, used ethyl acetate extraction.Organic phase is used saturated aqueous ammonium chloride, saturated sodium bicarbonate aqueous solution and salt water washing successively.The organic phase dried over mgso, vacuum-evaporation.Resistates obtains compound (1) by mixture (4: 1 to 2: 1) the wash-out purifying of silica gel chromatography with hexane and ethyl acetate, is light yellow amorphous substance (2.03g).

¹H-NMR(300MHz，DMSO-d ₆，δ)：1.50(3x3H，s)，3.66(2H，s)，6.62(1H，brs)，7.07-7.20(4H，m)，7.33(1H，m)，7.47(1H，m)，7.69(2x1H，d，J＝8.3Hz)，8.00(1H，brs)；

MASS(ES+)：m/e 453.

Preparation scheme 2

Under agitation, in compound (1) ethanol (300mL) solution (25.6g), add concentrated hydrochloric acid (30mL), the gained mixture was refluxed 1 hour.Boil off solvent with methylbenzene azeotropic in a vacuum.Residual solid is collected with the mixture (1: 10) of ethanol and ethyl acetate, obtains compound (2), is orange solids (20.0g).

¹H-NMR(300MHz，CDCl ₃，δ)：4.52(2H，s)，7.30(2x1H，d，J＝8.3Hz)，7.49-7.57(2H，m)，7.73-7.82(4H，m)；

MASS(ES+)：m/e 335.

Preparation scheme 3

Under 0 ℃ of stirring, (114mg) add Tosyl chloride (70mg) in the solution of De diox (3mL) and 1N sodium hydroxide (0.8mL) to compound (2).Allow the gained mixture be warming up to envrionment temperature, stirred 30 minutes.Add other Tosyl chloride (70mg), add 1N sodium hydroxide (0.5mL) then, make that final pH is 9.Mixture was stirred 2 hours at ambient temperature.Vacuum boils off solvent, gained solution ethyl acetate extraction.Organic phase salt water washing, dried over mgso, vacuum-evaporation.Resistates by preparation type thin layer chromatography (hexane: ethyl acetate=2: 1) purifying, obtain compound (3), be light yellow amorphous substance (130mg).

¹H-NMR(300MHz，DMSO-d ₆，δ)：2.35(3H，s)，4.56(2H，s)，7.05(2x1H，d，J＝8.5Hz)，7.32-7.44(4H，m)，7.63-7.70(3H，m)，7.78(2x1H，d，J＝8.5Hz)，7.94(1H，d，J＝6.5Hz)；

MASS(ES+)：m/e 489.

Preparation scheme 4

Under agitation, to compound (3) N (1137mg), add in dinethylformamide (15mL) solution vinylformic acid (0.8mL), acid chloride (II) (26mg), three (2-aminomethyl phenyl) phosphine (142mg) and N, N-diisopropylethylamine (1.25mL).The gained mixture stirred 90 minutes down at 120 ℃.Allow the gained mixture be chilled to envrionment temperature, be poured in the water, use ethyl acetate extraction.Organic phase salt water washing, dried over mgso, vacuum-evaporation.Resistates with chloroform and methanol mixture (20: 1) wash-out purifying, obtains compound (4) by silica gel column chromatography, is light yellow amorphous substance (455mg).

¹H-NMR(300MHz，DMSO-d ₆，δ)：2.32(3H，s)，4.63(2H，s)，6.51(1H，d，J＝16Hz)，7.26-7.44(6H，m)，7.54-7.69(4H，m)，7.79(2x1H，d，J＝8.4Hz)，7.94(1H，m)；

MASS(ES+)：m/e 433.

Preparation scheme 5

Under agitation, to compound (4) N (70mg), add in dinethylformamide (3mL) solution I-hydroxybenzotriazole (HOBT) (26mg), 1-ethyl-3-(3 '-dimethylamino-propyl) carbodiimide hydrochloride (37mg) and O-(tetrahydrochysene-2H-pyrans-2-yl) azanol (23mg), the gained mixture was stirred 14 hours at ambient temperature.In reaction mixture, add other I-hydroxybenzotriazole (HOBT) (13mg), 1-ethyl-3-(3 '-dimethylamino-propyl) carbodiimide hydrochloride (19mg) and O-(tetrahydrochysene-2H-pyrans-2-yl) azanol (12mg), with gained mixture stirring 6 hours.Reaction mixture dilutes with ethyl acetate, successively water, saturated ammonium chloride solution, saturated sodium bicarbonate solution and salt water washing.The organic phase dried over mgso, vacuum concentration.Resistates by preparation type thin layer chromatography (chloroform: purifying methyl alcohol=10: 1), obtain compound (5), be white amorphous substance (503mg).Compound (5) is used for embodiment 1.

¹H-NMR(300MHz，DMSO-d ₆，δ)：1.44-1.76(6H，m)，3.52(1H，m)，3.95(1H，m)，4.19(1H，m)，4.90(1H，m)，6.47(1H，d，J＝15.8Hz)，7.09-7.19(2H，m)，7.34-7.58(7H，m)，11.23(1H，s)，12.30(1H，s)；

MASS(ES+)：m/e 378.

Preparation scheme 6

Under agitation, to (4-bromophenyl) acetate (80.0g, N 372mmol), add in dinethylformamide (640mL) solution tert-butyl acrylate (95.4g), acid chloride (II) (1.67g), triphenylphosphine (3.91g) and N, N-diisopropylethylamine (162mL).The gained mixture stirred 7 hours down at 100 ℃.Allow the gained mixture be chilled to envrionment temperature, pour in the 1N hydrochloric acid, use twice of ethyl acetate extraction.The organic phase that merges extracts three times with saturated sodium bicarbonate solution.The water that merges to pH2, is used ethyl acetate extraction with dense hydrogenchloride acidifying.Organic phase salt water washing, dried over mgso, vacuum concentration obtains compound (6), is light yellow solid (78.1g).

¹H-NMR(300MHz，CDCl ₃，δ)：1.53(9H，s)，3.67(2H，s)，6.35(1H，d，J＝16Hz)，7.29(2H，d，J＝8Hz)，7.47(2H，d，J＝8Hz)，7.56(1H，d，J＝16Hz).

Preparation scheme 7

Under 4 ℃, to compound (6) (77.7g), 2-aminophenyl t-butyl carbamate (61.7g) and I-hydroxybenzotriazole (HOBT) N (44.0g), add 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (62.5g) in dinethylformamide (777mL) solution.The gained mixture heating up to envrionment temperature, was stirred 2 hours.In reaction mixture, add saturated sodium bicarbonate aqueous solution (777mL) and water (3.1L), with ethyl acetate (1.5L) extraction.Organic layer washs with 5% aqueous potassium hydrogen sulfate (500mL), saturated sodium bicarbonate aqueous solution (500mL) and salt solution (500mL), and dried over mgso is filtered, and vacuum-evaporation obtains compound (7) (135g).

¹H-NMR(300MHz，CDCl ₃，δ)：1.49(9H，s)，1.54(9H，s)，3.74(2H，s)，6.36(1H，d，J＝16Hz)，6.66(1H，brs)，7.10-7.20(2H，m)，7.33-7.40(3H，m)，7.44-7.54(3H，m)，7.57(1H，d，J＝16Hz)，7.98(1H，brs).

Preparation scheme 8

Under 120 ℃, with compound (7) 1N hydrogenchloride/acetate (60mL) solution heating (47.6g) 1 hour.Allow the gained mixture be chilled to envrionment temperature, dilute with ethyl acetate.Filtration gained precipitation, resistates washs with ethyl acetate, obtains compound (8) (28.9g).

¹H-NMR(300MHz，DMSO-d ₆，δ)：4.56(2H，s)，6.56(1H，d，J＝16Hz)，7.48-7.55(4H，m)，7.59(1H，d，J＝16Hz)，7.72-7.80(4H，m).

Preparation scheme 9

Under 9 ℃, to compound (8) (50.0g), the N of O-tetrahydrochysene-2H-pyrans-2-base azanol (29.8g) and I-hydroxybenzotriazole (34.3g), add 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (39.5g) in dinethylformamide (795mL) solution.The gained mixture heating up to envrionment temperature, was stirred 2 hours.In reaction mixture, add saturated sodium bicarbonate aqueous solution (795mL) and water (3.2L).Filter to collect the gained precipitation, with saturated sodium bicarbonate aqueous solution (250 * 2mL) and water (250 * 2mL) wash, and obtain compound (9) (57.2g).

¹H-NMR(300MHz，DMSO-d ₆，δ)：1.48-1.75(6H，m)，3.48-3.57(1H，m)，3.89-4.00(1H，m)，4.20(2H，s)，4.90(1H，brs)，6.47(1H，d，J＝16Hz)，7.07-7.16(2H，m)，7.34-7.57(7H，m)，11.2(1H，brs)，12.3(1H，brs).

Preparation scheme 10

Under 0 ℃ of stirring, in dimethyl formamide (5mL) solution of 2-(4-iodine benzyl)-1H-benzoglyoxaline (451mg), add sodium hydride (81mg, 60% oil dispersion) in batches.After 30 minutes, drip bromotoluene (0.19mL) in the gained mixture, described mixture stirred 30 minutes.The gained mixture is poured in the saturated ammonium chloride solution, used ethyl acetate extraction.Organic phase salt water washing, dried over sodium sulfate, vacuum concentration.Resistates by preparation type thin layer chromatography (chloroform: purifying methyl alcohol=10: 1), obtain compound (10), be light yellow oil (225mg).In this preparation scheme, (306mg), it is used for following preparation scheme 23 also to obtain by product (1-benzyl-2-[1-(4-iodophenyl)-2-phenylethyl]-1H-benzoglyoxaline).

¹H-NMR(300MHz，CDCl ₃，δ)：4.18(2H，s)，5.19(2H，s)，6.86-6.97(4H，m)，7.19-7.32(6H，m)，7.56(2x1H，J＝8.5Hz)，7.81(1H，d，J＝7.5Hz)；

MASS(ES+)：m/e 425.

Preparation scheme 11

Compound (11) is light yellow oil (142mg) by obtaining from compound (10) with preparation scheme 4 similar modes.

¹H-NMR(300MHz，CDCl ₃，δ)：1.33(3H，t，J＝7Hz)，4.26(2H，s)，4.26(2H，q，J＝7Hz)，5.21(2H，s)，6.38(1H，d，J＝16Hz)，6.88-6.96(2H，m)，7.18-7.32(8H，m)，7.41(2x1H，d，J＝8Hz)，7.62(1H，d，J＝16Hz)，7.81(1H，d，J＝8Hz)；

MASS(ES+)：m/e 397.

Preparation scheme 12

Under agitation, in compound (11) methyl alcohol (6mL) solution (140mg), add 1N sodium hydroxide solution (0.71mL).The gained mixture was stirred 7 hours at ambient temperature.Vacuum boils off solvent, and resistates is soluble in water, washs with diethyl ether.Water to pH3, is used ethyl acetate extraction three times with hcl acidifying.The organic phase salt water washing that merges, dried over sodium sulfate, vacuum-evaporation obtains compound (12), is buff powder (111mg).

¹H-NMR(300MHz，CDCl ₃，δ)：4.29(2H，s)，5.23(2H，s)，6.36(1H，d，J＝15.7Hz)，6.88-6.96(2H，m)，7.16-7.34(8H，m)，7.41(2x1H，d，J＝8Hz)，7.62(1H，d，J＝15.7Hz)，7.81(1H，d，J＝7.5Hz)；

MASS(ES+)：m/e 368.

Preparation scheme 13

Compound (13) is white amorphous substance (111mg) by obtaining from compound (12) with preparation scheme 9 similar modes.

¹H-NMR(300MHz，CDCl ₃，δ)：1.52-1.95(6H，m)，3.61(1H，m)，3.94(1H，m)，4.25(2H，s)，5.02(1H，m)，5.20(2H，s)，6.88-6.96(2H，m)，7.12-7.41(11H，m)，7.66(1H，d，J＝15.5Hz)，7.82(1H，d，J＝8Hz)；

MASS(ES+)：m/e 468.

Preparation scheme 14

Under agitation, in acetate (70mL) solution of 3-phenylpropionic acid (7.51g), add Periodic acid (2.39g), iodine (5.08g), the vitriol oil (1.5mL) and water (10mL), the gained mixture was stirred 7 hours down at 70 ℃.Vacuum boils off solvent, and residue diluted with water is used ethyl acetate extraction.Organic phase is used the salt water washing then with 10% hypo solution washed twice, dried over mgso, vacuum-evaporation.The crystallization from ethyl acetate and hexane of gained precipitation obtains compound (14) (5.80g).

¹H-NMR(300MHz，CDCl ₃，δ)：2.66(2H，t，J＝7Hz)，2.90(2H，t，J＝7Hz)，6.97(2x1H，d，J＝8.5Hz)，7.61(2x1H，d，J＝8.5Hz)；

MASS(ES-)：m/e 275.

Preparation scheme 15

Compound (15) is by obtaining (9.50g) with preparation scheme 1 similar mode from compound (14).

¹H-NMR(300MHz，CDCl ₃，δ)：1.51(3x3H，s)，2.64(2H，t，J＝7.5Hz)，3.00(2H，t，J＝7.5Hz)，6.69(1H，s)，7.00(2x1H，d，J＝8.5Hz)，7.12-7.20(2H，m)，7.33(1H，m)，7.45(1H，m)，7.62(2x1H，d，J＝8.5Hz)，7.97(1H，brs)；

MASS(ES+)：m/e 467.

Preparation scheme 16

Compound (16) is by obtaining (1.55g) with preparation scheme 2 similar modes from compound (15).

¹H-NMR(300MHz，DMSO-d ₆，δ)：3.20(2H，t，J＝7.5Hz)，3.41(2H，t，J＝7.5Hz)，7.10(2x1H，d，J＝8.5Hz)，7.48-7.56(2H，m)，7.66(2x1H，d，J＝8.5Hz)，7.74-7.82(2H，m)；

MASS(ES+)：m/e 349.

Preparation scheme 17

Compound (17) is by obtaining (7.10g) with preparation scheme 3 similar modes from compound (16).

¹H-NMR(300MHz，CDCl ₃，δ)：2.38(3H，s)，3.18(2H，t，J＝7Hz)，3.43(2H，t，J＝7Hz)，7.05(2x1H，d，J＝8.5Hz)，7.25(2x1H，d，J＝8.5Hz)，7.30-7.40(2H，m)，7.61(2x1H，d，J＝8.5Hz)，7.67(1H，m)，7.71(2x1H，d，J＝8.5Hz)，8.03(1H，m)；

MASS(ES+)：m/e 503.

Preparation scheme 18

Compound (18) is by obtaining (3.59g) with preparation scheme 4 similar modes from compound (17).

¹H-NMR(300MHz，CDCl ₃，δ)：2.38(3H，s)，3.27(2H，t，J＝7Hz)，3.47(2H，t，J＝7Hz)，6.44(1H，d，J＝16Hz)，7.25(2x1H，d，J＝8Hz)，7.31-7.40(4H，m)，7.50(2x1H，d，J＝8Hz)，7.66-7.81(4H，m)，8.04(1H，m)；

MASS(ES+)：m/e 447.

Preparation scheme 19

Compound (19) is by obtaining (2.20g) with preparation scheme 5 similar modes from compound (18).Compound (19) is used for embodiment 3.

¹H-NMR(300MHz，DMSO-d ₆，δ)：1.46-1.76(6H，m)，3.08-3.18(4H，m)，3.53(1H，m)，3.95(1H，m)，4.90(1H，m)，6.45(1H，d，J＝15.5Hz)，7.08-7.16(2H，m)，7.31(2x1H，d，J＝8Hz)，7.40-7.54(5H，m)，11.21(1H，s)，12.28(1H，br)；

MASS(ES+)：m/e 392.

Preparation scheme 20

Under 0 ℃ of stirring,, add sodium hydride (186mg, 60% oil dispersion) in dinethylformamide (10mL) solution to the N of 1H-benzoglyoxaline (500mg).After 90 minutes, 4-iodophenyl bromine is joined in the gained mixture, stirred described mixture at ambient temperature 1 hour.Reaction mixture saturated ammonium chloride solution quencher, dilute with water is used ethyl acetate extraction.Organic phase salt water washing, dried over sodium sulfate, vacuum concentration.Resistates grinds with hexane, obtains compound (20), is white solid (1.20g).

¹H-NMR(300MHz，CDCl ₃，δ)：5.31(2H，s)，6.92(2x1H，d，J＝8.5Hz)，7.21-7.33(3H，m)，7.67(2x1H，d，J＝8.5Hz)，7.84(1H，m)，7.95(1H，s)；

MASS(ES+)：m/e 335.

Preparation scheme 21

Compound (21) is by obtaining (614mg) with preparation scheme 4 similar modes from compound (20).

¹H-NMR(300MHz，DMSO-d ₆，δ)：5.53(2H，s)，6.50(1H，d，J＝16Hz)，7.15-7.24(2H，m)，7.32(2x1H，d，J＝8.5Hz)，7.51(1H，m)，7.52(1H，d，J＝16Hz)，7.61-7.70(3H，m)，8.43(1H，s)；

MASS(ES+)：m/e 279.

Preparation scheme 22

Compound (22) is by obtaining (536mg) with preparation scheme 5 similar modes from compound (21).Gained compound (22) is used for embodiment 4.

¹H-NMR(300MHz，DMSO-d ₆，δ)：1.45-1.76(6H，m)，3.52(1H，m)，3.94(1H，m)，4.89(1H，m)，5.53(2H，s)，6.46(1H，d，J＝16Hz)，7.16-7.25(2H，m)，7.33(2x1H，d，J＝8.5Hz)，7.44(1H，d，J＝16Hz)，7.51(1H，m)，7.54(2x1H，d，J＝8.5Hz)，7.67(1H，m)，8.42(1H，s)，11.24(1H，s)；

MASS(ES+)：m/e 378.

Preparation scheme 23

Compound (23) is pressed the by product that obtains with preparation scheme 4 similar modes and is obtained (150mg) from preparation scheme 10.

¹H-NMR(300MHz，CDCl ₃，δ)：1.32(3H，t，J＝7Hz)，3.35(1H，dd，J＝13.5，7.5Hz)，3.85(1H，dd，J＝13.5，7.5Hz)，4.25(2H，q，J＝7Hz)，4.28(1H，dd，J＝7.5，7.5Hz)，5.05(1H，d，J＝16.5Hz)，5.11(1H，d，J＝16.5Hz)，6.35(1H，d，J＝16Hz)，6.75(2x1H，dd，J＝7.5，1Hz)，6.93-7.00(2H，m)，7.09-7.38(13H，m)，7.59(1H，d，J＝16Hz)，7.91(1H，d，J＝8Hz)；

MASS(ES+)：m/e 487.

Preparation scheme 24

Compound (24) is by obtaining (135mg) with preparation scheme 12 similar modes from compound (23).

¹H-NMR(300MHz，CDCl ₃，δ)：3.37(1H，dd，J＝13.5，7.5Hz)，3.86(1H，dd，J＝13.5，7.5Hz)，4.31(1H，dd，J＝7.5，7.5Hz)，5.06(1H，d，J＝15.7Hz)，5.11(1H，d，J＝15.7Hz)，6.39(1H，d，J＝15.7Hz)，6.74(2x1H，d，J＝7Hz)，6.93-7.02(2H，m)，7.08-7.33(11H，m)，7.36(2x1H，d，J＝8Hz)，7.68(1H，d，J＝15.7Hz)，7.94(2x1H，d，J＝7.5Hz)；

MASS(ES+)：m/e 459.

Preparation scheme 25

Compound (25) is by obtaining (140mg) with preparation scheme 9 similar modes from compound (24).Gained compound (25) is used for embodiment 5.

¹H-NMR(300MHz，CDCl ₃，δ)：1.55-1.92(6H，m)，3.35(1H，dd，J＝13.5，7.5Hz)，3.64(1H，m)，3.84(1H，dd，J＝13.5，7.5Hz)，3.95(1H，m)，4.28(1H，dd，J＝7.5，7.5Hz)，5.00(1H，m)，5.04(1H，d，J＝17Hz)，5.11(1H，d，J＝17Hz)，6.75(2x1H，d，J＝7Hz)，6.92-7.00(2H，m)，7.08-7.37(14H，m)，7.64(1H，d，J＝15Hz)，7.90(1H，d，J＝8Hz)；

MASS(ES+)：m/e 558.

Preparation scheme 26

Compound (26) is by obtaining (6.20g) with preparation scheme 6 similar modes from (3-bromophenyl) acetate.

¹H-NMR(300MHz，CDCl ₃，δ)：1.53(3x3H，s)，3.06(2H，s)，6.37(1H，d，J＝15.8Hz)，7.25-7.46(4H，m)，7.56(1H，d，J＝15.8Hz)；

MASS(ES-)：m/e 261.

Preparation scheme 27

Compound (27) is by obtaining (6.96mg) with preparation scheme 7 similar modes from compound (26).

¹H-NMR(300MHz，CDCl ₃，δ)：1.48(3x3H，s)，1.53(3x3H，s)，3.74(2H，s)，6.39(1H，d，J＝15.8Hz)，6.70(1H，brs)，7.09-7.20(2H，m)，7.32-7.52(6H，m)，7.56(1H，d，J＝15.8Hz)，8.04(1H，brs)：

MASS(ES+)：m/e 453.

Preparation scheme 28

Compound (28) is by obtaining (4.19mg) with preparation scheme 8 similar modes from compound (27).

¹H-NMR(300MHz，DMSO-d ₆，δ)：4.58(2H，s)，6.58(1H，d，J＝16Hz)，7.42-7.58(5H，m)，7.58(1H，d，J＝16Hz)，7.66(1H，m)，7.74-7.82(2H，m)，7.87(1H，brs)；

MASS(ES+)：m/e 279.

Preparation scheme 29

Compound (29) is by obtaining (3.34g) with preparation scheme 9 similar modes from compound (28).Gained compound (29) is used for embodiment 6.

¹H-NMR(300MHz，DMSO-d ₆，δ)：1.44-1.76(6H，m)，3.53(1H，m)，3.95(1H，m)，4.20(2H，s)，4.90(1H，m)，6.50(1H，d，J＝16Hz)，7.08-7.16(2H，m)，7.32-7.60(7H，m)，11.25(1H，s)，12.31(1H，brs)；

MASS(ES+)：m/e 378.

Preparation scheme 30

Compound (30) by with preparation scheme 1 similar mode from 4-[(1E)-3-tert.-butoxy-3-oxo-1-propenyl] phenyl acetate acquisition (324mg).

¹H-NMR(300MHz，DMSO-d ₆，δ)：1.48(3x3H，s)，3.176(1H，s)，3.723(1H，s)，5.00(1H，s)，5.01(1H，s)，6.51(1H，d，J＝15.7Hz)，6.82(1H，m)，7.19-7.60(10H，m)，7.66(2x1H，d，J＝8Hz)，9.45(0.5H，s)，9.47(0.5H，s)；

MASS(ES+)：m/e 429.

Preparation scheme 31

Compound (31) is by obtaining (216mg) with preparation scheme 8 similar modes from compound (30).

¹H-NMR(300MHz，DMSO-d ₆，δ)：4.59(2H，s)，6.57(1H，d，J＝16Hz)，7.42(1H，m)，7.51(2x1H，d，J＝7.5Hz)，7.53(2x1H，d，J＝8.5Hz)，7.60(1H，d，J＝16Hz)，7.69-7.88(6H，m)，7.96(1H，s)；

MASS(ES+)：m/e 355.

Preparation scheme 32

Compound (32) is by obtaining (231mg) with preparation scheme 9 similar modes from compound (31).Gained compound (32) is used for embodiment 7.

¹H-NMR(300MHz，DMSO-d ₆，δ)：1.46-1.78(6H，m)，3.52(1H，m)，3.95(1H，m)，4.22(2H，s)，4.90(1H，m)，6.48(1H，d，J＝15Hz)，7.30-7.81(13H，m)，11.23(1H，s)，12.38(1/2H，s)，12.41(1/2H，s)；

MASS(ES+)：m/e 454.

Preparation scheme 33

Compound (33) is by obtaining (5.48g) with preparation scheme 7 and 8 similar modes from compound (6).

¹H-NMR(300MHz，DMSO-d ₆，δ)：4.50(2H，s)，6.55(1H，d，J＝16Hz)，7.47(2H，d，J＝8Hz)，7.59(1H，d，J＝16Hz)，7.56-7.75(4H，m)，7.97(1H，s).

MASS(ESI)：m/z 357(M+1).

Preparation scheme 34

Compound (34) is by obtaining (557mg) with preparation scheme 9 similar modes from compound (33).Compound (34) is used for embodiment 8.

¹H-NMR(300MHz，DMSO-d ₆，δ)：1.48-1.74(6H，m)，3.48-3.57(1H，m)，3.89-4.00(1H，m)，4.20(2H，s)，4.90(1H，brs)，6.47(1H，d，J＝16Hz)，7.26(1H，dd，J＝2，8Hz)，7.34-7.56(6H，m)，7.68(1H，brs).

MASS(ESI)：m/z 456(M+1).

Preparation scheme 35

To compound (34) (200mg), 4-acetylbenzene ylboronic acid (167mg) and dichloro two (triphenylphosphine) close palladium (II) and (10.7mg) add 2M yellow soda ash (2.5mL) in the mixture in diox (10mL), the gained mixture is 90 ℃ of heating 5 hours down.After the cooling, reaction mixture distributes between ethyl acetate and water.Separate inorganic layer, use the 1N hcl acidifying.Filter and collect the gained precipitation, water and ethyl acetate washing obtain compound (35) (193mg).Compound (35) is used for embodiment 9.

¹H-NMR(300MHz，DMSO-d ₆，δ)：2.63(3H，s)，4.57(2H，s)，6.56(1H，d，J＝16Hz)，7.52(2H，d，J＝8Hz)，7.59(1H，d，J＝16Hz)，7.74(2H，d，J＝8Hz)，7.85-7.92(4H，m)，8.03-8.10(3H，m)；

MASS(ESI)：m/z 397(M+1).

Preparation scheme 36

Compound (36) is by obtaining (163mg) with preparation scheme 35 similar modes from compound (34).Compound (36) is used for embodiment 10.

¹H-NMR(300MHz，DMSO-d ₆，δ)：4.37(2H，s)，6.53(1H，d，J＝16Hz)，7.12-7.16(1H，m)，7.45-7.71(9H，m)，7.81(1H，s)；

MASS(ESI)：m/z 361(M+1).

Preparation scheme 37

Compound (37) is by obtaining (183mg) with preparation scheme 35 similar modes from compound (34).Compound (37) is used for embodiment 11.

¹H-NMR(300MHz，DMSO-d ₆，δ)：4.55(2H，s)，6.56(1H，d，J＝16Hz)，7.40-8.01(11H，m)；

MASS(ESI)：m/z 361(M+1).

Preparation scheme 38

Compound (38) is by obtaining (2.07g) with preparation scheme 7 and 8 similar modes from compound (6).

¹H-NMR(300MHz，DMSO-d ₆，δ)：4.47(2H，s)，6.54(1H，d，J＝16Hz)，7.46(2H，d，J＝8Hz)，7.58(1H，d，J＝16Hz)，7.70(2H，d，J＝8Hz)，7.77(1H，d，J＝8Hz)，7.83(1H，d，J＝8Hz)，8.26(1H，s)；

MASS(ESI)：m/z 304(M+1).

Preparation scheme 39

Compound (39) is by obtaining (2.14g) with preparation scheme 9 similar modes from compound (38).Compound (39) is used for embodiment 12 and 18.

¹H-NMR(300MHz，DMSO-d ₆，δ)：1.49-1.72(6H，m)，3.50-3.56(1H，m)，3.91-3.99(1H，m)，4.26(2H，s)，4.91(1H，brs)，6.47(1H，d，J＝16Hz)，7.37(2H，d，J＝8Hz)，7.46(1H，d，J＝16Hz)，7.51-7.57(3H，m)，7.65(1H，d，J＝8Hz)，8.32(1H，brs)；

MASS(ESI)：m/z 401(M-1).

Preparation scheme 40

Compound (40) is by obtaining (955mg) with preparation scheme 7 and 8 similar modes from compound (6).Compound (40) is used for embodiment 13.

¹H-NMR(300MHz，DMSO-d ₆，δ)：4.50(2H，s)，6.55(1H，d，J＝16Hz)，7.32-7.39(1H，m)，7.47(2H，d，J＝8Hz)，7.59(1H，d，J＝16Hz)，7.62(1H，dd，J＝2，8Hz)，7.72(2H，d，J＝8Hz)，7.74-7.79(1H，m)；

MASS(ESI)：m/z 297(M+1).

Preparation scheme 41

Compound (41) is by obtaining (1.02g) with preparation scheme 7 and 8 similar modes from compound (6).

¹H-NMR(300MHz，DMSO-d ₆，δ)：4.52(2H，s)，6.55(1H，d，J＝16Hz)，7.48(2H，d，J＝8Hz)，7.50(1H，dd，J＝2，8Hz)，7.59(1H，d，J＝16Hz)，7.72(2H，d，J＝8Hz)，7.75(1H，d，J＝8Hz)，7.85(1H，J＝2Hz)；

MASS(ESI)：m/z 313(M+1).

Preparation scheme 42

Compound (42) is by obtaining (839mg) with preparation scheme 9 similar modes from compound (41).Compound (42) is used for embodiment 14.

¹H-NMR(300MHz，DMSO-d ₆，δ)：1.49-1.71(6H，m)，3.49-3.57(1H，m)，3.88-4.02(1H，m)，4.20(2H，s)，4.88-4.93(1H，m)，6.43-6.52(1H，m)，7.12-7.18(1H，m)，7.36(2H，d，J＝8Hz)，7.46(1H，d，J＝16Hz)，7.53(2H，d，J＝8Hz)，7.53-7.60(1H，m)，7.64(1H，d，J＝8Hz)；

MASS(ESI)：m/z 412(M+1).

Preparation scheme 43

Compound (43) is by obtaining (411mg) with preparation scheme 7 and 8 similar modes from compound (6).

¹H-NMR(300MHz，DMSO-d ₆，δ)：2.78-2.84(4H，m)，3.13-3.20(4H，m)，4.54(2H，s)，6.55(1H，d，J＝16Hz)，7.16-7.76(8H，m)；

MASS(ESI)：m/z 377(M+1).

Preparation scheme 44

Compound (44) is by obtaining (23mg) with preparation scheme 9 similar modes from compound (43).Compound (44) is used for embodiment 15.

¹H-NMR(300MHz，DMSO-d ₆，δ)：1.54-1.87(6H，m)，2.36(3H，s)，2.58-2.64(4H，m)，3.12-3.20(4H，m)，3.58-3.66(1H，m)，3.92-4.04(1H，m)，4.15(2H，s)，5.02-5.10(1H，m)，6.92-7.60(9H，m)；

MASS(ESI)：m/z 476(M+1).

Preparation scheme 45

Compound (45) is by obtaining (358mg) with preparation scheme 7 and 8 similar modes from compound (6).

¹H-NMR(300MHz，DMSO-d ₆，δ)：3.16-3.22(4H，m)，3.76-3.83(4H，m)，4.53(2H，s)，6.56(1H，d，J＝16Hz)，7.34-7.76(8H，m)；

MASS(ESI)：m/z 364(M+1).

Preparation scheme 46

Compound (46) is by obtaining (59mg) with preparation scheme 9 similar modes from compound (45).Compound (46) is used for embodiment 16.

¹H-NMR(300MHz，CDCl ₃，δ)：1.51-1.87(6H，m)，3.05-3.13(4H，m)，3.57-3.64(1H，m)，3.83-3.91(4H，m)，3.95-4.04(1H，m)，4.15(2H，s)，5.04-5.13(1H，m)，6.91-7.61(9H，m)；

MASS(ESI)：m/z 463(M+1).

Preparation scheme 47

Compound (47) is by obtaining (517mg) with preparation scheme 7 and 8 similar modes from compound (6).

¹H-NMR(300MHz，DMSO-d ₆，δ)：1.57-1.69(2H，m)，1.83-1.94(4H，m)，3.37-3.50(4H，m)，4.52(2H，s)，6.48-6.58(1H，m)，7.40-7.74(8H，m)；

MASS(ESI)：m/z 362(M+1).

Preparation scheme 48

Compound (48) is by obtaining (47mg) with preparation scheme 9 similar modes from compound (47).Compound (48) is used for embodiment 17.

¹H-NMR(300MHz，CDCl ₃，δ)：1.50-1.87(12H，m)，3.05-3.11(4H，m)，3.57-3.66(1H，m)，3.94-4.05(1H，m)，4.14(2H，s)，5.02-5.12(1H，m)，6.94-7.48(9H，m)；

MASS(ESI)：m/z 461(M+1).

Preparation scheme 49

Compound (49) is by obtaining (1.17g) with preparation scheme 7 and 8 similar modes from compound (6).

¹H-NMR(300MHz，DMSO-d ₆，δ)：3.90(3H，s)，4.49(2H，s)，6.54(1H，d，J＝16Hz)，7.47(2H，d，J＝8Hz)，7.59(1H，d，J＝16Hz)，7.72(2H，d，J＝8Hz)，7.78(1H，d，J＝8Hz)，8.00(1H，dd，J＝2，8Hz)，8.24(1H，brs)；

MASS(ESI)：m/z 337(M+1).

Preparation scheme 50

Compound (50) is by obtaining (1.30g) with preparation scheme 9 similar modes from compound (49).Compound (50) is used for embodiment 19.

¹H-NMR(300MHz，DMSO-d ₆，δ)：1.48-1.74(6H，m)，3.48-3.58(1H，m)，3.85(3H，s)，3.87-4.00(1H，m)，4.25(2H，brs)，4.90(1H，brs)，6.47(1H，d，J＝16Hz)，7.35-7.65(6H，m)，7.74-8.16(2H，m)；

MASS(ESI)：m/z 436(M+1).

Preparation scheme 51

(299mg) add 1N sodium hydroxide (2.1mL) in De diox (7mL) solution to compound (50).After stirring 1 hour under 80 ℃, in reaction mixture, add entry (25mL), with 1N hcl acidifying (to pH3-4).Filter and collect the gained precipitation, wash with water, obtain compound (51) (255mg).Compound (51) is used for embodiment 20.

¹H-NMR(300MHz，DMSO-d ₆，δ)：1.49-1.74(6H，m)，3.47-3.59(1H，m)，3.87-4.01(1H，m)，4.24(2H，s)，4.90(1H，brs)，6.47(1H，d，J＝16Hz)，7.38(2H，d，J＝8Hz)，7.43-7.62(4H，m)，7.73-8.14(2H，m)；

MASS(ESI)：m/z 422(M+1).

Preparation scheme 52

Compound (52) is by obtaining (384mg) with preparation scheme 7 and 8 similar modes from compound (6).

¹H-NMR(300MHz，DMSO-d ₆，δ)：2.68(3H，s)，4.55(2H，s)，6.55(1H，d，J＝16Hz)，7.50(2H，d，J＝8Hz)，7.59(1H，d，J＝16Hz)，7.73(2H，d，J＝8Hz)，7.81(1H，d，J＝8Hz)，8.04(1H，dd，J＝2，8Hz)，8.27(1H，s)；

MASS(ESI)：m/z 321(M+1).

Preparation scheme 53

Compound (53) is by obtaining (394mg) with preparation scheme 9 similar modes from compound (52).Compound (53) is used for embodiment 21.

¹H-NMR(300MHz，DMSO-d ₆，δ)：1.47-1.73(6H，m)，2.61(3H，s)，3.48-3.57(1H，m)，3.90-4.01(1H，m)，4.25(2H，brs)，4.90(1H，brs)，6.47(1H，d，J＝16Hz)，7.36-8.23(8H，m)；

MASS(ESI)：m/z 418(M-1).

Preparation scheme 54

Compound (54) is by obtaining (335mg) with preparation scheme 7 and 8 similar modes from compound (6).

¹H-NMR(300MHz，DMSO-d ⁶，δ)：4.58(2H，s)，6.53(1H，d，J＝16Hz)，7.30-7.36(1H，m)，7.47(2H，d，J＝8Hz)，7.54-7.73(5H，m)；

MASS(ESI)：m/z 357(M+1).

Preparation scheme 55

Compound (55) is by obtaining (364mg) with preparation scheme 9 similar modes from compound (54).Compound (55) is used for embodiment 22.

¹H-NMR(300MHz，DMSO-d ₆，δ)：1.48-1.74(6H，m)，3.48-3.58(1H，m)，3.89-4.02(1H，m)，4.24(2H，s)，4.90(1H，brs)，6.47(1H，d，J＝16Hz)，7.05-7.12(1H，m)，7.33-7.58(7H，m)；

MASS(ESI)：m/z 456(M+1).

Preparation scheme 56

Compound (56) is by obtaining (805mg) with preparation scheme 7 and 8 similar modes from compound (6).

¹H-NMR(300MHz，DMSO-d ₆，δ)：1.24(3H，s)，1.27(3H，s)，3.02-3.15(1H，m)，4.54(2H，s)，6.56(1H，d，J＝16Hz)，7.33-7.75(8H，m)；

MASS(ESI)：m/z 321(M+1).

Preparation scheme 57

Compound (57) is by obtaining (70mg) with preparation scheme 9 similar modes from compound (56).Compound (57) is used for embodiment 23.

¹H-NMR(300MHz，DMSO-d ₆，δ)：1.22(3H，s)，1.24(3H，s)，1.48-1.73(6H，m)，2.89-3.03(1H，m)，3.48-3.57(1H，m)，3.89-4.00(1H，m)，4.17(2H，s)，4.90(1H，brs)，6.47(1H，d，J＝16Hz)，7.01(1H，d，J＝8Hz)，7.20-7.57(7H，m)；

MASS(ESI)：m/z 420(M+1).

Preparation scheme 58

Compound (58) is by obtaining (925mg) with preparation scheme 7 and 8 similar modes from compound (6).

¹H-NMR(300MHz，DMSO-d ₆，δ)：4.50(2H，s)，5.37(2H，s)，6.54(1H，d，J＝16Hz)，7.13-7.75(13H，m)；

MASS(ESI)：m/z 385(M+1).

Preparation scheme 59

Compound (59) is by obtaining from compound (58) with preparation scheme 9 similar modes.Compound (59) is used for embodiment 24.

Preparation scheme 60

Compound (60) is by obtaining (1.25g) with preparation scheme 20 similar modes.

¹H-NMR(300MHz，CDCl ₃，δ)：2.56(3H，s)，5.27(2H，s)，6.79(2x1H，d，J＝8.4Hz)，7.15-7.29(3H，m)，7.63(2x1H，d，J＝8.4Hz)，7.73(1H，m)；

MASS(ES+)：m/e 349.

Preparation scheme 61

Compound (61) is by obtaining (625mg) with preparation scheme 4 similar modes from compound (60).

¹H-NMR(300MHz，CDCl ₃，δ)：2.57(3H，s)，5.36(2H，s)，6.40(1H，d，J＝16.2Hz)，7.07(2x1H，d，J＝8.5Hz)，7.20-7.29(3H，m)，7.48(2x1H，d，J＝8.5Hz)，7.64(1H，d，J＝16.2Hz)，7.71(1H，m)；

MASS(ES+)：m/e 293.

