CN107827908B

CN107827908B - Rapamycin triazole derivative and preparation method and application thereof

Info

Publication number: CN107827908B
Application number: CN201711159584.7A
Authority: CN
Inventors: 谢立君; 黄庆文; 黄捷; 程元荣; 李邦良; 陈晓明; 余辉; 郑从燊; 应加银; 吕裕斌; 潘福生
Original assignee: Fujian Institute of Microbiology
Current assignee: Fujian Institute of Microbiology
Priority date: 2017-11-20
Filing date: 2017-11-20
Publication date: 2020-01-21
Anticipated expiration: 2037-11-20
Also published as: CN107827908A

Abstract

The invention belongs to the field of medical technology, and particularly relates to a rapamycin triazole derivative, and a preparation method and application thereof. The derivative is a compound shown as a formula I or pharmaceutically acceptable salt, isomer and ester thereof, and the preparation method comprises the following steps: (1) preparing a compound of formula A-2 from the compound A-1; (2) the compound A-2 and R1 aryl substituted alkyne compound are reacted with cuprous iodide and N, N-diisopropylethylamine to obtain the compound of formula I. The invention also protects the application of the derivative in preparing antitumor drugs. The derivatives of the invention have stronger antitumor activity, and the preparation method is simple, thereby providing a more ideal choice for clinic.

Description

Rapamycin triazole derivative and preparation method and application thereof

Technical Field

The invention belongs to the field of medical technology, relates to a new rapamycin derivative, and particularly relates to a substituted rapamycin triazole derivative. The invention also relates to a preparation method thereof and a pharmaceutical composition containing the compound. The invention also relates to the research of potential compounds with excellent anticancer activity of the derivative.

Background

The targeted therapy of the tumor is another important treatment mode after surgical treatment, chemical drug therapy and radioactive therapy, and the treatment mode can specifically inhibit the growth and proliferation of tumor cells, promote the apoptosis of the tumor cells, programmed necrosis and the like according to the genetic background of the tumor to achieve the purpose of treating the tumor, so that compared with the chemical drug therapy and the radiation therapy, the targeted therapy of the tumor has strong selectivity, low toxic and side effects and good treatment effect; not only can be used independently, but also can be used together with chemical treatment drugs and radiotherapy, thereby improving the treatment effect of tumors. Therefore, the development of new high-efficiency low-toxicity targeted anticancer drugs becomes the development trend of antitumor drugs. Mammalian target of rapamycin (mTOR) is one of the most recently discovered targets for cancer therapy, rapamycin is the earliest discovered mTOR inhibitor, clinical trials of rapamycin for treating tumors are underway, and rapamycin derivatives temsirolimus and everolimus have been clinically applied as mTOR-targeting anticancer drugs. At present, structural modification aiming at rapamycin is mainly carried out at C43-OH, and the novel derivative can obviously improve the anticancer activity and the water solubility.

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

temsirolimus (Temsirolimus) has the following structure:

rapamycin CAS registry No. 53123-88-9, molecular formula C51H79NO13, molecular weight 914.17, colorless crystalline solid from diethyl ether, mp: 183 ℃, [ alpha ] D25-58.2 ℃ (methanol), dissolved in ether, chloroform, acetone, methanol and DMF, slightly soluble in hexane and petroleum ether, and insoluble in water. Mouse LD50(mg/Kg) > 600 (intraperitoneal injection) > 2,500 (oral) (Vezina).

Vezina et al, 1975, reported that rapamycin, a low-toxicity antifungal nitrogenous triene macrolide antibiotic, was obtained from Streptomyces hygroscopicus fermentation broth, with antifungal activity both in vivo and in vitro, especially against Candida albicans [ C.Vein et al; J.Antibiott.28, 721 (1975); s.n.sega et al; j.antiblock.28, 727 (1975); h.a.baker et al; J.Antibiott.31, 539 (1978); U.S. Pat. nos. 3,929,992; and U.S. Pat. No. 3,993,749 ]. In addition, rapamycin alone (U.S. Pat. No. 4,885,171) or in combination with sapelin (U.S. Pat. No. 4,401,653) has been shown to have antitumor activity.

Rapamycin has been found to have immunosuppressive effects and can be used to prevent transplant rejection [ r.y.calne et al, Lancet 1183 (1978); and U.S. Pat. No. 5,100,899. Martel et al [ Can, j. physiol. pharmacol.55,48(1977) ] found that rapamycin was effective in experimental allergic encephalomyelitis models, multiple sclerosis models, adjuvant arthritis models, rheumatoid arthritis models; and effectively inhibits the formation of IgE-like antibodies.

Rapamycin can also be used to prevent or treat systemic lupus erythematosus [ U.S. Pat. No. 5,078,999], pneumonia [ U.S. Pat. No. 5,080,899], insulin-dependent diabetes [ U.S. Pat. No. 5,321,009], skin disorders such as psoriasis [ U.S. Pat. No. 5,286,730], bowel disorders [ U.S. Pat. No. 5,286,731], smooth muscle cell proliferation and intimal thickening following vascular injury [ U.S. Pat. Nos. 5,288,711 and 5,516,781], adult T-cell leukemia/lymphoma [ European patent application 525,960Al ], ocular inflammation [ U.S. Pat. No. 5,387,589], malignant cancer disorders [ U.S. Pat. No. 5,206,018], cardioinflammatory disorders [ U.S. Pat. No. 5,496,832], and anemia [ U.S. Pat. No. 5,561,.

Over 20 years of effort, rapamycin has been successfully developed as a drug for the prevention and treatment of organ transplant rejection. Rapamycin has several ten times stronger immunosuppressive activity than cyclosporin and less toxic side effects than cyclosporin and FK 506. It is not only used for acute rejection of organ transplantation, but also can reverse ongoing transplant rejection; can be used for treating various autoimmune diseases.

In recent years, with the continuous and intensive research on rapamycin derivatives, rapamycin and derivatives thereof are found to have the effect of inhibiting the growth of various tumors, and the research on action mechanisms of rapamycin and derivatives thereof shows that rapamycin are mTOR allosteric inhibitors and are combined with an FKBP12 protein to form a compound, and the compound is combined with an FRB region of mTORC1 to inhibit the function of mTOR, so that the expression of downstream related factors is inhibited, the proliferation of tumor cells is inhibited, the apoptosis of the cells is promoted, and the like, and the rapamycin and derivatives thereof have unique targeted antitumor effects.

In recent years, only 3 chemically semisynthetic derivatives of rapamycin have been approved by FDA for use in cancer therapy or in clinical trials, temsirolimus (CCI-779) developed by hui's pharmaceutical (Wyeth) and everolimus developed by Novartis (Novartis) have been approved by FDA for use in advanced renal cancer therapy in 2007 and 2009, respectively; deferolimus was developed by Ariad and is now in clinical trials for the treatment of tumors.

mTOR is central to the complex signaling pathway within the cell, playing a key role in cell growth, proliferation, cellular metabolism, phagocytosis, and angiogenesis. mTOR allosteric inhibitors such as rapamycin and the like are combined with FKBP12 protein to form a compound to inhibit over-activation of mTORC1 and inhibit biogenesis and protein translation of ribosome, so that the cell cycle of tumor is inhibited in the G1 stage, apoptosis, autophagy and the like of tumor cells are promoted to inhibit growth and proliferation of the tumor cells, and the purpose of treating the tumor is achieved.

Although great efforts have been made in the research and clinical application of rapamycin and its derivatives, those skilled in the art still expect drugs with more clinical application value to provide a more ideal choice for clinical application.

Disclosure of Invention

The invention aims to provide a more application-value medicament, in particular to a rapamycin derivative for clinic. The inventor finds that a series of rapamycin C-28 triazole derivatives have strong antitumor activity on various tumor cell strains. The invention also provides a preparation method of the derivative.

To this end, the first aspect of the present invention provides a compound of formula i:

or a pharmaceutically acceptable salt, solvate, isomer, ester, prodrug thereof, wherein,

n is 1 or 2;

w is

R is hydrogen, methyl, or (C1-C4) alkyl;

r1 is hydroxy (C1-C4) alkyl-, phenyl-, N-diethylmethyl-, or anilinomethyl-, wherein the phenyl ring on the phenyl-or phenylaminomethyl-is optionally substituted by 1 to 4 identical or different R2 groups;

r2 is selected from: hydrogen, halogen, amino, carboxyl, cyano, trifluoromethyl, trifluoromethoxy, (C1-C6) alkyl, (C1-C4) alkylhydroxy, (C1-C4) alkoxy, (C1-C4) alkenyl, (C1-C4) alkynyl, N- (C1-C4) alkylamino, N-di (C1-C4) alkylamino, (C1-C4) alkylthio, (C1-C4) alkylsulfinyl, (C1-C4) alkylsulfonyl, (C1-C4) alkoxymethyl, (C1-C4) alkoxyethyl, (C1-C4) alkanoyl, carbamoyl, N- (C1-C4) alkylcarbamoyl, N-di (C1-C4) alkylcarbamoyl, (C1-C3) alkylenedioxy.

A compound according to any one of the embodiments of the first aspect of the invention, wherein n is 1 or 2.

A compound according to any one of the embodiments of the first aspect of the invention, wherein W is

A compound according to any one of the embodiments of the first aspect of the present invention, wherein R is hydrogen, methyl, or (C1-C4) alkyl.

A compound according to any one of the embodiments of the first aspect of the present invention wherein R1 is hydroxy (C1-C4) alkyl-, phenyl, N-diethylmethyl-, or anilinomethyl-, wherein the phenyl ring on phenyl-or phenylaminomethyl-is optionally substituted with 1 to 4 identical or different R2 groups; r2 is selected from: hydrogen, halogen, amino, carboxyl, cyano, trifluoromethyl, trifluoromethoxy, (C1-C6) alkyl, (C1-C4) alkylhydroxy, (C1-C4) alkoxy, (C1-C4) alkenyl, (C1-C4) alkynyl, N- (C1-C4) alkylamino, N-di (C1-C4) alkylamino, (C1-C4) alkylthio, (C1-C4) alkylsulfinyl, (C1-C4) alkylsulfonyl, (C1-C4) alkoxymethyl, (C1-C4) alkoxyethyl, (C1-C4) alkanoyl, carbamoyl, N- (C1-C4) alkylcarbamoyl, N-di (C1-C4) alkylcarbamoyl, (C1-C3) alkylenedioxy.

A compound according to any one of the embodiments of the first aspect of the invention wherein n is 1.

W is

R is hydrogen, methyl, or (C1-C4) alkyl;

A compound according to any one of the embodiments of the first aspect of the invention wherein n is 2.

W is

R is hydrogen, methyl, or (C1-C4) alkyl;

A compound according to any one of the embodiments of the first aspect of the invention selected from:

28-O- (2- (4- ((2,4 dichlorophenyl) aminomethyl) -1H-1, 2, 3-triazol-1-yl) acetyl) oxy rapamycin (which may be abbreviated as X-121 in the present invention) has the chemical structure

28-O- (2- (4-phenyl-1H-1, 2, 3-triazol-1-yl) acetyl) rapamycin (which may be abbreviated as X-122 in the present invention) has the chemical structure

28-O- (2- (4- (3-methylphenyl) -1H-1, 2, 3-triazol-1-yl) acetyl) rapamycin (which may be abbreviated as X-123 in the present invention) has the chemical structure of

28-O- (2- (4- (2-chlorophenyl) -1H-1, 2, 3-triazol-1-yl) acetyl) rapamycin (which may be abbreviated as X-124 in the present invention) has a chemical structure of

28-O- (2- (4- (4-methoxyphenyl) -1H-1, 2, 3-triazol-1-yl) acetyl) rapamycin oxide (which may be abbreviated as X-125 in the present invention) has a chemical structure of

28-O- (2- (4- (4-methylphenyl) -1H-1, 2, 3-triazol-1-yl) acetyl) rapamycin (which may be abbreviated as X-126 in the present invention) has the chemical structure of

28-O- (2- (4- (4-fluorophenyl) -1H-1, 2, 3-triazol-1-yl) acetyl) rapamycin (which may be abbreviated as X-127 in the present invention) has a chemical structure of

28-O- (2- (4- (2-hydroxyisopropyl) -1H-1, 2, 3-triazol-1-yl) acetyl) rapamycin (which may be abbreviated as X-128 in the present invention) has a chemical structure of

28-O- (2- (4- (hydroxyethyl) -1H-1, 2, 3-triazol-1-yl) acetyl) rapamycin (which may be abbreviated as X-129 in the present invention) has the chemical structure

28-O- (2- (4- (methylene- (N, N-diethyl)) -1H-1, 2, 3-triazol-1-yl) -acetyl) oxy rapamycin (which may be abbreviated herein as X-150) has the chemical structure

28-O- (2- (4- ((2-fluorophenyl) aminomethylene) -1H-1, 2, 3-triazol-1-yl) -acetyl) rapamycin oxide (which may be abbreviated as X-151 in the present invention) has a chemical structure of

28-O- (2- (4- ((2, 6-difluorophenyl) aminomethylene) -1H-1, 2, 3-triazol-1-yl) -acetyl) rapamycin (which may be abbreviated as X-152 in the present invention) has the chemical structure of

28-O- (2- (4- (3-aminophenyl) -1H-1, 2, 3-triazol-1-yl) -acetyl) rapamycin oxide (which may be abbreviated as X-153 in the present invention) has the chemical structure of

28-O- (2- (4-phenyl-1H-1, 2, 3-triazol-1-yl) propionyl) rapamycin (which may be abbreviated as X-154 in the present invention) has the chemical structure

Or pharmaceutically acceptable salts, solvates, isomers, esters, prodrugs of the above compounds.

