CN104341434B

CN104341434B - The rapamycin triazole derivatives replaced and purposes

Info

Publication number: CN104341434B
Application number: CN201410547357.1A
Authority: CN
Inventors: 黄捷; 谢立君; 程元荣; 李邦良; 潘福生; 李夸良; 余辉; 应加银; 杨国新; 金东伟; 郑从燊; 吕裕斌
Original assignee: Fujian Institute of Microbiology
Current assignee: Fujian Institute of Microbiology
Priority date: 2014-10-16
Filing date: 2014-10-16
Publication date: 2016-04-06
Anticipated expiration: 2034-10-16
Also published as: CN104341434A

Abstract

The present invention relates to rapamycin triazole derivatives and the purposes of replacement.Specifically, the present invention relates to compounds of Formula I: or its pharmacologically acceptable salts, solvate, isomer, ester, prodrug, wherein substituent X, R, R ₁with n, there is the implication provided in the description.The compound that the invention still further relates to general formula I is preparing the purposes treated and/or prevented in the medicine of cancer.The compounds of this invention has excellent biologic activity.

Description

The rapamycin triazole derivatives replaced and purposes

Technical field

The invention belongs to medical art, relate to new rapamycin type derivative, its optically active body and pharmacologically acceptable salts thereof, particularly relate to the rapamycin triazole derivatives that a class replaces.The invention still further relates to their preparation method and the pharmaceutical composition containing described compound.The invention still further relates to this derivative for the preparation of the purposes treated and/or prevented in the medicine of cancer.

Technical background

Cancer/malignant tumour serious harm human health, has become a global health problem, the life of the serious threat mankind.2009, WHO explicitly pointed out, and cancer is just becoming the mankind the most fatal " killer ", and the malignant tumour of more than 90% there is no gratifying medicine and measure.Annual whole world cancer patient about 1,000 ten thousand at present, has 7,600,000 people dead; China's pathogenesis of cancer number about 2,000,000,1,500,000 people is dead, has become the second largest fatal disease of China.The World Health Organization predicts, will become the maximum public health problem in the whole world to the year two thousand twenty cancer.Anti-tumor drug has become world's second largest medication field, and within 2009, anti-tumor drug market reaches 523.72 hundred million dollars, is only second to the medication of cardiovascular disorder.The conventional anti-cancer medicines of current clinical application mainly contains plant bases, alkylating agent class, antibiotics and hormones, and the overwhelming majority is cell toxicity medicament, and selectivity is low, toxic side effect is very large, and easily produces resistance, and curative effect is subject to obvious impact.Therefore the anticancer targeting medicine developing new high-efficiency low-toxicity has become the trend of antitumor drug research and development.In recent years, molecular targeted agents, because of advantages such as pointed strong, effective and toxic side effects are low, has become the focus of domestic and international therapeutic field of tumor research and development.Wherein Mammals rapamycin target position (mammaliantargetofrapamycin, mTOR) the cancer therapy target position that is latest find.

Rapamycin (Rapamycin, RPM), be also called sirolimus (Sirolimus), its chemical structural formula is as follows:

As shown in above structure, this area is usually carried out mother nucleus structure to rapamycin and is indicated, and wherein 1-position is double bond, and 28-position, 43-position are hydroxyl, and the new compound that the present invention obtains is the product replaced on 43-hydroxyl; In addition, also have in some document and said structure 43-position is denoted as 40-position, essentially the two is identical, just the difference of marking mode.

CCI-779 (Temsirolimus) is a kind of forms of rapamycin analogs used clinically, and the chemical structural formula of CCI-779 is as follows:

Known rapamycin CAS registration number 53123-88-9, molecular formula C51H79NO13, molecular weight 914.17, what obtain from ether is colorless crystalline solid, mp183-185 °, [α] D25-58.2 ° (methyl alcohol), is dissolved in ether, chloroform, acetone, methyl alcohol and DMF, is slightly soluble in hexane and sherwood oil, water insoluble, mouse LD50 (mg/kg) " 600 (i.p.), >2,500 (oral) (V é zina).

The report in 1975 such as Vezina obtains hypotoxicity antifungal antibiotic rapamycin from streptomyces hygroscopicus fermented liquid, by the effort in more than 20 years, is successfully developed as novel potent immunosuppressor.The immunosuppressive activity decades of times stronger than ciclosporin of rapamycin, toxic side effect than ciclosporin and FK506 little.It not only for the acute rejection of organ transplantation, and can also reverse ongoing graft-rejection; Various autoimmune disorder can be treated.

Rapamycin is the large ring triene antibiotic obtained by streptomyces hygroscopicus, and it is found in vivo and in vitro all has anti-mycotic activity, especially anti-candida albicans [the people such as C.Vein; J.Antibiot.28,721 (1975); The people such as S.N.Sega; J.Antibiot.28,727 (1975); The people such as H.A.Baker; J.Antibiot.31,539 (1978); United States Patent (USP) 3,929,992; With United States Patent (USP) 3,993,749].In addition, rapamycin separately (United States Patent (USP) 4,885,171) or combinationally use (United States Patent (USP) 4,401,653) with Sapylin and shown to have anti-tumor activity.

The immunosuppressive action of rapamycin is found, Ciclosporin A and FK-506 (other kind of macrocycle molecule) also show the validity as immunosuppressor, therefore can be used for preventing transplant rejection [people such as R.Y.Calne, Lancet1183 (1978); With United States Patent (USP) 5,100,899].The people such as R.Martel [Can, J.Physiol.Pharmacol.55,48 (1977)] find that rapamycin is all effective in experimental allergic encephalomyelitis model, Multiple Sclerosis Model, adjuvant arthritis model, model of rheumatoid arthritis; And effectively suppress the formation of class IgE antibody.

Rapamycin also can be used for preventing or treatment systemic lupus erythematosus [United States Patent (USP) 5, 078, 999], pneumonia [United States Patent (USP) 5, 080, 899], insulin-dependent diabetes [United States Patent (USP) 5, 321, 009], tetter is psoriasis [United States Patent (USP) 5 such as, 286, 730], enteropathy [United States Patent (USP) 5, 286, 731], intimal thickening [United States Patent (USP) 5 after smooth muscle cell proliferation and blood vessel injury, 288, 711 and 5, 516, 781], adult T-cell leukemia/lymphoma [european patent application 525, 960Al], ophthalmia disease [United States Patent (USP) 5, 387, 589], pernicious carninomatosis [United States Patent (USP) 5, 206, 018], heart diseases associated with inflammation [United States Patent (USP) 5, 496, 832], with anaemia [United States Patent (USP) 5, 561, 138].

In recent years, along with deepening continuously of studying rapamycin derivative, find that rapamycin and derivative thereof have the effect suppressing kinds of tumors growth, show its study on mechanism, rapamycin and derivative thereof are all that this mixture is combined with the FRB region of mTOR by generating mixture with FKBP212 albumen, suppress the function of mTOR, thus suppress the expression of downstream correlation factor, impel apoptosis, the targeting anti-tumor playing its uniqueness is active.

In recent years, the molecular design derivative of multiple rapamycin is successively had now to ratify to be applied to the treatment of cancer by FDA or for clinical trial, the everolimus that Novartis Co., Ltd (Novartis) researches and develops was treated for advanced renal cell cancer in 2009 by FDA approval.The CCI-779 (CCI-779) that Hui Shi pharmacy (Wyeth) is developed, by FDA approval treatment advanced renal cell cancer; Deferolimus is the research and development of Ariad company, without immunosuppressive activity, is now in clinical trial.

MTOR is the center of the signal transduction path that time multiplexed cell is mixed, and in Growth of Cells, propagation, cellular metabolism, engulfs and plays a crucial role in vascularization.MTOR inhibitors and FKBP12 protein binding form mixture and suppress mTOR overactivity, contain ribosomal biosynthesizing and protein translation, thus play the effect for the treatment of tumour.MTOR inhibitors is as important efficient non-cytotoxicity class Targeted cancer therapy medicine, that at present carries out anticancer research as mTOR inhibitors has sirolimus and three derivatives thereof: CCI-779 (temsirolimus, CCI-779), everolimus (everolimus, RAD001) and AP23573 (ridaforolimus).Wherein CCI-779 is first antineoplastic mTOR inhibitors gone on the market by U.S. FDA approval, for the Orphan drug of the treatment of advanced renal cell carcinoma.

Although people obtain great achievement in the studies and clinical application of rapamycin and derivative thereof, but those skilled in the art still expect have the product having more clinical value to think, and the clinical one that provides more preferably is selected.

Summary of the invention

The object of the invention is to provide a kind of medicine particularly rapamycin derivative having more using value for clinical.The present inventor finds the rapamycin triazole derivatives of a series of replacement, demonstrates and has powerful anti-tumor activity and/or other beat all advantage to various tumor cell strains.The present invention is based on this find and be accomplished.

For this reason, first aspect present invention provides with compounds of Formula I:

Or its pharmacologically acceptable salts, solvate, isomer, ester, prodrug, wherein,

N is 1,2 or 3;

X is or "-";

R is hydrogen, methyl or (C ₁-C ₄) alkyl;

R ₁for (C ₁-C ₄) alkylamidomethyl-, aminopropyltriethoxysilane-or phenyl-, wherein phenyl or aminopropyltriethoxysilane-on phenyl ring optionally by 1-4 identical or different R ₂group replaces;

R ₂be selected from: hydrogen, hydroxyl, halogen, trifluoromethyl, trifluoromethoxy, amino, carboxyl, cyano group, (C ₁-C ₄) alkyl, (C ₁-C ₆) alkyl, (C ₁-C ₄) alkoxyl group, (C ₁-C ₄) thiazolinyl, (C ₁-C ₄) alkynyl, N-(C ₁-C ₄) alkylamino, N, N-bis-(C ₁-C ₄) alkylamino, (C ₁-C ₄) alkyl sulfenyl, (C ₁-C ₄) alkyl sulphinyl, (C ₁-C ₄) alkyl sulphonyl, (C ₁-C ₄) alkoxy methyl, (C ₁-C ₄) alkoxyethyl, (C ₁-C ₄) alkyl acyl, formamyl, N-(C ₁-C ₄) alkyl-carbamoyl, N, N-bis-(C ₁-C ₄) alkyl-carbamoyl, (C ₁-C ₃) alkylenedioxy group.

The compound of arbitrary embodiment according to a first aspect of the present invention, wherein said (C ₁-C ₄) alkyl is selected from methyl, ethyl, propyl group, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl.

The compound of arbitrary embodiment according to a first aspect of the present invention, wherein said halogen is selected from fluorine, chlorine, bromine, iodine.

The compound of arbitrary embodiment according to a first aspect of the present invention, wherein saidly comprises (C ₁-C ₄) group (such as (C of moieties ₁-C ₄) (C in alkoxyl group ₁-C ₄) alkyl, N-(C ₁-C ₄) (C in alkylamino ₁-C ₄) alkyl etc.) and in (C ₁-C ₄) alkyl is selected from methyl, ethyl, propyl group, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl.

The compound of arbitrary embodiment according to a first aspect of the present invention, wherein R is hydrogen or methyl.

The compound of arbitrary embodiment according to a first aspect of the present invention, wherein X is n is 1.

The compound of arbitrary embodiment according to a first aspect of the present invention, wherein X is " singly-bound " (namely X is "-"), and n is 2 or 3;

The compound of arbitrary embodiment according to a first aspect of the present invention, it is be selected from following compound or its pharmacologically acceptable salts, solvate, isomer, ester, prodrug:

43-O-(2-(4-(4-fluorophenyl)-1H-1,2,3-triazole-1-base) ethyl) oxygen rapamycin

43-O-(2-(4-(4-chloro-phenyl-)-1H-1,2,3-triazole-1-base) ethyl) oxygen rapamycin

43-O-(2-(4-(4-aminomethyl phenyl)-1H-1,2,3-triazole-1-base) ethyl) oxygen rapamycin

43-O-(2-(4-(phenyl)-1H-1,2,3-triazole-1-base) ethyl) oxygen rapamycin

43-O-(2-(4-(4-amyl group phenyl)-1H-1,2,3-triazole-1-base) ethyl) oxygen rapamycin

43-O-(2-(4-(3-aminomethyl phenyl)-1H-1,2,3-triazole-1-base) ethyl) oxygen rapamycin

43-O-(2-(4-(2-chloro-phenyl-)-1H-1,2,3-triazole-1-base) ethyl) oxygen rapamycin

43-O-(2-(4-(4-bromophenyl)-1H-1,2,3-triazole-1-base) ethyl) oxygen rapamycin

43-O-(2-(4-(4-p-methoxy-phenyl)-1H-1,2,3-triazole-1-base) ethyl) oxygen rapamycin

43-O-(2-(4-((2,5 dichlorophenyl) amino methyl)-1H-1,2,3-triazole-1-base) ethyl) oxygen rapamycin

43-O-(2-(4-((2,4 dichlorophenyl) amino methyl)-1H-1,2,3-triazole-1-base) ethyl) oxygen rapamycin

43-O-(2-(4-((2,6 difluorophenyl) amino methyl)-1H-1,2,3-triazole-1-base) ethyl) oxygen rapamycin

43-O-(2-(4-((2-fluorophenyl) amino methyl)-1H-1,2,3-triazole-1-base) ethyl) oxygen rapamycin

43-O-(3-(4-(4-fluorophenyl)-1H-1,2,3-triazole-1-base) n-propyl) oxygen rapamycin

43-O-(3-(4-(4-chloro-phenyl-)-1H-1,2,3-triazole-1-base) n-propyl) oxygen rapamycin

43-O-(3-(4-(4-aminomethyl phenyl)-1H-1,2,3-triazole-1-base) n-propyl) oxygen rapamycin

43-O-(3-(4-phenyl-1H-1,2,3-triazole-1-base) n-propyl) oxygen rapamycin

43-O-(3-(4-(3-aminomethyl phenyl)-1H-1,2,3-triazole-1-base) n-propyl) oxygen rapamycin

43-O-(3-(4-(2-chloro-phenyl-)-1H-1,2,3-triazole-1-base) n-propyl) oxygen rapamycin

43-O-(3-(4-(4-bromophenyl)-1H-1,2,3-triazole-1-base) n-propyl) oxygen rapamycin

43-O-(3-(4-(4-p-methoxy-phenyl)-1H-1,2,3-triazole-1-base) n-propyl) oxygen rapamycin

43-O-(3-(4-((2,5 dichlorophenyl) amino methyl)-1H-1,2,3-triazole-1-base) n-propyl) oxygen rapamycin

43-O-(3-(4-((2,4 dichlorophenyl) amino methyl)-1H-1,2,3-triazole-1-base) n-propyl) oxygen rapamycin

43-O-(3-(4-((2,6 difluorophenyl) amino methyl)-1H-1,2,3-triazole-1-base) n-propyl) oxygen rapamycin

43-O-(3-(4-((2-fluorophenyl) amino methyl)-1H-1,2,3-triazole-1-base) n-propyl) oxygen rapamycin

43-O-(2-(4-(4-fluorophenyl)-1H-1,2,3-triazole-1-base) ethanoyl) oxygen rapamycin

43-O-(2-(4-(4-chloro-phenyl-)-1H-1,2,3-triazole-1-base) ethanoyl) oxygen rapamycin

43-O-(2-(4-(4-aminomethyl phenyl)-1H-1,2,3-triazole-1-base) ethanoyl) oxygen rapamycin

43-O-(2-(4-(phenyl)-1H-1,2,3-triazole-1-base) ethanoyl) oxygen rapamycin

43-O-(2-(4-(4-amyl group phenyl)-1H-1,2,3-triazole-1-base) ethanoyl) oxygen rapamycin

43-O-(2-(4-(3-aminomethyl phenyl)-1H-1,2,3-triazole-1-base) ethanoyl) oxygen rapamycin

43-O-(2-(4-(2-chloro-phenyl-)-1H-1,2,3-triazole-1-base) ethanoyl) oxygen rapamycin

43-O-(2-(4-(4-bromophenyl)-1H-1,2,3-triazole-1-base) ethanoyl) oxygen rapamycin

43-O-(2-(4-(4-p-methoxy-phenyl)-1H-1,2,3-triazole-1-base) ethanoyl) oxygen rapamycin

43-O-(2-(4-((2,5 dichlorophenyl) amino methyl)-1H-1,2,3-triazole-1-base) ethanoyl) oxygen rapamycin

43-O-(2-(4-((2-fluorophenyl) amino methyl)-1H-1,2,3-triazole-1-base) ethanoyl) oxygen rapamycin

43-O-(2-(4-(pyrrolidyl-1-methylene radical)-1H-1,2,3-triazole-1-base) ethanoyl) oxygen rapamycin

43-O-(2-(4-(Diethylaminomethyl)-1H-1,2,3-triazole-1-base) ethanoyl) oxygen rapamycin

43-O-(2-(4-(4-fluorophenyl)-1H-1,2,3-triazole-1-base) iso-propionyl) oxygen rapamycin

43-O-(2-(4-(4-chloro-phenyl-)-1H-1,2,3-triazole-1-base) iso-propionyl) oxygen rapamycin

43-O-(2-(4-(4-aminomethyl phenyl)-1H-1,2,3-triazole-1-base) iso-propionyl) oxygen rapamycin

43-O-(2-(4-(phenyl)-1H-1,2,3-triazole-1-base) iso-propionyl) oxygen rapamycin

43-O-(2-(4-(4-amyl group phenyl)-1H-1,2,3-triazole-1-base) iso-propionyl) oxygen rapamycin

43-O-(2-(4-(3-aminomethyl phenyl)-1H-1,2,3-triazole-1-base) iso-propionyl) oxygen rapamycin

43-O-(2-(4-(2-chloro-phenyl-)-1H-1,2,3-triazole-1-base) iso-propionyl) oxygen rapamycin

43-O-(2-(4-(4-bromophenyl)-1H-1,2,3-triazole-1-base) iso-propionyl) oxygen rapamycin

43-O-(2-(4-(4-p-methoxy-phenyl)-1H-1,2,3-triazole-1-base) iso-propionyl) oxygen rapamycin

43-O-(2-(4-((2,5 dichlorophenyl) amino methyl)-1H-1,2,3-triazole-1-base) iso-propionyl) oxygen rapamycin

43-O-(2-(4-((2,4 dichlorophenyl) amino methyl)-1H-1,2,3-triazole-1-base) iso-propionyl) oxygen rapamycin

43-O-(2-(4-((2-fluorophenyl) amino methyl)-1H-1,2,3-triazole-1-base) iso-propionyl) oxygen rapamycin

The compounds of this invention is the derivative that the 43-hydroxyl of rapamycin replaces in essence, and therefore its title can still be as the criterion with rapamycin nucleus, with the substituting group statement on 43-hydroxyl, i.e. and the rapamycin of 43-O-oxo as described above.

The compound of arbitrary embodiment according to a first aspect of the present invention, it is compound shown in following formula or its pharmacologically acceptable salts, solvate, isomer, ester, prodrug:

And this compound is the compound being selected from following table numbering 1-50, wherein X, R, R of each compound ₁, n is respectively as shown in the table:

Further, second aspect present invention provides a kind of pharmaceutical composition, comprising compound described in the arbitrary embodiment of first aspect present invention, and optional pharmaceutically acceptable carrier or auxiliary material.According in this respect, the invention still further relates to described pharmaceutical composition as preventing or treating the application in the medicine of the disease such as tumour and/or cancer.

Further, third aspect present invention provides the purposes of compound described in the arbitrary embodiment of first aspect present invention in the medicine for the preparation of prevention or treatment tumour and/or cancer.According to purposes of the present invention, wherein said tumour and/or cancer are selected from: lung cancer, carcinoma of the pancreas, esophagus cancer, cancer of the stomach, cervical cancer, prostate cancer, leukemia, kidney.

Further, fourth aspect present invention provides the method preventing and/or treating tumour and/or cancer, and the method comprises the formula I to there being the experimenter of these needs to prevent and/or treat the first aspect present invention of significant quantity.

Further, fifth aspect present invention provides the method preparing compound described in the arbitrary embodiment of first aspect present invention, and it comprises the following steps:

From following compd A-1: prepare with following formula A-2 compound:

Then the acetylene compound making A-2 compound and R1 aryl (such as phenyl) replace is obtained by reacting formula I through five water blue vitriol and sodium ascorbate:

Formula I is optionally made to form its pharmacologically acceptable salts, solvate, isomer, ester, prodrug.Wherein as described in each substituting group embodiment as arbitrary in first aspect present invention.

Method according to a fifth aspect of the present invention, wherein, when X is "-", when R is hydrogen, the preparation method of A-2 compound is:

With A-1 compound for raw material, be obtained by reacting B-2 compound with compound side chain triflated shown in B-1:

Then B-2 compound and reaction of sodium azide is made to obtain A-2 compound.

Method according to a fifth aspect of the present invention, wherein, when X is time, the preparation method of A-2 compound is:

React for raw material and trimethylchlorosilane with A-1 compound, obtain with following formula C-1 compound:

Then C-1 compound and formula is made the esterification of C-2 compound, obtain with following formula C-3 compound:

Then C-3 compound and reaction of sodium azide is made to obtain C-4 compound:

C-4 compound deprotection is finally made to obtain A-2 compound.

The feature that any one of either side of the present invention or this either side has is equally applicable to any one of other either side or this other either side, as long as they can not be conflicting, certainly at where applicable each other, necessary words can be done suitably to modify to individual features.In the present invention, such as, when mentioning " any one of first aspect present invention ", the arbitrary sub-aspect that " any one " refers to first aspect present invention is somebody's turn to do; When other side is mentioned in a similar manner, also there is identical meanings.

Be further described with feature to various aspects of the present invention below.

All documents that the present invention quotes from, their full content is incorporated to herein by reference, and if the implication expressed by these documents and the present invention inconsistent time, be as the criterion with statement of the present invention.In addition, the various term that the present invention uses and phrase have and well known to a person skilled in the art general sense, nonetheless, the present invention still wishes to be described in more detail at this these terms and phrase and to explain, the term mentioned and phrase, if any inconsistent with common art-recognized meanings, are as the criterion with the implication that the present invention states.

In the present invention, when X is "-", refer to there is not group herein, namely represent that X is chemical bond.

In the present invention, group " C ₁-C ₄alkyl ", " C _1-4alkyl ", " (C ₁-C ₄) alkyl " etc., they have identical meanings, all represent the straight or branched alkyl with 1-4 carbon atom.Other situation also can do similar understanding.

In the present invention, group " C _1-4alkyl ", comprise its separately statement and exist with other moiety combinations, such as can be selected from C _1-3alkyl, C _1-2alkyl.Similarly, C _1-4alkoxy is as being selected from C _1-3alkoxyl group, C _1-2alkoxyl group.

In the method for synthetic compound of formula i of the present invention, the various starting material reacting used are that those skilled in the art can prepare according to existing knowledge, or can be obtained by the known method of document, or can be buied by business.Intermediate used in above reaction scheme, starting material, reagent, reaction conditions etc. all can have knowledge according to those skilled in the art can make appropriate change.Or those skilled in the art also method can synthesize other not specifically enumerated formula I of the present invention according to a fifth aspect of the present invention.

