CN103450083A

CN103450083A - Geldanamycin derivatives and preparation method and applications thereof

Info

Publication number: CN103450083A
Application number: CN2013104184917A
Authority: CN
Inventors: 林国强; 吴晖; 冯陈国; 张薇; 朱建荣; 周屹峰
Original assignee: SHANGHAI RENZHOU BIOCHEMICAL TECHNOLOGY Co Ltd; Hangzhou Huadong Medicine Group Biological Engineering Research Institute Co Ltd
Current assignee: SHANGHAI RENZHOU BIOCHEMICAL TECHNOLOGY Co Ltd; Hangzhou Huadong Medicine Group Biological Engineering Research Institute Co Ltd
Priority date: 2013-09-13
Filing date: 2013-09-13
Publication date: 2013-12-18
Anticipated expiration: 2033-09-13
Also published as: CN103450083B

Abstract

The invention relates to new geldanamycin derivatives, a preparation method of the compounds and the applications of the compounds in preparation of cell killing agents with a cell killing activity, cell proliferation inhibitors and antineoplastic drugs.

Description

Geldanamycin derivant and its production and use

Technical field

The present invention relates to geldanamycin analog derivative that a class is new, prepare the method for this compounds, and this compounds is for the preparation of the purposes in antitumor drug.

Background technology

Geldanamycin was found [C.DeBoer, et al. from the streptomycete product early than 1970; Geldanamycin, a new antibiotic:J.Antibiot., 1970,23 (9), 442-447], thereafter, from microbial product or by synthetic, found successively many similar compounds and found that such compound has multiple biological activity.As document [M.Muroi, et al.; The structures of macbecin I and II:Tetrahedron, 1981,37, pp.1123-1131], document [R.C.Schnur, et al.; Inhibition of the oncogene product p185erbB-2in vitro and in vivo by geldanamycin and dihydrogeldanamycin derivatives:J.Med.Chem.; 1995; 38,3806-3812], document [M.Bendin, et al.; Geldanamycin, an inhibitor of the chaperone activity of HS90, induces MAPK-independent cell cycle arrest:Int.J.Cancer, 2004,109,643-652], document [Z.-Q.Tian et al.; Synthesis and biological activities of novel17-aminogeldanamycin derivatives:Bioorg.Med.Chem., 2004,12,5317-5329] and document [J.-Y.L.Brazidec, et al.; Synthesis and biological evaluation of a new class of geldanamycin derivatives as potent inhibitors of Hsp90:J.Med.Chem., 2004,47,3865-3873] etc. all once put down in writing geldanamycin compounds and the biological activity thereof of natural or synthetic.The biological activity of this compounds is how relevant with heat shock protein 90.Heat shock protein 90 is most active a kind of molecular chaperones in cell, many signal transduction paths all depend on heat shock protein 90, and its expression ratio normal cell in tumour cell exceeds 2～10 times, in growth of tumour cell and survival, may play important regulating effect.The geldanamycin compounds can and suppress its function with the heat shock protein 90 specific binding, cause the degraded of multiple oncoprotein and cell cycle regulating protein, thereby show the multiple biological activitys such as anticancer, therefore, this compounds has been subject to cancer research person's very big concern and further investigation.Wherein, for 17-allylamine-17-demethoxy geldanamycin (being called for short 17-AAG), 17-N, the medicinal research of N dimethylamine base ethylamino--17-AAG (be called for short 17-DMAG) is the most deep, and particularly anti-tumor aspect has entered clinical experimental stage many years ago.

Geldanamycin derivant of the present invention belongs to the ansamycins microbiotic, from structure, in all geldanamycin compounds on the books so far, not yet sees the similar compound with structure identical with the compounds of this invention.

Summary of the invention

The present invention aims to provide a kind of geldanamycin derivant with cell killing activity, cell inhibitory effect activity and anti-tumor activity.

The invention provides one group of new geldanamycin derivant, is specifically compound or pharmaceutically acceptable salt thereof as shown in formula I:

Wherein said R is formula (a) or formula (b)

Wherein,

The C1-C8-that R1 is the saturated or unsaturated alkyl of the C1-C8-that replaces of the saturated or unsaturated alkyl of C1-C8-, halogen, C3-C6 cycloalkyl substituted saturated or unsaturated alkyl, phenyl or substituted phenyl, benzyl or substituted benzyl, styroyl or substituted styroyl;

n=1～3；

R2 is H or hydroxyl;

R3 is H, C1-C8 saturated or unsaturated alkyl, benzyl or substituted benzyl, menaphthyl or substituted menaphthyl.

Preferably, wherein in R1

The C1-C8 saturated hydrocarbyl is straight chained alkyl, more preferably ethyl, octyl group, or

The C1-C8 unsaturated alkyl is allyl group; Or

The C1-C8 saturated hydrocarbyl that the C1-C8-that halogen replaces is saturated or unsaturated alkyl is the halogen replacement, more preferably chloroethyl; Or

Saturated or the unsaturated alkyl of the C1-C8-of C3-C6 cycloalkyl substituted is the C3-C6 methyl cycloalkyl, more preferably cyclopropyl methyl or cyclohexyl methyl; Or

Substituted phenyl is Trifluoromethoxyphen-l;

Substituted benzyl is the benzyl that fluorine replaces;

n=1～2；

In wherein said R3

The C1-C8 saturated hydrocarbyl is straight chained alkyl, preferable methyl; Or

The C1-C8 unsaturated alkyl is allyl group, propargyl, 3-methyl-but-2-ene base; Or

The benzyl that substituted benzyl is chlorine, bromine, methyl, trifluoromethyl replacement.

In the present invention, easy in order to describe, by the described organization definition of following structural formula (40), be GA, be also geldanamycin.And the application's derivative is exactly the replacement on its 17.

The invention discloses new geldanamycin derivant, be selected from formula (1)-(39) compound or its salt.

The compound that table 1:R is formula (a)

The compound that table 2:R is formula (b)

Wherein, preferably be numbered RZ864, RZ865, RZ867, RZ869, RZ871, RZ877, the geldanamycin derivant of RZ879.

Modified and obtained for 17 that are in formula (40) as table 1, the listed compound of table 2.

Pharmaceutical salts described in the present invention refers to " pharmacy acceptable salt ", can be medicinal inorganic or organic salt.

The pharmaceutical salts of formula I of the present invention can be the pharmaceutical salts formed with mineral acid, for example vitriol, hydrochloride, hydrobromate, phosphoric acid salt; Also can form pharmaceutical salts with organic acid, such as acetate, oxalate, Citrate trianion, gluconate, succinate, tartrate, tosilate, mesylate, benzoate, lactic acid salt, maleate etc.The compound that has acidic-group in formula of the present invention (I) can form pharmaceutical salts with basic metal or alkaline-earth metal, preferably but be not limited to sodium salt, sylvite, magnesium salts or calcium salt.

The present invention also provides the method for geldanamycin derivant shown in preparation formula (1)-(39).

The hydrochloride of formula (a) and geldanamycin stirring at room in the mixing solutions of methylene dichloride and methyl alcohol is reacted 3-5 days, and after stopped reaction, concentrated, the silica gel column chromatography of ordinary method is purified, and obtains compound shown in formula I.

Wherein, meter by volume, described methylene chloride/methanol volume ratio is 0.6～10/1, preferably 2～3/1.

Perhaps

Formula (b) is reacted 2-5 days with geldanamycin stirring at room in dichloromethane solution, after stopped reaction after concentrated, the silica gel column chromatography of ordinary method purify, obtain compound shown in formula I.

Formula of the present invention (a), formula (b) also claim the amine fragment, and wherein some can be bought and obtain by commercialization, or by obtaining below with reference to document

Organic&Biomolecular?Chemistry2010,8,3405-3417

Journal?of?Medicinal?Chemistry1992,35,1550-1557

Journal?of?Medicinal?Chemistry1968,11,848-854

For can't purchase available formula (a), formula (b), the preparation method that the present invention also provides.Certainly this method also can be for purchasing the preparation of available amine fragment.

Preparing R is the method for formula (a) hydrochloride:

Identical with in front compound of the definition of wherein said R1, be to save length, no longer repeats.

The method of the compound that wherein, preparation R is formula (b):

Identical with in front compound of wherein said R2, R3 definition, be to save length, no longer repetition.

In preparation, related separation and purification comprises the ordinary method of utilizing Separation of Natural Products purifying well known to those skilled in the art, as liquid-liquid extraction, column chromatography, thin-layer chromatography and recrystallization etc.

The present invention also provides a kind of cell growth inhibiting, has suppressed the method for cell proliferation or treatment tumour, and it comprises any geldanamycin derivant or its salt shown in chemical formula (1)-(39) that give the experimenter and treat significant quantity.

The invention also discloses a kind of pharmaceutical composition, contain any in formula I compound of the present invention or its salt as effective constituent.

Pharmaceutical composition disclosed by the invention, also contain pharmaceutically acceptable vehicle.

Formula I compound of the present invention can be used for treating tumour.

Formula I compound of the present invention and various pharmaceutically acceptable carrier, vehicle or supplementary product compatibility are made antitumor drug, for the treatment of tumour.

The compounds of this invention can be separately or with the form administration of pharmaceutical composition.Route of administration can be oral, non-enteron aisle or topical.Pharmaceutical composition can be made into various suitable formulations according to route of administration.

The pharmaceutical composition of the compounds of this invention can be used with following any-mode: oral, spraying sucks, rectal application, nasal cavity applied medicine, cheek medication, local application, non-enterally administer, as subcutaneous, vein, intramuscular, intraperitoneal, in sheath, in ventricle, in breastbone and intracranial injection or input, or by the medication of a kind of outer planting reservoir.Wherein preferred oral, intraperitoneal or intravenous administration mode.

When oral medication, the compounds of this invention can be made into oral acceptable dosage form arbitrarily, includes but not limited to tablet, capsule, the aqueous solution or aqeous suspension.Wherein, the carrier that tablet is used generally comprises lactose and W-Gum, also can add in addition lubricant as Magnesium Stearate.The thinner that capsule preparations is used generally comprises lactose and dried corn starch.Aqueous suspension preparation normally mixes use by activeconstituents with suitable emulsifying agent and suspension agent.Optionally, also can add some sweeting agents, perfume compound or tinting material in above oral preparations form.

When topical application, the compounds of this invention can be made into suitable ointment, lotion or creme dosage form, wherein activeconstituents is suspended or is dissolved in one or more carriers.The spendable carrier of ointment formulation includes but not limited to: mineral oil, Albolene, white vaseline, propylene glycol, polyoxyethylene, polyoxytrimethylene, emulsifying wax and water; The spendable carrier of lotion or creme includes but not limited to: mineral oil, sorbitan monostearate, polysorbate60, n-Hexadecane ester type waxes, cetene are fragrant and mellow, 2-Standamul G, benzyl alcohol and water.

The all right aseptic injection preparation form medication of the compounds of this invention, comprise aseptic injection water or oil suspension or aseptic injectable solution.Wherein, spendable carrier and solvent comprise water, Ringer's solution and isotonic sodium chlorrde solution.In addition, the fixed oil of sterilizing also can be used as solvent or suspension medium, as direactive glyceride or two glyceryl ester.

It may be noted that in addition, the compounds of this invention using dosage and using method depend on factors, comprise patient's age, body weight, sex, natural health situation, nutritional status, activity intensity, Time of Administration, metabolic rate, the severity of illness and diagnosis and treatment doctor's the subjective judgement of compound.Preferred using dosage is between 0.01～100mg/kg body weight/day.

Code interpreter:

Wherein, DCM is methylene dichloride;

MeOH is methyl alcohol;

(BOC) 2O is two dimethyl dicarbonate butyl methyl esters;

THF is tetrahydrofuran (THF);

PE is sherwood oil;

EA is ethanol;

DIEA is (DIPEA);

Dioxane is Isosorbide-5-Nitrae-dioxane;

Acetone is acetone

TLC represents tlc;

The Rf value be in tlc initial point to the spot center the distance and the ratio of initial point to the distance of solvent front.

Embodiment

The following example will further illustrate the present invention, but the present invention will not be construed as limiting.