The compounds of the present invention are essentially hydroxy-substituted derivatives of rapamycin at the C-28 position, and thus their names may still be based on the rapamycin nucleus, as described above with reference to the substituents on the hydroxy group at the C-28 position.

Further, the second aspect of the present invention provides a pharmaceutical composition comprising a compound according to any one of the embodiments 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 diseases such as tumors and/or cancers.

Further, the third aspect of the present invention provides a use of the compound according to any one of the embodiments of the first aspect of the present invention for the preparation of a medicament for the prevention or treatment of tumors and/or cancers. The use according to the invention, wherein the tumor and/or cancer is selected from the group consisting of: lung cancer, esophageal cancer, stomach cancer, prostate cancer, breast cancer, and kidney cancer.

Further, the fourth aspect of the present invention provides a method for the prophylaxis and/or treatment of tumors and/or cancers, which method comprises administering to a subject in need thereof a prophylactically and/or therapeutically effective amount of a compound of formula I according to the first aspect of the present invention.

Further, a fifth aspect of the present invention provides a process for the preparation of a compound according to any one of the embodiments of the first aspect of the present invention, comprising the steps of:

a compound of the following formula A-2 is prepared from the following compound A-1:

the A-2 compound is then reacted with an R1 aryl substituted alkyne via cuprous iodide and N, N-diisopropylethylamine to provide the compound of formula I:

optionally forming the compound of formula I into a pharmaceutically acceptable salt, solvate, isomer, ester, prodrug thereof. Wherein each substituent is as described in any embodiment of the first aspect of the invention.

According to the method of the fifth aspect of the invention, W isThe preparation method of the A-2 compound comprises the following steps:

a-1 compound is used as a raw material to react with trimethylchlorosilane to obtain a B-1 compound, and then the B-1 compound reacts with tert-butyldimethylsilyl chloride to obtain a compound B-2 with the following formula:

followed by reacting the B-2 compound with

Is esterified to give a compound of the following formula B-4:

subsequent deprotection of the B-4 compound affords compound B-5:

and finally, reacting the B-5 compound with sodium azide to obtain an A-2 compound.

Any aspect of the invention or any one of the aspects having features is equally applicable to any other aspect or any one of the other aspects as long as they are not mutually inconsistent, although appropriate modifications to the respective features may be made as necessary when applicable to each other. In the present invention, for example, reference to "any of the first aspects of the invention" means any sub-aspect of the first aspects of the invention; and in other respects, are referred to in a similar manner and have the same meaning.

Various aspects and features of the disclosure are described further below.

All documents cited herein are incorporated by reference in their entirety and to the extent such documents do not conform to the meaning of the present invention, the present invention shall control. Further, the various terms and phrases used herein have the ordinary meaning as is known to those skilled in the art, and even though such terms and phrases are intended to be described or explained in greater detail herein, reference is made to the term and phrase as being inconsistent with the known meaning and meaning as is accorded to such meaning throughout this disclosure.

In the context of the present invention, the radicals "C1-C4 alkyl", "C1-4 alkyl", "(C1-C4) alkyl"

Etc., which have the same meaning, each represent a straight-chain or branched alkyl group having 1 to 4 carbon atoms. Other situations may be similarly understood.

In the context of the present invention, the group "C1-4 alkyl" includes that which is stated individually and in combination with other groups, and may be chosen, for example, from C1-3 alkyl, C1-2 alkyl. Likewise, C1-4 alkoxy may be selected from C1-3 alkoxy, C1-2 alkoxy, for example.

In the process of the present invention for the synthesis of compounds of formula I, the various starting materials for the reaction are either prepared by methods known in the literature or are commercially available, as known to the person skilled in the art. The intermediates, starting materials, reagents, reaction conditions, etc. used in the above reaction schemes may be appropriately modified according to the knowledge of those skilled in the art. Alternatively, other compounds of formula I not specifically recited herein may also be synthesized by those skilled in the art according to the method of the second aspect of the invention.

The following schematic scheme A illustrates the preparation of compounds of formula I of this invention, all starting materials prepared by the methods described in these schematic schemes, by methods well known to those of ordinary skill in the art of organic chemistry or commercially available. All of the final compounds of the present invention are prepared by the methods described in these schemes or by methods analogous thereto, which are well known to those of ordinary skill in the art of organic chemistry. All variable factors applied in these illustrations are as defined below or in the claims.

Derivatives of general formula I according to the invention, in scheme A, R, R1, R2, W and n are as defined in the description.

Route a: synthetic route to the compounds of the general formula I

Reacting the compound A-1 through 2-6 steps to generate the azide compound A-2. The compound A-2 and alkynyl alcohol or phenyl alkyne compound are reacted by CuI and DIPEA to obtain the derivative shown as the general formula I.

Specifically, A-2 was prepared according to the method described in step 1: taking A-1 as a raw material, and obtaining A-2 through silicon ether protection, esterification, deprotection and azidation. (TMSCl is fully named as trimethylchlorosilane, TBSCl is fully named as tert-butyldimethylsilyl chloride).

Step 1 (route B)

The invention has the beneficial effects that: the derivatives of the invention have stronger antitumor activity. And the preparation method is simple, and provides a more ideal compound which is selected and prepared clinically and has better anti-tumor activity.

Detailed Description

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

The nuclear magnetic resonance hydrogen spectrum of the compound prepared by the invention is measured by BrukeraRx-300, and the mass spectrum is measured by Agilent1100 LC/MSD; all reagents used were analytically or chemically pure.

In some of the examples below, some exemplary compounds of the present invention were prepared, which are represented by the following general formula I, and the substituents and exemplary names of these compounds are shown in table 1, respectively.

Table 1: structural formulae of examples 1 to 9

Example 1: preparation of 28-O- (2- (4- ((2,4 dichlorophenyl) aminomethyl) -1H-1, 2, 3-triazol-1-yl) acetyl) oxy rapamycin (X-121)

Step A: preparation of 28-oxytrimethylsilyl-oxy rapamycin

Pouring 10g (10.94mmol) of rapamycin into a 250ml flask, adding 115ml of EA, stirring at room temperature for 10min, cooling to 0 ℃, adding 9.34g (137.19mmol) of imidazole, stirring for 5min, dropwise adding 9.3g (85.33mmol) of trimethylchlorosilane, separating out white solid during dropwise adding, completing dropwise adding after 38min, and detecting by TLC after 7min, wherein the rapamycin completely reacts. 66ml (33.37mmol) of 0.5N H were added₂SO₄Stirring, reacting for 3h, and detecting by TLC to obtain a single-protection product. Extracting with EA, sequentially adding water, 1N hydrochloric acid and saturated NaHCO₃Washing the solution with saturated NaCl solution, and finally, anhydrous Na₂SO₄The reaction mixture was dehydrated, filtered with suction, concentrated and dried under reduced pressure to obtain 12.28g of a white solid. MS (ESI) M/z 1008.6(M + Na)⁺。¹HNMR(600MHz,DMSO)δ6.47(s,1H),6.41(dd,J＝14.3,11.5Hz,1H),6.23(dd,J＝24.6,13.7Hz,1H),6.15(dd,J＝21.1,10.9Hz,1H),6.10(d,J＝15.1Hz,1H),5.46(dd,J＝14.8,9.6Hz,1H),5.11(d,J＝10.2Hz,1H),5.01(d,J＝3.6Hz,1H),4.95(d,J＝4.8Hz,1H),4.68–4.62(m,1H),4.02(t,J＝9.3Hz,2H),3.87(d,J＝5.7Hz,1H),3.61(dd,J＝33.1,18.7Hz,1H),3.45(d,J＝12.6Hz,1H),3.33(s,3H),3.29(dd,J＝19.4,8.7Hz,1H),3.17(s,3H),3.14(t,J＝5.7Hz,2H),3.08(d,J＝21.0Hz,3H),2.82(dd,J＝15.5,8.0Hz,1H),2.72(dd,J＝33.3,11.9Hz,1H),2.50(d,J＝12.8Hz,1H),2.23(s,1H),2.13(d,J＝9.6Hz,1H),2.05–2.01(m,1H),1.85(d,J＝9.3Hz,1H),1.83(s,1H),1.77(s,3H),1.67(s,1H),1.64(s,3H),1.61(s,1H),1.38(d,J＝12.7Hz,1H),1.30(s,1H),1.24(d,J＝11.3Hz,1H),1.20(d,J＝11.1Hz,1H),0.99(d,J＝6.3Hz,3H),0.88(d,J＝6.3Hz,3H),0.83(d,J＝6.3Hz,3H),0.78(d,J＝6.5Hz,3H),0.74(d,J＝6.4Hz,3H),0.03–-0.05(m,9H)。¹³C NMR(151MHz,DMSO)δ209.74,207.76,199.26,169.67,167.43,139.57,138.33,136.86,132.82,130.92,127.54,125.72,99.47,85.45,84.32,82.63,77.98,74.17,73.69,71.82,66.65,57.47,57.31,56.29,55.95,51.46,45.47,44.09,40.68,40.41,40.27,40.13,39.99,39.85,39.71,39.58,38.57,35.54,35.24,34.07,33.39,33.03,31.89,30.05,28.67,26.85,24.93,22.20,21.47,20.94,19.74,16.08,15.95,15.51,14.07,13.67,11.04。

And B: preparation of 43-oxy-tert-butyldimethylsilyl-oxy rapamycin

12.28g (12.45mmol) 28-oxytrimethylsilyl-rapamycin was poured into a 250ml flask, dissolved in 110ml N, N-Dimethylformamide (DMF), 24.54g (360.43mmol) imidazole was added, dissolved at 60 ℃ and finally 14.72g (138.26mmol) TBSCl was added in portions, reacted at 60 ℃ for 5h and checked by TLC. After the reaction, the mixture is extracted by EA, and water, 1N hydrochloric acid and saturated NaHCO are used for extracting the mixture in sequence₃Washing the solution with saturated NaCl solution, and finally anhydrous Na₂SO₄Dehydrating, filtering, and concentrating under reduced pressure to dryness to obtain light yellow solid. Performing silica gel column chromatography, and performing gradient elution on PE (polyethylene) and EA (ethylene oxide) in a ratio of 6: 1-4: 1 to obtain 6g of white solid. Yield: 46.3 percent. MS (ESI) M/z 1050.6(M + Na)⁺。¹H NMR(600MHz,DMSO)δ6.46(d,J＝1.4Hz,1H),6.44–6.37(m,1H),6.23(dd,J＝14.5,10.6Hz,1H),6.17–6.11(m,1H),6.11(d,J＝4.5Hz,1H),5.47(dd,J＝14.9,9.6Hz,1H),5.28(d,J＝4.5Hz,1H),5.11(d,J＝10.1Hz,1H),5.01–4.97(m,1H),4.95(d,J＝6.0Hz,1H),4.05–3.99(m,2H),3.95(d,J＝4.6Hz,1H),3.45(d,J＝12.7Hz,1H),3.33(s,4H),3.20–3.17(m,1H),3.16(s,3H),3.13(s,1H),3.06(s,3H),2.76–2.71(m,1H),2.44–2.39(m,1H),2.24–2.18(m,1H),2.14–2.08(m,1H),2.04(dd,J＝15.0,6.9Hz,1H),1.85–1.80(m,1H),1.74(s,4H),1.68(s,1H),1.68–1.66(m,1H),1.64(s,4H),1.60(d,J＝4.8Hz,1H),1.59–1.56(m,2H),1.53(s,2H),1.38(d,J＝10.5Hz,1H),1.29(d,J＝11.8Hz,3H),1.25(d,J＝11.1Hz,2H),0.98(d,J＝6.5Hz,3H),0.88(d,J＝6.5Hz,3H),0.86(s,9H),0.83(d,J＝6.4Hz,4H),0.78(d,J＝6.7Hz,3H),0.74(d,J＝6.7Hz,3H),0.04(d,J＝1.4Hz,6H)。¹³C NMR(151MHz,DMSO)δ210.93,207.98,199.35,169.68,167.48,139.83,138.36,137.66,132.82,130.87,127.49,125.44,99.51,85.96,84.08,82.76,76.24,75.75,74.13,66.67,57.58,57.39,55.94,51.25,45.71,44.00,40.53,40.41,40.27,40.13,39.99,39.86,39.72,39.58,38.78,35.89,35.74,35.29,33.95,32.79,31.52,30.14,26.94,26.72,26.23,24.96,22.15,20.89,18.32,16.04,15.24,13.92,13.88,10.96。

And C: preparation of 28-O- (2-bromoacetyl) -43-oxy-tert-butyldimethylsilyl-oxy rapamycin