Preparation scheme 62

Compound (62) is by obtaining (556mg) with preparation scheme 9 similar modes from compound (61).Compound (62) is used for embodiment 25.

¹H-NMR(300MHz，DMSO-d ₆，δ)：1.46-1.75(6H，m)，2.52(3H，s)，3.52(1H，m)，3.94(1H，m)，4.89(1H，m)，5.50(2H，s)，6.46(1H，d，J＝16Hz)，7.11-7.20(4H，m)，7.38-7.62(5H，m)；

MASS(ES+)：m/e 392.

Preparation scheme 63

Under agitation, in acetate (30mL) solution of 1-phenyl cyclopropane-carboxylic acid (3.25g), add Periodic acid (959mg), iodine (2.03g), dense H ₂SO ₄(0.6mL) and water (4mL), the gained mixture stirred 12 hours down at 70 ℃.(100mL) joins in the mixture with water, filters the collecting precipitation solid, washes with water, obtains compound (63) (4.31g).

¹H-NMR(300MHz，CDCl ₃，δ)：1.23(2H，ddd，J＝7，4，4Hz)，1.67(2H，ddd，J＝7，4，4Hz)，7.09(2x1H，d，J＝8.4Hz)，7.63(2x1H，d，J＝8.4Hz)；

MASS(ES-)：m/e 287.

Preparation scheme 64

Compound (64) is by obtaining (432mg) with preparation scheme 6 similar modes from compound (63).

¹H-NMR(300MHz，DMSO-d ₆，δ)：1.16(2H，ddd，J＝7，4，4Hz)，1.45(2H，ddd，J＝7，4，4Hz)，1.48(3x3H，s)，6.49(1H，d，J＝15.7Hz)，7.35(2x1H，d，J＝8Hz)，7.53(1H，d，J＝15.7Hz)，7.61(2x1H，d，J＝8Hz)；

MASS (ES-): m/e undetermined.

Preparation scheme 65

Compound (65) is by obtaining (1.67g) with preparation scheme 7 similar modes from compound (64).

¹H-NMR(300MHz，CDCl ₃，δ)：1.20(2H，m)，1.45(3x3H，s)，1.51(3x3H，s)，1.74(2H，m)，6.40(1H，d，J＝15.7Hz)，6.63(1H，br-s)，6.98-7.62(10H，m)；

MASS(ES+)：m/e 479.

Preparation scheme 66

Compound (66) is by obtaining (710mg) with preparation scheme 8 similar modes from compound (65).

¹H-NMR(300MHz，DMSO-d ₆，δ)：1.71(2H，m)，1.95(2H，m)，6.59(1H，d，J＝15.8Hz)，7.40-7.55(4H，m)，7.63(1H，d，J＝15.8Hz)，7.64-7.72(2H，m)，7.76(2x1H，d，J＝8.4Hz)；

MASS(ES+)：m/e 305.

Preparation scheme 67

Compound (67) is by obtaining (647mg) with preparation scheme 9 similar modes from compound (66).

¹H-NMR(300MHz，DMSO-d ₆，δ)：1.39(2H，m)，1.48-1.76(8H，m)，3.34(1H，m)，3.54(1H，m)，3.96(1H，m)，4.91(2H，s)，6.51(1H，d，J＝16Hz)，7.07-7.15(2H，m)，7.31-7.43(3H，m)，7.46-7.63(4H，m)；

MASS (ES+)：m/e 404.

Preparation scheme 68

Under agitation, (add 4-fluorophenyl boric acid (1.06g), PdCl in 1.37g) De diox (20mL) solution to 4-bromo-2-N-methyl-p-nitroaniline ₂(PPh ₃) ₂(133mg) with 2M sodium carbonate solution (12.7ml), the gained mixture stirred 2 hours down at 100 ℃.Boil off solvent, resistates distributes between ethyl acetate and water.Organic phase salt water washing, Na ₂SO ₄Drying, vacuum concentration.Gained solid recrystallization from toluene obtains compound (68) (1.13g), is white solid.

¹H-NMR(300MHz，CDCl ₃，δ)：6.18(2H，br-s)，6.89(1H，d，J＝8.7Hz)，7.12(2x1H，dd，J＝8.7，8.7Hz)，7.51(2x1H，dd，J＝8.7，5Hz)，7.59(1H，dd，J＝8.7，2.2Hz)，8.31(1H，d，J＝2.2Hz)；

MASS(ES-)m/e 231.

Preparation scheme 69

Under agitation, in compound (68) EtOH (15mL) solution (1.08g), add tin chloride (II) (1.32g).The gained mixture stirred 6 hours down at 100 ℃.Boil off solvent to half volume, resistates alkalizes to pH9 with 1N NaOH, uses ethyl acetate extraction.Organic phase salt water washing, Na ₂SO ₄Drying, vacuum concentration.Resistates grinds with ethyl acetate, obtains compound (69) (800mg), is orange powder.

¹H-NMR(300MHz，CDCl ₃，δ)：3.45(2x2H，br-s)，6.76(2x1H，d，J＝8.3Hz)，6.89(1H，d，J＝2.1Hz)，6.91(1H，dd，J＝8.3，2.1Hz)，7.06(2x1H，dd，J＝8.8，8.8Hz)，7.46(2x1H，dd，J＝8.8，5.4Hz)；

MASS(ES+)：m/e 203.

Preparation scheme 70

Compound (70) is by obtaining (552mg) with preparation scheme 7 similar modes from compound (69).

¹H-NMR(300MHz，CDCl ₃，δ)：1.54(3x3H，s)，3.81(2H，s)，6.39(1H，sd，J＝16Hz)，6.80-7.62(15H，m)；

MASS(ES+)：m/e 446.

Preparation scheme 71

Compound (71) is by obtaining (375mg) with preparation scheme 8 similar modes from compound (70).

¹H-NMR(300MHz，DMSO-d ₆，δ)：4.58(2H，s)，6.56(1H，d，J＝16Hz)，7.23-7.86(11H，m)，7.94(1H，s)；

MASS (ES+)：m/e 373.

Preparation scheme 72

Compound (72) is by obtaining (321mg) with preparation scheme 9 similar modes from compound (71).Compound (71) is used for embodiment 26.

¹H-NMR(300MHz，DMSO-d ₆，δ)：1.45-1.75(6H，m)，3.52(1H，m)，3.95(1H，m)，4.22(2H，s)，4.90(1H，m)，6.48(1H，d，J＝15.8Hz)，7.22-7.80(12H，m)，11.23(1H，br-s)，12.40(H，br-s)；

MASS(ES+)：m/e 472.

Preparation scheme 73

Compound (73) is by obtaining (228mg) with preparation scheme 7 similar modes from compound (6).

¹H-NMR(300MHz，DMSO-d ₆，δ)：1.53(3x3H，s)，3.75-3.87(4H，br)，6.41(1H，d，J＝15.7Hz)，6.81-7.54(13H，m)，7.58(1H，d，J＝15.7Hz)；

MASS(ES+)：m/e 429.

Preparation scheme 74

Compound (74) is by obtaining (165mg) with preparation scheme 8 similar modes from compound (73).

¹H-NMR(300MHz，DMSO-d ₆，δ)：4.59(2H，s)，6.59(1H，d，J＝16Hz)，7.38-7.55(5H，m)，7.59(1H，d，J＝16Hz)，7.67(1H，m)，7.73(2x1H，d，J＝7.5Hz)，7.78-7.85(2H，m)，7.87(1H，br)，7.96(1H，br-s)；

MASS(ES+)：m/e 355.

Preparation scheme 75

Compound (75) is by obtaining (185mg) with preparation scheme 9 similar modes from compound (74).Compound (75) is used for embodiment 27.

¹H-NMR(300MHz，DMSO-d ₆，δ)：1.46-1.76(6H，m)，3.53(1H，m)，3.94(1H，m)，4.23(2H，s)，4.90(1H，m)，6.50(1H，d，J＝16Hz)，7.28-7.52(10H，m)，7.57(1H，m)，7.66(2x1H，d，J＝7.5Hz)，11.25(1H，br)，12.38(1H，br)；

MASS(ES+)：m/e 454.

Preparation scheme 76

Compound (76) is by obtaining (320mg) with preparation scheme 35 similar modes.

¹H-NMR(300MHz，DMSO-d ₆，δ)：3.24(3H，s)，7.16(1H，d，J＝8.8Hz)，7.68(2H，s)，7.85-8.07(5H，m)，8.34(1H，d，J＝2.5Hz)；

MASS(ES-)：m/e 291.

Preparation scheme 77

Under agitation, to 4 '-(methyl sulphonyl)-3-nitro-1,1 '-add iron powder (583mg), NH in EtOH (15mL) solution of biphenyl-4-base amine (305g) ₄Cl (56mg) and water (1mL).The gained mixture was refluxed 5 hours.Remove by filter iron powder, vacuum-evaporation filtrate.Resistates is at CHCl ₃With saturated NaHCO ₃Distribute between the solution.Organic phase salt water washing, Na ₂SO ₄Drying, vacuum concentration obtains compound (77) (150mg), is orange powder.

¹H-NMR(300MHz，DMSO-d ₆，δ)：3.44(3H ，s)，4.45-5.20(4H，m)，6.65(1H，br)，6.82-7.22(2H，m)，7.62-8.22(4H，m)；

MASS(ES+)：m/e 263.

Preparation scheme 78

Compound (78) is by obtaining (200mg) with preparation scheme 7 similar modes from compound (77).

¹H-NMR(300MHz，CDCl ₃，δ)：1.54(3x3H，s)，3.07(3x1/2H，s)，3.08(3x1/2H，s)，3.83(2H，br-s)，6.39(1H，d，J＝16Hz)，6.84-7.10(2H，m)，7.29(1H，m)，7.42(2H，m)，7.53-7.73(5H，m)，7.95(2H，m)；

MASS(ES+)：m/e 507.

Preparation scheme 79

Compound (79) is by obtaining (162mg) with preparation scheme 8 similar modes from compound (78).

¹H-NMR(300MHz，DMSO-d ₆，δ)：3.28(3H，s)，4.59(2H，s)，6.57(1H，d，J＝15.8Hz)，7.52(2x1H，d，J＝8.2Hz)，7.59(1H，d，J＝15.8Hz)，7.74(2x1H，d，J＝8.2Hz)，7.86-7.90(2H，m)，7.95-8.10(5H，m)；

MASS(ES+)：m/e 432.

Preparation scheme 80

Compound (80) is by obtaining (190mg) with preparation scheme 9 similar modes from compound (79).Compound (80) is used for embodiment 28.

¹H-NMR(300MHz，DMSO-d ₆，δ)：1.46-1.76(6H，m)，3.25(3H，s)，3.53(1H，m)，3.94(1H，m)，4.24(2H，m)，4.90(1H，m)，6.48(1H，d，J＝16Hz)，7.39(2x1H，d，J＝8Hz)，7.42-8.02(10H，m)，11.23(0.5H，br)，12.50(0.5H，br)；

MASS(ES+)：m/e 532.

Preparation scheme 81

Compound (81) is by obtaining (137mg) with preparation scheme 7 similar modes from compound (6).

¹H-NMR(300MHz，CDCl ₃，δ)：1.33(3H，t，J＝7.5Hz)，4.26(2H，q，J＝7.5Hz)，4.38(2H，s)，6.41(1H，d，J＝16Hz)，7.18(1H，dd，J＝8，4.5Hz)，7.38(2x1H，d，J＝8Hz)，7.51(2x1H，d，J＝8Hz)，7.65(1H，d，J＝16Hz)，7.99-8.10(2H，m)；

MASS(ES+)：m/e 308.

Preparation scheme 82

Compound (82) is by obtaining (362mg) with preparation scheme 12 similar modes from compound (81).

¹H-NMR(300MHz，DMSO-d ₆，δ)：4.23(2H，s)，6.50(1H，d，J＝16Hz)，7.17(1H，dd，J＝8，5Hz)，7.38(2x1H，d，J＝8Hz)，7.56(1H，d，J＝16Hz)，7.65(2x1H，d，J＝8Hz)，7.91(1H，br)，8.25(1H，br)；

MASS(ES+)：m/e 280.

Preparation scheme 83

Compound (83) is by obtaining (312mg) with preparation scheme 9 similar modes from compound (82).Compound (83) is used for embodiment 29.

¹H-NMR(300MHz，DMSO-d ₆，δ)：1.46-1.76(6H，m)，3.53(1H，m)，3.95(1H，m)，4.21(2H，br-s)，4.90(1H，m)，6.48(1H，d，J＝15.5Hz)，7.17(1H，dd，J＝8，4.5Hz)，7.39(2x1H ，d，J＝8Hz)，7.46(1H，d，J＝15.5Hz)，7.54(2x1H，br-d，J＝8Hz)，7.88(1H，m)，8.27(1H，m)，11.24(1H，br-s)，12.58(0.5H，br)，13.00(0.5H，br)；

MASS(ES+)：m/e 379.

Preparation scheme 84

Compound (84) is by obtaining (9.77g) with preparation scheme 7 similar modes from compound (6).

¹H-NMR(300MHz，DMSO-d ₆，δ)：1.26(3H，t，J＝7Hz)，3.74(2H，s)，4.19(2H，q，J＝7Hz)，6.54(2H，s)，6.62(1H，d，J＝16Hz)，6.77(1H，d，J＝8.8Hz)，7.41(2x1H，d，J＝8Hz)，7.65(1H，d，J＝16Hz)，7.70(2x1H，d，J＝8Hz)，7.85(1H，dd，J＝8.8，2.5Hz)，8.20(1H，d，J＝2.5Hz)，9.46(1H，s)；

MASS(ES+)：：m/e 370.

Preparation scheme 85

Compound (85) is by obtaining (6.83g) with preparation scheme 8 similar modes from compound (84).

¹H-NMR(300MHz，DMSO-d ₆，δ)：1.25(3H，t，J＝7Hz)，4.18(2H，q，J＝7Hz)，4.44(2H，s)，6.64(1H，d，J＝16Hz)，7.46(2x1H，d，J＝8Hz)，7.64(1H，d，J＝16Hz)，7.73(2x1H，d，J＝8Hz)，7.80(1H，d，J＝9Hz)，8.20(1H，dd，J＝9，2.2Hz)，8.50(1H，d，J＝2.2Hz)；

MASS(ES+)：m/e 352.

Preparation scheme 86

Compound (86) is by obtaining (872mg) with preparation scheme 77 similar modes from compound (85).

¹H-NMR(300MHz，CDCl ₃，δ)：1.31(3H，br-t，J＝7Hz)，4.15-4.36(4H，m)，6.26(1H，br-d，J＝16Hz)，6.64(1H，m)，6.78(1H，m)，7.20-7.40(5H，m)，7.49(1H，br-d，J＝16Hz)；

MASS(ES+)：m/e 322.

Preparation scheme 87

Under agitation, (618mg) De diox (3mL) solution adds 1N NaOH (2.8mL) then, and the gained mixture stirred 12 hours at ambient temperature (303mg) to add tert-Butyl dicarbonate in De diox (10mL) suspension to compound (86).Vacuum boils off solvent, and resistates distributes between ethyl acetate and water.Organic phase salt water washing, Na ₂SO ₄Drying, vacuum concentration.Resistates by preparation type thin layer chromatography (hexane: ethyl acetate=1: 1) purifying, obtain compound (87) (379mg), be light brown amorphous substance (379mg).

¹H-NMR(300MHz，CDCl ₃，δ)：1.33(3H，t，J＝7Hz)，1.52(4.5H，s)，1.53(4.5H，s)，1.58(4.5H，s)，1.60(4.5H，s)，4.25(2H，q，J＝7Hz)，4.61(2H，s)，6.39(1H，d，J＝16Hz)，6.58(1H，br-d，J＝6Hz)，7.09(0.5H，dd，J＝8.8，2.2Hz)，7.23-7.30(2H，m)，7.42-7.48(2.5H，m)，7.567.68(2H，m)，7.77(0.5H，d，J＝8.8Hz)，8.24(0.5H，br)；

MASS(ES+)：m/e 522.

Preparation scheme 88

Under agitation in compound (87) methyl alcohol (5mL) solution (360mg), add 1NNaOH solution (1.4mL).The gained mixture stirred 2.5 hours at ambient temperature.Reaction mixture neutralizes with 1N HCl solution, and vacuum boils off solvent.Resistates distributes between ethyl acetate and water.Organic phase salt water washing, Na ₂SO ₄Drying, vacuum concentration.Resistates by preparation type thin layer chromatography (chloroform: purifying methyl alcohol=10: 1), obtain compound (88) (57mg), be orange powder, and as the methyl esters of the compound (88) of by product.

¹H-NMR(300MHz，DMSO-d ₆，δ)：1.48(3x3H，s)，4.16(2H，s)，6.49(1H，d，J＝16Hz)，7.12(1H，br)，7.31-7.42(3H，m)，7.55(1H，d，J＝16Hz)，7.60-7.72(3H，m)，9.25(1H，br)，12.12(1H，br)；

MASS(ES+)：m/e 394.

Preparation scheme 89

Compound (89) is pressed and the methyl esters acquisition (245mg) of preparation scheme 12 similar modes from compound (88).[compound (89) is similar with compound (88).]

¹H-NMR(300MHz，DMSO-d ₆，δ)：1.48(3x3H，s)，4.22(2H，s)，6.50(1H，d，J＝16Hz)，7.19(1H，br-d，J＝8.5Hz)，7.34-7.42(3H，m)，7.56(1H，d，J＝16Hz)，7.65(2x1H，d，J＝8.5Hz)，7.72(1H，br-s)，9.30(1H，br-s)，12.38(1H，br)；

MASS(ES+)：m/e 394.

Preparation scheme 90

Compound (90) is by obtaining (230mg) with preparation scheme 9 similar modes from compound (88).Compound (90) is used for embodiment 30.

¹H-NMR(300MHz，DMSO-d ₆，δ)：1.48(3x3H，s)，1.48-1.75(6H，m)，3.53(1H，m)，3.94(1H，m)，4.15(2H，s)，4.90(1H，m)，6.47(1H，br-d，J＝16Hz)，7.06-7.414(4H，m)，7.46(1H，d，J＝16Hz)，7.53(2x1H，br-d，J＝8.5Hz)，7.67(1H，m)，9.15(1/3H，br-s)，9.26(2/3H，br-s)，11.22(1H，br-s)，12.10(2/3H，br-s)，12.13(1/3H，br-s)；

MASS(ES+)：m/e 493.

Preparation scheme 91

Under agitation, add butyric acid (49mg), HOBT (76mg) and EDCI hydrochloride (107mg) in compound (86) DMF (2mL) solution (150mg), the gained mixture stirred 12 hours at ambient temperature.Reaction mixture dilutes with ethyl acetate, successively water, saturated NaHCO ₃Solution and salt water washing.Organic phase Na ₂SO ₄Drying, vacuum concentration.Resistates by preparation type thin layer chromatography (chloroform: purifying methyl alcohol=10: 1), obtain compound (91) (30mg), be light yellow amorphous substance.

¹H-NMR(300MHz，CDCl ₃，δ)：0.98(3H，t，J＝7.3Hz)，1.33(3H，t，J＝7Hz)，1.73(2H，tq，J＝7.3，7.3Hz)，2.33(2H，t，J＝7.3Hz)，4.09(2H，s)，4.24(2H，q，J＝7Hz)，6.31(1H，d，J＝16Hz)，7.05(1H，br-d，J＝8Hz)，7.15(2x1H，d，J＝8Hz)，7.32(2x1H，d，J＝8Hz)，7.36(1H，d，J＝8Hz)，7.53(1H，s)，7.58(1H，s)；

MASS(ES+)：m/e 392.

Preparation scheme 92

Compound (92) is by obtaining (28mg) with preparation scheme 11 similar modes from compound (91).

¹H-NMR(300MHz，CD ₃OD，δ)：1.00(3H，t，J＝7.3Hz)，1.73(2H，tq，J＝7.3，7.3Hz)，2.42(2H，t，J＝7.3Hz)，4.58(2H，s)，6.52(1H，d，J＝16Hz)，7.47-7.58(3H，m)，7.64-7.74(4H，m)，8.29(1H，s)；

MASS(ES+)：m/e 364.

Preparation scheme 93

Compound (93) is by obtaining (19mg) with preparation scheme 9 similar modes from compound (92).Compound (93) is used for embodiment 31.

¹H-NMR(300MHz，CD ₃OD-CDCl ₃，δ)：1.00(3H，t，J＝7.4Hz)，1.52-1.96(8H，m)，2.35(2H，t，J＝7.5Hz)，3.65(1H，m)，4.03(1H，m)，4.11(2H，s)，5.03(1H，m)，6.24(1H，m)，7.06-7.29(4H，m)，7.38(2x1H，d，J＝8.5Hz)，7.48(1H，m)，7.82(1H，s)；

MASS(ES+)：m/e 463.

Preparation scheme 94

Compound (94) is by obtaining (641mg) with preparation scheme 7 similar modes from compound (6).

¹H-NMR(300MHz，DMSO-d ₆，δ)：1.26(3H，t，J＝7Hz)，3.76(2H，s)，4.19(2H，q，J＝7Hz)，6.62(1H，d，J＝16Hz)，6.64(1H，dd，J＝8.5，8.5Hz)，7.12(2H，s)，7.40(2x1H，d，J＝8.5Hz)，7.45(1H，dd，J＝8.5，1Hz)，7.65(1H，d，J＝16Hz)，7.69(2x1H，d，J＝8.5Hz)，7.91(1H ，dd，J＝8.5，1Hz)，9.57(1H，s)；

MASS(ES+)：m/e 370.

Preparation scheme 95

Compound (95) is by obtaining (512mg) with preparation scheme 8 similar modes from compound (94).

¹H-NMR(300MHz，DMSO-d ₆，δ)：1.25(3H，t，J＝7Hz)，4.18(2H，q，J＝7Hz)，4.45(2H，s)，6.62(1H，d，J＝16Hz)，7.46(2x1H，d，J＝8.3Hz)，7.49(1H，dd，J＝8，8Hz)，7.63(1H，d，J＝16Hz)，7.71(2x1H，d，J＝8.3Hz)，8.11(1H，d，J＝8Hz)，8.20(1H，d，J＝8Hz)；

MASS(ES+)：m/e 352.

Preparation scheme 96

Compound (96) is by obtaining (119mg) with preparation scheme 12 similar modes from compound (95).

¹H-NMR(300MHz，DMSO-d ₆，δ)：4.34(2H，s)，6.49(1H，d，J＝16Hz)，7.36(1H，dd，J＝8，8Hz)，7.41(2x1H，d，J＝8Hz)，7.55(1H，d，J＝16Hz)，7.64(2x1H，d，J＝8Hz)，8.04(1H，d，J＝8Hz)，8.09(1H，d，J＝8Hz)，13.26(1H，br-s)；

MASS(ES+)：m/e 324.

Preparation scheme 97

Compound (97) is by obtaining (70mg) with preparation scheme 9 similar modes from compound (96).Compound (97) is used for embodiment 32.

¹H-NMR(300MHz，DMSO-d ₆，δ)：1.45-1.77(6H，m)，3.53(1H，m)，3.95(1H，m)，4.34(2H，s)，4.90(1H，m)，6.47(1H，d，J＝16Hz)，7.37(1H，dd，J＝8，8Hz)，7.42(2x1H，d，J＝8Hz)，7.46(1H，d，J＝16Hz)，7.53(2x1H，d，J＝8Hz)，8.05(1H，d，J＝8Hz)，8.10(1H，d，J＝8Hz)；

MASS(ES+)：m/e 423.

Preparation scheme 98

Compound (98) is by obtaining (160mg) with preparation scheme 7 similar modes from compound (6).

¹H-NMR(300MHz，DMSO-d ₆，δ)：1.26(3H，t，J＝7Hz)，3.75(2H，s)，4.19(2H，q，J＝7Hz)，6.47(2H，br-s)，6.62(1H，d，J＝16Hz)，6.70(1H，d，J＝6Hz)，7.40(2x1H，d，J＝8Hz)，7.65(1H，d，J＝16Hz)，7.69(2x1H，d，J＝8Hz)，7.91(1H，d，J＝6Hz)，8.18(1H，s)，9.61(1H，s)；

MASS(ES+)：m/e 326.

Preparation scheme 99

Compound (99) is by obtaining (91mg) with preparation scheme 8 similar modes from compound (6).

¹H-NMR(300MHz，DMSO-d ₆，δ)：4.26(2H，s)，6.50(1H，d，J＝16Hz)，7.38(2x1H，d，J＝8Hz)，7.48(1H，m)，7.56(1H，d，J＝16Hz)，7.65(2x1H，d，J＝8Hz)，8.25(1H，d，J＝3Hz)，8.81(1H，s)，12.75(1H，br)；

MASS(ES+)：m/e 280.

Preparation scheme 100

Compound (100) is by obtaining (33mg) with preparation scheme 9 similar modes from compound (99).Compound (100) is used for embodiment 33.

¹H-NMR(300MHz，DMSO-d ₆，δ)：1.40-1.80(6H，m)，3.52(1H，m)，3.96(1H，m)，4.26(2H，s)，4.91(1H，m)，6.50(1H，br-d，J＝15.5Hz)，7.35-7.60(6H，m)，8.22(1H，d，J＝5.5Hz)，8.81(1H，s)；

MASS(ES+)m/e 379.

Preparation scheme 101

Compound (101) is by obtaining (520mg) with preparation scheme 7 similar modes from compound (6).

¹H-NMR(300MHz，DMSO-d ₆，δ)：1.26(3H，t，J＝7Hz)，3.11(3H，s)，3.31(3H，s)，3.62(2H，s)，4.19(2H，q，J＝7Hz)，6.54-6.68(3H，m)，7.41(2x1H，d，J＝8Hz)，7.58-7.70(3H，m)，8.66(1H，s)；

MASS(ES+)：m/e 387.

Preparation scheme 102

Compound (102) is by obtaining (416mg) with preparation scheme 8 similar modes from compound (101).

¹H-NMR(300MHz，DMSO-d ₆，δ)：3.22(3H，s)，3.40(3H，s)，4.08(2H，s)，6.49(1H，d，J＝16Hz)，7.33(2x1H，d，J＝8.3Hz)，7.55(1H，d，J＝16Hz)，7.64(2x1H，d，J＝8、3Hz)，12.39(1H，s)，13.48(1H，s)；

MASS(ES+)：m/e 341.

Preparation scheme 103

Compound (103) is by obtaining (254mg) with preparation scheme 9 similar modes from compound (102).Compound (103) is used for embodiment 34.

¹H-NMR(300MHz，DMSO-d ₆，δ)：1.46-1.76(6H，m)，3.22(3H，s)，3.40(3H，s)，3.53(1H，m)，3.95(1H，m)，4.07(2H，s)，4.90(1H，m)，6.47(1H，d，J＝16Hz)，7.33(2x1H，d，J＝7.5Hz)，7.46(1H，d，J＝16Hz)，7.53(2x1H，d，J＝7.5Hz)，11.23(1H，br-s)，13.47(1H，br-s)；

MASS(ES-)：m/e 438.

Preparation scheme 104

Compound (104) is by obtaining (1.54g) with preparation scheme 12 similar modes from compound (85).

¹H-NMR(300MHz，DMSO-d ₆，δ)：4.38(2H，s)，6.52(1H，d，J＝16.2Hz)，7.42(2x1H，d，J＝8Hz)，7.57(1H，d，J＝16.2Hz)，7.68(2x1H，d，J＝8Hz)，7.74(1H，d，J＝8.8Hz)，8.14(1H，dd，J＝8.8，2.2Hz)，8.46(1H，d，J＝2.2Hz)；

MASS(ES+)：m/e 324.

Preparation scheme 105

Compound (105) is by obtaining (1.42g) with preparation scheme 9 similar modes from compound (104).Compound (105) is used for embodiment 35.

¹H-NMR(300MHz，DMSO-d ₆，δ)：1.45-1.76(6H，m)，3.53(1H，m)，3.95(1H，m)，4.30(2H，s)，4.90(1H，m)，6.48(1H，d，J＝15.8Hz)，7.39(2x1H，d，J＝8.5Hz)，7.47(1H，d，J＝15.8Hz)，7.55(2x1H，d，J＝8.5Hz)，7.67(1H，d，J＝8.8Hz)，8.08(2x1H，d，J＝8.8Hz)，8.41(1H，d，J＝2.2Hz)，11.25(1H，br)，13.02(1H，br)；

MASS(ES+)：m/e 423.

Preparation scheme 106

Under 0 ℃ of stirring, (1.75mL) is added drop-wise in the methyl alcohol with thionyl chloride.After 30 minutes, add 4-hydroxycinnamic acid (3.29g), the gained mixture refluxed 1.5 hours.Vacuum boils off solvent, and resistates crystallization from diisopropyl ether and hexane obtains compound (106) (2.41g), is white crystal.

¹H-NMR(300MHz，CDCl ₃，δ)：3.80(3H，s)，5.44(1H，s)，6.31(1H，d，J＝16Hz)，6.85(2x1H，d，J＝8.5Hz)，7.43(2x1H，d，J＝8.5Hz)，7.64(1H，d，J＝16Hz)；

MASS(ES-)：m/e 177.

Preparation scheme 107

Under 0 ℃ of stirring, in compound (106) dimethyl formamide (15mL) solution (609mg), add sodium hydride (164mg, 60% oil dispersion).After 30 minutes, dripping bromine tert.-butyl acetate (733mg), gained mixture stirred 2 hours at ambient temperature.The gained mixture is poured in 10% citric acid solution, used ethyl acetate extraction.The saturated NaHCO of organic phase ₃Solution and salt water washing, dried over sodium sulfate, vacuum concentration.Resistates by chromatography (hexane: ethyl acetate=4: 1) purifying, obtain compound (107) (962mg), be solid.

¹H-NMR(300MHz，CDCl ₃，δ)：1.49(3x3H，s)，3.80(3H，s)，4.55(2H，s)，6.32(1H，d，J＝15.8Hz)，6.90(2x1H，d，J＝8.8Hz)，7.47(2x1H，d，J＝8.8Hz)，7.65(1H，d，J＝15.8Hz)；

MASS (ES+): m/e undetermined.

Preparation scheme 108

Under 60 ℃, with compound (107) 0.5N hydrogenchloride/acetate (10mL) solution heating (906mg) 2 hours.Vacuum boils off solvent, and resistates grinds with diisopropyl ether, obtains compound (108) (645mg), is white solid.

¹H-NMR(300MHz，DMSO-d ₆，δ)：3.71(3H，s)，4.74(2H，s)，6.51(1H，d，J＝16Hz)，6.96(2x1H，d，J＝8.5Hz)，7.62(1H，d，J＝16Hz)，7.67(2x1H，d，J＝8.5Hz)，13.07(1H，br-s)；

MASS(ES-)：m/e 235.

Preparation scheme 109

Compound (109) is by obtaining (950mg) with preparation scheme 7 similar modes from compound (108).

¹H-NMR(300MHz，DMSO-d ₆，δ)：1.45(3x3H，s)，3.71(3H，s)，4.79(2H，s)，6.53(1H，d，J＝16Hz)，7.07(2x1H，d，J＝8.8Hz)，7.08-7.20(2H，m)，7.46(1H，m)，7.56(1H，m)，7.63(1H，d，J＝16Hz)，7.72(2x1H，d，J＝8.8Hz)，8.73(1H，br-s)，9.55(1H，br-s)；

MASS(ES+)：m/e 427.

Preparation scheme 110

Compound (110) is by obtaining (800mg) with preparation scheme 8 similar modes from compound (109).

¹H-NMR(300MHz，DMSO-d ₆，δ)：3.71(3H，s)，5.69(2H，s)，6.56(1H，d，J＝16Hz)，7.20(2x1H，d，J＝8.8Hz)，7.49-7.57(2H，m)，7.65(1H，d，J＝16Hz)，7.73-7.85(4H，m)；

MASS(ES+)：m/e 309.

Preparation scheme 111

Compound (111) is by obtaining (580mg) with preparation scheme 12 similar modes from compound (110).

¹H-NMR(300MHz，DMSO-d ₆，δ)：5.45(2H，s)，6.41(1H，d，J＝16Hz)，7.14(2x1H，d，J＝8.8Hz)，7.23-7.32(2H，m)，7.55(1H，d，J＝16Hz)，7.56-7.66(2H，m)，7.68(2x1H，d，J＝8.8Hz)，12.28(1H，br)；

MASS(ES+)：m/e 295.

Preparation scheme 112

Compound (112) is by obtaining (503mg) with preparation scheme 9 similar modes from compound (111).Compound (112) is used for embodiment 36.

¹H-NMR(300MHz，DMSO-d ₆，δ)：1.47-1.76(6H，m)，3.53(1H，m)，3.95(1H，m)，4.89(1H，m)，5.37(2H，s)，6.37(1H，d，J＝16Hz)，7.10-7.25(4H，m)，7.39-7.67(5H，m)，11.16(1H，s)，12.68(1H，s)；

MASS(ES+)：m/e 394.

Preparation scheme 113

Under agitation, in compound (86) methyl alcohol (3mL) solution (165mg), add cyclopentanone (52mg) and sodium cyanoborohydride (39mg).Add acetate to the gained mixture, make final pH transfer to 5.The gained mixture was stirred 2 hours at ambient temperature.Gained is poured in the water, used ethyl acetate extraction.Organic phase salt water washing, dried over mgso, vacuum concentration.Resistates by preparation type thin layer chromatography (chloroform: purifying methyl alcohol=10: 1), obtain compound (113) (140mg), be brown oil.

¹H-NMR(300MHz，CDCl ₃，δ)：1.34(3H，t，J＝7.3Hz)，1.40-1.77(6H，m)，1.95-2.08(2H，m)，3.76(1H，m)，4.24(2H，s)，4.26(2H，q，J＝7.3Hz)，6.41(1H，d，J＝16Hz)，6.56(1H，dd，J＝7，2.2Hz)，6.64(1H，s)，7.31(2x1H，d，J＝8Hz)，7.36(1H，d，J＝8.8Hz)，7.48(2x1H，d，J＝8Hz)，7.65(1H，d，J＝16Hz)；

MASS(ES+)：m/e 390.

Preparation scheme 114

Compound (114) is by obtaining (91mg) with preparation scheme 12 similar modes from compound (113).

¹H-NMR(300MHz，DMSO-d ₆，δ)：1.36-1.76(6H，m)，1.89(2H，m)，4.08(2H，s)，6.44-6.56(3H，m)，7.17(1H，m)，7.34(2x1H，d，J＝8Hz)，7.55(1H，d，J＝16Hz)，7.62(2x1H，d，J＝8Hz)，11.72(1H，br)；

MASS(ES+)：m/e 362.

Preparation scheme 115

Compound (115) is by obtaining (40mg) with preparation scheme 9 similar modes from compound (114).Compound (115) is used for embodiment 37.

¹H-NMR(300MHz，CDCl ₃，δ)：1.38-2.08(14H，m)，3.62(1H，m)，3.75(1H，m)，4.00(1H，m)，4.11(2H，s)，5.08(1H，m)，6.20(1H，br)，6.56(1H，d，J＝8Hz)，6.68(1H，s)，6.94-7.55(6H，m)；

MASS(ES+)：m/e 461.

Preparation scheme 116

Compound (116) is by obtaining (1.77g) with preparation scheme 106 similar modes.

¹H-NMR(300MHz，DMSO-d ₆，δ)：3.72(3H，s)，6.53(1H，d，J＝16Hz)，6.84(1H，br-dd，J＝8，2Hz)，7.04(1H，br-d，J＝2Hz)，7.14(1H，br-d，J＝8Hz)，7.22(1H，dd，J＝8，8Hz)，7.57(1H，d，J＝16Hz)，9.63(1H，s)；

MASS(ES-)：m/e 177.

Preparation scheme 117

Compound (117) is by obtaining (1.61g) with preparation scheme 107 similar modes from compound (116).

¹H-NMR(300MHz，CDCl ₃，δ)：1.49(3x3H，s)，3.81(3H，s)，4.54(2H，s)，6.41(1H，d，J＝16Hz)，6.92(1H，dd，J＝8，2.5Hz)，7.04(1H，dd，J＝2.5，2.5Hz)，7.15(1H，br-d，J＝8Hz)，7.31(1H，dd，J＝8，8Hz)，7.64(1H，d，J＝16Hz)；

MASS (ES+): m/e undetermined.

Preparation scheme 118

Compound (118) is by obtaining (1.25g) with preparation scheme 8 similar modes from compound (117).

¹H-NMR(300MHz，CDCl ₃，δ)：3.82(3H，s)，4.72(2H，s)，6.43(1H，d，J＝16Hz)，6.96(1H，dd，J＝8，2.5Hz)，7.07(1H，br-s)，7.20(1H，br-d，J＝8Hz)，7.34(1H，dd，J＝8，8Hz)，7.65(1H，d，J＝16Hz)；

MASS(ES-)：m/e 235.

Preparation scheme 119

Compound (119) is by obtaining (1.92g) with preparation scheme 7 similar modes from compound (118).

¹H-NMR(300MHz，CDCl ₃，δ)：1.49(3x3H，s)，3.82(3H，s)，4.69(2H，s)，6.45(1H，d，J＝16Hz)，6.69(1H，br-s)，7.03(1H，dd，J＝8，2.5Hz)，7.15-7.26(4H，m)，7.37(1H，dd，J＝8，8Hz)，7.41(1H，m)，7.63(1H，m)，7.66(1H，d，J＝16Hz)，9.00(1H，br-s)；

MASS(ES+)：m/e 427.

Preparation scheme 120

Compound (120) is by obtaining (1.67g) with preparation scheme 8 similar modes from compound (119).

¹H-NMR(300MHz，DMSO-d ₆，δ)：3.74(3H，s)，5.68(2H，s)，6.74(1H，d，J＝16Hz)，7.21(1H，m)，7.40-7.46(2H，m)，7.49-7.59(3H，m)，7.68(1H，d，J＝16Hz)，7.77-7.85(2H，m)；

MASS(ES+)：m/e 309.

Preparation scheme 121

Compound (121) is by obtaining (1.24g) with preparation scheme 12 similar modes from compound (120).

¹H-NMR(300MHz，DMSO-d ₆，δ)：5.37(2H，s)，6.58(1H，d，J＝16Hz)，7.11-7.26(3H，m)，7.27-7.40(2H，m)，7.45(1H，br-s)，7.50(1H，m)，7.57(1H，d，J＝16Hz)，7.63(1H，m)，12.69(1H，s)；

MASS(ES+)：m/e 295.

Preparation scheme 122

Compound (122) is by obtaining (1662mg) with preparation scheme 9 similar modes from compound (120).Compound (122) is used for embodiment 38.

¹H-NMR(300MHz，DMSO-d ₆，δ)：1.46-1.78(6H，m)，3.54(1H，m)，3.96(1H，m)，4.91(1H，m)，5.36(2H，s)，6.53(1H，d，J＝16Hz)，7.12(1H，dd，J＝8，2.5Hz)，7.15-7.26(3H，m)，7.32(1H，br-s)，7.36(1H，dd，J＝8，8Hz)，7.46-7.68(2H，m)，7.47(1H，d，J＝16Hz)，11.27(1H，br-s)，12.69(1H，br-s)；

MASS(ES+)：m/e 394.