Plant and instrument: nucleus magnetic resonance is by Varian EM-360A, EM-390 or Bruker AMX-400 type Instrument measuring.Mass spectrum is by Finnigan4021, HP5989A, Finnigan FTMS-2000 type Instrument measuring.Rapid column chromatography carries out on silica gel (300-400 order).The efficient plate of HSGF254 for thin-layer chromatography (TLC), with UV lamp 254 and 365nm wavelength or the detection of 5% phosphomolybdic acid ethanol solution.The terminal that completes of reaction is detected and is determined by TLC.

For the geldanamycin derivant of 17 modifications with entering clinical study carries out parallel comparison, the applicant has synthesized comparative example compound R ZCO2 and RZCO3:17-DMAG (17-N, N dimethylamine base ethylamino--17-AAG) and the 17-AAG (17-allylamino-17-demethoxygeldanamycin) that two shown in table 3 are used as comparison other.Synthetic method reference (Shen, Y., Xie, Q., Norberg, M., et al.Bioorg.Med.Chem.2005,13,4960.).

Table 3

The preparation of embodiment 1:RZ866

1) preparation of intermediate (1)

Substrate 1(10eq) be dissolved in methylene dichloride (2 times of volume dilution), ice bath.Extremely slowly drip the dichloromethane solution (0.2M) of substrate 2.Separate out a large amount of white solids.

Aftertreatment: filter and revolve partial solvent, washing.The rough post DCM/MeOH=10/1 that crosses.Obtain light yellow liquid, freezing (5 ℃), filter and obtain white solid intermediate (1), and yield is 80%.

2) preparation of intermediate (2)

Substrate 3 is that ready-made purchase is used.

Intermediate (1) (1eq) is dissolved in THF(0.3M), drip substrate 3(1eq), reaction overnight.

Aftertreatment: cross post, obtain white solid intermediate (2).（TLC：PE/EA=1/1,Rf=0.4）

3) preparation of intermediate (3)

Intermediate (2) 5 (1eq) is dissolved in methylene dichloride (0.15M), adds HCl/dioxane (2eq volume), stirs 4 hours.

Aftertreatment: revolve methylene dichloride, add the ether agitation and filtration, washing.Obtain white solid intermediate (3), yield approximately 60%.

1H-NMR(400MHz,D2O)δ:3.49-3.36(m,2H),3.19-3.05(m,4H),1.14-1.03(m,3H)。

4) preparation of RZ866

Get geldanamycin (280mg), add intermediate (3) 740mg, add methylene chloride/methyl alcohol of triethylamine (4.1mL) (20/5mL), stirring at room reaction 4day, the system color is purple.Stopped reaction, remove solvent under reduced pressure, the silica gel column chromatography (eluent: methylene chloride/methanol=500/12,500/15), obtain purple solid (145mg, yield approximately 44%) of purifying.

1H-NMR(400MHz,CDCl3)δ:9.16(s,1H),7.20(s,1H),7.00-6.90(m,2H),6.58(t,J=11.2Hz,1H),5.93-5.81(m,2H),5.16(s,1H),4.92-4.75(m,2H),4.57(t,J=5.2Hz,1H),4.38-4.29(m,1H),4.30(d,J=10.0Hz,1H),3.79-3.69(m,1H),3.68-3.54(m,2H),3.54-3.39(m,3H),3.35(s,3H),3.26(s,3H),3.25-3.15(m,2H),2.79-2.69(m,1H),2.62(d,J=13.6Hz,1H),2.44-2.34(m,1H),2.02(s,3H),1.80(s,3H),1.80-1.59(m,3H),1.14(t,J=7.2Hz,3H),1.02-0.92(m,6H).

13C-NMR(100MHz,DMSO-d6)δ:184.4,178.4,168.6,158.7,156.1,146.0,141.1,137.3,133.5,132.8,131.6,128.2,125.9,108.5,107.5,80.9,79.8,72.1,56.4,55.9,47.0.39.2,34.2,34.1,32.42,32.35,32.1,28.4,22.4,15.6,13.4,12.9,12.2.

ESI(m/z):681.8(M+Na+)。

Proof has obtained the product RZ866 that molecular formula is shown below:

The preparation of embodiment 2:RZ867

1) preparation of intermediate (1) is with 1 of embodiment 1) step;

2) preparation of intermediate (4)

Substrate 4 is that ready-made purchase is used.

Intermediate (1) (1eq) is dissolved in THF(0.3M), drip substrate 4(1eq), reaction overnight.

Aftertreatment: cross post, obtain white solid intermediate (4).（TLC：PE/EA=1/1,Rf=0.4）

3) preparation of intermediate (5)

Intermediate (4) (1eq) is dissolved in methylene dichloride (0.15M), adds HCl/dioxane (2eq volume), stirs 4hr.

Aftertreatment: revolve methylene dichloride, add the ether agitation and filtration, washing.Obtain white solid intermediate (5), yield approximately 78%.

1H-NMR(400MHz,D2O)δ:3.43(t,J=6.0Hz,2H),3.15-3.07(m,4H),1.54-1.43(m,2H),1.36-1.23(m,10H),0.88(t,J=6.4Hz,3H).

4) preparation of RZ867

Get geldanamycin (280mg), add intermediate (5) 820mg, add methylene chloride/methyl alcohol of triethylamine (4.0mL) (15/10mL), stirring at room reaction 4day, the system color is purple.Stopped reaction, remove solvent under reduced pressure, the silica gel column chromatography (eluent: methylene chloride/methanol=500/10), obtain purple solid (320mg, yield approximately 86%) of purifying.

1H-NMR(400MHz,MeOD)δ:7.13(d,J=11.2Hz,1H),7.04(s,1H),6.62(t,J=11.2Hz,1H),5.87(t,J=10.0Hz,1H),5.62(d,J=9.2Hz,1H),5.18(s,1H),4.51(d,J=8.4Hz,1H),3.72-3.57(m,3H),3.49-3.41(m,1H),3.41-3.36(m,2H),3.35(s,3H),3.29(s,3H),3.11(t,J=6.8Hz,2H),2.78-2.64(m,2H),2.40-2.30(m,1H),2.00(s,3H),1.88-1.78(m,1H),1.74(s,3H),1.74-1.55(m,2H),1.52-1.41(m,2H),1.7-1.21(m,10H),1.04-0.93(m,6H),0.89(t,J=6.8Hz,3H).

13C-NMR(100MHz,MeOD)δ:185.9,180.8,170.5,161.4,159.0,147.5,142.5,137.8,135.4,134.5,132.9,129.5,127.2,110.5,109.4,83.0,82.1,74.2,57.5,56.9,48.0,40.7,35.7,34.4,33.7,33.0,31.3,31.2,30.5,30.4,30.0,23.7,22.7,14.4,14.2,13.5,12.4.

ESI(m/z):765.9(M+Na+)。

Proof has obtained the product RZ867 that molecular formula is shown below:

The preparation of embodiment 3:RZ868

1) preparation of intermediate (6): the method with reference to embodiment 1 prepares

2) preparation of RZ868

Get geldanamycin (200mg), add intermediate (6) 1.90g, add methylene chloride/methyl alcohol of triethylamine (10.0mL) (10/15mL), stirring at room reaction 4day, the system color is purple.Stopped reaction, remove solvent under reduced pressure, the silica gel column chromatography (eluent: methylene chloride/methanol=500/10), obtain purple solid (220mg, yield approximately 84%) of purifying.

1H-NMR(400MHz,CDCl3)δ:9.14(s,1H),7.31-7.22(m,2H),7.22-7.10(m,4H),7.06-6.98(m,1H),6.93(d,J=11.2Hz,1H),6.56(d,J=11.2Hz,1H),5.94-5.77(m,2H),5.42-5.31(m,1H),5.13(s,1H),5.13-4.91(m,3H),4.34(br?s,1H),4.30(d,J=10.0Hz,1H),3.75-3.52(m,3H),3.52-3.34(m,5H),3.34(s,3H),3.26(s,3H),2.78(t,J=7.2Hz,2H),2.78-2.67(m,1H),2.67-2.53(m,1H),2.47-2.34(m,1H),1.99(s,3H),1.79(s,3H),1.85-1.63(m,3H),1.03-0.90(m,6H).

13C-NMR(100MHz,MeOD)δ:184.5,180.1,168.4,159.1,156.5,146.1,141.1,139.3,136.0,135.1,133.9,133.1,128.9,128.7,127.1,126.7,126.5,109.5,108.9,82.0,81.6,81.4,72.6,57.2,56.8,47.7,41.8,39.9,36.5,35.1,34.3,32.4,28.6,22.9,12.9,12.7,12.4.

ESI(m/z):758.4(M+Na+)。

Proof has obtained the product RZ8648 that molecular formula is shown below:

The preparation of embodiment 4:RZ869

1) preparation of intermediate (7): the method with reference to embodiment 1 prepares

2) preparation of RZ869

Get geldanamycin (200mg), add intermediate (7) 750mg, add methylene chloride/methyl alcohol of triethylamine (3.5mL) (10/15mL), stirring at room reaction 5day, the system color is purple.Stopped reaction, remove solvent under reduced pressure, the silica gel column chromatography (eluent: methylene chloride/methanol=500/10), obtain purple solid (100mg, yield approximately 35%) of purifying.

1H-NMR(400MHz,MeOD)δ:7.50-7.42(m,2H),7.18-7.07(m,3H),7.03(s,1H),6.61(t,J=11.6Hz,1H),5.86(t,J=9.6Hz,1H),5.61(d,J=10.0Hz,1H),5.17(s,1H),4.519(d,J=8.4Hz,1H),3.71(t,J=5.6Hz,2H),3.63-3.55(m,1H),3.52-3.44(m,2H),3.44-3.37(m,1H),3.30(s,3H),3.29(s,3H),2.78-2.63(m,2H),2.40-2.30(m,1H),1.99(s,3H),1.90-1.78(m,1H),1.74(s,3H),1.68-1.51(m,2H),1.02-0.92(m,6H).

13C-NMR(100MHz,MeOD)δ:185.9,180.7,170.4,159.0,158.3,147.5,145.1,142.3,140.0,137.8,135.4,134.5,132.7,129.4,127.2,122.60,122.06(1JC-F=254Hz),121.1,110.6,109.4,82.8,82.1,74.1,57.5,56.8,47.8,40.6,35.5,34.3,33.6,22.6,14.1,13.5,12.5.

ESI(m/z):814.2(M+Na+)。

Proof has obtained the product RZ869 that molecular formula is shown below:

The preparation of embodiment 5:RZ870

1) preparation of intermediate (8): the method with reference to embodiment 1 prepares

2) preparation of RZ870

Get geldanamycin (225mg), add intermediate (8) 137mg, add methylene chloride/methyl alcohol of triethylamine (2.0mL) (20/10mL), stirring at room reaction 4day, the system color is purple.Stopped reaction, remove solvent under reduced pressure, the silica gel column chromatography (eluent: methylene chloride/methanol=500/15), obtain purple solid (101mg, yield approximately 57%) of purifying.

1H-NMR(400MHz,CDCl3)δ:9.14(s,1H),7.36-7.22(m,5H),7.21(s,1H),7.00-6.85(m,2H),6.58(t,J=11.2Hz,1H),5.92-5.81(m,2H),5.16(s,1H),4.97(t,J=5.6Hz,1H),4.77(br?s,2H),4.37(d,J=6.0Hz,2H),4.30(d,J=9.6Hz,1H),4.33-4.23(m,1H),3.77-3.38(m,6H),3.35(s,3H),3.27(s,3H),2.80-2.69(m,1H),2.65-2.56(m,1H),2.44-2.31(m,1H),2.02(s,3H),1.80(s,3H),1.80-1.65(m,3H),1.02-0.91(m,6H).

13C-NMR(100MHz,MeOD)δ:185.9,180.9,170.6,161.3,159.1,147.5,142.5,141.2,137.9,135.4,134.5,132.8,129.5,128.2,128.0,127.2,110.6,109.4,83.0,82.1,74.3,57.5,56.9,49.8,47.8,44.8,40.8,35.7,34.4,33.6,31.2,22.7,14.2,13.5,12.4.