According to the present invention, the salt that the pharmaceutical salts of formula I can be acid salt or be formed with alkali.Acid salt citing says it can is that inorganic acid salt is such as but not limited to hydrochloride, vitriol, phosphoric acid salt, hydrobromate; Or organic acid salt is such as but not limited to acetate, oxalate, lemon salt, gluconate, succinate, tartrate, tosilate, mesylate, benzoate, lactic acid salt and maleate; Formula I and alkali formed salt illustrate say can be an alkali metal salt such as but be not limited to lithium, sodium and sylvite; Alkaline earth salt such as but be not limited to calcium and magnesium salts; Organic alkali salt is such as but not limited to diethanolamine salt and choline salt etc.; Or chirality alkali salt is such as but not limited to alkyl phenyl amine salt.

The solvate of compound of the present invention can be that hydrate or the recrystallisation solvent comprising other are as alcohols such as ethanol.

According to the present invention, can there is cis/trans isomer in formula I, the present invention relates to the mixture of cis form and trans forms and these forms.If needed, the preparation of single stereoisomers can split mixture according to conventional methods, or by such as Stereo-selective synthesis preparation.If there is motor-driven hydrogen atom, the present invention also relates to the tautomeric form of formula I.

Therefore the present invention also relates to containing at least one formula I as the effective dose of active ingredient, or the pharmaceutical composition of its pharmaceutical salts and/or its steric isomer and customary pharmaceutical excipients or assistant agent.Usual pharmaceutical composition of the present invention contains formula I and/or its physiologically acceptable salt of 0.1-90 % by weight.Pharmaceutical composition can be prepared according to methods known in the art.During for this object, if needed, formula I and/or steric isomer and one or more solids or liquid pharmaceutical excipients and/or assistant agent can be combined, make the suitable administration form or dosage form that can be used as people.

Formula I of the present invention or the pharmaceutical composition containing it can administrations in a unit, and route of administration can be enteron aisle or non-bowel, as in oral, muscle, subcutaneous, knurl, nasal cavity, oral mucosa, skin, peritonaeum or rectum etc.Form of administration is tablet, capsule, dripping pill, aerosol, pill, pulvis, solution, suspensoid, emulsion, granule, liposome, transdermal agent, buccal tablet, suppository, lyophilized injectable powder, injection etc. such as.Can be ordinary preparation, sustained release preparation, controlled release preparation and various particulate delivery system.In order to unit dosage forms for administration is made tablet, various carrier well known in the art can be widely used.Example about carrier is, such as thinner and absorption agent, as starch, dextrin, calcium sulfate, lactose, N.F,USP MANNITOL, sucrose, sodium-chlor, glucose, urea, calcium carbonate, white bole, Microcrystalline Cellulose, pure aluminium silicate etc.; Wetting agent and tackiness agent, as water, glycerine, polyoxyethylene glycol, ethanol, propyl alcohol, starch slurry, dextrin, syrup, honey, glucose solution, mucialga of arabic gummy, gelatine size, Xylo-Mucine, lac, methylcellulose gum, potassiumphosphate, polyvinylpyrrolidone etc.; Disintegrating agent, such as dry starch, alginates, agar powder, laminaran, sodium bicarbonate and Citric Acid, calcium carbonate, polyoxyethylene sorbitol fatty acid ester, sodium laurylsulfonate, methylcellulose gum, ethyl cellulose etc.; Disintegration inhibitor, such as sucrose, Tristearoylglycerol, theobroma oil, hydrogenation wet goods; Absorption enhancer, such as quaternary ammonium salt, sodium lauryl sulphate etc.; Lubricant, such as talcum powder, silicon-dioxide, W-Gum, stearate, boric acid, whiteruss, polyoxyethylene glycol etc.Tablet can also be made coating tablet further, such as sugar coated tablet, thin membrane coated tablet, ECT, or double-layer tablets and multilayer tablet.In order to administration unit is made pill, various carrier well known in the art can be widely used.Example about carrier is, such as thinner and absorption agent, as glucose, lactose, starch, theobroma oil, hydrogenated vegetable oil, polyvinylpyrrolidone, Gelucire, kaolin, talcum powder etc.; Tackiness agent is as gum arabic, tragacanth gum, gelatin, ethanol, honey, liquid sugar, rice paste or batter etc.; Disintegrating agent, as agar powder, dry starch, alginates, sodium laurylsulfonate, methylcellulose gum, ethyl cellulose etc.In order to administration unit is made suppository, various carrier well known in the art can be widely used.Example about carrier is, the ester, gelatin, semi-synthetic glyceryl ester etc. of such as polyoxyethylene glycol, Yelkin TTS, theobroma oil, higher alcohols, higher alcohols.In order to administration unit is made capsule, effective constituent formula I or its steric isomer are mixed with above-mentioned various carriers, and the mixture obtained thus is placed in hard obviously capsule or soft capsule.Also effective constituent formula I or its steric isomer can be made microcapsule, be suspended in aqueous medium and form suspensoid, also can load in hard capsule or make injection application.In order to administration unit is made injection preparation, as solution, emulsion, lyophilized injectable powder and suspensoid, all thinners that this area is conventional can be used, such as, the isooctadecanol of water, ethanol, polyoxyethylene glycol, 1,3-PD, ethoxylation, polyoxygenated isooctadecanol, Polyoxyethylene Sorbitol Fatty Acid Esters etc.In addition, in order to prepare isotonic injection liquid, appropriate sodium-chlor, glucose or glycerine can be added in injection preparation, in addition, conventional solubility promoter, buffer reagent, pH adjusting agent etc. can also be added.

In addition, as needs, also tinting material, sanitas, spices, correctives, sweeting agent or other material can be added in pharmaceutical preparation.

Formula I, or the dosage of its isomer depends on many factors, such as, to prevent or the character of disease therapy and severity, the sex of patient or animal, age, body weight and individual reaction, particular compound used, route of administration and administration number of times etc.Above-mentioned dosage can single dose form or be divided into several, such as two, three or four dosage forms for administration.

Term used herein " composition " means to comprise the product of each appointment composition comprising specified amount, and any product directly or indirectly produced from the combination of each appointment composition of specified amount.

The active compound amount of gained the actual dose level of each activeconstituents in pharmaceutical composition of the present invention can be changed, so that effectively can obtain required therapeutic response for concrete patient, composition and administering mode.Dosage level must according to the activity of particular compound, route of administration, treat the severity of the patient's condition and the patient's condition of patient to be treated and medical history and select.But the way of this area is, the dosage of compound, from lower than for obtaining level that required result for the treatment of requires, increases dosage, gradually until obtain required effect.

Compound of the present invention can be used for preparing antitumor drug.Described tumour is including but not limited to malignant tumour and leukemia such as melanoma, cancer of the stomach, lung cancer, mammary cancer, kidney, liver cancer, oral cavity epidermal carcinoma, cervical cancer, ovarian cancer, carcinoma of the pancreas, prostate cancer, colorectal carcinoma, bladder cancer, tumor of head and neck, nasopharyngeal carcinoma, skin carcinomas.Described cancer of the stomach comprises adenocarcinoma of stomach; Described lung cancer comprises adenocarcinoma of lung; Described colorectal carcinoma comprises adenocarcinoma of colon; Described ovarian cancer comprises adenocarcinoma ovaries; Described kidney comprises kidney clear cell adenocarcinoma; Leukemia comprises acute lymphoblastic leukemia, chronic leukemia, specific type leukemia.

When for above-mentioned treat and/or prevent or other treatment and/or prevention time, a kind of the compounds of this invention treating and/or preventing significant quantity can be applied in a pure form, or with the acceptable ester of pharmacy or prodrug forms (when there are these forms) application.Or described compound can accept the pharmaceutical composition administration of vehicle containing this object compound and one or more medicines.The compounds of this invention that word " prevents and/or treats significant quantity " refers to the compound of the q.s of the reasonable effect/Hazard ratio treatment obstacle being applicable to any medical prophylaxis and/or treatment.But it should be understood that total daily dosage portion of the compounds of this invention and composition must be maked decision within the scope of reliable medical judgment by attending physician.For any concrete patient, concrete treatment effective dose level must be determined according to many factors, and described factor comprises treated obstacle and the severity of this obstacle; The activity of the particular compound adopted; The concrete composition adopted; Age of patient, body weight, general health situation, sex and diet; The administration time of the particular compound adopted, route of administration and excretion rate; The treatment time length; The medicine combinationally using with adopted particular compound or use simultaneously; And the known similar factor of medical field.Such as, the way of this area is, the dosage of compound, from lower than for obtaining level that required result for the treatment of requires, increases dosage, gradually until obtain required effect.In general, formula I is used for the dosage of Mammals particularly people can between 0.001 ~ 1000mg/kg body weight/day, such as, between 0.01 ~ 100mg/kg body weight/day, such as, between 0.01 ~ 10mg/kg body weight/day.

Unless otherwise noted, term used herein " alkyl " and comprise " alkyl " that carbonatoms modifies and " alkyl " comprised in the moiety combinations of these " alkyl " refers to the alkyl of straight or branched, such as (C ₁-C ₄) alkyl includes but not limited to methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, the tertiary butyl etc.; " alkylidene group " refers to the alkylidene group of straight or branched; " cycloalkyl " refers to substituted or unsubstituted cycloalkyl.

The present invention includes pharmaceutical composition, said composition contains the rapamycin compounds of general formula I, its optically active isomer and pharmacologically acceptable salts thereof as activeconstituents, and the acceptable excipient of pharmacy.The acceptable excipient of described pharmacy refers to any thinner, auxiliary and/or the carrier that can be used for pharmaceutical field.Derivative of the present invention can use with other active ingredient combinations, such as, as long as they do not produce other disadvantageous effect, anaphylaxis.

Pharmaceutical composition of the present invention can be mixed with several formulation, wherein containing some vehicle conventional in pharmaceutical field; Such as, oral preparations (as tablet, capsule, solution or suspension); Injectable preparation (as injectable solution or suspension, or injectable dried powder, adding water for injection before the injection can use immediately); Topical formulations (such as ointment or solution).

Carrier for pharmaceutical composition of the present invention is available common type in pharmaceutical field, comprising: the tackiness agent, lubricant, disintegrating agent, solubility promoter, thinner, stablizer, suspension agent, non-pigment, correctives etc. of oral preparations; The sanitas, solubilizing agent, stablizer etc. of injectable formulation; The matrix, thinner, lubricant, sanitas etc. of topical formulations.Pharmaceutical preparation can oral administration or parenteral (such as intravenously, subcutaneous, intraperitoneal or local) administration, if some drugs is unstable under stomach condition, can be mixed with enteric coated tablets.

Derivative according to the present invention can be used as activeconstituents for the preparation for the treatment of and/or preventing various cancer, the present invention also provides treatment or prevents the method for above-mentioned disease, comprise the patient significant quantity suffering from or easily suffer from this disease according to derivative of the present invention.The clinical dosage that the rapamycin compounds of general formula I is used for patient must rely on be treated main body, administration concrete ways, be treated disease seriousness and change, and optimal dose is determined by the doctor treating concrete patient.

Active compound of the present invention can be used as unique cancer therapy drug and uses, or can with one or more other antitumor drug conbined usage.Combination therapy by by each treatment component simultaneously, order or separate administration to realize.

Derivative of the present invention can exist with stereoisomer form, and these stereoisomeric forms in any ratio can be enantiomorph or diastereomer.The present invention had both related to enantiomorph or diastereomer, also related to their respective mixtures, as diastereomer, according to self known method, racemic form can be separated into stereomeric one-component.

In addition, the present invention also comprises the prodrug of derivative of the present invention.According to the present invention, prodrug is the derivative of general formula I, they self may have more weak activity or even not have activity, but upon administration, (such as by metabolism, solvolysis or other mode) is converted to corresponding biologically active form in physiological conditions.

We have found that the compounds of this invention is external and have had growth inhibitory activity to tumor cell, and therefore, it can be used as the medicine that preparation treats and/or prevents cancer.Especially the cancer of mammary gland, lung, colon, rectum, stomach, prostate gland, bladder, pancreas and ovary is treated.The compounds of this invention is also supposed to may be used for treating other cell proliferative diseases as psoriasis, benign prostatauxe, atherosclerosis and restenosis.Expect that rapamycin compounds of the present invention will have leukemia, malignant lymphoma and solid tumor as organized the activity as the cancer in liver, kidney, prostate gland and pancreas and sarcoma scope in addition.

The embodiment hereinafter provided and preparation example are illustrated further and are illustrated the compounds of this invention and preparation method thereof.Should be appreciated that the scope of following embodiment and preparation example and limit the scope of the invention never in any form.

Synthetic route below describes the general preparation method of compound of Formula I of the present invention, and all raw materials are all methods by describing in these schematic diagram, prepared by the method known by organic chemistry filed those of ordinary skill or commercially available.Whole finalization compound of the present invention is all method by describing in these schematic diagram or is prepared by similar method, and these methods are that organic chemistry filed those of ordinary skill is known.The whole variable factors applied in these schematic diagram are as definition hereafter or as the definition in claim.

The compounds of this invention has excellent biologic activity and pharmaceutical properties.Such as adopt automatic absorbing analyser DVS-1 instrument, measure the water absorbability of hydrate prepared by various embodiments of the present invention, and compare with rapamycin and CCI-779.Measuring method is: accurately weighed and be placed in sample disc by the test material of about 25mg, is exposed in the humidity environment of relative humidity 0 ~ 90%; Within the scope of 0 ~ 15%RH, adopt 1%RH gradient to carry out detailed analysis, within the scope of 15 ~ 90%RH, adopt 15%RH gradient to carry out detailed analysis; Analysis temperature is 30 DEG C, and nitrogen flow rate is 200 cubic centimetres/min; Obtain the moisture sorption isotherm of each compound.Result shows, the whole compound of the present invention only absorbs the water lower than 0.3% (w/w) in the scope of 0%-90%RH, and rapamycin and CCI-779 water suction are all greater than 0.8%, show that the compounds of this invention is nonhygroscopic, this is a kind of excellent bulk drug character.

According to general formula I derivative of the present invention, in route A, R, R ₁, X and n as summary of the invention define.

By compd A-1 through the reaction of 2-4 step, generate triazo-compound A-2.Compd A-2 and arylalkyne compounds are obtained by reacting general formula for the derivative shown in I through five water blue vitriol and sodium ascorbate.

Wherein, when X is "-", when R is hydrogen, the method preparation that A-2 describes according to route B: take A-1 as raw material, be obtained by reacting B-2 with B-1 trifluoromethanesulfonic acid ester side chain, then through obtaining A-2 with reaction of sodium azide.

When X is time, the method preparation that A-2 describes according to route C: take A-1 as raw material, obtain A-2 through the protection of silicon ether, esterification, azide and deprotection.

Preparation method of the present invention is simple, and the compound of preparation all has significant anti-tumor activity.

In above-mentioned route, compound shown in raw material A-1, B-1, B-2, C-1 and C-2 can be known by organic chemistry filed those of ordinary skill method preparation or commercially available.Preparation method of the present invention is simple, and the compound of preparation has good anti-tumor activity.

Embodiment

Specific embodiment is below intended to set forth instead of limit the scope of the invention.

In the present invention, the proton nmr spectra BrukerARX-300 of prepared compound measures, and mass spectrum Agilent1100LC/MSD measures; Agents useful for same is analytical pure or chemical pure.

Embodiment 1:43-O-(2-(4-(4-fluorophenyl)-1H-1,2,3-triazole-1-base) ethyl) oxygen rapamycin (X-18)

The preparation of steps A: 43-O-(2-bromotrifluoromethane)-oxygen rapamycin

Rapamycin (10g, 10.9mmol), diisopropylethylamine (55mmol) are joined in the toluene solution of 300mL, adds 2-bromotrifluoromethane sulphonate side chain (25g, 98mmol), finish, be warming up to 60 DEG C of reaction 3h.After completion of the reaction, reaction solution is cooled to room temperature, respectively in dilute hydrochloric acid, saturated sodium bicarbonate and saturated aqueous common salt, organic layer is through anhydrous sodium sulfate drying, and evaporate to dryness obtains faint yellow solid, obtains 5.2g white solid finally by column chromatography for separation, yield: 46.7%, 1042.5 (M+Na) ⁺.

The preparation of step B:43-O-(2-azidoethyl)-oxygen rapamycin

Respectively by 43-O-(2-bromotrifluoromethane)-oxygen rapamycin (5.2g, 5.1mmol) with sodiumazide (0.97g, 15mmol) join in (30mL) DMF solution, add catalyzer KI (0.1g), after reinforced, be warmed up to 50 DEG C, after reacting completely, by in reaction solution impouring 90mL water, ethyl acetate extracts 2 times, united extraction liquid, washing, anhydrous sodium sulfate drying.Evaporate to dryness obtains oily matter, obtains 2.1g respectively through column chromatography for separation, and yield is 41.8%.MS(ESI)m/z:1005.5(M+Na) ⁺。

The preparation (X-18) of step C:43-O-(2-(4-(4-fluorophenyl)-1H-1,2,3-triazole-1-base) ethyl) oxygen rapamycin

By 43-O-(2-azidoethyl)-oxygen rapamycin (0.3mmoL, 0.3g) join in DMF (10mL) solution with 4-fluorobenzene acetylene (0.1g), sodium ascorbate (0.05g) and cupric sulfate pentahydrate (0.08g) is added in reaction solution, stirring at room temperature 2h, after completion of the reaction, reaction is added in 40mL water, separate out faint yellow solid, suction filtration, washing, dry faint yellow solid, is separated with C18 preparative chromatography through silica gel column chromatography, obtain sterling 0.15g, yield: 45.3%.MS(ESI)m/z:1125.7(M+Na) ⁺。 ¹HNMR(500MHz,DMSO)δ8.53(s,1H),7.87(dd,J＝8.7,5.5Hz,2H),7.28(t,J＝8.9Hz,2H),6.45(s,1H),6.43-6.32(m,1H),6.26-6.17(m,1H),6.16-6.06(m,2H),5.45(dd,J＝14.8,9.7Hz,1H),5.26(d,J＝4.5Hz,1H),5.09(d,J＝10.2Hz,1H),4.99-4.95(m,1H),4.94-4.89(m,1H),4.53(m,1H),4.06-3.87(m,4H),3.62(m,1H),3.47-3.38(m,1H),3.29-3.23(m,1H),3.21(s,3H),3.14(s,3H),3.05(s,3H),3.02-2.93(m,2H),2.83-2.75(m,1H),2.75-2.68(m,1H),2.43-2.33(m,2H),2.25-2.15(m,1H),2.10(m,1H),2.06-1.95(m,1H),1.93-1.77(m,2H),1.73(s,3H),1.62(s,3H),1.55(d,J＝39.0Hz,3H),1.45-1.00(m,9H),0.98(d,J＝6.5Hz,3H),0.87(d,J＝6.5Hz,3H),0.81(d,J＝6.4Hz,3H),0.76(d,J＝6.7Hz,3H),0.72(d,J＝6.5Hz,3H)。 ¹³CNMR(126MHz,DMSO)δ210.46,207.50,198.90,169.19,166.97,145.21,139.28,137.83,137.13,132.32,130.42,127.48,127.03,126.97,124.89,121.61,115.87,115.70,99.00,85.51,82.38,82.23,82.15,75.73,73.60,67.64,66.18,56.91,56.64,55.45,50.73,50.22,45.18,43.47,38.16,35.62,35.16,34.79,33.33,32.13,30.79,29.62,29.47,26.41,26.21,24.44,21.63,20.35,15.55,15.52,14.66,13.41,13.35,10.44。

Embodiment 2:43-O-(2-(4-(4-chloro-phenyl-)-1H-1,2,3-triazole-1-base) ethyl) oxygen rapamycin (X-48)

By 43-O-(2-azidoethyl)-oxygen rapamycin (0.3mmoL, 0.3g) join in DMF (10mL) solution with 4-chlorobenzene acetylene (0.1g), sodium ascorbate (0.1g) and cupric sulfate pentahydrate (0.08g) is added in reaction solution, stirring at room temperature 2h, after completion of the reaction, reaction is added in 40mL water, separate out faint yellow solid, suction filtration, washing, dry faint yellow solid, is separated with C18 preparative chromatography through silica gel column chromatography, obtain sterling 0.17g, yield: 50.7%.MS(ESI)m/z:1141.6(M+Na) ⁺。 ¹HNMR(500MHz,DMSO)δ8.59(s,1H),7.85(d,J＝8.6Hz,2H),7.51(d,J＝8.6Hz,2H),6.45(s,1H),6.43-6.33(m,1H),6.24-6.17(m,1H),6.15-6.07(m,2H),5.45(dd,J＝14.8,9.7Hz,1H),5.26(s,1H),5.09(d,J＝10.2Hz,1H),4.99-4.95(m,1H),4.95-4.90(m,1H),4.56-4.51(m,2H),4.03-3.88(m,5H),3.63-3.59(m,1H),3.46-3.40(m,1H),3.29-3.22(m,1H),3.20(s,3H),3.14(s,3H),3.05(s,3H),3.01-2.90(m,2H),2.86-2.68(m,2H),2.44-2.34(m,2H),2.25-2.16(m,1H),2.13-2.05(m,1H),2.05-1.95(m,2H),1.94-1.77(m,3H),1.73(s,3H),1.62(s,3H),1.59-1.00(m,10H),0.98(d,J＝6.5Hz,3H),0.87(d,J＝6.5Hz,3H),0.81(d,J＝6.4Hz,3H),0.76(d,J＝6.7Hz,3H),0.72(d,J＝6.6Hz,3H). ¹³CNMR(126MHz,DMSO)δ210.46,207.50,198.90,169.18,166.97,144.99,139.28,137.83,137.13,132.32,132.12,130.42,129.81,128.93,126.98,126.70,124.90,122.05,99.00,85.51,82.37,82.23,82.15,75.73,73.60,67.61,66.18,56.91,56.63,55.45,50.72,50.26,45.18,43.48,38.15,35.61,35.16,34.79,33.33,32.12,30.79,29.62,29.48,26.40,26.21,24.44,21.63,20.36,15.55,15.52,14.66,13.40,13.35,10.44。

Embodiment 3:43-O-(2-(4-(4-aminomethyl phenyl)-1H-1,2,3-triazole-1-base) ethyl) oxygen rapamycin (X-15)

