CN113735828B

CN113735828B - Compound for targeted degradation of EGFR (epidermal growth factor receptor), and preparation method and application thereof

Info

Publication number: CN113735828B
Application number: CN202111043085.8A
Authority: CN
Inventors: 伍小云; 李钦兰; 郭倩; 万山河; 李中皇; 张嘉杰
Original assignee: Southern Medical University
Current assignee: Southern Medical University
Priority date: 2021-09-07
Filing date: 2021-09-07
Publication date: 2022-10-28
Anticipated expiration: 2041-09-07
Also published as: CN113735828A

Abstract

The invention belongs to the field of medicines, and particularly relates to a compound for targeted degradation of EGFR, and a preparation method and application thereof. The compound for targeted degradation of EGFR is a compound shown as a general formula I or a pharmaceutically acceptable salt thereof:

the compound has high expression on EGFR ^L858R/T790M The H1975 cell strain and the PC-9 cell strain with high expression 19 exon deletion have stronger inhibition activity, have weaker activity to A549 cell strain with high expression wild type EGFR, show better selectivity, can effectively inhibit the growth of lung cancer cells, and can be applied to the preparation of medicaments for treating, preventing, delaying and assisting in treating or treating diseases related to EGFR activity excess and medicaments for treating tumor diseases.

Description

Compound for targeted degradation of EGFR (epidermal growth factor receptor), and preparation method and application thereof

Technical Field

The invention belongs to the field of medicines, and particularly relates to a compound for targeted degradation of EGFR, and a preparation method and application thereof.

Background

An Epidermal growth factor receptor (EGFR for short) belongs to a member of receptor tyrosine kinase family (ErbB), belongs to a tyrosine kinase type receptor, is mainly located in a cell plasma membrane, mediates proliferation, survival and migration of cells, and possibly participates in development of non-small cell lung cancer when mutation occurs. With the development of molecular biology, researchers found that EGFR is highly expressed in 20-80% of patients with non-small cell lung cancer (NSCLC), is the most common driver gene in the treatment target of advanced NSCLC, and has become an attractive target for developing anticancer drugs for treating non-small cell lung cancer.

First-generation EGFR inhibitors represented by Gefitinib (Gefitinib) and Erlotinib (Erlotinib) have good therapeutic effects on NSCLC carrying EGFR-sensitive mutations. However, the problem of drug resistance is rapidly emerging, wherein 50% of the drug resistance mechanism is the T790M mutation (threonine at position 790 is replaced by methionine) at the binding site of Adenosine Triphosphate (ATP), also called gated mutation (EGFRT 790M), which changes the affinity of ATP, resulting in the inability of EGFR inhibitors to effectively block the signaling pathway to generate drug resistance. To overcome T790M resistance, second and third generation EGFR inhibitors, such as Afatinib (Afatinib) and ositinib (Osimertinib), were developed. The two inhibitors are both irreversible inhibitors, and the tail group of the inhibitor and the sulfhydryl group of Cys797 undergo Michael addition reaction to form a covalent bond, so that the combination of ATP and EGFR is prevented, and the purpose of treating cancer is achieved. However, it was soon discovered in clinical studies that mutation of Cys797 to Ser (C797S) in the ATP binding region prevents the inhibitor from forming a covalent bond with the kinase, resulting in the development of resistance, which is the major resistance mechanism. Unfortunately, no effective drug that can overcome the resistance to C797S is currently available clinically.

The target protein degradation chimeras (PROTACs) are novel target protein degradation compounds developed based on the Ubiquitin Proteasome System (UPS) of the cell, and utilize a bifunctional chimeric small molecule to simultaneously combine target protein and intracellular E3 ligase, so that the target protein is ubiquitinated and marked, and enters a proteasome pathway to be degraded. PROTACs consist of three parts: a ligand that binds to the target protein, a ligand that binds to the E3 ubiquitin ligase, and a connecting chain therebetween. Crews et al developed PROTAC intercalator molecules with Gefitinib, afatinib, lapatinib as warheads, respectively, and the synthesized PROTAC could penetrate cell membrane and induce EGFR degradation at low concentration. Thus, PROTACs, as a potential therapeutic approach, are widely used in drug design procedures by targeting specific proteins for degradation. Compared with the traditional small-molecule inhibitor, the targeted EGFR small-molecule PROTAC degrading agent has the following obvious advantages: 1) Has the catalytic degradation function: the degradation of the PROTAC to the target protein is a catalytic process and can be recycled, and the property ensures that the PROTAC can generate good pharmacological activity only under a lower drug dosage; 2) Can overcome the drug resistance: the main reason for the drug resistance of the small molecule inhibitor of the EGFR is point mutation, so that the inhibitor loses the inhibition effect on the target protein, and the PROTAC technology can degrade the target protein and overcome the drug resistance generated by point mutation to a certain extent.

Therefore, it is necessary to provide a compound or a drug having an excellent EGFR degradation effect and a good antitumor activity.

Disclosure of Invention

The present invention is directed to solving at least one of the problems of the prior art described above. Therefore, the compound can be combined with target protein EGFR and intracellular E3 ligase simultaneously, so that the target protein is marked by ubiquitination, the EGFT target protein is degraded through a proteasome approach, and the compound has good antitumor activity and huge application prospects in the field of medical treatment.

Specifically, the first aspect of the present invention provides a compound represented by general formula I or a pharmaceutically acceptable salt thereof:

wherein L contains at least one of an alkyl group, a carbonyl group, an ether bond, and an amine group.

According to some embodiments of the invention, the pharmaceutically acceptable salts of the compounds include: addition salts with the following acids: hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, ethanesulfonic, p-toluenesulfonic, benzenesulfonic, theadisulfonic, acetic, propionic, lactic, trifluoroacetic, maleic, citric, fumaric, oxalic, tartaric, or benzoic acid; and acid salts of hydrochloric, hydrobromic, sulfuric, tartaric, phosphoric, benzenesulfonic, theadisulfonic, acetic, pyruvic, lactic, trifluoroacetic, maleic, citric, fumaric, oxalic, tartaric, or thionic acids.

According to some embodiments of the invention, L is

In the formula, n is an integer of 1-20, and the wave shape on the left in the formula represents connection with the group on the left of L in the general formula I; the right waved form represents the attachment to the group to the right of L in formula I.

According to some embodiments of the invention, L is

Wherein n is an integer of 2 to 15.

According to some embodiments of the invention, the compound is

A second aspect of the present invention provides a process for the preparation of the above compound or a pharmaceutically acceptable salt thereof, comprising the steps of:

(1) Respectively synthesizing a ligand derivative of a target protein EGFR and a ligand derivative of a target cereblon protein;

the step of synthesizing the ligand derivative of the target protein EGFR and the step of synthesizing the ligand derivative of the targeting cereblon protein have no sequence in execution time, and the step of synthesizing the ligand derivative of the target protein EGFR can be executed firstly, or the step of synthesizing the ligand derivative of the targeting cereblon protein can be executed firstly;

(2) And reacting the ligand derivative of the target protein EGFR with the ligand derivative of the target cereblon protein to obtain the compound.

According to some embodiments of the invention, the ligand derivative of the target protein EGFR and the ligand derivative of the targeted cereblon protein are reacted to obtain the compound.

According to some embodiments of the invention, the ligand derivative of the target protein EGFR:

the ligand derivative of the targeted cereblon protein is as follows:

according to some embodiments of the invention, the cereblon protein targeting ligand derivative is the compound of formula Z-3, and n is an integer from 2 to 6.

According to some embodiments of the invention, the cereblon protein targeting ligand derivative is the compound of formula Z-4, and n is an integer from 3 to 12.

According to some embodiments of the invention, the cereblon protein targeting ligand derivative is the compound of formula Z-5, and n is an integer from 2 to 6.

According to some embodiments of the invention, the cereblon protein targeting ligand derivative is the compound of formula Z-6, and n is an integer from 1 to 3.

According to some embodiments of the invention, the compound of formula Z-1 and the compound of formula Z-4 are subjected to amide condensation to give the compound, wherein L is

n is an integer of 3 to 12.

According to some embodiments of the invention, the compound of formula Z-2 and the compound of formula Z-3 are subjected to amide condensation to give said compound, wherein L is

n is an integer of 1 to 20.

According to some embodiments of the invention, the compound of formula Z-2 and the compound of formula Z-5 are subjected to amide condensation to give said compound, wherein L is

n is an integer of 1 to 20.

According to some embodiments of the invention, the compound of formula Z-1 and the compound of formula Z-6 are subjected to amide condensation to give said compound, wherein L is

n is an integer of 1 to 20.

According to some embodiments of the invention, the compound of formula Z-7:

and N- (3-aminophenyl) acrylamide to obtain the compound of the formula Z-1.

According to some embodiments of the invention, the compound of formula Z-8:

and carrying out hydrolysis reaction in the presence of lithium hydroxide to obtain the compound shown in the formula Z-2.

According to some embodiments of the invention, the compound of formula Z-9:

and reacting with diamine compound protected by single BOC to obtain the compound shown in the formula Z-3.

According to some embodiments of the invention, the compound of formula Z-10:

and reacting the diacid chlorides with different carbon chain lengths to obtain the compound of the formula Z-4.

According to some embodiments of the invention, the compound of formula Z-11:

and carrying out amide condensation on the diamine compound protected by the single BOC to obtain the compound shown in the formula Z-5.

According to some embodiments of the invention, the compound of formula Z-12 is reacted with a compound of formula i:

activating to obtain the compound of the formula Z-6.

According to some embodiments of the invention, a compound of formula Z-9 is reacted with tert-butyl glycinate in the presence of N, N-diisopropylethylamine to provide the compound of formula Z-11.

According to some embodiments of the invention, the compound of formula Z-9 is reacted with different ethanolamines to provide said compound of formula Z-12.

According to some embodiments of the invention, the compound of formula Z-13:

obtaining the compound of the formula Z-10 through nitro reduction reaction;

according to some embodiments of the invention, 3-fluorophthalic anhydride is acylated with 3-amino-2,6-piperidinedione hydrochloride in the presence of potassium acetate to provide said compound of formula Z-9;

according to some embodiments of the invention, the acylation of 3-nitrophthalic anhydride with 3-amino-2,6-piperidinedione hydrochloride in the presence of potassium acetate affords the compound of formula Z-13.

According to some embodiments of the invention, the compound of formula Z-14:

reacting with 2,4-dichloro-5- (trifluoromethyl) pyrimidine in the presence of triethylamine to obtain the compound of formula Z-7.

According to some embodiments of the invention, the compound of formula Z-15:

with N- (3-aminophenyl) in the presence of trifluoroacetic acid) And (3) carrying out reaction on acrylamide to obtain the compound of the formula Z-8.

According to some embodiments of the invention, the compound of formula Z-7 is subjected to a debioc reaction in trifluoroacetic acid, dichloromethane, and then reacted with ethyl bromoacetate in the presence of potassium carbonate, N-dimethylformamide at 50 ℃ to provide the compound of formula Z-15.

According to some embodiments of the invention, the compound of formula Z-16:

and carrying out nitro reduction under the catalysis of palladium carbon and hydrogen atmosphere to obtain the compound of the formula Z-14.

According to some embodiments of the invention, 1-tert-butoxycarbonylpiperazine is reacted with 5-nitro-2-fluoroanisole to provide the compound of formula Z-16.

In a third aspect, the present invention provides a medicament, which comprises the above compound or a pharmaceutically acceptable salt thereof, and an adjuvant.

According to some embodiments of the invention, the pharmaceutically acceptable excipient is selected from at least one of a filler, a lubricant, a disintegrant, a binder, or a glidant.

According to some embodiments of the present invention, the pharmaceutical dosage form is at least one selected from the group consisting of tablets, capsules, granules, injections, powder injections, eye drops, smears, suppositories, ointments, aerosols, powders, drop pills, emulsions, films, transdermal patches, controlled-release preparations, and nano-preparations.

The fourth aspect of the present invention provides the use of the above-mentioned compound or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment or prevention of a neoplastic disease.

According to some embodiments of the invention, the neoplastic disease is breast cancer, colon cancer, prostate cancer, pancreatic cancer, liver cancer, ovarian cancer, acute myelogenous leukemia, multiple myeloma, renal cancer, gastric cancer or non-small cell lung cancer.

According to some embodiments of the invention, the neoplastic disease is non-small cell lung cancer.

