CN104341434B - The rapamycin triazole derivatives replaced and purposes - Google Patents

Abstract

The present invention relates to substituted rapamycin triazole derivatives and uses. Specifically, the present invention relates to the following compounds of formula I: or pharmaceutically acceptable salts, solvates, isomers, esters, prodrugs thereof, wherein substituents X, R, R ₁ and n have given in the description meaning. The present invention also relates to the use of the compound of general formula I in the preparation of medicines for treating and/or preventing cancer. The compound of the present invention has excellent biological activity.

Description

Substituted rapamycin triazole derivatives and uses

technical field

The invention belongs to the technical field of medicine, and relates to novel rapamycin derivatives, their optically active bodies and pharmaceutically acceptable salts thereof, in particular to a class of substituted rapamycin triazole derivatives. The invention also relates to processes for their preparation and pharmaceutical compositions containing said compounds. The present invention also relates to the use of the derivative in the preparation of medicines for treating and/or preventing cancer.

technical background

Cancer/malignant tumors seriously endanger human health and have become a global health problem, seriously threatening human life. In 2009, WHO clearly pointed out that cancer is becoming the deadliest "killer" of human beings, and more than 90% of malignant tumors have no satisfactory treatment drugs and measures. At present, there are about 10 million cancer patients in the world every year, and 7.6 million people die. In my country, the number of cancer patients is about 2 million, and 1.5 million people die. It has become the second leading cause of death in my country. The World Health Organization predicts that cancer will become the world's largest public health problem by 2020. Anti-tumor drugs have become the second largest drug field in the world. In 2009, the anti-tumor drug market reached 52.372 billion US dollars, second only to drugs for cardiovascular diseases. The traditional anticancer drugs currently used in clinical practice mainly include plant alkaloids, alkylating agents, antibiotics and hormones. are visibly affected. Therefore, the development of new anti-cancer targeted drugs with high efficiency and low toxicity has become a trend in the research and development of anti-tumor drugs. In recent years, molecular targeted drugs have become a research and development hotspot in the field of tumor treatment at home and abroad because of their advantages of strong pertinence, effectiveness and low toxicity. Among them, mammalian target of rapamycin (mTOR) is the newly discovered target for cancer therapy.

Rapamycin (RPM), also known as Sirolimus, has the following chemical structure:

As shown in the above structure, the core structure of rapamycin is generally marked in the art, wherein the 1-position is a double bond, and the 28-position and 43-position are hydroxyl groups. The new compound obtained in the present invention is at 43- The product substituted on the hydroxyl group; in addition, in some documents, the 43-position of the above structure is also marked as the 40-position. Essentially, the two are the same, but the marking method is different.

Temsirolimus (Temsirolimus) is a clinically used rapamycin analogue, and the chemical structural formula of Temsirolimus is as follows:

Known rapamycin CAS registration number 53123-88-9, molecular formula C51H79NO13, molecular weight 914.17, obtained from ether is a colorless crystalline solid, mp183-185°, [α]D25-58.2° (methanol), dissolved In ether, chloroform, acetone, methanol and DMF, slightly soluble in hexane and petroleum ether, insoluble in water, mouse LD50 (mg/kg) > 600 (i.p.), > 2,500 (oral) (Vézina).

Vezina et al. reported in 1975 that rapamycin, a low-toxic antifungal antibiotic, was obtained from the fermentation broth of Streptomyces hygroscopicus. After more than 20 years of hard work, it was successfully developed into a new type of potent immunosuppressant. The immunosuppressive activity of rapamycin is dozens of times stronger than that of cyclosporine, and its toxic and side effects are less than those of cyclosporine and FK506. It is not only used for acute rejection of organ transplantation, but also for reversing ongoing transplant rejection; it can treat various autoimmune diseases.

Rapamycin, a macrocyclic triene antibiotic produced by Streptomyces hygroscopicus, was found to have antifungal activity both in vivo and in vitro, especially against Candida albicans [C. Vein et al.; J. Antibiot. 28,721 (1975); S.N. Sega et al; J. Antibiot. 28,727 (1975); H.A. Baker et al; J. Antibiot. Additionally, rapamycin has been shown to have antitumor activity alone (US Patent 4,885,171) or in combination with sapelin (US Patent 4,401,653).

The immunosuppressive effect of rapamycin has been found, and cyclosporine A and FK-506 (other macrocyclic molecules) have also been shown to be effective as immunosuppressants and thus can be used to prevent transplant rejection [R.Y.Calne et al., Lancet 1183 (1978); and US Patent 5,100,899]. R.Martel et al [Can, J.Physiol.Pharmacol.55,48 (1977)] found that rapamycin is effective in experimental allergic encephalomyelitis model, multiple sclerosis model, auxiliary arthritis model, rheumatoid It is effective in arthritis models; and effectively inhibits the formation of IgE-like antibodies.

Rapamycin can also be used to prevent or treat systemic lupus erythematosus [US Patent 5,078,999], pneumonia [US Patent 5,080,899], insulin-dependent diabetes [US Patent 5,321,009], skin diseases such as psoriasis [US Patent 5,286,730], enteropathy [US Patent 5,286,731], smooth muscle cell hyperplasia and intimal thickening after vascular injury [US Patents 5,288,711 and 5,516,781], adult T-cell leukemia/lymphoma [European Patent Application 525,960Al], ocular inflammation [US Patent 5,387,589] , malignant cancer [US Patent 5,206,018], cardiac inflammatory disease [US Patent 5,496,832], and anemia [US Patent 5,561,138].

In recent years, with the deepening of research on rapamycin derivatives, it has been found that rapamycin and its derivatives have the effect of inhibiting the growth of various tumors. They all form a complex with FKBP212 protein, and this complex binds to the FRB region of mTOR to inhibit the function of mTOR, thereby inhibiting the expression of downstream related factors, promoting cell apoptosis, and exerting its unique targeting anti-tumor activity.

In recent years, several chemical semi-synthetic derivatives of rapamycin have been approved by the FDA for cancer treatment or clinical trials. Everolimus, developed by Novartis, was approved by the FDA in 2009. For the treatment of advanced renal cancer. Tesirolimus (CCI-779), developed by Wyeth, has been approved by the FDA for the treatment of advanced renal cancer; Deferolimus, developed by Ariad, has no immunosuppressive activity and is currently in clinical trials.

mTOR is the center of complex signal transduction pathways in cells and plays a key role in cell growth, proliferation, cell metabolism, phagocytosis and angiogenesis. The mTOR inhibitor combines with the FKBP12 protein to form a complex to inhibit the excessive activation of mTOR, inhibit the biosynthesis of ribosomes and protein translation, and thus play a role in the treatment of tumors. mTOR inhibitors have been used as important high-efficiency non-cytotoxic targeted cancer therapy drugs. Currently, sirolimus and its three derivatives are being studied as mTOR inhibitors: temsirolimus (CCI- 779), everolimus (everolimus, RAD001) and AP23573 (ridaforolimus). Among them, temsirolimus is the first anti-tumor mTOR inhibitor approved by the US FDA, and it is an orphan drug for the treatment of advanced renal cell carcinoma.

Although people have made great achievements in the research and clinical application of rapamycin and its derivatives, those skilled in the art still look forward to products with more clinical application value in order to provide a more ideal choice for clinical practice.

Contents of the invention

The purpose of the present invention is to provide a drug with more application value, especially a rapamycin derivative for clinical use. The present inventors have discovered a series of substituted rapamycin triazole derivatives, which exhibit strong antitumor activity and/or other unexpected advantages against various tumor cell lines. The present invention has been accomplished based on this finding.

To this end, the first aspect of the present invention provides the following compounds of formula I:

or its pharmaceutically acceptable salt, 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 ₁ is (C ₁ -C ₄ ) alkylaminomethyl-, anilinomethyl-, or phenyl-, wherein the phenyl ring on the phenyl or anilinomethyl- is optionally replaced by 1-4 identical or Different R2 group substitution _;

R ₂ is selected from the group consisting of hydrogen, hydroxyl, halogen, trifluoromethyl, trifluoromethoxy, amino, carboxyl, cyano, (C ₁ -C ₄ ) alkyl, (C ₁ -C ₆ ) alkyl, ( C ₁ -C ₄ )alkoxy, (C ₁ -C ₄ )alkenyl, (C ₁ -C ₄ )alkynyl, N-(C ₁ -C ₄ )alkylamino, N,N-di(C ₁ -C ₄ )alkylamino, (C ₁ -C ₄ )alkylthio, (C ₁ -C ₄ )alkylsulfinyl, (C ₁ -C ₄ )alkylsulfonyl, (C ₁ - C ₄ )alkoxymethyl, (C ₁ -C ₄ )alkoxyethyl, (C ₁ -C ₄ )alkylacyl, carbamoyl, N-(C ₁ -C ₄ )alkylaminomethyl Acyl, N,N-di(C ₁ -C ₄ )alkylcarbamoyl, (C ₁ -C ₃ )alkylenedioxy.

The compound according to any embodiment of the first aspect of the present invention, wherein the (C ₁ -C ₄ ) alkyl group is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl base.

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

A compound according to any embodiment of the first aspect of the present invention, wherein said group comprising a (C ₁ -C ₄ ) alkyl moiety (for example (C _{1 -C 4 in (C 1 -C 4 )} alkoxy) ) alkyl, (C _{1 -C 4 ) alkyl in N-(C 1 -C 4 ) alkylamino, etc.) the (C 1 -C 4 ) alkyl is selected} from methyl, ethyl, propyl , isopropyl, n-butyl, isobutyl, tert-butyl.

A compound according to any embodiment of the first aspect of the invention, wherein R is hydrogen, or methyl.

A compound according to any embodiment of the first aspect of the invention, wherein X is n is 1.

A compound according to any embodiment of the first aspect of the present invention, wherein X is a "single bond" (that is, X is "—"), and n is 2 or 3;

The compound according to any embodiment of the first aspect of the present invention, which is a compound selected from the following compounds or pharmaceutically acceptable salts, solvates, isomers, esters, prodrugs thereof:

43-O-(2-(4-(4-fluorophenyl)-1H-1,2,3-triazol-1-yl)ethyl)oxrapamycin

43-O-(2-(4-(4-chlorophenyl)-1H-1,2,3-triazol-1-yl)ethyl)oxyrapamycin

43-O-(2-(4-(4-methylphenyl)-1H-1,2,3-triazol-1-yl)ethyl)oxyrapamycin

43-O-(2-(4-(phenyl)-1H-1,2,3-triazol-1-yl)ethyl)oxyrapamycin

43-O-(2-(4-(4-pentylphenyl)-1H-1,2,3-triazol-1-yl)ethyl)oxrapamycin

43-O-(2-(4-(3-methylphenyl)-1H-1,2,3-triazol-1-yl)ethyl)oxyrapamycin

43-O-(2-(4-(2-chlorophenyl)-1H-1,2,3-triazol-1-yl)ethyl)oxyrapamycin

43-O-(2-(4-(4-bromophenyl)-1H-1,2,3-triazol-1-yl)ethyl)oxrapamycin

43-O-(2-(4-(4-methoxyphenyl)-1H-1,2,3-triazol-1-yl)ethyl)oxrapamycin

43-O-(2-(4-((2,5dichlorophenyl)aminomethyl)-1H-1,2,3-triazol-1-yl)ethyl)oxyrapamycin

43-O-(2-(4-((2,4dichlorophenyl)aminomethyl)-1H-1,2,3-triazol-1-yl)ethyl)oxyrapamycin

43-O-(2-(4-((2,6difluorophenyl)aminomethyl)-1H-1,2,3-triazol-1-yl)ethyl)oxrapamycin

