CN113717245A - EGFR degradation agent containing 2,8, 9-trisubstituted-9H-purine structural fragment, and salt and application thereof - Google Patents

Abstract

The invention discloses an EGFR degradation agent containing 2,8, 9-trisubstituted-9H-purine structural fragment, salt and application thereof, belonging to the technical field of anti-cancer drugs. The compounds have novel structures, have remarkable activity of degrading Epidermal Growth Factor Receptor (EGFR) tyrosine kinase, have remarkable inhibitory activity on the growth of HCC827(EGFR single mutation) and H1975(EGFR double mutation) of human lung cancer cells, can be used for treating cancers related to EGFR mutation, and have easily available synthetic raw materials and easily realized synthetic methods.

Description

EGFR degradation agent containing 2,8, 9-trisubstituted-9H-purine structural fragment, and salt and application thereof

Technical Field

The invention belongs to the technical field of anti-cancer drugs, and particularly relates to an EGFR degradation agent containing a 2,8, 9-trisubstituted-9H-purine structural fragment, and a salt and an application thereof.

Background

The main treatment means of cancer still include surgical treatment, radiation treatment and drug treatment, but the drug treatment is mainly used to a great extent. The traditional antitumor drug has strong activity, but lacks selectivity and has high toxicity, and patients cannot take the drug for a long time. Therefore, research and development of new anticancer drugs are of great significance.

In recent years, with the progress of tumor molecular biology research, the pathogenesis of tumors is more understood, and a plurality of new targets of the action of anti-cancer drugs, such as Epidermal Growth Factor Receptor (EGFR) tyrosine kinase, PI3Ks, BTK and the like, are found. In non-small cell lung cancer, about 50% of patients exhibit mutations in EGFR. In response to this feature, first generation EGFR tyrosine kinase inhibitors such as gefitinib, erlotinib, second generation EGFR tyrosine kinase inhibitor afatinib, third generation EGFR tyrosine kinase inhibitor oxitinib have been developed for use as anti-cancer drugs. However, in some patients after about one year of kinase inhibitor application, the gene is easy to mutate, so that acquired drug resistance is generated, and the anti-tumor effect of the kinase inhibitor is greatly reduced. Therefore, the development of new antitumor therapies is of great significance.

In recent years, protein degradation technology is expected to become another heavy therapy following successful anticancer therapies such as small molecule inhibitors, immunotherapy, and the like. Proteolytic targeting complexes (PROTACs) are bifunctional molecules consisting of a ligand that binds to a target protein, a linker (linker), and an E3 ligase ligand. One end of the PROTAC is combined with a target Protein, the other end of the PROTAC is combined with E3 ligase (E3 ligase), after the ternary complex is formed, the target Protein is ubiquitinated and finally degraded by a ubiquitin-proteasome system (UPS), and the PROTAC molecules can be released after Protein degradation and enter the next degradation cycle. Compared with small-molecule inhibitors, ProTAC has unique advantages, including targeting some non-druggable proteins, overcoming drug resistance, generating required pharmacological effects with low drug concentration, etc. In recent years, the PROTAC technology is greatly developed and widely applied, more than twenty target proteins are degraded, the anti-cell proliferation activity of part of PROTACs reaches picomolar level and is far higher than that of corresponding small-molecule inhibitors, and the prospect is great.

EGFR is a transmembrane protein and can be degraded by PROTAC, but no good effect is achieved at present, and particularly, the research of transmembrane protein degradation agents for double-mutation EGFR (L858R/T790M) still faces huge challenges.