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

(1) The invention uses CRBN ligand pomalidomide and derivatives thereof as E3 ligase ligand, and couples EGFR inhibitor and E3 ligase through different types of L with different chain lengths to prepare the compound for EGFR ^L858R/T790M The H1975 cell strain and the PC-9 cell strain highly expressing the 19 exon deletion EGFR have stronger inhibitory activity;

(2) The compound provided by the invention has weaker activity on A549 cell strains of high-expression wild EGFR and shows better selectivity;

(3) The compound provided by the invention has obvious anti-lung cancer cell proliferation activity; can be used for preparing medicaments for treating and/or preventing and/or delaying and/or assisting in treating and/or treating diseases with over-high activity of EGFR.

Detailed Description

In order to make the technical solutions of the present invention more apparent to those skilled in the art, the following examples are given for illustration. It should be noted that the following examples are not intended to limit the scope of the claimed invention.

The starting materials, reagents or apparatuses used in the following examples are, unless otherwise specified, either commercially available from conventional sources or can be obtained by known methods.

Example 1

A compound of formula I or a pharmaceutically acceptable salt thereof,

wherein L is

n is 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12.

The preparation method of the compound comprises the following steps:

(1) Synthesis of Compounds of formula Z-16

70mL of N, N-dimethylformamide, 5g of 5-nitro-2-fluoroanisole (29.2 mmol), 6.5g of 1-tert-butoxycarbonylpiperazine (35 mmol) and 8.1g of potassium carbonate (58.4 mmol) are sequentially added into a 200mL round-bottom flask to obtain a reaction solution; reacting the reaction solution at the constant temperature of 80 ℃ for 20 hours; the reaction solution was cooled to room temperature, followed by sequentially adding ice water, filtering, washing with water, and drying to give a compound of formula Z-16 (9.76 g) in a yield of 99% as a yellow solid.

(2) Synthesis of Compounds of formula Z-14

Adding 5g of the compound (14.8 mmol) of the formula Z-16, 300mg of 5% palladium carbon and 180mL of methanol into a reaction kettle in sequence, and reacting for 18h; the reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure to give a compound of formula Z-14 (3.97 g) in 87% yield as a purple solid.

(3) Synthesis of Compounds of formula Z-7

Dropwise adding a zinc chloride diethyl ether solution (1M, 16.25mmol and 16mL) into a 2,4-dichloro-5- (trifluoromethyl) pyrimidine (0.9mL and 6.5 mmol) tert-butyl alcohol and 1,2-dichloroethane (1:1 and 15 mL) solution at 0 ℃ under the protection of nitrogen, and reacting for 1.5h to obtain a reaction solution; 2g of tert-butyl alcohol of the compound of the formula Z-14 (6.5 mmol) and a solution of 1,2-dichloroethane are added dropwise to the reaction solution and the reaction is continued for 1.5h; 1mL of tertiary butanol of triethylamine (7.15 mmol) and a solution of 1,2-dichloroethane are added dropwise to the reaction solution, and after the addition, the reaction solution reacts at room temperature for 18 hours, so that volatile substances in the reaction solution are volatilized in a ventilated place; vacuum decompression drying the reaction liquid; to the dried product was added 100mL of methanol, refluxed at 90 ℃ for 2h and then left overnight at room temperature, and filtered to give the compound of formula Z-7 (2.4 g) in a yield of 75% as a green solid.

(4) Synthesis of Compounds of formula Z-17

3g of N-BOC-m-phenylenediamine (14.4 mmol), 4mL of triethylamine (28.8 mmol) and 40mL of dichloromethane are mixed and sequentially added into a 200mL round-bottom flask; the reaction solution was cooled to 0 ℃ and 1.8mL of acryloyl chloride (21.6 mmol) was added; gradually increasing the temperature to room temperature, and reacting for 24 hours; adding 14mL of trifluoroacetic acid, and reacting at room temperature overnight; the reaction solution was evaporated to remove the solvent, the residue was dissolved in ethyl acetate, washed with a saturated sodium bicarbonate solution, washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (15% to 30%) to give the compound of formula Z-17 (1.2 g) in 60% yield as a pale yellow solid.

Characterization of the NMR spectrum of the compound of formula Z-17 is: ¹ H NMR(400MHz，DMSO-d ₆ )δ9.80(s，1H)，6.99(s，1H)，6.93(t，J＝7.9Hz，1H)，6.76(d，J＝7.9Hz，1H)，6.43(dd，J＝17.0，10.1Hz，1H)，6.28(d，J＝7.7Hz，1H)，6.21(d，J＝18.6Hz，1H)，5.70(d，J＝10.1Hz，1H)，5.07(s，2H)。

(5) Synthesis of Compounds of formula Z-1

10mL of a methanolic hydrochloric acid solution (the volume ratio of methanol to hydrochloric acid is 1.5), 200mg of a compound of formula Z-7 (0.41 mmol), and 80mg of a compound of formula Z-17 (0.49 mmol) were sequentially added to a 100mL round-bottomed flask, and the mixture was refluxed at 60 ℃ for 6 hours; the solvent was directly distilled off from the reaction solution to obtain a compound of the formula Z-1 (0.120 g) in a yield of 57%.

The compound of formula Z-1 is a brown solid and the mass spectrum results are: ESI-MS: m/z 515.14[ 2 ] M + H] ⁺ 。

(6) Synthesis of Compounds of formula Z-13

60mL of acetic acid, 5g of 3-nitrophthalic anhydride (25.9 mmol), 4.27g of 3-amino-2,6-piperidone hydrochloride (25.9 mmol) and 6.36g of potassium acetate (64.8 mmol) are mixed and added into a 200mL round-bottomed flask, and the temperature is raised to 90 ℃ for reaction for 17 hours; the reaction solution was cooled to room temperature, and ice water was sequentially added thereto, followed by filtration, washing with water, and drying to give a compound of formula Z-13 (5.8 g) in a yield of 74.0% as a purple solid.

(7) Synthesis of Compounds of formula Z-10

Mixing the reaction product obtained in the step (6), a palladium-carbon catalyst (Pd/C) and 80mL of N, N-dimethylformamide in a reaction kettle, and introducing hydrogen to react for 18 hours; the reaction solution was extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, and the solvent was evaporated to give a compound of formula Z-10.

The compound of formula Z-10 is a yellow solid; the characterization result of the mass spectrum is ESI-MS: m/z 274.96[ m ] +H ]] ⁺ (ii) a The characterization result of the nuclear magnetic resonance hydrogen spectrum is as follows: ¹ H NMR(400MHz，DMSO-d ₆ )δ11.10(s，1H)，7.48(d，J＝8.2Hz，1H)，7.11–6.95(m，2H)，6.53(s，2H)，5.13–5.01(m，1H)，2.90(d，J＝6.7Hz，1H)，2.65–2.53(m，2H)，2.04(s，1H)。

(8) Synthesis of Compounds of formula Z-4

(8.1) Synthesis of a Compound of formula Z-40

10mL of acetic acid solution, 200mg of the compound of formula Z-10 (0.732 mmol), 417mg of glutaric anhydride (3.66 mmol) and 430mg of potassium acetate (4.329 mmol) were sequentially added to a 50mL round bottom flask, reacted at 90 ℃ for 17h under nitrogen protection, and the completion of the reaction was monitored by TLC; the reaction solution was diluted with water, extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (dichloromethane: methanol =10 1) to obtain a compound of formula Z-40 (80 mg) with a yield of 28%.

The compound of formula Z-40 is a white solid; the mass spectrum characterization result is ESI-MS: m/z 410.05[ 2 ], [ M ] +Na ]] ⁺ (ii) a The nuclear magnetic resonance characterization result is as follows: ¹ H NMR(400MHz，DMSO-d ₆ )δ11.15(s，1H)，9.78(s，1H)，8.43(d，J＝8.4Hz，1H)，7.88–7.79(m，1H)，7.62(d，J＝7.2Hz，1H)，5.15(dd，J＝12.7，5.4Hz，1H)，2.91(ddd，J＝18.5，13.8，5.3Hz，2H)，2.65–2.53(m，2H)，2.29(t，J＝7.4Hz，2H)，2.23(d，J＝7.3Hz，1H)，2.11–2.01(m，1H)，1.84(p，J＝7.4Hz，2H)。

(8.2) Synthesis of Compound of formula Z-41

8mL of thionyl chloride and 485mg of adipic acid (3.32 mmol) were sequentially added to a 50mL round-bottom flask, and refluxed at 80 ℃ overnight; distilling the reaction liquid under reduced pressure to remove excessive thionyl chloride to obtain crude adipoyl chloride; 140mg of the compound of formula Z-10 (0.512 mmol) was added to the crude adipoyl chloride, 10mL of tetrahydrofuran was added simultaneously, the reaction was refluxed at 80 ℃ for 12h, monitored by TLC; the reaction mixture was purified by column chromatography on silica gel to give a compound of the formula Z-41 (167 mg) in a yield of 76%.

The compound of formula Z-41 is a milk white solid, and the mass spectrum characterization result is ESI-MS: m/Z424.77 [2 ], [ M ] +Na ]] ⁺ (ii) a The result of the nuclear magnetic resonance hydrogen spectrum characterization is ¹ H NMR(400MHz，DMSO-d ₆ )δ＝12.04(s，4H)，11.15(s，1H)，9.71(s，1H)，8.47(d，J＝8.4Hz，1H)，7.84(t，J＝7.9Hz，1H)，7.62(d，J＝7.2Hz，1H)，5.15(dd，J＝12.6，5.3Hz，1H)，2.96–2.85(m，1H)，2.62(d，J＝19.0Hz，1H)，2.30–2.23(m，3H)，2.06(dd，J＝12.8，6.3Hz，1H)，1.65–1.54(m，4H)。

(8.3) Synthesis of a Compound of formula Z-42

The preparation method is different from the step (8.2) in that pimelic acid is used for replacing adipic acid to obtain the compound of the formula Z-42, and the yield is 37%.

The compound of formula Z-42 is a milky white solid; the mass spectrum characterization result is as follows: ESI-MS: m/z 438.45[ 2 ] M + Na] ⁺ (ii) a The result of hydrogen spectrum characterization of nuclear magnetic resonance is ¹ H NMR(400MHz，DMSO-d ₆ )δ12.02(s，1H)，11.15(s，1H)，9.70(s，1H)，8.47(d，J＝8.4Hz，1H)，7.83(t，J＝7.9Hz，1H)，7.62(d，J＝7.2Hz，1H)，5.15(dd，J＝12.7，5.3Hz，1H)，2.97–2.86(m，1H)，2.68–2.53(m，2H)，2.47(t，J＝7.4Hz，2H)，2.22(t，J＝7.3Hz，2H)，2.11–2.03(m，1H)，1.68–1.60(m，2H)，1.58–1.51(m，2H)，1.34(dd，J＝11.1，3.7Hz，2H)。

(8.4) Synthesis of a Compound of formula Z-43

The preparation method is different from the step (8.2) in that suberic acid is used for replacing adipic acid to obtain the compound of the formula Z-43, and the yield is 72.6%.

The compound of formula Z-43 is a milky white solid and mass spectrometry results are: ESI-MS: m/z 453.15[ 2 ], [ M ] +Na ]] ⁺ (ii) a The result of the nuclear magnetic resonance hydrogen spectrum characterization is ¹ H NMR(400MHz，DMSO-d ₆ )δ11.15(s，1H)，9.70(s，1H)，8.47(d，J＝8.4Hz，1H)，7.83(t，J＝7.9Hz，1H)，7.62(d，J＝7.2Hz，1H)，5.15(dd，J＝12.7，5.4Hz，1H)，2.95–2.85(m，1H)，2.59(s，1H)，2.46(t，J＝7.4Hz，3H)，2.20(t，J＝7.3Hz，2H)，2.08(dd，J＝9.2，3.6Hz，1H)，1.61(q，J＝7.0Hz，2H)，1.50(q，J＝7.0Hz，2H)，1.35–1.28(m，4H)。

(8.5) Synthesis of Compound of formula Z-44

The difference in the preparation process compared to step (8.2) is that azelaic acid is used instead of adipic acid to give the compound of formula Z-44.

The compound of formula Z-44 is a milky white solid; the mass spectrum characterization result is ESI-MS, m/z 466.75, [ m ] +Na] ⁺ (ii) a The result of hydrogen spectrum characterization of nuclear magnetic resonance is ¹ H NMR(400MHz，DMSO-d ₆ )δ11.98(s，1H)，11.15(s，1H)，9.70(s，1H)，8.48(d，J＝8.4Hz，1H)，7.84(t，J＝7.9Hz，1H)，7.62(d，J＝7.3Hz，1H)，5.15(dd，J＝12.8，5.3Hz，1H)，2.90(t，J＝15.0Hz，1H)，2.62(d，J＝18.5Hz，2H)，2.47(t，J＝7.4Hz，2H)，2.20(t，J＝7.3Hz，2H)，2.11–2.04(m，1H)，1.70–1.56(m，2H)，1.52–1.46(m，2H)，1.31(s，6H)。

(8.6) Synthesis of a Compound of formula Z-45

Compared with the step (8.2), the preparation method is different in that sebacic acid is used for replacing adipic acid, and the compound of the formula Z-45 is obtained, and the yield is 62%.