ESI(m/z):744.4(M+Na+)。

Proof has obtained the product RZ870 that molecular formula is shown below:

The preparation of embodiment 6:RZ871

1) preparation of intermediate (9): the method with reference to embodiment 1 prepares

2) preparation of RZ871

Get geldanamycin (250mg), add intermediate (9) 1.13g, add methylene chloride/methyl alcohol of triethylamine (8.0mL) (15/20mL), stirring at room reaction 4day, the system color is purple.Stopped reaction, remove solvent under reduced pressure, the silica gel column chromatography (eluent: methylene chloride/methanol=500/15), obtain purple solid (48mg, yield approximately 15%) of purifying.

1H-NMR(400MHz,DMSO-d6)δ:9.16(s,1H),7.21(s,1H),7.00-6.89(m,2H),6.58(t,J=11.6Hz,1H),5.9-5.81(m,2H),5.17(s,1H),4.92-4.68(br?s,2H),4.79(t,J=6.0Hz,1H),4.58(t,J=6.0Hz,1H),4.34-4.24(m,2H),3.80-3.39(m,6H),3.36(s,3H),3.27(s,3H),3.00(t,J=6Hz,2H),2.80-2.69(m,1H),2.67-2.58(m,1H),2.45-2.33(m,1H),1.80(s,3H),1.79-1.60(m,8H),1.50-1.35(m,1H),1.29-1.06(m,3H),1.03-0.80(m,8H).

13C-NMR(100MHz,DMSO-d6)δ:184.5,178.4,168.7,158.9,156.2,146.1,141.1,137.4,133.6,132.8,131.6,128.1,125.9,108.5,107.5,80.9,79.8,72.1,55.4,55.9,38.0,32.4,32.1,30.4,28.4,26.1,25.4,22.4,13.3,12.9,12.2.

ESI(m/z):750.3(M+Na+)。

Proof has obtained the product RZ871 that molecular formula is shown below:

The preparation of embodiment 7:RZ872

1) intermediate (10) preparation: the method with reference to embodiment 1 prepares;

2) preparation of RZ872

Get geldanamycin (180mg), add intermediate (10) 1.12g, add methylene chloride/methyl alcohol of triethylamine (5.0mL) (25/10mL), stirring at room reaction 4day, the system color is purple.Stopped reaction, remove solvent under reduced pressure, the silica gel column chromatography (eluent: methylene chloride/methanol=500/15), obtain purple solid (46mg, yield approximately 20%) of purifying.

1H-NMR(400MHz,CDCl3)δ:9.14(s,1H),7.26-7.20(m,2H),7.18(s,1H),7.02-6.86(m,4H),6.58(t,J=11.6Hz,1H),5.90-5.81(m,2H),5.18-5.07(m,3H),4.83(br?s,2H),4.36-4.24(m,4H),3.77-3.38(m,6H),3.35(s,3H),3.27(s,3H),2.79-2.69(m,1H),2.65-2.55(m,1H),2.43-2.32(m,1H),2.02(s,3H),1.79(s,3H),1.83-1.66(m,3H),0.98(d,J=6.8Hz,3H),0.95(d,J=6.4Hz,3H).

13C-NMR(100MHz,MeOD)δ:185.9,180.9,170.7,164.6,162.1,161.2,159.1,147.5,142.6,137.9,137.30,137.27,135.4,134.5,132.8,130.2,130.1,129.6,127.2,116.2,115.9,110.5,109.4,83.0,82.0,74.3,57.5,56.8,49.8,47.8,44.1,40.8,35.7,34.5,33.6,31.3,22.6,13.5,12.4.

ESI(m/z):762.3(M+Na+)。

Proof has obtained the product RZ872 that molecular formula is shown below:

The preparation of embodiment 8:RZ873

1) intermediate (11) preparation: the method with reference to embodiment 1 prepares;

2) preparation of RZ873

Get geldanamycin (103mg), add intermediate (11) 1.36g, add methylene chloride/methyl alcohol of triethylamine (4.0mL) (30/5mL), stirring at room reaction 3day, the system color is purple.Stopped reaction, remove solvent under reduced pressure, the silica gel column chromatography (eluent: methylene chloride/methanol=500/15), obtain purple solid (43mg, yield approximately 34%) of purifying.

1H-NMR(400MHz,CDCl3)δ:9.16(s,1H),7.24(s,1H),6.99-6.89(m,2H),6.58(t,J=11.2Hz,1H),5.95-5.81(m,2H),5.18(s,1H),4.60(t,J=6.0Hz,1H),4.49(t,J=5.6Hz,1H),4.31(d,J=9.6Hz,2H),l.81-3.70(m,1H),3.70-3.54(m,2H),3.54-3.41(m,3H),3.36(s,3H),3.27(s,3H),3.08-3.00(m,2H),2.80-2.70(m,1H),2.64(d,J=12.4Hz,1H),2.45-2.34(m1H),2.00(s,3H),1.80(s,3H),1.89-1.67(m,3H),1.03-0.86(m,7H),0.55-0.42(m,2H),0.22-0.15(m,2H).

13C-NMR(100MHz,CDCl3)δ:184.6,180.2,168.5,159.0,156.4,146.2,141.1,136.0,135.1,133.9,133.0,127.1,126.7,109.6,109.0,82.0,81.6,81.4,72.7,57.2,56.8,47.8,45.6,40.1,35.1,34.3,32.4,28.6,22.9,12.9,12.7,11.3,3.45,3.44.

ESI(m/z):708.3(M+Na+)。

Proof has obtained the product RZ873 that molecular formula is shown below:

The preparation of embodiment 9:RZ874

1) preparation of intermediate (12): the method with reference to embodiment 1 prepares

2) preparation of RZ874

Get geldanamycin (250mg), add intermediate (12) 900mg, add methylene chloride/methyl alcohol of triethylamine (7.0mL) (20/10mL), stirring at room reaction 4day, the system color is purple.Stopped reaction, remove solvent under reduced pressure, the silica gel column chromatography (eluent: methylene chloride/methanol=500/15), obtain purple solid (50mg, yield approximately 17%) of purifying.

1H-NMR(400MHz,CDCl3)δ:9.14(s,1H),7.13(s,1H),7.11-7.01(m,1H),6.91(d,J=11.6Hz,1H),6.54(t,J=11.2Hz,1H),6.03-5.92(m,1H),5.88-5.74(m,3H),5.68-5.54(m,1H),5.21-4.99(m,5H),4.36(br?s,1H),4.27(d,J=9.6Hz,1H),3.84-3.35(m,5H),3.32(s,3H),3.23(s,3H),3.16-3.01(m,3H),2.77-2.65(m,1H),2.57(d,J=13.6Hz,1H),2.44-2.34(m,1H),1.99(s,3H),1.76(s,3H),1.76-1.63(m,3H),1.00-0.88(m,6H).

13C-NMR(100MHz,CDCl3)δ:184.5,180.1,168.5,159.2,156.5,146.1,141.1,136.0,135.4,135.1,133.8,133.1,127.1,126.7,115.9,109.4,108.9,81.9,81.5,81.4,72.6,57.2,56.8,47.7,43.2,39.9,35.1,34.3,32.4,28.6,22.9,12.9,12.7,12.4.

ESI(m/z):694.3(M+Na+)。

Proof has obtained the product RZ874 that molecular formula is shown below:

The preparation of embodiment 10:RZ875

1) preparation of intermediate (13): the method with reference to embodiment 2 prepares

2) preparation of RZ875

Get geldanamycin (280mg), add intermediate (13) 1.45g, add methylene chloride/methyl alcohol of triethylamine (9.0mL) (20/10mL), stirring at room reaction 4day, the system color is purple.Stopped reaction, remove solvent under reduced pressure, the silica gel column chromatography (eluent: methylene chloride/methanol=500/15), obtain purple solid (96mg, yield approximately 29%) of purifying.

1H-NMR(400MHz,CDCl3)δ:9.11(s,1H),7.12(d,J=1.6Hz,1H),6.90(d,J=11.2Hz,1H),6.72(t,J=5.2Hz,1H),6.54(t,J=11.2Hz,1H),5.88-5.73(m,2H),5.36-5.12(m,3H),5.08(s,1H),5.05-4.90(m,1H),4.39(br?s,1H),4.27(d,J=10.0Hz,1H),3.64-3.47(m,3H),3.44-3.35(m,1H),3.31(s,3H),3.31-3.09(m,4H),3.22(s,3H),2.76-2.64(m,1H),2.64-2.52(m,1H),2.50-2.20(m,2H),1.98(s,3H),1.87-1.58(m,4H),1.75(s,3H),1.07(t,J=6.8Hz,3H),0.99-0.83(m,6H).

13C-NMR(100MHz,CDCl3)δ:184.1,180.0,168.3,159.0,156.6,145.5,141.2,135.9,135.0,133.6,13l.1,127.0,126.6,108.8,108.7,81.8,81.5,81.3,72.6,57.0,56.7,43.3,37.4,35.2,35.0,34.3,32.3,31.0,28.6,22.9,15.6,12.8,12.6,12.4.

ESI(m/z):696.3(M+Na+)。

Proof has obtained the product RZ875 that molecular formula is shown below:

The preparation of embodiment 11:RZ876

1) preparation of intermediate (14): the method with reference to embodiment 2 prepares;

2) preparation of RZ876

Get geldanamycin (280mg), add intermediate (14) 1.65g, add methylene chloride/methyl alcohol of triethylamine (11.0mL) (20/10mL), stirring at room reaction 3day, the system color is purple.Stopped reaction, remove solvent under reduced pressure, the silica gel column chromatography (eluent: methylene chloride/methanol=500/10), obtain purple solid (68mg, yield approximately 18%) of purifying.

1H-NMR(400MHz,CDCl3)δ:9.11(s,1H),7.32-7.26(m,2H),7.23-7.14(m,4H),6.92(d,J=11.6Hz,1H),6.72(t,J=5.2Hz,1H),6.57(t,J=11.2Hz,1H),5.84(t,J=10.0Hz,2H),5.19-4.99(m,4H),4.98-4.86(m,1H),4.41(br?s,1H),4.30(d,J=9.6Hz,1H),3.63-3.51(m,3H),3.50-3.38(m,3H),3.34(s,3H),3.26(s,3H),3.31-3.20(m,1H),2.79(t,J=6.8Hz,2H),2.77-2.68(m,1H),2.61(d,J=13.6Hz,1H),2.44-2.33(m,1H),2.00(s,3H),1.79(s,3H),1.79-1.64(m,5H),1.04-0.91(m,6H).

13C-NMR(100MHz,CDCl3)δ:184.1,180.0,168.3,158.8,156.6,145.5,141.2,139.4,135.9,135.1,133.7,13l.1,128.9,126.9,126.7,126.4,108.8,81.9,81.5,81.3,72.6,57.1,56.7,43.3,41.6,37.4,36.6,35.1,34.3,32.3,31.1,28.5,22.9,12.8,12.6,12.4.

ESI(m/z):772.4(M+Na+)。

Proof has obtained the product RZ876 that molecular formula is shown below:

The preparation of embodiment 12:RZ877

1) preparation of intermediate (15): the method with reference to embodiment 2 prepares;

2) preparation of RZ877

Get geldanamycin (280mg), add intermediate (15) 1.47g, add methylene chloride/methyl alcohol of triethylamine (6.4mL) (20/10mL), stirring at room reaction 4day, the system color is purple.Stopped reaction, remove solvent under reduced pressure, the silica gel column chromatography (eluent: methylene chloride/methanol=500/15), obtain purple solid (40mg, yield approximately 10%) of purifying.

1H-NMR(400MHz,CDCl3)δ:9.05(s,1H),7.54(br?s,1H),7.36(d,J=8.8Hz,2H),7.14(s,1H),7.09(d,J=8.8Hz,2H),6.89(d,J=11.6Hz,1H),6.62(t,J=5.6Hz,1H),6.55(t,J=11.6Hz,1H),5.90-5.76(m,2H),5.75-5.56(m,1H),5.21-4.92(m,2H),5.08(s,1H),4.44(br?s,1H),4.30(d,J=9.6Hz,1H),3.67-3.47(m,3H),3.45-3.31(m,3H),3.28(s,3H),3.25(s,3H),2.73(t,J=5.7Hz,1H),2.56(d,J=13.6Hz,1H),2.44-2.29(m,1H),2.00(s,3H),1.79(s,3H),2.00-1.73(m,4H),1.73-1.54(m,1H),0.96(d,J=6.4Hz,3H),0.90(d,J=6.0Hz,3H).

