CN106478655A - There are gambogic acid compounds of anti-tumor activity and its production and use - Google Patents

Abstract

The present invention relates to having gambogic acid compounds of anti-tumor activity and its production and use, belong to medicinal chemistry art.On the basis of fully realizing existing compound activity, design has synthesized multiple gambogic acid-type derivatives to the present invention, and it is carried out with anti-tumor biological research, obtains the antitumoral compounds improving.The present invention is concrete to provide the compound shown in logical formula (I) or its pharmaceutically acceptable salt, its pharmaceutical composition, preparation method and the purposes for preparation treatment or prophylactic pharmaceutical composition.

Description

There are gambogic acid compounds of anti-tumor activity and its production and use

Technical field

The present invention relates to a kind of gambogic acid-type derivative of new antitumoral activity and its preparation method and application, belong to medicinal chemistry art.

Background technology

Resina garciniae, is the dry resin secreted by Garcinia maingayii Resina garciniae, and traditional Chinese medical science tradition uses it for detumescence, removing toxic substances, hemostasis.Recent study Show, Resina garciniae also has antitumor action, be used clinically for treating breast carcinoma, lymphosarcoma, skin carcinoma all obtain certain curative effect, therefore Paid high attention to.

Gamlogic acid (gambogic acid, GA) is to separate, from Chinese medicine gamboge, the compound with anti-tumor activity obtaining, and it has anti- The tumor spectrum feature relatively low compared with wide, toxicity, optionally can kill cancerous cell, and normal hemopoietic system and leukocyte is affected less.Should Compound and the antitumor drug as high-efficiency low-toxicity, can play antitumor action by different mechanisms, including inducing cell cycle arrest with carefully Born of the same parents' apoptosis, suppression telomerase and topoisomerase active, Antineoplastic angiogenesis and neoplasm metastasis, reverse multidrug drug resistance etc..However, Resina garciniae Acid also has that water solublity is poor, degradable and the more low deficiency urgently improved of bioavailability.For this reason, scientists are spread out to gambogic acid Biological exploitation shows keen interest, and the exploration to such compound also deepens continuously.

On the basis of fully realizing existing compound activity, design has synthesized multiple gambogic acid-type derivatives to the present invention, and it is carried out anti-swollen Tumor bioactivity research, obtains the antitumoral compounds improving.

Content of the invention

The present invention provides the compound shown in logical formula (I) or its pharmaceutically acceptable salt：

Wherein, R¹For H or selected from optionally by one or more R^aThe following groups replacing：C_1-6Alkyl-, C_2-6Thiazolinyl-, C₃-₁₀Cycloalkanes Base-, comprise 1-3 and be selected from N, O and S heteroatomic 3-10 circle heterocycles alkyl, C_6-14Aryl-, comprise 1-3 and be selected from N, O and S Heteroatomic 5-14 unit's heteroaryl-,-C (=O) R^b,-S (=O)₂R^b；

R²Selected from O, S, OH, SH or optionally by one or more R^aThe following groups replacing：C_1-6Alkyl oxy-, C_2-6Thiazolinyl epoxide -、C_3-10Cycloalkyl oxy-, comprise 1-3 selected from N, O and S heteroatomic 3-10 circle heterocycles alkyl oxy-, C_6-14Aryloxy-, Comprise 1-3 selected from N, O and S heteroatomic 5-14 unit's heteroaryl epoxide-, C_1-6Alkyl sulfenyl-, C_2-6Enylsulfanyl-, C_3-10Cycloalkyl sulfur Base-, comprise 1-3 selected from N, O and S heteroatomic 3-10 circle heterocycles alkyl sulfenyl-, C_6-14Artyl sulfo-, comprise 1-3 and be selected from N, O 5-14 unit's heteroaryl sulfenyl heteroatomic with S-,-OC (=O) R^b,-OS (=O)₂R^b, R²And between C-12Represent singly-bound or double bond, Wherein work as R²During for O or S, it forms double bond with C-12, works as R²During for other group in defined above, it forms singly-bound with C-12；

R³Selected from F, Cl, Br, I, OH, SH, CN or optionally by one or more R^aThe following groups replacing：C_1-6Alkyl-, C_2-6Alkene Base-, C₃-C₁₀Cycloalkyl-, NR^cR^d, comprise 1-3 selected from N, O and S heteroatomic 3-10 circle heterocycles alkyl-, C_6-14Aryl-, comprise 1-3 selected from N, O and S heteroatomic 5-14 unit's heteroaryl-,-C (=O) R^b,-S (=O)₂R^b,-OC (=O) R^b,-OS (=O)₂R^b；

R⁴It is selected from-CHO ,-CH=N-OR⁵,-CH=N-OC (=O)-R⁶,-CH=N-OC (=O) O-R⁷,-CH=N-OC (=O)-NH-R⁸、 - C (=O) O-N=CH-R⁹；

R⁵Selected from H, OH or optionally by one or more R^aThe C replacing_1-6Alkyl oxy-；Connect R⁵C-4 and C-3 between Represent singly-bound or double bond, wherein work as R⁵During for H, C-4 and C-3 forms double bond, works as R⁵When being not H, C-4 and C-3 forms singly-bound；

R^aIndependently selected from F, Cl, Br, I, OH, SH, CN ,=O, NR^cR^d、C_1-6Alkyl-, C_2-6Thiazolinyl-, C₃-C₁₀Cycloalkyl-, Comprise 1-3 selected from N, O and S heteroatomic 3-10 circle heterocycles alkyl-, C_6-14Aryl-, to comprise 1-3 heteroatomic selected from N, O and S 5-14 unit's heteroaryl-, C_1-6Alkyl oxy-, C_2-6Thiazolinyl epoxide-, C₃-C₁₀Cycloalkyl oxy-, comprise 1-3 and be selected from N, O and S hetero atom 3-10 circle heterocycles alkyl oxy-, C_6-14Aryloxy-, comprise 1-3 selected from N, O and S heteroatomic 5-14 unit's heteroaryl epoxide-, - C (=O) R^b,-S (=O)₂R^b；

R^bSelected from optionally by one or more R^aThe following groups replacing：C_1-6Alkyl-, C_2-6Thiazolinyl-, C₃-₁₀Cycloalkyl-, NR^cR^d, comprise 1-3 selected from N, O and S heteroatomic 3-10 circle heterocycles alkyl-, C_6-14Aryl-, comprise 1-3 and be selected from the heteroatomic 5-14 of N, O and S Unit's heteroaryl-；

R^cAnd R^dIt is independently selected from H or optionally by one or more R^aThe following groups replacing：C_1-6Alkyl-, C_2-6Thiazolinyl-, C₃-₁₀Ring Alkyl-, comprise 1-3 selected from N, O and S heteroatomic 3-10 circle heterocycles alkyl-, C_6-14Aryl-, to comprise 1-3 miscellaneous selected from N, O and S The 5-14 unit's heteroaryl of atom-.

According to the present invention, R¹It is preferably H or optionally by one or more R^aThe following groups replacing：C_1-6Alkyl-, C_2-6Thiazolinyl-, C₃-₁₀Ring Alkyl-,-C (=O) R^b,-S (=O)₂R^b；

R²It is preferably selected from O, S, OH, SH or optionally by one or more R^aThe following groups replacing：C_1-6Alkyl oxy-, C_2-6Thiazolinyl epoxide -、C₃-C₁₀Cycloalkyl oxy-, C_1-6Alkyl sulfenyl-, C_2-6Enylsulfanyl-, C₃-C₁₀Cycloalkylsulfanyl-,-OC (=O) R^b,-OS (=O)₂R^b, R²And between C-12Represent singly-bound or double bond, wherein work as R²During for O or S, it forms double bond with C-12, works as R²For other bases During group, it forms singly-bound with C-12；

R³It is preferably selected from F, Cl, Br, I, OH, SH, CN or optionally by one or more R^aThe following groups replacing：C_1-6Alkyl-, C_2-6 Thiazolinyl-, C₃-₁₀Cycloalkyl-, NR^cR^d, comprise 1-3 selected from N, O and S heteroatomic 3-10 circle heterocycles alkyl-, C_6-14Aryl-, comprise 1-3 selected from N, O and S heteroatomic 5-14 unit's heteroaryl-,-C (=O) R^b,-S (=O)₂R^b,-OC (=O) R^b,-OS (=O)₂R^b.

According to the present invention, R¹It is more preferably H or optionally by one or more R^aThe C replacing_1-6Alkyl-,-C (=O) R^b,-S (=O)₂R^b；

R²It is more preferably selected from O, S, OH, SH or optionally by one or more R^aThe following groups replacing：C_1-6Alkyl oxy-, C_1-6Alkyl sulfide Base-,-OC (=O) R^b,-OS (=O)₂R^b, R²And between C-12Represent singly-bound or double bond, wherein work as R²During for O or S, its Form double bond with C-12, work as R²During for other group, it forms singly-bound with C-12；

R³It is more preferably selected from F, Cl, Br, OH, SH or optionally by one or more R^aThe following groups replacing：C_1-6Alkyl-, C₃-₁₀Cycloalkanes Base-, NR^cR^d, comprise 1-3 selected from N, O and S heteroatomic 3-10 circle heterocycles alkyl-, C_6-14Aryl-, comprise 1-3 and be selected from N, O 5-14 unit's heteroaryl heteroatomic with S-,-OC (=O) R^b,-OS (=O)₂R^b；

Alternatively, R¹Selected from H, C_1-6Alkyl-or by one or more R^aThe C replacing_1-6Alkyl-；

R²Selected from O ,-OH or C_1-6Alkyl-；

R³Selected from optionally by one or more R^aThe following groups replacing：C_1-6Alkyl-, C₃-₁₀Cycloalkyl-, NR^cR^d, comprise 1-3 selected from N, O and S heteroatomic 3-10 circle heterocycles alkyl-, C_6-14Aryl-, comprise 1-3 selected from N, O and S heteroatomic 5-14 unit's heteroaryl- Or-OC (=O) R^b,-OS (=O)₂R^b.

According to the present invention, logical formula (I) compound can the compound shown in selected from following formula (I ') and (I ")：

Wherein, group R¹To R⁵It is each independently selected from the definition in logical formula (I).

According to the present invention, logical formula (I) compound can also exemplarily be selected from following formula (II ')～(VII ') and formula (II ")～(VII ") Shown compound：

Wherein, R¹～R²And R⁵Separately it is selected from the definition in above-mentioned logical formula (I), R³Selected from F, Cl, Br, I, OH, SH, CN Or optionally by one or more R^aThe following groups replacing：C_1-6Alkyl-, C_2-6Thiazolinyl-, C₃-C₁₀Cycloalkyl-, NR^cR^d, comprise 1-3 choosing From N, O and S heteroatomic 3-10 circle heterocycles alkyl-, C_6-14Aryl-, comprise 1-3 selected from N, O and S heteroatomic 5-14 unit heteroaryl Base-,-C (=O) R^b,-S (=O)₂R^b,-OC (=O) R^b,-OS (=O)₂R^b；

R⁶、R⁷、R⁸、R⁹、R¹⁰It is independently from each other H ,-C (=O) R^b,-S (=O)₂R^b, optionally by one or more R^aThe C replacing_1-6 Alkyl-, C_2-6Thiazolinyl-, C_3-10Cycloalkyl-, comprise 1-3 selected from N, O and S heteroatomic 3-10 circle heterocycles alkyl-, C_6-14Aryl-, bag Containing 1-3 selected from N, O and S heteroatomic 5-14 unit's heteroaryl-；

R^a、R^b、R^c、R^dSeparately there is the definition in above-mentioned logical formula (I).

Preferably, the present invention leads to the compound bag shown in formula (I), (I '), (I "), (II ')～(VII ') and (II ")～(VII ") Include its optical pure compound, stereoisomer mixture or its pharmaceutically acceptable salt.

Term definition and explanation

Term " C_1-6Alkyl " is interpreted as preferably representing the linear or branched saturation monovalent hydrocarbon with 1,2,3,4,5 or 6 carbon atoms Base, such as methyl, ethyl, propyl group, butyl, amyl group, hexyl, isopropyl, isobutyl group, sec-butyl, the tert-butyl group, isopentyl, 2- methyl fourth Base, 1- methyl butyl, 1- ethyl propyl, 1,2- dimethyl propyl, neopentyl, 1,1- dimethyl propyl, 4- methyl amyl, 3- methyl amyl, 2- Methyl amyl, 1- methyl amyl, 2- ethyl-butyl, 1- ethyl-butyl, 3,3- dimethylbutyl, 2,2- dimethylbutyl, 1,1- dimethylbutyl, 2,3- Dimethylbutyl, 1,3- dimethylbutyl or 1,2- dimethylbutyl or their isomer.Especially, described group has 1,2,3 or 4 Carbon atom (" C_1-4Alkyl "), such as methyl, ethyl, propyl group, butyl, isopropyl, isobutyl group, sec-butyl, the tert-butyl group, more special Not, described group has 1,2 or 3 carbon atom (" C_1-3Alkyl "), such as methyl, ethyl, n-pro-pyl or isopropyl.

Term " C_2-6Thiazolinyl " is interpreted as preferably representing linear or branched monovalent hydrocarbon, and it comprises one or more double bonds and has 2nd, 3,4,5 or 6 carbon atoms, particularly 2 or 3 carbon atom (" C_2-3Thiazolinyl ") it should be appreciated that comprising to be more than in described thiazolinyl In the case of one double bond, described double bond can be separated from each other or be conjugated.Described thiazolinyl is such as vinyl, pi-allyl, (E) -2- methyl second Thiazolinyl, (Z) -2- methyl ethylene, (E)-but-2-ene base, (Z)-but-2-ene base, (E)-but-1-ene base, (Z)-but-1-ene base, amyl- 4- thiazolinyl, (E)-amyl- 3- thiazolinyl, (Z)-amyl- 3- thiazolinyl, (E)-amyl- 2- thiazolinyl, (Z)-amyl- 2- thiazolinyl, (E)-amyl- 1- thiazolinyl, (Z)-amyl- 1- thiazolinyl, hex- 5- Thiazolinyl, (E)-hex- 4- thiazolinyl, (Z)-hex- 4- thiazolinyl, (E)-hex- 3- thiazolinyl, (Z)-hex- 3- thiazolinyl, (E)-hex- 2- thiazolinyl, (Z)-hex- 2- thiazolinyl, (E)-hex- 1- thiazolinyl, (Z)-hex- 1- thiazolinyl, isopropenyl, 2- methyl propyl- 2- thiazolinyl, 1- methyl propyl- 2- thiazolinyl, 2- methyl propyl- 1- thiazolinyl, (E) -1- Methyl propyl- 1- thiazolinyl, (Z) -1- methyl propyl- 1- thiazolinyl, 3- methyl butyl- 3- thiazolinyl, 2- methyl butyl- 3- thiazolinyl, 1- methyl butyl- 3- thiazolinyl, 3- methyl But-2-ene base, (E) -2- methyl but-2-ene base, (Z) -2- methyl but-2-ene base, (E) -1- methyl but-2-ene base, (Z) -1- methyl but-2-ene base, (E) -3- methyl but-1-ene base, (Z) -3- methyl but-1-ene base, (E) -2- methyl but-1-ene base, (Z) -2- methyl but-1-ene base, (E) -1- methyl But-1-ene base, (Z) -1- methyl but-1-ene base, 1,1- dimethyl propylene -2- thiazolinyl, 1- ethyl propyl- 1- thiazolinyl, 1- propyl ethylene base, 1- isopropyl Vinyl.