The compound of formula Z-45 is a milky white solid; the mass spectrum characterization result is as follows: ESI-MS: m/z 495.67[ m ] +Na ]] ⁺ (ii) a The result of the nuclear magnetic resonance hydrogen spectrum characterization is ¹ H NMR(400MHz，DMSO-d ₆ )δ11.98(s，1H)，11.15(s，1H)，9.70(s，1H)，8.48(d，J＝8.4Hz，1H)，7.84(t，J＝7.9Hz，1H)，7.62(d，J＝7.2Hz，1H)，5.15(dd，J＝12.7，5.3Hz，1H)，2.97–2.83(m，1H)，2.69–2.53(m，2H)，2.46(t，J＝7.4Hz，2H)，2.19(t，J＝7.3Hz，2H)，2.11–2.05(m，1H)，1.70–1.56(m，2H)，1.52–1.46(m，2H)，1.28(t，J＝12.5Hz，8H)。

(8.7) Synthesis of a Compound of formula Z-46

The preparation method is different from the step (8.2) in that undecanedioic acid is used for replacing adipic acid to obtain the compound of the formula Z-46 with the yield of 72%.

The compound of formula Z-46 is a milky white solid; the mass spectrum characterization result is ESI-MS: m/z 495.67[ 2 ], [ M + ] Na ]] ⁺ (ii) a The result of the nuclear magnetic resonance hydrogen spectrum characterization is ¹ H NMR(400MHz，DMSO-d ₆ )δ11.14(s，1H)，9.69(s，1H)，8.52–8.41(m，1H)，7.83(t，J＝7.9Hz，1H)，7.61(d，J＝7.3Hz，1H)，5.14(dd，J＝12.7，5.4Hz，1H)，2.95–2.84(m，1H)，2.69–2.52(m，2H)，2.46(t，J＝7.4Hz，2H)，2.18(t，J＝7.3Hz，2H)，2.10–2.03(m，1H)，1.67–1.57(m，2H)，1.48(s，2H)，1.28(d，J＝16.8Hz，10H)。

(8.8) Synthesis of Compound of formula Z-47

The difference in the preparation method compared with step (8.2) is that dodecanedioic acid is used instead of adipic acid to obtain the compound of formula Z-47 with a yield of 60%.

The compound of formula Z-47 is a milky white solid; the mass spectrum characterization result is ESI-MS: m/z 508.76[ M ] +Na ]] ⁺ (ii) a The result of the nuclear magnetic resonance hydrogen spectrum characterization is ¹ H NMR(400MHz，DMSO-d ₆ )δ11.97(s，1H)，11.16(s，1H)，9.70(s，1H)，8.48(d，J＝8.3Hz，1H)，7.84(t，J＝7.9Hz，1H)，7.62(d，J＝7.2Hz，1H)，5.15(dd，J＝12.8，5.2Hz，1H)，2.97–2.84(m，1H)，2.70–2.54(m，2H)，2.46(t，J＝7.4Hz，1H)，2.24–2.03(m，4H)，1.66–1.59(m，1H)，1.48(s，3H)，1.28(d，J＝20.6Hz，12H)。

(8.9) Synthesis of a Compound of formula Z-48

Compared with the step (8.2), the preparation method is different in that the adipic acid is replaced by the tridecanedioic acid to obtain the compound of the formula Z-48.

The compound of formula Z-48 is a milky white solid; the mass spectrum characterization result is ESI-MS: m/z 522.81[ 2 ], [ M + Na ]] ⁺ (ii) a The nuclear magnetic resonance hydrogen spectrum characterization result is as follows: ¹ H NMR(400MHz，DMSO-d ₆ )δ11.98(s，1H)，11.15(s，1H)，9.69(s，1H)，8.49(d，J＝8.4Hz，1H)，7.83(t，J＝7.9Hz，1H)，7.62(d，J＝7.3Hz，1H)，5.15(dd，J＝12.8，5.4Hz，1H)，2.91(ddd，J＝16.7，13.7，5.3Hz，1H)，2.46(t，J＝7.4Hz，2H)，2.21–2.17(m，4H)，2.08(ddd，J＝10.7，6.0，3.5Hz，1H)，1.49(t，J＝7.1Hz，4H)，1.25(s，14H)。

(8.10) Synthesis of a Compound of formula Z-49

Compared with the step (8.2), the preparation method thereof is different in that tetradecanedioic acid is used for replacing adipic acid to obtain the compound of the formula Z-49 with the yield of 53%.

The compound of formula Z-49 is a milky white solid; the mass spectrum characterization result is ESI-MS: m/z 537.28[ M ] +Na ]] ⁺ (ii) a The nuclear magnetic resonance hydrogen spectrum characterization result is as follows: ¹ H NMR(400MHz,DMSO-d ₆ )δ11.98(s,1H),11.15(s,1H),9.69(s,1H),8.48(d,J＝8.2Hz,1H),7.83(t,J＝7.8Hz,1H),7.61(d,J＝7.3Hz,1H),5.15(dd,J＝12.7,5.2Hz,1H),2.95–2.85(m,1H),2.67–2.54(m,2H),2.48–2.43(m,2H),2.18(t,J＝7.2Hz,2H),2.11–2.04(m,1H),1.68–1.56(m,2H),1.50–1.44(m,2H),1.24(s,16H)。

(9) Synthesis of the target Compound

(9.1) Synthesis of Compound of formula I-1

Adding 8mL of anhydrous N, N-dimethylformamide, 80mg of a compound of formula Z-1 (0.155 mmol), 40mg of a compound of formula Z-40 (0.103 mmol), 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HATU) (59mg, 0.155mmol) and N, N-diisopropylethylamine (80mg, 0.618mmol) into a 25mL round-bottomed flask, introducing nitrogen for protection, reacting at room temperature for 8h, and monitoring the completion of the reaction by TLC; the reaction solution was extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, evaporated to remove the solvent and purified by TLC (dichloromethane: methanol =12: 1) to obtain the compound of formula I-1 (0.036 g) in 40% yield.

The compound of formula I-1 is a yellow solid; the mass spectrum characterization result is ESI-MS: m/z 883.61[ m + H ]] ⁺ (ii) a The nuclear magnetic hydrogen spectrum and the carbon spectrum are characterized by the following results ¹ H NMR(400MHz，DMSO-d ₆ )δ11.15(s，1H)，10.16(s，1H)，9.74(s，1H)，8.64(s，1H)，8.47(d，J＝7.3Hz，1H)，8.29(s，1H)，8.08(s，1H)，7.91–7.71(m，2H)，7.63(d，J＝5.9Hz，1H)，7.58–7.47(m，2H)，7.32–7.23(m，1H)，7.17(s，1H)，6.61(s，1H)，6.44(dd，J＝15.9，10.6Hz，1H)，6.26(d，J＝17.2Hz，2H)，5.76(d，J＝9.3Hz，1H)，5.15(d，J＝8.6Hz，1H)，3.78(s，3H)，3.60(s，4H)，3.24–2.82(m，7H)，2.59(d，J＝30.9Hz，4H)，2.06(d，J＝9.5Hz，1H)，1.89(s，2H). ¹³ C NMR(101MHz，DMSO)δ173.14，172.18，170.54，170.17，168.03，167.08，163.48，156.17，139.38，138.91，138.84，136.87，136.48，132.30，131.87，128.91，127.31，126.89，120.79，120.51，118.78，117.61，116.29，107.37，100.97，49.81，49.45，49.31，45.10，41.29，40.55，36.22，31.81，31.32，22.40，20.90。

(9.2) Synthesis of Compound of formula I-2

Compared with the step (9.1), the preparation method is different in that the compound of the formula Z-41 is used for replacing the compound of the formula Z-40 to obtain the compound of the formula I-2 with the yield of 18%.

The compound of formula I-2 is a yellow solid; the mass spectrum characterization result is ESI-MS, M/z919.66[ M + Na ]] ⁺ (ii) a The nuclear magnetic hydrogen spectrum and the carbon spectrum are characterized by the following results ¹ H NMR(400MHz，DMSO-d ₆ )δ11.15(s，1H)，10.33(s，1H)，9.73(s，1H)，8.62(s，1H)，8.47(d，J＝8.4Hz，1H)，8.28(s，1H)，8.11(s，1H)，7.83(t，J＝7.9Hz，2H)，7.61(d，J＝7.2Hz，1H)，7.56(d，J＝8.0Hz，1H)，7.50(d，J＝8.7Hz，1H)，7.26(t，J＝8.0Hz，1H)，7.16(s，1H)，6.62–6.57(m，1H)，6.51(dd，J＝16.8，10.2Hz，1H)，6.32–6.15(m，2H)，5.78–5.70(m，1H)，5.15(dd，J＝12.8，5.3Hz，1H)，3.77(s，3H)，3.59(s，4H)，3.04(d，J＝19.7Hz，4H)，2.95–2.85(m，1H)，2.66–2.53(m，3H)，2.42(t，J＝7.1Hz，2H)，2.30(d，J＝6.5Hz，1H)，2.06(dd，J＝9.3，4.2Hz，1H)，1.72–1.65(m，2H)，1.63–1.55(m，2H). ¹³ C NMR(101MHz，DMSO)δ173.14，170.17，168.04，167.06，163.52，156.14，139.48，138.82，136.92，136.49，132.40，131.85，128.84，127.13，126.73，126.57，123.89，120.48，118.71，117.45，116.32，107.40，100.95，56.02，51.58，49.86，49.46，49.31，45.18，41.27，40.55，36.71，32.36，31.33，24.91，24.69，22.39。

(9.3) Synthesis of Compound of formula I-3

The preparation method is different from the step (9.1) in that the compound of the formula Z-42 is used for replacing the compound of the formula Z-40 to obtain the compound of the formula I-3, and the yield is 19%.

The compound of formula I-3 is a yellow solid; the mass spectrum characterization result is ESI-MS m/z 933.65[ m ] +Na ]] ⁺ (ii) a The nuclear magnetic resonance hydrogen spectrum and the carbon spectrum have the characterization results that ¹ H NMR(400MHz，DMSO-d ₆ )δ11.16(s，1H)，10.15(s，1H)，9.71(s，1H)，8.65(s，1H)，8.49(d，J＝8.4Hz，1H)，8.30(s，1H)，8.08(s，1H)，7.91–7.72(m，2H)，7.62(d，J＝6.9Hz，1H)，7.58–7.48(m，2H)，7.27(t，J＝7.5Hz，1H)，7.18(s，1H)，6.61(s，1H)，6.50–6.41(m，1H)，6.27(d，J＝16.9Hz，2H)，5.76(d，J＝9.4Hz，1H)，5.16(dd，J＝12.4，4.4Hz，1H)，3.78(s，3H)，3.58(s，4H)，3.04(d，J＝19.2Hz，4H)，2.89(d，J＝13.2Hz，1H)，2.62(d，J＝17.2Hz，1H)，2.42–2.30(m，2H)，2.06(s，2H)，1.76–1.61(m，2H)，1.62–1.50(m，2H)，1.38(dd，J＝14.1，7.3Hz，2H)，1.24(s，2H). ¹³ C NMR(101MHz，DMSO)δ173.13，172.40，170.95，170.17，168.60，168.10，167.06，163.48，161.29，157.67，156.17，139.39，138.85，136.96，136.49，132.30，131.85，128.91，127.30，126.67，123.89，120.84，120.52，118.68，117.37，116.27，107.39，100.96，56.03，49.33，45.19，36.87，32.48，31.34，29.42，28.71，25.07，24.94，22.40，21.59。

(9.4) Synthesis of Compound of formula I-4

The preparation method is different from the step (9.1) in that the compound of the formula Z-43 is used for replacing the compound of the formula Z-40 to obtain the compound of the formula I-4, and the yield is 15%.