6g (5.8mmol) 43-oxy-tert-butyldimethylsilyl-oxy-rapamycin was poured into a 250mL flask, dissolved with 100mL Dichloromethane (DCM), cooled to-2 ℃ and 18mL pyridine was added, after 5min 9mL (104.2mmol) bromoacetyl bromide was added dropwise, after 40min addition was complete, TLC detection was performed. After the reaction, the mixture was extracted with DCM, and water, 1N hydrochloric acid and saturated NaHCO were used in sequence₃Washing the solution with saturated NaCl solution, anhydrous Na₂SO₄Dehydrating, filtering, concentrating under reduced pressure, and drying to obtain red black solid. Purifying by silica gel column chromatography, and carrying out gradient elution on PE (polyethylene) and EA (ethylene oxide) at a ratio of 10: 1-4: 1 to obtain 4.77g of samples with the yield of 70.8%. MS (ESI) M/z 1170.5(M + Na)⁺。¹H NMR(600MHz,DMSO)δ6.42(d,J＝3.8Hz,1H),6.41–6.37(m,1H),6.23(dd,J＝10.3,4.8Hz,1H),6.15(dd,J＝12.9,7.1Hz,1H),6.12(d,J＝7.0Hz,1H),5.51–5.47(m,1H),5.05(d,J＝11.3Hz,1H),5.02–4.96(m,2H),4.94(d,J＝5.4Hz,5H),4.57(s,1H),4.08–3.98(m,3H),3.91(d,J＝2.8Hz,1H),3.63(dd,J＝20.6,9.3Hz,1H),3.45(d,J＝12.6Hz,1H),3.33(dd,J＝2.6,1.5Hz,3H),3.32–3.27(m,1H),3.22–3.19(m,3H),3.17(d,J＝2.2Hz,3H),3.15–3.13(m,2H),3.05(d,J＝2.8Hz,3H),2.88–2.80(m,1H),2.67(dd,J＝9.2,6.2Hz,1H),2.39(dd,J＝16.1,9.2Hz,1H),2.12(d,J＝13.1Hz,1H),2.04–1.99(m,1H),1.90(d,J＝13.1Hz,1H),1.86–1.80(m,1H),1.78–1.73(m,1H),1.67(s,1H),1.63–1.59(m,1H),1.55(d,J＝12.8Hz,1H),1.53(s,1H),1.27(s,1H),1.26–1.22(m,1H),1.21–1.16(m,1H),0.98(d,J＝2.1Hz,3H),0.87(d,J＝1.9Hz,3H),0.85–0.83(m,12H),0.83–0.82(m,3H),0.78(d,J＝7.8Hz,3H),0.74(dd,J＝6.5,2.4Hz,3H),0.59(dd,J＝23.8,11.9Hz,1H),-0.03–-0.06(m,6H)。¹³C NMR(151MHz,DMSO)δ212.26,204.25,198.86,169.73,167.47,138.66,138.47,132.85,129.92,127.49,126.40,123.31,99.33,84.28,83.07,82.15,76.84,74.21,73.58,66.94,59.76,57.23,55.85,51.21,49.03,45.52,40.40,40.26,40.12,39.98,39.84,39.70,39.56,39.49,35.66,35.19,33.42,32.77,31.57,31.49,26.67,26.27,24.95,21.76,20.86,18.25,16.06,15.40,13.84,10.68。

Step D: preparation of 28-O- (2-bromoacetyl) -oxorapamycin

4.77g (4.15mmol)28-O- (2-bromoacetyl) -43-oxy-tert-butyldimethylsilyl-oxy-rapamycin are poured into a 250ml flask, dissolved with 70ml Acetone (AC), cooled to 0 ℃ and 18ml (0.018mmol)2NH are then added₂SO₄Solution, 18h after TLC detection. After the reaction is finished, extracting with EA, and sequentially using water and saturated NaHCO₃Washing the solution with saturated NaCl solution, and finally anhydrous Na₂SO₄Dehydrating, and concentrating under reduced pressure to obtain light yellow solid. Purifying by silica gel column chromatography, and performing gradient elution on PE (polyethylene) and EA (ethylene oxide) in a ratio of 6: 1-1: 1 to obtain 3.6g of a sample, wherein the yield is as follows: 79.5 percent. MS (ESI) M/z 1056.5(M + Na)⁺。¹HNMR(600MHz,DMSO)δ6.42(d,J＝4.5Hz,1H),6.40(d,J＝3.6Hz,1H),6.23(d,J＝4.0Hz,1H),6.19–6.15(m,1H),6.12(s,1H),5.47(d,J＝5.3Hz,1H),5.09(s,1H),4.98(d,J＝3.8Hz,1H),4.94(s,1H),4.65(s,1H),4.02–4.00(m,2H),3.91(d,J＝2.7Hz,1H),3.62(d,J＝6.2Hz,1H),3.44(d,J＝2.1Hz,1H),3.33(s,3H),3.26(s,1H),3.22(s,3H),3.19(d,J＝2.1Hz,1H),3.05(s,3H),2.84–2.82(m,1H),2.73(dd,J＝8.8,5.2Hz,1H),2.51(dt,J＝3.6,1.8Hz,2H),2.46–2.42(m,1H),2.10(d,J＝11.8Hz,2H),1.82(s,3H),1.66–1.65(m,1H),1.61(s,3H),1.58(s,1H),1.41(s,1H),1.30(s,1H),0.99(d,J＝6.6Hz,3H),0.88–0.86(m,3H),0.84(dd,J＝4.8,3.8Hz,3H),0.77(d,J＝6.8Hz,3H),0.74(d,J＝6.6Hz,3H)。¹³C NMR(151MHz,DMSO)δ209.33,207.25,199.30,169.64,167.41,166.24,139.64,138.42,132.92,132.61,131.04,127.48,99.44,84.32,82.63,78.27,74.25,73.70,66.65,60.21,57.67,57.24,55.94,51.45,51.44,45.55,44.09,40.40,40.26,40.12,39.98,39.84,39.70,39.57,35.69,33.40,33.03,31.84,26.99,26.27,22.04,20.95,16.09,15.76,15.51,14.67,14.55,13.79,10.93。

Step E: preparation of 28-O- (2-azidoacetyl) -oxorapamycin

3.6g (3.48mmol) of 28-O- (2-bromoacetyl) -oxorapamycin was poured into a 250ml flask, followed by the addition of 50mLN, N-bisMethyl Formamide (DMF) and catalytic amount of KI were placed in an oil bath at 50 ℃ for 5min and 0.9g (13.8mmol) of NaN was added₃And (5) detecting by TLC. After the reaction is complete. Extracting with EA, sequentially using water, 1N hydrochloric acid and saturated NaHCO₃Washing the solution with saturated NaCl solution, and finally anhydrous Na₂SO₄Dehydrating, filtering, concentrating under reduced pressure, and drying to obtain white solid. Silica gel column chromatography, PE: EA ═ 3:1,2:1,1:1 gradient elution, finally yielded 1.4g of sample, yield: 40.3 percent. MS (ESI) M/z 1011.9(M + Na)⁺。¹HNMR(600MHz,DMSO)δ6.47(s,1H),6.40(dd,J＝14.6,11.3Hz,1H),6.24(dd,J＝14.5,10.7Hz,1H),6.15(dd,J＝15.7,5.3Hz,1H),6.12(d,J＝4.6Hz,1H),5.47(dd,J＝15.0,9.7Hz,1H),5.34(t,J＝5.9Hz,1H),5.05(d,J＝10.1Hz,1H),4.98–4.93(m,2H),4.61(s,1H),4.36(d,J＝3.8Hz,1H),4.09–3.97(m,2H),3.95(d,J＝9.8Hz,1H),3.63(dd,J＝17.2,5.6Hz,1H),3.46(d,J＝13.9Hz,1H),3.33(s,3H),3.30–3.27(m,1H),3.27–3.24(m,1H),3.22(s,3H),3.13–3.08(m,1H),3.05(s,3H),2.86–2.82(m,1H),2.67(dd,J＝17.5,2.7Hz,1H),2.52–2.49(m,1H),2.44–2.36(m,2H),2.24(s,2H),2.13(d,J＝12.5Hz,1H),1.85(s,1H),1.82(s,3H),1.62(s,3H),1.59–1.55(m,4H),1.28(s,1H),1.00(d,J＝6.5Hz,6H),0.89–0.86(m,6H),0.84–0.82(m,1H),0.77(d,J＝6.7Hz,3H),0.74(d,J＝6.6Hz,3H)。¹³C NMR(151MHz,DMSO)δ209.42,207.45,199.27,169.67,167.83,167.43,139.61,138.41,132.92,132.58,131.04,127.49,99.45,84.33,82.64,82.41,78.01,74.33,73.70,66.65,57.64,57.22,55.93,51.42,49.87,45.62,44.12,41.28,40.97,40.74,40.39,40.25,40.11,39.97,39.83,39.70,39.56,38.52,35.66,35.59,35.20,34.13,33.40,33.06,31.86,26.82,24.95,22.02,20.95,16.08,15.78,15.42,14.65,13.71,10.91.

Step F: preparation of 28-O- (2- (4- ((2,4 dichlorophenyl) aminomethyl) -1H-1, 2, 3-triazol-1-yl) acetyl) oxy rapamycin (X-121)

0.3g (0.3mmol) of 28-O- (2-azidoacetyl) -oxarapamycin was poured into a 50ml flask, dissolved by adding 10ml of acetonitrile, and a catalytic amount of CuI was added, followed by addition of N, N-Diisopropylethylamine (DIPEA) and finally 0.15g (0.81mmol) of 2, 4-dichlorophenylpropargylamine, reacted at room temperature for 30min, and checked by TLC. After the reaction is finishedThen, the mixture is extracted with EA, and then water, 1N HCl and saturated NaHCO are used in sequence₃And saturated NaCl washes, finally anhydrous Na₂SO₄Drying, suction filtering, vacuum concentrating and drying to obtain crude product. Purifying by silica gel column chromatography, and eluting with PE, EA and EA in a gradient of 3:1,2:1,1:1 and 1:2 to obtain 0.15g of sample. Yield: 42.9 percent. MS (ESI) M/z 1204.5(M + Na)⁺。¹H NMR(600MHz,DMSO)δ7.91–7.87(m,1H),7.36(t,J＝6.7Hz,1H),7.14(dt,J＝7.0,3.5Hz,1H),6.81(d,J＝8.9Hz,1H),6.47(s,1H),6.39(dd,J＝14.3,11.5Hz,1H),6.20(dd,J＝23.1,8.5Hz,1H),6.16–6.08(m,2H),6.06(d,J＝5.9Hz,1H),5.49(dd,J＝21.0,10.7Hz,1H),5.36–5.25(m,2H),5.08(d,J＝7.4Hz,1H),5.00(d,J＝9.9Hz,1H),4.96(d,J＝4.1Hz,1H),4.61(d,J＝4.0Hz,1H),4.44(d,J＝5.9Hz,2H),4.29(d,J＝3.5Hz,1H),4.05–3.94(m,2H),3.93(d,J＝7.1Hz,1H),3.63(d,J＝12.0Hz,1H),3.46(d,J＝12.8Hz,1H),3.34(s,3H),3.29–3.20(m,2H),3.19(d,J＝5.5Hz,3H),3.04(d,J＝18.5Hz,3H),2.85–2.79(m,1H),2.72–2.60(m,1H),2.44–2.31(m,2H),2.24(d,J＝28.6Hz,1H),2.17–2.11(m,1H),2.05–1.97(m,1H),1.89(dt,J＝25.7,14.6Hz,3H),1.68(s,3H),1.59–1.47(m,5H),1.45–1.35(m,2H),1.27(dd,J＝25.5,13.6Hz,2H),1.22–1.13(m,3H),1.08–1.03(m,2H),0.98(d,J＝6.3Hz,3H),0.94(d,J＝7.0Hz,1H),0.86(d,J＝6.4Hz,3H),0.85–0.82(m,1H),0.80(d,J＝6.3Hz,3H),0.74(t,J＝6.4Hz,6H),0.57(dd,J＝23.7,11.9Hz,1H)。¹³C NMR(151MHz,DMSO)δ209.37,207.29,199.29,169.72,167.42,166.19,145.47,143.24,139.51,138.40,132.94,132.23,130.97,128.65,128.17,127.46,126.50,124.70,119.75,118.87,112.92,107.45,99.45,84.29,82.63,82.29,78.15,74.29,73.71,71.83,66.64,57.67,57.23,55.94,51.42,50.60,45.66,44.14,41.00,40.41,40.27,40.13,39.99,39.85,39.71,39.57,38.71,35.66,35.20,34.17,33.39,33.01,31.85,30.07,26.52,25.11,22.04,20.99,19.59,16.08,15.77,15.44,14.45,13.78,10.94.

Example 2: preparation of 28-O- (2- (4- (phenyl) -1H-1, 2, 3-triazole-1-yl) acetyl) oxygen rapamycin (X-122)

Steps A-E are the same as the steps for synthesizing A-E in X-121.