Preparation scheme 123

Compound (123) is by obtaining (415mg) with preparation scheme 113 similar modes from compound (86).

¹H-NMR(300MHz，CDCl ₃，δ)：1.12(2x3H，t，J＝7Hz)，1.34(3H，t，J＝7Hz)，3.34(2x2H，q，J＝7Hz)，4.23(2H，s)，4.26(2H，q，J＝7Hz)，6.39(1H，d，J＝16Hz)，6.79(1H，dd，J＝9，2Hz)，6.91(1H，d，J＝2Hz)，7.30(2x1H，d，J＝8Hz)，7.44(1H，d，J＝9Hz)，7.45(2x1H，d，J＝8Hz)，7.63(1H，d，J＝16Hz)；

MASS(ES+)：m/e 378.

Preparation scheme 124

Compound (124) is by obtaining (227mg) with preparation scheme 12 similar modes from compound (123).

¹H-NMR(300MHz，DMSO-d ₆，δ)：1.05(2x3H，t，J＝7Hz)，3.28(2x2H，q，J＝7Hz)，4.12(2H，s)，6.49(1H，d，J＝16Hz)，6.61-6.72(2H，m)，7.28(1H，br-d，J＝8Hz)，7.35(2x1H，d，J＝8Hz)，7.56(1H，d，J＝16Hz)，7.63(2x1H，d，J＝8Hz)，11.82(1H，br-s)；

MASS(ES+)：m/e 350.

Preparation scheme 125

Compound (125) is by obtaining (132mg) with preparation scheme 9 similar modes from compound (124).Compound (125) is used for embodiment 39.

¹H-NMR(300MHz，CDCl ₃，δ)：1.12(2x3H，t，J＝7Hz)，1.50-1.92(6H，m)，3.32(2x3H，q，J＝7Hz)，3.62(1H，m)，4.00(1H，m)，4.15(2H，br-s)，5.07(1H，m)，6.22(1H，br)，6.71-6.83(2H，m)，6.96-7.28(3H，m)，7.38-7.54(3H，m)；

MASS(ES+)：m/e 449.

Preparation scheme 126

Compound (126) is by obtaining (4.19g) with preparation scheme 106 similar modes.

¹H-NMR(300MHz，CDCl ₃，δ)：3.80(3H，s)，3.93(3H，s)，5.85(1H，br-s)，6.30(1H，d，J＝16Hz)，6.92(1H，d，J＝8Hz)，7.03(1H，d，J＝2Hz)，7.08(1H，dd，J＝8，2Hz)，7.63(1H，d，J＝16Hz)；

MASS (ES+): m/e undetermined.

Preparation scheme 127

Compound (127) is by obtaining (5.16g) with preparation scheme 107 similar modes from compound (126).

¹H-NMR(300MHz，CDCl ₃，δ)：1.47(3x3H，s)，3.80(3H，s)，3.92(3H，s)，4.62(2H，s)，6.32(1H，d，J＝16Hz)，6.76(1H，d，J＝8.7Hz)，7.04-7.09(2H，m)，7.63(1H，d，J＝16Hz)；

MASS (ES+): m/e undetermined.

Preparation scheme 128

Compound (128) is by obtaining (4.28g) with preparation scheme 8 similar modes from compound (127).

¹H-NMR(300MHz，CDCl ₃，δ)：3.81(3H，s)，3.93(3H，s)，4.74(2H，s)，6.35(1H，d，J＝16Hz)，6.89(1H，d，J＝9Hz)，7.07-7.12(2H，m)，7.63(1H，d，J＝16Hz)；

MASS(ES-)：m/e 265.

Preparation scheme 129

Compound (129) is by obtaining (5.43g) with preparation scheme 7 similar modes from compound (128).

¹H-NMR(300MHz，DMSO-d ₆，δ)：1.42(3x3H，s)，3.72(3H，s)，3.86(3H，s)，4.76(2H，s)，6.61(1H，d，J＝16Hz)，7.02(1H，d，J＝8.5Hz)，7.08-7.19(2H，m)，7.25(1H，dd，J＝8.5，2Hz)，7.40-7.48(2H，m)，7.57-7.66(2H，m)，8.71(1H，s)，9.46(1H，s)；

MASS(ES+)：m/e 457.

Preparation scheme 130

Compound (130) is by obtaining (4.35g) with preparation scheme 8 similar modes from compound (129).

¹H-NMR(300MHz，DMSO-d ₆，δ)：3.72(3H，s)，3.85(3H，s)，5.67(2H，s)，6.65(1H，d，J＝16Hz)，7.20-7.32(2H，m)，7.49(1H，s)，7.54-7.62(2H，m)，7.63(1H，d，J＝16Hz)，7.80-7.88(2H，m)；

MASS(ES+)：m/e 339.

Preparation scheme 131

Compound (131) is by obtaining (1.63g) with preparation scheme 12 similar modes from compound (130).

¹H-NMR(300MHz，DMSO-d ₆，δ)：3.83(3H，s)，5.33(2H，s)，6.47(1H，d，J＝16Hz)，7.14-7.26(4H，m)，7.36(1H，s)，7.50(1H，m)，7.52(1H，d，J＝16Hz)，7.63(1H，m)，12.70(1H，s)；

MASS(ES+)：m/e 325.

Preparation scheme 132

Compound (132) is by obtaining (1.93g) with preparation scheme 9 similar modes from compound (131).Compound (132) is used for embodiment 40.

¹H-NMR(300MHz，DMSO-d ₆，δ)：1.45-1.77(6H，m)，3.53(1H，m)，3.82(3H，s)，3.95(1H，m)，4.90(1H，m)，5.32(2H，s)，6.41(1H，d，J＝16Hz)，7.10-7.28(5H，m)，7.43(1H，d，J＝16Hz)，7.50(1H，m)，7.62(1H，m)，11.13(1H，s)，12.69(1H，s)；

MASS(ES+)：m/e 424.

Preparation scheme 133

Compound (133) is by obtaining (437mg) with preparation scheme 113 similar modes from compound (86).

¹H-NMR(300MHz，CDCl ₃，δ)：1.34(3H，t，J＝7Hz)，2.92(2x3H，s)，4.21(2H，s)，4.26(2H，q，J＝7Hz)，6.39(1H，d，J＝16Hz)，6.75-6.84(2H，m)，7.24-7.32(2H，m)，7.42-7.50(3H，m)，7.63(1H，d，J＝16Hz)；

MASS(ES+)：m/e 350.

Preparation scheme 134

The ethyl carbonyl of compound (133) is pressed and preparation scheme 12 similar mode deprotections.Gained compound (300mg) is suspended in the diox (10mL).(407mg) De diox (4mL) solution, the gained mixture stirred 12 hours at ambient temperature to add 1NNaOH (3mL) and tert-Butyl dicarbonate in suspension.Add other tert-Butyl dicarbonate (407mg) and 1N NaOH (3mL), the gained mixture stirred 6 hours at ambient temperature.Vacuum boils off solvent, and resistates distributes between diisopropyl ether and water.To pH5, collecting precipitation washes with water water with hcl acidifying, obtains compound (134) (326mg), is light brown powder.Gained compound (134) is used for embodiment 41.

¹H-NMR(300MHz，CDCl ₃，δ)：1.45-1.95(15H，m)，2.94-3.03(6H，m)，3.65(1H，m)，3.96(1H，m)，4.54-4.64(2H，m)，5.00(1H，m)，6.30-7.80(9H，m)；

MASS(ES+)m/e 521.

Preparation scheme 135

Compound (135) is by obtaining (2.11g) with preparation scheme 106 similar modes.

¹H-NMR(300MHz，CDCl ₃，δ)：3.79(3H，s)，3.93(3H，s)，6.30(1H，d，J＝16Hz)，6.85(1H，d，J＝8Hz)，7.03(1H，dd，J＝8，2Hz)，7.14(1H，d，J＝2Hz)，7.60(1H，d，J＝16Hz)；

MASS(ES+)：m/e 209.

Preparation scheme 136

Compound (136) is by obtaining (3.12g) with preparation scheme 107 similar modes from compound (135).

¹H-NMR(300MHz，CDCl ₃，δ)：1.48(3x3H，s)，3.79(3H，s)，3.91(3H，s)，4.61(2H，s)，6.26(1H，d，J＝16Hz)，6.89(1H，d，J＝8.3Hz)，6.97(1H，d，J＝2Hz)，7.14(1H，dd，J＝8.3，2Hz)，7.60(1H，d，J＝16Hz)；

MASS(ES+)：m/e 323.

Preparation scheme 137

Compound (137) is by obtaining (2.03g) with preparation scheme 8 similar modes from compound (136).

¹H-NMR(300MHz，DMSO-d ₆，δ)：3.71(3H，s)，3.81(3H，s)，4.75(2H，s)，6.54(1H，d，J＝16Hz)，7.01(1H，d，J＝8Hz)，7.27(1H，dd，J＝8，2Hz)，7.31(1H，d，J＝2Hz)，7.57(1H，d，J＝16Hz)，12.87(1H，br)；

MASS(ES+)：m/e 267.

Preparation scheme 138

Compound (138) is by obtaining (2.97g) with preparation scheme 8 similar modes from compound (137).

¹H-NMR(300MHz，CDCl ₃，δ)：1.47(3x3H，s)，3.80(3H，s)，3.93(3H，s)，4.72(2H，s)，6.33(1H，d，J＝16Hz)，6.95(1H，d，J＝8Hz)，6.96(1H，br)，7.12-7.29(4H，m)，7.47(1H，br-d，J＝7.5Hz)，7.62(1H，d，J＝16Hz)，7.64(1H，br-d，J＝7.5Hz)，9.02(1H，s)；

MASS(ES+)m/e 457.

Preparation scheme 139

Compound (139) is by obtaining (2.29g) with preparation scheme 7 similar modes from compound (138).

¹H-NMR(300MHz，DMSO-d ₆，δ)：3.71(3H，s)，3.83(3H，s)，5.63(2H，s)，6.61(1H，d，J＝16Hz)，7.11(1H，d，J＝8.4Hz)，7.42(1H，dd，J＝8.4，2Hz)，7.50-7.58(2H，m)，7.61(1H，d，J＝16Hz)，7.65(1H，d，J＝2Hz)，7.78-7.96(2H，m)；

MASS(ES+)m/e 339.

Preparation scheme 140

Compound (140) is by obtaining (1.84g) with preparation scheme 12 similar modes from compound (139).

¹H-NMR(300MHz，DMSO-d ₆，δ)：3.81(3H，s)，5.36(2H，s)，6.45(1H，d，J＝16Hz)，7.04(1H，d，J＝8.8Hz)，7.20-7.28(2H，m)，7.28(1H，dd，J＝8.8，2Hz)，7.52(1H，d，J＝16Hz)，7.55-7.64(2H，m)，7.57(1H，d，J＝2Hz)，12.26(1H，br-s)；

MASS(ES+)m/e 325.

Preparation scheme 141

Compound (141) is by obtaining (609mg) with preparation scheme 9 similar modes from compound (140).Compound (141) is used for embodiment 42.

¹H-NMR(300MHz，DMSO-d ₆，δ)：1.42-1.78(6H，m)，3.53(1H，m)，3.81(3H，s)，3.96(1H，m)，4.90(1H，m)，5.32(2H，s)，6.40(1H，br-d，J＝16Hz)，7.05(1H，d，J＝8.4Hz)，7.16-7.26(3H，m)，7.36-7.47(2H，m)，7.50-7.66(2H，m)，11.18(1H，br)，12.69(1H，br)；

MASS(ES+)m/e 424.

Preparation scheme 142

Compound (142) is by obtaining (400mg) with preparation scheme 7 similar modes from compound (6).

¹H-NMR(300MHz，CDCl ₃，δ)：1.54(9H，s)，3.76(2H，s)，5.86(2H，s)，6.33(1H，s)，6.38(1H，d，J＝16.1Hz)，6.77(1H，s)，7.37(2H，d，J＝8.1Hz)，7.54(2H，d，J＝8.1Hz)，7.58(1H，d，J＝16.5Hz)；

MASS(ES+)：m/e 397(M+1).

Preparation scheme 143

Compound (143) is by obtaining (305mg) with preparation scheme 8 similar modes from compound (142).

¹H-NMR(300MHz，DMSO-d ₆，δ)：4.44(2H，s)，6.15(2H，s)，6.55(1H，d，J＝16.2Hz)，7.29(2H，s)，7.42(2H，d，J＝8.1Hz)，7.58(1H，d，J＝15.7Hz)，7.72(2H，d，J＝8.4Hz)；

MASS(ES+)：m/e 323(M+1).

Preparation scheme 144

Compound (144) is by obtaining (196mg) with preparation scheme 9 similar modes from compound (143).Compound (144) is used for embodiment 43.

¹H-NMR(300MHz，DMSO-d ₆，δ)：1.53(3H，br)，1.69(3H，br)，3.53(1H，m)，3.95(1H，m)，4.11(2H，s)，4.90(1H，s)，5.95(2H，s)，6.46(1H，d，J＝15.4Hz)，6.96(1H，s)，7.03(1H，s)，7.34(2H，d，J＝8.1Hz)，7.46(1H，d，J＝15.8Hz)，7.52(2H，d，J＝8.1Hz)；

MASS(ES+)：m/e 422(M+1).

Preparation scheme 145

Compound (145) is by obtaining (460mg) with preparation scheme 7 similar modes from compound (6).

¹H-NMR(300MHz，CDCl ₃，δ)：(1∶1mixture)1.54(9H，s)，3.71(3H，s)，3.82(2H，s)，6.30(1H，d，J＝8.1Hz)，6.39(1H，d，J＝16.1Hz)，6.41(1H，d，J＝8.0Hz)，6.98(1H，t，J＝8.4Hz)，7.40(2H，d，J＝8.4Hz)，7.54(2H，d，J＝8.4Hz)，7.59(1H，d，J＝15.7Hz)，1.54(9H，s)，3.77(2H，s)，3.83(3H，s)，6.37(1H，d，J＝15.8Hz)，6.65-6.74(sH，m)，6.80(1H，dd，J＝7.7，1.8Hz)，7.37(2H，d，J＝8.4Hz)，7.53(2H，d，J＝8.4Hz)，7.57(1H，d，J＝17.2Hz)；

MASS(ES+)：m/e 383(M+1).

Preparation scheme 146

Compound (146) is by obtaining (326mg) with preparation scheme 8 similar modes from compound (145).

¹H-NMR(300MHz，DMSO-d ₆，δ)：4.00(3H，s)，4.44(2H，s)，6.54(1H，d，J＝15.7Hz)，7.06(1H，d，J＝8.7Hz)，7.24(1H，d，J＝8.1Hz)，7.40(1H，t，J＝8.1Hz)，7.44(2H，d，J＝8.4Hz)，7.58(1H，d，J＝16.0Hz)，7.71(2H，d，J＝8.2Hz)；

MASS(ES+)：m/e 309(M+1).

Preparation scheme 147

Compound (147) is by obtaining (308mg) with preparation scheme 9 similar modes from compound (146).Compound (147) is used for embodiment 44.

¹H-NMR(300MHz，CDCl ₃，δ)：1.53(3H，br)，1.69(3H，br)，3.52(1H，m)，3.90(3H，s)，3.95(1H，m)，4.15(2H，s)，4.90(1H，s)，6.46(1H，d，J＝16.2Hz)，6.68(1H，br)，7.04(2H，m)，7.35(2H，d，J＝8.0Hz)，7.45(1H，d，J＝16.4Hz)，7.52(2H，d，J＝8.0Hz)；

MASS(ES+)：m/e 408(M+1).

Preparation scheme 148

Compound (148) is by obtaining (929mg) with preparation scheme 6 similar modes.

¹H-NMR(300MHz，CDCl ₃，δ)：1.50(3H，d，J＝6.9Hz)，1.53(9H，s)，3.75(1H，q，J＝7.1Hz)，6.33(1H，d，J＝16.1Hz)，7.32(2H，d，J＝8.5Hz)，7.45(2H，d，J＝8.1Hz)，7.55(1H，d，J＝16.1Hz)；

MASS (ES+): undetermined.

Preparation scheme 149

Compound (149) is by obtaining (1.09g) with preparation scheme 7 similar modes from compound (148).

¹H-NMR(300MHz，CDCl ₃，δ)：1.54(9H，s)，1.60(3H，d，J＝7.0Hz)，3.79(1H，q，J＝7.0Hz)，6.36(1H，d，J＝16.0Hz)，6.70-6.78(2H，m)，6.98-7.04(1H，m)，7.08-7.15(1H，m)，7.40(2H，d，J＝8.6Hz)，7.51(2H，d，J＝8.4Hz)，7.56(1H，d，J＝16.0Hz)；

MASS(ES+)：m/e 367(M+1).

Preparation scheme 150

Compound (150) is by obtaining (567mg) with preparation scheme 8 similar modes from compound (149).

¹H-NMR(300MHz，DMSO-d ₆，δ)：1.86(3H，d，J＝7.0Hz)，4.83(1H，q，J＝7.0Hz)，6.55(1H，d，J＝15.8Hz)，7.49(2H，d，J＝8.1Hz)，7.52-7.55(2H，m)，7.58(1H，d，J＝16.4Hz)，7.73(2H，d，J＝8.1Hz)，7.76-7.79(2H，m)；

MASS(ES+)：m/e 293(M+1).

Preparation scheme 151

Compound (151) is by obtaining (598mg) with preparation scheme 9 similar modes from compound (150).Compound (151) is used for embodiment 45.

¹H-NMR(300MHz，DMSO-d ₆，δ)：1.53(3H，br)，1.68(3H，br)，1.70(3H，d，J＝7.3Hz)，3.52(1H，m)，3.93(1H，m)，4.41(1H，q，J＝7.0Hz)，4.89(1H，s)，6.47(1H，d，J＝16.5Hz)，7.08-7.15(2H，m)，7.34-7.40(2H，m)，7.37(2H，d，J＝8.3Hz)，7.44(1H，d，J＝16.5Hz)，7.52(2H，d，J＝8.0Hz)；

MASS(ES+)：m/e 392(M+1).

Preparation scheme 152

Compound (152) is by obtaining (1.2g) with preparation scheme 6 similar modes.

¹H-NMR(300MHz，CDCl ₃，δ)：1.51(3H，d，J＝6.9Hz)，1.53(9H，s)，3.76(1H，q，J＝7.1Hz)，6.34(1H，d，J＝16.0Hz)，7.33(2H，d，J＝8.5Hz)，7.47(2H，d，J＝81Hz)，7.56(1H，d，J＝16.0Hz)；

MASS (ES+): undetermined.

Preparation scheme 153

Compound (153) is by obtaining (1.298g) with preparation scheme 7 similar modes from compound (152).

¹H-NMR(300MHz，CDCl ₃，δ)：1.54(9H，s)，1.61(3H，d，J＝7.0Hz)，3.79(1H，q，J＝7.0Hz)，6.36(1H，d，J＝16.0Hz)，6.70-6.75(2H，m)，6.97-7.05(1H，m)，7.09-7.14(1H，m)，7.24(2H，d，J＝8.4Hz)，7.51(2H，d，J＝8.5Hz)，7.56(1H，d，J＝16.2Hz)；

MASS(ES+)：m/e 367(M+1).

Preparation scheme 154

Compound (154) is by obtaining (611mg) with preparation scheme 8 similar modes from compound (153).

¹H-NMR(300MHz，DMSO-d ₆，δ)：1.86(3H，d，J＝7.4Hz)，4.83(1H，q，J＝7.1Hz)，6.55(1H，d，J＝15.7Hz)，7.49(2H，d，J＝8.0Hz)，7.52-7.55(2H，m)，7.58(1H，d，J＝16.2Hz)，7.74(2H，d，J＝8.4Hz)，7.76-7.79(2H，m)；

MASS(ES+)：m/e 293(M+1).

Preparation scheme 155

Compound (155) is by obtaining (700mg) with preparation scheme 9 similar modes from compound (154).Compound (155) is used for embodiment 46.

¹H-NMR(300MHz，DMSO-d ₆，δ)：1.52(3H，br)，1.68(3H，br)，1.70(3H，d，J＝6.9Hz)，3.50(1H，m)，3.93(1H，m)，4.41(1H，q，J＝7.1Hz)，4.89(1H，s)，6.48(1H，d，J＝16.1Hz)，7.08-7.14(2H，m)，7.34-7.40(2H，m)，7.37(2H，d，J＝8.3Hz)，7.47(2H，d，J＝16.1Hz)，7.51(2H，d，J＝8.9Hz)；

MASS(ES+)：m/e 392(M+1).

Preparation scheme 156

Compound (156) is by obtaining (536mg) with preparation scheme 7 similar modes.

¹H-NMR(300MHz，CDCl ₃，δ)：1.34(3H，t，J＝7.0Hz)，1.46(9H，s)，1.48(9H，s)，4.05(2H，q，J＝7.0Hz)，6.50(1H，d，J＝16.1Hz)，6.98(2H，d，J＝8.4Hz)，7.01(1H，d，J＝7.7Hz)，7.40(2H，d，J＝7.7Hz)，7.50(2H，d，J＝8.8Hz)，7.52(1H，d，J＝8.4Hz)，7.55(1H，d，J＝16.3Hz)，7.66(2H，d，J＝8.1Hz)，7.68(1H，s)；

MASS(ES+)：m/e 573(M+1).

Preparation scheme 157

Compound (157) is by obtaining (345mg) with preparation scheme 8 similar modes from compound (156).

¹H-NMR(300MHz，DMSO-d ₆，δ)：1.36(3H，t，J＝7.0Hz)，4.08(2H，q，J＝7.0Hz)，4.55(2H，s)，6.56(1H，d，J＝16.1Hz)，7.05(2H，d，J＝8.8Hz)，7.49(2H，d，J＝8.4Hz)，7.60(1H，d，J＝16.1Hz)，7.65(2H，d，J＝9.1Hz)，7.74(2H，d，J＝8.4Hz)，7.77(2H，m)，7.88(1H，s)；

MASS(ES+)：m/e 399(M+1).

Preparation scheme 158

Compound (158) is by obtaining (370mg) with preparation scheme 9 similar modes from compound (157).Compound (158) is used for embodiment 47.

¹H-NMR(300MHz，DMSO-d ₆，δ)：1.35(3H，t，J＝7.0Hz)，1.54(3H，br)，1.68(3H，br)，3.53(1H，m)，3.94(1H，m)，4.06(2H，q，J＝7.0Hz)，4.21(2H，s)，4.90(1H，s)，6.48(1H，d，J＝16.1Hz)，7.00(2H，dd，J＝8.8，2.2Hz)，7.38(3H，m)，7.44(1H，s)，7.50(1H，m)，7.53-7.60(5H，m)，7.72(1H，s)；

MASS(ES+)：m/e 498(M+1).

Preparation scheme 159

Compound (159) is by obtaining (652mg) with preparation scheme 7 similar modes from compound (6).

¹H-NMR(300MHz，DMSO-d ₆，δ)：1.47(9H，s)，1.49(9H，s)，3.77(2H，s)，6.50(1H，d，J＝16.1Hz)，7.40(2H，d，J＝7.9Hz)，7.49(1H，d，J＝7.9Hz)，7.50(1H，m)，7.60(1H，m)，7.67(2H，d，J＝8.1Hz)，8.00(1H，m)，8.51(1H，m)，8.55(1H，m)，8.83(1H，m)，9.76(1H，d，J＝7.7Hz)；

MASS(ES+)：m/e 530(M+1).

Preparation scheme 160

Compound (160) is by obtaining (458mg) with preparation scheme 8 similar modes from compound (159).

¹H-NMR(300MHz，DMSO-d ₆，δ)：4.58(2H，s)，6.56(1H，d，J＝16.1Hz)，7.51(2H，d，J＝8.1Hz)，7.59(1H，d，J＝16.1Hz)，7.74(2H，d，J＝8.4 Hz)，7.90(2H，s)，8.14(1H，s)，8.53(1H，d，J＝7.7Hz)，8.76(1H，d，J＝5.1Hz)，9.15(1H，s)；

MASS(ES+)：m/e 356(M+1).

Preparation scheme 161

Compound (161) is by obtaining (316mg) with preparation scheme 9 similar modes from compound (160).Compound (161) is used for embodiment 48.

¹H-NMR(300MHz，DMSO-d ₆，δ)：1.53(3H，br)，1.69(3H，br)，3.53(1H，m)，3.95(1H，m)，4.23(2H，s)，4.90(1H，s)，6.48(1H，d，J＝15.7Hz)，7.39(2H，d，J＝8.1Hz)，7.44-7.52(4H，m)，7.54(2H，d，J＝8.4Hz)，7.80(1H，br)，8.08(1H，m)，8.53(1H，m)，8.90(1H，m)；

MASS(ES+)：m/e 455(M+1).

Preparation scheme 162

Compound (162) is by obtaining (748mg) with preparation scheme 7 similar modes.

¹H-NMR(300MHz，CDCl ₃，δ)：1.54(9H，.s)，3.80(2H，s)，6.38(1H，d，J＝16.1Hz)，6.76(1H，d，J＝8.1Hz)，7.11(sH，)，7.38(2H，d，J＝7.7Hz)，7.47(2H，d，J＝7.7Hz)，7.52-7.60(5H，m)，7.71(2H，d，J＝7.0Hz)；

MASS(ES+)：m/e 457(M+1).

Preparation scheme 163

Compound (163) is by obtaining (521mg) with preparation scheme 8 similar modes from compound (162).

¹H-NMR(300MHz，DMSO-d ₆，δ)：4.49(2H，s)，6.54(1H，d，J＝16.1Hz)，7.47(2H，d，J＝7.7Hz)，7.56-7.62(3H，m)，7.67-7.77(3H，m)，7.81(2H，s)，7.98(1H，s)；

MASS(ES+)：m/e 383(M+1).

Preparation scheme 164

Compound (164) is by obtaining (185mg) with preparation scheme 9 similar modes from compound (163).Compound (164) is used for embodiment 49.

¹H-NMR(300MHz，DMSO-d ₆，δ)：1.53(3H，br)，1.69(3H，br)，3.53(1H，m)，3.95(1H，m)，4.27(2H，s)，4.90(1H，s)，6.48(1H，d，J＝16.1Hz)，7.39(2H，d，J＝8.0Hz)，7.46(1H，d，J＝15.7Hz)，7.56(5H，m)，7.62(2H，s)，7.67(3H，m)，7.73(2H，d，J＝7.0Hz)，7.86(1H，s)；

MASS(ES+)：m/e 482(M+1).

Preparation scheme 165

Under 5 ℃, in the EtOH of compound (60) (3mL) solution, add sodium borohydride (28mg), allow the gained mixture be warming up to envrionment temperature.Stir after 0.5 hour, add sodium borohydride (14mg) to mixture, then before compound (60) disappears, also other three times to mixture adding sodium borohydride (14mg).The gained mixture is poured in the water, washed with ether.Water to pH4, is used ethyl acetate extraction, the salt water washing with the 1N hcl acidifying.Organic phase Na ₂SO ₄Drying, vacuum boils off solvent, obtains compound (165) (120mg), is colourless form.

¹H-NMR(300MHz，DMSO-d ₆，δ)：4.44(2H，s)，5.86(1H，s)，6.06(1H，br)，6.53(1H，d，J＝16.1Hz)，7.19(1H，t，J＝7.3Hz)，7.29(2H，t，J＝7.3Hz)，7.38(3H，d，J＝7.0Hz)，7.42(2H，d，J＝8.1Hz)，7.56(1H，d，J＝5.5Hz)，7.60(1H，d，J＝1.8Hz)，7.67(1H，s)，7.70(2H，d，J＝8.4Hz)；

MASS(ES+)：m/e 385(M+1).

Preparation scheme 166

Compound (166) is by obtaining (104mg) with preparation scheme 9 similar modes from compound (165).Compound (166) is used for embodiment 50.

¹H-NMR(300MHz，DMSO-d ₆，δ)：1.53(3H，br)，1.68(3H，br)，3.50(1H，m)，3.93(1H，m)，4.16(2H，s)，4.90(1H，s)，5.77(1H，s)，5.82(1H，br)，6.45(1H，d，J＝16.5Hz)，7.12(1H，m)，7.18(1H，d，J＝6.6Hz)，7.27(2H，d，J＝7.5Hz)，7.32(2H，t，J＝7.3Hz)，7.34(1H，s)，7.36(2H，d，J＝7.4Hz)，7.42(2H，m)，7.51(2H，d，J＝8.1Hz)；

MASS(ES+)：m/e 484(M+1).

Preparation scheme 167

Compound (167) connects with preparation scheme 7 similar modes and obtains (234mg) from compound (6).

¹H-NMR(300MHz，CDCl ₃，δ)：2.96(3H，s)，2.98(3H，s)，3.80(2H，s)，6.38(1H，d，J＝16.8Hz)，6.75(2H，d，J＝8.5Hz)，6.95(1H，s)，6.99(1H，d，J＝7.3Hz)，7.14(1H，d，J＝7.3Hz)，7.40(2H，d，J＝7.0Hz)，7.43(2H，d，J＝7.0Hz)，7.54(2H，d，J＝7.3Hz)，7.59(1H，d，J＝15.0Hz)；

MASS(ES+)：m/e 472(M+1).

Preparation scheme 168

Compound (168) is by obtaining (263mg) with preparation scheme 8 similar modes from compound (167).

¹H-NMR(300MHz，DMSO-d ₆，δ)：3.04(6H，s)，4.60(2H，s)，6.57(1H，d，J＝16.1Hz)，7.42(1H，d，J＝8.1Hz)，7.60(1H，d，J＝16.1Hz)，7.61-7.72(2H，m)，7.74(2H，d，J＝8.4Hz)，7.80(2H，s)，7.90(1H，s)；

MASS(ES+)：m/e 398(M+1).

Preparation scheme 169

Compound (169) is by obtaining (116mg) with preparation scheme 9 similar modes from compound (168).Compound (169) is used for embodiment 51.

¹H-NMR(300MHz，DMSO-d ₆，δ)：1.54(3H，br)，1.69(3H，br)，2.93(6H，s)，3.53(1H，m)，3.94(1H，m)，4.20(2H，s)，4.90(1H，s)，6.47(1H，d，J＝15.8Hz)，6.81(2H，d，J＝9.1Hz)，7.38(4H，d，J＝8.4Hz)，7.43(1H，m)，7.50(2H，m)，7.54(2H，d，J＝8.4Hz)，7.69(1H，s)；

MASS(ES+)：m/e 497(M+1).

Preparation scheme 170

Compound (170) is by obtaining (334mg) with preparation scheme 7 similar modes from compound (6).

¹H-NMR(300MHz，CDCl ₃，δ)：1.54(9H，s)，3.81(2H，s)，4.02(2H，br)，6.39(1H，d，J＝16.1Hz)，7.03(1H，br)，7.29(1H，br)，7.38(2H，d，J＝8.0Hz)，7.44(1H，br)，7.55(2H，dd，J＝8.0Hz)，7.58(1H，d，J＝16.2Hz)；

MASS(ES+)：m/e 421(M+1).

Preparation scheme 171

Compound (171) is by obtaining (247mg) with preparation scheme 8 similar modes from compound (170).

¹H-NMR(300MHz，DMSO-d ₆，δ)：4.39(2H，s)，6.52(1H，d，J＝15.6Hz)，7.42(2H，d，J＝7.7Hz)，7.58(1H，d，J＝15.8Hz)，7.61.(1H，d，J＝8.8Hz)，7.69(2H，d，J＝8.1Hz)，7.79(1H，d，J＝9.5Hz)，7.97(1H，s)；

MASS(ES+)：m/e 347(M+1).

Preparation scheme 172

Compound (172) is by obtaining (308mg) with preparation scheme 9 similar modes from compound (171).Compound (172) is used for embodiment 52.

¹H-NMR(300MHz，DMSO-d ₆，δ)：1.53(3H，br)，1.76(3H，br)，3.52(1H，m)，3.96(1H，m)，4.27(2H，s)，4.90(1H，s)，6.48(1H，d，J＝16.4Hz)，7.38(2H，d，J＝8.5Hz)，7.46(1H，d，J＝8.4Hz)，7.47(1H，d，J＝16.0Hz)，7.55(2H，d，J＝7.9Hz)，7.69(1H，d，J＝8.1Hz)，7.85(1H，s)；

MASS(ES+)：m/e 346(M+1).

Preparation scheme 173

Compound (173) is by obtaining (617mg) with preparation scheme 7 similar modes from compound (6).

¹H-NMR(300MHz，CDCl ₃，δ)：1.48(9H，s)，3.69(2H，s)，5.25(2H，br)，6.50(1H，d，J＝15.7Hz)，6.49-6.55(1H，m)，6.95-7.00(1H，m)，7.37(2H，d，J＝8.1Hz)，7.54(1H，d，J＝16.1Hz)，7.65(2H，d，J＝8.4Hz)；

MASS(ES+)：m/e 389(M+1).

Preparation scheme 174

Compound (174) is by obtaining (466mg) with preparation scheme 8 similar modes from compound (173).

¹H-NMR(300MHz，DMSO-d ₆，δ)：4.36(2H，s)，6.52(1H，d，J＝16.1Hz)，7.31-7.40(2H，m)，7.43(2H，d，J＝8.1Hz)，7.57(1H，d，J＝15.7Hz)，7.69(2H，d，J＝8.1Hz)；

MASS(ES+)：m/e 315(M+1).

Preparation scheme 175

Compound (175) is by obtaining (542mg) with preparation scheme 9 similar modes from compound (174).Compound (175) is used for embodiment 53.

¹H-NMR(300MHz，DMSO-d ₆，δ)：1.53(3H，br)，1.69(3H，br)，3.52(1H，m)，3.96(1H，m)，4.22(2H，s)，4.90(1H，s)，6.47(1H，d，J＝16.1Hz)，7.13-7.22(2H，m)，7.37(2H，d，J＝8.0Hz)，7.47(1H，d，J＝15.7Hz)，7.54(2H，d，J＝8.0Hz)；

MASS(ES+)：m/e 414(M+1).

Preparation scheme 176

Compound (176) is by obtaining (555mg) with preparation scheme 7 similar modes from compound (6).

¹H-NMR(300MHz，CDCl ₃，δ)：0.93(6H，d，J＝6.6Hz)，1.54(9H，s)，1.62(2H，dt，J＝7.0，7.0Hz)，1.79(1H，hept，J＝6.8Hz)，3.76(2H，s)，3.90(2H，t，J＝6.5Hz)，6.30(2H，m)，6.38(1H，d，J＝16.1Hz)，6.91(1H，d，J＝9.5Hz)，7.53(2H，d，J＝8.7Hz)，7.55(1H，d，J＝16.6Hz)；

MASS(ES+)：m/e 439(M+1).

Preparation scheme 177

Compound (177) is by obtaining (398mg) with preparation scheme 8 similar modes from compound (176).

¹H-NMR(300MHz，DMSO-d ₆，δ)：0.94(6H，d，J＝6.7Hz)，1.64(2H，dt，J＝6.7，6.7Hz)，1.79(1H，hept，J＝6.7Hz)，4.07(2H，t，J＝6.7Hz)，4.50(2H，s)，6.55(1H，d，J＝16.3Hz)，7.10(1H，dd，J＝8.4，2.2Hz)，7.21(1H，d，J＝2.2Hz)，7.46(2H，d，J＝8.4Hz)，7.59(1H，d，J＝16.1Hz)，7.62(1H，d，J＝8.7Hz)，7.73(2H，d，J＝8.6Hz)；

MASS(ES+)：m/e 365(M+1).

Preparation scheme 178

Compound (178) is by obtaining (176mg) with preparation scheme 9 similar modes from compound (177).Compound (178) is used for embodiment 54.

¹H-NMR(300MHz，CDCl ₃，δ)：0.92(6H，d，J＝6.7Hz)，1.42-1.87(6H，m)，1.64(2H，dt，J＝6.7Hz)，1.80(1H，hept，J＝6.7Hz)，3.52(1H，m)，3.94(2H，t，J＝6.7Hz)，3.97(1H，m)，4.11(2H，s)，5.13(1H，s)，6.18(1H，br.s)，6.84(1H，dd，J＝8.8，2.5Hz)，6.90(4H，br.s)，7.04(1H，br.s)，7.29(1H，br.d)，7.45(1H，d，J＝8.8Hz)；

MASS(ES+)：m/e 464(M+1).

Preparation scheme 179

Compound (179) is by obtaining (414mg) with preparation scheme 7 similar modes from compound (6).

¹H-NMR(300MHz，CDCl ₃，δ)：1.28(6H，d，J＝6.3Hz)，3.76(2H，s)，4.44(1H，hept，J＝6.3Hz)，6.28(2H，m)，6.37(1H，d，J＝15.8Hz)，6.91(1H，d，J＝9.0Hz)，7.37(2H，d，J＝8.1Hz)，7.52(2H，d，J＝8.1Hz)，7.57(1H，d，J＝15.7Hz)；

MASS(ES+)：m/e 411(M+1).

Preparation scheme 180

Compound (180) is by obtaining (330mg) with preparation scheme 8 similar modes from compound (179).

¹H-NMR(300MHz，DMSO-d ₆，δ)：1.29(6H，d，J＝6.1Hz)，4.69(1H，hept，J＝6.1Hz)，6.55(1H，d，J＝16.2Hz)，7.08(1H，dd，J＝2.6，9.2Hz)，7.19(1H，d，J＝2.6Hz)，7.59(1H，d，J＝16.1Hz)，7.62(1H，d，J＝9.2Hz)，7.73(2H，d，J＝8.2Hz)；

MASS(ES+)：m/e 337(M+1).

Preparation scheme 181

Compound (181) is by obtaining (281mg) with preparation scheme 9 similar modes from compound (180).Compound (181) is used for embodiment 55.

¹H-NMR(300MHz，CDCl ₃，δ)：1.31(6H，d，J＝6.0Hz)，1.53(3H，br)，1.69(3H，br)，3.64(1H，m)，4.01(1H，m)，4.22(2H，s)，4.47(1H，hept，J＝6.0Hz)，5.05(1H，m)，6.30(1H，br)，6.85(1H，d，J＝9.0Hz)，7.00(1H，s)，707-7.20(2H，br)，7.26-7.35(1H，br)，7.42(2H，d，J＝8.8Hz)；

MASS(ES+)：m/e 436(M+1).

Preparation scheme 182

Compound (182) is by obtaining (546mg) with preparation scheme 7 similar modes from compound (6).

¹H-NMR(300MHz，DMSO-d ₆，δ)：3.78(2H，s)，6.38(1H，d，J＝16.1Hz)，6.40(2H，m)，6.89(1H，s)，7.00(2H，m)，7.09(1H，t，J＝7.3Hz)，7.31(2H，dd，J＝8.7，7.6Hz)，7.38(2H，d，J＝8.5Hz)，7.54(2H，d，J＝7.4Hz)，7.58(1H，d，J＝16.2Hz)；

MASS(ES+)：m/e 445(M+1).

Preparation scheme 183

Compound (183) is by obtaining (417mg) with preparation scheme 8 similar modes from compound (182).