The compound of formula I-4 is a yellow solid, and the mass spectrum characterization result is ESI-MS: m/z 947.65[ m ] +Na] ⁺ (ii) a The nuclear magnetic resonance hydrogen spectrum and the carbon spectrum have the characterization results that ¹ H NMR(400MHz，DMSO-d ₆ )δ11.14(s，1H)，10.34(s，1H)，9.71(s，1H)，8.61(s，1H)，8.47(d，J＝8.4Hz，1H)，8.27(s，1H)，8.10(s，1H)，7.82(t，J＝7.8Hz，2H)，7.60(d，J＝7.3Hz，1H)，7.56(d，J＝7.7Hz，1H)，7.49(d，J＝8.6Hz，1H)，7.25(t，J＝7.9Hz，1H)，7.15(s，1H)，6.59(s，1H)，6.50(dd，J＝16.7，10.1Hz，1H)，6.25(d，J＝16.9Hz，2H)，5.74(d，J＝10.1Hz，1H)，5.15(dd，J＝12.7，5.3Hz，1H)，3.77(s，3H)，3.57(s，4H)，3.02(d，J＝16.8Hz，4H)，2.89(s，2H)，2.66–2.53(m，2H)，2.35(t，J＝6.9Hz，3H)，2.06(q，J＝6.0，5.5Hz，1H)，1.68–1.60(m，2H)，1.55–1.50(m，2H)，1.35(s，4H). ¹³ C NMR(101MHz，DMSO)δ173.14，172.41，171.01，170.17，168.07，167.06，163.51，156.14，139.47，138.82，136.94，136.48，132.40，131.84，128.85，127.12，126.71，123.88，120.48，118.69，117.42，116.31，107.40，100.94，56.01，49.86，49.48，49.31，48.98，45.18，41.24，40.54，36.89，32.56，31.33，28.88，28.75，25.09，25.05，22.38。

(9.5) Synthesis of Compound of formula I-5

The preparation method is different from the step (9.1) in that the compound of the formula Z-44 is used for replacing the compound of the formula Z-40 to obtain the compound of the formula I-5, and the yield is 15%.

The compound of formula I-5 is a yellow solid; the nuclear magnetic resonance hydrogen spectrum and carbon spectrum characterization results are as follows: ¹ H NMR(400MHz，DMSO-d ₆ )δ11.16(s，1H)，10.18(s，1H)，9.69(s，1H)，8.63(s，1H)，8.48(d，J＝8.4Hz，1H)，8.29(s，1H)，8.08(s，1H)，7.83(t，J＝7.8Hz，1H)，7.61(d，J＝7.2Hz，1H)，7.54(dd，J＝13.5，8.5Hz，2H)，7.27(t，J＝7.9Hz，1H)，7.18(s，1H)，6.61(s，1H)，6.46(dd，J＝16.9，9.7Hz，1H)，6.26(d，J＝17.2Hz，2H)，5.82–5.68(m，1H)，5.16(dd，J＝12.6，5.1Hz，1H)，3.78(s，3H)，3.58(s，4H)，3.03(d，J＝16.2Hz，4H)，2.89(dd，J＝30.1，17.1Hz，2H)，2.68–2.54(m，2H)，2.47(d，J＝7.1Hz，1H)，2.35(t，J＝6.9Hz，2H)，2.11–2.04(m，1H)，1.64(s，2H)，1.53(s，2H)，1.34(s，6H). ¹³ CNMR(101MHz，DMSO-d ₆ )δ173.15，172.43，171.06，170.18，168.11，167.06，163.49，161.31，139.39，138.84，136.96，136.49，132.31，131.83，128.90，127.27，126.62，126.56，123.88，120.52，118.66，117.33，116.29，107.39，105.39，100.95，56.02，49.89，49.49，49.32，45.20，41.25，36.92，32.63，31.34，29.07，29.00，28.84，25.18，25.15，22.39。

(9.6) Synthesis of Compound of formula I-6

Compared with the step (9.1), the preparation method is different in that the compound of the formula Z-45 is used for replacing the compound of the formula Z-40 to obtain the compound of the formula I-6, and the yield is 26.5%.

The compound of formula I-6 is a yellow solid; the mass spectrum characterization result is ESI-MS m/z 989.92[ m ] +Na ]] ⁺ (ii) a The nuclear magnetic resonance hydrogen spectrum and the carbon spectrum have the characterization results that ¹ H NMR(400MHz，DMSO-d ₆ )δ11.15(s，1H)，9.87(s，0H)，9.69(s，1H)，8.62(d，J＝5.1Hz，1H)，8.48(d，J＝8.4Hz，1H)，8.27(s，1H)，8.20–7.98(m，1H)，7.83(d，J＝5.5Hz，1H)，7.71(d，J＝7.6Hz，1H)，7.65–7.58(m，1H)，7.56–7.39(m，1H)，7.32–7.10(m，1H)，6.61(s，1H)，6.26(d，J＝17.1Hz，1H)，5.15(dd，J＝12.5，5.1Hz，1H)，3.89(d，J＝26.3Hz，1H)，3.76(d，J＝13.1Hz，3H)，3.58(s，5H)，3.05(d，J＝18.1Hz，2H)，2.95–2.85(m，1H)，2.66–2.55(m，2H)，2.49–2.42(m，2H)，2.31(d，J＝20.6Hz，2H)，2.10–2.04(m，1H)，1.62(d，J＝7.1Hz，2H)，1.51(s，2H)，1.30(s，8H). ¹³ C NMR(101MHz，DMSO-d ₆ )δ173.17，172.46，171.10，170.17，168.11，167.06，138.77，136.94，136.50，131.82，131.79，126.64，126.57，118.66，117.36，117.26，100.88，56.01，49.90，49.31，45.23，41.28，36.93，32.65，31.32，29.14，29.05，28.89，28.86，25.53，25.21，25.17，22.38。

(9.7) Synthesis of Compound of formula I-7

The preparation method is different from the step (9.1) in that the compound of the formula Z-46 is used for replacing the compound of the formula Z-40 to obtain the compound of the formula I-7, and the yield is 21%.

The compound of formula I-7 is a yellow solid; the mass spectrum characterization result is as follows: ESI-MS: m/z 1003.71[ m ] +Na ]] ⁺ (ii) a The nuclear magnetic resonance hydrogen spectrum and the carbon spectrum have the characterization results that ¹ H NMR(400MHz，DMSO-d ₆ )δ11.16(s，1H)，10.27(s，1H)，9.69(s，1H)，8.65(s，1H)，8.48(d，J＝8.3Hz，1H)，8.29(s，1H)，8.09(s，1H)，7.89–7.73(m，2H)，7.61(d，J＝7.2Hz，1H)，7.57(d，J＝7.8Hz，1H)，7.52(d，J＝8.5Hz，1H)，7.27(t，J＝7.8Hz，1H)，7.18(s，1H)，6.61(s，1H)，6.49(dd，J＝16.7，10.0Hz，1H)，6.26(d，J＝16.9Hz，2H)，5.81–5.69(m，1H)，5.16(dd，J＝12.5，5.1Hz，1H)，3.78(s，3H)，3.58(s，4H)，3.04(d，J＝14.4Hz，4H)，2.91(s，1H)，2.70–2.55(m，2H)，2.34(t，J＝6.9Hz，2H)，2.11–2.04(m，1H)，1.63(s，2H)，1.51(s，2H)，1.29(s，10H). ¹³ C NMR(101MHz，DMSO-d ₆ )δ173.16，172.42，171.04，170.18，163.50，156.13，139.44，138.83，136.95，136.48，132.36，128.87，127.20，126.63，120.50，118.66，117.33，116.25，107.38，100.94，56.01，49.89，49.50，49.31，45.20，41.24，40.53，36.93，32.65，31.34，29.26，29.24，29.20，29.12，28.91，25.24，25.18，22.39。

(9.8) Synthesis of Compounds of formula I-8:

the preparation method is different from the step (9.1) in that the compound of the formula Z-47 is used for replacing the compound of the formula Z-40 to obtain the compound of the formula I-8, and the yield is 21%.

The compound of the formula I-8 is yellow solid, and the characterization results of the nuclear magnetic resonance hydrogen spectrum and the carbon spectrum are ¹ H NMR(400MHz，DMSO-d ₆ )δ11.16(s，1H)，10.17(s，1H)，9.68(s，1H)，8.64(s，1H)，8.49(d，J＝8.1Hz，1H)，8.29(s，1H)，8.08(s，1H)，7.87–7.70(m，2H)，7.61(d，J＝6.7Hz，1H)，7.59–7.47(m，2H)，7.34–7.10(m，2H)，6.61(s，1H)，6.46(dd，J＝16.4，10.2Hz，1H)，6.27(d，J＝16.8Hz，2H)，5.76(d，J＝9.7Hz，1H)，5.26–5.08(m，1H)，3.78(s，3H)，3.58(s，4H)，3.04(d，J＝17.2Hz，4H)，2.95–2.87(m，1H)，2.68–2.56(m，2H)，2.49–2.41(m，2H)，2.34(s，2H)，2.12–2.05(m，1H)，1.63(s，2H)，1.51(s，2H)，1.28(s，12H). ¹³ C NMR(101MHz，DMSO-d ₆ )δ173.14，172.42，171.05，170.16，163.48，156.14，139.39，138.84，136.97，136.49，132.31，128.90，127.26，126.58，120.53，118.64，116.28，107.38，100.94，56.02，49.89，49.50，49.32，45.21，41.24，36.94，32.65，31.34，29.33，29.28，29.21，29.13，28.91，25.24，25.17，22.40。

(9.9) Synthesis of Compound of formula I-9

Compared with the step (9.1), the preparation method is different in that the compound of the formula Z-48 is used for replacing the compound of the formula Z-40 to obtain the compound of the formula I-9, and the yield is 27.3%.

The compound of formula I-9 is a yellow solid; the nuclear magnetic resonance hydrogen spectrum and carbon spectrum characterization results are as follows: ¹ H NMR(400MHz，DMSO-d ₆ )δ11.16(s，1H)，10.22(d，J＝35.6Hz，1H)，9.69(s，1H)，8.71(d，J＝70.6Hz，1H)，8.48(d，J＝7.8Hz，1H)，8.29(s，1H)，8.05(d，J＝30.6Hz，1H)，7.94–7.71(m，2H)，7.59(dd，J＝15.4，7.1Hz，2H)，7.52(d，J＝8.6Hz，1H)，7.32–7.25(m，1H)，7.20(d，J＝8.7Hz，1H)，6.64(d，J＝23.0Hz，1H)，6.51(d，J＝13.6Hz，1H)，6.26(d，J＝16.7Hz，2H)，5.75(d，J＝8.5Hz，1H)，5.20–5.11(m，1H)，3.78(s，3H)，3.58(s，4H)，3.14–2.99(m，4H)，2.95–2.87(m，1H)，2.68–2.56(m，2H)，2.46(s，2H)，2.36–2.31(m，2H)，2.11–2.05(m，1H)，1.61(s，2H)，1.51(s，2H)，1.27(s，14H). ¹³ C NMR(101MHz，DMSO-d ₆ )δ173.14，172.42，171.05，170.16，168.11，163.50，136.97，136.49，132.37，131.82，128.87，127.17，127.06，126.60，118.65，107.39，100.94，56.02，49.89，49.32，45.21，41.25，36.94，32.65，31.34，29.37，29.30，29.21，29.14，28.91，25.24，25.17，22.39。

(9.10) Synthesis of Compound of formula I-10

The preparation method is different from the step (9.1) in that the compound of the formula Z-49 is used for replacing the compound of the formula Z-40 to obtain the compound of the formula I-10 with the yield of 20%.

Formula I-10 compound is a yellow solid; the mass spectrum characterization result is ESI-MS: m/z 1031.79[ m ] +Na] ⁺ (ii) a The nuclear magnetic resonance hydrogen spectrum and carbon spectrum characterization results are as follows: ¹ H NMR(400MHz，DMSO-d ₆ )δ11.16(s，1H)，10.17(s，1H)，9.68(s，1H)，8.64(s，1H)，8.48(d，J＝8.4Hz，1H)，8.29(s，1H)，8.08(s，1H)，7.83(t，J＝7.9Hz，1H)，7.80–7.67(m，1H)，7.61(d，J＝7.3Hz，1H)，7.54(dd，J＝14.1，8.5Hz，2H)，7.27(t，J＝8.0Hz，1H)，7.17(s，1H)，6.61(s，1H)，6.45(dd，J＝16.9，10.1Hz，1H)，6.26(d，J＝15.6Hz，1H)，5.79–5.72(m，1H)，5.15(dd，J＝12.7，5.3Hz，1H)，3.78(s，3H)，3.58(s，4H)，3.03(d，J＝18.7Hz，4H)，2.90(td，J＝13.5，6.5Hz，1H)，2.66–2.55(m，2H)，2.46(t，J＝7.4Hz，2H)，2.34(t，J＝7.3Hz，2H)，2.11–2.05(m，1H)，1.65–1.58(m，2H)，1.54–1.47(m，6H)，1.26(s，16H). ¹³ C NMR(101MHz，DMSO-d ₆ )δ173.13，172.42，171.04，170.16，139.40，138.84，136.97，136.49，132.32，131.83，128.89，127.25，126.61，120.53，118.65，116.28，107.38，100.96，56.02，49.89，49.32，45.21，41.24，36.94，32.64，31.34，29.39，29.30，29.20，29.13，28.90，25.24，25.17，22.39。

example 2

A compound of formula I or a pharmaceutically acceptable salt thereof,

wherein L is

n is 2, 3, 4, 5 or 6.