43-O-(2-(4-((2-fluorophenyl)aminomethyl)-1H-1,2,3-triazol-1-yl)ethyl)oxrapamycin

43-O-(3-(4-(4-fluorophenyl)-1H-1,2,3-triazol-1-yl)n-propyl)oxrapamycin

43-O-(3-(4-(4-chlorophenyl)-1H-1,2,3-triazol-1-yl)n-propyl)oxrapamycin

43-O-(3-(4-(4-methylphenyl)-1H-1,2,3-triazol-1-yl)n-propyl)oxrapamycin

43-O-(3-(4-Phenyl-1H-1,2,3-triazol-1-yl)n-propyl)oxyrapamycin

43-O-(3-(4-(3-methylphenyl)-1H-1,2,3-triazol-1-yl)n-propyl)oxrapamycin

43-O-(3-(4-(2-chlorophenyl)-1H-1,2,3-triazol-1-yl)n-propyl)oxrapamycin

43-O-(3-(4-(4-bromophenyl)-1H-1,2,3-triazol-1-yl)n-propyl)oxrapamycin

43-O-(3-(4-(4-methoxyphenyl)-1H-1,2,3-triazol-1-yl)n-propyl)oxrapamycin

43-O-(3-(4-((2,5dichlorophenyl)aminomethyl)-1H-1,2,3-triazol-1-yl)n-propyl)oxyrapamycin

43-O-(3-(4-((2,4dichlorophenyl)aminomethyl)-1H-1,2,3-triazol-1-yl)n-propyl)oxyrapamycin

43-O-(3-(4-((2,6difluorophenyl)aminomethyl)-1H-1,2,3-triazol-1-yl)n-propyl)oxrapamycin

43-O-(3-(4-((2-fluorophenyl)aminomethyl)-1H-1,2,3-triazol-1-yl)n-propyl)oxrapamycin

43-O-(2-(4-(4-fluorophenyl)-1H-1,2,3-triazol-1-yl)acetyl)oxrapamycin

43-O-(2-(4-(4-chlorophenyl)-1H-1,2,3-triazol-1-yl)acetyl)oxrapamycin

43-O-(2-(4-(4-methylphenyl)-1H-1,2,3-triazol-1-yl)acetyl)oxrapamycin

43-O-(2-(4-(phenyl)-1H-1,2,3-triazol-1-yl)acetyl)oxyrapamycin

43-O-(2-(4-(4-pentylphenyl)-1H-1,2,3-triazol-1-yl)acetyl)oxrapamycin

43-O-(2-(4-(3-methylphenyl)-1H-1,2,3-triazol-1-yl)acetyl)oxrapamycin

43-O-(2-(4-(2-chlorophenyl)-1H-1,2,3-triazol-1-yl)acetyl)oxrapamycin

43-O-(2-(4-(4-bromophenyl)-1H-1,2,3-triazol-1-yl)acetyl)oxrapamycin

43-O-(2-(4-(4-methoxyphenyl)-1H-1,2,3-triazol-1-yl)acetyl)oxrapamycin

43-O-(2-(4-((2,5dichlorophenyl)aminomethyl)-1H-1,2,3-triazol-1-yl)acetyl)oxyrapamycin

43-O-(2-(4-((2-fluorophenyl)aminomethyl)-1H-1,2,3-triazol-1-yl)acetyl)oxyrapamycin

43-O-(2-(4-(pyrrolidinyl-1-methylene)-1H-1,2,3-triazol-1-yl)acetyl)oxyrapamycin

43-O-(2-(4-(Diethylaminomethyl)-1H-1,2,3-triazol-1-yl)acetyl)oxrapamycin

43-O-(2-(4-(4-fluorophenyl)-1H-1,2,3-triazol-1-yl)isopropionyl)oxrapamycin

43-O-(2-(4-(4-chlorophenyl)-1H-1,2,3-triazol-1-yl)isopropionyl)oxrapamycin

43-O-(2-(4-(4-methylphenyl)-1H-1,2,3-triazol-1-yl)isopropionyl)oxrapamycin

43-O-(2-(4-(phenyl)-1H-1,2,3-triazol-1-yl)isopropionyl)oxrapamycin

43-O-(2-(4-(4-pentylphenyl)-1H-1,2,3-triazol-1-yl)isopropionyl)oxrapamycin

43-O-(2-(4-(3-methylphenyl)-1H-1,2,3-triazol-1-yl)isopropionyl)oxrapamycin

43-O-(2-(4-(2-chlorophenyl)-1H-1,2,3-triazol-1-yl)isopropionyl)oxrapamycin

43-O-(2-(4-(4-bromophenyl)-1H-1,2,3-triazol-1-yl)isopropionyl)oxrapamycin

43-O-(2-(4-(4-methoxyphenyl)-1H-1,2,3-triazol-1-yl)isopropionyl)oxrapamycin

43-O-(2-(4-((2,5dichlorophenyl)aminomethyl)-1H-1,2,3-triazol-1-yl)isopropionyl)oxrapamycin

43-O-(2-(4-((2,4dichlorophenyl)aminomethyl)-1H-1,2,3-triazol-1-yl)isopropionyl)oxyrapamycin

43-O-(2-(4-((2-fluorophenyl)aminomethyl)-1H-1,2,3-triazol-1-yl)isopropionyl)oxrapamycin

The compound of the present invention is essentially a 43-hydroxyl-substituted derivative of rapamycin, so its name can still be based on the mother nucleus of rapamycin, expressed as a substituent on the 43-hydroxyl group, as described above 43-O-oxo rapamycin.

A compound according to any embodiment of the first aspect of the present invention, which is a compound represented by the following formula or a pharmaceutically acceptable salt, solvate, isomer, ester, or prodrug thereof:

And the compound is selected from the compounds numbered 1-50 in the following table, wherein X, R, R ₁ and n of each compound are shown in the following table respectively:

Furthermore, the second aspect of the present invention provides a pharmaceutical composition, which includes the compound described in any embodiment of the first aspect of the present invention, and optionally a pharmaceutically acceptable carrier or adjuvant. According to this aspect, the present invention also relates to the use of the pharmaceutical composition as a medicament for preventing or treating tumors and/or cancers and other diseases.

Further, the third aspect of the present invention provides the use of the compound according to any embodiment of the first aspect of the present invention in the preparation of a medicament for preventing or treating tumor and/or cancer. According to the use of the present invention, wherein the tumor and/or cancer is selected from: lung cancer, pancreatic cancer, esophagus cancer, gastric cancer, cervical cancer, prostate cancer, leukemia, kidney cancer.

Further, the fourth aspect of the present invention provides a method for preventing and/or treating tumors and/or cancers, the method comprising administering a preventive and/or therapeutically effective amount of the formula of the first aspect of the present invention to a subject in need thereof I compound.

Further, the fifth aspect of the present invention provides a method for preparing the compound described in any embodiment of the first aspect of the present invention, which includes the following steps:

Compound A-1 from the following: The following compound of formula A-2 was prepared:

Then make A-2 compound and R1 aryl (such as phenyl) substituted alkyne compound to obtain formula I compound through sulfuric acid pentahydrate ketone and sodium ascorbate reaction:

The compounds of formula I are optionally formed into pharmaceutically acceptable salts, solvates, isomers, esters, prodrugs thereof. Wherein each substituent is as described in any embodiment of the first aspect of the present invention.

According to the method of the fifth aspect of the present invention, wherein, when X is "—" and R is hydrogen, the preparation method of A-2 compound is:

Using compound A-1 as a raw material, react with the side chain of the triflate compound shown in B-1 to obtain compound B-2:

Compound B-2 is then reacted with sodium azide to give compound A-2.

According to the method of the fifth aspect of the present invention, wherein, when X is When, the preparation method of A-2 compound is:

Using compound A-1 as a raw material reacts with trimethylchlorosilane to obtain the following compound of formula C-1:

Then compound C-1 is combined with the formula The C-2 compound is esterified to obtain the following formula C-3 compound:

Compound C-3 is then reacted with sodium azide to give compound C-4:

Finally, compound C-4 is deprotected to obtain compound A-2.

Any aspect of the present invention or the features of any one aspect of the present invention are also applicable to any other aspect or any one of the other aspects, as long as they are not mutually contradictory, of course when they are applicable to each other , if necessary, appropriate modifications can be made to the corresponding features. In the present invention, for example, when referring to "any one of the first aspect of the present invention", the "any one" refers to any sub-aspect of the first aspect of the present invention; when referring to other aspects in a similar manner, it also refers to have the same meaning.

Various aspects and features of the present invention are further described below.

All the documents cited in the present invention are incorporated herein by reference in their entirety, and if the meaning expressed in these documents is inconsistent with the present invention, the expression of the present invention shall prevail. In addition, various terms and phrases used in the present invention have common meanings known to those skilled in the art. Even so, the present invention still hopes to make a more detailed description and explanation of these terms and phrases here. The terms and phrases mentioned are as follows: If there is any inconsistency with the known meaning, the meaning expressed in the present invention shall prevail.

In the present invention, when X is "—", it means that there is no group here, which means that X is a chemical bond.

In the present invention, the groups "C ₁ -C ₄ alkyl", "C _1-4 alkyl", "(C ₁ -C ₄ ) alkyl" and the like have the same meaning, and they all mean that they have 1-4 straight-chain or branched-chain alkyl groups of carbon atoms. Other situations can also be understood similarly.

In the present invention, the group "C _1-4 alkyl", including its single representation and combination with other groups, can be selected from, for example, C _1-3 alkyl and C _1-2 alkyl. Likewise, C _1-4 alkoxy can be selected from, for example, C _1-3 alkoxy and C _1-2 alkoxy.

In the method for synthesizing the compound of formula I of the present invention, various raw materials used in the reaction can be prepared according to prior knowledge by those skilled in the art, or can be prepared by methods known in the literature, or can be purchased commercially of. The intermediates, raw materials, reagents, and reaction conditions used in the above reaction schemes can be appropriately changed according to the existing knowledge of those skilled in the art. Alternatively, those skilled in the art can also synthesize other compounds of formula I not specifically listed in the present invention according to the method of the fifth aspect of the present invention.

According to the invention, the pharmaceutically acceptable salts of the compounds of formula I may be acid addition salts or salts with bases. Acid addition salts may be, for example, inorganic acid salts such as but not limited to hydrochloride, sulfate, phosphate, hydrobromide; or organic acid salts such as but not limited to acetate, oxalate, citrate, glucose salts, succinates, tartrates, p-toluenesulfonates, methanesulfonates, benzoates, lactates and maleates; the compounds of formula I form salts with bases, for example alkali metal salts such as But not limited to lithium, sodium and potassium salts; alkaline earth metal salts such as but not limited to calcium and magnesium salts; organic base salts such as but not limited to diethanolamine salts and choline salts, etc.; or chiral base salts such as but not limited to alkylbenzene base amine salt.

Solvates of the compounds of the invention may be hydrates or contain other solvents of crystallization such as alcohols such as ethanol.

According to the present invention, the compounds of formula I may exist as cis/trans isomers, and the present invention relates to cis and trans forms and mixtures of these forms. Single stereoisomers can be prepared, if desired, by resolution of mixtures according to conventional methods, or by, for example, stereoselective synthesis. The present invention also relates to the tautomeric forms of the compounds of formula I, if a mobile hydrogen atom is present.

The present invention therefore also relates to pharmaceutical compositions comprising, as active ingredient, an effective dose of at least one compound of formula I, or a pharmaceutically acceptable salt thereof and/or stereoisomers thereof, together with customary pharmaceutical excipients or adjuvants. In general, the pharmaceutical compositions according to the invention contain 0.1-90% by weight of compounds of the formula I and/or their physiologically acceptable salts. Pharmaceutical compositions can be prepared according to methods known in the art. When used for this purpose, if necessary, the compound of formula I and/or stereoisomers can be combined with one or more solid or liquid pharmaceutical excipients and/or adjuvants to prepare suitable Administration form or dosage form.