¹H-NMR(300MHz，DMSO-d ₆，δ)：4.52(2H，s)，6.56(1H，d，J＝16.1Hz)，7.17(1H，t，J＝7.3Hz)，7.21(1H，dd，J＝9.1，2.3Hz)，7.30(1H，d，J＝2.3Hz)，7.41(2H，t，J＝8.1Hz)，7.48(2H，d，J＝8.5Hz)，7.59(1H，d，J＝16.3Hz)，7.73(2H，d，J＝8.8Hz)，7.76(1H，d，J＝9.1Hz)；

MASS(ES+)：m/e 371(M+1).

Preparation scheme 184

Compound (184) is by obtaining (442mg) with preparation scheme 9 similar modes from compound (183).Compound (184) is used for embodiment 56.

¹H-NMR(300MHz，DMSO-d ₆，δ)：1.54(3H，br)，1.69(3H，br)，3.52(1H，m)，3.95(1H，m)，4.19(2H，s)，4.90(1H，s)，6.47(1H，d，J＝16.5Hz)，6.88(1H，m)，6.94(2H，m)，7.06(2H，m)，7.35(2H，m)，7.37(3H，m)，7.46(1H，d，J＝16.4Hz)，7.54(2H，m)；

MASS(ES+)：m/e 470(M+1).

Preparation scheme 185

Compound (185) is by obtaining (163mg) with preparation scheme 7 similar modes from compound (6).

¹H-NMH(300MHz，CDCl ₃，δ)：3.74(3H，s)，3.78(2H，s)，6.31(2H，m)，6.38(1H，d，J＝16.1Hz)，6.93(1H，d，J＝10.0Hz)，7.38(2H，d，J＝8.0Hz)，7.54(2H，d，J＝8.4Hz)，7.58(1H，d，J＝16.1Hz)；

MASS(ES+)：m/e 383(M+1).

Preparation scheme 186

Compound (186) is by obtaining (127mg) with preparation scheme 8 similar modes from compound (185).

¹H-NMR(300MHz，DMSO-d ₆，δ)：3.84(3H，s)，4.52(2H，s)，6.55(1H，d，J＝16.1Hz)，7.12(1H，dd，J＝8.8，2.2Hz)，7.20(1H，d，J＝2.6Hz)，7.47(2H，d，J＝8.1Hz)，7.59(1H，d，J＝16.1Hz)，7.65(1H，d，J＝9.2Hz)，7.73(2H，d，J＝8.1Hz)；

MASS(ES+)：m/e 309(M+1).

Preparation scheme 187

Compound (187) is by obtaining (127mg) with preparation scheme 9 similar modes from compound (186).Compound (187) is used for embodiment 57.

¹H-NMR(300MHz，DMSO-d ₆，δ)：1.53(3H，br)，1.69(3H，br)，3.53(1H，m)，3.75(3H，s)，3.95(1H，m)，4.15(2H，s)，6.48(1H，d，J＝15.7Hz)，6.75(1H，dd，J＝8.8，2.6Hz)，6.98(1H，s)，7.35(3H，d，J＝8.4Hz)，7.46(1H，d，J＝15.7Hz)，7.53(2H，d，J＝8.0Hz)；

MASS(ES+)：m/e 408(M+1).

Preparation scheme 188

Under agitation, (be described in the following preparation scheme 247, add trifluoroacetic acid (20mL) in methylene dichloride 1.75g) (20mL) solution, the gained mixture stirred 3 hours at ambient temperature to compound (247).With the mixture vacuum concentration, resistates is dissolved in N, in the dinethylformamide (25mL).In ice bath, add I-hydroxybenzotriazole (731mg), O-(tetrahydrochysene-2H-pyrans-2-yl) azanol (588mg) and 1-[3-(dimethylamino) propyl group successively to this solution]-3-ethyl carbodiimide (840mg), stir the gained mixture at ambient temperature.After 16 hours, in mixture, add other I-hydroxybenzotriazole (157mg), O-(tetrahydrochysene-2H-pyrans-2-yl) azanol (136mg) and 1-[3-(dimethylamino) propyl group]-3-ethyl carbodiimide (180mg), gained mixture restir 4 hours.Mixture is with ethyl acetate (300mL) extraction and use 5% aqueous potassium hydrogen sulfate (100mL), saturated sodium bicarbonate aqueous solution (100mL) and salt solution (100mL) washing successively.The organic layer anhydrous sodium sulfate drying, vacuum concentration.Resistates obtains compound (188) (1.82g) by flash chromatography eluent ethyl acetate purifying, is colourless amorphous solid.Compound (188) is used for embodiment 60.

¹H-NMR(300MHz，CDCl ₃，δ)：1.50-1.91(6H，m)，3.58-3.71(1H，m)，3.82(3H，s)，3.88-4.21(1H，m)，4.87-5.09(3H，m)，6.17-6.40(1H，m)，7.03-7.61(5H，m)，7.74-7.87(4H，m)；

MASS(ES+)：m/z 496(M+1).

Preparation scheme 189

Compound (189) is by obtaining (142mg) with preparation scheme 188 similar modes from following compound (249).Compound (189) is used for embodiment 64.

¹H-NMR(300MHz，CDCl ₃，δ)：1.46-1.92(6H，m)，3.56-3.69(1H，m)，3.89-4.18(2H，m)，4.96-5.12(2H，m)，6.11-6.37(1H，m)，7.00-7.36(7H，m)，7.64(2H，d，J＝8.4Hz)；

MASS(ES+)：m/z 438(M+1).

Preparation scheme 190

Compound (190) is by obtaining (110mg) with preparation scheme 188 similar modes from following compound (250).Compound (190) is used for embodiment 68.

¹H-NMR(300MHz，CDCl ₃，δ)：1.43-1.90(6H，m)，3.58-3.71(1H，m)，3.91-4.12(3H，m)，5.03(1H，br.s)，5.95-6.21(1H，m)，7.00-7.42(9H，m)，7.67-7.76(2H，m)；

MASS(ES+)：m/z 404(M+1).

Preparation scheme 191

Compound (191) is by obtaining (78mg) with preparation scheme 188 similar modes from following compound (226).Compound (191) is used for embodiment 69.

¹H-NMR(300MHz，CDCl ₃，δ)：1.41-2.05(6H，m)，3.54-3.69(1H，m)，3.89-4.05(3H，m)，4.93(1H，br.s)，6.04-6.28(1H，m)，6.95-7.53(8H，m)，7.73(2H，d，J＝7.0Hz)；

MASS(ES+)：m/z 438(M+1).

Preparation scheme 192

Compound (192) is by obtaining (638mg) with preparation scheme 188 similar modes from following compound (242).Compound (192) is used for embodiment 86.

¹H-NMR(300MHz，DMSO-d ₆，δ)：1.26(3H，t，J＝7.0Hz)，1.54(3H，br.)，1.69(3H，br.)，3.53(1H，m)，3.95(1H，m)，4.07(2H，s)，4.24(2H，q，J＝7.0Hz)，4.90(1H，s)，6.46(1H，d，J＝16.1Hz)，7.36(5H，m)，7.52(3H，m)，7.85(2H，d，J＝7.3Hz)；

MASS(ES+)：m/e 476(M+1).

Preparation scheme 193

In envrionment temperature with under stirring, to compound (326) (200mg, be described in the preparation scheme 326 hereinafter) N, add 1-[3-(dimethylamino) propyl group in dinethylformamide (2mL) solution]-3-ethyl carbodiimide (90mg) and I-hydroxybenzotriazole (79mg), the gained mixture stirred 2 hours under same temperature.In this mixture, add 28% ammonium hydroxide aqueous solution (0.08mL), mixture was stirred 16 hours at ambient temperature.Mixture is used the washing of saturated sodium bicarbonate aqueous solution (25mL) and salt solution (25mL) successively with ethyl acetate (50mL) extraction.The organic layer anhydrous sodium sulfate drying, vacuum concentration.Resistates with methyl alcohol-chloroform (10: 90 (volume)) wash-out, obtains compound (193) (141mg) by preparation type thin layer chromatography, is colourless amorphous solid.Compound (193) is used for embodiment 61.

¹H-NMR(300MHz，CDCl ₃-CD3OD(9∶1v/v)，δ)：1.51-1.94(6H，m)，3.59-3.72(3H，m)，3.95-4.12(1H，m)，4.99(2H，br.s)，6.23-6.47(1H，m)，7.22-7.30(2H，m)，7.32-7.47(4H，m)，7.55-7.69(4H，m)；

MASS(ES+)：m/z 447(M+1).

Preparation scheme 194

Under in ice bath, stirring, in compound (193) pyridine (2mL) solution (138mg), add trifluoroacetic anhydride (84mg).The gained mixture stirred 2 hours under same temperature, allowed it be warming up to envrionment temperature then.After 2 hours, add other trifluoroacetic anhydride (84mg) to reaction mixture at ambient temperature, the gained mixture stirred 1 hour under same temperature.Vacuum concentrated mixture, resistates is used the washing of saturated sodium bicarbonate aqueous solution (25mL) and salt solution (25mL) successively with chloroform (50mL) extraction.The organic layer anhydrous sodium sulfate drying, evaporation.Resistates obtains compound (194) (55mg) by preparation type thin layer chromatography eluent ethyl acetate purifying, is colourless amorphous solid.Compound (194) is used for embodiment 62.

¹H-NMR(300MHz，CDCl ₃，δ)：1.32-2.01(6H，m)，3.48-4.10(3H，m)，4.16(2H，br.s)，4.86-5.06(1H，m)，6.97-7.52(8H，m)，7.81-7.92(2H，m)；

MASS(ES+)：m/z 429(M+1).

Preparation scheme 195

Under in ice bath, stirring, to compound (6) N (500mg), add 2 successively in dinethylformamide (8mL) solution, 2-diethoxy ethamine (305mg), 1-[3-(dimethylamino) propyl group]-3-ethyl-carbodiimide hydrochloride (439mg) and I-hydroxybenzotriazole (309mg), gained solution stirred 15 minutes under same temperature.Allow the gained mixture be warming up to envrionment temperature then and under same temperature, stirred 16 hours.The gained mixture is used 5% potassium sulfate solution (25mL), saturated sodium bicarbonate aqueous solution (25mL) and salt solution (25mL) washing successively with ethyl acetate (50mL) extraction.The organic layer anhydrous sodium sulfate drying, evaporation obtains crude product compound (195) (861mg), is water white oil, and it just is used for next step without being further purified.

¹H-NMR(300MHz，CDCl ₃，δ)：1.13(3H，t，J＝7.3Hz)，1.54(9H，s)，3.36(2H，t，J＝5.5Hz)，3.40-3.52(1H，m)，3.58(2H，s)，3.59-3.70(1H，m)，4.42(1H，t，J＝5.5Hz)，5.62(1H，br.s)，6.36(1H，d，J＝16.1Hz)，7.28(2H，d，J＝8.1Hz)，7.49(2H，d，J＝8.1Hz)，7.57(1H，d，J＝16.1Hz)；

MASS(ES+)：m/z 378(M+1).

Preparation scheme 196

Under 170 ℃, with compound (195) (603mg), the mixture heating up of ammonium acetate (616mg) and acetate (1.9g) and dimethylbenzene (12mL) 5 days, during in mixture, added the ammonium acetate and the acetate of other same amount every 12 hours.Vacuum concentrated mixture is with chloroform (100mL) extraction.Organic phase is used saturated sodium bicarbonate aqueous solution (25mL) and salt solution (25mL) washing successively.The organic layer anhydrous sodium sulfate drying, evaporation.Resistates grinds with acetonitrile, obtains compound 196 (200mg), is light brown amorphous solid.

¹H-NMR(300MHz，CDCl ₃，δ)：1.47(9H，s)，3.98(2H，s)，6.46(1H，d，J＝16.1Hz)，6.78(1H，br.s)，7.00(1H，br.s)，7.25(2H，d，J＝8.1Hz)，7.51(1H，d，J＝16.1Hz)，7.61(2H，d，J＝8.1Hz)；

MASS(ES+)：m/z 285(M+1).

Preparation scheme 197

Compound (197) is by obtaining (51mg) with preparation scheme 188 similar modes.Gained compound (197) is used for embodiment 112.

¹H-NMR(300MHz，CDCl ₃，δ)：1.18-2.23(6H，m)，3.48-4.20(5H，m)，5.02-5.12(1H，m)，6.90-7.53(7H，m)；

MASS(ES+)：m/z 328(M+1).

Preparation scheme 198

Compound (198) is by obtaining (638mg) with preparation scheme 188 similar modes from following compound (242).Gained compound (198) is used for embodiment 86.

(compound (198) is same compound with compound (192).)

MASS(ES+)：m/e 476(M+1).

Preparation scheme 199

Under 60 ℃, with 1N hydrogenchloride/acetate (10mL) solution heating of compound (248) (427mg, be described in hereinafter prepare in the scheme 248) 2 hours.Vacuum boils off solvent, and resistates grinds with the mixture (10: 1 (volume)) of ethyl acetate and acetate, obtains compound (199) (353mg), is pale solid.

¹H-NMR(300MHz，DMSO-d ₆，δ)：4.41(2H，s)，6.55(1H，d，J＝16Hz)，7.39(2x1H，dd，J＝8.8，8.8Hz)，7.47(2x1H，d，J＝8.2Hz)，7.58(1H，d，J＝16Hz)，7.71(2x1H，d，J＝8.2Hz)，7.91(2x1H，dd，J＝8.8，5Hz)，8.05(1H，s)；

MASS(ES+)：m/z 323.

Preparation scheme 200

Compound (200) is by obtaining (361mg) with preparation scheme 199 similar modes from following compound (207).

¹H-NMR(300MHz，DMSO-d ₆，δ)：2.51(3H，s)，2.53(3H，s)，4.28(2H，s)；

MASS(ES+)：m/z 285.

Preparation scheme 201

Compound (201) is by obtaining (433mg) with preparation scheme 199 similar modes from following compound (206).

¹H-NMR(300MHz，DMSO-d ₆，δ)：2.25(3H，s)，4.31(2H，s)，6.55(1H，d，J＝16Hz)，7.45(2x1H，d，J＝8Hz)，7.54-7.63(3H，m)，7.67-7.75(3H，m)，7.86(2x1H，d，J＝8Hz)；

MASS(ES+)：m/z 347.

Preparation scheme 202

Compound (202) is by obtaining (181mg) with preparation scheme 199 similar modes from following compound (256).

¹H-NMR(300MHz，DMSO-d ₆，δ)：1.65-1.79(6H，m)，1.85-1.91(6H，m)，2.00-2.07(3H，m)，4.32(2H，s)，6.54(1H，d，J＝16Hz)，7.25(1H，s)，7.40(2H，d，J＝8Hz)，7.57(1H，d，J＝16Hz)，7.70(2H，d，J＝8Hz).

MASS(ES+)：m/z 363(M+1).

Preparation scheme 203

Under agitation, to compound (199) N (316mg), add O-(tetrahydrochysene-2H-pyrans-2-yl) azanol (206mg), I-hydroxybenzotriazole (238mg) and 1-ethyl-3-(3 '-dimethylamino-propyl) carbodiimide hydrochloride (338mg) in dinethylformamide (5mL) solution, the gained mixture stirred 5 hours at ambient temperature.Reaction mixture dilutes with ethyl acetate, successively water, saturated sodium bicarbonate solution and salt water washing.The organic phase dried over sodium sulfate, vacuum concentration.Resistates by preparation type thin layer chromatography (chloroform: purifying methyl alcohol=10: 1), obtain compound (203) (341mg), be buff powder.

¹H-NMR(300MHz，DMSO-d ₆，δ)：1.45-1.75(6H，m)，3.53(1H，m)，3.95(1H，m)，4.03(2H，m)，4.90(1H，m)，6.46(1H，d，J＝16Hz)，7.14(2x1H，dd，J＝8.8，8.8Hz)，7.32(2x1H，d，J＝8.5Hz)，7.42-7.57(4H，m)，7.76(2x1H，dd，J＝8.8，6.0Hz)，11.22(1H，s)，11.98(1H，br-s)；

MASS(ES+)：m/z 422.

Preparation scheme 204

In to n-BuOH (15mL) suspension of iodophenylalanine (1.20g), add 1-phenyl-1,2,3-fourth triketone-2-oxime (788mg).The gained mixture refluxed 2 days, cooling, vacuum concentration then.Resistates grinds with ethyl acetate, obtains compound (204) (870mg), is light yellow solid.

¹H-NMR(300MHz，DMSO-d ₆，δ)：2.48(3H，s)，3.96(2H，s)，7.08(2x1H，d，J＝8.5Hz)，7.44-7.60(3H，m)，7.67(2x1H，d，J＝8.5Hz)，8.18(2x1H，d，J＝8Hz)，12.44(1H，s)；

MASS(ES+)：m/z 403.

Preparation scheme 205

Compound (205) by with preparation scheme 204 similar modes to iodophenylalanine acquisition (402mg).

¹H-NMR(300MHz，DMSO-d ₆，δ)：2.35(3H，s)，2.38(3H，s)，3.91(2H，s)，7.07(2x1H，d，J＝8Hz)，7.67(2x1H，d，J＝8Hz)；

MASS(ES+)：m/z 341.

Preparation scheme 206

Under agitation, in compound (204) DMF (10mL) solution (661mg), add tert-butyl acrylate (0.72mL), acid chloride (II) (18mg), three (2-aminomethyl phenyl) phosphine (100mg) and N, N-diisopropylethylamine (0.86mL).The gained mixture stirred 4 hours down at 90 ℃.Allow the cold envrionment temperature of gained mixture, pour in the water, use ethyl acetate extraction.Organic phase salt water washing, Na ₂SO ₄Drying, vacuum concentration.Resistates obtains compound (206) (707mg) by mixture (1: 1 (volume)) the wash-out purifying of silica gel column chromatography with hexane and ethyl acetate, is light yellow foam.

¹H-NMR(300MHz，DMSO-d ₆，δ)：1.47(3x3H，s)，2.48(3H，s)，4.02(2H，s)，6.48(1H，d，J＝16Hz)，7.30(2x1H，d，J＝8.5Hz)，7.44-7.58(4H，m)，7.64(2x1H，d，J＝8.5Hz)，8.19(2x1H，d，J＝7.5Hz)，12.49(1H，s)；

MASS(ES+)：m/z 403.

Preparation scheme 207

Compound (207) is by obtaining (370mg) with preparation scheme 206 similar modes from compound (205).

¹H-NMR(300MHz，CDCl ₃，δ)：1.54(3x3H，s)，2.45(3H，s)，2.54(3H，s)，4.08(2H，s)，6.36(1H，d，J＝16Hz)，7.25(2x1H，d，J＝8Hz)，7.48(2x1H，d，J＝8Hz)，7.56(1H，d，J＝16Hz)；

MASS(ES+)：m/z 341.

Preparation scheme 208

Compound (208) is by obtaining (461mg) with preparation scheme 188 similar modes from compound (201).Compound (208) is used for embodiment 66.

¹H-NMR(300MHz，DMSO-d ₆，δ)：1.46-1.76(6H，m)，3.53(1H，m)，3.95(1H，m)，4.02(2H，s)，4.90(1H，m)，6.47(1H，d，J＝16Hz)，7.31(2x1H，d，J＝8.5Hz)，7.42-7.68(6H，m)，8.19(2x1H，d，J＝7Hz)，11.22(1H，s)，11.48(1H，s)；

MASS(ES+)：m/z 446.

Preparation scheme 209

Compound (209) is by obtaining (268mg) with preparation scheme 188 similar modes from compound (200).Compound (209) is used for embodiment 65.

¹H-NMR(300MHz，DMSO-d ₆，δ)：1.46-1.78(6H，m)，2.36(3H，s)，2.39(3H，s)，3.53(1H，m)，3.96(1H，m)，3.97(2H，s)，4.90(1H，m)，

6.47(1H，d，J＝16Hz)，7.29(2x1H，d，J＝8Hz)，7.47(1H，d，J＝16Hz)，7.53(2x1H，d，J＝8Hz)，11.22(1H，s)，12.31(1H，br-s)；

MASS(ES+)：m/z 384.

Preparation scheme 210

Compound (210) is by obtaining (107mg) with preparation scheme 188 similar modes from following compound (340).Compound (210) is used for embodiment 96.

¹H-NMR(300MHz，DMSO-d ₆，δ)：1.48-1.73(6H，m)，1.92-2.00(4H，m)，3.18-3.24(4H，m)，3.48-3.57(1H，m)，3.88-4.01(1H，m)，4.10(2H，s)，4.87-4.93(1H，m)，6.42-6.52(3H，m)，7.25-7.37(3H，m)，7.46(1H，d，J＝16Hz)，7.52(2H，d，J＝8Hz)；

MASS(ES+)：m/z 447(M+1).

Preparation scheme 211

In ice bath, to (2E)-3-[4-(methylol) phenyl] drip the methylsulfonyl chloride (715mg) in methylene dichloride (5mL) in the mixture of methyl acrylate (1.0g) and triethylamine (1.26g) and methylene dichloride (10mL).The gained mixture stirred 1 hour under same temperature, allowed it be warming up to envrionment temperature then.After stirring 3 hours at ambient temperature, vacuum concentrated mixture.Resistates is with ethyl acetate (100mL) extraction, with 10% aqueous citric acid solution (25mL), saturated sodium bicarbonate aqueous solution (25mL) and salt solution (25mL) washing.Separate organic phase, use anhydrous sodium sulfate drying, vacuum-evaporation obtains compound (211) (655mg), is colourless amorphous solid, and it promptly is used for next step without being further purified.

¹H-NMR(300MHz，CDCl ₃，δ)：3.82(3H，s)，4.59(2H，s)，6.45(1H，d，J＝15.8Hz)，7.41(2H，d，J＝8.4Hz)，7.52(2H，d，J＝8.4Hz)，7.69(1H，d，J＝15.8Hz).

Preparation scheme 212

Under in ice bath, stirring, to the N of 4-phenyl-1H-imidazoles (115mg), add in dinethylformamide (0.5mL) solution sodium hydride (60% oil dispersion, 31mg).The gained mixture stirred 15 minutes under same temperature, allowed it be warming up to envrionment temperature then.After stirring 15 minutes at ambient temperature, mixture is cooled off in ice bath.Drip at N to this mixture, the compound (211) in the dinethylformamide (1.5mL) (180mg), the gained mixture stirred 2 hours under same temperature.Mixture is with ethyl acetate (50mL) extraction, with saturated sodium bicarbonate aqueous solution (25mL) and salt solution (25mL) washing.The organic phase anhydrous sodium sulfate drying filters vacuum concentration.Resistates obtains compound (212) (135mg) by mixture (3: 1 (volume)) the wash-out purifying of preparation type thin layer chromatography with ethyl acetate and hexane, is water white oil.

¹H-NMR(300MHz，CDCl ₃，δ)：3.81(3H，s)，5.17(2H，s)，6.44(1H，d，J＝15.8Hz)，7.17-7.29(4H，m)，7.33-7.41(2H，m)，7.53(2H，d，J＝8.4Hz)，7.63(1H，d，J＝15.8Hz)，7.68(1H，s)，7.76(2H，d，J＝8.4Hz)；

MASS(ES+)：m/z 319(M+1).

Preparation scheme 213

Compound (213) is by obtaining (457mg) with preparation scheme 212 similar modes from compound (211).

¹H-NMR(300MHz，CDCl ₃，δ)：2.40(3H，s)，3.81(3H，s)，5.10(2H，s)，6.43(1H，d，J＝16.1Hz)，7.13(2H，d，J＝6.7Hz)，7.14(1H，s)，7.22(1H，t，J＝7.0Hz)，7.36(2H，t，J＝8.1Hz)，7.51(2H，d，J＝8.1Hz)，7.67(1H，d，J＝16.1Hz)，7.74(2H，d，J＝7.0Hz)；

MASS(ES+)：m/e 333(M+1).

Preparation scheme 214

Compound (214) is by obtaining (723mg) with preparation scheme 212 similar modes from compound (211).

¹H-NMR(300MHz，DMSO-d ₆，δ)：2.25(3H，s)，3.72(3H，s)，5.28(2H，s)，6.64(1H，d，J＝16.1Hz)，7.20(2H，d，J＝8.4Hz)，7.42(2H，d，J＝8.4Hz)，7.64(2H，d，J＝8.4Hz)，7.65(1H，d，J＝16.1Hz)，7.74(2H，d，J＝8.1Hz)，7.84(1H，s)；

MASS(ES+)：m/z 367(M+1).

Preparation scheme 215

Compound (215) by with preparation scheme 212 similar modes from (2E)-3-[3-chloromethyl phenyl] tert-butyl acrylate acquisition (308mg).

¹H-NMR(300MHz，CDCl ₃，δ)：1.53(9H，s)，5.16(2H，s)，6.36(1H，d，J＝15.8Hz)，7.18(1H，d，J＝1.1Hz)，7.20(1H，m)，7.23(1H，t，J＝7.4Hz)，7.34-7.41(4H，m)，7.48(1H，d，J＝7.7Hz)，7.54(1H，d，J＝16.1Hz)，7.61(1H，d，J＝1.1Hz)，7.76(2H，dd，J＝8.4，1.5Hz)；

MASS(ES+)：m/z 361(M+1).

Preparation scheme 216

Compound (216) by with preparation scheme 212 similar modes from (2E)-3-[3-chloromethyl phenyl] tert-butyl acrylate acquisition (418mg).

¹H-NMR(300MHz，CDCl ₃，δ)：1.53(9H，s)，2.27(3H，s)，5.12(2H，s)，6.34(1H，d，J＝16.1Hz)，7.08(1H，br.d，J＝7.7Hz)，7.24(1H，s)，7.37(2H，d，J＝8.38Hz)，7.38(1H，t，J＝7.8Hz)，7.47(1H，d，J＝8.1Hz)，7.54(1H，d，J＝15.8Hz)，7.60(2H，d，J＝8.8Hz)；

MASS(ES+)：m/z 409(M+1).

Preparation scheme 217

Compound (217) is by obtaining (354mg) with preparation scheme 212 similar modes from compound (211).

¹H-NMR(300MHz，CDCl ₃，δ)：3.81(3H，s)，5.24(2H，s)，6.43(1H，d，J＝16.1Hz)，6.98(1H，s)，7.06-7.14(3H，m)，7.20-7.23(1H，m)，7.36-7.46(3H，m)，7.47-7.57(3H，m)，7.67(1H，d，J＝16.1Hz)；

MASS(ES+)：m/z 319(M+1).

Preparation scheme 218

Compound (218) is the mixture (291mg) of two kinds of regional isomers by obtaining from compound (211) with preparation scheme 212 similar modes.

¹H-NMR (300MHz, CDCl ₃, δ): (to the mixture of two kinds of regional isomers) 2.09 (1.2H, s), 2.22 (1.8H, s), 3.81 (3H, s), 5.06 (1.2H, s), 5.08 (0.8H, s), 6.43 (1H, d, J=16.1Hz), 6.60 (0.6H, s), 6.85 (0.4H, s), 7.05 (0.8H, d, J=8.1Hz), 7.16 (1.2H, d, J=8.1Hz), 7.44-7.55 (3H, m), 7.66 (1H, d, J=16.1Hz);

MASS (ES+): (to the mixture of two kinds of regional isomers) m/z 257 (M+1).

Preparation scheme 219

Under in envrionment temperature, stirring, (185mg) in methyl alcohol (1mL) and 1, add 1N sodium hydroxide (0.87mL) in the solution in the mixture of 4-diox (1mL) to compound (212).Gained solution stirred 2 hours under same temperature.Mixture is cooled off in ice bath, add concentrated hydrochloric acid, make the mixture acidifying to this mixture.Leach precipitation,, obtain compound (219) (130mg), be white amorphous solid with 50% methanol aqueous solution (1mL) washing.

¹H-NMR(300MHz，DMSO-d ₆，δ)：5.47(2H，s)，6.58(1H，d，J＝16.1Hz)，7.38-7.55(5H，m)，7.60(1H，d，J＝16.1Hz)，7.77(2H，d，J＝8.4Hz)，7.84(2H，d，J＝7.0Hz)，8.25(1H，s)，9.35(1H，s)；

MASS(ES+)：m/z 305(M+1).

Preparation scheme 220

Compound (220) is by obtaining (357mg) with preparation scheme 219 similar modes from compound (213).

¹H-NMR(300MHz，DMSO-d ₅，δ)：2.68(3H，s)，5.42(2H，s)，6.58(1H，d，J＝16.1Hz)，7.42(1H，t，J＝7.7Hz)，7.43(2H，d，J＝8.4Hz)，7.51(2H，t，J＝7.5Hz)，7.60(1H，d，J＝16.1Hz)，7.75(2H，d，J＝8.4Hz)，7.83(2H，d，J＝7.3Hz)，8.14(1H，s)；

MASS(EI+)319(M+1).

Preparation scheme 221

Compound (221) is by obtaining (564mg) with preparation scheme 219 similar modes from compound (214).

¹H-NMR(300MHz，DMSO-d ₆，δ)：2.25(3H，s)，5.30(2H，s)，6.52(1H，d，J＝16.1Hz)，7.21(2H，d，J＝8.1Hz)，7.43(2H，d，J＝8.4Hz)，7.57(1H，d，J＝15.8Hz)，7.64(2H，d，J＝8.1Hz)，7.70(2H，d，J＝8.1Hz)，7.94(1H，s)；

MASS(ES+)：m/z 353(M+1).

Preparation scheme 222

Under in ice bath, stirring, to compound (219) N (105mg), add I-hydroxybenzotriazole (61mg), O-(tetrahydrochysene-2H-pyrans-2-yl) azanol (49mg) and 1-[(3-dimethylamino in dinethylformamide (1.5mL) solution successively) propyl group]-3-ethyl-carbodiimide hydrochloride (86mg), the gained mixture stirred 3 days at ambient temperature.Mixture is with ethyl acetate (50mL) extraction, with saturated sodium bicarbonate aqueous solution (25mL) and salt solution (25mL) washing.The organic layer anhydrous sodium sulfate drying, vacuum concentration.Resistates obtains compound (222) (120mg) by mixture (10: 90 (volume)) the wash-out purifying of preparation type thin layer chromatography with methyl alcohol and chloroform, is colourless heavy-gravity oil.Compound (222) is used for embodiment 67.

¹H-NMR(300MHz，CDCl ₃，δ)：1.50-1.97(6H，m)，3.60-3.72(1H，m)，3.90-4.05(1H，m)，5.02(1H ，br.s)，5.17(2H，s)，7.14-7.30(6H，m)，7.32-7.42(2H，m)，7.44-7.56(2H，m)，7.62-7.82(3H，m)；

MASS(ES+)：m/z 404(M+1).

Preparation scheme 223

Compound (223) is by obtaining (431mg) with preparation scheme 203 similar modes from compound (220).Compound (223) is used for embodiment 78.

¹H-NMR(300MHz，DMSO-d ₆，δ)：1.54(3H，br.)，1.69(3H，br.)，2.29(3H，s)，3.52(1H，m)，3.94(1H，m)，4.90(1H，s)，5.21(2H，s)，6.49(1H，d，J＝16.8Hz)，7.16(1H，t，J＝7.5Hz)，7.24(2H，d，J＝8.1Hz)，7.32(2H，t，J＝7.9Hz)，7.47(1H，d，J＝16.8Hz)，7.58(2H，d，J＝8.1Hz)，7.63(1H，s)，7.71(2H，d，J＝7.0Hz)；

MASS(ES+)：m/e 418(M+1).

Preparation scheme 224

Compound (224) is by obtaining (569mg) with preparation scheme 203 similar modes from compound (221).Compound (224) is used for embodiment 79.

¹H-NMR(300MHz，DMSO-d ₆，δ)：1.54(3H，br.)，1.69(3H，br.)，2.25(3H，s)，3.53(1H，m)，3.95(1H，m)，4.90(1H，s)，5.27(2H，s)，6.48(1H，d，J＝15.8Hz)，7.21(2H，d，J＝8.1Hz)，7.42(2H，d，J＝8.4Hz)，7.47(1H，d，J＝15.8Hz)，7.58(2H，d，J＝8.1Hz)，7.65(2H，d，J＝8.4Hz)，7.84(1H，s)；

MASS(ES+)：m/z 452(M+1).

Preparation scheme 225

Compound (225) by with preparation scheme 203 similar modes from (2E)-3-[4-(1H-imidazoles-1-ylmethyl) phenyl] vinylformic acid acquisition (388mg).Compound (225) is used for embodiment 95.

¹H-NMR(300MHz，DMSO-d ₆，δ)：1.42-1.78(6H，m)，3.53(1H，m)，3.95(1H，m)，4.90(1H，m)，5.23(2H，s)，6.49(1H，d，J＝16Hz)，6.93(1H，s)，7.21(1H，s)，7.27(2x1H，d，J＝8Hz)，7.47(1H，d，J＝16Hz)，7.56(2x1H，d，J＝8Hz)，7.80(1H，s)，11.25(1H，s)；

MASS(ES+)：m/e 328.

Preparation scheme 226

Under in ice bath, stirring, in acetonitrile (2mL) solution of compound (250) (125mg, be described in hereinafter prepare in the scheme 250), add N-chloro-succinimide (70mg).The gained mixture stirred 2 days at ambient temperature.Vacuum concentrated mixture, resistates obtains compound (226) (100mg) by mixture (4: 96 (volume)) the wash-out purifying of preparation type thin layer chromatography with methyl alcohol and chloroform, is yellow oil.

¹H-NMR(300MHz，CDCl ₃，δ)：1.52(9H，s)，4.09(2H，s)，6.33(1H，d，J＝16.1Hz)，7.21-7.44(7H，m)，7.51(1H，d，J＝16.1Hz)，7.59(2H，d，J＝7.3Hz)；

MASS(ES+)：m/z 395(M+1).

Preparation scheme 227

Compound (227) is by obtaining (230mg) with preparation scheme 226 similar modes from following compound (245).

¹H-NMR(300MHz，CDCl ₃，δ)：1.53(9H，s)，4.09(2H，s)，6.32(1H，d，J＝15.8Hz)，7.27(2H，d，J＝7.7Hz)，7.29(1H，t，J＝7.7Hz)，7.40(2H，t，J＝7.4Hz)，7.45(2H，d，J＝8.1Hz)，7.53(1H，d，J＝16.1Hz)，7.57(2H，d，J＝8.1Hz)；

MASS(ES+)：m/e 395(M+1).

Preparation scheme 228

Compound (228) is by obtaining (157mg) with preparation scheme 226 similar modes from following compound (251).

¹H-NMR(300MHz，CDCl ₃，δ)：3.80(3H，s)，3.97(2H，s)，6.25(1H，d，J＝16.1Hz)，6.90(2H，d，J＝8.8Hz)，7.15(2H，d，J＝8.1Hz)，7.32(2H，d，J＝8.1Hz)，7.44(1H，d，J＝16.1Hz)，7.54(2H，d，J＝8.8Hz)；

MASS(ES+)：m/e 425(M+1).

Preparation scheme 229

Under 5 ℃, in compound (6) DMF (41mL) solution (4.1g), add HOBt (2.75g) and 1-ethyl-3-(3 '-dimethylamino-propyl) carbodiimide (EDCI, 3.15g).Under 5 ℃, slowly add 2-amino-1-methyl phenyl ketone hydrochloride (2.82g) to the gained mixture.Allow mixture be warming up to envrionment temperature, under same temperature, stirred 2 hours.The gained mixture is poured in the water (100mL), extracted with AcOEt.Organic phase is used NH successively ₄Cl, NaHCO ₃With salt water washing, NaSO ₄Dry.Solvent removed in vacuo, resistates is by silica gel flash column chromatography CHCl ₃: MeOH=95: 5 wash-out purifying obtain light yellow solid.The gained solid grinds with isopropyl ether, obtains compound (229) (5.425g), is buff powder.

¹H-NMR(300MHz，DMSO-d ₆，δ)：1.54(9H，s)，3.69(2H，s)，4.75(2H，d，J＝4.0Hz)，6.38(1H，d，J＝16.1Hz)，7.35(2H，d，J＝8.1Hz)，7.47-7.56(1+1+2+2H，m)，7.61(1H，m)，7.95(2H，d，J＝8.4Hz)；

MASS(ES+)：m/e 380(M+1).

Preparation scheme 230

Compound (230) is by obtaining (1.73g) with preparation scheme 229 similar modes from compound (26).

¹H-NMR(300MHz，CDCl ₃，δ)：1.53(9H，s)，3.67(2H，s)，3.70(3H，s)，6.19(1H，d，J＝7.3Hz)，6.38(1H，d，J＝16.1Hz)，6.85(1H，br.d，J＝7.3Hz)，7.25-7.59(7H，m)，7.60-7.68(1H，m)，8.06-8.13(2H，m)；

MASS(ES-)：m/z 436(M-1).

Preparation scheme 231

Compound (231) is by obtaining (5.69g) with preparation scheme 229 similar modes from compound (6).

¹H-NMR(300MHz，CDCl ₃，δ)：1.54(9H，s)，3.67(2H，s)，3.70(3H，s)，6.12(1H，d，J＝7.0Hz)，6.36(1H，d，J＝16.1Hz)，6.82(1H，br.d，J＝7.0Hz)，7.30(2H，d，J＝8.1Hz)，7.44-7.53(4H，m)，7.57(1H，d，J＝16.1Hz)，8.03(2H，d，J＝8.8Hz)；

MASS(ES+)：m/z 472(M+1).

Preparation scheme 232

Compound (232) is by obtaining (3.22g) with preparation scheme 229 similar modes from compound (6).

¹H-NMR(300MHz，DMSO-d ₆，δ)：1.48(3x3H，s)，3.57(2H，s)，4.61(2H，d，J＝5.5Hz)，6.49(1H，d，J＝16Hz)，7.30-7.42(4H，m)，7.53(1H，d，J＝16Hz)，7.δ3(2x1H，d，J＝8.5Hz)，8.02-8.11(2H，m)，8.48(1H，t，J＝5.5Hz)；

MASS(ES-)：m/z 442(M+HCO ₂H-1).

Preparation scheme 233

Compound (233) is by obtaining (1.74g) with preparation scheme 229 similar modes from compound (6).

¹H-NMR(300MHz，CDCl ₃，δ)：1.54(9H，s)，3.68(2H，s)，4.71(2H，d，J＝5.5Hz)，6.37(2H，d，J＝16.1Hz)，6.50(1H，br.s)，7.34(2H，d，J＝8.1Hz)，7.47(2H，d，J＝8.4Hz)，7.52(2H，d，J＝8.1Hz)，7.58(1H，d，J＝16.1Hz)，7.89(2H，d，J＝8.4Hz)；

MASS(ES+)：m/z 414(M+1).

Preparation scheme 234

Compound (234) is by obtaining (1.95g) with preparation scheme 229 similar modes from compound (26).

¹H-NMR(300MHz，CDCl ₃，δ)：1.53(9H，s)，3.68(2H，s)，4.75(2H，d，J＝4.4Hz)，6.40(1H，d，J＝16.1Hz)，6.56(1H，br.s)，7.25-7.70(8H，m)，7.91-8.02(2H，m)；

MASS(ES+)：m/z 380(M+1).