The preparation method of the compound comprises the following steps:

(1) By the procedure (3) of example 1, a compound of the formula Z-7 was synthesized

(2) Synthesis of Compounds of formula Z-15

Adding a compound of the formula Z-7 (200mg, 0.41mol) and dichloromethane into a 50mL round-bottom flask, dissolving, dropwise adding 500 mu L of trifluoroacetic acid to perform deprotection reaction, and directly evaporating dichloromethane under reduced pressure after the reaction is finished; adding the obtained BOC-removed intermediate (200mg, 0.41mmol), ethyl bromoacetate (120mg, 0.72mmol) and potassium carbonate (750mg, 5.43mmol) into 10mL of anhydrous N, N-Dimethylformamide (DMF), introducing nitrogen for protection, reacting at 60 ℃ for 1h, and monitoring the reaction completion by TLC; the reaction solution was extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, and separated and purified by silica gel column chromatography to give the compound of formula Z-15 (85 mg) in 44% yield.

The compound of formula Z-15 is a pale yellow solid; the mass spectrum characterization result is ESI-MS: m/z 474.76[ m ] +H] ⁺ (ii) a The result of the nuclear magnetic resonance hydrogen spectrum characterization is ¹ H NMR(400MHz，DMSO-d ₆ )δ9.58(s，1H)，8.62(s，1H)，7.20(d，J＝8.6Hz，1H)，6.63(s，1H)，6.51(d，J＝8.4Hz，1H)，4.15–4.09(m，2H)，3.76(s，3H)，3.29(s，2H)，3.18(s，4H)，2.67(s，4H)，1.24(d，J＝3.7Hz，3H)。

(3) Synthesis of Compounds of formula Z-8

In a 50mL round-bottom flask, 10mL of tetrahydrofuran, a compound of formula Z-15 (110mg, 0.243mmol), a compound of formula Z-17 (39mg, 0.243mmol) and 1.5mL of trifluoroacetic acid were added, and the mixture was reacted at room temperature for 8 hours; the reaction solution was extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, and separated and purified by silica gel column chromatography to give the compound of formula Z-8 (100 mg) in 69% yield.

The compound of formula Z-8 is a yellow-green solid; the nuclear magnetic resonance hydrogen spectrum characterization result is as follows: ESI-MS: m/z 600.75[ 2 ] M + H] ⁺ ； ¹ HNMR(400MHz，DMSO-d ₆ )δ10.46(s，1H)，8.60(s，1H)，8.28(s，1H)，8.13(s，1H)，7.87(s，1H)，7.58(d，J＝7.9Hz，1H)，7.48(d，J＝8.7Hz，1H)，7.26(t，J＝8.0Hz，1H)，7.15(s，1H)，6.61–6.51(m，2H)，6.25(d，J＝16.9Hz，2H)，5.74(d，J＝10.8Hz，1H)，4.12(q，J＝7.1Hz，2H)，3.77(s，3H)，3.31(s，2H)，3.09(s，4H)，2.67(s，4H)，1.21(d，J＝7.1Hz，3H)。

(4) Synthesis of Compounds of formula Z-2

In a 25mL round-bottom flask, the compound of formula Z-8 (65mg, 0.11mmol), lithium hydroxide (26.4 mg, 1.1mmol) were added in this order to 5mL of an aqueous tetrahydrofuran solution (v/v = 1/1) and reacted at room temperature for 1h; after the reaction is finished, adjusting the pH to be 3-4; and (3) evaporating the solvent from the reaction solution to obtain the compound of the formula Z-2. The product does not need to be purified.

The mass spectrometric characterization of the compound of formula Z-2 resulted in: ESI-MS: m/z 572.71[ 2 ] M + H] ⁺ 。

(5) By the step (6) of example 1, a compound of formula Z-13 was synthesized;

(6) By the step (7) of example 1, a compound of formula Z-10 was synthesized;

(7) Synthesis of a Compound of formula Z-3

(7.1) Synthesis of a Compound of formula Z-31

Sequentially adding 10mL of NMP, a compound of a formula Z-9 (100mg, 0.36mmol), N-tert-butoxycarbonyl-1,2-ethylenediamine (69mg, 0.43mmol) and N, N-diisopropylethylamine (192 mu L,1.08 mmol) into a 100mL round-bottom flask, introducing nitrogen for protection, carrying out microwave reaction at 90 ℃ for 30min, and monitoring by TLC (thin layer chromatography) to obtain the reaction; extracting the reaction liquid by ethyl acetate, washing by brine and drying by anhydrous sodium sulfate; purification by silica gel column chromatography (PE/EA = 10-80%) gave intermediate (60 mg) in 40% yield.

The intermediate is yellow solid, and the mass spectrum analysis result is ESI-MS [ m/z ] 439.53[ M ] +Na ]] ⁺ (ii) a The result of the nuclear magnetic resonance hydrogen spectrum characterization is ¹ H NMR (400mhz, chloroform-d) δ 8.46 (s, 1H), 7.51 (t, J =7.8hz, 1h), 7.13 (d, J =7.1hz, 1h), 7.00 (d, J =8.3hz, 1h), 6.42 (s, 1H), 4.96 (dt, J =11.3,6.3hz, 2h), 3.46 (s, 2H), 3.41-3.33 (m, 2H), 2.93-2.86 (m, 1H), 2.84-2.72 (m, 2H), 2.17-2.11 (m, 1H), 1.46 (s, 9H). The intermediate obtained was reacted with trifluoroacetic acid in 5mL of dichloromethane, and deprotection treatment and evaporation of the solvent gave a compound of formula Z-31.

The compound of formula Z-31 is a yellow solid, and the mass spectrometry result is ESI-MS m/Z339.66M + Na] ⁺ 。

(7.2) Synthesis of Compound of formula Z-32

Compared with the step (7.1), the difference is that N-tert-butyloxycarbonyl-1,3-propanediamine is used for replacing N-tert-butyloxycarbonyl-1,2-ethanediamine, and the compound of the formula Z-32 is prepared, and the yield is 65%.

A compound of formula Z-32 as a yellow solid; the mass spectrum characterization result is ESI-MS: m/z 353.8[ M ] +Na ]] ⁺ (ii) a The nuclear magnetic resonance hydrogen spectrum characterization result is as follows: ¹ H NMR(400MHz，DMSO-d ₆ )δ11.11(s，1H)，7.58(t，J＝7.7Hz，1H)，7.09(d，J＝8.6Hz，1H)，7.03(d，J＝7.0Hz，1H)，6.93(s，1H)，6.68(s，1H)，5.10–5.02(m，1H)，3.01(d，J＝5.8Hz，2H)，2.97–2.83(m，2H)，2.59(d，J＝14.9Hz，2H)，2.02(dd，J＝13.8，6.7Hz，2H)，1.70–1.63(m，2H)，1.39(s，9H).

(7.3) Synthesis of a Compound of formula Z-33

Compared with the step (7.1), the preparation method is different in that N-tert-butyloxycarbonyl-1,4-butanediamine is used for replacing N-tert-butyloxycarbonyl-1,2-ethylenediamine, so that the compound shown in the formula Z-33 is prepared, and the yield is 68%.

The compound of formula Z-33 is a yellow solid; the mass spectrum characterization result is ESI-MS: m/z 367.47[ 2 ], [ M + Na ]] ⁺ (ii) a The nuclear magnetic resonance hydrogen spectrum characterization result is as follows: ¹ H NMR(400MHz，DMSO-d ₆ )δ11.11(s，0H)，7.58(t，J＝7.8Hz，1H)，7.11(d，J＝8.6Hz，1H)，7.03(d，J＝7.0Hz，1H)，6.85(s，1H)，6.57(s，1H)，5.10–5.02(m，1H)，3.06–2.81(m，4H)，2.60(d，J＝20.1Hz，2H)，2.02(dd，J＝13.2，5.7Hz，2H)，1.55(d，J＝3.9Hz，2H)，1.46(d，J＝6.5Hz，2H)，1.37(s，9H)。

(7.4) Synthesis of a Compound of formula Z-34

Compared with the step (7.1), the preparation method is different in that N- (5-amino amyl) carbamic acid tert-butyl ester is used for replacing N-tert-butyloxycarbonyl-1,2-ethylenediamine, so that the compound shown in the formula Z-34 is obtained, and the yield is 48%.

The compound of formula Z-34 is a yellow solid, and the mass spectrum characterization result is ESI-MS, m/Z381.77 [ m ] +Na] ⁺ (ii) a The characterization result of the hydrogen spectrum of nuclear magnetic resonance is that ¹ H NMR(400MHz，DMSO-d ₆ )δ11.10(s，1H)，7.59(t，J＝7.2Hz，1H)，7.10(d，J＝8.5Hz，1H)，7.03(d，J＝7.0Hz，1H)，6.80(s，1H)，6.54(s，1H)，5.06(dd，J＝12.8，4.3Hz，1H)，3.29(d，J＝4.1Hz，2H)，2.95–2.89(m，2H)，2.59(d，J＝16.8Hz，2H)，2.03(dd，J＝14.7，6.1Hz，2H)，1.62–1.55(m，2H)，1.41(s，2H)，1.37(s，9H)，1.30(s，2H)。

(7.5) Synthesis of a Compound of formula Z-35

Compared with the step (7.1), the preparation method is different in that N- (6-aminohexyl) carbamic acid tert-butyl ester is used for replacing N-tert-butyloxycarbonyl-1,2-ethylenediamine, so that the compound shown in the formula Z-35 is obtained, and the yield is 30.7%.

The compound of formula Z-35 is a yellow solid; the mass spectrum characterization result is ESI-MS: m/z 395.67[ m ] +Na ]] ⁺ (ii) a The result of the nuclear magnetic resonance hydrogen spectrum characterization is ¹ H NMR(400MHz，DMSO-d ₆ )δ11.08(s，1H)，7.62–7.56(m，1H)，7.10(d，J＝8.6Hz，1H)，7.03(d，J＝7.0Hz，1H)，6.76(t，J＝4.9Hz，1H)，6.54(t，J＝5.9Hz，1H)，5.06(dd，J＝12.9，5.4Hz，1H)，3.31(s，2H)，3.29(s，2H)，2.93–2.86(m，3H)，2.62–2.57(m，1H)，1.95–1.87(m，6H)，1.56(d，J＝6.9Hz，2H)，1.37(s，9H)。

(8) Synthesis of the target Compound

(8.1) Synthesis of Compound of formula I-11

Sequentially adding a compound of the formula Z-2 (84mg, 0.15mmol), a compound of the formula Z-31 (57mg, 0.18mmol), 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethylurea Hexafluorophosphate (HATU) (86mg, 0.225mmol), N, N-diisopropylethylamine (194 mu L,1.5 mmol) in 10mL of anhydrous N, N-diisopropylethylamine, introducing nitrogen for protection, reacting at room temperature for 8h, monitoring by TLC, and finishing the reaction; extracting the reaction solution with water and ethyl acetate, washing with brine, and drying with anhydrous sodium sulfate; preparative TLC purification gave the compound of formula I-11 (32 mg) in 25% yield.

The compound of formula I-11 is a yellow solid; the mass spectrum characterization result is ESI-MS m/z 892.57[ M ] +Na ]] ⁺ (ii) a The nuclear magnetic resonance hydrogen spectrum characterization result is as follows: ¹ H NMR(400MHz，DMSO-d ₆ )δ11.09(s，1H)，10.16(s，1H)，8.62(s，1H)，8.29(s，1H)，8.05(d，J＝26.0Hz，2H)，7.77(s，1H)，7.66–7.58(m，1H)，7.54(d，J＝7.4Hz，1H)，7.49(d，J＝8.7Hz，1H)，7.41–7.11(m，3H)，7.05(d，J＝7.0Hz，1H)，6.74(s，1H)，6.55(s，1H)，6.45(dd，J＝16.9，10.1Hz，1H)，6.26(d，J＝16.6Hz，2H)，5.76(d，J＝10.0Hz，1H)，5.05(dd，J＝12.9，5.2Hz，1H)，3.77(s，3H)，3.44(s，6H)，3.08(s，3H)，2.98(s，2H)，2.92–2.81(m，1H)，2.54(d，J＝8.4Hz，5H)，2.05–1.94(m，1H)。

(8.2) Synthesis of Compound of formula I-12

Compared with the step (8.1), the preparation method is different in that the compound of the formula Z-32 is used for replacing the compound of the formula Z-31, and the compound of the formula I-12 is obtained with the yield of 43.7%.