For EGFR single mutant, degradation agents containing quinazoline (A in figure 1) and pyrido [3,4-d ] pyrimidine (B in figure 1) fragments have been studied in the literature, and the degradation agents only have good degradation effect on single-mutation EGFR, but the degradation activity on double-mutation EGFR is not reported. For EGFR double mutants, the literature reports that degradation agents containing quinazoline (D in figure 1) and pyrido [2,3-D ] pyrimidine (E in figure 1) fragments have weak activity. The inventors' laboratory also reported EGFR mutant degraders containing purine fragments (C in fig. 1). Although these double mutant EGFR degraders have some effect, the activity against tumor cell proliferation is generally poor, staying at the micromolar level. Recently, European Journal of Medicinal Chemistry (2021, 218, 113328) reported that an EGFR double mutant degradant (F in FIG. 1) based on canertinib, and that compound F induced double mutant EGFR degradation activity and cell level antiproliferative activity both reached nanomolar levels. Even in this way, the EGFR double-mutant degrading agent is still not fully developed, and the EGFR double-mutant degrading agent with good activity and high selectivity is found to be expected to solve the problem of drug resistance of the first generation of EGFR inhibitors after use and avoid the third mutation of the EGFR after the third generation of EGFR inhibitors are used.

Disclosure of Invention

In order to overcome the disadvantages of the prior art, the invention aims to provide an EGFR degradation agent containing a 2,8, 9-trisubstituted-9H-purine structural fragment, and a salt and application thereof. The compound has a novel structure, obviously improves the activity of degrading EGFR tyrosine kinase single mutation (del19) and double mutation (L858R/T790M), has obvious activity of resisting human lung cancer cell HCC827 and H1975 proliferation, can be applied to the preparation of anticancer pharmaceutical preparations, and has easily obtained synthetic raw materials and easily realized synthetic method.

In order to achieve the purpose, the invention adopts the following technical scheme to realize the purpose:

the invention discloses an EGFR degradation agent containing 2,8, 9-trisubstituted-9H-purine structural fragment, the structural formula of which is as follows:

in the formula, R¹Is acryloyl pyrrolidinyl or acryloyl piperidinyl; r²Is hydrogen or fluorine; r³Is methyl or hydrogen; the linker arm is an alkanoyl group.

Preferably, R¹Is N-acryloyl-3-pyrrolidinyl or N-acryloyl-3-piperidinyl.

Further preferably, the chiral center in the N-acryloyl-3-pyrrolidinyl and N-acryloyl-3-piperidinyl groups is S-type.

Preferably, the linker arm is a 5-substituted pentanoyl, 6-substituted hexanoyl, 7-substituted heptanoyl, 8-substituted octanoyl, 9-substituted nonanoyl, 6- (2-substituted acetamido) hexanoyl, or 7- (2-substituted acetamido) heptanoyl.

The invention also discloses a pharmaceutically acceptable salt of the EGFR degradation agent containing the 2,8, 9-trisubstituted-9H-purine structural fragment, wherein the pharmaceutically acceptable salt is hydrochloride, hydrobromide, nitrate, phosphate, sulfate, acetate, fumarate, malate, citrate, tartrate, maleate, lactate, citrate, camphorsulfonate, benzoate, gluconate, glutamate, isethionate, succinate or methanesulfonate.

The invention also discloses an application of the EGFR degradation agent containing the 2,8, 9-trisubstituted-9H-purine structural fragment or the pharmaceutically acceptable salt of the EGFR degradation agent containing the 2,8, 9-trisubstituted-9H-purine structural fragment in preparation of an anti-cancer medicinal preparation.

Preferably, the anti-cancer pharmaceutical preparation is an anti-cancer pharmaceutical preparation capable of degrading a single mutated EGFR or capable of degrading a double mutated EGFR.

Further preferably, the single mutated EGFR is carried by human lung cancer cell HCC 827; the double mutated EGFR is carried by human lung cancer cells H1975.

Preferably, the anticancer pharmaceutical preparation is an injection, a tablet or a capsule.

Further preferably, each anti-cancer pharmaceutical preparation contains 10-300 mg of the EGFR degradation agent of the 2,8, 9-trisubstituted-9H-purine structural fragment or the pharmaceutically acceptable salt thereof in each preparation.