13C-NMR(100MHz,CDCl3)δ:184.1,180.3,168.4,156.8,156.2,145.4,144.3,141.3,138.2,135.9,135.4,133.7,133.3,126.8,121.9,120.4,119.4,108.83,108.78,82.4,81.5,81.2,72.8,57.2,56.7,43.6,37.5,35.2,34.5,32.4,31.0,28.6,22.9,12.9,12.7,12.5.

ESI(m/z):828.3(M+Na+)。

Proof has obtained the product RZ877 that molecular formula is shown below:

The preparation of embodiment 13:RZ878

1) preparation of intermediate (16): the method with reference to embodiment 2 prepares;

2) preparation of RZ878

Get geldanamycin (280mg), add intermediate (16) 484mg, add methylene chloride/methyl alcohol of triethylamine (3.4mL) (20/10mL), stirring at room reaction 5day, the system color is purple.Stopped reaction, remove solvent under reduced pressure, the silica gel column chromatography (eluent: methylene chloride/methanol=500/20,500/30), obtain purple solid (60mg, yield approximately 17%) of purifying.

1H-NMR(400MHz,CDCl3)δ:9.14(s,1H),7.22-7.15(m,1H),6.94(d,J=11.2Hz,1H),6.70(t,J=5.6Hz,1H),6.58(t,J=11.2Hz,1H),5.93-5.79(m,3H),5.20(d,J=17.2Hz,1H),5.16-4.84(m,6H),4.38(br?s,1H),4.31(d,J=9.6Hz,1H),3.84-3.77(m,2H),3.66-3.53(m,3H),3.47-3.40(m,1H),3.38-3.28(m,2H),3.36(s,3H),3.27(s,3H),2.80-2.69(m,1H),2.68-2.58(m,1H),2.45-2.33(m,1H),2.03(s,3H),1.97-1.74(m,5H),1.80(s,3H),1.03-0.92(m,6H).

13C-NMR(100MHz,CDCl3)δ:184.2,180.2,168.4,158.2,156.5,145.5,141.3,135.9,135.6,135.1,133.8,133.0,127.0,126.7.115.7,108.8,81.9,81.5,81.3,72.6,57.2,56.8,43.4,43.0,37.6,35.1,34.4,32.3,31.0,28.6,23.0,12.9,12.7,12.5.

ESI(m/z):708.3(M+Na+)。

Proof has obtained the product RZ878 that molecular formula is shown below:

The preparation of embodiment 14:RZ879

1) preparation of intermediate (17): the method with reference to embodiment 2 prepares;

2) preparation of RZ879

Get geldanamycin (280mg), add intermediate (17) 1.90g, add methylene chloride/methyl alcohol of triethylamine (10.5mL) (30/10mL), stirring at room reaction 4day, the system color is purple.Stopped reaction, remove solvent under reduced pressure, the silica gel column chromatography (eluent: methylene chloride/methanol=500/15), obtain purple solid (60mg, yield approximately 16%) of purifying.

1H-NMR(400MHz,CDCl3)δ:9.14(s,1H),7.21-7.18(m,1H),6.94(d,J=12.0Hz,1H),6.72(t,J=5.6Hz,1H),6.57(t,J=11.6Hz,1H),5.90-5.80(m,2H),5.14(s,1H),5.03-4.63(m,4H),4.37(br?s,1H),4.30(d,10.0Hz,1H),3.67-3.51(m,3H),3.46-3.39(m,1H),3.35(s,3H),3.34-3.26(m,2H),3.26(s,3H),2.99(t,J=6.4Hz,2H),2.78-2.69(m,1H),2.63(d,J=13.6Hz,1H),2.44-2.33(m,1H),2.02(s,3H),1.90-1.75(m,6H),1.79(s,3H),1.75-1.59(m,5H),1.26-1.09(m,5H),1.02-0.93(m,6H).

13C-NMR(100MHz,CDCl3)δ:184.2,180.1,168.4,159.1,156.5,145.5,141.3,135.9,135.1,133.8,133.0,127.0,126.7,108.8,81.9,81.5,81.3,72.6,57.2,56.8,46.9,43.4,38.6,37.6,35.1,34.4,32.4,31.1,31.0,28.6,26.5,26.0,23.0,12.9,12.7,12.5.

ESI(m/z):764.3(M+Na+)。

Proof has obtained the product RZ879 that molecular formula is shown below:

The preparation of embodiment 15:RZ880

1) preparation of intermediate (18): the method with reference to embodiment 2 prepares;

2) preparation of RZ880

Get geldanamycin (280mg), add intermediate (18) 1.20g, add methylene chloride/methyl alcohol of triethylamine (8.0mL) (30/10mL), stirring at room reaction 4day, the system color is purple.Stopped reaction, remove solvent under reduced pressure, the silica gel column chromatography (eluent: methylene chloride/methanol=500/15), obtain purple solid (90mg, yield approximately 24%) of purifying.

1H-NMR(400MHz,CDCl3)δ:9.15(s,1H),7.21(s,1H),6.94(d,J=12.0Hz,1H),6.72(d,J=5.6Hz,1H),6.57(t,J=11.2Hz,1H),5.90-5.80(m,2H),5.15(s,1H),4.91(br?s,2H),4.76-4.66(m,1H),4.56-4.48(m,1H),4.35(br?s,1H),4.30(d,J=10.0Hz,1H),3.68-3.52(m,3H),3.47-3.39(m,1H),3.45(s,3H),3.45-3.26(m,2H),3.26(s,3H),3.18-3.09(m,2H),2.79-2.69(m,1H),2.64(d,J=13.6Hz,1H),2.44-2.34(m,1H),2.02(s,3H),1.89-1.70(m,5H),1.79(s,3H),1.53-1.42(m,2H),1.36-1.18(m,10H),1.02-0.93(m,6H),.087(t,J=6.4Hz,3H).

13C-NMR(100MHz,CDCl3)δ:184.2,180.2,168.4,158.8,156.4,145.6,141.3,135.9,135.2,133.9,133.0,127.0,126.7,108.9,81.9,81.6,81.4,72.6,57.2,56.8,43.4,40.8,37.6,35.1,34.4,32.3,31.9,31.1,30.4,29.44,29.38,28.6,27.1,23.0,22.8,14.2,12.9,12.7,12.5.

ESI(m/z):780.2(M+Na+)。

Proof has obtained the product RZ880 that molecular formula is shown below:

The preparation of embodiment 16:RZ881

1) preparation of intermediate (19): the method with reference to embodiment 2 prepares;

2) preparation of RZ881

Get geldanamycin (70mg), add intermediate (19) 285mg, add methylene chloride/methyl alcohol of triethylamine (3.0mL) (30/10mL), stirring at room reaction 4day, the system color is purple.Stopped reaction, remove solvent under reduced pressure, the silica gel column chromatography (eluent: methylene chloride/methanol=500/15), obtain purple solid (27mg, yield approximately 29%) of purifying.

1H-NMR(400MHz,CDCl3)δ:9.15(s,1H),7.37-7.26(m,5H),7.22(s,1H),6.94(d,J=12.0Hz,1H),6.70-6.62(m,1H),6.58(t,J=11.2Hz,1H),5.91-5.81(m,2H),5.16(s,1H),4.85(t,J=5.6Hz,1H),4.85-4.66(br?s,2H),4.65(t,J=5.6Hz,1H),4.38(d,J=5.6Hz,1H),4.31(d,J=9.6Hz,1H),3.76-3.67(m,1H),367-3.50(m,3H),3.47-3.39(m,1H),3.37-3.29(m,2H),3.35(s,3H),3.27(s,3H),2.78-2.68(m,1H),2.64(d,J=13.6Hz,1H),2.44-2.33(m,1H),2.02(s,3H),1.89-1.66(m,5H),1.79(s,3H),1.03-0.92(m,6H).

13C-NMR(100MHz,CDCl3)δ:184.2,180.3,168.4,158.7,156.4,145.6,141.3,139.4,135.9,135.2,133.9,133.1,128.8,127.6,127.5,127.0,126.7,109.0,108.9,82.0,81.6,81.4,72.7,57.2,56.8,44.7,43.5,37.7,35.2,34.4,32.4,31.1,28.7,23.0,12.9,12.7,12.5.

ESI(m/z):758.3(M+Na+)。

Proof has obtained the product RZ881 that molecular formula is shown below:

The preparation of embodiment 17:RZ882

1) preparation of intermediate (20): the method with reference to embodiment 2 prepares;

2) preparation of RZ882

Get geldanamycin (550mg), add intermediate (20) 1.59g, add methylene chloride/methyl alcohol of triethylamine (5.0mL) (50/5mL), stirring at room reaction 4day, the system color is purple.Stopped reaction, remove solvent under reduced pressure, the silica gel column chromatography (eluent: methylene chloride/methanol=500/15), obtain purple solid (266mg, yield approximately 39%) of purifying.

1H-NMR(400MHz,CDCl3)δ:9.14(s,1H),7.19(s,1H),6.94(d,J=11.2Hz,1H),6.89-6.82(m,1H),6.58(t,J=11.6Hz,1H),5.91-5.80(m,2H),5.32-5.22(m,2H),5.15(s,1H),4.86(br?s,2H),4.30(d,J=10.0Hz,1H),4.18(br?s,1H),3.80-3.68(m,1H),3.68-3.46(m,8H),3.46-3.40(m,1H),3.36(s,3H),3.26(s,3H),2.83-2.70(m,1H),2.62(d,J=13.2Hz,1H),2.45-2.32(m,1H),2.02(s,3H),1.80(s,3H),1.84-1.68(m,3H),1.03-0.92(m,6H).

13C-NMR(100MHz,CDCl3)δ:184.4,180.1,168.4,159.1,156.6,146.1,141.2,136.0,135.0,133.5,133.3,127.1,126.6,109.2,108.7,81.8,81.42,81.37,72.6,57.1,56.8,47.5,45.0,42.2,39.8,34.9,34.2,32.4,28.5,22.8,12.8,12.6,12.5.

ESI(m/z):658.3(M-Cl)+。

Proof has obtained the product RZ882 that molecular formula is shown below:

The preparation of embodiment 18:RZ883

Get geldanamycin (240mg), be dissolved in methylene dichloride (30mL), then add the N of direct purchase, two (2-amino-ethyl) 1，2-diaminoethane (440mg) of N-, stirring at room reaction.The system color is purple.Reaction 2day.Then add (Boc) 2O (1.0g), stirring at room 2day.Stopped reaction, remove solvent under reduced pressure, the silica gel column chromatography (eluent: methylene chloride/methanol=500/7), obtain purple solid (230mg, yield approximately 61%) of purifying.

1H-NMR(400MHz,CDCl3)δ:9.21(s,1H),7.29(s,1H),6.96(d,J=11.6Hz,1H),6.58(t,J=11.2Hz,1H),5.93-5.81(m,2H),5.37-5.2l(m,2H),5.17(s,1H),4.88(br?s,2H),4.34(br?s,1H),4.30(d,J=10.0Hz,1H),3.69-3.54(m,2H),3.48-3.35(m,2H),3.35(s,3H),3.26(s,3H),3.24-3.04(m,4H),2.82-2.69(m,3H),2.69-2.54(m,5H),2.48-2.36(m,1H),2.02(s,3H),1.79(s,3H),1.79-1.69(m,2H),1.46-1.34(m,1H),1.38(s,18H),1.02-0.92(m,6H).

13C-NMR(100MHz,CDCl3)δ:184.3,180.5,168.4,156.3,156.2,144.8,141.7,136.0,135.0,133.8,132.9,127.1,126.6,108.9,108.4,81.7,81.6,81.4,79.4,72.8,57.2,56.8,53.4,52.8,42.2,38.7,35.2,34.4,32.4,28.5,23.0,12.9,12.7,12.5.

ESI(m/z):875.9(M+H+)。

Proof has obtained the product RZ883 that molecular formula is shown below:

The preparation of embodiment 19:RZ864

1) preparation of intermediate (21):

Substrate 5 (1eq) is dissolved in CH3CN (0.4M), first in backward system, drips DIEA (2eq) and substrate 6 (1.2eq).Then stirred overnight at room temperature.