Step F: preparation of 28-O- (2- (4- (phenyl) -1H-1, 2, 3-triazole-1-yl) acetyl) oxygen rapamycin (X-122)

0.12g (0.12mmol) of 28-O- (2-azidoacetyl) -oxarapamycin was poured into a 50ml flask, dissolved by adding 10ml of acetonitrile, added with a catalytic amount of CuI, then DIPEA, and finally added with 0.06g (0.60mmol) of phenylacetylene for reaction at room temperature for 90min, and detected by TLC. After the reaction is finished, extracting with EA, then washing with water, 1N HCl and saturated NaHCO in sequence₃And saturated NaCl washes, finally anhydrous Na₂SO₄Dehydrating, filtering, concentrating under reduced pressure, and drying to obtain crude product. Purification by silica gel column chromatography, gradient elution PE: EA: 3:1,2:1,1:1,1:2 gave 0.09g of sample. Yield: 69.2 percent. MS (ESI) M/z 1107.6(M + Na)⁺。¹H NMR(500MHz,DMSO)δ8.43(s,1H),7.86(d,J＝1.0Hz,1H),7.84(s,1H),7.46(d,J＝7.4Hz,1H),7.43(s,1H),7.33(dd,J＝13.3,5.9Hz,1H),6.44(d,J＝1.1Hz,1H),6.37(dd,J＝14.3,11.4Hz,1H),6.22(dd,J＝17.0,6.4Hz,1H),6.19–6.11(m,1H),6.10(d,J＝4.1Hz,1H),5.63–5.48(m,1H),5.37(dd,J＝23.2,10.0Hz,2H),5.09(d,J＝7.3Hz,1H),5.03–4.94(m,2H),4.57–4.52(m,1H),4.35(d,J＝3.6Hz,1H),4.31–4.10(m,1H),4.06–3.96(m,1H),3.65(dd,J＝33.1,11.7Hz,1H),3.46(d,J＝13.5Hz,1H),3.29(d,J＝6.6Hz,3H),3.27–3.22(m,1H),3.21(s,3H),3.19–3.07(m,2H),3.03(d,J＝16.7Hz,3H),2.85–2.75(m,1H),2.72–2.60(m,1H),2.40(dd,J＝17.5,8.2Hz,1H),2.35–2.27(m,1H),2.16(dd,J＝27.4,14.1Hz,1H),2.02(dd,J＝15.4,7.9Hz,1H),1.90(d,J＝12.0Hz,1H),1.83(d,J＝13.9Hz,1H),1.74–1.64(m,3H),1.62–1.49(m,6H),1.41(dd,J＝27.3,13.6Hz,2H),1.24(dd,J＝13.6,7.8Hz,2H),1.20–1.10(m,3H),1.10–1.00(m,2H),0.98(t,J＝6.4Hz,3H),0.91–0.79(m,6H),0.79–0.69(m,6H),0.56(dd,J＝23.7,11.9Hz,1H)。¹³C NMR(126MHz,DMSO)δ208.76,206.89,198.66,169.24,166.89,165.58,146.35,139.05,137.91,132.36,131.75,130.51,128.79,127.85,126.99,125.66,125.16,122.65,98.95,83.77,82.11,81.75,77.81,73.95,73.15,66.14,57.10,56.65,55.42,50.93,50.34,45.22,43.64,40.85,40.64,40.01,39.84,39.67,39.51,39.34,39.17,39.01,37.93,35.12,35.01,34.68,33.76,32.85,32.51,31.35,29.73,28.64,26.18,24.45,22.47,21.48,20.46,19.45,18.99,15.55,15.24,14.93,14.11,13.01,11.10,10.42。

Example 3: 28-O- (2- (4- (3-methylphenyl) -1H-1, 2, 3-triazol-1-yl) acetyl) oxy rapamycin (X-123)

Steps A-E are the same as the steps for synthesizing A-E in X-121.

Step F: preparation of 28-O- (2- (4- (3-methylphenyl) -1H-1, 2, 3-triazole-1-yl) acetyl) rapamycin oxide (X-123)

0.12g (0.12mmol) of 28-O- (2-azidoacetyl) -oxarapamycin was poured into a 50ml flask, dissolved by adding 10ml of acetonitrile, and a catalytic amount of CuI was added, followed by DIPEA and finally 0.07g (0.60mmol) of 3-methylphenylacetylene were added, reacted at room temperature for 11 hours and detected by TLC. After the reaction is finished, extracting with EA, and then sequentially using water, 1NHCl and saturated NaHCO₃And saturated NaCl washes, anhydrous Na₂SO₄Dehydrating, filtering, concentrating under reduced pressure, and drying to obtain crude product. Purification by silica gel column chromatography, gradient elution PE: EA: 3:1,2:1,1:1,1:2 gave 0.05g of sample. Yield: 38.2 percent. MS (ESI) M/z 1198.6(M + Na)⁺。¹H NMR(500MHz,DMSO)δ8.40(d,J＝6.2Hz,1H),7.67(s,1H),7.63(d,J＝7.6Hz,1H),7.33(dd,J＝14.0,6.5Hz,1H),7.15(d,J＝7.2Hz,1H),5.45(dd,J＝22.4,12.7Hz,1H),5.38–5.31(m,2H),5.15–5.05(m,1H),5.03–4.93(m,2H),4.55(t,J＝6.2Hz,1H),4.35(d,J＝3.5Hz,1H),4.27(d,J＝3.9Hz,1H),4.06–3.95(m,1H),3.65(dd,J＝32.2,11.9Hz,1H),3.46(d,J＝13.5Hz,1H),3.29(d,J＝7.7Hz,3H),3.27–3.23(m,1H),3.19(d,J＝13.9Hz,3H),3.12(dd,J＝15.7,10.7Hz,2H),3.03(d,J＝16.4Hz,3H),2.84–2.76(m,1H),2.66(d,J＝15.3Hz,1H),2.43–2.37(m,1H),2.36(s,3H),2.33–2.29(m,1H),2.19–2.11(m,1H),2.02(dd,J＝15.0,7.6Hz,1H),1.86(dd,J＝30.5,14.0Hz,3H),1.74–1.66(m,3H),1.54(d,J＝14.8Hz,5H),1.45–1.36(m,2H),1.34–1.27(m,2H),1.22(d,J＝13.9Hz,2H),1.20–1.12(m,3H),1.04(dd,J＝18.7,6.3Hz,3H),0.97(d,J＝6.3Hz,3H),0.87(t,J＝9.6Hz,4H),0.77–0.70(m,8H),0.55(dd,J＝23.8,11.9Hz,1H)。¹³C NMR(126MHz,DMSO)δ208.72,206.88,198.71,169.24,166.89,165.64,146.45,139.07,137.89,132.38,131.85,130.42,128.69,128.51,126.99,125.72,122.54,122.35,110.00,98.95,83.77,82.10,81.70,77.83,73.97,73.15,66.15,57.11,56.64,55.42,50.93,50.31,45.27,43.66,40.91,40.62,40.01,39.84,39.68,39.51,39.34,39.18,39.01,37.89,35.15,34.96,34.68,33.80,32.85,32.50,31.36,29.74,26.19,24.46,21.48,20.98,20.47,15.55,15.20,14.93,14.16,13.02,10.41.

Example 4: 28-O- (2- (4- (2-chlorophenyl) -1H-1, 2, 3-triazol-1-yl) acetyl) oxy rapamycin (X-124)

Steps A-E are the same as the steps for synthesizing A-E in X-121.

Step F: preparation of 28-O- (2- (4- (2-chlorophenyl) -1H-1, 2, 3-triazole-1-yl) acetyl) oxygen rapamycin (X-124)

0.1g (0.1mmol) of 28-O- (2-azidoacetyl) -oxarapamycin was poured into a 50ml flask, dissolved by adding 10ml of acetonitrile, added with a catalytic amount of CuI, then DIPEA, and finally 0.068g (0.50mmol) of 2-chlorophenylacetylene, reacted at room temperature for 40min, and checked by TLC. After the reaction is finished, extracting with EA, and then sequentially using water, 1N HCl and saturated NaHCO₃And saturated NaCl washes, anhydrous Na₂SO₄Dehydrating, filtering, concentrating under reduced pressure, and drying to obtain crude product. Purification by silica gel column chromatography, gradient elution PE: EA: 3:1,2:1,1:1,1:2 gave 0.04g sample. Yield: 36.4 percent. MS (ESI) M/z 1141.5(M + Na)⁺。¹HNMR(600MHz,DMSO)δ8.63(d,J＝13.4Hz,1H),8.12(t,J＝8.6Hz,1H),7.60(dd,J＝31.5,7.7Hz,1H),7.55–7.44(m,1H),7.40(t,J＝7.1Hz,1H),6.47(s,1H),6.39(dd,J＝26.1,14.6Hz,1H),6.28(dd,J＝36.5,27.6Hz,1H),6.18(dd,J＝21.6,10.2Hz,1H),6.11(d,J＝10.9Hz,1H),5.47–5.40(m,1H),5.37(d,J＝14.6Hz,1H),5.03(d,J＝9.9Hz,1H),4.96(d,J＝18.6Hz,1H),4.58(dd,J＝15.6,11.9Hz,1H),4.30(dd,J＝30.2,11.6Hz,1H),4.23–4.10(m,1H),4.00(t,J＝19.6Hz,1H),3.65(dd,J＝37.1,12.7Hz,1H),3.46(d,J＝11.3Hz,2H),3.29(s,3H),3.25(dd,J＝12.4,4.7Hz,1H),3.20(s,1H),3.13(dd,J＝27.6,13.4Hz,3H),3.05(s,3H),2.81(dd,J＝15.3,8.2Hz,1H),2.68(t,J＝16.1Hz,1H),2.40(dd,J＝17.3,8.1Hz,1H),2.19(s,1H),2.12(t,J＝14.2Hz,1H),2.02(d,J＝7.2Hz,1H),1.89–1.81(m,3H),1.75–1.65(m,3H),1.59–1.50(m,5H),1.45–1.33(m,2H),1.25(dd,J＝40.0,14.1Hz,2H),1.16(dd,J＝21.8,7.9Hz,2H),1.04(dd,J＝18.6,6.3Hz,2H),1.00–0.95(m,3H),0.94(s,3H),0.88–0.81(m,6H),0.76–0.70(m,3H),0.56(dd,J＝23.9,12.0Hz,1H)。¹³C NMR(151MHz,DMSO)δ208.82,207.15,199.14,185.06,182.33,169.64,167.40,142.99,139.62,139.23,138.35,138.17,132.89,132.27,130.77,130.71,129.85,129.44,127.94,127.46,126.13,99.45,84.29,82.53,78.22,74.38,73.65,71.83,66.54,57.57,57.15,55.93,51.40,50.69,45.59,44.05,40.41,40.27,40.13,39.99,39.85,39.71,39.57,38.45,35.64,33.37,33.03,31.86,30.06,28.67,26.84,24.97,22.02,21.47,19.74,16.07,15.78,15.41,14.46,13.67,10.94,9.99.

Example 5: 28-O- (2- (4- (4-methoxyphenyl) -1H-1, 2, 3-triazol-1-yl) acetyl) oxy rapamycin (X-125)

Steps A-E are the same as the steps for synthesizing A-E in X-121.

Step F: preparation of 28-O- (2- (4- (4-methoxyphenyl) -1H-1, 2, 3-triazol-1-yl) acetyl) oxygen rapamycin (X-125)

0.12g (0.12mmol) of 28-O- (2-azidoacetyl) -rapamycin was poured into a 50ml flask, dissolved by adding 10ml of acetonitrile, added with a catalytic amount of CuI, then DIPEA, and finally 0.08g (0.60mmol) of 4-methoxyphenylacetylene, reacted at room temperature for 50min, and checked by TLC. After the reaction is finished, extracting with EA, and then sequentially using water, 1N HCl and saturated NaHCO₃And saturated NaCl washes, anhydrous Na₂SO₄Dehydrating, filtering, concentrating under reduced pressure, and drying to obtain crude product. Purifying by silica gel column chromatography, and eluting with PE with EA of 3:1,2:1,1:1 and 1:2 gradient to obtain 0.02g sample. Yield: 15.4 percent. MS (ESI) M/z 1137.6(M + Na)⁺。¹H NMR(600MHz,DMSO)δ8.32(d,J＝5.5Hz,1H),7.85–7.74(m,2H),7.12–6.99(m,2H),6.47(d,J＝8.0Hz,1H),6.38(dd,J＝14.5,11.4Hz,1H),6.21(dd,J＝14.4,10.9Hz,1H),6.11(dd,J＝18.5,10.6Hz,2H),5.43(dd,J＝15.0,9.8Hz,1H),5.39–5.32(m,2H),5.13–5.05(m,1H),5.02–4.92(m,2H),4.59(d,J＝4.0Hz,1H),4.37(d,J＝3.2Hz,1H),4.31–4.11(m,1H),4.03(d,J＝10.9Hz,1H),3.79(s,3H),3.63(dd,J＝32.8,21.3Hz,1H),3.47(d,J＝12.9Hz,1H),3.29(s,3H),3.21(s,3H),3.17–3.13(m,2H),3.05(s,3H),2.80(dd,J＝15.6,8.3Hz,1H),2.66(dd,J＝31.8,16.8Hz,1H),2.40(dd,J＝17.3,8.2Hz,2H),2.24–2.13(m,1H),2.10(d,J＝23.6Hz,1H),2.05–1.97(m,1H),1.87(dd,J＝38.0,13.4Hz,3H),1.75–1.65(m,3H),1.55–1.40(m,5H),1.33(d,J＝34.9Hz,2H),1.25(d,J＝14.3Hz,2H),1.20–1.12(m,3H),1.06(ddd,J＝22.1,14.7,6.2Hz,3H),0.98(d,J＝6.3Hz,3H),0.90–0.80(m,6H),0.76–0.70(m,6H),0.58–0.52(m,1H)。¹³C NMR(151MHz,DMSO)δ207.86,200.43,198.44,185.33,181.76,180.75,174.12,169.71,166.39,159.59,152.81,147.97,135.87,126.83,114.82,99.67,84.02,73.58,64.57,56.85,55.61,46.19,40.41,40.27,40.13,39.99,39.85,39.71,39.58,33.11,21.76,16.05,15.55,15.42,14.07,11.26,10.50。

Example 6: 28-O- (2- (4- (4-methylphenyl) -1H-1, 2, 3-triazol-1-yl) acetyl) oxy rapamycin (X-126)

Steps A-E are the same as the steps for synthesizing A-E in X-121.