The compound of formula I of the present invention or the pharmaceutical composition containing it can be administered in unit dosage form, and the route of administration can be enteral or parenteral, such as oral, intramuscular, subcutaneous, intratumoral, nasal cavity, oral mucosa, skin, peritoneal or rectum etc. Dosage forms such as tablets, capsules, drop pills, aerosols, pills, powders, solutions, suspensions, emulsions, granules, liposomes, transdermal agents, buccal tablets, suppositories, lyophilized powder injections , injections, etc. It can be common preparations, sustained-release preparations, controlled-release preparations and various microparticle drug delivery systems. Various carriers known in the art can be widely used for tableting unit dosage forms. Examples of carriers are, for example, diluents and absorbents such as starch, dextrin, calcium sulfate, lactose, mannitol, sucrose, sodium chloride, glucose, urea, calcium carbonate, kaolin, microcrystalline cellulose, silicic acid Aluminum, etc.; wetting agents and binders, such as water, glycerin, polyethylene glycol, ethanol, propanol, starch paste, dextrin, syrup, honey, glucose solution, acacia mucilage, gelatin paste, sodium carboxymethylcellulose , shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone, etc.; disintegrants, such as dry starch, alginate, agar powder, brown algae starch, sodium bicarbonate and citric acid, calcium carbonate, polyoxyethylene sorbate Sugar alcohol fatty acid esters, sodium lauryl sulfonate, methylcellulose, ethylcellulose, etc.; disintegration inhibitors, such as sucrose, tristearin, cocoa butter, hydrogenated oil, etc.; absorption enhancers , such as quaternary ammonium salts, sodium lauryl sulfate, etc.; lubricants, such as talc, silicon dioxide, corn starch, stearate, boric acid, liquid paraffin, polyethylene glycol, etc. Tablets can also be further made into coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or double-layer tablets and multi-layer tablets. In order to formulate a dosage unit into a pellet, various carriers known in the art can be widely used. Examples of carriers are, for example, diluents and absorbents such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oils, polyvinylpyrrolidone, Gelucire, kaolin, talc, etc.; binders such as acacia, tragacanth, gelatin , ethanol, honey, liquid sugar, rice paste or batter, etc.; disintegrants, such as agar powder, dry starch, alginate, sodium dodecylsulfonate, methylcellulose, ethylcellulose, etc. In order to formulate the administration unit into a suppository, various carriers known in the art can be widely used. Examples of carriers are, for example, polyethylene glycol, lecithin, cocoa butter, higher alcohols, esters of higher alcohols, gelatin, semi-synthetic glycerides and the like. To prepare the administration unit into a capsule, the active ingredient compound of formula I or its stereoisomer is mixed with the above-mentioned various carriers, and the mixture thus obtained is placed in a hard capsule or a soft capsule. The active ingredient compound of formula I or its stereoisomers can also be made into microcapsules, suspended in an aqueous medium to form a suspension, and can also be packed into hard capsules or made into injections for application. In order to prepare the dosage unit into injection preparations, such as solutions, emulsions, lyophilized powders and suspensions, all diluents commonly used in this field can be used, for example, water, ethanol, polyethylene glycol, 1,3 - Propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid esters, and the like. In addition, in order to prepare isotonic injection, an appropriate amount of sodium chloride, glucose or glycerin can be added to the preparation for injection, and in addition, conventional solubilizers, buffers, pH regulators, etc. can also be added.

In addition, colorants, preservatives, fragrances, correctives, sweeteners or other materials can also be added to the pharmaceutical preparations, if necessary.

The dosage of the compound of formula I of the present invention, or its isomer, depends on many factors, such as the nature and severity of the disease to be prevented or treated, the sex, age, body weight and individual response of the patient or animal, the specific compound used, Route of administration and frequency of administration, etc. The above dose can be administered in a single dose or divided into several, eg two, three or four doses.

As used herein, the term "composition" is meant to include a product comprising the specified amounts of each of the specified ingredients, as well as any product resulting, directly or indirectly, from the combination of the specified amounts of each of the specified ingredients.

Actual dosage levels of each active ingredient in the pharmaceutical compositions of this invention will be varied so that the amount of active compound obtained is effective to obtain the desired therapeutic response in a particular patient, composition and mode of administration. Dosage levels will be selected based on the activity of the particular compound, the route of administration, the severity of the condition being treated and the condition and prior medical history of the patient being treated. However, it is practice in the art to start doses of the compound at levels lower than that required to obtain the desired therapeutic effect and to gradually increase the dosage until the desired effect is obtained.

The compound of the present invention can be used to prepare antitumor drugs. The tumors include but are not limited to melanoma, gastric cancer, lung cancer, breast cancer, kidney cancer, liver cancer, oral epidermal cancer, cervical cancer, ovarian cancer, pancreatic cancer, prostate cancer, colon cancer, bladder cancer, head and neck tumors, Nasopharyngeal carcinoma, skin cancer and other malignant tumors and leukemia. The gastric cancer includes gastric adenocarcinoma; the lung cancer includes lung adenocarcinoma; the colon cancer includes colon adenocarcinoma; the ovarian cancer includes ovarian adenocarcinoma; the kidney cancer includes renal clear cell adenocarcinoma; Including acute lymphoblastic leukemia, chronic leukemia, special types of leukemia.

When used for the above treatment and/or prophylaxis or other treatment and/or prophylaxis, a therapeutically and/or prophylactically effective amount of a compound of the present invention may be used in pure form, or in the form of a pharmaceutically acceptable ester or prodrug (in the presence of In case of these forms) apply. Alternatively, the compound may be administered as a pharmaceutical composition comprising the compound of interest together with one or more pharmaceutically acceptable excipients. The phrase "prophylactically and/or therapeutically effective amount" of a compound of the invention refers to a sufficient amount of the compound to treat a disorder at a reasonable effect/risk ratio applicable to any medical prophylaxis and/or treatment. It should be recognized, however, that the total daily dosage of the compounds and compositions of the present invention must be determined by the attending physician within the scope of sound medical judgment. For any particular patient, the particular therapeutically effective dosage level will depend on a number of factors, including the disorder being treated and the severity of the disorder; the activity of the particular compound employed; the particular composition employed; The age, weight, general health, sex and diet of the patient; the timing, route of administration, and rate of excretion of the specific compound employed; the duration of treatment; drugs used in combination or concomitantly with the specific compound employed; and Similar factors are well known in the medical arts. For example, it is practice in the art to start doses of the compound at levels lower than that required to obtain the desired therapeutic effect and to gradually increase the dosage until the desired effect is obtained. Generally speaking, the dose of the compound of formula I of the present invention for mammals, especially humans, can be 0.001-1000 mg/kg body weight/day, for example, 0.01-100 mg/kg body weight/day, for example, 0.01-10 mg/kg body weight/day.

Unless otherwise indicated, the term "alkyl" used in the present invention and the "alkyl" containing the modification of the number of carbon atoms and the "alkyl" in the group combination including these "alkyl" refer to straight chain or branched chain For example, (C ₁ -C ₄ ) alkyl groups include but are not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, etc.; "alkylene" refers to straight-chain or branched chain alkylene; "cycloalkyl" means a substituted or unsubstituted cycloalkyl group.

The present invention includes a pharmaceutical composition, which contains the rapamycin compound of general formula I, its optical isomers, and pharmaceutically acceptable salts thereof as active ingredients, and pharmaceutically acceptable excipients. The pharmaceutically acceptable excipient refers to any diluent, adjuvant and/or carrier that can be used in the pharmaceutical field. The derivatives according to the invention can be used in combination with other active ingredients, provided they do not produce other adverse effects, such as allergic reactions.

The pharmaceutical composition of the present invention can be formulated into several dosage forms, which contain some excipients commonly used in the pharmaceutical field; for example, oral preparations (such as tablets, capsules, solutions or suspensions); injectable preparations (such as Injectable solution or suspension, or injectable dry powder, add water for injection immediately before injection); topical preparations (eg ointment or solution).

The carrier used for the pharmaceutical composition of the present invention is a common type available in the field of pharmacy, including: adhesives for oral preparations, lubricants, disintegrants, cosolvents, diluents, stabilizers, suspending agents, pigment-free , flavoring agents, etc.; preservatives, solubilizers, stabilizers, etc. for injectable preparations; bases, diluents, lubricants, preservatives, etc. for topical preparations. Pharmaceutical preparations can be administered orally or parenterally (eg intravenously, subcutaneously, intraperitoneally or topically), and if certain drugs are unstable under gastric conditions, they can be formulated as enteric-coated tablets.

The derivatives according to the present invention can be used as active ingredients for the preparation of treatment and/or prevention of various cancers, and the present invention also provides methods for the treatment or prevention of the above-mentioned diseases, comprising administering a therapeutically effective amount of Derivatives according to the invention. The clinical dose of the rapamycin compounds of general formula I for patients must vary depending on the subject to be treated, the specific route of administration, and the severity of the disease to be treated, and the optimal dose is determined by the doctor who treats the specific patient.

The active compound of the present invention can be used as the sole anticancer drug, or can be used in combination with one or more other anticancer drugs. Combination therapy is achieved by simultaneous, sequential or spaced administration of the individual therapeutic components.

The derivatives of the present invention may exist in stereoisomeric forms which may be enantiomers or diastereomers. The present invention relates both to the enantiomers or diastereomers, and also to their individual mixtures. Like the diastereomers, the racemic forms can be separated into the stereoisomeric individual components by methods known per se.

Furthermore, the present invention also includes prodrugs of the derivatives of the present invention. According to the invention, prodrugs are derivatives of the general formula I, which themselves may have weak activity or even no activity, but after administration, are destroyed under physiological conditions (for example by metabolism, solvolysis or otherwise) into the corresponding biologically active form.

We have found that the compound of the present invention has the activity of inhibiting the growth of tumor cells in vitro, therefore, it can be used as a medicine for treating and/or preventing cancer. In particular, cancers of the breast, lung, colon, rectum, stomach, prostate, bladder, pancreas, and ovary are treated. The compounds of the invention are also expected to be useful in the treatment of other cell proliferative diseases such as psoriasis, benign prostatic hypertrophy, atherosclerosis and restenosis. It is further expected that the rapamycins of the present invention will have activity against leukemias, malignant lymphomas and solid tumors such as carcinomas and sarcomas in tissues such as liver, kidney, prostate and pancreas.

The active compound of the present invention can be used as the sole anticancer drug, or can be used in combination with one or more other anticancer drugs. Combination therapy is achieved by simultaneous, sequential or spaced administration of the individual therapeutic components.

The Examples and Preparations provided hereinafter further illustrate and illustrate the compounds of the present invention and methods for their preparation. It should be understood that the scope of the following examples and preparations does not limit the scope of the invention in any way.

The following synthetic schemes describe the general preparation of compounds of general formula I of the present invention, all starting materials are prepared by the methods described in these schemes, by methods well known to those of ordinary skill in the field of organic chemistry or are commercially available. All final compounds of the invention are prepared by the methods described in these schemes or by methods analogous thereto, which methods are well known to those of ordinary skill in the art of organic chemistry. All variables used in these diagrams are as defined below or as defined in the claims.

The compound of the present invention has excellent biological activity and pharmaceutical properties. For example, the automatic adsorption analyzer DVS-1 instrument was used to measure the hygroscopicity of the hydrate prepared in each embodiment of the present invention, and rapamycin and temsirolimus were used as controls. The measurement method is: accurately weigh about 25mg of the test material and place it in the sample pan, and expose it to a humidity environment with a relative humidity of 0-90%; use a 1% RH gradient within the range of 0-15% RH for detailed Analysis, using a 15% RH gradient in the range of 15 to 90% RH for detailed analysis; the analysis temperature is 30° C., and the nitrogen flow rate is 200 cubic centimeters/min; the moisture absorption isotherm of each compound is obtained. The results show that all compounds of the present invention have only absorbed water lower than 0.3% (w/w) in the scope of 0%-90%RH, while rapamycin and temsirolimus have water absorption greater than 0.8%, indicating that The compounds of the present invention are non-hygroscopic, which is an excellent property of a drug substance.