Term " C_3-10Cycloalkyl " is understood to mean that the monovalent monocyclic of saturation or bicyclic hydrocarbon ring, and it has 3,4,5,6,7,8,9 Or 10 carbon atoms.Described C_3-10Cycloalkyl can be monocyclic alkyl, such as cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, suberyl, Cyclooctyl, cyclononyl or cyclodecyl, or for example decahydronaphthalene naphthalene nucleus of bicyclic alkyl.

Term " 3-10 circle heterocycles alkyl " means the monovalent monocyclic of saturation or bicyclic hydrocarbon ring, and it is individual miscellaneous former selected from N, O and S that it comprises 1-3 Son.Described Heterocyclylalkyl can pass through any one of described carbon atom or nitrogen-atoms (if present) are connected with the remainder of molecule. Especially, described Heterocyclylalkyl can include but is not limited to：4 yuan of rings, such as azetidinyl, oxetanyl；5 yuan of rings, such as four Hydrogen furyl, dioxa cyclopentenyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl；Or 6 yuan of rings, such as THP trtrahydropyranyl, Piperidyl, morpholinyl, dithiane base, tetrahydro-1,4-thiazine base, piperazinyl or trithiane base；Or 7 yuan of rings, such as Diazesuberane basic ring.Optionally Ground, described Heterocyclylalkyl can be benzo-fused.Described heterocyclic radical can be bicyclic, such as but not limited to 5,5 yuan of rings, such as hexahydro ring Penta simultaneously [c] pyrroles -2 (1H)-basic ring, or 5,6 membered bicyclics, such as hexahydropyrrolo simultaneously [1,2-a] pyrazine -2 (1H)-basic ring.Described nitrogen atom ring can To be partly undersaturated, that is, it can comprise one or more double bonds, such as but not limited to 2,5- dihydro -1H- pyrrole radicals, 4H- [1,3,4] Thiadiazine base, 4,5- dihydro oxazolyl or 4H- [Isosorbide-5-Nitrae] thiazine basic ring, or, it can be benzo-fused, and such as but not limited to dihydro is different Quinoline basic ring.

Term " C_6-14Aryl " is interpreted as preferably representing the monovalence with 6,7,8,9,10,11,12,13 or 14 carbon atoms Armaticity or monocyclic, bicyclic or tricyclic the hydrocarbon ring (" C of partial aromatic_6-14Aryl "), particularly there is the ring (" C of 6 carbon atoms₆ Aryl "), such as phenyl；Or xenyl, or there is the ring (" C of 9 carbon atoms₉Aryl "), such as indanyl or indenyl, Or there is the ring (" C of 10 carbon atoms₁₀Aryl "), such as tetrahydro naphthyl, ihydro naphthyl or naphthyl, or have 13 The ring (" C of individual carbon atom₁₃Aryl "), such as fluorenyl, or there is the ring (" C of 14 carbon atoms₁₄Aryl "), such as anthracene Base.

Term " 5-14 unit's heteroaryl " is understood to include such monovalent monocyclic, bicyclic or tricyclic aromatic ring system, it has 5,6,7, 8th, 9,10,11,12,13 or 14 annular atoms, particularly 5 or 6 or 9 or 10 carbon atoms, and its to comprise at least one permissible Identical or different hetero atom (described hetero atom is such as oxygen, nitrogen or sulfur), and, can be in addition benzo-fused at each occurrence. Especially, heteroaryl is selected from thienyl, furyl, pyrrole radicals, oxazolyl, thiazolyl, imidazole radicals, pyrazolyl, isoxazolyl, different thiophene Oxazolyl, di azoly, triazolyl, thiadiazolyl group, thiophene -4H- pyrazolyl etc. and their benzo derivative, such as benzofuranyl, benzene Bithiophene base, benzoxazolyl group, benzo isoxazolyl, benzimidazolyl, benzotriazole base, indazolyl, indyl, isoindolyl etc.； Or pyridine radicals, pyridazinyl, pyrimidine radicals, pyrazinyl, triazine radical etc., and their benzo derivative, such as quinolyl, quinazolyl, Isoquinolyl etc.；Or azocine base, indolizine base, purine radicals etc. and their benzo derivative；Or cinnolines base, phthalazinyl, quinazolyl, Quinoxalinyl, naphthyridinyl, pteridyl, carbazyl, acridinyl, phenazinyl, phenothiazinyl, phenazinyl etc..

Unless otherwise stated, described heteroaryl or inferior heteroaryl include its all possible isomeric form, such as its position isomer.Therefore, for Some illustrative non-limiting examples, term pyridine radicals or pyridylidene include pyridine -2- base, sub- pyridine -2- base, pyridin-3-yl, sub- pyridine -3- Base, pyridin-4-yl and sub- pyridin-4-yl；Or, term thienyl or sub- thienyl include thiophene -2- base, sub- thiophene -2- base, thiene-3-yl and Asia Thiene-3-yl.

Term " substituted " means one or more hydrogen on specified atom by listed substituent group, and condition is not less than specified atom Normal atom valency in the current situation and described replacement forms stable compound.The combination of substituent group and/or variable is only when this combination is formed Just it is allowed during stable compound.

Term " optionally quilt ... replace " refers to can be unsubstituted or by listed substituent group.

The substituent group of ring system refers to the substituent group being connected with aromatics or non-aromatic ring system, and for example described substituent group replaces available hydrogen in described ring system.

The each general formula compound of the present invention substituent group definition used in term " one or many " be understood to include once, twice, three times, four Secondary or five times, particularly once, twice, three times or four times, more particularly once, twice or thrice, for example once or twice.

The present invention also provides the preparation method of gambogic acid-type derivative or its pharmaceutically acceptable salt shown in formula (I), including selected from following one Or the combination of multiple step：

Step 1)：

Methods known in the art can be passed through, such as through over-churning, reduction, oxidation reaction, by compound (a) prepare compound (b).Wherein：

In the esterification reaction, preferably in catalyst such as 1- ethyl-(3- dimethylaminopropyl) carbodiimide hydrochloride (EDCI) and 4- dimethylamino In the presence of pyridine (DMAP), by compound (a) and alcohol (such as C_1-12Alcohol) reaction with the ester of prepare compound (a)；

In reduction reaction, the ester of compound (a) is reacted in the presence of a reducing agent, obtain corresponding reduzate, suffered reducing agent is preferred Diisobutyl aluminium hydride；

In the oxidation reaction, reduzate is reacted in the presence of oxidant, obtain compound (b).

As an example, the Chinese invention patent description [0004th] of such as application number 201310682918.4, publication number CN103613602A can be passed through The method recorded to [0019] section is carried out, and the content that the full text of this application is recorded is incorporated herein content of the invention.

According to specific embodiment of the present invention, step 1) comprise the following steps a)～c)：

a)：In the presence of catalyst, compound (a) (as gamlogic acid) and alcohols (as methanol) are condensed to yield the ester of compound (a) (such as Resina garciniae acid esters)；

Reaction temperature can be such as -30 DEG C～30 DEG C, and reaction is preferably carried out with nitrogen protection in organic solvent, the preferred dichloromethane of organic solvent, Catalyst preferred 1- ethyl-(3- dimethylaminopropyl) carbodiimide hydrochloride (EDCI) and/or DMAP (DMAP)；

b)：The ester of compound (a) reacts in the presence of a reducing agent in organic solvent, obtains corresponding reduzate；

Reaction temperature can be such as -78 DEG C～-40 DEG C, and reaction is preferably carried out in organic solvent, and organic solvent is preferably dichloromethane, reducing agent For diisobutyl aluminium hydride；

c)：The reduzate of step b) reacts in the presence of oxidant, obtains compound (b)；

Reaction temperature can be such as -30 DEG C～30 DEG C, and reaction is preferably carried out in organic solvent, and organic solvent is preferably dichloromethane, and oxidant is excellent Select phenmethylol conversion thewire (TEMPO) and/or iodobenzene diacetate (BAIB).

If necessary, carry out step 2)：

Wherein, described oxidation is carried out by any suitable reactions known in the art.As example, described oxidation can be selected from such as Ao Benao (Oppenauer Oxidation, oxidant is Al (O-i-Pr) for your oxidation₃/ acetone), Dai Si-Martin oxidation reaction (Dess-Martin Oxidation, oxidant crosses iodine alkane or DMP for Dai Si-Martin) or polite oxidation reaction (Swern Oxidation, oxidant is DMSO)；

Or

Wherein, described etherificate is carried out by any appropriate method known in the art.As example, described etherificate can by dehydration or Williamson synthesis (Williamson Synthesis) is carried out.For example compound (b) is dehydrated in presence of an acid with alcohol or mercaptan, or will Compound (b) is reacted with halogenated compound (as halogenated alkane) after being converted into sodium alkoxide or mercaptan sodium compound.

Step 3)：

Wherein, described reaction is preferably carried out in the basic conditions；It is highly preferred that described reaction is carried out in the presence of base；

Step 4)：

Wherein, each reaction is preferably carried out in the basic conditions；It is highly preferred that described reaction is carried out in the presence of base；

Or

Described reaction is preferably carried out in the presence of catalyst 1- ethyl-(3- dimethylaminopropyl) carbodiimide hydrochloride (EDCI) and/or alkali；

Or using identical method, corresponding compound (III ")～(VII ") is prepared by following compounds (e ") and (f ")：

And, step 5)：

Optionally, by step 1)～4) compound of gained prepares its pharmaceutically acceptable salt with suitable acid or alkali reaction；

Wherein, R¹～R³、R⁵To R¹⁰It is respectively provided with the definition being independently selected from logical formula (I)；

R^2aSelected from OH or SH；

R^2bSelected from O or S；

R^2cSelected from optionally by one or more R^aThe following groups replacing：C_1-6Alkyl oxy-, C_2-6Thiazolinyl epoxide-, C₃-C₁₀Cycloalkyloxy group Base-, comprise 1-3 selected from N, O and S heteroatomic 3-10 circle heterocycles alkyl oxy-, C_6-14Aryloxy-, comprise 1-3 selected from N, O and S heteroatomic 5-14 unit's heteroaryl epoxide-, C_1-6Alkyl sulfenyl-, C_2-6Enylsulfanyl-, C₃-C₁₀Cycloalkylsulfanyl-, comprise 1-3 Individual selected from N, O and S heteroatomic 3-10 circle heterocycles alkyl sulfenyl-, C_6-14Artyl sulfo-, to comprise 1-3 miscellaneous former selected from N, O and S Son 5-14 unit's heteroaryl sulfenyl-,-OC (=O) R^b,-OS (=O)₂R^b, wherein R^aAnd R^bIt is independently selected from the group that formula (I) defines；

X is selected from chlorine, bromine or iodine；

Z is selected from hydrogen, chlorine or bromine.

In the preparation process in accordance with the present invention, if it is desired, using any suitable method of this area, the group with reactivity can be protected Reacted again after shield.As example, can be used as alcoholic extract hydroxyl group protection group can be such as acetyl group, 2- methoxyl group ethoxymethyl ether, first Oxygen methyl ether, to methoxy-benzyl ether, pivaloyl group, Pentamethylene oxide. etc.；Can be used as amino protecting group can for such as benzyloxycarbonyl group, Tertbutyloxycarbonyl, benzyl, p-methoxyphenyl etc.；Can be used as carbonyl-protection base can be such as acetal and ketal, acylal, dithiane Deng；Can be used as carboxyl-protecting group can be methyl ester base, benzyl ester group, tert-butyl group ester group, silicon substrate ester group etc..

For example, can be by step 1) R of compound (a)^2bRadical protection, then through over-churning, reduction, deprotection reaction, obtain compound (c).

Above steps can be carried out in the presence of suitable solvent.Described solvent is any organic solvent inert at reaction conditions, bag Include the mixture selected from for example following one or more：Ketone, such as acetone and methyl ethyl ketone；Acyclic ethers and cyclic ethers, such as ether and four Hydrogen furan；Ester, such as ethyl acetate or butyl acetate；Hydrocarbon, such as benzene,toluene,xylene, hexane and hexamethylene；Chlorine Change hydrocarbon, such as monochloro methane, dichloromethane, chloroform, 1,2- dichloroethanes and chlorobenzene；Alcohol, such as methanol, ethanol, n-propanol, Isopropanol, n-butanol or tert-butanol；Or other solvents, such as DMF (DMF), dimethyl sulfoxide (DMSO), N-Methyl pyrrolidone (NMP), acetonitrile or pyridine；

Described alkali can be organic base, inorganic base or its mixture, is selected from alkali metal or alkaline earth metal carbonate or bicarbonate, example As lithium carbonate, sodium carbonate, potassium carbonate, Calcium Carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, calcium bicarbonate；Alkali metal alcoholates, for example Tert-butanol sodium or potassium tert-butoxide；Alkali metal hydride, such as sodium hydride or hydrofining；Amide, for example double (trimethyl silyls) Lithamide., double (trimethyl silyl) potassamide or lithium diisopropylamine (LDA)；Organic amine, such as triethylamine, N-methylmorpholine, N- methyl piperidine, N, N- diisopropylethylamine, 1,5- diazabicyclo [4.3.0] nonyl- 5- alkene (DBN), 1,8- diazabicyclo [5.4.0] decyl- 7- Alkene (DBU), pyridine or 4-N, N- dimethyl aminopyridine；Or phosphonitrile alkali triethylamine, pyridine, piperidines, DMAP (DMAP)；

Described alkali specifically can be selected from sodium carbonate, sodium bicarbonate, potassium carbonate, cesium carbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, hydrogen Change the mixture of one or more of sodium；

Wherein, described acid can be organic acid, mineral acid or its mixture, is selected from following one or more：Carboxylic acid, such as acetic acid or three Fluoroethanoic acid；Sulfonic acid, such as methanesulfonic acid, fluoroform sulphur or p- toluenesulfonic acid；Hydrochloric acid, sulphuric acid, phosphoric acid, phosphonic acids or phosphoric acid.

Above steps can independently be carried out at suitable temperature, such as -30 DEG C～30 DEG C (as room temperature).

As example, the compounds of this invention can be by the combination preparation selected from following one or more steps：

Wherein, R¹～R³And R⁵It is each independently selected from the definition in logical formula (I)；

R⁶、R⁷、R⁸、R⁹、R¹⁰It is independently from each other H ,-C (=O) R^b,-S (=O)₂R^b, optionally by one or more R^aThe C replacing_1-6 Alkyl-, C_2-6Thiazolinyl-, C_3-10Cycloalkyl-, comprise 1-3 selected from N, O and S heteroatomic 3-10 circle heterocycles alkyl-, C_6-14Aryl-, bag Containing 1-3 selected from N, O and S heteroatomic 5-14 unit's heteroaryl-.