Aftertreatment: concentrate system adds methylene dichloride again, and the sodium bicarbonate saturated solution is washed, washed.The methylene dichloride strip aqueous, dried over sodium sulfate.Concentrate post and obtained white solid intermediate (21) (70%).TLC：PE/EA=1/2，Rf：0.4。

2) preparation of intermediate (22):

Intermediate (21) 1eq, formalin (10eq) and HCOOH (10eq) are joined in tube sealing, be warming up to 50 ℃ and stir 1 hour.

Aftertreatment: add methylene dichloride, 10% sodium hydroxide solution to wash, washing, methylene dichloride strip aqueous, drying.PE/ acetone=2/1 is crossed post and is obtained white solid intermediate (22) (yield approximately 50%), TLC:PE/Acetone=1/1, Rf:0.4.

3) preparation of intermediate (23):

To newly steam the THF(anhydrous and oxygen-free under nitrogen protection processes) join in reaction flask the ice bath cooling.Then under nitrogen protection, add lithium aluminium hydride (2eq) in batches.Then slowly drip the THF solution of intermediate (22).Reaction system rises to room temperature, continues to stir 1 hour.

Aftertreatment: slowly drip a certain proportion of water and 10%NaOH solution extraction under ice bath and go out, then add the Na2SO4 drying.Concentrated after filtering, obtain intermediate (23) (yield approximately 20%).Directly throw next step.

Extract the method for going out: N g LiAlH4, with N ml water, the NaOH solution of 3N ml10%.

4) preparation of RZ864

Get geldanamycin (280mg), add intermediate (23) 376mg, add methylene chloride/methyl alcohol (30/10mL), stirring at room reaction 3day, the system color is purple.Stopped reaction, remove solvent under reduced pressure, the silica gel column chromatography (eluent: methylene chloride/methanol=500/20,500/25), obtain purple solid (160mg, yield approximately 42%) of purifying.

1H?NMR（CDCl3,400MHz）δ9.23(s,1H),7.28-7.19(m,2H),6.96(d,J=11.2Hz,1H),6.58(t,J=11.2Hz,1H),6.11-5.75(m,2H),5.30(s,1H),5.17(s,1H),5.13-4.85(m,2H),4.51(s,br,1H),4.31(d,J=10.0Hz,1H),3.79-3.54(m,2H),3.53-3.40(m,2H),3.40-3.32(m,3H),3.3-13.18(m,3H),2.91-2.48(m,4H),2.44(t,J=11.2Hz,1H),2.37-2.14(m,5H),2.13-1.89(m,5H),1.88-1.56(m,16H),1.18-0.91(m,6H).

13C-NMR(100MHz,CDCl3)δ:184.2,180.1,168.5,156.4,145.6,141.5,135.8,135.0,133.9,132.8,127.0,126.6,108.8,108.3,81.6,81.3,72.7.69.8,57.7,57.1,56.8,47.3,46.4,44.5,42.9,37.8,37.7,35.2,34.5,32.8,32.4,30.7,28.5,23.0,12.8,12.6,12.4.

ESI(m/z):753.8(M+H+)。

Proof has obtained the product RZ864 that molecular formula is shown below:

The preparation of embodiment 20:RZ865

1) preparation of intermediate (24):

Substrate 7 (1eq) is dissolved in CH3CN (0.4M), first in backward system, drips DIEA (2eq) and substrate 6(1.2eq).Then stirred overnight at room temperature.

Aftertreatment: concentrate system adds methylene dichloride again, and the sodium bicarbonate saturated solution is washed, washed.The methylene dichloride strip aqueous, dried over sodium sulfate.Concentrate post and obtained white solid intermediate (24) (94%).TLC：PE/EA=2/1，Rf：0.5。

2) preparation of intermediate (26):

By intermediate (25) (1eq), formalin (10eq) and HCOOH (10eq) join in tube sealing, be warming up to 50 ℃ and stir 1 hour.

Aftertreatment: add methylene dichloride, 10% sodium hydroxide solution to wash, washing, methylene dichloride strip aqueous, drying.PE/Acetone=20/1 crosses post and obtains white solid intermediate (26) (60%), TLC:PE/Acetone=8/1, Rf:0.7.

3) preparation of intermediate (27):

To newly steam the THF(anhydrous and oxygen-free under nitrogen protection processes) join in reaction flask the ice bath cooling.Then under nitrogen protection, add lithium aluminium hydride (LiAlH4) (2eq) in batches.Then slowly drip the THF solution of intermediate (26).Reaction system rises to room temperature, continues to stir 1 hour.

Aftertreatment: slowly drip a certain proportion of water and 10%NaOH solution extraction under ice bath and go out, then add the Na2SO4 drying.Concentrated after filtering, obtain intermediate (27).Directly throw next step.

1H-NMR(400MHz,CDCl3)δ:2.68(t,J=6.0Hz,2H),2.45(t,J=6.0Hz,2H),2.18(s,3H),2.05(br?s,4H),1.70-1.50(m,11H).

4) preparation of RZ865

Get geldanamycin (280mg), add intermediate (27) 850mg, add methylene chloride (50mL), stirring at room reaction 3day, the system color is purple.Stopped reaction, remove solvent under reduced pressure, the silica gel column chromatography (eluent: methylene chloride/methanol=500/10,500/15), obtain purple solid (107mg, yield approximately 29%) of purifying.

1H?NMR（CDCl3,400MHz）δ:9.22(s,1H),7.34(s,br,1H),7.23(s,1H),6.97(d,J=11.6Hz,1H),6.59(t,J=11.4Hz,1H);6.03-5.79(m,3H),5.17(s,1H),5.06(s,2H),4.50(s,br,1H),4.31(d,J=10.0Hz,1H),3.81-3.54(m,2H),3.53-3.42(m,2H),3.37(s,3H),3.26(s,3H),2.91-2.57(m,6H),2.56-2.38(m,1H),2.38-1.94(m,9H),1.93-1.55(m,16H),1.11-0.91(m,6H).

13C-NMR(100MHz,CDCl3)δ:184.6,179.8,168.4,156.4,145.8,141.2,135.8,135.0,133.8,132.8,126.9,126.5,108.9,81.6,81.3,72.6,57.0,56.7,42.8,40.9,38.6,36.6,35.1,34.4,32.3,28.4,22.9,12.7,12.6,12.3.

ESI(m/z):737.4(M+H+)。

Proof has obtained the product RZ865 that molecular formula is shown below:

The preparation of embodiment 21:RZ884

1) preparation of intermediate (28): the method with reference to embodiment 20 prepares

2) preparation of RZ884

Get geldanamycin (245mg), add intermediate (28) (410mg), add methylene chloride (20mL), stirring at room reaction 3day, the system color is purple.Stopped reaction, remove solvent under reduced pressure, the silica gel column chromatography (eluent: methylene chloride/methanol=500/20,500/25), obtain purple solid (240mg, yield approximately 72%) of purifying.

1H-NMR(400MHz,CDCl3)δ:9.23(s,1H),7.36-7.21(m,1H),7.25(s,1H),6.96(d,J=11.6Hz,1H),6.58(t,J=11.6Hz,1H),5.92(d,J=9.2Hz,1H),5.89-5.77(m,2H),5.18(s,1H),5.11(dd,J=17.2,1.2Hz,1H),4.99(d,J=10.0Hz,1H),4.9-4.62(br?s,2H),4.59-4.48(m,1H),4.31(d,J=10.0Hz,1H),3.64-3.53(m,2H),3.48-3.42(m,1H),3.40-3.29(m,1H),3.36(s,3H),3.29-3.17(m,2H),3.27(s,3H),2.89(t,J=6.0Hz,2H),2.78-2.68(m,1H),2.65(d,J=14.0Hz,1H),2.49-2.39(m,1H),2.14-2.06(m,3H),2.02(s,3H),1.84-1.61(m,15H),1.80(s,3H),1.00(d,J=7.2Hz,3H),0.95(d,J=6.8Hz,3H).

13C-NMR(100MHz,CDCl3)δ:184.2,180.0,168.5,156.4,145.4,141.6,138.6,135.7,135.1,133.9,132.8,126.9,126.6,115.6,108.8,108.1,81.6,81.4,72.6,57.1,56.8,55.3,50.6,45.4,44.1,40.2,36.7,35.2,34.5,32.4,29.7,28.4,23.0,12.8,12.6,12.4.

ESI(m/z):763.8(M+H+)。

Proof has obtained the product RZ884 that molecular formula is shown below:

The preparation of embodiment 22:RZ885

1) preparation of intermediate (29): the method with reference to embodiment 20 prepares;

2) preparation of RZ885

Get geldanamycin (335mg), add intermediate (29) 680mg, add methylene chloride (15mL), stirring at room reaction 2day, the system color is purple.Stopped reaction, remove solvent under reduced pressure, the silica gel column chromatography (eluent: DCM/MeOH=500/1), obtain purple solid (470mg, yield approximately 96%) of purifying.

1H-NMR(400MHz,CDCl3)δ:9.20(s,1H),7.32-7.26(m,2H),7.25(s,1H),7.21-7.15(m,2H),7.13-7.06(m,2H),6.94(d,J=12.0Hz,1H),6.58(t,J=11.2Hz,1H),5.93-5.80(m,2H),5.16(s,1H),4.96-4.70(br?s,2H),4.50-4.40(m,1H),4.29(d,J=10.0Hz,1H),3.87-3.74(m,2H),3.55-3.47(m,1H),3.43-3.36(m,1H),3.32(s,3H),3.28-3.18(m,1H),3.26(s,3H),3.12-3.01(m,1H),3.00-2.93(m,2H),2.76-2.65(m,1H),2.45(d,J=13.6Hz,1H),2.20-2.08(m,4H),2.03(s,3H),1.85-1.73(m,6H),1.78(s,3H),1.71-1.51(m,9H),0.98(d,J=6.8Hz,3H),0.64(d,J=6.4Hz,3H).

13C-NMR(100MHz,CDCl3)δ:184.0,180.0,168.5,156.4,145.0,142.3,141.6,135.7,135.1,133.9,132.7,128.2,127.6,126.9,126.7,108.7,107.9,81.7,81.6,81.4,72.6,57.1,56.7,55.7,53.2,48.0,44.5,39.9,36.7,35.1,34.4,32.3,29.7,28.1,22.8,12.8,12.7,12.3.

ESI(m/z):813.9(M+H+)。

Proof has obtained the product RZ885 that molecular formula is shown below:

The preparation of embodiment 23:RZ886

1) preparation of intermediate (30): the method with reference to embodiment 20 prepares;

2) preparation of RZ886

Get geldanamycin (250mg), add intermediate (30) 597mg, add methylene chloride (10mL), stirring at room reaction 2day, the system color is purple.Stopped reaction, remove solvent under reduced pressure, the silica gel column chromatography (eluent: methylene chloride/methanol=500/1), obtain purple solid (380mg, yield approximately 99%) of purifying.

1H-NMR(400MHz,CDCl3)δ:9.10(s,1H),7.75-7.64(m,4H),7.43-7.31(m,3H),7.21(s,1H),7.12-7.05(m,1H),6.90(d,J=12.0Hz,1H),6.57(t,J=11.2Hz,1H),5.90-5.80(m,2H),5.14(s,H),4.96-4.71(br?s,2H),4.36-4.29(m,1H),4.26(d,J=10.0Hz,1H),4.04-3.85(m,2H),3.46-3.39(m,1H),3.34-3.18(m,2H),3.25(s,3H),3.24(s,3H),3.17-2.95(m,3H),2.71-2.61(m,1H),2.31(d,J=13.6Hz,1H),2.18-2.10(m,3H),2.10-1.98(m,1H),2.04(s,3H),1.92-1.80(m,6H),1.76(s,3H),1.74-1.32(m,9H),0.95(d,J=7.2Hz,3H),0.42(d,J=6.8Hz,3H).

13C-NMR(100MHz,CDCl3)δ:184.0,179.9,168.4,156.3,144.8,141.4,139.9,135.8,135.1,134.0,133.4,132.7,132.6,127.9,127.7,127.6,126.8,126.6,126.2,126.1,125.9,125.4,108.7,107.8,81.7,81.5,81.4,72.5,57.1,56.6,55.8,53.4,48.1,44.6,40.0,36.7,34.8,34.2,32.3,29.8,27.9,22.4,12.7,12.7,12.3.