By 43-O-(2-azidoethyl)-oxygen rapamycin (0.3mmoL, 0.3g) join in DMF (10mL) solution with 4-methylbenzene acetylene (0.1g), sodium ascorbate (0.1g) and cupric sulfate pentahydrate (0.08g) is added in reaction solution, stirring at room temperature 2h, after completion of the reaction, reaction is added in 40mL water, separate out faint yellow solid, suction filtration, washing, dry faint yellow solid, is separated with C18 preparative chromatography through silica gel column chromatography, obtain sterling 0.13g, yield: 39.4%.MS(ESI)m/z:1121.8(M+Na) ⁺。 ¹HNMR(500MHz,DMSO)δ8.48(s,1H),7.71(d,J＝8.0Hz,2H),7.25(d,J＝7.9Hz,2H),6.45(s,1H),6.38(m,1H),6.27-6.16(m,1H),6.17-6.06(m,2H),5.45(dd,J＝13.8,10.8Hz,1H),5.26(s,1H),5.09(d,J＝10.4Hz,1H),4.97(m,1H),4.93(m,1H),4.59-4.46(m,2H),4.05-3.86(m,4H),3.62(m,1H),3.50-3.39(m,1H),3.29-3.23(m,1H),3.21(s,3H),3.14(s,3H),3.05(s,1H),2.85-2.75(m,1H),2.76-2.68(m,1H),2.43-2.34(m,2H),2.33(s,3H),2.28-2.15(m,1H),2.10(m,2H),2.06-1.95(m,1H),1.96-1.78(m,2H),1.73(s,3H),1.62(s,3H),1.61-1.01(m,9H),0.98(d,J＝6.5Hz,3H),0.87(d,J＝6.4Hz,3H),0.81(d,J＝6.3Hz,3H),0.76(d,J＝6.6Hz,3H),0.73(d,J＝6.5Hz,3H)。 ¹³CNMR(126MHz,DMSO)δ210.46,207.51,198.90,169.18,166.97,146.13,139.28,137.83,137.13,136.96,132.32,130.42,129.40,128.15,127.00,124.95,121.26,99.00,85.51,82.36,82.24,82.12,75.72,73.61,67.63,66.19,56.91,56.64,55.45,50.73,50.13,45.19,43.48,38.15,35.61,35.16,34.79,33.34,32.13,30.81,29.57,29.46,26.41,26.22,24.44,21.64,20.79,20.36,15.56,15.52,14.66,13.40,13.36,10.45。

Embodiment 4:43-O-(2-(4-(phenyl)-1H-1,2,3-triazole-1-base) ethyl) oxygen rapamycin (X-16)

By 43-O-(2-azidoethyl)-oxygen rapamycin (0.3mmoL, 0.3g) join in DMF (10mL) solution with phenylacetylene (0.1g), sodium ascorbate (0.1g) and cupric sulfate pentahydrate (0.08g) is added in reaction solution, stirring at room temperature 2h, after completion of the reaction, reaction is added in 40mL water, separate out faint yellow solid, suction filtration, washing, dry faint yellow solid, is separated with C18 preparative chromatography through silica gel column chromatography, obtain sterling 0.23g, yield: 70.7%.MS(ESI)m/z:1107.3(M+Na) ⁺。 ¹HNMR(500MHz,DMSO)δ8.54(s,1H),7.83(d,J＝7.3Hz,2H),7.44(t,J＝7.7Hz,2H),7.32(m,1H),6.45(s,1H),6.43-6.33(m,1H),6.22(m,1H),6.16-6.06(m,2H),5.50-5.42(m,1H),5.25(s,1H),5.09(d,J＝9.9Hz,1H),4.97(m,1H),4.93(m,1H),4.59-4.47(m,2H),4.06-3.87(m,4H),3.62(m,1H),3.43(m,3.6Hz,1H),3.30-3.23(m,1H),3.21(s,3H),3.14(s,3H),3.05(s,3H),3.02-2.93(m,2H),2.84-2.76(m,1H),2.72(m,1H),2.44-2.31(m,2H),2.22(m,1H),2.15-2.06(m,1H),2.05-1.96(m,1H),1.94-1.77(m,2H),1.73(s,3H),1.62(s,3H),1.60-1.00(m,10H),0.98(d,J＝6.5Hz,3H),0.87(d,J＝6.4Hz,3H),0.81(d,J＝6.3Hz,2H),0.76(d,J＝6.7Hz,2H),0.73(d,J＝6.5Hz,3H)。 ¹³CNMR(126MHz,DMSO)δ210.46,207.50,198.90,169.19,166.97,146.07,139.29,137.83,137.13,132.32,130.91,130.42,128.86,127.70,126.98,125.01,121.68,99.00,85.51,82.37,82.23,82.13,75.72,73.61,67.63,66.18,56.91,56.64,55.45,50.73,50.18,45.19,43.48,38.15,35.61,35.16,34.79,33.34,32.13,30.81,29.62,29.46,26.41,26.21,24.44,21.63,20.36,15.56,15.52,14.66,13.40,13.36,10.45。

Embodiment 5:43-O-(2-(4-(4-amyl group phenyl)-1H-1,2,3-triazole-1-base) ethyl) oxygen rapamycin (X-17)

By 43-O-(2-azidoethyl)-oxygen rapamycin (0.3mmoL, 0.3g) join in DMF (10mL) solution with 4-n-amylbenzene acetylene (0.1g), sodium ascorbate (0.1g) and cupric sulfate pentahydrate (0.08g) is added in reaction solution, stirring at room temperature 2h, after completion of the reaction, reaction is added in 40mL water, separate out faint yellow solid, suction filtration, washing, dry faint yellow solid, is separated with C18 preparative chromatography through silica gel column chromatography, obtain sterling 0.09g, yield: 27.4%.MS(ESI)m/z:1177.8(M+Na) ⁺。 ¹HNMR(500MHz,DMSO)δ8.48(s,1H),7.72(d,J＝7.7Hz,2H),7.25(d,J＝7.6Hz,2H),6.45(s,1H),6.43-6.34(m,1H),6.25-6.17(m,1H),6.16-6.07(m,2H),5.45(dd,J＝14.8,9.7Hz,1H),5.26(d,J＝4.3Hz,1H),5.09(m,1H),5.00-4.95(m,1H),4.93m,1H),4.56-4.48(m,2H),4.04-3.90(m,4H),3.62(m,1H),3.47-3.40(m,1H),3.21(s,3H),3.14(s,3H),3.05(s,3H),3.02-2.92(m,2H),2.83-2.77(m,1H),2.75-2.68(m,1H),2.59(m,2H),2.43-2.33(m,2H),2.26-2.17(m,1H),2.10(m,1H),2.05-1.96(m,1H),1.94-1.77(m,3H),1.73(s,3H),1.62(s,3H),1.59-1.00(m,15H),0.97(d,J＝6.3Hz,3H),0.87(s,6H),0.81(d,J＝5.9Hz,4H),0.76(d,J＝6.5Hz,3H),0.73(d,J＝6.3Hz,3H)。 ¹³CNMR(126MHz,DMSO)δ210.44,207.49,198.89,169.17,166.96,146.15,141.91,139.27,137.82,137.12,132.31,130.41,128.72,128.37,126.97,124.97,121.27,98.99,85.50,82.36,82.23,82.12,75.71,73.60,67.64,66.18,56.89,56.63,55.43,50.71,50.13,45.18,43.46,38.15,35.60,35.15,34.81,33.33,32.12,30.83,30.49,29.61,29.55,29.45,26.39,26.20,24.44,21.91,21.62,20.35,15.54,15.50,14.65,13.87,13.38,13.35,10.44。

Embodiment 6:43-O-(2-(4-(3-aminomethyl phenyl)-1H-1,2,3-triazole-1-base) ethyl) oxygen rapamycin (X-47)

By 43-O-(2-azidoethyl)-oxygen rapamycin (0.3mmoL, 0.3g) join in DMF (10mL) solution with 3-methylbenzene acetylene (0.1g), sodium ascorbate (0.1g) and cupric sulfate pentahydrate (0.08g) is added in reaction solution, stirring at room temperature 2h, after completion of the reaction, reaction is added in 40mL water, separate out faint yellow solid, suction filtration, washing, dry faint yellow solid, is separated with C18 preparative chromatography through silica gel column chromatography, obtain sterling 0.13g, yield: 39.2%.MS(ESI)m/z:1121.5(M+Na) ⁺。 ¹HNMR(500MHz,DMSO)δ8.52(s,1H),7.66(s,1H),7.61(d,J＝7.7Hz,1H),7.32(t,J＝7.6Hz,1H),7.14(d,J＝7.6Hz,1H),6.45(s,1H),6.43-6.33(m,1H),6.25-6.17(m,1H),6.16-6.07(m,2H),5.45(dd,J＝14.9,9.6Hz,1H),5.26(s,1H),5.09(d,J＝10.2Hz,1H),5.01-4.95(m,1H),4.93(t,J＝5.9Hz,1H),4.56-4.48(m,2H),4.03-3.89(m,5H),3.66-3.58(m,1H),3.47-3.39(m,1H),3.28-3.24(m,1H),3.22(s,3H),3.14(s,3H),3.05(s,3H),3.02-2.94(m,2H),2.84-2.68(m,2H),2.44-2.37(m,2H),2.35(s,3H),2.24-2.20(m,1H),2.13-2.04(m,1H),2.04-1.95(m,2H),1.94-1.77(m,3H),1.73(s,3H),1.62(s,3H),1.59-1.01(m,10H),0.97(d,J＝6.5Hz,3H),0.87(d,J＝6.5Hz,3H),0.81(d,J＝6.4Hz,3H),0.76(d,J＝6.7Hz,3H),0.73(d,J＝6.6Hz,3H)。 ¹³CNMR(126MHz,DMSO)δ210.46,207.50,198.90,197.22,169.18,166.97,146.16,139.28,137.96,137.82,137.13,132.32,130.83,130.42,128.75,128.34,126.99,125.56,124.91,122.19,121.60,99.00,85.52,82.35,82.24,82.12,75.72,73.61,67.60,66.19,56.91,56.63,55.45,50.72,50.15,45.19,43.48,38.16,35.60,35.16,34.79,33.34,32.30,32.13,30.81,29.62,29.57,29.45,26.40,26.21,24.44,21.63,21.03,20.36,15.55,15.52,14.66,13.39,13.37,10.45。

Embodiment 7:43-O-(2-(4-(2-chloro-phenyl-)-1H-1,2,3-triazole-1-base) ethyl) oxygen rapamycin (X-49)

By 43-O-(2-azidoethyl)-oxygen rapamycin (0.3mmoL, 0.3g) join in DMF (10mL) solution with 2-chlorobenzene acetylene (0.1g), sodium ascorbate (0.1g) and cupric sulfate pentahydrate (0.08g) is added in reaction solution, stirring at room temperature 2h, after completion of the reaction, reaction is added in 40mL water, separate out faint yellow solid, suction filtration, washing, dry faint yellow solid, is separated with C18 preparative chromatography through silica gel column chromatography, obtain sterling 0.11g, yield: 33.3%.MS(ESI)m/z:1141.8(M+Na) ⁺。 ¹HNMR(500MHz,DMSO)δ8.62(s,1H),8.06(d,J＝7.8Hz,1H),7.56(d,J＝8.0Hz,1H),7.48-7.43(m,1H),7.42-7.36(m,1H),6.45(s,1H),6.43-6.33(m,1H),6.25-6.17(m,1H),6.16-6.04(m,2H),5.45(dd,J＝14.8,9.7Hz,2H),5.26(s,1H),5.08(d,J＝10.2Hz,1H),4.99-4.95(m,1H),4.95-4.91(m,1H),4.62-4.56(m,2H),4.03-3.90(m,5H),3.65-3.58(m,1H),3.47-3.40(m,1H),3.29-3.23(m,1H),3.20(s,3H),3.14(s,3H),3.05(s,3H),2.99-2.92(m,2H),2.83-2.69(m,2H),2.43-2.33(m,2H),2.26-2.15(m,1H),2.13-2.06(m,1H),2.05-1.95(m,2H),1.94-1.78(m,3H),1.73(s,3H),1.62(s,3H),1.59-1.00(m,10H),0.97(d,J＝6.5Hz,3H),0.87(d,J＝6.5Hz,3H),0.81(d,J＝6.4Hz,3H),0.76(d,J＝6.7Hz,3H),0.72(d,J＝6.7Hz,3H)。 ¹³CNMR(126MHz,DMSO)δ210.51,207.49,198.93,169.17,166.97,142.38,139.29,137.82,137.15,132.31,130.41,130.20,129.45,129.34,129.31,127.50,126.98,124.98,124.62,110.94,99.00,85.54,82.45,82.25,82.13,75.70,73.61,67.72,66.19,56.93,56.65,55.45,50.69,50.22,45.18,43.46,38.14,35.59,35.17,34.79,33.35,32.12,30.82,29.57,29.52,26.41,26.21,24.44,21.64,20.35,15.55,15.51,14.65,13.41,13.34,10.45。

Embodiment 8:43-O-(2-(4-(4-bromophenyl)-1H-1,2,3-triazole-1-base) ethyl) oxygen rapamycin (X-50)

By 43-O-(2-azidoethyl)-oxygen rapamycin (0.3mmoL, 0.3g) join in DMF (10mL) solution with 4-bromobenzene acetylene (0.1g), sodium ascorbate (0.1g) and cupric sulfate pentahydrate (0.08g) is added in reaction solution, stirring at room temperature 2h, after completion of the reaction, reaction is added in 40mL water, separate out faint yellow solid, suction filtration, washing, dry faint yellow solid, is separated with C18 preparative chromatography through silica gel column chromatography, obtain sterling 0.12g, yield: 34.4%.MS(ESI)m/z:1186.3(M+Na) ⁺。 ¹HNMR(500MHz,DMSO)δ8.60(s,1H),7.79(d,J＝8.5Hz,2H),7.64(d,J＝8.5Hz,2H),6.45(s,1H),6.43-6.34(m,1H),6.25-6.18(m,1H),6.15-6.07(m,2H),5.45(dd,J＝14.7,9.7Hz,1H),5.26(s,1H),5.08(d,J＝10.2Hz,1H),4.99-4.95(m,1H),4.95-4.90(m,1H),4.57-4.50(m,2H),4.05-3.89(m,5H),3.64-3.59(m,1H),3.46-3.40(m,1H),3.29-3.23(m,1H),3.20(s,3H),3.14(s,3H),3.05(s,3H),3.01-2.90(m,2H),2.83-2.68(m,2H),2.45-2.33(m,2H),2.25-2.16(m,1H),2.13-2.07(m,1H),2.06-1.94(m,2H),1.94-1.77(m,3H),1.73(s,3H),1.62(s,3H),1.58-1.01(m,10H),0.98(d,J＝6.5Hz,3H),0.87(d,J＝6.5Hz,3H),0.81(d,J＝6.4Hz,3H),0.76(d,J＝6.7Hz,3H),0.72(d,J＝6.6Hz,3H). ¹³CNMR(126MHz,DMSO)δ210.46,207.50,198.90,188.64,169.18,166.97,145.02,139.28,137.83,137.13,132.32,131.84,130.42,130.16,126.99,124.89,122.07,120.64,99.00,85.50,82.37,82.23,82.14,75.72,73.60,67.60,66.18,56.91,56.63,55.45,50.73,50.27,45.19,43.47,38.15,35.61,35.16,34.79,33.33,32.12,30.79,29.57,29.47,26.40,26.21,24.44,21.64,20.36,15.56,15.52,14.66,13.40,13.36,10.45。

Embodiment 9:43-O-(2-(4-(4-p-methoxy-phenyl)-1H-1,2,3-triazole-1-base) ethyl) oxygen rapamycin (X-67)

By 43-O-(2-azidoethyl)-oxygen rapamycin (0.3mmoL, 0.3g) join in DMF (10mL) solution with 4-Methoxy-phenylacetylene (0.1g), sodium ascorbate (0.1g) and cupric sulfate pentahydrate (0.08g) is added in reaction solution, stirring at room temperature 2h, after completion of the reaction, reaction is added in 40mL water, separate out faint yellow solid, suction filtration, washing, dry faint yellow solid, is separated with C18 preparative chromatography through silica gel column chromatography, obtain sterling 0.10g, yield: 30.3%.MS(ESI)m/z:1137.5(M+Na) ⁺。 ¹HNMR(500MHz,DMSO)δ8.43(s,1H),7.75(d,J＝8.6Hz,2H),7.01(d,J＝8.6Hz,2H),6.45(s,1H),6.43-6.32(m,1H),6.25-6.18(m,2H),6.16-6.07(m,2H),5.46(dd,J＝14.7,9.6Hz,1H),5.27(s,1H),5.12-5.06(m,1H),5.01-4.94(m,1H),4.95-4.90(m,1H),4.56-4.47(m,2H),4.04-3.88(m,4H),3.79(s,3H),3.65-3.58(m,1H),3.47-3.40(m,1H),3.40-3.29(m,2H),3.22(s,3H),3.14(s,3H),3.05(s,3H),2.83-2.76(m,1H),2.74-2.71(m,1H),2.43-2.33(m,2H),2.25-2.17(m,1H),2.14-2.05(m,1H),2.05-1.96(m,2H),1.94-1.77(m,3H),1.73(s,3H),1.62(s,3H),1.56-1.00(m,10H),0.98(d,J＝6.4Hz,3H),0.87(d,J＝6.4Hz,3H),0.82(d,J＝6.3Hz,3H),0.76(d,J＝6.6Hz,3H),0.73(d,J＝6.5Hz,3H)。 ¹³CNMR(126MHz,DMSO)δ210.46,207.50,198.90,169.19,166.97,158.88,146.01,139.29,137.83,137.13,132.32,130.42,126.98,126.35,124.90,123.52,120.73,114.27,99.00,85.50,82.37,82.24,82.13,75.72,73.61,67.66,66.19,56.91,56.66,55.45,55.10,50.73,50.11,45.19,43.48,38.17,35.62,35.16,34.79,33.34,32.14,30.81,29.56,26.40,26.21,24.45,21.63,20.36,15.56,15.52,14.66,13.40,13.36,10.45。

Embodiment 10:43-O-(2-(4-((2,5 dichlorophenyl) amino methyl)-1H-1,2,3-triazole-1-base) ethyl) oxygen rapamycin (X-14)

By 43-O-(2-azidoethyl)-oxygen rapamycin (0.3mmoL, 0.3g) with N-(Propargyl)-2,5-dichlorphenamide bulk powder (0.1g) joins in DMF (10mL) solution, sodium ascorbate (0.1g) and cupric sulfate pentahydrate (0.08g) is added in reaction solution, stirring at room temperature 2h, after completion of the reaction, reaction is added in 40mL water, separate out faint yellow solid, suction filtration, washing, dry faint yellow solid, be separated with C18 preparative chromatography through silica gel column chromatography, obtain sterling 0.11g, yield: 31.1%.MS(ESI)m/z:1205.6(M+Na) ⁺。 ¹HNMR(500MHz,DMSO)δ7.91(s,1H),7.24(d,J＝8.3Hz,1H),6.78(s,1H),6.58(d,J＝8.3Hz,1H),6.45(s,1H),6.44-6.35(m,1H),6.26-6.18(m,2H),6.17-6.08(m,2H),5.46(dd,J＝14.7,9.4Hz,1H),5.25(s,1H),5.12-5.06(m,1H),5.00-4.96(m,1H),4.96-4.91(m,1H),4.49-4.38(m,4H),4.04-3.97(m,2H),3.95-3.92(m,1H),3.88-3.84(m,2H),3.65-3.59(m,1H),3.48-3.39(m,1H),3.15(s,3H),3.13(s,3H),3.05(s,3H),2.89-2.82(m,1H),2.75-2.69(m,1H),2.44-2.34(m,2H),2.27-2.16(m,1H),2.13-2.05(m,2H),2.06-1.94(m,1H),1.92-1.79(m,3H),1.74(s,3H),1.63(s,3H),1.61-1.03(m,9H),0.98(d,J＝6.3Hz,3H),0.87(d,J＝6.4Hz,3H),0.83(d,J＝6.2Hz,3H),0.77(d,J＝6.6Hz,3H),0.73(d,J＝6.5Hz,3H)。 ¹³CNMR(126MHz,DMSO)δ210.49,207.49,198.90,169.19,166.97,144.81,144.66,139.31,137.84,137.13,132.48,132.33,130.42,129.99,126.99,124.91,123.12,116.46,115.93,110.84,99.00,85.52,82.43,82.24,81.92,75.74,73.62,67.65,66.19,56.93,56.57,55.45,50.74,49.97,45.20,43.48,38.09,35.58,35.17,34.79,33.38,32.14,30.82,29.63,29.38,26.42,26.23,24.45,21.64,20.36,15.57,15.53,14.70,13.40,10.46。

Embodiment 11:43-O-(2-(4-((2,4 dichlorophenyl) amino methyl)-1H-1,2,3-triazole-1-base) ethyl) oxygen rapamycin (X-13)

By 43-O-(2-azidoethyl)-oxygen rapamycin (0.3mmoL, 0.3g) with N-(Propargyl)-2,4-dichlorphenamide bulk powder (0.1g) joins in DMF (10mL) solution, sodium ascorbate (0.1g) and cupric sulfate pentahydrate (0.08g) is added in reaction solution, stirring at room temperature 2h, after completion of the reaction, reaction is added in 40mL water, separate out faint yellow solid, suction filtration, washing, dry faint yellow solid, be separated with C18 preparative chromatography through silica gel column chromatography, obtain sterling 0.09g, yield: 25.5%.MS(ESI)m/z:1205.4(M+Na) ⁺。 ¹HNMR(500MHz,DMSO)δ7.88(s,1H),7.32(s,1H),7.12(d,J＝8.8Hz,1H),6.75(d,J＝8.9Hz,1H),6.44(s,1H),6.43-6.34(m,1H),6.25-6.17(m,1H),6.16-6.05(m,2H),5.46(dd,J＝14.8,9.7Hz,1H),5.25(s,1H),5.12-5.06(m,1H),5.00-4.95(m,1H),4.95-4.90(m,1H),4.46-4.38(m,4H),4.05-3.97(m,2H),3.95-3.90(m,1H),3.87-3.79(m,2H),3.65-3.59(m,1H),3.47-3.39(m,1H),3.15(s,3H),3.13(s,3H),3.05(s,3H),3.02-2.95(m,2H),2.89-2.78(m,1H),2.75-2.68(m,2H),2.44-2.34(m,1H),2.28-2.17(m,1H),2.13-2.06(m,2H),2.06-1.96(m,2H),1.91-1.79(m,2H),1.73(s,3H),1.63(s,3H),1.61-1.00(m,9H),0.98(d,J＝6.5Hz,3H),0.87(d,J＝6.4Hz,3H),0.83(d,J＝6.3Hz,3H),0.77(d,J＝6.5Hz,3H),0.73(d,J＝6.6Hz,3H)。 ¹³CNMR(126MHz,DMSO)δ210.99,207.99,199.39,169.69,167.48,145.35,143.29,139.82,138.36,137.63,132.85,130.94,128.61,128.14,125.46,123.59,119.67,118.87,113.02,100.00,99.51,86.06,82.94,82.77,82.46,76.26,74.16,68.18,66.72,57.46,57.09,55.97,51.27,50.48,45.71,43.98,38.81,36.12,35.67,35.30,33.91,32.71,31.33,30.15,29.90,28.28,26.94,26.74,24.97,22.15,20.88,16.07,16.06,15.24,13.93,13.90,10.99。

Embodiment 12:43-O-(2-(4-((2,6 difluorophenyl) amino methyl)-1H-1,2,3-triazole-1-base) ethyl) oxygen rapamycin (X-12)