Preparation scheme 235

Compound (235) is by obtaining (2.74g) with preparation scheme 229 similar modes from compound (6).

¹H-NMR(300MHz，CDCl ₃，δ)：1.54(9H，s)，3.68(2H，s)，3.88(3H，s)，4.68(2H，d，J＝4.4Hz)，6.37(1H，d，J＝15.8Hz)，6.95(2H，d，J＝9.1Hz)，7.34(2H，d，J＝8.1Hz)，7.52(2H，d，J＝8.1Hz)，7.58(1H，d，J＝16.1Hz)，7.92(2H，d，J＝8.8Hz)；

MASS(ES+)：m/e 410(M+1).

Preparation scheme 236

Compound (236) is by obtaining (2.86g) with preparation scheme 229 similar modes from compound (6).

¹H-NMR(300MHz，CDCl ₃，δ)：1.54(9H，s)，3.69(2H，s)，3.85(3H，s)，4.73(2H，d，J＝4.4Hz)，6.73(2H，d，J＝15.8Hz)，7.16(1H，dd，J＝8.1，2.6Hz)，7.34(2H，d，J＝8.1Hz)，7.39(1H，t，J＝8.1Hz)，7.45(1H，m)，7.52(2H，d，J＝8.4Hz)，7.58(1H，d，J＝16.1Hz)；

MASS(ES+)：m/e 410(M+1).

Preparation scheme 237

Compound (237) is by obtaining (1.82g) with preparation scheme 229 similar modes from compound (6).

¹H-NMR(300MHz，CDCl ₃，δ)：1.54(9H，s)，3.66(2H，s)，3.93(3H，s)，4.69(2H，d，J＝4.4Hz)，6.37(1H，d，J＝16.1Hz)，6.63(1H，br)，7.00(1H，t，J＝8.4Hz)，7.03(1H，t，J＝7.7Hz)，7.35(2H，d，J＝8.4Hz)，7.51(2H，d，J＝8.1Hz)，7.58(1H，d，J＝16.1Hz)，7.90(1H，dd，J＝7.7，1.8Hz)；

MASS(ES+)：m/e 410(M+1).

Preparation scheme 238

Compound (238) is by obtaining (4.20g) with preparation scheme 229 similar modes from 4-iodophenyl acetate.

¹H-NMR(300MHz，CDCl ₃，δ)：3.61(2H，s)，4.74(2H，d，J＝4.4Hz)，7.09(2H，d，J＝8.4Hz)，7.49(2H，t，J＝7.4Hz)，7.63(1H，t，J＝7.4Hz)，7.70(2H，d，J＝8.4Hz)，7.95(2H，d，J＝7.4Hz)；

MASS(ES+)：m/e 380(M+1).

Preparation scheme 239

Compound (239) is by obtaining (600mg) with preparation scheme 229 similar modes from compound (6).

¹H-NMR(300MHz，DMSO-d ₆，δ)：1.54(9H，s)，1.58-1.84(12H，m)，1.99-2.10(3H，m)，3.61(2H，s)，4.21(2H，d，J＝4.4Hz)，6.35(1H，d，J＝16.1Hz)，7.30(2H，d，J＝8.1Hz)，7.50(2H，d，J＝8.1Hz)，7.56(1H，d，J＝16.1Hz)；

MASS(ES+)：m/z 438(M+1).

Preparation scheme 240

Compound (240) is by obtaining (231mg) with preparation scheme 229 similar modes from compound (6).

¹H-NMR(300MHz，CDCl ₃，δ)：1.54(9H，s)，3.68(2H，s)，3.69(3H，s)，6.18(1H，d，J＝7.3Hz)，6.36(1H，d，J＝15.8Hz)，7.30(2H，d，J＝8.1 Hz)，7.51(4H，m)，7.62(2H，m)，8.08(2H，d，J＝7.0Hz)；

MASS(ES+)：m/e 438(M+1).

Preparation scheme 241

Compound (241) is by obtaining (1.33g) with preparation scheme 229 similar modes.

¹H-NMR(300MHz，CDCl ₃，δ)：1.17(9H，s)，1.54(9H，s)，3.62(2H，s)，4.25(2H，d，J＝4.4Hz)，6.36(1H，d，J＝15.8Hz)，7.31(2H，d，J＝8.4Hz)，7.51(2H，d，J＝8.1Hz)，7.57(1H，d，J＝16.1Hz)；

MASS(ES+)：m/e 360(M+1).

Preparation scheme 242

Compound (242) is by obtaining (1.58g) with preparation scheme 229 similar modes from compound (6).

¹H-NMR(300MHz，CDCl ₃，δ)：1.12(3H，t，J＝7.0Hz)，1.53(9H，s)，3.67(2H，s)，4.13(2H，q，J＝7.4Hz)，6.15(1H，d，J＝7.3Hz)，6.36(1H，d，J＝15.8Hz)，6.86(1H，br.d，J＝6.6Hz)，7.31(2H，d，J＝8.1Hz)，7.48(2H，t，J＝7.4Hz)，7.50(2H，d，J＝8.1Hz)，7.57(1H，d，J＝16.1Hz)，7.63(1H，t，J＝7.4Hz)，8.08(2H，d，J＝8.1Hz)；

MASS(ES+)：m/z 452(M+1).

Preparation scheme 243

Compound (243) is by obtaining (200mg) with preparation scheme 229 similar modes from compound (6).

¹H-NMR(300MHz，CDCl ₃，δ)：1.30(4H，m)，1.53(9H，s)，1.64(2H，m)，1.80(4H，m)，2.36(1H，m)，3.62(2H，s)，4.17(2H，d，J＝4.4Hz)，6.35(1H，d，J＝16.1Hz)，7.30(2H，d，J＝8.4Hz)，7.49(2H，d，J＝8.1Hz)，7.56(1H，d，J＝15.8Hz)；

MASS(ES+)：m/z 386(M+1).

Preparation scheme 244

Compound (244) is by obtaining (866mg) with preparation scheme 229 similar modes from compound (6).

¹H-NMR(300MHz，CDCl ₃，δ)：1.34(3H，t，J＝7Hz)，3.60(2H，s)，3.71(2H，s)，4.16(2H，d，J＝5Hz)，4.27(2H，q，J＝7Hz)，6.42(1H，d，J＝16Hz)，7.16-7.37(7H，m)，7.50(2H，d，J＝8Hz)，7.66(1H，d，J＝16Hz)；

MASS(ES+)：m/z 366(M+1).

Preparation scheme 245

In compound (229) dimethylbenzene (50mL) suspension (5.42g), add AcONH ₄And AcOH, the gained mixture refluxed 3 hours, the azeotropic removal of water branch.Gained solution is chilled to envrionment temperature, pours saturated NaHCO into ₃In the aqueous solution (100mL), extract with AcOEt.The saturated NaHCO of organic layer ₃Na is used in the aqueous solution, water and salt water washing ₂SO ₄Dry.Solvent removed in vacuo, residual solid is ground with isopropyl ether, obtains compound (245) (4.56g), is buff powder.

¹H-NMR(300MHz，CDCl ₃，δ)：1.53(9H，s)，4.19(2H，s)，6.35(1H，d，J＝15.7Hz)，7.21(1H，s)，7.25(1H，t，J＝7.0Hz)，7.29(2H，d，J＝8.4Hz)，7.38(2H，t，J＝7.0Hz)，7.48(2H，d，J＝7.7Hz)，7.56(1H，d，J＝15.4Hz)，7.69(2H，br.d)；

MASS(ES+)：m/e 361(M+1).

Preparation scheme 246

Compound (246) is by obtaining (1.10g) with preparation scheme 245 similar modes from compound (230).

¹H-NMR(300MHz，CDCl ₃，δ)：1.53(9H，s)，3.82(3H，s)，4.17(2H，s)，6.36(1H，d，J＝16.1Hz)，7.22-7.48(9H，m)，7.54(1H，d，J＝16.1Hz)，7.74-7.87(1H，m)；

MASS(ES+)：m/z 419(M+1).

Preparation scheme 247

Compound (247) is by obtaining (3.8g) with preparation scheme 245 similar modes from compound (231).

¹H-NMR(300MHz，CDCl ₃，δ)：1.54(9H，s)，3.82(3H，s)，4.1.7(2H，s)，6.36(1H，d，J＝16.1Hz)，7.29(2H，d，J＝8.1Hz)，7.38(2H，d，J＝8.1Hz)，7.49(2H，d，J＝8.1Hz)，7.55(1H，d，J＝16.1Hz)，7.78-7.90(2H，m)；

MASS(ES+)：m/z 453(M+1).

Preparation scheme 248

Compound (248) is by obtaining (2.08g) with preparation scheme 245 similar modes from compound (232).

¹H-NMR(300MHz，CDCl ₃，δ)：1.54(3x3H，s)，4.16(2H，s)，6.36(1H，d，J＝16.2Hz)，7.06(2x1H，dd，J＝8.8，8.7Hz)，7.14(1H，s)，7.27(2x1H，d，J＝8Hz)，7.46(2x1H，d，J＝8Hz)，7.54(1H，d，J＝16.2Hz)，7.73(2H，m)，8.84(1H，br)；

MASS(ES+)：m/z 379.

Preparation scheme 249

Compound (249) is by obtaining (1.12g) with preparation scheme 245 similar modes from compound (233).

¹H-NMR(300MHz，CDCl ₃，δ)：1.54(9H，s)，4.17(2H，s)，6.33(1H，d，J＝16.1Hz)，7.17(1H，s)，7.27(2H，d，J＝8.1Hz)，7.33(2H，d，J＝8.4Hz)，7.46(2H，d，J＝8.1Hz)，7.53(2H，d，J＝16.1Hz)，7.64(2H，d，J＝8.4Hz)；

MASS(ES+)：m/z 395(M+1).

Preparation scheme 250

Compound (250) is by obtaining (1.28g) with preparation scheme 245 similar modes from compound (234).

¹H-NMR(300MHz，CDCl ₃，δ)：1.52(9H，s)，4.16(2H，s)，6.33(1H，d，J＝16.1Hz)，7.17-7.44(8H，m)，7.52(1H，d，J＝16.1Hz)，7.64-7.73(2H，m)；

MASS(ES+)：m/z 361(M+1).

Preparation scheme 251

Compound (251) is by obtaining (2.00g) with preparation scheme 245 similar modes from compound (235).

¹H-NMR(300MHz，CDCl ₃，δ)：1.54(9H，s)，3.82(3H，s)，4.16(2H，s)，6.34(1H，d，J＝15.8Hz)，6.91(2H，d，J＝8.8Hz)，7.10(1H，s)，7.27(2H，d，J＝8.4Hz)，7.47(2H，d，J＝8.4Hz)，7.55(1H，d，J＝16.1Hz)，7.60(2H，br.d)；

MASS(ES+)：m/z 391(M+1).

Preparation scheme 252

Compound (252) is by obtaining (2.72g) with preparation scheme 245 similar modes from compound (236).

¹H-NMR(300MHz，CDCl ₃，δ)：1.53(9H，s)，3.78(3H，s)，4.05(2H，s)，6.28(1H，d，J＝16.1Hz)，6.78(1H，m)，7.17(2H，d，J＝8.1Hz)，7.18(1H，s)，7.247(2H，d，J＝5.17Hz)，7.37(2H，d，J＝8.4Hz)，7.49(1H，d，J＝15.7Hz)；

MASS(ES+)：m/e 391(M+1).

Preparation scheme 253

Compound (253) is by obtaining (1.56g) with preparation scheme 245 similar modes from compound (237).

¹H-NMR(300MHz，CDCl ₃，δ)：1.54(9H，s)，3.85(3H，s)，4.19(2H，s，J＝16.1Hz)，6.34(1H，d，J＝8.4Hz)，6.76(1H，d，J＝7.5Hz)，7.00(1H，t，J＝7.5Hz)，7.22(1H，t，J＝8.1Hz)，7.30(2H，d)，7.41(1H，s，J＝8.4Hz)，7.48(2H，d，J＝16.1Hz)，7.72(1H，d，J＝8.4Hz)，7.76(1H，br.d)；

MASS(ES+)：m/e 391(M+1).

Preparation scheme 254

Compound (254) is by obtaining (4.00g) with preparation scheme 245 similar modes from compound (238).

¹H-NMR(300MHz，CDCl ₃，δ)：4.08(2H，s)，7.03(2H，d，J＝8.4Hz)，7.24(1H，t，J＝7.4Hz)，7.37(2H，t，J＝7.7Hz)，7.65(2+2H，d，J＝8.4Hz)；

MASS(ES+)：m/e 361(M+1).

Preparation scheme 255

Compound (255) is by obtaining (803mg) with preparation scheme 245 similar modes from N-(2-oxo-2-phenylethyl) ethanamide.

¹H-NMR(300MHz，DMSO-d ₆，δ)：2.48(3H，s)，7.20(1H，s)，7.23(1H，t，J＝8.1Hz)，7.37(2H，t，J＝7.7Hz)，7.69(2H，d，J＝8.1Hz).

Preparation scheme 256

Compound (256) is by obtaining (460mg) with preparation scheme 245 similar modes from compound (239).

¹H-NMR(300MHz，CDCl ₃，δ)：1.53(9H，s)，1.69-1.81(6H，m)，1.83-1.91(6H，m)，1.99-2.08(3H，m)，4.09(2H，s)，6.34(1H，d，J＝16.l Hz)，6.57(1H，s)，7.23(2H，d，J＝8.2Hz)，7.45(2H，d，J＝8.2Hz)，7.55(1H，d，J＝16.1Hz)；

MASS(ES+)：m/z 419(M+1).

Preparation scheme 257

Compound (257) is by obtaining (58mg) with preparation scheme 245 similar modes from compound (240).

¹H-NMR(300MHz，CDCl ₃，δ)：1.54(9H，s)，3.82(3H，s)，4.17(2H，s)，6.35(1H，d，J＝16.1Hz)，7.28(2H，d，J＝7.7Hz)，7.39(3H，m)，7.48(2H，d，J＝7.7Hz)，7.55(1H，d，J＝16.1Hz)，7.87(2H，br.)；

MASS(ES+)：m/e 419(M+1).

Preparation scheme 258

Compound (258) is by obtaining (1.06g) with preparation scheme 245 similar modes from compound (241).

¹H-NMR(300MHz，CDCl ₃，δ)：1.28(9H，s)，1.53(9H，s)，4.07(2H，s)，6.31(1H，d，J＝16.1Hz)，6.60(1H，s)，7.21(2H，d，J＝8.1Hz)，7.43(2H，d，J＝8.4Hz)，7.52(1H，d，J＝15.8Hz)；

MASS(ES+)：m/e 341(M+1).

Preparation scheme 259

Compound (259) is by obtaining (80mg) with preparation scheme 245 similar modes from compound (243).

¹H-NMR(300MHz，CDCl ₃，δ)：1.32(4H，m)，1.53(9H，s)，1.73(4H，m)，1.98(2H，m)，2.50(1H，m)，4.04(2H，s)，6.31(1H，d，J＝16.1Hz)，6.58(1H，s)，7.20(2H，d，J＝8.1Hz)，7.42(2H，d，J＝8.1Hz)，7.52(1H，d，J＝16.1Hz)；

MASS(ES+)：m/z 367(M+1).

Preparation scheme 260

Compound (260) is by obtaining (232mg) with preparation scheme 245 similar modes from compound (244).

¹H-NMR(300MHz，CDCl ₃，δ)：1.39(3H，t，J＝7Hz)，3.92(2H，s)，4.09(2H，s)，4.26(2H，q，J＝7Hz)，6.41(1H，d，J＝16Hz)，7.21-7.33(7H，m)，7.48(2H，d，J＝8Hz)，7.65(1H，d，J＝16Hz)；

MASS(ES+)：m/z 347(M+1).

Preparation scheme 261

Add trifluoroacetic acid (2.74mL) in methylene dichloride (17mL) solution of compound (297) (2.56g, be described in hereinafter prepare in the scheme 297), the gained mixture stirred 1 hour.Solvent removed in vacuo, resistates grinds with isopropyl ether, obtains compound (261) (2.83g), is colourless powder.

¹H-NMR(300MHz，DMSO-d ₆，δ)：4.37(2H，s)，6.54(1H，d，J＝15.8Hz)，7.39(2H，d，J＝8.1Hz)，7.43(1H，t，J＝7.7Hz)，7.53(2H，t，J＝8.1Hz)，7.58(1H，d，J＝15.8Hz)，7.72(2H，d，J＝8.4Hz)，7.77(2H，d，J＝8.1Hz)，8.05(1H，s)；

MASS(ES+)：m/e 305(M+1).

Preparation scheme 262

Compound (262) is by obtaining (1.55g) with preparation scheme 261 similar modes from compound (246).

1H-NMR(300MHz，CDCl ₃-CD ₃OD(10∶1)，δ)：3.87(3H，s)，4.35(2H，s)，6.46(1H，d，J＝16.2Hz)，7.10-7.76(10H，m)；

MASS(ES+)：m/z 369(M+1，free).

Preparation scheme 263

Compound (263) is by obtaining (2.32g) with preparation scheme 261 similar modes from compound (251).

¹H-NMR(300MHz，DMSO-d ₆，δ)：3.81(3H，s)，4.37(2H，s)，6.55(1H，d，J＝16.1Hz)，7.10(2H，d，J＝8.8Hz)，7.40(2H，d，J＝8.4Hz)，7.59(1H，d，J＝16.1Hz)，7.71(2H，d，J＝8.8Hz)，7.72(2H，d，J＝8.4Hz)，7.95(1H，s)；

MASS(ES+)：m/z 335(M+1).

Preparation scheme 264

Compound (264) is by obtaining (1.27g) with preparation scheme 261 similar modes from compound (252).

¹H-NMR(300MHz，DMSO-d ₆，δ)：3.83(3H，s)，4.39(2H，s)，6.55(1H，d，J＝15.8Hz)，7.02(1H，d，J＝8.1Hz)，7.33-7.47(5H，m)，7.60(1H，d，J＝15.8Hz)，7.73(2H，d，J＝8.1Hz)，8.11(1H，s)；

MASS: undetermined.

Preparation scheme 265

Compound (265) is by obtaining (1.24g) with preparation scheme 261 similar modes from compound (253).

¹H-NMR(300MHz，DMSO-d ₆，δ)：3.93(3H，s)，4.40(2H，s)，6.54(1H，d，J＝16.1Hz)，7.12(1H，t，J＝7.3Hz)，7.22(1H，d，J＝7.7Hz)，7.39(2H，d，J＝8.1Hz)，7.46(1H，t，J＝7.9Hz)，7.58(1H，d，J＝16.1Hz)，7.72(2H，d，J＝8.1Hz)，7.89(1H，s)；

MASS(ES+)：m/e 335(M+1).

Preparation scheme 266

Compound (266) is by obtaining (208mg) with preparation scheme 261 similar modes from following compound (293).

¹H-NMR(300MHz，DMSO-d ₆，δ)：4.08(2H，s)，6.05(1H，d，J＝16.1Hz)，7.35(2H，d，J＝8.4Hz)，7.37(1H，t，J＝7.4Hz)，7.49(2H，d，J＝7.4Hz)，7.57(1H，d，J＝16.1Hz)，7.66(2H，d，J＝8.1Hz)，7.71(1H，d，J＝7.0Hz)；

MASS(ES+)：m/e 383(M+1).

Preparation scheme 267

Compound (267) is by obtaining (234mg) with preparation scheme 261 similar modes from compound (227).

¹H-NMR(300MHz，DMSO-d ₆，δ)：4.03(2H，s)，6.49(1H，d，J＝15.8Hz)，7.32(1H，t，J＝7.3Hz)，7.34(2H，d，J＝8.4Hz)，7.47(2H，t，J＝7.3Hz)，7.57(1H，d，J＝16.1Hz)，7.65(2H，d，J＝8.4Hz)，7.70(2H，d，J＝7.3Hz)；

MASS(ES+)：m/e 339(M+1).

Preparation scheme 268

Compound (268) is by obtaining (1.32g) with preparation scheme 261 similar modes from following compound (294).

¹H-NMR(300MHz，DMSO-d ₆，δ)：2.72(6H，s)，4.21(2H，s)，4.39(2H，s)，6.52(1H，d，J＝15.8Hz)，7.38(2H，d，J＝8.1Hz)，7.47(1H，m)，7.54(4H，m)，7.58(1H，d，J＝15.4Hz)，7.68(2H，d，J＝8.4Hz)；

MASS(ES+)：m/e 362(M+1).

Preparation scheme 269

Compound (269) is by obtaining (412mg) with preparation scheme 261 similar modes from following compound (295).

¹H-NMR(300MHz，DMSO-d ₆，δ)：1.48(2H，br.)，1.69(4H，br.)，2.91(2H，br.)，3.27(2H，br.)，4.24(2H，s)，4.38(2H，s)，6.53(1H，d，J＝16.1Hz)，7.38(2H，d，J＝8.1Hz)，7.47-7.61(6H，m)，7.69(2H，d，J＝8.1Hz)；

MASS(ES+)：m/e 402(M+1).

Preparation scheme 270

Compound (270) is by obtaining (407mg) with preparation scheme 261 similar modes from following compound (296).

¹H-NMR(300MHz，DMSO-d ₆，δ)：3.07(4H，br.)，3.75(4H，br.)，4.22(2H，s)，4.29(2H，s)，6.52(1H，d，J＝15.7Hz)，7.39(2H，d，J＝8.1Hz)，7.46(1H，t，J＝7.0Hz)，7.53(2H，t，J＝7.0Hz)，7.58(1H，d，J＝16.1Hz)，7.59(2H，d，J＝7.3Hz)，7.68(2H，d，J＝8.1Hz)；

MASS(ES+)：m/e 404(M+1).

Preparation scheme 271

Compound (271) is by obtaining (171mg) with preparation scheme 261 similar modes from compound (228).

¹H-NMR(300MHz，DMSO-d ₆，δ)：3.79(3H，s)，4.03(2H，s)，6.50(1H，d，J＝16.1Hz)，7.05(2H，d，J＝8.8Hz)，7.34(2H，d，J＝8.1Hz)，7.57(1H，d，J＝15.8Hz)，7.62(2H，d，J＝8.8Hz)，7.65(2H，d，J＝8.1Hz)；

MASS(ES+)：m/e 369(M+1).

Preparation scheme 272

Compound (272) is by obtaining (339mg) with preparation scheme 261 similar modes from compound (215).

¹H-NMR(300MHz，DMSO-d ₆，δ)：5.46(2H，s)，6.60(1H，d，J＝16.1Hz)，7.43(1H，t，J＝7.0Hz)，7.46-7.54(4H，m)，7.61(1H，d，J＝16.1Hz)，7.72(1H，m)，7.78(2H，d，J＝7.0Hz)，7.84(1H，s)，8.25(1H，s)，9.29(1H，s)；

MASS(ES+)：m/e 305(M+1).

Preparation scheme 273

Compound (273) is by obtaining (491mg) with preparation scheme 261 similar modes from compound (218).

¹H-NMR(300MHz，DMSO-d ₆，δ)：2.30(3H，s)，5.48(2H，s)，6.57(1H，d，J＝16.1Hz)，7.34-7.52(3H，m)，7.58(1H，d，J＝15.8Hz)，7.60(4H，s)，7.71(1H，s)，9.26(1H，s)；

MASS(ES+)：m/e 353(M+1).

Preparation scheme 274

Compound (274) is by obtaining (65mg) with preparation scheme 261 similar modes from compound (257).

¹H-NMR(300MHz，DMSO-d ₆，δ)：3.78(3H，s)，4.20(2H，s)，6.51(1H，d，J＝15.8Hz)，7.38(2H，d，J＝7.7Hz)，7.47(3H，m)，7.57(1H，d，J＝15.8Hz)，7.67(2H，d，J＝8.4Hz)，7.76(2H，m)；

MASS(ES+)：m/e 363(M+1).

Preparation scheme 275

Compound (275) is by obtaining (454mg) with preparation scheme 261 similar modes from compound (258).

¹H-NMR(300MHz，DMSO-d ₆，δ)：1.21(9H，s)，4.32(2H，s)，6.55(1H，d，J＝16.1Hz)，7.34(2H，d，J＝8.4Hz)，7.58(1H，d，J＝16.1Hz)，7.71(2H，d，J＝8.1Hz)；

MASS(ES+)：m/e 285(M+1).

Preparation scheme 276

Compound (276) is by obtaining (98.5mg) with preparation scheme 261 similar modes from compound (259).

¹H-NMR(300MHz，DMSO-d ₅，δ)：1.32(4H，m)，1.72(4H，m)，1.94(2H，m)，2.47(1H，m)，4.28(2H，s)，6.54(1H，d，J＝15.8Hz)，7.31(1H，s)，7.33(2H，d，J＝8.1Hz)，7.58(1H，d，J＝15.4Hz)，7.71(2H，d，J＝8.1Hz)；

MASS(ES+)：m/z 311(M+1).

Preparation scheme 277

At ambient temperature, add O-(tetrahydrochysene-2H-pyrans-2-yl) azanol (1.66g), HOBt (2.74g) and EDCI (3.15g) in compound (261) DMF (30mL) solution (2.46g), the gained mixture stirred 3 hours.The saturated NaHCO of gained mixture ₃Collecting precipitation is filtered in aqueous solution dilution.The gained powder washes with water, and drying obtains compound (277) (2.46g), is buff powder.Gained compound (277) is used for embodiment 58.

¹H-NMR(300MHz，DMSO-d ₆，δ)：1.54(3H，br.)，1.70(3H，br.)，3.51(1H，m)，3.96(1H，m)，4.04(2H，s)，4.90(1H，s)，6.46(1H，d，J＝16.1Hz)，7.16(1H，m)，7.31(4H，m)，7.46(1H，d，J＝15.7Hz)，7.51(3H，m)，7.73(2H，d，J＝7.3Hz)；

MASS(ES+)：m/e 304(M+1).

Preparation scheme 278

Compound (278) is by obtaining (896mg) with preparation scheme 277 similar modes from compound (262).Gained compound (278) is used for embodiment 59.

¹H-NMR(300MHz，CDCl ₃，δ)：1.48-1.86(6H，m)，3.58-3.69(1H，m)，3.81(3H，s)，3.91-4.09(3H，m)，4.95(1H，br.s)，6.09-6.30(1H，m)，7.17-7.31(6H，m)，7.33-7.43(4H，m)，7.74-7.84(2H，m)；

MASS(ES+)：m/z 462(M+1).

Preparation scheme 279

Compound (279) is by obtaining (1.67g) with preparation scheme 277 similar modes from compound (263).Gained compound (278) is used for embodiment 70.

¹H-NMR(300MHz，DMSO+d ₆，δ)：1.54(3H，br.)，1.69(3H，br.)，3.53(1H，m)，3.76(3H，s)，3.94(1H，m)，4.08(2H，s)，4.91(1H，s)，6.47(1H，d，J＝15.8Hz)，6.94(2H，d，J＝8.8Hz)，7.33(2H，d，J＝8.1Hz)，7.43(1H，s)，7.46(1H，d，J＝15.8Hz)，7.54(2H，d，J＝7.7Hz)，7.64(2H，d，J＝8.8Hz)；

MASS(ES+)：m/z 434(M+1).

Preparation scheme 280

Compound (280) is by obtaining (758mg) with preparation scheme 277 similar modes from compound (264).Gained compound (280) is used for embodiment 71.

¹H-NMR(300MHz，DMSO-d ₆，δ)：1.54(3H，br.)，1.69(3H，br.)，3.52(1H，m)，3.78(3H，s)，3.95(1H，m)，4.04(2H，s)，4.90(1H，s)，6.46(1H，d，J＝16.1Hz)，6.74(1H，d，J＝8.1Hz)，7.20-7.33(5H，m)，7.46(1H，d，J＝15.8Hz)，7.51(1H，s)，7.52(2H，d，J＝8.1Hz)；

MASS(ES+)：m/e 434(M+1).

Preparation scheme 281

Compound (281) is by obtaining (729mg) with preparation scheme 277 similar modes from compound (265).Gained compound (281) is used for embodiment 72.

¹H-NMR(300MHz，DMSO-d ₆，δ)：1.53(3H，br.s)，1.69(3H，br.s)，3.53(1H，m)，3.88(3H，s)，3.95(1H，m)，4.05(2H，s)，4.90(1H，s)，6.46(1H，d，J＝16.3Hz)，6.96(1H，t，J＝7.3Hz)，7.03(1H，d，J＝8.1Hz)，7.17(1H，t，J＝8.1Hz)，7.32(2H，d，J＝8.1Hz)，7.42(1H，br.s)，7.46(1H，d，J＝16.1Hz)，7.52(2H，d，J＝8.1Hz)；

MASS(ES+)：m/z 434(M+1).

Preparation scheme 282

Compound (282) is by obtaining (148mg) with preparation scheme 277 similar modes from compound (266).Gained compound (282) is used for embodiment 73.

¹H-NMR(300MHz，DMSO-d ₆，δ)：1.54(3H，br.)，1.69(3H，br.)，3.55(1H，m)，3.95(1H，m)，4.02(2H，s)，4.91(1H，s)，6.48(1H，d，J＝16.1Hz)，7.32(1H，t，J＝7.0Hz)，7.34(2H，d，J＝8.1Hz)，7.46(2H，t，J＝7.3Hz)，7.46(1H，d，J＝15.4Hz)，7.54(2H，d，J＝8.1Hz)，7.71(2H，d，J＝7.3Hz)；

MASS(ES+)：m/e 482(M+1).

Preparation scheme 283

Compound (283) is by obtaining (166mg) with preparation scheme 277 similar modes from compound (267).Gained compound (283) is used for embodiment 74.

¹H-NMR(300MHz，DMSO-d ₆，δ)：1.54(3H，br.)，1.69(3H，br.)，3.53(1H，m)，3.69(1H，m)，4.02(2H，s)，4.90(1H，s)，6.47(1H，d，J＝16.1Hz)，7.32(1H，t，J＝8.1Hz)，7.33(2H，d，J＝8.1Hz)，7.47(2H，t，J＝15.8Hz)，7.47(1H，d，J＝8.1Hz)，7.54(2H，d，J＝8.4Hz)，7.70(2H，d，J＝8.1Hz)；

MASS(ES+)：m/e 438(M+1).

Preparation scheme 284

Compound (284) is by obtaining (811mg) with preparation scheme 277 similar modes from compound (268).Gained compound (283) is used for embodiment 90 and 111.

¹H-NMR(300MHz，CDCl ₃，δ)：1.51-1.67(6H，br)，2.28(6H，s)，3.60(1H，m)，3.94(1H，m)，4.12(2H，s)，4.71(1H，s)，7.39(3H，m)，7.59(2H，d，J＝6.6Hz)，7.61(1H，d，J＝16.8Hz)；

MASS(ES+)：m/e 461(M+1).

Preparation scheme 285

Compound (285) is by obtaining (105mg) with preparation scheme 277 similar modes from compound (269).Gained compound (285) is used for embodiment 75.

¹H-NMR(300MHz，CDCl ₃，δ)：1.45(3H，br.)，1.59(3+4H，br.)，1.84(2H，br.)，2.48(4H，br.)，3.64(1H，m)，3.71(2H，s)，3.97(1H，m)，4.12(2H，s)，5.01(1H，s)，6.32(1H，d，J＝16.1Hz)，7.26(1+2H，m)，7.39(2+2H，m)，7.49(1H，d，J＝16.5Hz)，7.59(2H，d，J＝7.0Hz)；

MASS(ES+)：m/e 501(M+1).

Preparation scheme 286

Compound (286) is by obtaining (129mg) with preparation scheme 277 similar modes from compound (270).Gained compound (286) is used for embodiment 76.

¹H-NMR(300MHz，DMSO-d ₆，δ)：1.53(3H，br.)，1.69(3H，br.)，2.40(4H，br.)，3.52(1H，m)，3.57(4H，br.)，3.95(1H，m)，4.00(2H，s)，4.90(1H，s)，6.46(1H，d，J＝15.8Hz)，7.23(1H，br.)，7.33(2H，d，J＝8.4Hz)，7.36(2H，br.)，7.46(1H，d，J＝15.8Hz)，7.51(2H，d，J＝8.1Hz)，7.70(2H，br.)；

MASS(ES+)：m/e 503(M+1).

Preparation scheme 287

Compound (287) is by obtaining (108mg) with preparation scheme 277 similar modes from compound (271).Gained compound (285) is used for embodiment 77.

¹H-NMR(300MHz，DMSO-d ₆，δ)：1.53(3H，br.)，1.69(3H，br.)，3.54(1H，m)，3.79(3H，s)，3.94(1H，m)，3.98(2H，s)，4.90(1H，s)，6.47(1H，d，J＝16.1Hz)，7.04(2H，d，J＝8.8Hz)，7.33(2H，d，J＝7.7Hz)，7.47(1H，d，J＝15.4Hz)，7.53(2H，d，J＝7.7Hz)，7.61(2H，d，J＝8.8Hz)；

MASS(ES+)：m/e 468(M+1).

Preparation scheme 288

Compound (288) is by obtaining (215mg) with preparation scheme 277 similar modes from compound (272).Gained compound (288) is used for embodiment 80.

¹H-NMR(300MHz，DMSO-d ₆，δ)：1.53(3H，br.)，1.69(3H，br.)，3.53(1H，m)，3.94(1H，m)，4.90(1H，s)，5.25(2H，s)，6.50(1H，d，J＝16.1Hz)，7.18(1H，t，J＝7.3Hz)，7.32(3H，m)，7.38(1H，d，J＝15.4Hz)，7.44(1H，d，J＝7.3Hz)，7.52(1H，s)，7.56(1H，s)，7.73(3H，m)，7.86(1H，s)；

MASS(ES+)：m/e 404(M+1).

Preparation scheme 289

Compound (289) is by obtaining (419mg) with preparation scheme 277 similar modes from compound (273).Gained compound (289) is used for embodiment 81.

¹H-NMR(300MHz，DMSO-d ₆，δ)：1.53(3H，br.)，1.69(3H，br.)，3.52(1H，m)，3.95(1H，m)，4.91(1H，s)，5.26(2H，s)，6.48(1H，d，J＝15.8Hz)，7.19(1H，d，J＝7.7Hz)，7.43(5H，m)，7.51(1H，s)，7.65(2H，d，J＝8.8Hz)，7.86(1H，s)；

MASS(ES+)：m/e 452(M+1).

Preparation scheme 290

Compound (290) is by obtaining (43mg) with preparation scheme 277 similar modes from compound (274).Gained compound (290) is used for embodiment 84.

¹H-NMR(300MHz，CDCl ₃，δ)：1.60(3H，br.)，1.81(3H，br.)，6.64(1H，m)，3.82(3H，s)，3.97(1H，s)，4.03(2H，s)，5.00(1H，br.)，6.28(1H，br.)，7.12(2H，br.)，7.32(2H，br.)，7.39(3H，m)，7.54(1H，br.)，7.79(2H，br.)；

MASS(ES+)：m/e 462(M+1).

Preparation scheme 291

Compound (291) is by obtaining (85mg) with preparation scheme 277 similar modes from compound (275).Gained compound (291) is used for embodiment 85.

¹H-NMR(300MHz，DMSO-d ₆，δ)：1.54(3H，br.)，1.69(3H，br.)，3.53(1H，m)，3.94(2H，s)，3.97(1H，m)，4.91(1H，s)，6.45(1H，d，J＝15.3Hz)，6.56(1H，s)，7.27(2H，d，J＝8.1Hz)，7.47(1H，d，J＝16.1Hz)，7.50(2H，d，J＝8.8Hz)；

MASS(ES+)：m/e 384(M+1).

Preparation scheme 292

Compound (292) is by obtaining (42mg) with preparation scheme 277 similar modes from compound (276).Gained compound (292) is used for embodiment 110.

¹H-NMR(300MHz，CDCl ₃，δ)：1.30(6H，m)，1.62-2.00(10H，m)，2.51(1H，m)，3.67(1H，m)，4.02(1H，m)，4.02(2H，s)，5.01(1H，s)，6.37(1H，br.)，6.58(1H，s，J＝8.0Hz)，7.23(2H，d，J＝7.7Hz)，7.43(2H，d，J＝16.1Hz)，7.62(1H，d)；

MASS(ES+)：m/z 410(M+1).

Preparation scheme 293

Under 5 ℃, in compound (245) MeCN (20mL) suspension (2.0g), add N-bromine succinimide (988mg), the gained mixture stirred 0.5 hour down at 5 ℃.Pour mixture into 5%NaHSO ₃In the aqueous solution (100mL), extract mixture with AcOEt.The saturated NaHCO of organic layer ₃The aqueous solution and salt water washing, Na ₂SO ₄Dry.Solvent removed in vacuo, remaining brown oil passes through silica gel flash column chromatography hexane: AcOEt=1: 1 wash-out purifying, obtain compound (293) (1.68g), be orange form.

¹H-NMR(300MHz，CDCl ₃，δ)：1.53(9H，s)，4.13(2H，s)，6.34(1H，d，J＝16.1Hz)，7.28(2H，d，J＝8.1Hz)，7.31(1H，t，J＝7.4Hz)，7.40(2H，t，J＝7.4Hz)，7.47(2H，d，J＝8.1Hz)，7.54(1H，d，J＝16.1Hz)，7.57(2H，d，J＝7.4Hz)；

MASS(ES+)：m/e 439(M+1).

Preparation scheme 294

Add N to compound (245) solution (1.0g), N dimethylamine hydrochloride (339mg) and paraformaldehyde (125mg), the gained mixture heated 1 hour down at 90 ℃.Pour reaction mixture into saturated NaHCO ₃In the aqueous solution, extract with AcOEt.The saturated NaHCO of organic layer ₃The aqueous solution, water and salt water washing, Na ₂SO ₄Dry.Solvent removed in vacuo obtains compound (294) (742mg), is yellow form.

¹H-NMR(300MHz，CDCl ₃，δ)：1.53(9H，s)，2.23(6H，s)，3.58(2H，s)，4.16(2H，s)，6.35(1H，d，J＝15.8Hz)，7.29(1H，t，J＝8.1Hz)，7.30(2H，d，J＝8.1Hz)，7.39(2H，t，J＝8.1Hz)，7.48(2H，t，J＝8.1Hz)，7.57(1H，d，J＝16.1Hz)，7.58(1H，br.)；

MASS(ES+)：m/e 418(M+1).

Preparation scheme 295

Compound (295) is by obtaining (243mg) with preparation scheme 294 similar modes from compound (245).

¹H-NMR(300MHz，CDCl ₃，δ)：1.44(2H，br.)，1.53(9+4H，br.)，2.42(4H，br.)，3.63(2H，s)，4.11(2H，s)，6.34(1H，d，J＝15.8Hz)，7.27(1H，t，J＝8.1Hz)，7.28(2H，d，J＝8.1Hz)，7.37(2H，t，J＝8.1Hz)，7.45(2H，d，J＝8.4Hz)，7.55(1H，d，J＝15.7Hz)，7.58(2H，d，J＝8.1Hz)；

MASS(ES+)：m/e 458(M+1).

Preparation scheme 296

Compound (296) is by obtaining (297mg) with preparation scheme 294 similar modes from compound (245).