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

Compound A-1 is reacted through 2-4 steps to generate azide compound A-2. Compound A-2 is reacted with aryl alkynes via sulfuric acid pentahydrate and sodium ascorbate to obtain derivatives represented by general formula I.

Wherein, when X is "—" and R is hydrogen, A-2 is prepared according to the method described in route B: using A-1 as raw material, reacting with B-1 trifluoromethanesulfonate side chain to obtain B-2, Then react with sodium azide to obtain A-2.

when X is , A-2 was prepared according to the method described in route C: A-1 was used as raw material, and A-2 was obtained through silyl ether protection, esterification, azidation and deprotection.

The preparation method of the invention is simple, and all the prepared compounds have remarkable antitumor activity.

In the above route, the compounds represented by raw materials A-1, B-1, B-2, C-1 and C-2 can be prepared by methods well known to those skilled in the field of organic chemistry or are commercially available. The preparation method of the invention is simple, and the prepared compound has good antitumor activity.

detailed description

The following specific examples are intended to illustrate but not limit the scope of the invention.

The proton nuclear magnetic resonance spectrum of the compound prepared in the present invention is measured by BrukerARX-300, and the mass spectrum is measured by Agilent1100LC/MSD; all reagents used are analytically pure or chemically pure.

Example 1: 43-O-(2-(4-(4-fluorophenyl)-1H-1,2,3-triazol-1-yl)ethyl)oxrapamycin (X-18 )

Step A: Preparation of 43-O-(2-bromoethyl)-oxrapamycin

Add rapamycin (10g, 10.9mmol) and diisopropylethylamine (55mmol) to 300mL of toluene solution, add 2-bromoethylsulfonate side chain (25g, 98mmol), add and heat up Reaction at 60°C for 3h. After the reaction was completed, the reaction liquid was cooled to room temperature, respectively, through dilute hydrochloric acid, saturated sodium bicarbonate and saturated brine, the organic layer was dried over anhydrous sodium sulfate, and evaporated to dryness to give a light yellow solid, which was finally separated by column chromatography to obtain 5.2 g White solid, yield: 46.7%, 1042.5 (M+Na) ⁺ .

Step B: Preparation of 43-O-(2-azidoethyl)-oxrapamycin

43-O-(2-bromoethyl)-oxrapamycin (5.2g, 5.1mmol) and sodium azide (0.97g, 15mmol) were added to (30mL) DMF solution respectively, catalyst KI was added ( 0.1 g), after the addition, the temperature was raised to 50°C. After the reaction was complete, the reaction liquid was poured into 90 mL of water, extracted twice with ethyl acetate, the extracts were combined, washed with water, and dried over anhydrous sodium sulfate. Evaporate to dryness to obtain oily substances, which were separated by column chromatography to obtain 2.1 g, with a yield of 41.8%. MS (ESI) m/z: 1005.5 (M+Na) ⁺ .

Step C: Preparation of 43-O-(2-(4-(4-fluorophenyl)-1H-1,2,3-triazol-1-yl)ethyl)oxrapamycin (X- 18)

Add 43-O-(2-azidoethyl)-oxrapamycin (0.3mmoL, 0.3g) and 4-fluorophenylacetylene (0.1g) to the DMF (10mL) solution, and add Sodium ascorbate (0.05g) and copper sulfate pentahydrate (0.08g) were stirred at room temperature for 2 hours. After the reaction was completed, the reaction was poured into 40mL of water, and a light yellow solid was precipitated, which was filtered by suction, washed with water, and dried to obtain a light yellow solid. Chromatography and C18 preparative chromatographic separation gave 0.15 g of pure product, yield: 45.3%. MS (ESI) m/z: 1125.7 (M+Na) ⁺ . ¹ HNMR(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). ¹³ CNMR(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.

Example 2: 43-O-(2-(4-(4-chlorophenyl)-1H-1,2,3-triazol-1-yl)ethyl)oxyrapamycin (X-48 )

Add 43-O-(2-azidoethyl)-oxrapamycin (0.3mmoL, 0.3g) and 4-chlorophenylacetylene (0.1g) to the DMF (10mL) solution, and add Sodium ascorbate (0.1g) and copper sulfate pentahydrate (0.08g) were stirred at room temperature for 2 hours. After the reaction was completed, the reaction was poured into 40mL of water, and a light yellow solid was precipitated, filtered by suction, washed with water, dried to obtain a light yellow solid, and passed through a silica gel column. Chromatography and C18 preparative chromatographic separation gave 0.17g of pure product, yield: 50.7%. MS (ESI) m/z: 1141.6 (M+Na) ⁺ . ¹ H NMR (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). ¹³ CNMR(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.

Example 3: 43-O-(2-(4-(4-methylphenyl)-1H-1,2,3-triazol-1-yl)ethyl)oxyrapamycin (X- 15)

43-O-(2-azidoethyl)-oxrapamycin (0.3mmoL, 0.3g) and 4-methylphenylacetylene (0.1g) were added to the DMF (10mL) solution, and added to the reaction solution Add sodium ascorbate (0.1g) and copper sulfate pentahydrate (0.08g), stir at room temperature for 2h, after the reaction is completed, pour the reaction into 40mL of water, a light yellow solid precipitates, filter with suction, wash with water, dry to get a light yellow solid, pass through silica gel Column chromatography and C18 preparative chromatography separated to obtain 0.13 g of pure product, yield: 39.4%. MS (ESI) m/z: 1121.8 (M+Na) ⁺ . ¹ HNMR(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=10.4 Hz,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). ¹³ CNMR(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.

Example 4: 43-O-(2-(4-(phenyl)-1H-1,2,3-triazol-1-yl)ethyl)oxrapamycin (X-16)

43-O-(2-azidoethyl)-oxrapamycin (0.3mmoL, 0.3g) and phenylacetylene (0.1g) were added to the DMF (10mL) solution, and sodium ascorbate ( 0.1g) and copper sulfate pentahydrate (0.08g), stirred at room temperature for 2h, after the reaction was completed, the reaction was poured into 40mL water, and a light yellow solid was precipitated, filtered by suction, washed with water, and dried to obtain a light yellow solid, which was subjected to silica gel column chromatography and C18 was separated by preparative chromatography to obtain 0.23 g of pure product, yield: 70.7%. MS (ESI) m/z: 1107.3 (M+Na) ⁺ . ¹ HNMR (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). ¹³ CNMR(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.

Example 5: 43-O-(2-(4-(4-pentylphenyl)-1H-1,2,3-triazol-1-yl)ethyl)oxyrapamycin (X- 17)

Add 43-O-(2-azidoethyl)-oxrapamycin (0.3mmoL, 0.3g) and 4-n-pentylphenylacetylene (0.1g) to the DMF (10mL) solution, and add to the reaction solution Sodium ascorbate (0.1g) and copper sulfate pentahydrate (0.08g) were added to the mixture, and stirred at room temperature for 2h. After the reaction was completed, the reaction was poured into 40mL of water, and a light yellow solid was precipitated, filtered by suction, washed with water, and dried to obtain a light yellow solid. Silica gel column chromatography and C18 preparative chromatography separated to obtain 0.09 g of pure product, yield: 27.4%. MS (ESI) m/z: 1177.8 (M+Na) ⁺ . ¹ HNMR (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). ¹³ CNMR(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.

Example 6: 43-O-(2-(4-(3-methylphenyl)-1H-1,2,3-triazol-1-yl)ethyl)oxyrapamycin (X- 47)

43-O-(2-azidoethyl)-oxrapamycin (0.3mmoL, 0.3g) and 3-methylphenylacetylene (0.1g) were added to the DMF (10mL) solution, and added to the reaction solution Add sodium ascorbate (0.1g) and copper sulfate pentahydrate (0.08g), stir at room temperature for 2h, after the reaction is completed, pour the reaction into 40mL of water, a light yellow solid precipitates, filter with suction, wash with water, dry to get a light yellow solid, pass through silica gel Column chromatography and C18 preparative chromatography separated to obtain 0.13 g of pure product, yield: 39.2%. MS (ESI) m/z: 1121.5 (M+Na) ⁺ . ¹ HNMR (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). ¹³ CNMR(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.

Example 7: 43-O-(2-(4-(2-chlorophenyl)-1H-1,2,3-triazol-1-yl)ethyl)oxrapamycin (X-49 )

Add 43-O-(2-azidoethyl)-oxrapamycin (0.3mmoL, 0.3g) and 2-chlorophenylacetylene (0.1g) to the DMF (10mL) solution, and add Sodium ascorbate (0.1g) and copper sulfate pentahydrate (0.08g) were stirred at room temperature for 2 hours. After the reaction was completed, the reaction was poured into 40mL of water, and a light yellow solid was precipitated, filtered by suction, washed with water, dried to obtain a light yellow solid, and passed through a silica gel column. Chromatography and C18 preparative chromatographic separation gave pure product 0.11g, yield: 33.3%. MS (ESI) m/z: 1141.8 (M+Na) ⁺ . ¹ HNMR (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=6.7 Hz, 3H). ¹³ CNMR(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.

Example 8: 43-O-(2-(4-(4-bromophenyl)-1H-1,2,3-triazol-1-yl)ethyl)oxrapamycin (X-50 )

Add 43-O-(2-azidoethyl)-oxrapamycin (0.3mmoL, 0.3g) and 4-bromophenylacetylene (0.1g) to the DMF (10mL) solution, and add Sodium ascorbate (0.1g) and copper sulfate pentahydrate (0.08g) were stirred at room temperature for 2 hours. After the reaction was completed, the reaction was poured into 40mL of water, and a light yellow solid was precipitated, filtered by suction, washed with water, dried to obtain a light yellow solid, and passed through a silica gel column. Chromatography and C18 preparative chromatographic separation gave 0.12 g of pure product, yield: 34.4%. MS (ESI) m/z: 1186.3 (M+Na) ⁺ . ¹ H NMR (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). ¹³ CNMR(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.

Example 9: 43-O-(2-(4-(4-methoxyphenyl)-1H-1,2,3-triazol-1-yl)ethyl)oxyrapamycin (X -67)

43-O-(2-azidoethyl)-oxrapamycin (0.3mmoL, 0.3g) and 4-methoxyphenylacetylene (0.1g) were added to the DMF (10mL) solution, and the reaction liquid Sodium ascorbate (0.1g) and copper sulfate pentahydrate (0.08g) were added to the mixture, and stirred at room temperature for 2h. After the reaction was completed, the reaction was poured into 40mL of water, and a light yellow solid was precipitated, filtered by suction, washed with water, and dried to obtain a light yellow solid. Silica gel column chromatography and C18 preparative chromatography separated to obtain 0.10 g of pure product, yield: 30.3%. MS (ESI) m/z: 1137.5 (M+Na) ⁺ . ¹ HNMR(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＝6.4 Hz, 3H), 0.82 (d, J = 6.3Hz, 3H), 0.76 (d, J = 6.6Hz, 3H), 0.73 (d, J = 6.5Hz, 3H). ¹³ CNMR(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.

Example 10: 43-O-(2-(4-((2,5 dichlorophenyl)aminomethyl)-1H-1,2,3-triazol-1-yl)ethyl)oxurine Pamycin (X-14)

43-O-(2-azidoethyl)-oxrapamycin (0.3mmoL, 0.3g) and N-(prop-2-ynyl)-2,5-dichloroaniline (0.1g) were added Add sodium ascorbate (0.1g) and copper sulfate pentahydrate (0.08g) to the DMF (10mL) solution, and stir at room temperature for 2h. Filtered, washed with water, and dried to obtain a light yellow solid, which was separated by silica gel column chromatography and C18 preparative chromatography to obtain 0.11 g of pure product, yield: 31.1%. MS (ESI) m/z: 1205.6 (M+Na) ⁺ . ¹ HNMR (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). ¹³ CNMR(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.