By 43-O-(2-azidoethyl)-oxygen rapamycin (0.3mmoL, 0.3g) with N-(Propargyl)-2,6-difluoroaniline (0.1g) joins in DMF (10mL) solution, sodium ascorbate (0.1g) and cupric sulfate pentahydrate (0.08g) is added in reaction solution, stirring at room temperature 2h, after completion of the reaction, reaction is added in 40mL water, separate out faint yellow solid, suction filtration, washing, dry faint yellow solid, be separated with C18 preparative chromatography through silica gel column chromatography, obtain sterling 0.10g, yield: 29.0%.MS(ESI)m/z:1172.7(M+Na) ⁺。 ¹HNMR(500MHz,DMSO)δ7.82(s,1H),6.89(t,J＝9.1Hz,2H),6.67-6.60(m,1H),6.46(s,1H),6.43-6.32(m,1H),6.28-6.18(m,1H),6.17-6.03(m,2H),5.59-5.51(m,1H),5.46(dd,J＝14.9,9.6Hz,1H),5.27(s,1H),5.13-5.06(m,1H),5.02-4.96(m,1H),4.96-4.90(m,1H),4.47-4.38(m,4H),4.05-3.97(m,2H),3.97-3.92(m,1H),3.89-3.79(m,2H),3.65-3.59(m,1H),3.47-3.40(m,1H),3.32(s,3H),3.16(s,3H),3.05(s,3H),2.91-2.83(m,2H),2.77-2.69(m,1H),2.44-2.35(m,2H),2.28-2.18(m,1H),2.15-2.06(m,2H),2.05-1.98(m,2H),1.92-1.79(m,3H),1.74(s,3H),1.63(s,3H),1.58-1.01(m,10H),0.98(d,J＝6.5Hz,3H),0.87(d,J＝6.5Hz,3H),0.83(d,J＝6.3Hz,4H),0.78(d,J＝6.6Hz,3H),0.73(d,J＝6.6Hz,3H)。 ¹³CNMR(126MHz,DMSO)δ210.46,207.51,198.88,169.22,166.97,145.86,139.30,137.84,137.11,132.34,130.42,126.99,124.88,122.73,116.86,111.70,111.52,99.00,85.50,82.46,82.24,81.97,75.74,73.58,67.79,66.19,56.92,56.56,55.45,50.75,49.88,45.20,43.48,40.47,38.14,35.63,35.17,34.79,33.35,32.11,30.78,29.57,29.42,26.42,26.22,24.45,21.63,20.35,15.57,15.54,14.70,13.44,13.36,10.46。

Embodiment 13:43-O-(2-(4-((2-fluorophenyl) amino methyl)-1H-1,2,3-triazole-1-base) ethyl) oxygen rapamycin (X-19)

By 43-O-(2-azidoethyl)-oxygen rapamycin (0.3mmoL, 0.3g) join in DMF (10mL) solution with N-(Propargyl)-2-fluoroaniline (0.1g), sodium ascorbate (0.1g) and cupric sulfate pentahydrate (0.08g) is added in reaction solution, stirring at room temperature 2h, after completion of the reaction, reaction is added in 40mL water, separate out faint yellow solid, suction filtration, washing, dry faint yellow solid, is separated with C18 preparative chromatography through silica gel column chromatography, obtain sterling 0.08g, yield: 23.2%.MS(ESI)m/z:1154.7(M+Na) ⁺。 ¹HNMR(500MHz,DMSO)δ7.90(s,1H),6.98(dd,J＝12.2,8.0Hz,1H),6.91(t,J＝7.7Hz,1H),6.74(t,J＝8.5Hz,1H),6.56-6.49(m,1H),6.48(s,1H),6.44-6.36(m,1H),6.27-6.18(m,2H),5.95(m,1H),5.46(dd,J＝14.9,9.6Hz,1H),5.29(s,1H),5.08(d,J＝10.0Hz,1H),4.99-4.95(m,1H),4.97-4.91(m,1H),4.43(m,2H),4.36(s,2H),4.06-3.98(m,2H),3.96(m,1H),3.90-3.76(m,4H),3.63(m,1H),3.48-3.39(m,1H),3.29-3.21(m,1H),3.15(s,3H),3.14(s,3H),3.05(s,3H),2.93-2.83(m,1H),2.77-2.68(m,1H),2.45-2.31(m,2H),2.29-2.16(m,1H),2.10(m,1H),2.05-1.96(m,1H),1.90-1.79(m,3H),1.74(s,3H),1.63(s,3H),1.60-1.00(m,10H),0.98(d,J＝6.6Hz,3H),0.86(d,J＝6.5Hz,3H),0.82(d,J＝6.4Hz,3H),0.77(d,J＝6.8Hz,3H),0.73(d,J＝6.6Hz,3H)。 ¹³CNMR(126MHz,DMSO)δ210.47,207.55,198.93,169.24,167.00,151.88,149.99,145.47,139.33,137.87,137.15,136.30,136.20,132.36,130.46,127.05,124.85,124.59,123.06,115.72,115.67,114.28,114.13,112.25,99.03,85.48,82.40,82.25,81.98,75.76,73.60,67.71,66.20,56.93,56.60,55.49,50.78,49.92,45.23,43.51,38.18,35.64,35.20,34.82,33.37,32.12,30.80,29.63,29.40,29.01,26.45,26.24,24.49,21.66,20.40,15.62,15.54,14.70,13.51,13.33,10.48。

Embodiment 14:43-O-(3-(4-(4-fluorophenyl)-1H-1,2,3-triazole-1-base) n-propyl) oxygen rapamycin (X-26)

The preparation of steps A: 43-O-(3-bromopropyl)-oxygen rapamycin

Rapamycin (8.0g, 8.7mmol), diisopropylethylamine (5.6g, 44mmol) are joined in the toluene solution of 50mL, add 3-bromopropyl sulphonate side chain (11.8g, 28.5mmol), finish, be warming up to 60 DEG C of reaction 3h.After completion of the reaction, reaction solution is cooled to room temperature, respectively in dilute hydrochloric acid, saturated sodium bicarbonate and saturated aqueous common salt, organic layer is through anhydrous sodium sulfate drying, and evaporate to dryness obtains faint yellow solid, obtains 4.8g white solid through column chromatography for separation, yield: 53.3%, 1056.5 (M+Na) ⁺.

The preparation of step B:43-O-(3-nitrine propyl group)-oxygen rapamycin

Respectively by 43-O-(3-bromopropyl)-oxygen rapamycin (4.8g, 4.6mmol) with sodiumazide (1.3g, 19.5mmol) join in (30mL) DMF solution, add catalyzer KI (0.1g), after reinforced, be warmed up to 50 DEG C, after reacting completely, by in reaction solution impouring 100mL water, ethyl acetate extracts 2 times, united extraction liquid, washing, anhydrous sodium sulfate drying.Evaporate to dryness obtains oily matter, obtains 2.4g respectively through column chromatography for separation, yield: 52%.MS(ESI)m/z:1019.6(M+Na) ⁺。

The preparation (X-26) of step C:43-O-(3-(4-(4-fluorophenyl)-1H-1,2,3-triazole-1-base) n-propyl) oxygen rapamycin

By 43-O-(3-nitrine propyl group)-oxygen rapamycin (0.35mmoL, 0.35g) join in DMF (10mL) solution with 4-fluorobenzene acetylene (0.1g), sodium ascorbate (0.1g) and cupric sulfate pentahydrate (0.08g) is added in reaction solution, stirring at room temperature 2h, after completion of the reaction, reaction is added in 60mL water, separate out faint yellow solid, suction filtration, washing, dry faint yellow solid, is separated with C18 preparative chromatography through silica gel column chromatography, obtain sterling 0.19g, yield: 43.4%.MS(ESI)m/z:1139.7(M+Na) ⁺。 ¹HNMR(500MHz,DMSO)δ8.56(s,1H),7.87(dd,J＝7.9,5.8Hz,2H),7.28(t,J＝8.7Hz,2H),6.44(s,1H),6.41-6.32(m,1H),6.26-6.18(m,1H),6.17-6.08(m,2H),5.51-5.42(m,1H),5.25(s,1H),5.10(d,J＝10.2Hz,1H),5.02-4.97(m,1H),4.97-4.91(m,1H),4.50-4.43(m,2H),4.06-3.98(m,2H),3.97-3.91(m,1H),3.67-3.58(m,1H),3.57-3.42(m,3H),3.34(s,3H),3.16(s,3H),3.05(s,3H),2.90-2.65(m,2H),2.45-2.34(m,2H),2.28-2.17(m,1H),2.14-2.03(m,2H),2.01-1.90(m,2H),1.89-1.78(m,2H),1.74(s,3H),1.64(s,3H),1.60-1.04(m,10H),0.98(d,J＝6.3Hz,3H),0.88(d,J＝6.3Hz,3H),0.83(d,J＝6.1Hz,3H),0.78(d,J＝6.4Hz,3H),0.74(d,J＝6.4Hz,3H)。 ¹³CNMR(126MHz,DMSO)δ210.43,207.48,198.85,169.18,166.96,162.64,160.70,145.34,139.27,137.82,137.10,132.31,130.40,127.43,127.06,126.99,124.90,121.29,115.82,115.65,98.98,85.51,82.42,82.23,81.97,75.73,73.59,66.18,65.45,56.91,56.88,55.43,50.74,46.84,45.18,43.46,38.21,35.82,35.14,34.77,33.34,32.23,30.83,30.36,29.61,29.52,26.40,26.21,24.43,21.61,20.33,15.52,14.69,13.39,13.36,10.44。

Embodiment 15:43-O-(3-(4-(4-chloro-phenyl-)-1H-1,2,3-triazole-1-base) n-propyl) oxygen rapamycin (X-27)

By 43-O-(3-nitrine propyl group)-oxygen rapamycin (0.35mmoL, 0.35g) join in DMF (10mL) solution with 4-chlorobenzene acetylene (0.1g), sodium ascorbate (0.1g) and cupric sulfate pentahydrate (0.08g) is added in reaction solution, stirring at room temperature 2h, after completion of the reaction, reaction is added in 60mL water, separate out faint yellow solid, suction filtration, washing, dry faint yellow solid, is separated with C18 preparative chromatography through silica gel column chromatography, obtain sterling 0.16g, yield: 41.0%.MS(ESI)m/z:1155.7(M+Na) ⁺。 ¹HNMR(500MHz,DMSO)δ8.62(s,1H),7.86(d,J＝8.5Hz,2H),7.51(d,J＝8.6Hz,2H),6.45(s,1H),6.44-6.35(m,1H),6.26-6.17(m,1H),6.17-6.09(m,2H),5.46(dd,J＝14.9,9.6Hz,1H),5.26(s,1H),5.10(d,J＝10.1Hz,1H),5.01-4.96(m,1H),4.96-4.91(m,1H),4.50-4.42(m,2H),4.06-3.98(m,2H),3.97-3.93(m,1H),3.65-3.60(m,1H),3.58-3.38(m,3H),3.33(s,3H),3.29-3.22(m,1H),3.16(s,3H),3.05(s,3H),2.87-2.69(m,2H),2.44-2.33(m,2H),2.27-2.17(m,1H),2.13-2.01(m,2H),2.00-1.91(m,2H),1.90-1.79(m,2H),1.75(s,3H),1.63(s,3H),1.60-1.02(m,10H),0.98(d,J＝6.6Hz,3H),0.87(d,J＝6.5Hz,3H),0.82(d,J＝6.5Hz,3H),0.78(d,J＝6.7Hz,3H),0.73(d,J＝6.6Hz,3H)。 ¹³CNMR(126MHz,DMSO)δ210.43,207.51,198.88,169.20,166.98,145.13,139.28,137.84,137.12,132.33,132.15,130.42,129.77,128.91,127.01,126.73,124.87,121.77,99.00,85.50,82.43,82.23,81.98,75.74,73.60,66.19,65.46,56.91,55.46,50.76,46.91,45.19,43.49,38.23,35.82,35.16,34.79,33.34,32.22,30.84,30.35,29.63,29.54,26.42,26.23,24.45,21.63,20.36,15.57,15.53,14.69,13.44,13.34,10.46。

Embodiment 16:43-O-(3-(4-(4-aminomethyl phenyl)-1H-1,2,3-triazole-1-base) n-propyl) oxygen rapamycin (X-21)

By 43-O-(3-nitrine propyl group)-oxygen rapamycin (0.35mmoL, 0.35g) join in DMF (10mL) solution with 4-methylbenzene acetylene (0.1g), sodium ascorbate (0.1g) and cupric sulfate pentahydrate (0.08g) is added in reaction solution, stirring at room temperature 2h, after completion of the reaction, reaction is added in 60mL water, separate out faint yellow solid, suction filtration, washing, dry faint yellow solid, is separated with C18 preparative chromatography through silica gel column chromatography, obtain sterling 0.18g, yield: 46.1%.MS(ESI)m/z:1135.7(M+Na) ⁺。 ¹HNMR(500MHz,DMSO)δ8.52(s,1H),7.72(d,J＝8.0Hz,2H),7.25(d,J＝7.8Hz,2H),6.48(s,1H),6.44-6.36(m,1H),6.26-6.19(m,1H),6.17-6.08(m,2H),5.51-5.42(m,1H),5.30(s,1H),5.02-4.96(m,1H),4.94(m,1H),4.49-4.40(m,1H),4.06-3.97(m,2H),3.98-3.92(m,1H),3.66-3.57(m,1H),3.57-3.40(m,3H),3.30-3.23(m,1H),3.34(s,3H),3.15(s,3H),3.05(s,3H),2.85-2.78(m,1H),2.77-2.68(m,1H),2.43-2.34(m,1H),2.33(s,3H),2.27-2.17(m,1H),2.14-2.00(m,2H),2.00-1.87(m,2H),1.89-1.79(m,2H),1.75(s,3H),1.63(s,3H),1.60-1.02(m,10H),0.98(d,J＝6.5Hz,3H),0.87(d,J＝6.5Hz,3H),0.82(d,J＝6.4Hz,3H),0.78(d,J＝6.6Hz,3H),0.73(d,J＝6.6Hz,3H)。 ¹³CNMR(126MHz,DMSO)δ210.46,207.56,198.93,169.24,167.01,146.30,139.31,137.88,137.17,137.03,132.35,130.47,129.42,128.12,127.03,125.01,124.86,121.04,99.04,85.48,82.45,82.25,82.03,75.76,73.61,66.20,65.49,56.95,55.49,50.78,46.80,45.23,43.52,38.24,35.86,35.20,34.83,33.36,32.22,30.88,30.41,29.55,26.45,26.24,24.48,21.65,20.83,20.40,15.62,15.54,14.70,13.51,13.32,10.48。

Embodiment 17:43-O-(3-(phenyl-1H-1,2,3-triazole-1-base) n-propyl) oxygen rapamycin (X-22)

By 43-O-(3-nitrine propyl group)-oxygen rapamycin (0.35mmoL, 0.35g) join in DMF (10mL) solution with phenylacetylene (0.1g), sodium ascorbate (0.1g) and cupric sulfate pentahydrate (0.08g) is added in reaction solution, stirring at room temperature 2h, after completion of the reaction, reaction is added in 60mL water, separate out faint yellow solid, suction filtration, washing, dry faint yellow solid, is separated with C18 preparative chromatography through silica gel column chromatography, obtain sterling 0.15g, yield: 38.4%.MS(ESII)m/z:1121.7(M+Na) ⁺。 ¹HNMR(500MHz,DMSO)δ8.58(s,1H),7.83(d,J＝7.7Hz,2H),7.45(t,J＝7.6Hz,2H),7.37-7.28(m,1H),6.48(s,1H),6.45-6.37(m,1H),6.21(m,1H),6.17-6.09(m,2H),5.51-5.42(m,1H),5.29(s,1H),5.13-5.05(m,1H),5.00-4.96(m,1H),4.95(m,1H),4.50-4.42(m,2H),4.06-3.99(m,2H),3.96(d,J＝4.2Hz,1H),3.66-3.59(m,1H),3.57-3.41(m,3H),3.34(s,3H),3.27(m,1H),3.15(s,3H),3.05(s,3H),2.86-2.77(m,1H),2.77-2.69(m,1H),2.43-2.33(m,2H),2.22(m,1H),2.14-1.99(m,2H),2.01-1.88(m,2H),1.89-1.79(m,2H),1.75(s,3H),1.63(s,3H),1.60-1.00(m,10H),0.98(d,J＝6.5Hz,3H),0.87(d,J＝6.4Hz,3H),0.82(d,J＝6.4Hz,3H),0.78(d,J＝6.5Hz,3H),0.73(d,J＝6.6Hz,3H)。 ¹³CNMR(126MHz,DMSO)δ210.45,207.56,198.92,169.24,167.01,146.24,139.31,137.88,137.16,132.35,130.88,130.47,128.88,127.77,127.03,125.07,121.46,110.97,99.03,85.48,82.45,82.24,82.03,75.76,73.61,66.20,65.48,56.95,55.49,50.78,46.84,45.23,43.52,38.25,35.85,35.20,34.83,33.37,32.22,30.87,30.41,29.63,29.56,26.44,26.25,24.48,21.66,20.41,15.62,15.55,14.71,13.51,13.32,10.48。

Embodiment 18:43-O-(3-(4-(3-aminomethyl phenyl)-1H-1,2,3-triazole-1-base) n-propyl) oxygen rapamycin (X-31)

By 43-O-(3-nitrine propyl group)-oxygen rapamycin (0.35mmoL, 0.35g) join in DMF (10mL) solution with 3-methylbenzene acetylene (0.1g), sodium ascorbate (0.1g) and cupric sulfate pentahydrate (0.08g) is added in reaction solution, stirring at room temperature 2h, after completion of the reaction, reaction is added in 60mL water, separate out faint yellow solid, suction filtration, washing, dry faint yellow solid, is separated with C18 preparative chromatography through silica gel column chromatography, obtain sterling 0.19g, yield: 48.7%.MS(ESII)m/z:1135.4(M+Na) ⁺。 ¹HNMR(500MHz,DMSO)δ8.54(s,1H),7.67(s,1H),7.61(d,J＝7.8Hz,1H),7.32(t,J＝7.6Hz,1H),7.14(d,J＝7.6Hz,1H),6.45(s,1H),6.44-6.33(m,1H),6.27-6.17(m,1H),6.17-6.07(m,2H),5.46(dd,J＝14.8,9.7Hz,1H),5.27(s,1H),5.02-4.96(m,1H),4.96-4.92(m,1H),4.50-4.41(m,2H),4.06-3.97(m,2H),4.00-3.90(m,1H),3.67-3.59(m,1H),3.58-3.41(m,3H),3.34(s,3H),3.16(s,3H),3.05(s,3H),2.85-2.69(m,2H),2.45-2.37(m,2H),2.35(s,3H),2.27-2.18(m,1H),2.13-2.02(m,3H),1.97-1.90(m,2H),1.89-1.78(m,2H),1.74(s,3H),1.63(s,3H),1.60-1.02(m,10H),0.98(d,J＝6.5Hz,3H),0.87(d,J＝6.5Hz,3H),0.83(d,J＝6.4Hz,3H),0.78(d,J＝6.6Hz,3H),0.74(d,J＝6.6Hz,3H)。 ¹³CNMR(126MHz,DMSO)δ210.44,198.89,169.20,166.98,146.31,139.29,137.95,137.84,137.13,132.33,130.78,130.43,128.73,128.37,127.01,125.63,124.89,122.23,121.35,99.00,85.51,82.43,82.24,81.99,75.74,73.60,66.19,65.47,56.91,55.45,50.75,46.80,45.20,43.49,38.22,35.82,35.17,34.80,33.35,32.23,30.85,30.36,29.54,26.42,26.22,24.45,21.63,21.03,15.57,15.53,14.70,13.43,13.35,10.45。

Embodiment 19:43-O-(3-(4-(2-chloro-phenyl-)-1H-1,2,3-triazole-1-base) n-propyl) oxygen rapamycin (X-32)

By 43-O-(3-nitrine propyl group)-oxygen rapamycin (0.35mmoL, 0.35g) join in DMF (10mL) solution with 2-chlorobenzene acetylene (0.1g), sodium ascorbate (0.1g) and cupric sulfate pentahydrate (0.08g) is added in reaction solution, stirring at room temperature 2h, after completion of the reaction, reaction is added in 60mL water, separate out faint yellow solid, suction filtration, washing, dry faint yellow solid, is separated with C18 preparative chromatography through silica gel column chromatography, obtain sterling 0.16g, yield: 40.5%.MS(ESI)m/z:1155.6(M+Na) ⁺。 ¹HNMR(500MHz,DMSO)δ8.63(s,1H),8.07(d,J＝7.8Hz,1H),7.56(d,J＝9.1Hz,1H),7.47-7.43(m,1H),7.42-7.35(m,1H),6.45(s,1H),6.43-6.34(m,1H),6.26-6.18(m,1H),6.17-6.08(m,2H),5.46(dd,J＝14.8,9.7Hz,1H),5.27(s,1H),5.09(d,J＝10.2Hz,1H),5.01-4.95(m,1H),4.94-4.92(m,1H),4.55-4.49(m,2H),4.05-3.98(m,2H),3.96-3.91(m,1H),3.66-3.58(m,1H),3.57-3.39(m,3H),3.33(s,3H),3.30-3.23(m,1H),3.15(s,3H),3.05(s,3H),2.84-2.70(m,2H),2.47-2.35(m,2H),2.25-2.17(m,1H),2.14-2.04(m,3H),2.02-1.90(m,2H),1.89-1.79(m,2H),1.74(s,3H),1.63(s,3H),1.60-1.01(m,10H),0.98(d,J＝6.5Hz,3H),0.87(d,J＝6.5Hz,3H),0.82(d,J＝6.4Hz,3H),0.78(d,J＝6.7Hz,3H),0.73(d,J＝6.6Hz,3H)。 ¹³CNMR(126MHz,DMSO)δ210.47,207.50,198.90,169.18,166.97,142.46,139.28,137.83,137.13,132.31,130.41,130.26,130.16,129.46,129.32,127.47,127.00,124.92,124.41,110.92,98.99,85.51,82.41,82.24,82.04,75.72,73.60,66.18,65.39,56.90,55.44,50.72,46.81,45.18,43.47,38.19,35.79,35.16,34.79,33.34,32.21,30.86,30.40,29.52,26.41,26.21,24.44,21.62,20.35,15.55,15.52,14.68,13.37,10.45。

Embodiment 20:43-O-(3-(4-(4-bromophenyl)-1H-1,2,3-triazole-1-base) n-propyl) oxygen rapamycin (X-30)