¹H-NMR(300MHz，CDCl ₃，δ)：1.53(9H，s)，2.48(4H，br.)，3.64(2H，s)，3.68(4H，br.)，4.15(2H，s)，6.35(1H，d，J＝16.1Hz)，7.28(1H，t，J＝8.1Hz)，7.29(2H，d，J＝8.1Hz)，7.39(2H，t，J＝7.5Hz)，7.48(2H，d，J＝8.4Hz)，7.56(2H，br.)，7.56(1H，d，J＝16.1Hz)；

MASS(ES+)：m/e 460(M+1).

Preparation scheme 297

Under agitation, in compound (254) DMF (40mL) solution (4.0g), add tert-butyl acrylate (8.13mL), acid chloride (II) (125mg), triphenylphosphine (583mg) and N, N-diisopropylethylamine (3.2mL).The gained mixture stirred 1 hour at 100 ℃.Pour the gained mixture into saturated NaHCO ₃In the aqueous solution, extract with AcOEt.The saturated NaHCO of organic layer ₃The aqueous solution and salt water washing, Na ₂SO ₄Dry.Solvent removed in vacuo with AcOEt wash-out purifying, obtains compound (297) (2.56g) by silica gel column chromatography, is colorless solid.

¹H-NMR(300MHz，CDCl ₃，δ)：1.53(9H，s)，4.18(2H，s)，6.34(1H，d，J＝16.1Hz)，7.21(1H，s)，7.25(1H，m)，7.28(2H，d，J＝8.4Hz)，7.37(2H，t，J＝7.4Hz)，7.47(2H，d，J＝8.4Hz)，7.55(1H，d，J＝16.1Hz)；

MASS(ES+)：m/e 361(M+1).

Preparation scheme 298

In the DMF of 4-iodophenol (1.0g) (10mL) solution, add K ₂CO ₃(325 order powder, Aldrich produces, and 691mg), the gained mixture is stirred 15 minutes.In mixture, add 4-bromo-butyric acid ethyl ester (0.722mL), the gained mixture was stirred 65 hours at ambient temperature.The gained mixture is poured in the saturated aqueous ammonium chloride, extracted with AcOEt.Organic phase is water, saturated aqueous ammonium chloride, water and salt water washing successively, Na ₂SO ₄Dry.Solvent removed in vacuo, remaining water white oil with AcOEt and hexane (1: 4) wash-out purifying, obtains compound (298) (1.32g) by silica gel column chromatography, is water white oil.

¹H-NMR(300MHz，CDCl ₃，δ)：1.26(3H，t，J＝7.1Hz)，2.10(2H，quint.，J＝6.7Hz)，2.50(2H，t，J＝7.3Hz)，3.97(2H，t，J＝6.0Hz)，4.14(2H，q，J＝7.1Hz)，6.66(2H，d，J＝9.2Hz)，7.54(2H，d，J＝9.2Hz)；

MASS: undetermined.

Preparation scheme 299

Compound (299) is by obtaining (1.70g) with preparation scheme 298 similar modes from the 4-iodophenol.

¹H-NMR(300MHz，CDCl ₃，δ)：1.26(3H，t，J＝7.1Hz)，1.81(4H，m)，2.38(2H，m)，3.94(2H，m)，4.14(2H，q，J＝7.2Hz)，6.66(2H，d，J＝9.2Hz)，7.54(2H，d，J＝9.2Hz)；

MASS: undetermined.

Preparation scheme 300

(1.32g) add the 1N NaOH aqueous solution (11.9mL) in De diox (13mL) solution to compound (298), the gained mixture was stirred 15 hours.Vacuum is removed organic solvent, with 1N HCl the pH value of remaining water is transferred to 3.Filter collecting precipitation, vacuum-drying obtains compound (300) (1.047g), is colourless powder.

¹H-NMR(300MHz，DMSO-d ₆，δ)：1.91(2H，quint.，J＝6.8Hz)，2.36(2H，t，J＝7.3Hz)，3.95(2H，t，J＝6.4Hz)，6.78(2H，d，J＝8.9Hz)，7.58(2H，d，J＝9.2Hz)；

MASS (ES+): undetermined.

Preparation scheme 301

Compound (301) is by obtaining (883mg) with preparation scheme 300 similar modes from compound (299).

¹H-NMR(300MHz，DMSO-d ₆，δ)：1.56-1.76(4H，m)，2.26(2H，t，J＝7.1Hz)，3.94(2H，t，J＝6.2Hz)，6.78(2H，d，J＝8.8Hz)，7.57(2H，d，J＝8.8Hz)；

MASS: undetermined.

Preparation scheme 302

Compound (302) is by obtaining (1.026g) with preparation scheme 297 similar modes from compound (300).

¹H-NMR(300MHz，CDCl ₃，δ)：1.53(9H，s)，2.13(2H，quint.，J＝6.6Hz)，2.58(2H，t，J＝7.2Hz)，4.05(2H，t，J＝6.0Hz)，6.24(1H，d，J＝15.8Hz)，6.87(2H，d，J＝8.8Hz)，7.44(2H，d，J＝8.8Hz)，7.53(2H，d，J＝16.1Hz)；

The MASS undetermined.

Preparation scheme 303

Compound (303) is by obtaining (635mg) with preparation scheme 297 similar modes from compound (301).

¹H-NMR(300MHz，CDCl ₃，δ)：1.53(9H，s)，1.85(4H，m)，2.45(2H，t，J＝5.9Hz)，4.00(2H，t，J＝5.9Hz)，6.24(1H，d，J＝16.1Hz)，6.87(2H，d，J＝8.8Hz)，7.44(2H，d，J＝8.8Hz)，7.54(1H，d，J＝15.8Hz)；

MASS: undetermined.

Preparation scheme 304

Compound (304) is by obtaining (1.68mg) with preparation scheme 297 similar modes from 4-(4-iodophenyl) butyric acid.

¹H-NMR(300MHz，CDCl ₃，δ)：1.53(9H，s)，1.97(2H，quint.，J＝7.5Hz)，2.38(2H，t，J＝7.3Hz)，2.69(2H，t，J＝7.5Hz)，6.33(1H，d，J＝15.8Hz)，7.19(2H，d，J＝8.1Hz)，7.44(2H，d，J＝8.1Hz)，7.56(2H，d，J＝15.8Hz)；

MASS: undetermined.

Preparation scheme 305

Compound (305) is by obtaining (2.45g) with preparation scheme 297 similar modes from following compound (318).

¹H-NMR(300MHz，CDCl ₃，δ)：1.43(1H，s)，1.53(9H，s)，1.69(1H，s)，1.93(1H，s)，2.59(1H，s)，6.33(1H，d，J＝16.4Hz)，7.10(2H，d，J＝8.1Hz)，7.43(2H，d，J＝8.1Hz)，7.55(1H，d，J＝15.8Hz)；

MASS(ES-)：m/e 287(M-1).

Preparation scheme 306

In the DMF of compound (302) (3mL) solution, add 2-aminophenyl t-butyl carbamate (224mg), HOBt (172mg) and N-ethyl-N '-(3-dimethylamino-propyl) carbodiimide hydrochloride (EDCIHCl, 224mg), the gained mixture was stirred 2 hours at ambient temperature.Pour mixture into saturated NaHCO ₃In the aqueous solution, use ethyl acetate extraction.Organic phase is used saturated NH successively ₄C1 solution, saturated NaHCO ₃Solution and salt water washing, Na ₂SO ₄Dry.Solvent removed in vacuo, resistates by preparation type thin layer chromatography (chloroform: purifying methyl alcohol=10: 1), obtain compound (306) (379mg), be light yellow form.

¹H-NMR(300MHz，CDCl ₃，δ)：1.50(9H，s)，1.53(9H，s)，2.23(2H，quint.，J＝6.6Hz)，2.60(2H，t，J＝7.0Hz)，4.09(2H，t，J＝6.0Hz)，6.24(1H，d，J＝15.8Hz)，6.88(2H，d，J＝8.8Hz)，7.16(2H，m)，7.36(1H，m)，7.44(2H，d，J＝8.8Hz)，7.50(1H，m)，7.53(1H，d，J＝15.8Hz)；

MASS(ES+)：m/e 497(M+1).

Preparation scheme 307

Compound (307) is by obtaining (395mg) with preparation scheme 306 similar modes from compound (303).

¹H-NMR(300MHz，CDCl ₃，δ)：1.50(9H，s)，1.53(9H，s)，1.92(4H，m)，2.47(2H，m)，4.03(2H，m)，6.24(1H，d，J＝16.1Hz)，6.87(2H，d，J＝8.8Hz)，7.17(2H，m)，7.35(1H，m)，7.44(2H，d，J＝8.8Hz)，7.50(1H，m)，7.53(1H，d ，J＝16.1Hz)；

MASS(ES+)：m/e 511(M+1).

Preparation scheme 308

Compound (308) is by obtaining (249mg) with preparation scheme 306 similar modes from compound (304).

¹H-NMR(300MHz，CDCl ₃，δ)：1.48(9H，s)，1.53(9H，s)，2.07(2H，quint.，J＝7.7Hz)，2.40(2H，t，J＝7.9Hz)，2.73(2H，t，J＝7.9Hz)，6.33(1H，d，J＝7.9Hz)，7.18(2H，m，J＝16.1Hz)，7.21(2H，d)，7.35(1H，m ，J＝8.1Hz)，7.44(2H，d)，7.50(1H，m，J＝8.1Hz)，7.56(1H，d，J＝16.1Hz)；

MASS(ES+)：m/e 481(M+1).

Preparation scheme 309

Under agitation, add 1NHCl/AcOH (3.82mL) solution in compound (306) AcOH (4mL) solution (379mg), the gained mixture heated 2 hours down at 120 ℃.Reaction mixture is cooled to envrionment temperature, dilutes with AcOEt.Filter collecting precipitation, obtain compound (309) (199mg), be buff powder.

¹H-NMR(300MHz，DMSO-d ₆，δ)：2.36(2H，quint.，J＝6.5Hz)，3.30(2H，t，J＝7.5Hz)，4.16(2H，t，J＝5.9Hz)，6.37(1H，d，J＝16.1Hz)，6.79(2H，d，J＝8.4Hz)，7.52(1H，d，J＝16.5Hz)，7.55(2H，m)，7.59(2H，d，J＝8.8Hz)，7.79(2H，m)；

MASS(ES+)：m/e 323(M+1).

Preparation scheme 310

Compound (310) is by obtaining (205mg) with preparation scheme 309 similar modes from compound (307).

¹H-NMR(300MHz，DMSO-d ₆，δ)：1.84(2H，m)，2.03(2H，m)，3.21(2H，t，J＝7.6Hz)，4.08(2H，t，J＝5.9Hz)，6.38(1H，d，J＝16.1Hz)，6.96(2H，d，J＝8.8Hz)，7.53(2H，m)，7.54(1H，d，J＝15.8Hz)，7.63(2H，d，J＝9.1Hz)，7.78(2H，m)；

MASS(ES+)：m/e 337(M+1).

Preparation scheme 311

Compound (311) is by obtaining (174mg) with preparation scheme 309 similar modes from compound (308).

¹H-NMR(300MHz，DMSO-d ₆，δ)：2.19(2H，quint.，J＝7.1Hz)，2.75(2H，t，J＝7.3Hz)，3.12(2H，t，J＝7.5Hz)，6.48(1H，d，J＝16.1Hz)，7.30(2H，d，J＝7.7Hz)，7.52(2H，m)，7.56(1H，d，J＝15.0Hz)，7.62(2H，d，J＝8.4Hz)，7.76(2H，m)；

MASS(ES+)：m/e 307(M+1).

Preparation scheme 312

Under agitation, add O-(tetrahydrochysene-2H-pyrans-2-yl) azanol (71.5mg), HOBt (97.4mg) and EDCI (112mg) in compound (309) DMF (2mL) solution (234mg), the gained mixture stirred 16 hours at ambient temperature.Add saturated NaHCO to reaction mixture ₃The aqueous solution filters collecting precipitation, washes with water.The gained powder obtains compound (312) (161mg) through vacuum-drying, is colourless powder.Gained compound (312) is used for embodiment 103.

¹H-NMR(300MHz，CDCl ₃，δ)：1.62(3H，br.)，1.84(3H，br.)，2.38(2H，quint.，J＝7.1Hz)，3.13(2H，t，J＝7.1Hz)，3.65(1H，m)，3.98(1H，m)，4.05(2H，t，J＝6.0Hz)，5.02(1H，s)，6.78(2H，d，J＝8.8Hz)，7.23(2H，m)，7.37(2H，d，J＝8.4Hz)，7.56(2H，br.)，7.63(1H，d，J＝16.1Hz)；

MASS(ES+)：m/e 422(M+1).

Preparation scheme 313

Compound (313) is by obtaining (197mg) with preparation scheme 312 similar modes from compound (310).Gained compound (313) is used for embodiment 104.

¹H-NMR(300MHz，CDCl ₃，δ)：1.64(3H，br.)，1.84(3H，br.)，1.91(2H，m)，2.07(2H，m)，3.01(2H，t，J＝7.7Hz)，3.65(1H，m)，3.97(1H，m)，3.99(2H，t，J＝6.3Hz)，5.02(1H，s)，6.81(2H，d，J＝8.8Hz)，7.22(2H，m)，7.40(2H，d，J＝8.1Hz)，7.53(2H，br.m)，7.67(2H，d，J＝15.0Hz)；

MASS(ES+)：m/e 436(M+1).

Preparation scheme 314

Compound (314) is by obtaining (177mg) with preparation scheme 312 similar modes from compound (311).Gained compound (314) is used for embodiment 105.

¹H-NMR(300MHz，DMSO-d ₆，δ)：1.53(3H，br.)，1.69(3H，br.)，2.09(2H，quint.，J＝7.7Hz)，2.69(2H，t，J＝7.7Hz)，2.81(2H，t，J＝7.4Hz)，3.55(1H，m)，3.96(1H，m)，4.91(1H，s)，6.47(1H，d，J＝16.1Hz)，7.10(2H，m)，7.29(2H，d，J＝8.1Hz)，7.46(1H，d，J＝15.8Hz)，7.47(2H，m)，7.51(2H，d，J＝7.7Hz)；

MASS(ES+)：m/e 406(M+1)．

Preparation scheme 315

Compound (315) is by obtaining (287mg) with preparation scheme 312 similar modes from following compound (320).

¹H-NMR(300MHz，DMSO-d ₆，δ)：1.52(3H，br.)，1.66(1H，m)，1.69(3H，br.)，1.82(1H，m)，2.40(1H，m)，2.56(1H，m)，3.50(1H，m)，3.95(1H，m)，4.90(1H，s)，6.47(1H，d，J＝15.8Hz)，7.11(2H，m)，7.25(2H，d，J＝8.1Hz)，7.41(1H，d，J＝16.1Hz)，7.44(2H，m)，7.50(2H，d，J＝8.8Hz)；

MASS(ES+)：m/e 404(M+1).

Preparation scheme 316

Compound (316) is by obtaining (55mg) with preparation scheme 312 similar modes from following compound (335).Gained compound (316) is used for embodiment 100.

¹H-NMR(300MHz，CDCl ₃，δ)：1.60-1.90(6H，m)，3.64-3.73(1H，m)，3.80(3H，s)，3.94-4.04(1H，m)，4.13(2H，s)，4.82(2H，s)，4.97-5.07(1H，m)，6.81-7.31(8H，m)，7.45(2H，d，J＝8Hz)，7.71(1H，d，J＝16Hz)；

MASS(ES+)：m/z 516(M+1).

Preparation scheme 317

Compound (317) is by obtaining (177mg) with preparation scheme 312 similar modes from compound (202).Gained compound (317) is used for embodiment 101.

¹H-NMR(300MHz，DMSO-d ₆，δ)：1.49-2.02(21H，m)，3.49-3.58(1H，m)，3.88-4.01(3H，m)，4.87-4.93(1H，m)，6.45(1H，d，J＝16Hz)，7.18(1H，d，J＝8Hz)，7.26(2H，d，J＝8Hz)，7.41-7.53(3H，m).

MASS(ES+)：m/z 462(M+1).

Preparation scheme 318

Under agitation, to instead-add Periodic acid (3.13g), iodine (3.13g) and the vitriol oil (3.62mL) in acetate (30mL) solution of 2-phenyl cyclopropane-carboxylic acid (5.0g), the gained mixture stirred 5 hours down at 75 ℃.Pour the gained mixture into 5%NaHSO ₃In the aqueous solution (100mL), filter collecting precipitation.Filtrate extracts with AcOEt, and organic phase is used 5%NaHSO successively ₃The aqueous solution, saturated NH ₄The Cl aqueous solution and salt water washing, Na ₂SO ₄Dry.Solvent removed in vacuo, residual solid merges with the powder that filters acquisition, is dissolved among the AcOEt.The elimination precipitation, filtrate concentrates and crystallization from ethyl acetate and hexane (20mL:40mL), obtains compound (318) (3.88g).

¹H-NMR(300MHz，CDCl ₃，δ)：1.36(1H，m)，1.66(1H，m)，1.87(1H，m)，2.53(1H，m)，6.86(2H，d，J＝8.4Hz)，7.60(2H，d，J＝8.4Hz)；

MASS(ES-)：m/e 287(M-1).

Preparation scheme 319

In compound (305) DMF (5mL) solution (500mg), add 1,2-phenylenediamine (206mg), HOBt (305mg) and EDCIHCl (432mg), the gained mixture stirred 2 hours at ambient temperature.Pour mixture into saturated NaHCO ₃In the aqueous solution, extract with AcOEt.Organic phase is used saturated NaHCO successively ₃The aqueous solution, water and salt water washing, Na ₂SO ₄Dry.Solvent removed in vacuo, resistates is by preparation type thin layer chromatography (chloroform: purifying methyl alcohol=10: 1).The gained amorphous solid grinds with isopropyl ether, obtains compound (319) (341mg), is colourless powder.

¹H-NMR(300MHz，CDCl ₃，δ)：1.40(1H，m)，1.53(9H，s)，1.77(1H，m)，1.84(1H，m)，2.62(1H，m)，3.85(1H，br.)，6.34(1H，d，J＝15.8Hz)，6.80(2H，m)，7.07(2H，m)，7.13(2H，d，J＝8.4Hz)，7.34(2H，s)，7.45(2H，d，J＝8.4Hz)，7.56(1H ，d，J＝16.1Hz)；

MASS(ES+)：m/e 379(M+1).

Preparation scheme 320

In compound (319) AcOH (3.5mL) solution (341mg), add AcOH (3.6mL) solution of 1N hydrogenchloride, heated 2 hours down at 110 ℃.Allow the gained mixture be chilled to envrionment temperature, dilute with ethyl acetate.Filter collecting precipitation, drying obtains compound (320) (242mg).

¹H-NMR(300MHz，DMSO-d ₆，δ)：2.03(1H，m)，2.14(1H，m)，2.70(1H，m)，2.92(1H，m)，6.53(1H，d，J＝15.8Hz)，7.35(2H，d，J＝8.4Hz)，7.49(2H，m)，7.58(1H，d，J＝16.1Hz)，7.68(2H，d，J＝8.1Hz)，7.73(2H，m)；

MASS(ES+)：m/e 305(M+1).

Preparation scheme 321

Under in ice bath, stirring, in compound (217) methyl alcohol (3mL) solution (350mg), add 1N sodium hydroxide (1.65mL).After 1 hour, allow the gained mixture be warming up to envrionment temperature and under same temperature, stirred 16 hours.Add concentrated hydrochloric acid so that the mixture acidifying to this mixture, vacuum concentration gained mixture.Resistates is dissolved in N, dinethylformamide (5mL) adds O-(tetrahydrochysene-2H-pyrans-2-yl) azanol (167mg), 1-[3-(dimethylamino) propyl group successively to this solution at ambient temperature]-3-ethyl carbodiimide (222mg) and I-hydroxybenzotriazole (193mg).The gained mixture stirred two days under same temperature, with ethyl acetate extraction (100mL), used the washing of saturated sodium bicarbonate aqueous solution (25mL) and salt solution (25mL) successively.The organic layer anhydrous sodium sulfate drying, vacuum concentration.Resistates obtains compound (321) (387mg) by mixture (5: 95 (volume)) the wash-out purifying of flash chromatography on silica gel method with methyl alcohol and ethyl acetate, is colourless amorphous solid.Gained compound (321) is used for embodiment 82.

¹H-NMR(300MHz，CDCl ₃，δ)：1.43-1.82(6H，m)，3.43-3.59(1H，m)，3.84-4.07(1H，m)，4.89(1H，br.s)，5.36(2H，s)，6.47(1H，d，J＝16.1Hz)，7.00-7.09(3H，m)，7.33-7.59(10H，m)；

MASS(ES+)：m/z 404(M+1).

Preparation scheme 322

Compound (322) is the mixture (316mg altogether) of two kinds of regional isomers by obtaining from compound (218) with preparation scheme 321 similar modes.Gained compound (322) is used for embodiment 115.

¹H-NMR (300MHz, DMSO-d ₆, δ): (to the mixture of two kinds of regional isomers) 1.34-1.78 (6H, m), 2.03 (1.2H, s), 2.06 (1.8H, s), and 3.47-3.59 (1H, m), 3.85-4.04 (1H, m), 4.83-4.95 (1H, m), 5.13 (1.2H, s), 5.19 (0.8H, s), 6.49 (1H, d, J=16.4Hz), 6.67 (0.4H, s), 6.85 (0.6H, s), 7.13 (0.8H, d, J=8.1Hz), 7.26 (1.2H, d, J=8.1Hz), 7.39-7.72 (4H, m);

MASS (ES+): (to the mixture of two kinds of regional isomers) m/z 342 (M+1).

Preparation scheme 323

Under in envrionment temperature, stirring, to compound (326) (100mg, be described in and hereinafter prepare in the scheme 326) N, add methylamine hydrochloride (23mg), 1-[3-(dimethylamino) propyl group in dinethylformamide (2mL) solution]-3-ethyl carbodiimide (56mg) and I-hydroxybenzotriazole (48mg), the gained mixture stirred 20 hours under same temperature.The gained mixture is used the washing of saturated sodium bicarbonate aqueous solution (25mL) and salt solution (25mL) successively with ethyl acetate (50mL) extraction.The organic layer anhydrous sodium sulfate drying, vacuum concentration obtains crude product compound (324) (86mg), is colourless amorphous solid.Compound (324) is used for embodiment 83.

¹H-NMR(300MHz，CDCl ₃，δ)：1.42-1.97(6H，m)，2.85(3H，br.d，J＝4.4Hz)，3.54-3.68(1H，m)，3.89-4.07(2H，m)，4.98(2H，br.s)，6.05-6.34(1H，m)，6.95-7.73(10H，m)；

MASS(ES+)：m/z 461(M+1).

Preparation scheme 324

Add piperidines (0.015mL), HOBt (23.6mg) and EDCIHCl (33.4mg) in DMF (1mL) solution of compound (326) (60mg, be described in hereinafter prepare in the scheme 326), the gained mixture stirred 2 hours at ambient temperature.Mixture is poured in the water, and with the AcOEt extraction, organic phase is used saturated NH successively ₄The Cl aqueous solution, saturated NaHCO ₃The aqueous solution and salt water washing, Na ₂SO ₄Dry.Solvent removed in vacuo, resistates by preparation type thin layer chromatography (chloroform: purifying methyl alcohol=10: 1), obtain compound (324) (44mg), be colourless amorphous solid.Gained mixture (324) is used for embodiment 88.

¹H-NMR(300MHz，DMSO-d ₆，δ)：1.25(2H，br.)，1.53(7H，br.)，1.69(3H，br.)，3.25(4H，br.)，3.53(1H，m)，3.94(1H，m)，4.03(2H，s)，4.90(1H，s)，6.46(1H，d，J＝15.4Hz)，7.26(1H，t，J＝7.3Hz)，7.36(4H，m)，7.43(1H，d，J＝15.8Hz)，7.53(4H，m)；

MASS(ES+)：m/e 515(M+1).

Preparation scheme 325

Compound (325) is by obtaining (57g) with preparation scheme 325 similar modes from following compound (326).Gained compound (325) is used for embodiment 89.

¹H-NMR(300MHz，CDCl ₃，δ)：1.18(6H，br.)，1.60(3H，br.)，1.84(3H，br.)，3.65(1H，m)，3.98(1H，m)，4.09(2H，s)，4.18(1H，m)，5.00(1H，s)，7.22(1H，m)，7.39(6H，m)，7.67(3H，m)；

MASS(ES+)：m/e 489(M+1).

Preparation scheme 326

(200mg) add the 1N NaOH aqueous solution (1.3mL) in De diox (2mL) solution to compound (290), the gained mixture heated 6 hours down at 70 ℃.Vacuum is removed organic solvent, with 1N HCl the pH value of alkaline aqueous solution is transferred to 3.Filter collecting precipitation, drying obtains compound (326) (145mg), is buff powder.Gained compound (326) is used for embodiment 91.

¹H-NMR(300MHz，DMSO-d ₆，δ)：1.54(3H，br.)，1.69(3H，br.)，3.53(1H，m)，3.95(1H，m)，4.05(2H，s)，4.90(1H，s)，6.46(1H，d，J＝16.4Hz)，7.32-7.40(5H，m)，7.46(1H，d，J＝16.1Hz)，7.53(2H，d，J＝7.7Hz)，7.86(2H，br)；

MASS(ES+)：m/e 448(M+1).

Preparation scheme 327

Add compound (290) THF (5mL) solution (500mg) in the THF of lithium aluminum hydride (5mL) suspension, the gained mixture refluxed 6 hours.Add entry (50mL) to gained solution at ambient temperature, the gained mixture was stirred 1 hour.Filter collecting precipitation, the gained powder with chloroform and methanol mixture (10: 1) wash-out purifying, obtains compound (327) (110mg) by silica gel column chromatography.

¹H-NMR(300MHz，CDCl ₃，δ)：1.54(9H，s)，3.68(2H，s)，3.88(3H，s)，4.69(2H，d，J＝4.0Hz)，6.37(1H，d，J＝15.8Hz)，6.60(1H，br)，6.95(2H，d，J＝8.8Hz)，7.33(2H，d，J＝8.1Hz)，7.52(2H，d，J＝8.1Hz)，7.58(1H，d，J＝16.1Hz)，7.91(2H，d，J＝9.2Hz)；

MASS(ES+)：m/e 434(M+1).

Preparation scheme 328

Compound (328) is by obtaining (493mg) with preparation scheme 327 similar modes from compound (50).Gained compound (328) is used for embodiment 97.

¹H-NMR(300MHz，DMSO-d ₆，δ)：1.48-1.72(6H，m)，3.49-3.57(1H，m)，3.90-4.01(1H，m)，4.18(2H，s)，4.51-4.58(2H，m)，4.87-4.92(1H，m)，6.47(1H，d，J＝16Hz)，7.33-7.57(8H，m)；

MASS(ES+)：m/z 408(M+1).

Preparation scheme 329

Under 5 ℃, in compound (327) methylene dichloride (3mL) suspension (400mg), add triethylamine (0.154mL) and methylsulfonyl chloride (0.079mL), the gained mixture was stirred 1 hour.Solvent removed in vacuo, the gained benzyl chloride is dissolved among the MeOH.At ambient temperature, in gained solution, add the sodium methylate (5 equivalent) among the MeOH, the gained mixture was stirred 0.5 hour.Pour the gained mixture into saturated NH ₄In the Cl aqueous solution, extract with AcOEt.Organic phase water and salt water washing, Na ₂SO ₄Dry.Solvent removed in vacuo, (chloroform: purifying methyl alcohol=10: 1) obtains compound (329) (110mg) to resistates by preparation type thin layer chromatography.Gained compound (329) is used for embodiment 93.

¹H-NMR(300MHz，DMSO-d ₆，δ)：1.54(3H，br.)，1.69(3H，br.)，3.29(3H，s)，3.53(1H，m)，3.97(1H，m)，4.05(2H，s)，4.39(2H，s)，4.90(1H，s)，6.47(1H，d，J＝15.8Hz)，7.25-7.61(10H，m)；

MASS(ES+)：m/e 448(M+1).

Preparation scheme 330

Add N in compound (323) DMF (5mL) solution (1g), O-dimethyl hydroxylamine hydrochloride (240mg), HOBt (393mg) and EDCI (451mg) stir the gained mixture at ambient temperature.Add saturated NaHCO to the gained mixture ₃The aqueous solution filters collecting precipitation.Gained powder water and Et ₂The O washing obtains compound (330) (817mg), is buff powder.

¹H-NMR(300MHz，DMSO-d ₆，δ)：1.53(3H，br.)，1.69(3H，br.)，3.21(3H，s)，3.53(1H，m)，3.63(3H，s)，3.95(1H，m)，4.05(2H，s)，4.90(1H，s)，6.46(1H，d，J＝16.1Hz)，7.30-7.60(10H，m)；

MASS(ES+)：m/z 491(M+1).

Preparation scheme 331

In compound (330) THF (5mL) solution (300mg), add Et ₂Iodate methyl magnesium among the O (3.64mL, 0.84mol/L, Kanto Chemical, Co., Inc.), the gained mixture heated 3 hours down at 70 ℃.Add Et then ₂(0.84mol/L, 3.64mL), the gained mixture heated 2 hours down at 70 ℃ iodate methyl magnesium among the O again.With the mixture cooling, pour in the water, extract with AcOEt.Organic phase is used saturated NaHCO successively ₃The aqueous solution, water and salt water washing, Na ₂SO ₄Dry.Solvent removed in vacuo, resistates by preparation type thin layer chromatography (chloroform: purifying methyl alcohol=10: 1), obtain compound (331) (67mg), be orange form.Gained compound (331) is used for embodiment 94.

¹H-NMR(300MHz，DMSO-d ₆，δ)：1.54(3H，br.)，1.69(3H，br.)，2.36(3H，s)，3.55(1H，m)，3.95(1H，m)，4.22(2H，s)，4.90(1H，s)，6.48(1H，d，J＝15.8Hz)，7.31-7.57(10H，m)；

MASS(ES+)：m/z 446(M+1).

Preparation scheme 332

Compound (332) is by obtaining (124mg) with preparation scheme 330 similar modes from compound (326).Gained compound (332) is used for embodiment 87.

Preparation scheme 333

Under 4 ℃, to compound (51) (120mg), the N of tetramethyleneimine (0.029mL) and I-hydroxybenzotriazole (46.2mg), add 1-(3-dimethylamino-propyl)-3-ethyl carbodiimide (65.5mg) in dinethylformamide (2.6mL) solution.The gained mixture is warming up to envrionment temperature and stirred 8 hours.Add saturated NaHCO to reaction mixture ₃(3mL) and water (12mL).Filter and collect the gained precipitation, wash with water, obtain compound (333) (95mg).

¹H-NMR(300MHz，DMSO-d ₆，δ)：1.47-1.93(10H，m)，3.39-3.57(5H，m)，3.87-4.01(1H，m)，4.22(2H，s)，4.88-4.93(1H，m)，6.47(1H，d，J＝16Hz)，7.28-7.70(8H，m)；

MASS(ES+)：m/z 475(M+1).

Preparation scheme 334

Under 4 ℃, to compound (328) (170mg), N, add methylsulfonyl chloride (0.068mL) in the mixture of N-diisopropylethylamine (0.16mL) and THF (8.4mL).Reaction mixture was stirred 3 hours, add diethylamine (0.432mL).After at room temperature stirring 15 hours, the gained mixture is at ethyl acetate and H ₂Distribute between the O.The saturated NaHCO of organic layer ₃With salt water washing, MgSO ₄Drying is filtered, and vacuum-evaporation obtains compound (334) (38mg).

¹H-NMR(300MHz，DMSO-d ₆，δ)：1.03-1.22(6H，m)，1.48-1.72(6H，m)，3.31-3.44(4H，m)，3.49-3.57(1H，m)，3.88-4.03(1H，m)，4.10-4.41(4H，m)，4.87-4.95(1H，m)，6.48(1H，d，J＝16Hz)，7.22-7.87(8H，m).

MASS(ES+)：m/z 463(M+1).

Preparation scheme 335

Compound (335) is by obtaining (2.89g) with preparation scheme 199 and 229 similar modes from compound (6).

¹H-NMR(300MHz，CDCl ₃，δ)：1.34(3H，t，J＝7Hz)，3.64-4.08(7H，m)，4.27(2H，q，J＝7Hz)，4.53-4.64(2H，m)，6.42(1H，d，J＝16Hz)，6.81-6.92(2H，m)，7.01(1H，d，J＝8Hz)，7.27-7.35(3H，m)，7.45-7.53(2H，m)，7.66(1H，d，J＝16Hz)；

MASS(ES-)：m/z 410(M-1).

Preparation scheme 336

Under 4 ℃, (1.44g) and in the mixture of chloroform (12mL) add trifluoroacetic anhydride (1.48mL) to compound (335).After at room temperature stirring 3 hours, with reaction mixture vacuum-evaporation.Under 4 ℃,, add ammonium acetate (405mg) in the mixture of dinethylformamide (18mL) to above-mentioned product and N.After 2 hours, the gained mixture is at ethyl acetate and H 70 ℃ of stirrings ₂Distribute between the O.Organic layer H ₂O and salt water washing, MgSO ₄Drying is filtered vacuum-evaporation.Under 4 ℃, add phosphoryl chloride (0.3mL) to the mixture of above-mentioned product in pyridine (1mL).Stirring is after 2 hours down at 90 ℃, and the gained mixture is at ethyl acetate and H ₂Distribute between the O.Organic layer H ₂O and salt water washing, MgSO ₄Drying is filtered vacuum-evaporation.Resistates obtains compound (336) (313mg) by the silica gel column chromatography purifying.

¹H-NMR(300MHz，CDCl ₃，δ)：1.34(3H，t，J＝7Hz)，3.79(3H，s)，4.12(2H，s)，4.19(2H，q，J＝7Hz)，4.81(2H，s)，6.41(1H，d，J＝16Hz)，6.81-6.90(4H，m)，7.11-7.19(3H，m)，7.45(2H，d，J＝8Hz)，7.65(1H，d，J＝16Hz)；

MASS(ES+)：m/z 445(M+1).

Preparation scheme 337

(175mg) add 1N sodium hydroxide (1.18mL) in the mixture of Yu diox (4mL) to compound (336).After stirring 1 hour under 80 ℃, add H to reaction mixture ₂O (20mL) is with 1N hcl acidifying (to pH3-4).Filter and collect the gained precipitation, use H ₂The O washing obtains compound (337) (153mg).

¹H-NMR(300MHz，CDCl ₃，δ)：3.79(3H，s)，4.14(2H，s)，4.82(2H，s)，6.42(1H，d，J＝16Hz)，6.81-6.91(4H，m)，7.11-7.21(3H，m)，7.48(2H，d，J＝8Hz)，7.73(1H，d，J＝16Hz)；

MASS(ES-)：m/z 415(M-1).

Preparation scheme 338

In the mixture of (1Z)-2-(4-iodophenyl)-N '-hydroxyl acetamidine (2.17g) and EtOH (40mL), add ethyl propiolate (0.803mL), gained mixture reflux 6 hours.The vacuum-evaporation reaction mixture.Add phenyl ether (20mL) to resistates, stirred 2 hours down at 200 ℃.After the cooling, the gained mixture (is used CHCl by silica gel column chromatography ₃: MeOH=50: 1 wash-out), obtain compound (338) (845mg).

¹H-NMR(300MHz，CDCl ₃，δ)：1.30-1.43(3H，m)，4.06-4.13(2H，m)，4.26-4.43(2H，m)，6.97-7.06(2H，m)，7.61(1H，s)，7.65-7.72(2H，m)；

MASS(ES+)：m/z 357(M+1).

Preparation scheme 339

To compound (338) (400mg), acid chloride (II) (12.6mg) and in DMF (11mL) solution of triphenylphosphine (29.5mg) adds vinylformic acid (0.154mL) and N, N-di-isopropyl second ammonium (0.49mL), the gained mixture stirred 6 hours down at 70 ℃.With reaction mixture at ethyl acetate and H ₂Distribute the vacuum-evaporation inorganic layer between the O.Under 4 ℃, at N, the mixture in the N-dimethyl formyl ammonium (6mL) adds 1-(3-dimethylamino-propyl)-3-ethyl carbodiimide (1.5 equivalent) to gained reaction product, O-tetrahydrochysene-2H-pyrans-2-base azanol (1.5 equivalent) and I-hydroxybenzotriazole (1.5 equivalent).The gained mixture is warming up to envrionment temperature and stirred 6 hours.Add saturated NaHCO to reaction mixture ₃(6mL) and water (24mL), gained mixture ethyl acetate extraction.Organic layer H ₂O and salt water washing, MgSO ₄Drying is filtered vacuum-evaporation.Resistates obtains compound (339) (98mg) by the silica gel column chromatography purifying.

¹H-NMR(300MHz，DMSO-d ₆，δ)：1.25(3H，t，J＝7Hz)，1.44-1.75(6H，m)，3.45-3.59(1H，m)，3.88-4.01(1H，m)4.01(2H，s)，4.18(2H，q，J＝7Hz)，4.87-4.93(1H，m)，6.46(1H，d，J＝16Hz)，7.24-7.78(5H，m)，8.32(1H，s)；

MASS(ES+)：m/z 400(M+1).

Preparation scheme 340

Compound (340) is by obtaining (184mg) with preparation scheme 319 and 320 similar modes.

¹H-NMR(300MHz，DMSO-d ₆，δ)：1.95-2.08(4H，m)，3.22-3.34(4H，m)，4.50(2H，s)，6.55(1H，d，J＝16Hz)，6.62(1H，s)，6.84(1H，dd，J＝2，8Hz)，7.48-7.75(6H，m)；

MASS(ES+)：m/z 348(M+1).

Embodiment 1

Under agitation, add methanolic hydrogen chloride reagent 10 (Ltd. produces for 0.5mL, Tokyo Kasei Kogyo Co.) in compound (5) methyl alcohol (5mL) solution (125mg), the gained mixture stirred 30 minutes at ambient temperature.Vacuum evaporating solvent, resistates grinds with the mixture (1: 2) of methyl alcohol and ethyl acetate, obtains compd E 1, is white solid (81mg).

¹H-NMR(300MHz，DMSO-d ₆，δ)：4.57(2H，s)，6.50(1H，d，J＝15.7Hz)，7.41-7.56(5H，m)，7.60(2x1H，d，J＝8Hz)，7.73-7.81(2H，m)，10.84(1H，br)；

MASS(ES+)：m/e 294.

Embodiment 2

Compd E 2 obtains (79mg) by mode similar to Example 1 from compound (13).

¹H-NMR(300MHz，DMSO-d ₆，δ)：4.76(2H，s)，5.82(2H，s)，6.49(1H，d，J＝16Hz)，7.12-7.21(2H，m)，7.26-7.34(3H，m)，7.38-7.62(7H，m)，7.73(1H，dd，J＝7，1.5Hz)，7.83(1H，dd，J＝7，1.5Hz)；

MASS(ES+)：m/e 384.

Embodiment 3

Compd E 3 obtains (1.74mg) by mode similar to Example 1 from compound (19).