As example, the preparation method of the compounds of this invention is included selected from following one or more steps combination：

Step a)：In organic solvent, under nitrogen protection, in the presence of oxidant, compound 8 oxidation obtains compound 2；Organic solvent Preferably dichloromethane, oxidant preferably (1,1,1- triacetoxyl group) -1,1- dihydro -1,2- benzenesulfonyl -3 (1H) -one (Dess-Martin oxidant, DMP)；

Step b)：In organic solvent, under nitrogen protection, in the presence of alkali, compound 9 and oxammonium hydrochloride. react and obtain compound 10； Organic solvent is preferably ethanol, and alkali is preferably pyridine, triethylamine；

Step c)：In organic solvent, in the presence of alkali, compound 10 and halohydrocarbons reaction, obtain oximido ether compound 3；Have Machine solvent is preferably oxolane (THF), dimethylformamide (DMF)；Alkali is preferably sodium hydroxide (NaOH), sodium hydride (NaH) etc.；

Step d)：In organic solvent, in the presence of alkali and catalyst, compound 10 and acyl chlorides or carboxylic acid reaction, obtain corresponding Oxime ester compound 4；Organic solvent is preferably dichloromethane (DCM)；Described alkali can be organic base and inorganic base, preferably Pyridine, DMAP (DMAP), sodium hydroxide etc., catalyst preferred 1- ethyl-(3- dimethylaminopropyl) carbodiimide salt Hydrochlorate (EDCI)；

Step e)：In organic solvent, in the presence of alkali, compound 10 and chloro-formate react, and obtain corresponding oxime carbonates esters Compound 5；Organic solvent is preferably dichloromethane (DCM)；Described alkali can be organic base and inorganic base, preferably pyridine, 4- Dimethylamino naphthyridine (DMAP), sodium hydroxide etc.；

Step f)：In organic solvent, in the presence of alkali, compound 10 reacts with replacing isocyanates, obtains corresponding phosphinylidyne amidoxime Ester type compound 6；Organic solvent is preferably dichloromethane (DCM)；Described alkali can be organic base and inorganic base, preferably pyridine, DMAP (DMAP), triethylamine etc.；

Step g)：Under the conditions of -30 DEG C～30 DEG C (as room temperature), in organic solvent, in the presence of alkali and catalyst, gamlogic acid React with various oximes, obtain corresponding gamlogic acid oxime ester compound 7；Organic solvent is preferably dichloromethane (DCM)；Described alkali can To be organic base and inorganic base, preferably pyridine, DMAP (DMAP), sodium hydroxide etc., catalyst preferred 1- ethyl-(3- Dimethylaminopropyl) carbodiimide hydrochloride (EDCI).

According to the present invention, those skilled in the art also can be by step 1 each in above-mentioned preparation method)～5) and each step a)～g) in arbitrary One or more steps and its actual conditions are combined or combine, or with well known to a person skilled in the art step and actual conditions are combined Or combination, obtained method equally should be within the scope of the present invention.

The present invention also provides the pharmaceutical composition comprising one or more the compounds of this invention or its pharmaceutically acceptable salt.These groups can be utilized Compound is by being administered to realize desired pharmacotoxicological effect to patient in need.For purposes of the invention, patient is to need treatment tool Body disease or the mammal including people of disease.Therefore, the present invention includes such pharmaceutical composition, and it comprises pharmaceutically acceptable Carrier and the compound of the present invention of pharmacy effective dose or its pharmaceutically acceptable salt.

Pharmaceutically acceptable carrier is preferably such carrier, and it is under the concentration consistent with the effective active of active component to patient's nothing relatively Malicious and harmless, so that the beneficial effect of described active component will not be destroyed by any side effect that described carrier causes.Compound or its pharmacy The amount that the pharmacy effective dose of upper acceptable salt preferably produces result or produces impact on the concrete patient's condition treated.Can use and include speed Release, slow release and time release formulation in interior arbitrarily effective conventional dosage unit forms, by the compound of the present invention and medicine well known in the art On, acceptable carrier is administered together as follows：Oral, parenteral, locally, nasal cavity, eye, Sublingual, rectum, vagina administration Deng.

For oral administration, described compound or its pharmaceutically acceptable salt can be configured to solid or liquid preparation, such as capsule, ball Agent, tablet, containing lozenge (troche), lozenge (lozenge), melten gel agent (melt), powder, solution, suspensoid or Emulsion, and can root To prepare according to the method for preparing pharmaceutical composition known in the art.Solid unit dosage form can be capsule, and it can be common hard capsule Type or soft-capsule type, comprise such as surfactant, lubricant and inert filler (such as Lactose, sucrose, calcium phosphate and corn starch).

In another embodiment, can be by the compound of the present invention or its pharmaceutically acceptable salt and conventional tablet bases (such as Lactose, sugarcane Sugar and corn starch) together with and tabletted with following combinations of substances：Binding agent (such as arabic gum, corn starch or gelatin), use The decomposition of tablet and dissolution after adjunctive administration disintegrating agent (such as potato starch, alginic acid, corn starch and guar gum, gum tragacanth, Ah Draw primary glue), for improve tablet granulation mobility and prevent tablet material and tablet mould and drift surface adhesion lubricant (for example sliding Stone, stearic acid or magnesium stearate, calcium stearate or zinc stearate), dyestuff, coloring agent, and for improving the organoleptic properties of tablet and make them It is easier the flavoring agent (such as Oleum menthae, wintergreen oil or cherry essence) being accepted by patients.Suitable excipient for oral liquid dosage forms includes Dicalcium phosphate and diluent, such as water and alcohol (such as ethanol, benzyl alcohol and polyvinyl alcohol), add or live without pharmaceutically acceptable surface Property agent, suspending agent or emulsifying agent.There may be the physical form as coating or for changing dosage unit for the various other materials.Worm for example can be used Glue, sugar or the two by tablet, pill or capsule coating.

Also the compound of the present invention can be carried out parenteral with the injection dosage of described compound, that is, subcutaneous, intravenouss, ophthalmic, intrasynovial, Intramuscular or Intraperitoneal medication, preferably in the acceptable diluent of the physiology containing pharmaceutical carrier, described pharmaceutical carrier can be for no for described injection dosage Bacteria liquid or the mixture of liquid, described liquid such as water, saline, D/W and related sugar juice, alcohol such as ethanol, isopropanol or Hexadecanol, glycol such as propylene glycol or Polyethylene Glycol, glycerol ketals such as 2,2- dimethyl -1,1- dioxolanes -4- methanol, ether such as PEG400 (PEG400), oil, fatty acid, fatty acid ester or fatty glyceride or acetylated fatty acid glyceride, described diluent add or without There are pharmaceutically acceptable surfactant, such as soap or detergent, suspending agent such as pectin, Carbomer, methylcellulose, hypromellose Element or carboxymethyl cellulose, or emulsifying agent and other pharmaceutical auxiliaries.

Exemplary surfactants for parenteral administration are polyethylene sorbitan fatty acid esters, such as sorbitan list Oleic acid Ester, and the high molecular weight adducts of oxirane and hydrophobic base, described hydrophobic base is formed by expoxy propane and propylene glycol condensation.

Also the compositionss of the present invention can be administered the form of the suppository for the rectally of medicine.Can by by medicine with normal temperatures be solid but Being is liquid under rectal temperature and the suitable non-irritating excipient that therefore can dissolve in the rectum and discharge described medicine mixes and to prepare These compositionss.Such material is such as cocoa butter and Polyethylene Glycol.

Controlled release preparation for parenteral includes liposome microsphere known in the art, polymer microballoon and polymer gel preparation.

May need or described pharmaceutical composition must be delivered to by patient by mechanical delivery device.For delivering the structure of the mechanical delivery device of medicament It is well known in the art for making with purposes.The direct technology for example medicine being administered directly to brain is usually directed to the ventricles of the brain that drug delivery tube is inserted patient System is to bypass blood brain barrier.

The compound of the present invention can be administered as single medicament or be administered with one or more other pharmaceutical agent combinations, wherein said combination will not cause Unacceptable untoward reaction.The invention still further relates to such combination.For example, can be by the compound of the present invention and known chemotherapeutics or anticarcinogen (example Medicament as anti-excess proliferative disease or other indication etc.) and the mixture with them and combining be combined.Other indication medicaments include But it is not limited to anti-angiogenic agent, mitotic inhibitor, alkylating agent, antimetabolite, DNA- embed antibiotic, growth factor receptor inhibitors, thin Born of the same parents' cycle inhibitor, enzyme inhibitor, topoisomerase enzyme inhibitor, biological response modifier or hormone antagonist.

In general, cytotoxic agent and/or cytostatics are played following effect with the compound of the present invention or combination of compositions using meeting：

(1) produce more preferable effect in minimizing tumour growth or even elimination tumor side compared with being administered alone any one medicament,

(2) allow to be administered lesser amount of be administered chemotherapeutic agents,

(3) provide chemotherapeutic agent, harmful pharmacology's complication that it is well tolerated by the patient and has is than in single medicament chemotherapy and some other It is few what is observed in combination treatment,

(4) allow the various cancers type of the wider array of mammal of therapeutic domain (particularly people),

(5) provide higher response in subject,

(6) provide the longer time-to-live in subject compared with the chemotherapeutic treatment of standard,

(7) provide the longer tumor development time, and/or

(8), compared with combining with other cancer agents and producing the known case of antagonistic effect, obtain good effect at least as the medicament being used alone and resistance to By property.

Another aspect of the present invention provides compound to be as described above used for preparation treatment or the purposes of prophylactic pharmaceutical composition.

Described disease is by uncontrolled cell growth, propagation and/or survival, unsuitable cellullar immunologic response or unsuitable cellular inflammation response The disease causing, or with uncontrolled cell growth, propagation and/or survival, unsuitable cellullar immunologic response or unsuitable cellular inflammation The disease of response, especially, described disease is such as neoplastic hematologic disorder, solid tumor and/or their transfer, such as leukemia and myeloproliferative disorder Syndrome, malignant lymphoma, the head including cerebroma and brain metastes and tumor colli, inclusion non-fire power and minicell lung swell Tumor in interior breast tumor, gastroenteric tumor, endocrine tumorses, breast tumor and other gynecological tumor, include tumor of kidney, bladder tumor and front Row adenoma is in interior urologic neoplasms, cutaneous tumor and sarcoma and/or their transfer.More particularly, described disease is cancer such as pulmonary carcinoma.

In the linguistic context of the present invention, particularly as used herein in " unsuitable cellullar immunologic response or unsuitable cellular inflammation response " Linguistic context in, term " unsuitable " be interpreted as preferably representing weaker or higher than normal response and related to the pathology of described disease, Cause or lead to the response of the pathology of described disease.

Preferably, described purposes is the treatment for disease or prevention, and wherein said disease is neoplastic hematologic disorder, solid tumor and/or their transfer.

The present invention also provides the use in the medicine of the hyperproliferative disorders in preparation treatment mammal for the compound of the present invention and combinations thereof On the way.Can be suppressed using compound, cell proliferation and/or the cell division such as block, reduce, reducing and/or causing apoptosis.Excess proliferative Disease includes but is not limited to psoriasises, keloid and other cutaneous hypertrophy, benign prostatic hyperplasia (BPH), solid tumor for example Breast carcinoma, respiratory cancer, pulmonary carcinoma, the brain cancer, genital cancer, digestive tract cancer, urinary tract cancer, cancer eye, hepatocarcinoma, skin carcinoma, head and neck cancer, Thyroid carcinoma, parathyroid carcinoma and their far-end transfer.Described disease also includes lymphoma, sarcoma and leukemia.

These diseases have obtained good sign in the mankind, but are also present in other mammals with similar etiology, and can lead to The pharmaceutical composition crossing the administration present invention is treated.

The term " treatment " that presents refers in the whole text has well known to a person skilled in the art conventional sense, such as in order to resist, mitigate, subtract Less, alleviate, improve the purpose of situation of the disease of sarcoma or disease etc. to manage or to nurse individuality.

The present invention is led to compound shown in formula (I) and is had good inhibitory activity to human leukemia, hepatocarcinoma and lung cancer tumor cell strain, and it is to A-549 The IC of human lung carcinoma cell₅₀Value<0.05μg/mL.Specifically, the IC to A-549 human lung carcinoma cell for the embodiment of the present invention compound₅₀Value≤ 0.02μg/mL.Preferably, embodiment of the present invention compound 12,13,14,18,20, the IC to A-549 human lung carcinoma cell for the 25-30₅₀ Value≤0.01 μ g/mL.

And, the compounds of this invention also has relatively low cytotoxicity to normal cell.Specifically, the compounds of this invention, such as embodiment The IC of compound 12-19,21,27,37,38,40,41,42 couple HELF-6₅₀Value<0.4μg/mL.

Dosage and administration

Based on the known standard laboratory techniques for evaluating the compound for treating hyperproliferative disorders and angiogenesis disease, by mark Quasi- toxicity test and the standard pharmacological trials by the treatment to disease mentioned above in mammal for determination, and pass through these Result is compared with the result of the known drug for treating these diseases, is readily determined the basis for treating each expectation indication The effective dose of the compound of invention.The amount of the active component of medicine given in the treatment of one of these diseases can occur very according to considering as follows Big change：The particular compound being used and dosage unit, administering mode, the course for the treatment of, the age of subject and sex and treated disease The nature and extent of disease.For example, the total amount of active component to be administered is typically about 0.001mg/kg- about 200mg/kg body weight/day, and Preferably from about 0.01mg/kg- about 20mg/kg body weight/day.Clinically useful dosage regimen can be once a day to three times be administered to every four weeks Administration once.The desired therapeutic modality of the compound of the present invention or its pharmaceutically acceptable salt or ester or compositionss and administration quantity can be by Those skilled in the art are determined using conventional therapeutic test.

Specific embodiment

Below by way of exemplary specific embodiment, technical scheme is described in detail.But it is right should not to be construed to these embodiments The restriction of the scope of the present invention.All it is encompassed by the range of it is contemplated that protecting based on the technology that the above of the present invention is realized.

Unless otherwise stated, used in embodiment, raw material and reagent are commercial materials.

The preparation of embodiment 1 compound 2

Weigh the dichloromethane that monomethyl ether 8 (2.08g, 3.31mmol) is dissolved in 40mL, add DMP (2.813g, 6.62mmol) room temperature reaction 5 little When, the Na of saturation₂S₂O₃NaHCO with saturation₃Solution is quenched reaction.Absolute ether extracts, and merges organic faciess, and saturated common salt aqueous solution washs, Anhydrous sodium sulfate drying, is spin-dried for, and column chromatography purification obtains compound 2,1.83g, yield 88.4%.¹H NMR(300MHz,CDCl₃)δ9.54 (s, 1H), 7.44 (d, J=6.8Hz, 1H), 6.64 (d, J=10.2Hz, 1H), 6.13 (t, J=8.0Hz, 1H), 5.57 (d, J=10.2Hz, 1H), 5.20 (t, J=5.9Hz, 1H), 5.08 (t, J=6.5Hz, 1H), 3.78 (s, 3H), 3.55 3.45 (m, 1H), 3.44 3.26 (m, 2H), 3.13 (dd, J=14.9,9.8Hz, 1H), 2.88 (dd, J=14.8,6.5Hz, 1H), 2.55 (d, J=9.3Hz, 1H), 2.33 (dd, J=13.4,4.3Hz, 1H),2.12–1.97(m,2H),1.88–1.80(m,1H),1.78(s,3H),1.73(s,3H),1.66(s,6H),1.63–1.58(m,1H),1.56 (s,3H),1.51(s,3H),1.48(s,3H),1.42–1.37(m,1H),1.31(s,3H).ppm；¹³C NMR(101MHz,CDCl₃)δ203.4, 189.4,174.1,159.3159.1,155.4,140.6,137.3,135.5,133.6,132.4,131.9,127.8,123.8,121.6,116.5,112.7, 110.6,107.2,90.5,84.1,83.8,80.9,62.1,49.0,46.8,41.9,30.0,29.0,27.4,26.7,25.7,25.7,25.7,22.8,22.0,18.2, 17.6,16.4.ppm；HRMS(EI)m/z calcd for C₃₉H₄₇O₇627.3322,found for[M+H]⁺627.3305.