By 43-O-(3-nitrine propyl group)-oxygen rapamycin (0.35mmoL, 0.35g) join in DMF (10mL) solution with 4-bromobenzene acetylene (0.1g), sodium ascorbate (0.1g) and cupric sulfate pentahydrate (0.08g) is added in reaction solution, stirring at room temperature 2h, after completion of the reaction, reaction is added in 60mL water, separate out faint yellow solid, suction filtration, washing, dry faint yellow solid, is separated with C18 preparative chromatography through silica gel column chromatography, obtain sterling 0.14g, yield: 34.0%.MS(ESI)m/z:1200.3(M+Na) ⁺。 ¹HNMR(500MHz,DMSO)δ8.63(s,1H),7.79(d,J＝8.2Hz,2H),7.64(d,J＝8.2Hz,2H),6.46(s,1H),6.44-6.34(m,1H),6.27-6.19(m,1H),6.17-6.08(m,2H),5.46(dd,J＝14.7,9.6Hz,1H),5.27(s,1H),5.13-5.07(m,1H),5.02-4.96(m,1H),4.97-4.91(m,1H),4.52-4.42(m,2H),4.06-3.97(m,2H),3.98-3.91(m,1H),3.63(m,1H),3.57-3.40(m,3H),3.33(s,3H),3.16(s,3H),3.05(s,3H),2.86-2.68(m,2H),2.44-2.34(m,2H),2.25-2.18(m,1H),2.14-2.01(m,3H),1.98-1.90(m,2H),1.89-1.79(m,2H),1.75(s,3H),1.63(s,3H),1.60-1.02(m,10H),0.98(d,J＝6.4Hz,3H),0.87(d,J＝6.3Hz,3H),0.83(d,J＝6.3Hz,3H),0.78(d,J＝6.4Hz,3H),0.73(d,J＝6.5Hz,3H)。 ¹³CNMR(126MHz,DMSO)δ210.43,207.51,198.88,169.21,166.98,145.16,139.29,137.84,137.12,132.33,131.82,130.42,130.12,127.02,124.88,121.80,120.68,99.00,85.50,82.43,82.23,81.98,75.74,73.60,66.19,65.46,56.91,55.46,50.75,46.91,45.20,43.49,38.23,35.83,35.17,34.79,33.34,32.23,30.84,30.34,29.64,29.54,26.42,26.23,24.45,21.63,20.37,15.57,15.53,14.70,13.44,13.34,10.46。

Embodiment 21:43-O-(3-(4-(4-p-methoxy-phenyl)-1H-1,2,3-triazole-1-base) n-propyl) oxygen rapamycin (X-29)

By 43-O-(3-nitrine propyl group)-oxygen rapamycin (0.35mmoL, 0.35g) join in DMF (10mL) solution with 4-Methoxy-phenylacetylene (0.1g), sodium ascorbate (0.1g) and cupric sulfate pentahydrate (0.08g) is added in reaction solution, stirring at room temperature 2h, after completion of the reaction, reaction is added in 60mL water, separate out faint yellow solid, suction filtration, washing, dry faint yellow solid, is separated with C18 preparative chromatography through silica gel column chromatography, obtain sterling 0.19g, yield: 48.1%.MS(ESII)m/z:1151.5(M+Na) ⁺。 ¹HNMR(500MHz,DMSO)δ8.45(s,1H),7.75(d,J＝8.7Hz,2H),7.01(d,J＝8.8Hz,2H),6.45(s,1H),6.44-6.30(m,1H),6.27-6.19(m,1H),6.17-6.04(m,2H),5.46(dd,J＝14.8,9.6Hz,1H),5.28(s,1H),5.10(d,J＝10.2Hz,1H),5.02-4.96(m,1H),4.96-4.92(m,1H),4.48-4.37(m,2H),4.06-3.97(m,2H),3.97-3.89(m,1H),3.79(s,3H),3.66-3.59(m,1H),3.58-3.39(m,3H),3.34(s,3H),3.16(s,3H),3.05(s,3H),2.85-2.68(m,1H),2.44-2.34(m,2H),2.29-2.14(m,1H),2.15-2.01(m,3H),2.01-1.89(m,2H),1.89-1.77(m,2H),1.75(s,3H),1.63(s,3H),1.62-1.03(m,10H),0.98(d,J＝6.6Hz,3H),0.87(d,J＝6.5Hz,3H),0.83(d,J＝6.5Hz,3H),0.78(d,J＝6.7Hz,3H),0.74(d,J＝6.6Hz,3H)。 ¹³CNMR(126MHz,DMSO)δ210.44,207.51,198.88,169.20,166.98,158.90,146.15,139.29,137.84,137.13,132.33,130.42,127.01,126.38,124.88,123.47,120.45,114.25,99.00,85.50,82.43,82.23,82.00,75.74,73.60,66.19,65.48,56.92,55.45,55.10,50.75,46.74,45.20,43.49,38.23,35.83,35.16,34.79,33.35,32.23,30.86,30.40,29.64,29.54,26.42,26.23,24.45,21.63,20.37,15.57,15.52,14.70,13.44,13.34,10.46。

Embodiment 22:43-O-(3-(4-((2,5 dichlorophenyl) amino methyl)-1H-1,2,3-triazole-1-base) n-propyl) oxygen rapamycin (X-23)

By 43-O-(3-nitrine propyl group)-oxygen rapamycin (0.35mmoL, 0.35g) with N-(Propargyl)-2,5-dichlorphenamide bulk powder (0.1g) joins in DMF (10mL) solution, sodium ascorbate (0.1g) and cupric sulfate pentahydrate (0.08g) is added in reaction solution, stirring at room temperature 2h, after completion of the reaction, reaction is added in 60mL water, separate out faint yellow solid, suction filtration, washing, dry faint yellow solid, be separated with C18 preparative chromatography through silica gel column chromatography, obtain sterling 0.09g, yield: 21.5%.MS(ESII)m/z:1218.7(M+Na) ⁺。 ¹HNMR(500MHz,DMSO)δ7.92(s,1H),7.24(d,J＝8.4Hz,1H),6.75(s,1H),6.59(d,J＝8.4Hz,1H),6.44(s,1H),6.41-6.33(m,1H),6.26-6.17(m,2H),6.16-6.09(m,2H),5.47(dd,J＝14.9,9.6Hz,1H),5.26(s,1H),5.13-5.07(m,1H),5.03-4.96(m,1H),4.97-4.90(m,1H),4.47-4.35(m,4H),4.07-3.92(m,3H),3.66-3.59(m,1H),3.49-3.39(m,2H),3.29(s,3H),3.16(s,3H),3.05(s,3H),2.98-2.89(m,2H),2.87-2.77(m,1H),2.77-2.68(m,1H),2.46-2.35(m,2H),2.28-2.18(m,1H),2.16-2.06(m,1H),2.06-1.96(m,3H),1.94-1.79(m,3H),1.74(s,3H),1.63(s,3H),1.60-1.00(m,10H),0.98(d,J＝6.5Hz,3H),0.88(d,J＝6.5Hz,3H),0.83(d,J＝6.4Hz,3H),0.78(d,J＝6.7Hz,3H),0.74(d,J＝6.6Hz,3H)。 ¹³CNMR(126MHz,DMSO)δ210.44,207.47,198.85,169.19,166.95,144.83,144.72,139.28,137.82,137.10,132.44,132.32,130.00,126.96,124.89,122.85,116.50,115.96,110.87,98.98,85.51,82.33,82.24,81.96,75.73,73.59,66.31,66.18,65.27,56.92,56.82,55.44,50.75,46.53,45.19,43.46,38.22,35.74,35.15,34.77,33.36,32.22,30.81,30.38,29.62,29.43,26.41,26.22,24.44,21.61,20.34,15.55,15.52,14.73,13.40,13.37,10.45。

Embodiment 23:43-O-(3-(4-((2,4 dichlorophenyl) amino methyl)-1H-1,2,3-triazole-1-base) n-propyl) oxygen rapamycin (X-25)

By 43-O-(3-nitrine propyl group)-oxygen rapamycin (0.35mmoL, 0.35g) with N-(Propargyl)-2,4-dichlorphenamide bulk powder (0.1g) joins in DMF (10mL) solution, sodium ascorbate (0.1g) and cupric sulfate pentahydrate (0.08g) is added in reaction solution, stirring at room temperature 2h, after completion of the reaction, reaction is added in 60mL water, separate out faint yellow solid, suction filtration, washing, dry faint yellow solid, be separated with C18 preparative chromatography through silica gel column chromatography, obtain sterling 0.10g, yield: 23.9%.MS(ESI)m/z:1218.6(M+Na) ⁺。 ¹HNMR(500MHz,DMSO)δ7.89(s,1H),7.32(s,1H),7.13(d,J＝8.7Hz,1H),6.72(d,J＝8.8Hz,1H),6.44(s,1H),6.41-6.31(m,1H),6.29-6.17(m,1H),6.18-6.05(m,2H),5.51-5.41(m,1H),5.26(s,1H),5.10(d,J＝9.6Hz,1H),5.02-4.96(m,1H),4.96-4.93(m,1H),4.43(s,2H),4.41-4.32(m,2H),4.05-3.97(m,2H),3.94(m,1H),3.66-3.59(m,1H),3.49-3.38(m,3H),3.29(s,3H),3.16(s,3H),3.05(s,3H),2.97-2.86(m,2H),2.84-2.66(m,2H),2.44-2.34(m,2H),2.28-2.15(m,1H),2.14-2.00(m,2H),2.01-1.93(m,2H),1.93-1.79(m,2H),1.74(s,3H),1.63(s,3H),1.60-1.02(m,11H),0.98(d,J＝6.4Hz,3H),0.87(d,J＝6.5Hz,3H),0.83(d,J＝6.5Hz,3H),0.78(d,J＝6.6Hz,3H),0.73(d,J＝6.6Hz,3H)。 ¹³CNMR(126MHz,DMSO)δ210.42,207.46,198.84,169.18,166.95,144.92,142.79,139.27,137.82,137.09,132.31,130.39,128.12,127.60,126.95,124.88,122.83,119.14,118.38,112.45,98.98,85.50,82.32,82.23,81.95,75.73,73.57,66.17,65.26,56.91,56.80,55.43,50.75,46.48,45.18,43.46,38.40,38.19,35.73,35.14,34.77,33.37,32.22,30.77,30.36,29.42,26.41,26.22,24.43,21.61,20.34,15.55,15.52,14.75,13.40,13.36,10.45。

Embodiment 24:43-O-(3-(4-((2,6 difluorophenyl) amino methyl)-1H-1,2,3-triazole-1-base) n-propyl) oxygen rapamycin (X-24)

By 43-O-(3-nitrine propyl group)-oxygen rapamycin (0.35mmoL, 0.35g) with N-(Propargyl)-2,6-difluoroaniline (0.1g) joins in DMF (10mL) solution, sodium ascorbate (0.1g) and cupric sulfate pentahydrate (0.08g) is added in reaction solution, stirring at room temperature 2h, after completion of the reaction, reaction is added in 60mL water, separate out faint yellow solid, suction filtration, washing, dry faint yellow solid, be separated with C18 preparative chromatography through silica gel column chromatography, obtain sterling 0.12g, yield: 29.8%.MS(ESII)m/z:1186.7(M+Na) ⁺。 ¹HNMR(500MHz,DMSO)δ7.84(s,1H),6.89(t,J＝9.0Hz,2H),6.70-6.60(m,1H),6.44(s,1H),6.41-6.32(m,1H),6.28-6.17(m,1H),6.18-6.07(m,2H),5.53-5.42(m,2H),5.26(s,1H),5.10(d,J＝9.9Hz,1H),5.03-4.97(m,1H),4.96(m,1H),4.45(s,2H),4.38-4.33(m,2H),4.05-3.98(m,2H),3.98-3.92(m,1H),3.67-3.60(m,1H),3.48-3.36(m,3H),3.31(s,3H),3.16(s,3H),3.05(s,3H),2.99-2.93(m,2H),2.86-2.78(m,1H),2.76-2.70(m,1H),2.46-2.35(m,2H),2.27-2.17(m,1H),2.15-2.02(m,2H),1.99-1.89(m,2H),1.89-1.78(m,2H),1.75(s,3H),1.64(s,3H),1.58-1.01(m,10H),0.98(d,J＝6.4Hz,3H),0.88(d,J＝6.4Hz,3H),0.83(d,J＝6.4Hz,3H),0.78(d,J＝6.6Hz,3H),0.74(d,J＝6.5Hz,3H)。

Embodiment 25:43-O-(3-(4-((2-fluorophenyl) amino methyl)-1H-1,2,3-triazole-1-base) n-propyl) oxygen rapamycin (X-28)

By 43-O-(3-nitrine propyl group)-oxygen rapamycin (0.35mmoL, 0.35g) join in DMF (10mL) solution with N-(Propargyl)-2-fluoroaniline (0.1g), sodium ascorbate (0.1g) and cupric sulfate pentahydrate (0.08g) is added in reaction solution, stirring at room temperature 2h, after completion of the reaction, reaction is added in 60mL water, separate out faint yellow solid, suction filtration, washing, dry faint yellow solid, is separated with C18 preparative chromatography through silica gel column chromatography, obtain sterling 0.10g, yield: 24.7%.MS(ESII)m/z:1168.5(M+Na) ⁺。 ¹HNMR(500MHz,DMSO)δ7.91(s,1H),6.99(dd,J＝12.2,7.9Hz,1H),6.91(t,J＝7.6Hz,1H),6.74(t,J＝8.7Hz,1H),6.54(dd,J＝12.4,6.4Hz,1H),6.46(s,1H),6.44-6.34(m,1H),6.26-6.18(m,1H),6.17-6.08(m,2H),5.90(s,1H),5.51-5.43(m,1H),5.28(s,1H),5.10(d,J＝10.2Hz,1H),5.01-4.96(m,1H),4.97-4.90(m,1H),4.41-4.31(m,4H),4.05-3.97(m,2H),3.98-3.92(m,1H),3.66-3.58(m,1H),3.49-3.35(m,3H),3.32(s,3H),3.16(s,3H),3.05(s,3H),3.00-2.89(m,2H),2.85-2.69(m,2H),2.43-2.34(m,2H),2.27-2.17(m,1H),2.15-2.02(m,2H),2.02-1.93(m,2H),1.93-1.79(m,2H),1.75(s,3H),1.63(s,3H),1.62-1.02(m,10H),0.98(d,J＝6.5Hz,3H),0.87(d,J＝6.4Hz,3H),0.83(d,J＝6.3Hz,3H),0.78(d,J＝6.6Hz,3H),0.74(d,J＝6.5Hz,3H)。 ¹³CNMR(126MHz,DMSO)δ210.43,207.51,198.87,169.21,166.97,145.50,139.30,137.84,137.12,136.30,136.21,132.33,130.42,127.02,124.86,124.56,122.79,115.71,114.28,114.14,112.22,99.00,85.49,82.36,82.23,81.96,75.75,73.59,66.19,65.35,56.91,56.87,55.46,50.77,46.50,45.20,43.49,38.26,35.79,35.17,34.79,33.36,32.21,30.81,30.44,29.63,29.57,29.47,26.43,26.23,24.46,21.63,20.36,15.57,15.53,14.72,13.46,13.34,10.46。

Embodiment 26:43-O-(2-(4-(4-fluorophenyl)-1H-1,2,3-triazole-1-base) ethanoyl) oxygen rapamycin (X-39)

Steps A: the preparation of 28-oxygen base TMS-rapamycin

Respectively by rapamycin (5.5mmol, 5.0g) join in ethyl acetate (80mL) solution with imidazoles (1.5g), after reinforced, be cooled to 0-5 DEG C, drip trimethylchlorosilane (40mmol, 4.3g), insulation reaction 2 hours.When after formation two silicon ether protection product, incline to reaction solution and add dilute sulphuric acid (15mL, 1NH ₂sO ₄), continue stirring reaction and be about 16h, after completion of the reaction, reaction solution is respectively through saturated sodium bicarbonate, and saturated common salt water washing, organic layer is through anhydrous sodium sulfate drying, and evaporate to dryness obtains white foam solid 5.1g, yield: 95%.MS(ESI)m/z:1008.5(M+Na) ⁺。

The preparation of step B:28-oxygen base TMS-43-O-(2-chloracetyl)-oxygen rapamycin

28-OTMS-rapamycin (2.6g, 2.6mmol) and anhydrous methylene chloride (40mL) are joined in three-necked bottle, adds triethylamine (3mL), chloroacetyl chloride (0.59g is dropwise added at 0-5 DEG C, 5.2mmol), finish, 0-5 DEG C of reaction 6h.After completion of the reaction, by reaction solution impouring 300mL water, dichloromethane extraction, united extraction liquid, washing, anhydrous sodium sulfate drying.Evaporate to dryness obtains white solid 2.1g, yield: 76.1%MS (ESI) m/z:1084.6 (M+Na) ⁺.

The preparation of step C:43-O-(2-chloracetyl)-oxygen rapamycin

28-OTMS-43-O-(2-chloracetyl)-oxygen rapamycin (2mmol, 2.1g) is joined in acetone (36mL) solution, is cooled to 0-5 DEG C after reinforced, adds dilute sulphuric acid (10mL, 1NH to reaction solution ₂sO ₄), continue stirring reaction and be about 2h, after completion of the reaction, reaction solution is respectively through saturated sodium bicarbonate, and saturated common salt water washing, organic layer is through anhydrous sodium sulfate drying, and evaporate to dryness obtains white foam solid 1.8g, yield: 91%.MS(ESI)m/z:1012.5(M+Na) ⁺。

The preparation of step D:43-O-(2-acetyl azide)-oxygen rapamycin

Respectively by 43-O-(2-chloracetyl)-oxygen rapamycin (1.8g; 1.8mmol) with sodiumazide (0.3g; 4.6mmol) join in (300mL) DMF solution; 50 DEG C, after reacting completely are warmed up to, by reaction solution impouring 100mL water after reinforced; ethyl acetate extracts 2 times; united extraction liquid, washing, anhydrous sodium sulfate drying.Evaporate to dryness obtains oily matter, obtains 0.6g respectively through column chromatography for separation, and yield is 33%.MS(ESI)m/z:1019.5(M+Na) ⁺。

The preparation of step e: 43-O-(2-(4-(4-fluorophenyl)-1H-1,2,3-triazole-1-base) ethanoyl) oxygen rapamycin

By 43-O-(2-acetyl azide)-oxygen rapamycin (0.35mmoL; 0.35g) join in DMF (10mL) solution with propiolic alcohol (0.1g); sodium ascorbate (0.1g) and cupric sulfate pentahydrate (0.08g) is added in reaction solution; stirring at room temperature 2h; after completion of the reaction; reaction is added in 30mL water; separate out faint yellow solid; suction filtration; washing, dry faint yellow solid, is separated with C18 preparative chromatography through silica gel column chromatography; obtain sterling 0.14g, yield: 34.6%.MS(ESI)m/z:1139.6(M+Na) ⁺。 ¹HNMR(500MHz,DMSO)δ8.57(s,1H),7.94-7.87(m,2H),7.33-7.27(m,2H),6.46(s,1H),6.43-6.35(m,1H),6.26-6.18(m,1H),6.17-6.09(m,2H),5.51-5.43(m,2H),5.29(s,1H),5.10(d,J＝9.9Hz,1H),5.00-4.96(m,1H),4.96-4.92(m,1H),4.70-4.60(m,1H),4.05-3.98(m,2H),3.99-3.93(m,1H),3.66-3.58(m,1H),3.48-3.38(m,1H),3.27(s,3H),3.16(s,3H),3.05(s,3H),2.86-2.69(m,2H),241–2.37(m,2H),2.26-2.16(m,1H),2.14-2.06(m,2H),2.07-1.89(m,3H),1.87-1.77(m,2H),1.75(s,3H),1.63(s,3H),1.60-1.03(m,10H),0.98(d,J＝6.3Hz,3H),0.87(d,J＝6.4Hz,3H),0.82(d,J＝6.3Hz,3H),0.78(d,J＝6.5Hz,3H),0.73(d,J＝6.3Hz,3H)。 ¹³CNMR(126MHz,DMSO)δ210.38,207.53,198.86,169.22,166.99,166.70,160.82,145.48,139.31,137.86,137.15,132.34,130.41,127.21,127.14,127.09,126.99,124.81,122.66,115.94,115.77,99.01,85.46,82.22,79.85,77.74,75.73,73.65,66.19,56.89,56.76,55.45,50.78,50.67,45.23,43.50,38.01,35.16,34.80,33.32,31.87,30.43,29.65,29.14,26.40,26.23,24.44,21.62,20.37,15.52,14.63,13.50,13.29,10.45。

Embodiment 27:43-O-(2-(4-(4-chloro-phenyl-)-1H-1,2,3-triazole-1-base) ethanoyl) oxygen rapamycin (X-35)

By 43-O-(2-acetyl azide)-oxygen rapamycin (0.35mmoL; 0.35g) join in DMF (10mL) solution with 4-fluorobenzene acetylene (0.1g); sodium ascorbate (0.1g) and cupric sulfate pentahydrate (0.08g) is added in reaction solution; stirring at room temperature 2h; after completion of the reaction; reaction is added in 30mL water; separate out faint yellow solid; suction filtration; washing, dry faint yellow solid, is separated with C18 preparative chromatography through silica gel column chromatography; obtain sterling 0.13g, yield: 33.1%.MS(ESI)m/z:1155.6(M+Na) ⁺。 ¹HNMR(500MHz,DMSO)δ8.62(s,1H),7.89(d,J＝8.4Hz,2H),7.52(d,J＝8.4Hz,2H),6.44(s,1H),6.43-6.35(m,1H),6.26-6.17(m,1H),6.16-6.07(m,2H),5.47(s,2H),5.26(s,1H),5.10(d,J＝10.0Hz,1H),5.01-4.96(m,1H),4.95-4.90(m,1H),4.70-4.58(m,1H),4.06-3.97(m,2H),3.98-3.90(m,1H),3.66-3.58(m,1H),3.48-3.40(m,1H),3.27(s,3H),3.16(s,3H),3.05(s,3H),2.86-2.68(m,2H),2.44-2.33(m,2H),2.28-2.18(m,1H),2.15-2.07(m,2H),2.07-1.97(m,2H),1.96-1.79(m,3H),1.74(s,3H),1.63(s,3H),1.60-1.03(m,10H),0.98(d,J＝6.3Hz,3H),0.87(d,J＝6.4Hz,3H),0.82(d,J＝6.3Hz,3H),0.78(d,J＝6.5Hz,3H),0.73(d,J＝6.3Hz,3H)。 ¹³CNMR(126MHz,DMSO)δ210.38,207.49,198.83,169.19,166.97,166.63,145.25,139.29,137.83,137.12,132.34,130.38,129.41,128.95,126.96,126.83,124.84,123.07,98.98,85.48,82.22,79.85,77.74,75.71,73.64,66.18,56.89,56.73,55.42,50.76,50.68,45.21,43.47,37.98,35.27,35.14,34.78,33.32,31.88,30.42,29.64,29.54,29.12,26.39,26.21,24.42,21.60,20.34,15.52,15.50,14.63,13.45,13.32,10.43。

Embodiment 28:43-O-(2-(4-(4-aminomethyl phenyl)-1H-1,2,3-triazole-1-base) ethanoyl) oxygen rapamycin (X-36)