Step F: preparation of 28-O- (2- (4- (4-methylphenyl) -1H-1, 2, 3-triazole-1-yl) acetyl) rapamycin oxide (X-126)

0.15g (0.15mmol) of 28-O- (2-azidoacetyl) -oxarapamycin was poured into a 50ml flask, dissolved by adding 10ml of acetonitrile, added with a catalytic amount of CuI, then DIPEA, and finally 0.087g (0.75mmol) of 4-methylphenylacetylene were added and reacted at room temperature for 7 hours, followed by TLC detection. After the reaction is finished, extracting with EA, and then sequentially using water, 1NHCl and saturated NaHCO₃And saturated NaCl washes, finally anhydrous Na₂SO₄Dehydrating, filtering, concentrating under reduced pressure, and drying to obtain crude product. Purifying by silica gel column chromatography, and eluting with PE with EA of 3:1,2:1,1:1,1:2 gradient to obtain 0.1g sample. Yield: 62.5 percent. MS (ESI) M/z 1121.6(M + Na)⁺。¹H NMR(500MHz,DMSO)δ8.36(s,1H),7.73(d,J＝7.0Hz,2H),7.27(t,J＝17.0Hz,2H),6.43(s,1H),6.41–6.30(m,1H),6.30–6.15(m,1H),6.15–6.03(m,2H),5.54–5.41(m,1H),5.36(d,J＝23.1Hz,2H),5.05(d,J＝39.3Hz,1H),4.97(d,J＝11.1Hz,2H),4.30(d,J＝41.9Hz,2H),4.01(s,1H),3.62(d,J＝11.0Hz,1H),3.46(d,J＝11.5Hz,1H),3.28(s,3H),3.20(s,3H),3.18–3.10(m,2H),3.04(s,3H),2.79(s,1H),2.66(d,J＝16.8Hz,1H),2.44–2.38(m,1H),2.33(s,3H),2.15(d,J＝13.3Hz,1H),2.01(d,J＝6.6Hz,1H),1.86(dd,J＝33.4,12.8Hz,3H),1.78(s,1H),1.67(d,J＝8.8Hz,3H),1.50(d,J＝27.5Hz,5H),1.46–1.35(m,2H),1.23(s,2H),1.20–1.10(m,3H),1.05(d,J＝7.4Hz,3H),0.97(d,J＝5.4Hz,3H),0.83(dd,J＝17.8,5.8Hz,6H),0.74(s,6H),0.60–0.53(m,1H)。¹³C NMR(126MHz,DMSO)δ208.34,206.68,198.66,169.25,166.89,165.61,146.42,139.06,137.91,137.14,132.37,131.77,130.48,129.34,127.75,126.92,125.66,125.10,122.22,108.22,98.95,83.76,82.11,81.77,77.81,73.95,73.15,66.15,57.12,56.65,55.42,50.94,50.31,45.22,40.85,40.64,40.01,39.84,39.67,39.51,39.34,39.17,39.01,37.93,35.12,35.01,34.69,33.76,32.86,32.51,31.35,29.74,26.18,24.45,21.49,20.78,20.47,15.55,15.25,14.93,14.12,13.04,10.42。

Example 7: 28-O- (2- (4- (4-fluorophenyl) -1H-1, 2, 3-triazol-1-yl) acetyl) oxy rapamycin (X-127)

Steps A-E are the same as the steps for synthesizing A-E in X-121.

Step F: preparation of 28-O- (2- (4- (4-fluorophenyl) -1H-1, 2, 3-triazole-1-yl) acetyl) rapamycin oxide (X-127)

0.15g (0.15mmol) of 28-O- (2-azidoacetyl) -oxarapamycin was poured into a 50ml flask, dissolved by adding 10ml of acetonitrile, and a catalytic amount of CuI was added, followed by DIPEA and finally 0.09g (0.75mmol) of 4-fluorophenylacetylene was added, reacted at room temperature for 24 hours, and detected by TLC. After the reaction is finished, extracting with EA, and then sequentially using water, 1N HCl and saturated NaHCO₃And saturated NaCl washes, anhydrous Na₂SO₄Dehydrating, filtering, concentrating under reduced pressure, and drying to obtain crude product. Purification by silica gel column chromatography, gradient elution PE: EA: 3:1,2:1,1:1,1:2 gave 0.05g of sample. Yield: 30.3 percent. MS (ESI) M/z 1125.6(M + Na)⁺。¹H NMR(500MHz,DMSO)δ8.42(d,J＝4.9Hz,1H),7.88(dd,J＝8.5,5.5Hz,2H),7.29(t,J＝8.8Hz,2H),6.44(s,1H),6.37(dd,J＝14.4,11.3Hz,1H),6.24–6.16(m,1H),6.12(t,J＝12.6Hz,1H),6.08(d,J＝10.7Hz,1H),5.46–5.41(m,1H),5.33(s,2H),5.07(d,J＝22.9Hz,1H),4.98(d,J＝10.9Hz,2H),4.59–4.52(m,1H),4.35(d,J＝3.3Hz,1H),4.28(s,1H),4.05–3.97(m,1H),3.62(d,J＝12.3Hz,1H),3.46(d,J＝13.5Hz,1H),3.28(s,3H),3.26–3.22(m,1H),3.20(s,3H),3.17(d,J＝6.3Hz,2H),3.04(s,3H),2.80(dd,J＝15.6,8.3Hz,1H),2.66(d,J＝14.9Hz,1H),2.39(dd,J＝17.4,8.2Hz,1H),2.15(d,J＝13.5Hz,1H),2.03–1.98(m,1H),1.86(dd,J＝31.1,14.9Hz,3H),1.74–1.65(m,3H),1.54(d,J＝15.5Hz,5H),1.43(dd,J＝24.6,12.6Hz,2H),1.22(d,J＝15.2Hz,2H),1.19–1.13(m,3H),1.04(dd,J＝14.9,9.0Hz,3H),0.97(d,J＝6.4Hz,3H),0.85(d,J＝6.4Hz,6H),0.75–0.70(m,6H),0.55(d,J＝11.7Hz,1H)。¹³C NMR(126MHz,DMSO)δ208.74,206.58,198.79,169.29,166.90,165.55,160.77,145.49,139.04,137.92,132.36,131.75,130.49,127.22,127.16,122.58,115.82,115.65,98.95,83.76,82.10,81.70,77.81,73.96,73.14,66.14,57.08,56.65,55.43,50.97,50.36,45.21,43.64,40.89,40.59,40.01,39.85,39.68,39.51,39.35,39.18,39.01,37.94,35.11,35.01,34.68,33.75,32.85,32.51,31.34,26.28,24.46,21.47,20.47,15.55,15.24,14.91,14.14,12.92,10.42。

Example 8: 28-O- (2- (4- (2-hydroxyisopropyl) -1H-1, 2, 3-triazol-1-yl) acetyl) oxy rapamycin (X-128)

Steps A-E are the same as the steps for synthesizing A-E in X-121.

Step F: preparation of 28-O- (2- (4- (2-hydroxyisopropyl) -1H-1, 2, 3-triazole-1-yl) acetyl) rapamycin oxide

0.1g (0.1mmol) of 28-O- (2-azidoacetyl) -oxorapamycin was poured into a 50ml flask, dissolved by adding 10ml of acetonitrile, and a catalytic amount of CuI was added, followed by DIPEA and finally 0.042g (0.5mmol) of 2-ethynyl isopropanol were added, reacted at room temperature for 1 hour and checked by TLC. After the reaction is finished, extracting with EA, and then sequentially using water, 1N HCl and saturated NaHCO₃And saturated NaCl washes, anhydrous Na₂SO₄Dehydrating, filtering, concentrating under reduced pressure, and drying to obtain crude product. Purification by silica gel column chromatography, gradient elution PE: EA: 3:1,2:1,1:1,1:2 gave 0.04g sample. Yield: 37.7 percent. MS (ESI) M/z 1089.6(M + Na)⁺。¹H NMR(600MHz,DMSO)δ7.81(s,1H),6.47(d,J＝1.1Hz,1H),6.40(dd,J＝14.5,11.3Hz,1H),6.22(dd,J＝14.7,10.7Hz,1H),6.14(dd,J＝26.7,12.2Hz,2H),5.42(dd,J＝17.3,7.7Hz,1H),5.34(d,J＝3.0Hz,1H),5.12(d,J＝6.4Hz,1H),5.07(d,J＝3.3Hz,1H),4.99–4.93(m,2H),4.61(d,J＝4.3Hz,1H),4.31(d,J＝3.9Hz,1H),4.30–4.24(m,1H),4.04–3.97(m,1H),3.63(d,J＝13.3Hz,1H),3.46(d,J＝12.5Hz,1H),3.31(s,3H),3.28(d,J＝4.4Hz,1H),3.20(s,3H),3.15(d,J＝4.5Hz,2H),3.05(s,3H),2.84–2.80(m,1H),2.67(dd,J＝17.7,2.8Hz,1H),2.43(dd,J＝17.7,8.3Hz,2H),2.21(d,J＝8.6Hz,1H),2.12(s,1H),2.04–2.01(m,1H),1.88–1.81(m,3H),1.77(s,3H),1.69–1.65(m,3H),1.62(s,3H),1.60–1.50(m,5H),1.47(s,6H),1.44–1.35(m,2H),1.22–1.14(m,3H),1.10–1.01(m,3H),0.99(d,J＝6.5Hz,3H),0.88(d,J＝6.5Hz,3H),0.84(d,J＝6.5Hz,3H),0.74(t,J＝6.0Hz,6H),0.58(d,J＝11.9Hz,1H)。¹³C NMR(151MHz,DMSO)δ209.52,207.48,199.15,169.35,167.31,166.20,156.21,138.28,132.17,127.51,122.30,99.30,84.25,73.61,67.43,57.78,57.24,55.99,51.17,50.57,45.50,40.41,40.27,40.13,40.00,39.86,39.72,39.58,35.63,32.81,31.07,29.97,26.53,22.09,20.99,16.07,15.88,13.98,10.82。

Example 9: 28-O- (2- (4- (hydroxyethyl) -1H-1, 2, 3-triazol-1-yl) acetyl) oxy rapamycin (X-129)

Steps A-E are the same as the steps for synthesizing A-E in X-121.

Step F: preparation of 28-O- (2- (4- (hydroxyethyl) -1H-1, 2, 3-triazol-1-yl) acetyl) oxy rapamycin

0.12g (0.12mmol) of 28-O- (2-azidoacetyl) -oxarapamycin was poured into a 50ml flask, dissolved by adding 10ml of acetonitrile, and a catalytic amount of CuI was added, followed by DIPEA and finally 0.042g (0.6mmol) of 2-ethynyl ethanol were added, reacted at room temperature for 1 hour and checked by TLC. After the reaction, the reaction mixture is extracted by EA, and then washed by water, 1N HCl and saturated NaHCO in sequence₃And saturated NaCl washes, anhydrous Na₂SO₄Dehydrating, filtering, concentrating under reduced pressure, and drying to obtain crude product. Purification by silica gel column chromatography, gradient elution PE: EA: 3:1,2:1,1:1,1:2 gave 0.05g of sample. Yield: 39.7 percent. MS (ESI) M/z 1057.6(M + Na)⁺。¹H NMR(600MHz,DMSO)δ7.77(s,1H),6.47(d,J＝1.4Hz,1H),6.39(dd,J＝14.7,11.3Hz,1H),6.25–6.19(m,1H),6.15–6.12(m,1H),6.11(d,J＝10.5Hz,1H),5.50–5.43(m,1H),5.31(t,J＝4.7Hz,2H),5.27(s,1H),5.11–5.06(m,1H),5.00–4.93(m,2H),4.71–4.67(m,2H),4.62–4.57(m,1H),4.34(d,J＝3.7Hz,1H),4.26(dd,J＝18.8,3.8Hz,1H),4.01(t,J＝9.9Hz,1H),3.66–3.60(m,1H),3.49–3.43(m,1H),3.32–3.29(m,3H),3.29(d,J＝4.4Hz,1H),3.20(s,3H),3.16(dd,J＝6.6,3.9Hz,2H),3.06(d,J＝4.7Hz,3H),2.84–2.80(m,1H),2.77(dd,J＝12.7,5.6Hz,2H),2.66(dd,J＝17.6,2.6Hz,1H),2.40(dd,J＝17.6,8.4Hz,1H),2.21(d,J＝8.8Hz,1H),2.17–2.12(m,2H),2.02(dd,J＝15.4,7.4Hz,1H),1.85(t,J＝12.3Hz,3H),1.79(s,3H),1.71–1.65(m,3H),1.62(s,3H),1.60–1.50(m,5H),1.42(dd,J＝26.9,14.2Hz,2H),1.29–1.23(m,2H),1.22–1.13(m,3H),1.10–1.01(m,3H),0.99(d,J＝6.5Hz,3H),0.86(d,J＝6.5Hz,3H),0.81(d,J＝6.5Hz,3H),0.74(d,J＝6.6Hz,6H),0.57(dd,J＝23.8,12.0Hz,1H)。¹³C NMR(151MHz,DMSO)δ207.48,199.15,191.74,169.65,167.00,166.02,144.91,138.18,132.20,127.51,123.81,99.46,84.29,82.27,77.95,74.24,73.27,66.56,60.83,57.22,55.96,51.41,50.29,45.67,40.41,40.27,40.13,39.99,39.85,39.71,39.57,35.42,32.90,31.79,29.84,29.58,22.04,16.09,15.77,15.45,14.36,13.43,10.87。

Example 10: 28-O- (2- (4- (methylene- (N, N-diethyl)) -1H-1, 2, 3-triazol-1-yl) -acetyl) oxy rapamycin (X-150)

Steps A-E are the same as the steps for synthesizing A-E in X-121.