Example 11: 43-O-(2-(4-((2,4dichlorophenyl)aminomethyl)-1H-1,2,3-triazol-1-yl)ethyl)oxyradine Pamycin (X-13)

Add 43-O-(2-azidoethyl)-oxrapamycin (0.3mmoL, 0.3g) and N-(prop-2-ynyl)-2,4-dichloroaniline (0.1g) Add sodium ascorbate (0.1g) and copper sulfate pentahydrate (0.08g) to the DMF (10mL) solution, and stir at room temperature for 2h. Filtered, washed with water, and dried to obtain a light yellow solid, which was separated by silica gel column chromatography and C18 preparative chromatography to obtain 0.09 g of pure product, yield: 25.5%. MS (ESI) m/z: 1205.4 (M+Na) ⁺ . ¹ HNMR (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). ¹³ CNMR(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.

Example 12: 43-O-(2-(4-((2,6 difluorophenyl)aminomethyl)-1H-1,2,3-triazol-1-yl)ethyl)oxyradine Pamycin (X-12)

Add 43-O-(2-azidoethyl)-oxrapamycin (0.3mmoL, 0.3g) and N-(prop-2-ynyl)-2,6-difluoroaniline (0.1g) Add sodium ascorbate (0.1g) and copper sulfate pentahydrate (0.08g) to the DMF (10mL) solution, and stir at room temperature for 2h. Filtered, washed with water, and dried to obtain a light yellow solid, which was separated by silica gel column chromatography and C18 preparative chromatography to obtain 0.10 g of pure product, yield: 29.0%. MS (ESI) m/z: 1172.7 (M+Na) ⁺ . ¹ HNMR (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). ¹³ CNMR(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.

Example 13: 43-O-(2-(4-((2-fluorophenyl)aminomethyl)-1H-1,2,3-triazol-1-yl)ethyl)oxrapamycin Prime (X-19)

43-O-(2-Azidoethyl)-oxrapamycin (0.3mmoL, 0.3g) and N-(prop-2-ynyl)-2-fluoroaniline (0.1g) were added to DMF ( 10mL) solution, add sodium ascorbate (0.1g) and copper sulfate pentahydrate (0.08g) to the reaction solution, stir at room temperature for 2h, after the reaction is complete, pour the reaction into 40mL water, precipitate a light yellow solid, suction filter, wash with water , dried to obtain a light yellow solid, which was separated by silica gel column chromatography and C18 preparative chromatography to obtain 0.08 g of pure product, yield: 23.2%. MS (ESI) m/z: 1154.7 (M+Na) ⁺ . ¹ HNMR(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). ¹³ CNMR(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.

Example 14: 43-O-(3-(4-(4-fluorophenyl)-1H-1,2,3-triazol-1-yl)n-propyl)oxrapamycin (X- 26)

Step A: Preparation of 43-O-(3-bromopropyl)-oxrapamycin

Add rapamycin (8.0g, 8.7mmol), diisopropylethylamine (5.6g, 44mmol) to 50mL of toluene solution, add 3-bromopropylsulfonate side chain (11.8g, 28.5mmol ), the addition was completed, and the temperature was raised to 60° C. for 3 h. After the reaction was completed, the reaction liquid was cooled to room temperature, respectively, in dilute hydrochloric acid, saturated sodium bicarbonate and saturated brine, the organic layer was dried over anhydrous sodium sulfate, and evaporated to dryness to obtain a light yellow solid, which was separated by column chromatography to obtain 4.8 g of white Solid, yield: 53.3%, 1056.5 (M+Na) ⁺ .

Step B: Preparation of 43-O-(3-azidopropyl)-oxrapamycin

43-O-(3-bromopropyl)-oxrapamycin (4.8g, 4.6mmol) and sodium azide (1.3g, 19.5mmol) were added to (30mL) DMF solution respectively, catalyst KI was added (0.1g), after the addition, the temperature was raised to 50°C. After the reaction was complete, the reaction solution was poured into 100mL water, extracted twice with ethyl acetate, the extracts were combined, washed with water, and dried over anhydrous sodium sulfate. Evaporate to dryness to obtain oily matter, which were separated by column chromatography to obtain 2.4 g, yield: 52%. MS (ESI) m/z: 1019.6 (M+Na) ⁺ .

Step C: Preparation of 43-O-(3-(4-(4-fluorophenyl)-1H-1,2,3-triazol-1-yl)n-propyl)oxrapamycin (X -26)

Add 43-O-(3-azidopropyl)-oxrapamycin (0.35mmoL, 0.35g) and 4-fluorophenylacetylene (0.1g) to the DMF (10mL) solution, and add Sodium ascorbate (0.1g) and copper sulfate pentahydrate (0.08g) were stirred at room temperature for 2 hours. After the reaction was completed, the reaction was poured into 60mL of water, and a light yellow solid was precipitated, which was filtered by suction, washed with water, and dried to obtain a light yellow solid. Chromatography and C18 preparative chromatographic separation gave 0.19 g of pure product, yield: 43.4%. MS (ESI) m/z: 1139.7 (M+Na) ⁺ . ¹ HNMR(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). ¹³ CNMR(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.

Example 15: 43-O-(3-(4-(4-chlorophenyl)-1H-1,2,3-triazol-1-yl)n-propyl)oxyrapamycin (X- 27)

Add 43-O-(3-azidopropyl)-oxrapamycin (0.35mmoL, 0.35g) and 4-chlorophenylacetylene (0.1g) to the DMF (10mL) solution, and add Sodium ascorbate (0.1g) and copper sulfate pentahydrate (0.08g) were stirred at room temperature for 2 hours. After the reaction was completed, the reaction was poured into 60mL of water, and a light yellow solid was precipitated, which was filtered by suction, washed with water, and dried to obtain a light yellow solid. Chromatography and C18 preparative chromatographic separation gave 0.16 g of pure product, yield: 41.0%. MS (ESI) m/z: 1155.7 (M+Na) ⁺ . ¹ H NMR (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). ¹³ CNMR(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.

Example 16: 43-O-(3-(4-(4-methylphenyl)-1H-1,2,3-triazol-1-yl)n-propyl)oxyrapamycin (X -twenty one)

43-O-(3-azidopropyl)-oxrapamycin (0.35mmoL, 0.35g) and 4-methylphenylacetylene (0.1g) were added to the DMF (10mL) solution, and added to the reaction solution Add sodium ascorbate (0.1g) and copper sulfate pentahydrate (0.08g), stir at room temperature for 2h, after the reaction is completed, pour the reaction into 60mL of water, a light yellow solid precipitates, suction filter, wash with water, dry to obtain a light yellow solid, and Column chromatography and C18 preparative chromatography separated to obtain 0.18 g of pure product, yield: 46.1%. MS (ESI) m/z: 1135.7 (M+Na) ⁺ . ¹ H NMR (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). ¹³ CNMR(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.

Example 17: 43-O-(3-(phenyl-1H-1,2,3-triazol-1-yl)n-propyl)oxrapamycin (X-22)

43-O-(3-azidopropyl)-oxyrapamycin (0.35mmoL, 0.35g) and phenylacetylene (0.1g) were added to the DMF (10mL) solution, and sodium ascorbate ( 0.1g) and copper sulfate pentahydrate (0.08g), stirred at room temperature for 2h, after the reaction was completed, the reaction was poured into 60mL water, and a light yellow solid was precipitated, filtered by suction, washed with water, and dried to obtain a light yellow solid, which was subjected to silica gel column chromatography and C18 was separated by preparative chromatography to obtain 0.15 g of pure product, yield: 38.4%. MS (ESII) m/z: 1121.7 (M+Na) ⁺ . ¹ HNMR(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). ¹³ CNMR(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.

Example 18: 43-O-(3-(4-(3-methylphenyl)-1H-1,2,3-triazol-1-yl)n-propyl)oxyrapamycin (X -31)

43-O-(3-azidopropyl)-oxrapamycin (0.35mmoL, 0.35g) and 3-methylphenylacetylene (0.1g) were added to the DMF (10mL) solution, and added to the reaction solution Add sodium ascorbate (0.1g) and copper sulfate pentahydrate (0.08g), stir at room temperature for 2h, after the reaction is completed, pour the reaction into 60mL of water, a light yellow solid precipitates, suction filter, wash with water, dry to obtain a light yellow solid, and Column chromatography and C18 preparative chromatography separated to obtain 0.19 g of pure product, yield: 48.7%. MS (ESII) m/z: 1135.4 (M+Na) ⁺ . ¹ HNMR (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). ¹³ CNMR(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.

Example 19: 43-O-(3-(4-(2-chlorophenyl)-1H-1,2,3-triazol-1-yl)n-propyl)oxyrapamycin (X- 32)

Add 43-O-(3-azidopropyl)-oxrapamycin (0.35mmoL, 0.35g) and 2-chlorophenylacetylene (0.1g) to the DMF (10mL) solution, and add Sodium ascorbate (0.1g) and copper sulfate pentahydrate (0.08g) were stirred at room temperature for 2 hours. After the reaction was completed, the reaction was poured into 60mL of water, and a light yellow solid was precipitated, which was filtered by suction, washed with water, and dried to obtain a light yellow solid. Chromatography and C18 preparative chromatography gave 0.16 g of pure product, yield: 40.5%. MS (ESI) m/z: 1155.6 (M+Na) ⁺ . ¹ HNMR(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=6.6 Hz, 3H). ¹³ CNMR(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.

Example 20: 43-O-(3-(4-(4-bromophenyl)-1H-1,2,3-triazol-1-yl)n-propyl)oxyrapamycin (X- 30)

Add 43-O-(3-azidopropyl)-oxrapamycin (0.35mmoL, 0.35g) and 4-bromophenylacetylene (0.1g) to the DMF (10mL) solution, and add Sodium ascorbate (0.1g) and copper sulfate pentahydrate (0.08g) were stirred at room temperature for 2 hours. After the reaction was completed, the reaction was poured into 60mL of water, and a light yellow solid was precipitated, which was filtered by suction, washed with water, and dried to obtain a light yellow solid. Chromatography and C18 preparative chromatographic separation gave 0.14 g of pure product, yield: 34.0%. MS (ESI) m/z: 1200.3 (M+Na) ⁺ . ¹ H NMR (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). ¹³ CNMR(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.

Example 21: 43-O-(3-(4-(4-methoxyphenyl)-1H-1,2,3-triazol-1-yl) n-propyl)oxyrapamycin ( X-29)

43-O-(3-azidopropyl)-oxrapamycin (0.35mmoL, 0.35g) and 4-methoxyphenylacetylene (0.1g) were added to the DMF (10mL) solution, and the reaction liquid Sodium ascorbate (0.1g) and copper sulfate pentahydrate (0.08g) were added to the mixture, and stirred at room temperature for 2h. After the reaction was completed, the reaction was poured into 60mL of water, and a light yellow solid was precipitated, filtered by suction, washed with water, and dried to obtain a light yellow solid. Silica gel column chromatography and C18 preparative chromatography separated to obtain 0.19 g of pure product, yield: 48.1%. MS (ESII) m/z: 1151.5 (M+Na) ⁺ . ¹ H NMR (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). ¹³ CNMR(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 , 82.00,75.74,74,70,66.19,65.48,56.92,55.45,55.10, 50.75,46.74,45.20,49,38.23,35.16,33.3.3.3, 30.40,29.4,29. , 21.63, 20.37, 15.57, 15.52, 14.70, 13.44, 13.34, 10.46.