By 43-O-(2-acetyl azide)-oxygen rapamycin (0.35mmoL; 0.35g) join in DMF (10mL) solution with 4-methylbenzene acetylene (0.1g); sodium ascorbate (0.1g) and cupric sulfate pentahydrate (0.08g) is added in reaction solution; stirring at room temperature 2h; after completion of the reaction; reaction is added in 30mL water; separate out faint yellow solid; suction filtration; washing, dry faint yellow solid, is separated with C18 preparative chromatography through silica gel column chromatography; obtain sterling 0.15g, yield: 38.3%.MS(ESI)m/z:1135.7(M+Na) ⁺。 ¹HNMR(500MHz,DMSO)δ8.51(s,1H),7.74(d,J＝7.9Hz,2H),7.27(d,J＝7.8Hz,2H),6.46(s,1H),6.44-6.34(m,1H),6.26-6.17(m,1H),6.16-6.08(m,2H),5.51-5.41(m,3H),5.29(s,1H),5.10(d,J＝10.0Hz,1H),5.00-4.96(m,1H),4.96-4.92(m,1H),4.69-4.60(m,1H),4.05-3.99(m,2H),3.98-3.92(m,1H),3.66-3.58(m,1H),3.49-3.39(m,1H),3.27(s,3H),3.16(s,3H),3.05(s,3H),2.86-2.69(m,2H),2.42-2.35(m,2H),2.33(s,3H),2.24-2.21(m,1H),2.16-2.07(m,2H),2.05-1.96(m,2H),1.97-1.78(m,2H),1.75(s,3H),1.63(s,3H),1.61-1.02(m,10H),0.98(d,J＝6.4Hz,3H),0.87(d,J＝6.4Hz,3H),0.82(d,J＝6.3Hz,3H),0.78(d,J＝6.5Hz,3H),0.73(d,J＝6.4Hz,3H)。 ¹³CNMR(126MHz,DMSO)δ210.39,207.54,198.86,169.22,166.99,166.75,146.39,139.31,137.86,137.23,132.34,130.41,129.46,127.76,127.00,125.07,124.81,122.33,110.93,99.01,85.46,82.22,79.86,77.72,75.72,73.66,66.18,56.89,56.77,55.45,50.78,50.62,45.23,43.49,37.99,35.27,35.16,34.80,33.33,31.87,30.45,29.66,29.57,29.14,26.41,26.22,24.45,21.63,20.80,20.38,15.56,15.52,14.62,13.50,13.30,10.45。

Embodiment 29:43-O-(2-(4-(phenyl)-1H-1,2,3-triazole-1-base) ethanoyl) oxygen rapamycin (X-34)

By 43-O-(2-acetyl azide)-oxygen rapamycin (0.35mmoL; 0.35g) join in DMF (10mL) solution with phenylacetylene (0.1g); sodium ascorbate (0.1g) and cupric sulfate pentahydrate (0.08g) is added in reaction solution; stirring at room temperature 2h; after completion of the reaction; reaction is added in 30mL water; separate out faint yellow solid; suction filtration; washing, dry faint yellow solid, is separated with C18 preparative chromatography through silica gel column chromatography; obtain sterling 0.18g, yield: 44.0%.MS(ESII)m/z:1121.8(M+Na) ⁺。 ¹HNMR(400MHz,DMSO)δ8.59(s,1H),7.86(d,J＝7.3Hz,2H),7.46(t,J＝7.6Hz,2H),7.40-7.25(m,1H),6.48(s,1H),6.46-6.36(m,1H),6.27-6.17(m,1H),6.18-6.07(m,2H),5.47(s,2H),5.31(s,1H),5.14-5.04(m,1H),5.01-4.90(m,2H),4.71-4.59(m,1H),4.06-3.93(m,3H),3.67-3.58(m,1H),3.51-3.39(m,1H),3.27(s,3H),3.15(s,3H),3.05(s,3H),2.86-2.68(m,2H),2.43-2.30(m,2H),2.28-2.16(m,1H),2.16-2.07(m,1H),2.06-1.96(m,2H),1.96-1.78(m,3H),1.75(s,3H),1.63(s,3H),1.58-1.02(m,10H),0.98(d,J＝6.5Hz,3H),0.86(d,J＝6.5Hz,3H),0.82(d,J＝6.4Hz,3H),0.78(d,J＝6.6Hz,3H),0.73(d,J＝6.5Hz,3H)。 ¹³CNMR(101MHz,DMSO)δ210.90,208.05,199.37,169.72,167.49,167.23,146.84,139.82,138.36,137.65,132.85,131.02,130.91,129.43,128.43,127.50,125.64,125.32,123.26,99.51,85.97,82.72,80.36,78.24,76.23,74.17,66.69,57.40,57.27,55.96,51.28,51.16,45.73,44.01,38.49,35.78,35.67,35.30,33.83,32.37,30.96,30.15,29.65,26.92,26.72,24.95,22.13,20.88,16.06,16.02,15.13,14.00,13.81,10.95。

Embodiment 30:43-O-(2-(4-(4-amyl group phenyl)-1H-1,2,3-triazole-1-base) ethanoyl) oxygen rapamycin (X-37)

By 43-O-(2-acetyl azide)-oxygen rapamycin (0.35mmoL; 0.35g) join in DMF (10mL) solution with 4-n-amylbenzene acetylene (0.1g); sodium ascorbate (0.1g) and cupric sulfate pentahydrate (0.08g) is added in reaction solution; stirring at room temperature 2h; after completion of the reaction; reaction is added in 30mL water; separate out faint yellow solid; suction filtration; washing, dry faint yellow solid, is separated with C18 preparative chromatography through silica gel column chromatography; obtain sterling 0.13g, yield: 31.7%.MS(ESI)m/z:1191.7(M+Na) ⁺。 ¹HNMR(500MHz,DMSO)δ8.51(s,1H),7.75(d,J＝8.1Hz,2H),7.27(d,J＝8.1Hz,2H),6.46(s,1H),6.43-6.34(m,1H),6.25-6.18(m,1H),6.16-6.07(m,2H),5.45(s,2H),5.29(s,1H),5.10(d,J＝10.1Hz,1H),5.01-4.96(m,1H),4.95-4.89(m,1H),4.70-4.55(m,1H),4.06-3.98(m,2H),3.98-3.91(m,1H),3.66-3.58(m,1H),3.48-3.38(m,1H),3.27(s,3H),3.15(s,3H),3.05(s,3H),2.86-2.68(m,2H),2.62-2.56(m,2H),2.44-2.33(m,2H),2.26-2.17(m,1H),2.15-2.06(m,1H),2.05-1.97(m,2H),1.95-1.77(m,3H),1.74(s,3H),1.63(s,3H),1.60-1.03(m,10H),0.98(d,J＝6.5Hz,3H),0.89-0.84(m,5H),0.82(d,J＝6.4Hz,3H),0.78(d,J＝6.7Hz,3H),0.73(d,J＝6.6Hz,3H)。 ¹³CNMR(126MHz,DMSO)δ210.95,208.02,199.37,169.72,167.51,167.21,146.94,142.69,139.84,138.36,137.66,132.87,130.91,129.30,128.53,127.51,125.63,125.43,122.84,99.52,86.07,82.77,80.41,78.24,76.25,74.21,67.02,66.74,57.45,57.28,55.96,51.30,51.16,45.74,44.00,38.52,35.82,35.67,35.33,34.60,33.87,32.45,31.33,30.96,30.19,29.67,26.92,26.75,24.96,22.41,22.15,20.87,16.62,16.05,15.18,14.37,13.92,10.98。

Embodiment 31:43-O-(2-(4-(3-aminomethyl phenyl)-1H-1,2,3-triazole-1-base) ethanoyl) oxygen rapamycin (X-40)

By 43-O-(2-acetyl azide)-oxygen rapamycin (0.35mmoL; 0.35g) join in DMF (10mL) solution with propiolic alcohol (0.1g); sodium ascorbate (0.1g) and cupric sulfate pentahydrate (0.08g) is added in reaction solution; stirring at room temperature 2h; after completion of the reaction; reaction is added in 30mL water; separate out faint yellow solid; suction filtration; washing, dry faint yellow solid, is separated with C18 preparative chromatography through silica gel column chromatography; obtain sterling 0.16g, yield: 39.0%.MS(ESI)m/z:1135.5(M+Na) ⁺。 ¹HNMR(500MHz,DMSO)δ8.55(s,1H),7.70(s,1H),7.64(d,J＝7.8Hz,1H),7.34(t,J＝7.6Hz,1H),7.16(d,J＝7.6Hz,1H),6.46(s,1H),6.44-6.36(m,1H),6.26-6.18(m,1H),6.17-6.08(m,2H),5.50-5.42(m,3H),5.29(s,1H),5.10(d,J＝10.2Hz,1H),5.00-4.96(m,1H),4.95-4.93(m,1H),4.69-4.62(m,1H),4.05-3.99(m,2H),3.98-3.94(m,1H),3.65-3.60(m,1H),3.48-3.40(m,1H),3.27(s,3H),3.16(s,3H),3.05(s,3H),2.84-2.69(m,2H),2.44-2.38(m,2H),2.36(s,3H),2.27-2.17(m,1H),2.13-1.97(m,3H),1.96-1.88(m,2H),1.87-1.78(m,2H),1.75(s,3H),1.63(s,3H),1.56-1.01(m,10H),0.98(d,J＝6.5Hz,3H),0.87(d,J＝6.5Hz,3H),0.82(d,J＝6.4Hz,3H),0.78(d,J＝6.6Hz,3H),0.73(d,J＝6.6Hz,3H)。 ¹³CNMR(126MHz,DMSO)δ210.40,207.54,198.86,169.22,166.99,166.73,146.41,139.31,138.06,137.85,137.15,132.34,130.43,128.81,128.56,126.99,125.68,124.81,122.69,122.32,99.01,85.46,82.21,79.86,77.73,75.72,73.66,66.18,56.90,56.77,55.45,50.78,50.64,45.23,43.50,37.99,35.28,35.17,34.80,33.33,32.07,31.87,30.45,29.66,29.15,26.40,26.22,24.44,21.63,21.02,20.37,15.56,15.52,14.62,13.51,13.30,10.45。

Embodiment 32:43-O-(2-(4-(2-chloro-phenyl-)-1H-1,2,3-triazole-1-base) ethanoyl) oxygen rapamycin (X-38)

By 43-O-(2-acetyl azide)-oxygen rapamycin (0.35mmoL; 0.35g) join in DMF (10mL) solution with 2-chlorobenzene acetylene (0.1g); sodium ascorbate (0.1g) and cupric sulfate pentahydrate (0.08g) is added in reaction solution; stirring at room temperature 2h; after completion of the reaction; reaction is added in 30mL water; separate out faint yellow solid; suction filtration; washing, dry faint yellow solid, is separated with C18 preparative chromatography through silica gel column chromatography; obtain sterling 0.17g, yield: 41.4%.MS(ESI)m/z:1155.7(M+Na) ⁺。 ¹HNMR(500MHz,DMSO)δ8.73(s,1H),8.12(d,J＝7.8Hz,1H),7.58(d,J＝8.0Hz,1H),7.50-7.46(m,1H),7.43-7.39(m,1H),6.46(s,1H),6.44-6.34(m,1H),6.27-6.17(m,1H),6.17-6.07(m,2H),5.51(s,2H),5.49-5.43(m,1H),5.29(s,1H),5.10(d,J＝10.0Hz,1H),5.01-4.96(m,1H),4.96-4.92(m,1H),4.68-4.61(m,1H),4.05-3.98(m,2H),3.97-3.93(m,1H),3.64-3.62(m,1H),3.48-3.40(m,1H),3.32(s,3H),3.16(s,3H),3.05(s,3H),2.86-2.70(m,2H),2.42-2.34(m,2H),2.27-2.17(m,1H),2.14-1.98(m,3H),1.97-1.89(m,2H),1.89-1.79(m,2H),1.75(s,3H),1.63(s,3H),1.60-1.01(m,10H),0.98(d,J＝6.5Hz,3H),0.87(d,J＝6.4Hz,3H),0.82(d,J＝6.4Hz,3H),0.78(d,J＝6.6Hz,3H),0.73(d,J＝6.6Hz,3H)。 ¹³CNMR(126MHz,DMSO)δ210.41,207.53,198.88,169.21,166.99,166.67,142.45,139.31,137.86,137.16,132.34,130.28,130.23,129.49,129.39,128.96,127.58,126.99,125.74,99.01,85.48,82.23,79.86,77.77,75.72,73.65,66.19,56.90,56.81,55.45,50.76,50.61,45.23,43.50,37.99,35.31,35.17,34.80,33.34,31.89,30.44,29.65,29.15,26.41,26.23,24.45,21.63,20.38,15.52,14.64,13.49,13.32,10.45。

Embodiment 33:43-O-(2-(4-(4-bromophenyl)-1H-1,2,3-triazole-1-base) ethanoyl) oxygen rapamycin (X-41)

By 43-O-(2-acetyl azide)-oxygen rapamycin (0.35mmoL; 0.35g) join in DMF (10mL) solution with 4-bromobenzene acetylene (0.1g); sodium ascorbate (0.1g) and cupric sulfate pentahydrate (0.08g) is added in reaction solution; stirring at room temperature 2h; after completion of the reaction; reaction is added in 30mL water; separate out faint yellow solid; suction filtration; washing, dry faint yellow solid, is separated with C18 preparative chromatography through silica gel column chromatography; obtain sterling 0.10g, yield: 24.3%.MS(ESI)m/z:1200.3(M+Na) ⁺。 ¹HNMR(500MHz,DMSO)δ8.73(s,1H),8.12(d,J＝7.8Hz,1H),7.58(d,J＝8.0Hz,1H),7.50-7.46(m,1H),7.43-7.39(m,1H),6.46(s,1H),6.44-6.34(m,1H),6.27-6.17(m,1H),6.17-6.07(m,2H),5.51(s,2H),5.49-5.43(m,1H),5.29(s,1H),5.10(d,J＝10.0Hz,1H),5.01-4.96(m,1H),4.96-4.92(m,1H),4.68-4.61(m,1H),4.05-3.98(m,2H),3.97-3.93(m,1H),3.64-3.62(m,1H),3.48-3.40(m,1H),3.32(s,3H),3.16(s,3H),3.05(s,3H),2.86-2.70(m,2H),2.42-2.34(m,2H),2.27-2.17(m,1H),2.14-1.98(m,3H),1.97-1.89(m,2H),1.89-1.79(m,2H),1.75(s,3H),1.63(s,3H),1.60-1.01(m,10H),0.98(d,J＝6.5Hz,3H),0.87(d,J＝6.4Hz,3H),0.82(d,J＝6.4Hz,3H),0.78(d,J＝6.6Hz,3H),0.73(d,J＝6.6Hz,3H)。 ¹³CNMR(126MHz,DMSO)δ210.41,207.53,198.88,169.21,166.99,166.67,142.45,139.31,137.86,137.16,132.34,130.28,130.23,129.49,129.39,128.96,127.58,126.99,125.74,99.01,85.48,82.23,79.86,77.77,75.72,73.65,66.19,56.90,56.81,55.45,50.76,50.61,45.23,43.50,37.99,35.31,35.17,34.80,33.34,31.89,30.44,29.65,29.15,26.41,26.23,24.45,21.63,20.38,15.52,14.64,13.49,13.32,10.45。

Embodiment 34:43-O-(2-(4-(4-p-methoxy-phenyl)-1H-1,2,3-triazole-1-base) ethanoyl) oxygen rapamycin (X-66)

By 43-O-(2-acetyl azide)-oxygen rapamycin (0.35mmoL; 0.35g) join in DMF (10mL) solution with 4-Methoxy-phenylacetylene (0.1g); sodium ascorbate (0.1g) and cupric sulfate pentahydrate (0.08g) is added in reaction solution; stirring at room temperature 2h; after completion of the reaction; reaction is added in 30mL water; separate out faint yellow solid; suction filtration; washing, dry faint yellow solid, is separated with C18 preparative chromatography through silica gel column chromatography; obtain sterling 0.16g, yield: 39.4%.MS(ESII)m/z:1151.6(M+Na) ⁺。 ¹HNMR(500MHz,DMSO)δ8.46(s,1H),7.78(d,J＝8.7Hz,2H),7.02(d,J＝8.8Hz,2H),6.46(s,1H),6.45-6.34(m,1H),6.26-6.18(m,1H),6.17-6.06(m,2H),5.44(s,2H),5.27(s,1H),5.10(d,J＝10.1Hz,1H),5.00-4.91(m,2H),4.69-4.58(m,1H),4.06-3.98(m,2H),3.99-3.92(m,1H),3.79(s,3H),3.68-3.57(m,1H),3.49-3.39(m,1H),3.27(s,3H),3.16(s,3H),3.05(s,3H),2.88-2.67(m,2H),2.44-2.33(m,2H),2.27-2.18(m,2H),2.14-2.07(m,1H),2.05-1.96(m,2H),1.96-1.78(m,3H),1.75(s,3H),1.63(s,3H),1.55-1.03(m,10H),0.98(d,J＝6.5Hz,3H),0.87(d,J＝6.4Hz,3H),0.82(d,J＝6.4Hz,3H),0.78(d,J＝6.7Hz,3H),0.73(d,J＝6.5Hz,3H)。 ¹³CNMR(126MHz,DMSO)δ210.39,207.54,198.86,169.22,166.99,166.77,159.03,146.27,139.31,137.86,137.15,132.35,130.42,127.01,126.49,123.11,121.78,114.33,99.01,85.46,82.22,79.86,77.71,75.73,73.66,66.19,56.90,56.77,55.45,55.12,50.78,50.60,45.23,43.50,37.99,35.28,35.17,34.80,33.32,31.87,29.66,29.56,29.22,29.15,26.42,26.22,24.44,21.63,20.38,15.56,15.52,14.63,13.51,13.30,10.45。

Embodiment 35:43-O-(2-(4-((2,5 dichlorophenyl) amino methyl)-1H-1,2,3-triazole-1-base) ethanoyl) oxygen rapamycin (X-46)

By 43-O-(2-acetyl azide)-oxygen rapamycin (0.35mmoL; 0.35g) with N-(Propargyl)-2; 5-dichlorphenamide bulk powder (0.1g) joins in DMF (10mL) solution; sodium ascorbate (0.1g) and cupric sulfate pentahydrate (0.08g) is added in reaction solution; stirring at room temperature 2h; after completion of the reaction; reaction is added in 30mL water; separate out faint yellow solid, suction filtration, washing; dry faint yellow solid; be separated with C18 preparative chromatography through silica gel column chromatography, obtain sterling 0.15g, yield: 35.8%.MS(ESII)m/z:1218.5(M+Na) ⁺。 ¹HNMR(500MHz,DMSO)δ7.94(s,1H),7.25(d,J＝8.4Hz,1H),6.77(s,1H),6.58(d,J＝8.4Hz,1H),6.45(s,1H),6.43-6.35(m,1H),6.29(s,1H),6.26-6.17(m,1H),6.18-6.07(m,2H),5.46(dd,J＝14.8,9.5Hz,1H),5.37(s,2H),5.28(s,1H),5.14-5.05(m,1H),5.01-4.92(m,2H),4.62-4.56(m,1H),4.47(s,2H),4.06-3.96(m,2H),3.98-3.87(m,1H),3.66-3.57(m,1H),3.49-3.39(m,1H),3.39-3.24(m,2H),3.18(s,3H),3.16(s,3H),3.05(s,3H),2.85-2.69(m,2H),2.43-2.33(m,2H),2.28-2.17(m,1H),2.13-2.06(m,1H),2.05-1.90(m,2H),1.90-1.78(m,3H),1.74(s,3H),1.63(s,3H),1.60-1.03(m,10H),0.98(d,J＝6.6Hz,3H),0.87(d,J＝6.5Hz,3H),0.82(d,J＝6.4Hz,3H),0.79(d,J＝6.7Hz,3H),0.73(d,J＝6.6Hz,3H)。 ¹³CNMR(126MHz,DMSO)δ210.45,207.53,198.88,169.20,166.99,166.60,145.01,144.77,139.32,137.86,137.15,132.48,132.34,130.40,130.05,126.98,124.88,124.20,116.53,115.97,110.87,99.00,85.50,82.23,79.86,77.50,75.71,73.69,66.19,56.91,56.75,55.45,50.77,50.49,45.22,37.98,35.17,34.80,33.32,32.04,31.87,30.48,29.66,29.56,29.09,26.41,26.22,24.43,21.64,20.38,15.55,15.53,14.59,13.44,13.37,10.45。

Embodiment 36:43-O-(2-(4-((2-fluorophenyl) amino methyl)-1H-1,2,3-triazole-1-base) ethanoyl) oxygen rapamycin (X-43)

By 43-O-(2-acetyl azide)-oxygen rapamycin (0.35mmoL; 0.35g) join in DMF (10mL) solution with N-(Propargyl)-2-fluoroaniline (0.1g); sodium ascorbate (0.1g) and cupric sulfate pentahydrate (0.08g) is added in reaction solution; stirring at room temperature 2h; after completion of the reaction; reaction is added in 30mL water; separate out faint yellow solid; suction filtration; washing, dry faint yellow solid, is separated with C18 preparative chromatography through silica gel column chromatography; obtain sterling 0.13g, yield: 32.4%.MS(ESII)m/z:1168.6(M+Na) ⁺。 ¹HNMR(500MHz,DMSO)δ7.93(s,1H),6.99(dd,J＝11.9,8.1Hz,1H),6.92(t,J＝7.7Hz,1H),6.75(t,J＝8.5Hz,1H),6.57-6.50(m,1H),6.46(s,1H),6.43-6.33(m,1H),6.28-6.18(m,1H),6.18-6.08(m,2H),6.03-5.89(m,1H),5.54-5.42(m,1H),5.35(s,2H),5.28(s,1H),5.02-4.96(m,1H),5.12-5.08(m,1H),4.95-4.89(m,1H),4.64-4.51(m,1H),4.40(s,2H),4.05-3.97(m,2H),3.97-3.93(m,1H),3.65-3.59(m,1H),3.50-3.39(m,1H),3.20(s,3H),3.16(s,3H),3.05(s,3H),2.86-2.70(m,2H),2.43-2.34(m,2H),2.28-2.15(m,1H),2.14-2.06(m,1H),2.07-1.92(m,2H),1.91-1.80(m,3H),1.75(s,3H),1.63(s,3H),1.60-1.02(m,10H),0.98(d,J＝6.5Hz,3H),0.87(d,J＝6.4Hz,3H),0.82(d,J＝6.3Hz,3H),0.79(d,J＝6.6Hz,3H),0.73(d,J＝6.6Hz,3H)。 ¹³CNMR(126MHz,DMSO)δ210.41,207.54,198.87,169.22,166.99,166.68,151.90,150.01,145.75,139.32,137.86,137.15,136.21,136.12,132.35,130.42,127.01,124.60,124.13,115.71,114.31,114.16,112.27,99.01,85.47,82.22,79.81,77.52,75.72,73.66,66.18,56.90,56.75,55.45,50.78,50.41,45.23,43.50,38.05,35.24,35.17,34.80,33.32,31.86,30.44,29.66,29.57,29.09,28.98,26.41,26.22,24.45,21.63,20.37,15.56,15.52,14.60,13.49,13.31,10.45。