Compared with the prior art, the invention has the following beneficial effects:

the EGFR degradation agent or the salt compound thereof containing the 2,8, 9-trisubstituted-9H-purine structural fragment has the activity of degrading Epidermal Growth Factor Receptor (EGFR) tyrosine kinase. The compound structure contains acrylamide fragments and can be covalently combined with EGFR mutants. The strong binding force with the EGFR mutant ensures that the compound is easy to promote the formation of a ternary complex (EGFR: PROTAC: E3), so that the EGFR mutant is effectively ubiquitinated and then degraded. Has obvious antiproliferative effect on EGFR single mutation human lung cancer cell HCC827 and EGFR double mutation human lung cancer cell H1975, IC₅₀The value is nanomolar, and can be used for treating cancers related to EGFR mutation.

The EGFR degradation agent containing the 2,8, 9-trisubstituted-9H-purine structural fragment and the salt compound thereof can be applied to preparation of anti-cancer pharmaceutical preparations, wherein each medicine preparation contains 10-100 mg. When the active compound provided by the invention is used for preparing an anticancer medicine preparation, the medicine can be prepared into injection, tablets or capsules. The pharmaceutical preparations can be prepared according to the conventional preparation process of various preparations. The preferable content is 50-100 mg for a tablet or capsule. The oral preparation of the invention can contain pharmaceutic adjuvants including additives, stabilizers, solubilizers, lubricants, disintegrating agents and the like, such as starch, dextrin, glucose, lactose, cellulose, polyvinylpyrrolidone, cross-linked polyvinylpyrrolidone, pectin, cyclodextrin, Tween-80, polyvinyl alcohol, magnesium stearate, talcum powder and the like.

Drawings

FIG. 1 is a literature report of EGFR degraders; wherein A is a degradation agent containing quinazoline fragments aiming at EGFR single mutants; b is a degradation agent containing pyrido [3,4-d ] pyrimidine fragments; c is an EGFR mutant degrading agent containing purine fragments; d is a degradation agent containing quinazoline fragments aiming at EGFR double mutants; e is a degradation agent containing pyridone [2,3-d ] pyrimidine fragments; f is an EGFR double-mutant degrading agent based on canertinib;

FIG. 2 is a scheme for the synthesis of-9H-purines containing an acrylamido fragment at the 9-position; wherein, the first step is that b removes protective group under the existence of acid to obtain c; step two, the step c is that d is obtained through acrylation; step three, d is hydrolyzed to obtain e in the presence of alkali; step four, in the presence of a condensing agent, condensing e and f or g to obtain a target object T;

FIG. 3 is the activity of compounds to induce degradation of EGFR mutants; wherein A is the compound for inducing EGFR^L858R/T790MActivity of double mutant degradation; b is compound induced EGFR^del19Activity of single mutant degradation;

FIG. 4 shows that Compound 3 induces EGFR^L858R/T790MThe aging relationship of degradation;

FIG. 5 is a dose-effect relationship of Compound 3 in inducing degradation of EGFR mutants; wherein A is compound 3 for inducing EGFR^{L858R /T790M}Dose-effect relationship of degradation; b is compound 3 for inducing EGFR^del19Dose-effect relationship of degradation;

figure 6 is the effect of compound 3 on wild-type EGFR in a431 cells;

FIG. 7 is a graph of the effect of Compound 3 on phosphorylation of EGFR and its downstream effector molecules; wherein A is the EGFR of the compound 3^L858R/T790MAnd the effect of phosphorylation of downstream effector molecules; b is compound 3 to EGFR^del19And the effect of phosphorylation of downstream effector molecules.

Detailed Description

In order to make the technical solutions of the present invention better understood, the technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.