Example 22: 43-O-(3-(4-((2,5 dichlorophenyl)aminomethyl)-1H-1,2,3-triazol-1-yl)n-propyl)oxy Rapamycin (X-23)

43-O-(3-azidopropyl)-oxrapamycin (0.35mmoL, 0.35g) and N-(prop-2-ynyl)-2,5-dichloroaniline (0.1g) were added Add sodium ascorbate (0.1g) and copper sulfate pentahydrate (0.08g) to the DMF (10mL) solution, and stir at room temperature for 2h. Filtered, washed with water, and dried to obtain a light yellow solid, which was separated by silica gel column chromatography and C18 preparative chromatography to obtain 0.09 g of pure product, yield: 21.5%. MS (ESII) m/z: 1218.7 (M+Na) ⁺ . ¹ HNMR(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＝6.5 Hz, 3H), 0.83 (d, J = 6.4Hz, 3H), 0.78 (d, J = 6.7Hz, 3H), 0.74 (d, J = 6.6Hz, 3H). ¹³ CNMR(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.

Example 23: 43-O-(3-(4-((2,4dichlorophenyl)aminomethyl)-1H-1,2,3-triazol-1-yl)n-propyl)oxy Rapamycin (X-25)

Add 43-O-(3-azidopropyl)-oxrapamycin (0.35mmoL, 0.35g) and N-(prop-2-ynyl)-2,4-dichloroaniline (0.1g) Add sodium ascorbate (0.1g) and copper sulfate pentahydrate (0.08g) to the DMF (10mL) solution, and stir at room temperature for 2h. Filter, wash with water, and dry to obtain a light yellow solid, which is separated by silica gel column chromatography and C18 preparative chromatography to obtain 0.10 g of pure product, yield: 23.9%. MS (ESI) m/z: 1218.6 (M+Na) ⁺ . ¹ HNMR (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). ¹³ CNMR(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.

Example 24: 43-O-(3-(4-((2,6difluorophenyl)aminomethyl)-1H-1,2,3-triazol-1-yl)n-propyl)oxy Rapamycin (X-24)

Add 43-O-(3-azidopropyl)-oxrapamycin (0.35mmoL, 0.35g) and N-(prop-2-ynyl)-2,6-difluoroaniline (0.1g) Add sodium ascorbate (0.1g) and copper sulfate pentahydrate (0.08g) to the DMF (10mL) solution, and stir at room temperature for 2h. Filtered, washed with water, and dried to obtain a light yellow solid, which was separated by silica gel column chromatography and C18 preparative chromatography to obtain 0.12 g of pure product, yield: 29.8%. MS (ESII) m/z: 1186.7 (M+Na) ⁺ . ¹ HNMR (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).

Example 25: 43-O-(3-(4-((2-fluorophenyl)aminomethyl)-1H-1,2,3-triazol-1-yl)n-propyl)oxrapa Mycin (X-28)

43-O-(3-azidopropyl)-oxrapamycin (0.35mmoL, 0.35g) and N-(prop-2-ynyl)-2-fluoroaniline (0.1g) were added to DMF ( 10mL) solution, add sodium ascorbate (0.1g) and copper sulfate pentahydrate (0.08g) to the reaction solution, stir at room temperature for 2h, after the reaction is complete, pour the reaction into 60mL water, precipitate a light yellow solid, suction filter, wash with water , dried to give a light yellow solid, which was separated by silica gel column chromatography and C18 preparative chromatography to obtain 0.10 g of pure product, yield: 24.7%. MS (ESII) m/z: 1168.5 (M+Na) ⁺ . ¹ HNMR(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=6.6 Hz, 3H), 0.74 (d, J=6.5Hz, 3H). ¹³ CNMR(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.

Example 26: 43-O-(2-(4-(4-fluorophenyl)-1H-1,2,3-triazol-1-yl)acetyl)oxrapamycin (X-39 )

Step A: Preparation of 28-oxytrimethylsilyl-rapamycin

Add rapamycin (5.5mmol, 5.0g) and imidazole (1.5g) into ethyl acetate (80mL) solution respectively, cool to 0-5°C after addition, add trimethylchlorosilane (40mmol, 4.3g), heat preservation reaction for 2 hours. When the bissilyl ether protected product was formed, dilute sulfuric acid (15mL, 1NH ₂ SO ₄ ) was poured into the reaction solution, and the reaction was continued to stir for about 16h. After the reaction was completed, the reaction solution was washed with saturated sodium bicarbonate and saturated brine, and organic The layer was dried over anhydrous sodium sulfate and evaporated to dryness to obtain 5.1 g of white foamy solid, yield: 95%. MS (ESI) m/z: 1008.5 (M+Na) ⁺ .

Step B: Preparation of 28-oxytrimethylsilyl-43-O-(2-chloroacetyl)-oxrapamycin

Add 28-OTMS-rapamycin (2.6g, 2.6mmol) and anhydrous dichloromethane (40mL) into a three-necked flask, add triethylamine (3mL), and add ethyl chloride dropwise at 0-5°C Acyl chloride (0.59g, 5.2mmol), after addition, reacted at 0-5°C for 6h. After the reaction was completed, the reaction solution was poured into 300 mL of water, extracted with dichloromethane, the extracts were combined, washed with water, and dried over anhydrous sodium sulfate. Evaporated to dryness to obtain 2.1 g of white solid, yield: 76.1% MS (ESI) m/z: 1084.6 (M+Na) ⁺ .

Step C: Preparation of 43-O-(2-chloroacetyl)-oxrapamycin

Add 28-OTMS-43-O-(2-chloroacetyl)-oxrapamycin (2mmol, 2.1g) into the acetone (36mL) solution, cool to 0-5°C after the addition, and add to the reaction solution Add dilute sulfuric acid (10mL, 1NH ₂ SO ₄ ) and continue to stir for about 2 hours. After the reaction is complete, the reaction solution is washed with saturated sodium bicarbonate and saturated brine respectively. The organic layer is dried over anhydrous sodium sulfate and evaporated to dryness to obtain a white foam. 1.8 g of solid, yield: 91%. MS (ESI) m/z: 1012.5 (M+Na) ⁺ .

Step D: Preparation of 43-O-(2-azidoacetyl)-oxrapamycin

43-O-(2-Chloroacetyl)-oxrapamycin (1.8g, 1.8mmol) and sodium azide (0.3g, 4.6mmol) were added to (300mL) DMF solution respectively, after the addition was complete The temperature was raised to 50°C. After the reaction was complete, the reaction solution was poured into 100 mL of water, extracted twice with ethyl acetate, the extracts were combined, washed with water, and dried over anhydrous sodium sulfate. Evaporate to dryness to obtain oily substances, which were separated by column chromatography to obtain 0.6 g respectively, with a yield of 33%. MS (ESI) m/z: 1019.5 (M+Na) ⁺ .

Step E: Preparation of 43-O-(2-(4-(4-fluorophenyl)-1H-1,2,3-triazol-1-yl)acetyl)oxrapamycin

Add 43-O-(2-azidoacetyl)-oxyrapamycin (0.35mmoL, 0.35g) and propynyl alcohol (0.1g) to DMF (10mL) solution, add sodium ascorbate to the reaction solution (0.1g) and copper sulfate pentahydrate (0.08g), stirred at room temperature for 2h, after the reaction was completed, the reaction was poured into 30mL of water, a light yellow solid was precipitated, filtered by suction, washed with water, dried to obtain a light yellow solid, which was subjected to silica gel column chromatography and C18 preparative chromatography to obtain 0.14 g of pure product, yield: 34.6%. MS (ESI) m/z: 1139.6 (M+Na) ⁺ . ¹ HNMR(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=6.5 Hz, 3H), 0.73 (d, J=6.3Hz, 3H). ¹³ CNMR(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.

Example 27: 43-O-(2-(4-(4-chlorophenyl)-1H-1,2,3-triazol-1-yl)acetyl)oxrapamycin (X-35 )

Add 43-O-(2-azidoacetyl)-oxrapamycin (0.35mmoL, 0.35g) and 4-fluorophenylacetylene (0.1g) to the DMF (10mL) solution, and add Sodium ascorbate (0.1g) and copper sulfate pentahydrate (0.08g) were stirred at room temperature for 2 hours. After the reaction was completed, the reaction was poured into 30mL of water, and a light yellow solid was precipitated, which was filtered by suction, washed with water, and dried to obtain a light yellow solid. Chromatography and C18 preparative chromatographic separation gave 0.13 g of pure product, yield: 33.1%. MS (ESI) m/z: 1155.6 (M+Na) ⁺ . ¹ H NMR (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). ¹³ CNMR(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.

Example 28: 43-O-(2-(4-(4-methylphenyl)-1H-1,2,3-triazol-1-yl)acetyl)oxyrapamycin (X- 36)

43-O-(2-azidoacetyl)-oxrapamycin (0.35mmoL, 0.35g) and 4-methylphenylacetylene (0.1g) were added to the DMF (10mL) solution, and added to the reaction solution Add sodium ascorbate (0.1g) and copper sulfate pentahydrate (0.08g), and stir at room temperature for 2h. After the reaction is completed, pour the reaction into 30mL of water to precipitate a light yellow solid, suction filter, wash with water, and dry to obtain a light yellow solid. Column chromatography and C18 preparative chromatography separated to obtain 0.15 g of pure product, yield: 38.3%. MS (ESI) m/z: 1135.7 (M+Na) ⁺ . ¹ H NMR (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). ¹³ CNMR(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.

Example 29: 43-O-(2-(4-(phenyl)-1H-1,2,3-triazol-1-yl)acetyl)oxrapamycin (X-34)

43-O-(2-azidoacetyl)-oxyrapamycin (0.35mmoL, 0.35g) and phenylacetylene (0.1g) were added to the DMF (10mL) solution, and sodium ascorbate ( 0.1g) and copper sulfate pentahydrate (0.08g), stirred at room temperature for 2h, after the reaction was completed, the reaction was poured into 30mL water, and a pale yellow solid was precipitated, filtered by suction, washed with water, and dried to obtain a pale yellow solid, which was subjected to silica gel column chromatography and C18 was separated by preparative chromatography to obtain 0.18 g of pure product, yield: 44.0%. MS (ESII) m/z: 1121.8 (M+Na) ⁺ . ¹ HNMR (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). ¹³ CNMR(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.

Example 30: 43-O-(2-(4-(4-pentylphenyl)-1H-1,2,3-triazol-1-yl)acetyl)oxrapamycin (X- 37)

Add 43-O-(2-azidoacetyl)-oxrapamycin (0.35mmoL, 0.35g) and 4-n-pentylphenylacetylene (0.1g) into the DMF (10mL) solution, and add to the reaction solution Sodium ascorbate (0.1g) and copper sulfate pentahydrate (0.08g) were added to the mixture, and stirred at room temperature for 2h. After the reaction was completed, the reaction was poured into 30mL of water, and a light yellow solid was precipitated, which was suction filtered, washed with water, and dried to obtain a light yellow solid. Silica gel column chromatography and C18 preparative chromatography separated to obtain 0.13g of pure product, yield: 31.7%. MS (ESI) m/z: 1191.7 (M+Na) ⁺ . ¹ HNMR(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). ¹³ CNMR(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 , 80.41,78.24,76.25,74.21,67.02,66.74,57.45,57.28,5.96,51.30, 516,45.74, 44.00, 35.82,35.33,33.8.3.33.3.3.3.3.3.3.3.3. , 26.75, 24.96, 22.41, 22.15, 20.87, 16.62, 16.05, 15.18, 14.37, 13.92, 10.98.

Example 31: 43-O-(2-(4-(3-methylphenyl)-1H-1,2,3-triazol-1-yl)acetyl)oxrapamycin (X- 40)

Add 43-O-(2-azidoacetyl)-oxyrapamycin (0.35mmoL, 0.35g) and propynyl alcohol (0.1g) to DMF (10mL) solution, add sodium ascorbate to the reaction solution (0.1g) and copper sulfate pentahydrate (0.08g), stirred at room temperature for 2h, after the reaction was completed, the reaction was poured into 30mL of water, a light yellow solid was precipitated, filtered by suction, washed with water, dried to obtain a light yellow solid, which was subjected to silica gel column chromatography and C18 preparative chromatography to obtain 0.16 g of pure product, yield: 39.0%. MS (ESI) m/z: 1135.5 (M+Na) ⁺ . ¹ HNMR (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). ¹³ CNMR(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.