Embodiment 37:43-O-(2-(4-(pyrrolidyl-1-methylene radical)-1H-1,2,3-triazole-1-base) ethanoyl) oxygen rapamycin (X-92)

By 43-O-(2-acetyl azide)-oxygen rapamycin (0.35mmoL; 0.35g) join in DMF (10mL) solution with 1-(Propargyl) tetramethyleneimine (0.1g); sodium ascorbate (0.1g) and cupric sulfate pentahydrate (0.08g) is added in reaction solution; stirring at room temperature 2h; after completion of the reaction; reaction is added in 30mL water; separate out faint yellow solid; suction filtration; washing, dry faint yellow solid, is separated with C18 preparative chromatography through silica gel column chromatography; obtain sterling 0.11g, yield: 28.9%.MS(ESII)m/z:1093.4(M+H) ⁺。 ¹HNMR(400MHz,DMSO)δ7.96(s,1H),6.46(s,1H),6.41-6.32(m,1H),6.25-6.16(m,1H),6.16-6.09(m,2H),5.43(dd,J＝14.7,9.6Hz,1H),5.35(s,2H),5.32(s,1H),5.15-5.05(m,1H),5.02–4.90(m,2H),4.63-4.42(m,2H),4.32-4.10(m,2H),4.05-3.92(m,2H),3.75-3.57(m,2H),3.25(s,3H),3.16(s,3H),3.06(s,3H),2.91-2.67(m,2H),2.45-2.32(m,4H),2.29-2.16(m,1H),2.13-2.04(m,2H),2.03-1.94(m,2H),1.91-1.81(m,3H),1.76(s,3H),1.63(s,3H),1.57-1.06(m,10H),1.05-0.89(m,5H),0.85(d,J＝6.5Hz,3H),0.82(d,J＝6.5Hz,3H),0.79(d,J＝6.7Hz,3H),0.72(d,J＝6.5Hz,3H)。 ¹³CNMR(101MHz,DMSO)δ210.92,208.86,199.40,169.73,168.49,167.51,167.21,139.72,138.35,137.55,130.83,127.31,125.48,99.61,85.93,82.56,80.29,78.02,76.55,74.42,68.23,66.53,57.49,57.38,56.69,56.08,55.88,51.17,50.64,47.00,46.52,45.73,44.05,37.64,37.17,35.66,35.59,32.68,32.28,31.02,30.82,30.16,29.54,26.81,26.61,25.00,22.96,22.66,22.02,21.39,16.06,15.00,14.00,13.68,12.28,10.84。

Embodiment 38:43-O-(2-(4-(Diethylaminomethyl)-1H-1,2,3-triazole-1-base) ethanoyl) oxygen rapamycin (X-76)

By 43-O-(2-acetyl azide)-oxygen rapamycin (0.35mmoL; 0.35g) and N; N-diethyl propargylamine (0.1g) joins in DMF (10mL) solution; sodium ascorbate (0.1g) and cupric sulfate pentahydrate (0.08g) is added in reaction solution; stirring at room temperature 2h; after completion of the reaction; reaction is added in 30mL water; separate out faint yellow solid, suction filtration, washing; dry faint yellow solid; be separated with C18 preparative chromatography through silica gel column chromatography, obtain sterling 0.15g, yield: 39.1%.MS(ESII)m/z:1095.6(M+Na) ⁺。 ¹HNMR(400MHz,DMSO)δ7.97(s,1H),6.50(s,1H),6.45-6.36(m,1H),6.27-6.18(m,1H),6.16-6.07(m,2H),5.46(dd,J＝14.7,9.6Hz,1H),5.37(s,2H),5.33(s,1H),5.13-5.03(m,1H),5.01-4.91(m,2H),4.67-4.54(m,2H),4.30-4.13(m,2H),4.07-3.94(m,3H),3.75-3.57(m,3H),3.26(s,3H),3.15(s,3H),3.05(s,3H),2.90-2.66(m,2H),2.46-2.33(m,4H),2.28-2.15(m,1H),2.14-2.06(m,2H),2.04-1.93(m,2H),1.92-1.80(m,3H),1.75(s,3H),1.62(s,3H),1.56-1.08(m,10H),1.07-0.89(m,5H),0.86(d,J＝6.4Hz,3H),0.81(d,J＝6.4Hz,3H),0.78(d,J＝6.7Hz,3H),0.73(d,J＝6.7Hz,3H)。 ¹³CNMR(101MHz,DMSO)δ210.91,208.86,199.39,169.72,168.39,167.50,167.31,139.82,138.37,137.66,130.93,127.51,125.57,99.51,85.95,82.72,80.37,78.08,76.22,74.12,68.98,66.67,57.39,57.28,56.29,56.18,55.96,51.27,50.84,46.98,46.52,45.73,44.00,37.74,37.27,35.67,35.58,32.58,32.38,31.12,30.92,30.06,29.44,26.91,26.71,24.96,22.86,22.16,22.12,21.59,16.07,16.00,15.10,14.00,13.78,12.38,10.94。

Embodiment 39:43-O-(2-(4-(4-fluorophenyl)-1H-1,2,3-triazole-1-base) iso-propionyl) oxygen rapamycin (X-57)

Steps A: the preparation of 28-oxygen base TMS-43-O-(2-bromine iso-propionyl)-oxygen rapamycin

By 28-OTMS-rapamycin (2.5g, 2.5mmol) join in three-necked bottle with anhydrous methylene chloride (40mL), add triethylamine (3mL, 20mmol), 2 bromo propionyl bromide (1.62g is dropwise added at 0-5 DEG C, 7.5mmol), finish, 0-5 DEG C of reaction 8h.After completion of the reaction, by reaction solution impouring 300mL water, dichloromethane extraction, united extraction liquid, washing, anhydrous sodium sulfate drying.Evaporate to dryness obtains white solid 1.9g, yield: 67.8%MS (ESI) m/z:1142.5 (M+Na) ⁺.

The preparation of step B:43-O-(2-bromine iso-propionyl)-oxygen rapamycin

28-OTMS-43-O-(2-bromine iso-propionyl)-oxygen rapamycin (1.9g, 1.8mmol) is joined in acetone (40mL) solution, is cooled to 0-5 DEG C after reinforced, adds dilute sulphuric acid (10mL, 1NH to reaction solution ₂sO ₄), continue stirring reaction and be about 2h, after completion of the reaction, reaction solution is respectively through saturated sodium bicarbonate, and saturated common salt water washing, organic layer is through anhydrous sodium sulfate drying, and evaporate to dryness obtains white foam solid 1.6g, yield 84.8%.MS(ESI)m/z:1070.5(M+Na) ⁺。

The preparation of step C:43-O-(2-nitrine iso-propionyl)-oxygen rapamycin

Respectively by 43-O-(2-bromine iso-propionyl)-oxygen rapamycin (1.6g; 1.5mmol) with sodiumazide (0.2g; 3mmol) join in (30mL) DMF solution; 50 DEG C, after reacting completely are warmed up to, by reaction solution impouring 90mL water after reinforced; ethyl acetate extracts 2 times; united extraction liquid, washing, anhydrous sodium sulfate drying.Evaporate to dryness obtains oily matter, obtains 0.8g through column chromatography for separation, and yield is 52.7%.MS(ESI)m/z:1033.6(M+Na) ⁺。

The preparation of step D:43-O-(2-(4-(4-fluorophenyl)-1H-1,2,3-triazole-1-base) iso-propionyl) oxygen rapamycin (X-57)

By 43-O-(2-nitrine iso-propionyl)-oxygen rapamycin (0.2mmoL; 0.2g) join in DMF (10mL) solution with 4-fluorobenzene acetylene (0.07g); sodium ascorbate (0.08g) and cupric sulfate pentahydrate (0.09g) is added in reaction solution; stirring at room temperature 2h; after completion of the reaction; reaction is added in 30mL water; separate out faint yellow solid; suction filtration; washing; dry faint yellow solid, obtains sterling 0.10g through column chromatography for separation, yield: 42.9%.MS(ESI)m/z:1153.7(M+Na) ⁺。 ¹HNMR(500MHz,DMSO)δ8.74(s,1H),8.00-7.87(m,2H),7.36-7.22(m,2H),6.45(s,1H),6.43-6.34(m,1H),6.25-6.17(m,1H),6.17-6.06(m,2H),5.75-5.57(m,1H),5.48-5.41(m,1H),5.27(s,1H),5.12-5.06(m,1H),4.99-4.91(m,2H),4.70-4.57(m,1H),4.04-3.91(m,3H),3.64-3.57(m,1H),3.46-3.40(m,1H),3.24(s,3H),3.15(s,3H),3.04(s,3H),2.85-2.66(m,2H),2.44-2.31(m,2H),2.25-2.16(m,1H),2.12-2.05(m,2H),2.05-1.91(m,2H),1.90-1.77(m,5H),1.74(s,3H),1.62(s,3H),1.57-1.01(m,10H),0.97(d,J＝6.5Hz,3H),0.86(d,J＝6.3Hz,3H),0.81(d,J＝6.3Hz,3H),0.77(d,J＝6.4Hz,3H),0.72(d,J＝6.6Hz,3H)。 ¹³CNMR(126MHz,DMSO)δ210.38,207.52,198.85,169.20,168.98,166.97,162.72,160.78,145.35,139.30,137.84,137.13,132.34,130.39,127.12,127.06,126.98,124.79,120.97,115.90,115.73,98.99,85.44,82.20,80.10,77.48,75.71,73.65,68.46,66.17,57.69,56.88,56.67,55.44,50.76,45.21,43.48,37.96,35.14,34.79,33.33,32.05,31.87,30.41,29.55,28.98,26.38,26.20,24.43,21.61,20.35,17.05,15.54,15.50,14.63,13.28,10.43。

Embodiment 40:43-O-(2-(4-(4-chloro-phenyl-)-1H-1,2,3-triazole-1-base) iso-propionyl) oxygen rapamycin (X-52)

By 43-O-(2-nitrine iso-propionyl)-oxygen rapamycin (0.2mmoL; 0.2g) join in DMF (10mL) solution with 4-chlorobenzene acetylene (0.07g); sodium ascorbate (0.08g) and cupric sulfate pentahydrate (0.09g) is added in reaction solution; stirring at room temperature 2h; after completion of the reaction; reaction is added in 30mL water; separate out faint yellow solid; suction filtration; washing; dry faint yellow solid, obtains sterling 0.11g through column chromatography for separation, yield: 46.6%.MS(ESI)m/z:1169.7(M+Na) ⁺。 ¹HNMR(500MHz,DMSO)δ8.80(s,1H),7.90(d,J＝8.4Hz,2H),7.53(d,J＝8.4Hz,2H),6.46(s,1H),6.44-6.35(m,1H),6.27-6.16(m,1H),6.16-6.04(m,2H),5.73-5.61(m,1H),5.46(dd,J＝14.6,9.7Hz,1H),5.28(s,1H),5.14-5.05(m,1H),5.00-4.90(m,2H),4.68-4.54(m,1H),4.05-3.96(m,2H),3.97-3.88(m,1H),3.66-3.56(m,1H),3.48-3.37(m,1H),3.24(s,3H),3.15(s,3H),3.04(s,3H),2.85-2.65(m,2H),2.44-2.32(m,2H),2.30-2.16(m,1H),2.15-2.05(m,2H),2.05-1.92(m,2H),1.93-1.77(m,6H),1.74(s,3H),1.62(s,3H),1.53-1.01(m,10H),0.97(d,J＝6.4Hz,3H),0.86(d,J＝6.4Hz,3H),0.81(d,J＝6.3Hz,3H),0.77(d,J＝6.4Hz,3H),0.72(d,J＝6.6Hz,3H)。 ¹³CNMR(126MHz,DMSO)δ210.91,208.03,199.37,169.73,169.47,167.49,145.66,139.83,138.36,137.65,132.83,130.91,130.04,129.48,127.50,127.29,125.34,121.96,99.52,85.99,82.74,80.63,78.03,76.24,74.18,66.70,58.26,57.41,57.19,55.96,51.28,45.74,44.01,38.49,35.67,35.31,33.86,32.41,30.93,30.17,29.51,26.91,26.74,24.96,22.14,20.88,17.56,17.44,16.06,16.03,15.17,14.00,13.83,10.96。

Embodiment 41:43-O-(2-(4-(4-aminomethyl phenyl)-1H-1,2,3-triazole-1-base) iso-propionyl) oxygen rapamycin (X-54)

By 43-O-(2-nitrine iso-propionyl)-oxygen rapamycin (0.2mmoL; 0.2g) join in DMF (10mL) solution with 4-methylbenzene acetylene (0.07g); sodium ascorbate (0.08g) and cupric sulfate pentahydrate (0.09g) is added in reaction solution; stirring at room temperature 2h; after completion of the reaction; reaction is added in 30mL water; separate out faint yellow solid; suction filtration; washing; dry faint yellow solid, obtains sterling 0.13g through column chromatography for separation, yield: 56.6%.MS(ESI)m/z:1149.7(M+Na) ⁺。 ¹HNMR(500MHz,DMSO)δ8.68(s,1H),7.76(d,J＝7.1Hz,2H),7.26(d,J＝6.8Hz,2H),6.46(s,1H),6.43-6.33(m,1H),6.29-6.17(m,1H),6.17-6.05(m,2H),5.71-5.59(m,1H),5.52-5.40(m,1H),5.27(s,1H),5.14-5.04(m,1H),5.00-4.88(m,2H),4.64-4.55(m,1H),4.08-3.92(m,3H),3.67-3.55(m,1H),3.49-3.38(m,1H),3.24(s,3H),3.15(s,3H),3.04(s,3H),2.85-2.68(m,2H),2.44-2.34(m,1H),2.33(s,3H),2.26-2.15(m,1H),2.13-2.06(m,1H),2.06-1.90(m,3H),1.82(d,J＝6.8Hz,3H),1.74(s,3H),1.62(s,3H),1.58-1.02(m,10H),0.97(d,J＝5.1Hz,3H),0.86(d,J＝5.1Hz,3H),0.81(d,J＝5.1Hz,3H),0.77(d,J＝5.0Hz,3H),0.73(d,J＝4.9Hz,3H)。 ¹³CNMR(126MHz,DMSO)δ210.95,208.01,199.36,169.72,169.51,167.50,146.80,139.83,138.36,137.68,132.87,130.90,129.92,128.40,127.49,125.56,125.43,121.12,99.51,86.06,82.77,80.65,78.01,76.25,74.23,66.74,58.19,58.14,57.45,57.20,55.95,51.29,45.74,44.00,38.50,35.67,35.32,33.88,32.46,30.98,30.19,29.52,26.98,26.91,26.75,24.95,22.15,21.30,20.87,17.57,17.46,16.06,16.04,15.19,13.92,10.98。

Embodiment 42:43-O-(2-(4-(phenyl)-1H-1,2,3-triazole-1-base) iso-propionyl) oxygen rapamycin (X-53)

By 43-O-(2-nitrine iso-propionyl)-oxygen rapamycin (0.2mmoL; 0.2g) join in DMF (10mL) solution with phenylacetylene (0.07g); sodium ascorbate (0.08g) and cupric sulfate pentahydrate (0.09g) is added in reaction solution; stirring at room temperature 2h; after completion of the reaction; reaction is added in 30mL water; separate out faint yellow solid; suction filtration; washing; dry faint yellow solid, obtains sterling 0.12g through column chromatography for separation, yield: 52.2%.MS(ESI)m/z:1135.8(M+Na) ⁺。 ¹HNMR(500MHz,DMSO)δ8.75(s,1H),7.87(d,J＝7.5Hz,2H),7.46(t,J＝7.4Hz,2H),7.37-7.31(m,1H),6.46(s,1H),6.43-6.35(m,1H),6.26-6.18(m,1H),6.17-6.06(m,2H),5.72-5.62(m,1H),5.50-5.42(m,1H),5.28(s,1H),5.10(d,J＝10.7Hz,1H),4.99-4.96(m,1H),4.95-4.92(m,1H),4.67-4.56(m,1H),4.06-3.97(m,2H),3.97-3.92(m,1H),3.66-3.59(m,1H),3.47-3.40(m,1H),3.24(s,3H),3.15(s,3H),3.05(s,3H),2.84-2.68(m,2H),2.43-2.34(m,2H),2.25-2.18(m,1H),2.14-2.07(m,2H),2.05-1.93(m,2H),1.89-1.79(m,5H),1.74(s,3H),1.62(s,3H),1.60-1.02(m,10H),0.98(d,J＝6.4Hz,3H),0.87(d,J＝6.2Hz,3H),0.82(d,J＝6.2Hz,3H),0.78(d,J＝6.3Hz,3H),0.73(d,J＝6.6Hz,3H)。 ¹³CNMR(126MHz,DMSO)δ210.39,207.53,198.86,169.21,169.02,166.98,146.22,139.31,137.85,137.14,132.35,130.63,130.41,128.88,127.88,126.99,125.08,124.81,121.07,99.00,85.46,82.22,80.11,77.49,75.72,73.68,66.18,57.69,56.89,56.70,55.45,50.77,45.23,43.50,37.97,35.16,34.80,33.35,31.88,30.44,29.66,29.00,26.40,26.22,24.44,21.62,20.37,17.06,16.96,15.52,14.64,13.50,13.30,10.45。

Embodiment 43:43-O-(2-(4-(4-amyl group phenyl)-1H-1,2,3-triazole-1-base) iso-propionyl) oxygen rapamycin (X-55)

By 43-O-(2-nitrine iso-propionyl)-oxygen rapamycin (0.2mmoL; 0.2g) join in DMF (10mL) solution with 4-n-amylbenzene acetylene (0.07g); sodium ascorbate (0.08g) and cupric sulfate pentahydrate (0.09g) is added in reaction solution; stirring at room temperature 2h; after completion of the reaction; reaction is added in 30mL water; separate out faint yellow solid; suction filtration; washing; dry faint yellow solid, obtains sterling 0.05g through column chromatography for separation, yield: 21.2%.MS(ESI)m/z:1205.8(M+Na) ⁺。 ¹HNMR(500MHz,DMSO)δ8.67(s,1H),7.76(d,J＝7.9Hz,2H),7.26(d,J＝8.0Hz,2H),6.45(s,1H),6.43-6.33(m,1H),6.27-6.17(m,1H),6.14-6.09(m,2H),5.70-5.60(m,1H),5.46(dd,J＝14.7,9.7Hz,1H),5.27(s,1H),5.13-5.06(m,1H),4.99-4.91(m,2H),4.67-4.53(m,1H),4.04-3.97(m,2H),3.98-3.90(m,1H),3.66-3.56(m,1H),3.47-3.38(m,1H),3.24(s,3H),3.15(s,3H),3.04(s,3H),2.84-2.68(m,2H),2.62-2.56(m,2H),2.40-2.36(m,2H),2.25-2.16(m,1H),2.14-2.06(m,1H),2.06-1.94(m,2H),1.85-1.78(m,6H),1.74(s,3H),1.62(s,3H),1.60-1.00(m,15H),0.97(d,J＝6.5Hz,3H),0.93-0.81(m,6H),0.81(d,J＝6.3Hz,3H),0.77(d,J＝6.5Hz,3H),0.72(d,J＝6.5Hz,3H)。 ¹³CNMR(126MHz,DMSO)δ210.37,207.51,198.85,169.19,169.01,166.96,146.29,142.10,139.30,137.84,137.13,132.34,130.39,128.74,128.09,126.97,125.04,124.80,120.64,98.99,85.45,82.21,80.10,79.89,77.46,75.71,66.17,57.64,56.87,56.69,55.43,50.75,45.21,43.48,37.94,35.15,34.81,33.33,31.87,30.82,30.47,29.65,29.55,28.98,26.38,26.20,24.43,21.90,21.61,20.36,17.04,15.54,15.50,14.62,13.87,13.48,13.29,10.43。

Embodiment 44:43-O-(2-(4-(3-aminomethyl phenyl)-1H-1,2,3-triazole-1-base) iso-propionyl) oxygen rapamycin (X-58)

By 43-O-(2-nitrine iso-propionyl)-oxygen rapamycin (0.2mmoL; 0.2g) join in DMF (10mL) solution with 3-methylbenzene acetylene (0.07g); sodium ascorbate (0.08g) and cupric sulfate pentahydrate (0.09g) is added in reaction solution; stirring at room temperature 2h; after completion of the reaction; reaction is added in 30mL water; separate out faint yellow solid; suction filtration; washing; dry faint yellow solid, obtains sterling 0.10g through column chromatography for separation, yield: 43.5%.MS(ESI)m/z:1149.5(M+Na) ⁺。 ¹HNMR(500MHz,DMSO)δ8.72(s,1H),7.71(s,1H),7.65(d,J＝7.7Hz,1H),7.33(t,J＝7.6Hz,1H),7.15(d,J＝7.5Hz,1H),6.45(s,1H),6.43-6.34(m,1H),6.25-6.18(m,1H),6.16-6.06(m,2H),5.70-5.63(m,1H),5.46(dd,J＝14.8,9.8Hz,1H),5.27(s,1H),5.09(d,J＝10.1Hz,1H),4.98-4.95(m,1H),4.95-4.92(m,1H),4.66-4.57(m,1H),4.03-3.98(m,2H),3.97-3.93(m,1H),3.65-3.58(m,1H),3.46-3.39(m,1H),3.24(s,3H),3.15(s,3H),3.04(s,3H),2.83-2.69(m,2H),2.42-2.38(m,2H),2.36(s,3H),2.25-2.17(m,1H),2.14-2.06(m,2H),2.05-1.95(m,3H),1.90-1.83(m,2H),1.82(d,J＝7.3Hz,3H),1.74(s,3H),1.62(s,3H),1.58-1.02(m,10H),0.97(d,J＝6.5Hz,3H),0.86(d,J＝6.4Hz,3H),0.81(d,J＝6.3Hz,3H),0.77(d,J＝6.5Hz,3H),0.72(d,J＝6.6Hz,3H)。 ¹³CNMR(126MHz,DMSO)δ210.38,207.51,198.85,169.20,169.01,166.96,146.29,139.30,138.00,137.84,137.13,132.33,130.53,130.39,128.76,128.50,126.97,125.64,124.79,122.24,120.97,98.99,85.45,82.21,80.11,77.47,75.70,73.66,66.17,57.66,56.87,56.69,55.44,50.75,45.21,43.48,37.95,35.15,34.79,33.33,31.87,30.43,29.65,28.99,26.39,26.20,24.43,21.61,21.01,20.35,17.04,16.93,15.54,15.50,14.62,13.49,13.29,10.43。

Embodiment 45:43-O-(2-(4-(2-chloro-phenyl-)-1H-1,2,3-triazole-1-base) iso-propionyl) oxygen rapamycin (X-56)