¹H-NMR(300MHz，DMSO-d ₆，δ)：3.28(2x1H，t，J＝7.5Hz)，3.47(2x1H，t，J＝7.5Hz)，6.45(1H，d，J＝16Hz)，7.32(2x1H，d，J＝8Hz)，7.41(1H，d，J＝16Hz)，7.46-7.60(4H，m)，7.73-7.83(2H，m)，10.80(1H，s)，15.10(1H，br)；

MASS(ES+)：m/e 308.

Embodiment 4

Compd E 4 obtains (377mg) by mode similar to Example 1 from compound (22).

¹H-NMR(300MHz，DMSO-d ₆，δ)：5.79(2H，s)，6.50(1H，d，J＝16Hz)，7.43(1H，d，J＝16Hz)，7.48-7.64(6H，m)，7.86-7.94(2H，m)，9.84(1H，s)；

MASS(ES+)：m/e 294.

Embodiment 5

Compd E 5 obtains (102mg) by mode similar to Example 1 from compound (25).

¹H-NMR(300MHz，DMSO-d ₆，δ)：3.31(1H，m)，3.70(1H，dd，J＝13，8Hz)，4.74(1H，br-t，J＝8Hz)，5.34(1H，d，J＝17Hz)，5.41(1H，d，J＝17Hz)，6.37(1H，d，J＝15.5Hz)，6.73(2x1H，d，J＝6.5Hz)，7.07-7.45(16H，m)，7.71(1H，d，J＝7.5Hz)，9.02(1H，brs)，10.73(1H，brs)；

MASS(ES+)：m/e 474.

Embodiment 6

Compd E 6 obtains (1.88mg) by mode similar to Example 1 from compound (29).

¹H-NMR(300MHz，DMSO-d ₆，δ)：4.57(2H，s)，6.51(1H，d，J＝16Hz)，7.40-7.56(6H，m)，7.68(1H，s)，7.73-7.81(2H，m)，10.88(1H，s)；

MASS(ES+)：m/e 294.

Embodiment 7

Compd E 7 obtains (162mg) by mode similar to Example 1 from compound (32).

¹H-NMR(300MHz，DMSO-d ₆，δ)：4.58(2H，s)，6.50(1H，d，J＝15.7Hz)，7.38-7.56(6H，m)，7.61(2x1H，d，J＝8Hz)，7.73(2x1H，d，J＝7Hz)，7.78-7.88(2H，m)，7.96(1H，s)，10.84(1H，s)；

MASS(ES+)：m/e 370.

Embodiment 8

Compd E 8 obtains (75mg) by mode similar to Example 1 from compound (34).

¹H-NMR(300MHz，DMSO-d ₆，δ)：4.50(2H，s)，6.48(1H，d，J＝16Hz)，7.42-7.48(3H，m)，7.56-7.71(4H，m)，7.97(1H，d，J＝2Hz)；

MASS(ESI)：m/z 372(M+1).

Embodiment 9

Compd E 9 is by obtaining (152mg) with preparation scheme 9 and embodiment 1 similar mode from compound (35).

¹H-NMR(300MHz，DMSO-d ₆，δ)：2.63(3H，s)，4.58(2H，s)，6.49(1H，d，J＝16Hz)，7.46(1H，d，J＝16Hz)，7.50(2H，d，J＝8Hz)，7.61(2H，d，J＝8Hz)，7.85-7.93(4H，m)，8.04-8.10(3H，m)；

MASS(ESI)：m/z 412(M+1).

Embodiment 10

Compd E 10 is by obtaining (138mg) with preparation scheme 9 and embodiment 1 similar mode from compound (36).

¹H-NMR(300MHz，DMSO-d ₆，δ)：4.58(2H，s)，6.50(1H，d，J＝16Hz)，7.17-7.21(1H，m)，7.46(1H，d，J＝16Hz)，7.51(2H，d，J＝8Hz)，7.59-7.65(4H，m)，7.80-7.83(2H，m)，7.95(1H，s)；

MASS(ESI)：m/z 376(M+1).

Embodiment 11

Compd E 11 is by obtaining (120mg) with preparation scheme 9 and embodiment 1 similar mode from compound (37).

¹H-NMR(300MHz，DMSO-d ₆，δ)：4.58(2H，s)，6.49(1H，d，J＝16Hz)，7.46(1H，d，J＝16Hz)，7.51(2H，d，J＝8Hz)，7.61(2H，d，J＝8Hz)，7.64-7.73(2H，m)，7.79(1H，d，J＝8Hz)，7.90(1H，dd，J＝2，8Hz)，8.00-8.05(2H，m)；

MASS(ESI)：m/z 376(M+1).

Embodiment 12

Compd E 12 obtains (142mg) by mode similar to Example 1 from compound (39).

¹H-NMR(300MHz，DMSO-d ₆，δ)：4.42(2H，s)，6.46(1H，d，J＝16Hz)，7.41-7.47(3H，m)，7.56(2H，d，J＝8Hz)，7.73(1H，d，J＝8Hz)，7.80(1H，d，J＝8Hz)，8.22(1H，s)；

MASS(ESI)：m/z 317(M-1).

Embodiment 13

Compd E 13 is by obtaining (710mg) with preparation scheme 9 and embodiment 1 similar mode from compound (40).

¹H-NMR(300MHz，DMSO-d ₆，δ)：4.55(2H，s)，6.50(1H，d，J＝16Hz)，7.36-7.44(1H，m)，7.45(1H，d，J＝16Hz)，7.50(2H，d，J＝8Hz)，7.59(2H，d，J＝8Hz)，7.66(1H，dd，J＝2，8Hz)，7.77-7.83(1H，m)；

MASS(ESI)：m/z 312(M+1).

Embodiment 14

Compd E 14 obtains (504mg) by mode similar to Example 1 from compound (42).

¹H-NMR(300MHz，DMSO-d ₆，δ)：4.51(2H，s)，6.48(1H，d，J＝16Hz)，7.45(1H，d，J＝16Hz)，7.47(2H，d，J＝8Hz)，7.52(1H，dd，J＝2，8Hz)，7.59(2H，d，J＝8Hz)，7.76(1H，d，J＝8Hz)，7.86(1H，J＝2Hz)；

MASS(ESI)：m/z 328(M+1).

Embodiment 15

Compd E 15 obtains (14mg) by mode similar to Example 1 from compound (44).

¹H-NMR(300MHz，DMSO-d ₆，δ)：2.79-2.85(4H，m)，3.11-3.22(4H，m)，4.52(2H，s)，6.48(1H，d，J＝16Hz)，7.15-7.67(8H，m)；

MASS(ESI)：m/z 392(M+1).

Embodiment 16

Compd E 16 obtains (45mg) by mode similar to Example 1 from compound (46).

¹H-NMR(300MHz，DMSO-d ₆，δ)：3.15-3.21(4H，m)，3.75-3.81(4H，m)，4.52(2H，s)，6.49(1H，d，J＝16Hz)，7.10(1H ，d，J＝2Hz)，7.29(1H，dd，J＝2，8Hz)，7.42-7.50(3H，m)，7.57-7.64(3H，m)；

MASS(ESI)：m/z 379(M+1).

Execute example 17

Compd E 17 obtains (27mg) by mode similar to Example 1 from compound (48).

¹H-NMR(300MHz，DMSO-d ₆，δ)：1.60-1.70(2H，m)，1.83-2.00(4H，m)，3.39-3.54(4H，m)，4.54(2H，s)，6.49(1H，d，J＝16Hz)，7.40-7.86(8H，m)；

MASS(ESI)：m/z 377(M+1).

Embodiment 18

Under 130 ℃, with compound (39), sodiumazide (485mg) and triethylamine hydrochloride (1.54g) and N, the mixture heating up of dinethylformamide (7.5mL) 6 hours.After the cooling, reaction mixture distributes between ethyl acetate (20mL) and water (40mL).Organic layer salt water washing, MgSO ₄Drying is filtered vacuum-evaporation.Crude product grinds with ethyl acetate-water.Product is handled by mode similar to Example 1, obtains compd E 18 (18mg).

¹H-NMR(300MHz，DMSO-d ₆，δ)：4.30(2H，s)，6.44(1H，d，J＝16Hz)，7.40(2H，d，J＝8Hz)，7.44(1H，d，J＝16Hz)，7.55(2H，d，J＝8Hz)，7.72(1H，d，J＝8Hz)，7.90(1H，d，J＝8Hz)，8.21(1H，s)；

MASS(ESI)：m/z 362(M+1).

Embodiment 19

Compd E 19 obtains (101mg) by mode similar to Example 1 from compound (50).

¹H-NMR(300MHz，DMSO-d ₆，δ)：3.91(3H，s)，4.55(2H，s)，6.49(1H，d，J＝16Hz)，7.46(1H，d，J＝16Hz)，7.50(2H，d，J＝8Hz)，7.60(2H，d，J＝8Hz)，7.84(1H，d，J＝8Hz)，8.05(1H，d，J＝8Hz)，8.27(1H，s)；

MASS(ESI)：m/z 352(M+1).

Embodiment 20

Compd E 20 obtains (72mg) by mode similar to Example 1 from compound (51).

¹H-NMR(300MHz，DMSO-d ₆，δ)：4.55(2H，s)，6.49(1H，d，J＝16Hz)，7.45(1H，d，J＝16Hz)，7.49(2H，d，J＝8Hz)，7.60(2H，d，J＝8Hz)，7.81(1H，d，J＝8Hz)，8.04(1H，dd，J＝2，8Hz)，8.25(1H，s)；

MASS(ESI)：m/z 338(M+1).

Embodiment 21

Compd E 21 obtains (55mg) by mode similar to Example 1 from compound (53).

¹H-NMR(300MHz，DMSO-d ₆，δ)：2.68(3H，s)，4.56(2H，s)，6.49(1H，d，J＝16Hz)，7.45(1H，d，J＝16Hz)，7.50(2H，d，J＝8Hz)，7.59(2H，d，J＝8Hz)，7.83(1H，d，J＝8Hz)，8.06(1H，dd，J＝2，8Hz)，8.28(1H，s)；

MASS(ESI)：m/z 336(M+1).

Embodiment 22

Compd E 22 obtains (279mg) by mode similar to Example 1 from compound (55).

¹H-NMR(300MHz，DMSO-d ₆，δ)：4.48(2H，s)，6.47(1H，d，J＝16Hz)，7.33-7.49(4H，m)，7.57(2H，d，J＝8Hz)，7.65-7.72(4H，m)；

MASS(ESI)：m/z 372(M+1).

Embodiment 23

Compd E 23 obtains (50mg) by mode similar to Example 1 from compound (57).

¹H-NMR(300MHz，DMSO-d ₆，δ)：1.25(3H，s)，1.27(3H，s)，3.04-3.16(1H，m)，4.55(2H，s)，6.49(1H，d，J＝16Hz)，7.42-7.52(4H，m)，7.56-7.62(3H，m)，7.68(1H，d，J＝8Hz)；

MASS(ESI)：m/z 336(M+1).

Embodiment 24

Compd E 24 is by obtaining (249mg) with preparation scheme 9 and embodiment 1 similar mode from compound (59).

¹H-NMR(300MHz，DMSO-d ₆，δ)：4.42(2H，s)，5.35(2H，s)，6.45(1H，d，J＝16Hz)，7.10-7.61(13H，m)；

MASS(ESI)：m/z 400(M+1).

Embodiment 25

Compd E 25 obtains (417mg) by mode similar to Example 1 from compound (62).

MASS(ES+)：m/e 370.

Embodiment 26

Compd E 26 obtains (207mg) by mode similar to Example 1 from compound (72).

¹H-NMR(300MHz，DMSO-d ₆，δ)：4.57(2H，s)，6.50(1H，d，J＝15.7Hz)，7.35(2x1H，dd，J＝8.8，8.8Hz)，7.46(1H，d，J＝15.7Hz)，7.50(2x1H，d，J＝8Hz)，7.61(2x1H，d，J＝8Hz)，7.74-7.86(4H，m)，7.94(1H，s)；

MASS(ES+)：m/e 388.

Embodiment 27

Compd E 27 obtains (123mg) by mode similar to Example 1 from compound (75).

¹H-NMR(300MHz，DMSO-d ₆，δ)：4.58(2H，s)，6.51(1H，d，J＝15.8Hz)，7.38-7.59(7H，m)，7.65-7.87(5H，m)，7.96(1H，s)，10.86(1H，br)；

MASS(ES+)：m/e 370.

Embodiment 28

Compd E 28 obtains (103mg) by mode similar to Example 1 from compound (80).

¹H-NMR(300MHz，DMS0-d ₆，δ)：3.28(3H，s)，4.59(2H，s)，6.49(1H，d，J＝16Hz)，7.42-7.65(5H，m)，7.87-7.92(2H，m)，7.98-8.10(5H，m)；

MASS(ES+)：m/e 447.

Embodiment 29

Compd E 29 obtains (200mg) by mode similar to Example 1 from compound (83).

¹H-NMR(300MHz，DMSO-d ₆，δ)：4.49(2H，s)，6.49(1H，d，J＝16Hz)，7.44(1H，d，J＝16Hz)，7.47(2x1H，d，J＝8Hz)，7.57(2x1H，d，J＝8Hz)，7.57(1H，dd，J＝8，5Hz)，8.34(1H，d，J＝8Hz)，8.58(1H，d，J＝5Hz)；

MASS(ES+)：m/e 295.

Embodiment 30

Compd E 30 obtains (175mg) by mode similar to Example 1 from compound (90).

¹H-NMR(300MHz，DMSO-d ₆，δ)：4.52(2H，s)，6.50(1H，d，J＝16Hz)，7.23(1H，br-d，J＝8.5Hz)，7.41-7.53(4H，m)，7.59(2x1H，d，J＝8Hz)，7.69(1H，d，J＝8.5Hz)；

MASS(ES+)：m/e 309.

Embodiment 31

Compd E 31 obtains (14mg) by mode similar to Example 1 from compound (93).

¹H-NMR(300MHz，DMSO-d ₆，δ)：0.92(3H，t，J＝7.5Hz)，1.63(2H，tq，J＝7.5，7.5Hz)，2.34(2H，t，J＝7.5Hz)，4.54(2H，s)，6.49(1H，d，J＝15.7Hz)，7.41-7.51(3H，m)，7.55(1H，dd，J＝9，2Hz)，7.60(2x1H，d，J＝8.5Hz)，7.69(1H，d，J＝9Hz)，8.31(1H，d，J＝2Hz)；

MASS(ES+)：m/e 379.

Embodiment 32

Compd E 32 obtains (73mg) by mode similar to Example 1 from compound (97).

¹H-NMR(300MHz，DMSO-d ₆，δ)：4.45(2H，s)，6.45(1H，d，J＝16Hz)，7.43(1H，d，J＝16Hz)，7.45(2x1H，d，J＝8Hz)，7.50(2x1H，dd，J＝8，8Hz)，7.54(2x1H，d，J＝8Hz)，8.11(1H，d，J＝8Hz)，8.21(1H，d，J＝8Hz)；

MASS(ES+)：m/e 339.

Embodiment 33

Compd E 33 obtains (15mg) by mode similar to Example 1 from compound (100).

¹H-NMR(300MHz，DMSO-d ₆，δ)：4.43(2H ，s)，6.48(1H ，d，J＝16Hz)，7.39-7.60(5H，m)，8.08(1H，d，J＝6.5Hz)，8.55(1H，d，J＝6.5Hz)，9.35(1H，s)；

MASS(ES+)：m/e 295.

Embodiment 34

Compd E 34 obtains (240mg) by mode similar to Example 1 from compound (103).

¹H-NMR(300MHz，DMSO-d ₆，δ)：3.22(3H，s)，3.40(3H，s)，4.08(2H，s)，6.44(1H，d，J＝15.8Hz)，7.32(2x1H，d，J＝8Hz)，7.42(1H，d，J＝15.8Hz)，7.51(2x1H，d，J＝8Hz)；

MASS(ES+)：m/e 356.

Embodiment 35

Compd E 35 obtains (160mg) by mode similar to Example 1 from compound (105).

¹H-NMR(300MHz，DMSO-d ₆，δ)：4.42(2H，s)，6.47(1H，d，J＝16Hz)，7.44(1H，d，J＝16Hz)，7.44(2x1H，d，J＝8Hz)，7.56(2x1H，d，J＝8Hz)，7.80(1H，d，J＝9Hz)，8.19(1H，dd，J＝9，2.2Hz)，8.50(1H，d，J＝2.2Hz)；

MASS(ES+)：m/e 339.

Embodiment 36

Compd E 36 obtains (375mg) by mode similar to Example 1 from compound (112).

¹H-NMR(300MHz，CDCl ₃，δ)：5.66(2H，s)，6.38(1H，d，J＝15.7Hz)，7.19(2x1H，d，J＝8.8Hz)，7.43(1H，d，J＝15.7Hz)，7.48-7.56(2H，m)，7.58(2x1H，d，J＝8.8Hz)，7.76-7.84(2H，m)，10.75(1H，br-s)；

MASS(ES+)：m/e 310.

Embodiment 37

Compd E 37 obtains (40mg) by mode similar to Example 1 from compound (115).

¹H-NMR(300MHz，DMSO-d ₆，δ)：1.40-1.94(8H，m)，3.85(1H，m)，4.54(2H，s)，6.51(1H，d，J＝15.8Hz)，7.28-7.80(8H，m)；

MASS(ES+)：m/e 377.

Embodiment 38

Compd E 38 obtains (1.19g) by mode similar to Example 1 from compound (122).

¹H-NMR(300MHz，DMSO-d ₆，δ)：5.67(2H，s)，6.53(1H，d，J＝16Hz)，7.14(1H，m)，7.27(1H，m)，7.35(1H，s)，7.41(1H，dd，J＝8，8Hz)，7.46(1H，d，J＝16Hz)，7.47-7.79(2H，m)，7.77-7.87(2H，m)，10.90(1H，br)；

MASS(ES+)：m/e 310.

Embodiment 39

Compd E 39 obtains (110mg) by mode similar to Example 1 from compound (125).

¹H-NMR(300MHz，DMSO-d ₆，δ)：1.05(2x3H，t，J＝7Hz)，3.52(4H，m)，4.51(2H，s)，6.49(1H，d，J＝15.8Hz)，7.41-7.53(5H，m)，7.56-7.64(3H，m)；

MASS(ES+)：m/e 365.

Embodiment 40

Compd E 40 obtains (1472mg) by mode similar to Example 1 from compound (132).

¹H-NMR(300MHz，DMSO-d ₆，δ)：3.84(3H，s)，5.62(2H，s)，6.43(1H，d，J＝15.8Hz)，7.14(1H，d，J＝8Hz)，7.21(1H，d，J＝8Hz)，7.28(1H，s)，7.42(1H，d，J＝15.8Hz)，7.50-7.58(2H，m)，7.78-7.86(2H，m)；

MASS(ES+)：m/e 340.

Embodiment 41

Compd E 41 is by obtaining (115mg) with preparation scheme 9 and embodiment 1 similar mode from compound (134).

¹H-NMR(300MHz，DMSO-d ₆，δ)：3.02(2x3H，s)，4.52(2H，s)，6.50(1H，d，J＝16Hz)，6.90-7.70(8H，m)；

MASS(ES+)m/e 337.

Embodiment 42

Compd E 42 obtains (450mg) by mode similar to Example 1 from compound (141).

¹H-NMR(300MHz，DMSO-d ₆，δ)：3.82(3H，s)，5.61(2H，s)，6.40(1H，d，J＝15.8Hz)，7.11(1H，d，J＝8.8Hz)，7.28(1H，dd，J＝8.8，1.7Hz)，7.40(1H，d，J＝15.8Hz)，7.43(1H，d，J＝1.7Hz)，7.50-7.58(2H，m)，7.78-7.86(2H，m)；

MASS(ES+)：m/e 340.

Embodiment 43

Compd E 43 obtains (160.8mg) by mode similar to Example 1 from compound (144).

¹H-NMR(300MHz，DMSO-d ₆，δ)：4.45(2H，s)，6.16(2H，s)，6.47(1H，d，J＝15.8Hz)，7.43(1H，d，J＝8.1Hz)，7.46(1H，d，J＝16.0Hz)，7.59(2H，d，J＝8.1Hz)；

MASS(ES+)：m/e 338(M+1).

Embodiment 44

Compd E 44 obtains (160.8mg) by mode similar to Example 1 from compound (147).

¹H-NMR(300MHz，DMSO-d ₆，δ)：4.00(3H，s)，4.42(2H，s)，6.44(1H，d，J＝16.2Hz)，7.04(1H，d，J＝8.0Hz)，7.27(1H，d，J＝8.4Hz)，7.41(1H，t，J＝8.2Hz)，7.42(2H，d，J＝8.0Hz)，7.45(1H，d，J＝16.0Hz)，7.57(2H，d，J＝8.0Hz)；

MASS(ES+)：m/e 324(M+1).

Embodiment 45

Compd E 45 obtains (481.2mg) by mode similar to Example 1 from compound (151).

¹H-NMR(300MHz，DMSO-d ₆，δ)：1.87(3H，d，J＝7.4Hz)，4.85(1H，q，J＝7.4Hz)，6.49(1H，d，J＝16.1Hz)，7.43(1H，d，J＝15.7Hz)，7.49-7.52(2H，m)，7.51(2H，d，J＝8.5Hz)，7.58(2H，d，J＝8.5Hz)，7.74-7.77(2H，m)；

MASS(ES+)：m/e 308(M+1).

Embodiment 46

Compd E 46 obtains (576.3mg) by mode similar to Example 1 from compound (155).

¹H-NMR(300MHz，DMSO-d ₆，δ)：1.88(3H，d，J＝7.3Hz)，4.83(1H，q，J＝7.4Hz)，6.50(1H，d，J＝15.7Hz)，7.43(1H，d，J＝15.4Hz)，7.48-7.51(2H，m)，7.53(2H，d，J＝8.2Hz)，7.58(2H，d，J＝8.4Hz)，7.74-7.77(2H，m)；

MASS(ES+)：m/e 308(M+1).

Embodiment 47

Compd E 47 obtains (274.9mg) by mode similar to Example 1 from compound (158).

¹H-NMR(300MHz，DMSO-d ₆，δ)：1.36(3H，t，J＝7.0Hz)，4.08(2H，q，J＝7.0Hz)，4.58(2H，s)，6.49(1H，d，J＝15.7Hz)，7.05(2H，d，J＝8.8Hz)，7.46(1H，d，J＝17.0Hz)，7.50(2H，d，J＝8.4Hz)，7.61(2H，d，J＝8.4Hz)，7.66(2H，d，J＝8.8Hz)，7.77(1H，dd，J＝8.8，1.5Hz)，7.81(1H，d，J＝8.4Hz)，7.90(1H，s)；

MASS(ES+)：m/e 414(M+1).

Embodiment 48

Compd E 48 obtains (231.1mg) by mode similar to Example 1 from compound (161).

¹H-NMR(300MHz，DMSO-d ₆，δ)：4.60(2H，s)，6.49(1H，d，J＝15.8Hz)，7.46(1H，d，J＝16.1Hz)，7.52(2H，d，J＝8.4Hz)，7.60(2H，d，J＝8.4Hz)，7.93(2H，s)，8.19(1H，s)，8.66(1H，d，J＝9.0Hz)，8.81(1H，dd，J＝5.5，1.5Hz)，9.21(1H，d，J＝1.8Hz)；

MASS(ES+)：m/e 371(M+1).

Embodiment 49

Compd E 49 obtains (130.9mg) by mode similar to Example 1 from compound (164).

¹H-NMR(300MHz，DMSO-d ₆，δ)：4.54(2H，s)，6.48(1H，d，J＝15.8Hz)，7.46(1H，d，J＝15.8Hz)，7.47(2H，d，J＝8.1Hz)，7.58(2H，t，J＝7.0Hz)，7.60(2H，d，J＝8.1Hz)，7.71(1H，t，J＝7.7Hz)，7.76(2H，d，J＝7.4Hz)，7.83(1H，dd，J＝8.8，1.5Hz)，7.87(2H，d，J＝8.4Hz)，8.01(1H，s)；

MASS(ES+)：m/e 398(M+1).

Embodiment 50

Compd E 50 obtains (69.3mg) by mode similar to Example 1 from compound (166).

¹H-NMR(300MHz，DMSO-d ₆，δ)：4.51(2H，s)，5.89(1H，s)，6.46(1H，d，J＝45.8Hz)，7.20(1H，t，J＝7.0Hz)，7.30(2H，t，J＝7.3Hz)，7.39(2H，d，J＝7.3Hz)，7.46(4H，m)，7.59(2H，d，J＝8.4Hz)，7.65(1H，d，J＝8.4Hz)，7.74(1H，s)；

MASS(ES+)：m/e 398(M+1).

Embodiment 51

Compd E 51 obtains (103.9mg) by mode similar to Example 1 from compound (169).

¹H-NMR(300MHz，DMSO-d ₆，δ)：3.00(6H，s)，4.57(2H，s)，6.48(1H，d，J＝15.8Hz)，7.47(1H，d，J＝15.0Hz)，7.50(1H，d，J＝8.1Hz)，7.61(2H，d，J＝8.4Hz)，7.65(2H，d，J＝9.1Hz)，7.79(2H，s)，7.87(1H，s)；

MASS(ES+)：m/e 413(M+1).

Embodiment 52

Compd E 52 obtains (203.9mg) by mode similar to Example 1 from compound (172).

¹H-NMR(300MHz，DMSO-d ₆，δ)：4.46(2H，s)，6.46(1H，d，J＝16.1Hz)，7.44(2H，d，J＝8.5Hz)，7.45(1H，d，J＝16.0Hz)，7.57(2H，d，J＝8.5Hz)，7.69(1H，d，J＝8.5Hz)，7.85(1H，d，J＝7.8Hz)，8.03(1H，s)；

MASS(ES+)：m/e 361(M+1).

Embodiment 53

Compd E 53 obtains (419.6mg) by mode similar to Example 1 from compound (175).

¹H-NMR(300MHz，DMSO-d ₆，δ)：4.35(2H，s)，6.46(1H，d，J＝15.7Hz)，7.31-7.40(2H，m)，7.42(2H，d，J＝8.0Hz)，7.43(1H，d，J＝16.0Hz)，7.56(2H，d，J＝8.0Hz)；

MASS(ES+)：m/e 330(M+1).

Embodiment 54

Compd E 54 obtains (90.7mg) by mode similar to Example 1 from compound (178).

¹H-NMR(300MHz，DMSO-d ₆，δ)：0.94(6H，d，J＝6.6Hz)，1.64(2H，dt，J＝6.6，6.6Hz)，1.80(1H，hept，J＝6.6Hz)，4.07(2H，t，J＝6.6Hz)，4.51(2H，s)，6.48(1H，d，J＝16.2Hz)，7.11(1H，dd，J＝2.1，9.0Hz)，7.21(1H，d，J＝2.1Hz)，7.44(2H，d，J＝8.4Hz)，7.45(1H，d，J＝16.2Hz)，7.59(2H，d，J＝8.5Hz)，7.63(1H，d，J＝9.0Hz)；

MASS(ES+)：m/e 380(M+1).

Embodiment 55

Compd E 55 obtains (215.8mg) by mode similar to Example 1 from compound (181).

¹H-NMR(300MHz，DMSO-d ₆，δ)：1.29(6H，d，J＝6.1Hz)，4.51(2H，s)，4.70(1H，hept，J＝6.1Hz)，6.48(1H，d，J＝16.0Hz)，7.09(1H，dd，J＝2.2，8.9Hz)，7.20(1H，d，J＝2.2Hz)，7.45(1H，d，J＝16.0Hz)，7.47(2H，d，J＝8.5Hz)，7.59(2H，d，J＝8.1Hz)，7.63(1H，d，J＝8.9Hz)；

MASS(ES+)：m/e 352(M+1).

Embodiment 56

Compd E 56 obtains (387.8mg) by mode similar to Example 1 from compound (184).

¹H-NMR(300MHz，DMSO-d ₆，δ)：4.52(2H，s)，6.48(1H，d，J＝16.1Hz)，7.04(2H，d，J＝7.7Hz)，7.18(1H，t，J＝7.7Hz)，7.22(1H，dd，J＝8.8，2.2Hz)，7.30(1H，d，J＝2.2Hz)，7.41(2H，t，J＝8.0Hz)，7.46(1H，d，J＝16.0Hz)，7.47(2H，d，J＝8.1Hz)，7.57(2H，d，J＝7.7Hz)，7.77(1H，d，J＝9.2Hz)；

MASS(ES+)：m/e 386(M+1).

Embodiment 57

Compd E 57 obtains (78.2mg) by mode similar to Example 1 from compound (187).

¹H-NMR(300MHz，DMSO-d ₆，δ)：3.85(3H，s)，4.52(2H，s)，6.48(1H，d，J＝15.7Hz)，7.12(1H，dd，J＝8.8，2.2Hz)，7.20(1H，d，J＝2.2Hz)，7.45(1H，d，J＝15.0Hz)，7.46(2H，d，J＝8.4Hz)，7.60(2H，d，J＝8.4Hz)，7.65(1H，d，J＝9.2Hz)；

MASS(ES+)：m/e 324(M+1).

Embodiment 58

(Ltd.), the gained mixture stirred 2 hours at ambient temperature for 15mL, Tokyo Kasei Kogyo Co. to add methanolic hydrogen chloride reagent 10 in compound (277) MeOH (12mL) solution (2.46g).Reaction mixture filters collecting precipitation with isopropyl ether (50mL) dilution.The gained buff powder is with mixing solvent (EtOH: H ₂O=6: 4,100mL) crystallization obtains compd E 58 (1.23g), is colourless powder.

¹H-NMR(300MHz，DMSO-d ₆，δ)：4.39(2H，s )，6.46(1H，d，J＝15.7Hz)，7.43(3H，m)，7.50(1H，t，J＝6.6Hz)，7.52(2H，t，J＝7.0Hz)，7.58(2H，d，J＝8.0Hz)，7.82(2H，d，J＝7.4Hz)，8.06(1H，s)；

MASS(ES+)：m/e 320(M+1).

Embodiment 59

Compd E 59 is by obtaining (274mg) with embodiment 58 similar modes from compound (278).

¹H-NMR(300MHz，DMSO-d ₆，δ)：3.81(3H，s)，4.33(2H，s)，6.49(1H，d，J＝16.1Hz)，7.36-7.65(8H，m)，7.74-7.85(2H，m)；

MASS(ES+)：m/z 378(M+1，free).

Embodiment 60

Compd E 60 is by obtaining (1.36g) with embodiment 58 similar modes from compound (188).

¹H-NMR(300MHz，DMSO-d ₆，δ)：3.80(3H，s)，4.26(2H，s)，6.45(1H，d，J＝15.8Hz)，7.38-7.48(3H，m)，7.52-7.61(4H，m)，7.82(2H，d)；

MASS(ES+)：m/z 412(M+1，free).

Embodiment 61

Compd E 61 is by obtaining (68mg) with embodiment 58 similar modes from compound (193).

¹H-NMR(300MHz，DMSO-d ₆，δ)：4.32(2H，s)，6.47(1H，d，J＝16.1Hz)，7.39-7.61(6H，m)，7.62-7.89(4H，m)；

MASS(ES+)：m/z 363(M+1，free).

Embodiment 62

Compd E 62 is by obtaining (40mg) with embodiment 58 similar modes from compound (194).

¹H-NMR(300MHz，DMSO-d ₆，δ)：4.10(2H，s)，6.44(1H，d，J＝15.8Hz)，7.31-7.64(8H，m)，7.76-7.86(2H，m)；

MASS(ES+)：m/z 345(M+1，free).

Embodiment 63

Compd E 63 is by obtaining (212mg) with embodiment 58 similar modes from compound (203).

¹H-NMR(300MHz，DMSO-d ₆，δ)：4.40(2H，s)，6.47(1H，d，J＝16Hz)，7.34-7.50(5H，m)，7.58(2x1H，d，J＝8Hz)，7.87-7.96(2H，m)，8.05(1H，s)，10.81(1H，s)；

MASS(ES+)：m/z 338.

Embodiment 64

Compd E 64 is by obtaining (81mg) with embodiment 58 similar modes from compound (189).

¹H-NMR(300MHz，DMSO-d ₆，δ)：4.40(2H，s)，6.47(1H，d，J＝15.2Hz)，7.44(1H，d，J＝15.2Hz)，7.45(2H，d，J＝8.4Hz)，7.55-7.66(4H，m，J＝8.4Hz)，7.89(2H，d，J＝8.8Hz)，8.11(1H，s)；

MASS(ES+)：m/z 354(M+1，free).

Embodiment 65

Compd E 65 is by obtaining (145mg) with embodiment 58 similar modes from compound (209).

¹H-NMR(300MHz，DMSO-d ₆，δ)：2.52(3H，s)，2.53(3H，s)，4.27(2H，s)，6.47(1H，d，J＝16Hz)，7.41(2x1H，d，J＝8Hz)，7.44(1H，d，J＝16Hz)，7.56(2x1H，d，J＝8Hz)，10.82(1H，br-s)；

MASS: undetermined.

Embodiment 66

Compd E 66 is by obtaining (364mg) with embodiment 58 similar modes from compound (208).

¹H-NMR(300MHz，DMSO-d ₆，δ)：2.25(3H，s)，4.29(2H，s)，6.48(1H，d，J＝16Hz)，7.39-7.50(3H，m)，7.53-7.63(4H，m)，7.71(1H，m)，7.87(2x1H，d，J＝7.5Hz)，10.81(1H，br-s)；MASS (ES+)：m/z 362.

Embodiment 67

Compd E 67 is by obtaining (90mg) with embodiment 58 similar modes from compound (222).

¹H-NMR(300MHz，DMSO-d ₆，δ)：6.52(1H，d，J＝16.1Hz)，7.40-7.57(6H，m)，7.63(2H，d，J＝8.1Hz)，7.86(2H，d，J＝7.0Hz)，8.29(1H，s)，9.47(1H，s)；

MASS(ES+)：m/z 320(M+1，free).

Embodiment 68

Compd E 68 is by obtaining (80mg) with embodiment 58 similar modes from compound (190).

¹H-NMR(300MHz，DMSO-d ₆，δ)：4.43(2H，s)，6.49(1H，d，J＝16.1Hz)，7.38-7.57(7H，m)，7.64(1H，s)，7.87(2H，d，J＝7.0Hz)，8.09(1H，s)；

MASS(ES+)：m/z 320(M+1，free).

Embodiment 69

Compd E 69 is by obtaining (47mg) with embodiment 58 similar modes from compound (191).

¹H-NMR(300MHz，DMSO-d ₆，δ)：4.09(2H，s)，6.47(1H，d，J＝16.1Hz)，7.29-7.59(8H，m)，7.70-7.77(2H，m)；

MASS(ES+)：m/z 354(M+1，free).

Embodiment 70

Compd E 70 is by obtaining (1.34mg) with embodiment 58 similar modes from compound (279).

¹H-NMR(300MHz，DMSO-d ₆，δ)：3.81(3H，s)，4.38(2H，s)，6.47(1H，d，J＝16.1Hz)，7.08(2H，d，J＝8.8Hz)，7.44(2H，d，J＝8.4Hz)，7.45(1H，d，J＝15.1Hz)，7.58(2H，d，J＝8.4Hz)，7.77(2H，d，J＝8.8Hz)，7.94(1H，s)；

MASS(ES+)：m/e 350(M+1).

Embodiment 71

Compd E 71 is by obtaining (482mg) with embodiment 58 similar modes from compound (280).

¹H-NMR(300MHz，DMSO-d ₆，δ)：3.83(3H，s)，4.40(2H，s)，6.47(1H，d，J＝15.8Hz)，7.00(1H，m)，7.39-7.47(6H，m)，7.58(2H，d，J＝8.1Hz)，8.09(1H，s)；

MASS(ES+)：m/e 350(M+1).

Embodiment 72

Compd E 72 is by obtaining (498mg) with embodiment 58 similar modes from compound (281).

¹H-NMR(300MHz，DMSO-d ₆，δ)：3.93(3H，s)，4.40(2H，s)，6.46(1H，d，J＝15.7Hz)，7.11(1H，t，J＝8.1Hz)，7.21(1H，d，J＝8.1Hz)，7.43(2+1+1H，d，J＝8.1Hz)，7.58(2H，d，J＝8.1Hz)，7.80(1H，dd，J＝8.1，1.6Hz)，7.88(1H，s)；

MASS(ES+)：m/z 350(M+1).

Embodiment 73

Compd E 73 is by obtaining (94.8mg) with embodiment 58 similar modes from compound (282).

¹H-NMR(300MHz，DMSO-d ₆，δ)：4.13(2H，s)，6.44(1H，d，J＝15.8Hz)，7.37(2H，d，J＝8.4Hz)，7.38(2H，t，J＝＝8.1Hz)，7.43(1H，d，J＝15.4Hz)，7.50(2H，t，J＝8.1Hz)，7.54(2H，d，J＝8.4Hz)，7.74(2H，d，J＝8.1Hz)；

MASS(ES+)：m/e 398(M+1).

Embodiment 74

Compd E 74 is by obtaining (76mg) with embodiment 58 similar modes from compound (283).

¹H-NMR(300MHz，DMSO-d ₆，δ)：4.03(2H，s)，6.43(1H，d，J＝16.1Hz)，7.32(1H，t，J＝7.4Hz)，7.34(2H，d，J＝7.4Hz)，7.43(1H，d，J＝15.4Hz)，7.47(2H，t，J＝7.7Hz)，7.52(2H，d，J＝8.4Hz)，7.70(2H，d，J＝8.1Hz)；

MASS(ES+)：m/e 354(M+1).

Embodiment 75

Compd E 75 is by obtaining (74.3mg) with embodiment 58 similar modes from compound (285).

¹H-NMR(300MHz，DMSO-d ₆，δ)：1.64(2H，br.)，1.72(4H，br.)，2.88(2H，br.)，3.27(2H，br.)，4.35(2H，s)，4.43(2H，s)，6.47(1H，d，J＝15.7Hz)，7.45(1H，d，J＝15.7Hz)，7.49(2+1H，m)，7.56(2+2H，m)，7.67(2H，d，J＝7.4Hz)；

MASS(ES+)：m/e 417(M+1).

Embodiment 76

Compd E 76 is by obtaining (76.8mg) with embodiment 58 similar modes from compound (286).

¹H-NMR(300MHz，DMSO-d ₆，δ)：3.15(4H，br.)，3.81(4H，br.)，4.36(2H，s)，4.46(2H，s)，6.48(1H，d，J＝15.8Hz)，7.45(1H，d，J＝16.1Hz)，7.49(2+1H，m)，7.55(2+2H，m)，7.71(2H，d，J＝7.3Hz)；

MASS(ES+)：m/e 419(M+1).

Embodiment 77

Compd E 77 is by obtaining (76mg) with embodiment 58 similar modes from compound (287).

¹H-NMR(300MHz，DMSO-d ₆，δ)：3.79(3H，s)，4.05(2H，s)，6.44(1H，d，J＝15.8Hz)，7.05(2H，d，J＝8.1Hz)，7.34(2H，d，J＝8.4Hz)，7.43(1H，d，J＝16.1Hz)，7.52(2H，d，J＝8.1Hz)，7.64(2H，d，J＝8.1Hz)；

MASS(ES+)：m/e 384(M+1).