It should be noted that the terms "first," "second," and the like in the description and claims of the present invention and in the drawings described above are used for distinguishing between similar elements and not necessarily for describing a particular sequential or chronological order. It is to be understood that the data so used is interchangeable under appropriate circumstances such that the embodiments of the invention described herein are capable of operation in sequences other than those illustrated or described herein. Furthermore, the terms "comprises," "comprising," and "having," and any variations thereof, are intended to cover a non-exclusive inclusion, such that a process, method, system, article, or apparatus that comprises a list of steps or elements is not necessarily limited to those steps or elements expressly listed, but may include other steps or elements not expressly listed or inherent to such process, method, article, or apparatus.

The invention is described in further detail below with reference to fig. 2:

1. specific examples of Synthesis of Compounds 1 to 7

The structural formula and the number of the representative compound are as follows:

examples of the synthesis of the above compounds, whose structures were characterized by HRMS, are given below.

The first embodiment is as follows: synthesis of (2S, 4R) -1- ((S) -2- (7- (4- (4- ((9- ((S) -1-acryloyl-3-pyrrolidinyl) -8-phenylamino-9H-2-purinyl) amino) phenyl) -1-piperazinyl) heptanoylamino) -3- (3, 3-dimethyl) -butyryl) -4-hydroxy-N- (4- (4-methyl-5-thiazolyl) benzyl) pyrrolidine-2-carboxamide (Structure 1)

The method comprises the following steps: synthesis of (S) -2- ((4- (4- (7-ethoxy-7-oxoheptyl) -1-piperazinyl) phenyl) amino) -8-phenylamino-9- (3-pyrrolidinyl) -9H-purine (c1)

References j.med.chem.2012,55,10685-10699, eur.j.med.chem.2020,186, 111888 and eur.j.med.chem.2020,208,112781 synthesize intermediate b 1; reference eur.j. med.chem.2020,186,111888 prepared c1 in 60% yield.

Step two: synthesis of (S) -2- ((4- (4- (7-ethoxy-7-oxoheptyl) -1-piperazinyl) phenyl) amino) -8-phenylamino-9- (N-acryloyl-3-pyrrolidinyl) -9H-purine (d1)

C1(0.27g, 0.57mmol) was suspended in acetone (2mL), cooled in an ice bath and stirred for 5min, then acryloyl chloride (70 μ L, 0.86mmol) was dissolved in acetone (3mL) and the mixture was dropped, after dropping, the ice bath was removed, stirred at room temperature for 10min, then several drops of saturated sodium carbonate solution were added to quench the reaction, the solvent was evaporated, water (10mL) and saturated sodium carbonate solution (20mL) were added to the residue, DCM was extracted (5 × 30 mL), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, sodium sulfate was filtered off, the filtrate was evaporated and separated by silica gel column chromatography (DCM: MeOH 30:1-10:1), the product was crystallized with ethyl acetate to give d1, yield 48%.

Step three: synthesis of (S) -7- (4- (4- (8-phenylamino-9- (N-acryloyl-3-pyrrolidinyl) -9H-2-purinylamino) phenyl) -1-piperazinyl) heptanoic acid (e1)

D1(0.10g, 0.15mmol) was suspended in a mixed solvent of absolute ethanol (4mL) and water (2mL), cooled in an ice bath and stirred for 5min, then NaOH (0.12g, 3.0mmol) solid particles were added and stirred for 2h while maintaining the ice bath. After the reaction is finished, 3 mol.L is used^-1The pH was adjusted to 7 with HCl, the solvent was evaporated to dryness, water (3mL) was added and 1 mol. L was added^-1Adjusting the pH value to 4 by HCl, separating out a solid, filtering, washing by water, and drying to obtain e1 with the yield of 75%.