ESI(m/z):864.0(M+H+)。

Proof has obtained the product RZ886 that molecular formula is shown below:

The preparation of embodiment 24:RZ887

1) preparation of intermediate (31): the method with reference to embodiment 20 prepares;

2) preparation of RZ887

Get geldanamycin (250mg), add intermediate (31) 532mg, add methylene chloride (10mL), stirring at room reaction 3day, the system color is purple.Stopped reaction, remove solvent under reduced pressure, the silica gel column chromatography (eluent: methylene chloride/methanol=500/1), obtain purple solid (360mg, yield approximately 98%) of purifying.

1H-NMR(400MHz,CDCl3)δ:9.10(s,1H),7.52(s,1H),7.21-7.14(m,1H),7.10(s,1H),7.08-7.02(m,2H),6.98-6.88(m,2H),6.58(t,J=11.2Hz,1H),5.93-5.80(m,2H),5.16(s,1H),5.00-4.70(br?s,2H),4.54-4.42(m,1H),4.29(d,J=10.0Hz,1H),3.84-3.68(m,2H),3.56-3.47(m,1H),3.43-3.35(m,1H),3.33(s,3H),3.28-3.16(m,1H),3.25(s,3H),3.14-3.01(m,1H),3.01-2.90(m,2H),2.78-2.65(m,1H),2.46(d,J=13.6Hz,1H),2.22(s,3H),2.21-2.07(m,4H),2.03(s,3H),1.87-1.72(m,6H),1.78(s,3H),1.73-1.47(m,9H),0.98(d,J=7.2Hz,3H),0.63(d,J=6.8Hz,3H).

13C-NMR(100MHz,CDCl3)δ:184.0,180.0,168.5,156.3,144.9,142.2,141.6,137.8,135.8,135.1,134.0,132.8,128.4,128.1,127.5,126.9,126.7,124.6,108.7,107.8,81.8,81.7,81.4,72,7,57.1,56.8,55.7,53.2,47.9,44.5,39.9,36.7,35.1,34.4,32.4,29.8,28.1,22.7,21.5,12.8,12.7,12.4.

ESI(m/z):828.0(M+H+)。

Proof has obtained the product RZ887 that molecular formula is shown below:

The preparation of embodiment 25:RZ888

1) preparation of intermediate (32): the method with reference to embodiment 20 prepares;

2) preparation of RZ888

Get geldanamycin (250mg), add intermediate (32) 550mg, add methylene chloride (10mL), stirring at room reaction 4day, the system color is purple.Stopped reaction, remove solvent under reduced pressure, the silica gel column chromatography (eluent: methylene chloride/methanol=500/1), obtain purple solid (270mg, yield approximately 76%) of purifying.

1H-NMR(400MHz,CDCl3)δ:9.24(s,1H),7.40(br?s,1H),7.25(s,1H),6.96(d,J=11.6Hz,1H),6.59(t,J=11.6Hz,1H),5.93(d,J=9.6Hz,1H),5.85(t,J=10.8Hz,1H),5.18(s,1H),5.17-5.14(m,1H),4.76(br?s,2H),4.60(brs,1H),4.31(d,J=10.0Hz,1H),3.62-3.52(m,2H),3.49-3.43(m,1H),3.39-3.30(m,1H),3.36(s,3H),3.27(s,3H),3.25-3.18(m,2H),2.86(t,J=6.0Hz,2H),2.79-2.70(m,1H),2.66(d,J=13.6Hz,1H),2.50-2.38(m,1H),2.10(br?s,3H),2.03(s,3H),1.80(s,3H),1.80-1.68(m,9H),1.68-1.54(m,12H),1.00(d,J=6.8Hz,3H),0.95(d,J=6.0Hz,3H).

13C-NMR(100MHz,CDCl3)δ:184.1,179.8,168.4,156.4,145.5,141.5,135.7,135.0,133.9,132.7,132.0,126.8,126.6,124.8,108.8,108.0,81.6,81.3,72.6,57.0,56.7,55.2,45.2,45.0,44.3,40.2,36.7,35.2,34.5,32.3,29.7,28.4,25.9,23.0,17.9,12.8,12.6,12.3.

ESI(m/z):791.8(M+H+)。

Proof has obtained the product RZ888 that molecular formula is shown below:

The preparation of embodiment 26:RZ889

1) preparation of intermediate (33): the method with reference to embodiment 20 prepares;

2) preparation of RZ889

Get geldanamycin (260mg), add intermediate (33) 1.0g, add methylene chloride (30mL), stirring at room reaction 3day, the system color is purple.Stopped reaction, remove solvent under reduced pressure, the silica gel column chromatography (eluent: methylene chloride/methanol=500/3,500/8), obtain purple solid (390mg, yield approximately 99%) of purifying.

1H-NMR(400MHz,CDCl3)δ:9.20(s,1H),7.26(s,1H),7.23(d,J=8.8Hz,2H),7.16(d,J=8.4Hz,2H),7.05-6.98(m,1H),6.95(d,J=11.6Hz,1H),6.58(t,J=11.2Hz,1H),5.93-5.81(m,2H),5.17(s,1H),4.77(br?s,2H),4.42(brs1H),4.30(d,J=9.6Hz,1H),3.86-3.67(m,2H),3.56-3.48(m,1H),3.43-3.37(m,1H),3.33(s,3H),3.26(s,3H),3.28-3.18(m,1H),3.18-3.07(m,1H),3.03-2.89(m,2H),2.76-2.66(m,1H),2.50(d,J=13.6Hz,1H),2.18(d,J=11.2Hz,1H),2.16-2.08(m,3H),2.03(s,3H),1.85-1.72(m,6H),1.79(s,3H),1.73-1.52(m,9H),0.98(d,J=6.8Hz,3H),0.64(d,J=6.4Hz,3H).

13C-NMR(100MHz,CDCl3)δ:183.9,179.9,168.3,156.4,144.7,141.5,140.9,135.7,134.9,133.7,132.7,132.1,128.7,128.2,126.8,126.5,108.4,107.8,81.4,81.2,72.5,56.9,56.6,55.6,52.4,48.0,44.4,39.8,36.5,34.9,34.2,32.2,29.5,28.0,22.4,12.7,12.6,12.3.

ESI(m/z):847.7(M+H+)。

Proof has obtained the product RZ889 that molecular formula is shown below:

The preparation of embodiment 27:RZ890

1) preparation of intermediate (34): the method with reference to embodiment 20 prepares;

2) preparation of RZ890

Get geldanamycin (260mg), add intermediate (34) 1.2g, add methylene chloride (30mL), stirring at room reaction 4day, the system color is purple.Stopped reaction, remove solvent under reduced pressure, the silica gel column chromatography (eluent: methylene chloride/methanol=500/0,500/5), obtain purple solid (400mg, yield approximately 97%) of purifying.

1H-NMR(400MHz,CDCl3)δ:9.19(s,1H),7.27(s,1H),7.26-7.00(m,5H)6.94(d,J=11.2Hz,1H),6.58(t,J=11.2Hz,1H),5.94-5.80(m,2H),5.16(s,1H),4.81(br?s,2H),4.41(br?s1H),4.29(d,J=10.0Hz,1H),3.89-3.65(m,2H),3.56-3.48(m,1H),3.43-3.36(m,1H),3.30(s,3H),3.26(s,3H),3.26-3.17(m,1H),3.17-3.05(m,1H),3.05-2.89(m,2H),2.80-2.65(m,1H),2.49(d,J=13.6Hz,1H),2.23-2.05(m,4H),2.03(s,3H),1.86-1.74(m,6H),1.79(s,3H),1.74-1.50(m,9H),0.98(d,J=7.2Hz,3H),0.63(d,J=6.4Hz,3H).

13C-NMR(100MHz,CDCl3)δ:183.7,180.0,168.3,156.4,144.9,144.5,141.4,135.6,134.8,133.7,132.7,130.2,129.62,129.58,126.7,126.5,108.6,107.8,81.4,81.2,72.4,56.9,56.6,55.6,52.6,48.0,44.2,39.8,36.5,34.8,34.2,32.2,29.5,28.0,22.5,12.7,12.6,12.2.

ESI(m/z):893.7(M+H+)。

Proof has obtained the product RZ890 that molecular formula is shown below:

The preparation of embodiment 28:RZ891

1) preparation of intermediate (35): the method with reference to embodiment 20 prepares;

2) preparation of RZ891

Get geldanamycin (260mg), add intermediate (35) 900mg, add methylene chloride (30mL), stirring at room reaction 4day, the system color is purple.Stopped reaction, remove solvent under reduced pressure, the silica gel column chromatography (eluent: methylene chloride/methanol=500/5,500/10), obtain purple solid (320mg, yield approximately 80%) of purifying.

1H-NMR(400MHz,CDCl3)δ:9.16(s,1H),8.19(d,J=8.0Hz,1H),7.74(d,J=7.6Hz,1H),7.67(d,J=8.0Hz,1H),7.57(d,J=7.2Hz,1H),7.46-7.29(m,3H),7.20(s,1H),7.00-6.88(m,2H),6.58(t,J=11.2Hz,1H),5.90-5.80(m,2H),5.14(s,1H),4.76(br?s,2H),4.44-4.30(m,2H),4.30-4.19(m,2H),3.46-3.39(m,1H),3.33-3.25(m,1H),3.27(s,3H),3.25(s,3H),3.09-2.89(m,2H),2.87-2.77(m,1H),2.72-2.62(m,1H),2.61-2.52(m,1H),2.25-2.13(m,4H),2.04(s,3H),2.00-1.89(m,6H),1.87-1.77(m,1H),1.77(s,3H),1.74-1.64(m,6H),1.55-1.33(m,3H),0.96(d,J=6.8Hz,3H),0.35(d,J=6.4Hz,3H).

13C-NMR(100MHz,CDCl3)δ:183.8,179.6,168.,156.4,136.5,144.6,141.4,135.7,135.0,133.8,133.6,132.7,131.5,128.6,127.7,126.8,126.6,126.3,125.8,125.6,125.2,123.7,108.5,107.4,81.6,81.4,81.3,72.4,57.0,56.6,56.1,50.7,47.0,44.7,39.3,36.6,34.7,34.1,32.2,29.7,27.7,22.3,12.7,12.6,12.2.

ESI(m/z):863.8(M+H+)。

Proof has obtained the product RZ891 that molecular formula is shown below:

The preparation of embodiment 29:RZ892

1) preparation of intermediate (36): the method with reference to embodiment 20 prepares;

2) preparation of RZ892

Get geldanamycin (280mg), add intermediate (36) 760mg, add methylene chloride (20mL), stirring at room reaction 5day, the system color is purple.Stopped reaction, remove solvent under reduced pressure, the silica gel column chromatography (eluent: methylene chloride/methanol=500/1,500/7), obtain purple solid (330mg, yield approximately 87%) of purifying.

1H-NMR(400MHz,CDCl3)δ:9.21(s,1H),7.24(s,1H),7.13-7.04(m,1H),6.95(d,J=11.6Hz,1H),6.58(t,J=11.6Hz,1H),5.92(d,J=9.6Hz,1H),5.85(t,J=10.4Hz,1H),5.18(s,1H),4.83(br?s,2H),4.96(br?s,1H),4.30(d,J=10.0Hz,1H),3.73-3.62(m,1H),3.62-3.53(m,1H),3.51-3.38(m,4H),3.36(s,3H),3.26(s,3H),3.12-3.02(m,2H),2.79-2.70(m,1H),2.67(d,J=14.0Hz,1H),2.52-2.39(m,1H),2.18(s,1H),2.11(br?s,3H),2.02(s,3H),1.90-1.76(m,8H),1.80(s,3H),1.76-1.55(m6H),1.05-0.91(m,6H).

13C-NMR(100MHz,CDCl3)δ:184.0,180.0,168.3,156.4,145.2,141.3,135.7,134.9,133.7,132.8,126.8,126.5,108.6,108.2,81.9,81.5,81.4,81.2,72.8,72.5,56.9,56.7,55.3,42.8,42.5,40.2,36.5,35.0,34.4,33.8,32.2,29.6,28.3,22.9,12.7,12.6,12.3.

ESI(m/z):761.8(M+H+)。

Proof has obtained the product RZ892 that molecular formula is shown below:

The preparation of embodiment 30:RZ893

1) preparation of intermediate (37): the method with reference to embodiment 20 prepares;

2) preparation of RZ893

Get geldanamycin (380mg), add intermediate (37) 920mg, add methylene chloride (15mL), stirring at room reaction 5day, the system color is purple.Stopped reaction, remove solvent under reduced pressure, the silica gel column chromatography (eluent: methylene chloride/methanol=500/7,500/10), obtain purple solid (520mg, yield approximately 87%) of purifying.