Embodiment 78

Compd E 78 is by obtaining (280mg) with embodiment 58 similar modes from compound (223).

¹H-NMR(300MHz，DMSO-d ₆，δ)：2.69(3H，s)，5.43(2H，s)，6.49(1H，d，J＝15.8Hz)，7.44(3H，m)，7.47(1H，d，J＝15.8Hz)，7.53(2H，t，J＝7.3Hz)，7.62(2H，d，J＝8.4Hz)，7.81(2H，d，J＝7.0Hz)，8.16(1H，s)；

MASS(ES+)：m/e 334(M+1).

Embodiment 79

Compd E 79 is by obtaining (432.4mg) with embodiment 58 similar modes from compound (224).

¹H-NMR(300MHz，DMSO-d ₆，δ)：2.31(3H，s)，5.53(2H，s)，6.50(1H，d，J＝15.8Hz)，7.40(2H，d，J＝8.1Hz)，7.47(1H，d，J＝15.8Hz)，7.63(2H，d，J＝8.1Hz)，7.64(4H，s)，9.36(1H，s)；

MASS(ES+)：m/z 368(M+1).

Embodiment 80

Compd E 80 is by obtaining (176mg) with embodiment 58 similar modes from compound (288).

¹H-NMR(300MHz，DMSO-d ₆，δ)：5.47(2H，s)，6.52(1H，d，J＝15.8Hz)，7.41-7.53(6H，m)，7.60(1H，d，J＝6.2Hz)，7.68(1H，s)，7.84(2H，d，J＝7.0Hz)，8.26(1H，s)，9.34(1H，s)；

MASS(ES+)：m/e 319(M+1).

Embodiment 81

Compd E 81 is by obtaining (268mg) with embodiment 58 similar modes from compound (289).

¹H-NMR(300MHz，DMSO-d ₆，δ)：2.33(3H，s)，5.54(2H，s)，6.53(1H，d，J＝16.1Hz)，7.369-7.54(4H，m)，7.58(1H，s)，7.63(2H，d，J＝8.4Hz)，7.68(2H，d，J＝8.4Hz)，9.42(1H，s)；

MASS(ES+)：m/e 368(M+1).

Embodiment 82

Compd E 82 is by obtaining (220mg) with embodiment 58 similar modes from compound (321).

¹H-NMR(300MHz，DMSO-d ₆，δ).5.50(2H，s)，6.48(1H，d，J＝16.1Hz)，7.15(2H，d，J＝8.1Hz)，7.41(1H，d，J＝16.1Hz)，7.53(2H，d，J＝8.1Hz)，7.59-7.78(5H，m)，7.88-7.97(2H，m)；

MASS(ES+)：m/z 320(M+1，free).

Embodiment 83

Compd E 83 is by obtaining (60mg) with embodiment 58 similar modes from compound (323).

¹H-NMR(300MHz，DMSO-d ₆，δ)：2.73(3H，d，J＝4.8Hz)，4.28(2H，s)，6.46(1H，d，J＝15.8Hz)，7.35-7.61(7H，m)，7.70-7.80(2H，m)，8.24-8.37(1H，m)；

MASS(ES+)：m/z 377(M+1，free).

Embodiment 84

Compd E 84 is by obtaining (22.2mg) with embodiment 58 similar modes from compound (290).

¹H-NMR(300MHz，DMSO-d ₆，δ)：3.78(3H，s)，4.22(2H，s)，6.44(1H，d，J＝15.8Hz)，7.39(2H，d，J＝8.1Hz)，7.43(1H，d，J＝15.8Hz)，7.48(3H，m)，7.54(2H，d，J＝8.4Hz)，7.76(2H，m)；

MASS(ES+)：m/e 378(M+1).

Embodiment 85

Compd E 85 is by obtaining (13.5mg) with embodiment 58 similar modes from compound (291).

¹H-NMR(300MHz，DMSO-d ₆，δ)：1.29(9H，s)，4.32(2H，s)，6.46(1H，d，J＝15.8Hz)，7.29(1H，s)，7.39(2H，d，J＝8.4Hz)，7.44(1H，d，J＝16.1Hz)，7.57(2H，d，J＝8.1Hz)；

MASS(ES+)：m/z 300(M+1).

Embodiment 86

Compd E 86 is by obtaining (491mg) with embodiment 58 similar modes from compound (198).

¹H-NMR(300MHz，DMSO-d ₆，δ)：1.23(3H，t，J＝7.0Hz)，4.24(2H，s)，4.26(2H，q，J＝7.0Hz)，6.44(1H，d，J＝15.8Hz)，7.41(2H，d，J＝8.0Hz)，7.43(1H，d，J＝15.4Hz)，7.48(3H，m)，7.55(2H，d，J＝8.1Hz)，7.75(2H，m)；

MASS(ES+)：m/e 392(M+1).

Embodiment 87

Compd E 87 is by obtaining (86.7mg) with embodiment 58 similar modes from compound (332).

¹H-NMR(300MHz，DMSO-d ₆，δ)：2.71(3H，s)，2.98(3H，s)，4.32(2H，s)，6.46(1H，d，J＝16.1Hz)，7.41-7.60(10H，m)；

MASS: undetermined.

Embodiment 88

Compd E 88 is by obtaining (35.8mg) with embodiment 58 similar modes from compound (325).

¹H-NMR(300MHz，DMS0-d ₆，δ)：1.09(2H，br.)，1.49(4H，br.)，3.12(4H，br.)，4.34(2H，s)，6.47(1H，d，J＝15.8Hz)，7.42-7.60(10H，m)；

MASS(ES+)：m/e 431(M+1).

Embodiment 89

Compd E 89 is by obtaining (40.5mg) with embodiment 58 similar modes from compound (326).

¹H-NMR(300MHz，DMSO-d ₆，δ)：1.11(6H，d，J＝6.6Hz)，4.02(1H，m)，4.23(2H，s)，6.44(1H，d，J＝15.8Hz)，7.40(2H，d，J＝7.7Hz)，7.48(4H，m)，7.56(2H，d，J＝8.1Hz)，7.73(2H，d，J＝8.1Hz)；

MASS(ES+)：m/e 405(M+1).

Embodiment 90

Compd E 90 is by obtaining (11.1mg) with embodiment 58 similar modes from compound (284).

¹H-NMR(300MHz，DMSO-d ₆，δ)：2.71(6H，s)，4.21(2H，s)，4.38(2H，s)，6.44(1H，d，J＝16.1Hz)，7.40(3H，m)，7.48(2H，m)，7.55(5H，m)；

MASS(ES+)：m/e 377(M+1).

Embodiment 91

Compd E 91 is by obtaining (40.1mg) with embodiment 58 similar modes from compound (323).

¹H-NMR(300MHz，DMSO-d ₆，δ)：4.27(2H，s)，6.45(1H，d，J＝15.8Hz)，7.41-7.58(8H，m)，7.78(2H，m)；

MASS: undetermined.

Embodiment 92

Compd E 92 is by obtaining (14.8mg) with embodiment 58 similar modes from compound (327).

¹H-NMR(300MHz，DMSO-d ₆，δ)：4.37(2H，s)，4.60(2H，s)，6.47(1H，d，J＝15.0Hz)，7.42-7.60(8H，m)，7.67(2H，d，J＝7.0Hz)；

MASS(ES+)：m/e 350(M+1).

Embodiment 93

Compd E 93 is by obtaining (145mg) with embodiment 58 similar modes from compound (329).

¹H-NMR(300MHz，DMSO-d ₆，δ)：3.34(3H，s)，4.37(2H，s)，4.51(2H，s)，6.46(1H，d，J＝15.8Hz)，7.43-7.65(10H，m)；

MASS(ES+)：m/e 364(M+1).

Embodiment 94

Compd E 94 is by obtaining (42.4mg) with embodiment 58 similar modes from compound (330).

¹H-NMR(300MHz，DMSO-d ₆，δ)：2.17(3H，s)，4.41(2H，s)，6.46(1E，d，J＝16.1Hz)，7.37-7.44(2H，m)，7.45(1H，d，J＝15.8Hz)，7.52-7.60(6H，m)，7.71(1H，m)；

MASS(ES+)：m/z362(M+1).

Embodiment 95

Compd E 95 is by obtaining (176mg) with embodiment 58 similar modes from compound (225).

¹H-NMR(300MHz，DMSO-d ₆，δ)：5.47(2H，s)，6.53(1H，d，J＝16Hz)，7.44(1H，d，J＝16Hz)，7.45(2x1H，d，J＝8.5Hz)，7.60(2x1H，d，J＝8.5Hz)，7.72(1H，dd，J＝1.7，1.5Hz)，7.81(1H，dd，J＝1.7，1.3Hz)，9.34(1H，dd，J＝1.5，1.3Hz)，10.89(1H ，br-s)，14.73(1H，br-s)；

MASS(ES+)：m/e 244.

Embodiment 96

Compd E 96 is by obtaining (21mg) with embodiment 58 similar modes from compound (210).

¹H-NMR(300MHz，DMSO-d ₆，δ)：1.96-2.03(4H，m)，3.24-3.31(4H，m)，4.49(2H，s)，6.49(1H，d，J＝16Hz)，6.60(1H，s)，6.83(1H，dd，J＝2，8Hz)，7.42-7.62(6H，m)；

MASS(ES+)：m/z 363(M+1).

Embodiment 97

Compd E 97 is by obtaining (7.9mg) with embodiment 58 similar modes from compound (328).

¹H-NMR(300MHz，DMSO-d ₆，δ)：4.55(2H，s)，4.66(2H，s)，6.48(1H，d，J＝16Hz)，7.43-7.51(4H，m)，7.60(2H，d，J＝8Hz)，7.71(2H，d，J＝8Hz)；

MASS(ES+)：m/z 324(M+1).

Embodiment 98

Compd E 98 is by obtaining (72mg) with embodiment 58 similar modes from compound (333).

¹H-NMR(300MHz，DMSO-d ₆，δ)：1.77-1.92(4H，m)，3.33-3.54(4H，m)，4.57(2H，s)，6.50(1H，d，J＝16Hz)，7.45(1H，d，J＝16Hz)，7.50(2H，d，J＝8Hz)，7.60(2H，d，J＝8Hz)，7.64(1H，dd，J＝2，8Hz)，7.80(1H，d，J＝8Hz)，7.88(1H，s)；

MASS(ES+)：m/z 391(M+1).

Embodiment 99

Compd E 99 is by obtaining (12mg) with embodiment 58 similar modes from compound (334).

¹H-NMR(300MHz，DMSO-d ₆，δ)：1.24(6H，t，J＝7Hz)，2.93-3.09(4H，m)，4.25(2H，s)，4.32-4.39(2H，m)，6.78(1H，d，J＝16Hz)，7.38-7.65(7H，m)，7.82(1H，s)；

MASS(ES+)：m/z 379(M+1).

Embodiment 100

Compd E 100 is by obtaining (40mg) with embodiment 58 similar modes from compound (316).

¹H-NMR(300MHz，DMSO-d ₆，δ)：3.71(3H，s)，4.10(2H，s)，5.11(2H，s)，6.41(1H，d，J＝16Hz)，6.86(2H，d，J＝8Hz)，7.09(2H，d，J＝8Hz)，7.16(2H，d，J＝8Hz)，7.36-7.52(3H，m)，7.80(1H，s)；

MASS(ES-)：m/z 430(M-1).

Embodiment 101

Compd E 101 is by obtaining (164mg) with embodiment 58 similar modes from compound (317).

¹H-NMR(300MHz，DMSO-d ₆，δ)：1.65-1.79(6H，m)，1.84-1.93(6H，m)，2.00-2.07(3H，m)，4.32(2H，s)，6.47(1H，d，J＝16Hz)，7.25(1H，s)，7.38-7.48(3H，m)，7.56(2H，d，J＝8Hz)；

MASS(ES+)：m/z 378(M+1).

Embodiment 102

Compd E 102 is by obtaining (35mg) with embodiment 58 similar modes from compound (338).

¹H-NMR(300MHz，DMSO-d ₆，δ)：1.31(3H，t，J＝7Hz)，4.28(2H，s)，4.33(2H，q，J＝7Hz)，6.47(1H，d，J＝16Hz)，7.37(2H，d，J＝8Hz)，7.43(1H，d，J＝16Hz)，7.55(2H，d，J＝8Hz)，8.23(1H，s)；

MASS(ES+)：m/z 316(M+1).

Embodiment 103

Compd E 103 is by obtaining (138mg) with embodiment 58 similar modes from compound (312).

¹H-NMR(300MHz，DMSO-d ₆，δ)：2.36(2H，m)，3.30(2H，t，J＝7.4Hz)，4.15(2H，t，J＝5.8Hz)，6.30(1H，d，J＝16.1Hz)，6.79(2H，d，J＝8.8Hz)，7.38(1H，d，J＝15.8Hz)，7.45(2H，d，J＝8.8Hz)，7.54(2H，m)，7.78(2H，m)；

MASS(ES+)：m/e 338(M+1).

Embodiment 104

Compd E 104 is by obtaining (174mg) with embodiment 58 similar modes from compound (313).

¹H-NMR(300MHz，DMSO-d ₆，δ)：1.84(2H，m)，2.03(2H，m)，3.21(2H，t，J＝7.4Hz)，4.07(2H，t，J＝6.4Hz)，6.31(1H，d，J＝15.4Hz)，6.96(2H，d，J＝8.8Hz)，7.40(1H，d，J＝15.8Hz)，7.49(2H，d，J＝8.1Hz)，7.53(2H，m)，7.78(2H，m)；

MASS(ES+)：m/e 352(M+1).

Embodiment 105

Compd E 105 is by obtaining (153mg) with embodiment 58 similar modes from compound (314).

¹H-NMR(300MHz，DMSO-d ₆，δ)：2.21(2H，quint.，J＝7.3Hz)，2.74(2H，t，J＝7.3Hz)，3.14(2H，t，J＝7.7Hz)，6.42(1H，d，J＝16.1Hz)，7.29(2H，d，J＝8.0Hz)，7.41(1H，d，J＝15.8Hz)，7.48(2H，d，J＝7.7Hz)，7.52(2H，m)，7.76(2H，m)；

MASS(ES+)：m/e 322(M+1).

Embodiment 106

With compd E 116 (1.23g is described in hereinafter among the embodiment 116) and the suspension of Phenylsulfonic acid (732mg) in 80% aqueous ethanolic solution (20mL) 90 ℃ of dissolvings down.Remove by filter insolubles, vacuum-evaporation filtrate obtains the crude product solid.This solid obtains compd E 106 from 80% aqueous ethanolic solution recrystallization, is pale yellow crystals (820mg).

¹H-NMR(300MHz，DMSO-d ₆，δ)：4.53(2H，s)，6.47(1H，d，J＝16Hz)，7.28-7.36(3H，m)，7.41-7.56(5H，m)，7.57-7.66(4H，m)，7.72-7.81(2H，m)，10.78(1H，s)；

MASS(ES+)：m/z 294.

Embodiment 107

With compd E 116 (1.80g is described in hereinafter among the embodiment 116) and (1R)-(-)-suspension of 10-camphorsulfonic acid (855mg) in 80% aqueous ethanolic solution (20mL) is 90 ℃ of dissolvings down.Remove by filter insolubles, vacuum-evaporation filtrate obtains the crude product solid.This solid obtains compd E 107 from 80% aqueous ethanolic solution recrystallization, is white crystal (1.30g).

¹H-NMR(300MHz，DMSO-d ₆，δ)：0.74(3H，s)，1.05(3H，s)，1.20-1.35(2H，m)，1.74-1.96(3H，m)，2.24(1H，m)，2.39(1H，d，J＝14.7Hz)，2.69(1H，m)，2.89(1H，d，J＝14.7Hz)，4.55(2H，s)，6.48(1H，d，J＝15.7Hz)，7.42-7.58(5H，m)，7.61(2x1H，d，J＝8Hz)，7.74-7.82(2H，m)，10.79(1H，s)；

MASS(ES+)：m/z 294.

Embodiment 108

Under in envrionment temperature, stirring, in ethanol (20mL) suspension of E116 (1.0g is described among the embodiment 116 hereinafter), add a hydration 4-toluene sulfonic acide (713mg).Gained suspension stirred 1 hour down at 70 ℃, during in mixture, add entry (0.1mL) so that some insolubless dissolvings.Allow the gained mixture be chilled to envrionment temperature, continue to stir 1 hour.Filtering-depositing, with washing with alcohol (5mL, 2 times), drying obtains crude product compd E 108 (1.58g), is light brown solid.Compd E 110 can use without being further purified.

Embodiment 109

(salt, 710mg) suspension in 80% acetonitrile solution (20mL) heated 15 minutes down at 90 ℃ with crude product compd E 108.Remove by filter insolubles, allow gained filtrate be chilled to envrionment temperature.Solution stirred 1 hour at ambient temperature, stirred 0.5 hour in ice bath then.With formed sedimentation and filtration, with acetonitrile washing (5mL, 2 times), drying obtains compd E 111 (370mg), is light brown solid.

Fusing point 228.5-230.5 ℃

¹H-NMR(300MHz，DMSO-d ₆，δ)：2.29(3H，s)，4.54(2H，s)，6.47(1H，d，J＝15.8Hz)，7.11(2H，d，J＝7.7Hz)，7.42-7.57(7H，m)，7.61(2H，d，J＝8.4Hz)，7.72-7.82(2H，m)；

MASS(ES+)：m/z 294(M+1，free).

Embodiment 110

Add methanolic hydrogen chloride reagent 10 (Ltd. produces for 0.8mL, Tokyo Kasei Kogyo Co.) in compound (292) MeOH (1mL) solution (42mg), the gained mixture stirred 2 hours at ambient temperature.Add saturated NaHCO to reaction mixture ₃The aqueous solution extracts with AcOEt.Organic phase is used saturated NaHCO successively ₃The aqueous solution, water and salt water washing, solvent removed in vacuo.The gained colorless solid grinds with MeCN, obtains compd E 110 (4.8mg), is colourless powder.

¹H-NMR(300MHz，DMSO-d ₆，δ)：1.28(4H，m)，1.69(4H，m)，1.90(2H，m)，2.37(1H，m)，3.91(2H，s)，6.41(1H，d，J＝15.8Hz)，6.62(1H，s)，7.26(2H，d，J＝8.1Hz)，7.41(1H，d，J＝15.8Hz)，7.47(2H，d，J＝7.7Hz)；

MASS(ES+)：m/z 326(M+1).

Embodiment 111

Compd E 111 is by obtaining (289mg) with embodiment 110 similar modes from compound (284).

¹H-NMR(300MHz，DMSO-d ₆，δ)：2.16(6H，s)，3.44(2H，s)，4.00(2H，s)，6.41(1H，d，J＝16.5Hz)，7.18(1H，t，J＝7.0Hz)，7.32(2H，d，J＝7.3Hz)，7.33(2H，t，J＝7.3Hz)，7.41(1H，d，J＝15.8Hz)，7.50(2H，d，J＝7.7Hz)，7.70(2H，d，J＝7.3Hz)；

MASS(ES+)：m/z 377(M+1).

Embodiment 112

Compd E 112 is by obtaining (22.5mg) with embodiment 58 similar modes from compound (197).

Fusing point 235-239 ℃

¹H-NMR(300MHz，DMSO-d ₆，δ)：4.34(2H，s)，6.47(1H，d，J＝15.8Hz)，7.37(2H，d，J＝8.1Hz)，7.44(1H，d，J＝15.8Hz)，7.57(2H，d，J＝8.1Hz)，7.60(2H，s)；

MASS(ES+)m/z 243(M+1，free).

Embodiment 113

Under in envrionment temperature, stirring, to [(1S, 4R)-7,7-dimethyl-2-oxo two rings [2.2.1] heptan-1-yl] methylsulfonic acid (832mg, be described among the embodiment 116 hereinafter) ethanol (10mL) solution in add compd E 116 (1.0g is described in hereinafter among the embodiment 118).Gained suspension heated 1 hour down at 60 ℃, allowed it be chilled to envrionment temperature then.With suspension restir 1 hour at ambient temperature.Filtering-depositing, with washing with alcohol (2mL, 3 times), drying obtains compd E 113 (1.73g), is light brown solid.Compd E 113 promptly is used for following examples 114 without being further purified.

Embodiment 114

(salt, 700mg) suspension in 90% acetonitrile solution (20mL) heated 5 minutes down at 90 ℃ with crude product compd E 113.Remove by filter insolubles, gained filtrate is again 90 ℃ of heating down.Allow solution be chilled to envrionment temperature and under same temperature, stirred 1 hour.Filtering-depositing, with acetonitrile washing (2mL, 2 times), drying obtains compd E 114 (522mg), is light brown solid.

Fusing point 185.5-194.5 ℃

¹H-NMR(300MHz，DMSO-d ₆，δ)：0.74(3H，s)，1.05(3H，s)，1.20-1.35(2H，m)，1.79(1H，d，J＝18.0Hz)，1.80-1.90(1H，m)，1.93(1H，t，J＝4.2Hz)，2.23(1H，dt，J＝18.0，4.2Hz)，2.39(1H，d，J＝14.7Hz)，2.61-2.76(1H，m)，2.89(1H，d，J＝14.7Hz)，4.54(2H，s)，6.48(1H，d，J＝16.1Hz)，7.41-7.57(5H，m)，7.61(2H，d，J＝8.1Hz)，7.73-7.82(2H，m)，10.79(1H，br.s)；

MASS(ES+)：m/z 294(M+1，free).

Embodiment 115

At ambient temperature, in 20 minutes, in the mixture of compound (322) (be the mixture of two kinds of regional isomers, be total to 310mg) and methyl alcohol (1mL), add methyl alcohol (3mL) solution of 10% hydrogenchloride.Vacuum concentration gained mixture, (chromatographic column: Mightysil RP-18GP 250-20 Kanto Chemical Co., Inc.) usefulness acetonitrile/water (10: 90 (volume)) is to the gradient solvent system wash-out purifying of acetonitrile/water (50: 50 (volume)) by preparative high performance liquid chromatography for resistates.With the resistates freeze-drying, obtain the mixture of compd E 115, be the mixture (85mg altogether) of two kinds of regional isomers, be light red heavy-gravity oil.

¹H-NMR (300MHz, DMSO-d ₆, δ): (to the mixture of two kinds of regional isomers) 2.17 (1.2H, s), 2.25 (1.8H, s), 5.39 (1.2H, s), 5.47 (0.8H, s), 6.52 (1H, d, J=15.8Hz), 7.18-7.37 (1.2H, m), 7.39-7.54 (2.8H, m), 7.60 (1.2H, d, J=8.1Hz), 7.75 (0.8H, d, J=8.1Hz), 9.20 (0.6H, s), 9.25 (0.4H, s);

MASS (ES+): (to the mixture of two kinds of regional isomers) m/z 258 (M+1).

Embodiment 116

Add 1N sodium hydroxide solution (3.0mL) in ethanol (10mL) suspension of compd E 1 (990mg), the gained mixture stirred 2 hours down at 70 ℃.Filter and collect the gained precipitation, with ethanol and H ₂The O washing obtains compd E 116 (810mg), is white powder.

¹H-NMR(300MHz，DMSO-d ₆，δ)：4.19(2H，s)，6.41(1H，d，J＝16Hz)，7.07-7.16(2H，m)，7.33-7.55(7H，m).

Embodiment 117

Add 1N sodium hydroxide solution (0.501mL) in ethanol (5mL) suspension of compd E 116 (147mg), the gained mixture at room temperature stirred 1 hour.Vacuum-evaporation gained mixture grinds with isopropyl ether, obtains compd E 117 (162mg), is shallow green powder.

¹H-NMR(300MHz，DMSO-d ₆，δ)：4.13(2H，s)，6.32(1H，d，J＝16Hz)，6.89(1H，d，J＝16Hz)，7.07-7.14(2H，m)，7.24(2H，d，J＝8Hz)，7.36(2H，d，J＝8Hz)，7.43-7.50(2H，m).

Embodiment 118

Add 1N methanesulfonic acid solution (0.501mL) in ethanol (5mL) suspension of compd E 116 (147mg), the gained mixture at room temperature stirred 2 hours.Filter and collect the gained precipitation, use washing with alcohol, obtain compd E 118 (91mg), be white powder.

¹H-NMR(300MHz，DMSO-d ₆，δ)：2.32(3H，s)，4.54(2H，s)，6.47(1H，d，J＝16Hz)，7.46(2H，d，J＝8Hz)，7.48-7.56(3H，m)，7.61(2H，d，J＝8Hz)，7.74-7.81(2H，m).

Embodiment 119

Add 1N sulfuric acid (1.0mL) in ethanol (5mL) suspension of compd E 116 (147mg), the gained mixture stirred 2 hours down at 70 ℃.Filter and collect the gained precipitation, use washing with alcohol, obtain compd E 119 (177mg), be white powder.

¹H-NMR(300MHz，DMSO-d ₆，δ)：4.44(2H，s)，6.46(1H，d，J＝16Hz)，7.39-7.49(5H，m)，7.59(2H，d，J＝8Hz)，7.67-7.71(2H，m).

Embodiment 120

To compound (6) (1.0g), 3-(benzyloxy)-1, the N of 2-phenylenediamine (817mg) and I-hydroxybenzotriazole (567mg) adds 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (804mg) in dinethylformamide (19mL) solution.Stir after 6 hours, add saturated NaHCO to reaction mixture ₃The aqueous solution (20mL) and water (80mL).Filter and collect the gained precipitation, wash with water.Acetate (13mL) solution that in the mixture of this product and acetate (7mL), adds hydrogenchloride.After stirring 1 hour under 100 ℃, the gained mixture is chilled to 4 ℃, with ethyl acetate (40mL) dilution.Filter and collect the gained precipitation, wash with ethyl acetate.Under 4 ℃, the N to this product, O-tetrahydrochysene-2H-pyrans-2-base azanol (1.5 equivalent) and I-hydroxybenzotriazole (1.5 equivalent) adds 1-(3-dimethylamino-propyl)-3-ethyl carbodiimide (1.5 equivalent) in dinethylformamide (11mL) solution.The gained mixture is warming up to envrionment temperature, stirred 8 hours.Add saturated NaHCO to reaction mixture ₃(11mL) and water (44mL).With the gained sedimentation and filtration, filtrate is used ethyl acetate extraction.Organic layer H ₂O and salt water washing, MgSO ₄Drying is filtered vacuum-evaporation.Crude product is handled with trifluoroacetic acid, obtains compd E 120 (52mg).

¹H-NMR(300MHz，DMSO-d ₆，δ)：4.43(2H，s)，6.46(1H，d，J＝16Hz)，6.86(1H，d，J＝8Hz)，7.12(1H，d，J＝8Hz)，7.23-7.30(1H，m)，7.39-7.62(5H，m)；

MASS(ES+)：m/z 310(M+1).

Embodiment 121

To compound (6) (1.0g), 4-(benzyloxy)-1, the N of 2-phenylenediamine (817mg) and I-hydroxybenzotriazole (567mg) adds 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (804mg) in dinethylformamide (19mL) solution.Stir after 6 hours, add saturated NaHCO to reaction mixture ₃(20mL) and water (80mL).Filter and collect the gained precipitation, wash with water.Acetate (13mL) solution that in acetate (7mL) solution of this product, adds hydrogenchloride.After stirring 1 hour under 100 ℃, the gained mixture is chilled to 4 ℃, with ethyl acetate (40mL) dilution.Filter and collect the gained precipitation, wash with ethyl acetate.Under 4 ℃, this product, O-tetrahydrochysene-2H-pyrans-2-base azanol (1.5 equivalent) and I-hydroxybenzotriazole (1.5 equivalent) are dissolved in N, in the dinethylformamide (9mL), and add 1-(3-dimethylamino-propyl)-3-ethyl carbodiimide (1.5 equivalent).The gained mixture is warming up to envrionment temperature, stirred 8 hours.Add saturated NaHCO to reaction mixture ₃(10mL) and water (40mL).Filter and collect the gained precipitation, wash with water.The hydrogenchloride that crude product is used in the methyl alcohol is handled, and obtains compd E 121 (35mg).

¹H-NMR(300MHz，DMS)-d ₆，δ)：4.52(2H，s)，5.22(2H，s)，6.49(1H，d，J＝16Hz)，7.21(1H，dd，J＝2，8Hz)，7.30(1H，d，J＝2Hz)，7.34-7.50(8H，m)，7.59(2H，d，J＝8Hz)，7.67(1H，d，J＝8Hz)；

MASS(ES+)：m/z 400(M+1).

Embodiment 122

To compound (51) N (70mg), add N in dinethylformamide (1.5mL) solution, N '-carbonyl dimidazoles (40mg).The gained mixture was stirred 30 minutes, add Toluidrin (24mg) and 1,8-diazabicylo [5.4.0]-7-hendecene (0.037mL).Reaction mixture was stirred 8 hours down at 80 ℃.The gained mixture is used the 1N hcl acidifying down at 0 ℃, adds entry (7.5mL).Filter and collect the gained precipitation, wash with water.The hydrogenchloride that crude product is used in the methyl alcohol is handled, and obtains compd E 122 (7.9mg).

¹H-NMR(300MHz，DMSO-d ₆，δ)：3.40(3H，s)，4.46(2H，s)，6.47(1H，d，J＝16Hz)，7.41-7.49(3H，m)，7.58(2H，d，J＝8Hz)，7.76(1H，d，J＝8Hz)，7.95(1H，d，J＝8Hz)，8.29(1H，s)；

MASS(ES+)：m/z 415(M+1).

Embodiment 123

Add toxilic acid (198mg) in methyl alcohol (5mL) suspension of compd E 116 (500mg), the gained mixture stirred 2 hours down at 70 ℃.Filter and collect the gained precipitation, with ethanol and water washing.The gained solid is recrystallization from the 50%EtOH aqueous solution, obtains compd E 123 (374mg), is buff powder.

¹H-NMR(300MHz，DMSO-d ₆，δ)：4.33(2H，s)，6.17(2H，s)，6.44(1H，d，J＝16Hz)，7.24-7.32(2H，m)，7.38-7.48(3H，m)，7.53-7.62(4H，m).

Embodiment 124

Compd E 124 by with preparation scheme 337 and 208 and embodiment 58 similar modes from compound (260) acquisition (7mg).

¹H-NMR(300MHz，DMSO-d ₆，δ)：3.93(2H，s)，4.18(2H，s)，6.45(1H，d，J＝16Hz)，7.13(1H，s)，7.23-7.38(7H，m)，7.43(1H，d，J＝16Hz)，7.54(2H，d，J＝8Hz)；

MASS(ES+)：m/z 334(M+1).

The compound that obtains in above-mentioned preparation scheme shows that in following table 2 (comprising table 2-1 to 2-44) compound of Huo Deing shows in the above-described embodiments in following table 3 (comprising table 3-1 to 3-17).

Table 2

Table 2-1

Table 2-2

Table 2-3

Table 2-4

Table 2-5

Table 2-6

Table 2-7

Table 2-8

Table 2-9

Table 2-10

Table 2-11

Table 2-12

Table 2-13

Table 2-14

Table 2-15

Table 2-16

Table 2-17

Table 2-18

Table 2-19

Table 2-20

Table 2-21

Table 2-22

Table 2-23

Table 2-24

Table 2-25

Table 2-26

Table 2-27

Table 2-28

Table 2-29

Table 2-30

Table 2-31

Table 2-32

Table 2-33

Table 2-34

Table 2-35

Table 2-36

Table 2-37

Table 2-38

Table 2-39

Table 2-40

Table 2-41

Table 2-42

Table 2-43

Table 2-44

Table 3

Table 3-1

Table 3-2

Table 3-3

Table 3-4

Table 3-5

Table 3-6

Table 3-7

Table 3-8

Table 3-9

Table 3-10

Table 3-11

Table 3-12

Table 3-13

Table 3-14

Table 3-15

Table 3-16

Table 3-17

Industrial usability

As mentioned above, the present invention can provide the pharmaceutical composition that the histone deacetylase activity is had the new compound of establishment effect and comprises this compound. Described compound can be used as the active component of immunosuppressive drug and antineoplastic, and is used as the therapeutic of following disease or the active component of preventive medicine: such as inflammatory conditions, diabetes, diabetic complication, homozygote thalassemia, fibrillatable, cirrhosis, acute promyelocytic leukemia (APL), organ-graft refection, autoimmune disease, protozoal infections, tumour etc.

The application is based on the Australian patent application of submitting to No. 2003900116 and No. 2003905406, and its content is attached to herein by reference.

Claims

1. compound or its salt with following formula (I):

Wherein

R ²Be hydroxylamino,

R ³Be hydrogen or suitable substituents,

L ²It is lower alkenylene.

2. the compound or its salt of claim 1, wherein

R ¹Be be expressed from the next contain the N heterocycle:

Or

Wherein

R ⁴Be hydrogen or be selected from following group:

(2) lower alkoxy,

(4) low-grade alkane acidyl,

(5) elementary alkoxy carbonyl,

(6) aryl carbonyl,

(7) aryl (rudimentary) alkoxyl group,

(9) halo (rudimentary) alkyl,

(10) aryloxy,

(11) optional aryl (rudimentary) alkyl that is replaced by hydroxyl,

(12) carboxyl,

(13) nitro,

(14) cyano group,

(15) halogen,

(16) heteroaryl,

(18) hydroxyl,

(19) (rudimentary) alkyl sulfonyl-amino formyl radical

(20) non-aromatic heterocyclic carbonyl;

R ⁶, R ⁷And R ⁸Each is hydrogen or low alkyl group naturally,

R ⁹For hydrogen or be selected from following group:

(2) the optional aryl that is replaced by lower alkoxy,

(3) (rudimentary) alkoxy carbonyl,

(4) cyano group,

(6) halogen,

(7) (rudimentary) alkyl-carbonyl,

(8) aryl carbonyl,

(9) ring (rudimentary) alkyl,

R ¹⁰Be hydrogen or be selected from following group:

(1) (rudimentary) alkyl-carbamoyl,

(2) two (rudimentary) alkyl-carbamoyl,

(3) the optional aryl that is replaced by halogen,

(4) (rudimentary) alkoxy carbonyl,

(5) carboxyl,

(6) non-aromatic heterocyclic carbonyl,

(7) halogen,

(9) adamantyl,

R ¹³Be hydrogen or be selected from low alkyl group and the group of aryl,

R ¹⁴Be hydrogen or low alkyl group,

R ²Be hydroxylamino,

R ³Be hydrogen or lower alkoxy,

L ²It is vinylene.

3. the compound of claim 2, wherein

R ¹Be following formula represent contain the N annelated heterocycles:

R wherein ⁴And R ⁵Separately as defined in claim 2.

4. the compound or its salt of claim 3, wherein

R ⁴And R ⁵The hydrogen of respectively doing for oneself,

R ²Be hydroxylamino,

R ³Be hydrogen,

L ¹Be-CH ₂-,

L ²It is vinylene.

5. the compound of claim 2, wherein

R ¹Be following formula represent contain the N heterocycle:

R wherein ⁹, R ¹⁰And R ¹¹Separately as defined in claim 2.

6. the compound or its salt of claim 5, wherein

R ⁹Be hydrogen or the optional aryl that is replaced by lower alkoxy,

R ¹⁰Be hydrogen or the optional aryl that is replaced by halogen,

R ¹¹Be hydrogen,

R ²Be hydroxylamino,

R ³Be hydrogen,

L ¹Be-CH ₂-,

L ²It is vinylene.

7. the compound or its salt of a following formula:

Or

8. compound or its salt with following formula (I '):

Wherein

R ²Be hydroxylamino,

R ³Be hydrogen or suitable substituents,

L ¹Be to choose wantonly to be replaced-(CH by one or more suitable substituents ₂) _n-(wherein n is the integer of 0-6), wherein one or more methylene radical can be replaced by suitable heteroatoms,

L ²It is lower alkenylene.

9. the compound or its salt of claim 8, wherein

R ¹Be following formula represent contain the N annelated heterocycles:

Or

Wherein

R ⁴Be hydrogen or be selected from following group:

(1) low alkyl group,

(2) lower alkoxy,

(4) low-grade alkane acidyl,

(5) elementary alkoxy carbonyl,

(6) aryl carbonyl,

(7) aryl (rudimentary) alkoxyl group,

(9) halo (rudimentary) alkyl,

(10) aryloxy,

(11) optional aryl (rudimentary) alkyl that is replaced by hydroxyl,

(12) carboxyl,

(13) nitro,

(14) cyano group,

(15) halogen,

(16) heteroaryl,

R ⁶, R ⁷And R ⁸Respectively do for oneself hydrogen or low alkyl group,

R ²Be hydroxylamino,

R ³Be hydrogen or lower alkoxy,

L ²It is vinylene.

One kind have following formula (compound or its salt of I "):

Wherein

R ²Be hydroxylamino,

L ²It is lower alkenylene.

11. the compound or its salt of claim 10, wherein

R ¹Be following formula represent contain the N annelated heterocycles:

Or

Wherein

R ⁴Be hydrogen or be selected from low alkyl group and the group of aryl;

R ²Be hydroxylamino,

L ²It is vinylene.

12. a histone deacetylase inhibitor, described histone deacetylase inhibitor comprise claim 1,7,8 and 10 each compounds.

13. pharmaceutical composition, described pharmaceutical composition is used for the treatment of or prevention of inflammatory conditions, diabetes, diabetic complication, homozygote thalassemia, fibrosis, cirrhosis, acute promyelocytic leukemia (APL), organ-graft refection, autoimmune disorder, protozoal infections or tumour, and described pharmaceutical composition comprises claim 1,7,8 and 10 each compounds.

14. a pharmaceutical composition, described pharmaceutical composition contain claim 1,7,8 and 10 each compounds as activeconstituents, acceptable nontoxic basically carrier of described compound and medicine or excipient composition.

15. claim 1,7,8 and 10 each compounds, described compound is as medicine.

16. comprising, the method for an inhibition of histone deacetylase, described method use claim 1,7,8 and 10 each compounds.

17. claim 1,7,8 and 10 each compounds are used for the purposes of the medicine of inhibition of histone deacetylase in preparation.

A 18. treatment or prevent the method for following disease: inflammatory conditions, diabetes, diabetic complication, homozygote thalassemia, fibrosis, cirrhosis, acute promyelocytic leukemia (APL), organ-graft refection, autoimmune disorder, protozoal infections or tumour, described method comprise the claim 1,7 that gives the mankind or animal effective dose, 8 and 10 each compounds.

19. claim 1,7,8 and 10 each compounds are used for the treatment of or prevent purposes in the medicine of following disease in preparation: inflammatory conditions, diabetes, diabetic complication, homozygote thalassemia, fibrosis, cirrhosis, acute promyelocytic leukemia (APL), organ-graft refection, autoimmune disorder, protozoal infections or tumour.

20. commodity package, described commodity package comprises the pharmaceutical composition of claim 13 and appended written document, and described written document illustrates that described pharmaceutical composition can maybe should be used for the treatment of or prevention of inflammatory conditions, diabetes, diabetic complication, homozygote thalassemia, fibrosis, cirrhosis, acute promyelocytic leukemia (APL), organ-graft refection, autoimmune disorder, protozoal infections or tumour.