Step four: synthesis of (2S, 4R) -1- ((S) -2- (7- (4- (4- ((9- ((S) -1-acryloyl-3-pyrrolidinyl) -8-phenylamino-9H-2-purinyl) amino) phenyl) -1-piperazinyl) heptanoylamino) - (3, 3-dimethyl) -butyryl) -4-hydroxy-N- (4- (4-methyl-5-thiazolyl) benzyl) pyrrolidine-2-carboxamide (1)

Reference eur.j.med.chem.2020,208,112781 preparation 1 in 29% yield. Hrms (esi); calculated values: 1050.55001[ M + H]⁺And (3) measuring the following values: 1050.55514.

example two: synthesis of (2S, 4R) -1- ((S) -2- (7- (4- (4- ((9- ((S) -1-acryloyl-3-piperidinyl) -8-phenylamino-9H-2-purinyl) amino) phenyl) -1-piperazinyl) heptanoylamino) - (3, 3-dimethyl) butyryl) -4-hydroxy-N- (4- (4-methyl-5-thiazolyl) benzyl) pyrrolidine-2-carboxamide (Structure 2)

Compound 2 was prepared as in example one. Hrms (esi): calculated values: 1064.56566[ M + H]⁺And (3) measuring the following values: 1064.57031.

example three: synthesis of (2S, 4R) -1- ((S) -2- (8- (4- (4- ((9- ((S) -1-acryloyl-3-piperidinyl) -8-phenylamino-9H-2-purinyl) amino) phenyl) -1-piperazinyl) octanoylamino) - (3, 3-dimethyl) butyryl) -4-hydroxy-N- (4- (4-methyl-5-thiazolyl) benzyl) pyrrolidine-2-carboxamide (Structure 3)

Compound 3 was prepared as in example one. Hrms (esi): calculated values: 1078.58131[ M + H]⁺And (3) measuring the following values: 1078.58234.

example four: synthesis of (2S, 4R) -1- ((S) -2- (6- (2- (4- (4- ((9- ((S) -1-acryloyl-3-piperidinyl) -8-phenylamino-9H-2-purinyl) amino) phenyl) -1-piperazinyl) acetamido) hexanoylamino) - (3, 3-dimethyl) butyryl) -4-hydroxy-N- (4- (4-methyl-5-thiazolyl) benzyl) pyrrolidine-2-carboxamide (Structure 4)

Compound 4 was prepared as in example one. Hrms (esi): calculated values: 1107.57147[ M + H]⁺And (3) measuring the following values: 1107.57479.

example five: synthesis of (2S, 4R) -1- ((S) -2- (7- (2- (4- (4- ((9- ((S) -1-acryloyl-3-piperidinyl) -8-phenylamino-9H-2-purinyl) amino) phenyl) -1-piperazinyl) acetamido) heptanoylamino) - (3, 3-dimethyl) butyryl) -4-hydroxy-N- (4- (4-methyl-5-thiazolyl) benzyl) pyrrolidine-2-carboxamide (Structure 5)

Compound 5 was prepared as in example one. Hrms (esi): calculated values: 1121.58712[ M + H]⁺And (3) measuring the following values: 1121.58943.

example six: synthesis of (2S, 4R) -1- ((S) -2- (8- (4- (4- ((9- ((S) -1-acryloyl-3-piperidinyl) -8-phenylamino-9H-2-purinyl) amino) phenyl) -1-piperazinyl) octanoylamino) - (3, 3-dimethyl) butyryl) -4-hydroxy-N- ((S) -1- (4- (4-methyl-5-thiazolyl) phenyl) ethyl) pyrrolidine-2-carboxamide (Structure 6)

Compound 6 was prepared as in example one. Hrms (esi): calculated values: 1092.59696[ M + H]⁺And (3) measuring the following values: 1092.60196.

example seven: synthesis of (2S, 4R) -1- ((S) -2- (8- (4- (4- ((9- ((S) -1-acryloyl-3-piperidinyl) -8- (4-fluorophenylamino) -9H-2-purinyl) amino) phenyl) -1-piperazinyl) octanoylamino) - (3, 3-dimethyl) butyryl) -4-hydroxy-N- (4- (4-methyl-5-thiazolyl) benzyl) pyrrolidine-2-carboxamide (Structure 7)

Compound 7 was prepared as in example one. Hrms (esi): calculated values: 1096.57189[ M + H]⁺And (3) measuring the following values: 1096.57643.