Step F: preparation of 28-O- (2- (4- (methylene- (N, N-diethyl)) -1H-1, 2, 3-triazole-1-yl) -acetyl) oxygen rapamycin

0.2g (0.2mmol) of 28-O- (2-azidoacetyl) -oxarapamycin was poured into a 50ml flask, dissolved by adding 10ml of acetonitrile, and a catalytic amount of CuI was added, followed by DIPEA and finally 0.1g (1mmol) of N, N-diethylpropyne were added and reacted at room temperature for 1.5 hours, detected by TLC. After the reaction is finished, extracting with EA, and then sequentially using water, 1N HCl and saturated NaHCO₃And saturated NaCl washes, finally anhydrous Na₂SO₄Dehydrating, filtering, decompressing, concentrating and drying to obtain a crude product. Purification by silica gel column chromatography eluting with a gradient of PE: AC 2:1,1:1,1:2 gave 0.15g of sample. Yield: 67.6 percent. MS (ESI) M/z 1108.6(M + H)⁺。¹H NMR(600MHz,DMSO)δ7.91(s,1H),6.45(d,J＝22.6Hz,1H),6.39(dd,J＝14.3,11.5Hz,1H),6.21(dd,J＝24.1,9.5Hz,1H),6.16–6.12(m,1H),6.11(d,J＝9.9Hz,1H),5.47–5.41(m,1H),5.32(s,2H),5.00(d,J＝9.9Hz,1H),4.95(d,J＝3.7Hz,2H),4.59(d,J＝27.7Hz,1H),4.34(d,J＝3.4Hz,1H),4.27(d,J＝18.1Hz,1H),4.00(dd,J＝12.6,9.0Hz,1H),3.77(s,2H),3.63(d,J＝11.6Hz,1H),3.46(d,J＝12.8Hz,1H),3.30(d,J＝7.7Hz,3H),3.28(d,J＝8.1Hz,1H),3.20(s,3H),3.16(d,J＝12.6Hz,2H),3.05(s,3H),2.84–2.78(m,1H),2.65(d,J＝15.7Hz,1H),2.53–2.46(m,4H),2.39(dd,J＝17.5,8.3Hz,1H),2.23(s,1H),2.14(d,J＝18.0Hz,1H),2.04–1.99(m,1H),1.85(t,J＝11.8Hz,3H),1.79(s,3H),1.68(dd,J＝18.4,9.8Hz,3H),1.62(s,3H),1.56(dd,J＝18.9,12.3Hz,5H),1.41(dd,J＝21.6,12.6Hz,2H),1.31–1.24(m,2H),1.17(dd,J＝18.5,11.2Hz,3H),1.04(t,J＝6.9Hz,9H),0.99(d,J＝6.4Hz,3H),0.87(d,J＝6.3Hz,3H),0.82(d,J＝6.4Hz,3H),0.74(dd,J＝5.9,3.5Hz,6H),0.56(d,J＝11.8Hz,1H)。¹³C NMR(151MHz,DMSO)δ209.12,207.15,199.14,169.64,167.42,166.27,138.55,132.33,127.48,99.45,84.29,82.56,78.22,74.31,73.68,68.91,66.64,57.64,57.23,55.94,51.36,50.49,46.54,45.72,44.08,41.24,40.40,40.26,40.13,39.99,39.85,39.71,39.57,38.44,35.65,34.21,33.39,33.01,31.88,30.06,26.65,24.82,22.01,20.90,16.08,15.74,15.42,14.60,13.69,12.07,10.93。

Example 11: 28-O- (2- (4- ((2-fluorophenyl) aminomethylene) -1H-1, 2, 3-triazol-1-yl) -acetyl) oxorapamycin (X-151)

Steps A-E are the same as the steps for synthesizing A-E in X-121.

Step F: preparation of 28-O- (2- (4- ((2-fluorophenyl) aminomethylene) -1H-1, 2, 3-triazole-1-yl) -acetyl) rapamycin oxide

0.25g (0.25mmol) of 28-O- (2-azidoacetyl) -oxyrapamycin was poured into a 50ml flask, dissolved by adding 10ml of acetonitrile, and a catalytic amount of CuI was added, followed by DIPEA and finally 0.58g (3.9mmol) of 3- (2-fluorophenyl) imine propyne, reacted at room temperature for 4 hours and checked by TLC. After the reaction is finished, extracting with EA, and then sequentially using water, 1NHCl and saturated NaHCO₃And saturated NaCl washes, anhydrous Na₂SO₄Dehydrating, filtering, concentrating under reduced pressure, and drying to obtain crude product. Performing silica gel column chromatography, and performing gradient elution on PE (polyethylene) and EA (ethylene-acetic acid) in a ratio of 6: 1-2: 1 to obtain 0.2g of a sample. Yield: 69.7 percent. MS (ESI) M/z 1168.6(M + Na)⁺。¹H NMR(600MHz,DMSO)δ7.89(s,1H),7.20–7.12(m,1H),7.02–6.98(m,1H),6.93(d,J＝8.0Hz,1H),6.82–6.77(m,1H),6.57–6.52(m,1H),6.47(s,1H),6.39(dd,J＝14.7,11.3Hz,1H),6.25–6.19(m,1H),6.17–6.12(m,1H),6.12–6.09(m,1H),5.43(dd,J＝14.8,9.8Hz,1H),5.31(d,J＝5.4Hz,2H),5.09(d,J＝4.1Hz,1H),5.00(d,J＝10.0Hz,1H),4.96(d,J＝5.0Hz,1H),4.61(dd,J＝6.4,4.4Hz,1H),4.39(d,J＝5.8Hz,2H),4.01(dd,J＝19.4,9.2Hz,1H),3.95(dd,J＝6.3,1.1Hz,1H),3.63(d,J＝12.8Hz,1H),3.45(t,J＝14.0Hz,1H),3.31(s,3H),3.29(d,J＝3.9Hz,1H),3.19(t,J＝5.6Hz,3H),3.05(s,3H),2.85–2.80(m,1H),2.66(d,J＝15.6Hz,1H),2.43–2.37(m,2H),2.24–2.20(m,1H),2.16–2.12(m,1H),2.02(dd,J＝14.6,7.1Hz,1H),1.85(t,J＝13.1Hz,3H),1.70–1.64(m,3H),1.59–1.50(m,5H),1.40(dd,J＝27.2,13.9Hz,2H),1.27(dd,J＝14.2,9.2Hz,2H),1.22–1.16(m,3H),1.05(ddd,J＝16.3,10.9,9.1Hz,3H),0.99(d,J＝6.4Hz,3H),0.87(d,J＝6.4Hz,3H),0.82(d,J＝6.5Hz,3H),0.74(dd,J＝6.4,3.1Hz,6H),0.58(d,J＝11.8Hz,1H)。¹³C NMR(151MHz,DMSO)δ209.12,207.46,199.28,169.63,167.42,166.23,152.24,150.27,146.02,143.67,139.60,138.44,136.66,132.91,132.24,130.98,127.48,125.10,121.80,118.51,116.28,114.77,112.69,99.45,84.29,82.62,79.59,78.22,76.31,74.31,74.03,73.70,71.83,66.64,57.65,57.23,55.94,51.43,50.47,45.60,44.13,40.41,40.27,40.13,39.99,39.85,39.71,39.57,38.59,35.66,35.20,33.39,33.00,31.86,30.06,28.67,26.65,22.04,21.48,20.99,19.75,16.09,15.75,15.43,14.48,13.75,10.94,10.00。

Example 12: 28-O- (2- (4- ((2, 6-difluorophenyl) aminomethylene) -1H-1, 2, 3-triazol-1-yl) -acetyl) oxorapamycin (X-152)

Steps A-E are the same as the steps for synthesizing A-E in X-121.

Step F: preparation of 28-O- (2- (4- ((2, 6-fluorophenyl) aminomethylene) -1H-1, 2, 3-triazol-1-yl) -acetyl) oxygen rapamycin

0.25g (0.25mmol) of 28-O- (2-azidoacetyl) -rapamycin was poured into a 50ml flask, dissolved by adding 10ml of acetonitrile, and a catalytic amount of CuI was added, followed by DIPEA and finally 0.28g (1.68mmol) of 3- (2, 6-difluorophenyl) iminepropropyne, and reacted at room temperature for 5 hoursAnd (5) detecting by TLC. After the reaction is finished, extracting with EA, and then sequentially using water, 1N HCl and saturated NaHCO₃And saturated NaCl washes, anhydrous Na₂SO₄Dehydrating, filtering, concentrating under reduced pressure, and drying to obtain crude product. Purifying by silica gel column chromatography, and carrying out gradient elution on PE (polyethylene) and EA (ethylene-acetic acid) in a ratio of 6: 1-2: 1 to obtain 0.18g of sample. Yield: 61.9 percent. Ms (esi) M/z 1186.6(M + Na) +.1H NMR (600MHz, DMSO) δ 7.84(s,1H), 7.07-6.94 (M,2H),6.91(d, J ═ 7.7Hz,1H),6.66(s,1H),6.47(s,1H), 6.43-6.35 (M,1H), 6.24-6.17 (M,1H),6.12(d, J ═ 8.1Hz,2H), 5.47-5.38 (M,1H),5.28(d, J ═ 24.9Hz,2H),5.12(d, J ═ 31.5Hz,1H), 5.03-4.92 (M,2H),4.59(t, J ═ 16.4, 1H),4.48(d, J ═ 0, 3.65, 3.7H), 3.19 (d, 3.9H), 3.19H, 3.9H, 3H, 3.9H, 3, 3.9H, 3H, 3, 2H) 3.05(s,3H),2.82(s,1H),2.65(d, J ═ 16.2Hz,1H),2.39(dd, J ═ 17.5,8.8Hz,1H),2.22(s,1H),2.13(s,1H), 2.04-1.97 (m,1H),1.85(s,3H),1.77(s,3H),1.68(s,3H),1.62(s,3H), 1.59-1.50 (m,5H),1.42(d, J ═ 10.4Hz,2H),1.27(s,2H),1.17(dd, J ═ 22.2,8.5Hz,3H),1.05(d, J ═ 12.6Hz,3H),0.99(d, J ═ 1.5H), 0.84 (d, 3.84H), 3.89 (d, 3H), 3.6H, 3H, 0.9H, 3H, and 1.9 (d, J ═ 10.6 Hz, 1.6H).¹³C NMR(151MHz,DMSO)δ209.14,207.47,199.45,169.34,166.25,153.62,152.26,146.57,139.63,138.41,132.84,132.14,130.93,127.48,125.60,124.39,117.53,112.80,112.20,102.10,99.47,84.30,82.64,82.25,78.02,74.29,73.71,71.85,66.61,57.68,57.22,55.95,51.37,50.46,45.63,41.00,40.41,40.27,40.14,40.00,39.86,39.72,39.58,35.54,35.14,33.01,31.84,30.31,28.68,26.67,24.96,22.04,19.63,16.09,15.76,15.42,14.45,13.80,10.94,10.00。

Example 13: 28-O- (2- (4- (3-aminophenyl) -1H-1, 2, 3-triazol-1-yl) -acetyl) oxy rapamycin (X-153)

Steps A-E are the same as the steps for synthesizing A-E in X-121.

Step F: preparation of 28-O- (2- (4- (3-aminophenyl) -1H-1, 2, 3-triazole-1-yl) -acetyl) rapamycin oxide

0.25g (0.25mmol) of 28-O- (2-azidoacetyl) -oxorapamycin was poured into a 50ml flask, dissolved by adding 10ml of acetonitrile, and a catalytic amount of CuI was added, followed by DIPEA, and finallyThen, 0.293g (2.5mmol) of 3-aminophenylacetylene was added, and the reaction was carried out at room temperature for 4 hours, followed by TLC detection. After the reaction is finished, extracting with EA, and then washing with water, 1N HCl and saturated NaHCO in sequence₃And saturated NaCl washes, anhydrous Na₂SO₄Dehydrating, filtering, concentrating under reduced pressure, and drying to obtain crude product. Purifying by silica gel column chromatography, and carrying out gradient elution on PE (polyethylene) and EA (ethylene-acetic acid) in a ratio of 6: 1-3: 1 to obtain 0.22g of sample. Yield: 79.1 percent. MS (ESI) M/z 1136.6(M + Na)⁺。1HNMR(600MHz,DMSO)δ8.27(s,1H),7.12(s,1H),7.09–7.04(m,1H),6.95(t,J＝7.2Hz,1H),6.54(dd,J＝7.9,1.5Hz,1H),6.47(s,1H),6.39(dd,J＝14.6,11.4Hz,1H),6.21(dd,J＝14.5,10.8Hz,1H),6.11(dd,J＝14.5,11.0Hz,2H),5.43(dd,J＝14.9,9.7Hz,1H),5.35(dd,J＝10.3,7.4Hz,2H),5.16(s,2H),5.10(d,J＝9.1Hz,1H),5.01–4.95(m,2H),4.61–4.57(m,1H),4.34(d,J＝3.7Hz,1H),4.31–4.25(m,1H),4.02(t,J＝8.1Hz,1H),3.63(d,J＝12.9Hz,1H),3.47(d,J＝12.8Hz,1H),3.30(s,3H),3.27(s,1H),3.21(s,3H),3.05(d,J＝3.9Hz,3H),2.84–2.79(m,1H),2.70–2.65(m,1H),2.42(dd,J＝17.5,8.2Hz,1H),2.20(s,1H),2.16(d,J＝13.0Hz,1H),2.02(dd,J＝14.7,7.2Hz,1H),1.88–1.81(m,3H),1.79(s,3H),1.68(d,J＝11.2Hz,3H),1.61(d,J＝6.4Hz,3H),1.60–1.50(m,5H),1.46–1.36(m,2H),1.31–1.23(m,2H),1.22–1.13(m,3H),1.10–1.01(m,3H),0.98(d,J＝6.5Hz,3H),0.86(t,J＝5.7Hz,3H),0.77(d,J＝6.5Hz,3H),0.74(t,J＝6.9Hz,6H),0.57(d,J＝11.8Hz,1H)。¹³C NMR(151MHz,DMSO)δ209.32,207.41,199.30,169.74,167.40,166.16,149.44,147.53,139.52,138.41,132.88,132.24,131.46,130.99,129.72,127.50,122.71,114.08,113.55,110.99,99.47,84.28,82.62,78.27,74.43,73.67,66.65,57.64,57.18,55.94,55.37,51.41,50.74,45.71,44.10,41.16,40.70,40.40,40.26,40.12,39.98,39.85,39.71,39.57,38.45,35.67,35.53,35.21,34.25,33.37,33.01,31.88,30.23,30.14,26.80,24.97,22.03,20.99,16.08,15.81,15.46,14.56,13.67,10.95。