The preparation of embodiment 2 compound 12

The hydrochlorate (50.2mg, 0.723mmol) of azanol is dissolved in 5mL dehydrated alcohol, instills pyridine (0.194mL, 2.41mmol) and treat no solid When being that the hydrochlorate of azanol is released complete, add the ethanol solution of aldehyde 11 (370mg, 0.602mmol), room temperature reaction overnight, go out instead by water quenching Should, absolute ether extracts, and merges organic faciess, and saturated common salt aqueous solution washs, and anhydrous sodium sulfate drying is spin-dried for, column chromatography purification obtains compound 12,0.321g, yield 84.7%.¹H NMR(400MHz,CDCl₃) δ 13.00 (s, 1H), 7.90 (s, 1H), 7.64 (d, J=7.2Hz, 1H), 6.67 (d, J=10.1Hz, 1H), 5.56 (t, J=7.7Hz, 1H), 5.43 (d, J=10.1Hz, 1H), 5.13 5.02 (m, 2H), 3.41 3.29 (m, 2H), 3.30 3.20 (m, 1H), 3.08 (dd, J=5.3,2.2Hz, 1H), 2.96 2.86 (m, 1H), 2.58 (dd, J=14.8,5.8Hz, 1H), 2.35 (dd, J=14.2,4.1Hz, 1H), 2.28 2.21 (m, 1H), 2.18 (d, J=10.1Hz, 1H), 2.09 2.01 (m, 2H), 1.81 (s, 3H),1.79–1.76(m,1H),1.75(s,3H),1.74(s,3H),1.65(s,6H),1.61–1.57(m,1H),1.56(s,3H),1.53(s,3H), 1.43(s,3H),1.33–1.25(m,1H)ppm；¹³C NMR(101MHz,CDCl₃)δ179.8,161.2,158.1,157.6,148.0,142.1, 131.8,131.7,131.6,131.0,129.1,124.5,123.8,122.5,116.0,107.5,102.5,100.2,92.5,84.4,84.2,81.2,70.6, 49.1,42.1,36.9,32.2,30.2,28.5,27.8,25.7,25.7,25.0,22.7,21.9,19.2,18.2,17.6ppm；HRMS(EI)m/z calcd for C₃₈H₄₆NO₇628.3275,found for[M-H]⁺628.3285.

The preparation of embodiment 3 compound 13

With embodiment 2, difference is to replace compound 11 to react with compound 8, obtains compound 13, yield 93.1%.¹H NMR(400 MHz,CDCl₃) δ 7.88 (s, 1H), 7.52 (d, J=7.1Hz, 1H), 6.67 (d, J=10.1Hz, 1H), 5.60 (t, J=7.4Hz, 1H), 5.53 (d, J=10.1Hz, 1H), 5.11 (s, 1H), 5.06 (t, J=6.9Hz, 1H), 3.84 (s, 3H), 3.45 (dd, J=14.6,7.6Hz, 1H), 3.39 3.31 (m, 1H), 3.23 (s, 1H), 2.87 (br, 1H), 2.58 (dd, J=14.7,7.1Hz, 1H), 2.35 2.26 (m, 2H), 2.24–2.12(m,3H),2.08–1.99(m,2H),1.83–1.72(m,10H),1.70–1.59(m,7H),1.55(s,3H),1.52(s, 3H),1.43(s,3H),1.37–1.29(m,1H)ppm；¹³C NMR(101MHz,CDCl₃)δ175.7,160.1,158.8,155.3, 147.9,140.6,133.5,132.0,131.9,131.3,129.2,127.3,123.8,122.1,116.7,112.6,109.9,107.4,92.5,84.5, 84.0,80.5,70.8,62.2,49.0,42.0,36.7,32.2,30.2,28.5,27.6,25.7,25.6,25.2,22.7,22.4,19.3,18.2,17.6 ppm；HRMS(EI)m/z calcd for C₃₉H₅₀NO₇644.3578,found for[M+H]⁺644.3578.

The preparation of embodiment 4 compound 14

With embodiment 2, difference is to replace compound 11 to react with compound 2, obtains compound 14, yield 72.3%.¹H NMR(400 MHz,CDCl₃) δ 7.64 (s, 1H), 7.58 (s, 1H), 7.38 (d, J=6.9Hz, 1H), 6.64 (d, J=10.2Hz, 1H), 5.51 (d, J= 10.2Hz, 1H), 5.28 (t, J=6.7Hz, 1H), 5.24 5.15 (m, 1H), 5.06 (t, J=7.1Hz, 1H), 3.79 (s, 3H), 3.50 3.43 (m, 1H), 3.42 3.33 (m, 2H), 2.75 (dd, J=14.9,9.7Hz, 1H), 2.63 (dd, J=15.1,5.3Hz, 1H), 2.49 (d, J =9.3Hz, 1H), 2.31 (dd, J=13.4,4.5Hz, 1H), 2.09 1.98 (m, 2H), 1.83 1.74 (m, 4H), 1.71 (s, 3H), 1.68 (s,3H),1.65(s,3H),1.62–1.59(m,1H),1.57(s,3H),1.55(s,3H),1.42(s,3H),1.38–1.35(m,1H),1.29 (s,3H)ppm；¹³C NMR(101MHz,CDCl₃)δ203.8,174.3,159.5,159.0,155.4,147.2,135.7,133.0,132.3, 131.9,130.5,129.2,127.2,123.8,122.0,116.7,112.7,110.2,107.2,90.4,84.2,83.5,80.6,62.1,49.1,46.8, 42.1,30.0,29.1,27.7,27.7,25.8,25.7,25.7,22.7,22.1,19.0,18.3,17.6ppm；HRMS(EI)m/z calcd for C₃₉H₄₈NO₇642.3431,found for[M+H]⁺642.3430.

The preparation of embodiment 5 compound 15

NaH (25.36mg, 1.06mmol) is dissolved in 10mL DMF, under the conditions of ice-water bath will dissolved with substrate 12 (133mg, 0.211 Mmol DMF solution) is added drop-wise in the former mixture, ice-water bath reaction 30min after move to room temperature, be added dropwise to isopropyl bromide (0.1mL, 1.06 Mmol), the oil bath then moving to 50 DEG C is reacted 11 hours.Water quenching is gone out reaction, and absolute ether extracts, and merges organic faciess, and saturated common salt aqueous solution is washed Liquid washs, and anhydrous sodium sulfate drying is spin-dried for, column chromatography purification obtains compound 15,0.62mg, yield 81.9%.¹H NMR(400MHz, CDCl₃) δ 13.01 (s, 1H), 7.82 (s, 1H), 7.63 (d, J=7.2Hz, 1H), 6.68 (d, J=10.1Hz, 1H), 5.53 (t, J=7.6Hz, 1H), 5.43 (d, J=10.1Hz, 1H), 5.11 5.02 (m, 2H), 4.28 (dq, J=12.5,6.4Hz, 1H), 3.38 3.26 (m, 2H), 3.21 (s, 1H), 3.01 (s, 1H), 2.93 2.87 (m, 1H), 2.56 (dd, J=14.3,5.9Hz, 1H), 2.33 (dd, J=14.2,4.2Hz, 1H), 2.17 (dd, J=12.3,9.2Hz, 2H), 2.10 2.01 (m, 2H), 1.84 1.71 (m, 10H), 1.65 (s, 3H), 1.65 (s, 3H), 1.60 (dd, J=6.9,2.5 Hz, 1H), 1.56 (s, 3H), 1.53 (s, 3H), 1.44 (s, 3H), 1.32 1.24 (m, 1H), 1.21 (d, J=1.8Hz, 3H), 1.19 (d, J=1.8 Hz,3H)ppm；¹³C NMR(101MHz,CDCl₃)δ179.9,161.2,158.2,157.6,145.9,142.2,132.1,131.8,131.6, 131.0,127.8,124.5,123.8,122.6,116.0,107.5,102.6,100.0,92.6,84.4,84.1,81.1,75.4,70.7,49.0,42.0,36.9, 32.2,30.3,28.5,27.7,25.7,25.7,25.0,22.7,21.9,21.6,21.6,19.4,18.2,17.6ppm；HRMS(EI)m/z calcd for C₄₁H₅₄NO₈672.3900,found for[M+H]⁺672.3897.

The preparation of embodiment 6 compound 16

Weigh substrate 12 (615mg, 0.98mmol) respectively, NaOH (78.2mg, 1.95mmol) and tetrabutyl ammonium bromide (TBAB, 50.4mg, 0.156mmol), it is subsequently adding 20mL THF and 4mL water, add benzyl bromine (0.174mL, 1.47mmol) in room temperature reaction 8 hours, water Reaction is quenched, absolute ether extracts, merges organic faciess, saturated common salt aqueous solution washs, anhydrous sodium sulfate drying is spin-dried for, column chromatography purification obtains Compound 16,0.447g, yield 61.3%.¹H NMR(400MHz,CDCl₃) δ 13.00 (s, 1H), 7.90 (s, 1H), 7.62 (d, J=7.2Hz, 1H), 7.34 7.27 (m, 5H), 6.68 (d, J=10.1Hz, 1H), 5.56 (t, J=7.6Hz, 1H), 5.43 (d, J=10.1Hz, 1H), 5.10 5.05 (m, 2H), 5.04 (s, 2H), 3.34 (dd, J=14.6,7.7Hz, 1H), 3.27 (dd, J=14.8,5.6Hz, 1H), 3.22 3.17 (m, 1H), 3.00 (d, J=5.4Hz, 1H), 2.92 2.86 (m, 1H), 2.55 (dd, J=14.8,5.8Hz, 1H), 2.32 (dd, J=14.1,4.0Hz, 1H), 2.20 2.12 (m, 2H), 2.04 (dd, J=15.8,7.8Hz, 2H), 1.78 (s, 3H), 1.77 (s, 3H), 1.77 1.73 (m, 1H), 1.73 (s, 3H), 1.64(s,3H),1.62(s,3H),1.60–1.57(m,1H),1.55(s,3H),1.52(s,3H),1.42(s,3H),1.30–1.24(m,1H)ppm；¹³C NMR(101MHz,CDCl₃)δ179.9,161.2,158.1,157.7,147.0,142.2,137.4,131.8,131.7,131.6,131.0,128.8, 128.4,128.4,127.9,124.5,123.9,122.5,116.1,107.5,102.6,100.3,92.5,84.4,84.1,81.1,76.2,70.7,49.1,42.0, 36.9,32.3,30.2,28.5,27.7,25.7,25.7,25.0,22.7,21.9,19.3,18.2,17.6ppm；HRMS(EI)m/z calcd for C₄₅H₅₃NO₇Na 742.3720,found for[M+Na]⁺742.3720.

The preparation of embodiment 7 compound 17

With embodiment 6, difference is to replace compound 12 to react with compound 14, obtains compound 17, yield 21.2%.¹H NMR(400MHz, CDCl₃) δ 7.64 (s, 1H), 7.38 (d, J=6.9Hz, 1H), 7.33 7.25 (m, 5H), 6.67 (d, J=10.2Hz, 1H), 5.53 (d, J= 10.2Hz, 1H), 5.30 5.20 (m, 2H), 5.05 (t, J=7.1Hz, 1H), 4.97 4.87 (m, 2H), 3.77 (s, 3H), 3.45 (dd, J= 6.7,4.5Hz, 1H), 3.39 3.32 (m, 2H), 2.70 (dd, J=15.0,9.1Hz, 1H), 2.59 (dd, J=15.2,6.4Hz, 1H), 2.49 (d, J=9.3Hz, 1H), 2.30 (dd, J=13.4,4.6Hz, 1H), 2.08 1.98 (m, 2H), 1.78 1.73 (m, 4H), 1.71 (s, 3H), 1.69–1.63(m,7H),1.60(s,3H),1.54(s,3H),1.40(s,3H),1.37–1.32(m,1H),1.28(s,3H)ppm；¹³C NMR(101MHz,CDCl₃)δ203.7,174.3,159.5,158.9,155.3,146.2,137.7,135.7,133.1,132.2,131.9, 130.8,128.8,128.2,128.1,127.6,127.4,123.8,122.0,116.8,112.8,110.2,107.3,90.5,84.2,83.5,80.5,75.9, 62.1,49.1,46.8,41.9,30.0,29.0,27.6,27.5,25.7,25.7,25.7,22.6,22.1,19.1,18.2,17.6ppm；HRMS(EI) m/z calcd for C₄₆H₅₄NO₇732.3900,found for[M+H]⁺732.3902.

The preparation of embodiment 8 compound 18

Substrate 12 (108mg, 0.172mmol) is dissolved in 5mL CH₂Cl₂, add (13.8 μ L, 0.172mmol) pyridine, add (12.1 afterwards μ L, 0.172mmol) chloroacetic chloride, room temperature reaction 4 hours, water quenching is gone out reaction, and absolute ether extracts, and merges organic faciess, and saturated common salt is water-soluble Liquid washs, and anhydrous sodium sulfate drying is spin-dried for, column chromatography purification obtains compound 18,71mg, yield 61.6%.¹H NMR(400MHz, CDCl₃) δ 12.99 (s, 1H), 8.12 (s, 1H), 7.67 (d, J=7.2Hz, 1H), 6.67 (d, J=10.1Hz, 1H), 5.85 (t, J=7.9Hz, 1H), 5.44 (d, J=10.1Hz, 1H), 5.06 (m, 2H), 3.35 (dd, J=14.6,7.5Hz, 1H), 3.28 (d, J=5.5Hz, 1H), 3.23 (s, 1H), 2.96 2.90 (m, 1H), 2.59 (dd, J=14.7,6.6Hz, 1H), 2.34 (dd, J=14.0,4.1Hz, 1H), 2.22 2.14 (m, 3H), 2.15 (s, 3H), 2.04 (dd, J=16.0,7.7Hz, 2H), 1.87 (s, 3H), 1.83 1.72 (m, 7H), 1.65 (s, 6H), 1.62 –1.58(m,1H),1.55(s,3H),1.53(s,3H),1.44(s,3H),1.31–1.23(m,1H)ppm；¹³C NMR(101MHz, CDCl₃)δ179.8,168.8,161.3,157.9,157.6,153.1,142.4,134.2,131.9,131.7,130.9,130.8,124.7,123.8, 122.4,115.8,107.4,102.7,100.2,92.5,84.3,84.2,81.3,70.9,49.1,42.0,36.9,32.5,30.2,28.5,27.7,25.7, 25.6,24.9,22.7,21.9,19.7,19.0,18.2,17.6ppm；HRMS(EI)m/z calcd for C₄₀H₅₀NO₈672.3536,found for[M+H]⁺672.3528.

The preparation of embodiment 9 compound 19

With embodiment 8, difference is to replace excess acetyl chloride with isobutyryl chloride, obtains compound 19, yield 78.0%.¹H NMR(400 MHz,CDCl₃) δ 12.99 (s, 1H), 8.16 (s, 1H), 7.67 (d, J=7.2Hz, 1H), 6.67 (d, J=10.1Hz, 1H), 5.87 (t, J= 7.8Hz, 1H), 5.44 (d, J=10.1Hz, 1H), 5.06 (t, J=6.9Hz, 2H), 3.36 (dd, J=14.6,7.6Hz, 1H), 3.26 (dd, J =15.1,5.6Hz, 1H), 3.21 (d, J=5.4Hz, 1H), 2.98 (d, J=5.5Hz, 1H), 2.95 2.89 (m, 1H), 2.69 2.59 (m, 2H), 2.34 (dd, J=14.2,4.2Hz, 1H), 2.23 2.17 (m, 1H), 2.14 (dd, J=14.8,8.2Hz, 1H), 2.09 2.00 (m, 2H),1.90(s,3H),1.81–1.72(m,7H),1.68–1.61(m,7H),1.55(s,3H),1.53(s,3H),1.43(s,3H),1.34– 1.26 (m, 1H), 1.23 (d, J=6.8Hz, 3H), 1.23 (d, J=6.8Hz, 3H) ppm；¹³C NMR(101MHz,CDCl₃)δ179.8, 174.3,161.2,158.0,157.6,153.5,142.5,134.0,131.8,131.6,131.0,130.8,124.6,123.8,122.4,115.8,107.4, 102.6,100.2,92.5,84.2,84.2,81.3,71.0,49.1,42.0,36.9,32.8,32.5,30.1,28.5,27.7,25.7,25.6,24.9,22.7,21.9, 21.9,19.0,19.0,18.9,18.2,17.6ppm；HRMS(EI)m/z calcd for C₄₂H₅₄NO₈700.3849,found for[M+H]⁺ 700.3837.