1H-NMR(400MHz,CDCl3)δ:9.18(s,1H),7.52-7.37(m,4H),7.04-6.89(m,2H),6.57(t,J=11.2Hz,1H),5.92-5.80(m,2H),5.16(s,1H),4.86(br?s,2H),4.38(br?s,1H),4.28(d,J=10.0Hz,1H),3.97-3.75(m,2H),3.55-3.46(m,1H),3.43-3.35(m,1H),3.31(s,3H),3.31-3.19(m,1H),3.25(s,3H),3.19-3.08(m,1H),3.06-2.91(m,2H),2.77-2.63(m,1H),2.49(d,J=13.6Hz,1H),2.22-2.08(m,4H),2.02(s,3H),1.85-1.73(m,3H),1.79(s,3H),1.78(s,3H),1.74-1.56(m,10H),0.97(d,J=6.8Hz,3H),0.58(d,J=6.8Hz,3H).

13C-NMR(100MHz,CDCl3)δ:184.0,180.1,168.4,156.4,146.9,144.8,141.5,135.7,134.9,133.7,132.8,128.8(q,2JCF=32Hz),127.5,126.9,126.6,125.1(q,3JCF=4Hz),124.2(q,1JCF=270Hz),108.5,108.0,81.5,81.4,81.2,72.6,57.0,56.6,55.8,52.8,48.3,44.5,39.9,36.5,34.9,34.2,32.3,29.6,28.2,22.4,12.8,12.6,12.3.

ESI(m/z):881.9(M+H+)。

Proof has obtained the product RZ893 that molecular formula is shown below:

The preparation of embodiment 31:RZ896

1) preparation of intermediate (38): the method with reference to embodiment 19 prepares;

2) preparation of RZ896

Get geldanamycin (1.50g), add intermediate (38) 2.80g, add methylene chloride (40mL), stirring at room reaction 4day, the system color is purple.Stopped reaction, remove solvent under reduced pressure, the silica gel column chromatography (eluent: methylene chloride/methanol=500/7,500/10), obtain purple solid (1.53g, yield approximately 72%) of purifying.

1H-NMR(400MHz,CDCl3)δ:9.22(s,1H),7.24(s,1H),6.95(d,J=11.6Hz,1H),6.58(t,J=11.6Hz,1H),5.95-5.75(m,3H),5.17(s,1H),5.12(d,J=18.0Hz,1H),5.00(d,J=10.0Hz,1H),4.87(br?s,2H),4.49(br?s,1H),4.30(d,J=10.0Hz,1H),3.65-3.51(m,2H),3.50-3.40(m,1H),3.40-3.19(m,3H),3.35(s,3H),3.26(s,3H),2.93-2.85(m,2H),2.78-2.68(m,1H),2.64(d,J=13.2Hz,1H),2.49-2.37(m,1H),2.29(s,2H),2.02(s,3H),1.88-1.58(m,15H),1.79(s,3H),1.51(s,2H),0.99(d,J=6.8Hz,3H),0.94(d,J=6.4Hz,3H).

13C-NMR(100MHz,CDCl3)δ:183.9,179.8,168.3,156.4,145.1,141.4,138.0,135.6,134.7,133.5,132.7,126.8,126.4,115.7,108.5,107.9,81.4,81.24,81.16,72.5,69.4,58.4,56.8,56.6,50.6,47.5,45.6,44.2,44.1,43.8,38.8,35.0,32.2,30.6,28.3,23.4,22.8,12.7,12.5,12.3.

ESI(m/z):779.8(M+H+)。

Proof has obtained the product RZ896 that molecular formula is shown below:

The preparation of embodiment 32:RZ897

1) preparation of intermediate (39): the method with reference to embodiment 19 prepares;

2) preparation of RZ897

Get geldanamycin (1.10g), add intermediate (39) 1.20g, add methylene chloride (40mL), stirring at room reaction 4day, the system color is purple.Stopped reaction, remove solvent under reduced pressure, the silica gel column chromatography (eluent: methylene chloride/methanol=500/5,500/10), obtain purple solid (1.03g, yield approximately 62%) of purifying.

1H-NMR(400MHz,CDCl3)δ:9.19(s,1H),7.28(s,1H),7.18(t,J=7.6Hz,2H),7.15-7.08(m,1H),7.07-700(m,1H),6.94(d,J=12.0Hz,1H),6.58(t,J=11.6Hz,1H),5.93-5.80(m,2H),5.17(s,1H),4.80(br?s,2H),4.42(br?s,1H),4.29(d,J=10.0Hz,1H),3.87-3.76(m,2H),3.56-3.45(m,1H),3.43-3.36(m,1H),3.33(s,3H),3.26(s,3H),3.26-3.18(m,1H),3.14-3.02(m,1H),3.01-2.92(m,2H),2.76-2.64(m,1H),2.50-2.40(m,1H),2.32(br?s,2H),2.21-2.08(m,1H),2.03(s,3H),1.78(s,3H),1.78-1.57(m,18H),0.98(d,J=7.2Hz,3H),0.64(d,J=6.4Hz,3H).

13C-NMR(100MHz,CDCl3)δ:183.9,179.9,168.4,156.4,144.8,141.7,141.5,135.7,134.9,133.7,132.7,128.2,127.4,126.9,126.7,126.6,108.5,107.8,81.4,81.2,77.5,77.4,77.1,76.8,72.5,69.6,58.9,57.0,56.6,53.4,48.2,47.2,44.3,38.7,35.0,34.9,34.2,32.2,30.6,28.0,12.7,12.6.

ESI(m/z):829.8(M+H+)。

Proof has obtained the product RZ897 that molecular formula is shown below:

The preparation of embodiment 33:RZ898

1) preparation of intermediate (40): the method with reference to embodiment 19 prepares;

2) preparation of RZ898

Get geldanamycin (1.10g), add intermediate (40) 1.30g, add methylene chloride (40mL), stirring at room reaction 4day, the system color is purple.Stopped reaction, remove solvent under reduced pressure, the silica gel column chromatography (eluent: methylene chloride/methanol=500/5,500/10), obtain purple solid (950mg, yield approximately 54%) of purifying.

1H-NMR(400MHz,CDCl3)δ:9.09(s,1H),7.75-7.63(m,4H),7.43-7.32(m,3H),7.22(s,1H),706-6.97(m,1H),6.90(d,J=11.6Hz,1H),6.58(t,J=11.2Hz,1H),5.89-5.78(m,2H),5.15(s,1H),4.79(br?s,2H),4.36-4.21(m,2H),4.06-3.87(m,2H),3.47-3.38(m,1H),3.34-3.19(m,2H),3.26(s,3H),3.25(s,3H),3.18-2.95(m,3H),2.72-2.61(m,1H),2.38-2.26(m,3H),2.10-1.91(m,2H),2.04(s,3H),1.87-1.47(m,16H),0.95(d,J=6.8Hz,3H),0.43(d,J=6.4Hz,3H).

13C-NMR(100MHz,CDCl3)δ:184.0,179.9,168.4,156.4,144.7,141.3,139.4,135.8,135.0,133.9,133.4,132.71,132.66,128.0,127.7,127.6,126.9,126.6,126.2,126.0,125.9,125.5,108.6,107.9,81.7,81.5,81.3,72.5,69.8,59.1,57.1,56.6,53.7,48.4,47.4,44.5,44.4,38.9,38.8,35.2,34.8,33.9,32.3,32.0,30.8,28.0,12.8,12.7,12.4.

ESI(m/z):879.8(M+H+)。

Proof has obtained the product RZ898 that molecular formula is shown below:

The preparation of embodiment 34:RZ899

1) preparation of intermediate (41): the method with reference to embodiment 19 prepares;

2) preparation of RZ899

Get geldanamycin (500mg), add intermediate (41) 920mg, add methylene chloride (30mL), stirring at room reaction 4day, the system color is purple.Stopped reaction, remove solvent under reduced pressure, the silica gel column chromatography (eluent: methylene chloride/methanol=500/3,500/5), obtain purple solid (480mg, yield approximately 67%) of purifying.

1H-NMR(400MHz,CDCl3)δ:9.22(s,1H),7.34(br?s,1H),7.25(s,1H),6.95(d,J=11.6Hz,1H),6.58(t,J=11.6Hz,1H),5.92(d,J=9.6Hz,1H),5.85(t,J=10.8Hz,1H),5.29(s,1H),5.20-5.12(m,1H),5.18(s,1H),4.84(br?s,1H),4.56(br?s,1H),4.30(d,J=10.0Hz,1H),3.64-3.51(m,2H),3.50-3.40(m,1H),3.40-3.30(m,1H),3.36(s,3H),3.26(s,3H),3.26-3.15(m,2H),2.91-2.81(m,2H),2.79-2.59(m,2H),2.48-2.37(m,1H),2.29(br?s,2H),2.02(s,3H),1.79(s,3H),1.79-1.53(m,25H),0.99(d,J=7.2Hz,3H),0.94(d,J=6.4Hz,3H).

13C-NMR(100MHz,CDCl3)δ:184.1,179.9,168.5,156.4,145.4,141.5,135.7,135.0,133.8,132.7,132.4,126.9,126.6,124.2,108.7,108.0,81.6,81.3,72.6,69.7,58.5,57.0,56.7,47.6,45.5,45.3,44.4,44.3,44.1,39.0,35.1,34.5,32.3,30.7,28.4,25.9,23.0,18.0,12.8,12.6,12.4.

ESI(m/z):807.8(M+H+)。

Proof has obtained the product RZ899 that molecular formula is shown below:

The preparation of embodiment 35:RZ900

1) preparation of intermediate (42): the method with reference to embodiment 19 prepares;

2) preparation of RZ900

Get geldanamycin (600mg), add intermediate (42) 1.30g, add methylene chloride (40mL), stirring at room reaction 4day, the system color is purple.Stopped reaction, remove solvent under reduced pressure, the silica gel column chromatography (eluent: methylene chloride/methanol=500/3,500/5), obtain purple solid (560mg, yield approximately 61%) of purifying.

1H-NMR(400MHz,CDCl3)δ:9.20(s,1H),7.26(s,1H),7.14-7.00(m,4H),6.98-6.89(m,2H),6.58(t,J=11.6Hz,1H),5.93-5.81(m,2H),5.17(s,1H),4.80(br?s,2H),4.45(br?s,1H),4.29(d,J=10.0Hz,1H),3.85-3.70(m,2H),3.55-3.46(m,1H),3.44-3.63(m,1H),3.33(s,3H),3.26(s,3H),3.26-3.18(m,1H),3.14-3.03(m,1H),3.00-2.92(m,2H),2.76-2.65(m,1H),2.46(d,J=14.0Hz,1H),2.36-2.26(m,2H),2.22(s,3H),2.20-2.11(m,1H),2.03(s,3H),1.79(s,3H),1.79-1.55(m,16H),0.98(d,J=7.2Hz,3H),0.64(d,J=6.4Hz,3H).

13C-NMR(100MHz,CDCl3)δ:183.9,179.9,168.4,156.4,144.7,141.7,141.6,137.8,135.7,135.0,133.8,132.7,128.2,128.1,127.5,126.9,126.6,124.5,108.6,107.8,81.6,81.3,72.6,69.7,58.9,57.0,56.7,53.4,48.2,47.2,44.4,44.3,44.2,38.8,38.7,35.1,35.0,34.3,32.3,30.7,28.1,22.7,21.4,12.8,12.6,12.4.

ESI(m/z):843.9(M+H+)。

Proof has obtained the product RZ900 that molecular formula is shown below:

The preparation of embodiment 36:RZ902

1) preparation of intermediate (43): the method with reference to embodiment 19 prepares;

Get geldanamycin (170mg), add intermediate (43) 440mg, add methylene chloride (20mL), stirring at room reaction 4day, the system color is purple.Stopped reaction, remove solvent under reduced pressure, the silica gel column chromatography (eluent: methylene chloride/methanol=500/5,500/7), obtain purple solid (160mg, yield approximately 59%) of purifying.