Example 14: 28-O- (2- (4-phenyl-1H-1, 2, 3-triazol-1-yl) propanoyl) oxy rapamycin (X-154)

Step A: preparation of 28-oxytrimethylsilyl-oxy rapamycin

10g (10.94mmol) of rapamycin was poured into a 250ml flask and EA was added115ml, stirring for 10min at room temperature, cooling to 0 ℃, adding 9.34g (137.19mmol) of imidazole, stirring for 5min, dropwise adding 9.3g (85.33mmol) of trimethylchlorosilane, separating out white solid in the dropwise adding process, completing the dropwise adding after 38min, and detecting by TLC after 7min, wherein the rapamycin is completely reacted. 66ml (33.37mmol) of 0.5NH were added₂SO₄Stirring, reacting for 3h, detecting by TLC, and completely obtaining a single protection product. Extracting with EA, sequentially adding water, 1N hydrochloric acid and saturated NaHCO₃Solution, saturated NaCl solution washing, anhydrous Na₂SO₄The reaction mixture was dehydrated, filtered with suction, and concentrated to dryness under reduced pressure to give 12.28g of a white solid. MS (ESI) M/z 1008.6(M + Na)⁺。¹H NMR(600MHz,DMSO)δ6.47(s,1H),6.41(dd,J＝14.3,11.5Hz,1H),6.23(dd,J＝24.6,13.7Hz,1H),6.15(dd,J＝21.1,10.9Hz,1H),6.10(d,J＝15.1Hz,1H),5.46(dd,J＝14.8,9.6Hz,1H),5.11(d,J＝10.2Hz,1H),5.01(d,J＝3.6Hz,1H),4.95(d,J＝4.8Hz,1H),4.68–4.62(m,1H),4.02(t,J＝9.3Hz,2H),3.87(d,J＝5.7Hz,1H),3.61(dd,J＝33.1,18.7Hz,1H),3.45(d,J＝12.6Hz,1H),3.33(s,3H),3.29(dd,J＝19.4,8.7Hz,1H),3.17(s,3H),3.14(t,J＝5.7Hz,2H),3.08(d,J＝21.0Hz,3H),2.82(dd,J＝15.5,8.0Hz,1H),2.72(dd,J＝33.3,11.9Hz,1H),2.50(d,J＝12.8Hz,1H),2.23(s,1H),2.13(d,J＝9.6Hz,1H),2.05–2.01(m,1H),1.85(d,J＝9.3Hz,1H),1.83(s,1H),1.77(s,3H),1.67(s,1H),1.64(s,3H),1.61(s,1H),1.38(d,J＝12.7Hz,1H),1.30(s,1H),1.24(d,J＝11.3Hz,1H),1.20(d,J＝11.1Hz,1H),0.99(d,J＝6.3Hz,3H),0.88(d,J＝6.3Hz,3H),0.83(d,J＝6.3Hz,3H),0.78(d,J＝6.5Hz,3H),0.74(d,J＝6.4Hz,3H),0.03–-0.05(m,9H)。¹³C NMR(151MHz,DMSO)δ209.74,207.76,199.26,169.67,167.43,139.57,138.33,136.86,132.82,130.92,127.54,125.72,99.47,85.45,84.32,82.63,77.98,74.17,73.69,71.82,66.65,57.47,57.31,56.29,55.95,51.46,45.47,44.09,40.68,40.41,40.27,40.13,39.99,39.85,39.71,39.58,38.57,35.54,35.24,34.07,33.39,33.03,31.89,30.05,28.67,26.85,24.93,22.20,21.47,20.94,19.74,16.08,15.95,15.51,14.07,13.67,11.04。

And B: preparation of 43-oxy-tert-butyldimethylsilyl-oxy rapamycin

12.28g (12.45mmol) 28-oxytrimethylsilyl-oxyRapamycin was poured into a 250ml flask, dissolved in 110ml N, N-Dimethylformamide (DMF), added with 24.54g (360.43mmol) of imidazole, dissolved at 6 ℃ and added with 14.72g (138.26mmol) of TBSCl in portions, reacted for 5h and checked by TLC. After the reaction, the mixture is extracted by EA, and water, 1N hydrochloric acid and saturated NaHCO are used for extracting the mixture in sequence₃Washing the solution with saturated NaCl solution, anhydrous Na₂SO₄Dehydrating, filtering, and concentrating under reduced pressure to dryness to obtain light yellow solid. Purifying by silica gel column chromatography, and performing gradient elution on PE (polyethylene) EA (ethylene oxide) in a ratio of 6: 1-4: 1 to obtain 6g of white solid with the yield: 46.3 percent. MS (ESI) M/z 1050.6(M + Na)⁺。¹H NMR(600MHz,DMSO)δ6.46(d,J＝1.4Hz,1H),6.44–6.37(m,1H),6.23(dd,J＝14.5,10.6Hz,1H),6.17–6.11(m,1H),6.11(d,J＝4.5Hz,1H),5.47(dd,J＝14.9,9.6Hz,1H),5.28(d,J＝4.5Hz,1H),5.11(d,J＝10.1Hz,1H),5.01–4.97(m,1H),4.95(d,J＝6.0Hz,1H),4.05–3.99(m,2H),3.95(d,J＝4.6Hz,1H),3.45(d,J＝12.7Hz,1H),3.33(s,4H),3.20–3.17(m,1H),3.16(s,3H),3.13(s,1H),3.06(s,3H),2.76–2.71(m,1H),2.44–2.39(m,1H),2.24–2.18(m,1H),2.14–2.08(m,1H),2.04(dd,J＝15.0,6.9Hz,1H),1.85–1.80(m,1H),1.74(s,4H),1.68(s,1H),1.68–1.66(m,1H),1.64(s,4H),1.60(d,J＝4.8Hz,1H),1.59–1.56(m,2H),1.53(s,2H),1.38(d,J＝10.5Hz,1H),1.29(d,J＝11.8Hz,3H),1.25(d,J＝11.1Hz,2H),0.98(d,J＝6.5Hz,3H),0.88(d,J＝6.5Hz,3H),0.86(s,9H),0.83(d,J＝6.4Hz,4H),0.78(d,J＝6.7Hz,3H),0.74(d,J＝6.7Hz,3H),0.04(d,J＝1.4Hz,6H)。¹³C NMR(151MHz,DMSO)δ210.93,207.98,199.35,169.68,167.48,139.83,138.36,137.66,132.82,130.87,127.49,125.44,99.51,85.96,84.08,82.76,76.24,75.75,74.13,66.67,57.58,57.39,55.94,51.25,45.71,44.00,40.53,40.41,40.27,40.13,39.99,39.86,39.72,39.58,38.78,35.89,35.74,35.29,33.95,32.79,31.52,30.14,26.94,26.72,26.23,24.96,22.15,20.89,18.32,16.04,15.24,13.92,13.88,10.96.

And C: preparation of 28-O- (3-bromopropionyl) -43-oxy-tert-butyldimethylsilyl-oxy rapamycin

6g (5.8mmol) 43-oxy-tert-butyldimethylsilyl-oxy-rapamycin was poured into a 250mL flask, dissolved with 100mL DCM, cooled to-2 ℃ and 18mL pyridine was added, and after 5min 9mL (104.2 m) was added dropwisemol) 3-bromopropionyl bromide, and detecting by TLC after finishing dropping for 40 min. After the reaction, the mixture was extracted with DCM, and water, 1N hydrochloric acid and saturated NaHCO were used in sequence₃Washing the solution with saturated NaCl solution, anhydrous Na₂SO₄Dehydrating, filtering, and concentrating under reduced pressure to dryness to obtain red black solid. Purifying by silica gel column chromatography, and carrying out gradient elution on PE (polyethylene) and EA (ethylene-acetic acid) in a ratio of 10: 1-4: 1 to obtain 4.5g of a sample with the yield of 60%. MS (ESI) M/z 1184.5(M + Na)⁺。¹H NMR(600MHz,DMSO)δ6.45(d,J＝3.8Hz,1H),6.41–6.35(m,1H),6.22(dd,J＝10.3,4.8Hz,1H),6.14(dd,J＝12.9,7.1Hz,1H),6.12(d,J＝7.0Hz,1H),5.51–5.47(m,1H),5.05(d,J＝11.3Hz,1H),5.02–4.96(m,2H),4.94(d,J＝5.4Hz,5H),4.57(s,1H),4.08–3.98(m,3H),3.91(d,J＝2.8Hz,1H),3.63(dd,J＝20.6,9.3Hz,1H),3.45(d,J＝12.6Hz,1H),3.33(dd,J＝2.6,1.5Hz,3H),3.32–3.27(m,1H),3.22–3.19(m,3H),3.17(d,J＝2.2Hz,3H),3.15–3.13(m,2H),3.05(d,J＝2.8Hz,3H),2.88–2.80(m,1H),2.67(dd,J＝9.2,6.2Hz,1H),2.39(dd,J＝16.1,9.2Hz,1H),2.12(d,J＝13.1Hz,1H),2.04–1.99(m,1H),1.90(d,J＝13.1Hz,1H),1.86–1.80(m,1H),1.78–1.73(m,1H),1.67(s,1H),1.63–1.59(m,1H),1.55(d,J＝12.8Hz,1H),1.53(s,1H),1.27(s,1H),1.26–1.22(m,1H),1.21–1.16(m,1H),0.98(d,J＝2.1Hz,3H),0.87(d,J＝1.9Hz,3H),0.85–0.83(m,12H),0.83–0.82(m,3H),0.78(d,J＝7.8Hz,3H),0.74(dd,J＝6.5,2.4Hz,3H),0.59(dd,J＝23.8,11.9Hz,1H),-0.03–-0.06(m,6H)。¹³C NMR(151MHz,DMSO)δ211.25,204.25,198.86,168.73,167.47,138.66,138.47,132.85,129.92,127.49,126.40,123.31,99.33,84.28,83.07,82.15,76.84,74.21,73.58,66.94,59.76,57.23,55.85,51.21,49.03,45.52,40.40,40.26,40.12,39.98,39.84,39.70,39.56,39.49,35.66,35.19,33.42,32.77,31.57,31.49,26.67,26.27,24.95,21.76,20.86,18.25,16.06,15.40,13.84,10.68。

Step D: preparation of 28-O- (3-bromopropionyl) -oxorapamycin

4.77g (4.15mmol) of 28-O- (3-bromopropionyl) -43-oxy-tert-butyldimethylsilyl-oxy-rapamycin are poured into a 250ml flask, dissolved with 70ml of Acetone (AC), cooled to 0 ℃ and 18ml (0.018mmol) of 2NH are added₂SO₄Solution, 18h after TLC detection. After the reaction is finished, extracting with EA, and sequentially usingWater, saturated NaHCO₃Washing the solution with saturated NaCl solution, anhydrous Na₂SO₄Dehydrating, filtering, and concentrating under reduced pressure to dryness to obtain light yellow solid. Purifying by silica gel column chromatography, eluting with PE (polyethylene) EA (6: 1) -1: 1 to obtain 3.8g of a sample, wherein the yield is as follows: 80.2 percent. MS (ESI) M/z 1170.4(M + Na)⁺。¹HNMR(600MHz,DMSO)δ6.43(d,J＝4.5Hz,1H),6.40(d,J＝3.6Hz,1H),6.22(d,J＝4.0Hz,1H),6.18–6.15(m,1H),6.12(s,1H),5.47(d,J＝5.3Hz,1H),5.08(s,1H),4.98(d,J＝3.8Hz,1H),4.94(s,1H),4.65(s,1H),4.02–4.00(m,2H),3.91(d,J＝2.7Hz,1H),3.62(d,J＝6.2Hz,1H),3.44(d,J＝2.1Hz,1H),3.33(s,3H),3.26(s,1H),3.22(s,3H),3.19(d,J＝2.1Hz,1H),3.05(s,3H),2.84–2.82(m,1H),2.73(dd,J＝8.8,5.2Hz,1H),2.51(dt,J＝3.6,1.8Hz,2H),2.46–2.42(m,1H),2.10(d,J＝11.8Hz,2H),1.82(s,3H),1.66–1.65(m,1H),1.61(s,3H),1.58(s,1H),1.41(s,1H),1.30(s,1H),0.99(d,J＝6.6Hz,3H),0.88–0.86(m,3H),0.84(dd,J＝4.8,3.8Hz,3H),0.77(d,J＝6.8Hz,3H),0.74(d,J＝6.6Hz,3H)。¹³C NMR(151MHz,DMSO)δ208.33,207.25,199.30,168.64,167.41,166.24,139.64,138.42,132.92,132.61,131.04,127.48,99.44,84.32,82.63,78.27,74.25,73.70,66.65,60.21,57.67,57.24,55.94,51.45,51.44,45.55,44.09,40.40,40.26,40.12,39.98,39.84,39.70,39.57,35.69,33.40,33.03,31.84,26.99,26.27,22.04,20.95,16.09,15.76,15.51,14.67,14.65,13.79,10.83。