Example 32: 43-O-(2-(4-(2-chlorophenyl)-1H-1,2,3-triazol-1-yl)acetyl)oxrapamycin (X-38 )

Add 43-O-(2-azidoacetyl)-oxrapamycin (0.35mmoL, 0.35g) and 2-chlorophenylacetylene (0.1g) to the DMF (10mL) solution, and add Sodium ascorbate (0.1g) and copper sulfate pentahydrate (0.08g) were stirred at room temperature for 2 hours. After the reaction was completed, the reaction was poured into 30mL of water, and a light yellow solid was precipitated, which was filtered by suction, washed with water, and dried to obtain a light yellow solid. Chromatography and C18 preparative chromatographic separation gave 0.17 g of pure product, yield: 41.4%. MS (ESI) m/z: 1155.7 (M+Na) ⁺ . ¹ HNMR(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). ¹³ CNMR(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.

Example 33: 43-O-(2-(4-(4-bromophenyl)-1H-1,2,3-triazol-1-yl)acetyl)oxrapamycin (X-41 )

Add 43-O-(2-azidoacetyl)-oxrapamycin (0.35mmoL, 0.35g) and 4-bromophenylacetylene (0.1g) to the DMF (10mL) solution, and add Sodium ascorbate (0.1g) and copper sulfate pentahydrate (0.08g) were stirred at room temperature for 2 hours. After the reaction was completed, the reaction was poured into 30mL of water, and a light yellow solid was precipitated, which was filtered by suction, washed with water, and dried to obtain a light yellow solid. Chromatography and C18 preparative chromatographic separation gave 0.10 g of pure product, yield: 24.3%. MS (ESI) m/z: 1200.3 (M+Na) ⁺ . ¹ HNMR(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). ¹³ CNMR(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.

Example 34: 43-O-(2-(4-(4-methoxyphenyl)-1H-1,2,3-triazol-1-yl)acetyl)oxrapamycin (X -66)

43-O-(2-azidoacetyl)-oxrapamycin (0.35mmoL, 0.35g) and 4-methoxyphenylacetylene (0.1g) were added to the DMF (10mL) solution, and the reaction solution Sodium ascorbate (0.1g) and copper sulfate pentahydrate (0.08g) were added to the mixture, and stirred at room temperature for 2h. After the reaction was completed, the reaction was poured into 30mL of water, and a light yellow solid was precipitated, which was suction filtered, washed with water, and dried to obtain a light yellow solid. Silica gel column chromatography and C18 preparative chromatography separated to obtain 0.16 g of pure product, yield: 39.4%. MS (ESII) m/z: 1151.6 (M+Na) ⁺ . ¹ H NMR (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). ¹³ CNMR(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.

Example 35: 43-O-(2-(4-((2,5-dichlorophenyl)aminomethyl)-1H-1,2,3-triazol-1-yl)acetyl)oxyridine Pamycin (X-46)

43-O-(2-azidoacetyl)-oxrapamycin (0.35mmoL, 0.35g) and N-(prop-2-ynyl)-2,5-dichloroaniline (0.1g) were added Add sodium ascorbate (0.1g) and copper sulfate pentahydrate (0.08g) to the DMF (10mL) solution, and stir at room temperature for 2h. Filtered, washed with water, and dried to obtain a light yellow solid, which was separated by silica gel column chromatography and C18 preparative chromatography to obtain 0.15 g of pure product, yield: 35.8%. MS (ESII) m/z: 1218.5 (M+Na) ⁺ . ¹ HNMR(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＝6.6 Hz,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). ¹³ CNMR(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.

Example 36: 43-O-(2-(4-((2-fluorophenyl)aminomethyl)-1H-1,2,3-triazol-1-yl)acetyl)oxrapamycin Prime (X-43)

43-O-(2-Azidoacetyl)-oxrapamycin (0.35mmoL, 0.35g) and N-(prop-2-ynyl)-2-fluoroaniline (0.1g) were added to DMF ( 10mL) solution, add sodium ascorbate (0.1g) and copper sulfate pentahydrate (0.08g) to the reaction solution, stir at room temperature for 2h, after the reaction is complete, pour the reaction into 30mL water, precipitate a light yellow solid, suction filter, wash with water , dried to obtain a light yellow solid, which was separated by silica gel column chromatography and C18 preparative chromatography to obtain 0.13 g of pure product, yield: 32.4%. MS (ESII) m/z: 1168.6 (M+Na) ⁺ . ¹ HNMR(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). ¹³ CNMR(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.

Example 37: 43-O-(2-(4-(Pyrrolidinyl-1-methylene)-1H-1,2,3-triazol-1-yl)acetyl)oxrapamycin (X-92)

43-O-(2-azidoacetyl)-oxrapamycin (0.35mmoL, 0.35g) and 1-(prop-2-ynyl)pyrrolidine (0.1g) were added to DMF (10mL) solution , add sodium ascorbate (0.1g) and copper sulfate pentahydrate (0.08g) to the reaction solution, stir at room temperature for 2h, after the reaction is completed, pour the reaction into 30mL of water, and precipitate a pale yellow solid, suction filter, wash with water, and dry to obtain The light yellow solid was separated by silica gel column chromatography and C18 preparative chromatography to obtain 0.11 g of pure product, yield: 28.9%. MS (ESII) m/z: 1093.4 (M+H) ⁺ . ¹ HNMR (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). ¹³ CNMR(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, 56.08, 56.08,88,88,88, 517, 5.8, 5.8, 5.8, 5.8, 5.8, 5.8, 5.8, 5.8, 5.8, 5.8, 5.8, 5.8, 5.8, 50.8, 5, 5, 5, 5, 5, 5, 57.38, 5, 5, 57.3, 5, 5, 57.4, 5, 5, 5, 57.8, 5, 5, 57.4, 57.8, 57.8, 57.8, 57.8, and 4, 3, 3, 3, 3, 3, 3, 3, 3, 3, 37.8, 5, 57.08,5, 56.888888, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3,, 5 , 22.66, 22.02, 21.39, 16.06, 15.00, 14.00, 13.68, 12.28, 10.84.

Example 38: 43-O-(2-(4-(Diethylaminomethyl)-1H-1,2,3-triazol-1-yl)acetyl)oxrapamycin (X-76 )

43-O-(2-azidoacetyl)-oxrapamycin (0.35mmoL, 0.35g) and N,N-diethylpropynylamine (0.1g) were added to the DMF (10mL) solution, Add sodium ascorbate (0.1g) and copper sulfate pentahydrate (0.08g) to the reaction solution, stir at room temperature for 2h, after the reaction is complete, pour the reaction into 30mL of water, a pale yellow solid precipitates, suction filter, wash with water, and dry to obtain a pale yellow The solid was separated by silica gel column chromatography and C18 preparative chromatography to obtain 0.15 g of pure product, yield: 39.1%. MS (ESII) m/z: 1095.6 (M+Na) ⁺ . ¹ HNMR (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). ¹³ CNMR(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.

Example 39: 43-O-(2-(4-(4-fluorophenyl)-1H-1,2,3-triazol-1-yl)isopropionyl)oxrapamycin (X- 57)

Step A: Preparation of 28-oxytrimethylsilyl-43-O-(2-bromoisopropionyl)-oxrapamycin

28-OTMS-rapamycin (2.5g, 2.5mmol) and anhydrous dichloromethane (40mL) were added to a three-necked flask, triethylamine (3mL, 20mmol) was added dropwise at 0-5°C 2-Bromopropionyl bromide (1.62g, 7.5mmol) was added and reacted at 0-5°C for 8h. After the reaction was completed, the reaction solution was poured into 300 mL of water, extracted with dichloromethane, the extracts were combined, washed with water, and dried over anhydrous sodium sulfate. Evaporate to dryness to obtain 1.9 g of white solid, yield: 67.8% MS (ESI) m/z: 1142.5 (M+Na) ⁺ .

Step B: Preparation of 43-O-(2-bromoisopropionyl)-oxrapamycin

Add 28-OTMS-43-O-(2-bromoisopropionyl)-oxrapamycin (1.9g, 1.8mmol) into acetone (40mL) solution, cool to 0-5°C after addition, Dilute sulfuric acid (10mL, 1NH ₂ SO ₄ ) was added to the reaction solution, and the reaction was continued to stir for about 2 hours. After the reaction was completed, the reaction solution was washed with saturated sodium bicarbonate and saturated brine respectively, and the organic layer was dried over anhydrous sodium sulfate and evaporated to dryness to obtain White foamy solid 1.6g, yield 84.8%. MS (ESI) m/z: 1070.5 (M+Na) ⁺ .

Step C: Preparation of 43-O-(2-azidoisopropionyl)-oxrapamycin

43-O-(2-bromoisopropionyl)-oxrapamycin (1.6g, 1.5mmol) and sodium azide (0.2g, 3mmol) were added to (30mL) DMF solution respectively, after the addition was complete The temperature was raised to 50°C. After the reaction was complete, the reaction solution was poured into 90 mL of water, extracted twice with ethyl acetate, the extracts were combined, washed with water, and dried over anhydrous sodium sulfate. Evaporated to dryness to obtain an oily substance, which was separated by column chromatography to obtain 0.8 g with a yield of 52.7%. MS (ESI) m/z: 1033.6 (M+Na) ⁺ .

Step D: 43-O-(2-(4-(4-fluorophenyl)-1H-1,2,3-triazol-1-yl)isopropionyl)oxrapamycin (X-57 ) preparation

43-O-(2-azidoisopropionyl)-oxrapamycin (0.2mmoL, 0.2g) and 4-fluorophenylacetylene (0.07g) were added to the DMF (10mL) solution, and added to the reaction solution Add sodium ascorbate (0.08g) and copper sulfate pentahydrate (0.09g), stir at room temperature for 2h, after the reaction is complete, pour the reaction into 30mL of water, a light yellow solid precipitates, suction filter, wash with water, dry to obtain a light yellow solid, pass through the column Chromatography separated 0.10 g of pure product, yield: 42.9%. MS (ESI) m/z: 1153.7 (M+Na) ⁺ . ¹ HNMR(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=6.6 Hz, 3H). ¹³ CNMR(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.

Example 40: 43-O-(2-(4-(4-chlorophenyl)-1H-1,2,3-triazol-1-yl)isopropionyl)oxrapamycin (X- 52)

43-O-(2-azidoisopropionyl)-oxyrapamycin (0.2mmoL, 0.2g) and 4-chlorophenylacetylene (0.07g) were added to the DMF (10mL) solution, and added to the reaction solution Add sodium ascorbate (0.08g) and copper sulfate pentahydrate (0.09g), stir at room temperature for 2h, after the reaction is complete, pour the reaction into 30mL of water, a light yellow solid precipitates, suction filter, wash with water, dry to obtain a light yellow solid, pass through the column Chromatography separated 0.11 g of pure product, yield: 46.6%. MS (ESI) m/z: 1169.7 (M+Na) ⁺ . ¹ HNMR (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). ¹³ CNMR(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.

Example 41: 43-O-(2-(4-(4-methylphenyl)-1H-1,2,3-triazol-1-yl)isopropionyl)oxrapamycin (X -54)

43-O-(2-azidoisopropionyl)-oxrapamycin (0.2mmoL, 0.2g) and 4-methylphenylacetylene (0.07g) were added to the DMF (10mL) solution, and the reaction solution Sodium ascorbate (0.08g) and copper sulfate pentahydrate (0.09g) were added to the mixture, and stirred at room temperature for 2h. After the reaction was completed, the reaction was poured into 30mL of water, and a light yellow solid was precipitated, which was suction filtered, washed with water, and dried to obtain a light yellow solid. 0.13 g of pure product was separated by column chromatography, yield: 56.6%. MS (ESI) m/z: 1149.7 (M+Na) ⁺ . ¹ HNMR (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). ¹³ CNMR(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.