The preparation of embodiment 10 compound 20

With embodiment 8, difference is to replace excess acetyl chloride with phenyllacetyl chloride, obtains compound 20, yield 64.0%.¹H NMR(400MHz, CDCl₃) δ 13.00 (s, 1H), 8.13 (s, 1H), 7.67 (t, J=9.4Hz, 1H), 7.34 7.26 (m, 5H), 6.67 (d, J=9.8Hz, 1H), 5.86 (s, 1H), 5.42 (t, J=10.7Hz, 1H), 5.06 (s, 2H), 3.72 (s, 2H), 3.36 (dd, J=14.6,7.6Hz, 1H), 3.27 (dd, J= 15.1,5.6Hz, 1H), 3.20 (d, J=5.2Hz, 1H), 2.99 (d, J=5.5Hz, 1H), 2.95 2.89 (m, 1H), 2.60 (dd, J=14.3,7.2 Hz, 1H), 2.33 (d, J=13.8Hz, 1H), 2.21 2.11 (m, 2H), 2.09 1.99 (m, 2H), 1.87 (s, 3H), 1.82 1.72 (m, 7H), 1.68–1.60(m,7H),1.56(s,3H),1.51(s,3H),1.43(s,3H),1.33–1.24(m,1H)ppm；¹³C NMR(101MHz, CDCl₃)δ179.8,169.0,161.3,158.0,157.7,153.6,142.6,134.4,133.3,131.8,131.7,130.9,130.8,129.3,128.6, 127.2,124.7,123.8,122.4,115.8,107.4,102.7,100.2,92.5,84.3,84.2,81.3,71.0,49.1,42.0,39.9,36.9,32.5, 30.2,28.5,27.7,25.7,25.7,24.9,22.7,21.9,19.0,18.3,17.7ppm；HRMS(EI)m/z calcd for C₄₆H₅₄NO₈ 748.3849,found for[M+H]⁺748.3843.

The preparation of embodiment 11 compound 21

At ambient temperature, nitrogen protection, substrate 12 (200mg, 0.32mmol) is dissolved in 10mL dichloromethane, is separately added into EDCI (73.12 Mg, 0.38mmol), DMAP (3.88mg, 0.032mmol), it is eventually adding parabromobenzoic acid (89.44mg, 0.44mmol), room temperature reaction 5h, Absolute ether extracts, and merges organic faciess, and saturated common salt aqueous solution washs, and anhydrous sodium sulfate drying is spin-dried for, column chromatography obtains compound 21,210mg, Yield 86.1%.¹H NMR(400MHz,CDCl₃) δ 13.00 (s, 1H), 8.30 (s, 1H), 7.94 (d, J=8.6Hz, 1H), 7.69 (d, J= 7.2Hz, 1H), 7.61 (d, J=8.6Hz, 1H), 6.61 (d, J=10.2Hz, 1H), 5.94 (t, J=7.9Hz, 1H), 5.38 (d, J=10.2Hz, 1H), 5.23 4.95 (m, 1H), 3.37 (dd, J=14.7,7.8Hz, 1H), 3.30 3.21 (m, 2H), 3.00 (d, J=5.5Hz, 1H), 2.97 2.91 (m, 1H), 2.64 (dd, J=14.6,7.2Hz, 1H), 2.35 (dd, J=14.2,4.2Hz, 1H), 2.25 2.16 (m, 2H), 2.06 1.97 (m,2H),1.95(s,3H),1.81(s,3H),1.76–1.73(m,1H),1.71(s,3H),1.64(s,3H),1.62(s,3H),1.58–1.56(m, 1H),1.54(s,6H),1.36(s,3H),1.33–1.26(m,1H)ppm；¹³C NMR(101MHz,CDCl₃)δ179.8,163.1,161.3, 157.9,157.6,154.3,142.6,134.8,131.8,131.8,131.7,131.2,130.8,128.4,127.6,124.6,123.8,122.3,115.7, 107.3,102.7,100.2,92.6,84.3,84.2,81.3,71.2,49.1,42.0,36.9,32.6,30.1,28.5,27.7,25.7,25.7,24.8,22.7, 21.9,19.1,18.2,17.6.ppm；HRMS(EI)m/z calcd for C₄₅H₅₁BrNO₈812.2798,found for[M+H]⁺ 812.2783.

The preparation of embodiment 12 compound 22

With embodiment 11, difference is to replace parabromobenzoic acid to react with parafluorobenzoic acid, obtains compound 22, yield 72.0%.¹H NMR (400MHz,CDCl₃) δ 13.00 (s, 1H), 8.30 (s, 1H), 8.14 8.05 (m, 2H), 7.68 (d, J=7.1Hz, 1H), 7.13 (t, J= 8.5Hz, 2H), 6.61 (d, J=10.1Hz, 1H), 5.92 (t, J=7.7Hz, 1H), 5.38 (d, J=10.1Hz, 1H), 5.12 4.99 (m, 2H), 3.42 3.33 (m, 1H), 3.33 3.21 (m, 2H), 3.01 (br, 1H), 2.94 (br, 1H), 2.64 (dd, J=14.6,7.4Hz, 1H), 2.34 (d, J=13.5Hz, 1H), 2.22 2.16 (m, 2H), 2.08 1.98 (m, 2H), 1.95 (s, 3H), 1.81 (s, 3H), 1.76 1.73 (m,1H),1.72(s,3H),1.64(s,4H),1.62(s,3H),1.54(s,6H),1.36(s,3H),1.33–1.28(m,1H)ppm；¹³C NMR(101MHz,CDCl₃)δ179.8,166.0,162.9,161.4,157.9,157.6,154.1,142.6,134.6,132.4,131.9, 131.7,130.9,130.8,125.0,124.6,123.7,122.3,115.8,115.7,107.4,102.7,100.2,92.6,84.3,84.2,81.4,71.2, 49.1,42.0,36.9,32.6,30.1,28.5,27.7,25.7,25.6,24.8,22.7,21.9,19.1,18.2,17.6ppm；HRMS(EI)m/z calcd for C₄₅H₅₁FNO₈752.3598,found for[M+H]⁺752.3589.

The preparation of embodiment 13 compound 23

With embodiment 11, difference is to replace parabromobenzoic acid to react with Nitrodracylic acid, obtains compound 23, yield 83.8%.¹H NMR(400MHz,CDCl₃) δ 13.01 (s, 1H), 8.34 8.30 (m, 3H), 8.26 (d, J=9.0Hz, 2H), 7.70 (d, J=7.2Hz, 1H), 6.59 (d, J=10.2Hz, 1H), 6.00 (t, J=8.0Hz, 1H), 5.38 (d, J=10.2Hz, 1H), 5.09 5.00 (m, 2H), 3.37 (dd, J=14.7,7.8Hz, 1H), 3.30 3.20 (m, 2H), 3.00 (d, J=5.6Hz, 1H), 2.97 2.91 (m, 1H), 2.64 (dd, J=14.6,7.9Hz, 1H), 2.35 (dd, J=14.2,4.0Hz, 1H), 2.27 2.18 (m, 2H), 2.05 1.97 (m, 2H), 1.96 (s, 3H),1.82(s,3H),1.78–1.69(m,4H),1.64(s,3H),1.63(s,3H),1.60–1.56(m,1H),1.55(s,3H),1.54(s, 3H),1.37(s,3H),1.34–1.29(m,1H)ppm；¹³C NMR(101MHz,CDCl₃)δ179.8,162.0,161.4,157.9, 157.6,154.8,150.7,142.7,135.7,134.3,131.9,131.8,130.9,130.8,130.5,124.7,123.7,123.6,122.3,115.7, 107.3,102.7,100.2,92.6,84.4,84.2,81.4,71.4,49.1,42.0,36.9,32.7,30.1,28.5,27.8,25.7,25.6,24.8,22.7, 21.9,19.0,18.2,17.6.ppm；HRMS(EI)m/z calcd for C₄₅H₅₁N₂O₁₀779.3543,found for[M+H]⁺ 779.3526.

The preparation of embodiment 14 compound 24

With embodiment 11, difference is to replace parabromobenzoic acid to react with m-trifluoromethylbenzoic acid, obtains compound 24, yield 82.5%.¹H NMR(400MHz,CDCl₃) δ 13.00 (s, 1H), 8.35 (s, 2H), 8.27 (d, J=7.5Hz, 1H), 7.85 (d, J=7.7Hz, 1H), 7.69 (d, J=7.1Hz, 1H), 7.62 (t, J=7.7Hz, 1H), 6.60 (d, J=10.1Hz, 1H), 5.96 (t, J=7.8Hz, 1H), 5.37 (d, J= 10.1Hz, 1H), 5.10 4.99 (m, 2H), 3.37 (dd, J=14.7,7.8Hz, 1H), 3.26 (d, J=10.7Hz, 2H), 3.02 (br, 1H), 2.94 (br, 1H), 2.66 (dd, J=15.0,7.7Hz, 1H), 2.35 (dd, J=14.2,4.0Hz, 1H), 2.28 2.18 (m, 2H), 2.06 1.96 (m,2H),1.95(s,3H),1.82(s,3H),1.77–1.70(m,1H),1.68(s,3H),1.64(s,3H),1.62–1.50(m,10H),1.35(s, 3H),1.31–1.26(m,1H)ppm；¹³C NMR(101MHz,CDCl₃)δ179.8,162.6,161.3,157.9,157.6,154.6,142.6, 135.0,133.0,131.9,131.8,130.8,130.7,129.8,129.8,129.7,129.2,126.6,126.6,124.7,123.7,122.3,115.7, 107.4,102.7,100.2,92.6,84.4,84.2,81.4,71.3,49.1,42.0,36.9,32.6,30.1,28.5,27.7,25.7,25.6,24.8,22.7, 21.8,19.1,18.1,17.6ppm；HRMS(EI)m/z calcd for C₄₆H₅₁F₃NO₈802.3567,found for[M+H]⁺802.3556.

The preparation of embodiment 14 compound 25

With embodiment 8, difference is to replace compound 12 to react with compound 13, obtains compound 25, yield 84.0%.¹H NMR(400MHz, CDCl₃) δ 8.10 (s, 1H), 7.54 (d, J=7.1Hz, 1H), 6.66 (d, J=10.2Hz, 1H), 5.87 (t, J=7.9Hz, 1H), 5.55 (d, J= 10.2Hz, 1H), 5.09 (t, J=6.4Hz, 1H), 5.05 (t, J=7.1Hz, 1H), 3.85 (s, 3H), 3.44 (dd, J=14.5,7.8Hz, 1H), 3.33 (dd, J=14.5,5.3Hz, 1H), 3.20 (s, 1H), 2.90 2.85 (m, 1H), 2.59 (dd, J=14.6,7.3Hz, 1H), 2.34 2.26 (m,2H),2.22–2.16(m,2H),2.15(s,3H),2.09–1.99(m,2H),1.87(s,3H),1.79(m,3H),1.78–1.71(m,4H), 1.65(s,6H),1.61–1.57(m,1H),1.55(s,3H),1.52(s,3H),1.44(s,3H),1.36–1.27(m,1H)ppm；¹³C NMR (101MHz,CDCl₃)δ175.6,168.7,160.0,158.9,155.3,153.3,140.8,134.6,133.3,132.0,131.9,130.7,127.5, 123.7,122.0,116.5,112.6,110.1,107.5,92.5,84.2,84.2,80.6,71.1,62.3,49.0,41.9,36.7,32.5,30.1,28.5,27.6, 25.7,25.6,25.2,22.6,22.4,19.6,19.0,18.2,17.6ppm；HRMS(EI)m/z calcd for C₄₁H₅₂NO₈686.3693,found for[M+H]⁺686.3688.

The preparation of embodiment 15 compound 26

With embodiment 14, difference is to replace excess acetyl chloride with isobutyryl chloride, obtains compound 26, yield 86.7%.R_f=0.3 (PE:AE=2:1)；¹H NMR(400MHz,CDCl₃) δ 8.15 (s, 1H), 7.54 (d, J=7.1Hz, 1H), 6.66 (d, J=10.1Hz, 1H), 5.88 (t, J=7.7Hz, 1H), 5.54 (d, J=10.2Hz, 1H), 5.10 (t, J=6.4Hz, 1H), 5.05 (t, J=6.8Hz, 1H), 3.85 (s, 3H), 3.45 (dd, J=14.3,7.9Hz, 1H), 3.38 3.30 (m, 1H), 3.20 (s, 1H), 2.93 2.82 (m, 1H), 2.68 2.60 (m, 1H), 2.36 2.26 (m, 2H), 2.24 2.16 (m, 2H), 2.12 (dd, J=15.0,8.1Hz, 1H), 2.08 1.99 (m, 2H),1.90(s,3H),1.87–1.72(m,7H),1.65(s,6H),1.62–1.58(m,1H),1.55(s,3H),1.52(s,3H),1.44(s, 3H), 1.37 1.31 (m, 1H), 1.23 (d, J=6.8Hz, 6H) ppm；¹³C NMR(101MHz,CDCl₃)δ175.6,174.3, 160.0,158.8,155.2,153.6,140.8,134.3,133.3,131.9,131.8,130.9,127.4,123.7,122.0,116.5,112.5,110.0, 107.5,92.5,84.2,84.1,80.6,71.1,62.2,49.0,41.9,36.7,32.8,32.5,30.1,28.5,27.6,25.7,25.6,25.2,22.6, 22.4,19.0,19.0,18.9,18.2,17.6ppm；HRMS(EI)m/z calcd for C₄₃H₅₆NO₈714.4006,found for[M+H]⁺ 714.4007.

The preparation of embodiment 16 compound 27

With embodiment 14, difference is to replace excess acetyl chloride with phenyllacetyl chloride, obtains compound 27, yield 58.2%.R_f=0.20 (PE:AE=2:1)；¹H NMR(400MHz,CDCl₃) δ 8.12 (s, 1H), 7.55 (d, J=7.0Hz, 1H), 7.37 7.22 (m, 5H), 6.64 (d, J=10.2Hz, 1H), 5.88 (t, J=7.6Hz, 1H), 5.53 (d, J=10.1Hz, 1H), 5.15 5.03 (m, 2H), 3.83 (s, 3H), 3.71 (s, 3H), 3.45 (dd, J=14.3,7.7Hz, 1H), 3.34 (d, J=13.5Hz, 1H), 3.20 (s, 1H), 2.87 (br, 1H), 2.59 (dd, J=14.5,7.4Hz, 1H), 2.32 (d, J=11.9Hz, 1H), 2.19 (d, J=9.6Hz, 1H), 2.12 (dd, J=15.0,8.1 Hz,1H),2.09–1.98(m,2H),1.87(s,3H),1.83–1.72(m,7H),1.70–1.60(m,7H),1.55(s,3H),1.51(s, 3H),1.43(s,3H),1.37–1.26(m,1H)ppm；¹³C NMR(101MHz,CDCl₃)δ175.6,169.0,160.0,158.9, 155.2,153.7,140.9,134.7,133.3,133.2,132.0,131.9,130.7,129.3,128.6,127.5,127.2,123.7,122.0,116.5, 112.6,110.1,107.5,92.5,84.2,84.1,80.6,71.1,62.3,49.0,42.0,39.9,36.7,32.5,30.1,28.5,27.6,25.7, 25.7,25.1,22.6,22.4,19.0,18.3,17.6ppm；HRMS(EI)m/z calcd for C₄₇H₅₆NO₈762.4006,found for[M +H]⁺762.4003.