2. cellular activity

In order to verify the anticancer activity of the EGFR degradation agent containing the 2,8, 9-trisubstituted-9H-purine structural fragment and the salt thereof, the compounds 1-7 were tested on three human cancer cells HCC827 (EGFR) by using an in vitro MTT method and using AZD9291 (Oxitinib) as a positive control drug^del19)，H1975(EGFR^L858R/T790M) And A431 (EGFR)^WT) The growth inhibitory effect of (1).

The verification method comprises the following steps: culturing tumor cells in RPMI1640 medium containing 10% fetal calf serum and containing penicillins 100 U.mL^-1Streptomycin 100. mu.g.mL^-1At 37 ℃ and 5% CO₂Subculturing in an incubator. Taking 0.25% pancreatin to digest adherent tumor cells, preparing cell suspension from RPMI1640 culture solution containing 10% fetal bovine serumAt a concentration of 2.5X 10⁴Individual cells/ml. mu.L (containing about 5000 tumor cells) per well of 96-well culture plate was inoculated and cultured at 37 ℃ for 24 hours. The administration groups were added with different concentrations of drugs, each set at 0.0003, 0.001, 0.003, 0.01, 0.03, 0.1, 0.3, 1, 3 and 10. mu. mol. L ^-110 concentration gradients, 3 parallel wells per group. Adding solvent with the same volume as the medicine into the control group, placing at 37 deg.C and 5% CO₂Culturing for 72h in incubator, discarding culture solution, adding 20 μ L of 5 mg/mL^-1After incubation for 4h, the supernatant was discarded, 200. mu.L of DMSO was added to each well, and the Optical Density (OD) was measured at 490nm using a microplate reader after gentle shaking.

And (4) calculating a result: taking tumor cells treated by solvent control as a control group, and calculating the inhibition rate of the drug on the tumor cells according to the following formula:

and further using linear regression to determine the median Inhibitory Concentration (IC)₅₀) The results are shown in Table 1.

TABLE 1 antiproliferative activity (IC) of compounds on three human cancer cells₅₀，nmol·L^-1)

IC in watch₅₀As an average of three tests, "ND" means not determined.

The data in table 1 show that the compound provided by the invention has a remarkable inhibitory effect on the proliferation of H1975 and HCC827 cells, but has a very weak effect on A431 cells, which indicates that the compound has strong cell selectivity.

3. Western Blotting analysis

In order to further verify the activity of the synthesized-9H-purine compounds containing acrylamide fragments at the 9-position in the invention for inducing EGFR degradation, the influence of the compounds on EGFR level and downstream signal transduction is measured by using a Western Blotting method.

The method comprises the following steps: h1975 cells were arranged at 8X 10⁵One well per well was inoculated in six well plates at 37 ℃ with 5% CO₂Culturing for 24 hours in an incubator, adding 2 mu L of DMSO solutions of compounds 1-4 with different concentration gradients, continuously culturing for 24 hours, cracking cells by using a lysate containing a protease inhibitor and a phosphatase inhibitor, centrifuging at 12000rpm for 20min, taking supernatant, adding a loading buffer, uniformly mixing, heating in a water bath kettle at 95 ℃ for 10min for denaturation, separating proteins by using 8% SDS-PAGE according to the sample amount of 25 mu g per hole, transferring to a PVDF membrane, sealing the PVDF membrane in 5% skimmed milk for 1 hour, incubating overnight at 4 ℃ in a primary antibody solution, incubating in a secondary antibody solution for 1 hour at room temperature, and finally exposing and photographing, wherein the result is shown in figures 3-7, wherein figure 3 shows that the compounds can promote the degradation of EGFR mutants; FIG. 4 illustrates that Compound 3 degrades EGFR 48h after administration^L858R/T790MThe degradation rate reaches the maximum; FIG. 5 shows that Compound 3 has a strong effect of inducing EGFR degradation, and is a DC against double-and single-mutated EGFR₅₀Are respectively 1.56 and 0.49 nmol.L^-1(ii) a FIG. 6 shows that the compounds do not degrade wild-type EGFR and have better selectivity. These results are consistent with the results of cell viability; figure 7 illustrates that degradant 3 inhibits transduction of its signaling pathway by degrading EGFR in H1975 cells and HCC827 cells.