The compound of formula I-12 is a yellow solid; the mass spectrum characterization result is ESI-MS: m/z 906.57[ m ] +Na ]] ⁺ (ii) a The characterization results of the hydrogen spectrum and the carbon spectrum of the nuclear magnetic resonance are as follows: ¹ H NMR(400MHz，DMSO-d ₆ )δ11.11(s，1H)，10.17(s，1H)，8.63(s，1H)，8.29(s，1H)，8.08(s，1H)，7.97(s，1H)，7.77(s，1H)，7.58(dd，J＝17.7，9.4Hz，2H)，7.51(d，J＝8.7Hz，1H)，7.27(t，J＝7.8Hz，1H)，7.19(s，1H)，7.10(d，J＝8.5Hz，1H)，7.03(d，J＝6.9Hz，1H)，6.75(s，1H)，6.57(s，1H)，6.46(dd，J＝16.9，10.1Hz，1H)，6.27(d，J＝16.8Hz，2H)，5.76(d，J＝10.1Hz，1H)，5.07(dd，J＝12.7，5.0Hz，1H)，3.77(s，3H)，3.29–3.18(m，3H)，3.13(s，4H)，3.04(s，2H)，2.88(d，J＝12.8Hz，1H)，2.60(d，J＝10.8Hz，5H)，2.51(s，2H)，2.04(d，J＝11.2Hz，1H)，1.74(s，2H). ¹³ C NMR(101MHz，DMSO-d ₆ )δ173.21，170.49，169.20，167.70，163.51，157.65，146.66，139.39，138.87，136.64，132.69，132.27，128.90，127.29，119.96，117.50，116.24，110.79，109.58，106.85，100.22，55.98，53.97，53.21，48.96，40.81，36.25，31.39，29.27，22.59。

(8.3) Synthesis of Compound of formula I-13

Compared with the step (8.1), the preparation method is different from the step (8.1) in that the compound of the formula Z-33 is used for replacing the compound of the formula Z-31, and the compound of the formula I-13 is obtained with the yield of 48.7 percent.

The compound of formula I-13 is a yellow solid, and the mass spectrum characterization result is ESI-MS: m/z 920.59[ M ] +Na] ⁺ (ii) a The result of the nuclear magnetic resonance hydrogen spectrum characterization is ¹ H NMR(400MHz，DMSO-d ₆ )δ11.10(s，1H)，10.18(s，1H)，8.62(s，1H)，8.29(s，1H)，8.09(s，1H)，7.81(d，J＝33.5Hz，2H)，7.65–7.54(m，2H)，7.50(d，J＝7.8Hz，1H)，7.27(s，1H)，7.24–7.08(m，2H)，7.03(s，1H)，6.57(s，2H)，6.46(dd，J＝15.9，10.6Hz，1H)，6.27(d，J＝17.1Hz，2H)，5.76(d，J＝9.0Hz，1H)，5.06(d，J＝11.0Hz，1H)，3.81(d，J＝29.5Hz，3H)，3.62(s，1H)，3.10(t，J＝33.1Hz，9H)，2.89(s，1H)，2.57(d，J＝14.5Hz，6H)，2.03(s，1H)，1.56(s，4H). ¹³ C NMR(101MHz，DMSO-d ₆ )δ173.19，170.48，169.33，167.69，163.50，156.10，146.79，139.39，138.87，136.66，132.60，132.29，128.89，127.27，119.96，117.60，116.22，110.79，109.43，106.86，100.25，55.98，53.92，53.18，48.95，42.18，41.94，40.82，38.30，31.38，27.09，26.61，22.56。

(8.4) Synthesis of Compound of formula I-14

The preparation method is different from the step (8.1) in that the compound of the formula Z-34 is used for replacing the compound of the formula Z-31 to obtain the compound of the formula I-14 with the yield of 11%.

The compounds of formula I-14 are yellow solids; the mass spectrum characterization result is ESI-MS: m/z 934.52[ m ] +Na ]] ⁺ (ii) a The characterization results of the hydrogen spectrum and the carbon spectrum of the nuclear magnetic resonance are as follows: ¹ H NMR(400MHz，DMSO-d ₆ )δ11.10(s，1H)，10.17(s，1H)，8.62(s，1H)，8.29(s，1H)，8.08(s，1H)，7.77(s，2H)，7.57(s，2H)，7.50(d，J＝8.3Hz，1H)，7.22(d，J＝35.2Hz，2H)，7.11(d，J＝7.5Hz，1H)，7.04(s，1H)，6.56(d，J＝8.1Hz，2H)，6.50–6.40(m，1H)，6.27(d，J＝16.6Hz，2H)，5.82–5.72(m，1H)，5.18–4.98(m，1H)，3.77(s，3H)，3.12(s，6H)，3.07–2.80(m，4H)，2.67(d，J＝56.5Hz，2H)，2.57(s，5H)，2.04(s，1H)，1.61(s，2H)，1.50(s，2H)，1.36(s，2H). ¹³ C NMR(101MHz，DMSO-d ₆ )δ173.21，169.35，169.31，146.81，138.86，136.68，132.27，128.90，127.30，119.91，117.59，116.22，110.80，106.82，100.22，61.70，55.97，53.22，49.00，48.94，42.20，38.48，31.37，29.35，28.76，24.09，22.56。

(8.5) Synthesis of Compound of formula I-15

Compared with the step (8.1), the preparation method is different in that the compound of the formula Z-35 is used for replacing the compound of the formula Z-31, and the compound of the formula I-15 is obtained with the yield of 65%.

The compound of the formula I-15 is a yellow solid, and the nuclear magnetic resonance hydrogen spectrum and the carbon spectrum have the following characteristic results: ¹ H NMR(400MHz，DMSO-d ₆ )δ11.09(s，1H)，10.15(s，1H)，8.62(s，1H)，8.29(s，1H)，8.07(s，1H)，7.76(s，2H)，7.61–7.52(m，2H)，7.49(d，J＝8.7Hz，1H)，7.26(t，J＝7.9Hz，1H)，7.19(s，1H)，7.09(d，J＝8.6Hz，1H)，7.06–6.99(m，1H)，6.55(d，J＝12.3Hz，2H)，6.45(dd，J＝16.8，10.1Hz，1H)，6.26(d，J＝16.8Hz，2H)，5.76(d，J＝10.1Hz，1H)，5.05(dd，J＝12.9，5.2Hz，1H)，3.76(s，3H)，3.29(d，J＝7.2Hz，2H)，3.12(q，J＝6.6Hz，6H)，3.06–2.75(m，4H)，2.70(d，J＝2.1Hz，1H)，2.64–2.56(m，4H)，2.04(s，1H)，1.59(t，J＝7.3Hz，2H)，1.46(t，J＝7.0Hz，2H)，1.35(s，4H). ¹³ CNMR(101MHz，DMSO-d ₆ )δ173.19，170.48，169.35，167.69，163.48，146.81，139.38，138.87，136.68，132.59，132.28，128.89，127.27，117.55，116.21，110.79，109.42，100.27，55.98，53.14，48.95，42.20，40.83，38.59，31.38，29.56，29.05，26.54，26.43，22.56。

example 3

A compound of formula I or a pharmaceutically acceptable salt thereof,

wherein L is

n is 2, 3, 4, 5 or 6. The preparation method of the compound comprises the following steps:

(1) By the step (4) in example 2, the compound of the formula Z-2 was obtained

(2) Synthesis of a Compound of formula Z-9

1g of 3-fluorophthalic anhydride (6 mmol), 0.99g of 3-amino-2,6-piperidone hydrochloride (6 mmol), 1.47g of potassium acetate (15 mmol) and 20mL of acetic acid are sequentially added into a 50mL round-bottom flask, and the mixture is reacted at a constant temperature of 90 ℃ for 4 hours; the reaction solution was cooled to room temperature, followed by sequentially adding ice water, filtering, washing with water, and drying to obtain a compound of formula Z-9 (1.08 g) with a yield of 68.0%.

The compound of formula Z-9 is a pale purple solid; the mass spectrum characterization result is ESI-MS, m/z 276.19[ m-H ]]-; the result of hydrogen spectrum characterization of nuclear magnetic resonance is ¹ H NMR(400MHz，DMSO-d ₆ )δ11.15(s，1H)，7.95(td，J＝7.9，4.4Hz，1H)，7.80(d，J＝7.3Hz，1H)，7.74(t，J＝8.9Hz，1H)，5.16(dd，J＝12.9，5.4Hz，1H)，2.90(ddd，J＝16.9，13.9，5.4Hz，1H)，2.70–2.52(m，2H)，2.13–2.02(m，1H)。

(3) Synthesis of Compounds of formula Z-11

In a 100mL round bottom flask, 10mL dimethyl sulfoxide (DMSO), 100mg of the compound of formula Z-9 (0.362 mmol), 62mg of tert-butyl glycinate (0.471 mmol), N, N-diisopropylethylamine (300. Mu.L, 1.81 mmol) were added sequentially, protected with nitrogen, reacted in an oil bath at 100 ℃ overnight, monitored by TLC; extracting the reaction solution with ethyl acetate, washing with brine, drying with anhydrous sodium sulfate, filtering, concentrating, and separating and purifying by silica gel column chromatography (petroleum ether/ethyl acetate is 25-60%) to obtain a yellow-gray solid with a yield of 57%;

the result of nuclear magnetic resonance hydrogen spectrum characterization of the gray yellow solid is as follows: ¹ H NMR(400MHz，DMSO-d ₆ )δ11.11(s，1H)，7.59(t，J＝7.8Hz，1H)，7.09(d，J＝7.0Hz，1H)，6.99(d，J＝8.5Hz，1H)，6.86(t，J＝5.8Hz，1H)，5.09(dd，J＝12.9，5.3Hz，1H)，4.11(d，J＝5.9Hz，2H)，2.94–2.86(m，1H)，2.65–2.54(m，2H)，2.09–2.03(m，1H)，1.45(s，9H)。

the resulting pale yellow solid was reacted with trifluoroacetic acid in 5mL of Dichloromethane (DCM), subjected to deprotection treatment, and the solvent was distilled off to give a compound of formula Z-11 (54 mg) in 84% yield.

The compound of formula Z-11 is a yellow solid; the mass spectrum characterization result is as follows: ESI-MS: m/z 332.90[ 2 ] M + H] ⁺ 。

(4) Synthesis of Compounds of formula Z-5

(4.1) Synthesis of a Compound of formula Z-51

In a 50mL round bottom flask, the compound of formula Z-11 (54mg, 0.116mmol), N-t-butoxycarbonyl-1,2-ethylenediamine (31mg, 0.192mmol), 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HATU) (80mg, 0.208mmol), N, N-Diisopropylethylamine (DIPEA) (110 μ L,0.65 mmol) were added in sequence in 10mL anhydrous DMSO, nitrogen blanket, room temperature reaction for 4h, TLC monitored reaction completion; extracting the reaction solution with ethyl acetate, washing with brine, and drying with anhydrous sodium sulfate; separating and purifying by silica gel column chromatography (dichloromethane/methanol = 1-7%) to obtain yellow solid (70 mg) with yield of 90%, and mass spectrum characterization result is ESI-MS: m/z 496.35[ 2 ], [ M ] +Na ]] ⁺ (ii) a The result of the nuclear magnetic resonance hydrogen spectrum characterization is ¹ H NMR(400MHz，Chloroform-d)δ8.32(s，1H)，7.56(t，J＝7.8Hz，1H)，7.24(d，J＝7.1Hz，1H)，7.14(s，1H)，6.83(d，J＝8.5Hz，1H)，4.97(dd，J＝11.8，5.0Hz，1H)，3.98(s，2H)，3.45–3.35(m，2H)，3.25(t，J＝5.3Hz，2H)，2.96–2.89(m，1H)，2.87–2.73(m，2H)，2.66(s，2H)，2.19–2.13(m，1H)，1.41(s，9H)。

Reacting the yellow solid with 50mL of trifluoroacetic acid and 5mL of dichloromethane, carrying out deprotection treatment, and evaporating the solvent to obtain a compound shown in a formula Z-51, namely the yellow solid; the mass spectrum characterization result is as follows: ESI-MS: m/z 373.76[ m ] +H] ⁺ 。

(4.2) Synthesis of Compound of formula Z-52

Compared with the step (4.1), the preparation method is different in that N-tert-butyloxycarbonyl-1,3-propane diamine is used for replacing N-tert-butyloxycarbonyl-1,2-ethane diamine, and a yellow solid (the yield is 74%) and the compound of the formula Z-52 are obtained.