Step E: preparation of 28-O- (3-azidopropionyl) -oxorapamycin

3.6g (3.48mmol) of 28-O- (3-bromopropionyl) -rapamycin was poured into a 250ml flask, 50ml of DMF and catalytic amount of KI were added, the flask was heated in an oil bath at 50 ℃ for 5min, and 0.9g (13.8mmol) of NaN was added₃And reacting for 1 hour, and detecting by TLC. After the reaction is completed, extracting with EA, sequentially adopting water, 1N hydrochloric acid and saturated NaHCO₃Washing the solution with saturated NaCl solution, anhydrous Na₂SO₄Dehydrating, filtering, concentrating under reduced pressure, and drying to obtain white solid. Purification by silica gel column chromatography, gradient elution PE: EA ═ 3:1,2:1,1:1, gave 1.6g sample, yield: 44.5 percent. MS (ESI) M/z 1033.5(M + Na)⁺。¹HNMR(600MHz,DMSO)δ6.45(s,1H),6.38(dd,J＝14.6,11.3Hz,1H),6.24(dd,J＝14.5,10.7Hz,1H),6.14(dd,J＝15.7,5.3Hz,1H),6.11(d,J＝4.6Hz,1H),5.47(dd,J＝15.0,9.7Hz,1H),5.34(t,J＝5.9Hz,1H),5.05(d,J＝10.1Hz,1H),4.98–4.93(m,2H),4.61(s,1H),4.36(d,J＝3.8Hz,1H),4.09–3.97(m,2H),3.95(d,J＝9.8Hz,1H),3.63(dd,J＝17.2,5.6Hz,1H),3.46(d,J＝13.9Hz,1H),3.33(s,3H),3.30–3.27(m,1H),3.27–3.24(m,1H),3.22(s,3H),3.13–3.08(m,1H),3.05(s,3H),2.86–2.82(m,1H),2.67(dd,J＝17.5,2.7Hz,1H),2.52–2.49(m,1H),2.44–2.36(m,2H),2.24(s,2H),2.13(d,J＝12.5Hz,1H),1.85(s,1H),1.82(s,3H),1.62(s,3H),1.59–1.55(m,4H),1.28(s,1H),1.00(d,J＝6.5Hz,6H),0.89–0.86(m,6H),0.84–0.82(m,1H),0.77(d,J＝6.7Hz,3H),0.74(d,J＝6.6Hz,3H)。¹³C NMR(151MHz,DMSO)δ210.42,207.45,199.27,168.67,167.83,167.43,139.61,138.41,132.92,132.58,131.04,127.49,99.45,84.33,82.64,82.41,78.01,74.33,73.70,66.65,57.64,57.22,55.93,51.42,49.87,45.62,44.12,41.28,40.97,40.74,40.39,40.25,40.11,39.97,38.83,39.70,39.56,38.52,35.66,35.59,35.20,34.13,33.40,33.06,31.86,26.82,24.95,22.02,20.95,16.08,15.78,15.42,14.65,13.71,10.81。

Step F: preparation of 28-O- (2- (4-phenyl-1H-1, 2, 3-triazole-1-yl) propionyl) rapamycin

0.12g (0.12mmol) of 28-O- (3-azidopropionyl) -rapamycin was poured into a 50ml flask, dissolved by adding 10ml of acetonitrile, and a catalytic amount of CuI was added, followed by DIPEA and finally 0.042g (0.6mmol) of phenylacetylene was added, reacted at room temperature for 1 hour, and detected by TLC. After the reaction is finished, extracting with EA, and then sequentially using water, 1N HCl and saturated NaHCO₃And saturated NaCl washes, anhydrous Na₂SO₄Dehydrating, filtering, concentrating under reduced pressure, and drying to obtain crude product. Purification by silica gel column chromatography, gradient elution PE: EA: 3:1,2:1,1:1,1:2 gave 0.05g of sample. Yield: 39.7 percent. MS (ESI) M/z 1120.6(M + Na)⁺。¹HNMR(500MHz,DMSO)δ8.33(s,1H),7.76(d,J＝1.0Hz,1H),7.84(s,1H),7.45(d,J＝7.4Hz,1H),7.42(s,1H),7.35(dd,J＝13.3,5.9Hz,1H),6.44(d,J＝1.1Hz,1H),6.36(dd,J＝14.3,11.4Hz,1H),6.22(dd,J＝17.0,6.4Hz,1H),6.19–6.11(m,1H),6.10(d,J＝4.1Hz,1H),5.63–5.48(m,1H),5.37(dd,J＝23.2,10.0Hz,2H),5.09(d,J＝7.3Hz,1H),5.03–4.94(m,2H),4.57–4.52(m,1H),4.35(d,J＝3.6Hz,1H),4.31–4.10(m,1H),4.06–3.96(m,1H),3.65(dd,J＝33.1,11.7Hz,1H),3.46(d,J＝13.5Hz,1H),3.29(d,J＝6.6Hz,3H),3.27–3.22(m,1H),3.21(s,3H),3.19–3.07(m,2H),3.03(d,J＝16.7Hz,3H),2.85–2.75(m,1H),2.72–2.60(m,1H),2.40(dd,J＝17.5,8.2Hz,1H),2.35–2.27(m,1H),2.16(dd,J＝27.4,14.1Hz,1H),2.02(dd,J＝15.4,7.9Hz,1H),1.90(d,J＝12.0Hz,1H),1.83(d,J＝13.9Hz,1H),1.74–1.64(m,3H),1.62–1.49(m,6H),1.41(dd,J＝27.3,13.6Hz,2H),1.24(dd,J＝13.6,7.8Hz,2H),1.20–1.10(m,3H),1.10–1.00(m,2H),0.98(t,J＝6.4Hz,3H),0.91–0.79(m,6H),0.79–0.69(m,6H),0.56(dd,J＝23.7,11.9Hz,1H)。¹³C NMR(126MHz,DMSO)δ207.76,208.89,199.66,168.24,167.89,164.58,146.35,139.05,137.91,132.36,131.75,130.51,128.79,127.85,126.99,125.66,125.16,122.65,98.95,83.77,82.11,81.75,77.81,73.95,73.15,66.14,57.10,56.65,55.42,50.93,50.34,45.22,43.64,40.85,40.64,40.01,39.84,39.67,39.51,39.34,39.17,39.01,37.93,35.12,35.01,34.68,33.76,32.85,32.51,31.35,29.73,28.64,26.18,24.45,22.47,21.48,20.46,19.45,18.99,15.55,15.24,14.93,14.11,13.01,11.10,10.42。

Test example 1: antitumor Activity test

Step 1 preparation of samples

10.0mg of each compound sample was accurately weighed, dissolved in 1ml of dimethyl sulfoxide, and stored at-20 ℃ for later use.

Step 2 tumor cell culture

Human non-small cell lung cancer cell strain A549, human prostate cancer cell strain PC-3, and human gastric cancer cell strain AGS, cultured in F12 culture medium containing 10% fetal calf serum and 80000 U.L-1 gentamycin, and human breast cancer cell strain T47D cultured in F12 culture medium containing 10% fetal calf serum and 80000 U.L^-1Culturing human esophageal cancer cell strain ECA109 and human renal cancer cell strain 769-P in DEME culture medium containing gentamicin in 10% fetal calf serum and 80000 U.L^-1Gentamicin in RPMI medium at 37 deg.C with 5% CO₂Under saturated humidity conditions.

Step 3, sulforhodamine B (SRB) protein staining method is used for detecting anti-cancer effect of compound

10000 cancer cells/well of logarithmic growth phase were inoculated to 96-well culture plates, respectively, at 37 ℃ with 5% CO₂Culturing for 24h in respective corresponding culture medium under saturated humidity condition, adding various compounds diluted to required different concentration gradients by the corresponding culture medium, taking rapamycin with the same concentration gradient as a positive control, and taking no drug-added culture medium as a blank control. Each concentration of each compound was provided with 3 replicate wells. Culturing for 48h under the same conditions, fixing the cells with 10% trichloroacetic acid of precooled volume fraction, standing for 1h at 4 ℃, washing with distilled water for 5 times, and naturally drying at room temperature. Adding 0.4% SRB solution prepared from 1% glacial acetic acid, dyeing at room temperature for 15min, removing supernatant, washing with 1% acetic acid for 5 times, and naturally drying at room temperature. Finally, 10 mmol. L of the solution is added^-1Tris solution (pH 10.5) was used, and OD was measured at a wavelength of 540 nm. The cell growth inhibition ratio (%) (1-experimental group/blank control group) × 100%, and the IC of each compound on cancer cells was calculated₅₀。

Step 4 statistical analysis

The experiments were repeated 3 times, data are expressed as ± S, data were analyzed using SPSS20 software, single factor variance test was used for the comparisons between groups, group t test was used for the comparisons between two groups, P <0.05 indicated that the differences were statistically significant. The results are shown in Table 1.

TABLE 1 IC50 values for the compounds of the examples of the invention

Table 1 shows that the compounds listed in the examples of the present invention all have inhibitory activity against the 6 tumor cell lines tested (except that X125 does not inhibit human breast cancer strain T47D and X129 does not inhibit human breast cancer strain T47D and human esophageal cancer strain ECA-109). The inhibition activity of most compounds on human non-small cell lung cancer strain A549, human gastric cancer strain AGS and human breast cancer strain T47D is stronger than that of rapamycin, and the activity on human prostate cancer strain PC-3 is relatively weak.

Although specific embodiments of the invention have been described above, it will be understood by those skilled in the art that the specific embodiments described are illustrative only and are not limiting upon the scope of the invention, and that equivalent modifications and variations can be made by those skilled in the art without departing from the spirit of the invention, which is to be limited only by the appended claims.

Claims

1. A rapamycin triazole derivative is characterized in that: is a compound represented by the following formula I:

or a pharmaceutically acceptable salt thereof, wherein,

n is 1 or 2;

w is

R is hydrogen or (C1-C4) alkyl;

r1 is hydroxy (C1-C4) alkyl, phenyl, or anilinomethyl, wherein the phenyl ring on the phenyl or phenylaminomethyl group is optionally substituted with 1-4 identical or different R2 groups;

r2 is selected from: hydrogen, halogen, amino, (C1-C6) alkyl, (C1-C4) alkoxy.

2. The rapamycin triazole derivative according to claim 1, wherein: the (C1-C4) alkyl is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl and tert-butyl.

3. The rapamycin triazole derivative according to claim 1, wherein: the halogen is selected from fluorine, chlorine, bromine and iodine.

4. The rapamycin triazole derivative according to claim 1, wherein: which is a compound selected from the group consisting of;

28-O- (2- (4- ((2,4 dichlorophenyl) aminomethylene) -1H-1, 2, 3-triazol-1-yl) acetyl) oxy rapamycin

28-O- (2- (4-phenyl-1H-1, 2, 3-triazol-1-yl) acetyl) oxy rapamycin

28-O- (2- (4- (3-methylphenyl) -1H-1, 2, 3-triazol-1-yl) acetyl) oxy rapamycin

28-O- (2- (4- (2-chlorophenyl) -1H-1, 2, 3-triazol-1-yl) acetyl) oxy rapamycin

28-O- (2- (4- (4-methoxyphenyl) -1H-1, 2, 3-triazol-1-yl) acetyl) oxy rapamycin

28-O- (2- (4- (4-methylphenyl) -1H-1, 2, 3-triazol-1-yl) acetyl) oxy rapamycin

28-O- (2- (4- (4-fluorophenyl) -1H-1, 2, 3-triazole-1-yl) acetyl) rapamycin oxide

28-O- (2- (4- (2-hydroxyisopropyl) -1H-1, 2, 3-triazol-1-yl) acetyl) oxy rapamycin

28-O- (2- (4- (hydroxyethyl) -1H-1, 2, 3-triazol-1-yl) acetyl) oxy rapamycin

28-O- (2- (4- ((2-fluorophenyl) aminomethylene) -1H-1, 2, 3-triazol-1-yl) -acetyl) oxy rapamycin

28-O- (2- (4- ((2, 6-difluorophenyl) aminomethylene) -1H-1, 2, 3-triazol-1-yl) -acetyl) oxorapamycin

28-O- (2- (4- (3-aminophenyl) -1H-1, 2, 3-triazol-1-yl) -acetyl) oxy rapamycin

28-O- (2- (4-phenyl-1H-1, 2, 3-triazol-1-yl) propionyl) rapamycin.

5. A pharmaceutical composition comprising the rapamycin triazole derivative as claimed in any one of claims 1 to 4, and optionally a pharmaceutically acceptable carrier or adjuvant.

6. The use of the rapamycin triazole derivatives as claimed in any one of claims 1 to 4 in the preparation of anti-tumor medicaments.

7. Use according to claim 6, characterized in that: the tumor is selected from: lung cancer, esophageal cancer, stomach cancer, prostate cancer, leukemia, and kidney cancer.

8. A process for the preparation of the rapamycin triazole derivatives as claimed in any one of claims 1 to 4, wherein: comprises the following steps;

(1) a compound of the following formula A-2 is prepared from the following compound A-1:

(2) reacting the A-2 compound with an R1 substituted alkyne compound with cuprous iodide and N, N-diisopropylethylamine to provide a compound of formula I:

9. the method of claim 8, wherein: the specific preparation method of the A-2 compound comprises the following steps:

(1) a-1 compound is used as a raw material to react with trimethylchlorosilane to obtain a B-1 compound, and then the B-1 compound reacts with tert-butyldimethylsilyl chloride to obtain a compound B-2 with the following formula:

(2) b-2 Compounds and B-3 Compounds

Esterification to give the following compound of formula B-4:

(3) deprotection of the B-4 compound affords compound B-5:

(4) the compound B-5 is reacted with sodium azide to give the compound A-2.