The test methods not described in detail in the present invention are those commonly used in the art or existing methods, and are not described herein.

The above-mentioned contents are only for illustrating the technical idea of the present invention, and the protection scope of the present invention is not limited thereby, and any modification made on the basis of the technical idea of the present invention falls within the protection scope of the claims of the present invention.

Claims (10)

1. An EGFR degradation agent containing a 2,8, 9-trisubstituted-9H-purine structural fragment, characterized by the structural formula:

in the formula, R¹Is acryloyl pyrrolidinyl or acryloyl piperidinyl; r²Is hydrogen or fluorine; r³Is methyl or hydrogen; the linker arm is an alkanoyl group.

2. The EGFR degrader comprising a 2,8, 9-trisubstituted-9H-purine structural fragment of claim 1, wherein R is¹Is N-acryloyl-3-pyrrolidinyl or N-acryloyl-3-piperidinyl.

3. The EGFR degradation agent comprising a 2,8, 9-trisubstituted-9H-purine structural fragment according to claim 2, wherein the chiral center in the N-acryloyl-3-pyrrolidinyl and N-acryloyl-3-piperidinyl groups is S-type.

4. The EGFR degradation agent according to claim 1, comprising a 2,8, 9-trisubstituted-9H-purine structural fragment, wherein the linker arm is a 5-substituted pentanoyl group, a 6-substituted hexanoyl group, a 7-substituted heptanoyl group, an 8-substituted octanoyl group, a 9-substituted nonanoyl group, a 6- (2-substituted acetamido) hexanoyl group or a 7- (2-substituted acetamido) heptanoyl group.

5. The pharmaceutically acceptable salt of an EGFR degrading agent containing a 2,8, 9-trisubstituted-9H-purine structural fragment according to any of claims 1 to 4, wherein the pharmaceutically acceptable salt is a hydrochloride, hydrobromide, nitrate, phosphate, sulfate, acetate, fumarate, malate, citrate, tartrate, maleate, lactate, citrate, camphorsulfonate, benzoate, gluconate, glutamate, isethionate, succinate or mesylate salt.

6. Use of an EGFR-degrading agent containing a 2,8, 9-trisubstituted-9H-purine structural fragment according to any one of claims 1 to 4 or a pharmaceutically acceptable salt of an EGFR-degrading agent containing a 2,8, 9-trisubstituted-9H-purine structural fragment according to claim 5 for the preparation of an anti-cancer pharmaceutical preparation.

7. The use of claim 6, wherein said anti-cancer drug formulation is an anti-cancer drug formulation capable of degrading a single mutated EGFR or capable of degrading a double mutated EGFR.

8. The use according to claim 7, wherein the single mutant EGFR is carried by human lung cancer cell HCC 827; the double mutated EGFR is carried by human lung cancer cells H1975.

9. The use of claims 6 to 8, wherein the anticancer pharmaceutical formulation is an injection, a tablet or a capsule.

10. The use according to claim 9, wherein each dose, tablet or granule of the anti-cancer pharmaceutical formulation comprises 10 to 300mg of the EGFR-degrading agent of 2,8, 9-trisubstituted-9H-purine structural fragment, or a pharmaceutically acceptable salt thereof.

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