By 43-O-(2-nitrine iso-propionyl)-oxygen rapamycin (0.2mmoL; 0.2g) join in DMF (10mL) solution with 2-chlorobenzene acetylene (0.07g); sodium ascorbate (0.08g) and cupric sulfate pentahydrate (0.09g) is added in reaction solution; stirring at room temperature 2h; after completion of the reaction; reaction is added in 30mL water; separate out faint yellow solid; suction filtration; washing; dry faint yellow solid, obtains sterling 0.13g through column chromatography for separation, yield: 56.5%.MS(ESI)m/z:1169.7(M+Na) ⁺。 ¹HNMR(400MHz,DMSO)δ8.76(s,1H),8.08(d,J＝7.3Hz,1H),7.58(d,J＝7.7Hz,1H),7.50-7.40(m,1H),6.48(s,1H),6.46-6.33(m,1H),6.29-6.17(m,1H),6.17-6.03(m,2H),5.81-5.67(m,1H),5.46(dd,J＝14.4,9.9Hz,1H),5.30(s,1H),5.13-5.03(m,1H),5.01-4.88(m,2H),4.68-4.55(m,1H),4.07-3.90(m,3H),3.68-3.55(m,1H),3.53-3.41(m,1H),3.24(s,3H),3.15(s,3H),3.04(s,3H),2.83-2.67(m,2H),2.43-2.30(m,2H),2.28-2.15(m,2H),2.14-1.98(m,2H),1.94-1.78(m,5H),1.74(s,3H),1.62(s,3H),1.56-1.03(m,9H),0.97(d,J＝6.1Hz,3H),0.86(d,J＝5.9Hz,3H),0.81(d,J＝6.0Hz,3H),0.77(d,J＝5.7Hz,3H),0.72(d,J＝6.1Hz,3H)。 ¹³CNMR(101MHz,DMSO)δ210.95,208.03,199.38,169.71,169.38,167.48,142.97,139.82,138.35,137.65,132.85,130.90,130.84,130.74,130.03,129.58,128.03,127.48,125.36,124.69,99.50,82.73,80.62,78.07,76.21,74.17,66.69,58.25,57.41,57.27,55.95,51.25,45.73,44.00,38.46,35.81,35.67,35.31,33.86,32.41,30.93,30.16,29.51,26.90,26.72,24.95,22.13,20.86,17.46,17.38,16.04,16.02,15.15,13.96,13.84,10.95。

Embodiment 46:43-O-(2-(4-(4-bromophenyl)-1H-1,2,3-triazole-1-base) iso-propionyl) oxygen rapamycin (X-59)

By 43-O-(2-nitrine iso-propionyl)-oxygen rapamycin (0.2mmoL; 0.2g) join in DMF (10mL) solution with 4-bromobenzene acetylene (0.08g); sodium ascorbate (0.08g) and cupric sulfate pentahydrate (0.09g) is added in reaction solution; stirring at room temperature 2h; after completion of the reaction; reaction is added in 30mL water; separate out faint yellow solid; suction filtration; washing; dry faint yellow solid, obtains sterling 0.07g through column chromatography for separation, yield: 29.2%.MS(ESI)m/z:1214.3(M+Na) ⁺。 ¹HNMR(500MHz,DMSO)δ8.81(s,1H),7.84(d,J＝8.3Hz,2H),7.66(d,J＝8.3Hz,2H),6.46(s,1H),6.43-6.35(m,1H),6.26-6.17(m,1H),6.16-6.08(m,2H),5.72-5.65(m,1H),5.46(dd,J＝14.6,9.7Hz,1H),5.28(s,1H),5.10(d,J＝9.7Hz,1H),5.00-4.96(m,1H),4.96-4.89(m,1H),4.66-4.57(m,1H),4.04-3.98(m,2H),3.98-3.91(m,1H),3.64-3.59(m,1H),3.47-3.39(m,1H),3.24(s,3H),3.15(s,3H),3.05(s,3H),2.84-2.68(m,2H),2.44-2.33(m,2H),2.26-2.17(m,1H),2.14-2.06(m,1H),2.05-1.94(m,2H),1.93-1.84(m,2H),1.82(d,J＝7.4Hz,3H),1.74(s,3H),1.62(s,3H),1.57-1.02(m,10H),0.98(d,J＝6.4Hz,3H),0.87(d,J＝6.4Hz,3H),0.82(d,J＝6.3Hz,3H),0.78(d,J＝6.4Hz,3H),0.73(d,J＝6.5Hz,3H)。 ¹³CNMR(126MHz,DMSO)δ210.39,207.52,198.86,169.21,168.95,166.98,145.19,139.31,137.85,137.14,132.35,131.87,130.41,129.88,127.07,126.99,124.81,121.48,120.86,99.00,85.46,82.22,80.11,77.51,75.73,73.66,66.18,57.75,56.89,56.68,55.45,50.77,45.23,43.49,37.98,35.16,34.80,33.34,31.88,30.42,29.67,28.99,26.40,26.22,24.44,21.63,20.37,17.05,15.55,15.52,14.65,13.50,13.30,10.45。

Embodiment 47:43-O-(2-(4-(4-p-methoxy-phenyl)-1H-1,2,3-triazole-1-base) iso-propionyl) oxygen rapamycin (X-66)

By 43-O-(2-nitrine iso-propionyl)-oxygen rapamycin (0.2mmoL; 0.2g) join in DMF (10mL) solution with 4-methylbenzene acetylene (0.07g); sodium ascorbate (0.08g) and cupric sulfate pentahydrate (0.09g) is added in reaction solution; stirring at room temperature 2h; after completion of the reaction; reaction is added in 30mL water; separate out faint yellow solid; suction filtration; washing; dry faint yellow solid, obtains sterling 0.10g through column chromatography for separation, yield: 43.4%.MS(ESI)m/z:1165.7(M+Na) ⁺。 ¹HNMR(500MHz,DMSO)δ8.46(s,1H),7.78(d,J＝8.7Hz,2H),7.02(d,J＝8.8Hz,2H),6.46(s,1H),6.45-6.34(m,1H),6.26-6.18(m,1H),6.17-6.06(m,2H),5.44(s,2H),5.27(s,1H),5.10(d,J＝10.1Hz,1H),5.00-4.91(m,2H),4.69-4.58(m,1H),4.06-3.98(m,2H),3.99-3.92(m,1H),3.79(s,3H),3.68-3.57(m,1H),3.49-3.39(m,1H),3.27(s,3H),3.16(s,3H),3.05(s,3H),2.88-2.67(m,2H),2.44-2.33(m,2H),2.27-2.18(m,2H),2.14-2.07(m,1H),2.05-1.96(m,2H),1.96-1.78(m,3H),1.75(s,3H),1.63(s,3H),1.55-1.03(m,10H),0.98(d,J＝6.5Hz,3H),0.87(d,J＝6.4Hz,3H),0.82(d,J＝6.4Hz,3H),0.78(d,J＝6.7Hz,3H),0.73(d,J＝6.5Hz,3H)。 ¹³CNMR(126MHz,DMSO)δ210.39,207.54,198.86,169.22,166.99,166.77,159.03,146.27,139.31,137.86,137.15,132.35,130.42,127.01,126.49,123.11,121.78,114.33,99.01,85.46,82.22,79.86,77.71,75.73,73.66,66.19,56.90,56.77,55.45,55.12,50.78,50.60,45.23,43.50,37.99,35.28,35.17,34.80,33.32,31.87,29.66,29.56,29.22,29.15,26.42,26.22,24.44,21.63,20.38,15.56,15.52,14.63,13.51,13.30,10.45。

Embodiment 48:43-O-(2-(4-((2,5 dichlorophenyl) amino methyl)-1H-1,2,3-triazole-1-base) iso-propionyl) oxygen rapamycin (X-65)

By 43-O-(2-nitrine iso-propionyl)-oxygen rapamycin (0.2mmoL; 0.2g) with N-(Propargyl)-2; 5-dichlorphenamide bulk powder (0.07g) joins in DMF (10mL) solution; sodium ascorbate (0.08g) and cupric sulfate pentahydrate (0.09g) is added in reaction solution; stirring at room temperature 2h; after completion of the reaction; reaction is added in 30mL water; separate out faint yellow solid; suction filtration, washing, dry faint yellow solid; sterling 0.11g is obtained, yield: 45.8% through column chromatography for separation.MS(ESI)m/z:1232.6(M+Na) ⁺。 ¹HNMR(400MHz,DMSO)δ8.11(s,1H),7.31(d,J＝8.3Hz,1H),6.84(s,1H),6.64(d,J＝8.4Hz,1H),6.53(s,1H),6.51-6.40(m,1H),6.35-6.27(m,1H),6.26-6.13(m,2H),5.75-5.62(m,1H),5.52(dd,J＝14.2,9.6Hz,1H),5.35(s,1H),5.20-5.11(m,1H),5.07-4.95(m,2H),4.64-4.54(m,1H),4.52(s,2H),4.12-3.96(m,3H),3.71–3.65(m,1H),3.54-3.44(m,1H),3.21(s,3H),3.19(s,3H),3.11(s,3H),2.98-2.72(m,2H),2.51-2.39(m,2H),2.36-2.24(m,1H),2.21-2.05(m,2H),2.03-1.86(m,3H),1.80(s,3H),1.68(s,3H),1.65-1.08(m,10H),1.04(d,J＝6.2Hz,3H),0.93(d,J＝6.3Hz,3H),0.88(d,J＝6.3Hz,3H),0.84(d,J＝5.5Hz,3H),0.79(d,J＝6.2Hz,3H)。 ¹³CNMR(101MHz,DMSO)δ210.46,207.50,198.86,169.18,168.79,166.97,144.79,139.32,137.83,137.14,132.44,132.33,130.38,129.99,126.96,124.91,122.65,116.53,115.94,110.87,98.98,85.51,82.22,80.04,77.33,75.69,73.72,66.18,57.43,56.91,56.69,55.42,50.74,45.20,43.47,38.05,37.83,35.15,35.04,34.78,33.34,31.86,30.47,29.65,28.86,26.38,26.18,24.41,21.61,20.36,20.34,16.88,15.52,14.59,13.39,10.44。

Embodiment 49:43-O-(2-(4-((2,4 dichlorophenyl) amino methyl)-1H-1,2,3-triazole-1-base) iso-propionyl) oxygen rapamycin (X-64)

By 43-O-(2-nitrine iso-propionyl)-oxygen rapamycin (0.2mmoL; 0.2g) with N-(Propargyl)-2; 4-dichlorphenamide bulk powder (0.07g) joins in DMF (10mL) solution; sodium ascorbate (0.08g) and cupric sulfate pentahydrate (0.09g) is added in reaction solution; stirring at room temperature 2h; after completion of the reaction; reaction is added in 30mL water; separate out faint yellow solid; suction filtration, washing, dry faint yellow solid; sterling 0.09g is obtained, yield: 37.5% through column chromatography for separation.MS(ESI)m/z:1232.4(M+Na) ⁺。 ¹HNMR(400MHz,DMSO)δ8.09(s,1H),7.39(s,1H),7.20(d,J＝8.8Hz,1H),6.82(d,J＝8.9Hz,1H),6.54(s,1H),6.50-6.41(m,1H),6.34-6.23(m,1H),6.23-6.11(m,2H),5.70-5.61(m,1H),5.52(dd,J＝14.7,9.6Hz,1H),5.36(s,1H),5.20-5.11(m,1H),5.07-4.93(m,2H),4.66-4.53(m,1H),4.51(s,2H),4.13-3.98(m,3H),3.73-3.63(m,1H),3.56-3.46(m,1H),3.22(s,3H),3.21(s,3H),3.11(s,3H),2.91-2.74(m,2H),2.49–2.40(m,2H),2.34-2.21(m,1H),2.22-2.11(m,2H),2.11-1.97(m,2H),1.96-1.83(m,3H),1.80(s,3H),1.69(s,3H),1.66-1.08(m,10H),1.04(d,J＝6.5Hz,3H),0.93(d,J＝6.5Hz,3H),0.88(d,J＝6.4Hz,3H),0.85(d,J＝6.6Hz,3H),0.79(d,J＝6.6Hz,3H)。 ¹³CNMR(101MHz,DMSO)δ227.19,210.43,207.50,198.86,169.17,168.81,166.97,144.94,142.73,139.32,137.84,137.13,132.33,130.38,128.10,127.63,126.97,122.62,119.19,118.41,112.51,98.99,85.51,82.22,80.02,77.34,75.70,73.73,66.18,57.42,56.90,56.68,55.43,50.74,45.22,43.47,38.22,37.91,35.15,34.79,33.35,31.93,30.48,29.65,28.91,26.39,26.22,24.42,21.62,20.35,16.91,15.52,14.62,13.38,10.44。

Embodiment 50:43-O-(2-(4-((2-fluorophenyl) amino methyl)-1H-1,2,3-triazole-1-base) iso-propionyl) oxygen rapamycin (X-62)

By 43-O-(2-nitrine iso-propionyl)-oxygen rapamycin (0.2mmoL; 0.2g) join in DMF (10mL) solution with N-(Propargyl)-2-fluoroaniline (0.07g); sodium ascorbate (0.08g) and cupric sulfate pentahydrate (0.09g) is added in reaction solution; stirring at room temperature 2h; after completion of the reaction; reaction is added in 30mL water; separate out faint yellow solid; suction filtration; washing; dry faint yellow solid, obtains sterling 0.08g through column chromatography for separation, yield: 34.7%.MS(ESI)m/z:1182.7(M+Na) ⁺。 ¹HNMR(500MHz,DMSO)δ8.04(s,1H),7.04-6.96(m,1H),6.95-6.87(m,1H),6.79-6.70(m,1H),6.56-6.50(m,1H),6.46(s,1H),6.44-6.32(m,1H),6.26-6.17(m,1H),6.17-6.07(m,2H),5.97-5.91(m,1H),5.63-5.55(m,1H),5.52-5.43(m,1H),5.28(s,1H),5.14-5.07(m,1H),5.00-4.90(m,2H),4.59-4.50(m,1H),4.39(s,2H),4.08-3.93(m,3H).67-3.59(m,1H),3.49-3.39(m,1H),3.17(s,3H),3.16(s,3H),3.05(s,3H),2.85-2.68(m,2H),2.45-2.31(m,2H),2.27-2.16(m,1H),2.16-2.06(m,2H),2.06-1.92(m,3H),1.90-1.78(m,2H),1.74(s,3H),1.62(s,3H),1.57-1.01(m,10H),0.98(d,J＝5.5Hz,3H),0.87(d,J＝5.8Hz,3H),0.82(d,J＝4.9Hz,3H),0.78(d,J＝4.0Hz,3H),0.73(d,J＝5.7Hz,3H)。 ¹³CNMR(126MHz,DMSO)δ210.42,207.53,198.85,191.52,169.20,168.88,166.97,152.23,151.88,149.98,147.76,145.51,139.31,137.84,137.13,136.24,136.15,132.34,130.39,126.97,124.80,124.58,122.53,122.47,115.75,115.69,114.26,114.12,112.25,112.23,99.73,98.99,85.46,82.21,79.99,77.34,75.70,73.66,66.18,57.39,56.89,56.68,55.44,50.77,45.21,43.49,42.12,38.12,37.89,35.15,34.79,33.32,31.84,30.41,29.64,29.55,28.95,28.93,26.39,26.22,24.43,21.61,20.35,16.97,15.54,15.52,14.60,13.47,13.31,10.44。

test example 1: anti-tumor activity is tested

Lung cell A549, lung carcinoma cell NCI-H1299, original position carcinoma of the pancreas BxPC-3, stomach cancer cell MGC80-3, cervical cancer cell Caski, human leukemia cell line HL-60 and human leukemia cell K-562 cell strain are recovered and gone down to posterity 2-3 time, makes cell viability stable for cell in vitro active testing.Suspension cell does not need digestion, attached cell trypsin 0.25%) digest, the cell culture fluid added containing serum stops digestion, with transfer pipet transitional cell liquid to centrifuge tube, centrifugal 3min under 1500r/min, adds 5mL nutrient solution gently after abandoning supernatant, piping and druming mixing cell, counting, attached cell 5000-10000/hole, suspension cell 20000/hole, adds 96 orifice plates, in 37 DEG C, 5%CO2 cultivation, cell cultures added testing drug after 24 hours.The biologic activity of test the compounds of this invention, and compare with rapamycin (Rapa) and CCI-779 (CCI-779), with dmso solution given the test agent as mother liquor, then given the test agent is diluted with cell culture fluid: get 10ul sample mother liquor, add 990ul cell culture fluid, dilute sample is to test concentrations.Added by sample diluting liquid and cultivate in the cell culture fluid of 24h in 96 orifice plates, each concentration adds 3 holes, if blank (not adding drug treating).By 96 orifice plates in 37 DEG C, 5%CO2 continuation cultivation 96h, MTT (tetrazole) (5mg/mL) 20 μ L is added in every hole, after putting into incubator 8h, suspension cell is in the centrifugal 10min of 4000r/min, abandoning supernatant, adds dimethyl sulfoxide (DMSO) 150 μ L, and survivaling cell and MTT reaction product formazan are fully dissolved, put into microplate reader measurement result, medicine IC can be obtained by Bliss method ₅₀value (μm ol/L).Result shows, and compound prepared by the present invention all has the biologic activity obviously more excellent than rapamycin and CCI-779 to various cancer cells, such as: to A549 cell, and the IC of Rapa and CCI-779 ₅₀value (μm ol/L) is respectively 24 and 15, and the IC of each compound of embodiment of the present invention 1-50 ₅₀be worth (μm ol/L) all in 0.1 ~ 13 scope, the such as IC of embodiment 38 compound ₅₀value (μm ol/L) is 0.1; To H1299 cell, the IC of Rapa and CCI-779 ₅₀value (μm ol/L) is respectively 14 and 19, and the IC of each compound of embodiment of the present invention 1-50 ₅₀be worth (μm ol/L) all in 1 ~ 15 scope, the such as IC of embodiment 38 compound ₅₀value (μm ol/L) is 1.1; To the IC of cervical cancer cell Caski, Rapa ₅₀value (μm ol/L) is 23, and the IC of each compound of embodiment of the present invention 1-50 ₅₀be worth (μm ol/L) all in 1 ~ 26 scope, the such as IC of embodiment 7 compound ₅₀value (μm ol/L) is 2.1; To human leukemia cell line HL-60, the IC of Rapa ₅₀value (μm ol/L) is 25, and the IC of each compound of embodiment of the present invention 1-50 ₅₀be worth (μm ol/L) all in 0.6 ~ 19 scope, the such as IC of embodiment 40 compound ₅₀value (μm ol/L) is 0.3.

Industrial applicability: the compounds of this invention biologic activity such as antitumour activity, can be prepared into cancer therapy drug to treat and/or prevent cancer.

Claims

1. with compounds of Formula I:

Or its pharmacologically acceptable salts, isomer, wherein,

N is 1,2 or 3;

X is or "-";

R is hydrogen, methyl or (C ₁-C ₄) alkyl;

R ₂be selected from: hydrogen, hydroxyl, halogen, trifluoromethyl, trifluoromethoxy, amino, carboxyl, cyano group, (C ₁-C ₄) alkyl, (C ₁-C ₆) alkyl, (C ₁-C ₄) alkoxyl group, N-(C ₁-C ₄) alkylamino, N, N-bis-(C ₁-C ₄) alkylamino, (C ₁-C ₄) alkyl sulfenyl, (C ₁-C ₄) alkyl sulphinyl, (C ₁-C ₄) alkyl sulphonyl, (C ₁-C ₄) alkoxy methyl, (C ₁-C ₄) alkoxyethyl, (C ₁-C ₄) alkyl acyl, formamyl, N-(C ₁-C ₄) alkyl-carbamoyl, N, N-bis-(C ₁-C ₄) alkyl-carbamoyl, (C ₁-C ₃) alkylenedioxy group.

2. the compound of claim 1, wherein said (C ₁-C ₄) alkyl is selected from methyl, ethyl, propyl group, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl.

3. the compound of claim 1, wherein said halogen is selected from fluorine, chlorine, bromine, iodine.

4. the compound of claim 1, wherein R is hydrogen or methyl.

5. the compound of claim 1, wherein X is n is 1.

6. the compound of claim 1, wherein X is singly-bound, and n is 2 or 3.

7. the compound of claim 1, it is be selected from following compound or its pharmacologically acceptable salts, isomer:

43-O-(2-(4-(4-fluorophenyl)-1H-1,2,3-triazole-1-base) ethyl) oxygen rapamycin

43-O-(2-(4-(4-chloro-phenyl-)-1H-1,2,3-triazole-1-base) ethyl) oxygen rapamycin

43-O-(2-(4-(phenyl)-1H-1,2,3-triazole-1-base) ethyl) oxygen rapamycin

43-O-(2-(4-(2-chloro-phenyl-)-1H-1,2,3-triazole-1-base) ethyl) oxygen rapamycin

43-O-(2-(4-(4-bromophenyl)-1H-1,2,3-triazole-1-base) ethyl) oxygen rapamycin

43-O-(3-(phenyl-1H-1,2,3-triazole-1-base) n-propyl) oxygen rapamycin

43-O-(3-(4-(4-bromophenyl)-1H-1,2,3-triazole-1-base) n-propyl) oxygen rapamycin

43-O-(2-(4-(phenyl)-1H-1,2,3-triazole-1-base) ethanoyl) oxygen rapamycin

43-O-(2-(4-(4-bromophenyl)-1H-1,2,3-triazole-1-base) ethanoyl) oxygen rapamycin

43-O-(2-(4-(phenyl)-1H-1,2,3-triazole-1-base) iso-propionyl) oxygen rapamycin

43-O-(2-(4-((2-fluorophenyl) amino methyl)-1H-1,2,3-triazole-1-base) iso-propionyl) oxygen rapamycin.

8. a pharmaceutical composition, it comprises the compound of any one of claim 1-7, and optional pharmaceutically acceptable carrier or auxiliary material.

9. the purposes of compound in the medicine for the preparation of prevention or treatment tumour and/or cancer of any one of claim 1-7.

10. the purposes of claim 9, described tumour and/or cancer are selected from: lung cancer, carcinoma of the pancreas, esophagus cancer, cancer of the stomach, cervical cancer, prostate cancer, leukemia, kidney.

The method of the compound of 11. any one of preparation claim 1-7, it comprises the following steps:

From following compd A-1: prepare with following formula A-2 compound:

Then A-2 compound and R is made ₁the acetylene compound that aryl replaces is obtained by reacting formula I through five water blue vitriol and sodium ascorbate:

Formula I is optionally made to form its pharmacologically acceptable salts, isomer; Wherein each substituting group is as described in any one of claim 1-7.

The method of 12. claims 11, when X is "-", when R is hydrogen, the preparation method of A-2 compound is:

With A-1 compound for raw material, with triflate shown in B-1 be compounds in side chain is obtained by reacting B-2 compound:

Then B-2 compound and reaction of sodium azide is made to obtain A-2 compound.

The method of 13. claims 11, when X is time, the preparation method of A-2 compound is:

Then C-3 compound and reaction of sodium azide is made to obtain C-4 compound:

C-4 compound deprotection is finally made to obtain A-2 compound.