1H-NMR(400MHz,CDCl3)δ:9.14(s,1H),8.14(d,J=8.0Hz,1H),7.72(d,J=9.6Hz,1H),7.66(d,J=10.0Hz,1H),7.53(d,J=6.8Hz,1H),7.44-7.27(m,4H),7.18(s,1H),6.97-6.82(m,2H),6.55(t,J=11.2Hz,1H),5.89-5.789(m,2H),5.13(s,1H),5.02(br?s,2H),4.40-4.16(m,4H),3.47-3.37(m,1H),3.33-3.18(m,1H),3.25(s,3H),3.23(s,3H),3.09-2.86(m,2H),2.85-2.50(m,3H),2.34(br?s,2H),2.19(d,J=14.0Hz,1H),2.01(s,3H),1.97-1.45(m,16H),1.79(s,3H),0.92(d,J=6.8Hz,3H),0.32(d,J=6.0Hz,3H).

13C-NMR(100MHz,CDCl3)δ:183.6,179.5,168.2,156.4,144.4,141.3,136.0,135.6,134,7,133.4,132.6,131.4,128.5,127.7,126.8,126.4,126.2,125.8,125.5,125.1,123.5,81.l,81.2,72.4,69.5,59.2,56.8,56.5,51.0,47.5,47.2,44.4,44.2,43.5,40.8,38.1,35.0,34.5,33.9,32.1,30.6,30.4,27.6,22.2,12.6,12.5,12.2.

ESI(m/z):880.0(M+H+)。

Proof has obtained the product RZ902 that molecular formula is shown below:

The preparation of embodiment 37:RZ903

1) preparation of intermediate (44): the method with reference to embodiment 19 prepares;

2) preparation of RZ903

Get geldanamycin (450mg), add intermediate (44) 1.10g, add methylene chloride (50mL), stirring at room reaction 4day, the system color is purple.Stopped reaction, remove solvent under reduced pressure, the silica gel column chromatography (eluent: methylene chloride/methanol=500/5,500/7), obtain purple solid (590mg, yield approximately 84%) of purifying.

1H-NMR(400MHz,CDCl3)δ:9.19(s,1H),7.26(s,1H),7.22(d,J=8.4Hz,2H),7.16(d,J=8.4Hz,2H),6.99-6.89(m,2H),6.58(t,J=11.2Hz,1H),5.92-5.80(m,2H),5.17(s,1H),4.80(br?s,2H),4.37(br?s,1H),4.29(d,J=10.0Hz,1H),3.86-3.68(m,2H),3.56-3.47(m,1H),3.44-3.36(m,1H),3.30(s,3H),3.26(s,3H),3.26-3.18(m,1H),3.18-3.05(m,1H),3.02-2.88(m,2H),2.77-2.66(m,1H),2.50(d,J=13.6Hz,1H),2.32(br?s,2H),2.20-2.08(m,1H),2.03(s,3H),1.78(s,3H),1.78-1.50(m,16H),0.98(d,J=6.8Hz,3H),0.64(d,J=6.8Hz,3H).

13C-NMR(100MHz,CDCl3)δ:184.0,180.1,168.5,156.4,144.7,141.6,140.5,135.8,135.0,133.7,132.7,132.4,128.7,128.4,127.0,126.6,108.6,108.0,81.5,81.2,72.6,69.7,59.0,57.0,56.7,52.8,48.4,47.2,44.4,44.3,44.2,38.8,38.7,35.05,34.96,34.2,32.3,30.7,28.1,22.5,12.8,12.7,12.4.

ESI(m/z):863.8(M+H+)。

Proof has obtained the product RZ903 that molecular formula is shown below:

The preparation of embodiment 38:RZ904

1) preparation of intermediate (45): the method with reference to embodiment 19 prepares;

2) preparation of RZ904

Get geldanamycin (1.0g), add intermediate (45) 1.30g, add methylene chloride (50mL), stirring at room reaction 4day, the system color is purple.Stopped reaction, remove solvent under reduced pressure, the silica gel column chromatography (eluent: methylene chloride/methanol=500/5,500/7), obtain purple solid (840mg, yield approximately 62%) of purifying.

1H-NMR(400MHz,CDCl3)δ:9.14(s,1H),7.20(s,1H),7.17-7.08(m,1H),7.94(d,J=11.2Hz,1H),6.57(t,J=11.2Hz,1H),5.92-5.79(m,2H),5.16(s,1H),4.96(br?s,2H),4.37-4.19(m,2H),3.87-3.50(m,3H),3.47(s,1H),3.45-3.37(m,1H),3.34(s,3H),3.26(s,3H),3.12-2.96(m,2H),2.80-2.67(m,1H),2.62(d,J=12.8Hz,1H),2.47-2.35(m,1H),2.31(br?s,2H),2.01(s,3H),1.90-1.60(m,16H),1.78(s,3H),1.04-0.90(m,6H).

13C-NMR(100MHz,CDCl3)δ:184.9,180.2,168.6,156.,146.0,140.9,136.0,135.0,133.9,132.9,127.2,126.7,109.3,81.8,81.6,81.4,72.7,69.4,57.2,56.9,44.0,35.1,34.8,34.3,32.4,30.6,28.8,23.1,12.9,12.7,12.5.

ESI(m/z):739.8(M+H+)。

Proof has obtained the product RZ904 that molecular formula is shown below:

The preparation of embodiment 39:RZ905

1) preparation of intermediate (46): the method with reference to embodiment 19 prepares;

2) preparation of RZ905

Get geldanamycin (1.0g), add intermediate (46) 2.70g, add methylene chloride (50mL), stirring at room reaction 4day, the system color is purple.Stopped reaction, remove solvent under reduced pressure, the silica gel column chromatography (eluent: methylene chloride/methanol=500/5,500/7), obtain purple solid (850mg, yield approximately 64%) of purifying.

1H-NMR(400MHz,CDCl3)δ:9.20(s,1H),7.24(s,1H),7.22-7.14(m,1H),6.96(d,J=11.2Hz,1H),6.58(t,J=11.6Hz,1H),5.95-5.80(m,2H),5.18(s,1H),4.83(br?s,2H),4.42(br?s,1H),4.31(d,J=10.0Hz,1H),3.69-3.53(m,2H),3.52-3.40(m,2H),3.36(s,3H),3.26(s,3H),2.97-2.84(m,2H),2.80-2.70(m,1H),2.66(d,J=14.0Hz,1H),2.47-2.33(m,1H),2.15-2.03(m,3H),2.02(s,3H),1.80(s,3H),1.80-1.51(m,16H),1.05-0.92(m,6H).

13C-NMR(100MHz,CDCl3)δ:184.4,180.1,168.5,156.2,145.7,141.4,135.8,135.1,134.0,132.8,127.0,126.7,109.0,81.9,81.7,81.4,72.7,57.2,56.9,46.0,42.9,39.4,36.7,35.2,34.6,32.4,29.6,28.5,23.2,12.9,12.7,12.4.

ESI(m/z):723.8(M+H+)。

Proof has obtained the product RZ905 that molecular formula is shown below:

The preparation of embodiment 40 tablets

Get the RZ867 of 20 grams by embodiment 2 preparation, add disintegrating agent cross-linked carboxymethyl cellulose 2.5g, Microcrystalline Cellulose 25g, Magnesium Stearate 2.0g, mix, granulation, compressing tablet, makes 100, obtains.

The bioactive detection of embodiment 41 Ge Erde derivatives

For each derivative to preparing in previous embodiment 1-39 carries out the biological activity checking, the applicant adopts 3 kinds of cell strains to detect 10 μ M growth inhibition ratios of each derivative.

Concrete grammar is as follows:

1 key instrument: Molecular Decvice(ν max); Fisher Scientific company CO2gas incubator; Be inverted opticmicroscope; 96 porocyte culture plates;

2 main agents: MTT tetramethyl-azo azoles indigo plant; Dimethyl sulfoxide (DMSO) (DMSO, analytical pure);

RPMI-1640, DEME substratum; Adopt cell strain: A549, AGS, the above-mentioned cell strain of Hela229(is all purchased from Shanghai Inst. of Life Science, CAS cell resource center)

3 experimental techniques

1) the cell administration is cultivated:

Get 96 porocyte culture plates, every hole inoculated tumour cell suspension 100 μ L(4 * 104/ hole), in 37 ℃, in the 5%CO2 incubator, to cultivate 24 hours, every hole adds the medicine 100 μ L after dilution; The blank group adds nutrient solution 100 μ L.Every group of concentration is established 3 multiple holes.Put 37 ℃, the incubator of 5%CO2 and saturated humidity is cultivated 48h.

2) cytoactive detection:

Take out Tissue Culture Plate before experiment stops, first observe with under inverted microscope, after add MTT working fluid 20 μ L in every hole, final concentration 0.5g/L, put in incubator 4 hours.After end, every hole adds 100 μ l DMSO, treats that the MTT reduzate dissolves fully, on microplate reader, selects take 490nm to measure optical density value (OD value) as detecting ripple, calculates the growth inhibition ratio of cell.

Inhibiting rate=[(blank group OD mean value)-(test group OD mean value)]/(blank group OD mean value) * 100%

Table 4: the growth-inhibiting detected result of geldanamycin derivant 10 μ M to 3 kinds of different clones

In table, A549, AGS and Hela229 represent respectively lung cancer, cancer of the stomach and cervical cancer.

As shown in Table 4, formula (1)-(39) compound has the inhibiting tumour cells effect, and wherein some its restraining effect to tumour cell surpasses control compound RZC02 and RZC03.With entering clinical medicine RZC02, compare,

The anti-lung cancer activity of compound R Z864, RZ865, RZ867, RZ877, RZ878 is higher;

The anti-cancer of the stomach activity of compound R Z865, RZ867, RZ877 is higher;

The anti-cervical cancer activity of compound R Z864, RZ867, RZ869, RZ871, RZ877, RZ879 is higher;

Although the specific embodiment of the present invention has obtained detailed description, it will be understood to those of skill in the art that.According to disclosed all instructions, can carry out various modifications and replacement to those details, these change all within protection scope of the present invention.Four corner of the present invention is provided by claims and any equivalent thereof.

Claims

1. geldanamycin derivant, compound or pharmaceutically acceptable salt thereof as shown in formula I:

Wherein said R is formula (a) or formula (b)

Wherein,

n=1～3；

R2 is H or hydroxyl;

2. geldanamycin derivant according to claim 1, in wherein said R1

The C1-C8 saturated hydrocarbyl is straight chained alkyl, preferred ethyl, octyl group, or

The C1-C8 unsaturated alkyl is allyl group; Or

The C1-C8 saturated hydrocarbyl that the C1-C8-that halogen replaces is saturated or unsaturated alkyl is the halogen replacement, preferably chloroethyl; Or

Saturated or the unsaturated alkyl of the C1-C8-of C3-C6 cycloalkyl substituted is the C3-C6 methyl cycloalkyl, preferably cyclopropyl methyl or cyclohexyl methyl; Or

Substituted phenyl is Trifluoromethoxyphen-l;

Substituted benzyl is the benzyl that fluorine replaces;

n=1～2；

In wherein said R3

3. geldanamycin derivant according to claim 1, be selected from following compound or its salt.

4. geldanamycin derivant according to claim 3, wherein said compound is selected from compound R Z864, RZ865, RZ867, RZ869, RZ871, RZ877, RZ879.

5. a method for preparing compound shown in formula I as claimed in claim 1:

The hydrochloride of formula (a) and geldanamycin stirring at room in the mixing solutions of methylene dichloride and methyl alcohol is reacted to 3-5 days, or

Formula (b) is reacted to 2-5 days with geldanamycin stirring at room in dichloromethane solution,

The stopped reaction ordinary method is concentrated, silica gel column chromatography is purified.

6. a method for preparing the hydrochloride that R as claimed in claim 1 is formula (a):

Wherein said R1 is identical with claim 1.

7. a method for preparing the compound that R as claimed in claim 1 is formula (b):

Wherein said R2, R3 are identical with claim 1.

8. pharmaceutical composition, contain any in compound as claimed in claim 1 or its salt as effective constituent.

9. pharmaceutical composition as claimed in claim 8, wherein also contain pharmaceutically acceptable vehicle.

Any geldanamycin derivant claimed in claim 1 or its salt for the preparation of the treatment tumour medicine in purposes.