The preparation of embodiment 17 compound 28

With embodiment 8, difference is to replace compound 12 to react with compound 14, obtains compound 28, yield 49.2%.¹H NMR(300MHz, CDCl₃) δ 7.87 (s, 1H), 7.41 (d, J=6.9Hz, 1H), 6.63 (d, J=10.1Hz, 1H), 5.60 5.47 (m, 2H), 5.28 (t, J=6.2 Hz, 1H), 5.03 (t, J=6.2Hz, 1H), 3.82 (s, 3H), 3.51 3.43 (m, 1H), 3.38 (d, J=6.6Hz, 2H), 2.75 (dd, J=14.7, 9.7Hz, 1H), 2.64 (dd, J=15.3,7.2Hz, 1H), 2.51 (d, J=9.3Hz, 1H), 2.33 (dd, J=13.2,4.3Hz, 1H), 2.14 1.97(m,5H),1.86–1.60(m,17H),1.53(s,3H),1.47(s,3H),1.44–1.37(m,1H),1.30(s,3H)ppm；¹³C NMR (101MHz,CDCl₃)δ203.4,174.1,168.6,159.2,158.9,155.3,152.3,135.5,134.4,133.3,132.4,132.0,130.1, 127.8,123.6,121.9,116.6,112.9,110.5,107.4,90.5,84.0,83.6,80.7,62.2,49.0,46.8,41.7,30.0,29.1,27.9,27.2, 25.8,25.7,25.6,22.5,22.1,19.7,18.8,18.3,17.6ppm；HRMS(EI)m/z calcd for C₄₁H₅₀NO₈684.3536,found for[M+H]⁺684.3531.

The preparation of embodiment 18 compound 29

With embodiment 17, difference is to replace excess acetyl chloride with isobutyryl chloride, obtains compound 29, yield 77.8%.¹H NMR(400MHz, CDCl₃) δ 7.92 (s, 1H), 7.41 (d, J=6.8Hz, 1H), 6.63 (d, J=10.1Hz, 1H), 5.64 5.51 (m, 2H), 5.22 (t, J=6.6 Hz, 1H), 5.04 (t, J=6.6Hz, 1H), 3.81 (s, 3H), 3.52 3.43 (m, 1H), 3.43 3.32 (m, 2H), 2.76 2.55 (m, 3H), 2.51 (d, J=9.3Hz, 1H), 2.32 (dd, J=13.2,4.1Hz, 1H), 2.09 1.96 (m, 2H), 1.80 1.60 (m, 17H), 1.54 (s, 3H), 1.47(s,3H),1.42–1.37(m,1H),1.29(s,3H),1.21–1.15(m,6H)ppm；¹³C NMR(101MHz,CDCl₃)δ203.5, 174.2,159.3,159.0,155.3,152.7,135.5,134.0,133.5,132.3,131.9,130.1,127.7,123.7,121.8,116.6,112.9, 110.5,107.4,90.5,83.9,83.6,80.6,62.2,49.0,46.8,41.8,32.6,30.0,29.0,27.7,27.2,25.7,25.7,25.6,25.2,22.6, 22.1,19.0,18.9,18.2,17.6ppm；HRMS(EI)m/z calcd for C₄₃H₅₄NO₈712.3849,found for[M+H]⁺712.3844.

The preparation of embodiment 19 compound 30

With embodiment 17, difference is to replace excess acetyl chloride with phenyllacetyl chloride, obtains compound 30, yield 61.5%.¹H NMR(400MHz, CDCl₃) δ 7.89 (s, 1H), 7.41 (d, J=6.8Hz, 1H), 7.35 7.24 (m, 5H), 6.61 (d, J=10.2Hz, 1H), 5.62 5.50 (m, 2H), 5.25 (t, J=6.5Hz, 1H), 5.03 (t, J=6.5Hz, 1H), 3.81 (s, 3H), 3.66 (s, 2H), 3.46 (dd, J=11.1,5.8Hz, 1H), 3.42 3.33 (m, 2H), 2.71 (dd, J=14.9,9.2Hz, 1H), 2.62 (dd, J=14.9,7.2Hz, 1H), 2.52 (d, J=9.2 Hz, 1H), 2.32 (dd, J=13.3,4.1Hz, 1H), 2.09 1.99 (m, 2H), 1.80 (s, 3H), 1.78 1.75 (m, 1H), 1.72 (s, 6H),1.68(s,3H),1.64(s,3H),1.62–1.58(m,1H),1.54(s,3H),1.47(s,3H),1.42–1.32(m,1H),1.29(s, 3H)ppm；¹³C NMR(101MHz,CDCl₃)δ203.5,174.2,168.9,159.3,159.0,155.3,152.6,135.4,134.5, 133.6,133.3,132.3,131.9,129.9,129.3,128.6,127.8,127.2,123.7,121.8,116.6,112.9,110.5,107.4,90.5, 83.9,83.6,80.7,62.2,49.0,46.7,41.7,39.7,30.0,29.0,27.8,27.3,25.7,25.7,25.7,22.5,22.1,18.8,18.3, 17.6ppm；HRMS(EI)m/z calcd for C₄₇H₅₄NO₈760.3849,found for[M+H]⁺760.3840.

The preparation of embodiment 20 compound 31

With embodiment 8, difference is to replace excess acetyl chloride with chloro-carbonic acid -4- methoxyl group phenyl ester, obtains compound 31, yield 85.6%.¹H NMR(400MHz,CDCl₃) δ 12.99 (s, 1H), 8.22 (s, 1H), 7.67 (d, J=7.2Hz, 1H), 7.12 (d, J=9.0Hz, 3H), 6.89 (d, J=9.1Hz, 2H), 6.68 (d, J=10.1Hz, 1H), 5.87 (t, J=7.8Hz, 1H), 5.43 (d, J=10.1Hz, 1H), 5.09 (d, J=6.4Hz, 1H), 5.06 (d, J=6.4Hz, 1H), 3.80 (s, 3H), 3.38 (dd, J=14.7,7.6Hz, 1H), 3.31 (dd, J= 14.8,5.0Hz, 1H), 3.24 (d, J=5.3Hz, 1H), 3.01 (d, J=5.5Hz, 1H), 2.93 (br, 1H), 2.63 (dd, J=14.5,6.9 Hz, 1H), 2.34 (dd, J=14.2,4.0Hz, 1H), 2.21 (dd, J=12.4,7.9Hz, 2H), 2.04 (dd, J=14.5,8.8Hz, 2H), 1.89(s,3H),1.81(s,3H),1.78(s,3H),1.75–1.72(m,1H),1.66(s,3H),1.65(s,3H),1.64–1.61(m,1H), 1.55(s,3H),1.53(s,3H),1.43(s,3H),1.35–1.25(m,1H)ppm；¹³C NMR(101MHz,CDCl₃)δ179.7, 161.3,157.9,157.6,157.4,153.9,152.4,144.5,142.5,134.8,131.9,131.8,130.9,130.5,124.6,123.8,122.4, 121.7,115.9,114.5,107.4,102.7,100.2,92.5,84.3,84.2,81.3,70.8,55.6,49.1,42.0,36.9,32.5,30.2,28.5, 27.7,25.7,25.7,24.9,22.7,21.9,18.9,18.2,17.6ppm；HRMS(EI)m/z calcd for C₄₆H₅₃NO₁₀780.3733, found for[M+H]⁺780.3726.

The preparation of embodiment 21 compound 32

With embodiment 8, difference is, with chloro-methyl-chloroformate replacement excess acetyl chloride, to obtain compound 32, yield 69.0%.¹H NMR (400MHz,CDCl₃) δ 12.97 (s, 1H), 8.16 (s, 1H), 7.66 (d, J=7.1Hz, 1H), 6.66 (d, J=10.1Hz, 1H), 5.88 (t, J=7.4Hz, 1H), 5.80 (s, 2H), 5.43 (d, J=10.2Hz, 1H), 5.10 5.02 (m, 2H), 3.33 (dd, J=14.8,6.8Hz, 1H), 3.30 3.20m, 2H), 2.99 (d, J=5.6Hz, 1H), 2.93 (br, 1H), 2.60 (dd, J=14.9,7.0Hz, 1H), 2.33 (dd, J=13.8,3.8Hz, 1H), 2.23 2.16 (m, 2H), 2.04 (dd, J=15.1,8.3Hz, 2H), 1.87 (s, 3H), 1.84 1.80 (m, 1H),1.79(s,3H),1.76(s,3H),1.64(s,6H),1.63–1.60(m,1H),1.55(s,3H),1.52(s,3H),1.42(s,3H), 1.33–1.26(m,1H)ppm；¹³C NMR(101MHz,CDCl₃)δ179.7,161.2,157.9,157.6,154.4,151.9,142.4, 135.3,132.0,131.8,130.8,130.3,124.7,123.8,122.3,115.8,107.4,102.7,100.1,92.4,84.4,84.2,81.3,72.3, 70.8,49.0,42.0,36.9,32.5,30.1,28.5,27.7,25.7,25.7,24.9,22.7,21.9,18.8,18.2,17.6ppm；HRMS(EI) m/z calcd for C₄₀H₄₉ClNO₉722.3083,found for[M+H]⁺322.3103.

The preparation of embodiment 22 compound 33

With embodiment 8, difference is, with isobutyl chlorocarbonate replacement acyl chloride reaction, to obtain compound 33, yield 92.2%.¹H NMR(400 MHz,CDCl₃) δ 12.98 (s, 1H), 8.14 (s, 1H), 7.65 (d, J=7.1Hz, 1H), 6.66 (d, J=10.1Hz, 1H), 5.82 (t, J=7.7 Hz, 1H), 5.42 (d, J=10.1Hz, 1H), 5.11 5.02 (m, 2H), 4.00 (d, J=5.7Hz, 2H), 3.35 (dd, J=14.8,7.6Hz, 1H), 3.27 (dd, J=14.5,5.6Hz, 1H), 3.21 (d, J=5.1Hz, 1H), 2.99 (d, J=5.5Hz, 1H), 2.95 2.88 (m, 1H), 2.60 (dd, J=14.8,6.9Hz, 1H), 2.33 (dd, J=14.2,3.9Hz, 1H), 2.18 (d, J=10.3Hz, 2H), 2.07 2.02 (m, 2H), 1.98 (dd, J=13.5,6.9Hz, 1H), 1.87 (s, 3H), 1.79 (s, 3H), 1.77 1.72 (m, 4H), 1.66 1.61 (m, 7H), 1.55 (s, 3H), 1.52 (s, 3H), 1.42 (s, 3H), 1.33 1.22 (m, 1H), 0.96 (d, J=6.4Hz, 6H) ppm；¹³C NMR(101MHz,CDCl₃)δ 179.7,161.2,157.9,157.6,153.8,153.1,142.4,134.2,131.8,131.8,130.9,130.7,124.6,123.8,122.4,115.9, 107.4,102.6,100.2,92.5,84.3,84.2,81.2,74.5,70.8,49.0,42.0,36.9,32.5,30.2,28.5,27.8,27.7,25.7,25.7, 24.9,22.7,21.9,18.9,18.9,18.2,17.6ppm；HRMS(EI)m/z calcd for C₄₃H₅₆NO₉730.3940,found for[M+ H]⁺730.3954.

The preparation of embodiment 23 compound 34

Substrate 12 (100mg, 0.159mmol) is dissolved in 5mL CH₂Cl₂, add (44.6 μ L, 0.318mmol) triethylamine, add afterwards (50 μ L, 0.794mmol) ethyl isocyanate, room temperature reaction 4 hours, water quenching is gone out reaction, and absolute ether extracts, and merges organic faciess, saturated common salt aqueous solution Washing, anhydrous sodium sulfate drying, it is spin-dried for, column chromatography purification obtains compound 34,110.0mg, yield 98.8%.¹H NMR(400MHz,CDCl₃) δ 12.99 (s, 1H), 8.10 (s, 1H), 7.65 (d, J=7.2Hz, 1H), 6.65 (d, J=10.1Hz, 1H), 6.07 (t, J=5.5Hz, 1H), 5.77 (t, J=7.8Hz, 1H), 5.42 (d, J=10.1Hz, 1H), 5.11 4.99 (m, 2H), 3.36 (dd, J=15.5,8.2Hz, 2H), 3.32 3.27 (m, 2H), 3.25 (s, 1H), 3.02 (d, J=5.6Hz, 1H), 2.95 2.89 (m, 1H), 2.58 (dd, J=14.7,6.5Hz, 1H), 2.33 (dd, J= 14.1,4.0Hz, 1H), 2.25 (dd, J=14.6,9.2Hz, 1H), 2.17 (d, J=10.0Hz, 1H), 2.07 1.98 (m, 2H), 1.79 (s, 3H), (1.78 s, 3H), 1.77 (s, 3H), 1.76 1.70 (m, 1H), 1.64 (s, 6H), 1.58 (dd, J=7.1,3.0Hz, 1H), 1.54 (s, 3H), 1.52 (s, 3H), 1.43 (s, 3H), 1.33 1.25 (m, 1H), 1.18 (t, J=7.2Hz, 3H) ppm；¹³C NMR(101MHz,CDCl₃)δ179.7, 161.3,157.9,157.6,155.0,150.3,142.2,134.1,132.0,131.8,130.9,130.5,124.7,123.8,122.2,115.8,107.5, 102.6,100.1,92.4,84.3,84.3,81.2,70.5,49.0,42.0,36.9,36.0,32.4,30.2,28.5,27.6,25.7,25.7,24.9,22.6,21.9, 19.0,18.3,17.6,15.1ppm；HRMS(EI)m/z calcd for C₄₁H₅₃N₂O₈701.3802,found for[M+H]⁺701.3799.

The preparation of embodiment 24 compound 35

At ambient temperature, nitrogen protection, substrate GA (300mg, 0.48mmol) is dissolved in 10mL dichloromethane, is separately added into EDCI (109.91mg, 0.57mmol), DMAP (5.83mg, 0.048mmol), be eventually adding p-bromobenzaldehyde oxime (133.06mg, 0.67 Mmol), room temperature reaction 5h, absolute ether extracts, and merges organic faciess, and saturated common salt aqueous solution washs, and anhydrous sodium sulfate drying is spin-dried for, Column chromatography purification obtains compound 35,312mg, yield 80.7%.¹H NMR(400MHz,CDCl₃)δ12.82(s,1H),8.07(s, 1H), 7.60 7.49 (m, 5H), 6.58 (d, J=10.1Hz, 1H), 6.17 (t, J=6.7Hz, 1H), 5.34 (d, J=10.1Hz, 1H), 5.09 4.98 (m, 2H), 3.47 (s, 1H), 3.31 (dd, J=14.3,8.1Hz, 1H), 3.17 (d, J=12.8Hz, 1H), 3.05 2.89 (m, 2H), 2.52 (d, J=9.2Hz, 1H), 2.31 (d, J=13.1Hz, 1H), 2.06 1.95 (m, 2H), 1.81 (s, 3H), 1.77 1.67 (m, 7H), 1.63 (s, 3H), 1.63 1.56 (m, 4H), 1.54 (s, 3H), 1.39 (d, J=12.5Hz, 1H), 1.32 (s, 3H), 1.29 (s, 3H) ppm；¹³C NMR(101MHz,CDCl₃)δ203.4,178.9,164.0,161.4,157.5,157.7,155.1,138.2,135.5,133.3, 132.0,131.8,131.6,129.8,129.3,126.0,126.0,124.6,123.7,122.2,116.0,107.7,102.5,100.4,90.9,83.8, 83.3,81.2,49.0,46.9,41.9,29.9,29.7,28.8,27.6,25.7,25.7,25.2,22.7,21.7,20.6,18.1,17.6ppm；HRMS (EI)m/z calcd for C₄₅H₄₉BrNO₈810.2641,found for[M+H]⁺810.2606.