Example 42: 43-O-(2-(4-(phenyl)-1H-1,2,3-triazol-1-yl)isopropionyl)oxrapamycin (X-53)

43-O-(2-azidoisopropionyl)-oxyrapamycin (0.2mmoL, 0.2g) and phenylacetylene (0.07g) were added to the DMF (10mL) solution, and sodium ascorbate was added to the reaction solution (0.08g) and copper sulfate pentahydrate (0.09g), stirred at room temperature for 2h, after the reaction was completed, the reaction was poured into 30mL of water, a pale yellow solid was precipitated, suction filtered, washed with water, dried to obtain a pale yellow solid, separated by column chromatography 0.12 g of pure product was obtained, yield: 52.2%. MS (ESI) m/z: 1135.8 (M+Na) ⁺ . ¹ HNMR(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＝6.2 Hz, 3H), 0.82 (d, J = 6.2Hz, 3H), 0.78 (d, J = 6.3Hz, 3H), 0.73 (d, J = 6.6Hz, 3H). ¹³ CNMR(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.

Example 43: 43-O-(2-(4-(4-pentylphenyl)-1H-1,2,3-triazol-1-yl)isopropionyl)oxrapamycin (X -55)

43-O-(2-azidoisopropionyl)-oxrapamycin (0.2mmoL, 0.2g) and 4-n-pentylphenylacetylene (0.07g) were added to the DMF (10mL) solution, and the reaction Sodium ascorbate (0.08g) and copper sulfate pentahydrate (0.09g) were added to the solution, and stirred at room temperature for 2h. After the reaction was completed, the reaction was poured into 30mL of water, and a light yellow solid was precipitated, filtered by suction, washed with water, and dried to obtain a light yellow solid. After separation by column chromatography, 0.05 g of pure product was obtained, yield: 21.2%. MS (ESI) m/z: 1205.8 (M+Na) ⁺ . ¹ H NMR (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). ¹³ CNMR(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.

Example 44: 43-O-(2-(4-(3-methylphenyl)-1H-1,2,3-triazol-1-yl)isopropionyl)oxrapamycin (X -58)

43-O-(2-azidoisopropionyl)-oxyrapamycin (0.2mmoL, 0.2g) and 3-methylphenylacetylene (0.07g) were added to the DMF (10mL) solution, and added to the reaction solution Sodium ascorbate (0.08g) and copper sulfate pentahydrate (0.09g) were added to the mixture, and stirred at room temperature for 2h. After the reaction was completed, the reaction was poured into 30mL of water, and a light yellow solid was precipitated, which was suction filtered, washed with water, and dried to obtain a light yellow solid. Column chromatography separated 0.10 g of pure product, yield: 43.5%. MS (ESI) m/z: 1149.5 (M+Na) ⁺ . ¹ HNMR (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). ¹³ CNMR(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.

Example 45: 43-O-(2-(4-(2-chlorophenyl)-1H-1,2,3-triazol-1-yl)isopropionyl)oxrapamycin (X- 56)

43-O-(2-azidoisopropionyl)-oxrapamycin (0.2mmoL, 0.2g) and 2-chlorophenylacetylene (0.07g) were added to the DMF (10mL) solution, and added to the reaction solution Add sodium ascorbate (0.08g) and copper sulfate pentahydrate (0.09g), stir at room temperature for 2h, after the reaction is complete, pour the reaction into 30mL of water, a light yellow solid precipitates, suction filter, wash with water, dry to obtain a light yellow solid, pass through the column Chromatography separated 0.13g of pure product, yield: 56.5%. MS (ESI) m/z: 1169.7 (M+Na) ⁺ . ¹ HNMR (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 = 6.1 Hz, 3H). ¹³ CNMR(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 80.62,78.07,76.21,74.17,669,58.25,57.41,57.27,51.25,45.73,44.00, 35.81,35.31,32.93.93,29.51,29.51,29.51,29.51,29.9.51,26.9.51,26.9.51,26.9.51,26.9. , 20.86, 17.46, 17.38, 16.04, 16.02, 15.15, 13.96, 13.84, 10.95.

Example 46: 43-O-(2-(4-(4-bromophenyl)-1H-1,2,3-triazol-1-yl)isopropionyl)oxrapamycin (X- 59)

43-O-(2-azidoisopropionyl)-oxrapamycin (0.2mmoL, 0.2g) and 4-bromophenylacetylene (0.08g) were added to the DMF (10mL) solution, and added to the reaction solution Add sodium ascorbate (0.08g) and copper sulfate pentahydrate (0.09g), stir at room temperature for 2h, after the reaction is complete, pour the reaction into 30mL of water, a light yellow solid precipitates, suction filter, wash with water, dry to obtain a light yellow solid, pass through the column Chromatography separated 0.07g of pure product, yield: 29.2%. MS (ESI) m/z: 1214.3 (M+Na) ⁺ . ¹ H NMR (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). ¹³ CNMR(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.

Example 47: 43-O-(2-(4-(4-methoxyphenyl)-1H-1,2,3-triazol-1-yl)isopropionyl)oxrapamycin ( X-66)

43-O-(2-azidoisopropionyl)-oxrapamycin (0.2mmoL, 0.2g) and 4-methylphenylacetylene (0.07g) were added to the DMF (10mL) solution, and the reaction solution Sodium ascorbate (0.08g) and copper sulfate pentahydrate (0.09g) were added to the mixture, and stirred at room temperature for 2h. After the reaction was completed, the reaction was poured into 30mL of water, and a light yellow solid was precipitated, which was suction filtered, washed with water, and dried to obtain a light yellow solid. Column chromatography separated 0.10 g of pure product, yield: 43.4%. MS (ESI) m/z: 1165.7 (M+Na) ⁺ . ¹ H NMR (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). ¹³ CNMR(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.

Example 48: 43-O-(2-(4-((2,5Dichlorophenyl)aminomethyl)-1H-1,2,3-triazol-1-yl)isopropionyl)oxy Rapamycin (X-65)

43-O-(2-azidoisopropionyl)-oxyrapamycin (0.2mmoL, 0.2g) and N-(prop-2-ynyl)-2,5-dichloroaniline (0.07g) Added to DMF (10mL) solution, added sodium ascorbate (0.08g) and copper sulfate pentahydrate (0.09g) to the reaction solution, stirred at room temperature for 2h, after the reaction was completed, poured the reaction into 30mL water, and precipitated a pale yellow solid. Suction filtration, washing with water, and drying to obtain a light yellow solid, which was separated by column chromatography to obtain 0.11 g of pure product, yield: 45.8%. MS (ESI) m/z: 1232.6 (M+Na) ⁺ . ¹ HNMR(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). ¹³ CNMR(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.

Example 49: 43-O-(2-(4-((2,4dichlorophenyl)aminomethyl)-1H-1,2,3-triazol-1-yl)isopropionyl)oxy Rapamycin (X-64)

43-O-(2-azidoisopropionyl)-oxyrapamycin (0.2mmoL, 0.2g) and N-(prop-2-ynyl)-2,4-dichloroaniline (0.07g) Added to DMF (10mL) solution, added sodium ascorbate (0.08g) and copper sulfate pentahydrate (0.09g) to the reaction solution, stirred at room temperature for 2h, after the reaction was completed, poured the reaction into 30mL water, and precipitated a pale yellow solid. Suction filtration, washing with water, and drying to obtain a light yellow solid, which was separated by column chromatography to obtain 0.09 g of pure product, yield: 37.5%. MS (ESI) m/z: 1232.4 (M+Na) ⁺ . ¹ HNMR(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). ¹³ CNMR(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.

Example 50: 43-O-(2-(4-((2-Fluorophenyl)aminomethyl)-1H-1,2,3-triazol-1-yl)isopropionyl)oxrapa Mycin (X-62)

43-O-(2-Azidoisopropionyl)-oxrapamycin (0.2mmoL, 0.2g) and N-(prop-2-ynyl)-2-fluoroaniline (0.07g) were added to DMF (10mL) solution, sodium ascorbate (0.08g) and copper sulfate pentahydrate (0.09g) were added to the reaction solution, and stirred at room temperature for 2h. After the reaction was completed, the reaction was poured into 30mL water, and a light yellow solid was precipitated. Suction filtration, Washed with water and dried to obtain a light yellow solid, which was separated by column chromatography to obtain 0.08 g of pure product, yield: 34.7%. MS (ESI) m/z: 1182.7 (M+Na) ⁺ . ¹ HNMR (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). ¹³ CNMR(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 .

Test Example 1: Antitumor Activity Test

Lung cancer cell A549, lung cancer cell NCI-H1299, pancreatic cancer in situ BxPC-3, gastric cancer cell MGC80-3, cervical cancer cell Caski, human leukemia cell HL-60 and human leukemia cell K-562 cell lines were recovered and passaged for 2- 3 times to stabilize cell viability for in vitro cell viability testing. The suspension cells do not need to be digested, and the adherent cells are digested with trypsin (0.25%), and the cell culture medium containing serum is added to stop the digestion, and the cell liquid is transferred to a centrifuge tube with a pipette, centrifuged at 1500r/min for 3min, and discarded gently After the supernatant, add 5mL of culture medium, pipette and mix the cells, count, adherent cells 5000-10000/well, suspension cells 20000/well, add to 96-well plate, culture at 37°C, 5% CO2, cell culture 24 Add the test drug after 4 hours. Test the biological activity of the compound of the present invention, and use rapamycin (Rapa) and temsirolimus (CCI-779) as contrast, dissolve the test sample with dimethyl sulfoxide as mother solution, then use cell culture Dilute the test sample with liquid: take 10ul sample mother liquid, add 990ul cell culture medium, dilute the sample to the test concentration. The sample dilution was added to the cell culture solution that had been cultured in the 96-well plate for 24 hours, each concentration was added to 3 wells, and a blank control (no drug treatment) was set up. Continue culturing the 96-well plate at 37°C and 5% CO2 for 96 hours, add 20 μL of MTT (tetrazolium) (5 mg/mL) to each well, put it in the incubator for 8 hours, and centrifuge the suspended cells at 4000 r/min for 10 minutes. Discard the supernatant, add 150 μL of dimethyl sulfoxide to fully dissolve the formazan, the product of the reaction between the surviving cells and MTT, put it into a microplate reader to measure the results, and use the Bliss method to obtain the drug IC ₅₀ value (μmol/L) . The results show that the compound prepared by the present invention has significantly better biological activity _than rapamycin and temsirolimus to various cancer cells, for example: to A549 cells, the IC value of Rapa and CCI-779 ( μmol/L) are 24 and 15 respectively, and the IC ₅₀ value (μmol/L) of each compound of embodiment 1-50 of the present invention is all in the range of 0.1～13, for example the IC ₅₀ value of embodiment 38 compound (μmol/L ) was 0.1; to H1299 cells, the IC ₅₀ values (μmol/L) of Rapa and CCI-779 were 14 and 19 respectively, while the IC ₅₀ values (μmol/L) of each compound of Examples 1-50 of the present invention were all within 1 In the range of ~15, for example, the _IC50 value (μmol/L) of the compound of Example 38 is 1.1; the _IC50 value (μmol/L) of the cervical cancer cell Caski and Rapa is 23, and each of Examples 1-50 of the present invention The _IC50 value (μmol/L) of compound is all in the range of 1～26, for example the _IC50 value (μmol/L) of embodiment 7 compound is 2.1; To human leukemia cell HL-60, the _IC50 value of Rapa (μmol /L) was 25, while the _IC50 values (μmol/L) of the compounds of Examples 1-50 of the present invention were all in the range of 0.6-19, for example, the _IC50 value (μmol/L) of the compound of Example 40 was 0.3.

Industrial Applicability: The biological activity of the compounds of the present invention, such as anticancer activity, can be prepared into anticancer drugs to treat and/or prevent cancer.

Claims (13)

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 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, 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-(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-(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.

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:

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.