The mass spectrum characterization result of the yellow solid is ESI-MS m/z 510.73[ M ] +Na] ⁺ (ii) a The result of hydrogen spectrum characterization of nuclear magnetic resonance is ¹ HNMR(400MHz，Chloroform-d)δ8.13(s，1H)，7.56(t，J＝7.8Hz，1H)，7.23(d，J＝7.2Hz，1H)，6.84(d，J＝8.4Hz，1H)，4.96(dd，J＝11.9，5.2Hz，1H)，4.84(s，1H)，4.01(s，2H)，3.73(s，1H)，3.36–3.32(m，2H)，3.11(t，J＝5.7Hz，2H)，2.93(d，J＝13.8Hz，1H)，2.88–2.75(m，2H)，2.18–2.12(m，1H)，1.65–1.60(m，2H)，1.38(s，9H)。

The compound of formula Z-52 is a yellow solid; the mass spectrum characterization result is ESI-MS, m/z 387.46[ M ] +H ]] ⁺ 。

(4.3) Synthesis of Compound of formula Z-53

Compared with the step (4.1), the preparation method is different in that N-tert-butyloxycarbonyl-1,4-butanediamine is used for replacing N-tert-butyloxycarbonyl-1,2-ethylenediamine, and the compound of the formula Z-53 is obtained.

The compound of formula Z-53 is a yellow solid; the mass spectrum characterization result is ESI-MS m/z 438.64[M+Na] ⁺ 。

(4.4) Synthesis of Compound of formula Z-54

Compared with the step (4.1), the preparation method is different in that N- (5-amino amyl) carbamic acid tert-butyl ester is used for replacing N-tert-butyloxycarbonyl-1,2-ethylenediamine, and the compound of the formula Z-54 is obtained.

The mass spectrum characterization result of the compound of formula Z-54 is ESI-MS m/Z438.64M + Na] ⁺ 。

(4.5) Synthesis of a Compound of formula Z-55

Compared with the step (4.1), the preparation method is different in that N- (6-amino hexyl) carbamic acid tert-butyl ester is used for replacing N-tert-butyloxycarbonyl-1,2-ethylenediamine, and the compound of the formula Z-55 is obtained.

The mass spectrum characterization result of the compound of formula Z-55 is ESI-MS m/Z452.54M + Na] ⁺ 。

(5) Synthesis of the target Compound

(5.1) Synthesis of Compound of formula I-16

The preparation method comprises the following steps: sequentially adding a compound of the formula Z-2 (0.15 mmol), a compound of the formula Z-51 (0.18 mmol), 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethylurea Hexafluorophosphate (HATU) (86mg, 0.225mmol), N, N-diisopropylethylamine (194 mu L,1.5 mmol) in 10mL of anhydrous N, N-Diisopropylethylamine (DMSO), introducing nitrogen for protection, reacting at room temperature for 8h, monitoring by TLC, and finishing the reaction; extracting the reaction solution by using water and ethyl acetate, washing by using brine, and drying by using anhydrous sodium sulfate; preparative TLC purification gave the compound of formula I-16 in 40% yield.

Nuclear magnetic resonance of compounds of formula I-16The hydrogen spectrum and the carbon spectrum are characterized by ¹ H NMR(400MHz，DMSO-d ₆ )δ11.11(s，1H)，10.19(s，1H)，8.61(s，1H)，8.29(s，1H)，8.20(s，1H)，8.08(s，1H)，7.82(d，J＝31.1Hz，2H)，7.56(s，2H)，7.49(s，1H)，7.23(d，J＝28.4Hz，2H)，7.08(s，1H)，6.97(s，1H)，6.88(s，1H)，6.56(s，1H)，6.45(d，J＝9.6Hz，1H)，6.27(d，J＝17.3Hz，2H)，5.77(s，1H)，5.18–4.98(m，1H)，3.96(s，2H)，3.76(s，3H)，3.23(s，4H)，3.12(s，4H)，2.93(d，J＝28.4Hz，3H)，2.56(s，6H)，2.03(s，1H). ¹³ C NMR(101MHz，DMSO-d ₆ )δ173.18，170.42，169.20，167.70，163.51，146.18，139.40，136.61，132.44，132.30，128.87，127.27，117.83，116.20，111.39，110.31，106.83，100.23，55.95，53.23，48.97，45.64，40.34，38.96，38.62，31.38，22.58。

(5.2) Synthesis of Compound of formula I-17

The preparation method is different from the step (5.1) in that the compound of the formula Z-52 is used for replacing the compound of the formula Z-51 to obtain the compound of the formula I-17, and the yield is 25%.

The mass spectrum characterization result of the compound of formula I-17 is ESI-MS, m/z 941.47, M + H] ⁺ (ii) a The characterization results of the hydrogen spectrum and the carbon spectrum of the nuclear magnetic resonance are as follows ¹ H NMR(400MHz，DMSO-d ₆ )δ11.12(s，1H)，10.23(s，1H)，8.64(s，1H)，8.30(s，1H)，8.13(d，J＝23.2Hz，2H)，7.86(s，2H)，7.70–7.45(m，3H)，7.23(d，J＝35.6Hz，2H)，7.09(s，1H)，6.94(d，J＝37.8Hz，2H)，6.58(s，1H)，6.47(s，1H)，6.27(d，J＝16.6Hz，1H)，5.77(s，2H)，5.08(s，1H)，3.96(s，2H)，3.78(s，3H)，3.14(s，8H)，2.95(d，J＝33.8Hz，3H)，2.59(s，6H)，2.05(s，1H)，1.59(s，2H). ¹³ C NMR(101MHz，DMSO-d ₆ )δ173.19，170.43，169.42，169.08，168.96，167.71，163.51，156.15，146.24，139.42，138.86，136.60，132.44，132.31，128.88，127.23，119.91，117.85，116.21，111.38，106.83，100.22，61.65，55.98，55.31，53.24，48.97，45.70，36.64，36.17，31.39，29.82，22.58。

(5.3) Compounds of formula I-18

The preparation method differs from the step (5.1) in that the compound of the formula Z-51 is replaced by the compound of the formula Z-53 to obtain the compound of the formula I-18 with a yield of 25%.

The nuclear magnetic resonance hydrogen spectrum and the carbon spectrum of the compound of the formula I-18 are characterized by ¹ H NMR(400MHz，DMSO-d ₆ )δ11.10(s，1H)，10.17(s，1H)，8.62(s，1H)，8.29(s，1H)，8.15–8.05(m，2H)，7.78(s，2H)，7.58(dt，J＝15.8，7.8Hz，2H)，7.49(d，J＝8.7Hz，1H)，7.27(t，J＝7.9Hz，1H)，7.19(s，1H)，7.07(d，J＝7.1Hz，1H)，6.95(t，J＝5.4Hz，1H)，6.86(d，J＝8.5Hz，1H)，6.57(s，1H)，6.46(dd，J＝16.8，10.1Hz，1H)，6.26(d，J＝16.9Hz，2H)，5.76(dd，J＝8.0，3.6Hz，1H)，5.08(dd，J＝12.8，5.4Hz，1H)，3.93(d，J＝5.3Hz，2H)，3.77(s，3H)，3.66–3.48(m，2H)，3.12(s，8H)，2.97(d，J＝13.7Hz，2H)，2.92–2.85(m，1H)，2.62(s，4H)，2.07–1.99(m，1H)，1.43(s，4H). ¹³ C NMR(101MHz，DMSO-d ₆ )δ173.19，170.44，169.09，168.67，167.71，163.50，146.21，139.39，136.60，132.45，132.29，128.89，127.28，119.95，117.83，111.34，106.85，100.25，55.98，53.95，53.20，48.97，45.58，42.18，40.84，38.76，38.33，31.38，27.14，26.94，22.57。

(5.4) Synthesis of Compound of formula I-19

The preparation method is different from the step (5.1) in that the compound of the formula Z-54 is used for replacing the compound of the formula Z-51 to obtain the compound of the formula I-19, and the yield is 29%.

The mass spectrum characterization result of the compound of formula I-19 is ESI-MS: m/z 969.45[ deg. ] M + H +] ⁺ (ii) a The characterization results of the hydrogen spectrum and the carbon spectrum of the nuclear magnetic resonance are as follows ¹ H NMR(400MHz，DMSO-d ₆ )δ11.10(s，1H)，10.15(s，1H)，8.62(s，1H)，8.28(s，1H)，8.08(d，J＝9.1Hz，2H)，7.75(s，2H)，7.63–7.57(m，1H)，7.54(d，J＝7.9Hz，1H)，7.49(d，J＝8.8Hz，1H)，7.27(t，J＝8.0Hz，1H)，7.18(s，1H)，7.07(d，J＝7.1Hz，1H)，6.95(t，J＝5.5Hz，1H)，6.86(d，J＝8.5Hz，1H)，6.57(s，1H)，6.45(dd，J＝16.9，10.1Hz，1H)，6.26(d，J＝18.6Hz，2H)，5.76(d，J＝11.8Hz，1H)，5.08(dd，J＝12.9，5.4Hz，1H)，3.97–3.88(m，2H)，3.77(s，3H)，3.10(s，8H)，2.97(s，2H)，2.92–2.85(m，1H)，2.64–2.53(m，6H)，2.06–1.99(m，1H)，1.49–1.39(m，4H)，1.29(d，J＝15.5Hz，2H). ¹³ C NMR(101MHz，DMSO-d ₆ )δ173.20，170.44，168.65，167.71，146.21，136.60，132.45，132.27，128.91，127.30，117.82，111.35，106.84，106.81，55.98，53.19，48.97，45.57，40.82，40.54，38.95，38.55，31.38，29.32，29.12，24.15，22.56。

(5.5) Compounds of formula I-20

The preparation method differs from the step (5.1) in that the compound of the formula Z-51 is replaced by the compound of the formula Z-55 to obtain the compound of the formula I-20 with a yield of 39%. .

The mass spectrum characterization of the compound of formula I-20 resulted in: ESI-MS: m/z 983.57[ 2 ], [ M + H ]] ⁺ (ii) a The characterization results of the hydrogen spectrum and the carbon spectrum of the nuclear magnetic resonance are as follows ¹ H NMR(400MHz，DMSO-d ₆ )δ11.11(s，1H)，10.21(s，1H)，8.63(s，2H)，8.28(s，1H)，8.14–8.05(m，2H)，7.78(s，2H)，7.58(dd，J＝17.4，9.0Hz，2H)，7.50(d，J＝8.6Hz，1H)，7.27(t，J＝7.6Hz，1H)，7.18(s，1H)，7.07(d，J＝6.9Hz，1H)，6.95(s，1H)，6.86(d，J＝8.3Hz，1H)，6.58(s，1H)，6.47(dd，J＝16.9，10.1Hz，1H)，6.26(d，J＝16.8Hz，2H)，5.08(dd，J＝12.7，4.4Hz，1H)，3.96–3.89(m，2H)，3.77(s，3H)，3.11(s，8H)，3.01(s，2H)，2.88(d，J＝12.1Hz，1H)，2.60(d，J＝15.6Hz，6H)，2.04(d，J＝11.2Hz，1H)，1.42(s，8H). ¹³ C NMR(101MHz，DMSO-d ₆ )δ173.24，170.45，169.08，168.70，163.55，146.20，139.36，138.83，136.59，132.42，132.24，128.92，127.32，117.81，116.27，111.37，106.85，100.25，55.98，53.93，53.12，48.96，48.83，45.58，40.74，38.91，38.57，31.36，29.54，29.36，26.43，26.38，22.56。

Example 4

A compound of formula I or a pharmaceutically acceptable salt thereof

Wherein L is

n is 1,2 or 3.

The preparation method of the compound comprises the following steps:

(1) By the step (5) in example 1, a compound of the formula Z-1 was obtained:

(2) By the step (2) in example 3, a compound of the formula Z-9 is obtained:

(3) Synthesis of Compounds of formula Z-12

(3.1) Synthesis of Compound of formula Z-121

In a 25mL round-bottom flask, sequentially adding a compound of the formula Z-9 (153mg, 0.55mmol), diglycolamine (87. Mu.L, 0.869 mmol), N, N-diisopropylethylamine (240. Mu.L, 1.45 mmol) in 10mL of anhydrous DMSO (dimethyl sulfoxide), introducing nitrogen for protection, heating to 100 ℃ for overnight reaction, and monitoring the reaction completion by TLC; the reaction solution was extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, and separated and purified by silica gel column chromatography (dichloromethane/methanol =3% -7%) to obtain the compound of formula Z-121 (112 mg) in 56% yield.