The preparation of embodiment 25 compound 36

With embodiment 24, difference is to replace p-bromobenzaldehyde oxime to react with 3-bromobenzaldehyde oxime, obtains compound 36, yield 77.3%.¹H NMR(400MHz,CDCl₃) δ 12.83 (s, 1H), 8.07 (s, 1H), 7.89 (s, 1H), 7.64 7.52 (m, 3H), 7.30 (t, J=7.8 Hz, 1H), 6.60 (d, J=10.1Hz, 1H), 6.15 (t, J=6.7Hz, 1H), 5.35 (d, J=10.1Hz, 1H), 5.09 4.98 (m, 2H), 3.48 (t, J=4.8Hz, 1H), 3.32 (dd, J=14.4,8.0Hz, 1H), 3.18 (d, J=12.4Hz, 1H), 3.04 (dd, J=16.4,7.2 Hz, 1H), 2.94 (dd, J=16.6,6.6Hz, 1H), 2.53 (d, J=9.2Hz, 1H), 2.37 2.28 (m, 1H), 2.06 1.95 (m, 2H), 1.82(s,3H),1.77–1.67(m,7H),1.67–1.59(m,7H),1.54(s,3H),1.44–1.33(m,1H),1.32(s,3H),1.29 (s,3H)ppm；¹³C NMR(101MHz,CDCl₃)δ203.4,178.9,164.0,161.4,157.5,154.7,138.2,135.4,134.3, 133.3,132.4,131.8,131.6,130.8,130.3,127.3,126.0,124.6,123.7,122.9,122.2,116.0,107.8,102.6,100.4, 90.9,83.8,83.4,81.2,49.0,46.9,41.9,29.9,29.7,28.8,27.5,25.7,25.7,25.2,22.7,21.7,20.6,18.1,17.6 ppm；HRMS(EI)m/z calcd for C₄₅H₄₉BrNO₈810.2641,found for[M+H]⁺810.2616.

The preparation of embodiment 26 compound 37

With embodiment 24, difference is, with replacing p-bromobenzaldehyde oxime to react to fluorobenzene first oxime, to obtain compound 37, yield 76.5%.¹H NMR (400MHz,CDCl₃) δ 12.83 (s, 1H), 8.09 (s, 1H), 7.71 (dd, J=8.6,5.4Hz, 2H), 7.54 (d, J=6.9Hz, 1H), 7.10 (t, J=8.6Hz, 2H), 6.59 (d, J=10.1Hz, 1H), 6.17 (t, J=6.6Hz, 1H), 5.35 (d, J=10.4Hz, 1H), 5.08 4.99 (m, 2H), 3.48 (dd, J=6.5,4.7Hz, 1H), 3.31 (dd, J=14.6,8.0Hz, 1H), 3.22 3.14 (m, 1H), 2.98 (qd, J=16.6,6.5 Hz, 2H), 2.53 (d, J=9.3Hz, 1H), 2.32 (dd, J=13.5,4.7Hz, 1H), 2.05 1.95 (m, 2H), 1.82 (s, 3H), 1.77 1.72 (m,1H),1.71(s,6H),1.64(s,3H),1.62(s,3H),1.59–1.54(m,1H),1.53(s,3H),1.40–1.35(m,1H),1.32(s, 3H),1.29(s,3H)ppm；¹³C NMR(101MHz,CDCl₃)δ203.4,178.9,164.7,164.2,161.4,157.5,155.0,138.0, 135.4,133.3,131.8,131.6,130.6,126.7,126.6,126.1,124.6,123.7,122.2,116.1,116.0,107.8,102.6,100.4,91.0, 83.8,83.3,81.2,49.0,46.9,41.9,29.9,29.6,28.8,27.6,25.7,25.6,25.2,22.7,21.7,20.6,18.1,17.6ppm；HRMS (EI)m/z calcd for C₄₅H₄₉FNO₈750.3442,found for[M+H]⁺750.3432.

The preparation of embodiment 27 compound 38

With embodiment 24, difference be between fluorobenzene first oxime replace p-bromobenzaldehyde oxime react, obtain compound 38, yield 73.5%.¹H NMR (400MHz,CDCl₃) δ 12.83 (s, 1H), 8.10 (s, 1H), 7.54 (d, J=6.9Hz, 1H), 7.49 7.43 (m, 2H), 7.38 (td, J=8.1, 5.8Hz, 1H), 7.19 7.12 (m, 1H), 6.59 (d, J=10.1Hz, 1H), 6.15 (dd, J=7.2,6.0Hz, 1H), 5.34 (d, J=10.1Hz, 1H), 5.09 4.99 (m, 2H), 3.48 (dd, J=6.6,4.7Hz, 1H), 3.31 (dd, J=14.6,8.1Hz, 1H), 3.18 (dd, J=14.5,4.9 Hz, 1H), 3.03 (dd, J=16.2,6.7Hz, 1H), 2.94 (dd, J=17.3,6.5Hz, 1H), 2.53 (d, J=9.3Hz, 1H), 2.32 (dd, J= 13.5,4.6Hz, 1H), 2.05 1.95 (m, 2H), 1.82 (d, J=0.9Hz, 3H), 1.77 1.72 (m, 1H), 1.70 (s, 6H), 1.63 (s, 3H), 1.63(s,3H),1.59–1.54(m,1H),1.53(s,3H),1.40–1.34(m,1H),1.32(s,3H),1.29(s,3H)ppm；¹³C NMR (101MHz,CDCl₃)δ203.4,178.9,162.8,161.5,157.6,157.5,155.1,155.0,138.2,135.4,133.4,132.6,131.8, 131.6,130.4,126.0,124.6,124.6,123.7,122.2,118.5,116.0,114.7,107.8,102.6,100.4,90.9,83.8,83.4,81.2, 49.0,46.9,41.9,29.9,29.7,28.8,27.5,25.7,25.6,25.2,22.6,21.7,20.6,18.1,17.6ppm；HRMS(EI)m/z calcd for C₄₅H₄₉FNO₈750.3442,found for[M+H]⁺750.3422.

The preparation of embodiment 28 compound 39

With embodiment 24, difference be between chlorobenzene first oxime replace p-bromobenzaldehyde oxime react, obtain compound 39, yield 45.1%.¹H NMR(400MHz,CDCl₃) δ 12.83 (s, 1H), 8.08 (s, 1H), 7.74 (s, 1H), 7.57 (d, J=13.2,1H), 7.55 (d, J= 12.4,1H), 7.43 (d, J=8.4Hz, 1H), 7.35 (t, J=7.8Hz, 1H), 6.60 (d, J=10.1Hz, 1H), 6.15 (dd, J=7.2, 6.0Hz, 1H), 5.35 (d, J=10.1Hz, 1H), 5.08 4.99 (m, 2H), 3.48 (dd, J=6.6,4.6Hz, 1H), 3.32 (dd, J= 14.6,8.0Hz, 1H), 3.18 (dd, J=14.4,4.9Hz, 1H), 3.04 (dd, J=16.6,6.3Hz, 1H), 2.94 (dd, J=16.7,6.0 Hz, 1H), 2.53 (d, J=9.3Hz, 1H), 2.32 (dd, J=13.5,4.7Hz, 1H), 2.05 1.96 (m, 2H), 1.82 (d, J=0.8Hz, 3H),1.78–1.72(m,1H),1.71(s,3H),1.71(s,3H),1.64(s,6H),1.59–1.55(m,1H),1.54(s,3H),1.39 (dd, J=13.4,9.5Hz, 1H), 1.32 (s, 3H), 1.30 (s, 3H) ppm；¹³C NMR(101MHz,CDCl₃)δ203.4,178.9, 164.0,161.4,157.5,157.5,154.8,138.2,135.4,134.9,133.4,132.2,131.8,131.6,131.4,130.0,128.0,126.8, 126.0,124.6,123.7,122.2,116.0,107.8,102.6100.4,90.9,83.8,83.4,81.2,49.0,46.9,41.9,29.9,29.7,28.8, 27.5,25.7,25.7,25.2,22.7,21.7,20.6,18.1,17.6ppm；HRMS(EI)m/z calcd for C₄₅H₄₉ClNO₈766.3146, found for[M+H]⁺766.3131.

The preparation of embodiment 29 compound 40

With embodiment 24, difference is to replace p-bromobenzaldehyde oxime to react with o-chlorobenzaldehyde oxime, obtains compound 40, yield 45.7%.¹H NMR(400MHz,CDCl₃) δ 12.81 (s, 1H), 8.62 (s, 1H), 8.08 (d, J=7.4Hz, 1H), 7.55 (d, J=6.9Hz, 1H), 7.42 7.35 (m, 2H), 7.33 7.27 (m, 1H), 6.57 (d, J=10.1Hz, 1H), 6.16 (t, J=6.7Hz, 1H), 5.31 (d, J= 10.1Hz, 1H), 5.09 4.98 (m, 2H), 3.51 3.45 (m, 1H), 3.33 (dd, J=14.7,8.1Hz, 1H), 3.22 3.12 (m, 1H), 3.10 2.95 (m, 2H), 2.52 (d, J=9.3Hz, 1H), 2.32 (dd, J=13.4,4.7Hz, 1H), 1.99 (dd, J=15.7,7.9 Hz, 2H), 1.83 (s, 3H), 1.76 1.69 (m, 7H), 1.64 (s, 6H), 1.58 1.54 (m, 1H), 1.53 (s, 3H), 1.38 (dd, J= 13.4,9.6Hz,1H),1.33(s,3H),1.30(s,3H)ppm；¹³C NMR(101MHz,CDCl₃)δ203.5,178.9,163.9, 161.4,157.7,157.4,152.8,138.8,135.2,134.9,133.4,132.4,131.8,131.5,129.8,128.6,128.4,127.1,125.9, 124.4,123.8,122.3,116.0,107.6,102.6,100.4,90.9,83.8,83.5,81.1,49.0,46.9,42.0,29.9,29.5,28.8,27.6, 25.7,25.7,25.2,22.6,21.7,20.5,18.1,17.6ppm；HRMS(EI)m/z calcd for C₄₅H₄₉ClNO₈766.3146,found for[M+H]⁺766.3133.

The preparation of embodiment 30 compound 41

With embodiment 24, difference is to replace p-bromobenzaldehyde oxime to react with p-nitrophenyl first oxime, obtains compound 41, yield 40.4%.¹H NMR (400MHz,CDCl₃) δ 12.83 (s, 1H), 8.28 (d, J=8.8Hz, 2H), 8.19 (s, 1H), 7.90 (d, J=8.8Hz, 2H), 7.55 (d, J= 6.9Hz, 1H), 6.57 (d, J=10.1Hz, 1H), 6.23 (dd, J=7.2,5.9Hz, 1H), 5.35 (d, J=10.0Hz, 1H), 5.08 4.98 (m, 2H), 3.49 (dd, J=6.7,4.6Hz, 1H), 3.31 (dd, J=14.5,8.1Hz, 1H), 3.21 3.14 (m, 1H), 3.05 2.91 (m, 2H), 2.54 (d, J=9.3Hz, 1H), 2.33 (dd, J=13.5,4.7Hz, 1H), 2.05 1.95 (m, 2H), 1.83 (d, J=1.0Hz, 3H), 1.75 (dd, J=12.1,4.6Hz, 1H), 1.71 (s, 6H), 1.63 (s, 6H), 1.57 1.54 (m, 1H), 1.53 (s, 3H), 1.40 1.35 (dd, J=13.4,9.6 Hz,1H),1.32(s,3H),1.30(s,3H)ppm；¹³C NMR(101MHz,CDCl₃)δ203.4,179.0,163.8,161.5,157.6,153.9, 149.4,138.8,136.4,135.5,133.3,131.9,131.7,129.2,125.7,124.7,124.0,123.6,122.1,115.9,107.8,102.6, 100.4,91.0,83.9,83.3,81.2,49.0,46.9,41.9,29.9,29.7,28.8,27.6,25.7,25.6,25.2,22.6,21.7,20.6,18.1,17.6 ppm；HRMS(EI)m/z calcd for C₄₅H₄₉N₂O₁₀777.3387,found for[M+H]⁺777.3360.

The preparation of embodiment 31 compound 42

With embodiment 24, difference is to replace p-bromobenzaldehyde oxime to react with acetone oxime, obtains compound 42, yield 38.4%.¹H NMR(400 MHz,CDCl₃) δ 12.82 (s, 1H), 7.53 (d, J=6.9Hz, 1H), 6.64 (d, J=10.1Hz, 1H), 6.16 (t, J=6.3Hz, 1H), 5.42 (d, J=10.1Hz, 1H), 5.09-5.01 (m, 2H), 3.46 (dd, J=6.6,4.6Hz, 1H), 3.32 (dd, J=14.7,8.0Hz, 1H), 3.21 (dd, J=14.6,5.1Hz, 1H), 3.04 (dd, J=16.6,7.1Hz, 1H), 2.88 (ddd, J=17.0,6.1,1.4Hz, 1H), 2.52 (d, J=9.3 Hz, 1H), 2.31 (dd, J=13.4,4.6Hz, 1H), 2.07 1.98 (m, 5H), 1.83 (s, 3H), 1.81 (d, J=0.9Hz, 3H), 1.79 1.75 (m,1H),1.73(s,3H),1.70(s,3H),1.65(s,3H),1.63(s,3H),1.61-1.56(m,1H),1.55(s,3H),1.44(s,3H),1.38 (dd, J=13.3,9.5Hz, 1H), 1.29 (s, 3H) ppm；¹³C NMR(101MHz,CDCl₃)δ203.6,178.9,164.2,163.6,161.5, 157.6,157.5,137.8,135.3,133.3,131.8,131.5,126.6,124.5,123.8,122.3,116.0,107.7,102.6,100.4,90.9,83.7, 83.2,81.2,49.0,47.0,42.0,30.0,29.7,28.8,27.8,25.7,25.7,25.3,22.7,22.1,21.7,20.5,18.1,17.6,17.1；HRMS (EI)m/z calcd for C₄₁H₅₀NO₈684.3536,found for[M+H]⁺684.3527.

The preparation of embodiment 32 compound 43

With embodiment 24, difference is to replace p-bromobenzaldehyde oxime to react with isobutyl aldoxime, obtains compound 43, yield 36.5%.¹H NMR (400MHz,CDCl₃) δ 12.83 (s, 1H), 7.54 (d, J=6.9Hz, 1H), 7.34 (d, J=6.9Hz, 1H), 6.65 (d, J=10.1Hz, 1H), 6.24 (t, J=6.4Hz, 1H), 5.43 (d, J=10.1Hz, 1H), 5.09-5.00 (m, 2H), 3.46 (dd, J=6.6,4.6Hz, 1H), 3.32 (dd, J=14.5,8.1Hz, 1H), 3.17 (dd, J=14.5,4.7Hz, 1H), 2.99 2.82 (m, 2H), 2.65 (dq, J=13.7,6.9 Hz, 1H), 2.53 (d, J=9.3Hz, 1H), 2.30 (dd, J=13.5,4.6Hz, 1H), 2.04 (dd, J=15.9,7.7Hz, 2H), 1.84 1.76 (m, 4H), 1.73 (s, 3H), 1.71 (s, 3H), 1.65 (s, 3H), 1.63 (s, 3H), 1.60 (dd, J=7.0,3.0Hz, 1H), 1.55 (s, 3H), 1.44 (s, 3H), 1.38 (dd, J=13.3,9.6Hz, 1H), 1.29 (s, 3H), 1.13 (d, J=6.8Hz, 3H), 1.12 (d, J=6.8Hz, 3H)ppm；¹³C NMR(101MHz,CDCl₃)δ203.5,178.9,164.7,164.1,161.4,157.6,157.5,137.3,135.5, 133.3,131.9,131.6,126.0,124.5,123.8,122.2,116.0,107.6,102.5,100.4,91.1,83.8,83.2,81.2,49.0,46.9, 42.0,29.4,29.6,29.5,28.8,27.9,25.7,25.7,25.2,22.8,21.7,20.6,19.7,19.7,18.1,17.6ppm；HRMS(EI) m/z calcd for C₄₂H₅₂NO₈698.3693,found for[M+H]⁺698.3685.