The compound of the formula Z-121 is a yellow solid, and the mass spectrum characterization result is ESI-MS: m/Z385.28 [ m ] +Na] ⁺ (ii) a The result of hydrogen spectrum characterization of nuclear magnetic resonance is ¹ H NMR(400MHz，DMSO-d ₆ )δ11.09(s，1H)，7.63–7.55(m，1H)，7.15(d，J＝8.6Hz，1H)，7.05(d，J＝7.0Hz，1H)，6.61(t，J＝5.7Hz，1H)，5.06(dd，J＝12.9，5.4Hz，1H)，4.61(t，J＝5.2Hz，1H)，3.63(t，J＝5.4Hz，2H)，3.50(dt，J＝15.0，5.1Hz，6H)，2.95–2.83(m，1H)，2.65–2.53(m，2H)，2.09–1.98(m，1H)。

(3.2) Synthesis of Compound of formula Z-122

The preparation method is different from the step (3.1) in that 2- [2- (2-aminoethoxy) ethoxy ] ethanol is used for replacing diglycolamine, so that the compound (112 mg) shown as the formula Z-122 is obtained, and the yield is 77%.

A compound of formula Z-122 is a yellow solid; the mass spectrum characterization result is ESI-MS: m/z 428.92[ m ] +Na ]] ⁺ (ii) a The result of the nuclear magnetic resonance hydrogen spectrum characterization is ¹ H NMR(400MHz，Chloroform-d)δ8.62(s，1H)，7.50(t，J＝7.8Hz，1H)，7.11(d，J＝7.1Hz，1H)，6.92(d，J＝8.5Hz，1H)，6.57(t，J＝4.9Hz，1H)，4.92(dd，J＝11.9，5.3Hz，1H)，3.76–3.73(m，8H)，3.64–3.60(m，2H)，3.48(q，J＝5.3Hz，2H)，2.91–2.70(m，4H)，2.17–2.07(m，1H)。

(3.3) Synthesis of a Compound of formula Z-123

The preparation method is different from the step (3.1) in that 1-amino-3,6,9-trioxa-11-undecanol is used for replacing diglycolamine, and the compound of the formula Z-123 is obtained, and the yield is about 89%.

The mass spectrum characterization result of the compound of formula Z-123 is ESI-MS m/Z483.2 [ M ] +Na] ⁺ (ii) a The characterization results of the hydrogen spectrum and the carbon spectrum of the nuclear magnetic resonance are as follows ¹ H NMR(400MHz，Chloroform-d)δ8.38(s，1H)，7.54–7.49(m，1H)，7.13(d，J＝7.1Hz，1H)，6.95(d，J＝8.5Hz，1H)，4.94(dd，J＝11.9，5.4Hz，1H)，3.74(t，J＝4.7Hz，4H)，3.70(s，8H)，3.64–3.62(m，2H)，3.50(t，J＝5.1Hz，2H)，2.83–2.74(m，3H)，2.65(s，1H)，2.17–2.13(m，1H)。

(6) Synthesis of a Compound of formula Z-6

(6.1) Synthesis of a Compound of formula Z-61

Adding the compound of the formula Z-121 (126mg, 0.35mmol) into a 25mL round-bottom flask, adding the compound of the formula Z-121 into a 5mL anhydrous dichloromethane solution, adding TEA (250 mu L,1.75 mmol), introducing nitrogen for protection, stirring at 0 ℃, dropwise adding excessive methylsulfonyl chloride (400 mu L), reacting the mixed solution at room temperature overnight, and finishing the reaction; the reaction solution was sequentially subjected to solvent evaporation, ethyl acetate extraction, brine washing, anhydrous sodium sulfate drying, and silica gel column chromatography (PE/EA =70% -85%) to give a compound of formula Z-61 (98 mg) with a yield of 63%.

The compound of formula Z-61 is a yellow solid; the mass spectrum characterization result is ESI-MS: m/z 463.31[ M ] +Na ]] ⁺ (ii) a The result of the nuclear magnetic resonance hydrogen spectrum characterization is ¹ H NMR(400MHz，Chloroform-d)δ8.06(s，1H)，7.53(t，J＝7.7Hz，1H)，7.15(d，J＝6.9Hz，1H)，6.95(d，J＝8.4Hz，1H)，6.51(s，1H)，4.93(dd，J＝12.0，5.1Hz，1H)，4.39(s，2H)，3.81–3.74(m，4H)，3.51(s，2H)，3.06(s，3H)，2.91(d，J＝17.3Hz，1H)，2.78(t，J＝13.2Hz，2H)，2.16(d，J＝11.6Hz，1H)。

(6.2) Synthesis of a Compound of formula Z-62

The preparation method is different from the step (6.1) in that the compound of the formula Z-122 is used for replacing the compound of the formula Z-121 to obtain the compound of the formula Z-62, and the yield is 70%.

The compound of formula Z-62 is a yellow solid and the mass spectrum characterization result is ESI-MS: m/Z507.67 [2 ], [ M ] +Na] ⁺ (ii) a The characterization results of the hydrogen spectrum and the carbon spectrum of the nuclear magnetic resonance are as follows ¹ H NMR(400MHz，Chloroform-d)δ8.32(s，1H)，7.55–7.49(m，1H)，7.13(d，J＝7.0Hz，1H)，6.93(d，J＝8.5Hz，1H)，4.96(dd，J＝12.0，5.3Hz，1H)，4.43–4.38(m，2H)，3.84–3.80(m，2H)，3.73(dt，J＝10.8，5.0Hz，6H)，3.48(t，J＝5.1Hz，2H)，3.07(s，3H)，2.87(s，1H)，2.79(s，2H)，2.17–2.12(m，1H)。

(6.3) Synthesis of a Compound of formula Z-63

The preparation method is different from the step (6) in that the compound of the formula Z-123 is used for replacing the compound of the formula Z-121 to obtain the compound of the formula Z-63, and the yield is 55%.

The compound of formula Z-63 is a yellow solid; the mass spectrum characterization result is ESI-MS: m/z 551.34[ m ] +Na ]] ⁺ (ii) a The result of the nuclear magnetic resonance hydrogen spectrum characterization is ¹ H NMR(400MHz，Chloroform-d)δ8.21(s，1H)，7.55–7.49(m，1H)，7.13(d，J＝7.1Hz，1H)，6.94(d，J＝8.5Hz，1H)，4.95(dd，J＝11.7，5.2Hz，1H)，4.42–4.37(m，2H)，3.81–3.77(m，2H)，3.75(t，J＝5.2Hz，2H)，3.69(s，8H)，3.50(t，J＝5.1Hz，2H)，3.09(s，3H)，2.93(s，1H)，2.82–2.75(m，2H)，2.18–2.13(m，1H)。

(7) Synthesis of the target Compound

(7.1) Synthesis of Compound of formula I-21

In a 50mL round-bottom flask, a compound of the formula Z-1 (120mg, 0.234mmol), a compound of the formula Z-61 (96mg, 0.219mmol), sodium iodide (13mg, 0.09mmol), N, N-diisopropylethylamine (389 mu L,2.19 mmol) are sequentially added into 15mL anhydrous dioxane, protected by nitrogen, and reacted at 90 ℃ for 12 hours; the reaction solution was subjected to extraction with water and ethyl acetate in this order, washed with brine, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (dichloromethane/methanol = 0-9%) to give the compound of formula I-21 (44 mg) in 23.5% yield.

The compound of formula I-21 is an orange solid with the mass spectrometry result of ESI-MS: m/z 857.17[ 2 ], [ M + H ]] ⁺ (ii) a The characterization results of the hydrogen spectrum and the carbon spectrum of the nuclear magnetic resonance are ¹ H NMR(400MHz，DMSO-d ₆ )δ11.09(s，1H)，10.23(s，1H)，8.60(s，1H)，8.28(s，1H)，8.09(s，1H)，7.78(s，1H)，7.63–7.57(m，1H)，7.54(d，J＝8.2Hz，1H)，7.47(d，J＝8.8Hz，1H)，7.25(t，J＝8.1Hz，1H)，7.18(d，J＝8.5Hz，2H)，7.05(d，J＝7.0Hz，1H)，6.63(t，J＝5.5Hz，1H)，6.54(s，1H)，6.47(dd，J＝16.9，10.2Hz，1H)，6.27(d，J＝1.6Hz，1H)，6.25–6.17(m，1H)，5.75(dd，J＝10.2，1.7Hz，1H)，5.05(dd，J＝12.5，5.3Hz，1H)，3.76(s，3H)，3.70–3.59(m，4H)，3.51(t，J＝5.0Hz，3H)，3.04(s，4H)，2.55(d，J＝6.3Hz，4H)，2.00(q，J＝7.8Hz，2H). ¹³ C NMR(101MHz，DMSO-d ₆ )δ173.16，170.45，169.35，167.69，163.51，146.87，139.44，138.86，136.62，132.48，132.34，128.85，127.18，126.59，123.91，119.92，117.94，111.07，109.63，106.83，100.21，70.19，69.27，57.45，55.96，53.39，48.97，42.09，31.36，29.42，22.55。

(7.2) Synthesis of Compound of formula I-22

The preparation method is different from the step (7.1) in that the compound of the formula Z-62 is used for replacing the compound of the formula Z-61 to obtain the compound of the formula I-22 with the yield of about 20%.

(7.3) Synthesis of Compound of formula I-23

The preparation method thereof was different from the step (7.1) in that the compound of the formula Z-63 was used instead of the compound of the formula Z-61 to give the compound of the formula I-23 (44 mg) in a yield of 18%. The compound of formula I-23 is an orange solid.

Product effectiveness testing

In order to better determine the inhibition activity of the compound shown in the formula I of the invention on the proliferation of tumor cells, the inhibition activity of the compound provided by each embodiment of the invention on the tumor cells in vitro is determined by a standard MTT method.

Test compounds: the compounds of formula I-1 to formula I-23 and Rociletinib provided in embodiments 1 to 4 of the present invention; among them, rociletinib is a known EGFR inhibitor.

Cell lines used in this experiment include H1975 (EGFR) ^L858R/T790M )，PC-9(EGFR ^{Exon 19del} )，A549(EGFR ^WT )。

The experimental method comprises the following steps:

taking tumor cells in logarithmic growth phase, digesting with pancreatin, centrifuging, re-suspending with fresh culture medium, blowing into single cell suspension, inoculating the cells into 96-well culture plate according to proper density, wherein each well of culture medium is 100 μ l,37 deg.C, and 5% CO ₂ The culture was carried out overnight in an incubator. After the cells adhere to the wall, adding test compounds with different concentrations respectively, and continuously culturing for 72 hours in an incubator; then, 10 mul of MTT solution with the mass concentration of 5mg/mL is added into each hole, and the culture is continued for 4h; the supernatant was aspirated, 100. Mu.L of dimethyl sulfoxide was added to each well, and the plate was placed on a microplate shaker and shaken for 15min to dissolve the crystals. The OD value of the absorbance at a wavelength of 570nm was measured by a microplate reader and determined by the following formula: inhibition (%) = [1- (experimental OD value-blank OD value)/(control)Group OD value-blank group OD value)]X 100%, the inhibition rate was calculated. The compound concentration at 50% Inhibition (IC) was calculated using GraphPadprism5 software ₅₀ ). The test results are shown in table 1, wherein a: 0-10 μm; b: 10-100 mu m; c:>100μΜ。IC ₅₀ values are the average of three experimental tests.

The results of the in vitro cell viability assay are shown in table 1.

According to the table 1, the compound obtained by coupling the ligand derivative of the target protein EGFR and the ligand derivative of the target cereblon protein can effectively inhibit the growth of lung cancer cells, particularly the high-expression EGFR ^L858R/T790M The H1975 cell strain and the PC-9 cell strain highly expressing the 19 exon-deleted EGFR have stronger inhibitory activity, but have weaker activity on the A549 cell strain highly expressing the wild type EGFR and show better selectivity. In conclusion, the compound of the embodiment of the invention has obvious anti-lung cancer cell proliferation activity.

TABLE 1 in vitro anti-cell proliferation Activity of the target Compounds (IC) ₅₀ Value)

N.T untested

The above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such changes, modifications, substitutions, combinations, and simplifications are intended to be included in the scope of the present invention.

Claims

1. Any one of the compounds shown below, or a pharmaceutically acceptable salt thereof:

2. a medicament comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof, and an adjuvant.

3. The medicament of claim 2, wherein the pharmaceutically acceptable excipient is selected from at least one of a filler, a lubricant, a disintegrant, a binder, or a glidant.

4. The medicament of claim 2, wherein the dosage form of the medicament is at least one selected from the group consisting of tablets, capsules, granules, injections, powder injections, eye drops, smears, suppositories, ointments, aerosols, powders, dropping pills, emulsions, films, transdermal patches, controlled release preparations and nano preparations.

5. Use of a compound of claim 1 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment or prevention of a neoplastic disease.