BIOLOGICAL ACTIVITY EXAMPLES gamlogic acid analog anti-tumor biological body outer screening test

1. material

1.1. sample and reagent：

Test specimen dimethyl sulfoxide (DMSO, final concentration 0.8%) dissolves, with being made into 2mg/ml containing 15% calf serum RPMI1640 culture medium Standby, the used time is diluted to desired concn.

Cisplatin for injection (CDDP CISPLATIN FOR INJECTION), 10mg/ bottle, Qilu Pharmaceutical Co., Ltd. produces.

RPMI1640 culture medium：GIBGO company of the U.S. produces.

Dimethyl sulfoxide (DMSO)：Tianjin Fu Yu Fine Chemical Co., Ltd, lot number：In October, 2013 23B.

MTT：Sigma company produces.

1.2. cell：A549 (human lung adenocarcinoma), is purchased from Chinese Academy of Sciences's cell bank.HELF-6 (human embryonic lung cell) cell, medical science section of Shandong Province Institute is given on basis.All using the RPMI1640 culture medium containing 15% calf serum, put 37 DEG C, 5%CO₂Culture in incubator.

1.3. instrument：

Forma3111 water-jacket typ CO2 gas incubator, Forma company of the U.S. produces.

Victor1420 multi-functional mark analyser, the U.S..

96 orifice plates, Americanized.

2. method

2.1 cell culture and medicine effect：Take A549 (human lung adenocarcinoma) and the cell warp of HELF-6 (human embryonic lung cell) exponential phase of growth respectively After washing, counted with after 0.25% pancreatin digestion, adjustment cell concentration is 1 × 10⁵/ ml, is inoculated in 96 orifice plates respectively, and every hole 0.1ml puts 37 DEG C, 5%CO₂Culture in incubator.Culture was loaded product after 24 hours.Act on A549 (human lung adenocarcinoma) and HELF-6 (human embryonic lung cell) 12 sample maximum dose level group drug level of cell are 100 μ g/ml, are diluted to 0.01 μ g/ml successively by 5 times, totally 5 dosage groups.Each Concentration sets 3 multiple holes, and sets Vehicle controls hole (DMSO, 0.8%), after cultivating 48 hours, measures OD value with MTT method, calculates thin Born of the same parents' suppression ratio.This experiment is repeated twice.

The calculating of 2.2 cell inhibitory rates：After cell terminates culture, every hole adds 10 μ l 0.5%MTT to put CO₂In incubator, take out after 4 hours In the hole of inclining liquid adds DMSO (0.2ml/ hole), fully vibrates, and so that bluish violet first is dissolved, in multi-functional mark analyser 570nm wavelength Place's detection OD value, using suppression ratio and the IC of the mean value computation cell of variable concentrations test medicine 3 multiple holes OD value₅₀.

2.3. result judges：

According to new drug preclinical study guideline (bureau of drug administration of Ministry of Health of the People's Republic of China 1993.7：139)

Plant extract IC₅₀≤ 30 μ g/ml think there is certain inhibitory action；

Synthetic drug IC₅₀≤ 10 μ g/ml think there is certain inhibitory action.

Table 1：Suppression ratio % to growth of tumour cell

Claims (10)

1. lead to the compound shown in formula (I) or its pharmaceutically acceptable salt：

Wherein, R¹For H or selected from optionally by one or more R^aThe following groups replacing：C_1-6Alkyl-, C_2-6Thiazolinyl-, C₃-₁₀Cycloalkanes Base-, comprise 1-3 and be selected from N, O and S heteroatomic 3-10 circle heterocycles alkyl, C_6-14Aryl-, comprise 1-3 and be selected from N, O and S Heteroatomic 5-14 unit's heteroaryl-,-C (=O) R^b,-S (=O)₂R^b；

R²Selected from O, S, OH, SH or optionally by one or more R^aThe following groups replacing：C_1-6Alkyl oxy-, C_2-6Thiazolinyl epoxide -、C_3-10Cycloalkyl oxy-, comprise 1-3 selected from N, O and S heteroatomic 3-10 circle heterocycles alkyl oxy-, C_6-14Aryloxy-, Comprise 1-3 selected from N, O and S heteroatomic 5-14 unit's heteroaryl epoxide-, C_1-6Alkyl sulfenyl-, C_2-6Enylsulfanyl-, C_3-10Cycloalkanes Base sulfenyl-, comprise 1-3 selected from N, O and S heteroatomic 3-10 circle heterocycles alkyl sulfenyl-, C_6-14Artyl sulfo-, comprise 1-3 choosing From N, O and S heteroatomic 5-14 unit's heteroaryl sulfenyl-,-OC (=O) R^b,-OS (=O)₂R^b, R²And between C-12Table Show singly-bound or double bond, wherein work as R²During for O or S, it forms double bond with C-12, works as R²During for other group in defined above, its Form singly-bound with C-12；

R³Selected from F, Cl, Br, I, OH, SH, CN or optionally by one or more R^aThe following groups replacing：C_1-6Alkyl-, C_2-6 Thiazolinyl-, C₃-C₁₀Cycloalkyl-, NR^cR^d, comprise 1-3 selected from N, O and S heteroatomic 3-10 circle heterocycles alkyl-, C_6-14Aryl-, Comprise 1-3 selected from N, O and S heteroatomic 5-14 unit's heteroaryl-,-C (=O) R^b,-S (=O)₂R^b,-OC (=O) R^b,-OS (=O)₂R^b；

R⁴It is selected from-CHO ,-CH=N-OR⁵,-CH=N-OC (=O)-R⁶,-CH=N-OC (=O) O-R⁷,-CH=N-OC (=O)-NH-R⁸、 - C (=O) O-N=CH-R⁹；

R⁵Selected from H, OH or optionally by one or more R^aThe C replacing_1-6Alkyl oxy-；Connect R⁵C-4 and C-3 between Represent singly-bound or double bond, wherein work as R⁵During for H, C-4 and C-3 forms double bond, works as R⁵When being not H, C-4 and C-3 forms singly-bound；

R^aIndependently selected from F, Cl, Br, I, OH, SH, CN ,=O, NR^cR^d、C_1-6Alkyl-, C_2-6Thiazolinyl-, C₃-C₁₀Cycloalkanes Base-, comprise 1-3 selected from N, O and S heteroatomic 3-10 circle heterocycles alkyl-, C_6-14Aryl-, comprise 1-3 and be selected from N, O and S Heteroatomic 5-14 unit's heteroaryl-, C_1-6Alkyl oxy-, C_2-6Thiazolinyl epoxide-, C₃-C₁₀Cycloalkyl oxy-, comprise 1-3 selected from N, O and S heteroatomic 3-10 circle heterocycles alkyl oxy-, C_6-14Aryloxy-, comprise 1-3 and be selected from the heteroatomic 5-14 of N, O and S Unit's heteroaryl epoxide-,-C (=O) R^b,-S (=O)₂R^b；

R^bSelected from optionally by one or more R^aThe following groups replacing：C_1-6Alkyl-, C_2-6Thiazolinyl-, C₃-₁₀Cycloalkyl-, NR^cR^d, bag Containing 1-3 selected from N, O and S heteroatomic 3-10 circle heterocycles alkyl-, C_6-14Aryl-, comprise 1-3 and be selected from N, O and S hetero atom 5-14 unit's heteroaryl-；

R^cAnd R^dIt is independently selected from H or optionally by one or more R^aThe following groups replacing：C_1-6Alkyl-, C_2-6Thiazolinyl-, C₃-₁₀ Cycloalkyl-, comprise 1-3 selected from N, O and S heteroatomic 3-10 circle heterocycles alkyl-, C_6-14Aryl-, comprise 1-3 and be selected from N, O 5-14 unit's heteroaryl heteroatomic with S-.

2. compound as claimed in claim 1 or its pharmaceutically acceptable salt, wherein：

R¹For H or optionally by one or more R^aThe following groups replacing：C_1-6Alkyl-, C_2-6Thiazolinyl-, C₃-₁₀Cycloalkyl-,-C (=O) R^b、 - S (=O)₂R^b；

R²Selected from O, S, OH, SH or optionally by one or more R^aThe following groups replacing：C_1-6Alkyl oxy-, C_2-6Thiazolinyl epoxide-, C₃-C₁₀Cycloalkyl oxy-, C_1-6Alkyl sulfenyl-, C_2-6Enylsulfanyl-, C₃-C₁₀Cycloalkylsulfanyl-,-OC (=O) R^b,-OS (=O)₂R^b, R² And between C-12Represent singly-bound or double bond, wherein work as R²During for O or S, it forms double bond with C-12, works as R²For other groups When, it forms singly-bound with C-12；

R³Selected from F, Cl, Br, I, OH, SH, CN or optionally by one or more R^aThe following groups replacing：C_1-6Alkyl-, C_2-6Alkene Base-, C₃-₁₀Cycloalkyl-, NR^cR^d, comprise 1-3 selected from N, O and S heteroatomic 3-10 circle heterocycles alkyl-, C_6-14Aryl-, comprise 1-3 Individual selected from N, O and S heteroatomic 5-14 unit's heteroaryl-,-C (=O) R^b,-S (=O)₂R^b,-OC (=O) R^b,-OS (=O)₂R^b.

3. compound as claimed in claim 1 or 2 or its pharmaceutically acceptable salt, wherein：

R¹For H or optionally by one or more R^aThe C replacing_1-6Alkyl-,-C (=O) R^b,-S (=O)₂R^b；

R²Selected from O, S, OH, SH or optionally by one or more R^aThe following groups replacing：C_1-6Alkyl oxy-, C_1-6Alkyl sulfenyl-, - OC (=O) R^b,-OS (=O)₂R^b, R²And between C-12Represent singly-bound or double bond, wherein work as R²During for O or S, itself and C-12 Form double bond, work as R²During for other group, it forms singly-bound with C-12；

R³Selected from F, Cl, Br, OH, SH or optionally by one or more R^aThe following groups replacing：C_1-6Alkyl-, C₃-₁₀Cycloalkyl-, NR^cR^d, comprise 1-3 selected from N, O and S heteroatomic 3-10 circle heterocycles alkyl-, C_6-14Aryl-, comprise 1-3 and be selected from N, O and S Heteroatomic 5-14 unit's heteroaryl-,-OC (=O) R^b,-OS (=O)₂R^b.

4. compound as claimed in claim 1 or its pharmaceutically acceptable salt, be selected from following formula (II ')～(VII ') and formula (II ")～ Compound shown in (VII ") or its pharmaceutically acceptable salt：

Wherein, R¹～R²And R⁵Separately it is selected from the definition in claim 1, R³Selected from F, Cl, Br, I, OH, SH, CN Or optionally by one or more R^aThe following groups replacing：C_1-6Alkyl-, C_2-6Thiazolinyl-, C₃-C₁₀Cycloalkyl-, NR^cR^d, comprise 1-3 Selected from N, O and S heteroatomic 3-10 circle heterocycles alkyl-, C_6-14Aryl-, comprise 1-3 selected from N, O and S heteroatomic 5-14 unit Heteroaryl-,-C (=O) R^b,-S (=O)₂R^b,-OC (=O) R^b,-OS (=O)₂R^b；

R⁶、R⁷、R⁸、R⁹、R¹⁰It is independently from each other H ,-C (=O) R^b,-S (=O)₂R^b, optionally by one or more R^aReplace C_1-6Alkyl-, C_2-6Thiazolinyl-, C_3-10Cycloalkyl-, comprise 1-3 selected from N, O and S heteroatomic 3-10 circle heterocycles alkyl-, C_6-14 Aryl-, comprise 1-3 selected from N, O and S heteroatomic 5-14 unit's heteroaryl-；

R^a、R^b、R^c、R^dSeparately it is selected from the definition in claim 1.

5. compound as claimed in claim 1 or its pharmaceutically acceptable salt, the compound shown in selected from following formula or it is pharmaceutically acceptable Salt：

6. as described in any one of claim 1-5 compound or its pharmaceutically acceptable salt preparation method, including selected from following one or more The combination of step：

Step 1)：

If necessary, carry out step 2)：

Step 3)：

Step 4)：

Described reaction preferably depositing in catalyst agent 1- ethyl-(3- dimethylaminopropyl) carbodiimide hydrochloride (EDCI) and/or alkali Under carry out；

Or

Using identical method, by the compound (III ") in following compounds (e ") and (f ") preparation claim 4～(VII ")：

And, step 5)：

Optionally, by step 1)～4) compound of gained prepares its pharmaceutically acceptable salt with suitable acid or alkali reaction；

Wherein, R¹～R³、R⁵To R¹⁰It is respectively provided with the definition as described in claim 1-5；

R^2aSelected from OH or SH；

R^2bSelected from O or S；

R^2cSelected from optionally by one or more R^aThe following groups replacing：C_1-6Alkyl oxy-, C_2-6Thiazolinyl epoxide-, C₃-C₁₀Cycloalkyloxy group Base-, comprise 1-3 selected from N, O and S heteroatomic 3-10 circle heterocycles alkyl oxy-, C_6-14Aryloxy-, comprise 1-3 selected from N, O and S heteroatomic 5-14 unit's heteroaryl epoxide-, C_1-6Alkyl sulfenyl-, C_2-6Enylsulfanyl-, C₃-C₁₀Cycloalkylsulfanyl-, comprise 1-3 Individual selected from N, O and S heteroatomic 3-10 circle heterocycles alkyl sulfenyl-, C_6-14Artyl sulfo-, to comprise 1-3 miscellaneous former selected from N, O and S Son 5-14 unit's heteroaryl sulfenyl-,-OC (=O) R^b,-OS (=O)₂R^b, wherein R^aAnd R^bIt is independently selected from the definition in claim 1-5；

X is selected from chlorine, bromine or iodine；

Z is selected from hydrogen, chlorine or bromine.

7. method as claimed in claim 6, including the combination selected from following one or more steps：

Wherein, R¹～R³And R⁵It is each independently selected from the definition in logical formula (I), R⁶～R¹⁰It is each independently selected from the definition in claim 4.

8. pharmaceutical composition, comprises the compound as described in any one of claim 1-5 or its pharmaceutically acceptable salt.

9. the compound as described in any one of claim 1-5 or its pharmaceutically acceptable salt are used for preparation treatment or prophylactic pharmaceutical composition Purposes.

10. purposes as claimed in claim 9, wherein said disease is by uncontrolled cell growth, propagation and/or survival, inappropriate Cellullar immunologic response or the disease that causes of unsuitable cellular inflammation response, or with uncontrolled cell growth, propagation and/or survival, Unsuitable cellullar immunologic response or the disease of unsuitable cellular inflammation response, especially, described disease is such as neoplastic hematologic disorder, solid tumor And/or their transfer, such as leukemia and myelodysplastic syndrome, malignant lymphoma, the head including cerebroma and brain metastes and neck Portion's tumor, the breast tumor including non-fire power and small cell lung tumor, gastroenteric tumor, endocrine tumorses, breast tumor With other gynecological tumors, the urologic neoplasms including tumor of kidney, bladder tumor and prostate tumor, cutaneous tumor and sarcoma and/or they Transfer；Preferably, described disease is cancer such as pulmonary carcinoma.